a novel use of biomarkers in the modeling of cancer activity based on the theory of endobiogeny v1.5
DESCRIPTION
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.TRANSCRIPT
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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
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(C) 2014 Systems Biology Research Group 2
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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
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IF…
Cancer = Abnormal cellular activity
Chemotherapy, Radiation, Surgery = CURE of ALL cancers, EVERY TIME.
(C) 2014 Systems Biology Research Group 4
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! 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
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(C) 2014 Systems Biology Research Group 6
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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
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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
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! Unifactorial—Cancer multifactorial ! Lacks global vision of physiology ! Reactive modality ! Lacks predictive assessment ! Downstream: Does not determine
causative factors
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Hematologic: cell-free DNA
DNA Methylation patterns
MicroRNA: Microarray, PCR
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http://rams.biop.lsa.umich.edu/research/metabolomics
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! 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
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! Evaluate cancer as Systemic disease expressed in cells
! Use GLOBAL systems approach
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! Quantitative ! Function of the parts ! Hierarchy ! Categorical ! Separate ! Independent ! Static ! Control
! Qualitative ! Function of the
System ! Relationships ! Individualized ! Interconnected ! Interdependence ! Dynamic ! Creative chaos
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Reductionism Holism
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Creation of Structure Maintenance of STRUCTURE
Functional adaptation
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! 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
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! 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
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(C) 2014 Systems Biology Research Group
METABOLISM
CATABOLISM ANABOLISM ANABOLISM CATABOLISM
CRH
ACTH
ADRENALS
LHRH
FSH LH
GONADS
TRH
TSH
THYROID
GHRH
GH PL
PANCREAS πΣ
αΣ
βΣ
Corticotropic Gonadotropic Thyrotropic Somatotropic
ANS
ENDOCRINE MANAGEMENT
20
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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
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ADVANTAGES ! Objective ! Quantitative ! Accurate ! Reproducible ! Minimally invasive
DISADVANTAGES ! Binary ! Reductionist ! Confusion of ◦ Cause vs. Effect ◦ Cause vs. Effect vs.
Mechanism
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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
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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
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! 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)
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! 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
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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
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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
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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
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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
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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
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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
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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
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INDEX N ACTIVE MEAN±STD
CONTROLS 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
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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
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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
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! 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
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! Genito-Thyroid, as the Neutrophil/Lymphocyte ratio is incorporated into a series of indices that have relevance to numerous disorders, including cancer
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Neutrophil to Lymphocyte Ratio = Genito-Thyroid index
Catabolism/Anabolism Index
Cortisol index
Adrenal Cortex Index
Metabolic yield
Somatostatin index
Histamine index
Ischemia Index
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! 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
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