Laura Buehning MD, MPH, Kamyar M. Hedayat, MD, Aarti
Sachdevi, Shah Golshan PhD, Jean Claude Lapraz, MD
Presentation by:
K...
(C) 2014 Systems Biology Research Group 2
scanning electron microscope, shows T cells (orange) attached to a tumor cell.
http://www.mskcc.org/blog/cancer-immunother...
IF…
Cancer
= Abnormal cellular activity
Chemotherapy, Radiation, Surgery
= CURE of ALL cancers, EVERY TIME.
(C) 2014 Syste...
(C) 2014 Systems Biology Research Group 5
!  Short-term survival is improving BUT
!  We see more
◦  New onset, late stage ...
(C) 2014 Systems Biology Research Group 6
Imaging: Structural Imaging: Functional
PET-CT: Left internal jugular node metastases
with extranodal invasion;Akira Kouch...
Histology
Infiltrating ductal carcinoma of breast
Hematologic, Gross
Circulating tumor cells:A-C: Prostate cancer, D:
Meta...
!  Unifactorial—Cancer multifactorial
!  Lacks global vision of physiology
!  Reactive modality
!  Lacks predictive assess...
Hematologic: cell-free DNA
DNA Methylation patterns
MicroRNA: Microarray, PCR
(C) 2014 Systems Biology Research Group 10
http://rams.biop.lsa.umich.edu/research/metabolomics
(C) 2014 Systems Biology Research Group 11
!  Advantages:
◦  Reinforce concept of cancer as complex and
multi-factorial
◦  Nuanced, sensitive and specific
◦  Individ...
!  Evaluate cancer as Systemic
disease expressed in cells
!  Use GLOBAL systems
approach
(C) 2014 Systems Biology Research...
(C) 2014 Systems Biology Research Group 14
!  Quantitative
!  Function of the parts
!  Hierarchy
!  Categorical
!  Separate
!  Independent
!  Static
!  Control
!  Qu...
(C) 2014 Systems Biology Research Group 16
(C) 2014 Systems Biology Research Group 17
Creation of Structure
Maintenance of STRUCTURE
Functional adaptation
!  Endocrine system
!  Sole system to possess:
1) Ubiquity of interaction with each structural
element
2) Constancy of reg...
!  The illness
◦  Exogenous factors
◦  Rate of development
◦  Degree Invasiveness
!  The patient
◦  Endogenous factors
◦  ...
(C) 2014 Systems Biology Research Group
METABOLISM
CATABOLISM ANABOLISMANABOLISM CATABOLISM
CRH
ACTH
ADRENALS
LHRH
FSH LH
...
(C) 2014 Systems Biology Research Group 21
The purpose of the Biology of
Functions is to quantify the
functional abilities of the
organism, before and after the
effe...
ADVANTAGES
!  Objective
!  Quantitative
!  Accurate
!  Reproducible
!  Minimally invasive
DISADVANTAGES
!  Binary
!  Reduc...
(C) 2014 Systems Biology Research Group 24
Origin Biomarker
Bone Marrow
Red blood cell
White blood cell, total
Neutrophil
Lymphocytes
Eosinophils
Monocytes
Basophils...
DIRECT relationship of biomarkers
!  Genital Ratio (GR)
◦  RBC/WBC
!  Genito-Thyroid
◦  % Neutrophils / % Lymphocytes
INDI...
(C) 2014 Systems Biology Research Group 27
!  Retrospective Case Control Design
◦  92 patients in a single practice
◦  All types of cancers (hematologic and non-
hem...
!  Biology of Functions were available for all
92 patients
!  62 of 150 indexes were selected for
relevance to oncobiology...
Table 1. Baseline Characteristics of Cancer Cases and Matched Controls
N	

 MALES	

 FEMALES	

AVE
AGE	

STD	

MIN
AGE	

M...
CANCER DIAGNOSIS MALE FEMALE ACTIVE INACTIVE
Abdominal Sarcoma 1 1
Acute Lymphocytic Leukemia 1 1
B Cell Lymphoma 1 1
Blad...
Adaptation:
βMSH/αMSH Index (6-8): It expresses the
relative level of participation of the beta- and
alpha-melanocyte stim...
Anabolic Hormones:
!  Estrogen fraction #5 (7-20): It expresses the
relative part of estrogens consecrated to the
growth o...
Anabolic-Catabolic endocrine harmony:
!  Genito-Thyroid Index (1.5-2.5) (=PMN/
Lymphocytes): It expresses the relative
act...
INDEX	

 N	

TOTAL
CASES	

MEAN±STD	

TOTAL
CONTROLS
MEAN±STD	

PVAL	

Estrogen Fraction #5	

 45	

 18.64±16.87 	

 10.58...
INDEX	

 N	

ACTIVE	

MEAN±STD	

CONTROLS
MEAN±STD	

PVAL	

Estrogen Fraction #5	

 32	

 21.47±19.15	

 10.91±5.78	

 0.0...
INDEX	

 N	

ACTIVE	

MEAN±STD	

CONTROL
S MEAN
±STD	

PVAL	

ACTIVE
VS
INACTIVE	

Estrogen Fraction #5	

 13	

 11.68±4.7...
INDEX N
TOTAL CASES
MEAN±STD
TOTAL
CONTROLS
MEAN±STD
PVAL
Estrogen Fraction #5 13 23.29±22.89 11.38±7.24 0.03*
Genito-Thyr...
INDEX N
TOTAL CASES
MEAN±STD
TOTAL
CONTROLS
MEAN±STD
PVAL
Estrogen Fraction #5 5 20.60±21.18 7.20±1.48 0.23
Genito-Thyroid...
!  Genito-Thyroid index =
Neutrophil to Lymphocyte ratio
!  Over 400 studies in cancer patients,
predictive of mortality
!...
(C) 2014 Systems Biology Research Group 41
!  Genito-Thyroid, as the Neutrophil/Lymphocyte ratio is
incorporated into a series of indices that have relevance
to nume...
!  Theory of Endobiogeny offers a whole-
system approach to cancer
!  In a retrospective, case-controlled study of
all can...
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A novel use of biomarkers in the modeling of cancer activity based on the theory of Endobiogeny v1.5

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Learn about a new approach to evaluating cancer that uses common biomarkers, but evaluates them using system theory. It looks as cancer as a whole-body disease expressed at the level of the cells, rather than a cellular disease expressed throughout the body.

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A novel use of biomarkers in the modeling of cancer activity based on the theory of Endobiogeny v1.5

  1. 1. Laura Buehning MD, MPH, Kamyar M. Hedayat, MD, Aarti Sachdevi, Shah Golshan PhD, Jean Claude Lapraz, MD Presentation by: Kamyar M. Hedayat, MD President,American Society of Endobiogenic Medicine and Integrative Physiology “Research is to see what everybody else has seen and to think what nobody else has thought.” — Albert Szent-György (C) 2014 Systems Biology Research Group 1
  2. 2. (C) 2014 Systems Biology Research Group 2
  3. 3. scanning electron microscope, shows T cells (orange) attached to a tumor cell. http://www.mskcc.org/blog/cancer-immunotherapy-named-science-magazine-breakthrough-year (C) 2014 Systems Biology Research Group 3
  4. 4. IF… Cancer = Abnormal cellular activity Chemotherapy, Radiation, Surgery = CURE of ALL cancers, EVERY TIME. (C) 2014 Systems Biology Research Group 4
  5. 5. (C) 2014 Systems Biology Research Group 5 !  Short-term survival is improving BUT !  We see more ◦  New onset, late stage cancer IN… ◦  Younger populations WITH… ◦  Increasing relapses and metastasis Formula from: Hanin, L and Zaider, M. Effects of surgery and chemotherapy on metastatic progression of prostate cancer: Evidence from the natural history of the disease reconstructed through mathematical modeling. Cancers 2011(3):3632-3660
  6. 6. (C) 2014 Systems Biology Research Group 6
  7. 7. Imaging: Structural Imaging: Functional PET-CT: Left internal jugular node metastases with extranodal invasion;Akira Kouchiyama, http://commons.wikimedia.org/wiki/File:PET- CT_scanning_of_lymph_node_metastases_in_cancer.jpg Breast Cancer, Mammography Astrocytoma, Rt Frontal Lobe, MRI Breast Cancer,: University Medical Imaging Group (C) 2014 Systems Biology Research Group 7
  8. 8. Histology Infiltrating ductal carcinoma of breast Hematologic, Gross Circulating tumor cells:A-C: Prostate cancer, D: Metastatic lung cancer; PNAS v.107 (43), 2010 Oncobiologic Survivn protein and apoptosis regulation Telomerase and immortality (C) 2014 Systems Biology Research Group 8
  9. 9. !  Unifactorial—Cancer multifactorial !  Lacks global vision of physiology !  Reactive modality !  Lacks predictive assessment !  Downstream: Does not determine causative factors (C) 2014 Systems Biology Research Group 9
  10. 10. Hematologic: cell-free DNA DNA Methylation patterns MicroRNA: Microarray, PCR (C) 2014 Systems Biology Research Group 10
  11. 11. http://rams.biop.lsa.umich.edu/research/metabolomics (C) 2014 Systems Biology Research Group 11
  12. 12. !  Advantages: ◦  Reinforce concept of cancer as complex and multi-factorial ◦  Nuanced, sensitive and specific ◦  Individualized !  Shortcoming ◦  STILL Reductionist: views cancer at the level of the cell (C) 2014 Systems Biology Research Group 12
  13. 13. !  Evaluate cancer as Systemic disease expressed in cells !  Use GLOBAL systems approach (C) 2014 Systems Biology Research Group 13
  14. 14. (C) 2014 Systems Biology Research Group 14
  15. 15. !  Quantitative !  Function of the parts !  Hierarchy !  Categorical !  Separate !  Independent !  Static !  Control !  Qualitative !  Function of the System !  Relationships !  Individualized !  Interconnected !  Interdependence !  Dynamic !  Creative chaos (C) 2014 Systems Biology Research Group 15 Reductionism Holism
  16. 16. (C) 2014 Systems Biology Research Group 16
  17. 17. (C) 2014 Systems Biology Research Group 17 Creation of Structure Maintenance of STRUCTURE Functional adaptation
  18. 18. !  Endocrine system !  Sole system to possess: 1) Ubiquity of interaction with each structural element 2) Constancy of regulation of those elements 3) Constancy of regulation of itself (C) 2014 Systems Biology Research Group 18
  19. 19. !  The illness ◦  Exogenous factors ◦  Rate of development ◦  Degree Invasiveness !  The patient ◦  Endogenous factors ◦  Adaptation capability of terrain ◦  Evolution of terrain over time !  Illness + Patient ◦  Degree of coexistence ◦  Levels of adaptation activities in structure vs. function ◦  Dominance of one over the other (C) 2014 Systems Biology Research Group 19
  20. 20. (C) 2014 Systems Biology Research Group METABOLISM CATABOLISM ANABOLISMANABOLISM CATABOLISM CRH ACTH ADRENALS LHRH FSH LH GONADS TRH TSH THYROID GHRH GH PL PANCREASπΣ αΣ βΣ Corticotropic Gonadotropic Thyrotropic Somatotropic ANS ENDOCRINE MANAGEMENT 20
  21. 21. (C) 2014 Systems Biology Research Group 21
  22. 22. The purpose of the Biology of Functions is to quantify the functional abilities of the organism, before and after the effects of adaptation. Because it is in permanent movement, functionality can only be measured by a dynamic, integrated and evolutionary methodology. --C. Duraffourd and JC Lapraz (C) 2014 Systems Biology Research Group 22
  23. 23. ADVANTAGES !  Objective !  Quantitative !  Accurate !  Reproducible !  Minimally invasive DISADVANTAGES !  Binary !  Reductionist !  Confusion of ◦  Cause vs. Effect ◦  Cause vs. Effect vs. Mechanism (C) 2014 Systems Biology Research Group 23
  24. 24. (C) 2014 Systems Biology Research Group 24
  25. 25. Origin Biomarker Bone Marrow Red blood cell White blood cell, total Neutrophil Lymphocytes Eosinophils Monocytes Basophils Hemoglobin Platelets Marrow-Blood interaction Erythrocyte sedimentation rate Bone Stroma Enzymes Osteocalcin Alkaline phosphatase bone isoenzyme General Enzymes Lactate dehydrogenase Creatine phosphokinase Endocrine: Pituitary Thyroid stimulating hormone Electrolytes Potassium Calcium, total serum 70% bone and blood 30% other (C) 2014 Systems Biology Research Group 25
  26. 26. DIRECT relationship of biomarkers !  Genital Ratio (GR) ◦  RBC/WBC !  Genito-Thyroid ◦  % Neutrophils / % Lymphocytes INDIRECT Relationship of Biomarkers ± Direct indexes ± Indirect indexes !  Catabolism/Anabolism ratio = Genito-Thyroid / Genital ratio corrected (C) 2014 Systems Biology Research Group 26
  27. 27. (C) 2014 Systems Biology Research Group 27
  28. 28. !  Retrospective Case Control Design ◦  92 patients in a single practice ◦  All types of cancers (hematologic and non- hematologic) ◦  Age and sex-matched controls ◦  Three arm study "  Active Cancer (n=33) "  Cancer remission (n=13) "  Control group (n=46) (C) 2014 Systems Biology Research Group 28
  29. 29. !  Biology of Functions were available for all 92 patients !  62 of 150 indexes were selected for relevance to oncobiology !  Paired Wilcoxin Rank Sum ◦  Active Cancer vs. Control ◦  Remission vs. Control !  Independent Wilcoxin Rank Sum ◦  Active Cancer vs. Remission (C) 2014 Systems Biology Research Group 29
  30. 30. Table 1. Baseline Characteristics of Cancer Cases and Matched Controls N MALES FEMALES AVE AGE STD MIN AGE MAX AGE P- VALUE Cancer Cases 46 19 27 54.15 13.48 9 78 0.705 Control 46 19 27 54.75 13.38 10 84 (C) 2014 Systems Biology Research Group 30
  31. 31. CANCER DIAGNOSIS MALE FEMALE ACTIVE INACTIVE Abdominal Sarcoma 1 1 Acute Lymphocytic Leukemia 1 1 B Cell Lymphoma 1 1 Bladder and Ureter Carcinoma 1 1 Breast Carcinoma 13 8 5 Cervical Carcinoma 1 1 Chronic NonHodgkin’s Lymphoma 1 1 Chronic Lymphocytic Leukemia 1 1 2 Colon Carcinoma 5 4 1 Hepatocellular Carcinoma 2 2 Liposarcoma 2 2 Lung Carcinoma 1 1 Melanoma 1 1 Myelodysplastic Syndrome 1 1 Ovarian Carcinoma 1 1 Parathyroid Carcinoma 1 1 Prostate Carcinoma 6 2 4 Renal Cell Carcinoma 1 1 Stomach Carcinoma 1 1 Testicular Carcinoma 1 1 Thalamic Glioblastoma 1 1 Uterine Carcinoma 1 1 TOTAL = 46 19 27 33 13 (C) 2014 Systems Biology Research Group 31
  32. 32. Adaptation: βMSH/αMSH Index (6-8): It expresses the relative level of participation of the beta- and alpha-melanocyte stimulating hormones (MSH) in directly stimulating cortisol activity vs. the general adaptation syndrome at the level of the pituitary. Immunity: !  Proinflammatory index (0.1-0.4):The pro- inflammatory index looks at the endogenous potential for inflammation due to thyrotropic over-activity and the degree to which cortisol is able to compensate for this (C) 2014 Systems Biology Research Group 32
  33. 33. Anabolic Hormones: !  Estrogen fraction #5 (7-20): It expresses the relative part of estrogens consecrated to the growth of tissues and organs. !  Comparative Genital Androgeny index (0.1-0.3): It indicates the metabolic activity of androgen receptors at the tissue level and the anabolism of tissue. Catabolic hormones: !  Thyroid Index (3.5-5.5): It indicates the degree of efficiency of thyroid hormones in managing the metabolic energetic activity of the cell (C) 2014 Systems Biology Research Group 33
  34. 34. Anabolic-Catabolic endocrine harmony: !  Genito-Thyroid Index (1.5-2.5) (=PMN/ Lymphocytes): It expresses the relative activity of the gonads in relationship to that of the thyroid. Metabolism: !  Catabolism/Anabolism Index (1.8-3): It expresses the relative catabolic activity in relation to that of anabolic activity within the scheme of global metabolism of the organism (C) 2014 Systems Biology Research Group 34
  35. 35. INDEX N TOTAL CASES MEAN±STD TOTAL CONTROLS MEAN±STD PVAL Estrogen Fraction #5 45 18.64±16.87 10.58±5.30 0.004* Genito-Thyroid Index 45 3.46±2.68 2.25±0.85 0.005* Comparative Genital Androgeny 36 2.27±3.81 7.12±11.6 0.007* Thyroid Index 39 5.17±3.64 3.72±1.73 0.039* Beta MSH/Alpha MSH Index 39 5.64±3.86 4.11±1.98 0.042* Catabolism/Anabolism Index 45 6.11±9.95 2.997±1.57 0.050* Proinflammatory Index 42 1.64±2.80 0.73±0.70 0.056 (C) 2014 Systems Biology Research Group 35
  36. 36. INDEX N ACTIVE MEAN±STD CONTROLS MEAN±STD PVAL Estrogen Fraction #5 32 21.47±19.15 10.91±5.78 0.007* Genito-Thyroid Index 32 3.70±3.05 2.32±0.80 0.067 Comparative Genital Androgeny 26 2.75±4.37 8.03±13.3 0.06 Thyroid Index 27 5.90±4.06 3.64±1.98 0.009* Beta MSH/Alpha MSH Index 27 6.45±4.30 4.00±2.25 0.012* Catabolism/Anabolism Index 29 6.82±12.11 3.09±1.70 0.198 Proinflammatory Index 29 1.91±3.26 0.72±0.54 0.249 (C) 2014 Systems Biology Research Group 36
  37. 37. INDEX N ACTIVE MEAN±STD CONTROL S MEAN ±STD PVAL ACTIVE VS INACTIVE Estrogen Fraction #5 13 11.68±4.73 9.77±3.96 0.310 0.437 Genito-Thyroid Index 13 2.86±1.32 2.07±0.97 0.006* 0.622 Comparative Genital Androgeny 10 1.03±1.05 4.74±4.21 0.028* 0.568 Thyroid Index 12 3.51±1.58 3.89±0.99 0.433 0.006 Beta MSH/Alpha MSH Index 12 3.83±1.59 4.38±1.20 0.433 0.003 Catabolism/Anabolism Index 14 3.47±1.77 2.85±1.74 0.363 0.910 Proinflammatory Index 13 1.04±1.25 0.74±1.01 0.019* 0.990 (C) 2014 Systems Biology Research Group 37
  38. 38. INDEX N TOTAL CASES MEAN±STD TOTAL CONTROLS MEAN±STD PVAL Estrogen Fraction #5 13 23.29±22.89 11.38±7.24 0.03* Genito-Thyroid Index 13 3.56±1.98 2.35±0.81 0.25 Comparative Genital Androgeny 13 2.14±2.95 6.38±12.61 0.24 Thyroid Index 13 5.45±5.66 4.50±2.05 0.64 Beta MSH/Alpha MSH Index 13 5.99±5.97 5.02±2.35 0.70 Catabolism/Anabolism Index 13 4.94±4.80 3.24±1.96 0.38 Proinflammatory Index 13 1.25±1.73 0.71±0.48 0.94 (C) 2014 Systems Biology Research Group 38
  39. 39. INDEX N TOTAL CASES MEAN±STD TOTAL CONTROLS MEAN±STD PVAL Estrogen Fraction #5 5 20.60±21.18 7.20±1.48 0.23 Genito-Thyroid Index 5 3.51±1.45 2.03±0.64 0.14 Comparative Genital Androgeny 4 2.61±4.28 14.50±21.79 0.07 Thyroid Index 5 6.08±5.23 2.42±1.21 0.23 Beta MSH/Alpha MSH Index 5 6.51±5.18 2.66±1.42 0.23 Catabolism/Anabolism Index 5 6.69±4.83 2.40±1.07 0.23 Proinflammatory Index 5 1.23±0.92 0.65±0.40 0.23 (C) 2014 Systems Biology Research Group 39
  40. 40. !  Genito-Thyroid index = Neutrophil to Lymphocyte ratio !  Over 400 studies in cancer patients, predictive of mortality !  Also studied in Chronic Heart Failure, Diabetes mellitus, etc. !  Considered a general, non-specific marker of inflammation (C) 2014 Systems Biology Research Group 40
  41. 41. (C) 2014 Systems Biology Research Group 41
  42. 42. !  Genito-Thyroid, as the Neutrophil/Lymphocyte ratio is incorporated into a series of indices that have relevance to numerous disorders, including cancer (C) 2014 Systems Biology Research Group 42 Neutrophil to Lymphocyte Ratio = Genito-Thyroid index Catabolism/Anabolism Index Cortisol index Adrenal Cortex Index Metabolic yield Somatostatin index Histamine index Ischemia Index
  43. 43. !  Theory of Endobiogeny offers a whole- system approach to cancer !  In a retrospective, case-controlled study of all cancer types, Biology of functions distinguishes cancer patients from controls !  Future studies should look at homogenous cancer patients vs. controls to better characterize specific cancer types, and sub- groups of responders and non-responders to chemotherapy (C) 2014 Systems Biology Research Group 43

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