Introduction to the Biology of Functions and its application to Cancer
+Introduction tothe Biology ofFunctions and itsapplication to CancerBy:Jean Claude Lapraz, MDKamyar M. Hedayat, MD
+Cancer: Introduction Cancer is a deregulation of cell growth Modern research has focused on the role of oncogenes andproto-oncogenes in the etiology of tumors However, oncogenes and proto-oncogenes Require some type of stimulation (i.e. viral infections, environmentaltoxins), thus the detection of oncogenes alone is not sufficient topredict risk of cancer in all cases The degree and duration of their expression is managed by theendocrine system and modulated by the immune andneurovegetative systems and this cannot be determined by currentbinary lab testing services
+Presentation of Cancer Regardless of whether a cancer is slow or fast growing, there isa time period in which there is dysplastic then dedifferentiatedcell growth before a diagnosis of cancer is made due to Palpation of a sufficient number of cancerous cells Mass effect from a space-occupying lesion Disruption of cellular metabolism By the time many cancers are detected by the above notedmethods, it is often in an advanced state The ability to detect a cancer in a less advanced state would beinvaluable
+Cancer: Screening Tests The efficacy of common screening tests to diagnosis metastaticcancers, such as yearly mammograms and PSA testing havecome in to question due to Detection and biopsy of benign masses1,2 Treatment of tumors which may have spontaneously regressed3 Inability to anticipate aggressive tumors which grow in a short periodof time1,21. Esserman L, Shieh Y, Thompson I. Rethinking screening for breast cancer and prostatecancer. JAMA. Oct 21 2009;302(15):1685-1692.2. Woolf SH. The accuracy and effectiveness of routine population screening withmammography, prostate-specific antigen, and prenatal ultrasound: a review of publishedscientific evidence. Int J Technol Assess Health Care. Summer 2001;17(3):275-304.3. Zahl PH, Maehlen J, Welch HG. The natural history of invasive breast cancers detected byscreening mammography. Arch Intern Med. Nov 24 2008;168(21):2311-2316.
+Cancer: Prevention and RiskAssessment Large scale nutritional interventions aimed at preventing cancerhave been equivocal, or, even showed an increased rates ofcancer Diets rich in fruits and vegetables: equivocal1 High doses of antioxidants: increased incidence of lung cancer2 The short-coming in these studies was two Inappropriate or lack of stratification of subjects based on metabolictype: catabolic vs. anabolic vs. mixed Inappropriate understanding of the quality and types of supplements1. Hung HC, Joshipura KJ, Jiang R, et al. Fruit and vegetable intake and risk of major chronicdisease. J Natl Cancer Inst. Nov 3 2004;96(21):1577-1584.2. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancersin male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. NEngl J Med. Apr 14 1994;330(15):1029-1
+Short comings in Cancer research Modern cancer research has been impressive in elucidating thegenetic, cellular, and sub-cellular mechanisms of cancer,however, two issues continue to hamper cancer treatment The ability to account for individual metabolic, endocrine andgenetic factors in cancer risk assessment and treatment The ability to account for multiple risk factors simultaneously in adynamic, quantitative and qualitative manner in order to differentiate What is needed is a functional, dynamic testing system to bothanticipate, determine the causes of, and witness the efficacy oftreatment of cancers
+Laboratory studies• Classical lab data is based on binary considerations:• disease vs. no disease• normal vs. abnormal value• In many instances, patients have normal lab values but exhibitsymptoms or physiological irregularities consistent with a sub-optimal state of health.• Binary considerations cannot be applied with any realassurance of its functional relevance to a system as complex asthe human body.
+Laboratory studies• Biological systems, like social interactions are complex, multi-tiered, dynamic interrelated and integrated systemsYeast Protein Interaction NetworkBader and Hogue (2002) NaturePattern of cellular phone callsbetween friends
+Integrated systems• Objective quantitative data (laboratory values) are required toassess the organism• However, the true utility of binary values is when they are ableto provide functional descriptions of quantitative and qualitativeactivity:• Within a particular unit of activity• Of one unit to another,• Of the system as a whole• Only then can a truly dynamic and individualized assessment ofthe patient occur
+Laboratory studies• The endocrine system, as the manager of the metabolic activity of thebody is the ideal object of evaluation• Serum levels of hormones only reflect quantitative organ output, notfunctional activity, which can be affected by:• Hormone receptor binding1• Intracellular messenger activity1• Epigenetic changes2• Heavy metal toxicity3, etc.• Moreover, serum levels of hormones do not reflect the degree ofstimulation needed or the metabolic costs incurred in producing aparticular hormone1) Raison CL, Miller AH. When not enough is too much: the role of insufficientglucocorticoid signaling in the pathophysiology of stress-related disorders. Am JPsychiatry. Sep 2003;160(9):1554-15652) Chiam K, Tilley WD, Butler LM, Bianco-Miotto T. The dynamic and static modification ofthe epigenome by hormones: A role in the developmental origin of hormone relatedcancers. Biochim Biophys Acta. Apr 2009;1795(2):104-109.3) Gerhard I, Waibel S, Daniel V, Runnebaum B. Impact of heavy metals on hormonal andimmunological factors in women with repeated miscarriages. Hum Reprod Update. May-Jun 1998;4(3):301-309.
+Laboratory studies• The ideal system of measurement of biological processes thusshould examine the metabolic products of hormonalmanagement of cellular activity• In conclusion, the ideal laboratory system must• Reflect the complex, integrated and dynamic nature of biologicalsystems• Describe the functionality of the system in its• Qualitative function• Quantitative function• Individual unit, relative to other units and as a whole• Assess the organism at the metabolic and interstitial level
+Biology of functions• Biology of Functions (BoF) quantifies functional abilities ofthe organism, before, during and after theeffects ofadaptation to stressors. Because functionality is dynamic, adynamic, integrated and evolutionary methodology must beused instead of static lab values• BoF is based on a number of specific indices defined bymathematical relations between commonly used bloodanalysis data• The algorithms that permit the calculation of these indicesare based on the physiological relations that exist betweenthe direct or indirect products of hormonal activity:cells, hormones or enzymes (eosinophils, monocytes, lactatedehydrogenase, for example).
+Biology of functions• These relations allow one to visualize the functioning of theorganism at every level:• maintenance of homeostasis• Adaptation to stressors• Recovery after aggression• Immunity, etc.• Each function is quantified by an index, specified by a level ofactivity. The index expresses the actual activity of that function,both in and of itself and in relation to the metabolic and tissueneeds of the organism.• The whole set of indices gives an evolutionary assessment ofan individual body’s functionality, system by system, organ byorgan.
+Biology of Functions and Cancer With respect to cancer, the BoF accounts for individual factorsthat contribute to dedifferentiated cell growth: Endocrine: TRH, Estrogen, Testosterone, Insulin, etc. Neurovegetative: Norepinephrine, histamine, serotonin, etc. Immunologic: Interleukins, inflammatory activity As well as cumulative effects of these factors on Metabolism: Active and passive membrane permeability,mitochondria strain, Redox status, etc. Cellular function: nucleocytoplasmic cytopathogenecity, membranefracture, membrane expansion, apoptosis, necrosis
+Biology of Functions and Cancer By assessing the current, functional activity of theorganism, the Biology of Functions is able to assess multiplerisk factors in relationship to each other Carcinogenesis Index: The degree of dysplastic activity Cancerous Index: The relative degree of endocrino-metabolicfactors which are propitious to cancerous activity Expansiveness index no.2: the relative risk of anarchic cellulardevelopment due to adaptive phenomenon Active Carcinogenesis: The actual functional rate of cancer cellgrowth after assessing for the rate of pathological cell death fromapoptosis or necrosis Active effective carcinogenesis: Witnesses the insufficiency ofthe organism’s defenses in the face of cancer over activity Carcinogenesis expansion: the degree and speed of a cancer’sevolution
+Biology of functions• SUMMARY: Biology of Functions allows one to determine:• Pathogenic tendencies of the organism• The stage of development and the degree of severity of a potentialpathology (i.e. cancer, cardiac disease, degenerative neurologicaldisease)• Biology of functions can be used as a tool to track• the natural development of pathology• To derive a rational therapeutic treatment• To evaluate the efficacy of the treatment over time
+ CASE STUDYGLIOBLASTOMA MULTIFORMEREFRACTORY TO RADIOTHERAPYAND TEMOZOLOMIDE IN A 9 YEAROLD FEMALE
+Case History 9 year old female was diagnosed with a right thalamic tumor in1/07. She underwent resection with post-operative morbiditiesincluding intracerebral hemorrhage. Tumor size was noted to be increasing on a follow up MRI on8/08 A repeat MRI on 10/31/08 indicated continued growth of thelesion. Partial resection was performed and a pathological assessmentdetermined the tumor to be a glioblastoma multiforme
+Case History Patient underwent focal radiotherapy and daily Temozolomidein early 2009, completed 3/09 Follow up MRI 4/09 revealed progressive local disease in theresection cavity, which was not considered to be resectable Patient sought a second opinion for assessment and treatmentusing the endobiogenic system and the biology of functions Initial assessment performed 4/09, with subsequent follow upon 10/09. Follow up MRI’s on 8/09 and 11/09 revealed stable tumor sizewith no further growth or metastasis
+Initial Assessment: 4/09 The biology of functions revealed an encapsulated adenoidtype growth Fibrosis index: 9.82 (6-8) Adenoid index: 421 (10-30) The cancer was quite active, though the cancer wascharacterized as a relatively slow-developing growth and notextremely anarchic in its growth pattern and insufficientapoptosis Active cancer index: 1,831 (0.01-4.8) Cancer expansion index: 0.004 (0.02-3.08) Expansivity index no.2: 6.47 (1-4) Apoptosis index: 0.15 (0.9-1.4)
+Initial assessment:Thyrotropic factors The hypothalamic-metabolic factors, namely TRH and cellularmetabolic factors were found to play the most important role inthe patient’s cancer growth. We have noted that in brain cancers in general, and pediatricbrain cancers in particular, that TRH plays a very important rolein the etiology and growth of the cancer TRH-influenced factors DNA fracture: 10.27 (0.5-1.5) Global TRH adaptation index: 18.6 (3-9) Pro-inflammatory index: 0.44 (0.1-0.4)
+Initial Assessment:Metabolic factors The cancer had a catabolic, acidic quality with a high degree ofintracellular communication: Active cellular permeability: 1,482 (6-9) With poor passive permeability, contributing to the high degreeof nucleocytoplasmic pathogenicity and toxin accumulationwithin the cell, and excessive nutrient oxidation with free radicalaccumulation Passive cellular permeability: 3.06 (4-9) Nucleocytoplasmic pathogenicity: 37 (0.8-1.5) Harmful free radical index: 122 (2-6)
+Initial Assessment:Other Factors There was a significant elevation in androgenic activity, as wellas an up-regulation of both peripheral androgen and estrogenreceptors Androgen index: 0.52 (0.05-0.09) Androgen index comparative: 0.31 (0.1-0.3) Quantitative estrogen organo-tissular yield: 23,635 (67-1006) Growth factors also played an important role Metabolic Growth Index: 16.53 (2-6) Membrane Expansion: 0.48 (0.08-0.16)
+Initial Treatment Medicinal Plants: Prunusamygdalis(Sweet almond): reduces peripheral growth factors Quercuspedunculatus(English oak): Glucocorticoid activity to reducetumor size Tiliatomentosa (Silver linden): reduces TRH activity, anti-inflammatory, neuro-calmative, liver regenerative Juglansregia(Black walnut): exo- and endocrine pancreatic activity,reducing TRH and para-sympathetic stimulation of pancreas;stimulates hepatic macrophages and plasmocytes Brassicanapus (Cabbage): blocks TSH stimulation of thyroxineproduction and release, anti-inflammatory Ilex acquafolium(Holly tree):anti-fibrotic
+Initial Treatment Supplements: Vitamin C 6gm/d + Vitamin K 2, K3: anti-tumoral activity in conjunctionwith Vitamin C1 Melatonin2 10 gm qHS to reduce estrogen receptors2, Leutinizinghormone3 and for its anti-tumoral activity4 Exocrine digestive enzymes: to reduce parasympathetic activity Diet: Dietary changes aimed to reduce the degree of highlyassimilable nitrogenous proteins and parasympathetic and insulinactivity: Low-glycemic, dairy and gluten-free vegetarian diet withwhey protein supplements1. Verrax J, Taper H, Calderon P. Targeting cancer cells by an oxidant-based therapy. CurrentMolecular Pharmacology. 2008;1:80-92.2. del Rio B, Garcia Pedrero JM, Martinez-Campa C, Zuazua P, Lazo PS, Ramos S.Melatonin, an endogenous-specific inhibitor of estrogen receptor alpha via calmodulin. J BiolChem. Sep 10 2004;279(37):38294-38302.3. Kripke DF, Kline LE, Shadan FF, Dawson A, Poceta JS, Elliott JA. Melatonin effects onluteinizing hormone in postmenopausal women: a pilot clinical trial NCT00288262. BMCWomens Health. 2006;6:8.4. Lissoni P, Barni S, Ardizzoia A, et al. A randomized study with the pineal hormone melatoninversus supportive care alone in patients with brain metastases due to solid neoplasms.Cancer 1994;73:699-701.
+Follow Up Assessment: 11/09Laboratory ChemistriesChemistry 4/09 11/09 CommentLDH 300 194 Reduction in chronic metabolic strainCPK 137 90 Reduction in acute metabolic strainCEA 0.7 <0.5 Cell adhesion moleculeCA 15-3 34 23 Associated with gonadotropic activity andthyroid’s role in hyperplasia and inflammation1,2CA 19-9 40 34 Associated with abdominal cancers; repre-sentsmetabolic role of thyro-somatotropic activity
+Follow Up Assessment: 11/09Laboratory ChemistriesChemistry 4/09 11/09 CommentOsteocalcin 17.8 42 Serum levels are inversely related cellularmetabolic activity as inducers of anabolism, asit stimulates insulin release1BUN/Cr 29 15 Elevated BUN/Cr ratio can be associated witha hyper-catabolic stateNa 155 138ALT 96 38Hg 9.5 10.7 Improvement in anemia1. Atkinson SA. Vitamin D status and bone biomarkers in childhood cancer.Pediatr Blood Cancer. Feb 2008;50(2 Suppl):479-482; discussion 486.
+ Follow up assessment: Biology of Functions:APOPTOSIS INDEX: Global rate of apoptosis relative tothe rate of dysfunctional apoptosis during adaptation (nl0.3-0.7)04/27/05 11/01/05index dapoptose (0,3 à 0,7) 0.15 0.860.000.100.200.300.400.500.600.700.800.90
+ Follow up assessment: BoFDNA FRACTURE: Degree of nuclear fragility and its risk ofrupture, and by extension, of transcription errors (nl: 0.5-1.5)04/27/05 11/01/05index de fracture adn (0,5 à 1,5) 10.27 5.550.002.004.006.008.0010.0012.00
+ Follow up assessment: BoF:Carcinogenesis index: Rate of dysplastic activity(nl: 1-3)1.0010.00100.001000.0004/27/0504/29/0505/01/0505/03/0505/05/0505/07/0505/09/0505/11/0505/13/0505/15/0505/17/0505/19/0505/21/0505/23/0505/25/0505/27/0505/29/0505/31/0506/02/0506/04/0506/06/0506/08/0506/10/0506/12/0506/14/0506/16/0506/18/0506/20/0506/22/0506/24/0506/26/0506/28/0506/30/0507/02/0507/04/0507/06/0507/08/0507/10/0507/12/0507/14/0507/16/0507/18/0507/20/0507/22/0507/24/0507/26/0507/28/0507/30/0508/01/0508/03/0508/05/0508/07/0508/09/0508/11/0508/13/0508/15/0508/17/0508/19/0508/21/0508/23/0508/25/0508/27/0508/29/0508/31/0509/02/0509/04/0509/06/0509/08/0509/10/0509/12/0509/14/0509/16/0509/18/0509/20/0509/22/0509/24/0509/26/0509/28/0509/30/0510/02/0510/04/0510/06/0510/08/0510/10/0510/12/0510/14/0510/16/0510/18/0510/20/0510/22/0510/24/0510/26/0510/28/0510/30/0511/01/05index de carcinogenèse (1 à 3)
+ Follow up assessment: BoF:Cancer index: : The relative degree of endocrino-metabolicfactors which are propitious to cancerous activity (nl: 6-10)0.000.010.101.0010.0004/27/0504/29/0505/01/0505/03/0505/05/0505/07/0505/09/0505/11/0505/13/0505/15/0505/17/0505/19/0505/21/0505/23/0505/25/0505/27/0505/29/0505/31/0506/02/0506/04/0506/06/0506/08/0506/10/0506/12/0506/14/0506/16/0506/18/0506/20/0506/22/0506/24/0506/26/0506/28/0506/30/0507/02/0507/04/0507/06/0507/08/0507/10/0507/12/0507/14/0507/16/0507/18/0507/20/0507/22/0507/24/0507/26/0507/28/0507/30/0508/01/0508/03/0508/05/0508/07/0508/09/0508/11/0508/13/0508/15/0508/17/0508/19/0508/21/0508/23/0508/25/0508/27/0508/29/0508/31/0509/02/0509/04/0509/06/0509/08/0509/10/0509/12/0509/14/0509/16/0509/18/0509/20/0509/22/0509/24/0509/26/0509/28/0509/30/0510/02/0510/04/0510/06/0510/08/0510/10/0510/12/0510/14/0510/16/0510/18/0510/20/0510/22/0510/24/0510/26/0510/28/0510/30/0511/01/0504/27/05 11/01/05index de cancérose (6 à 10) 1.13 0.00index de cancérose (6 à 10)
+Follow up assessment: BoF:Expansivity no. 2: Rate of anarchic cellulardevelopment (Pink square) (nl: 1-4)1.0010.0004/27/0504/29/0505/01/0505/03/0505/05/0505/07/0505/09/0505/11/0505/13/0505/15/0505/17/0505/19/0505/21/0505/23/0505/25/0505/27/0505/29/0505/31/0506/02/0506/04/0506/06/0506/08/0506/10/0506/12/0506/14/0506/16/0506/18/0506/20/0506/22/0506/24/0506/26/0506/28/0506/30/0507/02/0507/04/0507/06/0507/08/0507/10/0507/12/0507/14/0507/16/0507/18/0507/20/0507/22/0507/24/0507/26/0507/28/0507/30/0508/01/0508/03/0508/05/0508/07/0508/09/0508/11/0508/13/0508/15/0508/17/0508/19/0508/21/0508/23/0508/25/0508/27/0508/29/0508/31/0509/02/0509/04/0509/06/0509/08/0509/10/0509/12/0509/14/0509/16/0509/18/0509/20/0509/22/0509/24/0509/26/0509/28/0509/30/0510/02/0510/04/0510/06/0510/08/0510/10/0510/12/0510/14/0510/16/0510/18/0510/20/0510/22/0510/24/0510/26/0510/28/0510/30/0511/01/0504/27/05 11/01/05index dexpansivité (0,06 à 2) 3.58 1.19index dexpansivité bis (1 à 4) 6.47 1.17index dexpansivité global (0,01 à 3,2) 7.62 4.62
+ Follow up assessment: BoF:Active Carcinogenesis: Current functional state of cancer activityafter accounting for cell death by apoptosis or necrosis (nl 0.01-9.6)1.0010.00100.001000.0010000.0004/27/0504/29/0505/01/0505/03/0505/05/0505/07/0505/09/0505/11/0505/13/0505/15/0505/17/0505/19/0505/21/0505/23/0505/25/0505/27/0505/29/0505/31/0506/02/0506/04/0506/06/0506/08/0506/10/0506/12/0506/14/0506/16/0506/18/0506/20/0506/22/0506/24/0506/26/0506/28/0506/30/0507/02/0507/04/0507/06/0507/08/0507/10/0507/12/0507/14/0507/16/0507/18/0507/20/0507/22/0507/24/0507/26/0507/28/0507/30/0508/01/0508/03/0508/05/0508/07/0508/09/0508/11/0508/13/0508/15/0508/17/0508/19/0508/21/0508/23/0508/25/0508/27/0508/29/0508/31/0509/02/0509/04/0509/06/0509/08/0509/10/0509/12/0509/14/0509/16/0509/18/0509/20/0509/22/0509/24/0509/26/0509/28/0509/30/0510/02/0510/04/0510/06/0510/08/0510/10/0510/12/0510/14/0510/16/0510/18/0510/20/0510/22/0510/24/0510/26/0510/28/0510/30/0511/01/0504/27/05 11/01/05index de carcinogenèse active (0,01 à 9,6) 1831.81 198.22index de carcinogenèse active comparée(0,01 à 4,8) 42.64 13.92
+ Follow up assessment: BoF:Estrogen index: Endocrino-metabolic activity of estrogens(nl, females: 0.2-0.4)04/27/05 11/01/05index oestrogénique (0,20 à 0,40 F)(0,15 à 0,25 H)0.36 0.200.000.050.188.8.131.52.300.350.40
+ Follow up assessment:BoF: Total Androgens (Blue diamond): total androgenactivity (nl, females: 0.2-0.25)04/27/05 11/01/05taux dandrogènes totaux (0,2 àO,25 F) (0,2 à O,3 H)0.44 0.26taux dandrogènes corticosurrénaliens (0,05 à 0,09)0.08 0.04taux dandrogènes génitaux (0,12 à0,17 F) (0,18 à 0,22 H)0.36 0.220.000.050.184.108.40.206.300.350.400.450.50
+ Follow up assessment: BoF:(Intracellular) Growth Index (nl 2-6)04/27/05 11/01/05index de croissance (2 à 6) 16.53 9.040.002.004.006.008.0010.0012.0014.0016.0018.00
+ Follow up assessment: BoF:Proinflammatory (Blue): endogenous potential forinflammation (nl 0.1-0.4)Inflammation index (Pink): Current functional state ofinflammation (nl 0.3-2.5)04/27/05 11/01/05index proinflammatoire (0,1 à 0,4) 0.44 0.22index dinflammation (0,3 à 2,5) 1.35 0.07index dinflammation comparée (0,2à 2,5)2.69 0.000.010.101.0010.00
+Conclusions The endobiogenic concept is an approach to integrativephysiology based on the management of the organism by theendocrine system It is a whole model system, integrative in its approach tounderstanding the functioning of the individual parts and theirrelationship to the whole Cancer is a multifactor disorder of disregulated cell growth The endobiogenic system is well suited to analyze the causesof cancer and its possible treatments because of its ability tosimultaneously assess multiple factors that influence cellgrowth
+Conclusions (cont.) The biology of functions is biological modeling software that isable to assess the quantitative, qualitative and functionalactivity of the organism The biology of functions is able to provide a rational basis oftreatment It provides for longitudinal assessment of the progression of apatient’s tumor as well as their response to treatment
+Contact For research in North and Central America, Middle East: Kamyar M. Hedayat, MD, International Society of EndobiogenicMedicine and Experimental Physiology Email: firstname.lastname@example.org Phone: 1-318-525-6311 For research in Europe and North Africa: Jean Claude Lapraz, MD, President, International Society ofEndobiogenic Medicine and Experimental Physiology Email: email@example.com Phone: 011 33 6 07 71 94 00