Medicine and Health Sciences Commons^™

Identification Of Genes Required For Eye Development By High-Throughput Screening Of Mouse Knockouts., Bret A Moore, Brian C Leonard, Lionel Sebbag, Sydney G Edwards, Ann Cooper, Denise M Imai, Ewan Straiton, Luis Santos, Christopher Reilly, Stephen M Griffey, Lynette Bower, David Clary, Jeremy Mason, Michel J Roux, Hamid Meziane, Yann Herault, Colin Mckerlie, Ann M Flenniken, Lauryl M J Nutter, Zorana Berberovic, Celeste Owen, Susan Newbigging, Hibret Adissu, Mohammed Eskandarian, Chih-Wei Hsu, Sowmya Kalaga, Uchechukwu Udensi, Chinwe Asomugha, Ritu Bohat, Juan J Gallegos, John R Seavitt, Jason D Heaney, Arthur L Beaudet, Mary E Dickinson, Monica J Justice, Vivek M. Philip, Vivek Kumar, Karen L. Svenson, Robert E Braun, Sara Wells, Heather Cater, Michelle Stewart, Sharon Clementson-Mobbs, Russell Joynson, Xiang Gao, Tomohiro Suzuki, Shigeharu Wakana, Damian Smedley, J K Seong, Glauco Tocchini-Valentini, Mark Moore, Colin Fletcher, Natasha Karp, Ramiro Ramirez-Solis, Jacqueline K White, Martin Hrabe De Angelis, Wolfgang Wurst, Sara M Thomasy, Paul Flicek, Helen Parkinson, Steve D M Brown, Terrence F Meehan, Patsy M. Nishina, Stephen A. Murray, Mark P. Krebs, Ann-Marie Mallon, K C Kent Lloyd, Christopher J Murphy, Ala Moshiri

Faculty Research 2018

Despite advances in next generation sequencing technologies, determining the genetic basis of ocular disease remains a major challenge due to the limited access and prohibitive cost of human forward genetics. Thus, less than 4,000 genes currently have available phenotype information for any organ system. Here we report the ophthalmic findings from the International Mouse Phenotyping Consortium, a large-scale functional genetic screen with the goal of generating and phenotyping a null mutant for every mouse gene. Of 4364 genes evaluated, 347 were identified to influence ocular phenotypes, 75% of which are entirely novel in ocular pathology. This discovery greatly increases the …

High-Resolution Deconstruction Of Evolution Induced By Chemotherapy Treatments In Breast Cancer Xenografts., Hyunsoo Kim, Pooja A Kumar, Francesca Menghi, Javad Noorbakhsh, Eliza Cerveira, Mallory Ryan, Qihui Zhu, Guruprasad Ananda, Joshy George, Henry C Chen, Susan Mockus, Chengsheng Zhang, Yan Yang, James G. Keck, Radha Krishna Murthy Karuturi, Carol J Bult, Charles Lee, Edison Liu, Jeffrey H Chuang

Faculty Research 2018

The processes by which tumors evolve are essential to the efficacy of treatment, but quantitative understanding of intratumoral dynamics has been limited. Although intratumoral heterogeneity is common, quantification of evolution is difficult from clinical samples because treatment replicates cannot be performed and because matched serial samples are infrequently available. To circumvent these problems we derived and assayed large sets of human triple-negative breast cancer xenografts and cell cultures from two patients, including 86 xenografts from cyclophosphamide, doxorubicin, cisplatin, docetaxel, or vehicle treatment cohorts as well as 45 related cell cultures. We assayed these samples via exome-seq and/or high-resolution droplet digital …

Mean-Variance Qtl Mapping Identifies Novel Qtl For Circadian Activity And Exploratory Behavior In Mice., Robert W Corty, Vivek Kumar, Lisa M Tarantino, Joseph S Takahashi, William Valdar

Faculty Research 2018

We illustrate, through two case studies, that "mean-variance QTL mapping"-QTL mapping that models effects on the mean and the variance simultaneously-can discover QTL that traditional interval mapping cannot. Mean-variance QTL mapping is based on the double generalized linear model, which extends the standard linear model used in interval mapping by incorporating not only a set of genetic and covariate effects for mean but also set of such effects for the residual variance. Its potential for use in QTL mapping has been described previously, but it remains underutilized, with certain key advantages undemonstrated until now. In the first case study, a …

Ectopic High Endothelial Venules In Pancreatic Ductal Adenocarcinoma: A Unique Site For Targeted Delivery., Baharak Bahmani, Mayuko Uehara, Farideh Ordikhani, Xiaofei Li, Liwei Jiang, Naima Banouni, Takaharu Ichimura, Vivek Kasinath, Siawosh K Eskandari, Nasim Annabi, Jonathan S Bromberg, Leonard D. Shultz, Dale L Greiner, Reza Abdi

Faculty Research 2018

BACKGROUND: Nanomedicine offers an excellent opportunity to tackle treatment-refractory malignancies by enhancing the delivery of therapeutics to the tumor site. High endothelial venules (HEVs) are found primarily in lymph nodes or formed de novo in peripheral tissues during inflammatory responses. They express peripheral node addressin (PNAd), which is recognized by the monoclonal antibody MECA79.

METHODS: Here, we demonstrated that HEVs form de novo in human pancreatic ductal adenocarcinoma (PDAC). We engineered MECA79 coated nanoparticles (MECA79-NPs) that recognize these ectopic HEVs in PDAC.

FINDINGS: The trafficking of MECA79-NPs following intravenous delivery to human PDAC implanted in a humanized mouse model was …

Detection Of Correlated Hidden Factors From Single Cell Transcriptomes Using Iteratively Adjusted-Sva (Ia-Sva)., Donghyung Lee, Anthony Cheng, Nathan Lawlor, Mohan Bolisetty, Duygu Ucar

Faculty Research 2018

Single cell RNA-sequencing (scRNA-seq) precisely characterizes gene expression levels and dissects variation in expression associated with the state (technical or biological) and the type of the cell, which is averaged out in bulk measurements. Multiple and correlated sources contribute to gene expression variation in single cells, which makes their estimation difficult with the existing methods developed for batch correction (e.g., surrogate variable analysis (SVA)) that estimate orthogonal transformations of these sources. We developed iteratively adjusted surrogate variable analysis (IA-SVA) that can estimate hidden factors even when they are correlated with other sources of variation by identifying a set of genes …

Oral Pathobiont Activates Anti-Apoptotic Pathway, Promoting Both Immune Suppression And Oncogenic Cell Proliferation., Pachiappan Arjunan, Mohamed M Meghil, Wenhu Pi, Jinxian Xu, Liwei Lang, Ahmed El-Awady, William Sullivan, Mythilypriya Rajendran, Mariana Sousa Rabelo, Tong Wang, Omnia K Tawfik, Govindarajan Kunde-Ramamoorthy, Nagendra Singh, Thangaraju Muthusamy, Cristiano Susin, Yong Teng, Roger M Arce, Christopher W Cutler

Faculty Research 2018

Chronic periodontitis (CP) is a microbial dysbiotic disease linked to increased risk of oral squamous cell carcinomas (OSCCs). To address the underlying mechanisms, mouse and human cell infection models and human biopsy samples were employed. We show that the 'keystone' pathogen Porphyromonas gingivalis, disrupts immune surveillance by generating myeloid-derived dendritic suppressor cells (MDDSCs) from monocytes. MDDSCs inhibit CTLs and induce FOXP3 + T

A Pan-Cancer Analysis Of Driver Gene Mutations, Dna Methylation And Gene Expressions Reveals That Chromatin Remodeling Is A Major Mechanism Inducing Global Changes In Cancer Epigenomes., Ahrim Youn, Kyung In Kim, Raul Rabadan, Benjamin Tycko, Yufeng Shen, Shuang Wang

Faculty Research 2018

BACKGROUND: Recent large-scale cancer sequencing studies have discovered many novel cancer driver genes (CDGs) in human cancers. Some studies also suggest that CDG mutations contribute to cancer-associated epigenomic and transcriptomic alterations across many cancer types. Here we aim to improve our understanding of the connections between CDG mutations and altered cancer cell epigenomes and transcriptomes on pan-cancer level and how these connections contribute to the known association between epigenome and transcriptome.

METHOD: Using multi-omics data including somatic mutation, DNA methylation, and gene expression data of 20 cancer types from The Cancer Genome Atlas (TCGA) project, we conducted a pan-cancer analysis …

Role Of Noise And Parametric Variation In The Dynamics Of Gene Regulatory Circuits., Vivek Kohar, Mingyang Lu

Faculty Research 2018

Stochasticity in gene expression impacts the dynamics and functions of gene regulatory circuits. Intrinsic noises, including those that are caused by low copy number of molecules and transcriptional bursting, are usually studied by stochastic simulations. However, the role of extrinsic factors, such as cell-to-cell variability and heterogeneity in the microenvironment, is still elusive. To evaluate the effects of both the intrinsic and extrinsic noises, we develop a method, named sRACIPE, by integrating stochastic analysis with random circuit perturbation (RACIPE) method. RACIPE uniquely generates and analyzes an ensemble of models with random kinetic parameters. Previously, we have shown that the gene …

A Neural Network Based Model Effectively Predicts Enhancers From Clinical Atac-Seq Samples., Asa Thibodeau, Asli Uyar, Shubham Khetan, Michael L. Stitzel, Duygu Ucar

Faculty Research 2018

Enhancers are cis-acting sequences that regulate transcription rates of their target genes in a cell-specific manner and harbor disease-associated sequence variants in cognate cell types. Many complex diseases are associated with enhancer malfunction, necessitating the discovery and study of enhancers from clinical samples. Assay for Transposase Accessible Chromatin (ATAC-seq) technology can interrogate chromatin accessibility from small cell numbers and facilitate studying enhancers in pathologies. However, on average, ~35% of open chromatin regions (OCRs) from ATAC-seq samples map to enhancers. We developed a neural network-based model, Predicting Enhancers from ATAC-Seq data (PEAS), to effectively infer enhancers from clinical ATAC-seq samples by …

Inhibition Of Glucose Metabolism Selectively Targets Autoreactive Follicular Helper T Cells., Seung-Chul Choi, Anton A Titov, Georges Abboud, Howard R Seay, Todd M Brusko, Derry C. Roopenian, Shahram Salek-Ardakani, Laurence Morel

Faculty Research 2018

Follicular helper T (T_FH) cells are expanded in systemic lupus erythematosus, where they are required to produce high affinity autoantibodies. Eliminating T_FH cells would, however compromise the production of protective antibodies against viral and bacterial pathogens. Here we show that inhibiting glucose metabolism results in a drastic reduction of the frequency and number of T_FH cells in lupus-prone mice. However, this inhibition has little effect on the production of T-cell-dependent antibodies following immunization with an exogenous antigen or on the frequency of virus-specific T_FH cells induced by infection with influenza. In contrast, glutaminolysis inhibition reduces …

A Multi-Tissue Full Lifespan Epigenetic Clock For Mice., Michael J Thompson, Karolina Chwiałkowska, Liudmilla Rubbi, Aldons J Lusis, Richard C Davis, Anuj Srivastava, Ron Korstanje, Gary A Churchill, Steve Horvath, Matteo Pellegrini

Faculty Research 2018

Human DNA-methylation data have been used to develop highly accurate biomarkers of aging ("epigenetic clocks"). Recent studies demonstrate that similar epigenetic clocks for mice (Mus Musculus) can be slowed by gold standard anti-aging interventions such as calorie restriction and growth hormone receptor knock-outs. Using DNA methylation data from previous publications with data collected in house for a total 1189 samples spanning 193,651 CpG sites, we developed 4 novel epigenetic clocks by choosing different regression models (elastic net- versus ridge regression) and by considering different sets of CpGs (all CpGs vs highly conserved CpGs). We demonstrate that accurate age …

Viable Mice With Extensive Gene Humanization (25-Kbp) Created Using Embryonic Stem Cell/Blastocyst And Crispr/Zygote Injection Approaches., Tiffany Leidy-Davis, Kai Cheng, Leslie Goodwin, Judith L Morgan, Wen Chun Juan, Xavier Roca, S Tiong Ong, David E. Bergstrom

Faculty Research 2018

Here, we describe an expansion of the typical DNA size limitations associated with CRISPR knock-in technology, more specifically, the physical extent to which mouse genomic DNA can be replaced with donor (in this case, human) DNA at an orthologous locus by zygotic injection. Driving our efforts was the desire to create a whole animal model that would replace 17 kilobase pairs (kbp) of the mouse Bcl2l11 gene with the corresponding 25-kbp segment of human BCL2L11, including a conditionally removable segment (2.9-kbp) of intron 2, a cryptic human exon immediately 3' of this, and a native human exon some 20 kbp …

Whole-Exome Sequencing Capture Kit Biases Yield False Negative Mutation Calls In Tcga Cohorts., Victor G Wang, Hyunsoo Kim, Jeffrey Chuang

Faculty Research 2018

The Cancer Genome Atlas (TCGA) provides a genetic characterization of more than ten thousand tumors, enabling the discovery of novel driver mutations, molecular subtypes, and enticing drug targets across many histologies. Here we investigated why some mutations are common in particular cancer types but absent in others. As an example, we observed that the gene CCDC168 has no mutations in the stomach adenocarcinoma (STAD) cohort despite its common presence in other tumor types. Surprisingly, we found that the lack of called mutations was due to a systematic insufficiency in the number of sequencing reads in the STAD and other cohorts, …

Living Inside The Box: Environmental Effects On Mouse Models Of Human Disease., John P Sundberg, Paul N Schofield

Faculty Research 2018

The impact of the laboratory environment on animal models of human disease, particularly the mouse, has recently come under intense scrutiny regarding both the reproducibility of such environments and their ability to accurately recapitulate elements of human environmental conditions. One common objection to the use of mice in highly controlled facilities is that humans live in much more diverse and stressful environments, which affects the expression and characteristics of disease phenotypes. In this Special Article, we review some of the known effects of the laboratory environment on mouse phenotypes and compare them with environmental effects on humans that modify phenotypes …

Spontaneous Posterior Segment Vascular Disease Phenotype Of A Mouse Model, Rnv3, Is Dependent On The Crb1rd8 Allele., Bo Chang, Bernie Fitzmaurice, Jieping Wang, Benjamin E. Low, Michael V. Wiles, Patsy M. Nishina

Faculty Research 2018

Purpose: To determine the molecular basis of lesion development in a murine model of spontaneous retinal vascularization, rnv3 (retinal vascularization 3, aka JR5558).

Methods: Disease progression of rnv3 was examined in longitudinal studies by clinical evaluation, electroretinography (ERG) and light microscopy analyses. The chromosomal position for the recessive rnv3 mutation was determined by DNA pooling and genome-wide linkage analysis. The causative mutation was discovered by comparison of whole exome sequences of rnv3 mutant and wild-type (WT) controls. In order to confirm the causative mutation, transcription activator-like effector nuclease (TALEN)-mediated oligonucleotide directed repair (ODR) was utilized to correct the mutant allele. …

Adipor1 Is Essential For Vision And Its Rpe Expression Is Lost In The Mfrp, Valentin M Sluch, Angela Banks, Hui Li, Maura A Crowley, Vanessa Davis, Chuanxi Xiang, Junzheng Yang, John T Demirs, Joanna Vrouvlianis, Barrett Leehy, Shawn Hanks, Alexandra M Hyman, Jorge Aranda, Bo Chang, Chad E Bigelow, Dennis S Rice

Faculty Research 2018

The knockout (KO) of the adiponectin receptor 1 (AdipoR1) gene causes retinal degeneration. Here we report that ADIPOR1 protein is primarily found in the eye and brain with little expression in other tissues. Further analysis of AdipoR1 KO mice revealed that these animals exhibit early visual system abnormalities and are depleted of RHODOPSIN prior to pronounced photoreceptor death. A KO of AdipoR1 post-development either in photoreceptors or the retinal pigment epithelium (RPE) resulted in decreased expression of retinal proteins, establishing a role for ADIPOR1 in supporting vision in adulthood. Subsequent analysis of the Mfrp

Cortical Network Synchrony Under Applied Electrical Field, Min D Tang-Schomer, Taylor Jackvony, Sabato Santaniello

Faculty Research 2018

Synchronous network activity plays a crucial role in complex brain functions. Stimulating the nervous system with applied electric field (EF) is a common tool for probing network responses. We used a gold wire-embedded silk protein film-based interface culture to investigate the effects of applied EFs on random cortical networks of in vitro cultures. Two-week-old cultures were exposed to EF of 27 mV/mm for <1 h and monitored by time-lapse calcium imaging. Network activity was represented by calcium signal time series mapped to source neurons and analyzed by using a community detection algorithm. Cortical cultures exhibited large scale, synchronized oscillations under alternating EF of changing frequencies. Field polarity and frequency change were both found to be necessary for network synchrony, as monophasic pulses of similar frequency changes or EF of a constant frequency failed to induce correlated activities of neurons. Group-specific oscillatory patterns were entrained by network-level synchronous oscillations when the alternating EF frequency was increased from 0.2 Hz to 200 kHz. Binary responses of either activity increase or decrease contributed to the opposite phase patterns of different sub-populations. Conversely, when the EF frequency decreased over the same range span, more complex behavior emerged showing group-specific amplitude and phase patterns. These findings formed the basis of a hypothesized network control mechanism for temporal coordination of distributed neuronal activity, involving coordinated stimulation by alternating polarity, and time delay by change of frequency. These novel EF effects on random neural networks have important implications for brain functional studies and neuromodulation applications.

Inhibition Of Glycolysis Reduces Disease Severity In An Autoimmune Model Of Rheumatoid Arthritis., Georges Abboud, Seung-Chul Choi, Nathalie Kanda, Leilani Zeumer-Spataro, Derry C. Roopenian, Laurence Morel

Faculty Research 2018

The K/BxN mouse is a spontaneous model of arthritis driven by T cell receptor transgenic CD4⁺ T cells from the KRN strain that are activated by glucose-6-phosphate isomerase (GPI) peptides presented by the H-2^g7 allele from the NOD strain. It is a model of autoimmune seropositive arthritis because the production of anti-GPI IgG is necessary and sufficient for joint pathology. The production of high levels of anti-GPI IgG requires on the expansion of CD4⁺ follicular helper T (Tfh) cells. The metabolic requirements of this expansion have never been characterized. Based on the therapeutic effects of the combination …

Immunomodulatory Interventions In Myocardial Infarction And Heart Failure: A Systematic Review Of Clinical Trials And Meta-Analysis Of Il-1 Inhibition., Mona Panahi, Angelos Papanikolaou, Azam Torabi, Ji-Gang Zhang, Habib Khan, Ali Vazir, Muneer G. Hasham, John G F Cleland, Nadia Rosenthal, Sian E Harding, Susanne Sattler

Faculty Research 2018

Following a myocardial infarction (MI), the immune system helps to repair ischaemic damage and restore tissue integrity, but excessive inflammation has been implicated in adverse cardiac remodelling and development towards heart failure (HF). Pre-clinical studies suggest that timely resolution of inflammation may help prevent HF development and progression. Therapeutic attempts to prevent excessive post-MI inflammation in patients have included pharmacological interventions ranging from broad immunosuppression to immunomodulatory approaches targeting specific cell types or factors with the aim to maintain beneficial aspects of the early post-MI immune response. These include the blockade of early initiators of inflammation including reactive oxygen species …

A Robust Pax7egfp Mouse That Enables The Visualization Of Dynamic Behaviors Of Muscle Stem Cells., Elisia D Tichy, David K Sidibe, Christopher D Greer, Nicholas M Oyster, Panteleimon Rompolas, Nadia Rosenthal, Helen M Blau, Foteini Mourkioti

Faculty Research 2018

BACKGROUND: Pax7 is a transcription factor involved in the specification and maintenance of muscle stem cells (MuSCs). Upon injury, MuSCs leave their quiescent state, downregulate Pax7 and differentiate, contributing to skeletal muscle regeneration. In the majority of regeneration studies, MuSCs are isolated by fluorescence-activated sorting (FACS), based on cell surface markers. It is known that MuSCs are a heterogeneous population and only a small percentage of isolated cells are true stem cells that are able to self-renew. A strong Pax7 reporter line would be valuable to study the in vivo behavior of Pax7-expressing stem cells.

METHODS: We generated and characterized …

Mutant Klf1 In Adult Anemic Nan Mice Leads To Profound Transcriptome Changes And Disordered Erythropoiesis., Danitza Nébor, Joel H. Graber, Steven L. Ciciotte, Ray F. Robledo, Julien Papoin, Emily Hartman, Kevin R Gillinder, Andrew C Perkins, James J Bieker, Lionel Blanc, Luanne L. Peters

Faculty Research 2018

Anemic Nan mice carry a mutation (E339D) in the second zinc finger of erythroid transcription factor KLF1. Nan-KLF1 fails to bind a subset of normal KLF1 targets and ectopically binds a large set of genes not normally engaged by KLF1, resulting in a corrupted fetal liver transcriptome. Here, we performed RNAseq using flow cytometric-sorted spleen erythroid precursors from adult Nan and WT littermates rendered anemic by phlebotomy to identify global transcriptome changes specific to the Nan Klf1 mutation as opposed to anemia generally. Mutant Nan-KLF1 leads to extensive and progressive transcriptome corruption in adult spleen erythroid precursors such that stress …

Interaction Between The Microbiome And Tp53 In Human Lung Cancer., K Leigh Greathouse, James R White, Ashely J Vargas, Valery V Bliskovsky, Jessica A Beck, Natalia Von Muhlinen, Eric C Polley, Elise D Bowman, Mohammed A Khan, Ana I Robles, Tomer Cooks, Bríd M Ryan, Noah Padgett, Amiran H Dzutsev, Giorgio Trinchieri, Marbin A Pineda, Sven Bilke, Paul S Meltzer, Alexis N Hokenstad, Tricia M Stickrod, Marina R Walther-Antonio, Joshua P Earl, Joshua C Mell, Jaroslaw E Krol, Sergey V Balashov, Archana S Bhat, Garth D Ehrlich, Alex Valm, Clayton Deming, Sean Conlan, Julia Oh, Julie A Segre, Curtis C Harris

Faculty Research 2018

BACKGROUND: Lung cancer is the leading cancer diagnosis worldwide and the number one cause of cancer deaths. Exposure to cigarette smoke, the primary risk factor in lung cancer, reduces epithelial barrier integrity and increases susceptibility to infections. Herein, we hypothesize that somatic mutations together with cigarette smoke generate a dysbiotic microbiota that is associated with lung carcinogenesis. Using lung tissue from 33 controls and 143 cancer cases, we conduct 16S ribosomal RNA (rRNA) bacterial gene sequencing, with RNA-sequencing data from lung cancer cases in The Cancer Genome Atlas serving as the validation cohort.

RESULTS: Overall, we demonstrate a lower alpha …

Low Peripheral T Follicular Helper Cells In Perinatally Hiv-Infected Children Correlate With Advancing Hiv Disease., Bret Mccarty, Mussa Mwamzuka, Fatma Marshed, Matthew Generoso, Patricia Alvarez, Tiina Ilmet, Adam Kravietz, Aabid Ahmed, William Borkowsky, Derya Unutmaz, Alka Khaitan

Faculty Research 2018

Background: T follicular helper (Tfh) cells are crucial for B cell differentiation and antigen-specific antibody production. Dysregulation of Tfh-mediated B cell help weakens B cell responses in HIV infection. Moreover, Tfh cells in the lymph node and peripheral blood comprise a significant portion of the latent HIV reservoir. There is limited data on the effects of perinatal HIV infection on Tfh cells in children. We examined peripheral Tfh (pTfh) cell frequencies and phenotype in HIV-infected children and their associations with disease progression, immune activation, and B cell differentiation.

Methods: In a Kenyan cohort of 76 perinatally HIV-infected children, comprised of …

Deletion Of Nkx2-5 In Trabecular Myocardium Reveals The Developmental Origins Of Pathological Heterogeneity Associated With Ventricular Non-Compaction Cardiomyopathy., Caroline Choquet, Thi Hong Minh Nguyen, Pierre Sicard, Emeline Buttigieg, Thi Thom Tran, Frank Kober, Isabelle Varlet, Rachel Sturny, Mauro W Costa, Richard P Harvey, Catherine Nguyen, Pascal Rihet, Sylvain Richard, Monique Bernard, Robert G Kelly, Nathalie Lalevée, Lucile Miquerol

Faculty Research 2018

Left ventricular non-compaction (LVNC) is a rare cardiomyopathy associated with a hypertrabeculated phenotype and a large spectrum of symptoms. It is still unclear whether LVNC results from a defect of ventricular trabeculae development and the mechanistic basis that underlies the varying severity of this pathology is unknown. To investigate these issues, we inactivated the cardiac transcription factor Nkx2-5 in trabecular myocardium at different stages of trabecular morphogenesis using an inducible Cx40-creERT2 allele. Conditional deletion of Nkx2-5 at embryonic stages, during trabecular formation, provokes a severe hypertrabeculated phenotype associated with subendocardial fibrosis and Purkinje fiber hypoplasia. A milder phenotype was observed …

Studying Cancer Immunotherapy Using Patient-Derived Xenografts (Pdxs) In Humanized Mice., Yunsik Choi, Sanghyuk Lee, Kapyoul Kim, Soo-Hyun Kim, Yeun-Jun Chung, Charles Lee

Faculty Research 2018

Cancer immunotherapy is a promising way to eliminate tumor cells by using the patient's own immune system. Selecting the appropriate animal models to develop or validate preclinical immunotherapeutic trials is now an important aspect of many cancer research programs. Here we discuss the advantages and limitations of using genetically engineered immunodeficient mouse models, patient-derived xenografts (PDXs), and humanized mouse models for developing and testing immunotherapeutic strategies.

Distribution-Based Measures Of Tumor Heterogeneity Are Sensitive To Mutation Calling And Lack Strong Clinical Predictive Power., Javad Noorbakhsh, Hyunsoo Kim, Sandeep Namburi, Jeffrey H Chuang

Faculty Research 2018

Mutant allele frequency distributions in cancer samples have been used to estimate intratumoral heterogeneity and its implications for patient survival. However, mutation calls are sensitive to the calling algorithm. It remains unknown whether the relationship of heterogeneity and clinical outcome is robust to these variations. To resolve this question, we studied the robustness of allele frequency distributions to the mutation callers MuTect, SomaticSniper, and VarScan in 4722 cancer samples from The Cancer Genome Atlas. We observed discrepancies among the results, particularly a pronounced difference between allele frequency distributions called by VarScan and SomaticSniper. Survival analysis showed little robust predictive power …

Etidronate Prevents, But Does Not Reverse, Ectopic Mineralization In A Mouse Model Of Pseudoxanthoma Elasticum (, Qiaoli Li, Joshua Kingman, John P Sundberg, Michael A Levine, Jouni Uitto

Faculty Research 2018

Pseudoxanthoma elasticum (PXE) and generalized arterial calcification of infancy (GACI) are heritable disorders manifesting with ectopic tissue mineralization. Most cases of PXE and some cases of GACI are caused by mutations in the ABCC6 gene, resulting in reduced plasma pyrophosphate (PPi) levels. There is no effective treatment for these disorders. It has been suggested that administration of bisphosphonates, stable and non-hydrolyzable PPi analogs, could counteract ectopic mineralization in these disorders. In this study we tested the potential efficacy of etidronate, a first generation bisphosphonate, on ectopic mineralization in the muzzle skin of Abcc6^-/- mice, a model of PXE. The …

Opposing Tumor-Promoting And -Suppressive Functions Of Rictor/Mtorc2 Signaling In Adult Glioma And Pediatric Shh Medulloblastoma., Seçkin Akgül, Yinghua Li, Siyuan Zheng, Marcel Kool, Daniel M Treisman, Chaoyang Li, Yuan Wang, Susanne Gröbner, Tsuneo Ikenoue, Yiping Shen, Sandra Camelo-Piragua, Gerald Tomasek, Sebastian Stark, Vinay Guduguntla, James F Gusella, Kun-Liang Guan, Stefan M Pfister, Roel G W Verhaak, Yuan Zhu

Faculty Research 2018

Most human cancers arise from stem and progenitor cells by the sequential accumulation of genetic and epigenetic alterations, while cancer modeling typically requires simultaneous multiple oncogenic events. Here, we show that a single p53 mutation, despite causing no defect in the mouse brain, promoted neural stem and progenitor cells to spontaneously accumulate oncogenic alterations, including loss of multiple chromosomal (chr) regions syntenic to human chr10 containing Pten, forming malignant gliomas with PI3K/Akt activation. Rictor/mTORC2 loss inhibited Akt signaling, greatly delaying and reducing glioma formation by suppressing glioma precursors within the subventricular zone stem cell niche. Rictor/mTORC2 loss delayed timely differentiation …

Rhbdf2-Regulated Growth Factor Signaling In A Rare Human Disease Tylosis With Esophageal Cancer: What Can We Learn From Murine Models?, Vishnu Hosur, Benjamin E. Low, Michelle L Farley, Lisa M. Burzenski, Leonard D. Shultz, Michael V. Wiles

Faculty Research 2018

Tylosis with esophageal cancer syndrome (TOC) is a rare autosomal dominant proliferative skin disease caused by missense mutations in the rhomboid 5 homolog 2 (RHBDF2) gene. TOC is characterized by thickening of the skin in the palms and feet and is strongly linked with the development of esophageal squamous cell carcinoma. Murine models of human diseases have been valuable tools for investigating the underlying genetic and molecular mechanisms of a broad range of diseases. Although current mouse models do not fully recapitulate all aspects of human TOC, and the molecular mechanisms underlying TOC are still emerging, the available mouse models …

Despite High Levels Of Expression In Thymic Epithelial Cells, Mir-181a1 And Mir-181b1 Are Not Required For Thymic Development., Heather E Stefanski, Yan Xing, Patricia A Taylor, Stefano Maio, Jorge Henao-Meija, Adam Williams, Richard A Flavell, Georg A Hollander, Bruce R Blazar

Faculty Research 2018

MicroRNAs (miRNAs) have been shown to be key modulators of post-transcriptional gene silencing in many cellular processes. In previous studies designed to understand the role of miRNAs in thymic development, we globally deleted miRNA exclusively in thymic epithelial cells (TECs), which are critical in thymic selection. This resulted in the loss of stromal cells that instruct T cell lineage commitment and affect thymocyte positive selection, required for mature T cell development. Since murine miR-181 is expressed in the thymus and miR-181 deficiency disrupts thymocyte development, we first quantified and thereby demonstrated that miR181a1 and miR181b1 are expressed in purified TECs. …