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Advances In The Creation And Use Of Genetically Modified Rodent Models, Laura Lambert

All ETDs from UAB

Rodents have been the model of choice for decades in biomedical research due to their relatively high physiological similarity to humans and amenability to genomic modification. While transgenic constructs were first used in mouse blastocysts in 1974 and the first mouse embryonic stem (ES) cell line created in 1981, the lack of reliable methods to produce ES cells or culture embryos from the rat led to the limitation of its use in spite of several advantages such as larger size and higher genetic homology with humans. Use of genetic modification has recently expanded due to the advent of tailored nucleases …

Aav-Mediated Expression Of Anti-Tau Scfvs Decreases Tau Accumulation In A Mouse Model Of Tauopathy, Christina Ising, Gilbert Gallardo, Cheryl E.G. Leyns, Connie H. Wong, Hong Jiang, Floy Stewart, Lauren J. Koscal, Joseph Roh, Grace O. Robinson, Javier Remolina Serrano, David M. Holtzman

Open Access Publications

Tauopathies are characterized by the progressive accumulation of hyperphosphorylated, aggregated forms of tau. Our laboratory has previously demonstrated that passive immunization with an anti-tau antibody, HJ8.5, decreased accumulation of pathological tau in a human P301S tau-expressing transgenic (P301S-tg) mouse model of frontotemporal dementia/tauopathy. To investigate whether the F

Analyzing And Modeling The Dysfunction Of Inhibitory Neurons In Alzheimer’S Disease, Carlos Perez, Jokubas Ziburkus, Ghamim Ullah

Physics Faculty Publications

Alzheimer’s disease (AD) is characterized by the abnormal proteolytic processing of amyloid precursor protein, resulting in increased production of a self-aggregating form of beta amyloid (Aβ). Several lines of work on AD patients and transgenic mice with high Aβ levels exhibit altered rhythmicity, aberrant neuronal network activity and hyperexcitability reflected in clusters of hyperactive neurons, and spontaneous epileptic activity. Recent studies highlight that abnormal accumulation of Aβ changes intrinsic properties of inhibitory neurons, which is one of the main reasons underlying the impaired network activity. However, specific cellular mechanisms leading to interneuronal dysfunction are not completely …

Fibroblast Growth Requires Ct10 Regulator Of Kinase (Crk) And Crk-Like (Crkl)., Taeju Park, Mateusz Koptyra, Tom Curran

Manuscripts, Articles, Book Chapters and Other Papers

CT10 regulator of kinase (Crk) and Crk-like (CrkL) are the cellular counterparts of the viral oncogene v-Crk Elevated levels of Crk and CrkL have been observed in many human cancers; inhibition of Crk and CrkL expression reduced the tumor-forming potential of cancer cell lines. Despite a close relationship between the Crk family proteins and tumorigenesis, how Crk and CrkL contribute to cell growth is unclear. We ablated endogenous Crk and CrkL from cultured fibroblasts carrying floxed alleles of Crk and CrkL by transfection with synthetic Cre mRNA (synCre). Loss of Crk and CrkL induced by synCre transfection blocked cell proliferation …

Selective Suppression Of The Α Isoform Of P38 Mapk Rescues Late-Stage Tau Pathology, Nicole Maphis, Shanya Jiang, Guixiang Xu, Olga N. Kokiko-Cochran, Saktimayee M. Roy, Linda J. Van Eldik, D. Martin Watterson, Bruce T. Lamb, Kiran Bhaskar

Sanders-Brown Center on Aging Faculty Publications

Background: Hyperphosphorylation and aggregation of tau protein are the pathological hallmarks of Alzheimer’s disease and related tauopathies. We previously demonstrated that the microglial activation induces tau hyperphosphorylation and cognitive impairment via activation of p38 mitogen-activated protein kinase (p38 MAPK) in the hTau mouse model of tauopathy that was deficient for microglial fractalkine receptor CX3CR1.

Method: We report an isoform-selective, brain-permeable, and orally bioavailable small molecule inhibitor of p38α MAPK (MW181) and its effects on tau phosphorylation in vitro and in hTau mice.

Results: First, pretreatment of mouse primary cortical neurons with MW181 completely blocked inflammation-induced p38α MAPK activation and AT8 …

Recombinant Listeria Adhesion Protein Expressing Probiotics Protect Against Listeria Monocytogenes Infection In Animal Models, Valerie E. Ryan

Open Access Theses

Listeria monocytogenes (Lm) is a foodborne pathogen, found ubiquitously in nature, and has a high morbidity rate among immunocompromised individuals, the elderly, and especially pregnant women and their fetuses resulting in abortion, stillbirth, and neonatal infection. There are currently no preventative medical interventions against Lm infection. The Listeria adhesion protein (LAP) is present in both pathogenic and non-pathogenic Listeria (i.e., L. innocua) and has shown to interact with host epithelial proteins causing tight junction dysregulation aiding in pathogen attachment and paracellular translocation across the host intestinal epithelium. Our lab has demonstrated that recombinant probiotics, Lactobacillus casei (LbcWT) expressing LAP …

Nicotinamide Adenine Dinucleotide Phosphate Oxidase 2 Regulates Lps-Induced Inflammation And Alveolar Remodeling In The Developing Lung., Heather Menden, Sheng Xia, Sherry M. Mabry, Angels Navarro, Michael F. Nyp, Venkatesh Sampath

Manuscripts, Articles, Book Chapters and Other Papers

In premature infants, sepsis is associated with alveolar simplification manifesting as bronchopulmonary dysplasia. The redox-dependent mechanisms underlying sepsis-induced inflammation and alveolar remodeling in the immature lung remain unclear. We developed a neonatal mouse model of sepsis-induced lung injury to investigate whether nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) regulates Toll-like receptor (TLR)-mediated inflammation and alveolar remodeling. Six-day-old NOX2

Development Of Activity In The Mouse Visual Cortex., Jing Shen, Matthew T Colonnese

Pharmacology and Physiology Faculty Publications

No abstract provided.

Effect Of The Butyrate Prodrug Pivaloyloxymethyl Butyrate (An9) On A Mouse Model For Spinal Muscular Atrophy., Jonathan D. Edwards, Matthew E.R. Butchbach

Department of Pediatrics Faculty Papers

Spinal muscular atrophy (SMA) is an early-onset motor neuron disease that leads to loss of muscle function. Butyrate (BA)-based compounds markedly improve the survival and motor phenotype of SMA mice. In this study, we examine the protective effects of the BA prodrug pivaloyloxymethyl butyrate (AN9) on the survival of SMNΔ7 SMA mice. Oral administration of AN9 beginning at PND04 almost doubled the average lifespan of SMNΔ7 SMA mice. AN9 treatment also increased the growth rate of SMNΔ7 SMA mice when compared to vehicle-treated SMNΔ7 SMA mice. In conclusion, BA prodrugs like AN9 have ameliorative effects on SMNΔ7 SMA mice.

Respective Contributions Of Single And Compound Granule Fusion To Secretion By Activated Platelets, Anita Eckly, Jean-Yves Rinckel, Fabienne Proamer, Neslihan Ulas, Smita Joshi, Sidney W. Whiteheart, Christian Gachet

Molecular and Cellular Biochemistry Faculty Publications

Although granule secretion is pivotal in many platelet responses, the fusion routes of α and δ granule release remain uncertain. We used a 3D reconstruction approach based on electron microscopy to visualize the spatial organization of granules in unstimulated and activated platelets. Two modes of exocytosis were identified: a single mode that leads to release of the contents of individual granules and a compound mode that leads to the formation of granule-to-granule fusion, resulting in the formation of large multigranular compartments. Both modes occur during the course of platelet secretion. Single fusion events are more visible at lower levels of …

V-Src Oncogene Induces Trop2 Proteolytic Activation Via Cyclin D1., Xiaoming Ju, Xuanmao Jiao, Adam Ertel, Mathew C. Casimiro, Gabriele Disante, Shengqiong Deng, Zhiping Li, Agnese Di Rocco, Tingting Zhan, Adam Hawkins, Tanya Stoyanova, Sebastiano Andò, Alessandro Fatatis, Michael P. Lisanti, Leonard G. Gomella, Lucia R. Languino, Richard G. Pestell

Department of Cancer Biology Faculty Papers

Proteomic analysis of castration-resistant prostate cancer demonstrated the enrichment of Src tyrosine kinase activity in approximately 90% of patients. Src is known to induce cyclin D1, and a cyclin D1-regulated gene expression module predicts poor outcome in human prostate cancer. The tumor-associated calcium signal transducer 2 (TACSTD2/Trop2/M1S1) is enriched in the prostate, promoting prostate stem cell self-renewal upon proteolytic activation via a γ-secretase cleavage complex (PS1, PS2) and TACE (ADAM17), which releases the Trop2 intracellular domain (Trop2 ICD). Herein, v-Src transformation of primary murine prostate epithelial cells increased the proportion of prostate cancer stem cells as characterized by gene expression, …

Quantitative Proteomic Profiling Reveals Hepatic Lipogenesis And Liver X Receptor Activation In The Pander Transgenic Model., Mark G. Athanason, Whitney A. Ratliff, Dale Chaput, Catherine B. Marelia, Melanie N. Kuehl, Stanley M. Stevens Jr., Brant R. Burkhardt

Molecular Biosciences Faculty Publications

PANcreatic-DERived factor (PANDER) is a member of a superfamily of FAM3 proteins modulating glycemic levels by metabolic regulation of the liver and pancreas. The precise PANDER-induced hepatic signaling mechanism is still being elucidated and has been very complex due to the pleiotropic nature of this novel hormone. Our PANDER transgenic (PANTG) mouse displays a selective hepatic insulin resistant (SHIR) phenotype whereby insulin signaling is blunted yet lipogenesis is increased, a phenomena observed in type 2 diabetes. To examine the complex PANDER-induced mechanism of SHIR, we utilized quantitative mass spectrometry-based proteomic analysis using Stable Isotope Labeling by Amino Acids in Cell …

The Somewhat True Adventures Of Sammy Shine, Tessa Mcmillan

Children's Book and Media Review

Jimmy has built a flight-ready, small aircraft, and he’s itching for a test pilot. So, he steals Hanks’ pet mouse, Sammy Shine. But the launch goes awry when Jimmy accidentally destroys the plane’s remote. Sammy takes over the controls, but he eventually crashes inside the wild Great Woods. Once there, Sammy meets a mouse clan and their friendly leader, Osmund. Osmund believes Sammy is magical because of his airplane, but warns that Mustela, the evil weasel, will want it to take over the woods. When Sammy’s aircraft disappears and Mustela isn’t to blame, Sammy searches for Goggles, an old and …

One-Dog Sleigh, Aylea Stephens

Children's Book and Media Review

When her dog wants to play, she decides to let him come along in an adventure in a one-dog sleigh. As they start off on their journey, a squirrel wants to join and jumps into the sleigh. Soon they are also joined by Owl, Lynx, Deer, Bear, Mouse, and Moose in the sleigh to form a one-pony, one-mouse, one-bear, one-deer, one-lynx, one-owl, one-squirrel, one-dog sleigh. Their new friends help the girl and her dog get home before a blizzard.

Plant Expression Of Cocaine Hydrolase-Fc Fusion Protein For Treatment Of Cocaine Abuse, Guojun Wang, Ting Zhang, Haifeng Huang, Shurong Hou, Xiabin Chen, Fang Zheng, Chang-Guo Zhan

Molecular Modeling and Biopharmaceutical Center Faculty Publications

BACKGROUND: A recently reported cocaine hydrolase (CocH3) fused with fragment crystallizable (Fc) region of human immunoglobulin G1, denoted as CocH3-Fc, is known as a promising therapeutic candidate for the treatment of cocaine overdose and addiction. A challenge for practical therapeutic use of this enzyme exists in the large-scale protein production and, therefore, it is interesting to identify a low-cost and feasible, sustainable source of CocH3-Fc production.

RESULTS: CocH3-Fc was transiently expressed in plant Nicotiana benthamiana leaves. The plant-expressed protein, denoted as pCocH3-Fc, was as active as that expressed in mammalian cells both in vitro and in vivo. However, compared to …

Pleckstrin Homology (Ph) Domain Leucine-Rich Repeat Protein Phosphatase Controls Cell Polarity By Negatively Regulating The Activity Of Atypical Protein Kinase C, Xiaopeng Xiong, Xin Li, Yang-An Wen, Tianyan Gao

Markey Cancer Center Faculty Publications

The proper establishment of epithelial polarity allows cells to sense and respond to signals that arise from the microenvironment in a spatiotemporally controlled manner. Atypical PKCs (aPKCs) are implicated as key regulators of epithelial polarity. However, the molecular mechanism underlying the negative regulation of aPKCs remains largely unknown. In this study, we demonstrated that PH domain leucine-rich repeat protein phosphatase (PHLPP), a novel family of Ser/Thr protein phosphatases, plays an important role in regulating epithelial polarity by controlling the phosphorylation of both aPKC isoforms. Altered expression of PHLPP1 or PHLPP2 disrupted polarization of Caco2 cells grown in 3D cell cultures …

Whose Shoe?, Sydnee Burr

Children's Book and Media Review

When a helpful mouse finds a lost shoe, he desperately tries to locate its owner. Walking all over the wild neighborhood, Mouse asks his neighbors if the precarious shoe belongs to them. The various animals give their reasons why that big blue shoe could not possibly be theirs, and the mouse continues onward until the owner is found.

Sphingosine 1-Phosphate Activation Of Egfr As A Novel Target For Meningitic Escherichia Coli Penetration Of The Blood-Brain Barrier, Xiangru Wang, Ravi Maruvada, Andrew J. Morris, Jun O. Liu, Michael J. Wolfgang, Dong Jae Baek, Robert Bittman, Kwang Sik Kim

Internal Medicine Faculty Publications

Central nervous system (CNS) infection continues to be an important cause of mortality and morbidity, necessitating new approaches for investigating its pathogenesis, prevention and therapy. Escherichia coli is the most common Gram-negative bacillary organism causing meningitis, which develops following penetration of the blood–brain barrier (BBB). By chemical library screening, we identified epidermal growth factor receptor (EGFR) as a contributor to E. coli invasion of the BBB in vitro. Here, we obtained the direct evidence that CNS-infecting E. coli exploited sphingosine 1-phosphate (S1P) for EGFR activation in penetration of the BBB in vitro and in vivo. We …

Tumor Vessel Normalization After Aerobic Exercise Enhances Chemotherapeutic Efficacy., Keri L Schadler, Nicholas J Thomas, Peter Galie, Dong Ha Bhang, Kerry C Roby, Prince Addai, Jacob E Till, Kathleen Sturgeon, Alexander Zaslavsky, Christopher S Chen, Sandra Ryeom

Henry M. Rowan College of Engineering Departmental Research

Targeted therapies aimed at tumor vasculature are utilized in combination with chemotherapy to improve drug delivery and efficacy after tumor vascular normalization. Tumor vessels are highly disorganized with disrupted blood flow impeding drug delivery to cancer cells. Although pharmacologic anti-angiogenic therapy can remodel and normalize tumor vessels, there is a limited window of efficacy and these drugs are associated with severe side effects necessitating alternatives for vascular normalization. Recently, moderate aerobic exercise has been shown to induce vascular normalization in mouse models. Here, we provide a mechanistic explanation for the tumor vascular normalization induced by exercise. Shear stress, the mechanical …

Reduced Efficacy Of Anti-AΒ Immunotherapy In A Mouse Model Of Amyloid Deposition And Vascular Cognitive Impairment Comorbidity, Erica M. Weekman, Tiffany L. Sudduth, Carly N. Caverly, Timothy J. Kopper, Oliver W. Phillips, David K. Powell, Donna M. Wilcock

Sanders-Brown Center on Aging Faculty Publications

Vascular cognitive impairment and dementia (VCID) is the second most common form of dementia behind Alzheimer's disease (AD). It is estimated that 40% of AD patients also have some form of VCID. One promising therapeutic for AD is anti-Aβ immunotherapy, which uses antibodies against Aβ to clear it from the brain. While successful in clearing Aβ and improving cognition in mice, anti-Aβ immunotherapy failed to reach primary cognitive outcomes in several different clinical trials. We hypothesized that one potential reason the anti-Aβ immunotherapy clinical trials were unsuccessful was due to this high percentage of VCID …

Stress-Induced Reinstatement Of Nicotine Preference Requires Dynorphin/Kappa Opioid Activity In The Basolateral Amygdala, Stephanie K. Nygard, Nicholas J. Hourguettes, Gabe G. Sobczak, William A. Carlezon, Michael R. Bruchas

Open Access Publications

UNLABELLED: The dynorphin (DYN)/kappa-opioid receptor (KOR) system plays a conserved role in stress-induced reinstatement of drug seeking for prototypical substances of abuse. Due to nicotine's high propensity for stress-induced relapse, we hypothesized that stress would induce reinstatement of nicotine seeking-like behavior in a KOR-dependent manner. Using a conditioned place preference (CPP) reinstatement procedure in mice, we show that both foot-shock stress and the pharmacological stressor yohimbine (2 mg/kg, i.p.) induce reinstatement of nicotine CPP in a norbinaltorphimine (norBNI, a KOR antagonist)-sensitive manner, indicating that KOR activity is necessary for stress-induced nicotine CPP reinstatement. After reinstatement testing, we visualized robust c-fos …

Epithelial Cell Integrin Β1 Is Required For Developmental Angiogenesis In The Pituitary Gland, Kathleen M. Scully, Dorota Skowronska-Krawczyk, Michal Krawczyk, Daria Merkurjev, Havilah Taylor, Antonia Livolsi, Jessica Tollkuhn, Radu V. Stan, Michael G. Rosenfeld

Dartmouth Scholarship

As a key component of the vertebrate neuroendocrine system, the pituitary gland relies on the progressive and coordinated development of distinct hormone-producing cell types and an invading vascular network. The molecular mechanisms that drive formation of the pituitary vasculature, which is necessary for regulated synthesis and secretion of hormones that maintain homeostasis, metabolism, and endocrine function, remain poorly understood. Here, we report that expression of integrin β1 in embryonic pituitary epithelial cells is required for angiogenesis in the developing mouse pituitary gland. Deletion of pituitary epithelial integrin β1 before the onset of angiogenesis resulted in failure of invading endothelial cells …

M-Track: A New Software For Automated Detection Of Grooming Trajectories In Mice, Annalisa Scimemi, Lin Zhang, Kelsey E. Fleming, Sheldon L. Reeves

Biological Sciences Faculty Scholarship

Grooming is a complex and robust innate behavior, commonly performed by most vertebrate species. In mice, grooming consists of a series of stereotyped patterned strokes, performed along the rostro-caudal axis of the body. The frequency and duration of each grooming episode is sensitive to changes in stress levels, social interactions and pharmacological manipulations, and is therefore used in behavioral studies to gain insights into the function of brain regions that control movement execution and anxiety. Traditional approaches to analyze grooming rely on manually scoring the time of onset and duration of each grooming episode, and are often performed on grooming …

Conditional Ablation Of Hdac3 In Islet Beta Cells Results In Glucose Intolerance And Enhanced Susceptibility To Stz-Induced Diabetes, Wen-Bin Chen, Ling Gao, Jie Wang, Yan-Gang Wang, Zheng Dong, Jiajun Zhao, Qing-Sheng Mi, Li Zhou

Dermatology Articles

Histone deacetylases (HDACs) are enzymes that regulate gene expression by modifying chromatin structure through removal of acetyl groups from target histones or non-histone proteins. Previous in vitro studies suggest that HDACs may be novel pharmacological targets in immune-mediated islet β-cell destruction. However, the role of specific HDAC in islet β-cell development and function remain unclear. Here, we generated a conditional islet β-cells specific HDAC3 deletion mouse model to determine the consequences of HDAC3 depletion on islet β-cell differentiation, maintenance and function. Islet morphology, insulin secretion, glucose tolerance, and multiple low-dose streptozotocin (STZ)-induced diabetes incidence were evaluated and compared between HDAC3 …

Chemical Modification Of Extracellular Matrix By Cold Atmospheric Plasma-Generated Reactive Species Affects Chondrogenesis And Bone Formation., Peter Eisenhauer, Natalie Chernets, You Song, Danil Dobrynin, Nancy Pleshko, Marla J Steinbeck, Theresa A. Freeman

Department of Orthopaedic Surgery Faculty Papers

The goal of this study was to investigate whether cold plasma generated by dielectric barrier discharge (DBD) modifies extracellular matrices (ECM) to influence chondrogenesis and endochondral ossification. Replacement of cartilage by bone during endochondral ossification is essential in fetal skeletal development, bone growth and fracture healing. Regulation of this process by the ECM occurs through matrix remodelling, involving a variety of cell attachment molecules and growth factors, which influence cell morphology and protein expression. The commercially available ECM, Matrigel, was treated with microsecond or nanosecond pulsed (μsp or nsp, respectively) DBD frequencies conditions at the equivalent frequencies (1 kHz) or …

Adam17 Substrate Release In Proximal Tubule Drives Kidney Fibrosis, Eirini Kefaloyianni, Muthu Lakshmi Muthu, Jakob Kaeppler, Xiaoming Sun, Venkata Sabbisetti, Athena Chalaris, Stefan Rose-John, Eitan Wong, Irit Sagi, Sushrut S. Waikar, Helmut Rennke, Benjamin D. Humphreys, Joseph V. Bonventre, Andreas Herrlich

Open Access Publications

Kidney fibrosis following kidney injury is an unresolved health problem and causes significant morbidity and mortality worldwide. In a study into its molecular mechanism, we identified essential causative features. Acute or chronic kidney injury causes sustained elevation of a disintegrin and metalloprotease 17 (ADAM17); of its cleavage-activated proligand substrates, in particular of pro-TNFα and the EGFR ligand amphiregulin (pro-AREG); and of the substrates' receptors. As a consequence, EGFR is persistently activated and triggers the synthesis and release of proinflammatory and profibrotic factors, resulting in macrophage/neutrophil ingress and fibrosis. ADAM17 hypomorphic mice, specific ADAM17 inhibitor-treated WT mice, or mice with inducible …

Lipophosphoglycans From Leishmania Amazonensis Strains Display Immunomodulatory Properties Via Tlr4 And Do Not Affect Sand Fly Infection, Paula M. Nogueira, Rafael R. Assis, Ana C. Torrecilhas, Elvira M. Saraiva, Natália L. Pessoa, Marco A. Campos, Eric F. Marialva, Cláudia M. Ríos-Velasquez, Felipe A. Pessoa, Nágila F. Secundino, Jerônimo N. Rugani, Elsa Nieves, Salvatore J. Turco, Maria N. Melo, Rodrigo P. Soares

Molecular and Cellular Biochemistry Faculty Publications

The immunomodulatory properties of lipophosphoglycans (LPG) from New World species of Leishmania have been assessed in Leishmania infantum and Leishmania braziliensis, the causative agents of visceral and cutaneous leishmaniasis, respectively. This glycoconjugate is highly polymorphic among species with variation in sugars that branch off the conserved Gal(β1,4)Man(α1)-PO₄ backbone of repeat units. Here, the immunomodulatory activity of LPGs from Leishmania amazonensis, the causative agent of diffuse cutaneous leishmaniasis, was evaluated in two strains from Brazil. One strain (PH8) was originally isolated from the sand fly and the other (Josefa) was isolated from a human case. The ability of …

Mitochondrial Akt Regulation Of Hypoxic Tumor Reprogramming., Young Chan Chae, Valentina Vaira, M. Cecilia Caino, Hsin-Yao Tang, Jae Ho Seo, Andrew V. Kossenkov, Luisa Ottobrini, Cristina Martelli, Giovanni Lucignani, Irene Bertolini, Marco Locatelli, Kelly G. Bryant, Jagadish C. Ghosh, Sofia Lisanti, Bonsu Ku, Silvano Bosari, Lucia R. Languino, David W. Speicher, Dario C. Altieri

Department of Cancer Biology Faculty Papers

Hypoxia is a universal driver of aggressive tumor behavior, but the underlying mechanisms are not completely understood. Using a phosphoproteomics screen, we now show that active Akt accumulates in the mitochondria during hypoxia and phosphorylates pyruvate dehydrogenase kinase 1 (PDK1) on Thr346 to inactivate the pyruvate dehydrogenase complex. In turn, this pathway switches tumor metabolism toward glycolysis, antagonizes apoptosis and autophagy, dampens oxidative stress, and maintains tumor cell proliferation in the face of severe hypoxia. Mitochondrial Akt-PDK1 signaling correlates with unfavorable prognostic markers and shorter survival in glioma patients and may provide an "actionable" therapeutic target in cancer.

Integrated Molecular Pathway Analysis Informs A Synergistic Combination Therapy Targeting Pten/Pi3k And Egfr Pathways For Basal-Like Breast Cancer, Qing-Bai She, Sofia K. Gruvberger-Saal, Matthew Maurer, Yilun Chen, Mervi Jumppanen, Tao Su, Meaghan Dendy, Ying-Ka Ingar Lau, Lorenzo Memeo, Hugo M. Horlings, Marc J. Van De Vijver, Jorma Isola, Hanina Hibshoosh, Neal Rosen, Ramon Parsons, Lao H. Saal

Markey Cancer Center Faculty Publications

Background: The basal-like breast cancer (BLBC) subtype is characterized by positive staining for basal mammary epithelial cytokeratin markers, lack of hormone receptor and HER2 expression, and poor prognosis with currently no approved molecularly-targeted therapies. The oncogenic signaling pathways driving basal-like tumorigenesis are not fully elucidated.

Methods: One hundred sixteen unselected breast tumors were subjected to integrated analysis of phosphoinositide 3-kinase (PI3K) pathway related molecular aberrations by immunohistochemistry, mutation analysis, and gene expression profiling. Incidence and relationships between molecular biomarkers were characterized. Findings for select biomarkers were validated in an independent series. Synergistic cell killing in vitro and in vivo tumor …

Simultaneous Quantitation Of Oxidized And Reduced Glutathione Via Lc-Ms/Ms: An Insight Into The Redox State Of Hematopoietic Stem Cells, Dustin W. Carroll, Diana Howard, Haining Zhu, Christian M. Paumi, Mary Vore, Subbarao Bondada, Ying Liang, Chi Wang, Daret K. St. Clair

Toxicology and Cancer Biology Faculty Publications

Cellular redox balance plays a significant role in the regulation of hematopoietic stem-progenitor cell (HSC/MPP) self-renewal and differentiation. Unregulated changes in cellular redox homeostasis are associated with the onset of most hematological disorders. However, accurate measurement of the redox state in stem cells is difficult because of the scarcity of HSC/MPPs. Glutathione (GSH) constitutes the most abundant pool of cellular antioxidants. Thus, GSH metabolism may play a critical role in hematological disease onset and progression. A major limitation to studying GSH metabolism in HSC/MPPs has been the inability to measure quantitatively GSH concentrations in small numbers of HSC/MPPs. Current methods …