Note: Intro -- Foreword -- Preface -- Acknowledgments -- Contents -- Editors and Contributors -- Introduction -- 1 PI3K-Akt-mTOR Signaling in Cancer and Cancer Therapeutics -- Introduction -- The PI3K-Akt-mTOR Signaling Pathway -- PI3K-Akt-mTOR Signaling in Human Physiology: Anabolic Metabolism -- PI3K-Akt-mTOR Signaling in Human Physiology: Regulation of Cell Cycle Progression and Survival -- PI3K-Akt-mTOR in Human Disease: Germline Disorders of Overgrowth and Cancer Susceptibility -- PI3K-Akt-mTOR in Human Disease: Somatic Genetic Mutations in Syndromes of Segmental Overgrowth and Cancer -- Targeting Oncogenic PI3K-Akt-mTOR Signaling for Cancer Therapy -- Clinical Responses to PI3K-Akt-mTOR Inhibitors -- Putative Mechanisms Underlying Suboptimal Drug Responses: Incomplete Pathway Suppression -- Putative Mechanisms Underlying Suboptimal Drug Responses: PI3K Inhibitors Cause Hyperglycemia and Hyperinsulinemia -- Putative Mechanisms Underlying Suboptimal Drug Responses: Drug-Induced Signaling Adaptation and Feedback -- Future Directions: Identifying Effective Drug Combinations -- Conclusion -- Acknowledgments -- References -- Part I PI3K-mTOR Pathway in Cancers -- 2 The mTOR Complexes in Cancer Cell Metabolism -- Introduction -- Glucose Metabolism (Glycolysis) -- Oxidative and Mitochondrial Metabolism -- Glutamine Metabolism -- Amino Acid Metabolism -- Pentose Phosphate Pathway and Nucleotide Synthesis -- Lipid Metabolism -- Acetylation -- Clinical Relevance -- Conclusions and Future Perspectives -- Acknowledgments -- References -- 3 PI3K-AKT-mTOR Pathway Cooperates with the DNA Damage Repair Pathway: Carcinogenesis in Triple-Negative Breast Cancers and Beyond -- Introduction -- Alterations of PI3K-AKT-mTOR Pathway in BC -- Alterations of PI3K-AKT-mTOR Pathway in Subtypes of BC -- Alteration(S) of PI3K-AKT-mTOR Pathway in BC Is Contextual. , PI3K-AKT-mTOR Pathway Alterations in the Context of DNA Damage Response -- DNA Damage in Invasive Carcinoma of Breast: Alterations of DDR Pathway Genes and HRD Genes in Basal-Like BC -- PI3K-AKT-mTOR Pathway and DDR Pathway in Basal-like BC: Protein-Protein Interactions -- 17 PI3K-AKT-mTOR Signaling Pathway Genes: Proteins (Amino Acid -- Aa) and Their Cellular Functions -- 12 DNA Damage Repair Pathway Genes: Proteins and Their Cellular Functions -- PI3K-AKT-mTOR Pathway Inhibition in the Context of DDR: PARP Inhibitors in BC -- PARP Inhibitors as Chemo/Radiopotentiating Agents: TNBC and Beyond -- A Combination of PARP Inhibitors and PI3K-AKT-mTOR Pathway Inhibitors: Drug Sensitivity and Drug Resistance -- Acknowledgments -- References -- 4 The AKT-mTOR Signaling Pathway for Drug Response Prediction and Prognostic Signatures -- The PI3K-AKT-mTOR Signaling Pathway in Cancer: An Overview -- The PI3K-AKT-mTOR Pathway: Kinase Activation and Signaling Cascades -- The PI3K-AKT-mTOR Pathway: Association Between PIK3CA Mutation and Activation of the PI3K-AKT-mTOR Signaling Network -- Activation of the PI3K-AKT-mTOR Signaling Pathway as Prognostic and Predictive Biomarker -- High Throughput Multiplexed Platforms for Functional Analysis of the PI3K-AKT-mTOR Pathway of Clinical Samples -- Antibody-Based Technologies -- Multiplex Immunoassays -- Reverse Phase Protein Microarray -- Phosphoflow -- Tissue Microarrays -- Non-antibody-Based Technologies -- Concluding Remarks -- References -- 5 Resistance to PI3K Pathway Inhibition -- Introduction -- The PI3K-AKT-mTOR Pathway -- Drug-Induced Relief of Feedback Results in Pathway Reactivation -- mTORC1 Inhibition Promotes AKT Activation -- mTORC1 Inhibition Relieves GRB10-Mediated PI3K Suppression -- mTOR Kinase Inhibition Causes Feedback-Dependent Biphasic Regulation of AKT Signaling. , AKT Feedback Regulation of RTK Expression -- Drug-Induced Adaptive/Compensatory Activation of Parallel Signaling Pathways in the Network -- Activation of ERK Signaling -- Coordinated Activation of RAS/RAF Signaling in Resistance -- Feedback Regulation of Nuclear Hormone Signaling -- Wnt-β-Catenin Cooperation with PI3K Signaling -- Myc Amplification -- JAK2/STAT5 Inhibition Circumvents PI3K Resistance -- Additional Implicated Mechanisms of PI3K Resistance, Mechanisms not yet Elucidated -- mTORC1 Inhibition Is Required for Sensitivity to PI3K-Alpha Inhibition -- Inactivating PTEN Mutations Result in PI3K-Beta Hyperactivation -- Mechanisms of Resistance Common to Cellular Signaling Pathways -- Ligand-Mediated Activation of Distinct, Non-inhibited Kinases with Shared Downstream Targets -- Tumor Microenvironment May Confer Targeted Therapy Resistance -- Drug-Resistance-Conferring Oncogene Alterations -- Conclusion and Future Directions -- References -- Part II PI3K-mTOR Pathway in Cancer Medicine -- 6 Combination Therapies Targeting the PI3K/AKT/mTOR Pathways -- Introduction -- Positive Regulators of PI3K/AKT/mTOR Pathways -- PI3K -- Agents Targeting PI3K Isoforms -- AKT -- Agents Targeting AKT -- mTOR Complex -- Agents Targeting mTORC1 -- Dual Kinase Inhibitors -- Negative Regulators of PI3K/AKT/mTOR Pathways -- PTEN -- Tuberous Sclerosis Complex (TSC) and the TSC1-TSC2 Complex -- AMPK -- Toxicity of PI3K/AKT/mTOR Inhibitors -- PI3K/AKT/mTOR Combination Strategies -- PI3K/AKT/mTOR Inhibitor and Chemotherapy -- PI3K/AKT/mTOR Inhibitor and Hormonal Agents -- PI3K/AKT/mTOR Inhibitor and Immunotherapy -- PI3K/AKT/mTOR Inhibitor and Biological Therapy -- Proximal/Distal Inhibition (mTOR Inhibitor and IGF Receptor [IGFR], PI3K, or AKT Inhibitor) -- Parallel Signaling Inhibition -- PI3K/AKT/mTOR Inhibitor and Other Targeted Therapies -- Triple Combinations. , Biomarkers -- Conclusion -- References -- 7 Phospho-Inositol-3-Kinase Activity and Dysregulation in Pediatric Leukemia and Lymphoma -- Introduction -- Phosphatidylinositol-3-Kinase (PI3K)-AKT-mTOR Signaling -- PI3K and Cancer -- The Catalytic Subunit p110δ as a Potential Target in Hematologic Malignancies -- Acute Lymphoblastic Leukemia (ALL) -- Lymphoma -- Acute Myeloid Leukemia (AML) -- Chronic Myeloid Leukemia (CML) -- Juvenile Myelomonocytic Leukemia (JMML) -- Clinical Trials -- Conclusions -- Review Criteria -- Acknowledgements -- References -- 8 HER2 Signaling Network in Advanced Breast Cancer: Opportunities for Combination Therapies -- Background -- The PI3K-AKT-mTOR Pathway in HER2 Positive Breast Cancer -- An Overview of the Pathway -- Involvement of the PI3K Pathway HER2+ Breast Cancer -- Activation of PTEN-PI3K-AKT-mTOR Pathway and Anti-HER2 Therapy Resistance -- PI3K-AKT-mTOR Pathway-Specific Inhibitors Either Approve or Active in Clinical Trial -- Pan HER Inhibitors in HER2+ Breast Cancer -- Conclusion -- Acknowledgments -- References -- 9 The PI3K-mTOR Pathway in Prostate Cancer: Biological Significance and Therapeutic Opportunities -- Introduction -- PI3K-mTOR Signaling and Function -- PI3K-mTOR Signaling in Prostate Cancer -- The PI3K-mTOR Pathway and Epigenetic Programming in Prostate Cancer Pathogenesis -- Crosstalk with AR and Other Signaling in Castration-Resistant Prostate Cancer -- The PI3K-mTOR Pathway in Prostate Cancer Metastasis -- Targeting the PI3K-mTOR Pathway in Prostate Cancer -- PI3K Inhibitors -- AKT Inhibitors -- mTOR Inhibitors -- Dual PI3K-mTOR Inhibitors -- Future Perspectives -- References -- Index.

Note: Intro -- Preface -- Contents -- 1 Introduction -- 1.1 Introduction -- 1.2 Physiography of the Cayman Islands -- 1.3 Cayman Research-University of Alberta -- 1.4 Methods -- 1.4.1 Field Work and Drilling -- 1.4.2 Thin Sections -- 1.4.3 Scanning Electron Microscopy -- 1.4.4 X-Ray Diffraction Analysis -- 1.4.5 Electron Microprobe -- 1.4.6 Stable Isotope Analyses -- 1.4.7 87Sr/86Sr Analyses -- 1.4.8 Elemental and Rare Earth Elements -- 1.4.9 U/Th Dating -- References -- 2 Tectonic Setting of the Cayman Islands -- Abstract -- 2.1 Introduction -- 2.2 Earthquakes and Tsunamis -- 2.3 Tectonic Elements on the Cayman Islands -- 2.4 Conclusions -- References -- 3 Bluff Group-the Brac Formation -- Abstract -- 3.1 Introduction -- 3.2 Distribution -- 3.3 Lower Boundary -- 3.4 Upper Boundary -- 3.5 Thickness -- 3.6 Lithology -- 3.6.1 Cayman Brac -- Lepidocyclina Facies -- Mollusc Facies -- Foraminifera Facies -- Fabric Retentive Dolomite Facies -- Fabric Destructive Finely Crystalline Dolomite Facies -- Sucrosic Dolomite Facies -- 3.6.2 Grand Cayman -- 3.7 Porosity -- 3.8 Diagenesis -- 3.9 Dolomite Stoichiometry -- 3.10 Stable Isotopes -- 3.11 87Sr/86Sr Geochronology -- 3.12 Age -- 3.13 Depositional Regimes -- 3.14 Conclusions -- References -- 4 Bluff Group-The Cayman Formation -- Abstract -- 4.1 Introduction -- 4.2 Distribution -- 4.3 Lower Boundary -- 4.4 Upper Boundary -- 4.5 Thickness -- 4.6 Limestone-Dolostone Distribution -- 4.7 Biota -- 4.8 Facies -- 4.8.1 Grand Cayman -- 4.8.2 Cayman Brac -- 4.9 Depositional Regimes -- 4.10 Porosity and Permeability -- 4.11 Stable Isotopes -- 4.12 87Sr/86Sr Ratios -- 4.13 Age -- 4.13.1 Fossils -- 4.13.2 87Sr/86Sr Geochronology -- 4.13.3 Sea Level -- 4.14 Conclusions -- References -- 5 Bluff Group-Pedro Castle Formation -- Abstract -- 5.1 Introduction -- 5.2 Distribution -- 5.3 Lower Boundary -- 5.4 Upper Boundary. , 5.5 Thickness -- 5.6 Lithology -- 5.6.1 Grand Cayman -- 5.6.2 Cayman Brac -- 5.7 Stable Isotopes -- 5.8 Porosity and Permeability -- 5.9 87Sr/86Sr Geochronology -- 5.10 Age -- 5.11 Depositional Regimes -- 5.12 Conclusions -- References -- 6 Diagenesis-Bluff Group -- Abstract -- 6.1 Introduction -- 6.2 Dolostones of the Bluff Group -- 6.2.1 Dolomite Crystals -- Crystal Size -- Internal Structures and Compositional Zoning in Dolomite of the Cayman Islands -- Hollow Dolomite Crystals -- 6.2.2 Low and High Calcian Dolomite -- 6.2.3 Distribution of Low and High Calcian Dolomite -- Cayman Brac -- Grand Cayman -- 6.2.4 Stable Isotopes -- Brac Formation -- Cayman Formation -- Pedro Castle Formation -- 6.2.5 Trace Elements -- Na in Dolomite/Limestones -- Mn in Dolostones/Limestones -- Fe in Dolostones/Limestones -- Sr in Dolostones/Limestones -- Rare Earth Elements in Dolostones/Limestones -- 6.2.6 87Sr/86Sr Ratios -- Brac Formation -- Cayman Formation -- Pedro Castle Formation -- Modern Seawater -- Potential Problems with 87Sr/86Sr Ratios -- Brac Formation -- Cayman Formation and Pedro Castle Formation -- Comparison with Other Island Dolostones -- 6.3 Discussion -- 6.4 Conclusions -- References -- 7 Ironshore Formation -- Abstract -- 7.1 Introduction -- 7.2 Distribution -- 7.3 Lower Boundary -- 7.4 Upper Boundary -- 7.5 Thickness -- 7.6 Internal Stratigraphy -- 7.6.1 Lithological and Biological Characteristics of Units A to F -- 7.7 The 6 m Sea Level Notch -- 7.8 Key Exposures of the Ironshore Formation -- 7.8.1 Grand Cayman -- Salt Creek -- Canary Lane Quarry -- Boat Launch, Northwest Coast -- 7.8.2 Cayman Brac -- 7.8.3 Little Cayman -- Little Cayman Quarry -- Salt Rocks -- Unnamed Hill -- 7.9 Biota of the Ironshore Formation -- 7.9.1 Corals -- 7.9.2 Rhodolites -- 7.9.3 Stromatolites -- 7.9.4 Bivalves and Gastropods -- 7.10 Trace Elements. , 7.11 Diagenesis in the Ironshore Formation -- 7.11.1 Alteration of Skeletal Material -- Strombus Gigas Shells -- Corals -- 7.11.2 Calcretes -- 7.11.3 Rhizoliths -- 7.11.4 Roots and Caliche -- 7.11.5 Roots and Peloids -- 7.12 Conclusions -- References -- 8 Modern Carbonate Environments -- Abstract -- 8.1 Introduction -- 8.2 The Coastal Shelves of the Cayman Islands -- 8.3 Corals and Coral Reefs -- 8.3.1 Modern Corals of the Cayman Islands -- 8.3.2 Shelf-Edge Reef of Grand Cayman -- 8.4 Lagoons of Grand Cayman -- 8.4.1 North Sound -- The Fresh-Brackish Water Association -- The Marine Facies Association -- Rare Earth Elements -- Age -- Facies Architecture -- 8.4.2 South Sound -- Facies -- Age of Sediments -- Facies Changes Through Time -- Sedimentary Processes -- 8.4.3 Frank Sound and Pease Bay -- Facies -- Facies Changes Through Time -- Foraminifera in Frank Sound -- 8.4.4 East Sound -- 8.5 Bioerosion -- 8.6 Temporal Changes in Surface Seawater Temperatures -- 8.7 The Critical Role of Thalassia in the Lagoons of the Cayman Islands -- 8.8 Impact of Storms on the Coastal Areas of the Cayman Islands -- 8.8.1 Storm Boulders -- 8.8.2 Boulder Ramparts -- 8.8.3 Storm Impact on Lagoonal Sediments -- 8.9 Vermetid Buildups -- 8.10 Beachrock -- 8.11 Conclusions -- References -- 9 Karst on the Cayman Islands -- Abstract -- 9.1 Introduction -- 9.2 Modern Karst of the Cayman Islands -- 9.2.1 Phytokarst -- 9.2.2 Caves and Speleothems on Cayman Brac -- Caves in the Brac Formation -- Caves in the Cayman Formation -- Cave Speleothems -- Notch Speleothems -- 9.2.3 Caves and Speleothems on Grand Cayman -- The Twilight Zone -- Stalactites and Stalagmites -- Cave Pearls -- Calcite Versus Aragonite Precipitation -- Comparison of Notch Speleothems and Cave Speleothems -- 9.3 Vertebrate Fossils -- 9.4 Paleokarst on the Cayman Islands -- 9.4.1 Paleokarst Surfaces. , The Brac Unconformity -- The Cayman Unconformity -- The Pedro Castle Unconformity -- 9.5 Subsurface Paleokarst Features -- 9.5.1 Caymanite -- 9.5.2 Paleo-Caves -- 9.5.3 Sinkholes, Joints, and Other Cavities -- 9.6 Conclusions -- References -- 10 Terra Rossa, Phosphate, and Mangrove Swamps -- Abstract -- 10.1 Introduction -- 10.2 Terra Rossa -- 10.2.1 Stratigraphic Distribution of Lithified Terra Rossa on the Cayman Islands -- 10.2.2 Composition -- Clays, X-ray Amorphous Material, Anatase, Hematite, Goethite, and Manganese Precipitates -- Biofragments -- Glaebules -- Clay-Coated Grains and Terra Rossa Ooids -- Fractures -- 10.2.3 Stable Isotopes -- 10.2.4 Rare Earth Elements -- 10.2.5 Origin of Terra Rossa on the Cayman Islands -- 10.3 Phosphate Deposits -- 10.3.1 Composition of Phosphatic Limestone -- 10.3.2 Petrography of Phosphatic Limestones -- Lithoclasts and Detrital Phosphate Grains -- Glaebules -- Phosphate Rafts -- Matrix -- Microbes -- Calcite Cement -- 10.3.3 Stable Isotopes -- 10.3.4 Rare Earth Elements -- 10.3.5 Origin of Phosphate Deposits -- 10.4 Mangrove Deposits -- 10.4.1 Barkers Peninsula and West Bay Peninsula -- 10.4.2 Barkers Peninsula and West Bay Peninsula -- Laminated and Non-laminated Crusts -- Plastic Mud -- Peat -- 10.4.3 South Sound -- 10.4.4 Age and Development of Mangrove Swamps -- 10.5 Conclusions -- References -- 11 Hydrogeology -- Abstract -- 11.1 Introduction -- 11.1.1 Stage I -- 11.1.2 Stage II -- 11.1.3 Stage III -- 11.2 Bedrock Geology -- 11.3 Porosity and Permeability -- 11.4 Rainfall -- 11.5 Freshwater Lenses -- 11.5.1 Joints, Factures, and Water Lenses -- 11.5.2 Groundwater on the Cayman Islands -- Seawater -- Rainwater -- Pond Water -- Water in Sinkholes -- Cave Water -- Groundwater-Perched Water Zone -- Groundwater-Highly Brackish to Saline Water -- 11.5.3 Hydrochemical Facies -- Chloride Ions. , Bicarbonate Ions -- Calcium and Magnesium Ions -- 11.6 Groundwater Calcite and Dolomite Saturation States -- 11.6.1 Rainwater -- 11.6.2 Perched Water -- 11.6.3 Groundwater-Fresh Water Zone -- 11.6.4 Groundwater-Lightly Brackish Water Zone -- 11.6.5 Groundwater-Types I and II -- 11.7 Groundwater and Bedrock in and Around the East End Freshwater Lens -- 11.8 Development of Reverse Osmosis Plants -- 11.9 Conclusions -- References -- Appendix_1.