**7. Acknowledgment**

This study was supported in part by "Program to Disseminate Tenure Tracking System", Promoting Science and Technology of the Ministry of Education, Culture, Sports, Science and Technology, Japan.

Salivary Hormones, Immunes and Other Secretory Substances as Possible Stress Biomarker 267

awakening. *International Journal of Psychophysiology*, Vol.64, No.2, pp.141-145 Izawa, S.; Shirotsuki, K.; Sugaya, N.; Ogawa, N.; Suzuki, K. & Nomura, S. (2004). The

Jemmott III, J.B.; Borysenko, J.Z.; Borysenko, M.; McClelland, D.C.; Chapman, R.; Meyer, D.

Jemmott III, J.B. & Magloire, K. (1988). Academic stress, social support, and secretory

Jemmott III, J.B. & McClelland, D.C. (1989). Secretory IgA as a measure of resistance to

Kanamaru, Y.; Kikukawa, A. & Shimamura, K. (2006). Salivary chromogranin-A as a marker

Kim, Y. & Loh, Y.P. (2005). Chromogranin A: a surprising link between granule biogenesis

Kimura, K.; Isowa, T.; Ohira, H. & Murashima, S. (2005). Temporal variation of acute stress

Kirschbaum, C.; Pirke, K.M. & Hellhammer, D.H. (1993). The 'Trier Social Stress Test' -a tool

Kirschbaum, C. & Hellhammer, D.H. (1994). Salivary cortisol in psychoneuroendocrine

Knight, W.E. & Rickard, N.S. (2001). Relaxing music prevents stress-induced increase in

Martin, R.A. & Dobbin, J.P. (1988). Sense of humor, hassles, and Immunoglobulin A:

Martin, R.B.; Guthrie, C.A. & Pitts, C.G. (1993). Emotional crying, depressed mood, and secretory Immunoglobulin A. *Behavioral Medicine*, Vol.19, No.3, pp.111-114 McNair, M.; Heuchert, P. & Shilony, E. (2003). *Profile of mood states Bibliography 1964-2002*.

and hypertension. *J Clin Invest*. Vol.115, No.7, pp.1711-1713

*Neuropsychobiology*. Vol.28, No.1-2, pp.76-81

females. *Journal of Music Therapy*,Vol.38, pp.254-272

Multi-Health-Systems Inc, North Tonawanda, NewYork

psychological changes. *Biological Psychology*, Vol.79, No.3, pp.294-298 Izawa, S.; Sugaya, N.; Ogawa, N.; Nagano, Y.; Nakano, M.; Nakase, E.; Shirotsuki, K.;

*Complementary and Alternative Medicine*, Vol.4, No.3, pp.91-101

1402

810

*Medicine*, Vol.15, pp.63- 71

No.3, pp.127-131

Vol.70, pp.131-139

No.1, pp.313-333

*in medicine*, Vol.18, pp.93-105

response to acute psychosocial stress and its correlations with biological and

Yamada, K. C.; Machida, K.; Kodama, M. & Nomura, S. (2007). Episodic stress associated with writing a graduation thesis and free cortisol secretion after

application of saliva to an assessment of stress: procedures for collecting and analyzing saliva and characteristics of salivary substances. *Japanese Journal of* 

& Benson, H. (1983). Academic stress, power motivation, and decrease in secretion rate of salivary secretory Immunoglobulin A. *Lancet*, Vol.321, No.8339, pp.1400-

Immunoglobulin A. *Journal of Personality and Social Psychology*, Vol.55, No.5, pp.803-

infectious disease: comments on Stone, Cox, Valdimarsdottir, and Neale. *Behavioral* 

of psychological stress during a cognitive test battery in humans. *Stress*,. Vol.9,

responses in sympathetic nervous and immune systesm. *Biological Psychology*,

for investigating psychobiological stress responses in a laboratory setting.

research: recent developments and applications. *Psychoneuroendocrinology*, Vol.19,

subjective anxiety, systolic blood Pressure, and heart rate in healthy males and

evidence for a stress-moderating effect of humor. *International journal of psychiatry* 

#### **8. References**


Ader, R.; Felten, L. & Cohen, N. (Ed(s.). (2001) *Psychoneruoimmunology* (3rd ed.), Academic

Ali, N. & Pruessner, J.C.. (2011). The Salivary Alpha-amylase Over Cortisol Ratio as a

Andreassi, J.L. (2007). *Psychophysiology: Human Behavior & Physiological Response* (5th ed.),

Bosch, J.A.; Ring, C.; de Geus, E.J.; Veerman, E.C. & Amerongen, A.V. (2002). Stress and secretory immunity. *International Review of Neurobiology*, Vol.52, No.1, pp.213-253 Buchsbaum, M.S.; Muscettola, G. & Goodwin, F.K. (1981). Urinary MHPG, stress response,

Clow, A.; Thorn, L.; Evans, P. & Hucklebridge, F. (2004). The awakening cortisol response: methodological issues and significance. *Stress*, Vol.7, No.1, pp.29-37 Deguchi, M.; Wakasugi, J.; Ikegami, T.; Nanba, S. & Yamgaguchi, M. (2006). Evaluation of

Dickerson, S.S. & Kemeny, M.E. (2004). Acute stressors and cortisol responses: A theoretical

Evans, P.; Bristow, M.; Hucklebridge, F.; Clow, A. & Pang, F.Y. (1994). Stress, arousal,

Gabriel, P. & Liimatainen, M.R. (2000). *Mental health in the workplace*. International Labor

Green, R.G. & Green, M.L. (1987). Relaxation increases salivary Immunoglobulin A.

Gregory, R.L.; Kim, D.E.; Kindle, J.C.; Hobbs, L.C. & Lloyd, D.R. (1992). Immunoglobulin-

Hansen, A.M.; Garde, A.H. & Persson, R. (2008). Source of biological and methodological

Hellhammer, D.H.; Wüst, S. & Kudielka, B.M. (2009). Salivary cortisol as a biomarker in

Hucklebridge, F.; Hussain, T.; Evans, P. & Clow, A. (2005). The diurnal patterns of the

Isowa, T.; Ohira, H. &d Murashima, S. (2004). Reactivity of immune, endocrine and

Izawa, S.; Sugaya, N.; Shirotsuki, K.; Yamada, K.C.; Ogawa, N.; Ouchi, Y.; Nagano, Y.;

stress research. *Psychoneuroendocrinology*, Vol.34, No.2, pp.163-171

awakening; *Psychoneuroendocrinology*, Vol.30, No.1, pp.51-57

Marker to Assess Dysregulations of the Stress Systems. *Physiology & Behavior*,

personality factors and patients with major affective disorders.

driver stress using motor-vehicle driving simulator. *IEEJ Trans. Sensors and* 

integration and synthesis of laboratory research. *Psychological Bulletin*, Vol.130,

cortisol and secretory Immunoglobulin A in students undergoing assessment. *The* 

degrading enzymes in localized juvenile periodontitis. *Journal of periodontal research*,

variation in salivary cortisol and their impact on measurement among healthy adults: A review. *The Scandinavian Journal of Clinical & Laboratory Investigation*,

adrenal steroids cortisol and dehydroepiandrosterone (DHEA) in relation to

cardiovascular parameters to active and passive acute stress. *Biological Psychology*,

Suzuki, K. & Nomura, S. (2008). Salivary Dehydroepiandrosterone secretion in

Press, Waltham, Massachusetts, USA

Psychology Press, London, England

*Neuropsychology*,Vol.7, pp.212-224

*Micromachines*, Vol.126, No.8, pp.438-444

*Psychological Reports*, Vol.61, pp.623-629

*British journal of clinical psychology*, Vol.33, pp.575-576

Organization. 10.11.2011, Available from http://ilo.org

[Epub ahead of print]

No.3, pp.335-391

Vol.27 No.3, pp.176-183

Vol.68, No.6, pp.448-458

Vol.65, pp.101-120

**8. References** 

response to acute psychosocial stress and its correlations with biological and psychological changes. *Biological Psychology*, Vol.79, No.3, pp.294-298


Salivary Hormones, Immunes and Other Secretory Substances as Possible Stress Biomarker 269

Pruessner, J.C.; Wolf, O.T.; Hellhammer, D.H.; Buske-Kirschbaum, A.; von Auer. K.; Jobst.

Schoofs, D. & Wolfa, O.T. (2011) Are Salivary Gonadal Steroid Concentrations Influenced by

Schulz, P.; Kirschbaum, C.; Prüßner, J. & Hellhammer, D. (1998). Increased free cortisol

Shirtcliff, E.; Zahn-Waxler, C.; Klimes-Dougan, B. & Slattery, M. (2007). Salivary

internalizing problems. *J Child Psychol Psychiatry.*, Vol.48, No.6, pp. 580-591 Steptoe. A.; Cropley. M.; Griffith. J. & Kirschbaum, C. (2000). Job strain and anger expression

Steptoe, A. & Wardle, J. (2005). Positive affect and biological function in everyday life.

Strahler, J.; Berndt, C.; Kirschbaum, C. & Rohleder, N. (2010). Aging Diurnal Rhythms and

Stone, A.A.; Neale, J.M.; Cox, D.S.; Napoli, A.; Valdimarsdottir, H. & Kennedy-Moore, E.

Sugaya, N.; Izawa, S.; Ouchi, Y.; Shirotsuki,K.; Yamada, K.C.; Ogawa, N.; Nagano, Y. &

Toda, M.; Kusakabe, S.; Nagasawa, S.; Kitamura, K. & Morimoto, K. (2007). Effect of

Tsujita, S. & Morimoto, K. (1999). Secretory IgA in saliva can be a useful stress maker.

Valdimarsdottir, H.B. & Stone, A.A. (1997). Psychosocial factors and secretory

van Stegeren, A.; Rohleder, N.; Everaerd, W. & Wolf, O.T. (2006). Salivary alpha amylase as

Wakida, S.; Tanaka, Y. & Nagai., H. (2004). High throughput screening for stress marker.

Williams, R.B. (1986). *Patterns of reactivity and stress; Handbook of stress, reactivity, and cardiovascular disease*, John Wiley & Sons, Hoboken, New Jersey, USA

*International Journal of Psychophysiology*, Vol.80, No.1, pp.36-43

*Psychosomatic Medicine*, Vol.64, No.3, pp.502-509

Vol.61, pp.2539-2549

No.2, pp.286-292

*Stress Med*. Vol.14, No.2, pp.91–97

*Nuerobiology of Aging*, Vol.26, No.1, pp.108-112

*Medicine*, Vol.47, No.12, pp.1013-1022

Vol.28, No.2, pp.15-18

*Bunseki*, Vol.2004, pp.309-316

474

and Cortisol. *Biological Psychology*, Vol.84, No.2, pp.248-256

antigen in men. *Health Psychology*, Vol.13, No.5, pp.440-446

*Environmental Health and Preventive Medicine*, Vol.4, pp.1-8

*Psychoneuroendocrinology*, Vol.31, No.1, pp.137-141

Physiologic markers of chronic stress in premenopausal, middle-aged women.

S.; Kaspers. F. & Kirschbaum, C. (1997). Free cortisol levels after awakening: a reliable biological marker for the assessment of adrenocortical activity. *Life Sci*.

Acute Psychosocial Stress? A Study Using the Trier Social Stress Test (TSST).

secretion after awakening in chronically stressed individuals due to work overload.

dehydroepiandrosterone responsiveness to social challenge in adolescents with

predict early morning elevations in salivary cortisol. *Psychosomatic Medicine*, Vol.62,

Chronic Stress: Distinct Alteration of Diurnal Rhythmicity of Salivary α-amylase

(1994). Daily events are associated with a secretory immune response to an oral

Nomura, S. (2007). Adrenal and Autonomic Responses to Psychosocial Stress in Individuals with Irritable Bowel Syndrome. *Japanese Journal of Psychosomatic* 

laughter on salivary endocrinological stress marker Chromogranin A. *Biomed Res.*,

Immunoglobulin A. *Critical Reviews in Oral Biology & Medicine*, Vol.8, No.4, pp.461-

marker for adrenergic activity during stress: effect of betablockade.


Michael, A.; Jenaway, A.; Paykel, E.S. & Herbert, J. (2000). Altered salivary

Miyakawa, M.; Matsui, T.; Kishikawa, H.; Murayama, R.; Uchiyama, I.; Itoh, T. & Yoshida,

Morgan, C.A. 3rd.; Rasmusson, A.; Pietrzak, R.H.; Coric, V. & Southwick, S.M. (2009).

Nakane, H. (1999). Salivary Chromogranin A as index of psychosomatic stress response.

Nomura, S.; Tanaka, H. & Moriyama, T. (2006). Pilot Study of SIgA as a Stress Maker with

Nomura, S.; Mizuno, T.; Nozawa, A.; Asano, H. & Ide, H. (2009). Salivary cortisol as a

Nomura, S.; Mizuno, T.; Nozawa, A.; Asano, H. & Ide, H. (2010a). Characteristics of Salivary

Nomura, S.; Mizuno, T.; Nozawa, A.; Asano, H. & Ide, H. (2010b). Salivary DHEA as a

Noto, Y.; Sato, T.; Kudo, M.; Kurata, K. & Hirota, K. (2005). The relationship between

Ohira, H. (2004). Social support and salivary secretory Immunoglobulin A response in

Ohira, H. (2001). Controllability of aversive stimuli unconsciously determines volume of

Ohira, H.; Watanabe, Y.; Kobayashi, K. & M. Kawai. (1999). The Type A behavior pattern

Immunoglobulin A in saliva. *Perceptual and Motor Skills*, Vol.89, pp.423-430 Okamura, H.; Tsuda, A.; Yajima, J.; Mark, H.; Horiuchi, S.; Toyoshima, N. & Matsuishi, T.

International Journal of Psychophysiology, Vol.78, No.3, pp.209-214 Powell, L.H.; Lovallo, W.R.; Matthews, K.A.; Meyer, P.; Midgley, A.R.; Baum, A.; Stone,

arithmetic stress: a pilot study. *Anesth Analg*., Vol.101, pp.1873-1876 Ockenfels, M.C.; Porter, L.; Smyth, J.; Kirschbaum, C.; Hellhammer, D.H. & Stone, A.A.

*Cognitive Science*, pp.169-170, Vancouver, Canada, July 26-29, 2006

Vol.48, No.10, pp.989-995

Vo.36, No.1, pp.23-32

*Health*. Vol.8, No.32, pp.108-113

*Psychiatry.*, Vol.66, No.4, pp.334-340

*Engineering*, Vol.48, No.2, pp.207-212

*Interface Society*, Vol.12, No.3, pp.33-40

*Medicine*, Vol.57, No.5, pp.460-467

pp.1241-1250

pp.16-28

*R&D Review of Toyota CRDL.*, Vol.34, No.3, pp.17-22

Dehydroepiandrosterone levels in major depression in adults. *Biological Psychiatry*,

T. (2006). Salivary Chromogranin A as a measure of stress response to noise. *Noise* 

Relationships among plasma dehydroepiandrosterone and dehydroepiandrosterone sulfate, cortisol, symptoms of dissociation, and objective performance in humans exposed to underwater navigation stress; *Biological* 

Repetitive Saliva Collection, *Proceedings of the 5th International Conference of the* 

possible physiological biomarker for mild mental workload. *Biofeedback Research,*

Chromogranin A as a Short-term Mental Stress Biomarker. *Journal of Biomedical* 

Possible Stress-biomarker for a Mild Mental Workload. *Transactions of Human* 

salivary biomarkers and State-Trait Anxiety Inventory score under mental

(1995). Effect of chronic stress associated with unemployment on salivary cortisol: overall cortisol levels, diurnal rhythm, and acute stress reactivity. *Psychosomatic* 

women to stress of making a public speech. *Perceptual and Motor Skills*, Vol.98,

secretory Immunoglobulin A in saliva. *Japanese Journal of Behavioral Medicine*, Vol.6,

and immune reactivity to brief stress: change of volume of secretory

(2010). Short Sleeping Time and Psychobiological Responses to Acute Stress.

A.A.; Underwood, L.; McCann, J.J.; Janikula Herro, K. & Ory, M.G. (2002).

Physiologic markers of chronic stress in premenopausal, middle-aged women. *Psychosomatic Medicine*, Vol.64, No.3, pp.502-509


**1. Introduction** 

biomarkers.

**13** 

*USA* 

**Novel Tissue Types for the** 

Mollie McWhorter and Mark L. Parrish

*Covance Genomics Laboratory,* 

*Seattle, Washington,* 

Zinaida Sergueeva, Heather Collins, Sally Dow,

**Development of Genomic Biomarkers** 

Imagine a simple clinical test that can not only diagnose a disease, but that can also identify the exact, personal therapeutic regime to cure it. Not only that, imagine tests that can accurately predict the potential of developing a disease and provide an individualized roadmap on how it will progress. Now imagine that all you had to do was to spit in a vial, or have a few hairs plucked for the analysis. While the promise of "personalized medicine" is technologically a reality, it relies on the development of disease and progression

The ideal biomarker should have a number of characteristics, including: having an analyte that is accessible using noninvasive protocols, inexpensive to quantify, specific to the disease of interest, translatable from model systems to humans, and the ability to provide a reliable early indication of disease before clinical symptoms appear. Biomarkers that can be used to

Although most current biomarkers utilize protein or metabolic analytes, it can be difficult to develop new protein-based biomarkers. This is due to the inherent complexity of the protein composition of biological samples, the assorted posttranslational modifications of proteins, and the low abundance of many proteins of interest in most biological samples (especially blood). Similarly, the detection of metabolic analytes is difficult due to the complex

Detecting specific nucleic acids, while not trivial, is generally much easier. Synthetic complimentary oligonucleotides can deliver sufficient detection specificity in most cases, and PCR or other DNA amplification methods can be used to improve the detection limit. There are numerous examples of genomic biomarkers that have become powerful tools for molecular diagnostics and outcome prediction (Cronin et al., 2007; Guttmacher & Collins, 2002; Hamburg & Collins, 2010; Klein et al., 2009; Tainsky, 2009; L. J. van 't Veer et al., 2002). RNA and DNA biomarkers are used routinely for screening patients to diagnose and subtype disease, as well as to monitor therapy and predict progression. Discovery of microRNAs, and lately lncRNAs (long non–coding RNAs), further increased their importance and broadened their clinical application (Gibb, Brown, & Lam, 2011; Laterza et

stratify disease and assess response to therapeutics are also medically valuable.

biological matrix from which they are measured.

