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Medical Epigenetics

Second Edition
 Translational Epigenetics Series
Trygve Tollefsbol - Series Editor
Transgenerational Epigenetics
Edited by Trygve O. Tollefsbol, 2014
Personalized Epigenetics
Edited by Trygve O. Tollefsbol, 2015
Epigenetic Technological Applications
Edited by Y. George Zheng, 2015
Epigenetic Cancer Therapy
Edited by Steven G. Gray, 2015
DNA Methylation and Complex Human Disease
By Michel Neidhart, 2015
Epigenomics in Health and Disease
Edited by Mario F. Fraga and Agustin F. Fernández, 2015
Epigenetic Gene Expression and Regulation
Edited by Suming Huang, Michael Litt and C. Ann
Blakey, 2015
Epigenetic Biomarkers and Diagnostics
Edited by Jose Luis García-Giménez, 2015
Drug Discovery in Cancer Epigenetics
Edited by Gerda Egger and Paola Barbara Arimondo,
2015
Medical Epigenetics
Edited by Trygve O. Tollefsbol, 2016
Chromatin Signaling and Diseases
Edited by Olivier Binda and Martin Fernandez-Zapico,
2016
Genome Stability
Edited by Igor Kovalchuk and Olga Kovalchuk, 2016
Chromatin Regulation and Dynamics
Edited by Anita Göndör, 2016
Neuropsychiatric Disorders and Epigenetics
Edited by Dag H. Yasui, Jacob Peedicayil and Dennis R.
Grayson, 2016
Polycomb Group Proteins
Edited by Vincenzo Pirrotta, 2016
Epigenetics and Systems Biology
Edited by Leonie Ringrose, 2017
Cancer and Noncoding RNAs
Edited by Jayprokas Chakrabarti and Sanga Mitra,
2017
Nuclear Architecture and Dynamics
Edited by Christophe Lavelle and Jean-Marc Victor, 2017
Epigenetic Mechanisms in Cancer
Edited by Sabita Saldanha, 2017
Epigenetics of Aging and Longevity
Edited by Alexey Moskalev and Alexander M. Vaiserman,
2017
The Epigenetics of Autoimmunity
Edited by Rongxin Zhang, 2018
Epigenetics in Human Disease, Second Edition
Edited by Trygve O. Tollefsbol, 2018
Epigenetics of Chronic Pain
Edited by Guang Bai and Ke Ren, 2018
Epigenetics of Cancer Prevention
Edited by Anupam Bishayee and Deepak Bhatia, 2018
Computational Epigenetics and Diseases
Edited by Loo Keat Wei, 2019
Pharmacoepigenetics
Edited by Ramón Cacabelos, 2019
Epigenetics and Regeneration
Edited by Daniela Palacios, 2019
Chromatin Signaling and Neurological Disorders
Edited by Olivier Binda, 2019
Transgenerational Epigenetics, Second Edition
Edited by Trygve Tollefsbol, 2019
Nutritional Epigenomics
Edited by Bradley Ferguson, 2019
Prognostic Epigenetics
Edited by Shilpy Sharma, 2019
Epigenetics of the Immune System
Edited by Dieter Kabelitz, 2020
Stem Cell Epigenetics
Edited by Eran Meshorer and Giuseppe Testa, 2020
Epigenetics Methods
Edited by Trygve Tollefsbol, 2020
Histone Modifications in Therapy
Edited by Pedro Castelo-Branco and Carmen Jeronimo,
2020
Environmental Epigenetics in Toxicology and Public Health
Edited by Rebecca Fry, 2020
Developmental Human Behavioral Epigenetics
Edited by Livio Provenzi and Rosario Montirosso, 2020
Epigenetics in Cardiovascular Disease
Edited by Yvan Devaux and Emma Robinson, 2021
Epigenetics of Exercise and Sports
Edited by Stuart M. Raleigh, 2021
Genome Stability, Second Edition
Edited by Igor Kovulchuk and Olga Kovulchuk, 2021
Twin and Family Studies of Epigenetics
Edited by Shuai Li and John L. Hopper, 2021
Epigenetics and Metabolomics
Edited by Paban K. Agrawala and Poonam Rana, 2021
Translational Epigenetics Series
Medical Epigenetics
Second Edition
Volume 29

Edited by

Trygve O. Tollefsbol
Distinguished Professor of Biology, Senior Scientist, Comprehensive Cancer Center, Comprehensive
Center for Healthy Aging, University of Alabama at Birmingham, AL, United States
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Contents

Contributors xvii Infection 23

Preface xxi Conclusions and perspectives 23
Acknowledgment 25
Abbreviations 25
Section A References 26
Overview
3. Lifestyle and preventive medical
1. Advances in medical epigenetics epigenetics
Trygve O. Tollefsbol Kamaldeen Olalekan Sanusi, Yaaqub Abiodun
Uthman, Der Jiun Ooi, Maznah Ismail, and
Introduction 3 Mustapha Umar Imam
Basic principles of epigenetics 3
General medical aspects of epigenetics 4 Introduction 33
Epigenetics of system disorders 4 Epigenetics 33
Multisystem medical epigenetics 5 How epigenetics influence risk of diseases 33
Bioinformatics of epigenetic medicine 5 How lifestyle determines epigenetics 34
Pharmacology of epigenetics 6 How knowledge on epigenetics could be
Therapeutic epigenetics 6 used to prevent diseases 34
Medical epigenetics: Future prospects 7 Impact of dietary pattern on the epigenome 35
Conclusion 7 Carbohydrates and epigenetic modifications 35
References 8 Proteins and epigenetic modifications 36
Fatty acids and epigenetic modifications 37
Role of micronutrients in epigenetics 37
Section B Bioactive compounds 38
General medical aspects Exercise and epigenetics 39
Environmental factors and epigenetic
of epigenetics modification 41
Lifestyle modification as a preventive tool
2. Environmental epigenetic for medical epigenetics 41
epidemiology Conclusion 43
Alexander Vaiserman, Oleh Lushchak, and References 43
Alexander Koliada
Introduction 11 4. Environmental medical
Malnutrition 11 epigenetics: A review of
Environmental pollutants 13 epigenetically induced medical
Air pollution 13 risks generated from exposures in
Endocrine-disrupting chemicals 16 our air, food, and personal products
Heavy metals 16
Rachel L. Miller and Jessica Oh
Substance abuse 18
Alcohol 18 Introduction 51
Tobacco smoking 19 Allergens 51
Marijuana smoking 20 Aeroallergens 51
Opioids 20 Food allergens 53

v
vi  Contents

Secondhand cigarette smoke and vaping 53 Interconnectivity of the neurotransmitter

Traffic-related air pollution 55 systems 88
PM2.5 56 The dopaminergic system 89
Diesel exhaust particles 56 Behavioral disorders associated with the
Polycyclic aromatic hydrocarbons 57 dopaminergic system 90
Trace metals 58 Evidence for glucocorticoid effect on
Heavy metals 58 dopaminergic transmission 90
Chromium 58 Glucocorticoids and dopamine in drug
Arsenic 58 addiction 90
Lead 59 Epigenetic mediators of glucocorticoids on
Cadmium 60 dopamine-related behavior 91
Endocrine-disrupting chemicals 60 Adrenergic and noradrenergic systems 92
Bisphenol A 60 Behavioral disorders associated with the
Phthalates 62 adrenergic and noradrenergic system 92
Parabens 63 Evidence for glucocorticoid effect on
Flame retardants/polybrominated adrenergic and noradrenergic
diphenyl ethers 63 transmission 92
Pesticides and fungicides 63 Epigenetic mediators of glucocorticoids on
Vinclozolin 63 adrenaline- and noradrenaline-related
Persistent organic pollutants and other behavior 93
pesticides 64 The serotonergic (5-HT) system 93
Volatile organic compounds 65 Behavioral disorders associated with the
Farm exposure 65 serotonergic system 93
Diet 66 Evidence for glucocorticoid effect on
Folic acid and other methyl donors 66 serotonergic transmission 93
Additional vitamin and antioxidant Epigenetic mediators of glucocorticoids on
supplementation 67 serotonin-related behavior 94
Dietary fat, sucrose 67 Glutamate and GABA systems 94
Famine 68 Behavioral disorders associated with the
Conclusions/outstanding questions 69 glutamate and GABA system 94
Abbreviations 72 Evidence for glucocorticoid effect on
Glossary 73 glutamate and GABA system 95
References 73 Epigenetic mediators of glucocorticoids on
glutamate and GABA-related behavior 95
5. Behavioral medical epigenetics Conclusion 95
References 96
O.H. Cox and R.S. Lee
Introduction 81 6. Medical epigenetics and twins
Impact of environmental factors on behavior 81
J.C. Eissenberg
Animal models and studies of human behavior 82
Environmental stressors and epigenetic Introduction 103
mediators of the stress response 82 Monogenic disorders: Twin studies and the
Nonepigenetic and alternate mechanisms epigenetics of imprinting disorders 104
of stress 83 Twin studies and Beckwith–Wiedemann
The HPA axis and the stress response 83 syndrome 104
Glucocorticoid signaling and epigenetics 84 Twin studies and Silver–Russell syndrome 105
HPA axis genes: Genes that regulate Twin studies and the epigenetics of
glucocorticoid signaling 85 multifactorial disorders 106
Chronic stress and glucocorticoid resistance 85 Twin studies and the epigenetics of
Glucocorticoid resistance and epigenetics 86 cardiovascular diseases 106
HPA axis genes: Genes that regulate Twin studies and the epigenetics of
tissue-specific processes 87 psychiatric disorders 106
Environmental stressors and Twin studies and the epigenetics of
neurotransmitters 88 aging 108
 Contents  vii

Twin studies and the epigenetics The future 161

of metabolic traits and disease 108 Conflict of interest statement 162
Twin studies and epigenetic mechanisms 109 References 162
Caveats 110
Future directions 111
Conclusions 111 Section C
References 112
Epigenetics of system disorders
7. Epigenetic biomarkers of disease 9. Autoimmune disease and epigenetics
Patricia Chaves, Juan Luis Onieva, and Sarah J. Blossom
Isabel Barragán
Autoimmune disease overview 171
Introduction 117 Autoimmune disease etiology 171
Epigenetic biomarkers 117 Epigenetics and autoimmunity 172
Disruption of the “epigenetic machinery” Epigenetic regulation of T cell subset
in cancer 117 differentiation 172
Epigenetic mechanisms of acquired drug DNA methylation and autoimmune disease 173
resistance 118 Histone modifications and autoimmune
Types of epigenetic modifications 118 disease 174
Epigenetic biomarkers in cancer 119 RNA modifications in autoimmune disease 175
Diagnosis, prognosis, and drug response Environmental epigenetics 176
epigenetic biomarkers in solid biopsies 119 Environmental epigenetics and
Diagnosis, prognosis, and drug response autoimmunity 176
biomarkers in liquid biopsies 121 Xenobiotic-induced epigenetic changes
Methods for assessing epigenetic changes for and autoimmunity 176
biomarkers 124 Trichloroethylene 176
Genome-wide epigenetic analysis 126 Trichloroethylene-mediated immunotoxicity 177
Locus-specific epigenetic analysis 127 Trichloroethylene and autoimmunity 177
Specific methods for liquid biopsy 128 Trichloroethylene-induced autoimmunity
Bioinformatic analysis 129 in experimental models 177
Clinical application of epigenetic biomarkers 129 Trichloroethylene-mediated epigenetic
Epigenetic biomarkers in precision medicine 129 changes in CD4+ T cells 177
Epigenetic plasticity as a therapeutic target 133 Conclusions 178
Epigenomic modulation drugs 133 References 178
Future perspectives 134
Conclusion 135
Abbreviations 135
10. Epigenetics of pulmonary diseases
References 136 Akshaya Thoutam and Narasaiah Kolliputi
Introduction 185
8. Prognostic epigenetics Epigenetic basics 185
Epigenetics in disease 186
Adriana Fodor, Adriana Rusu, Gabriela Roman,
Epigenetics in the lungs 188
Ramona Suharoschi, Romana Vulturar,
Epigenetics in pulmonary diseases 190
Adela Sitar-Taut, and Angela Cozma
Lung cancer 190
Introduction 143 Pulmonary hypertension 191
DNA methylation markers of cancer Chronic obstructive pulmonary disease 192
prognosis 143 Idiopathic pulmonary fibrosis 193
Histone modifications as markers of cancer Tuberculosis 193
prognosis 153 Conclusion 194
Noncoding RNA prognostic markers in Grants 194
cancer 156 Disclosures 194
Prognostic epigenetic markers in Author contributions 194
nonmalignant pathology 158 References 194
viii  Contents

11. Cardiovascular disorders and Epigenetics in dermatomyositis 236

epigenetics Epigenetics in atopic dermatitis 237
Infectious skin diseases 238
Charbel Abi Khalil Introduction 238
Introduction 197 Epigenetics in HSV infection 238
Early heart development and the fetal Epigenetics in HPV infection 239
origin of cardiovascular disease 197 Skin tumors 239
Epigenetic involvement in cardiovascular Introduction 239
risk factors 198 Epigenetics in melanoma 240
Smoking 198 Epigenetics in cutaneous T-cell lymphoma 242
Age 199 Skin aging 243
Hypertension 199 Introduction 243
Obesity and dyslipidemia 199 Epigenetic changes of skin 243
Diabetes 200 Epigenetic therapeutics for aged skin 244
Epigenetics and cardiovascular disease 202 Conclusions 244
Endothelial dysfunction and atherosclerosis 202 Abbreviations 244
Ischemic heart disease 203 Acknowledgments 245
Stroke 204 References 245
Vascular disease 204
Cardiac hypertrophy 204 14. Epigenetics in bone and joint
Heart failure 205 disorders
Epigenetic-based cardiovascular therapy 206 N. Altorok, V. Nagaraja, and B. Kahaleh
Conclusion 206
References 207 Introduction 251
Epigenetic regulation of the immune
12. Epigenomics of intestinal disease system in rheumatic diseases 251
Systemic lupus erythematosus 253
S. Hashimoto-Hill, D.R. Kelly, and T. Alenghat Systemic sclerosis 256
Introduction 213 Rheumatoid arthritis 259
Epigenetics and intestinal development 214 Sjögren syndrome 262
Intestinal homeostasis and the microbiota 215 Osteoarthritis 264
Epigenetics, intestinal homeostasis, Osteoporosis 265
and the microbiota 216 Psoriasis 267
Microbiota-derived metabolites 217 DNA methylation aberrancies and psoriasis 267
Diet and the intestinal epigenome 219 Vasculitis 268
Colon cancer 220 Epigenetics therapy in rheumatic diseases 269
Inflammatory bowel disease 221 Epigenetic therapeutics for SLE 269
Irritable bowel syndrome 223 Epigenetic therapeutics for rheumatoid
Celiac disease 224 arthritis 269
Therapeutics 224 Epigenetic therapeutics for systemic
Future directions 225 sclerosis 270
Glossary 225 miRNAs as biomarkers for rheumatology
Acknowledgments 226 and bone diseases 270
References 226 Conclusions 271
References 271
13. Epigenetics of skin disorders
15. Epigenetics of muscle disorders
Shuaihantian Luo and Qianjin Lu
Elisa Oltra
Immunologic skin diseases 231
Introduction 231 Introduction 279
Epigenetics in systemic lupus Atrial fibrillation 279
erythematosus 231 Pathophysiology, demographics, diagnosis,
Epigenetics in psoriasis 234 and treatment options of AF 279
Epigenetics in vitiligo 236 Genetic determinants of AF 280
 Contents  ix

Epigenetic determinants of AF 281 Intraocular tumors 360

Limitations and prospective challenges Discussion and conclusions 362
of AF epigenetic studies 288 Conflict of interest 363
Fibromyalgia 288 References 363
Pathophysiology, demographics, diagnosis,
and treatment options of FM 288
Genetic determinants of FM 289 Section D
Epigenetic determinants of FM 289 Multi-system medical epigenetics
Limitations and prospective challenges
of FM epigenetic studies 293 18. Pediatric diseases and epigenetics
Gastrointestinal disorders 293
J.G. Hall and R. Weksberg
Pathophysiology, demographics, diagnosis,
and treatment options of GI 293 Introduction 377
Genetic determinants of GI 295 Specific syndromes and disorders whose
Epigenetic determinants of GI 295 genes are involved in the processes and
Limitations and prospective challenges mechanisms of epigenetic regulation of
of GI epigenetic studies 297 gene expression 377
Abbreviations 298 Rett syndrome (reader) 385
References 298 Alpha thalassemia/mental retardation
syndrome X-linked syndrome (remodeler) 385
16. Reproductive disease epigenetics ICF syndrome (writer) 385
Rubinstein–Taybi syndrome (writer) 386
Maricarmen Colon-Diaz, Alexander J. Jaramillo,
Floating–Harbor syndrome (remodeler) 386
Edwin Y. Soto, and Perla M. Elosegui
Microdeletions and duplications of
Introduction 309 chromosomes 386
Gametogenesis 309 Disorders of genomic imprinting 387
Spermatogenesis 309 Descriptions of particularly well-known
Oogenesis 311 syndromes involving parental imprinting 387
Male reproductive disorders 312 Prader–Willi syndrome 387
Male infertility 312 Angelman syndrome 388
Testicular cancer 315 Beckwith–Wiedemann syndrome (aka
Female reproductive disorders 316 Wiedemann–Beckwith syndrome) 388
Female infertility 316 Russell–Silver syndrome (aka Silver–Russell
Endometrial disorders 317 syndrome) 389
Ovarian disorders 323 Molecular diagnosis for epigenetic
Placental syndromes 327 disorders 389
Preeclampsia 327 Known environmental exposures which are
Intrauterine growth restriction (idiopathic) 330 likely to have disturbances in epigenetic
Hydatidiform mole 331 regulation 390
Human papillomavirus and cervical cancer 332 Teratogens 390
Summary 334 Endocrine disruptors 390
References 334 Folic acid 390
Developmental disorders that are likely
17. Epigenetics in ocular medicine to involve epigenetic mechanisms 392
Intellectual disability 392
Ji Liu
Autism spectrum disorders 392
Introduction 347 Other pediatric disorders 392
Epigenetics and the eye 347 Human malformations (birth defects) 392
Epigenetics in ocular disease 348 Monozygotic twins 393
Myopia 348 Preconception and periconception
Anterior segment diseases 349 effects 393
Glaucoma 352 Microbiome 393
Vitreoretinal diseases 354 Developmental origins of health
Uveitis 359 and disease (DOHaD) 394
x  Contents

The application of epigenetic research to 21. Epigenetics in acute myeloid

public health policy of the future 396 leukemia
Not overfeeding IUGR infants 396
Placental dimensions predict prenatal Carmela Dell’Aversana, Cristina Giorgio,
predisposition to chronic disease 396 Francesco Paolo Tambaro, Giulia Sgueglia,
A new type of family history 396 and Lucia Altucci
The future impact of epigenetics on pediatrics 396 Introduction 447
Acknowledgments 397 Epigenetic regulation of the genome 447
Abbreviations 397 Normal hematopoiesis 447
References 397 Acute myeloid leukemia 448
Environment 448
19. Epigenetics of infectious diseases Genetic and cytogenetic anomalies 449
K.L. Seib and M.P. Jennings Epigenetics in acute myeloid leukemia 450
DNA methylation and AML 451
Introduction 407 DNA hydroxymethylation and AML 451
Pathogen-induced epigenetic modifications Alterations of histone-targeting players
in host cells 408 in AML 452
DNA methylation 408 Noncoding RNA deregulation in AML 454
Helicobacter pylori and altered DNA Epigenetic-based therapy 456
methylation in infection and gastric cancer 410 DNMT inhibitors 456
Histone modifications 411 HDAC inhibitors 458
Epigenetic modifications in bacterial pathogens 412 HMT inhibitors 460
Methylation of DNA in bacterial pathogens 412 HDM inhibitors 461
The Dam N6-Adenine DNA methyltransferase 414 IDH1/2 inhibitors 461
Phasevarions—Phase-variable DNA Conclusions 462
methyltransferases controlling global References 462
gene expression 415
Conclusions 418
Glossary 418 22. Epigenetic regulation in cancer
Abbreviations 419 metastasis
Acknowledgments 419
Guanying Bianca Xu, Huan Wang,
References 419
Shijia Alexia Chen, and Hong Chen
20. Clinical utility of solid tumor Overview of cancer metastasis 471
epigenetics Epigenetic control 472
Molecular pathways of EMT 473
Engin Demirdizen, Julian Taranda, and
DNA methylation and EMT 474
Sevin Turcan
Histone modification and EMT 474
Epigenetic drugs 425 MicroRNA regulation of EMT 475
Combination epigenetic therapy 428 Long noncoding RNA (lncRNA)
Epigenetics and immunity 432 regulation of EMT 476
Challenges 433 Anoikis resistance 476
DNA-methylation-based classification Epigenetic regulations of apoptosis through
of tumors 433 FLIP and caspase-8 477
Liquid biopsy 435 Anchorage-independent growth 477
Tumor-associated features in blood 436 Extravasation and colonization 479
Blood- and cancer-specific DNA Epigenome-wide big data analysis for
methylation patterns 436 mechanistic understanding of
Mapping nucleosome positions 437 metastasis 480
Liquid biopsies for solid tumors in RNA-seq 480
clinical care 437 ChIP-seq 481
Concluding remarks 438 MeDIP-seq 482
Acknowledgments 438 scRNA-seq 482
Abbreviations 439 Abbreviations 483
References 440 References 483
 Contents  xi

23. Epigenetics in exercise science Opportunities in preclinical safety

and sports medicine assessment 545
Potential tools for screening of
A. Schenk, S. Proschinger, and P. Zimmer epigenetic effects 546
Introduction 491 Conclusion and future perspective 549
General findings 491 Disclaimer 550
Muscle tissue 492 Abbreviations 550
Blood cells 496 References 553
Cardiovascular tissues 498
Brain 500 26. Pharmacoepigenomics in
Other tissues 502
neurodegenerative diseases
Conclusion 503
Acknowledgments 503 Nicoletta Nuzziello and Maria Liguori
Abbreviations 503
Introduction 559
References 504
NDD-specific pharmacoepigenomic
signatures 560
DNA methylation as a pharmacoepigenomic
Section E target for NDDs 563
Bioinformatics of epigenetic medicine Histone posttranslational modifications
affecting chromatin remodeling as
24. Machine learning in epigenetic diseases pharmacoepigenomic targets for NDDs 565
MiRNAs as pharmacoepigenomic targets
Karyn G. Robinson and Robert E. Akins for NDDs 565
Introduction 513 Epigenetic-modifying drugs for NDDs 568
Fundamentals of machine learning 513 Potential epidrugs targeting DNA
Machine learning applications in epigenetics 517 methylation 568
Performance and limitations of machine Targeting histone modifications for
learning approaches 521 therapeutic purposes 571
Summary 524 Potential epidrugs targeting miRNAs 572
References 524 Epigenetic regulation of pharmacokinetics
and pharmacodynamics 573
Epigenomics in regulating drug
ADME genes 575
Section F Conclusion 576
Pharmacology of epigenetics References 576

25. Epigenetics in toxicology and drug

development
Section G
J. Tajbakhsh and J. Singh Therapeutic epigenetics
Introduction 529
Epigenetics and diseases 531 27. Therapeutics and DNA
Aberrant epigenetic features and methylation inhibitors
mechanisms 531
Shyamala C. Navada
Cancer 533
Other complex human diseases 537 Introduction 585
Microbiota 538 Mechanism of action 585
Environmental etiology and influence 539 Application of DNMT inhibitors 586
Considerations in pharmacology and Benign hematology 586
toxicology 541 Myelodysplastic syndromes 587
Role of epigenetics in drug-related Acute myeloid leukemia 589
toxicology 541 Hypomethylating agent combinations
Pharmaceutical exploitation of epigenetic in AML 590
readers 544 Chronic myeloid leukemia 590
xii  Contents

Solid tumors 590 HDAC inhibitors for the treatment of

Epigenetic agents in combination—DNMT diabetes mellitus 617
and HDAC inhibitors 591 Effects of HDAC inhibitors on the
Other DNMT inhibitors 591 pancreatic β-cells in diabetes 617
Novel nucleoside DNMT inhibitors 591 Effects of HDAC inhibitors in diabetic
Orally available 5-aza and 5-azadC 592 kidneys 618
Nonnucleoside DNMT inhibitors 592 Safety issues with the use of HDAC inhibitors 619
Conclusions 592 Conclusions 619
References 593 Abbreviations 620
References 621
28. Histone deacetylase inhibitors in
medical therapeutics 29. Sirtuins as NAD+-dependent
P. Chun deacetylases and their potential in
medical therapy
Introduction 597
Classification of histone deacetylases 597 Ashok Kumar and Mona Dvir-Ginzberg
Classification of HDAC inhibitors 598
Introduction 633
HDAC inhibitors for the treatment of cancer 599
Sirtuins 633
HDACs and cancer 599
Sirtuin activity and function 634
Role of HDAC inhibitors in cancer 599
Chemical reaction and structural insight 637
HDAC inhibitors and clinical outcomes 601
NAD+ cofactor 637
Combination therapy with immune
Modulators of sirtuin activity 642
checkpoint inhibitors 603
Sirtuins as potential therapeutic targets
Conclusions 605
in disease 644
HDAC inhibitors for the treatment of heart
Summary 653
diseases 605
Abbreviations 655
Effects of HDAC inhibition on cardiac
Acknowledgments 656
hypertrophy 606
Conflict of interest 656
Effects of HDAC inhibition on cardiac
References 656
hypertension 608
Effects of HDAC inhibition on myocardial
infarction 608 30. Experimental approaches
Effects of HDAC inhibition on heart failure 609 toward histone acetyltransferase
Effects of HDAC inhibition on atrial modulators as therapeutics
fibrillation 609
D. Chen, H. Wapenaar, and F.J. Dekker
HDAC inhibitors for the treatment
of kidney disease 609 Introduction 665
Effects of HDAC inhibition on renal fibrosis 609 The "histone code" 665
Effects of HDAC inhibitors on renal Histone acetylation 665
inflammation 610 Histone acetyltransferases 666
HDAC inhibitors for the treatment of HAT function 667
idiopathic pulmonary fibrosis 610 HATs in disease 672
HDAC inhibitors for the treatment of Cancer 673
inflammatory bowel disease 612 Inflammatory diseases 674
HDAC inhibitors for the treatment of Neurological disorders 675
rheumatoid arthritis 613 Viral infections 676
HDAC inhibitors for the treatment of HAT modulators 676
schizophrenia 615 Bisubstrate inhibitors 677
HDAC inhibitors for the treatment of Natural products and derivatives 677
Parkinson’s disease 616 Other small-molecule inhibitors 677
Suppression of nuclear α-synuclein 616 Bromodomain inhibitors and other HAT
Inhibition of neuroinflammation and protein inhibitors 679
oxidative stress 616 PROTACs for HATs 680
Increase in GDNF and BDNF 617 HAT activators 681
 Contents  xiii

Challenges in the development of HAT ncRNA as biomarkers of human disorders 723

modulators 682 Cardiovascular disease 724
Therapeutic possibilities of HAT modulators 683 Autoimmune and other inflammatory
HAT modulators in cancers 683 diseases 724
HAT modulators in inflammatory diseases Nervous system disorders 726
and neurological diseases 683 Cancer 727
Conclusion 684 Therapeutic potential of miRNA 728
References 684 Central nervous system 730
Cancer 730
Delivery methods 731
31. Histone methylation modifiers in
siRNAs and saRNAs in clinical trials 731
medical therapeutics Concluding remarks 732
P. Trojer References 732
Introduction 693
33. Nutrients and phytonutrients as
Enhancer of zeste homolog 2 (EZH2, KMT6A) 697
promising epigenetic nutraceuticals
EZH2 functions in transcriptional repression 697
Discovery of EZH2 inhibitors 699 Anait S. Levenson
Therapeutic application of EZH2
Abbreviations 741
inhibitors in NHL 699
Introduction 750
Therapeutic application of EZH2
Epigenetic mechanisms 750
inhibitors in other cancer types 700
Nutrients, phytonutrients, and epigenetics 751
Disruptor of telomeric silencing like
Dietary phytochemicals and nutrients as
(DOT1L, KMT4) 702
modulators of DNA methylation and
DOT1L functions in transcription elongation 702
histone modifications 751
Discovery of DOT1L inhibitors 704
Apigenin 753
Therapeutic application of DOT1L
Curcumin 753
inhibitors in AML 704
Epigallocatechin-3-gallate 766
Lysine-specific demethylase 1 (LSD1, KDM1A) 705
Folate (vitamin B9) 767
LSD1 functions in activation and repression
Genistein 768
of transcription 705
Isothiocyanates 769
Discovery of LSD1 inhibitors 707
Indoles 769
Therapeutic application of LSD1
Lycopene 769
inhibitors in AML and MPNs 707
Organosulfur compounds 770
Therapeutic application of LSD1
Polyunsaturated fatty acids 770
inhibitors in solid tumors 708
Quercetin 770
Targeting other histone methylation
Resveratrol and analogues 771
modifiers 708
Retinoic acid (vitamin A) 772
Conclusions 710
Selenium (Se) 772
Glossary 712
Tannins 773
Abbreviations 712
Dietary phytochemicals and nutrients as
References 712
regulators of miRNAs 773
Apigenin 773
32. Modulation of noncoding RNAs Curcumin 786
(ncRNAs) and their potential role Epigallocatechin-3-gallate 787
as therapeutics Folate (vitamin B9) 787
Genistein 788
Luciano Pirola, Oskar Ciesielski,
Isothiocyanates 788
Marta Biesiekierska, and Aneta Balcerczyk
Indoles 789
Introduction 721 Lycopene 789
Noncoding RNA in the regulation of gene Organosulfur compounds 789
expression 721 Polyunsaturated fatty acids 790
Mechanism of gene regulation by miRNAs 722 Quercetin 790
RNA activation 723 Resveratrol and analogues 790
xiv  Contents

Retinoic acid (vitamin A) 791 Epigenetic modifications contribute to drug

Selenium (Se) 792 response and prognosis 844
Tannins 792 Response to clofarabine 845
Epigenetic clinical trials with dietary Response to cancer immunotherapy 845
phytochemicals and nutrients 795 Predicting prognosis and survival
Conclusions 795 in cancer 845
Acknowledgments 796 Novel cytosine modifications for precision
References 796 medicine 846
Diffuse large B-cell lymphoma 846
34. Epigenetics of pain management Multiple myeloma 846
Neuroblastoma 847
T. Louwies, A.C. Johnson, C.O. Ligon,
Challenges and perspectives 847
and B. Greenwood-Van Meerveld
Technical development 847
Introduction 817 Integrative and systems biology
Chronic pain states 817 approaches 848
Somatic pain 817 Conclusions 848
Visceral pain 819 References 849
Neuropathic pain 820
Role of epigenetic mechanisms 36. Epigenetics and regenerative medicine
in chronic pain 821
Devon Ehnes, Shiri Levy, and Hannele
DNA methylation 821
Ruohola-Baker
Histone tail modifications 822
Noncoding RNAs 824 Introduction 853
Future approaches to exploit the role of Epigenetic defects in aged tissues 853
epigenetics in chronic pain 825 Epigenetics and aging from a muscle
Role of sex differences in chronic pain 825 regeneration perspective: Satellite
Role of environmental stimuli stem cells 853
in chronic pain 826 New insights into epigenetics and aging
Role of immune-mediated disorders in other tissues can inform nascent fields:
in chronic pain 828 The salivary gland 856
Challenges and hurdles for epigenetic Epigenetic dysregulation in cognition and
therapies 831 neurodegeneration 859
Conclusion 831 Epigenetic dysregulation in developmental
References 831 plasticity and non-age-related brain
diseases 859
35. Precision medical epigenetics Age-related decline in cognition is linked
to the deregulation of epigenetic marks 859
Chang Zeng, Zhou Zhang, Xiaolong Cui,
Epigenetic remodeling tools used in
and Wei Zhang
regenerative medicine therapeutics 861
Enabling technologies for precision Epigenetic chemical inhibitors 861
epigenetic medicine 841 Epigenetic noncoding RNA used in
Conventional approaches 842 regenerative medicine 861
Single-cell approaches 842 Novel targeted epigenetic remodeler tools 862
Technologies for novel cytosine Applications of epigenetic remodelers in
modifications 843 regenerative medicine 863
Epigenetic modifications contribute to gene Epigenetic application tools in hESC
expression variations 843 and iPSC 863
Interindividual and interpopulation Future promise for epigenetic medical
epigenetic variation 844 therapy 866
Epigenetic variation partially explained Conclusion 866
by local genetic background 844 References 866
 Contents  xv

37. Stem cell epigenetics in medical Section H

therapy Medical epigenetics: Future prospects
Baoli Cheng, Liqi Shu, Emily G Allen,
and Peng Jin 39. Epigenetics: Future prospective in
human disorders and therapeutics
Introduction 873
Stem cells 873 Shriram N. Rajpathak, Vinayak S. Biradar, and
Epigenetics of stem cells 875 Deepti D. Deobagkar
DNA methylation 875
Introduction 903
Histone modifications 877
Epigenetics in stress and related disorders 903
Noncoding RNA 878
Early life events and stress biology 903
RNA modifications 878
Oxidative stress as a mediator for
Therapeutic prospects of stem cells 879
epigenetic changes 904
Summary 880
Stress and epigenetics machinery 904
Glossary 880
Stress-related disorders 905
Abbreviation 881
Epigenetics in human chromosomal disorders 907
References 881
Outline for an association between
aneuploidy and epigenetic machinery 907
38. The clinical landscape of HDAC Autosomal aneuploidy conditions 909
inhibitors Sex chromosomal aneuploidy 909
Non-coding RNAs as regulators in
A. Ganesan X monosomy and trisomy 913
Nucleosome modification and Future perspective 914
transcriptional regulation 885 References 914
One to eleven: The human zinc-dependent
HDACs 885 40. Prospective advances in medical
Nuclear protein deacetylases HDAC1, epigenetics
HDAC2, and HDAC3 885
Jiali Deng, Mengying Guo, and Junjie Xiao
Cytoplasmic protein deacetylase
HDAC6 886 Introduction 919
Protein fatty acid deacylases HDAC8 and Prospective advances of DNA methylation in
HDAC11 886 medical epigenetics 921
Polyamine deacetylase HDAC10 886 Prospective advances of DNA methylation
Pseudoenzymes HDAC4, HDAC5, HDAC7, in vitiligo 923
and HDAC9 886 Prospective advances of DNA methylation
HDAC inhibitors—A pharmacological in liver 923
classification 886 Prospective advances of DNA methylation age 926
Nonselective HDAC inhibitors 887 Prospective advances of DNA
Nuclear isoform selective HDAC methylation in neuron 926
inhibitors 889 Prospective advances of histone modification
HDAC6 and HDAC8 isoform selective in medical epigenetics 927
inhibitors 890 Prospective advances of noncoding RNAs
Dual mechanism HDAC inhibitors 891 in medical epigenetics 928
Advanced clinical trials—Hematological International Human Epigenome Consortium
cancers 892 and epigenetical precision medicine 930
Advanced clinical trials—Non-blood Limitations 931
cancers 893 Prospect 931
Advanced clinical trials—Beyond Acknowledgments 932
cancer 894 References 932
Summary 895
References 896 Index 937
This page intentionally left blank
Contributors
Numbers in parenthesis indicate the pages on which the authors’
­contributions begin.
Charbel Abi Khalil (197), Epigenetics Cardiovascular
Lab, Research Department, Weill Cornell Medicine-
Qatar, Doha, Qatar; Department of Genetic Medicine,
Weill Cornell Medicine, New York, United States; Joan
and Sanford I. Weill Department of Medicine, Weill
Cornell Medicine, New York, United States
Robert E. Akins (513), Center for Pediatric Clinical
Research and Development, Alfred I. duPont Hospital
for Children, Nemours Children’s Health System,
Wilmington, DE, United States
T. Alenghat (213), Division of Immunobiology and Center
for Immunology and Tolerance, Cincinnati Children’s
Hospital Medical Center; Department of Pediatrics,
University of Cincinnati College of Medicine,
Cincinnati, OH, United States
Emily G Allen (873), Department of Human Genetics,
Emory University, Atlanta, GA, United States
N. Altorok (251), Division of Rheumatology and
Immunology, Department of Internal Medicine,
University of Toledo Medical Center, Toledo, OH,
United States
Lucia Altucci (447), Department of Precision Medicine,
University of Campania “Luigi Vanvitelli”, Naples, Italy
Aneta Balcerczyk (721), Department of Molecular
Biophysics, Faculty of Biology and Environmental
Protection, University of Lodz, Lodz, Poland
Isabel Barragán (117), Medical Oncology Service,
Section of Immuno-Oncology, Hospitales Universitarios
Regional y Virgen de la Victoria, Institute of Biomedical
Research in Malaga (IBIMA), Málaga, Spain; Group
of Pharmacoepigenetics, Department of Physiology
and Pharmacology, Karolinska Institutet, Stockholm,
Sweden
Marta Biesiekierska (721), Department of Molecular
Biophysics, Faculty of Biology and Environmental
Protection, University of Lodz, Lodz, Poland
Vinayak S. Biradar (903), Molecular Biology Research
Laboratory, Department of Zoology, Savitribai Phule
Pune University, Pune, India
Sarah J. Blossom (171), Department of Pharmaceutical
Sciences, College of Pharmacy, University of New
Mexico Health Science Center, Albuquerque, NM,
United States
Patricia Chaves (171), Medical Oncology Service, Section
of Immuno-Oncology, Hospitales Universitarios
Regional y Virgen de la Victoria, Institute of Biomedical
Research in Malaga (IBIMA); University of Málaga,
Málaga, Spain
D. Chen (665), Department of Chemical and Pharmaceutical
Biology, University of Groningen, Groningen, The
Netherlands
Hong Chen (471), Department of Food Science and Human
Nutrition; Division of Nutritional Sciences, University
of Illinois at Urbana-Champaign, Urbana, IL, United
States
Shijia Alexia Chen (471), Department of Food Science
and Human Nutrition, University of Illinois at Urbana-
Champaign, Urbana, IL, United States
Baoli Cheng (873), Department of Human Genetics, Emory
University, Atlanta, GA, United States
P. Chun (597), College of Pharmacy, Inje University,
Gimhae, South Korea
Oskar Ciesielski (721), Department of Molecular
Biophysics, Faculty of Biology and Environmental
Protection; The Bio-Med-Chem Doctoral School of the
University of Lodz and Lodz Institutes of the Polish
Academy of Sciences, University of Lodz, Lodz, Poland
Maricarmen Colon-Diaz (309), San Juan Bautista Medical
School, Caguas, Puerto Rico
O.H. Cox (81), The Johns Hopkins Mood Disorders Center,
Department of Psychiatry and Behavioral Sciences,
Johns Hopkins University School of Medicine,
Baltimore, MD, United States
xvii
xviii  Contributors
Angela Cozma (143), University of Medicine and
Pharmacy; Department of 4th Internal Medicine, Cluj-
Napoca, Romania
Xiaolong Cui (839), Department of Chemistry, University
of Chicago, Chicago, IL, United States
F.J. Dekker (665), Department of Chemical and
Pharmaceutical Biology, University of Groningen,
Groningen, The Netherlands
Carmela Dell’Aversana (447), Institute for Experimental
Endocrinology and Oncology “Gaetano Salvatore”
(IEOS) – National Research Council (CNR); Department
of Precision Medicine, University of Campania “Luigi
Vanvitelli”, Naples, Italy
Engin Demirdizen (425), Neurology Clinic and National
Center for Tumor Diseases, University Hospital
Heidelberg, Heidelberg, Germany
Jiali Deng (919), Institute of Geriatrics (Shanghai
University), Affiliated Nantong Hospital of Shanghai
University (The Sixth People’s Hospital of Nantong),
School of Medicine, Shanghai University, Nantong;
Cardiac Regeneration and Ageing Lab, Institute of
Cardiovascular Sciences, Shanghai Engineering
Research Center of Organ Repair, School of Life
Science, Shanghai University, Shanghai, China
Deepti D. Deobagkar (903), Molecular Biology Research
Laboratory, Department of Zoology, Savitribai Phule
Pune University, Pune, India
Mona Dvir-Ginzberg (633), Institute of Bio-Medical and
Oral Research, Faculty of Dental Medicine, Hebrew
University of Jerusalem, Jerusalem, Israel
Devon Ehnes (853), Institute for Stem Cell and
Regenerative Medicine; Department of Biochemistry,
School of Medicine, University of Washington, Seattle,
WA, United States
J.C. Eissenberg (103), Edward A. Doisy Department
of Biochemistry and Molecular Biology, Saint Louis
University School of Medicine, Doisy Research Center,
St Louis, MO, United States
Perla M. Elosegui (309), San Juan Bautista Medical
School, Caguas, Puerto Rico
Adriana Fodor (143), University of Medicine and
Pharmacy; Department of Diabetes, Nutrition and
Metabolic Diseases, Cluj-Napoca, Romania
A. Ganesan (885), School of Pharmacy, University of East
Anglia, Norwich, United Kingdom
Cristina Giorgio (447), Department of Precision Medicine,
University of Campania “Luigi Vanvitelli”, Naples, Italy
Mengying Guo (919), Institute of Geriatrics (Shanghai
University), Affiliated Nantong Hospital of Shanghai
University (The Sixth People’s Hospital of Nantong),
School of Medicine, Shanghai University, Nantong;
Cardiac Regeneration and Ageing Lab, Institute of
Cardiovascular Sciences, Shanghai Engineering
Research Center of Organ Repair, School of Life
Science, Shanghai University, Shanghai, China
J.G. Hall (377), Department of Medical Genetics and
Pediatrics, University of British Columbia; BC
Children’s Hospital, Vancouver, BC, Canada
S. Hashimoto-Hill (213), Division of Immunobiology
and Center for Immunology and Tolerance, Cincinnati
Children’s Hospital Medical Center; Department of
Pediatrics, University of Cincinnati College of Medicine,
Cincinnati, OH, United States
Mustapha Umar Imam (33), Centre for Advanced
Medical Research and Training; Department of Medical
Biochemistry, Faculty of Basic Medical Sciences,
Usmanu Danfodiyo University, Sokoto, Nigeria
Maznah Ismail (33), Laboratory of Molecular Biomedicine,
Institute of Bioscience, Universiti Putra Malaysia, UPM,
Serdang, Selangor, Malaysia
Alexander J. Jaramillo (309), San Juan Bautista Medical
School, Caguas, Puerto Rico
M.P. Jennings (407), Institute for Glycomics, Griffith
University, Gold Coast, QLD, Australia
Peng Jin (873), Department of Human Genetics, Emory
University, Atlanta, GA, United States
A.C. Johnson (817), Oklahoma Center for Neuroscience,
University of Oklahoma Health Sciences Center; Veterans
Affairs Health Care System; Department of Physiology,
University of Oklahoma Health Sciences Center;
Department of Neurology, University of Oklahoma Health
Sciences Center, Oklahoma City, OK, United States
B. Kahaleh (251), Division of Rheumatology and
Immunology, Department of Internal Medicine, University
of Toledo Medical Center, Toledo, OH, United States
D.R. Kelly (213), Division of Immunobiology and Center
for Immunology and Tolerance, Cincinnati Children’s
Hospital Medical Center; Department of Pediatrics,
University of Cincinnati College of Medicine,
Cincinnati, OH, United States
Alexander Koliada (11), Molecular Genetic Laboratory
Diagen, Kyiv, Ukraine
Narasaiah Kolliputi (185), Division of Allergy and
Immunology, Department of Internal Medicine,
University of South Florida, Tampa, FL, Unites States

Ashok Kumar (633), Department of Biochemistry and
Biophysics, University of Rochester, Rochester, NY,
United States
R.S. Lee (81), The Johns Hopkins Mood Disorders Center,
Department of Psychiatry and Behavioral Sciences,
Johns Hopkins University School of Medicine,
Baltimore, MD, United States
Anait S. Levenson (741), Department of Veterinary
Biomedical Sciences, College of Veterinary Medicine,
Long Island University, Brookville, NY, United States
Shiri Levy (853), Institute for Stem Cell and Regenerative
Medicine; Department of Biochemistry, School of
Medicine, University of Washington, Seattle, WA,
United States
C.O. Ligon (817), Oklahoma Center for Neuroscience,
University of Oklahoma Health Sciences Center,
Oklahoma City, OK, United States
Maria Liguori (559), National Research Council, Institute
of Biomedical Technologies, Bari Unit, Bari, Italy
Ji Liu (347), Department of Ophthalmology and Visual
Science, Yale University School of Medicine, New
Haven, CT, United States
T. Louwies (817), Oklahoma Center for Neuroscience,
University of Oklahoma Health Sciences Center,
Oklahoma City, OK, United States
Qianjin Lu (231), Department of Dermatology, Second
Xiangya Hospital of Central South University, Hunan
Key Laboratory of Medical Epigenetics, Changsha,
Hunan, People’s Republic of China
Shuaihantian Luo (231), Department of Dermatology,
Second Xiangya Hospital of Central South University,
Hunan Key Laboratory of Medical Epigenetics,
Changsha, Hunan, People’s Republic of China
Oleh Lushchak (11), Department of Biochemistry and
Biotechnology, Vasyl Stefanyk Precarpathian National
University, Ivano-Frankivsk, Ukraine
B. Greenwood-Van Meerveld (817), Oklahoma Center
for Neuroscience, University of Oklahoma Health
Sciences Center; Veterans Affairs Health Care System;
Department of Physiology, University of Oklahoma
Health Sciences Center, Oklahoma City, OK, United
States
Rachel L. Miller (51), Icahn School of Medicine at Mount
Sinai Hospital, New York, NY, United States
V. Nagaraja (251), Division of Rheumatology, Department
of Internal Medicine University of Michigan, Ann
Arbor, MI, United States
Contributors  xix
Shyamala C. Navada (585), Tisch Cancer Institute, Icahn
School of Medicine at Mount Sinai, New York, NY,
United States
Nicoletta Nuzziello (559), National Research Council,
Institute of Biomedical Technologies, Bari Unit, Bari, Italy
Jessica Oh (51), Icahn School of Medicine at Mount Sinai
Hospital, New York, NY, United States
Elisa Oltra (279), Department of Pathology, School of
Health Sciences, Catholic University of Valencia,
Valencia, Spain
Juan Luis Onieva (117), Medical Oncology Service,
Section of Immuno-Oncology, Hospitales Universitarios
Regional y Virgen de la Victoria, Institute of Biomedical
Research in Malaga (IBIMA), Málaga, Spain
Der Jiun Ooi (33), Department of Oral Biology &
Biomedical Sciences, Faculty of Dentistry, MAHSA
University, Jenjarom, Selangor, Malaysia
Luciano Pirola (721), Cardiology, Metabolism and Nutrition
Laboratory, INSERM U1060, Lyon-1 University, South
Lyon Medical Faculty, Pierre Benite, France
S. Proschinger (491), Department for Molecular and
Cellular Sports Medicine, German Sport University
Cologne, Cologne, Germany
Shriram N. Rajpathak (903), Molecular Biology Research
Laboratory, Department of Zoology, Savitribai Phule
Pune University, Pune, India
Karyn G. Robinson (513), Tissue Engineering and
Regenerative Medicine Laboratory, Alfred I. duPont
Hospital for Children, Nemours Children’s Health
System, Wilmington, DE, United States
Gabriela Roman (143), University of Medicine and
Pharmacy; Department of Diabetes, Nutrition and
Metabolic Diseases, Cluj-Napoca, Romania
Hannele Ruohola-Baker (853), Institute for Stem Cell and
Regenerative Medicine; Department of Biochemistry,
School of Medicine, University of Washington, Seattle,
WA, United States
Adriana Rusu (143), University of Medicine and
Pharmacy; Department of Diabetes, Nutrition and
Metabolic Diseases, Cluj-Napoca, Romania
Kamaldeen Olalekan Sanusi (33), Department of
Physiology, Faculty of Basic Medical Sciences; Centre
for Advanced Medical Research and Training, Usmanu
Danfodiyo University, Sokoto, Nigeria
A. Schenk (491), Institute for Sport and Sport science, TU
Dortmund University, Dortmund, Germany
xx  Contributors
K.L. Seib (407), Institute for Glycomics, Griffith University,
Gold Coast, QLD, Australia
Giulia Sgueglia (447), Department of Precision Medicine,
University of Campania “Luigi Vanvitelli”, Naples, Italy
Liqi Shu (873), Department of Human Genetics, Emory
University, Atlanta, GA, United States
J. Singh (529), Forma Therapeutics, Watertown, MA,
United States
Adela Sitar-Tăut (143), University of Medicine and
Pharmacy; Department of 4th Internal Medicine, Cluj-
Napoca, Romania
Edwin Y. Soto (309), San Juan Bautista Medical School,
Caguas, Puerto Rico
Ramona Suharoschi (143), University of Agricultural
Sciences and Veterinary Medicine Cluj-Napoca;
Molecular Nutrition and Proteomics Research
Laboratory, Cluj-Napoca, Romania
J. Tajbakhsh (529), Cedars-Sinai Medical Center, Los
Angeles, CA, United States
Francesco Paolo Tambaro (447), Center for Bone Marrow
Transplant and Blood Transfusion, Children’s Hospital
“Santobono-Pausilipon”, Naples, Italy
Julian Taranda (425), Neurology Clinic and National
Center for Tumor Diseases, University Hospital
Heidelberg, Heidelberg, Germany
Akshaya Thoutam (185), Division of Allergy and
Immunology, Department of Internal Medicine,
University of South Florida, Tampa, FL, Unites States
Trygve O. Tollefsbol (3), Distinguished Professor,
Department of Biology; O’Neal Comprehensive
Cancer Center; Integrative Center for Aging Research;
Nutrition Obesity Research Center; Comprehensive
Diabetes Center, University of Alabama at Birmingham,
Birmingham, AL, United States
P. Trojer (693), Constellation Pharmaceuticals Inc.,
Cambridge, MA, United States
Sevin Turcan (425), Neurology Clinic and National Center
for Tumor Diseases, University Hospital Heidelberg,
Heidelberg, Germany
Yaaqub Abiodun Uthman (33), Department of Physiology,
Faculty of Basic Medical Sciences; Centre for Advanced
Medical Research and Training, Usmanu Danfodiyo
University, Sokoto, Nigeria
Alexander Vaiserman (11), Laboratory of Epigenetics,
D.F. Chebotarev Institute of Gerontology, NAMS, Kyiv,
Ukraine
Romana Vulturar (143), University of Medicine and
Pharmacy; Department of Cell and Molecular Biology,
Cluj-Napoca, Romania
Huan Wang (471), Department of Food Science and Human
Nutrition, University of Illinois at Urbana-Champaign,
Urbana, IL; Human Genetics, David Geffen School of
Medicine, University of California, Los Angeles, CA,
United States
H. Wapenaar (665), Wellcome Trust Centre for Cell Biology,
University of Edinburgh, Edinburgh, United Kingdom
R. Weksberg (377), Division of Clinical and Metabolic
Genetics and Genetics and Genome Biology
Program, The Hospital for Sick Children; Department
of Pediatrics and Institute of Medical Science,
University of Toronto, Toronto, ON, Canada
Junjie Xiao (919), Institute of Geriatrics (Shanghai
University), Affiliated Nantong Hospital of Shanghai
University (The Sixth People’s Hospital of Nantong),
School of Medicine, Shanghai University, Nantong;
Cardiac Regeneration and Ageing Lab, Institute of
Cardiovascular Sciences, Shanghai Engineering
Research Center of Organ Repair, School of Life
Science, Shanghai University, Shanghai, China
Guanying Bianca Xu (471), Department of Food Science
and Human Nutrition, University of Illinois at Urbana-
Champaign, Urbana, IL, United States
Chang Zeng (839), Department of Preventive Medicine,
Northwestern University Feinberg School of Medicine,
Chicago, IL, United States
Wei Zhang (839), Department of Preventive Medicine,
Northwestern University Feinberg School of Medicine,
Chicago, IL, United States; Institute of Precision
Medicine, Jining Medical University, Jining, China;
The Robert H. Lurie Comprehensive Cancer Center,
Northwestern University Feinberg School of Medicine,
Chicago, IL, United States
Zhou Zhang (839), Department of Preventive Medicine,
Northwestern University Feinberg School of Medicine,
Chicago, IL, United States
P. Zimmer (491), Institute for Sport and Sport science, TU
Dortmund University, Dortmund, Germany
Preface

It has been several years since the first volume of Medical Epigenetics appeared, and a second volume is not only timely but
also appropriate given the rapid developments in the areas covered in this field. The field of medical epigenetics has indeed
undergone rapid growth, and the chapters contained in this new edition have been updated and revised to reflect these new
changes. The first edition of Medical Epigenetics received Honorable Mention in the Clinical Medicine Award Category
by the American Publishers Awards for Professional and Scholarly Excellence (PROSE) and also a “Highly Commended”
Award by the British Medical Association, which attests to the high standards of this book. Many of the chapters in the
second edition are authored by the same leaders in this field who contributed to the first edition of this award-winning book.
Medical Epigenetics, Second Edition provides a comprehensive analysis of the importance of epigenetics to health
management. The purpose of this book is to fill a current need for a comprehensive volume on the medical aspects of
epigenetics with a focus on human systems, epigenetic diseases that affect these systems, and modes of treating epigenetic-
based disorders and diseases. The intent of this book is to provide a stand-alone comprehensive volume that will cover all
human systems relevant to epigenetic maladies and all major aspects of medical epigenetics. The overall goal is to provide
the leading book on medical epigenetics that will be useful not only to physicians, nurses, medical students, and many oth-
ers directly involved with health care but also to investigators in life sciences, biotech companies, graduate students, and
many others who are interested in more applied aspects of epigenetics. Research in the area of translational epigenetics is
a cornerstone of this volume.
The first volume of Medical Epigenetics was published about 5 years ago, and many developments in the numerous
areas of epigenetic involvement in medicine have taken place since that time. There has also been a surge of interest in
precision medicine since 2015, and the second edition of Medical Epigenetics will cover this new and exciting area as well
with a focus on epigenetics in precision medicine. A few areas that have not changed considerably over the 5 years or that
were of lesser interest in the first edition have been removed from the second edition of Medical Epigenetics.
The overall design of this book is to build from the fundamental mechanisms of epigenetics as they apply to humans to
approaches for treating epigenetic-based diseases. The book begins with the basic tenets of epigenetics in human systems
and progresses through general medical aspects of epigenetics, epigenetics of system disorders, multisystem medical epi-
genetics, pharmacology of epigenetics, and therapeutic epigenetics. The volume closes with two chapters on future pros-
pects in medical epigenetics. It is intended that this book will be among the most comprehensive and leading books in the
area of medical epigenetics and improve upon the award-winning first volume of this book.

Trygve O. Tollefsbol

xxi
Section A

Overview
This page intentionally left blank
Chapter 1

Advances in medical epigenetics

Trygve O. Tollefsbola,b,c,d,e
a
Distinguished Professor, Department of Biology, University of Alabama at Birmingham, Birmingham, AL, United States, bO’Neal Comprehensive
Cancer Center, University of Alabama at Birmingham, Birmingham, AL, United States, cIntegrative Center for Aging Research, University of Alabama
at Birmingham, Birmingham, AL, United States, dNutrition Obesity Research Center, University of Alabama at Birmingham, Birmingham, AL, United
States, eComprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL, United States

Introduction
Epigenetic processes consist of biochemical changes to the DNA or its associated proteins or RNA that does not change
the DNA sequence itself but does impact the level of gene expression. Epigenetics in general has a highly important role in
medicine that provides previously unimagined new opportunities to disease management that span from diagnosis to treat-
ment and extend as well to prognosis [1]. Virtually all systems of the body are affected by epigenetic processes and in many
cases, epigenetic processes impact many different biological systems [2]. DNA methylation, histone modifications, and
noncoding RNA comprise three major components of the epigenetic machinery that has relevance to medical conditions
[3–8]. All of these mechanisms are capable of regulating gene expression leading to many of the pathological features that
are manifested by epigenetic aberrations.

Basic principles of epigenetics

The most studied of the major epigenetic mechanisms is DNA methylation and for many years led the way to our under-
standing of the power of epigenetics in many biological phenomena such as X chromosome inactivation and mitotic inheri-
tance of epigenetics as well as many other processes. The study of DNA methylation also was critical in the developmental
stages of the field of epigenetics in leading the way toward our realization that modifications of DNA, no matter how simple
can have a major impact on health when these modifications are altered [9].
5-Methylcytosine (5mC), the product of the DNA methyltransferases (DNMTs) that catalyze DNA methylation, is ame-
nable to further modifications and leads to a number of biological changes [6]. The ten-eleven translocase dioxygenases
(TET enzymes) can modify 5mC to produce 5-hydroxymethylcytosine (5hmC) that can further become modified by the
TET enzymes to produce 5-formylcytosine and 5-carboxylcytosine. Once corrected by the DNA repair mechanisms, one
of the significant outcomes is an enzymatic conversion of 5mC to cytosine. Therefore, DNA methylation cannot only be
placed enzymatically into the genome, but it can also be lost through an enzymatic demethylation process. This reversibility
of DNA methylation could have many implications in medical diseases that have changes in gene expression secondary
to fluctuations in DNA methylation. The histones also undergo reversible changes in their modifications during disease
formation and progression and this is also driven by enzymatic processes. For example, histone acetyltransferases (HATs)
add acetyl moieties to the N-terminal tails of histones that can often lead to an increase in gene expression. Also highly
relevant are the histone deacetylases (HDACs) that remove acetyl groups from the histones. In fact, HDAC inhibitors may
serve as an important therapeutic target with respect to cognitive decline as a component of neurodegenerative disease [6].
The noncoding RNAs (ncRNAs) comprise the third major mediator of epigenetic changes that occur in human cells and that
appear to have considerable potential for impacting medical diagnosis, treatment, and prognosis [3].
Taken together, these three major mechanisms for mediating epigenetic changes result in a large percentage of epigen-
etic control of gene expression that is a major component of medical diseases. Perhaps even more important is that these
epigenetic modifiers frequently do not act alone but often participate in a cross talk process. DNA methylation may interact
with histone modifications to silence the expression of a gene as well as many other permutations on this theme that be-
come possible between intraepigenetic interactions. Moreover, these epigenetic mechanisms also often interact with other
important mediators of gene control such as transcription factors.

Medical Epigenetics. https://doi.org/10.1016/B978-0-12-823928-5.00002-5

Copyright © 2021 Elsevier Inc. All rights reserved. 3
4 SECTION | A Overview

General medical aspects of epigenetics

Although much has been learned about epigenetics and its role in medicine, much less is known about the lifetime temporal
aspects of epigenetic changes. For instance, as described in Chapter 2, there is evidence that epigenetic changes during sen-
sitive stages of early life may be critical to the health of adults. One of the primary factors that can contribute to early-life
epigenetic modifications is environmental insults that can result in epigenetic aberrations that may give rise to disease for-
mation later in life. Moreover, lifestyle factors such as one’s diet, the quality or quantity of exercise, or environmental fac-
tors can result in epigenetic modifications that, depending on the type of lifestyle change, may either increase or decrease
health in general (Chapter 3). Disease prevention and promotion of health are extremely important in medical care and
collectively will greatly decrease the amount of human suffering from diseases as well as reduce spiraling health care costs.
By focusing on the impact of epigenetic prevention of disease, we may be able to “get ahead of the curve” so to speak and
to prevent many medically related diseases before they begin or at least slow their progression. Environmental exposures
to air, food, and personal products can have a major effect on epigenetic mechanisms that can also occur at specific time
windows of exposure. As discussed in Chapter 4, these environmental factors include dietary exposures, chemicals, aller-
gens, and pollutants. Advances in this field are rapidly developing and the impact of the environment on epigenetic aspects
of disease, although a classic aspect of the field of epigenetics, is still understudied and it is likely that major discoveries
will continue to unfold in this area that is critical to medical epigenetics. In fact, early life experiences can greatly influence
behavior and this can be mediated through epigenetic modifications. Factors such as stress and cortisol can alter epigenetic
marks that may influence gene expression and subsequently lead to changes in behavior (Chapter 5). For example, genes of
the hypothalamic-pituitary-adrenal axis have been implicated in glucocorticoid-related behavioral disorders and epigenetic
mechanisms such as DNA methylation and histone modifications can be affected by glucocorticoids that subsequently
affect neurotransmitter genes. These changes may precipitate or worsen behavioral aberrations and perhaps psychiatric
disorders as well.
The proverbial nature vs nurture influence of disease has perplexed investigators for about as long as it has been known
that each of these important factors can influence disease formation. Through the study of twins, especially monozygotic
twins, we now know that phenotypic variation increases with aging of organisms and that this is due at least in part to envi-
ronmental factors that alter the epigenetic machinery. In a fascinating review by Joel Eissenberg (Chapter 6), twin studies
have tremendous potential to tether out the epigenetic roles in complex traits and multifactorial diseases. A major challenge
in this endeavor, however, will be to fully resolve the mechanisms for age-related “epigenetic drift” and to deduce which
of the epigenetic changes that are divergent in twins as they age are contributing to the etiology of diseases and which are
by-products of pathology. This involves another major challenge in medicine besides the relative contribution of nature vs
nurture, that is, cause and effect. Twin studies will likely reveal a wealth of information about the role of epigenetics in
medicine and my estimate is that this field, although still in an early phase, has tremendous potential to answer many of the
significant questions that persist with respect to medical epigenetics.
In addition to increasing our understanding, the mechanisms of epigenetics in medicine, on a more practical level
we also need to enhance the ability to diagnose diseases and to better predict the outcomes of diseases. In fact, advances
in medical epigenetics are contributing significantly to the development of epigenetic biomarkers useful for diagnosis
(Chapter 7) as well as the prognosis (Chapter 8) of many diseases such as cancer. The identification of epigenetic aber-
rations in medical disorders opens important opportunities for the development of biomarkers for earlier diagnosis and
perhaps prevention of diseases. Epigenetic biomarkers of interest include not only DNA methylation and histone modifica-
tions, but also noncoding RNAs (Chapter 7). Many of these epigenetic biomarkers are also greatly enhancing the predictive
power of disease outcome that can be an important factor for monitoring and adjusting treatment regimens such as various
disease progress (Chapter 8).

Epigenetics of system disorders

Since epigenetic mechanisms can have a significant impact on gene expression, it is not surprising that epigenetic aberra-
tions influence virtually all systems of the body ranging from the disorders of the intestinal tract, to cardiovascular disorders
to dermatological diseases. It is now apparent that immune-based disorders can occur secondary to epigenetic aberrations
that involve both the initiation and perpetuation of these disorders (Chapter 9). Recent discoveries have suggested that the
immune system may carry a “memory” of prior exposures to pathogens that are encoded in the maintenance of altered
epigenetic marks. This new direction may lead to increased precision medicine for diseases of the immune system that
has fascinating potential. The pulmonary system is also very prone to aberrations of an epigenetic nature (Chapter 10) and
chronic obstructive pulmonary disease, asthma, interstitial lung diseases such as idiopathic pulmonary fibrosis and other
 Medical epigenetics advances Chapter | 1 5

pulmonary disorders have been shown to have epigenetic components as part of their pathology. Moreover, the cardiovas-
cular system is prone to epigenetic alterations that can personalize the epigenome and lead to biomarkers of diseases of
this system. Cardiovascular risk factors such as hypertension, smoking, and obesity have been associated with epigenetic
alterations and epigenetic-modifying agents may have a potential in ameliorating the effects of these common conditions
(Chapter 11). Along with aberrations of an epigenetic nature in these systems, the microbiome, which is environmentally
sensitive through factors such as diet, can also be influenced by epigenetic factors that may be integrated with genetic, diet-
derived, and microbial cues that influence gastrointestinal health as described in Chapter 12.
Many skin and bone and joint disorders also have an epigenetic basis. Epigenetic modifications may contribute to
the aging of the skin, cancers of the skin, and immunologic skin diseases and treatments may be on the horizon for
­epigenetic-based skin disorders (Chapter 13) as well as for bone and joint disorders such as rheumatic diseases as described
in Chapter 14. Epigenetic factors are even involved in cardiac, skeletal muscle, and smooth muscle diseases. For example,
atrial fibrillation (cardiac muscle), fibromyalgia (skeletal muscle), and gastrointestinal tract (smooth muscle) disorders
have been described to be involved with epigenetic aberrations as reviewed in Chapter 15. These may be areas for novel
approaches to new therapies for these disorders that are often recalcitrant to therapy.
The reproductive system can also be impacted by epigenetic processes that can be manifested as fertility disorders and
even imprinting diseases as well as polycystic ovary syndrome and endometriosis (Chapter 16). Epigenetic aberrations can
occur at any stage of reproductive life and give rise to transcriptome dysregulations that can lead to human reproductive
disorders in both males and females. Finally, in Chapter 17, we see that ocular medicine is increasingly benefitting from the
exponential increase in epigenetic knowledge. In fact, inherited retinal diseases, myopia, age-related macular degeneration,
glaucoma, and many other ocular disorders such as diabetic retinopathy, uveitis, and keratoconus can be mediated through
epigenetic processes that later manifest as disease.

Multisystem medical epigenetics

Many epigenetic processes that contribute to disease are not confined to just one system of the body but can manifest as
multisystem disorders. As aforementioned, environmental insults at an early age can have a major impact on many differ-
ent systems either in the young or late in life. Factors such as the influence of epigenetics on birth weight or childhood
obesity are important and a new area that is showing promise is multigenerational pediatrics that takes many factors into
account such as the impact of epigenetics on environmental exposures, birth weight, and pregnancy histories (Chapter 18).
Infections may extend beyond one body system and epigenetic modifications in bacterial pathogens as well as in the host
can influence the virulence and nature of a number of different infectious diseases as described in Chapter 19. Of course,
tumor formation is in a class of its own, but it also shares features with many other epigenetic disorders in that it is often
multisystematic in its pathology. The role of epigenetics in cancer is well known and solid malignant tumors seen in the
lung, liver, breast and many other systems have been historically difficult to treat because of the more limited bioavailability
of epigenetic drugs to the solid tumors (Chapter 20). Despite this, however, early detection of cancer through epigenetic
biomarkers and prognostic potential and therapy, especially combination therapeutic strategies, are advancing for many
solid tumors.
Besides solid tumors, epigenetic aberrations are also important in hematological cancers and this is nicely illustrated
with respect to acute myeloid leukemia as shown in Chapter 21. Although epigenetic-based treatments for acute myeloid
leukemia have been limited, many approaches involving DNMT and HDAC inhibitors are being developed in addition to
potential novel therapies affecting other aspects of the epigenetic machinery such as the histone methyltransferases (HMTs),
the HATs, and microRNA (miRNA). Cancer metastasis is also influenced by epigenetics as reviewed in Chapter 22 and
fundamental epigenomic alterations could be important in the metastatic process. This will likely involve critical steps of
the final stages of cancer progression.
Another multisystem aspect of epigenetics involves sports medicine. In fact, both acute and chronic exercise can al-
ter epigenetic processes as reviewed in Chapter 23. The impact of exercise on the epigenetic machinery affects not only
muscle, but also extends to blood and fat cells and even brain tissue. These epigenetic changes may therefore affect many
different systems and may even collectively impact the aging of the systems (e.g., epigenetic clock) affected by exercise.

Bioinformatics of epigenetic medicine

Bioinformatics is rapidly becoming a mainstay of epigenetics and its role in medicine. Perhaps most notably and as
described in Chapter 24, machine learning, which involves the means by which algorithm-based machines can “learn”
from and adapt to information to increase efficiency and accuracy, can process epigenetic phenomena for the prediction
6 SECTION | A Overview

of d­ iseases. It is obvious that a very powerful addition to the field of epigenetics would be enhancing the prediction of
phenotypes for more accurate diagnoses as well as the prediction of the clinical course of a disease. DNA methylation
has been shown to be especially useful for machine learning applications as applied especially to complex diseases. The
potential for the application of machine learning in epigenetic diseases appears to be especially high and may eventually
revolutionize our approaches to epigenetic-based diseases.

Pharmacology of epigenetics
With the development of many new epigenetic drugs and given the pervasiveness of epigenetics itself, the relative safety of
epigenetic agents is a highly pertinent issue with respect to medical epigenetics. It is important to be able to have selective
targeting of the novel drug and to avoid off-target effects. Chapter 25 reviews the importance of epigenetic drug assessment
not only for efficacy, but also for potential toxicity in human safety assessment. As more developed epigenetic drugs are
coming forward, clinical trials and full toxicity evaluation of these drugs will be an important aspect of medical epigenetics.
These points are most apparent in Chapter 26 on pharmacoepigenomics. Further considerations in this chapter include in-
dividualized response to the same treatment and ongoing clinical trials to search for epigenomic-modifying drugs against
neurodegenerative disease. A goal is to develop individualized and personalized novel applications to drug therapy based on
epigenetic analyses. Taken together, it is apparent that the field of pharmacoepigenetics is currently in a renaissance stage
of development. The future development of these drugs that impact epigenetic-based diseases will be highly important to
the overall success of the field of medical epigenetics.

Therapeutic epigenetics
A major goal of medical epigenetics is to ultimately devise a means to modify or correct epigenetic aberrations that con-
tribute to diseases. An area of therapeutic epigenetics that has grown considerably is the use of DNA methylation inhibitors
as reviewed in Chapter 27. For example, agents such as 5-azacytidine (azacitidine) and 5-aza-2′-deoxycytidine (decitabine)
have been used to demethylate and reactivate tumor suppressor genes in cancer cells. These demethylating agents used ei-
ther alone or in combination have had the most success in treating hematologic diseases such as myelodysplastic syndromes
and acute myeloid leukemia in part because of increased bioavailability. Many efforts are now directed toward the use of
demethylating agents for solid tumor treatment in part through combinatorial approaches and for applications to diseases
other than cancer.
Use of HDAC inhibitors is also a major area of medical epigenetics therapy and is rapidly advancing as well.
HDAC inhibitors are relatively widespread treatment modalities and include potential treatment for not only cancer,
but also rheumatoid arthritis, diabetes, inflammatory diseases, schizophrenia, and many other disorders as reviewed in
Chapter 28. The NAD+-dependent deacetylases are also emerging as an important class of epigenetic-modifying com-
pounds. Notably, the sirtuins that require NAD+ for their catalytic activity have been an area of focus for this group and
many inhibitors of the sirtuins are currently in development (Chapter 29). Other aspects of epigenetic histone modifi-
cations have also received attention for potential therapeutic approaches in medical epigenetics. Among these are the
versatile HAT inhibitors that are described in Chapter 30 and have potential applications for therapeutic approaches for
inflammatory lung and cardiovascular diseases, viral infections, and neurological disorders. The histone methylation
modifiers are also of interest in medical epigenetics (Chapter 31). These include lysine methyltransferases and demeth-
ylases as well as the protein arginine methyltransferases and others and several drugs are in preclinical assessments for
use in many different therapeutic scenarios such as cancer therapy.
A completely different approach for therapy in medical epigenetics consists of noncoding RNA targets as well as novel
miRNA-based drugs. Several of these are in clinical trials and may have a clinical application to a large array of epigenetic-
based medical disorders such as cancer, metabolic diseases, and neurological disorders (Chapter 32).
There appears to be considerable potential for the development of natural epigenetic-modifying molecules in medical
therapy as reviewed by Levenson in Chapter 33. Strong evidence has emerged in recent years that dietary natural com-
pounds such as polyphenols and other phytochemicals are able to either prevent epigenetic aberrations from occurring or
reverse the epigenetic alterations once they are formed. An important aspect of these approaches is the relatively low risk of
toxicity and the higher patient compliance associated with the consumption of natural dietary compounds. It is likely that
this area of medical epigenetics will continue to grow at a high rate as known compounds are further characterized and new
compounds are discovered. Another area of epigenetic medical therapeutics that is developing at a rapid rate is combinato-
rial approaches and the use of nutraceuticals in combination is showing considerable promise as the risk of toxicity of these
approaches remains low despite the multicompound approach.
 Medical epigenetics advances Chapter | 1 7

Epigenetic therapy applied to conditions that have been shown to have an epigenetic basis is of course a major goal of
epigenetic medical therapy. Although the epigenetics of pain management is in its early stages of development, animal stud-
ies have provided some enticing findings that suggest that epigenetic modification approaches to chronic pain management
may have important applications to humans (Chapter 34). This area of medical epigenetics, although currently in its infancy
and the exact epigenetic mechanisms underlying chronic pain perception remain to be established, will be closely watched
as the potential for advancements could carry high importance. Also in the early stages of development but poised for excit-
ing breakthroughs is the area of precision medical epigenetics. Interindividual natural variation in human populations as
well as pathogenesis is a significant aspect of medical epigenetics and it is clear that personalized medicine will be of high
importance in the future as new technology is being developed that allows monitoring of disease processes in individuals
as well as monitoring the impact of epigenetic therapy in these individuals (Chapter 35).
The potential of epigenetic drugs to modify somatic cell reprograming has considerable potential and this could be a
basis for the application of epigenetic drugs to regenerative medicine. An important aspect of regenerative medicine is the
heterogeneity of regenerative potential for different tissues within the human body. Epigenetic mechanisms may contribute
to the disparity of regenerative potential for various human tissues/organs, especially during the aging process, and the
use of epigenetic drugs to facilitate regeneration in humans will almost certainly be an area for considerable activity as
epigenetic medical therapy approaches advance. Epigenetic editing tools may also have considerable potential with respect
to regenerative medicine (Chapter 36). An important aspect of regenerative medicine is stem cell therapy, and Chapter 37
covers the role of stem cell epigenetics in medical therapy. As knowledge of epigenetic machinery in stem cells advances,
so too will the potential for the application of epigenetic-modifying drugs to modify cells such as induced pluripotent stem
cells (iPSCs) that can be used for directing reprograming of stem cells and ultimately regeneration of tissues as a compo-
nent of epigenetic medical therapy.
HDAC inhibitors serve as an excellent example of the power of epigenetic-based therapy, and the development of these
drugs from bench to bedside has advanced notably in the past few decades. As described in Chapter 38, many HDAC
inhibitors have been approved for therapeutic uses and numerous compounds are in the near-approval stages of develop-
ment. Some of these compounds are highly selective and their use in solid tumors is on the rise. The application of HDAC
inhibitors in the clinical setting is also expanding to noncancerous medical conditions through corrections of epigenetic
aberrations that are becoming a hallmark of many diseases.

Medical epigenetics: Future prospects

The epigenetic machinery is impacted by external signals such as nutrition, lifestyle, and environment as well as psycho-
logical factors that can generate stress signals that can lead to epigenetic-based disease processes. Increased understanding
of the role of stress in medical epigenetics will likely be a focus of many future studies (Chapter 39). Moreover, with the
development of new epigenetic codes such as the “histone code” as well as the advent of advanced technologies for epig-
enomic profiling has also come exciting and important avenues for major advances in medical epigenetics. As described in
Chapter 40 by Deng et al., many new epigenetics drugs have now been approved by the US Food and Drug Administration
(FDA) and the potential for the approval of many more epigenetic-modifying agents is very high. The International Human
Epigenome Consortium is actively involved in mapping reference epigenomes that will serve as an important resource for
guiding medical management. This new information will be highly important not only as reference material for diagnosis,
prognosis, and therapy, but also with respect to applications to precision epigenetic medicine.

Conclusion
Exciting advances in epigenetics are giving way to new avenues for patient management that was not feasible just a decade
or so ago. Epigenetic processes are highly sensitive to changes in the environment, and as we witness major changes in
our environment, we also need to better understand how this impacts epigenetic mechanisms and their aberrations in the
formation and progression of an array of medical diseases. It was not long ago that epigenetic medicine was focused almost
entirely on cancer and few other diseases were known to have an epigenetic component. Now, it is apparent that virtually
every system of the human body is affected by epigenetic processes and that these epigenetic mechanisms also manifest
across many different systems that give relevance of epigenetic medicine to multisystem conditions as well. Recent ad-
vances in epigenetic medical therapeutics are now revealing the potential power of epigenetic-based therapy for application
to a large array of medical conditions including by not limited to neurological conditions, cancer, metabolic disorders, pain
management, and pediatric and infectious disease management. Epigenetic therapy is likely to also be an important com-
ponent of precision medicine as novel advances are rapidly developing in personalized epigenetic diagnoses and therapies.
Another random document with
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States medical corps, who was appointed chief sanitary officer, and
with the assistance of local doctors and nurses and those furnished
by the Red Cross, these organizations soon established control of the
entire city in a comprehensive and effective manner.
The Ohio State Board of Health engineers were assigned to assist
in the water works, sewerage, and general cleaning up. Then, in co-
operation with the city board and Major Rhoades, the city was
divided into sixteen sanitary districts, with a physician in charge of
each. These physicians inspected their districts, reported to
headquarters, conditions requiring particular attention, instructed
people in sanitation and followed up all reported cases of illness to
guard against contagion.
The city bacteriologist reestablished his laboratory, which had
been inundated, and took up diagnostic and analytical work. The
state plumbing inspector and the state inspector of workshops and
factories established offices, and joined with the city inspectors in
pushing inspection work rapidly. Men were sent out to trace all
contagious cases that were on the books at the time of the floods, and
the reporting of infectious diseases and deaths were resumed as
rapidly as possible.
Four contagious disease wards were established in addition to the
tuberculosis and small-pox hospitals, two in the St. Elizabeth and
Miami Valley Hospitals in the city and one each in North Dayton and
Riverdale. As fast as infectious cases were reported or discovered,
they were removed to one of these wards, and the houses placarded
and disinfected.
A food inspection office was also opened, and all food arriving on
relief cars was inspected before distribution to relief stations, that
which had already been distributed being inspected at the stations.
The medical corps of the Ohio National Guard established a base
field hospital in the new courthouse, and a supply depot in the
probate court room of the old courthouse. In addition, seven relief
hospitals were established in Dayton View, Miami City, Edgemont,
South Park, the Davis Sewing Machine Company’s plant, North
Dayton, and Riverdale, with a surgeon of the medical corps of the
National Guard and a corps of civilian physicians and Red Cross
nurses in charge of each. These stations had maternity, general, and
infectious wards. Hospital and proved infectious cases were
promptly forwarded to St. Elizabeth’s or the Miami Valley Hospital.
The base hospital received all cases among the companies of the
National Guard on duty; those which would obviously not recover in
time for useful service were returned to their homes. The supply
depot of the field hospital not only furnished the base hospital and
the seven field stations, but supplies were also furnished to the
sixteen stations of the sanitary committee, at the request of Major
Rhoades.
An efficiently manned hospital doing all classes of work was
established by the National Cash Register Company and the
American Red Cross in the administration building at the National
Cash Register Company’s plant, and other medical relief stations
were maintained in the city by the Red Cross.
Up to the close of the first week following the flood no unusual
prevalence of infectious disease had developed. Some cases of
diphtheria, pneumonia, and measles were reported, but the number
was not substantially larger than that previous to the flood. When the
conditions that prevailed during the first three days after the disaster
are considered, with the strain on the entire population during the
first days of reconstruction, it seems impossible that Dayton will
escape without a considerable number of cases of intestinal and
exposure diseases, such as typhoid and pneumonia. But the
complete, efficient, and harmonious system of public health
organization that has been established gives promise that no
epidemic will follow and that the first cases, due to infection before
control was established, will be the last.
 THE FRIEDMANN CURE
ALICE HAMILTON, M.D.
As the interest in Dr. Friedrich Franz Friedmann and his
tuberculin increases and a large part of the world is anxiously
waiting to have its hopes confirmed that at last a real cure for
tuberculosis has been discovered, it will be interesting to state what
is positively known about this treatment, to what extent it is a new
discovery and why the medical profession has shown such hostility to
its originator.
In the first place Friedmann’s remedy is not a “serum.” Anti-
toxins, such as those used against diphtheria and lock-jaw are sera.
An antitoxin is the serum of an animal which has been treated with
toxin-forming germs till his blood serum is full of defensive
substances against that toxin. An antitoxin, as its name indicates, is
an antidote to a poison.
Friedmann’s tuberculin belongs to the class which we have of late
begun to call vaccines, a term formerly applied only to the virus of
cowpox but now made to cover all forms of virus which are used to
stimulate the production of defensive substances. The real difference
between an antitoxin and a vaccine is that the first contains an
antidote and is an emergency remedy for an acute disease, while the
second is a weak form of virus which causes the body of the patient
to manufacture its own antidote.
What Friedmann claims as novel in his tuberculin is that it
consists of living tubercle bacilli, while those in general use consist of
dead bacilli or their extractives. It has long been known that living
bacilli would call forth a more rapid production of defensive
substances than dead. Dr. Trudeau of Saranac Lake demonstrated
this twenty years ago, experimenting on rabbits with bacilli of bird
tuberculosis. Later several Americans confirmed his results, using
non-virulent strains of human tubercle bacilli. Von Behring’s famous
experiments on immunizing calves were made with living bacilli. So
far therefore as is yet known, there is nothing new in the principle
Friedmann is following. As to the details of his cure, we are in
ignorance.
It will be long before any dependable word can be given out as to
the results of Friedmann’s work in New York city. Every physician
knows that optimism, eagerness to grasp at every hopeful sign, are
characteristics of a fair majority of consumptives. We shall need a
much longer period of observation before we can be sure that this
tuberculin has any superiority to the many previously tested, almost
all of which have had initial success followed by more or less
disillusionment.
Still greater caution must be used in estimating the immunizing
properties of Friedmann’s tuberculin. Friedmann treated over 300
children eighteen months ago and states that during this interval
none of them have developed tuberculosis. It will be at least fifteen
years before positive statements can be made concerning these
children and then only by comparing them with a similar group of
non-treated children living in conditions as nearly as possible
identical with those of the treated children.
As to the attitude of American physicians to Dr. Friedmann one
can hardly accuse them of unfairness and of narrow-minded
professional jealousy if one realizes that he has violated three of the
fundamental laws of medical ethics and, however impatient the non-
medical world may be of much that comes under this head, no one
can think that secrecy, exclusiveness or self-advertisement are in
accordance with the best traditions of medicine.
A significant contrast could be drawn between the methods
pursued by Dr. Friedmann and those pursued by Paul Ehrlich when
he announced his new cure for syphilis. No charge of charlatanism or
commercialism could ever be brought against Ehrlich. From the first,
the medical world knew all about salvarsan, and knew that it would
be put into everyone’s hands as soon as Ehrlich thought it safe to give
it out for general use. He insisted that it first must be carefully tested,
not by himself alone but by approved clinicians, who would agree to
use it only on patients that could be kept under constant supervision
in hospitals, and who also would agree to make detailed reports of
these cases. After this thorough trying out of the new cure, it was
given unreservedly to the medical profession the world over.
Undoubtedly Ehrlich could have come to America and reaped golden
profits by keeping the cure in his own hands, for thousands of cases
were eager to have it administered.
The Friedmann tuberculin may be what its discoverer claims it is,
but the confidence felt in its promoter can never be the same as that
which Ehrlich has won.
 COURSES ON SEX HYGIENE
JANE R. McCRADY

ELLIS MEMORIAL CLUB, BOSTON

Last spring I attended in Boston a course of lectures on sex
hygiene given expressly for social workers. The course was given at
the request of a number who had been meeting for some time
previously to discuss “what women social workers can do now to
promote a better knowledge of the meaning of sex in life.”
The course was planned by approaching the subject from various
aspects, physiological, psychological, neurological, ideal and simply
human. Talks were given by people whose interest in the subject was
vastly different—physicians, social workers and mothers, and all
showed a spirit of earnestness and willingness to help.
The first few lectures were crowded—overcrowded, in fact—which
showed the great need people feel in being aided and enlightened on
a subject which touches all to some extent.
When the course was over, there was a feeling of disappointment
among some who had attended throughout. Many others had
dropped out because they “could not give the time as they were not
getting out of it what they hoped for.” What did they hope for? The
best answer is that when the opportunity for written questions came,
nearly all the inquiries were “What shall I say to so and so when she
asks so and so?” “What should be said to a young man under such
and such circumstances?” and similar definite demands.
That was the point! People so often want absolute information on
subjects in which “circumstances alter cases!” No human being can
tell any other human being what he or she “should say” to a third
person on any subject at any given time. Each of us has to give of his
knowledge which is fed by his experience and modified by his
temperament. We give this knowledge (if we are wise) to
whomsoever happens to need it in such language as shall appeal to
his knowledge, apply to his experience and adapt itself to his
temperament. We can not learn how to do that at any lecture or set
of lectures, and just as long as we expect it on this or any other
subject, we are sure to be disappointed.
The great importance of a right knowledge of sex is borne in upon
social workers daily, often hourly, on account of the many people
they meet whose lives are exposed to dangers which with either
wrong or incomplete knowledge they are not fitted to meet safely. It
is frequently the duty of the social worker either to supply the
knowledge or help in the situation brought about by lack of it. Often
they feel unequal to the task and become morbid over the sorrows
brought about by ignorance and their own inability to help matters.
Lectures or books on sex hygiene are advertised; to them they turn
for assistance. All too often are they disappointed, gaining no
concrete knowledge of how to give an answer to problems on their
minds at the time. Likewise some people go to a lecture or course
given by some one who has been successful in connecting his or her
knowledge and experience and giving it out. Afterward they come
away thrilled and inspired and proceed to repeat like parrots the
words they have heard.
Bitter disappointment at the lack of interest on the part of the
audience is the result. I knew of some mothers who attended Laura
B. Garrett’s talks in Philadelphia, and came away eager to instruct
their children. In each case the result was wholly unsatisfactory.
They tried to reproduce Miss Garrett’s words, instead of simply
getting knowledge and suggestion from her talks. What they were
imparting was not a part of themselves, not their own, therefore not
theirs to give.
Miss Garrett has worked out her talks from years of patient,
earnest work and hours of thought. She can tell us of her methods
and can illustrate, but if we are going to use her methods we have to
make them our own first. We must adapt them to our own
experience and apply them to the experience of those to whom we
are giving them.
The same is true of any other speaker on this subject. There is no
fixed method by which a right knowledge of sex in life can be
universally taught. We may learn how to teach biology or physiology,
or how to adapt the law of life and of coming to life in plants or
animals to human laws, but that does not necessarily qualify us to
meet the problems of sex in life or to teach others to meet them.
There are a few essentials to the proper teaching of the meaning of
sex in life and if we possess these we ought to be able to deal with our
problems as they come, if we are capable of using our possessions.
First, a real living belief that our bodies are the “temples of the
Holy Spirit,” a belief which applies to all parts and functions of the
body and makes it a sacred duty to keep them healthy and clean and
strong.
Second, an intelligent knowledge of the body as a machine so that
we may use it and not abuse it.
Third, a calm, moderate knowledge of the more common
perversions of sex and their relations to other forms of nervous
troubles, and a belief in human ability to overcome weakness and sin
as well as to cure disease.
These things we can learn and keep on learning at lectures, but
how to give them out from our personality to other personalities is
for each person his or her own individual problem. It must be solved
by bringing his or her own experience of life, plus specific knowledge,
plus sympathy, plus common sense, to bear on each problem and so
to adapt it to the understanding of the person in question that it will
help the existing need.
When the Wise Men of Bethlehem presented gifts, each brought
his own gifts, not another’s. They were wise men. If we social
workers are wise, we shall cease to try to gain from others words in
which to express the knowledge of the meaning of sex in life and will
bend our energies to gaining high ideals, simple workable knowledge
of the use of the body and the evils of its abuse and an understanding
heart and common sense.
Then we shall be able to bring our gifts to this subject and present
it to those who need it in such forms as to be practical and effective.
 A PLEA FOR COMFORT STATIONS
RELL M. WOODWARD
Surgeon United States Public Health Service

Travelers from almost all foreign countries describe the public

convenience stations of foreign cities. In London there are many
places where crooked streets converge, leaving perhaps an irregular
open space or plaza. These are not all occupied by statues, as the city
has attempted to provide comfort for the living as well as honor to
the dead. Two modest iron stairways with suitable signs lead to two
rooms below ground, one for women, the other for men, where
toilets and urinals are found.
On the continent the provisions are usually less complete and in
many instances in the eyes of Anglo-Saxon observers seem much too
public. For instance in Paris urinals for men are located at
convenient points, but some of them only cover the user from the
breast to the knees. In Antwerp and Brussels urinals are attached to
posts at the edge of the narrow sidewalk, and some of them have no
screen at all. In Rotterdam at frequent intervals scrolls of sheet iron
shaped somewhat like a letter C are located in the gutters of the
sidewalks; the open side of the scroll facing the street. They reach
from a point above the head to about a foot from the ground. In Italy
there are places, notably Naples, where two slabs of slate set in a wall
at an angle serve the purpose of a urinal. They are usually at the
entrance to a small street or alley, and are not screened. The custom
of ages causes the natives to pass by these without a glance, but to
use them is embarrassing to the tourist.
It is not the intention to advocate such crude contrivances, but to
present a plea for the establishment at frequent intervals of
convenience stations designed for the use of both men and women,
and with such surroundings that one may enter and leave without
feeling the blush of shame.
Many American cities have provided a few such places, for
instance in parks, and some of these are admirable in conception and
in structure; but one cannot always remain near a park, and in
winter when the kidneys are most active, these stations are often
closed. One of the most practical stations of this kind that I have seen
is in the Boston Common. It is underground in a small hill, with a
wide stairway leading to it.
As one approaches it he sees that the room is lighted and is lined
with white tiling. There are urinals, closets, washstands, and a shoe-
blacking establishment. It has the appearance of a toilet room in a
hotel, and the place is well ventilated and kept clean. I do not recall
how it is heated, but such places could be heated with steam from
adjacent buildings or by stoves.
Cities must of course consider the economic side of any new
enterprise. I believe that such stations, outside of the cost of original
construction, could be made almost if not quite self-supporting, in
the following way. Lease the shoe-blacking privilege to an individual
for a good round fee, said individual to be subject to certain rigid
rules and regulations, and the place to be subject to periodical
inspections. The lessee should be required to keep the place in
perfect sanitary condition. In addition to his income from blacking
shoes the lessee might be allowed to rent a few closets, ordinarily
kept locked, and charge a small prescribed fee. If the patronage of
the station in Boston Common is a criterion it would seem to me that
the city could demand a fee from the lessee that would cover all
ordinary running expenses.
A woman attendant in the ladies’ station could be allowed the
privilege of renting closets, and could also be provided with pins,
buttons, and other necessaries such as are kept in the ladies’ waiting
rooms at department stores.
As a public health measure the subject must be considered from
two standpoints, the health of the individual, and the health of the
community.
Physiology teaches us that the normal adult bladder, when fully
distended, holds twenty ounces, but that a discomfort begins when it
contains more than four ounces. As one advances in years prolonged
retention of urine causes ammoniacal decomposition, with
consequent irritation of the bladder. If the retention is frequent,
disease of the kidneys must follow.
 At present in most American cities there are few convenience
stations available to the public outside of hotels and saloons. In
nearly all hotels one finds a sign stating that the toilet facilities are
for the exclusive use of the guests. This makes a stranger feel
unwelcome.
Saloons are open to the public, but one dislikes to make use of the
sanitary privileges offered without purchasing something. To a man
of mature age, who is perhaps in the habit of taking an occasional
drink, this phase of the subject has little importance; but for a young
man in a strange city, driven for lack of comfort stations into a saloon
the question assumes a moral side. The only way to avoid the saloon
is to make use of an alley or other dark place, thereby breaking a city
ordinance and creating a nuisance which gives the offence a public
health aspect. The frequency with which this is done is evidenced by
the familiar sign “Commit No Nuisance.” In London I saw a sign that
to my mind was much less objectionable and equally effective; it read
simply “Decency Forbids.”
The establishment of comfort stations at convenient points would I
think contribute greatly to public health.
 JOTTINGS

INFANT MORTALITY RATE IN N. Y.

The January Bulletin of the Department of Health in New York city

shows that the downward curve of the death rate during 1910 and
1911 was continued in 1912 and that the lowest point ever recorded in
the city has been reached. In 1911 the death rate was 15.13 for 1,000,
while in 1912 it was 14.11. The difference of 1.02 between the two
years means that 5,276 lives were saved in 1912, for, if the rate of
1911 had prevailed last year, New York’s death roll would have been
larger by just that number. In analyzing the returns it is found that
the decrease has affected those diseases which the Department of
Health seeks to control; namely, the acute infectious diseases,
tuberculosis of the lungs, and the diarrhoea of children. On the other
hand, there is a decided increase in the mortality from those diseases
which seem to be peculiar to our modern society and which are not
under public health control, organic heart disease and Bright’s
disease.
The infant mortality rate is low. Calculated on the basis of reported
births the deaths of children under one year number only 105 per
thousand born, and in all probability this is a little too high, for New
York city does not claim to have more than from 90 to 95 per cent
birth registration. The record is encouraging when compared with
the figures for Great Britain and Germany. The rate for England and
Wales in 1911 was 130; that for Berlin in 1910 was 157.

HEALTH OF LONDON SCHOOL CHILDREN

Only in the last few years has the law required every child
attending an elementary school to be physically examined on
entering and leaving and, therefore, statistics on the health of school
children in England are only now available. About a million and a
half children are now examined annually. The report of Sir George
Newman, chief medical officer of the Board of Education for 1911,
has just been issued. It shows the condition of 186,652 children in
thirteen counties and sixteen urban areas and is far from
satisfactory. Only in one urban area did the percentage of “good”
nutrition reach 45, and from this figure it ranged down as low as 3.8.
Of 200,000 children examined in London more than half were found
to be defective and over 78,000 were recommended for treatment.
According to this report the malnutrition is due in the great majority
of cases to ignorance of the relative value of foodstuffs and the means
of using them economically, and only in the minority to poverty.
About .5 per cent of the children are feeble-minded and of these
about one-seventh are of such low grade as to be uneducable.

INTERNATIONAL CONGRESS ON SCHOOL HYGIENE

The preliminary bulletin of the Fourth International Congress for

School Hygiene announces a meeting, which is to be held in Buffalo,
N. Y., August 23 to 30 next. The three preceding congresses were
held in 1904 in Nuremberg; in 1907 in London, and in 1910 in Paris.
The president of the congress is Charles W. Eliot, president emeritus
of Harvard University; the vice-presidents are: Dr. W. H, Welch,
professor of pathology at Johns Hopkins University and Dr. Henry P.
Walcott, chairman of the Massachusetts Board of Health. The lists of
vice-presidents and members of the international committee
includes the names of some of the foremost men of science in Europe
and Asia. Buffalo has raised $40,000 to meet the expenses of the
Congress and to entertain the delegates.

3 TO 1 FOR TUBERCULOSIS HOSPITAL

That the people are coming to favor taxing themselves for public
measures to control tuberculosis is indicated by a referendum vote
on the establishment of a county tuberculosis hospital in eight towns
of St. Lawrence county, New York. The public health committee of
the board of supervisors failed to draw up a question to be voted
upon in all the towns of the county as instructed by the board. But
eight town supervisors took an informal vote on the question. The
question carried in all eight towns. The ballots stood more than three
to one in the affirmative. This is the first time that this question has
been submitted to a vote of the people in New York state. Three of
the towns are distinctly rural and only one of the eight communities
is a city.
 CALENDAR OF CONFERENCES

CONFERENCES
April and May Conferences

Alabama Sociological Congress, Birmingham, Ala. April 22–24,

1913. William M. McGrath, Pres., Associated Charities,
Birmingham.
Baptist Convention, Northern, Detroit, Mich., May 13–20, 1913.
Con. Sec’y. Rev. W. C. Bitting, St. Louis.
Boys, General Assembly of Workers with. Culver, Ind., May 17–30,
1913. Information may be secured from the Boys’ Work Dept., Y.
M. C. A., 124 E. 28th Street, New York.
Charities and Correction, New York City Conference on. May
14–15, 1913. Sec’y, John B. Prest, 287 Fourth Avenue, New York.
Charities and Correction, Semi-annual Conference, Colorado
State Board of. Denver. May 13, 1913. Sec’y, William Thomas,
Capitol Building, Denver.
Charities and Corrections, Arkansas Conference of, Little Rock,
Ark., May 13–15, 1913. Sec’y, Murray A. Auerbach, Little Rock.
City Planning, National Conference On. Chicago, May 5–7, 1913.
Sec’y, Flavel Shurtlett, 19 Congress Street, Boston.
Conservation of Human Life, Conference on. Portland, Ore., May
9–11, 1913. Information can be secured by addressing Reed
College, Portland.
Colored People, Fifth Annual Conference of National Association
for Advancement of. Philadelphia, Pa., April 23–25, 1913. Sec’y,
May Childs Nerney, 26 Vesey St., New York City.
Jewish Social Workers, Third Informal Conference, National
Association of. Atlantic City, N. J. May 29–30, 1913.
Mothers, National Congress of. Boston, May 15–20, 1913. Sec’y,
Mrs. A. A. Birney, 806 Loan and Trust Bldg., Washington, D. C.
Peace Conference, Fourth American. St. Louis, Mo., May 1–4,
1913. James E. Smith, Chairman. St. Louis.
Playground and Recreation Association of America.
Richmond, Va., May 6–10, 1913. Sec’y, H. S. Braucher, 1 Madison
Avenue, New York.
Southern Sociological Congress, Atlanta, Ga., April 25–29,
1913. Gen. Sec’y, J. E. McCulloch, Nashville, Tenn.
Women’s Clubs, New Jersey Federation of Atlantic City, May 2
and 3, 1913. Sec’y, Mrs. Joseph M. Middleton, 46 Prospect St.,
Trenton.
Young Men’s Christian Association, International Conference of.
Cincinnati, May 15–18, 1913.
 LATER MEETINGS

International

Blind, Fourth Triennial International Conference on the London,

England, 1914; probably July 20. Sec’y, Henry Stainsby, 206
Great Portland St., London, W.
Children’s Welfare, International Congress for. Amsterdam,
Netherlands, 1914. President, Dr. Treub, Huygenstraat 106,
Amsterdam.
Christian Citizenship Conference, World’s. Portland, Ore., June
29–July 6, 1913. Chairman, Rev. James S. Martin, 209 9th St.,
Pittsburgh, Pa.
Farm Women, International Congress of. Tulsa, Okla., October
22–November 1, 1913. Sec’y, Mrs. John T. Burns, Tulsa, Okla.
Housing, International Congress on. The Hague, Holland,
September 8–13, 1913. Sec’y, M. O. Veighe, director general
Ministry of Agriculture, Brussels. Executive secretary section for
United States, William H. Tolman, 29 West 39th Street, New
York.
Infant Mortality, English-speaking conference on. London,
England. August 4 and 5, 1913. Under auspices of the British
National Association for the Prevention of Infant Mortality and
for the Welfare of Infancy, London.
Prison Congress, Quinquennial. London, Eng., 1915. Sec’y, F.
Simon Van der Aa, Groningen, Holland.
School Hygiene, Fourth International Congress on. Buffalo, N. Y.,
Aug. 25–30, 1913. Sec’y Gen., Dr. Thomas A. Storey, College of
the City of New York.
Student Christian Federation, World’s, Lake Mohawk, N. Y.,
June 2–8, 1913. Gen. Sec’y, John R. Mott, 124 East 28th Street,
 New York.
Students (“Corda Fratres”), Eighth International Congress of.
Ithaca, N. Y., August 20–September 13, 1913. Information can be
secured by addressing the Cornell Cosmopolitan Club, Ithaca, N.
Y.
Town Planning and Organisation of Municipal Life, First
International Congress on Art of. Ghent, Belgium, Summer 1913.
General Sec’y, Paul Saintenoy, Brussels.
Unemployment, International Association on. Ghent, Belgium,
September 3–6, 1913. American Section secretary, John B.
Andrews, 121 East 23rd St., New York City.

National

Charities and Correction, National Conference of. Seattle,

Wash., July 5–12, 1913. Sec’y, Alexander Johnson, Angola, Ind.
Home Economics, American Association of. Ithaca, N. Y., June
27–July 4, 1913. Information may be secured from Marguerite B.
Lake, Forest Hill, Md.
Infant Mortality, American Association for Study and
Prevention of. Fourth annual meeting. Kansas City, Mo., Oct.
23–25, 1913. Exec. Sec’y, Gertrude B. Knipp, 1211 Cathedral St.,
Baltimore.
Medicine, American Academy of. Thirty-eighth Annual Meeting.
Minneapolis, Minn., June 13, 14, 1913.
Officials of Charities and Correction, American Association
of. Fourth Annual Meeting. Springfield, Ill., June 24–26, 1913.
Sec’y, W. T. Cross, Columbia, Mo.
Prison Association, American, Indianapolis, Ind., Oct. 11–16,
1913. Sec’y, Joseph P. Byers, Trenton, N. J.
Social Insurance, First American Conference on. Chicago, Ill.,
June 6–7, 1913. Sec’y, John B. Andrews, 131 East 23rd St., New
York City.
 State and Local

Charities and Correction, Ohio State Conference of. Akron, O.,

October, 1913. Sec’y, H. H. Shirer, 1010 Hartman Bldg,
Columbus, O.
 EXHIBITIONS

International

Panama-Pacific Exposition, San Francisco, Cal., Feb. 20–Dec. 4,

1915. Social Economy Department—Frank A. Wolff, Washington,
D. C.
Panama-California Exposition, San Diego, Cal., Jan. 1–Dec. 31,
1915. Director of Exhibits, E. L. Hewett, San Diego.
Student Christian Federation World’s, Lake Mohawk, N. Y.,
June 2–8, 1913. Exhibits including “social study and service.”
Gen. Sec’y, John R. Mort, 124 East 28th St., New York.
School Hygiene, Fourth International Congress on. Buffalo, N. Y.,
Aug. 25–30, 1913. Chairman. Committee on Scientific Exhibit,
Dr. Fletcher B. Dressler, Bureau of Education, Washington, D. C.

National

Conservation Exposition, National, Knoxville, Tenn., Sept.-Oct.,

1913.

Local

Child Welfare Exhibit, New Britain, Conn., April 25–May 2.

Sec’y, E. W. Pelton.
Taxation in New Jersey. Charts prepared by the Bureau of
Municipal Research will be shown at the New Jersey Federation
of Women’s Clubs. Atlantic City, May 2 and 3. Sec’y, Mrs. Joseph
M. Middleton, 46 Prospect St., Trenton, N. J.
 JOTTING

KENTUCKY SCHOOL LAW

A newly enacted state-wide compulsory school attendance law
brings Tennessee into line with its neighbor Kentucky. Attendance at
school is required of all between the ages of eight and fourteen and of
all between fourteen and sixteen who are not “actively and regularly
and lawfully” employed or who are unable to read and write. This
new law takes from the map printed in The Survey of February 15
one of the five gray southern states that have had compulsory
attendance only in certain counties.
 Is the best Fire Escape in the world too good for
you or the children in your care? If not, tell your
School Board about the

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 THAT the upbringing of the children demands more study than
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The pioneer party went last year. Its success will be increased
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SAILINGS
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SITUATIONS WANTED

MAN—45—Single,—protestant—twenty years executive in

correctional, probation and boy’s work—now engaged—distance not
considered. Address 1105 Survey.

WORKERS WANTED
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Settlement House. Must have experience in both lines of work.
Address 1106 Survey.

SOCIAL AND CIVIC TOURS OF EUROPE

Social Tour, June 28—$480
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First-hand observation of civic, social, and industrial affairs in

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HELP THE SURVEY BY MENTIONING US WHEN WRITING TO ADVERTISERS

 TRANSCRIBER’S NOTES
1. P. 81, added title “The Survey, Volume XXX, No. 3, Apr
19, 1913.”
2. Silently corrected obvious typographical errors and
variations in spelling.
3. Retained archaic, non-standard, and uncertain spellings
as printed.
*** END OF THE PROJECT GUTENBERG EBOOK THE SURVEY,
VOLUME 30, NUMBER 3, APR 19, 1913 ***

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