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Oncolog, Volume 60, Number 11 - 12, November - December 2015, Joe Munch, Bryan Tutt, C. Graber

OncoLog MD Anderson's Report to Physicians (All issues) Archives

• Multidisciplinary Treatment Maximizes Outcomes for malignant Tumors of the Anterior Skull Base: Malignant tumors of the anterior skull base occur in a delicate area but often need aggressive treatment. Determining the best course of therapy for patients with these tumors takes a multidisciplinary effort.
• Management of Eyelid and Conjunctival Tumors with Preservation of Slight, Function and Cosmesis: Tumors of the eyelid and extent of disease, and which treatments, if any, are needed after surgical excision depends on several factors, including the potential for metastasis.
• HOUSE CALL: "Other" Health Risks from Smoking-Besides cancer, tobacco causes many diseases.

Osats For Total Knee Replacement: Assessment Of Surgical Competence In The Operating Room, Shahryar Noordin, Salim Allana

Department of Surgery Docs

No abstract provided.

Abcc9/Sur2 In The Brain: Implications For Hippocampal Sclerosis Of Aging And A Potential Therapeutic Target, Peter T. Nelson, Gregory A. Jicha, Wang-Xia Wang, Eseosa T. Ighodaro, Sergey C. Artiushin, Colin G. Nichols, David W. Fardo

Sanders-Brown Center on Aging Faculty Publications

The ABCC9 gene and its polypeptide product, SUR2, are increasingly implicated in human neurologic disease, including prevalent diseases of the aged brain. SUR2 proteins are a component of the ATP-sensitive potassium (“K _ATP ”) channel, a metabolic sensor for stress and/or hypoxia that has been shown to change in aging. The K _ATP channel also helps regulate the neurovascular unit. Most brain cell types express SUR2, including neurons, astrocytes, oligodendrocytes, microglia, vascular smooth muscle, pericytes, and endothelial cells. Thus it is not surprising that ABCC9 gene variants are associated with risk for human brain diseases. For example, Cantu syndrome is …

Enos Transfection Of Adipose-Derived Stem Cells Yields Bioactive Nitric Oxide Production And Improved Results In Vascular Tissue Engineering., Stephen Mcilhenny, Ping Zhang, Thomas Tulenko, Jason Comeau, Sarah Fernandez, Aleksandra Policha, Matthew Ferroni, Elizabeth J Faul, Gabor Bagameri, Irving Shapiro, Paul J. Dimuzio

Department of Surgery Faculty Papers

This study evaluates the durability of a novel tissue engineered blood vessel (TEBV) created by seeding a natural vascular tissue scaffold (decellularized human saphenous vein allograft) with autologous adipose-derived stem cells (ASC) differentiated into endothelial-like cells. Previous work with this model revealed the graft to be thrombogenic, likely due to inadequate endothelial differentiation as evidenced by minimal production of nitric oxide (NO). To evaluate the importance of NO expression by the seeded cells, we created TEBV using autologous ASC transfected with the endothelial nitric oxide synthase (eNOS) gene to produce NO. We found that transfected ASC produced NO at levels …

Right Ventricular Dysfunction After Resuscitation Predicts Poor Outcomes In Cardiac Arrest Patients Independent Of Left Ventricular Function., Vimal Ramjee, Anne V. Grossestreuer, Yuan Yao, Sarah M. Perman, Marion Leary, James N. Kirkpatrick, Paul R. Forfia, Daniel M. Kolansky, Benjamin S. Abella, David F. Gaieski

Department of Emergency Medicine Faculty Papers

OBJECTIVE: Determination of clinical outcomes following resuscitation from cardiac arrest remains elusive in the immediate post-arrest period. Echocardiographic assessment shortly after resuscitation has largely focused on left ventricular (LV) function. We aimed to determine whether post-arrest right ventricular (RV) dysfunction predicts worse survival and poor neurologic outcome in cardiac arrest patients, independent of LV dysfunction.

METHODS: A single-center, retrospective cohort study at a tertiary care university hospital participating in the Penn Alliance for Therapeutic Hypothermia (PATH) Registry between 2000 and 2012.

PATIENTS: 291 in- and out-of-hospital adult cardiac arrest patients at the University of Pennsylvania who had return of spontaneous …

Deletion Of Cyclophilin D Impairs Β-Oxidation And Promotes Glucose Metabolism., Michele Tavecchio, Sofia Lisanti, Michael J Bennett, Lucia R Languino, Dario C Altieri

Department of Cancer Biology Faculty Papers

Cyclophilin D (CypD) is a mitochondrial matrix protein implicated in cell death, but a potential role in bioenergetics is not understood. Here, we show that loss or depletion of CypD in cell lines and mice induces defects in mitochondrial bioenergetics due to impaired fatty acid β-oxidation. In turn, CypD loss triggers a global compensatory shift towards glycolysis, with transcriptional upregulation of effectors of glucose metabolism, increased glucose consumption and higher ATP production. In vivo, the glycolytic shift secondary to CypD deletion is associated with expansion of insulin-producing β-cells, mild hyperinsulinemia, improved glucose tolerance, and resistance to high fat diet-induced liver …

Alkali Therapy In Lactic Acidosis, Zeid J. Khitan, Md, Deepak Malhotra, Md, Dominic S. Raj, Md, Antonios H. Tzamaloukas, Md, Joseph I. Shapiro, Md

Marshall Journal of Medicine

This report attempts to frame the debate about clinical administration of sodium bicarbonate in the setting of lactic acidosis in terms of simple questions. Specifically, we address why we develop lactic acidosis in some circumstances, how acute lactic acidosis impairs cardiovascular function and why sodium bicarbonate may have deleterious effects which limit its utility. We also attempt to explore treatment alternatives to sodium bicarbonate.

Theaflavin-3, 3'-Digallate Decreases Human Ovarian Carcinoma Ovcar-3 Cell-Induced Angiogenesis Via Akt And Notch-1 Pathways, Not Via Mapk Pathways, Ying Gao, Gary O. Rankin, Youying Tu, Yi Charlie Chen

Biochemistry and Microbiology

Theaflavin-3, 3'-digallate (TF3) is a black tea polyphenol produced from polymerization and oxidization of the green tea ployphenols epicatechin gallate and (-)-epigallocatechin-3-gallate (EGCG) during fermentation of fresh tea leaves. TF3 has been reported to have anticancer properties. However, the effect of TF3 on tumor angiogenesis and the underlying mechanisms are not clear. In the present study, TF3 was verified to inhibit tumor angiogenesis. Compared with EGCG, TF3 was more potent. TF3 inhibited human ovarian carcinoma OVCAR-3 cell-induced angiogenesis in human umbilical vein endothelial cell model and in chick chorioallantoic membrane model. TF3 reduced tumor angiogenesis by downregulating HIF-1α and VEGF. …

Hdl In Sepsis - Risk Factor And Therapeutic Approach, Emily E. Morin, Ling Guo, Anna Schwendeman, Xiang-An Li

Pediatrics Faculty Publications

High-density lipoprotein (HDL) is a key component of circulating blood and plays essential roles in regulation of vascular endothelial function and immunity. Clinical data demonstrate that HDL levels drop by 40-70% in septic patients, which is associated with a poor prognosis. Experimental studies using Apolipoprotein A-I (ApoAI) null mice showed that HDL deficient mice are susceptible to septic death, and overexpressing ApoAI in mice to increase HDL levels protects against septic death. These clinical and animal studies support our hypothesis that a decrease in HDL level is a risk factor for sepsis, and raising circulating HDL levels may provide an …

Connexin26 Gap Junction Mediates Mirna Intercellular Genetic Communication In The Cochlea And Is Required For Inner Ear Development, Yan Zhu, Liang Zong, Ling Mei, Hong-Bo Zhao

Otolaryngology--Head & Neck Surgery Faculty Publications

Organ development requires well-established intercellular communication to coordinate cell proliferations and differentiations. MicroRNAs (miRNAs) are small, non-coding RNAs that can broadly regulate gene expression and play a critical role in the organ development. In this study, we found that miRNAs could pass through gap junctions between native cochlear supporting cells to play a role in the cochlear development. Connexin26 (Cx26) and Cx30 are predominant isoforms and co-express in the cochlea. Cx26 deficiency but not Cx30 deficiency can cause cochlear developmental disorders. We found that associated with Cx26 deletion induced the cochlear developmental disorders, deletion of Cx26 but not Cx30 disrupted …

A Critical Role For Alpha-Synuclein In Development And Function Of T Lymphocytes, Afshin Shameli, Wenbin Xiao, Yan Zheng, Susan Shyu, John Sumodi, Howard J. Meyerson, Clifford V. Harding, Robert W. Maitta

Faculty Scholarship

Alpha-synuclein is highly expressed in the central nervous system and plays an important role in pathogenesis of neurodegenerative disorders such as Parkinson's disease and Lewy body dementia. Previous studies have demonstrated the expression of α-synuclein in hematopoietic elements and peripheral blood mononuclear cells, although its roles in hematopoiesis and adaptive immunity are not studied. Using an α-synuclein knock out (KO) mouse model, we have recently shown that α-synuclein deficiency is associated with a mild defect in late stages of hematopoiesis. More importantly, we demonstrated a marked defect in B lymphocyte development and IgG, but not IgM production in these mice. …

Loss Of Glycosaminoglycan Receptor Binding After Mosquito Cell Passage Reduces Chikungunya Virus Infectivity, Amber M. Paul, Dhiraj Acharya, John F. Anderson, Faqing Huang, Fengwei Bai

Publications

Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that can cause fever and chronic arthritis in humans. CHIKV that is generated in mosquito or mammalian cells differs in glycosylation patterns of viral proteins, which may affect its replication and virulence. Herein, we compare replication, pathogenicity, and receptor binding of CHIKV generated in Vero cells (mammal) or C6/36 cells (mosquito) through a single passage. We demonstrate that mosquito cell derived CHIKV (CHIKVmos) has slower replication than mammalian cell derived CHIKV (CHIKVvero), when tested in both human and murine cell lines. Consistent with this, CHIKVmos infection in both cell lines produce less cytopathic …

Pnaktide Inhibits Na/K-Atpase Reactive Oxygen Species Amplification And Attenuates Adipogenesis, Komal Sodhi, Kyle Maxwell, Yanling Yan, Jiang Liu, Muhammad Chaudhry, Morgan Getty, Zijian Xie, Nader G. Abraham, Joseph I. Shapiro Md

Biochemistry and Microbiology

Obesity has become a worldwide epidemic and is a major risk factor for metabolic syndrome. Oxidative stress is known to play a role in the generation and maintenance of an obesity phenotype in both isolated adipocytes and intact animals. Because we had identified that the Na/K-ATPase can amplify oxidant signaling, we speculated that a peptide designed to inhibit this pathway, pNaKtide, might ameliorate an obesity phenotype. To test this hypothesis, we first performed studies in isolated murine preadipocytes (3T3L1 cells) and found that pNaKtide attenuated oxidant stress and lipid accumulation in a dose-dependent manner. Complementary experiments in C57Bl6 mice fed …

Autophagy Protects Against Cyp2e1/Chronic Ethanol-Induced Hepatotoxicity, Yongke Lu, Arthur I. Cederbaum

Pharmacology, Physiology and Toxicology

Autophagy is an intracellular pathway by which lysosomes degrade and recycle long-lived proteins and cellular organelles. The effects of ethanol on autophagy are complex but recent studies have shown that autophagy serves a protective function against ethanol-induced liver injury. Autophagy was found to also be protective against CYP2E1-dependent toxicity in vitro in HepG2 cells which express CYP2E1 and in vivo in an acute alcohol/CYPE1-dependent liver injury model. The goal of the current report was to extend the previous in vitro and acute in vivo experiments to a chronic ethanol model to evaluate whether autophagy is also protective against CYP2E1-dependent liver …

Naturally Occurring Deletion Mutants Of The Pig-Specific, Intestinal Crypt Epithelial Cell Protein Clca4b Without Apparent Phenotype., Stephanie Plog, Nikolai Klymiuk, Stefanie Binder, Matthew J. Van Hook, Wallace B. Thoreson, Achim D. Gruber, Lars Mundhenk

Journal Articles: Ophthalmology

The human CLCA4 (chloride channel regulator, calcium-activated) modulates the intestinal phenotype of cystic fibrosis (CF) patients via an as yet unknown pathway. With the generation of new porcine CF models, species-specific differences between human modifiers of CF and their porcine orthologs are considered critical for the translation of experimental data. Specifically, the porcine ortholog to the human CF modulator gene CLCA4 has recently been shown to be duplicated into two separate genes, CLCA4a and CLCA4b. Here, we characterize the duplication product, CLCA4b, in terms of its genomic structure, tissue and cellular expression patterns as well as its in vitro electrophysiological …

The Trial Of Calcium And Vitamin D For The Prevention Of Colorectal Adenomas, John A. Baron, Elizabeth L. Barry, Leila A. Mott, Judy R. Rees

Dartmouth Scholarship

BACKGROUND Epidemiologic and preclinical data suggest that higher intake and serum levels of vitamin D and higher intake of calcium reduce the risk of colorectal neoplasia. To further study the chemopreventive potential of these nutrients, we conducted a randomized, double-blind, placebo-controlled trial of supplementation with vitamin D, calcium, or both for the prevention of colorectal adenomas. METHODS We recruited patients with recently diagnosed adenomas and no known colorectal polyps remaining after complete colonoscopy. We randomly assigned 2259 participants to receive daily vitamin D3 (1000 IU), calcium as carbonate (1200 mg), both, or neither in a partial 2Å~2 factorial design. Women …

Mitochondrial Mass, A New Metabolic Biomarker For Stem-Like Cancer Cells: Understanding Wnt/Fgf-Driven Anabolic Signaling., Rebecca Lamb, Gloria Bonuccelli, Béla Ozsvári, Maria Peiris-Pagès, Marco Fiorillo, Duncan L Smith, Generoso Bevilacqua, Chiara Maria Mazzanti, Liam A Mcdonnell, Antonio Giuseppe Naccarato, Maybo Chiu, Luke Wynne, Ubaldo E Martinez-Outschoorn, Federica Sotgia, Michael P. Lisanti

Kimmel Cancer Center Faculty Papers

Here, we developed an isogenic cell model of "stemness" to facilitate protein biomarker discovery in breast cancer. For this purpose, we used knowledge gained previously from the study of the mouse mammary tumor virus (MMTV). MMTV initiates mammary tumorigenesis in mice by promoter insertion adjacent to two main integration sites, namely Int-1 (Wnt1) and Int-2 (Fgf3), which ultimately activates Wnt/β-catenin signaling, driving the propagation of mammary cancer stem cells (CSCs). Thus, to develop a humanized model of MMTV signaling, we over-expressed WNT1 and FGF3 in MCF7 cells, an ER(+) human breast cancer cell line. We then validated that MCF7 cells …

Emerging Novel Therapies For Heart Failure., Anthony M Szema, Sophia Dang, Jonathan C Li

Department of Medicine Faculty Papers

Heart function fails when the organ is unable to pump blood at a rate proportional to the body's need for oxygen or when this function leads to elevated cardiac chamber filling pressures (cardiogenic pulmonary edema). Despite our sophisticated knowledge of heart failure, even so-called ejection fraction-preserved heart failure has high rates of mortality and morbidity. So, novel therapies are sorely needed. This review discusses current standard therapies for heart failure and launches an exploration into emerging novel treatments on the heels of recently-approved sacubitril and ivbradine. For example, Vasoactive Intestinal Peptide (VIP) is protective of the heart, so in the …

Plant-Derived Sac Domain Of Par-4 (Prostate Apoptosis Response 4) Exhibits Growth Inhibitory Effects In Prostate Cancer Cells, Shayan Sarkar, Sumeet Jain, Vineeta Rai, Dipak K. Sahoo, Sumita Raha, Sujit Suklabaidya, Shantibhusan Senapati, Vivek M. Rangnekar, Indu B. Maiti, Nrisingha Dey

Radiation Medicine Faculty Publications

The gene Par-4 (Prostate Apoptosis Response 4) was originally identified in prostate cancer cells undergoing apoptosis and its product Par-4 showed cancer specific pro-apoptotic activity. Particularly, the SAC domain of Par-4 (SAC-Par-4) selectively kills cancer cells leaving normal cells unaffected. The therapeutic significance of bioactive SAC-Par-4 is enormous in cancer biology; however, its large scale production is still a matter of concern. Here we report the production of SAC-Par-4-GFP fusion protein coupled to translational enhancer sequence (5′ AMV) and apoplast signal peptide (aTP) in transgenic Nicotiana tabacum cv. Samsun NN plants under the control of a unique recombinant promoter M24. …

Cerium Oxide Nanoparticle Treatment Ameliorates Peritonitis-Induced Diaphragm Dysfunction, Shinichi Asano, Ravikumar Arvapalli, Nandini D. Manne, Mani Maheshwari, Bing Ma, Kevin M. Rice, Vellaisamy Selvaraj, Eric Blough

MIIR Faculty Research

The severe inflammation observed during sepsis is thought to cause diaphragm dysfunction, which is associated with poor patient prognosis. Cerium oxide (CeO₂) nanoparticles have been posited to exhibit anti-inflammatory and antioxidative activities suggesting that these particles may be of potential use for the treatment of inflammatory disorders. To investigate this possibility, Sprague Dawley rats were randomly assigned to the following groups: sham control, CeO₂ nanoparticle treatment only (0.5 mg/kg iv), sepsis, and sepsis+CeO₂ nanoparticles. Sepsis was induced by the introduction of cecal material (600 mg/kg) directly into the peritoneal cavity. Nanoparticle treatment decreased sepsis-associated impairments in …

The Perception Of Menstruation And Treatment Of Menstrual Ailments Among Tibetan Women In Mcleod Ganj, Himachal Pradesh, Kara Spafford

India: Public Health, Policy Advocacy, and Community

Despite recent incorporation of quality of life assessments into goal setting, menstrual ailments are still left out of public health initiatives in developing countries. Due to lack of studies on perceptions of menstruation and treatment options for menstrual ailments, the specific health needs of Tibetan women are not met. The present study seeks to determine how Tibetan women are influenced by societal views of menstruation and to explore access to treatment for menstrual problems in McLeod Ganj, Himachal Pradesh. A total of thirty-seven semi-structured interviews were conducted among Tibetan doctors at Men-Tsee-Khang (Tibetan Medical and Astronomy Institute) and Tibetan women …

Myricetin Inhibits Proliferation Of Cisplatin-Resistant Cancer Cells Through A P53-Dependent Apoptotic Pathway, Haizhi Huang, Allen Y. Chen, Xingqian Ye, Bingyun Li, Yon Rojanasakul, Gary O. Rankin, Yi Charlie Chen

Pharmacology, Physiology and Toxicology

Cisplatin is a commonly used drug for cancer treatment by crosslinking DNA, leading to apoptosis of cancer cells, resistance to cisplatin treatment often occurs, leading to relapse. Therefore, there is a need for the development of more effective treatment strategies that can overcome chemoresistance. Myricetin is a flavonoid from fruits and vegetables, showing anticancer activity in various cancer cells. In this study, we found myricetin exhibited greater cytotoxicity than cisplatin in two cisplatin-resistant ovarian cancer cell lines, OVCAR-3 and A2780/CP70, and it was less cytotoxic to the normal ovarian cell line IOSE-364. Myricetin selectively induced apoptosis in both cisplatinresistant cancer …

The P53 Tumor Suppressor Protein Protects Against Chemotherapeutic Stress And Apoptosis In Human Medulloblastoma Cells., Sarah Waye, Aisha Naeem, Muhammad Umer Choudhry, Erika Parasido, Lucas Tricoli, Brian R. Rood, +6 Additional Authors

Pediatrics Faculty Publications

Medulloblastoma (MB), a primitive neuroectodermal tumor, is the most common malignant childhood brain tumor and remains incurable in about a third of patients. Currently, survivors carry a significant burden of late treatment effects. The p53 tumor suppressor protein plays a crucial role in influencing cell survival in response to cellular stress and while the p53 pathway is considered a key determinant of anti-tumor responses in many tumors, its role in cell survival in MB is much less well defined. Herein, we report that the experimental drug VMY-1-103 acts through induction of a partial DNA damage-like response as well induction of …

The Axillary View Typically Does Not Contribute To Decision Making In Care For Proximal Humeral Fractures, Marschall B Berkes, Joshua S Dines, Jacqueline F Birnbaum, Lionel E Lazaro, Tristan C Lorich, Milton T M Little, Joseph T Nguyen, Dean G Lorich

Faculty, Staff and Student Publications

Background: Convention dictates that an axillary view be obtained when evaluating proximal humerus fractures (PHF). However, the axillary view is frequently omitted because of pain and technical considerations. Furthermore, its diagnostic utility is unclear in this setting.

Questions/purposes: The purpose of this study was to (1) determine the rate of obtaining an adequate axillary X-ray and complete shoulder series at a level I trauma center, (2) understand the cost of ordering and attempting an axillary radiograph, and (3) determine if axillary radiographs influence the management of PHF.

Patients and methods: PHF treated between 2009 and 2011 that were ordered for …

Oncolog, Volume 60, Number 10, October 2015, Joe Munch, Bryan Tutt, Jill Delsigne, K. Nair

OncoLog MD Anderson's Report to Physicians (All issues) Archives

• New Targeted Therapy Offers Hope to Patients with Blastic Plasmacytoid Dendritic Cell Neoplasm, Related Diseases: The treatment of common hematological malignancies is based on reams of study data and years of physician experience with the diseases. But such information is often limited for rare, little-researched blood cancers like blastic plasmacytoid dendritic cell neoplasm (BPDCN). This situation may soon change, thanks to the discovery of a new molecular target, which has led to a spate of innovative treatment approaches and the first dedicated clinical trials for this uncommon malignancy.
• Laparoscopic Free Omental Lymphatic Flap Transfers Offer a Powerful Alternative for Lymphedema …

Use Of High-Speed X Ray And Video To Analyze Distal Radius Fracture Pathomechanics., Christina Gutowski, Kurosh Darvish, Frederic E. Liss, Asif M. Ilyas, Christopher M. Jones

Department of Orthopaedic Surgery Faculty Papers

The purpose of this study is to investigate the failure sequence of the distal radius during a simulated fall onto an outstretched hand using cadaver forearms and high-speed X ray and video systems. This apparatus records the beginning and propagation of bony failure, ultimately resulting in distal radius or forearm fracture. The effects of 3 different wrist guard designs are investigated using this system. Serving as a proof-of-concept analysis, this study supports this imaging technique to be used in larger studies of orthopedic trauma and protective devices and specifically for distal radius fractures.

Effects Of Adipocyte Aryl Hydrocarbon Receptor Deficiency On Pcb-Induced Disruption Of Glucose Homeostasis In Lean And Obese Mice, Nicki A. Baker, Robin Shoemaker, Victoria English, Nika Larian, Manjula Sunkara, Andrew J. Morris, Mary Walker, Frederique Yiannikouris, Lisa A. Cassis

Saha Cardiovascular Research Center Faculty Publications

BACKGROUND: Coplanar polychlorinated biphenyls (PCBs) promote adipocyte inflammation and impair glucose homeostasis in lean mice. The diabetes-promoting effects of lipophilic PCBs have been observed only during weight loss in obese mice. The molecular mechanisms linking PCB exposures to impaired glucose metabolism are unclear.

OBJECTIVES: In this study we tested the hypothesis that coplanar PCBs act at adipocyte aryl hydrocarbon receptors (AhRs) to promote adipose inflammation and impair glucose homeostasis in lean mice and in obese mice during weight loss.

METHODS AND RESULTS: PCB-77 administration impaired glucose and insulin tolerance in LF (low fat diet)-fed control (AhR^fl/fl) mice …

Orphan Nuclear Receptor Nur77 Inhibits Cardiac Hypertrophic Response To Beta-Adrenergic Stimulation., Guijun Yan, Ni Zhu, Shengdong Huang, Bing Yi, Xiying Shang, Ming Chen, Nadan Wang, Guan-Xin Zhang, Jennifer A Talarico, Douglas G Tilley, Erhe Gao, Jianxin Sun

Center for Translational Medicine Faculty Papers

The orphan nuclear receptor Nur77 plays critical roles in cardiovascular diseases, and its expression is markedly induced in the heart after beta-adrenergic receptor (β-AR) activation. However, the functional significance of Nur77 in β-AR signaling in the heart remains unclear. By using Northern blot, Western blot, and immunofluorescent staining assays, we showed that Nur77 expression was markedly upregulated in cardiomyocytes in response to multiple hypertrophic stimuli, including isoproterenol (ISO), phenylephrine (PE), and endothelin-1 (ET-1). In a time- and dose-dependent manner, ISO increases Nur77 expression in the nuclei of cardiomyocytes. Overexpression of Nur77 markedly inhibited ISO-induced cardiac hypertrophy by inducing nuclear translocation …

Janus Kinase 2/Signal Transducer And Activator Of Transcription 3 Inhibitors Attenuate The Effect Of Cardiotrophin-Like Cytokine Factor 1 And Human Focal Segmental Glomerulosclerosis Serum On Glomerular Filtration Barrier., Mukut Sharma, Jianping Zhou, Jean-François Gauchat, Ram Sharma, Ellen T. Mccarthy, Tarak Srivastava, Virginia J. Savin

Manuscripts, Articles, Book Chapters and Other Papers

Recurrence of idiopathic focal segmental glomerulosclerosis (FSGS) after renal transplantation is believed to be caused by a circulating factor(s). We detected cardiotrophin-like cytokine factor 1 (CLCF1), a member of the interleukin 6 family, in the plasma from patients with recurrent FSGS. We hypothesized that CLCF1 contributes to the effect of FSGS serum on the glomerular filtration barrier in vitro. Presently, we studied the effect of CLCF1 on isolated rat glomeruli using an in vitro assay of albumin permeability (P(alb)). CLCF1 (0.05-100 ng/mL) increased P(alb) and caused maximal effect at 5-10 ng/mL (P < 0.001). The increase in Palb was analogous to the effect of FSGS serum. Anti-CLCF1 monoclonal antibody blocked the CLCF1-induced increase in P(alb) and significantly attenuated the effect of FSGS serum (P < 0.001). The heterodimer composed of CLCF1 and cosecreted molecule cytokine receptor-like factor 1 (CRLF1) attenuated the increase in P(alb) caused by CLCF1 or FSGS serum. Western blot analysis showed that CLCF1 upregulated phosphorylation of signal transducer and activator of transcription 3 (STAT3) (Tyr705) in glomeruli. This effect was diminished by the heterodimer CLCF1-CRLF1. Janus kinase 2 (JAK2) inhibitor BMS-1119543 or STAT3 inhibitor Stattic significantly blocked the effect of CLCF1 or FSGS serum on P(alb) (P < 0.001). These novel findings suggest that when monomeric CLCF1 increases P(alb), the heterodimer CLCF1-CRLF1 may protect the glomerular filtration barrier. We speculate that albuminuria in FSGS is related to qualitative or quantitative changes in the CLCF1-CRLF1 complex, and that JAK2 or STAT3 inhibitors may be novel therapeutic agents to treat FSGS.

Deubiquitinase Usp47/Ubp64e Regulates Β-Catenin Ubiquitination And Degradation And Plays A Positive Role In Wnt Signaling, Jiandang Shi, Yajuan Liu, Xuehe Xu, Wen Zhang, Tianxin Yu, Jianhang Jia, Chunming Liu

Markey Cancer Center Faculty Publications

Wnt signaling plays important roles in development and tumorigenesis. A central question about the Wnt pathway is the regulation of β-catenin. Phosphorylation of β-catenin by CK1α and GSK3 promotes β-catenin binding to β-TrCP, leading to β-catenin degradation through the proteasome. The phosphorylation and ubiquitination of β-catenin have been well characterized; however, it is unknown whether and how a deubiquitinase is involved. In this study, by screening RNA interference (RNAi) libraries, we identified USP47 as a deubiquitinase that prevents β-catenin ubiquitination. Inactivation of USP47 by RNAi increased β-catenin ubiquitination, attenuated Wnt signaling, and repressed cancer cell growth. Furthermore, USP47 deubiquitinates itself, …