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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, …

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.

Published in: Health & Medicine, Technology

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  • 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. (C) 2014 Systems Biology Research Group 2
  • 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. IF… Cancer = Abnormal cellular activity Chemotherapy, Radiation, Surgery = CURE of ALL cancers, EVERY TIME. (C) 2014 Systems Biology Research Group 4
  • 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. (C) 2014 Systems Biology Research Group 6
  • 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. 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. !  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. Hematologic: cell-free DNA DNA Methylation patterns MicroRNA: Microarray, PCR (C) 2014 Systems Biology Research Group 10
  • 11. http://rams.biop.lsa.umich.edu/research/metabolomics (C) 2014 Systems Biology Research Group 11
  • 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. !  Evaluate cancer as Systemic disease expressed in cells !  Use GLOBAL systems approach (C) 2014 Systems Biology Research Group 13
  • 14. (C) 2014 Systems Biology Research Group 14
  • 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. (C) 2014 Systems Biology Research Group 16
  • 17. (C) 2014 Systems Biology Research Group 17 Creation of Structure Maintenance of STRUCTURE Functional adaptation
  • 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. !  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. (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. (C) 2014 Systems Biology Research Group 21
  • 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. 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. (C) 2014 Systems Biology Research Group 24
  • 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. 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. (C) 2014 Systems Biology Research Group 27
  • 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. !  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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. !  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. (C) 2014 Systems Biology Research Group 41
  • 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. !  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