Digital Commons Network^™

Tumor Cell Targeting By Iron Oxide Nanoparticles Is Dominated By Different Factors In Vitro Versus In Vivo, Christian Ndong, Jennifer A. Tate, Warren C. Kett, Jaya Batra, Eugene Demidenko, Lionel D. Lewis, P. Jack Hoopes, Tillmann U. Gerngross, Karl E. Griswold

Dartmouth Scholarship

Realizing the full potential of iron oxide nanoparticles (IONP) for cancer diagnosis and therapy requires selective tumor cell accumulation. Here, we report a systematic analysis of two key determinants for IONP homing to human breast cancers: (i) particle size and (ii) active vs passive targeting. In vitro, molecular targeting to the HER2 receptor was the dominant factor driving cancer cell association. In contrast, size was found to be the key determinant of tumor accumulation in vivo, where molecular targeting increased tumor tissue concentrations for 30 nm but not 100 nm IONP. Similar to the in vitro results, PEGylation …

Novel Actions Of Next-Generation Taxanes Benefit Advanced Stages Of Prostate Cancer., Renée De Leeuw, Lisa D. Berman-Booty, Matthew J. Schiewer, Stephen J Ciment, Robert Den, Adam P. Dicker, William Kelly, Edouard J. Trabulsi, Costas D. Lallas, Leonard G. Gomella, Karen E. Knudsen

Department of Cancer Biology Faculty Papers

PURPOSE: To improve the outcomes of patients with castration-resistant prostate cancer (CRPC), there is an urgent need for more effective therapies and approaches that individualize specific treatments for patients with CRPC. These studies compared the novel taxane cabazitaxel with the previous generation docetaxel, and aimed to determine which tumors are most likely to respond.

EXPERIMENTAL DESIGN: Cabazitaxel and docetaxel were compared via in vitro modeling to determine the molecular mechanism, biochemical and cell biologic impact, and cell proliferation, which was further assessed ex vivo in human tumor explants. Isogenic pairs of RB knockdown and control cells were interrogated in vitro …

Diversification Of Importin-Α Isoforms In Cellular Trafficking And Disease States., Ruth A. Pumroy, Gino Cingolani

Department of Biochemistry and Molecular Biology Faculty Papers

The human genome encodes seven isoforms of importin α which are grouped into three subfamilies known as α1, α2 and α3. All isoforms share a fundamentally conserved architecture that consists of an N-terminal, autoinhibitory, importin-β-binding (IBB) domain and a C-terminal Arm (Armadillo)-core that associates with nuclear localization signal (NLS) cargoes. Despite striking similarity in amino acid sequence and 3D structure, importin-α isoforms display remarkable substrate specificity in vivo. In the present review, we look at key differences among importin-α isoforms and provide a comprehensive inventory of known viral and cellular cargoes that have been shown to associate preferentially with specific …

Amyloid Precursor-Like Protein 2 (Aplp2) Affects The Actin Cytoskeleton And Increases Pancreatic Cancer Growth And Metastasis., Poomy Pandey, Satyanarayana Rachagani, Srustidhar Das, Parthasarathy Seshacharyulu, Yuri Sheinin, Naava Naslavsky, Zenggang Pan, Brittney L. Smith, Haley L. Peters, Prakash Radhakrishnan, Nicole R. Mckenna, Sai Srinivas Panapakkam Giridharan, Dhanya Haridas, Sukhwinder Kaur, Michael A. Hollingsworth, Richard G. Macdonald, Jane L. Meza, Steve Caplan, Surinder K. Batra, Joyce C. Solheim

Journal Articles: Biochemistry & Molecular Biology

Amyloid precursor-like protein 2 (APLP2) is aberrantly expressed in pancreatic cancer. Here we showed that APLP2 is increased in pancreatic cancer metastases, particularly in metastatic lesions found in the diaphragm and intestine. Examination of matched human primary tumor-liver metastasis pairs showed that 38.1% of the patients had positive APLP2 expression in both the primary tumor and the corresponding liver metastasis. Stable knock-down of APLP2 expression (with inducible shRNA) in pancreatic cancer cells reduced the ability of these cells to migrate and invade. Loss of APLP2 decreased cortical actin and increased intracellular actin filaments in pancreatic cancer cells. Down-regulation of APLP2 …

Tsc2/Mtorc1 Signaling Controls Paneth And Goblet Cell Differentiation In The Intestinal Epithelium, Y. Zhou, Piotr G. Rychahou, Q. Wang, Heidi L. Weiss, B. Mark Evers

Markey Cancer Center Faculty Publications

The intestinal mucosa undergoes a continual process of proliferation, differentiation and apoptosis, which is regulated by multiple signaling pathways. Notch signaling is critical for the control of intestinal stem cell maintenance and differentiation. However, the precise mechanisms involved in the regulation of differentiation are not fully understood. Previously, we have shown that tuberous sclerosis 2 (TSC2) positively regulates the expression of the goblet cell differentiation marker, MUC2, in intestinal cells. Using transgenic mice constitutively expressing a dominant negative TSC2 allele, we observed that TSC2 inactivation increased mTORC1 and Notch activities, and altered differentiation throughout the intestinal epithelium, with a marked …

Modeling Neurovascular Coupling From Clustered Parameter Sets For Multimodal Eeg-Nirs, M. Tanveer Talukdar, H. Robert Frost, Solomon G. G. Diamond

Dartmouth Scholarship

Despite significant improvements in neuroimaging technologies and analysis methods, the fundamental relationship between local changes in cerebral hemodynamics and the underlying neural activity remains largely unknown. In this study, a data driven approach is proposed for modeling this neurovascular coupling relationship from simultaneously acquired electroencephalographic (EEG) and near-infrared spectroscopic (NIRS) data. The approach uses gamma transfer functions to map EEG spectral envelopes that reflect time-varying power variations in neural rhythms to hemodynamics measured with NIRS during median nerve stimulation. The approach is evaluated first with simulated EEG-NIRS data and then by applying the method to experimental EEG-NIRS data measured from …

Shbg Gene Polymorphism (Rs1799941) Associates With Metabolic Syndrome In Children And Adolescents, Marquitta J. White, Fatih Eren, Deniz Agirbasli, Scott M. Williams, Mehmet Agirbasli

Dartmouth Scholarship

Background: Metabolic syndrome (MetS) is a complex disorder characterized by coexistence of several cardiometabolic (CM) factors, i.e. hyperlipidemia, obesity, high blood pressure and insulin resistance. The presence of MetS is strongly associated with increased risk of cardiovascular disease (CVD). The syndrome was originally defined as an adult disorder, but MetS has become increasingly recognized in children and adolescents.

Methods: Genetic variants influence biological components common to the CM factors that comprise MetS. We investigated single locus associations between six single nucleotide polymorphisms (SNPs), previously shown to modulate lipid or sex hormone binding globulin (SHBG) levels, with MetS in a Turkish …

The Value Of The Follow-Through Derives From Motor Learning Depending On Future Actions., Ian S. Howard, Daniel M. Wolpert, David W. Franklin

School of Engineering, Computing and Mathematics

In ball sports, we are taught to follow through, despite the inability of events after contact or release to influence the outcome [1, 2]. Here we show that the specific motor memory active at any given moment critically depends on the movement that will be made in the near future. We demonstrate that associating a different follow-through movement with two motor skills that normally interfere [3-7] allows them to be learned simultaneously, suggesting that distinct future actions activate separate motor memories. This implies that when learning a skill, a variable follow-through would activate multiple motor memories across practice, whereas a …

A Quick Guide For Building A Successful Bioinformatics Community., Aidan Budd, Manuel Corpas, Michelle D Brazas, Jonathan C Fuller, Jeremy Goecks, Nicola J Mulder, Magali Michaut, B F Francis Ouellette, Aleksandra Pawlik, Niklas Blomberg

Computational Biology Institute

"Scientific community" refers to a group of people collaborating together on scientific-research-related activities who also share common goals, interests, and values. Such communities play a key role in many bioinformatics activities. Communities may be linked to a specific location or institute, or involve people working at many different institutions and locations. Education and training is typically an important component of these communities, providing a valuable context in which to develop skills and expertise, while also strengthening links and relationships within the community. Scientific communities facilitate: (i) the exchange and development of ideas and expertise; (ii) career development; (iii) coordinated funding …

Characterization Of Ranbpm Molecular Determinants That Control Its Subcellular Localization, Louisa M Salemi, Sandra O Loureiro, Caroline Schild-Poulter

Biochemistry Publications

RanBPM/RanBP9 is a ubiquitous, nucleocytoplasmic protein that is part of an evolutionary conserved E3 ubiquitin ligase complex whose function and targets in mammals are still unknown. RanBPM itself has been implicated in various cellular processes that involve both nuclear and cytoplasmic functions. However, to date, little is known about how RanBPM subcellular localization is regulated. We have conducted a systematic analysis of RanBPM regions that control its subcellular localization using RanBPM shRNA cells to examine ectopic RanBPM mutant subcellular localization without interference from the endogenously expressed protein. We show that several domains and motifs regulate RanBPM nuclear and cytoplasmic localization. …

Cytometric Characterization Of Circulating Tumor Cells Captured By Microfiltration And Their Correlation To The Cellsearch(®) Ctc Test., Daniel L Adams, Steingrimur Stefansson, Christian Haudenschild, Stuart S Martin, Monica Charpentier, Saranya Chumsri, Massimo Cristofanilli, Cha-Mei Tang, R Katherine Alpaugh

Pathology Faculty Publications

Recent studies reporting hundreds, to thousands, of circulating tumor cells (CTCs) in the blood of cancer patients have raised questions regarding the prevalence of CTCs, as enumerated by the CellSearch(®) CTC Test. Although CellSearch has been shown to consistently detect clinically relevant CTCs; the ability to only capture EpCAM positive cells has led to speculation that it captures limited subsets of CTCs. In contrast, alternative approaches to CTC isolation are often cited as capturing large numbers of CTCs from patient blood. Not surprisingly the number of cells isolated by alternative approaches show poor correlations when compared to CellSearch, even when …

Lifelong Physical Exercise Delays Age-Associated Skeletal Muscle Decline., S Zampieri, L Pietrangelo, S Loefler, H Fruhmann, M Vogelauer, S Burggraf, A Pond, M Grim-Stieger, J Cvecka, M Sedliak, V Tirpáková, W Mayr, N Sarabon, K Rossini, L Barberi, M De Rossi, V Romanello, S Boncompagni, A Musarò, M Sandri, F Protasi, U Carraro, H Kern

Publications

Aging is usually accompanied by a significant reduction in muscle mass and force. To determine the relative contribution of inactivity and aging per se to this decay, we compared muscle function and structure in (a) male participants belonging to a group of well-trained seniors (average of 70 years) who exercised regularly in their previous 30 years and (b) age-matched healthy sedentary seniors with (c) active young men (average of 27 years). The results collected show that relative to their sedentary cohorts, muscle from senior sportsmen have: (a) greater maximal isometric force and function, (b) better preserved fiber morphology and ultrastructure …

On Voxel-By-Voxel Accumulated Dose For Prostate Radiation Therapy Using Deformable Image Registration., Jialu Yu, Nicholas Hardcastle, Kyoungkeun Jeong, Edward T. Bender, Mark A. Ritter, Wolfgang A. Tomé

Department of Radiation Oncology Faculty Papers

Since delivered dose is rarely the same with planned, we calculated the delivered total dose to ten prostate radiotherapy patients treated with rectal balloons using deformable dose accumulation (DDA) and compared it with the planned dose. The patients were treated with TomoTherapy using two rectal balloon designs: five patients had the Radiadyne balloon (balloon A), and five patients had the EZ-EM balloon (balloon B). Prostate and rectal wall contours were outlined on each pre-treatment MVCT for all patients. Delivered fractional doses were calculated using the MVCT taken immediately prior to delivery. Dose grids were accumulated to the last MVCT using …

Designer Receptors Enhance Memory In A Mouse Model Of Down Syndrome, Ashley M. Fortress, Eric D. Hamlett, Elena M. Vazey, Gary Aston-Jones, Wayne A. Cass, Heather A. Boger, Ann-Charlotte E. Granholm

Neuroscience Faculty Publications

Designer receptors exclusively activated by designer drugs (DREADDs) are novel and powerful tools to investigate discrete neuronal populations in the brain. We have used DREADDs to stimulate degenerating neurons in a Down syndrome (DS) model, Ts65Dn mice. Individuals with DS develop Alzheimer's disease (AD) neuropathology and have elevated risk for dementia starting in their 30s and 40s. Individuals with DS often exhibit working memory deficits coupled with degeneration of the locus coeruleus (LC) norepinephrine (NE) neurons. It is thought that LC degeneration precedes other AD-related neuronal loss, and LC noradrenergic integrity is important for executive function, working memory, and attention. …

Opposing Regulation Of Endolysosomal Pathways By Long-Acting Nanoformulated Antiretroviral Therapy And Hiv-1 In Human Macrophages., Mariluz Araínga, Dongwei Guo, Jayme Wiederin, Pawel Ciborowski, Joellyn Mcmillan, Howard Gendelman

Journal Articles: Pharmacology & Experimental Neuroscience

BACKGROUND: Long-acting nanoformulated antiretroviral therapy (nanoART) is designed to improve patient regimen adherence, reduce systemic drug toxicities, and facilitate clearance of human immunodeficiency virus type one (HIV-1) infection. While nanoART establishes drug depots within recycling and late monocyte-macrophage endosomes, whether or not this provides a strategic advantage towards viral elimination has not been elucidated.

RESULTS: We applied quantitative SWATH-MS proteomics and cell profiling to nanoparticle atazanavir (nanoATV)-treated and HIV-1 infected human monocyte-derived macrophages (MDM). Native ATV and uninfected cells served as controls. Both HIV-1 and nanoATV engaged endolysosomal trafficking for assembly and depot formation, respectively. Notably, the pathways were deregulated …

Opposing Regulation Of Endolysosomal Pathways By Long-Acting Nanoformulated Antiretroviral Therapy And Hiv-1 In Human Macrophages., Mariluz Araínga, Dongwei Guo, Jayme Wiederin, Pawel Ciborowski, Joellyn Mcmillan, Howard Gendelman

Journal Articles: Pharmacology & Experimental Neuroscience

BACKGROUND: Long-acting nanoformulated antiretroviral therapy (nanoART) is designed to improve patient regimen adherence, reduce systemic drug toxicities, and facilitate clearance of human immunodeficiency virus type one (HIV-1) infection. While nanoART establishes drug depots within recycling and late monocyte-macrophage endosomes, whether or not this provides a strategic advantage towards viral elimination has not been elucidated.

RESULTS: We applied quantitative SWATH-MS proteomics and cell profiling to nanoparticle atazanavir (nanoATV)-treated and HIV-1 infected human monocyte-derived macrophages (MDM). Native ATV and uninfected cells served as controls. Both HIV-1 and nanoATV engaged endolysosomal trafficking for assembly and depot formation, respectively. Notably, the pathways were deregulated …

Experimentally-Derived Fibroblast Gene Signatures Identify Molecular Pathways Associated With Distinct Subsets Of Systemic Sclerosis Patients In Three Independent Cohorts, Michael E. Johnson, J. Matthew Mahoney, Jaclyn Taroni, Jennifer L. Sargent, Eleni Marmarelis, Ming-Ru Wu, John Varga, Monique E. Hinchcliff, Michael L. Whitfield

Dartmouth Scholarship

Genome-wide expression profiling in systemic sclerosis (SSc) has identified four ‘intrinsic’ subsets of disease (fibroproliferative, inflammatory, limited, and normal-like), each of which shows deregulation of distinct signaling pathways; however, the full set of pathways contributing to this differential gene expression has not been fully elucidated. Here we examine experimentally derived gene expression signatures in dermal fibroblasts for thirteen different signaling pathways implicated in SSc pathogenesis. These data show distinct and overlapping sets of genes induced by each pathway, allowing for a better understanding of the molecular relationship between profibrotic and immune signaling networks. Pathway-specific gene signatures were analyzed across a …

Zhx2 Enhances The Cytotoxicity Of Chemotherapeutic Drugs In Liver Tumor Cells By Repressing Mdr1 Via Interfering With Nf-Ya, Hongxin Ma, Xuetian Yue, Lifen Gao, Xiaohong Liang, Wenjiang Yan, Zhenyu Zhang, Haixia Shan, Hualin Zhang, Brett T. Spear, Chunhong Ma

Microbiology, Immunology, and Molecular Genetics Faculty Publications

We previously reported the tumor suppressor function of Zinc-fingers and homeoboxes 2 (ZHX2) in hepatocellular carcinoma (HCC). Other studies indicate the association of increased ZHX2 expression with improved response to high dose chemotherapy in multiple myeloma. Here, we aim to test whether increased ZHX2 levels in HCC cells repress multidrug resistance 1(MDR1) expression resulting in increased sensitivity to chemotherapeutic drugs. We showed evidence that increased ZHX2 levels correlated with reduced MDR1 expression and enhanced the cytotoxicity of CDDP and ADM in different HCC cell lines. Consistently, elevated ZHX2 significantly reduced ADM efflux in HepG2 cells and greatly increased the CDDP-mediated …

Cohort Of Birth Modifies The Association Between Fto Genotype And Bmi, James Niels Rosenquist, Steven F. Lehrer, A. James O'Malley, Alan M. Zaslavsky, Jordan W. Smoller, Nicholas A. Christakis

Dartmouth Scholarship

A substantial body of research has explored the relative roles of genetic and environmental factors on phenotype expression in humans. Recent research has also sought to identify gene-environment (or g-by-e) interactions, with mixed success. One potential reason for these mixed results may relate to the fact that genetic effects might be modified by changes in the environment over time. For example, the noted rise of obesity in the United States in the latter part of the 20th century might reflect an interaction between genetic variation and changing environmental conditions that together affect the penetrance of genetic influences. To evaluate this …

Mapping The Pareto Optimal Design Space For A Functionally Deimmunized Biotherapeutic Candidate, Regina S. Salvat, Andrew S. Parker, Yoonjoo Choi, Chris Bailey-Kellogg, Karl E. Griswold

Dartmouth Scholarship

The immunogenicity of biotherapeutics can bottleneck development pipelines and poses a barrier to widespread clinical application. As a result, there is a growing need for improved deimmunization technologies. We have recently described algorithms that simultaneously optimize proteins for both reduced T cell epitope content and high-level function. In silico analysis of this dual objective design space reveals that there is no single global optimum with respect to protein deimmunization. Instead, mutagenic epitope deletion yields a spectrum of designs that exhibit tradeoffs between immunogenic potential and molecular function. The leading edge of this design space is the Pareto frontier, i.e. the …

Systems Level Analysis Of Systemic Sclerosis Shows A Network Of Immune And Profibrotic Pathways Connected With Genetic Polymorphisms, J. Matthew Mahoney, Jaclyn Taroni, Viktor Martyanov, Tammara A. A. Wood, Casey S. Greene, Patricia A. Pioli, Monique E. Hinchcliff, Michael L. Whitfield

Dartmouth Scholarship

Systemic sclerosis (SSc) is a rare systemic autoimmune disease characterized by skin and organ fibrosis. The pathogenesis of SSc and its progression are poorly understood. The SSc intrinsic gene expression subsets (inflammatory, fibroproliferative, normal-like, and limited) are observed in multiple clinical cohorts of patients with SSc. Analysis of longitudinal skin biopsies suggests that a patient's subset assignment is stable over 6-12 months. Genetically, SSc is multi-factorial with many genetic risk loci for SSc generally and for specific clinical manifestations. Here we identify the genes consistently associated with the intrinsic subsets across three independent cohorts, show the relationship between these genes …

Biomarkers Of Animal Health: Integrating Nutritional Ecology, Endocrine Ecophysiology, Ecoimmunology, And Geospatial Ecology, Robin Warne, Glenn Proudfoot, Erica Crespi

Publications

Diverse biomarkers including stable isotope, hormonal, and ecoimmunological assays are powerful tools to assess animal condition. However, an integrative approach is necessary to provide the context essential to understanding how biomarkers reveal animal health in varied ecological conditions. A barrier to such integration is a general lack of awareness of how shared extraction methods from across fields can provide material from the same animal tissues for diverse biomarker assays. In addition, the use of shared methods for extracting differing tissue fractions can also provide biomarkers for how animal health varies across time. Specifically, no study has explicitly illustrated the depth …

Current And Emerging Treatment Options For Anca-Associated Vasculitis: Potential Role Of Belimumab And Other Baff/April Targeting Agents, Aleksander Lenert, Petar Lenert

Internal Medicine Faculty Publications

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) comprises several clinical entities with diverse clinical presentations, outcomes, and nonunifying pathogenesis. AAV has a clear potential for relapses, and shows unpredictable response to treatment. Cyclophosphamide-based therapies have remained the hallmark of induction therapy protocols for more than four decades. Recently, B-cell depleting therapy with the anti-CD20 antibody rituximab has proved beneficial in AAV, leading to Food and Drug Administration approval of rituximab in combination with corticosteroids for the treatment of AAV in adults. Rituximab for ANCA-associated vasculitis and other clinical trials provided clear evidence that rituximab was not inferior to cyclophosphamide for remission …

Finding Our Way Through Phenotypes, Andrew R. Deans, Suzanna E. Lewis, Eva Huala, Salvatore S. Anzaldo, Michael Ashburner, James P. Balhoff, David C. Blackburn, Judith A. Blake, J. Gordon Burleigh, Bruno Chanet, Laurel D. Cooper, Mélanie Courtot, Sándor Csösz, Hong Cui, Wasila Dahdul, Sandip Das, T. Alexander Dececchi, Agnes Dettai, Rui Diogo, Robert E. Druzinsky, Michel Dumontier, Nico M. Franz, Frank Friedrich, George V. Gkoutos, Melissa Haendel, Luke J. Harmon, Terry F Hayamizu, Yongqun He, Heather M. Hines, Nizar Ibrahim, Laura M. Jackson, Pankaj Jaiswal, Christina James-Zorn, Sebastian Köhler, Guillaume Lecointre, Hilmar Lapp, Carolyn J. Lawrence, Nicolas Le Novère, John G. Lundberg, James Macklin, Austin R. Mast, Peter E. Midford, István Mikó, Christopher J. Mungall, Anika Oellrich, David Osumi-Sutherland, Helen Parkinson, Martín J. Ramírez, Stefan Richter, Peter N. Robinson, Alan Ruttenberg, Katja S. Schulz, Erik Segerdell, Katja C. Seltmann, Michael Sharkey, Aaron D. Smith, Barry Smith, Chelsea D. Specht, R. Burke Squires, Robert W. Thacker, Anne Thessen, Jose Fernandez-Triana, Mauno Vihinen, Peter D. Vize, Lars Vogt, Christine E. Wall, Ramona L. Walls, Monte Westerfeld, Robert A. Wharton, Christian S. Wirkner, James B. Woolley, Matthew J. Yoder, Aaron M. Zorn, Paula Mabee

Entomology Faculty Publications

Despite a large and multifaceted effort to understand the vast landscape of phenotypic data, their current form inhibits productive data analysis. The lack of a community-wide, consensus-based, human- and machine-interpretable language for describing phenotypes and their genomic and environmental contexts is perhaps the most pressing scientific bottleneck to integration across many key fields in biology, including genomics, systems biology, development, medicine, evolution, ecology, and systematics. Here we survey the current phenomics landscape, including data resources and handling, and the progress that has been made to accurately capture relevant data descriptions for phenotypes. We present an example of the kind of …

Alternative Splicing Of Mef2c Pre-Mrna Controls Its Activity In Normal Myogenesis And Promotes Tumorigenicity In Rhabdomyosarcoma Cells., Meiling Zhang, Bo Zhu, Judith Davie

Articles

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Many cellular disruptions contribute to the progression of this pediatric cancer, including aberrant alternative splicing. The MEF2 family of transcription factors regulates many developmental programs, including myogenesis. MEF2 gene transcripts are subject to alternate splicing to generate protein isoforms with divergent functions. We found that MEF2Cα1 was the ubiquitously expressed isoform that exhibited no myogenic activity and that MEF2Cα2, the muscle-specific MEF2C isoform, was required for efficient differentiation. We showed that exon α in MEF2C was aberrantly alternatively spliced in RMS cells, with the ratio of α2/α1 highly down-regulated …

Trail-Based High Throughput Screening Reveals A Link Between Trail-Mediated Apoptosis And Glutathione Reductase, A Key Component Of Oxidative Stress Response., Dmitri Rozanov, Anton Cheltsov, Eduard Sergienko, Stefan Vasile, Vladislav Golubkov, Alexander E Aleshin, Trevor Levin, Elie Traer, Byron Hann, Julia Freimuth, Nikita Alexeev, Max A Alekseyev, Sergey P Budko, Hans Peter Bächinger, Paul Spellman

Computational Biology Institute

A high throughput screen for compounds that induce TRAIL-mediated apoptosis identified ML100 as an active chemical probe, which potentiated TRAIL activity in prostate carcinoma PPC-1 and melanoma MDA-MB-435 cells. Follow-up in silico modeling and profiling in cell-based assays allowed us to identify NSC130362, pharmacophore analog of ML100 that induced 65-95% cytotoxicity in cancer cells and did not affect the viability of human primary hepatocytes. In agreement with the activation of the apoptotic pathway, both ML100 and NSC130362 synergistically with TRAIL induced caspase-3/7 activity in MDA-MB-435 cells. Subsequent affinity chromatography and inhibition studies convincingly demonstrated that glutathione reductase (GSR), a key …

Bioxpress: An Integrated Rna-Seq-Derived Gene Expression Database For Pan-Cancer Analysis., Quan Wan, Hayley Dingerdissen, Yu Fan, Naila Gulzar, Yang Pan, Tsung-Jung Wu, Cheng Yan, Haichen Zhang, Raja Mazumder

Biochemistry and Molecular Medicine Faculty Publications

BioXpress is a gene expression and cancer association database in which the expression levels are mapped to genes using RNA-seq data obtained from The Cancer Genome Atlas, International Cancer Genome Consortium, Expression Atlas and publications. The BioXpress database includes expression data from 64 cancer types, 6361 patients and 17 469 genes with 9513 of the genes displaying differential expression between tumor and normal samples. In addition to data directly retrieved from RNA-seq data repositories, manual biocuration of publications supplements the available cancer association annotations in the database. All cancer types are mapped to Disease Ontology terms to facilitate a uniform …

Atrial Fibrillation: Biophysics, Molecular Mechanisms, And Novel Therapies., Alexey V. Glukhov, Leonid V. Rosenshtraukh, Anamika Bhargava, Michele Miragoli, Bas J. D. Boukens

Anatomy and Regenerative Biology Faculty Publications

No abstract provided.

Intracellular Cd24 Disrupts The Arf-Npm Interaction And Enables Mutational And Viral Oncogene-Mediated P53 Inactivation., Lizhong Wang, Runhua Liu, Peiying Ye, Chunshu Wong, Guo-Yun Chen, Penghui Zhou, +11 Additional Authors

Pediatrics Faculty Publications

CD24 is overexpressed in nearly 70% human cancers, whereas TP53 is the most frequently mutated tumour-suppressor gene that functions in a context-dependent manner. Here we show that both targeted mutation and short hairpin RNA (shRNA) silencing of CD24 retard the growth, progression and metastasis of prostate cancer. CD24 competitively inhibits ARF binding to NPM, resulting in decreased ARF, increase MDM2 and decrease levels of p53 and the p53 target p21/CDKN1A. CD24 silencing prevents functional inactivation of p53 by both somatic mutation and viral oncogenes, including the SV40 large T antigen and human papilloma virus 16 E6-antigen. In support of the …

Mllt1 Yeats Domain Mutations In Clinically Distinctive Favourable Histology Wilms Tumours., Elizabeth J Perlman, Samantha Gadd, Stefan T Arold, Anand Radhakrishnan, Daniela S Gerhard, Jeffrey S. Dome, +19 Additional Authors

Pediatrics Faculty Publications

Wilms tumour is an embryonal tumour of childhood that closely resembles the developing kidney. Genomic changes responsible for the development of the majority of Wilms tumours remain largely unknown. Here we identify recurrent mutations within Wilms tumours that involve the highly conserved YEATS domain of MLLT1 (ENL), a gene known to be involved in transcriptional elongation during early development. The mutant MLLT1 protein shows altered binding to acetylated histone tails. Moreover, MLLT1-mutant tumours show an increase in MYC gene expression and HOX dysregulation. Patients with MLLT1-mutant tumours present at a younger age and have a high prevalence of precursor intralobar …