Medical Pathology Commons^™

Case Report: Immune Checkpoint Inhibitor-Induced Multiorgan Vasculitis Successfully Treated With Rituximab, Sehrish Qureshi, Naszrin Arani, Vishnu Parvathareddy, Amanda Tchakarov, Maen Abdelrahim, Maria Suarez-Almazor, Jianjun Zhang, Don Lynn Gibbons, John Heymach, Mehmet Altan, Ala Abudayyeh

Faculty, Staff and Student Publications

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer. ICIs have a unique side effect profile, generally caused by inflammatory tissue damage, with clinical features similar to autoimmune conditions. Acute kidney injury from ICIs has been well studied; incidence ranges from 1% to 5%, with higher incidence when combination ICI therapies are used. Although the overall reported incidence of ICI-associated glomerulonephritis is less than 1%, vasculitis is the most commonly reported ICI-related glomerulonephritis. Other biopsy findings include thrombotic microangiopathy, focal segmental glomerulosclerosis, minimal change disease, and IgA nephropathy with secondary amyloidosis. We report a case in which a woman …

Futility In Acute Care Surgery: First Do No Harm, Melissa Hornor, Uzer Khan, Michael W Cripps, Allyson Cook Chapman, Jennifer Knight-Davis, Thaddeus J Puzio, Bellal Joseph

Faculty, Staff and Student Publications

The consequences of the delivery of futile or potentially ineffective medical care and interventions are devastating on the healthcare system, our patients and their families, and healthcare providers. In emergency situations in particular, determining if escalating invasive interventions will benefit a frail and/or severely critically ill patient can be exceedingly difficult. In this review, our objective is to define the problem of potentially ineffective care within the specialty of acute care surgery and describe strategies for improving the care of our patients in these difficult situations.

Comprehensive Identification And Expression Analyses Of The Snrk Gene Family In Casuarina Equisetifolia In Response To Salt Stress, Di Ai, Yujiao Wang, Yongcheng Wei, Jie Zhang, Jingxiang Meng, Yong Zhang

Faculty, Staff and Student Publications

Background

Sucrose nonfermenting-1 (SNF1)-related protein kinases (SnRKs) play crucial roles in plant signaling pathways and stress adaptive responses by activating protein phosphorylation pathways. However, there have been no comprehensive studies of the SnRK gene family in the widely planted salt-tolerant tree species Casuarina equisetifolia. Here, we comprehensively analyze this gene family in C. equisetifolia using genome-wide identification, characterization, and profiling of expression changes in response to salt stress.

Results

A total of 26 CeqSnRK genes were identified, which were divided into three subfamilies (SnRK1, SnRK2, and SnRK3). The intron–exon structures and protein‑motif compositions were similar within each subgroup but …

A High-Resolution 3d Atlas Of The Spectrum Of Tuberculous Andcovid-19 Lung Lesions, Gordon Wells, Joel N Glasgow, Kievershen Nargan, Kapongo Lumamba, Rajhmun Madansein, Kameel Maharaj, Leon Y Perumal, Malcolm Matthew, Robert L Hunter, Hayden Pacl, Jacelyn E Peabody Lever, Denise D Stanford, Satinder P Singh, Prachi Bajpai, Upender Manne, Paul V Benson, Steven M Rowe, Stephan Le Roux, Alex Sigal, Muofhe Tshibalanganda, Carlyn Wells, Anton Du Plessis, Mpumelelo Msimang, Threnesan Naidoo, Adrie J C Steyn

Faculty, Staff and Student Publications

Our current understanding of the spectrum of TB and COVID-19 lesions in the human lung is limited by a reliance on low-resolution imaging platforms that cannot provide accurate 3D representations of lesion types within the context of the whole lung. To characterize TB and COVID-19 lesions in 3D, we applied micro/nanocomputed tomography to surgically resected, postmortem, and paraffin-embedded human lung tissue. We define a spectrum of TB pathologies, including cavitary lesions, calcium deposits outside and inside necrotic granulomas and mycetomas, and vascular rearrangement. We identified an unusual spatial arrangement of vasculature within an entire COVID-19 lobe, and 3D segmentation of …

Exploration Of The Minimum Necessary Fviii Level At Different Physical Activity Levels In Pediatric Patients With Hemophilia A, Di Ai, Kun Huang, Gang Li, Yingzi Zhen, Xinyi Wu, Ningning Zhang, Aihua Huo, Zhenping Chen, Runhui Wu

Faculty, Staff and Student Publications

BACKGROUND: Physical activity can increase joint stability and reduce the risk of injury in hemophilia patients. There is limited clinical data on target trough FVIII levels during physical activity in hemophilia A patients. Hence, this study aimed to explore the target trough FVIII level required to avoid bleeding during different physical activities in hemophilia A patients.

METHODS: Patients with severe or moderate hemophilia A, who underwent pharmacokinetics (PK) tests at our center were enrolled in this study. Physical activities and clinical information such as bleeding were recorded. The FVIII level during physical activity was calculated by the WAPPS-Hemo.

RESULTS: A …

Aortic Root Dissection Due To An Automated Fastener Device, Ismael A Salas De Armas, L Maximilian Buja, Manish K Patel, Jayeshkumar Patel, Mehmet H Akay, Emre Gok, Igor D Gregoric

Faculty, Staff and Student Publications

Minimally invasive aortic valve replacement through a right thoracotomy is frequently performed in patients with aortic valve disease. The Cor-Knot Device (LSI Solutions) is an automated fastener that secures valve sutures. This case report is for a patient who developed postcardiotomy shock during a minimally invasive aortic valve surgery. The patient was found to have an aortic root dissection involving 90% of the aortic root circumference, including bilateral coronary ostia. The autopsy revealed that the aortic damage could be explained by a direct aortic intimal tear from the distal tip of the device shaft. The device was most likely not …

B-Lymphoblastic Leukemia With Burkitt-Like Morphology And Aberrant Myeloperoxidase Expression: A Diagnostic Conundrum, Karen A Nahmod, Wei Wang, Karan Saluja, Zhenya Tang, L Jeffrey Medeiros, Beenu Thakral

Faculty, Staff and Student Publications

No abstract provided.

Pathologic Predictors Of Response To Treatment Of Immune Checkpoint Inhibitor-Induced Kidney Injury, Ala Abudayyeh, Liye Suo, Heather Lin, Omar Mamlouk, Noha Abdel-Wahab, Amanda Tchakarov

Faculty, Staff and Student Publications

Background: Immune-related adverse events are a management challenge in patients receiving immune checkpoint inhibitors (ICIs). The most common renal immune-related adverse event, acute interstitial nephritis (AIN), is associated with patient morbidity and mortality. AIN, characterized by infiltration of renal tissue with immune cells, may be analogous to kidney transplant rejection. We evaluated clinical variables and pathologic findings to identify predictors of renal response and overall survival (OS) in patients with ICI-induced AIN. Design, setting, participants, and measurements: We reviewed the records and biopsy specimens of all 35 patients treated for ICI-induced AIN at our institution, between August 2007 and August …

Inequity In National Institutes Of Health Predoctoral Fellowships, 2001-2020, Mytien Nguyen, Nghia D Nguyen, Sarwat I Chaudhry, Mayur M Desai, Jose E Cavazos, Dowin Boatright

Faculty, Staff and Student Publications

This cross-sectional study examines trends in number of awards and funding of general and diversity F31 predoctoral fellowships from 2001 to 2020.

Low-Dose Immune Tolerance Induction In Children With Severe Hemophilia A With High-Titer Inhibitors: Type Of Factor 8 Mutation And Outcomes, Jie Sun, Zekun Li, Gang Li, Kun Huang, Di Ai, Guoqing Liu, Wanru Yao, Xingjuan Xie, Hao Gu, Yingzi Zhen, Zhenping Chen, Runhui Wu

Faculty, Staff and Student Publications

BACKGROUND: No studies evaluated the role of

OBJECTIVES: To explore the association between

METHODS: Children SHA with high-titer inhibitors who received low-dose ITI therapy at least for 1 year were included in this study. Based on the risk of inhibitor development,

RESULTS: Of 104 children included, 101 had

CONCLUSIONS: Types of

The Intricate Interplay Between Cancer Stem Cells And Cell-Of-Origin Of Cancer: Implications For Therapeutic Strategies, Luis Alberto Vega, Misu A Sanson, María Belén Cubria, Shrijana Regmi, Brittany J Shah, Samuel A Shelburne, Anthony R Flores

Faculty, Staff and Student Publications

Antimicrobial resistance-encoding mobile genetic elements (MGEs) may contribute to the disease potential of bacterial pathogens. We previously described the association of Group A Streptococcus (GAS) derived from invasive disease with increasingly frequent antimicrobial resistance (AMR). We hypothesized that a 65-kb AMR-encoding MGE (ICESpyM92), highly conserved among closely related emergent invasive emm92 GAS, contributes to GAS disease potential. Here, we provide evidence that a combination of ICESpyM92- and core genome-dependent differential gene expression (DGE) contributes to invasive disease phenotypes of emergent emm92 GAS. Using isogenic ICESpyM92 mutants generated in distinct emm92 genomic backgrounds, we determined the presence of ICESpyM92 enhances GAS …

The Impact Of Age And Sex On Aortic Dissection Outcomes: A True Controversy Or Lack Of Standardization?, Erin F Mccaffrey, Michele Donato, Leeat Keren, Zhenghao Chen, Alea Delmastro, Megan B Fitzpatrick, Sanjana Gupta, Noah F Greenwald, Alex Baranski, William Graf, Rashmi Kumar, Marc Bosse, Christine Camacho Fullaway, Pratista K Ramdial, Erna Forgó, Vladimir Jojic, David Van Valen, Smriti Mehra, Shabaana A Khader, Sean C Bendall, Matt Van De Rijn, Daniel Kalman, Deepak Kaushal, Robert L Hunter, Niaz Banaei, Adrie J C Steyn, Purvesh Khatri, Michael Angelo

Faculty, Staff and Student Publications

Tuberculosis (TB) in humans is characterized by formation of immune-rich granulomas in infected tissues, the architecture and composition of which are thought to affect disease outcome. However, our understanding of the spatial relationships that control human granulomas is limited. Here, we used multiplexed ion beam imaging by time of flight (MIBI-TOF) to image 37 proteins in tissues from patients with active TB. We constructed a comprehensive atlas that maps 19 cell subsets across 8 spatial microenvironments. This atlas shows an IFN-γ-depleted microenvironment enriched for TGF-β, regulatory T cells and IDO1

Ahcc® Supplementation To Support Immune Function To Clear Persistent Human Papillomavirus Infections, Judith A Smith, Anjali A Gaikwad, Lata Mathew, Barbara Rech, Jonathan P Faro, Joseph A Lucci, Yu Bai, Randall J Olsen, Teresa T Byrd

Faculty, Staff and Student Publications

OBJECTIVE: To determine the efficacy, safety, and durability of the use of AHCC supplementation for 6 months to support the host immune system to clear high-risk human papillomavirus (HPV) infections. The AHCC supplement is a proprietary, standardized extract of cultured lentinula edodes mycelia (AHCC

STUDY DESIGN: This was a randomized, double-blind, placebo-controlled study (CTN: NCT02405533) in 50 women over 30 years of age with confirmed persistent high-risk HPV infections for greater than 2 years. Patients were randomized to placebo once daily for 12 months (N = 25) or AHCC 3-g supplementation by mouth once daily on empty stomach for 6 …

Career Transitions: Reflections Of Former Chairs And Academic Health Center Leaders, David N Bailey, L Maximilian Buja, Avrum I Gotlieb, Deborah E Powell, Fred Sanfilippo

Faculty, Staff and Student Publications

The 2022 Association of Pathology Chairs Annual Meeting included a live discussion session and a pre-meeting recorded panel webinar sponsored by the Senior Fellows Group (former chairs of academic departments of pathology who have remained active in the Association of Pathology Chairs). The presentation was focused on transition planning for academic health center leaders. Each of the discussion group panelists had served as a pathology department chair as well as in more senior leadership positions, and they provided perspectives based upon their personal experiences. It was noted that such positions are often "at will" appointments of indeterminate length and that …

Clinicopathological Correlations In Heart Transplantation Recipients Complicated By Death Or Re-Transplantation, Michelle M Mcdonald, Maks Mihalj, Bihong Zhao, Sriram Nathan, Stanislava Matejin, Giulia Ottaviani, Mateja K Jezovnik, Rajko Radovancevic, Biswajit Kar, Igor D Gregoric, L Maximilian Buja

Faculty, Staff and Student Publications

PURPOSE: This study aimed to identify and correlate pathological findings with clinical outcomes in patients after orthotopic heart transplantation (OHT) who either died or underwent a re-transplantation.

METHODOLOGY AND STUDY DESIGN: Single-center retrospective analysis of primary OHT patients who died or were re-transplanted between October 2012 and July 2021. Clinical data were matched with corresponding pathological findings from endomyocardial biopsies on antibody-mediated rejection, cellular rejection, and cardiac allograft vasculopathy. Re-assessment of available tissue samples was performed to investigate acute myocardial injury (AMI) as a distinct phenomenon. These were correlated with clinical outcomes, which included severe primary graft dysfunction. Patients were …

Urinary T Cells Are Detected In Patients With Immune Checkpoint Inhibitor-Associated Immune Nephritis That Are Clonotypically Identical To Kidney T Cell Infiltrates, Shailbala Singh, Leticia C Clemente, Edwin R Parra, Amanda Tchakarov, Chao Yang, Yisheng Li, James P Long, Cassian Yee, Jamie S Lin

Faculty, Staff and Student Publications

Acute kidney injury (AKI) occurs in ~20% of patients receiving immune checkpoint inhibitor (ICI) therapy; however, only 2-5% will develop ICI-mediated immune nephritis. Conventional tests are nonspecific in diagnosing disease pathology and invasive procedures (i.e. kidney biopsy) may not be feasible. In other autoimmune renal diseases, urinary immune cells correlated with the pathology or were predictive of disease activity. Corresponding evidence and analysis are absent for ICI-mediated immune nephritis. We report the first investigation analyzing immune cell profiles of matched kidney biopsies and urine of patients with ICI-AKI. We demonstrated the presence of urinary T cells in patients with immune …

Evaluation Of Contemporary Echocardiographic And Histomorphology Parameters In Predicting Mortality In Patients With Endomyocardial Biopsy-Proven Cardiac Al Amyloidosis, Efstratios Koutroumpakis, Adam Niku, Christopher K Black, Abdelrahman Ali, Humaira Sadaf, Juhee Song, Nicolas Palaskas, Cezar Iliescu, Jean-Bernard Durand, Syed Wamique Yusuf, Hans C Lee, L Maximilian Buja, Anita Deswal, Jose Banchs

Faculty, Staff and Student Publications

INTRODUCTION: This study examined the role of echocardiographic and cardiac histomorphology parameters in predicting mortality in patients with cardiac AL amyloidosis.

METHODS: Patients with endomyocardial biopsy-proven cardiac AL amyloidosis treated at MD Anderson Cancer Center between 6/2011 and 6/2020 were identified. Stored echocardiographic images and endomyocardial biopsy samples were processed for myocardial strain analysis and a detailed histomorphology characterization.

RESULTS: Of 43 patients; 44% were women and 63% white. Median age was 65 years; 51% underwent stem cell transplantation (SCT). Thirty patients (70%) died during follow up (median follow up: 4.1 years). Lower LA strain (

CONCLUSION: Lower LA strain …

Limitations Of Available Blood Products For Massive Transfusion During Mass Casualty Events At Us Level 1 Trauma Centers, James Williams, Michael Gustafson, Yu Bai, Samuel Prater, Charles E Wade, Oscar D Guillamondegui, Mansoor Khan, Megan Brenner, Paula Ferrada, Derek Roberts, Tal Horer, David Kauvar, Andrew Kirkpatrick, Carlos Ordonez, Bruno Perreira, Artai Priouzram, Juan Duchesne, Bryan A Cotton

Faculty, Staff and Student Publications

INTRODUCTION: Exsanguination remains a leading cause of preventable death in traumatically injured patients. To better treat hemorrhagic shock, hospitals have adopted massive transfusion protocols (MTPs) which accelerate the delivery of blood products to patients. There has been an increase in mass casualty events (MCE) worldwide over the past two decades. These events can overwhelm a responding hospital's supply of blood products. Using a computerized model, this study investigated the ability of US trauma centers (TCs) to meet the blood product requirements of MCEs.

METHODS: Cross-sectional survey data of on-hand blood products were collected from 16 US level-1 TCs. A discrete …

A Selective Antibiotic For Lyme Disease, Nadja Leimer, Xiaoqian Wu, Yu Imai, Madeleine Morrissette, Norman Pitt, Quentin Favre-Godal, Akira Iinishi, Samta Jain, Mariaelena Caboni, Inga V Leus, Vincent Bonifay, Samantha Niles, Rachel Bargabos, Meghan Ghiglieri, Rachel Corsetti, Megan Krumpoch, Gabriel Fox, Sangkeun Son, Dorota Klepacki, Yury S Polikanov, Cecily A Freliech, Julie E Mccarthy, Diane G Edmondson, Steven J Norris, Anthony D'Onofrio, Linden T Hu, Helen I Zgurskaya, Kim Lewis

Faculty, Staff and Student Publications

Lyme disease is on the rise. Caused by a spirochete Borreliella burgdorferi, it affects an estimated 500,000 people in the United States alone. The antibiotics currently used to treat Lyme disease are broad spectrum, damage the microbiome, and select for resistance in non-target bacteria. We therefore sought to identify a compound acting selectively against B. burgdorferi. A screen of soil micro-organisms revealed a compound highly selective against spirochetes, including B. burgdorferi. Unexpectedly, this compound was determined to be hygromycin A, a known antimicrobial produced by Streptomyces hygroscopicus. Hygromycin A targets the ribosomes and is taken up by B. burgdorferi, explaining …

Comparison Of Transcriptional Profiles Of Treponema Pallidum During Experimental Infection Of Rabbits And In Vitro Culture: Highly Similar, Yet Different, Bridget D De Lay, Todd A Cameron, Nicholas R De Lay, Steven J Norris, Diane G Edmondson

Faculty, Staff and Student Publications

Treponema pallidum ssp. pallidum, the causative agent of syphilis, can now be cultured continuously in vitro utilizing a tissue culture system, and the multiplication rates are similar to those obtained in experimental infection of rabbits. In this study, the RNA transcript profiles of the T. pallidum Nichols during in vitro culture and rabbit infection were compared to examine whether gene expression patterns differed in these two environments. To this end, RNA preparations were converted to cDNA and subjected to RNA-seq using high throughput Illumina sequencing; reverse transcriptase quantitative PCR was also performed on selected genes for validation of results. The …

Imaging Based Prediction Of Pathology In Adult Diffuse Glioma With Applications To Therapy And Prognosis, Evan Gates

Dissertations and Theses (Open Access)

The overall aggressiveness of a glioma is measured by histologic and molecular analysis of tissue samples. However, the well-known spatial heterogeneity in gliomas limits the ability for clinicians to use that information to make spatially specific treatment decisions. Magnetic resonance imaging (MRI) visualizes and assesses the tumor. But, the exact degree to which MRI correlates with the actual underlying tissue characteristics is not known.

In this work, we derive quantitative relationships between imaging and underlying pathology. These relations increase the value of MRI by allowing it to be a better surrogate for underlying pathology and they allow evaluation of the …

Sars-Cov-2 Infects Human Engineered Heart Tissues And Models Covid-19 Myocarditis, Adam L Bailey, Oleksandr Dmytrenko, Lina Greenberg, Andrea L Bredemeyer, Pan Ma, Jing Liu, Vinay Penna, Emma S Winkler, Sanja Sviben, Erin Brooks, Ajith P Nair, Kent A Heck, Aniket S Rali, Leo Simpson, Mehrdad Saririan, Dan Hobohm, W Tom Stump, James A Fitzpatrick, Xuping Xie, Xianwen Zhang, Pei-Yong Shi, J Travis Hinson, Weng-Tein Gi, Constanze Schmidt, Florian Leuschner, Chieh-Yu Lin, Michael S Diamond, Michael J Greenberg, Kory J Lavine

Faculty, Staff and Student Publications

There is ongoing debate as to whether cardiac complications of coronavirus disease-2019 (COVID-19) result from myocardial viral infection or are secondary to systemic inflammation and/or thrombosis. We provide evidence that cardiomyocytes are infected in patients with COVID-19 myocarditis and are susceptible to severe acute respiratory syndrome coronavirus 2. We establish an engineered heart tissue model of COVID-19 myocardial pathology, define mechanisms of viral pathogenesis, and demonstrate that cardiomyocyte severe acute respiratory syndrome coronavirus 2 infection results in contractile deficits, cytokine production, sarcomere disassembly, and cell death. These findings implicate direct infection of cardiomyocytes in the pathogenesis of COVID-19 myocardial pathology …

Parameters Affecting Continuous In Vitro Culture Of Treponema Pallidum Strains, Diane G Edmondson, Bridget D Delay, Lindsay E Kowis, Steven J Norris

Faculty, Staff and Student Publications

The bacterium that causes syphilis, Treponema pallidum subsp. pallidum, has now been cultured in vitro continuously for periods exceeding 3 years using a system consisting of coculture with Sf1Ep rabbit epithelial cells in TpCM-2 medium and a low-oxygen environment. In addition, long-term culture of several other syphilis isolates (SS14, Mexico A, UW231B, and UW249B) and the T. pallidum subsp. endemicum Bosnia A strain has been achieved. During in vitro passage, T. pallidum subsp. pallidum exhibited a typical bacterial growth curve with logarithmic and stationary phases. Sf1Ep cells are required for sustained growth and motility; however, high initial Sf1Ep cell …

Primary Effusion Lymphoma: A Clinicopathological Study Of 70 Cases, Zhihong Hu, Zenggang Pan, Weina Chen, Yang Shi, Wei Wang, Ji Yuan, Endi Wang, Shanxiang Zhang, Habibe Kurt, Brenda Mai, Xiaohui Zhang, Hui Liu, Adan A Rios, Hilary Y Ma, Nghia D Nguyen, L Jeffrey Medeiros, Shimin Hu

Faculty, Staff and Student Publications

Primary effusion lymphoma (PEL) is a rare type of large B-cell lymphoma associated with human herpesvirus 8 (HHV8) infection. Patients with PEL usually present with an effusion, but occasionally with an extracavitary mass. In this study, we reported a cohort of 70 patients with PEL: 67 men and 3 women with a median age of 46 years (range 26–91). Of these, 56 (80%) patients had human immunodeficiency virus (HIV) infection, eight were HIV-negative, and six had unknown HIV status. Nineteen (27%) patients had Kaposi sarcoma. Thirty-five (50%) patients presented with effusion only, 27 (39%) had an extracavitary mass or masses …

Biomarkers In Acute Myeloid Leukemia: Leveraging Next Generation Sequencing Data For Optimal Therapeutic Strategies, Hanadi El Achi, Rashmi Kanagal-Shamanna

Faculty, Staff and Student Publications

Next generation sequencing (NGS) is routinely used for mutation profiling of acute myeloid leukemia. The extensive application of NGS in hematologic malignancies, and its significant association with the outcomes in multiple large cohorts constituted a proof of concept that AML phenotype is driven by underlying mutational signature and is amenable for targeted therapies. These findings urged incorporation of molecular results into the latest World Health Organization (WHO) sub-classification and integration into risk-stratification and treatment guidelines by the European Leukemia Net. NGS mutation profiling provides a large amount of information that guides diagnosis and management, dependent on the type and number …

Effects Of Image Quantity And Image Source Variation On Machine Learning Histology Differential Diagnosis Models, Elham Vali-Betts, Kevin J Krause, Alanna Dubrovsky, Kristin Olson, John Paul Graff, Anupam Mitra, Ananya Datta-Mitra, Kenneth Beck, Aristotelis Tsirigos, Cynthia Loomis, Antonio Galvao Neto, Esther Adler, Hooman H Rashidi

Faculty, Staff and Student Publications

Aims:

Histology, the microscopic study of normal tissues, is a crucial element of most medical curricula. Learning tools focused on histology are very important to learners who seek diagnostic competency within this important diagnostic arena. Recent developments in machine learning (ML) suggest that certain ML tools may be able to benefit this histology learning platform. Here, we aim to explore how one such tool based on a convolutional neural network, can be used to build a generalizable multi-classification model capable of classifying microscopic images of human tissue samples with the ultimate goal of providing a differential diagnosis (a list of …

The Bmal1/Hif2a Heterodimer Modulates Circadian Variations Of Myocardial Injury, Hui Li, Xinwei Kuang, Long Liang, Youqiong Ye, Yongchang Zhang, Jialu Li, Fangyu Ma, Juan Tao, Guang Lei, Shuang Zhao, Juan Su, Nong Yang, Cong Peng, Xiaowei Xu, Mien-Chie Hung, Leng Han, Hong Liu, Jing Liu, Xiang Chen

Faculty, Staff and Student Publications

Immune checkpoints blockades have shown promising clinical effects in various malignancies, but the overall response rate is low. Here, the immune features are comprehensively characterized in >10 000 cancer patients from The Cancer Genome Atlas and significantly positive correlations are observed between targets of Sunitinib and inhibitory immune checkpoints and suppressive immune cells. It is further confirmed that Sunitinib treatment increases the antitumor immunity in a phase III trial. Mechanistically, it is discovered that Sunitinib regulates the stability of tumor PD‐L1 via p62, that p62 can bind to PD‐L1 and specifically promote its translocation into autophagic lysosome for degradation. Preclinically, …

Variable Expression Of Msh6 In Endometrial Carcinomas With Intact Mismatch Repair And With Mlh1 Loss Due To Mlh1 Methylation, Nidhi Tandon, Courtney Hudgens, Bryan Fellman, Michael T Tetzlaff, Russell R Broaddus

Faculty, Staff and Student Publications

Immunohistochemistry for mismatch repair proteins MLH1, MSH2, MSH6, and PMS2 is an effective screen to detect individuals at risk for Lynch syndrome. College of American Pathologists guidelines stipulate that protein expression should be reported as present versus absent, as most patients with germline mutations in a mismatch repair gene have complete loss of protein expression in tumor cells. A similar approach is employed to screen for cancer patients eligible for immune checkpoint blockade. This "all or none" interpretive approach ignores substantial evidence that mismatch repair may be more finely regulated by other mechanisms. We have observed clinically that MSH6 expression …

Cd123 As A Biomarker In Hematolymphoid Malignancies: Principles Of Detection And Targeted Therapies, Hanadi El Achi, Edouard Dupont, Shilpa Paul, Joseph D Khoury

Faculty, Staff and Student Publications

CD123, the α chain of the interleukin 3 receptor, is a cytokine receptor that is overexpressed in multiple hematolymphoid neoplasms, including acute myeloid leukemia, blastic plasmacytoid dendritic cell neoplasm, acute lymphoblastic leukemia, hairy cell leukemia, and systemic mastocytosis. Importantly, CD123 expression is upregulated in leukemic stem cells relative to non-neoplastic hematopoietic stem cells, which makes it a useful diagnostic and therapeutic biomarker in hematologic malignancies. Varying levels of evidence have shown that CD123-targeted therapy represents a promising therapeutic approach in several cancers. Tagraxofusp, an anti-CD123 antibody conjugated to a diphtheria toxin, has been approved for use in patients with blastic …

Yebc Regulates Variable Surface Antigen Vlse Expression And Is Required For Host Immune Evasion In Borrelia Burgdorferi, Yan Zhang, Tong Chen, Sajith Raghunandanan, Xuwu Xiang, Jing Yang, Qiang Liu, Diane G Edmondson, Steven J Norris, X Frank Yang, Yongliang Lou

Faculty, Staff and Student Publications

Borrelia burgdorferi, the Lyme disease pathogen causes persistent infection by evading the host immune response. Differential expression of the surface-exposed lipoprotein VlsE that undergoes antigenic variation is a key immune evasion strategy employed by B. burgdorferi. Most studies focused on the mechanism of VlsE antigen variation, but little is known about VlsE regulation and factor(s) that regulates differential vlsE expression. In this study, we investigated BB0025, a putative YebC family transcriptional regulator (and hence designated BB0025 as YebC of B. burgdorferi herein). We constructed yebC mutant and complemented strain in an infectious strain of B. burgdorferi. The yebC mutant could …