Digital Commons Network^™

Identifying Signatures Of Ev Secretion In Metastatic Breast Cancer Through Functional Single-Cell Profiling, Mohsen Fathi, Melisa Martinez-Paniagua, Ali Rezvan, Melisa J Montalvo, Vakul Mohanty, Ken Chen, Sendurai A Mani, Navin Varadarajan

Faculty, Staff and Student Publications

Extracellular vesicles (EVs) regulate the tumor microenvironment by facilitating transport of biomolecules. Despite extensive investigation, heterogeneity in EV secretion among cancer cells and the mechanisms that support EV secretion are not well characterized. We developed an integrated method to identify individual cells with differences in EV secretion and performed linked single-cell RNA-sequencing on cloned single cells from the metastatic breast cancer cells. Differential gene expression analyses identified a four-gene signature of breast cancer EV secretion: HSP90AA1, HSPH1, EIF5, and DIAPH3. We functionally validated this gene signature by testing it across cell lines with different metastatic potential …

Synaptic Scaling Of Corticostriatal Circuits Underlies Hyperactivity In Gaba Transporter-1 Deficient Mice, Yan-Jiao Wu, Xin Yi, Xue Gu, Qi Wang, Qin Jiang, Ying Li, Michael X Zhu, Jianqing Ding, Wei-Guang Li, Tian-Le Xu

Faculty, Staff and Student Publications

Homeostatic synaptic scaling entails adjustment of synaptic strength on a cell to prolonged changes of neuronal activity, which is postulated to participate in neuropsychiatric disorders in vivo. Here, we find that sustained elevation in ambient GABA levels, by either genetic deletion or pharmacological blockade of GABA transporter-1 (GAT1), leads to synaptic scaling up of corticostriatal pathways, which underlies locomotor hyperactivity. Meanwhile, medium spiny neurons of the dorsal striatum exhibit an aberrant increase in excitatory synaptic transmission and corresponding structural changes in dendritic spines. Mechanistically, GAT1 deficiency dampens the expression and function of metabotropic glutamate receptors (mGluRs) and endocannabinoid (eCB)-dependent …

Nivolumab Plus Ipilimumab Versus Extreme Regimen As First-Line Treatment For Recurrent/Metastatic Squamous Cell Carcinoma Of The Head And Neck: The Final Results Of Checkmate 651, Robert I Haddad, Kevin Harrington, Makoto Tahara, Robert L Ferris, Maura Gillison, Jerome Fayette, Amaury Daste, Piotr Koralewski, Bogdan Zurawski, Miren Taberna, Nabil F Saba, Milena Mak, Andrzej Kawecki, Gustavo Girotto, Miguel Angel Alvarez Avitia, Caroline Even, Joaquin Gabriel Reinoso Toledo, Alexander Guminski, Urs Müller-Richter, Naomi Kiyota, Mustimbo Roberts, Tariq Aziz Khan, Karen Miller-Moslin, Li Wei, Athanassios Argiris

Faculty, Staff and Student Publications

PURPOSE: CheckMate 651 (ClinicalTrials.gov identifier: NCT02741570) evaluated first-line nivolumab plus ipilimumab versus EXTREME (cetuximab plus cisplatin/carboplatin plus fluorouracil ≤ six cycles, then cetuximab maintenance) in recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN).

METHODS: Patients without prior systemic therapy for R/M SCCHN were randomly assigned 1:1 to nivolumab plus ipilimumab or EXTREME. Primary end points were overall survival (OS) in the all randomly assigned and programmed death-ligand 1 combined positive score (CPS) ≥ 20 populations. Secondary end points included OS in the programmed death-ligand 1 CPS ≥ 1 population, and progression-free survival, objective response rate, and duration …

Consensus On The Ras Dimerization Hypothesis: Strong Evidence For Lipid-Mediated Clustering But Not For G-Domain-Mediated Interactions, Dhirendra K Simanshu, Mark R Philips, John F Hancock

Faculty, Staff and Student Publications

One of the open questions in RAS biology is the existence of RAS dimers and their role in RAF dimerization and activation. The idea of RAS dimers arose from the discovery that RAF kinases function as obligate dimers, which generated the hypothesis that RAF dimer formation might be nucleated by G-domain-mediated RAS dimerization. Here, we review the evidence for RAS dimerization and describe a recent discussion among RAS researchers that led to a consensus that the clustering of two or more RAS proteins is not due to the stable association of G-domains but, instead, is a consequence of RAS C-terminal …

Redox And Nucleophilic Reactions Of Naphthoquinones With Small Thiols And Their Effects On Oxidization Of H2s To Inorganic And Organic Hydropolysulfides And Thiosulfate, Kenneth R Olson, Kasey J Clear, Yan Gao, Zhilin Ma, Nathaniel M Cieplik, Alyssa R Fiume, Dominic J Gaziano, Stephen M Kasko, Jennifer Luu, Ella Pfaff, Anthony Travlos, Cecilia Velander, Katherine J Wilson, Elizabeth D Edwards, Karl D Straub, Gang Wu

Faculty, Staff and Student Publications

Naphthoquinone (1,4-NQ) and its derivatives (NQs, juglone, plumbagin, 2-methoxy-1,4-NQ, and menadione) have a variety of therapeutic applications, many of which are attributed to redox cycling and the production of reactive oxygen species (ROS). We previously demonstrated that NQs also oxidize hydrogen sulfide (H2S) to reactive sulfur species (RSS), potentially conveying identical benefits. Here we use RSS-specific fluorophores, mass spectroscopy, EPR and UV-Vis spectrometry, and oxygen-sensitive optodes to examine the effects of thiols and thiol-NQ adducts on H2S-NQ reactions. In the presence of glutathione (GSH) and cysteine (Cys), 1,4-NQ oxidizes H2S to both inorganic and organic hydroper-/hydropolysulfides (R2Sn, R=H, Cys, GSH; …

Development And Characterization Of Inducible Astrocyte-Specific Aromatase Knockout Mice, Jing Wang, Uday P Pratap, Yujiao Lu, Gangadhara R Sareddy, Rajeshwar R Tekmal, Ratna K Vadlamudi, Darrell W Brann

Faculty, Staff and Student Publications

17β-estradiol (E2) is produced in the brain as a neurosteroid, in addition to being an endocrine signal in the periphery. The current animal models for studying brain-derived E2 include global and conditional non-inducible knockout mouse models. The aim of this study was to develop a tamoxifen (TMX)-inducible astrocyte-specific aromatase knockout mouse line (GFAP-ARO-iKO mice) to specifically deplete the E2 synthesis enzymes and aromatase in astrocytes after their development in adult mice. The characterization of the GFAP-ARO-iKO mice revealed a specific and robust depletion in the aromatase expressions of their astrocytes and a significant decrease in their hippocampal E2 levels after …

Assessment And Prediction Of Glioblastoma Therapy Response: Challenges And Opportunities, Dan Qi, Jing Li, C Chad Quarles, Ekokobe Fonkem, Erxi Wu

Faculty, Staff and Student Publications

Glioblastoma is the most aggressive type of primary adult brain tumour. The median survival of patients with glioblastoma remains approximately 15 months, and the 5-year survival rate is < 10%. Current treatment options are limited, and the standard of care has remained relatively constant since 2011. Over the last decade, a range of different treatment regimens have been investigated with very limited success. Tumour recurrence is almost inevitable with the current treatment strategies, as glioblastoma tumours are highly heterogeneous and invasive. Additionally, another challenging issue facing patients with glioblastoma is how to distinguish between tumour progression and treatment effects, especially when relying on routine diagnostic imaging techniques in the clinic. The specificity of routine imaging for identifying tumour progression early or in a timely manner is poor due to the appearance similarity of post-treatment effects. Here, we concisely describe the current status and challenges in the assessment and early prediction of therapy response and the early detection of tumour progression or recurrence. We also summarize and discuss studies of advanced approaches such as quantitative imaging, liquid biomarker discovery and machine intelligence that hold exceptional potential to aid in the therapy monitoring of this malignancy and early prediction of therapy response, which may decisively transform the conventional detection methods in the era of precision medicine.

Modeling Collective Cell Behavior In Cancer: Perspectives From An Interdisciplinary Conversation, Frederick R Adler, Alexander R A Anderson, Abhinav Bhushan, Paul Bogdan, Jose Javier Bravo-Cordero, Amy Brock, Yun Chen, Edna Cukierman, Kathleen E Delgiorno, Gerald V Denis, Meghan C Ferrall-Fairbanks, Zev Jordan Gartner, Ronald N Germain, Deborah M Gordon, Ginger Hunter, Mohit Kumar Jolly, Loukia Georgiou Karacosta, Karthikeyan Mythreye, Parag Katira, Rajan P Kulkarni, Matthew L Kutys, Arthur D Lander, Ashley M Laughney, Herbert Levine, Emil Lou, Pedro R Lowenstein, Kristyn S Masters, Dana Pe'er, Shelly R Peyton, Manu O Platt, Jeremy E Purvis, Gerald Quon, Jennifer K Richer, Nicole C Riddle, Analiz Rodriguez, Joshua C Snyder, Gregory Lee Szeto, Claire J Tomlin, Itai Yanai, Ioannis K Zervantonakis, Hannah Dueck

Faculty, Staff and Student Publications

Collective cell behavior contributes to all stages of cancer progression. Understanding how collective behavior emerges through cell-cell interactions and decision-making will advance our understanding of cancer biology and provide new therapeutic approaches. Here, we summarize an interdisciplinary discussion on multicellular behavior in cancer, draw lessons from other scientific disciplines, and identify future directions.

Loss-Of-Function Variants In Mycbp2 Cause Neurobehavioural Phenotypes And Corpus Callosum Defects, Lama Alabdi, Muriel Desbois, Domniţa-Valeria Rusnac, Raashda A Sulaiman, Jill A Rosenfeld, Seema Lalani, David R Murdock, Lindsay C Burrage, Ping Yee Billie Au, Shelley Towner, William G Wilson, Lawrence Wong, Theresa Brunet, Gertrud Strobl-Wildemann, Jennifer E Burton, George Hoganson, Kirsty Mcwalter, Amber Begtrup, Yuri A Zarate, Elyse L Christensen, Karla J Opperman, Andrew C Giles, Rana Helaby, Artur Kania, Ning Zheng, Brock Grill, Fowzan S Alkuraya

Faculty, Staff and Student Publications

The corpus callosum is a bundle of axon fibres that connects the two hemispheres of the brain. Neurodevelopmental disorders that feature dysgenesis of the corpus callosum as a core phenotype offer a valuable window into pathology derived from abnormal axon development. Here, we describe a cohort of eight patients with a neurodevelopmental disorder characterized by a range of deficits including corpus callosum abnormalities, developmental delay, intellectual disability, epilepsy and autistic features. Each patient harboured a distinct de novo variant in MYCBP2, a gene encoding an atypical really interesting new gene (RING) ubiquitin ligase and signalling hub with evolutionarily conserved functions …

The Non-Coding Rna Journal Club: Highlights On Recent Papers—12, Patrick K T Shiu, Mirolyuba Ilieva, Anja Holm, Shizuka Uchida, Johanna K Distefano, Agnieszka Bronisz, Ling Yang, Yoh Asahi, Ajay Goel, Liuqing Yang, Ashok Nuthanakanti, Alexander Serganov, Suresh K Alahari, Chunru Lin, Barbara Pardini, Alessio Naccarati, Jing Jin, Beshoy Armanios, Xiao-Bo Zhong, Nikolaos Sideris, Salih Bayraktar, Leandro Castellano, André P Gerber, He Lin, Simon J Conn, Doha Magdy Mostafa Sleem, Lisa Timmons

Faculty, Staff and Student Publications

We are delighted to share with you our twelfth Journal Club and highlight some of the most interesting papers published recently [...].

Brain Connectivity Signature Extractions From Tms Invoked Eegs, Deepa Gupta, Xiaoming Du, Ann Summerfelt, L Elliot Hong, Fow-Sen Choa

Faculty, Staff and Student Publications

(1) Background: The correlations between brain connectivity abnormality and psychiatric disorders have been continuously investigated and progressively recognized. Brain connectivity signatures are becoming exceedingly useful for identifying patients, monitoring mental health disorders, and treatment. By using electroencephalography (EEG)-based cortical source localization along with energy landscape analysis techniques, we can statistically analyze transcranial magnetic stimulation (TMS)-invoked EEG signals, for obtaining connectivity among different brain regions at a high spatiotemporal resolution. (2) Methods: In this study, we analyze EEG-based source localized alpha wave activity in response to TMS administered to three locations, namely, the left motor cortex (49 subjects), left prefrontal cortex …

Interrogating Bromodomain Inhibitor Resistance In Kmt2a-Rearranged Leukemia Through Combinatorial Crispr Screens, Shaela Wright, Jianzhong Hu, Hong Wang, Judith Hyle, Yang Zhang, Guoqing Du, Marina Y Konopleva, Steven M Kornblau, Mohamed Nadhir Djekidel, Wojciech Rosikiewicz, Beisi Xu, Rui Lu, Jun J Yang, Chunliang Li

Faculty, Staff and Student Publications

Bromo- and extra-terminal domain inhibitors (BETi) have exhibited therapeutic activities in many cancers. However, the mechanisms controlling BETi response and resistance are not well understood. We conducted genome-wide loss-of-function CRISPR screens using BETi-treated KMT2A-rearranged (KMT2A-r) cell lines. We revealed that Speckle-type POZ protein (SPOP) gene (Speckle Type BTB/POZ Protein) deficiency caused significant BETi resistance, which was further validated in cell lines and xenograft models. Proteomics analysis and a kinase-vulnerability CRISPR screen indicated that cells treated with BETi are sensitive to GSK3 perturbation. Pharmaceutical inhibition of GSK3 reversed the BETi-resistance phenotype. Based on this observation, a combination therapy regimen inhibiting both …

Zoster-Associated Prothrombotic Plasma Exosomes And Increased Stroke Risk, Andrew N Bubak, Christina Coughlan, Janelle Posey, Anthony J Saviola, Christy S Niemeyer, Serena W R Lewis, Sara Bustos Lopez, Adriana Solano, Stephen K Tyring, Cassidy Delaney, Keith B Neeves, Ravi Mahalingam, Kirk C Hansen, Maria A Nagel

Faculty, Staff and Student Publications

Herpes zoster (HZ; shingles) caused by varicella zoster virus reactivation increases stroke risk for up to 1 year after HZ. The underlying mechanisms are unclear, however, the development of stroke distant from the site of zoster (eg, thoracic, lumbar, sacral) that can occur months after resolution of rash points to a long-lasting, virus-induced soluble factor (or factors) that can trigger thrombosis and/or vasculitis. Herein, we investigated the content and contributions of circulating plasma exosomes from HZ and non-HZ patient samples. Compared with non-HZ exosomes, HZ exosomes (1) contained proteins conferring a prothrombotic state to recipient cells and (2) activated platelets …

Association Of Suppressive Myeloid Cell Enrichment With Aggressive Oropharynx Squamous Cell Carcinoma, Changlin Yang, Rekha Garg, Kristanna Fredenburg, Frances Weidert, Hector Mendez-Gomez, Robert Amdur, Ji-Hyun Lee, Jamie Ku, Jesse Kresak, Stephanie Staras, Andrew G Sikora, Lily Wang, Daniel Mcgrail, Duane Mitchell, Elias Sayour, Natalie Silver

Faculty, Staff and Student Publications

BACKGROUND: While immune-cell infiltrated tumors, such as human papillomavirus positive (HPV+) ororpharyngeal squamous cell carcinomas (OPSCC) have been associated with an improved clinical prognosis, there is evidence to suggest that OPSCCs are also subjected to increased immunoregulatory influence. The objective of this study was to assess whether patients with clinically aggressive OPSCC have a distinct immunosuppressive immune signature in the primary tumor.

METHODS: This retrospective case-control study analyzed 37 pre-treatment tissue samples from HPV+ and HPV-negative OPSCC patients treated at a single institution. The cases were patients with known disease recurrence and the controls were patients without disease recurrence. An …

Stranger Things: New Roles And Opportunities For Androgen Receptor In Oncology Beyond Prostate Cancer, Javier Leo, Eleonora Dondossola, Kaitlin J Basham, Nathaniel R Wilson, Omar Alhalabi, Jianjun Gao, Katherine C Kurnit, Michael G White, Jennifer L Mcquade, Shannon N Westin, Elizabeth A Wellberg, Daniel E Frigo

Faculty, Staff and Student Publications

The androgen receptor (AR) is one of the oldest therapeutic targets in oncology and continues to dominate the treatment landscape for advanced prostate cancer, where nearly all treatment regimens include some form of AR modulation. In this regard, AR remains the central driver of prostate cancer cell biology. Emerging preclinical and clinical data implicate key roles for AR in additional cancer types, thereby expanding the importance of this drug target beyond prostate cancer. In this mini-review, new roles for AR in other cancer types are discussed as well as their potential for treatment with AR-targeted agents. Our understanding of these …

Ether Phospholipids Are Required For Mitochondrial Reactive Oxygen Species Homeostasis, Ziheng Chen, I-Lin Ho, Melinda Soeung, Er-Yen Yen, Jintan Liu, Liang Yan, Johnathon L Rose, Sanjana Srinivasan, Shan Jiang, Q Edward Chang, Ningping Feng, Jason P Gay, Qi Wang, Jing Wang, Philip L Lorenzi, Lucas J Veillon, Bo Wei, John N Weinstein, Angela K Deem, Sisi Gao, Giannicola Genovese, Andrea Viale, Wantong Yao, Costas A Lyssiotis, Joseph R Marszalek, Giulio F Draetta, Haoqiang Ying

Faculty, Staff and Student Publications

Mitochondria are hubs where bioenergetics, redox homeostasis, and anabolic metabolism pathways integrate through a tightly coordinated flux of metabolites. The contributions of mitochondrial metabolism to tumor growth and therapy resistance are evident, but drugs targeting mitochondrial metabolism have repeatedly failed in the clinic. Our study in pancreatic ductal adenocarcinoma (PDAC) finds that cellular and mitochondrial lipid composition influence cancer cell sensitivity to pharmacological inhibition of electron transport chain complex I. Profiling of patient-derived PDAC models revealed that monounsaturated fatty acids (MUFAs) and MUFA-linked ether phospholipids play a critical role in maintaining ROS homeostasis. We show that ether phospholipids support mitochondrial …

Cancer Cell-Extrinsic Roles For The Androgen Receptor In Prostate Cancer, Andrew W Hahn, Bilal A Siddiqui, Javier Leo, Eleonora Dondossola, Kaitlin J Basham, Cindy K Miranti, Daniel E Frigo

Faculty, Staff and Student Publications

Given the central role of the androgen receptor (AR) in prostate cancer cell biology, AR-targeted therapies have been the backbone of prostate cancer treatment for over 50 years. New data indicate that AR is expressed in additional cell types within the tumor microenvironment. Moreover, targeting AR for the treatment of prostate cancer has established side effects such as bone complications and an increased risk of developing cardiometabolic disease, indicating broader roles for AR. With the advent of novel technologies, such as single-cell approaches and advances in preclinical modeling, AR has been identified to have clinically significant functions in other cell …

Distinct Astrocytic Modulatory Roles In Sensory Transmission During Sleep, Wakefulness, And Arousal States In Freely Moving Mice, Fushun Wang, Wei Wang, Simeng Gu, Dan Qi, Nathan A Smith, Weiguo Peng, Wei Dong, Jiajin Yuan, Binbin Zhao, Ying Mao, Peng Cao, Qing Richard Lu, Lee A Shapiro, S Stephen Yi, Erxi Wu, Jason H Huang

Faculty, Staff and Student Publications

Despite extensive research on astrocytic Ca2+ in synaptic transmission, its contribution to the modulation of sensory transmission during different brain states remains largely unknown. Here, by using two-photon microscopy and whole-cell recordings, we show two distinct astrocytic Ca2+ signals in the murine barrel cortex: a small, long-lasting Ca2+ increase during sleep and a large, widespread but short-lasting Ca2+ spike when aroused. The large Ca2+ wave in aroused mice was inositol trisphosphate (IP3)-dependent, evoked by the locus coeruleus-norepinephrine system, and enhanced sensory input, contributing to reliable sensory transmission. However, the small Ca2+ transient was IP3-independent and contributed to decreased extracellular K+, …

The Melanocortin Action Is Biased Toward Protection From Weight Loss In Mice, Hongli Li, Yuanzhong Xu, Yanyan Jiang, Zhiying Jiang, Joshua Otiz-Guzman, Jessie C Morrill, Jing Cai, Zhengmei Mao, Yong Xu, Benjamin R Arenkiel, Cheng Huang, Qingchun Tong

Faculty, Staff and Student Publications

The melanocortin action is well perceived for its ability to regulate body weight bidirectionally with its gain of function reducing body weight and loss of function promoting obesity. However, this notion cannot explain the difficulty in identifying effective therapeutics toward treating general obesity via activation of the melanocortin action. Here, we provide evidence that altered melanocortin action is only able to cause one-directional obesity development. We demonstrate that chronic inhibition of arcuate neurons expressing proopiomelanocortin (POMC) or paraventricular hypothalamic neurons expressing melanocortin receptor 4 (MC4R) causes massive obesity. However, chronic activation of these neuronal populations failed to reduce body weight. …

Deep-Learning-Based Hepatic Ploidy Quantification Using H&E Histopathology Images, Zhuoyu Wen, Yu-Hsuan Lin, Shidan Wang, Naoto Fujiwara, Ruichen Rong, Kevin W Jin, Donghan M Yang, Bo Yao, Shengjie Yang, Tao Wang, Yang Xie, Yujin Hoshida, Hao Zhu, Guanghua Xiao

Faculty, Staff and Student Publications

Polyploidy, the duplication of the entire genome within a single cell, is a significant characteristic of cells in many tissues, including the liver. The quantification of hepatic ploidy typically relies on flow cytometry and immunofluorescence (IF) imaging, which are not widely available in clinical settings due to high financial and time costs. To improve accessibility for clinical samples, we developed a computational algorithm to quantify hepatic ploidy using hematoxylin-eosin (H&E) histopathology images, which are commonly obtained during routine clinical practice. Our algorithm uses a deep learning model to first segment and classify different types of cell nuclei in H&E images. …

Anthracycline-Containing And Taxane-Containing Chemotherapy For Early-Stage Operable Breast Cancer: A Patient-Level Meta-Analysis Of 100 000 Women From 86 Randomised Trials, Early Breast Cancer Trialists’ Collaborative Group (Ebctcg)

Faculty, Staff and Student Publications

BACKGROUND: Anthracycline-taxane chemotherapy for early-stage breast cancer substantially improves survival compared with no chemotherapy. However, concerns about short-term and long-term side-effects of anthracyclines have led to increased use of taxane chemotherapy without anthracycline, which could compromise efficacy. We aimed to better characterise the benefits and risks of including anthracycline, and the comparative benefits of different anthracycline-taxane regimens.

METHODS: We did an individual patient-level meta-analysis of randomised trials comparing taxane regimens with versus without anthracycline, and updated our previous meta-analysis of anthracycline regimens with versus without taxane, as well as analysing 44 trials in six related comparisons. We searched databases, including …

The Potential Regulation Of A-To-I Rna Editing On Genes In Parkinson's Disease, Sijia Wu, Qiuping Xue, Xinyu Qin, Xiaoming Wu, Pora Kim, Jacqueline Chyr, Xiaobo Zhou, Liyu Huang

Faculty, Staff and Student Publications

Parkinson's disease (PD) is characterized by dopaminergic neurodegeneration and an abnormal accumulation of α-synuclein aggregates. A number of genetic factors have been shown to increase the risk of PD. Exploring the underlying molecular mechanisms that mediate PD's transcriptomic diversity can help us understand neurodegenerative pathogenesis. In this study, we identified 9897 A-to-I RNA editing events associated with 6286 genes across 372 PD patients. Of them, 72 RNA editing events altered miRNA binding sites and this may directly affect miRNA regulations of their host genes. However, RNA editing effects on the miRNA regulation of genes are more complex. They can (1) …

Molecular Disparity Of Hla-Dpb1 Is Associated With The Development Of Subsequent Solid Cancer After Allogeneic Hematopoietic Stem Cell Transplantation, Jun Zou, Piyanuch Kongtim, Betül Oran, Samer A Srour, Uri Greenbaum, Yudith Carmazzi, Gabriela Rondon, Stefan O Ciurea, Qing Ma, Elizabeth J Shpall, Richard E Champlin, Kai Cao

Faculty, Staff and Student Publications

Background: An increased incidence of subsequent solid cancers (SSCs) has been reported in long-term survivors of allogeneic hematopoietic stem cell transplantation (allo-HSCT), and SSC is associated with inferior mortality and morbidity. Previous studies showed that the incidence of SSC is significantly higher in those who underwent allo-HSCT from HLA-mismatched donors, suggesting that persistent alloimmunity may predispose patients to SSCs. It was recently reported that, in a cohort of patients who received allo-HSCT from an unrelated donor matched at HLA-A, -B, -C, -DRB1/3/4/5, and -DQB1 loci, HLA-DPB1 alloimmunity determined by high mismatched eplets (MEs) and Predicted Indirectly Recognizable HLA Epitopes (PIRCHE) …

Nuclear Export Signal Mutation Of Epidermal Growth Factor Receptor Enhances Malignant Phenotypes Of Cancer Cells, Lei Nie, Ying-Nai Wang, Jung-Mao Hsu, Junwei Hou, Yu-Yi Chu, Li-Chuan Chan, Longfei Huo, Yongkun Wei, Rong Deng, Jun Tang, Yi-Hsin Hsu, How-Wen Ko, Seung-Oe Lim, Kebin Huang, Mei-Kuang Chen, Tai-Jan Chiu, Chien-Chia Cheng, Yueh-Fu Fang, Chia-Wei Li, Aarthi Goverdhan, Hsing-Ju Wu, Cheng-Chung Lee, Wen-Ling Wang, Jennifer Hsu, Paul Chiao, Shao-Chun Wang, Mien-Chie Hung

Faculty, Staff and Student Publications

Nuclear epidermal growth factor receptor (EGFR) has been shown to be correlated with drug resistance and a poor prognosis in patients with cancer. Previously, we have identified a tripartite nuclear localization signal (NLS) within EGFR. To comprehensively determine the functions and underlying mechanism of nuclear EGFR and its clinical implications, we aimed to explore the nuclear export signal (NES) sequence of EGFR that is responsible for interacting with the exportins. We combined in silico prediction with site-directed mutagenesis approaches and identified a putative NES motif of EGFR, which is located in amino acid residues 736-749. Mutation at leucine 747 (L747) …

Serinc5 Restricts Hiv Membrane Fusion By Altering Lipid Order And Heterogeneity In The Viral Membrane, Amanda E Ward, Daria Sokovikova, Melvin Neal Waxham, Frederick A Heberle, Ilya Levental, Kandice R Levental, Volker Kiessling, Judith M White, Lukas K Tamm

Faculty, Staff and Student Publications

The host restriction factor, Serinc5, incorporates into budding HIV particles and inhibits their infection by an incompletely understood mechanism. We have previously reported that Serinc5 but not its paralogue, Serinc2, blocks HIV cell entry by membrane fusion, specifically by inhibiting fusion pore formation and dilation. A body of work suggests that Serinc5 may alter the conformation and clustering of the HIV fusion protein, Env. To contribute an additional perspective to the developing model of Serinc5 restriction, we assessed Serinc2 and Serinc5's effects on HIV pseudoviral membranes. By measuring pseudoviral membrane thickness via cryo-electron microscopy and order via the fluorescent dye, …

Bayesian Adaptive Model Selection Design For Optimal Biological Dose Finding In Phase I/Ii Clinical Trials, Ruitao Lin, Guosheng Yin, Haolun Shi

Faculty, Staff and Student Publications

Identification of the optimal dose presents a major challenge in drug development with molecularly targeted agents, immunotherapy, as well as chimeric antigen receptor T-cell treatments. By casting dose finding as a Bayesian model selection problem, we propose an adaptive design by simultaneously incorporating the toxicity and efficacy outcomes to select the optimal biological dose (OBD) in phase I/II clinical trials. Without imposing any parametric assumption or shape constraint on the underlying dose-response curves, we specify curve-free models for both the toxicity and efficacy endpoints to determine the OBD. By integrating the observed data across all dose levels, the proposed design …

The Abscopal Effect In Patients With Cancer Receiving Immunotherapy, Blessie Elizabeth Nelson, Jacob J Adashek, Steven H Lin, Vivek Subbiah

Faculty, Staff and Student Publications

Interest in the abscopal effect has been rekindled over the past decade with the advent of immunotherapy. Although purportedly elusive, this phenomenon is being increasingly reported. Venturing further using a multimodality approach with an array of systemic agents and unconventional modalities is direly needed. In this perspective, we describe the fundamentals of abscopal responses (ARs), explore combinations with systemic therapies that hold promise in eliciting ARs, and reconnoiter unconventional modalities that may induce ARs. Finally, we scrutinize prospective agents and modalities that exhibit preclinical ability to elicit ARs and discuss prognostic biomarkers, their limitations, and pathways of abscopal resistance for …

Feature Selection For Support Vector Regression Using A Genetic Algorithm, Shannon B Mckearnan, David M Vock, G Elisabeta Marai, Guadalupe Canahuate, Clifton D Fuller, Julian Wolfson

Faculty, Staff and Student Publications

Support vector regression (SVR) is particularly beneficial when the outcome and predictors are nonlinearly related. However, when many covariates are available, the method's flexibility can lead to overfitting and an overall loss in predictive accuracy. To overcome this drawback, we develop a feature selection method for SVR based on a genetic algorithm that iteratively searches across potential subsets of covariates to find those that yield the best performance according to a user-defined fitness function. We evaluate the performance of our feature selection method for SVR, comparing it to alternate methods including LASSO and random forest, in a simulation study. We …

Mmp9 Clears The Way For Metastatic Cell Penetration Across The Blood-Brain Barrier, Joseph H Mccarty

Faculty, Staff and Student Publications

Although brain metastases are 10-fold more prevalent than primary brain cancers, relatively little is understood about the genes and pathways that promote metastatic cell entry, growth, and survival in the brain. Hence, determining how metastatic tumors colonize the brain and thrive within the neural microenvironment is a topic of both fundamental importance and direct clinical relevance. In this issue, a report by Karreman and colleagues explores pathways that are exploited by metastatic tumor cells to arrest in the circulation, cross the endothelial blood-brain barrier (BBB), and thrive in the brain microenvironment. The authors used elegant imaging tools including intravital fluorescence …

Mechanisms Of Response And Resistance To Combined Decitabine And Ipilimumab For Advanced Myeloid Disease, Livius Penter, Yang Liu, Jacquelyn O Wolff, Lin Yang, Len Taing, Aashna Jhaveri, Jackson Southard, Manishkumar Patel, Nicole M Cullen, Kathleen L Pfaff, Nicoletta Cieri, Giacomo Oliveira, Seunghee Kim-Schulze, Srinika Ranasinghe, Rebecca Leonard, Taylor Robertson, Elizabeth A Morgan, Helen X Chen, Minkyung H Song, Magdalena Thurin, Shuqiang Li, Scott J Rodig, Carrie Cibulskis, Stacey Gabriel, Pavan Bachireddy, Jerome Ritz, Howard Streicher, Donna S Neuberg, F Stephen Hodi, Matthew S Davids, Sacha Gnjatic, Kenneth J Livak, Jennifer Altreuter, Franziska Michor, Robert J Soiffer, Jacqueline S Garcia, Catherine J Wu

Faculty, Staff and Student Publications

The challenge of eradicating leukemia in patients with acute myelogenous leukemia (AML) after initial cytoreduction has motivated modern efforts to combine synergistic active modalities including immunotherapy. Recently, the ETCTN/CTEP 10026 study tested the combination of the DNA methyltransferase inhibitor decitabine together with the immune checkpoint inhibitor ipilimumab for AML/myelodysplastic syndrome (MDS) either after allogeneic hematopoietic stem cell transplantation (HSCT) or in the HSCT-naïve setting. Integrative transcriptome-based analysis of 304 961 individual marrow-infiltrating cells for 18 of 48 subjects treated on study revealed the strong association of response with a high baseline ratio of T to AML cells. Clinical responses were …