Digital Commons Network^™

Glutamate Dysregulation And Hippocampal Dysfunction In Epileptogenesis, Seth R. Batten

Theses and Dissertations--Medical Sciences

Epileptogenesis is the complex process of the brain developing epileptic acitivity. Due to the role of glutamate and the hippocampus in synaptic plasticity a dysregulation in glutamate neurotransmission and hippocampal dysfunction are implicated in the process of epileptogenesis. However, the exact causal factors that promote epileptogenesis are unknown.

We study presynaptic proteins that regulate glutamate neurotransmission and their role in epileptogenesis. The presynaptic protein, tomosyn, is believed to be a negative regulator of glutamate neurotransmission; however, no one has studied the effects of this protein on glutamate transmission in vivo. Furthermore, evidence suggests that mice lacking tomosyn have a …

Defining The Role Of Reactive Oxygen Species, Nitric Oxide, And Sphingolipid Signaling In Tumor Necrosis Factor - Induced Skeletal Muscle Weakness, Shawn Stasko

Theses and Dissertations--Physiology

In many chronic inflammatory diseases, patients suffer from skeletal muscle weakness, exacerbating their symptoms. Serum levels of tumor necrosis factor-alpha (TNF) and sphingomyelinase are increased, suggesting their possible role in the progression of this weakness. This dissertation focuses on the role that reactive oxygen species (ROS) and nitric oxide (NO) play in mediating TNF-induced skeletal muscle weakness and to what extent sphingolipid signaling mediates cellular response to TNF.

The first aim of this work was to identify which endogenous oxidant species stimulated by TNF contributes to skeletal muscle weakness. In C57BL/6 mice (n=38), intraperitoneal injection of TNF elicited a 25% …

Microglia Activation In A Rodent Model Of An Alcohol Use Disorder: The Importance Of Phenotype, Initiation, And Duration Of Activation, Simon A. Marshall

Theses and Dissertations--Pharmacy

Chronic ethanol exposure results in neuroadaptations that drive the progression of an alcohol use disorder (AUD). One such driving force is alcohol-induced neurodegeneration. Neuroinflammation has been proposed as a mechanism underlying this damage. Although neuroinflammation is a physiological response to damage, overactivation of its pathways can lead to neurodegeneration. A hallmark indicator of neuroinflammation is microglial activation, but microglial activation is a heterogeneous continuum of phenotypes that can promote or inhibit neuroinflammation. Furthermore acute microglial activation is necessary to restore homeostasis, but prolonged activation can exacerbate damage. The diversity of microglia makes both the level and timecourse of activation vital …

Regulation Of Alpha Synuclein Following Chronic Methamphetamine Administration In Guinea Pigs: Correlation With Memory And Synaptic Plasticity, Adnouse Blanc

PCOM Biomedical Studies Student Scholarship

Methamphetamine (METH) is a highly addictive drug of abuse that has a severe impact on neuronal changes in the brain including modulations of plasticity, cognitive dysfunction, as well as memory impairment. These changes can be seen as modifications in the expression of biochemical markers associated with synaptic plasticity. One such marker associated with memory impairment is alpha synuclein (α-syn). Alteration of α-syn expression has been linked to memory impairment in patients with Alzheimer’s disease (AD) and Parkinson’s disease (PD). Here we assess the effect of chronic METH treatment in correlation to cognitive functions.

Twenty-nine guinea pigs (male, 150-250 g) were …

Molecular Mechanisms Related To Endotoxemia In Primary Human Cardiomyocytes In Culture, Atijah J. Collins

PCOM Biomedical Studies Student Scholarship

Cardiovascular disease (CVD) is the leading cause of death in the United States and has been for the past 80 years. Development of novel therapeutic agents to address the large number of CVD deaths requires an in depth understanding of the structural and functional properties of human cardiomyocytes. Over the last few years we have been developing an in vitro paradigm to assess molecular cardiodynamics in Primary Human Cardiomyocyte in culture (PHCC). We tested the hypothesis whether endotoxemia would exhibit a marked decrease in contractile proteins and cause apoptosis in PHCC. In the current series of experiments, we induced endotoxemia …

Cytokeratin 18 And H-Fabp Levels In Intestinal Ischemia–Reperfusion Injury: Role Of Coenzyme Q10, Muaz Belvi̇ranli, Ni̇lsel Okudan, Hakki Gökbel, Aysel Kiyici, Mehmet Öz, Ayşe Kumak

Turkish Journal of Medical Sciences

The objective of this study was to investigate whether coenzyme Q10 (CoQ10) supplementation affects M30 and heart-type fatty acid binding protein (h-FABP) levels in intestinal ischemia-reperfusion injury-induced rats. Materials and methods: Thirty-two male Wistar rats were randomly divided into 4 groups. 1) Sham: Animals exposed to laparotomy without clamping the superior mesenteric artery (SMA); 2) ischemia-reperfusion (IR): rats exposed to laparotomy with occlusion of the SMA for 45 min, followed by 120 min of reperfusion period; 3) CoQ10 plus sham: 10 mg kg body weight^{-1} CoQ10 was administrated via intraperitoneal injection for 20 days, and thereafter animals were exposed to …

Leptin Regulation Of Pubertal Maturation In Intact And Pinealectomized Female Rats, Emi̇ne Kaçar, Si̇ğnem Eyuboğlu Di̇nç, Bayram Yilmaz, Haluk Keleşti̇mur

Turkish Journal of Medical Sciences

To explore the roles of leptin and melatonin in early pubertal maturation. Materials and methods: Wistar female rats were used as experimental animals. Leptin was subcutaneously infused for 28 days through osmotic minipumps starting from postnatal day 15 (preweaning). Pinealectomy was performed on postnatal day 21 (weaning), and the animals were decapitated when estrus was detected by vaginal smearing. Results: Chronic preweaning, by peripheral infusion of leptin through subcutaneous routes, advanced the onset of puberty in leptin-treated sham and pinealectomized groups as determined by vaginal opening, while causing no significant change in serum estradiol levels and uterus weight. Mean body …

Rhodopsin Trafficking And Retinal Function, Nicholas Joseph Reish

All ETDs from UAB

The health and maintenance of rod photoreceptors depends on the high-fidelity vectorial transport of rhodopsin from its site of synthesis in the inner segment to its final resting place in the outer segment disks. Multiple molecular interactions play a role in this process, including the interaction of the small GTPase rab11a with rhodopsin that was first described in vertebrates in amphibians. We found that the interaction of the small GTPase rab11a and rhodopsin is conserved in mammalian retina. This interaction is direct, is abrogated by human disease-causing truncation mutations in rhodopsin, and does not depend on the nucleotide binding status …

Gabaergic Dysfunction In Huntington Disease, Sarah Elizabeth Dougherty

All ETDs from UAB

GABAergic neurons are responsible for regulation of neuronal signaling through inhibition. Alterations in the delicate balance of excitation and inhibition have been observed in many neurological disorders, including neurodegenerative diseases. Huntington disease (HD) is an autosomal dominant neurodegenerative disorder that is characterized by motor, psychiatric, and cognitive disturbances. As the hallmark movement pathology of HD is hyperkinesis it is intriguing to postulate that alterations in inhibition, and by extension within GABAergic cell networks, could be part of the pathogenesis of this disorder. In order to elucidate the role of GABAergic cell populations in HD we have used behavioral paradigms, molecular …

The Impairment Of Macrophage-To-Feces Reverse Cholesterol Transport During Inflammation Does Not Depend On Serum Amyloid A, Maria C. De Beer, Joanne M. Wroblewski, Victoria P. Noffsinger, Ailing Ji, Jason M. Meyer, Deneys R. Van Der Westhuyzen, Frederick C. De Beer, Nancy R. Webb

Saha Cardiovascular Research Center Faculty Publications

Studies suggest that inflammation impairs reverse cholesterol transport (RCT). We investigated whether serum amyloid A (SAA) contributes to this impairment using an established macrophage-to-feces RCT model. Wild-type (WT) mice and mice deficient in SAA1.1 and SAA2.1 (SAAKO) were injected intraperitoneally with ³H-cholesterol-labeled J774 macrophages 4 hr after administration of LPS or buffered saline. ³H-cholesterol in plasma 4 hr after macrophage injection was significantly reduced in both WT and SAAKO mice injected with LPS, but this was not associated with a reduced capacity of serum from LPS-injected mice to promote macrophage cholesterol efflux in vitro. Hepatic accumulation of ^{3 …}

Thc-Mediated Induction Of Δfosb And Its Modulation Of Cb1r Signaling And Adaptation, Lazenka Matthew

Theses and Dissertations

The main psychoactive and therapeutic effects of Δ9-tetrahydrocannabinol (THC) are mediated through cannabinoid type 1 receptors (CB1Rs). The therapeutic uses of THC are mitigated by the development of tolerance to these therapeutic effects, whereas tolerance does not readily develop to some of the side-effects of THC, like motor impairment and reward. The development of tolerance occurs through adaptations at CB1Rs, which include desensitization (G-protein uncoupling) and downregulation (receptor degradation). Brain region-dependent differences in THC-mediated adaptations are proposed to explain the differences in tolerance to various THC-mediated effects. These studies focused on whether ΔFosB, a stable transcription factor, could regulate CB1R …

Structured Genome-Scale Variant And Clinical Data Reporting For Meta-Analysis In An Era Of Genomic Medicine, Darrell L. Dinwiddie, Carol J. Saunders, Emily G. Farrow, Sarah E. Soden, Neil A. Miller, Stephen F. Kingsmore

Manuscripts, Articles, Book Chapters and Other Papers

The Journal of Genomes and Exomes is a new, peer-reviewed, open-access, online publication whose scope comprises reporting of high quality genome, exome, and gene panel sequences with attendant, detailed phenotypes. The intent of this journal is to facilitate comparisons between genome, exome and gene panel sequencing studies in order to assist significance testing of the genotypephenotype associations, particularly those in uncommon genetic diseases. While there is yet to be a consensus regarding these classifications, the definition of an empiric set is helpful in understanding error models. Herein we have suggested structured templates for submissions and the rationale for the data …

The Characterisation Of Pax3 Expressant Cells In Adult Peripheral Nerve [Journal Article], Judith Blake, Melanie Ziman

Research outputs 2013

Pax3 has numerous integral functions in embryonic tissue morphogenesis and knowledge of its complex function in cells of adult tissue continues to unfold. Across a variety of adult tissue lineages, the role of Pax3 is principally linked to maintenance of the tissue’s resident stem/progenitor cell population. In adult peripheral nerves, Pax3 is reported to be expressed in nonmyelinating Schwann cells, however, little is known about the purpose of this expression. Based on the evidence of the role of Pax3 in other adult tissue stem and progenitor cells, it was hypothesised that the cells in adult peripheral nerve that express Pax3 …

Molecular Characterization Of Acanthamoeba Isolated From Kayseri Well Water, Sali̇h Kuk, Süleyman Yazar, Süheyla Doğan, Ülfet Çeti̇nkaya, Çağri Şakalar

Turkish Journal of Medical Sciences

Potentially pathogenic free-living amoebae have a cosmopolitan distribution in soil, dust, air, and water. Generally, environmental free-living amoebae do not threaten human health. This study aimed to investigate the presence of Acanthamoeba in well waters drawn from different locations in Kayseri, Turkey, which are mainly used for drinking or irrigation by the residents in the region. Materials and methods: Twenty-nine samples, including 26 well water sediment samples and 3 tap water samples as the control, were collected from 3 different locations. Melting snow feeds 5, rain water 18, and tap water 3 of these wells. Results: Five of 26 well …

The Effects Of Formaldehyde Intoxication On The Inducible Nitric Oxide Synthase Expression And Nitric Oxide Level In The Liver Tissue Of Rats, Ergün Uçmakli, Ferah Armutcu, Alaatti̇n Öztürk

Turkish Journal of Medical Sciences

To investigate inductive activity of formaldehyde (FA) on the expression of inducible nitric oxide synthase (iNOS) and level of nitric oxide (NO) in the liver of rats. Materials and methods: Sixteen male Wistar albino rats of the same age (3 months old) were divided into 2 experimental groups, with 8 rats as the control and 8 rats formaldehyde-treated (FAt). The FAt group received intraperitoneal injection of 10 mg/kg FA for 10 days. Activity of iNOS was shown with immunohistochemical stain kits, and the concentration of NO level was measured by spectrophotometric method in the liver tissue. Results: The FAt group …

The Dose-Dependent Effect Of Grayanotoxin On The Cardiovascular System, Süha Türkmen, Ülkü Karagöz, Abdülkadi̇r Gündüz, Süleyman Türedi̇, Metehan Akça, Mehmet Yildirim

Turkish Journal of Medical Sciences

Mad honey (grayanotoxin, GTX) poisoning is caused by a toxin binding to the sodium channels of a cell membrane. This study investigates the dose-dependent effect of GTX on the cardiovascular system. Materials and methods: Twenty-four male Sprague Dawley rats were divided into 4 equal groups. Group 1 was the control group and was administered only saline. GTX-III was administered in doses of 200, 400, and 800 µg/kg for Groups 2, 3, and 4, respectively. After GTX-III injection, blood pressure and heart rate were recorded using an electrophysiological data acquisition system. Results: After 200 µg/kg GTX-III injection, at 31-60 min, the …

Ankaferd Blood Stopper: Does It Have A Role In Fracture Healing?, Murat Günay, Ramazan Amanvermez, Gökhan Keleş

Turkish Journal of Medical Sciences

To examine the effect of Ankaferd Blood Stopper (ABS) on bone healing using a rat femur fracture model. Materials and methods: Eight rats were used as a control group (group 1), which was not subjected to fractures. The remaining 48 rats were divided into 6 groups of 8 each. The femoral shaft fractures were produced by cutting with bone scissors. One milliliter of ABS was applied to the fracture region of groups 3 (day 7), 5 (day 21), and 7 (day 45), or rats treated with saline instead of ABS on the fracture region in groups 2 (day 7), 4 …

Influence Of Alpha Lipoic Acid On Epithelial Apoptosis In Experimental Periodontitis, Adem Kara, Sümeyra Akman, Tevfi̇k Demi̇rci̇, Taner Arabaci, Varol Çanakçi, Bünyami̇ Ünal

Turkish Journal of Medical Sciences

Alpha lipoic acid (ALA) is a powerful antioxidant. Its antiinflammatory effects and apoptotic mechanism have recently been studied in many diseases. This study aimed to investigate the effects of ALA on apoptotic activity in the treatment of periodontitis. Materials and methods: Thirty male Wistar rats were randomly divided into 3 groups: control (without ligature), PED (ligature + placebo, saline; oral gavage), and ALA+PED (ligature + alpha lipoic acid at 50 mg/kg/day in saline; oral gavage). Histological and biochemical analyses were performed on the mandibular first molars of sacrificed rats. Results: Biochemical myeloperoxidase activity in gingivo-mucosal tissue was measured. For immunohistochemical …

The Effects Of Thyroid Hormones On Uroflowmetry Parameters In Asymptomatic Women, Ersi̇n Çi̇mentepe, Mehmet Erol Yildirim, İlkay Beki̇r İncebay, Ayşe Çarlioğlu, Ömer Faruk Karataş, Doğan Ünal

Turkish Journal of Medical Sciences

To investigate whether there is any association between uroflowmetry parameters and blood levels of thyroid hormones in asymptomatic women. Materials and methods: Included in the study were 110 consecutive female patients with no urinary complaints who had thyroid function tests performed in an endocrinology clinic. Uroflowmetric measurements were performed for each patient in a sitting position. The patients were divided into 3 groups, hypo-, hyper-, and euthyroidism, and were investigated for statistical difference among them regarding maximum flow rate (Qmax), average flow rate (Qave), voided volume (VV), and voiding time (VT). Results: The mean Qmax and Qave values of hypo-, …

Glutaredoxin-2 Is Required To Control Proton Leak Through Uncoupling Protein-3, Ryan J. Mailloux, Jian Ying Xuan, Brittany Beauchamp, Marjorie F. Lou, Mary-Ellen Harper

School of Veterinary and Biomedical Sciences: Faculty Publications

Glutathionylation has emerged as a key modification required for controlling protein function in response to changes in cell redox status. Recently, we showed that the glutathionylation state of uncoupling protein-3 (UCP3) modulates the leak of protons back into the mitochondrial matrix, thus controlling reactive oxygen species production. However, whether or not UCP3 glutathionylation is mediated enzymatically has remained unknown because previous work relied on the use of pharmacological agents, such as diamide, to alter the UCP3 glutathionylation state. Here, we demonstrate that glutaredoxin-2 (Grx2), a matrix oxidoreductase, is required to glutathionylate and inhibit UCP3. Analysis of bioenergetics in skeletal muscle …

Electroporation-Mediated Gene Transfer Directly To The Swine Heart, Barbara Hargrave, Harre Downey, Cathryn Lundberg, Annelise Israel, Yeong-Jer Chen, Richard Heller

Bioelectrics Publications

In vivo gene transfer to the ischemic heart via electroporation holds promise as a potential therapeutic approach for the treatment of heart disease. In the current study, we investigated the use of in vivo electroporation for gene transfer using three different penetrating electrodes and one non-penetrating electrode. The hearts of adult male swine were exposed through a sternotomy. Eight electric pulses synchronized to the rising phase of the R wave of the electrocardiogram were administered at varying pulse widths and field strengths following an injection of either a plasmid encoding luciferase or one encoding green fluorescent protein. Four sites on …

Different Mechanisms Of Inflammation Induced In Virus And Autoimmune-Mediated Models Of Multiple Sclerosis In C57bl6 Mice., Abhinoy Kishore, Anurag Kanaujia, Soma Nag, A M Rostami, Lawrence C. Kenyon, Kenneth S Shindler, Jayasri Das Sarma

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the human central nervous system (CNS). Neurotropic demyelinating strain of MHV (MHV-A59 or its isogenic recombinant strain RSA59) induces MS-like disease in mice mediated by microglia, along with a small population of T cells. The mechanism of demyelination is at least in part due to microglia-mediated myelin stripping, with some direct axonal injury. Immunization with myelin oligodendrocyte glycoprotein (MOG) induces experimental autoimmune encephalomyelitis (EAE), a mainly CD4(+) T-cell-mediated disease, although CD8(+) T cells may play a significant role in demyelination. It is possible that both autoimmune and nonimmune mechanisms such as …

Exome Sequencing Reveals De Novo Germline Mutation Of The Mammalian Target Of Rapamycin (Mtor) In A Patient With Megalencephaly And Intractable Seizures, Laurie D. Smith, Carol J. Saunders, Darrell L. Dinwiddie, Andrea M. Atherton, Neil A. Miller, Sarah E. Soden, Emily G. Farrow, Ahmed T G Abdelmoity, Stephen F. Kingsmore

Manuscripts, Articles, Book Chapters and Other Papers

A de novo somatic mutation in the mammalian target of rapamycin (MTOR) has previously been described in one patient with hemimegalencephaly and epilepsy. Here, we present a case of a young girl with megalencephaly and intractable seizures who was found to have an MTOR mutation in multiple cell lineages (p.Cys1483Phe) and, therefore, presumed to be of germline origin. The mutation was detected in peripheral blood DNA by exome sequencing of the patient and her parents, substantiating the utility of this approach for detection of clinically relevant de novo variations.

Is Rimonabant A Safe And Effective Treatment For Patients With Alcohol Dependence?, Samantha L. Hughes

PCOM Physician Assistant Studies Student Scholarship

OBJECTIVE: The objective of this selective EBM review is to determine whether or not Rimonabant is a safe and effective treatment for patients with alcohol dependence.

STUDY DESIGN: Systematic review of three English language randomized control trials published in 2005, 2008 and 2010.

DATA SOURCES: Three double-blind, placebo controlled randomized trials comparing Rimonabant or Naltrexone to placebo were found using PubMed, OVID, Medline and Cochrane.

OUTCOMES MEASURED: Outcomes measured include event rate of heavy drinking days using the timeline follow back method, which facilitates self-reporting of drinking habits by utilizing calendars and personal recall. Other outcomes measured include …

Does The Addition Of Muramyl Tripeptide To Chemotherapy Improve Overall Survival For Patients With Osteosarcoma?, Jennifer Jones

PCOM Physician Assistant Studies Student Scholarship

OBJECTIVE: The objective of this selective EBM review is to determine whether or not “Does the addition of muramyl tripeptide to chemotherapy improve overall survival for patients with osteosarcoma?”

STUDY DESIGN: Review of three English language primary randomized controlled trials published between 2005 and 2009.

DATA SOURCES: Randomized controlled trials evaluating the addition of muramyl tripeptide (MTP) to chemotherapy for patients with osteosarcoma were found using Medline/PubMed databases.

OUTCOMES MEASURED: Event-free survival (EFS) and overall survival were the outcome measures used to determine the effectiveness of the additional chemotherapy treatment in osteosarcoma patients. EFS was defined as …

Is Phlogenzym Effective In Reducing Moderate To Severe Osteoarthritis Pain In Adults?, Vanessa K. Wood

PCOM Physician Assistant Studies Student Scholarship

OBJECTIVE: The objective of this selective EBM review is to determine whether or not Phlogenzym (or ERC) effective in reducing moderate to severe osteoarthritis pain in adults.

STUDY DESIGN: Review of three randomized controlled trials in the English language from 2001 to 2006.

DATA SOURCES: Two double blind RCTs and one open RCT was found using Cochrane Library EBM Online Database, Ovid Medline, and PubMed Online.

OUTCOMES MEASURED: Each of the three studies measured for pain at rest, pain with motion, and restricted function at baseline assessing efficacy using the Lequesne’s Algofunctional Index, visual analog scales, and …

Does N-Acetylcysteine Supplementation Alleviate Compulsive Behavior In Adults With Impulse Control Disorders?, Tova Diamond

PCOM Physician Assistant Studies Student Scholarship

OBJECTIVE: The objective of this systematic review is to determine whether or not “Does N-acetylcysteine supplementation alleviate compulsive behavior in adults with impulse control disorders?”

STUDY DESIGN: Review of three English primary studies published between 2007 and 2009.

DATA SOURCES: One double-blind RCT, one open label trial followed by double-blind RCT, one case study. Studies were found using PubMed, Cochrane Systematic Reviews, OVID and Ebsco databases.

OUTCOMES MEASURED: Primary outcomes measured include severity of trichotillomania symptoms measured by MGHHPS, reduction of pathological gambling symptoms measured by YBOCS-PG, and reduction of compulsive grooming urges measured by patient reports.

RESULTS: In …

Inhibition Of The Host Translation Shutoff Response By Herpes Simplex Virus 1 Triggers Nuclear Envelope-Derived Autophagy, Kerstin Radtke, Luc English, Christiane Rondeau, David Leib

Dartmouth Scholarship

Macroautophagy is a cellular pathway that degrades intracellular pathogens and contributes to antigen presentation. Herpes simplex virus 1 (HSV-1) infection triggers both macroautophagy and an additional form of autophagy that uses the nuclear envelope as a source of membrane. The present study constitutes the first in-depth analysis of nuclear envelope-derived autophagy (NEDA). We established LC3a as a marker that allowed us to distinguish between NEDA and macroautophagy in both immunofluorescence and flow cytometry. NEDA was observed in many different cell types, indicating that it is a general response to HSV-1 infection. This autophagic pathway is known to depend on the …

Progress Towards Understanding Of Mechanisms Of Action Of Potent Multifunctional Disease Modifying Therapeutics For Parkinson's Disease & Investigating The Methamphetamine-Induced Striatal Microglia Activation., Mrudang M. Shah

Wayne State University Dissertations

PROGRESS TOWARDS UNDERSTANDING OF MECHANISMS OF ACTION OF POTENT MULTIFUNCTIONAL DISEASE MODIFYING

THERAPEUTICS FOR PARKINSON'S DISEASE.

by

MRUDANG MANOJKUMAR SHAH

December 2013

Advisor: Dr. Aloke Dutta

Major: Pharmaceutical Sciences

Degree: Doctor of Philosophy

Our long term goal is to design and develop potent multifunctional disease modifying therapeutics for Parkinson's disease. The objective of my dissertation was to understand the mechanisms of action of some potent small molecules (synthesized in our lab) as a disease modifying Parkinson's disease therapeutic. The objective was achieved by pursuing the following two specific aims:

1. Investigating anti-oxidant and neuroprotective effects of a lead molecule (D-512) …

Hypoxia-Inducing Factors As Master Regulators Of Stemness Properties And Altered Metabolism Of Cancer- And Metastasis-Initiating Cells., Murielle Mimeault, Surinder K. Batra

Journal Articles: Biochemistry & Molecular Biology

Accumulating lines of experimental evidence have revealed that hypoxia-inducible factors, HIF-1α and HIF-2α, are key regulators of the adaptation of cancer- and metastasis-initiating cells and their differentiated progenies to oxygen and nutrient deprivation during cancer progression under normoxic and hypoxic conditions. Particularly, the sustained stimulation of epidermal growth factor receptor (EGFR), insulin-like growth factor-1 receptor (IGF-1R), stem cell factor (SCF) receptor KIT, transforming growth factor-β receptors (TGF-βRs) and Notch and their downstream signalling elements such as phosphatidylinositol 3'-kinase (PI3K)/Akt/molecular target of rapamycin (mTOR) may lead to an enhanced activity of HIFs. Moreover, the up-regulation of HIFs in cancer cells may …