Medicine and Health Sciences Commons^™

Longitudinal Ultrasound Imaging And Network Modeling In Rats Reveal Sex-Dependent Suppression Of Liver Regeneration After Resection In Alcoholic Liver Disease, Benjamin K. Barnhart, Toshiki Kan, Ankita Srivastava, Corinne E. Wessner, John Waters, Manju Ambelil, John R. Eisenbrey, Jan B. Hoek, Rajanikanth Vadigepalli

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Liver resection is an important surgical technique in the treatment of cancers and transplantation. We used ultrasound imaging to study the dynamics of liver regeneration following two-thirds partial hepatectomy (PHx) in male and female rats fed via Lieber-deCarli liquid diet protocol of ethanol or isocaloric control or chow for 5–7 weeks. Ethanol-fed male rats did not recover liver volume to the pre-surgery levels over the course of 2 weeks after surgery. By contrast, ethanol-fed female rats as well as controls of both sexes showed normal volume recovery. Contrary to expectations, transient increases in both portal and hepatic artery blood flow …

Supporting A Culture Of Patient Safety: Resident-Led Patient Safety Event Reviews In A Pathology Residency Training Program, Catherine Tucker, Rebecca C. Jaffe,, Allison F Goldberg

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Patient safety is a critical component of quality patient care at any healthcare institution. In order to support a culture of patient safety, and in the context of a hospital-wide patient safety initiative at our institution, we have created and implemented a new patient safety curriculum within our training program. The curriculum is embedded in an introductory course for first-year residents, in which residents gain an understanding of the multifaceted role of the pathologist in patient care. The patient safety curriculum is a resident-centered event review process and includes 1) identification and reporting of a patient safety event, 2) event …

Estimated Impact Of Low Isolate Numbers On The Reliability Of Cumulative Antibiogram Data, Christian Tran, John Hargy, Bryan Hess, Matthew Pettengill

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Antibiograms are cumulative reports of antimicrobial susceptibility results that are used to guide the selection of empirical antibiotic therapy. Although Clinical and Laboratory Standards Institute (CLSI) guidelines recommend including only organisms that have at least 30 isolates in an antibiogram, previous studies demonstrated that adherence to this recommendation is highly variable. This paper aims to model the impact of small sample sizes on expected levels of error in cumulative antibiograms by comparing percent susceptibility results for random samples to those of the larger, entire data set. The results demonstrate relatively high error rates when utilizing low numbers of isolates in …

Modeling And Analysis Of The Intrinsic Cardiac Nervous System In Closed-Loop Cardiovascular Control, Michelle M. Gee, Abraham M. Lenhoff, James S. Schwaber, Babatunde A. Ogunnaike, Rajanikanth Vadigepalli

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The baroreceptor reflex is a multi-input, multi-output physiological control system that regulates short-term blood pressure by modulating nerve activity between the brainstem and the heart. The computational model by Park et al. (2020) is the most recent iteration in our exploration of the system. However, the contributions of”the little brain of the heart”, the intrinsic cardiac nervous system (ICN), to local control of the heart and to the integration of sensory information is unknown and has been overlooked in previous models. We have incorporated a high-fidelity representation of the ICN into a model of the baroreceptor reflex based on anatomical, …

Autophagy Requirements For Eye Lens Differentiation And Transparency, Lisa Brennan, M Joseph Costello, J Fielding Hejtmancik, A. Menko, S Amer Riazuddin, Alan Shiels, Marc Kantorow

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Recent evidence points to autophagy as an essential cellular requirement for achieving the mature structure, homeostasis, and transparency of the lens. Collective evidence from multiple laboratories using chick, mouse, primate, and human model systems provides evidence that classic autophagy structures, ranging from double-membrane autophagosomes to single-membrane autolysosomes, are found throughout the lens in both undifferentiated lens epithelial cells and maturing lens fiber cells. Recently, key autophagy signaling pathways have been identified to initiate critical steps in the lens differentiation program, including the elimination of organelles to form the core lens organelle-free zone. Other recent studies using ex vivo lens culture …

Undergraduate Medical Student Perspectives On The Role Of Autopsy In Medical Education, Patrick Hearle, Wing Fei Wong, Joanna Chan

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Medical autopsy has historically been considered a valued experience in undergraduate medical education; however, student participation has declined in recent years. Medical education literature from the educator point of view supports autopsy as an educational tool, but more data are needed on undergraduate medical students' (UMS) perspectives on autopsy. This study aims to assess UMS opinions on the role of autopsy in undergraduate medical education. A 5-point Likert scale survey concerning autopsy and medical education was offered to all UMS at Sidney Kimmel Medical College. In addition, 28 senior students were assigned a 500 word essay on hospital autopsy and …

Exploring The Past, Present, And Future Of Anti-Angiogenic Therapy In Glioblastoma., Ashley B. Zhang, Khashayar Mozaffari, Brian Aguirre, Victor Li, Rohan Kubba, Nilay C Desai, Darren Wei, Isaac Yang, Madhuri Wadehra

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Glioblastoma, a WHO grade IV astrocytoma, constitutes approximately half of malignant tumors of the central nervous system. Despite technological advancements and aggressive multimodal treatment, prognosis remains dismal. The highly vascularized nature of glioblastoma enables the tumor cells to grow and invade the surrounding tissue, and vascular endothelial growth factor-A (VEGF-A) is a critical mediator of this process. Therefore, over the past decade, angiogenesis, and more specifically, the VEGF signaling pathway, has emerged as a therapeutic target for glioblastoma therapy. This led to the FDA approval of bevacizumab, a monoclonal antibody designed against VEGF-A, for treatment of recurrent glioblastoma. Despite the …

Closed-Loop Modeling Of Central And Intrinsic Cardiac Nervous System Circuits Underlying Cardiovascular Control, Michelle M. Gee, Abraham M. Lenhoff, James S. Schwaber, Babatunde A. Ogunnaike, Rajanikanth Vadigepalli

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The baroreflex is a multi-input, multi-output physiological control system that regulates blood pressure by modulating nerve activity between the brainstem and the heart. Existing computational models of the baroreflex do not explicitly incorporate the intrinsic cardiac nervous system (ICN), which mediates central control of heart function. We developed a computational model of closed-loop cardiovascular control by integrating a network representation of the ICN within central control reflex circuits. We examined central and local contributions to the control of heart rate, ventricular functions, and respiratory sinus arrhythmia (RSA). Our simulations match the experimentally observed relationship between RSA and lung tidal volume. …

Complexity Of Progranulin Mechanisms Of Action In Mesothelioma, Elisa Ventura, Christopher Xie, Simone Buraschi, Antonino Belfiore, Renato V. Iozzo, Antonio Giordano, Andrea Morrione

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Background: Mesothelioma is an aggressive disease with limited therapeutic options. The growth factor progranulin plays a critical role in several cancer models, where it regulates tumor initiation and progression. Recent data from our laboratories have demonstrated that progranulin and its receptor, EphA2, constitute an oncogenic pathway in bladder cancer by promoting motility, invasion and in vivo tumor formation. Progranulin and EphA2 are expressed in mesothelioma cells but their mechanisms of action are not well defined. In addition, there are no data establishing whether the progranulin/EphA2 axis is tumorigenic for mesothelioma cells.

Methods: The expression of progranulin in various mesothelioma cell …

Data Supporting The Roles Of Bap1, Sting, And Ifn-Β In Isgf3 Activation In Ccrcc, Lauren E Langbein, Eleonora Sementino, Zhijiu Zhong, Wei Jiang, Li Li, Joseph R Testa, Haifeng Yang

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The data presented in this article are companion materials to our manuscript titled "BAP1 maintains HIF-dependent interferon beta induction to suppress tumor growth in clear cell renal cell carcinoma" (Langbein et al., 2022), where we investigated the downstream effects of BAP1 (BRCA1-associated protein 1) expression in clear cell renal cell carcinoma (ccRCC) cell lines and mouse xenograft models. In the manuscript, we showed that BAP1 upregulates STING (stimulator of interferon genes) expression and activity in ccRCC cells, leading to IFN-β transcription and activation of interferon stimulated gene factor 3 (ISGF3), the transcription factor that mediates the effects of type I …

Altered Expression Of Glycobiology-Related Genes In Parkinson’S Disease Brain, Jay S Schneider, Garima Singh

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The precise mechanisms initiating and perpetuating the cellular degeneration in Parkinson's disease (PD) remain unclear. There is decreased expression of the main brain gangliosides, and GM1 ganglioside in particular, in the PD brain along with decreased expression of the genes coding for the glycosyltranferase and the sialyltransferase responsible for the synthesis of these brain gangliosides. However, potentially important pathogenic mechanisms contributing to the neurodegeneration in PD may also include altered levels of expression of genes involved in glycosylation, sialylation and sphingolipid synthesis and metabolism. Although various studies have described pathological lipid and glycolipid changes in PD brain, there have been …

Genome-Scale Metabolic Modeling Reveals Sequential Dysregulation Of Glutathione Metabolism In Livers From Patients With Alcoholic Hepatitis, Alexandra Manchel, Radhakrishnan Mahadevan, Ramon Bataller, Jan B. Hoek, Rajanikanth Vadigepalli

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Alcoholic hepatitis (AH) is the most severe form of alcoholic liver disease for which there is no efficacious treatment aiding most patients. AH manifests differently in individuals, with some patients showing debilitating symptoms more so than others. Previous studies showed significant metabolic dysregulation associated with AH. Therefore, we sought to analyze how the activity of metabolic pathways differed in the liver of patients with varying degrees of AH severity. We utilized a genome-scale metabolic modeling approach that allowed for integration of a generic human cellular metabolic model with specific RNA-seq data corresponding to healthy and multiple liver disease states to …

Human Dectin-1 Deficiency Impairs Macrophage-Mediated Defense Against Phaeohyphomycosis, Rebecca A. Drummond, Jigar V. Desai, Amy P. Hsu, Vasileios Oikonomou, Donald C. Vinh, Joshua A. Acklin, Michael S. Abers, Magdalena A. Walkiewicz, Sarah L. Anzick, Muthulekha Swamydas, Simon Vautier, Mukil Natarajan, Andrew J. Oler, Daisuke Yamanaka, Katrin D. Mayer-Barber, Yoichiro Iwakura, David Bianchi, Brian Driscoll, Ken Hauck, Ahnika Kline, Nicholas S.P. Viall, Christa S. Zerbe, Elise M.N. Ferré, Monica M. Schmitt, Tom Dimaggio, Stefania Pittaluga, John A. Butman, Adrian M. Zelazny, Yvonne R. Shea, Cesar A. Arias, Cameron Ashbaugh, Maryam Mahmood, Zelalem Temesgen, Alexander G. Theofiles, Masayuki Nigo, Varsha Moudgal, Karen C. Bloch, Sean G. Kelly, M. Suzanne Whitworth, Ganesh Rao, Cindy J. Whitener, Neema Mafi, Juan Gea-Banacloche, Lawrence C. Kenyon, William R. Miller, Katia Boggian, Andrea Gilbert, Matthew Sincock, Alexandra F. Freeman, John E. Bennett, Rodrigo Hasbun, Constantinos M. Mikelis, Kyung J. Kwon-Chung, Yasmine Belkaid, Gordon D. Brown, Jean K. Lim, Douglas B. Kuhns, Steven M. Holland, Michail S. Lionakis

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Subcutaneous phaeohyphomycosis typically affects immunocompetent individuals following traumatic inoculation. Severe or disseminated infection can occur in CARD9 deficiency or after transplantation, but the mechanisms protecting against phaeohyphomycosis remain unclear. We evaluated a patient with progressive, refractory Corynespora cassiicola phaeohyphomycosis and found that he carried biallelic deleterious mutations in CLEC7A encoding the CARD9-coupled, β-glucan-binding receptor, Dectin-1. The patient's PBMCs failed to produce TNF-α and IL-1β in response to β-glucan and/or C. cassiicola. To confirm the cellular and molecular requirements for immunity against C. cassiicola, we developed a mouse model of this infection. Mouse macrophages required Dectin-1 and CARD9 for IL-1β and …

Capture At The Er-Mitochondrial Contacts Licenses Ip, Máté Katona, Ádám Bartók, Zuzana Nichtova, György Csordás, Elena Berezhnaya, David Weaver, Arijita Ghosh, Péter Várnai, David I. Yule, György Hajnóczky

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Endoplasmic reticulum-mitochondria contacts (ERMCs) are restructured in response to changes in cell state. While this restructuring has been implicated as a cause or consequence of pathology in numerous systems, the underlying molecular dynamics are poorly understood. Here, we show means to visualize the capture of motile IP3 receptors (IP3Rs) at ERMCs and document the immediate consequences for calcium signaling and metabolism. IP3Rs are of particular interest because their presence provides a scaffold for ERMCs that mediate local calcium signaling, and their function outside of ERMCs depends on their motility. Unexpectedly, in a cell model with little ERMC Ca2+ coupling, IP3Rs …

Pi3k Isoform-Specific Regulation Of Leader And Follower Cell Function For Collective Migration And Proliferation In Response To Injury, Morgan D Basta, A. Menko, Janice L Walker

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

To ensure proper wound healing it is important to elucidate the signaling cues that coordinate leader and follower cell behavior to promote collective migration and proliferation for wound healing in response to injury. Using an ex vivo post-cataract surgery wound healing model we investigated the role of class I phosphatidylinositol-3-kinase (PI3K) isoforms in this process. Our findings revealed a specific role for p110α signaling independent of Akt for promoting the collective migration and proliferation of the epithelium for wound closure. In addition, we found an important role for p110α signaling in orchestrating proper polarized cytoskeletal organization within both leader and …

Bap1 Maintains Hif-Dependent Interferon Beta Induction To Suppress Tumor Growth In Clear Cell Renal Cell Carcinoma., Lauren Langbein, Rayan El Hajjar, Shen He, Eleonora Sementino, Zhijiu Zhong, Wei Jiang, Benjamin E Leiby, Li Li, Robert G Uzzo, Joseph R Testa, Haifeng Yang

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

BRCA1-associated protein 1 (BAP1) is a deubiquitinase that is mutated in 10-15% of clear cell renal cell carcinomas (ccRCC). Despite the association between BAP1 loss and poor clinical outcome, the critical tumor suppressor function(s) of BAP1 in ccRCC remains unclear. Previously, we found that hypoxia-inducible factor 2α (HIF2α) and BAP1 activate interferon-stimulated gene factor 3 (ISGF3), a transcription factor activated by type I interferons and a tumor suppressor in ccRCC xenograft models. Here, we aimed to determine the mechanism(s) through which HIF and BAP1 regulate ISGF3. We found that in ccRCC cells, loss of the von Hippel-Lindau tumor suppressor (VHL) …

Germline Polymorphisms In Mgmt Associated With Temozolomide-Related Myelotoxicity Risk In Patients With Glioblastoma Treated On Nrg Oncology/Rtog 0825, Michael E Scheurer, Renke Zhou, Mark R Gilbert, Melissa L Bondy, Erik P Sulman, Ying Yuan, Yanhong Liu, Elizabeth Vera, Merideth M Wendland, Emad F Youssef, Volker W Stieber, Ritsuko R Komaki, John C Flickinger, Lawrence C. Kenyon, H Ian Robins, Grant K Hunter, Ian R Crocker, Samuel T Chao, Stephanie L Pugh, Terri S Armstrong

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Background: We sought to identify clinical and genetic predictors of temozolomide-related myelotoxicity among patients receiving therapy for glioblastoma.

Methods: Patients (n = 591) receiving therapy on NRG Oncology/RTOG 0825 were included in the analysis. Cases were patients with severe myelotoxicity (grade 3 and higher leukopenia, neutropenia, and/or thrombocytopenia); controls were patients without such toxicity. A risk-prediction model was built and cross-validated by logistic regression using only clinical variables and extended using polymorphisms associated with myelotoxicity.

Results: 23% of patients developed myelotoxicity (n = 134). This toxicity was first reported during the concurrent phase of therapy for 56 patients; …

Patient-Specific Genome-Scale Metabolic Models For Individualized Predictions Of Liver Disease, Alexandra Manchel, Jan B. Hoek, Ramon Bataller, Radhakrishnan Mahadevan, Rajanikanth Vadigepalli

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The prevalence of liver disease is steadily increasing, coupled with the limited availability of therapeutic treatments. Recent literature points to metabolic reprogramming as a key feature of liver failure. Hence, we sought to uncover the metabolic pathways and mechanisms associated with liver disease and acute liver failure. We generated patient-specific genome scale metabolic models by integrating RNA-seq data from patient liver samples with a generalized human metabolic model. Flux balance analysis simulations showed a distinct separation of non-alcohol associated and alcohol-associated disease states. Our analysis suggests that the alcohol associated liver has an increased flux through nucleotide and glycerophospholipid metabolic …

Unreliable Automated Complete Blood Count Results: Causes, Recognition, And Resolution, Gene Gulati, Guldeep Uppal, Jerald Z. Gong

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Automated hematology analyzers generate accurate complete blood counts (CBC) results on nearly all specimens. However, every laboratory encounters, at times, some specimens that yield no or inaccurate result(s) for one or more CBC parameters even when the analyzer is functioning properly and the manufacturer's instructions are followed to the letter. Inaccurate results, which may adversely affect patient care, are clinically unreliable and require the attention of laboratory professionals. Laboratory professionals must recognize unreliable results, determine the possible cause(s), and be acquainted with the ways to obtain reliable results on such specimens. We present a concise overview of the known causes …

The Pro-Fibrotic Response To Lens Injury Is Signaled In A Pi3k Isoform-Specific Manner, A. Sue Menko, Janice L. Walker

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The signaling inputs that function to integrate biochemical and mechanical cues from the extracellular environment to alter the wound-repair outcome to a fibrotic response remain poorly understood. Here, using a clinically relevant post-cataract surgery wound healing/fibrosis model, we investigated the role of Phosphoinositide-3-kinase (PI3K) class I isoforms as potential signaling integrators to promote the proliferation, emergence and persistence of collagen I-producing alpha smooth muscle actin (αSMA+) myofibroblasts that cause organ fibrosis. Using PI3K isoform specific small molecule inhibitors, our studies revealed a requisite role for PI3K p110α in signaling the CD44+ mesenchymal leader cell population that we previously identified as …

Glucose Uptake By Glut1 In Photoreceptors Is Essential For Outer Segment Renewal And Rod Photoreceptor Survival, Lauren L. Daniele, John Y.S. Han, Ivy S Samuels, Ravikiran Komirisetty, Nikhil Mehta, Jessica L Mccord, Minzhong Yu, Yekai Wang, Kathleen Boesze-Battaglia, Brent A Bell, Jianhai Du, Neal S Peachey, Nancy J. Philp

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Photoreceptors consume glucose supplied by the choriocapillaris to support phototransduction and outer segment (OS) renewal. Reduced glucose supply underlies photoreceptor cell death in inherited retinal degeneration and age-related retinal disease. We have previously shown that restricting glucose transport into the outer retina by conditional deletion of Slc2a1 encoding GLUT1 resulted in photoreceptor loss and impaired OS renewal. However, retinal neurons, glia, and the retinal pigment epithelium play specialized, synergistic roles in metabolite supply and exchange, and the cell-specific map of glucose uptake and utilization in the retina is incomplete. In these studies, we conditionally deleted Slc2a1 in a pan-retinal or …

Patient With Multiple Genetically Distinct Thyroid Nodules Including Papillary Thyroid Carcinoma Harboring Novel Ywhag-Braf Fusion, Ruihe Lin, Zi-Xuan Wang, Elizabeth Cottrill, Nitika Badjatia, Stacey Gargano

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Next-generation sequencing (NGS) analysis of thyroid samples aids in risk stratification of cytologically indeterminate nodules and contributes to our understanding of molecular mechanisms in thyroid neoplasia. Several genes, including BRAF, RAS, and EIF1AX, are known to play a role in thyroid tumorigenesis. Here we report a case of papillary thyroid carcinoma (PTC) in which a single lesion harbored a novel YWHAG-BRAF fusion and EIF1AX mutation and displayed mixed morphological findings. The patient is a 74-year-old female with multiple incidentally discovered thyroid nodules, two of which were sampled by ultrasound-guided fine needle aspiration (FNA). Cytologic diagnosis for both nodules was suspicious …

Altered Genome-Wide Hippocampal Gene Expression Profiles Following Early Life Lead Exposure And Their Potential For Reversal By Environmental Enrichment, Garima Singh, V Singh, T Kim, A Ertel, W Fu, J S Schneider

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Early life lead (Pb) exposure is detrimental to neurobehavioral development. The quality of the environment can modify negative influences from Pb exposure, impacting the developmental trajectory following Pb exposure. Little is known about the molecular underpinnings in the brain of the interaction between Pb and the quality of the environment. We examined relationships between early life Pb exposure and living in an enriched versus a non-enriched postnatal environment on genome-wide transcription profiles in hippocampus CA1. RNA-seq identified differences in the transcriptome of enriched vs. non-enriched Pb-exposed animals. Most of the gene expression changes associated with Pb exposure were reversed by …

A Mathematical Model Of Glut1 Modulation In Rods And Rpe And Its Differential Impact In Cell Metabolism, Andrea Aparicio, Erika T Camacho, Nancy J. Philp, Stephen A Wirkus

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

We present a mathematical model of key glucose metabolic pathways in two cells of the human retina: the rods and the retinal pigmented epithelium (RPE). Computational simulations of glucose transporter 1 (GLUT1) inhibition in the model accurately reproduce experimental data from conditional knockout mice and reveal that modification of GLUT1 expression levels of both cells differentially impacts their metabolism. We hypothesize that, under glucose scarcity, the RPE’s energy producing pathways are altered in order to preserve its functionality, impacting the photoreceptors’ outer segment renewal. On the other hand, when glucose is limited in the rods, aerobic glycolysis is preserved, which …

Bacille Calmette-Guérin Vaccine Reprograms Human Neonatal Lipid Metabolism In Vivo And In Vitro, Joann Diray-Arce, Asimenia Angelidou, Kristoffer Jarlov Jensen, Maria Giulia Conti, Rachel S Kelly, Matthew Pettengill, Mark Liu, Simon D Van Haren, Scott D Mcculloch, Greg Michelloti, Olubukola Idoko, Tobias R Kollmann, Beate Kampmann, Hanno Steen, Al Ozonoff, Jessica Lasky-Su, Christine S Benn, Ofer Levy

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Vaccines have generally been developed with limited insight into their molecular impact. While systems vaccinology enables characterization of mechanisms of action, these tools have yet to be applied to infants, who are at high risk of infection and receive the most vaccines. Bacille Calmette-Guérin (BCG) protects infants against disseminated tuberculosis (TB) and TB-unrelated infections via incompletely understood mechanisms. We employ mass-spectrometry-based metabolomics of blood plasma to profile BCG-induced infant responses in Guinea-Bissau in vivo and the US in vitro. BCG-induced lysophosphatidylcholines (LPCs) correlate with both TLR-agonist- and purified protein derivative (PPD, mycobacterial antigen)-induced blood cytokine production in vitro, raising the …

Reduced Er-Mitochondria Connectivity Promotes Neuroblastoma Multidrug Resistance., Jorida Çoku, David M. Booth, Jan Skoda, Madison C Pedrotty, Jennifer Vogel, Kangning Liu, Annette Vu, Erica L Carpenter, Jamie C Ye, Michelle A Chen, Peter Dunbar, Elizabeth Scadden, Taekyung D Yun, Eiko Nakamaru-Ogiso, Estela Area-Gomez, Yimei Li, Kelly C Goldsmith, C Patrick Reynolds, György Hajnóczky, Michael D Hogarty

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Most cancer deaths result from progression of therapy resistant disease, yet our understanding of this phenotype is limited. Cancer therapies generate stress signals that act upon mitochondria to initiate apoptosis. Mitochondria isolated from neuroblastoma cells were exposed to tBid or Bim, death effectors activated by therapeutic stress. Multidrug-resistant tumor cells obtained from children at relapse had markedly attenuated Bak and Bax oligomerization and cytochrome c release (surrogates for apoptotic commitment) in comparison with patient-matched tumor cells obtained at diagnosis. Electron microscopy identified reduced ER-mitochondria-associated membranes (MAMs; ER-mitochondria contacts, ERMCs) in therapy-resistant cells, and genetically or biochemically reducing MAMs in therapy-sensitive …

Gm1 Ganglioside Modifies Microglial And Neuroinflammatory Responses To Α-Synuclein In The Rat Aav-A53t Α-Synuclein Model Of Parkinson's Disease, Jay S Schneider, Garima Singh, Courtney K. Williams, Vikrant Singh

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Among the pathological events associated with the dopaminergic neurodegeneration characteristic of Parkinson's disease (PD) are the accumulation of toxic forms of α-synuclein and microglial activation associated with neuroinflammation. Although numerous other processes may participate in the pathogenesis of PD, the two factors mentioned above may play critical roles in the initiation and progression of dopamine neuron degeneration in PD. In this study, we employed a slowly progressing model of PD using adeno-associated virus-mediated expression of human A53T α-synuclein into the substantia nigra on one side of the brain and examined the microglial response in the striatum on the injected side …

Patterns Of Crystallin Gene Expression In Differentiation State Specific Regions Of The Embryonic Chicken Lens, Zhiwei Ma, Daniel Chauss, Joshua Disatham, Xiaodong Jiao, Lisa Ann Brennan, A Sue Menko, Marc Kantorow, J Fielding Hejtmancik

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Purpose: Transition from lens epithelial cells to lens fiber cell is accompanied by numerous changes in gene expression critical for lens transparency. We identify expression patterns of highly prevalent genes including ubiquitous and enzyme crystallins in the embryonic day 13 chicken lens.

Methods: Embryonic day 13 chicken lenses were dissected into central epithelial cell (EC), equatorial epithelial cell (EQ), cortical fiber cell (FP), and nuclear fiber cell (FC) compartments. Total RNA was prepared, subjected to high-throughput unidirectional mRNA sequencing, analyzed, mapped to the chicken genome, and functionally grouped.

Results: A total of 77,097 gene-specific transcripts covering 17,450 genes were expressed, …

The Pro-Fibrotic Response Of Mesenchymal Leader Cells To Lens Wounding Involves Hyaluronic Acid, Its Receptor Rhamm, And Vimentin, A. Sue Menko, Alison Romisher, Janice L Walker

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Hyaluronic Acid/Hyaluronan (HA) is a major component of the provisional matrix deposited by cells post-wounding with roles both in regulating cell migration to repair a wound and in promoting a fibrotic outcome to wounding. Both are mediated through its receptors CD44 and RHAMM. We now showed that HA is present in the provisional matrix assembled on the substrate surface in a lens post-cataract surgery explant wound model in which mesenchymal leader cells populate the wound edges to direct migration of the lens epithelium across the adjacent culture substrate onto which this matrix is assembled. Inhibiting HA expression with 4-MU blocked …

68-Year Old Man With Progressive Weakness And Ventilator Dependent Respiratory Failure: A Case Report Of Sporadic Late Onset Nemaline Myopathy, P. Kirupaharan, Daniel Kramer, Alan Gandler, Lawrence C. Kenyon, Ross Summer

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Background: Neuromuscular pathologies must be considered when caring for patients with persistent or progressive respiratory failure. Pertinent disease states may involve skeletal muscles of respiration or associated neurologic structures including motor neurons, peripheral neurons and the neuromuscular junction. Diagnosis may require pulmonary function testing, neurophysiologic studies, imaging, and/or muscle biopsy.

Case presentation: A 68-year-old male was transferred to our intensive care unit (ICU) for management of ventilator dependent respiratory failure. Upon further historical review, he described gradually worsening gait instability and muscle weakness, which was previously attributed to vascular Parkinsonism in the setting of known cerebrovascular disease. Upon arrival to …