Medical Specialties Commons^™

A Clustering Of Heterozygous Missense Variants In The Crucial Chromatin Modifier Wdr5 Defines A New Neurodevelopmental Disorder, Lot Snijders Blok, Jolijn Verseput, Dmitrijs Rots, Hanka Venselaar, A Micheil Innes, Connie Stumpel, Katrin Õunap, Karit Reinson, Eleanor G Seaby, Shane Mckee, Barbara Burton, Katherine Kim, Johanna M Van Hagen, Quinten Waisfisz, Pascal Joset, Katharina Steindl, Anita Rauch, Dong Li, Elaine H Zackai, Sarah E Sheppard, Beth Keena, Hakon Hakonarson, Andreas Roos, Nicolai Kohlschmidt, Anna Cereda, Maria Iascone, Erika Rebessi, Kristin D Kernohan, Philippe M Campeau, Francisca Millan, Jesse A Taylor, Hanns Lochmüller, Martin R Higgs, Amalia Goula, Birgitta Bernhard, Danita J Velasco, Andrew A Schmanski, Zornitza Stark, Lyndon Gallacher, Lynn Pais, Paul C Marcogliese, Shinya Yamamoto, Nicholas Raun, Taryn E Jakub, Jamie M Kramer, Joery Den Hoed, Simon E Fisher, Han G Brunner, Tjitske Kleefstra

Faculty, Staff and Students Publications

WDR5 is a broadly studied, highly conserved key protein involved in a wide array of biological functions. Among these functions, WDR5 is a part of several protein complexes that affect gene regulation via post-translational modification of histones. We collected data from 11 unrelated individuals with six different rare de novo germline missense variants in WDR5; one identical variant was found in five individuals and another variant in two individuals. All individuals had neurodevelopmental disorders including speech/language delays (n = 11), intellectual disability (n = 9), epilepsy (n = 7), and autism spectrum disorder (n = 4). Additional phenotypic features …

The Role Of Pharmacotherapy In Treatment Of Meningioma: A Systematic Review, Ataollah Shahbandi, Darsh S Shah, Caroline C Hadley, Akash J Patel

Faculty, Staff and Students Publications

The safety and efficacy of various pharmacotherapeutic regimens on refractory meningiomas have been the focus of investigations. We present a comprehensive review of the previous efforts and the current state of ongoing clinical trials. A PRISMA-compliant review of the MEDLINE and ClinicalTrial.gov databases of the National Library of Medicine were performed. The primary outcomes of interest for included articles were radiographic response, overall survival, progression-free survival, six-month progression-free survival, and adverse events. Overall, 34 completed trials and 27 ongoing clinical trials were eligible. Six-month progression-free survival was reported in 6-100% of patients in the completed studies. Hematological disorders were the …

Microrna-Mrna Networks Are Dysregulated In Opioid Use Disorder Postmortem Brain: Further Evidence For Opioid-Induced Neurovascular Alterations, Sandra L Grimm, Emily F Mendez, Laura Stertz, Thomas D Meyer, Gabriel R Fries, Tanmay Gandhi, Rupa Kanchi, Sudhakar Selvaraj, Antonio L Teixeira, Thomas R Kosten, Preethi Gunaratne, Cristian Coarfa, Consuelo Walss-Bass

Faculty, Staff and Student Publications

INTRODUCTION: To understand mechanisms and identify potential targets for intervention in the current crisis of opioid use disorder (OUD), postmortem brains represent an under-utilized resource. To refine previously reported gene signatures of neurobiological alterations in OUD from the dorsolateral prefrontal cortex (Brodmann Area 9, BA9), we explored the role of microRNAs (miRNA) as powerful epigenetic regulators of gene function.

METHODS: Building on the growing appreciation that miRNAs can cross the blood-brain barrier, we carried out miRNA profiling in same-subject postmortem samples from BA9 and blood tissues.

RESULTS: miRNA-mRNA network analysis showed that even though miRNAs identified in BA9 and blood …

Enhanced Neutralization Resistance Of Sars-Cov-2 Omicron Subvariants Bq1, Bq11, Ba46, Bf7, And Ba2752, Panke Qu, John P Evans, Julia N Faraone, Yi-Min Zheng, Claire Carlin, Mirela Anghelina, Patrick Stevens, Soledad Fernandez, Daniel Jones, Gerard Lozanski, Ashish Panchal, Linda J Saif, Eugene M Oltz, Kai Xu, Richard J Gumina, Shan-Lu Liu

Faculty, Staff and Student Publications

The continued evolution of SARS-CoV-2 has led to the emergence of several new Omicron subvariants, including BQ.1, BQ.1.1, BA.4.6, BF.7, and BA.2.75.2. Here, we examine the neutralization resistance of these subvariants against sera from 3-dose vaccinated healthcare workers, hospitalized BA.1-wave patients, and BA.4/5-wave patients. We found enhanced neutralization resistance in all new subvariants, especially in the BQ.1 and BQ.1.1 subvariants driven by N460K and K444T mutations, as well as the BA.2.75.2 subvariant driven largely by its F486S mutation. All Omicron subvariants maintained their weakened infectivity in Calu-3 cells, with the F486S mutation driving further diminished titer for the BA.2.75.2 subvariant. …

Global Biobank Analyses Provide Lessons For Developing Polygenic Risk Scores Across Diverse Cohorts, Ying Wang, Shinichi Namba, Esteban Lopera, Sini Kerminen, Kristin Tsuo, Kristi Läll, Masahiro Kanai, Wei Zhou, Kuan-Han Wu, Marie-Julie Favé, Laxmi Bhatta, Philip Awadalla, Ben Brumpton, Patrick Deelen, Kristian Hveem, Valeria Lo Faro, Reedik Mägi, Yoshinori Murakami, Serena Sanna, Jordan W Smoller, Jasmina Uzunovic, Brooke N Wolford, Global Biobank Meta-Analysis Initiative, Cristen Willer, Eric R Gamazon, Nancy J Cox, Ida Surakka, Yukinori Okada, Alicia R Martin, Jibril Hirbo

Faculty, Staff and Student Publications

Polygenic risk scores (PRSs) have been widely explored in precision medicine. However, few studies have thoroughly investigated their best practices in global populations across different diseases. We here utilized data from Global Biobank Meta-analysis Initiative (GBMI) to explore methodological considerations and PRS performance in 9 different biobanks for 14 disease endpoints. Specifically, we constructed PRSs using pruning and thresholding (P + T) and PRS-continuous shrinkage (CS). For both methods, using a European-based linkage disequilibrium (LD) reference panel resulted in comparable or higher prediction accuracy compared with several other non-European-based panels. PRS-CS overall outperformed the classic P + T method, especially …

Individual And Neighborhood Socioeconomic Status And Long-Term Individual Trajectories Of Sleep Duration Among Black And White Adults: The Southern Community Cohort Study, Samuel H Nyarko, Liying Luo, David G Schlundt, Qian Xiao

Faculty, Staff and Student Publications

STUDY OBJECTIVES: Sleep duration can change over the life course; however, previous studies rarely investigated the association between socioeconomic status (SES) and individual sleep trajectories over time. We examined the association between baseline socioeconomic characteristics and long-term sleep trajectories among Black and White adults.

METHODS: This study used data from the Southern Community Cohort Study (N = 45 035). Diverse trajectories of sleep duration were constructed using self-reported sleep duration at baseline and after ~10 years of follow-up. The associations between baseline socioeconomic characteristics and sleep trajectories were examined using multinomial logistic regression.

RESULTS: Both Black and White participants experienced …

Editorial: Hallmark Of Cancer: Reprogramming Of Cellular Metabolism, Baljinder Kaur, Yahya Sohrabi, Abhinav Achreja, Michael P. Lisanti, Ubaldo Emilio Martinez-Outshoorn

Department of Medical Oncology Faculty Papers

No abstract provided.

Antibody-Drug Conjugates In Lung Cancer: Dawn Of A New Era?, Niamh Coleman, Timothy A Yap, John V Heymach, Funda Meric-Bernstam, Xiuning Le

Faculty, Staff and Student Publications

Antibody-drug conjugates (ADCs) are one of fastest growing classes of oncology drugs in modern drug development. By harnessing the powers of both cytotoxic chemotherapy and targeted therapy, ADCs are unique in offering the potential to deliver highly potent cytotoxic agents to cancer cells which express a pre-defined cell surface target. In lung cancer, the treatment paradigm has shifted dramatically in recent years, and now ADCs are now joining the list as potential options for lung cancer patients. Since 2020, the first ADC for NSCLC patients has been FDA-approved (trastuzumab deruxtecan) and two ADCs have been granted FDA Breakthrough Therapy Designation, …

Reconstructing Mutational Lineages In Breast Cancer By Multi-Patient-Targeted Single-Cell Dna Sequencing, Jake Leighton, Min Hu, Emi Sei, Funda Meric-Bernstam, Nicholas E Navin

Faculty, Staff and Student Publications

Single-cell DNA sequencing (scDNA-seq) methods are powerful tools for profiling mutations in cancer cells; however, most genomic regions sequenced in single cells are non-informative. To overcome this issue, we developed a multi-patient-targeted (MPT) scDNA-seq method. MPT involves first performing bulk exome sequencing across a cohort of cancer patients to identify somatic mutations, which are then pooled together to develop a single custom targeted panel for high-throughput scDNA-seq using a microfluidics platform. We applied MPT to profile 330 mutations across 23,500 cells from 5 patients with triple negative-breast cancer (TNBC), which showed that 3 tumors were monoclonal and 2 tumors were …

3q262/Mecom Rearrangements By Pericentric Inv(3): Diagnostic Challenges And Clinicopathologic Features, Zhenya Tang, Wei Wang, Su Yang, Hanadi El Achi, Hong Fang, Karen Amelia Nahmod, Gokce A Toruner, Jie Xu, Beenu Thakral, Edward Ayoub, Ghayas C Issa, C Cameron Yin, M James You, Roberto N Miranda, Joseph D Khoury, L Jeffrey Medeiros, Guilin Tang

Faculty, Staff and Student Publications

MECOM rearrangement (MECOM-R) resulting from 3q26.2 aberrations is often associated with myeloid neoplasms and inferior prognosis in affected patients. Uncommonly, certain 3q26.2/MECOM-R can be subtle/cryptic and consequently overlooked by karyotyping. We identified 17 acute myeloid leukemia (AML) patients (male/female: 13/4 with a median age of 67 years, range 42 to 85 years) with a pericentric inv(3) leading to MECOM-R, with breakpoints at 3p23 (n = 11), 3p25 (n = 3), 3p21 (n = 2) and 3p13 (n = 1) on 3p and 3q26.2 on 3q. These pericentric inv(3)s were overlooked by karyotyping initially in 16 of 17 …

Outcomes Of Patients Treated For Hepatoblastoma With Low Alpha-Fetoprotein And/Or Small Cell Undifferentiated Histology: A Report From The Children's Hepatic Tumors International Collaboration (Chic), Angela D Trobaugh-Lotrario, Rudolf Maibach, Daniel C Aronson, Arun Rangaswami, Beate Häberle, Allison F O'Neill, Irene Schmid, Marc Ansari, Tomoro Hishiki, Sarangarajan Ranganathan, Rita Alaggio, Ronald R De Krijger, Yukichi Tanaka, Soo-Jin Cho, Christian Vokuhl, Rebecca Maxwell, Mark Krailo, Eiso Hiyama, Piotr Czauderna, Milton Finegold, James H Feusner, Marcio H Malogolowkin, Rebecka L Meyers, Dolores Lopez-Terrada

Faculty, Staff and Students Publications

Small cell undifferentiated (SCU) histology and alpha-fetoprotein (AFP) levels below 100 ng/mL have been reported as poor prognostic factors in hepatoblastoma (HB); subsequent studies reported SMARCB1 mutations in some SCU HBs confirming the diagnosis of rhabdoid tumor. The Children's Hepatic tumors International Collaboration (CHIC) database was queried for patients with HB who had AFP levels less than 100 ng/mL at diagnosis or were historically diagnosed as SCU HBs. Seventy-three of 1605 patients in the CHIC database were originally identified as SCU HB, HB with SCU component, or HB with low AFP levels. Upon retrospective review, they were re-classified as rhabdoid …

Correction: Carnitine Palmitoyl Transferase 1 A Is A Novel Diagnostic And Predictive Biomarker For Breast Cancer, Zheqiong Tan, Yaru Zou, Man Zhu, Zhenzhao Luo, Tangwei Wu, Chao Zheng, Aqing Xie, Hui Wang, Shiqiang Fang, Shuiyi Liu, Yong Li, Zhongxin Lu

Faculty, Staff and Students Publications

No abstract provided.

Feasibility Of Group-Based Implementation Facilitation For Video Telemental Health, Anthony H Ecker, Giselle Day, Amber B Amspoker, Jennifer L Bryan, Stephanie C Day, Miryam Wassef, Kendra Weaver, Jan Lindsay

Faculty, Staff and Students Publications

Video telehealth experienced rapid growth throughout the COVID-19 pandemic in many healthcare sectors, including mental health. The Veterans Health Administration’s video telehealth platform, VA Video Connect, has been widely used to reach veterans who may have experienced difficulty accessing care, such as those living in rural areas or other barriers (e.g., transportation). Implementing VVC requires a multifaceted approach, including training providers on technical skills, increasing access to equipment for providers and veterans, and integrating VVC within the culture and processes of the clinic unit. Prior successful VVC implementation efforts in rural areas have focused on simultaneous one-on-one provider and leadership …

Sgc-Camkk2-1: A Chemical Probe For Camkk2, Carrow Wells, Yi Liang, Thomas L Pulliam, Chenchu Lin, Dominik Awad, Benjamin Eduful, Sean O'Byrne, Mohammad Anwar Hossain, Carolina Moura Costa Catta-Preta, Priscila Zonzini Ramos, Opher Gileadi, Carina Gileadi, Rafael M Couñago, Brittany Stork, Christopher G Langendorf, Kevin Nay, Jonathan S Oakhill, Debarati Mukherjee, Luigi Racioppi, Anthony R Means, Brian York, Donald P Mcdonnell, John W Scott, Daniel E Frigo, David H Drewry

Faculty, Staff and Student Publications

The serine/threonine protein kinase calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) plays critical roles in a range of biological processes. Despite its importance, only a handful of inhibitors of CAMKK2 have been disclosed. Having a selective small molecule tool to interrogate this kinase will help demonstrate that CAMKK2 inhibition can be therapeutically beneficial. Herein, we disclose SGC-CAMKK2-1, a selective chemical probe that targets CAMKK2.

Inhibition Of Ribosome Assembly Factor Pno1 By Crispr/Cas9 Technique Suppresses Lung Adenocarcinoma And Notch Pathway: Clinical Application, Sanjit K. Roy, Shivam Srivastava, Andrew Hancock, Anju Shrivastava, Jason Morvant, Sharmila Shankar, Rakesh K. Srivastava

School of Medicine Faculty Publications

Growth is crucially controlled by the functional ribosomes available in cells. To meet the enhanced energy demand, cancer cells re-wire and increase their ribosome biogenesis. The RNA-binding protein PNO1, a ribosome assembly factor, plays an essential role in ribosome biogenesis. The purpose of this study was to examine whether PNO1 can be used as a biomarker for lung adenocarcinoma and also examine the molecular mechanisms by which PNO1 knockdown by CRISPR/Cas9 inhibited growth and epithelial–mesenchymal transition (EMT). The expression of PNO1 was significantly higher in lung adenocarcinoma compared to normal lung tissues. PNO1 expression in lung adenocarcinoma patients increased with …

Efficacy Of Eltrombopag With Immunosuppressive Therapy For Children With Acquired Aplastic Anemia, Yufei Zhao, Wenrui Yang, Xin Zhao, Xiangrong Hu, Jing Hu, Xu Liu, Jianping Li, Lei Ye, Youzhen Xiong, Yang Yang, Baohang Zhang, Xiaoxia Li, Xiawan Yang, Yimeng Shi, Guangxin Peng, Yuan Li, Huihui Fan, Kang Zhou, Liping Jing, Li Zhang, Fengkui Zhang

Faculty, Staff and Student Publications

BACKGROUND: Eltrombopag (EPAG), an oral thrombopoietin receptor agonist (TPO-RA), has been proven to improve the hematologic response without increasing toxic effects as a first-line therapy combined with standard immunosuppressive treatment (IST) in adults with severe aplastic anemia (SAA). Nevertheless, the clinical evidence on the efficacy of EPAG in children with acquired aplastic anemia is limited and controversial.

METHODS: We performed a single-center, retrospective study to analyze the clinical outcomes of fifteen patients aged ≤18 years with newly diagnosed acquired SAA who received first-line IST and EPAG (EPAG group) compared with those of forty-five patients who received IST alone (IST group) …

Diverticular Disease And Cancer Risk: More Than A Gut Feeling, Veronika Fedirko, Scott Kopetz, Carrie R Daniel

Faculty, Staff and Student Publications

No abstract provided.

Prospective Association Of Daily Steps With Cardiovascular Disease: A Harmonized Meta-Analysis, Amanda E Paluch, Shivangi Bajpai, Marcel Ballin, David R Bassett, Thomas W Buford, Mercedes R Carnethon, Ariel Chernofsky, Erin E Dooley, Ulf Ekelund, Kelly R Evenson, Deborah A Galuska, Barbara J Jefferis, Lingsong Kong, William E Kraus, Martin G Larson, I-Min Lee, Charles E Matthews, Robert L Newton, Anna Nordström, Peter Nordström, Priya Palta, Alpa V Patel, Kelley Pettee Gabriel, Carl F Pieper, Lisa Pompeii, Erika Rees-Punia, Nicole L Spartano, Ramachandran S Vasan, Peter H Whincup, Shengping Yang, Janet E Fulton, Steps For Health Collaborative

Faculty, Staff and Students Publications

Background: Taking fewer than the widely promoted "10 000 steps per day" has recently been associated with lower risk of all-cause mortality. The relationship of steps and cardiovascular disease (CVD) risk remains poorly described. A meta-analysis examining the dose-response relationship between steps per day and CVD can help inform clinical and public health guidelines.

Methods: Eight prospective studies (20 152 adults [ie, ≥18 years of age]) were included with device-measured steps and participants followed for CVD events. Studies quantified steps per day and CVD events were defined as fatal and nonfatal coronary heart disease, stroke, and heart failure. Cox proportional …

Differential Co-Expression Networks Of The Gut Microbiota Are Associated With Depression And Anxiety Treatment Resistance Among Psychiatric Inpatients, Dominique S Thompson, Chenlian Fu, Tanmay Gandhi, J Christopher Fowler, B Christopher Frueh, Benjamin L Weinstein, Joseph Petrosino, Julia K Hadden, Marianne Carlson, Cristian Coarfa, Alok Madan

Faculty, Staff and Students Publications

BACKGROUND: Comorbid anxiety and depression are common and are associated with greater disease burden than either alone. Our recent efforts have identified an association between gut microbiota dysfunction and severity of anxiety and depression. In this follow-up, we applied Differential Co-Expression Analysis (DiffCoEx) to identify potential gut microbiota biomarker(s) candidates of treatment resistance among psychiatric inpatients.

METHODS: In a sample of convenience, 100 psychiatric inpatients provided clinical data at admission and discharge; fecal samples were collected early during the hospitalization. Whole genome shotgun sequencing methods were used to process samples. DiffCoEx was used to identify clusters of microbial features significantly …

A Bioengineered Probiotic For The Oral Delivery Of A Peptide Kv13 Channel Blocker To Treat Rheumatoid Arthritis, Yuqing Wang, Duolong Zhu, Laura C Ortiz-Velez, Jacob L Perry, Michael W Pennington, Joseph M Hyser, Robert A Britton, Christine Beeton

Faculty, Staff and Students Publications

New therapeutics that combine efficacy with limited side effects and can be delivered noninvasively are needed to adequately treat patients with rheumatoid arthritis (RA) and other autoimmune diseases. Kv1.3 channel-expressing CCR7− effector memory T (TEM) lymphocytes are significant players in the pathogenesis of multiple autoimmune diseases, and blocking Kv1.3 reduces disease severity in rat models of RA and patients with plaque psoriasis. However, peptide therapeutics require repeated injections, reducing patient compliance. We used a bioengineered Lactobacillus reuteri as an oral delivery method of a Kv1.3 blocker for immunomodulation in rat models of atopic dermatitis and RA. This study demonstrates a …

Disabling Uncompetitive Inhibition Of Oncogenic Idh Mutations Drives Acquired Resistance, Junhua Lyu, Yuxuan Liu, Lihu Gong, Mingyi Chen, Yazan F Madanat, Yuannyu Zhang, Feng Cai, Zhimin Gu, Hui Cao, Pranita Kaphle, Yoon Jung Kim, Fatma N Kalkan, Helen Stephens, Kathryn E Dickerson, Min Ni, Weina Chen, Prapti Patel, Alice S Mims, Uma Borate, Amy Burd, Sheng F Cai, C Cameron Yin, M James You, Stephen S Chung, Robert H Collins, Ralph J Deberardinis, Xin Liu, Jian Xu

Faculty, Staff and Student Publications

Mutations in IDH genes occur frequently in acute myeloid leukemia (AML) and other human cancers to generate the oncometabolite R-2HG. Allosteric inhibition of mutant IDH suppresses R-2HG production in a subset of patients with AML; however, acquired resistance emerges as a new challenge, and the underlying mechanisms remain incompletely understood. Here we establish isogenic leukemia cells containing common IDH oncogenic mutations by CRISPR base editing. By mutational scanning of IDH single amino acid variants in base-edited cells, we describe a repertoire of IDH second-site mutations responsible for therapy resistance through disabling uncompetitive enzyme inhibition. Recurrent mutations at NADPH …

A Molecular Switch Between Mammalian Mll Complexes Dictates Response To Menin-Mll Inhibition, Yadira M Soto-Feliciano, Francisco J Sánchez-Rivera, Florian Perner, Douglas W Barrows, Edward R Kastenhuber, Yu-Jui Ho, Thomas Carroll, Yijun Xiong, Disha Anand, Alexey A Soshnev, Leah Gates, Mary Clare Beytagh, David Cheon, Shengqing Gu, X Shirley Liu, Andrei V Krivtsov, Maximiliano Meneses, Elisa De Stanchina, Richard M Stone, Scott A Armstrong, Scott W Lowe, C David Allis

Faculty, Staff and Student Publications

Menin interacts with oncogenic MLL1-fusion proteins, and small molecules that disrupt these associations are in clinical trials for leukemia treatment. By integrating chromatin-focused and genome-wide CRISPR screens with genetic, pharmacologic, and biochemical approaches, we discovered a conserved molecular switch between the MLL1-Menin and MLL3/4-UTX chromatin-modifying complexes that dictates response to Menin-MLL inhibitors. MLL1-Menin safeguards leukemia survival by impeding the binding of the MLL3/4-UTX complex at a subset of target gene promoters. Disrupting the Menin-MLL1 interaction triggers UTX-dependent transcriptional activation of a tumor-suppressive program that dictates therapeutic responses in murine and human leukemia. Therapeutic reactivation of this program using CDK4/6 inhibitors …

Many People With Chronic Lymphocytic Leukemia Or Small Lymphocytic Lymphoma Benefit From Ibrutinib Treatment Up To 8 Years: A Plain Language Summary, Paul M Barr, Carolyn Owen, Tadeusz Robak, Alessandra Tedeschi, Osnat Bairey, Jan A Burger, Peter Hillmen, Claire Dearden, Sebastian Grosicki, Helen Mccarthy, Jian Yong Li, Fritz Offner, Carol Moreno, Mandy Jermain, Cathy Zhou, Emily Hsu, Anita Szoke, Thomas J Kipps, Paolo Ghia

Faculty, Staff and Student Publications

What is this summary about?: This is a plain language summary of a publication describing long-term results from the RESONATE-2 study with up to 8 years of follow-up. The original paper was published in Blood Advances in June 2022.

What were the results?: Researchers looked at 269 adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who had not received any treatment for their CLL/SLL. Study participants were randomly divided into two groups: 136 participants received treatment with a drug called ibrutinib, and 133 participants received treatment with a drug called chlorambucil. Participants in the study were treated …

Technology Meets Tils: Deciphering T Cell Function In The -Omics Era, William H Hudson, Andreas Wieland

Faculty, Staff and Students Publications

T cells are at the centerstage of cancer immunology due to their ability to recognize mutations within tumor cells and directly mediate cancer cell killing. Immunotherapies to rejuvenate exhausted T cell responses have transformed the clinical management of several malignancies. In parallel, the development of novel multidimensional analysis platforms such as single-cell RNA-sequencing and high-dimensional flow cytometry has yielded unprecedented insights into immune cell biology. This convergence has revealed substantial heterogeneity of tumor-infiltrating immune cells, both within single tumors, across tumor types, and among cancer patients. Here, we discuss the opportunities and challenges of studying the complex tumor microenvironment with …

Histopathologic And Proteogenomic Heterogeneity Reveals Features Of Clear Cell Renal Cell Carcinoma Aggressiveness, Yize Li, Tung-Shing M Lih, Saravana M Dhanasekaran, Rahul Mannan, Lijun Chen, Marcin Cieslik, Yige Wu, Rita Jiu-Hsien Lu, David J Clark, Iga Kołodziejczak, Runyu Hong, Siqi Chen, Yanyan Zhao, Seema Chugh, Wagma Caravan, Nataly Naser Al Deen, Noshad Hosseini, Chelsea J Newton, Karsten Krug, Yuanwei Xu, Kyung-Cho Cho, Yingwei Hu, Yuping Zhang, Chandan Kumar-Sinha, Weiping Ma, Anna Calinawan, Matthew A Wyczalkowski, Michael C Wendl, Yuefan Wang, Shenghao Guo, Cissy Zhang, Anne Le, Aniket Dagar, Alex Hopkins, Hanbyul Cho, Felipe Da Veiga Leprevost, Xiaojun Jing, Guo Ci Teo, Wenke Liu, Melissa A Reimers, Russell Pachynski, Alexander J Lazar, Arul M Chinnaiyan, Brian A Van Tine, Bing Zhang, Karin D Rodland, Gad Getz, D R Mani, Pei Wang, Feng Chen, Galen Hostetter, Mathangi Thiagarajan, W Marston Linehan, David Fenyö, Scott D Jewell, Gilbert S Omenn, Rohit Mehra, Maciej Wiznerowicz, Ana I Robles, Mehdi Mesri, Tara Hiltke, Eunkyung An, Henry Rodriguez, Daniel W Chan, Christopher J Ricketts, Alexey I Nesvizhskii, Hui Zhang, Li Ding, Clinical Proteomic Tumor Analysis Consortium

Faculty, Staff and Students Publications

Clear cell renal cell carcinomas (ccRCCs) represent ∼75% of RCC cases and account for most RCC-associated deaths. Inter- and intratumoral heterogeneity (ITH) results in varying prognosis and treatment outcomes. To obtain the most comprehensive profile of ccRCC, we perform integrative histopathologic, proteogenomic, and metabolomic analyses on 305 ccRCC tumor segments and 166 paired adjacent normal tissues from 213 cases. Combining histologic and molecular profiles reveals ITH in 90% of ccRCCs, with 50% demonstrating immune signature heterogeneity. High tumor grade, along with BAP1 mutation, genome instability, increased hypermethylation, and a specific protein glycosylation signature define a high-risk disease subset, where UCHL1 …

Technology Meets Tils: Deciphering T Cell Function In The -Omics Era, William H Hudson, Andreas Wieland

Faculty, Staff and Students Publications

T cells are at the centerstage of cancer immunology due to their ability to recognize mutations within tumor cells and directly mediate cancer cell killing. Immunotherapies to rejuvenate exhausted T cell responses have transformed the clinical management of several malignancies. In parallel, the development of novel multidimensional analysis platforms such as single-cell RNA-sequencing and high-dimensional flow cytometry has yielded unprecedented insights into immune cell biology. This convergence has revealed substantial heterogeneity of tumor-infiltrating immune cells, both within single tumors, across tumor types, and among cancer patients. Here, we discuss the opportunities and challenges of studying the complex tumor microenvironment with …

Interdependent Progression Of Bidirectional Sister Replisomes In E Coli, Po Jui Chen, Anna B Mcmullin, Bryan J Visser, Qian Mei, Susan M Rosenberg, David Bates

Faculty, Staff and Students Publications

Bidirectional DNA replication complexes initiated from the same origin remain colocalized in a factory configuration for part or all their lifetimes. However, there is little evidence that sister replisomes are functionally interdependent, and the consequence of factory replication is unknown. Here, we investigated the functional relationship between sister replisomes in Escherichia coli, which naturally exhibits both factory and solitary configurations in the same replication cycle. Using an inducible transcription factor roadblocking system, we found that blocking one replisome caused a significant decrease in overall progression and velocity of the sister replisome. Remarkably, progression was impaired only if the block …

Evaluation Of Serum Concentration Of Acute-Phase Proteins (Haptoglobin And Serum Amyloid A) In The Affected Arabian Foals With Rhodococcosis, Ali Hassanpour, Sina Moghaddam

Faculty, Staff and Students Publications

BACKGROUND: Early detection of Rhodococcus equi pneumonia in foals is essential for horse health and for veterinarians.

OBJECTIVES: This study aimed to demonstrate the usefulness of assessing the serum concentration of acute-phase proteins (APPs) in the early diagnosis of pneumonia.

METHODS: The study evaluated APPs in 19 Arabian foals with R. equi pneumonia and compared them with 18 normal Arabian foals in equestrian clubs in Tabriz, Iran. Affected foals were identified through history, clinical findings and bacterial culture of tracheal washing. Biochemical methods and polymerase chain reaction tests were performed by examining the 16S rRNA and vapA genes to confirm …

Trends And Racial/Ethnic Differences In Predictors Of Cervical Cancer Screening Among Us Women Ages 30-64 Years, Itunu O Sokale, Jane R Montealegre, Abiodun O Oluyomi, Aaron P Thrift

Faculty, Staff and Students Publications

BACKGROUND: Cervical cancer screening (CCS) participation has decreased in the United States over the last several decades, contributing to cervical cancer's sustained incidence and mortality. This study examined recent trends and racial/ethnic differences in predictors of CCS uptake among US women.

METHODS: We analyzed combined data from the 2016 to 2020 Behavioral Risk Factor Surveillance System (BRFSS) and included 235,713 women ages 30 to 64 years without a hysterectomy. We used simple linear regression to assess trends over time and multivariable logistic regression models to evaluate racial/ethnic differences in predictors of up-to-date CCS.

RESULTS: We found little change in CCS …

Multicenter International Study Of The Consensus Immunoscore For The Prediction Of Relapse And Survival In Early-Stage Colon Cancer, Bernhard Mlecnik, Alessandro Lugli, Gabriela Bindea, Florence Marliot, Carlo Bifulco, Jiun-Kae Jack Lee, Inti Zlobec, Tilman T Rau, Martin D Berger, Iris D Nagtegaal, Elisa Vink-Börger, Arndt Hartmann, Carol I Geppert, Julie Kolwelter, Susanne Merkel, Robert Grützmann, Marc Van Den Eynde, Anne Jouret-Mourin, Alex Kartheuser, Daniel Léonard, Christophe Remue, Julia Wang, Prashant Bavi, Michael H A Roehrl, Pamela S Ohashi, Linh T Nguyen, Seongjun Han, Heather L Macgregor, Sara Hafezi-Bakhtiari, Bradly G Wouters, Giuseppe V Masucci, Emilia K Andersson, Eva Zavadova, Michal Vocka, Jan Spacek, Lubos Petruzelka, Bohuslav Konopasek, Pavel Dundr, Helena Skalova, Kristyna Nemejcova, Gerardo Botti, Fabiana Tatangelo, Paolo Delrio, Gennaro Ciliberto, Michele Maio, Luigi Laghi, Fabio Grizzi, Tessa Fredriksen, Bénédicte Buttard, Lucie Lafontaine, Pauline Maby, Amine Majdi, Assia Hijazi, Carine El Sissy, Amos Kirilovsky, Anne Berger, Christine Lagorce, Christopher Paustian, Carmen Ballesteros-Merino, Jeroen Dijkstra, Carlijn Van De Water, Shannon Van Lent-Van Vliet, Nikki Knijn, Ana-Maria Mușină, Dragos-Viorel Scripcariu, Boryana Popivanova, Mingli Xu, Tomonobu Fujita, Shoichi Hazama, Nobuaki Suzuki, Hiroaki Nagano, Kiyotaka Okuno, Toshihiko Torigoe, Noriyuki Sato, Tomohisa Furuhata, Ichiro Takemasa, Prabhu Patel, Hemangini H Vora, Birva Shah, Jayendrakumar B Patel, Kruti N Rajvik, Shashank J Pandya, Shilin N Shukla, Yili Wang, Guanjun Zhang, Yutaka Kawakami, Francesco M Marincola, Paolo A Ascierto, Bernard A Fox, Franck Pagès, Jérôme Galon

Faculty, Staff and Student Publications

Background: The prognostic value of Immunoscore was evaluated in Stage II/III colon cancer (CC) patients, but it remains unclear in Stage I/II, and in early-stage subgroups at risk. An international Society for Immunotherapy of Cancer (SITC) study evaluated the pre-defined consensus Immunoscore in tumors from 1885 AJCC/UICC-TNM Stage I/II CC patients from Canada/USA (Cohort 1) and Europe/Asia (Cohort 2). METHODS: Digital-pathology is used to quantify the densities of CD3+ and CD8+ T-lymphocyte in the center of tumor (CT) and the invasive margin (IM). The time to recurrence (TTR) was the primary endpoint. Secondary endpoints were disease-free survival (DFS), overall survival …