Browsing by Author "Zhang, Shanxiang"
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Item Aberrant ERG expression associates with downregulation of miR‐4638‐5p and selected genomic alterations in a subset of diffuse large B‐cell lymphoma(Wiley, 2019-10) Zhang, Shanxiang; Wang, Lin; Cheng, Liang; Pathology and Laboratory Medicine, School of MedicineERG (avian v‐ets erythroblastosis virus E26 oncogene homolog), an oncoprotein in prostate carcinoma and Ewing's sarcoma is associated with poor prognosis in patients with acute myeloid leukemia and T lymphoblastic leukemia. However little is known about ERG in lymphoma. Here we studied ERG in diffuse large B‐cell lymphoma (DLBCL) by immunohistochemistry, fluorescence in situ hybridization (FISH), genome‐wide microRNA (miRNA) expression profiling, real‐time reverse‐transcriptase polymerase chain reaction (RT‐PCR) and whole exome sequencing (WES). Approximately 30% of de novo DLBCLs (37 of 118) expressed ERG (ERG+). ERG expression showed no significant correlation with DLBCL cell‐of‐origin classification, patient's age, sex, nodal, or extranodal disease status, tumor expression of p53 or p63. There was no ERG rearrangement in 10 randomly selected ERG+ DLBCLs by FISH. Forty‐three miRNAs showed significant differential expression between ERG+ and ERG− DLBCLs. Downregulation of miR‐4638‐5p was confirmed by real‐time RT‐PCR. WES not only confirmed known gene mutations in DLBCLs but also revealed multiple novel gene mutations in POLA1, E2F1, PSMD8, AXIN1, GAB2, and GNB2L1, which occur more frequently in ERG+ DLBCLs. In conclusion, our studies demonstrated aberrant ERG expression in a subset of DLBCL, which is associated with downregulation of miR‐4638‐5p. In comparison with ERG‐negative DLBCL, ERG+ DLBCL more likely harbors mutations in genes important in cell cycle control, B‐cell receptor‐mediated signaling and degradation of β‐catenin. Further clinicopathological correlation and functional studies of ERG‐related miRNAs and pathways may provide new insight into the pathogenesis of DLBCL and reveal novel targets for better management of patients with DLBCL.Item Acute appendicitis caused by acute myeloid leukemia(Wiley, 2014-10) Zhang, Shanxiang; Chen, Shaoxiong; Pathology & Laboratory Medicine, School of MedicineKEY CLINICAL MESSAGE: A case of appendiceal involvement by acute myeloid leukemia (AML) in an adult with recent history of AML transformed from myelodysplastic syndrome (MDS) was presented. Being aware of this rare presentation in particular in a patient with history of MDS and/or AML is important for prompt clinical diagnosis and management.Item Clinical characteristics and outcomes of Castleman disease: a multicenter Consortium study of 428 patients with 15-year follow-up(e-Century Publishing, 2022-09-15) Liu, Wanying; Cai, Qingqing; Yu, Tiantian; Strati, Paolo; Hagemeister, Frederick B.; Zhai, Qiongli; Zhang, Mingzhi; Li, Ling; Fang, Xiaosheng; Li, Jianyong; Sun, Ruifang; Zhang, Shanxiang; Yang, Hanjin; Wang, Zhaoming; Qian, Wenbian; Iwaki, Noriko; Sato, Yasuharu; Oksenhendler, Eric; Xu-Monette, Zijun Y.; Young, Ken H.; Yu, Li; Pathology and Laboratory Medicine, School of MedicineCastleman disease (CD) has been reported as a group of poorly understood lymphoproliferative disorders, including unicentric CD (UCD) and idiopathic multicentric CD (iMCD) which are human immunodeficiency virus (HIV) negative and human herpes virus 8 (HHV-8) negative. The clinical and independent prognostic factors of CD remain poorly elucidated. We retrospectively collected the clinical information of 428 patients with HIV and HHV-8 negative CD from 12 large medical centers with 15-year follow-up. We analyzed the clinicopathologic features of 428 patients (248 with UCD and 180 with iMCD) with a median age of 41 years. The histology subtypes were hyaline-vascular (HV) histopathology for 215 patients (56.58%) and plasmacytic (PC) histopathology for 165 patients (43.42%). Most patients with UCD underwent surgical excision, whereas the treatment strategies of patients with iMCD were heterogeneous. The outcome for patients with UCD was better than that for patients with iMCD, 5-year overall survival (OS) rates were 95% and 74%, respectively. In further analysis, a multivariate analysis using a Cox regression model revealed that PC subtype, hepatomegaly and/or splenomegaly, hemoglobin ≤ 80 g/L, and albumin ≤ 30 g/L were independent prognostic factors of CD for OS. The model of iMCD revealed that age > 60 years, hepatomegaly and/or splenomegaly, and hemoglobin ≤ 80 g/L were independent risk factors. In UCD, single-factor analysis identified two significant risk factors: hemoglobin ≤ 100 g/L and albumin ≤ 30 g/L. Our study emphasizes the distinction of clinical characteristics between UCD and iMCD. The importance of poor risk factors of different clinical classifications may direct more precise and appropriate treatment strategies.Item EBV-positive DLBCL frequently harbors somatic mutations associated with clonal hematopoiesis of indeterminate potential(American Society of Hematology, 2023) Li, Yong; Xu-Monette, Zijun Y.; Abramson, Jeremy; Sohani, Aliyah R.; Bhagat, Govind; Tzankov, Alexandar; Visco, Carlo; Zhang, Shanxiang; Dybkaer, Karen; Pan, Zenggang; Xu, Min; Tam, Wayne; Zu, Youli; Hsi, Eric D.; Hagemeister, Fredrick B.; Go, Heounjeong; van Krieken, J. Han; Winter, Jane N.; Ponzoni, Maurilio; Ferreri, Andrés J. M.; Møller, Michael B.; Piris, Miguel A.; Wang, Yingjun; Zhang, Mingzhi; Young, Ken H.; Pathology and Laboratory Medicine, School of MedicineItem EGR1 addiction in diffuse large B cell lymphoma(American Association for Cancer Research, 2021) Kimpara, Shuichi; Lu, Li; Hoang, Nguyet M.; Zhu, Fen; Bates, Paul D.; Daenthanasanmak, Anusara; Zhang, Shanxiang; Yang, David T.; Kelm, Amanda; Liu, Yunxia; Li, Yangguang; Rosiejka, Alexander; Kondapelli, Apoorv; Bebel, Samantha; Chen, Madelyn; Waldmann, Thomas A.; Capitini, Christian M.; Rui, Lixin; Pathology and Laboratory Medicine, School of MedicineEarly growth response gene (EGR1) is a transcription factor known to be a downstream effector of B-cell receptor signaling and Janus kinase 1 (JAK1) signaling in diffuse large B-cell lymphoma (DLBCL). While EGR1 is characterized as a tumor suppressor in leukemia and multiple myeloma, the role of EGR1 in lymphoma is unknown. Here we demonstrate that EGR1 is a potential oncogene that promotes cell proliferation in DLBCL. IHC analysis revealed that EGR1 expression is elevated in DLBCL compared with normal lymphoid tissues and the level of EGR1 expression is higher in activated B cell-like subtype (ABC) than germinal center B cell-like subtype (GCB). EGR1 expression is required for the survival and proliferation of DLBCL cells. Genomic analyses demonstrated that EGR1 upregulates expression of MYC and E2F pathway genes through the CBP/p300/H3K27ac/BRD4 axis while repressing expression of the type I IFN pathway genes by interaction with the corepressor NAB2. Genetic and pharmacologic inhibition of EGR1 synergizes with the BRD4 inhibitor JQ1 or the type I IFN inducer lenalidomide in growth inhibition of ABC DLBCL both in cell cultures and xenograft mouse models. Therefore, targeting oncogenic EGR1 signaling represents a potential new targeted therapeutic strategy in DLBCL, especially for the more aggressive ABC DLBCL. IMPLICATIONS: The study characterizes EGR1 as a potential oncogene that promotes cell proliferation and defines EGR1 as a new molecular target in DLBCL, the most common non-Hodgkin lymphoma.Item Excessive matrix metalloproteinase-1 and hyperactivation of endothelial cells occurred in COVID-19 patients and were associated with the severity of COVID-19(Cold Spring Harbor Laboratory Press, 2021-01) Syed, Fahim; Li, Wei; Relich, Ryan F.; Russell, Patrick M.; Zhang, Shanxiang; Zimmerman, Michelle K.; Yu, Qigui; Microbiology and Immunology, School of MedicineCOVID-19 starts as a respiratory disease that can progress to pneumonia, severe acute respiratory syndrome (SARS), and multi-organ failure. Growing evidence suggests that COVID-19 is a systemic illness that primarily injures the vascular endothelium, yet the underlying mechanisms remain unknown. SARS-CoV-2 infection is believed to trigger a cytokine storm that plays a critical role in the pathogenesis of endothelialitis and vascular injury, eventually leading to respiratory and multi-organ failure in COVID-19 patients. We used a multiplex immunoassay to systematically profile and compare 65 inflammatory cytokines/chemokines/growth factors in plasma samples from 24 hospitalized (severe/critical) COVID-19 patients, 14 mild/moderate cases, and 13 healthy controls (HCs). Patients with severe/critical and mild/moderate COVID-19 had significantly higher plasma levels of 20 analytes than HCs. Surprisingly, only one cytokine (MIF) was among these altered analytes, while the rest were chemokines and growth factors. In addition, only MMP-1 and VEGF-A were significantly elevated in hospitalized COVID-19 patients when compared to mild/moderate cases. Given that excessive MMP-1 plays a central role in tissue destruction in a wide variety of vascular diseases and that elevated VEGF-A, an EC activation marker, increases vascular permeability, we further studied MMP-1 enzymatic activity and other EC activation markers such as soluble forms of CD146, ICAM-1, and VCAM-1. We found that plasma MMP-1 enzymatic activity and plasma levels of MMP-1 and EC activation markers were highly dysregulated in COVID-19 patients. Some dysregulations were associated with patients’ age or gender, but not with race. Our results demonstrate that COVID-19 patients have distinct inflammatory profiles that are distinguished from the cytokine storms in other human diseases. Excessive MMP-1 and hyperactivation of ECs occur in COVID-19 patients and are associated with the severity of COVID-19.Item Florid splenic γ/δ T-cell proliferation in patients with splenomegaly and cytopenias: a “high stakes” diagnostic challenge(Elsevier, 2017-08) Zhang, Shanxiang; Bayerl, Michael G.; Department of Pathology and Laboratory Medicine, School of MedicineSplenic γ/δ T-cell proliferation is rare, and correct diagnosis is critical for adequate clinical management. Two splenectomy cases from patients with splenomegaly and cytopenias were studied by morphological evaluation, extensive immunophenotyping, FISH and molecular studies. The clinicopathologic findings were compared with splenic T γ/δ neoplasia, notably hepatosplenic T-cell lymphoma (HSTL) and T-cell large granular lymphocytic leukemia (TLGL) of the variety T γ/δ. The enlarged spleens showed expanded red pulp with markedly increased γ/δ T cells, which share significant to complete overlapping morphology and immunophenotype with the neoplastic γ/δ T cells in HSTL and γ/δ TLGL. However, they were polyclonal by molecular study and showed no evidence of isochromosome 7q. Splenectomy alone led to long-term clinical remission in both patients. Two florid reactive splenic γ/δ T-cell proliferations mimicking γ/δ T-cell neoplasia were reported for the first time in English literature. Recognition of this exceedingly rare phenomenon is critical in prevention of misdiagnosis with potentially catastrophic consequences.Item MMPs/TIMPs imbalances in the peripheral blood and cerebrospinal fluid are associated with the pathogenesis of HIV-1-associated neurocognitive disorders: A pilot study(Elsevier, 2017) Xing, Yanyan; Shepherd, Nicole; Lan, Jie; Rane, Sushmita; Gupta, Samir K.; Zhang, Shanxiang; Dong, Jun; Yu, Qigui; Department of Microbiology and Immunology, IU School of MedicineHIV-1-associated neurocognitive disorders (HAND) continue to be a major concern in the infected population, despite the widespread use of combined antiretroviral therapy (cART). Growing evidence suggests that an imbalance between matrix metalloproteinases (MMPs) and endogenous tissue inhibitors of MMPs (TIMPs) contributes to the pathogenesis of HAND. In our present study, we examined protein levels and enzymatic activities of MMPs and TIMPs in both plasma and cerebrospinal fluid (CSF) samples from HIV-1 patients with or without HAND and HIV-1-negative controls. Imbalances between MMPs and TIMPs with distinct patterns were revealed in both the peripheral blood and CSF of HIV-1 patients, especially those with HAND. In the peripheral blood, the protein levels of MMP-2, MMP-9, TIMP-1, TIMP-2, and the enzymatic activities of MMP-2 and MMP-9 were increased in HIV-1 patients with or without HAND when compared with HIV-1-negative controls. The enzymatic activity of MMP-2, but not MMP-9, was further increased in plasma samples of HAND patients than that of HIV-1 patients without HAND. Notably, the ratio of MMP-2/TIMP-2 in plasma was significantly increased in HAND patients, not in patients without HAND. In the CSF, MMP-2 activity was increased, but the ratio of MMP-2/TIMP-2 was not altered. De novo induction and activation of MMP-9 in the CSF of HAND patients was particularly prominent. The imbalances between MMPs and TIMPs in the blood and CSF were related to the altered profiles of inflammatory cytokines/chemokines and monocyte activation in these individuals. In addition, plasma from HIV-1 patients directly induced integrity disruption of an in vitro blood-brain barrier (BBB) model, leading to increased BBB permeability and robust transmigration of monocytes/macrophages. These results indicate that imbalances between MMPs and TIMPs are involved in BBB disruption and are implicated in the pathogenesis of neurological disorders such as HAND in HIV-1 patients.Item A Novel Predictive Model for Idiopathic Multicentric Castleman Disease: The International Castleman Disease Consortium Study(Wiley, 2020-11) Yu, Li; Shi, Menghan; Cai, Qingqing; Strati, Paolo; Hagemeister, Fredrick; Zhai, Qiongli; Li, Ling; Fang, Xiaosheng; Li, Jianyong; Sun, Ruifang; Zhang, Shanxiang; Yang, Hanjin; Wang, Zhaoming; Qian, Wenbin; Iwaki, Noriko; Sato, Yasuharu; Zhang, Lu; Li, Jian; Oksenhendler, Eric; Xu-Monette, Zijun Y.; Young, Ken H.; Pathology and Laboratory Medicine, School of MedicineBACKGROUND: Patients with multicentric Castleman disease (MCD) who are negative for human immunodeficiency virus and human herpesvirus 8 are considered to have idiopathic MCD (iMCD). The clinical presentation of iMCD varies from mild constitutional symptoms to life-threatening symptoms or death. The treatment strategy varies from "watchful waiting" to high-dose chemotherapy. This diverse clinical presentation calls for a classification stratification system that takes into account the severity of the disease. SUBJECTS, MATERIALS, AND METHODS: We analyzed the clinical, laboratory, and pathologic abnormalities and treatment outcomes of 176 patients with iMCD (median follow-up duration 12 years) from the U.S. and China to better understand the characteristics and prognostic factors of this disease. This discovery set of iMCD results was confirmed from the validation set composed of additional 197 patients with iMCD organized from The International Castleman Disease Consortium. RESULTS: Using these data, we proposed and validated the iMCD international prognostic index (iMCD-IPI), which includes parameters related to patient characteristics (age > 40 years), histopathologic features (plasma cell variant), and inflammatory consequences of iMCD (hepatomegaly and/or splenomegaly, hemoglobin <80 g/L, and pleural effusion). These five factors stratified patients according to their performance status and extent of organ dysfunction into three broad categories: low risk, intermediate risk, and high risk. The iMCD-IPI score accurately predicted outcomes in the discovery study cohort, and the results were confirmed on the validation study cohort. CONCLUSION: This study represents the largest series of studies on patients with iMCD in the field and proposed a novel risk-stratification model for iMCD-IPI that could be used to guide risk-stratified treatment strategies in patients with iMCD. IMPLICATIONS FOR PRACTICE: Patients with idiopathic multicentric Castleman disease (iMCD) can benefit from care based on clinical symptoms and disease severity. This study in 176 patients with iMCD constructed an iMCD-IPI score based on five clinical factors, including age >40 years, plasmacytic variant subtype, hepatomegaly and/or splenomegaly, hemoglobin <80 g/L, and pleural effusion, and stratified patients into three risk categories: low risk, intermediate risk, and high risk. The predictive value was validated in an independent set of 197 patients with iMCD from The International Castleman Disease Consortium. The proposed novel model is valuable for predicting clinical outcome and selecting optimal therapies using clinical parameters.Item Pediatric B-cell lymphoma, unclassifiable, with intermediate features between those of diffuse large B-cell lymphoma and Burkitt lymphoma: a report of two cases(Korean Society for Laboratory Medicine (KAMJE), 2015-03) Zhang, Shanxiang; Wilson, David; Czader, Magdalena; Department of Pathology and Laboratory Medicine, IU School of Medicine