•  CONTENTS .....c

•  FOREWORD .....i

•  PREFACE .....ii

•  List of Contributors .....iii

[+] CHAPTER 1 Cell Proliferation, Differentiation and Apoptosis .....3                INTRODUCTION .....3                Life in Cycles .....3                Cyclins and Kinases in Cell Cycle Control .....3                CDK Inhibitors .....4          [+] Cell Cycle Phosphatases .....5                         Cell Cycle Step 1: Transcribe Cyclin D1 Gene .....5                         Step 2: Begin DNA Synthesis in S-phase .....6                         Step 3: Toward Mitosis- Cyclin B/CDK 1 Checking for Correct DNA Distribution .....6                Ubiquitin Proteosome System: Degradation Control of the Cell Cycle .....7                Final Step: Leaving Mitosis.....7                Cell Cycle Checkpoints .....7                Cell Cycle and Cell Differentiation .....8                What is Apoptosis? .....9                Two Ways into Apoptosis .....9                Apoptosis Serves Several Purposes .....12                APOPTOSIS IN CANCER THERAPEUTICS .....13                REFERENCES .....13

[+] CHAPTER 2 Causes of Cancer .....18          [+] I. The Influence of the Environment .....18                         INTRODUCTION.....18                         GENE-ENVIRONMENT INTERACTION .....18                   [+] ENVIRONMENTAL CHEMICAL CARCINOGENS .....20                             Tobacco Smoking .....20                             Radiation .....20                             Pesticides .....21                             Dioxins and Organic Compounds .....21                             Benzene .....22                             Estrogens .....22                             Metals and Metalloids .....22                             Chromium .....23                             Cadmium .....23                             Arsenic .....23                             Air Pollution .....24                         CONCLUSIONS .....25                         REFERENCES .....25          [+] II. Obesity and Cancer.....28                         OBESITY AND CANCER .....28                   [+] MOLECULAR MECHANISMS THAT LINK OBESITY AND CANCER RISK .....29                             Adipose Derived Hormones .....29                             Insulin-IGF Cancer Hypothesis .....29                             Sex Steroids .....30                         REFERENCES .....31          [+] III. Estrogens and Cancer .....33                         INTRODUCTION .....33                         BIOSYNTHESIS OF ESTROGENS .....34                         PHYSIOLOGICAL ACTIONS OF ESTROGENS .....34                         ESTROGEN RECEPTORS .....35                         MOLECULAR MECHANISM OF ESTROGENS .....36                         CANCER-ESTROGEN IMPLICATIONS .....37                         Estrogen Metabolite-Cancer Connections .....38                         METABOLIC FATE OF ESTROGENS .....38                         SELECTIVE ESTROGEN RECEPTOR MODULAT ORS AND AROMATASE INHIBITORS .....39                         CONCLUSIONS .....39                         REFERENCES .....40          [+] IV. Example 1: Hepa tocellular Carcinoma .....44                         INTRODUCTION .....44                         STEROID HORMONES AND HCC .....44                         HCC GEOGRAPHIC DISTRIBUTION AND ITS RELATION WITH ETIOLOGY .....44                         GENE EXPRESSION IN HCC .....45                         REFERENCES .....46          [+] V. Example 2: Estrogens, Retinoids and Cervical Cancer Development * .....48                         INTRODUCTION .....48                   [+] COFACTORS FOR CERVICAL CANCER .....49                             A) ESTROGENS AND CERVICAL CANCER .....49                         CERVICAL CANCER AND ESTROGEN RECEPTORS .....51                         ESTROGENS UPREGULATE E6/E7 IN CERVICAL CANCER CELLS .....51                   [+] THE EFFECT OF ESTROGENS IN HPV TRANSGENIC MICE .....53                             1) HPV18 Transgenic Mice .....53                             2) HPV16 Transgenic Mice .....53                   [+] ESTROGENS ALTER THE IMMUNE MICROENV IRONMENT OF THE UTERINE CERVIX .....54                             B) RETINOIDS AND CERVICAL CANCER .....55                         RETINOIDS INHIBIT CELLULAR PROLIFERATION AND INDUCE APOPTOSIS. .....56                         RARβ2 ISOFORM IS A TUMOR SUPPRESSOR.....56                         RAR 2 BLOCKS AP1 ACTIVITY.....57                         CONCLUSION.....57                         REFERENCES .....58

[+] CHAPTER 3 Oncogenes and Tumor Suppressor Genes .....64          [+] INTRODUCTION .....64                         A. ONCOGENES .....64                   [+] B. TUMOR SUPPRESSOR GENES .....72                             1. Retinoblastoma Protein (Rb) .....72                             2. Chromatin Structure Remodeling .....73                             3. p53 .....74                             4. The Pten Gene .....76                             5. The Apc Gene .....76                             6. Nf1 .....77                CONCLUSION .....78                REFERENCES .....79

[+] CHAPTER 4 Epigenetics of Cancer .....83                INTRODUCTION .....83                CHROMATIN ORGANIZATION AND EPIGENETIC CONTROL OF NUCLEAR ARCHITECTURE .....84                DNA METHYLATION .....85                DNA HYPOMETHYLATION IN TUMORS .....86                HYPERMETHYLATION IN TUMOURS .....86                HISTONE COVALENT MODIFICATIONS .....86                HISTONE LYSINE ACETYLATION .....87                HISTONE METHYLATION .....87                HISTONE SERINE PHOSPHORYLATION .....88                AN EPIGENETIC ROLE FOR RNA .....88                EPIGENETIC ALTERATIONS IN TUMOURS .....88                CLINIC IMPLICATIONS FOR EPIGENETICS .....89                EPIGENETIC THERAPY .....89                Clinical Development of Epigenetic Therapy with Hydralazine and Valproate.....90                Epigenetic Therapy: Beyond DNA Methylation and Class I-II-IV HDAC Inhibitors .....91                Targeted Cancer Therapy .....92                CONCLUDING REMARKS AND FUTURE DIRECTIONS .....92                REFERENCES .....93

[+] CHAPTER 5 Signal Transduction Pathways in Cancer .....98                INTRODUCTION .....98                SIGNALING THROUGH RECEPTOR TYROSINE KINASES .....99                RAS-MAPK SIGNALING PATHWAY .....100                PI3K-AKT-NF- B SIGNALING.....101                NF-B Signaling Pathway .....104                JAK-STAT SIGNALING PATHWAY.....104                FAK-SRC SIGNALING .....106                MOLECULAR MECHANISM OF APOPTOTIC SIGNALING IN CANCER .....107                CONCLUSIONS .....110                REFERENCES .....110

[+] CHAPTER 6 Metastasis .....112                1. INTRODUCTION .....112          [+] 2. NEOPLASTIC PROGRESSION .....113                         Tumor Microenvironment .....114          [+] 3. ANGIOGENESIS .....114                         Difference Between Physiologi cal and Tumor Angiogenesis.....115                   [+] Tumor Angiogenesis .....115                             A. Growth Factor Release from Tumor Cells .....115                             B. Extracellular Matrix Degradation by Proteinases .....115                             C. Migration Through Extracellular Matrix and Formation of Immature Blood Vessel .....115                             D. Stabilization of the Immature Vessels .....116          [+] 3. CELL MOTILITY AND INVASION .....117                         A. Actin-Cytoskeleton Remodelling: Protrusion of Lamellipodia and Filopodia .....117                         B. Focal Adhesion Complexes .....117                         C. Extracellular Matrix Degradation by Proteinases .....119                         D. Cell Body Contraction .....119                         E. Cell Detachment .....119                         Epithelial-Mesenchymal Transition .....120          [+] 4. INTRAVASATION .....120                         A. Active Intravasation .....121                         B. Passive Intravasation .....122                6. EMBOLISMS/ CIRCULATION .....122          [+] 7. EXTRAVASATION .....122                         A. Rolling Motion of Tumor Cells .....123                         B. Adhesion to the Vasculature Endothelium.....124                         C. Diapedesis .....125          [+] 8. METASTATIC TUMOR ESTABLISHMENT .....125                         A. Apoptosis .....125                         B. Tumor Dormancy .....125                         C. Proliferation and Formation of Secondary Tumors .....125                CONCLUSIONS .....126                REFERENCES .....127

[+] CHAPTER 7 Cancer Immunology and Novel Strategies for Immunotherapy .....130                INTRODUCTION .....130                IMMUNE RESPONSE, INFLAMMATION AND CANCER .....130          [+] FROM IMMUNOSURVEILLANCE TO IMMUNOESCAPE IN CANCER .....132                         Elimination .....132                         Equilibrium .....133                         Escape .....134          [+] CANCER IMMUNOTHERAPY .....135                         Boosting Immune Elements .....136                         Blocking Suppressive Elements .....139                CONCLUDING REMARKS .....141                REFERENCES .....142

[+] CHAPTER 8 In Vitro and In Vivo Models for Cancer Research .....148                INTRODUCTION .....148          [+] IN VIVO MODELS FOR CANCER RESEARCH .....149                         Chemical Carcinogenesis .....149                         Mouse Skin Tumor Assay .....151                         Induction of Oral Cavity Tumors .....151                         Induction of Stomach Tumors .....152                         Rodent Models for Liver Cancer .....153                         Induction of Tumors in Lung .....154                         Induction of Tumors in Kidney.....154                         Genetically Modified Animals: Transgenic and Knockout Mice Models .....154          [+] IN VITRO MODELS FOR CANCER RESEARCH .....156                         Immortal and Immortalized Cancer Cell Lines .....157                         Gene Knockdown by Small Interfering RNA .....158                         Cancer Stem Cells .....158                CONCLUSIONS .....159                REFERENCES .....159

[+] CHAPTER 9 Molecular Diagnosis and Prognosis .....163                INTRODUCTION .....163                STRATEGIES TO SEARCH AND VALIDATE CANCER BIOMARKERS .....165                METHODS MOST COMMONLY USED IN CANCER MOLECULAR DIAGNOSIS .....165                HEMATO ONCOLOGY .....166                SARCOMAS .....168                CARCINOMAS.....169                CONCLUSIONS .....170                REFERENCES .....170

[+] CHAPTER 10 Chemotherapy and Design of New Antineoplastic Compounds .....172                INTRODUCTION .....172          [+] MEDICINAL CHEMISTRY .....173                   [+] I. Drug Discovery .....173                             Lead Compounds from Natural Sources .....173                             Lead Compounds from Synthetic Sources .....174                   [+] II. Drug Design .....174                             The Pharmacophore .....174                             Binding Interactions in Drugs Design .....175                             Functional Groups as Binding Groups .....175                             Bioinorganic Chemistry .....175                             Structure-Activity Relationships .....176                   [+] III. Drug Testing and Development .....178                             Testing A Lead Compound .....178                             Biological Testing Drugs .....179                             Preclinical Testing .....180                             Toxicity Studies .....180                             Formulation Studies .....181                             Clinical Trials .....181          [+] DRUG DEVELOPMENT FOR NEW ANTINEOPLASTIC COMPOUNDS .....181                         I. Metal Compound in Chemotherapy .....181                         II. Copper Compounds Design .....182                         III: The Proposal for a New Antineoplastic: Casiopeínas® .....183                   [+] IV. Casiopeínas Testing .....184                             Structure-Activity Relationships.....184                             In Vitro and In Vivo Testing .....185                             Mechanism of Action.....185                             Metabolism Studies .....187                             Toxicity .....187                REFERENCES.....188

[+] CHAPTER 11 Mechanisms of Therapy Resistance in Cancer .....192                INTRODUCTION .....192                MULTI DRUG RESISTANCE.....192          [+] DRUG TARGET ALTERATIONS .....193                         Tyrosine Kinase Inhibitors (TKI) .....193                         Hormone Resistance .....194                         Antibodies Resistance .....196                CONCLUSIONS .....196                REFERENCES .....196

[+] CHAPTER 12 Antisense Oligodeoxyribonucleotides (A S-ODNs) for Cancer Gene Therapy: A Clinical Perspective .....198                INTRODUCTION .....198                Antisense Oligonucleotides (AS-ODNs) .....199          [+] AS-ODN Design Considerations .....199                         Target Accessibility .....199                         Cell Uptake .....199                         Stability in Biofluids .....200                         Immunostimulatory Issues .....201                   [+] Clinical Trials for Anticancer AS-ODNs .....201                             Target: c-myc .....201                             Target: H-ras .....203                             Target: Protein Kinase C (PKC) .....205                             Target: PKC- α AND RAF-1 .....205                             Target: Clusterin .....207                             Target: Ribonucleotide Reductase (RNR) .....207                             Target: BCL-2 .....208                         CONCLUDING REMARKS .....211                         REFERENCES .....212

[+] CHAPTER 13 Directions of Future Cancer Research .....219                INTRODUCTION .....219                Epidemiology .....219                Early Detection .....220                Cancer Models .....220                Drug Design and Clinical Trials .....220                “Personalized” Diagnosis and Therapy .....221                Cancer Prevention .....221                CONCLUSIONS .....222                REFERENCES .....222

•  Author Index .....223

•  Subject Index .....224

•  CONTENTS .....c

•  FOREWORD .....i

•  PREFACE .....iii

•  List of Contributors .....iv

[+] CHAPTER 1 Synchronizing Bench and Bedside: A Clinical Overview of Networks and Oscillations .....3                INTRODUCTION .....3                The Network Approach: Anatomy and Physiology .....4                Networks .....4                Overview of Clinical Applications .....6                Oscillations .....5                Normal Brain Function .....6                Epilepsy .....7                Sleep .....7                Aging and Dementia .....7                Parkinson’s Disease .....8                Pain .....8                Malignancy .....8                Psychiatric Disorders .....9                Toward a Pathophysiology Framework .....9                GLOSSARY .....10                REFERENCES .....10

[+] CHAPTER 2 A Primer on Networks in Neuroscience .....13                INTRODUCTION .....13                STRUCTURAL AND FUNCTIONAL NETWORKS .....13                SIMPLE MEASURES TO CHARACTERIZE NETWORK STRUCTURE .....15                SIMPLE NETWORK MODELS .....17                CONCLUSIONS .....19                REFERENCES .....19

[+] CHAPTER 3 Neural Networks in the Developing Human Brain .....21                INTRODUCTION .....21                ANATOMICAL DEVELOPMENT .....21                PHYSIOLOGICAL DEVELOPMENT .....24                FUNCTIONAL CONNECTIVITY .....25                CLINICAL IMPLICATIONS .....28                CONCLUSIONS .....28                REFERENCES .....29

[+] CHAPTER 4 Brain Anatomy and Small-World Networks .....32                SMALL-WORLD NETWORKS .....32                INTRODUCTORY CONCEPTS .....33                WHY WOULD WE EXPECT BRAIN ANATOMY TO SHOW SMALL-WORLD PROPERTIES? .....35                WHAT OTHER PATTERNS MIGHT WE EXPECT? .....36                EVIDENCE FOR SMALL-WORLD BRAIN ORGANIZATION .....36                HUMAN ANATOMICAL NETWORKS: CORTICAL THICKNESS AND GRAY MATTER VOLUME IN HEALTH AND DISEASE .....38                HUMAN ANATOMICAL NETWORKS: DIFFUSION IMAGING .....43                METHODOLOGICAL CONSIDERATIONS .....44                THE COMPLEX STRUCTURE-FUNCTION RELATIONSHIP .....46                CONCLUSION AND FUTURE DIRECTIONS .....46                GLOSSARY .....46                REFERENCES .....48

[+] CHAPTER 5 Sleep Physiology Dynamics: Network Analysis and other Quantitative Approaches .....51                INTRODUCTION .....51                SLOW WAVE OSCILLATIONS IN NREM SLEEP .....52                METABOLIC IMAGING IN SLEEP .....53                THE DEFAULT NETWORK IN SLEEP .....53                FUNCTIONAL CONNECTIVITY NETWORKS IN SLEEP .....54                EMERGING APPROACHES TO QUANTIFY SLEEP ARCHITECTURE: STATE TRANSITION MODELS .....55                EMERGING APPROACHES TO QUANTIFY SLEEP ARCHITECTURE: QUANTITATIVE PHYSIOLOGICAL MODELS .....56                EMERGING APPROACHES TO QUANTIFY SLEEP ARCHITECTURE: ECG-DERIVED SPECTROGRAM .....57                AUTONOMIC MEASUREMENTS OF SLEEP PHYSIOLOGY .....57                COMPUTATIONAL APPROACHES TO ACTIGRAPHY DATA .....58                CLINICAL IMPLICATIONS .....58                METHODOLOGICAL AND PRACTICAL CONSIDERATIONS .....59                CONCLUSIONS .....59                REFERENCES .....60

[+] CHAPTER 6 Multimodal Imaging in Epilepsy: Combining EEG and fMRI.....64                THE RELATIONSHIP OF NETWORKS AND BRAIN STATES .....64                STUDYING “ACTION VERSUS REST” VERSUS STUDYING “REST” .....64                METHODS TO STUDY THE BRAIN AT REST .....65                MULTIMODAL IMAGING EXAMPLES IN DISEASES .....65                THE COMBINATION OF EEG AND fMRI .....65                THE PHYSIOLOGY OF THE SIGNALS AND THEIR CONCEPTUAL LINK .....66                MOTIVATION AND FEASIBILITY OF COMBINING EEG AND fMRI .....66          [+] ENDOGENOUS NEURONAL OSCILLATIONS IN HEALTHY VOLUNTEERS AT REST .....67                         EEG/fMRI of Ongoing Neuronal Oscillations in the Awake State .....67                         EEG/fMRI of Endogenous Neuronal Oscillations During Sleep and Reduced Consciousness .....69                         Endogenous Neuronal Activity in Epilepsy .....70                         Technical Remarks .....70          [+] THE PAST AND FUTURE ROUTE OF EEG/FMRI RESEARCH IN EPILEPSY .....70                         Feasibility .....70                         Initial Aim: Mapping the Origin of Epileptic Activity .....71                         Inconclusive Results: Methodological Refinement .....71                         Ictal and Interictal Activity: Analysing Epileptic Networks.....71                         Clinical Implications: Validation Studies .....71                         Controversial Findings: Possible Explainations .....72                         A Different Application: Insights into the Neurobiology of Epilepsy? .....72                THE FUTURE .....74                EEG/FMRI STUDIES IN CHILDREN .....74                SUMMARY AND FUTURE DIRECTIONS .....74                ACKNOWLEDGEMENT .....74                REFERENCES .....75

[+] CHAPTER 7 Abnormal Synchrony and Oscillations in Neuropsychiatric Disorders .....81                INTRODUCTION .....81                DISTRIBUTED PROCESSING AND NEURONAL SYNCHRONIZATION .....81                STUDIES IN HUMAN SUBJECTS .....83                MEASURES OF OSCILLATORY ACTIVITY AND SYNCHRONY .....83                ANATOMICAL SUBSTRATES, TRANSMITTER-SYSTEMS AND THE GENERATION OF NEURAL SYNCHRONY .....84                NEURAL SYNCHRONY IN SCHIZOPHRENIA .....84                NEURAL SYNCHRONY IN EPILEPSY .....87                NEURAL SYNCHRONY IN AUTISM.....89                NEURAL SYNCHRONY IN ALZHEIMER'S DISEASE .....90                NEURAL SYNCHRONY IN PARKINSON'S DISEASE .....92          [+] DISCUSSION .....93                         Neural Synchrony and Pathological Brain States .....93                         Neural Synchrony and Pathological Brain States: Implications for Normal Brain Functioning .....93                         Future Perspectives of Research on Neural Synchrony in Pathological Brain States .....94                CONCLUSIONS .....94                REFERENCES .....95

[+] CHAPTER 8 Brain Stimulation Techniques and Network Studies of Brain Function.....100                INTRODUCTION .....100                TRANSCRANIAL MAGNETIC STIMULATION: BASIC BIOPHYSICS .....101                TMS PARADIGMS: PHYSIOLOGICAL EFFECTS AND MECHANISMS OF ACTION .....102                tDCS: BIOPHYSICS AND MECHANISMS OF ACTION .....105                CLINICAL UTILITY OF BRAIN STIMULATION TECHNIQUES .....105                TRANSCRANIAL BRAIN STIMULATION AND NETWORK ANALYSIS .....106                ASSESSING THE ROLE OF OSCILLATIONS .....111                BRAIN STIMULATION AND SLEEP .....112                BRAIN STIMULATION AND DEPRESSION .....114                MOTOR RECOVERY AFTER STROKE .....115                CONCLUSIONS .....117                REFERENCES .....117

•  SUBJECT INDEX .....124

•  CONTENTS .....c

•  FOREWORD.....i

•  PREFACE.....ii

•  List of Contributors .....iv

•  ACKNOWLEDGEMENTS .....vii

[+] CHAPTER 1 The Relationship between Liver Fibrosis and Hepatocellular Carcinoma.....3                1. EPIDEMIOLOGY, ADVANCED LIVER FIBROSIS AND CIRRHOSIS ARE PRECURSORS TO HCC.....3                2. MECHANISMS OF HCC DEVELOPMENT IN THE CONTEXT OF LIVER FIBROSIS AND CIRRHOSIS.....4                3. DIAGNOSIS .....5                4. TREATMENT OF HCC.....5                KEY CONCEPTS.....6                ABBREVIATIONS.....6                REFERENCES.....6

[+] CHAPTER 2 A Possible Link between Non-Alcoholic Steatohepatitis and Hepatocellular Cancer.....8                INTRODUCTION .....8                CONCLUSIONS AND PERSPECTIVES.....16                DECLARATION OF INTEREST.....17                ABBREVIATIONS.....17                REFERENCES .....18

[+] CHAPTER 3 Viral Associated Hepatocellular Carcinoma .....21                1. EPIDEMIOLOGY OF THE VIRUS ASSOCIATED HEPATOCELLULAR CARCINOMA.....21                2. HBV AND HCC .....21                3. HCV AND HCC.....25                ACKNOWLEDGEMENTS.....26                DECLARATION OF CONFLICT OF INTEREST.....26                ABBREVIATIONS.....26                REFERENCES .....27

[+] CHAPTER 4 Non-Viral Cause of Liver Cirrhosis: Do they Lead to Hepatocellular Carcinoma?.....32                ETIOLOGY AND RISK FACTORS OF CIRRHOSIS.....32                DO NON-VIRUS CAUSES OF CIRRHOSIS LEAD TO HCC?.....32                WHAT ARE THE MOLECULAR MECHANISMS BY WHICH NON-VIRUS CIRRHOSIS LEADS TO HCC?.....35                SUMMARY.....36                ABBREVIATIONS.....36                REFERENCES.....37

[+] CHAPTER 5 Signaling Pathways Involved in Molecular Carcinogenesis of Hepatocellular Carcinoma.....39                1. INTRODUCTION .....39                2. MOLECULAR PATHWAY IN HCC.....39                3. MOLECULAR TARGETED THERAPY AGAINST HCC.....46                4. CONCLUSIONS.....47                CONFLICT OF INTEREST.....48                ABBREVIATIONS .....48                REFERENCES .....49

[+] CHAPTER 6 MicroRNAs in Human Hepatocellular Carcinoma.....56                INTRODUCTION .....56                CONCLUDING REMARKS.....61                ACKNOWLEDGEMENTS .....63                ABBREVIATIONS.....63                REFERENCES.....64

[+] CHAPTER 7 Characteristics of Liver Stem/Progenitor Cells and their Relation to Cancer: Response to Inflammatory and Cell Death Signals.....67                INTRODUCTION.....67                SUMMARY.....76                REFERENCES.....76

[+] CHAPTER 8 Aging and Hepatocellular Carcinoma: Possible Molecular Mechanisms.....80                1. INTRODUCTION.....80                2. POSSIBLE MOLECULAR MECHANISMS INVOLVED IN AGING-RELATED HCC.....81                3. SUMMARY.....83                FINANCIAL SUPPORT.....83                ABBREVIATIONS.....83                REFERENCES.....83

[+] CHAPTER 9 Molecular Mechanisms of Liver Cancer Metastasis.....86                INTRODUCTION.....86                SUMMARY .....97                VEGF .....99                EGFR/Erb .....100                SUMMARY .....101                ABBREVIATIONS .....101                REFERENCES.....102

[+] CHAPTER 10 Biomarkers for Diagnosis and Surveillance in Hepatocellular Carcinoma.....106                BRIEF ACCOUNT ON THE EPIDEMIOLOGY AND ETIOLOGY OF HEPATOCELLULAR CANCER (HCC).....106                CONCLUSIONS.....113                REFERENCES.....113

[+] CHAPTER 11 Animal Models of Hepatocellular Carcinoma.....116                INTRODUCTION.....116                ANIMAL MODELS OF INFECTION-ASSOCIATED HEPATOCARCINOGENESIS.....117                CARCINOGEN-INDUCED ANIMAL MODELS OF HCC.....120                TRANSGENIC MOUSE MODELS OF HCC .....121                INFLAMMATION-ASSOCIATED ANIMAL MODELS OF HCC.....123                ANIMAL MODELS OF METASTATIC HCC.....124                ANIMAL MODELS OF THERAPEUTIC INTERVENTIONS .....124                CONCLUSIONS.....125                FINANCIAL SUPPORT.....125                ABBREVIATIONS .....125                REFERENCES.....126

[+] CHAPTER 12 Chemoprevention of Hepatocellular Carcinoma.....129                INTRODUCTION.....129                HEPATITIS B RELATED TUMOR .....129                HEPATITIS C RELATED TUMOR.....133                CONCLUSIONS.....135                ABBREVIATIONS.....135                REFERENCES.....136

[+] CHAPTER 13 An Overview on Molecular Therapy for Hepatocellular Carcinoma.....138                INTRODUCTION.....138                TUMOR ANGIOGENESIS .....140                GROWTH RECEPTORS.....141                AGENTS THAT TARGET PI3K/AKT/MTOR PATHWAY.....145                SUMMARY AND FUTURE PROSPECTS .....145                FINANCIAL SUPPORT .....145                ABBREVIATIONS.....145                REFERENCES.....146

[+] CHAPTER 14 Role of Angiogenesis in HCC Development and Therapy.....149                INTRODUCTION.....149                HCC AND ANGIOGENESIS .....150                VASCULAR ENDOTHELIAL GROWTH FACTOR.....150                ANGIOPOIETINS.....151                BASIC FIBROBLAST GROWTH FACTOR.....152                OTHER MOLECULES THAT REGULATE HCC ANGIOGENSIS.....152                HEPATITIS.....153                NAFLD/NASH AND THE METABOLIC SYNDROME.....154                TARGETED HUMAN HCC ANTI-ANGIOGENIC THERAPY.....154                POTENTIAL DRAWBACKS OF ANTI-ANGIOGENIC THERAPY.....156                FUTURE PERSPECTIVES.....157                ACKNOWLEDGEMENTS.....157                REFERENCES.....157

[+] CHAPTER 15 Non-Surgical Management of Hepatocellular Carcinoma: Possible Mechanisms.....162                INTRODUCTION.....162                MOLECULAR CLASSIFICATION OF HCC.....163                POSSIBLE MOLECULAR MECHANISMS ASSOCIATED WITH COMMON ADJUVANT THERAPIES IN HCC .....163                ABBREVIATIONS.....165                REFERENCES .....165

[+] CHAPTER 16 Treatment of Hepatocellular Carcinoma with Traditional Chinese Medicine: Possible Molecular Mechanisms.....167                INTRODUCTION .....167                MOLECULAR MECHANISMS OF TCM IN THE TREATMENT OF HCC .....167                SUMMARY.....171                FINANCIAL SUPPORT.....171                ABBREVIATIONS .....171                REFERENCES.....172

[+] CHAPTER 17 Randomised Controlled Trials in the Primary Treatment of Hepatocellular Carcinoma.....174                BACKGROUND.....174                I. TREATMENTS WITH CURATIVE INTENT .....176                II. PALLIATIVE TREATMENTS.....185                CONCLUSIONS.....192                ABBREVIATIONS .....192                ACKNOWLEDGEMENT.....193                REFERENCES .....193

•  SUBJECT INDEX.....196

•  CONTENTS .....c

•  FOREWORD .....i

•  PREFACE .....ii

•  ACKNOWLEDGEMENT .....iii

•  LIST OF ABBREVIATIONS .....iv

[+] CHAPTER 1 Comparative Retinae and Visual Cells .....3                VISUAL CELLS.....3          [+] RETINAL LAYERS .....4                         1. STURGEON .....6                         2. EEL .....18                         3. GOLDFISH .....21                         4. LIP SHARK .....24                         5. ORIENTAL WEATHER FISH .....34                         6. GARPIKE .....40                         7. SOUTHERN FLOUNDER .....48                         8. MUDSKIPPER .....52                         9. LUNGFISH .....57                         10. JAPANESE FIRE BELLY NEWT .....68                         11. CHINESE EDIBLE FROG .....78                         12. AFRICAN CLAWED FROG .....87                         13. CHINESE POND TURTLE .....92                         14. CROCODILE .....99                         16. GOLDEN GECKO .....114                         17. SOFTSHELL TURTLE .....120                         18. DOMESTIC DUCK .....125                         19. CHINESE FRANCOLIN .....130                         20. DOMESTIC CHICKEN .....134                         21. COW .....143                         22. ARABIAN CAMEL.....149                         23. DOG .....151                         24. CAT .....156                         25. MONKEY .....161                         26 MOUSE. .....179                         27 PIG. .....182                REFERENCES .....189

[+] CHAPTER 2 Other Retinal Layers – From Development to Maturation (A Chicken Model) .....191                INTRODUCTION .....191                OUTER NUCLEAR LAYER .....191                OUTER PLEXIFORM LAYER .....191                HORIZONTAL CELLS .....192                DIFFERENTIATION OF HORIZONTAL CELLS .....193                BIPOLAR CELLS .....195                MÜLLER CELLS .....197                AMACRINE CELLS .....201                INNER PLEXIFORM LAYER .....206          [+] GANGLION CELL LAYER .....212                         Ganglion Cell Nucleus in Development .....212                         Ganglion Cell Cytoplasm in Development .....212                         Nissl Bodies .....213                         Neurotransmitter in Ganglion Cells .....213                NERVE FIBER LAYER AND INTERNAL LIMITING MEMBRANE .....216                REFERENCES .....217

[+] CHAPTER 3 Developing Retinae of Different Species .....222                INTRODUCTION .....222                REFERENCES .....236

[+] CHAPTER 4 Degeneration .....237                INTRODUCTION .....237                BLACK MOORE GOLDFISH CARASSIUS AURATUS.....238                RCS RAT (THE ROYAL COLLEGE OF SURGEONS RAT) RATTUS NORVEGICUS.....243                ANDERSON’S SHREW (TREESHREW) SUNCUS STOL ICZKANUS.....250                HUMAN HOMO SAPIENS.....252                DRUG TREATMENT KETAMINE TOXICITY – ICR MICE (INSTITUTE FOR CANCER RESEARCH MICE) MUS MUSCU LUS .....256                REFERENCES .....257

•  Index .....259

•  CONTENTS.....d

•  FOREWORD.....ii

•  PREFACE.....iii

•  List of Contributors.....iv

[+] CHAPTER 1 Regulation of Synaptic Plasticity and Long-Term Memory by CREB:Implications for Targeting Memory Disorders Including Alzheimer's Diseaseand Rubinstein-Taybi Syndrome.....3                INTRODUCTION.....3                STRUCTURE OF CREB AND MECHANISM OF CREB SIGNALING.....4          [+] CREB AND SYNAPTIC PLASTICITY.....6                         Activation of CREB During LTP.....6                         LTP in CREB Mutant Mice.....6                         LTP and CREB Overexpression.....7                   [+] CREB and LTD.....7                             Role of CREB in the Induction of Synaptic Plasticity.....7                   [+] CREB AND MEMORY.....8                             Manipulations of CREB for Assessment of LTM In vivo.....8                   [+] CREB AND MEMORY DISORDERS.....13                             Coffin-Lowry Syndrome and Rubinstein-Taybi Syndrome.....14                             CREB and Age-Related Memory Decline.....14                             CREB and Alzheimer’s Disease.....15                             Other Disorders.....15                         CONCLUSIONS.....15                         ACKNOWLEDGEMENTS.....16                         REFERENCES.....16

[+] CHAPTER 2 The Role of CREB in Neuronal Plasticity, Learning and Memory, and inNeuropsychiatric Disorders.....22          [+] MOLECULAR BASIS OF LONG-LASTING ALTERATIONS IN CENTRAL NERVOUS SYSTEM.....22                         Protein Synthesis is Required for Long-Lasting Changes in the Nervous System.....22                         Immediate Early Genes in Long-Term Plasticity.....23                CREB FAMILY TRANSCRIPTION FACTORS: MOLECULAR STRUCTURE.....24                CREB ACTIVATION BY EXTRACELLULAR SIGNALS DURING SYNAPTIC PLASTICITY.....25          [+] THE SIGNALLING PATHWAYS AND KINASES THAT LEAD TO CREB PHOSPHORYLATION.....26                         i) cAMP Signalling to CREB.....26                         The Role of CREB in Neuronal Plasticity Transcription Factors CREB and NF-kB 27ii) Ca2+ Signalling to CREB.....27                         iii) Growth Factor Signalling to CREB.....27                PHOSPHATASES INVOLVED IN CREB DEPHOSPHORYLATION.....27          [+] REGULATION OF CREB-DEPENDENT GENE EXPRESSION.....28                         The Classical View of CREB-Dependent Transcription.....28                         Additional CREB Phosphorylation Sites Influence CREB-Dependent Transcription.....29                         TORC (Transducers of Regulated CREB Activity) in CRE-Dependent Transcription.....29                         Transcriptional Repressors Modulate CREB Activity.....30                         Role of Histone Deacetylase (HDAC) in Attenuating CREB-Dependent Transcription.....30                CREB TARGET GENES.....30          [+] THE ROLE OF CREB IN LEARNING, MEMORY AND SYNAPTIC PLASTICITY.....32                         CREB is Required for Long-Term Plasticity in Invertebrates.....32                         CREB Modulates Learning and Memory in Vertebrates.....32          [+] THE ROLE OF CREB IN NEUROPSYCHIATRIC DISEASES.....34                         CREB in Depression.....35                         CREB in Anxiety.....35                CONCLUSIONS.....36                ACKNOWLEDGEMENTS.....36                REFERENCES.....37

[+] CHAPTER 3 Transcriptional Profiling of Hippocampal Memory-Associated SynapticPlasticity: Old Friends and New Faces.....43                INTRODUCTION.....43          [+] TRANSCRIPTIONAL PROFILING OF MEMORY-ASSOCIATED SYNAPTIC PLASTICITY:COHERENT GENE CLUSTERS AND NOVEL TRANSCRIPTIONAL CONTROL EMERGE.....45                         Challenges for Microarray-Based Study of Memory-Associated Synaptic Plasticity.....46                         Synaptic Plasticity-Associated Gene Clusters Identified by Microarray Approaches.....46                         Control of Transcription and Translation.....47                         Selective Synapse Destabilization.....48                         Cytoskeletal Structural Control.....49                   [+] Transcription Factors in Memory-Associated Synaptic Plasticity.....49                             In silico Transcription Factor Binding Site (TFBS) Analysis.....49                             Serum Response Factor - SRF.....51                             SRF and Immediate Early Genes.....52                             SRF and Structural Regulation.....52                             cAMP Response Element-Binding Protein - CREB.....53                             Nuclear Factor-κB - NF-κB.....54                             A Novel Role for HIF-1 in Memory-Associated Synaptic Plasticity.....55                             Nuclear Factor of Activated T-Cells - NFAT.....57                CONCLUSIONS.....58          [+] MATERIALS AND METHODS.....58                         Animal Maintenance and Behavioural Assessment in the Open Field Arena.....58                         Morris Water Maze Training and Tissue Collection.....58                         Immunofluorescent Double-Labelling of HIF-1α and GFAP.....59                         Image Analysis.....59                ACKNOWLEDGEMENTS.....59                REFERENCES.....59

[+] CHAPTER 4 Roles for NF-κB in Regulating Gene Expression in Synaptic Plasticity and Memory.....66          [+] INTRODUCTION.....66                         Transcriptional and Translational Control of Synaptic Plasticity and Memory.....67                         Transcription Factor NF-kB.....68                         NF-κB Activity in Neurons.....68                         NF-κB in Synaptic Plasticity and Memory.....68                         Gene Targets of NF-κB.....71                         Interactions Between NF-κB and CREB in Synaptic Plasticity and Memory.....72                         Chromatin Modification in Regulating Transcription for Memory.....72                         Alternative Models for Long Term Memory.....73                         Drug Therapy for Memory Improvement.....73                FUTURE DIRECTIONS.....75                ACKNOWLEDGEMENTS.....76                REFERENCES.....76

[+] CHAPTER 5 NF-κB Proteins in Adult Neurogenesis: Relevance for Learning and Memoryin Physiology and Pathology.....79                THE NF-κB FAMILY OF TRANSCRIPTION FACTORS.....79                NF-κB ROLE IN SYNAPTIC PLASTICITY IN LEARNING AND MEMORY PROCESSES.....80                ADULT NEUROGENESIS.....82                LINKS BETWEEN LEARNING/MEMORY AND ADULT HIPPOCAMPAL NEUROGENESIS.....82                DISREGULATED NF-κB SIGNALING AND NEUROGENESIS IN CNS DISORDERS.....83                ADULT NEUROGENESIS AND NF-κB.....85                POTENTIAL MOLECULAR PARTICIPANTS LINKING NF-κB SIGNALING, NEUROGENESIS ANDCOGNITION.....87                CONCLUSIONS.....88                ACKNOWLEDGEMENTS.....89                ABBREVIATIONS.....89                REFERENCES.....92

[+] CHAPTER 6 NF-kB Transcription Factor: A Model for the Study of TranscriptionRegulation in Memory Consolidation, Reconsolidation and Extinction.....97          [+] INTRODUCTION.....97                         The NF-kB System of Gene Expression Regulation.....100                         The Role of NF-kB in the Synapse to Nucleus Communication.....100                         NF-kB in Neural Plasticity.....102                         NF-kB IN MEMORY CONSOLIDATION.....102                         NF-kB in Invertebrates’ Memory Processes.....103                         NF-kB in Mammalian Memory Models.....104                         KO Mice for NF-kB Components.....104                         Neurotransmiters and Neuromodulators that Activate NF-kB in Neuroplasticity and Memory.....106                         Downstream Effectors of NF-kB Associated with the Formation and Expression of Memory.....106                         NF-kB IN MEMORY RECONSOLIDATION.....106          [+] NF-kB IN EXTINCTION MEMORY.....107                         Inhibition of NF-kB During the Formation of Extinction Memory.....107                CONCLUSIONS.....109                ACKNOWLEDGEMENTS.....109                REFERENCES.....109

[+] CHAPTER 7 NF-κB in Neurons—Mechanisms and Myths.....113                INTRODUCTION TO NF-ΚB AND ITS ACTIVATION.....113                PHOSPHORYLATION OF RELA.....115                Untitled.....116                METHODS APPLIED TO MONITOR NF-κB.....116                EXPERIMENTAL MANIPULATION OF NF-κB.....117                NF-κB IN NEURONS: EVIDENCE AND ERRORS.....118                NF-κB INHIBITION—PROSPECTS FOR THERAPY.....125                ACKNOWLEDGEMENTS.....125                REFERENCES.....125

•  INDEX.....130

•  CONTENTS.....c

•  FOREWORD.....i

•  PREFACE.....ii

•  List of Contributors.....iii

•  ACKNOWLEDGEMENTS.....v

[+] SECTION I: MOLECULAR AND CELLULAR PROCESS IN THEFORMATION AND GROWTH OF HEMATOLOGICAL TUMORS.....vi          [+] CHAPTER 1 Normal and Leukemic Hematopoietic Cells Niche.....3                         INTRODUCTION.....3                         REFERENCES.....8          [+] CHAPTER 2 Cancer Stem Cells.....10                         INTRODUCTION.....10                         THERAPEUTIC OPPORTUNITIES.....11                         REFERENCES.....12          [+] CHAPTER 3 Programmed Cell Death: Apoptosis, Autophagy, Necrosis and OxidativeStress in Hematological Malignacies.....14                         1.-INTRODUCTION.....14                         2.-CELLULAR DEATH.....14                   [+] 3.-APOPTOSIS.....16                             3.1- Apoptosis and Hematological Malignacies.....18                   [+] 4.-NECROSIS.....20                             4.1- Necrosis and Hematological Malignacies.....21                   [+] 5.-AUTOPHAGY.....22                             5.1-Autophagy and Hematological Malignancies.....23                   [+] 6.- OXIDATIVE STRESS.....24                             6.1- Oxidative Stress and Hematological Malignancies.....25                         REFERENCES.....29          [+] CHAPTER 4 Proteasome Inhibition in Hematological Malignancies.....34                   [+] INTRODUCTION.....34                             Protein Degradation and Cellular Homeostasis.....34                             Some Intriguing Questions about Intracellular Proteolysis and the Lysosome Pathway.....35                             The Discovery of the Ubiquitin-Proteasome System.....35                             The Mammalian Proteasome.....39                             Why Cancer Cells are Susceptible to Inhibition of Protein Degradation?.....41                             The Development of Bortezomib (PS-341)......43                             The Rationale for Bortezomib use in the Treatment of Multiple Myeloma (MM).....44                             Bortezomib in Frontline Therapy for MM.....44                             Bortezomib in other Clinical Settings Besides MM.....45                             Other Drugs in Investigation.....45                             Perspective.....45                         REFERENCES.....45          [+] CHAPTER 5 Epigenetics and DNA Methylation Modifications.....50                         1.-INTRODUCTION.....50                         2.-PATHWAYS AFFECTED BY EPIGENETIC CHANGES IN HEMATOPOIETICMALIGNANCIES.....52                   [+] 3. - EPIGENETIC ALTERATIONS AS A TREATMENT TARGET.....53                             3.1. DNA Methyltransferase Inhibitors.....53                             3.2. Histone Deacetylase Inhibitors.....55                         REFERENCES.....55          [+] CHAPTER 6 microRNAs and Non-Coding RNAs in Hematological Malignancies.....60                         1.-INTRODUCTION.....60                         2.-miRNAs AND NORMAL HEMATOPOIESIS.....63                         3.0-miRNAs AND LYMPHOID MALIGNANCIES.....67                         4.-miRNAs AND LYMPHOMAS.....70                         5.-miRNAs AND CHRONIC MYELOID LEUKEMIA.....71                         6.-miRNAs, MYELODYSPLASTIC DISORDERS AND ACUTE MYELOID LEUKEMIAS.....72                         REFERENCES.....74          [+] CHAPTER 7 Transcription Factors in Hematological Malignancies.....78                         1.-INTRODUCTION.....78                   [+] 2. –TRANSCRIPTION FACTORS AND HEMATOLOGICAL MALIGNANCIES.....79                             2.1 - Hypoxia-Inducible Factors (HIFs).....79                             2.2 – Nuclear Factor-kB (NF-kB).....82                             2.3 – Signal Transducer and Activator Of Transcription.....87                             2.4. - Homeobox (HOX).....91                   [+] 3.- THERAPEUTIC STRATEGIES TARGETING TRANSCRIPTION FACTORS.....93                             3.1 – Some Agents and Transcription Factors Targets.....93                         REFERENCES.....94          [+] CHAPTER 8 Protein Prenylation and Hematological Malignancies.....103                         1.-INTRODUCTION.....103                         2.0-SYNTHESIS OF ISOPRENOIDS.....103                         3.-PROTEIN PRENYLATION.....105                   [+] 4.-ROLE OF PRENYLATED PROTEINS IN THE BIOLOGY OF HEMATOLOGICALMALIGNANCIES.....106                             Ras GTPases: Molecular Regulation and Downstream Signaling Pathways.....106                         5.-PRENYLATED PROTEINS: RELEVANCE OF RAS IN LEUKEMOGENESIS.....107                   [+] 6.-DOWNSTREAM EFFECTORS OF RAS SIGNALING.....109                             MAPK Pathway.....109                             MAPK Pathway Signaling and Hematopoietic Cells.....110                             PI3K/PKB/AKT Pathway.....110                             6.-PI3K/PKB/AKT IN HEMATOPOIESIS AND HEMATOLOGICAL MALIGNANCIES.....111                         7.-OTHER PRENYLATED PROTEINS AND HEMATOLOGICAL MALIGNANCIES.....112                         8.-PHARMACOLOGICAL INHIBITION OF PROTEIN PRENYLATION.....113                         9.-INHIBITORS OF HMG-COA REDUCTASE.....114                         10.-FARNESYL TRANSFERASE INHIBITORS.....114                         11.-CONCLUSION.....116                         REFERENCES.....117          [+] CHAPTER 9 Hematological Neoplasia and Angiogenesis: A Review.....122                         1.– ANGIOGENESIS OVERVIEW.....122                   [+] 2.-FEATURES OF PHYSIOLOGIC VERSUS TUMORS VESSELS BLOOD.....122                             2.1 – Factors Involved in the Angiogenic Switch.....123                             2.2 – Vascular Endothelial Growth Factor and Vegf Receptors (VEGFRs)......126                             2.3 – Molecular Mechanisms of Angiogenic Switch.....129                             2.4–Contribution of Bone Marrow-Derived Endothelial Precursors (EPCs).....130                         3.- LYMPHANGIOGENESIS IN HEMATOLOGICAL CANCER.....131                         4.- MICROENVIRONMENT AND ANGIOGENESIS IN HEMATOLOGIC MALIGNANCIES.....132                   [+] 5.– ANGIOGENESIS IN MULTIPLE MYELOMA.....133                             5.1- Interactions in the BM Microenvironment Mediated by Angiogenic Factors in Multiple Myeloma.....134                             5.2-The Importance of Autocrine and Paracrine Angiogenic Loops in Multiple Myeloma.....134                   [+] 6.– ANGIOGENESIS IN LEUKEMIA.....135                             6.1 – The Importance of VEGF and VEGF Receptor in Leukemia.....136                             6.2- Role of Autocrine and Paracrine Angiogenic Loops in Leukemia.....136                         7. – ANGIOGENESIS IN MYELODYSPLASTIC SYNDROMES.....137                   [+] 8.– ANGIOGENESIS IN LYMPHOMA.....138                             8.1-The Roles of Angiogenesis and Lymphangiogenesis in Lymphoma.....139                   [+] 9.- METHODS TO ASSESS ANGIOGENESIS IN HEMATOLOGIC MALIGNANCIES.....140                             9.1- Methods.....140                             9.2-Advantages and Disadvantages of the Direct Methods.....141                             9.3-Indirect Methods.....141                             9.4-Advantage and Disadvantages of the Indirect Methods.....141                         10– ANTIANGIOGENIC TREATMENT.....141                         CONCLUSIONS.....142                         REFERENCES.....142

[+] SECTION II: MOLECULAR PATHOGENESIS OFLYMPHOPROLIFERATIVE DISEASES.....151          [+] CHAPTER 10 Physiopathogenesis of Lymphoma.....152                         1.0-INTRODUCTION.....152                         2.0-BIOLOGY AND CELLULAR ORIGIN.....153                         3.0-MOLECULAR PATHOGENESIS.....155                         4.0-EPIDEMIOLOGY.....157                         5.0-CLINICAL PRESENTATION.....158                         6.0-DIAGNOSIS.....159                         7.0-STAGING AND PRETREATMENT EVALUATION.....162                         8.0-PRINCIPLES OF TREATMENT AND PROGNOSIS.....165                         REFERENCES.....166          [+] CHAPTER 11 Molecular Basis of Acute Lymphoblastic Leukemia.....169                         1.0-INTRODUCTION.....169