Biomedical Informatics Commons^™

Multiple Approaches Converge On Three Biological Subtypes Of Meningioma And Extract New Insights From Published Studies, James C Bayley, Caroline C Hadley, Arif O Harmanci, Akdes S Harmanci, Tiemo J Klisch, Akash J Patel

Faculty, Staff and Student Publications

One-fifth of meningiomas classified as benign by World Health Organization (WHO) histopathological grading will behave malignantly. To better diagnose these tumors, several groups turned to DNA methylation, whereas we combined RNA-sequencing (RNA-seq) and cytogenetics. Both approaches were more accurate than histopathology in identifying aggressive tumors, but whether they revealed similar tumor types was unclear. We therefore performed unbiased DNA methylation, RNA-seq, and cytogenetic profiling on 110 primary meningiomas WHO grade I and II). Each technique distinguished the same three groups (two benign and one malignant) as our previous molecular classification; integrating these methods into one classifier further improved accuracy. Computational …

Interplay Between Soluble Cd74 And Macrophage-Migration Inhibitory Factor Drives Tumor Growth And Influences Patient Survival In Melanoma, Yasunari Fukuda, Matias A Bustos, Sung-Nam Cho, Jason Roszik, Suyeon Ryu, Victor M Lopez, Jared K Burks, Jeffrey E Lee, Elizabeth A Grimm, Dave S B Hoon, Suhendan Ekmekcioglu

Faculty, Staff and Student Publications

Soluble forms of receptors play distinctive roles in modulating signal-transduction pathways. Soluble CD74 (sCD74) has been identified in sera of inflammatory diseases and implicated in their pathophysiology; however, few relevant data are available in the context of cancer. Here we assessed the composition and production mechanisms, as well as the clinical significance and biological properties, of sCD74 in melanoma. Serum sCD74 levels were significantly elevated in advanced melanoma patients compared with normal healthy donors, and the high ratio of sCD74 to macrophage-migration inhibitory factor (MIF) conferred significant predictive value for prolonged survival in these patients (p = 0.0035). Secretion of …

Examining Rural-Urban Differences In Fatalism And Information Overload: Data From 12 Nci-Designated Cancer Centers, Jakob D Jensen, Jackilen Shannon, Ronaldo Iachan, Yangyang Deng, Sunny Jung Kim, Wendy Demark-Wahnefried, Babalola Faseru, Electra D Paskett, Jinxiang Hu, Robin C Vanderpool, Deann Lazovich, Jason A Mendoza, Sanjay Shete, Linda B Robertson, Rajesh Balkrishnan, Katherine J Briant, Benjamin Haaland, David A Haggstrom, Bernard F Fuemmeler, Rural Workgroup Of The Population Health Assessment In Cancer Center Catchment Areas Consortium

Faculty, Staff and Student Publications

BACKGROUND: Rural populations experience a disproportionate cancer burden relative to urban populations. One possibility is that rural populations are more likely to hold counterproductive cancer beliefs such as fatalism and information overload that undermine prevention and screening behaviors.

METHODS: Between 2016 and 2020, 12 U.S. cancer centers surveyed adults in their service areas using online and in-person survey instruments. Participants (

RESULTS: Compared with urban residents, rural residents were more likely to believe that (i) everything causes cancer (OR = 1.29; 95% CI, 1.17-1.43); (ii) prevention is not possible (OR = 1.34; 95% CI, 1.19-1.51); and (iii) there are too …

Breast Radiation Therapy-Related Treatment Outcomes In Patients With Or Without Germline Mutations On Multigene Panel Testing, Bhavana V Chapman, Diane Liu, Yu Shen, Oluwafikayo O Olamigoke, David S Lakomy, Angelica M Gutierrez Barrera, Shane R Stecklein, Gabriel O Sawakuchi, Scott J Bright, Isabelle Bedrosian, Jennifer K Litton, Benjamin D Smith, Wendy A Woodward, George H Perkins, Karen E Hoffman, Michael C Stauder, Eric A Strom, Banu K Arun, Simona F Shaitelman

Faculty, Staff and Student Publications

PURPOSE: Multigene panel testing has increased the detection of germline mutations in patients with breast cancer. The implications of using radiation therapy (RT) to treat patients with pathogenic variant (PV) mutations are not well understood and have been studied mostly in women with only BRCA1 or BRCA2 PVs. We analyzed oncologic outcomes and toxicity after adjuvant RT in a contemporary, diverse cohort of patients with breast cancer who underwent genetic panel testing.

METHODS AND MATERIALS: We retrospectively reviewed the records of 286 women with clinical stage I-III breast cancer diagnosed from 1995 to 2017 who underwent surgery, breast or chest …

Clinical And Molecular Characterization Of Pole Mutations As Predictive Biomarkers Of Response To Immune Checkpoint Inhibitors In Advanced Cancers, Benjamin Garmezy, Jinesh Gheeya, Heather Y Lin, Yuefan Huang, Taebeom Kim, Xianli Jiang, Kyaw Z Thein, Patrick G Pilié, Fadl Zeineddine, Wanlin Wang, Kenna R Shaw, Jordi Rodon, John Paul Shen, Ying Yuan, Funda Meric-Bernstam, Ken Chen, Timothy A Yap

Faculty, Staff and Student Publications

Purpose: DNA polymerase epsilon is critical to DNA proofreading and replication. Mutations in POLE have been associated with hypermutated tumors and antitumor response to immune checkpoint inhibitor (ICI) therapy. We present a clinicopathologic analysis of patients with advanced cancers harboring POLE mutations, the pattern of co-occurring mutations, and their response to ICI therapy within the context of mutation pathogenicity.

Methods: We conducted a retrospective analysis of next-generation sequencing data at MD Anderson Cancer Center to identify patient tumors with POLE mutations and their co-occurring mutations. The pathogenicity of each mutation was annotated using InterVar and ClinVar. Differences in therapeutic response …

Ces2 Sustains Hnf4Α Expression To Promote Pancreatic Adenocarcinoma Progression Through An Epoxide Hydrolase-Dependent Regulatory Loop, Yihui Chen, Michela Capello, Mayrim V Rios Perez, Jody V Vykoukal, David Roife, Ya'an Kang, Laura R Prakash, Hiroyuki Katayama, Ehsan Irajizad, Alia Fleury, Sammy Ferri-Borgogno, Dodge L Baluya, Jennifer B Dennison, Kim-Anh Do, Oliver Fiehn, Anirban Maitra, Huamin Wang, Paul J Chiao, Matthew H G Katz, Jason B Fleming, Samir M Hanash, Johannes F Fahrmann

Faculty, Staff and Student Publications

Objective: Intra-tumoral expression of the serine hydrolase carboxylesterase 2 (CES2) contributes to the activation of the pro-drug irinotecan in pancreatic ductal adenocarcinoma (PDAC). Given other potential roles of CES2, we assessed its regulation, downstream effects, and contribution to tumor development in PDAC.

Methods: Association between the mRNA expression of CES2 in pancreatic tumors and overall survival was assessed using The Cancer Genome Atlas. Cell viability, clonogenic, and anchorage-independent growth assays as well as an orthotopic mouse model of PDAC were used to evaluate the biological relevance of CES2 in pancreatic cancer. CES2-driven metabolic changes were determined by untargeted and targeted …

Effects Of Placebo Administration On Immune Mechanisms And Relationships With Central Endogenous Opioid Neurotransmission, Alan Prossin, Alisa Koch, Phillip Campbell, Geoffroy Laumet, Christian S Stohler, Robert Dantzer, Jon-Kar Zubieta

Faculty, Staff and Student Publications

Behavioral conditioning and expectation can have profound impact on animal and human physiology. Placebo, administered under positive expectation in clinical trials, can have potent effects on disease pathology, obscuring active medications. Emerging evidence suggests placebo-responsive neurotransmitter systems (e.g., endogenous opioid) regulate immune function by manipulating inflammatory proteins including IL-18, a potent pro-inflammatory, nociceptive cytokine implicated in pathophysiology of various diseases. Validation that neuroimmune interactions involving brain μ-opioid receptor (MOR) activity and plasma IL-18 underlie placebo analgesic expectation could have widespread clinical applications. Unfortunately, current lack of mechanistic clarity obfuscates clinical translation. To elucidate neuroimmune interactions underlying placebo analgesia, we exposed …

Final Results Of The Choroid Plexus Tumor Study Cpt-Siop-2000, Johannes E Wolff, Stefaan W Van Gool, Tezer Kutluk, Blanca Diez, Rejin Kebudi, Beate Timmermann, Miklos Garami, Jaroslav Sterba, Gregory N Fuller, Brigitte Bison, Uwe R Kordes

Faculty, Staff and Student Publications

INTRODUCTION: Standards for chemotherapy against choroid plexus tumors (CPT) have not yet been established.

METHODS: CPT-SIOP-2000 (NCT00500890) was an international registry for all CPT nesting a chemotherapy randomization for high-risk CPT with Carboplatin/Etoposide/Vincristine (CarbEV) versus Cyclophosphamide/Etoposide/Vincristine (CycEV). Patients older than three years were recommended to receive irradiation: focal fields for non-metastatic CPC, incompletely resected atypical choroid plexus papilloma (APP) or metastatic choroid plexus papilloma (CPP); craniospinal fields for metastatic CPC/APP and non-responsive CPC. High risk was defined as choroid plexus carcinoma (CPC), incompletely resected APP, and all metastatic CPT. From 2000 until 2010, 158 CPT patients from 23 countries were …

Construction And Validation Of Prognostic Nomogram For Metaplastic Breast Cancer, Yongfeng Li, Daobao Chen, Haojun Xuan, Mihnea P Dragomir, George A Calin, Xuli Meng, Meng Chen, Hongchuan Jin

Faculty, Staff and Student Publications

In this study we aimed to develop nomogram models for predicting the overall survival (OS) and cancer-specific survival (CSS) of patients with metaplastic breast cancer (MBC). Data of patients diagnosed with MBC from 1973 to 2015 were collected from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate Cox analyses were performed to identify independent prognostic factors for OS and CSS of MBC patients. The obtained prognostic variables were combined to construct nomogram models for predicting OS and CSS in patients with MBC. Model performance was evaluated using concordance index (C-index) and calibration plots. Data from 1125 patients …

Combined Il-2, Agonistic Cd3 And 4–1bb Stimulation Preserve Clonotype Hierarchy In Propagated Non-Small Cell Lung Cancer Tumor-Infiltrating Lymphocytes, Parin Shah, Marie-Andrée Forget, Meredith L Frank, Peixin Jiang, Donastas Sakellariou-Thompson, Lorenzo Federico, Roohussaba Khairullah, Chantal Alexia Neutzler, Ignacio Wistuba, Chi-Wan B Chow, Yan Long, Junya Fujimoto, Shiaw-Yih Lin, Anirban Maitra, Marcelo V Negrao, Kyle Gregory Mitchell, Annikka Weissferdt, Ara A Vaporciyan, Tina Cascone, Jack A Roth, Jianjun Zhang, Boris Sepesi, Don L Gibbons, John V Heymach, Cara L Haymaker, Daniel J Mcgrail, Alexandre Reuben, Chantale Bernatchez

Faculty, Staff and Student Publications

Background: Adoptive cell transfer (ACT) of tumor-infiltrating lymphocytes (TIL) yielded clinical benefit in patients with checkpoint blockade immunotherapy-refractory non-small cell lung cancer (NSCLC) prompting a renewed interest in TIL-ACT. This preclinical study explores the feasibility of producing a NSCLC TIL product with sufficient numbers and enhanced attributes using an improved culture method.

Methods: TIL from resected NSCLC tumors were initially cultured using (1) the traditional method using interleukin (IL)-2 alone in 24-well plates (TIL 1.0) or (2) IL-2 in combination with agonistic antibodies against CD3 and 4-1BB (Urelumab) in a G-Rex flask (TIL 3.0). TIL subsequently underwent a rapid expansion …

Evaluation Of Programmed Death Ligand 1 Expression In Cytology To Determine Eligibility For Immune Checkpoint Inhibitor Therapy In Patients With Head And Neck Squamous Cell Carcinoma, Zhonghua Liu, Michelle Williams, John Stewart, Bonnie S Glisson, Clifton Fuller, Sinchita Roy-Chowdhuri

Faculty, Staff and Student Publications

Background: Immune checkpoint inhibitors targeting the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway have recently emerged as a frontline treatment for head and neck squamous cell carcinoma (HNSCC). The evaluation of PD-L1 expression by immunohistochemistry in histologic samples is used to determine the eligibility of patients with HNSCC for immunotherapy. Patients with newly diagnosed HNSCC are frequently diagnosed by fine-needle aspiration (FNA) of lymph nodes with metastatic disease. However, the evaluation of PD-L1 expression with the proposed combined positive score (CPS) has not been well established in cytology specimens.

Methods: This study retrospectively identified 21 …

Body Region-Specific 3d Age-Scaling Functions For Scaling Whole-Body Computed Tomography Anatomy For Pediatric Late Effects Studies, Aashish C Gupta, Constance A Owens, Suman Shrestha, Choonsik Lee, Susan A Smith, Rita E Weathers, Tucker Netherton, Peter A Balter, Stephen F Kry, David S Followill, Keith T Griffin, James P Long, Gregory T Armstrong, Rebecca M Howell

Faculty, Staff and Student Publications

Purpose:

Radiation epidemiology studies of childhood cancer survivors treated in the pre-computed tomography (CT) era reconstruct the patients’ treatment fields on computational phantoms. For such studies, the phantoms are commonly scaled to age at the time of radiotherapy treatment because age is the generally available anthropometric parameter. Several reference size phantoms are used in such studies, but reference size phantoms are only available at discrete ages (e.g.: newborn, 1, 5, 10, 15, and Adult). When such phantoms are used for RT dose reconstructions, the nearest discrete-aged phantom is selected to represent a survivor of a specific age. In this work, …

A Mechanistic Modeling Framework Reveals The Key Principles Underlying Tumor Metabolism, Shubham Tripathi, Jun Hyoung Park, Shivanand Pudakalakatti, Pratip K Bhattacharya, Benny Abraham Kaipparettu, Herbert Levine

Faculty, Staff and Student Publications

While aerobic glycolysis, or the Warburg effect, has for a long time been considered a hallmark of tumor metabolism, recent studies have revealed a far more complex picture. Tumor cells exhibit widespread metabolic heterogeneity, not only in their presentation of the Warburg effect but also in the nutrients and the metabolic pathways they are dependent on. Moreover, tumor cells can switch between different metabolic phenotypes in response to environmental cues and therapeutic interventions. A framework to analyze the observed metabolic heterogeneity and plasticity is, however, lacking. Using a mechanistic model that includes the key metabolic pathways active in tumor cells, …

A Human Breast Cancer-Derived Xenograft And Organoid Platform For Drug Discovery And Precision Oncology, Katrin P Guillen, Maihi Fujita, Andrew J Butterfield, Sandra D Scherer, Matthew H Bailey, Zhengtao Chu, Yoko S Derose, Ling Zhao, Emilio Cortes-Sanchez, Chieh-Hsiang Yang, Jennifer Toner, Guoying Wang, Yi Qiao, Xiaomeng Huang, Jeffery A Greenland, Jeffery M Vahrenkamp, David H Lum, Rachel E Factor, Edward W Nelson, Cindy B Matsen, Jane M Poretta, Regina Rosenthal, Anna C Beck, Saundra S Buys, Christos Vaklavas, John H Ward, Randy L Jensen, Kevin B Jones, Zheqi Li, Steffi Oesterreich, Lacey E Dobrolecki, Satya S Pathi, Xing Yi Woo, Kristofer C Berrett, Mark E Wadsworth, Jeffrey H Chuang, Michael T Lewis, Gabor T Marth, Jason Gertz, Katherine E Varley, Bryan E Welm, Alana L Welm

Faculty, Staff and Students Publications

Microscaled proteogenomics was deployed to probe the molecular basis for differential response to neoadjuvant carboplatin and docetaxel combination chemotherapy for triple-negative breast cancer (TNBC). Proteomic analyses of pretreatment patient biopsies uniquely revealed metabolic pathways, including oxidative phosphorylation, adipogenesis, and fatty acid metabolism, that were associated with resistance. Both proteomics and transcriptomics revealed that sensitivity was marked by elevation of DNA repair, E2F targets, G₂–M checkpoint, interferon-gamma signaling, and immune-checkpoint components. Proteogenomic analyses of somatic copy-number aberrations identified a resistance-associated 19q13.31–33 deletion where LIG1, POLD1, and XRCC1 are located. In orthogonal datasets, LIG1 (DNA ligase I) gene …

Gene-Gene Interaction Of Ahrwith And Within The Wntcascade Affects Susceptibility To Lung Cancer, Albert Rosenberger, Nils Muttray, Rayjean J Hung, David C Christiani, Neil E Caporaso, Geoffrey Liu, Stig E Bojesen, Loic Le Marchand, Demetrios Albanes, Melinda C Aldrich, Adonina Tardon, Guillermo Fernández-Tardón, Gad Rennert, John K Field, Michael P A Davies, Triantafillos Liloglou, Lambertus A Kiemeney, Philip Lazarus, Bernadette Wendel, Aage Haugen, Shanbeh Zienolddiny, Stephen Lam, Matthew B Schabath, Angeline S Andrew, Eric J Duell, Susanne M Arnold, Gary E Goodman, Chu Chen, Jennifer A Doherty, Fiona Taylor, Angela Cox, Penella J Woll, Angela Risch, Thomas R Muley, Mikael Johansson, Paul Brennan, Maria Teresa Landi, Sanjay S Shete, Christopher I Amos, Heike Bickeböller, Integral-Ilcco Consortium

Faculty, Staff and Student Publications

Background: Aberrant Wnt signalling, regulating cell development and stemness, influences the development of many cancer types. The Aryl hydrocarbon receptor (AhR) mediates tumorigenesis of environmental pollutants. Complex interaction patterns of genes assigned to AhR/Wnt-signalling were recently associated with lung cancer susceptibility.

Aim: To assess the association and predictive ability of AhR/Wnt-genes with lung cancer in cases and controls of European descent.

Methods: Odds ratios (OR) were estimated for genomic variants assigned to the Wnt agonist and the antagonistic genes DKK2, DKK3, DKK4, FRZB, SFRP4 and Axin2. Logistic regression models with variable selection were trained, validated and tested to predict lung …

Impact Of Frontline Treatment Approach On Outcomes In Patients With Secondary Aml With Prior Hypomethylating Agent Exposure, Nicholas J Short, Sangeetha Venugopal, Wei Qiao, Tapan M Kadia, Farhad Ravandi, Walid Macaron, Courtney D Dinardo, Naval Daver, Marina Konopleva, Gautam Borthakur, Elizabeth J Shpall, Uday Popat, Richard E Champlin, Rohtesh Mehta, Gheath Al-Atrash, Betul Oran, Elias Jabbour, Guillermo Garcia-Manero, Ghayas C Issa, Guillermo Montalban-Bravo, Musa Yilmaz, Abhishek Maiti, Hagop Kantarjian

Faculty, Staff and Student Publications

BACKGROUND: Treated secondary acute myeloid leukemia (ts-AML)-i.e., AML arising from a previously treated antecedent hematologic disorder-is associated with very poor outcomes. The optimal frontline treatment regimen for these patients is uncertain.

METHODS: We retrospectively analyzed 562 patients who developed AML from preceding myelodysplastic syndrome or chronic myelomonocytic leukemia for which they had received a hypomethylating agent (HMA). Patients with ts-AML were stratified by frontline AML treatment with intensive chemotherapy (IC, n = 271), low-intensity therapy (LIT) without venetoclax (n = 237), or HMA plus venetoclax (n = 54).

RESULTS: Compared with IC or LIT without venetoclax, HMA plus venetoclax resulted …

Transcribed Ultraconserved Regions Are Associated With Clinicopathological Features In Breast Cancer, Erika Pereira Zambalde, Douglas Adamoski, Daniela Fiori Gradia, Iris Rabinovich, Ana Carolina Rodrigues, Cristina Ivan, Enilze M S F Ribeiro, George Adrian Calin, Jaqueline Carvalho De Oliveira

Faculty, Staff and Student Publications

Ultraconserved regions (UCRs) are 481 genome segments, with length longer than 200 bp, that are 100% conserved among humans, mice, and rats. The majority of UCRs are transcriptionally active (T-UCRs) as many of them produce non-coding RNAs. In a previous study, we evaluated the expression level of T-UCRs in breast cancer (BC) patients and found that 63% of transcripts correlated with some clinical and/or molecular parameter of BC. In this study, we delved into the expression levels of 12 T-UCRs and correlated them with clinicopathological parameters, immunohistochemical markers, and overall survival in two breast cancer cohorts: TCGA and Brazilian patients. …

Systematic Decomposition Of Sequence Determinants Governing Crispr/Cas9 Specificity, Rongjie Fu, Wei He, Jinzhuang Dou, Oscar D Villarreal, Ella Bedford, Helen Wang, Connie Hou, Liang Zhang, Yalong Wang, Dacheng Ma, Yiwen Chen, Xue Gao, Martin Depken, Han Xu

Faculty, Staff and Student Publications

The specificity of CRISPR/Cas9 genome editing is largely determined by the sequences of guide RNA (gRNA) and the targeted DNA, yet the sequence-dependent rules underlying off-target effects are not fully understood. To systematically explore the sequence determinants governing CRISPR/Cas9 specificity, here we describe a dual-target system to measure the relative cleavage rate between off- and on-target sequences (off-on ratios) of 1902 gRNAs on 13,314 synthetic target sequences, and reveal a set of sequence rules involving 2 factors in off-targeting: 1) a guide-intrinsic mismatch tolerance (GMT) independent of the mismatch context; 2) an "epistasis-like" combinatorial effect of multiple mismatches, which are …

Efficacy And Safety Of Enasidenib And Azacitidine Combination In Patients With Idh2 Mutated Acute Myeloid Leukemia And Not Eligible For Intensive Chemotherapy, Sangeetha Venugopal, Koichi Takahashi, Naval Daver, Abhishek Maiti, Gautam Borthakur, Sanam Loghavi, Nicholas J Short, Maro Ohanian, Lucia Masarova, Ghayas Issa, Xuemei Wang, Bueso-Ramos Carlos, Musa Yilmaz, Tapan Kadia, Michael Andreeff, Farhad Ravandi, Marina Konopleva, Hagop M Kantarjian, Courtney D Dinardo

Faculty, Staff and Student Publications

Preclinically, enasidenib and azacitidine (ENA + AZA) synergistically enhance cell differentiation, and venetoclax (VEN), a small molecule Bcl2 inhibitor (i) is particularly effective in IDH2 mutated acute myeloid leukemia (IDH2mutAML). This open label phase II trial enrolled patients (pts) with documented IDH2mutAML. All patients received AZA 75 mg/m2/d x 7 d/cycle and ENA 100 mg QD continuously. Concomitant Bcl2i and FLT3i were allowed (NCT03683433).Twenty-six pts received ENA + AZA (median 68 years, range, 24-88); 7 newly diagnosed (ND) and 19 relapsed/refractory (R/R). In R/R AML patients, three had received prior ENA and none had received prior VEN. The …

Iam Hiq-A Novel Pair Of Accuracy Indices For Imputed Genotypes, Albert Rosenberger, Viola Tozzi, Heike Bickeböller, Integral-Ilcco Consortium

Faculty, Staff and Student Publications

BACKGROUND: Imputation of untyped markers is a standard tool in genome-wide association studies to close the gap between directly genotyped and other known DNA variants. However, high accuracy with which genotypes are imputed is fundamental. Several accuracy measures have been proposed and some are implemented in imputation software, unfortunately diversely across platforms. In the present paper, we introduce Iam hiQ, an independent pair of accuracy measures that can be applied to dosage files, the output of all imputation software. Iam (imputation accuracy measure) quantifies the average amount of individual-specific versus population-specific genotype information in a linear manner. hiQ (heterogeneity in …

B Cell Receptor Isotypes Differentially Associate With Cell Signaling, Kinetics, And Outcome In Chronic Lymphocytic Leukemia, Andrea N Mazzarello, Eva Gentner-Göbel, Marcus Dühren-Von Minden, Tatyana N Tarasenko, Antonella Nicolò, Gerardo Ferrer, Stefano Vergani, Yun Liu, Davide Bagnara, Kanti R Rai, Jan A Burger, Peter J Mcguire, Palash C Maity, Hassan Jumaa, Nicholas Chiorazzi

Faculty, Staff and Student Publications

In chronic lymphocytic leukemia (CLL), the B cell receptor (BCR) plays a critical role in disease development and progression, as indicated by the therapeutic efficacy of drugs blocking BCR signaling. However, the mechanism(s) underlying BCR responsiveness are not completely defined. Selective engagement of membrane IgM or IgD on CLL cells, each coexpressed by more than 90% of cases, leads to distinct signaling events. Since both IgM and IgD carry the same antigen-binding domains, the divergent actions of the receptors are attributed to differences in immunoglobulin (Ig) structure or the outcome of signal transduction. We showed that IgM, not IgD, level …

Epigenetic Silencing Of Tumor Suppressor Lncrna Nkila: Implication On Nf-Κb Signaling In Non-Hodgkin’S Lymphoma, Min-Yue Zhang, George Calin, Ming-Dan Deng, Rex K H Au-Yeung, Lu-Qian Wang, Chor-Sang Chim

Faculty, Staff and Student Publications

The long non-coding RNA (lncRNA) NKILA, localized to 20q13.31, is a negative regulator of NF-κB signaling implicated in carcinogenesis. As a CpG island is embedded in the promoter region of NKILA, it is hypothesized as a tumor suppressor lncRNA silenced by promoter DNA methylation in non-Hodgkin’s lymphoma (NHL). By pyrosequencing-verified methylation-specific PCR, NKILA methylation was detected in 1/10 (10%) NHL cell lines, but not in normal peripheral blood buffy coats or tonsils. NKILA methylation correlated with the repression of NKILA in cell lines. Hypomethylation treatment with 5-Aza-2′-deoxycytidine resulted in promoter demethylation and the re-expression of NKILA. In 102 …

The Allergy Mediator Histamine Confers Resistance To Immunotherapy In Cancer Patients Via Activation Of The Macrophage Histamine Receptor H1, Hongzhong Li, Yi Xiao, Qin Li, Jun Yao, Xiangliang Yuan, Yuan Zhang, Xuedong Yin, Yohei Saito, Huihui Fan, Ping Li, Wen-Ling Kuo, Angela Halpin, Don L Gibbons, Hideo Yagita, Zhongming Zhao, Da Pang, Guosheng Ren, Cassian Yee, J Jack Lee, Dihua Yu

Faculty, Staff and Student Publications

Reinvigoration of antitumor immunity remains an unmet challenge. Our retrospective analyses revealed that cancer patients who took antihistamines during immunotherapy treatment had significantly improved survival. We uncovered that histamine and histamine receptor H1 (HRH1) are frequently increased in the tumor microenvironment and induce T cell dysfunction. Mechanistically, HRH1-activated macrophages polarize toward an M2-like immunosuppressive phenotype with increased expression of the immune checkpoint VISTA, rendering T cells dysfunctional. HRH1 knockout or antihistamine treatment reverted macrophage immunosuppression, revitalized T cell cytotoxic function, and restored immunotherapy response. Allergy, via the histamine-HRH1 axis, facilitated tumor growth and induced immunotherapy resistance in mice and humans. …

The Allergy Mediator Histamine Confers Resistance To Immunotherapy In Cancer Patients Via Activation Of The Macrophage Histamine Receptor H1, Hongzhong Li, Yi Xiao, Qin Li, Jun Yao, Xiangliang Yuan, Yuan Zhang, Xuedong Yin, Yohei Saito, Huihui Fan, Ping Li, Wen-Ling Kuo, Angela Halpin, Don L Gibbons, Hideo Yagita, Zhongming Zhao, Da Pang, Guosheng Ren, Cassian Yee, J Jack Lee, Dihua Yu

Faculty, Staff and Student Publications

Reinvigoration of antitumor immunity remains an unmet challenge. Our retrospective analyses revealed that cancer patients who took antihistamines during immunotherapy treatment had significantly improved survival. We uncovered that histamine and histamine receptor H1 (HRH1) are frequently increased in the tumor microenvironment and induce T cell dysfunction. Mechanistically, HRH1-activated macrophages polarize toward an M2-like immunosuppressive phenotype with increased expression of the immune checkpoint VISTA, rendering T cells dysfunctional. HRH1 knockout or antihistamine treatment reverted macrophage immunosuppression, revitalized T cell cytotoxic function, and restored immunotherapy response. Allergy, via the histamine-HRH1 axis, facilitated tumor growth and induced immunotherapy resistance in mice and humans. …

Lncrnafunc: A Knowledgebase Of Lncrna Function In Human Cancer, Mengyuan Yang, Huifen Lu, Jiajia Liu, Sijia Wu, Pora Kim, Xiaobo Zhou

Faculty, Staff and Student Publications

The long non-coding RNAs associating with other molecules can coordinate several physiological processes and their dysfunction can impact diverse human diseases. To date, systematic and intensive annotations on diverse interaction regulations of lncRNAs in human cancer were not available. Here, we built lncRNAfunc, a knowledgebase of lncRNA function in human cancer at https://ccsm.uth.edu/lncRNAfunc, aiming to provide a resource and reference for providing therapeutically targetable lncRNAs and intensive interaction regulations. To do this, we collected 15 900 lncRNAs across 33 cancer types from TCGA. For individual lncRNAs, we performed multiple interaction analyses of different biomolecules including DNA, RNA, and protein levels. …

Fusiongdb 20: Fusion Gene Annotation Updates Aided By Deep Learning, Pora Kim, Hua Tan, Jiajia Liu, Haeseung Lee, Hyesoo Jung, Himanshu Kumar, Xiaobo Zhou

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A knowledgebase of the systematic functional annotation of fusion genes is critical for understanding genomic breakage context and developing therapeutic strategies. FusionGDB is a unique functional annotation database of human fusion genes and has been widely used for studies with diverse aims. In this study, we report fusion gene annotation updates aided by deep learning (FusionGDB 2.0) available at https://compbio.uth.edu/FusionGDB2/. FusionGDB 2.0 has substantial updates of contents such as up-to-date human fusion genes, fusion gene breakage tendency score with FusionAI deep learning model based on 20 kb DNA sequence around BP, investigation of overlapping between fusion breakpoints with 44 human …

Transcranial Stimulation Of Alpha Oscillations Up-Regulates The Default Mode Network, Kevin J Clancy, Jeremy A Andrzejewski, Yuqi You, Jens T Rosenberg, Mingzhou Ding, Wen Li

Faculty, Staff and Student Publications

The default mode network (DMN) is the most-prominent intrinsic connectivity network, serving as a key architecture of the brain's functional organization. Conversely, dysregulated DMN is characteristic of major neuropsychiatric disorders. However, the field still lacks mechanistic insights into the regulation of the DMN and effective interventions for DMN dysregulation. The current study approached this problem by manipulating neural synchrony, particularly alpha (8 to 12 Hz) oscillations, a dominant intrinsic oscillatory activity that has been increasingly associated with the DMN in both function and physiology. Using high-definition alpha-frequency transcranial alternating current stimulation (α-tACS) to stimulate the cortical source of alpha oscillations, …

Sensei: How Many Samples To Tell A Change In Cell Type Abundance?, Shaoheng Liang, Jason Willis, Jinzhuang Dou, Vakul Mohanty, Yuefan Huang, Eduardo Vilar, Ken Chen

Faculty, Staff and Student Publications

Cellular heterogeneity underlies cancer evolution and metastasis. Advances in single-cell technologies such as single-cell RNA sequencing and mass cytometry have enabled interrogation of cell type-specific expression profiles and abundance across heterogeneous cancer samples obtained from clinical trials and preclinical studies. However, challenges remain in determining sample sizes needed for ascertaining changes in cell type abundances in a controlled study. To address this statistical challenge, we have developed a new approach, named Sensei, to determine the number of samples and the number of cells that are required to ascertain such changes between two groups of samples in single-cell studies. Sensei expands …

Venetoclax Plus Azacitidine In Japanese Patients With Untreated Acute Myeloid Leukemia Ineligible For Intensive Chemotherapy, Kazuhito Yamamoto, Atsushi Shinagawa, Courtney D Dinardo, Keith W Pratz, Kenichi Ishizawa, Toshihiro Miyamoto, Norio Komatsu, Yasuhiro Nakashima, Chikashi Yoshida, Noriko Fukuhara, Kensuke Usuki, Takahiro Yamauchi, Noboru Asada, Norio Asou, Ilseung Choi, Yasushi Miyazaki, Hideyuki Honda, Sumiko Okubo, Misaki Kurokawa, Ying Zhou, Jiuhong Zha, Jalaja Potluri, Itaru Matsumura

Faculty, Staff and Student Publications

Background: The phase 3 VIALE-A trial (NCT02993523) reported that venetoclax-azacitidine significantly prolonged overall survival compared with placebo-azacitidine in patients with newly diagnosed acute myeloid leukemia ineligible for intensive chemotherapy. Herein, efficacy and safety of venetoclax-azacitidine are analyzed in the Japanese subgroup of VIALE-A patients.

Methods: Eligible Japanese patients were randomized 2:1 to venetoclax-azacitidine (N = 24) or placebo-azacitidine (N = 13). Primary endpoints for Japan were overall survival and complete response (CR) + CR with incomplete hematologic recovery (CRi). Venetoclax (target dose 400 mg) was given orally once daily. Azacitidine (75 mg/m2) was administered subcutaneously or intravenously on …

Quantification Of Infarct Core Signal Using Ct Imaging In Acute Ischemic Stroke, Uma Maria Lal-Trehan Estrada, Grant Meeks, Sergio Salazar-Marioni, Fabien Scalzo, Mudassir Farooqui, Juan Vivanco-Suarez, Santiago Ortega Gutierrez, Sunil A Sheth, Luca Giancardo

Faculty, Staff and Student Publications

In stroke care, the extent of irreversible brain injury, termed infarct core, plays a key role in determining eligibility for acute treatments, such as intravenous thrombolysis and endovascular reperfusion therapies. Many of the pivotal randomized clinical trials testing those therapies used MRI Diffusion-Weighted Imaging (DWI) or CT Perfusion (CTP) to define infarct core. Unfortunately, these modalities are not available 24/7 outside of large stroke centers. As such, there is a need for accurate infarct core determination using faster and more widely available imaging modalities including Non-Contrast CT (NCCT) and CT Angiography (CTA). Prior studies have suggested that CTA provides improved …