Medicine and Health Sciences Commons^™

Genetic Drivers Of Kidney Defects In The Digeorge Syndrome., Esther Lopez-Rivera, Yangfan P. Liu, Miguel Verbitsky, Blair R. Anderson, Valentina P. Capone, Edgar A. Otto, Zhonghai Yan, Adele Mitrotti, Jeremiah Martino, Nicholas J. Steers, David A. Fasel, Katarina Vukojevic, Rong Deng, Silvia E. Racedo, Qingxue Liu, Max Werth, Rik Westland, Asaf Vivante, Gabriel S. Makar, Monica Bodria, Matthew G. Sampson, Christopher E. Gillies, Virginia Vega-Warner, Mariarosa Maiorana, Donald S. Petrey, Barry Honig, Vladimir J. Lozanovski, Rémi Salomon, Laurence Heidet, Wassila Carpentier, Dominique Gaillard, Alba Carrea, Loreto Gesualdo, Daniele Cusi, Claudia Izzi, Francesco Scolari, Joanna A E Van Wijk, Adela Arapovic, Mirna Saraga-Babic, Marijan Saraga, Nenad Kunac, Ali Samii, Donna M. Mcdonald-Mcginn, Terrence B. Crowley, Elaine H. Zackai, Dorota Drozdz, Monika Miklaszewska, Marcin Tkaczyk, Przemyslaw Sikora, Maria Szczepanska, Malgorzata Mizerska-Wasiak, Grazyna Krzemien, Agnieszka Szmigielska, Marcin Zaniew, John M. Darlow, Prem Puri, David Barton, Emilio Casolari, Susan L. Furth, Bradley A. Warady, Zoran Gucev, Hakon Hakonarson, Hana Flogelova, Velibor Tasic, Anna Latos-Bielenska, Anna Materna-Kiryluk, Landino Allegri, Craig S. Wong, Iain A Drummond, Vivette D'Agati, Akira Imamoto, Jonathan M. Barasch, Friedhelm Hildebrandt, Krzysztof Kiryluk, Richard P. Lifton, Bernice E. Morrow, Cecile Jeanpierre, Virginia E. Papaioannou, Gian Marco Ghiggeri, Ali G. Gharavi, Nicholas Katsanis, Simone Sanna-Cherchi

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: The DiGeorge syndrome, the most common of the microdeletion syndromes, affects multiple organs, including the heart, the nervous system, and the kidney. It is caused by deletions on chromosome 22q11.2; the genetic driver of the kidney defects is unknown.

METHODS: We conducted a genomewide search for structural variants in two cohorts: 2080 patients with congenital kidney and urinary tract anomalies and 22,094 controls. We performed exome and targeted resequencing in samples obtained from 586 additional patients with congenital kidney anomalies. We also carried out functional studies using zebrafish and mice.

RESULTS: We identified heterozygous deletions of 22q11.2 in 1.1% …

Neuroinflammatory And Cognitive Consequences Of Combined Radiation And Immunotherapy In A Novel Preclinical Model., Gwendolyn J Mcginnis, David Friedman, Kristina H Young, Eileen Ruth S Torres, Charles R Thomas, Michael J Gough, Jacob Raber

Articles, Abstracts, and Reports

BACKGROUND: Cancer patients often report behavioral and cognitive changes following cancer treatment. These effects can be seen in patients who have not yet received treatment or have received only peripheral (non-brain) irradiation. Novel treatments combining radiotherapy (RT) and immunotherapy (IT) demonstrate remarkable efficacy with respect to tumor outcomes by enhancing the proinflammatory environment in the tumor. However, a proinflammatory environment in the brain mediates cognitive impairments in other neurological disorders and may affect brain function in cancer patients receiving these novel treatments. Currently, gaps exist as to whether these treatments impact the brain in individuals with or without tumors and …

Mosaic Expression Of Atrx In The Mouse Central Nervous System Causes Memory Deficits, Renee J Tamming, Jennifer R Siu, Yan Jiang, Marco A M Prado, Frank Beier, Nathalie G Bérubé

Paediatrics Publications

The rapid modulation of chromatin organization is thought to play a crucial role in cognitive processes such as memory consolidation. This is supported in part by the dysregulation of many chromatin-remodelling proteins in neurodevelopmental and psychiatric disorders. A key example is ATRX, an X-linked gene commonly mutated in individuals with syndromic and nonsyndromic intellectual disability. The consequences of Atrx inactivation for learning and memory have been difficult to evaluate because of the early lethality of hemizygous-null animals. In this study, we evaluated the outcome of brain-specific Atrx deletion in heterozygous female mice. These mice exhibit a mosaic pattern of ATRX …

Myocardial Relaxation Is Accelerated By Fast Stretch, Not Reduced Afterload, Charles S. Chung, Charles W. Hoopes, Kenneth S. Campbell

Physiology Faculty Publications

Fast relaxation of cross-bridge generated force in the myocardium facilitates efficient diastolic function. Recently published research studying mechanisms that modulate the relaxation rate has focused on molecular factors. Mechanical factors have received less attention since the 1980s when seminal work established the theory that reducing afterload accelerates the relaxation rate. Clinical trials using afterload reducing drugs, partially based on this theory, have thus far failed to improve outcomes for patients with diastolic dysfunction. Therefore, we reevaluated the protocols that suggest reducing afterload accelerates the relaxation rate and identified that myocardial relengthening was a potential confounding factor. We hypothesized that the …

Early Gadolinium Enhancement For Area At Risk Determination: A Preclinical Validation Study, Sophia Hammer-Hansen, Steve W. Leung, Li-Yueh Hsu, Joel R. Wilson, Joni Taylor, Anders M. Greve, Jens Jakob Thune, Lars Køber, Peter Kellman, Andrew E. Arai

Internal Medicine Faculty Publications

Objectives—The aim of this study was to determine if early gadolinium enhancement (EGE) by cardiovascular magnetic resonance (CMR) imaging in a canine model of reperfused myocardial infarction depicts the area at risk (AAR) as determined by microsphere blood flow analysis.

Background—It remains controversial whether only the irreversibly injured myocardium enhances when performing CMR imaging in the setting of acute myocardial infarction. Recently, EGE has been proposed as a measure of the AAR in acute myocardial infarction as it correlates well with T2-weighted imaging of the AAR, but still requires pathological validation.

Methods—Eleven dogs underwent 2 hours of …

The Distinct Metabolic Phenotype Of Lung Squamous Cell Carcinoma Defines Selective Vulnerability To Glycolytic Inhibition, Justin Goodwin, Michael L. Neugent, Shin Yup Lee, Joshua H. Choe, Hyunsung Choi, Dana M. R. Jenkins, Robin J. Ruthenborg, Maddox W. Robinson, Ji Yun Jeong, Masaki Wake, Hajime Abe, Norihiko Takeda, Hiroko Endo, Masahiro Inoue, Zhenyu Xuan, Hyuntae Yoo, Min Chen, Jung-Mo Ahn, John D. Minna, Kristi L. Helke, Pankaj K. Singh, David B. Shackelford, Jung-Whan Kim

Journal Articles: Eppley Institute

Adenocarcinoma (ADC) and squamous cell carcinoma (SqCC) are the two predominant subtypes of non-small cell lung cancer (NSCLC) and are distinct in their histological, molecular and clinical presentation. However, metabolic signatures specific to individual NSCLC subtypes remain unknown. Here, we perform an integrative analysis of human NSCLC tumour samples, patient-derived xenografts, murine model of NSCLC, NSCLC cell lines and The Cancer Genome Atlas (TCGA) and reveal a markedly elevated expression of the GLUT1 glucose transporter in lung SqCC, which augments glucose uptake and glycolytic flux. We show that a critical reliance on glycolysis renders lung SqCC vulnerable to glycolytic inhibition, …

The Impact Of Sglt2 Inhibitors, Compared With Insulin, On Diabetic Bone Disease In A Mouse Model Of Type 1 Diabetes, Kathryn M. Thrailkill, Jeffry S. Nyman, R. Clay Bunn, Sasidhar Uppuganti, Katherine L. Thompson, Charles K. Lumpkin, Evangelia Kalaitzoglou, John L. Fowlkes

Barnstable Brown Diabetes Center Faculty Publications

Skeletal co-morbidities in type 1 diabetes include an increased risk for fracture and delayed fracture healing, which are intertwined with disease duration and the presence of other diabetic complications. As such, chronic hyperglycemia is undoubtedly a major contributor to these outcomes, despite standard insulin-replacement therapy. Therefore, using the streptozotocin (STZ)-induced model of hypoinsulinemic hyperglycemia in DBA/2J male mice, we compared the effects of two glucose lowering therapies on the fracture resistance of bone and markers of bone turnover. Twelve week-old diabetic (DM) mice were treated for 9 weeks with: 1) oral canagliflozin (CANA, dose range ~10-16 mg/kg/day), an inhibitor of …

Sustained Nitric Oxide-Releasing Nanoparticles Interfere With Methicillin-Resistant Staphylococcus Aureus Adhesion And Biofilm Formation In A Rat Central Venous Catheter Model., Mircea Radu Mihu, Vitor Cabral, Rodney Pattabhi, Moses T Tar, Kelvin P Davies, Adam J Friedman, Luis R Martinez, Joshua D Nosanchuk

Dermatology Faculty Publications

Staphylococcus aureus is frequently isolated in the setting of infections of indwelling medical devices, which are mediated by the microbe's ability to form biofilms on a variety of surfaces. Biofilm-embedded bacteria are more resistant to antimicrobial agents than their planktonic counterparts and often cause chronic infections and sepsis, particularly in patients with prolonged hospitalizations. In this study, we demonstrate that sustained nitric oxide-releasing nanoparticles (NO-np) interfere with S. aureus adhesion and prevent biofilm formation on a rat central venous catheter (CVC) model of infection. Confocal and scanning electron microscopy showed that NO-np-treated staphylococcal biofilms displayed considerably reduced thicknesses and bacterial …

The Current Consensus On The Clinical Management Of Intracranial Ependymoma And Its Distinct Molecular Variants., Kristian W Pajtler, Stephen C Mack, Vijay Ramaswamy, Christian A Smith, Hendrik Witt, Amy Smith, Eugene Hwang, +Several Additional Authors

Pediatrics Faculty Publications

Multiple independent genomic profiling efforts have recently identified clinically and molecularly distinct subgroups of ependymoma arising from all three anatomic compartments of the central nervous system (supratentorial brain, posterior fossa, and spinal cord). These advances motivated a consensus meeting to discuss: (1) the utility of current histologic grading criteria, (2) the integration of molecular-based stratification schemes in future clinical trials for patients with ependymoma and (3) current therapy in the context of molecular subgroups. Discussion at the meeting generated a series of consensus statements and recommendations from the attendees, which comment on the prognostic evaluation and treatment decisions of patients …

Peripheral Huntingtin Silencing Does Not Ameliorate Central Signs Of Disease In The B6.Httq111/+ Mouse Model Of Huntington's Disease., Sydney R Coffey, Robert M Bragg, Shawn Minnig, Seth A Ament, Jeffrey P Cantle, Anne Glickenhaus, Daniel Shelnut, José M Carrillo, Dominic D Shuttleworth, Julie-Anne Rodier, Kimihiro Noguchi, C Frank Bennett, Nathan D Price, Holly B Kordasiewicz, Jeffrey B Carroll

Articles, Abstracts, and Reports

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease whose predominant neuropathological signature is the selective loss of medium spiny neurons in the striatum. Despite this selective neuropathology, the mutant protein (huntingtin) is found in virtually every cell so far studied, and, consequently, phenotypes are observed in a wide range of organ systems both inside and outside the central nervous system. We, and others, have suggested that peripheral dysfunction could contribute to the rate of progression of striatal phenotypes of HD. To test this hypothesis, we lowered levels of huntingtin by treating mice with antisense oligonucleotides (ASOs) targeting the murine …

Astrocytes Promote Progression Of Breast Cancer Metastases To The Brain Via A Kiss1-Mediated Autophagy., Natalya Kaverina, Anton V Borovjagin, Zaira Kadagidze, Anatoly Baryshnikov, Maria Baryshnikova, Dmitry Malin, Dhimankrishhna Ghosh, Nameeta Shah, Danny R Welch, Patrik Gabikian, Apollon Karseladze, Charles Cobbs, Ilya V Ulasov

Articles, Abstracts, and Reports

Formation of metastases, also known as cancer dissemination, is an important stage of breast cancer (BrCa) development. KISS1 expression is associated with inhibition of metastases development. Recently we have demonstrated that BrCa metastases to the brain exhibit low levels of KISS1 expression at both mRNA and protein levels. By using multicolor immunofluorescence and coculture techniques here we show that normal adult astrocytes in the brain are capable of promoting metastatic transformation of circulating breast cancer cells localized to the brain through secretion of chemokine CXCL12. The latter was found in this study to downregulate KISS1 expression at the post-transcriptional level …

Sting Expression And Response To Treatment With Sting Ligands In Premalignant And Malignant Disease., Jason R Baird, Zipei Feng, Hong D Xiao, David Friedman, Ben Cottam, Bernard A Fox, Gwen Kramer, Rom S Leidner, Richard Bryan Bell, Kristina H Young, Marka R Crittenden, Michael J Gough

Articles, Abstracts, and Reports

Human papilloma virus positive (HPV+) tumors represent a large proportion of anal, vulvar, vaginal, cervical and head and neck squamous carcinomas (HNSCC) and late stage invasive disease is thought to originate from a premalignant state. Cyclic dinucleotides that activate STimulator of INterferon Genes (STING) have been shown to cause rapid regression of a range of advanced tumors. We aimed to investigate STING ligands as a novel treatment for papilloma. We tested therapies in a spontaneous mouse model of papilloma of the face and anogenital region that histologically resembles human HPV-associated papilloma. We demonstrate that STING ligands cause rapid regression of …

Foxc1 Is Associated With Estrogen Receptor Alpha And Affects Sensitivity Of Tamoxifen Treatment In Breast Cancer., Jinhua Wang, Yali Xu, Li Li, Lin Wang, Ru Yao, Qiang Sun, Guanhua Du

Articles, Abstracts, and Reports

FOXC1 is a member of Forkhead box transcription factors that participates in embryonic development and tumorigenesis. Our previous study demonstrated that FOXC1 was highly expressed in triple-negative breast cancer. However, it remains unclear what is the relation between FOXC1 and ERα and if FOXC1 regulates expression of ERα. To explore relation between FOXC1 and ERα and discover regulation of ERα expression by FOXC1 in breast cancer, we analyzed data assembled in the Oncomine and TCGA, and found that there was significantly higher FOXC1 expression in estrogen receptor-negative breast cancer than that in estrogen receptor-positive breast cancer. Overexpression of FOXC1 reduced …

Differential Phenotypes Of Memory Cd4 And Cd8 T Cells In The Spleen And Peripheral Tissues Following Immunostimulatory Therapy., Gail D Sckisel, Annie Mirsoian, Christine M Minnar, Marka R Crittenden, Brendan Curti, Jane Q Chen, Bruce R Blazar, Alexander D Borowsky, Arta M Monjazeb, William J Murphy

Articles, Abstracts, and Reports

BACKGROUND: Studies assessing immune parameters typically utilize human PBMCs or murine splenocytes to generate data that is interpreted as representative of immune status. Using splenocytes, we have shown memory CD4-T cells that expand following systemic immunostimulatory therapies undergo rapid IFNg-mediated activation induced cell death (AICD) resulting in a net loss of total CD4-T cells which correlates with elevated PD-1 expression. This is in contrast to CD8-T cells which expand with minimal PD-1 upregulation and apoptosis. In this study we expand upon our previous work by evaluating CD4 and CD8-T cell phenotype and distribution in peripheral organs which are more representative …

Targeting The Nrf2-Heme Oxygenase-1 Axis After Intracerebral Hemorrhage., Jing Chen-Roetling, Raymond F. Regan

Department of Emergency Medicine Faculty Papers

BACKGROUND: Injury to cells adjacent to an intracerebral hemorrhage (ICH) is likely mediated at least in part by toxins released from the hematoma that initiate complex and interacting injury cascades. Pharmacotherapies targeting a single toxin or pathway, even if consistently effective in controlled experimental models, have a high likelihood of failure in a variable clinical setting. Nuclear factor erythroid-2 related factor 2 (Nrf2) regulates the expression of heme oxygenase-1 (HO-1) and multiple other proteins with antioxidant and antiinflammatory effects, and may be a target of interest after ICH.

METHODS: Studies that tested the effect of HO and Nrf2 in models …

Multiple Targets For Novel Therapy Of Fsgs Associated With Circulating Permeability Factor., Virginia J. Savin, Mukut Sharma, Jianping Zhou, David Genochi, Ram Sharma, Tarak Srivastava, Amna Ilahe, Pooja Budhiraja, Aditi Gupta, Ellen T. Mccarthy

Manuscripts, Articles, Book Chapters and Other Papers

A plasma component is responsible for altered glomerular permeability in patients with focal segmental glomerulosclerosis. Evidence includes recurrence after renal transplantation, remission after plasmapheresis, proteinuria in infants of affected mothers, transfer of proteinuria to experimental animals, and impaired glomerular permeability after exposure to patient plasma. Therapy may include decreasing synthesis of the injurious agent, removing or blocking its interaction with cells, or blocking signaling or enhancing cell defenses to restore the permeability barrier and prevent progression. Agents that may prevent the synthesis of the permeability factor include cytotoxic agents or aggressive chemotherapy. Extracorporeal therapies include plasmapheresis, immunoadsorption with protein A …

Effect Of Pulse Shaping On Subharmonic Aided Pressure Estimation In Vitro And In Vivo., Ipshita Gupta, John R. Eisenbrey, Maria Stanczak, Anush Sridharan, Jaydev K. Dave, Ji-Bin Liu, Christopher Hazard, Xinghua Wang, Ping Wang, Huiwen Li, Kirk Wallace, Flemming Forsberg

Department of Radiology Faculty Papers

OBJECTIVES: Subharmonic imaging (SHI) is a technique that uses the nonlinear oscillations of microbubbles when exposed to ultrasound at high pressures transmitting at the fundamental frequency ie, f

METHODS: Eight waveforms with different envelopes were optimized with respect to acoustic power at which the SHAPE study is most sensitive. The study was run with four input transmit cycles, first in vitro and then in vivo in three canines to select the waveform that achieved the best sensitivity for detecting changes in portal pressures using SHAPE. A Logiq 9 scanner with a 4C curvi-linear array was used to acquire 2.5 MHz …

Adiponectin Partially Rescues High Glucose/High Fat-Induced Impairment Of Mitochondrial Biogenesis And Function In A Pgc-1Α Dependent Manner., H. Wang, W.-J. Yan, J.-L. Zhang, F.-Y. Zhang, C. Gao, Y.-J. Wang, W.B. Lau, L. Tao

Department of Emergency Medicine Faculty Papers

OBJECTIVE: Plasma adiponectin (APN) levels are decreased in diabetic patients. Dysfunctional mitochondrial biogenesis is involved in type 2 diabetes (T2DM) pathogenesis, by unclear mechanisms. The present study determined (1) whether myocardial mitochondrial biogenesis was impaired in cardiomyocytes exposed to a high glucose/high fat (HGHF) medium (a T2DM in vitro model), (2) the effects of APN administration upon mitochondrial biogenesis in cardiomyocytes affected by HGHF incubation, and 3) the involved underlying mechanisms.

MATERIALS AND METHODS: Neonatal rat ventricular myocytes (NRVMs) were isolated and incubated in HGHF medium. Mitochondrial function was assessed by ATP content, and fluorescent microscopic analysis of myocardial apoptosis …