IT IS ALL ABOUT THE CYTOKINES!

The discovery of DNA and nuclear material has led to the emphasis on the alteration of Nuclear functions to fight cancer, indeed most of the original chemotherapy drugs had mechanisms of action centered on breaking or somehow impairing DNA.  This focus to a certain extent affected our judgement in the evaluation of certain drugs.  We are now finding out that the strength of certain drug  (and weakness /susceptibility to resistance) is not really due to their main effect on DNA (ie. epigenetic disturbances induced by  Etoposide).  The discovery that BCL-2 has a mechanism of resistance to certain drugs is point in case that nuclear material induced disturbances have significant limitations that occur away from the nucleus (at the Mitochondria).  Anti-proliferative chemotherapies have now shown their limits and scientists have kept this in our panoply of options against cancer.

Scientists have long been fascinated by the laws of nature, these driving forces that drive in certain ways or directions the chains of chemical reactions within the cells.  From Glycogenolysis to the Krebs' cycle, to the cellular pathways, role of enzymes these catalysts of chemical reaction and gene regulators, our focus has been progressively shifting.   The maximal effect of standard chemotherapy having been realized, the shift now has gone to driver Mutations, blocking pathways and modulating reactions etc.   But beyond the mutation, gene alterations and so forth, one thing that make a cancer spread like a wild fire is its stimulation by a growth factor, or its self dependence in achieving survival most of the time at very different levels of energy expenditure!  This role squarely falls into the area of epigenetics which is the critical area of Cytokine production determination.  Now, once produced, Cytokines, to be effective, must connect to their receptors!  This is where the wheels rub the asphalt to speed up the chemical reactions!

One of the mechanisms of increased cytokine production, aside from their gene amplification, is failure at the receptor.  Indeed, when a receptor fails, the normal reaction (law of nature) is to concur the resistance by sending more of the same cytokine.  While this increase could be partially succesful in restoring homeostasis depending on the level of abnormality at the receptor, the relative increase has other side effects due to the non specificity of receptors.  Co-receptors or other receptors susceptible to the same cytokine find themselves super excited and are driving downstream reactions at higher rates.  A SIGNIFICANT PHENOMENON NEEDS TO OCCUR AT THIS POINT, THAT IS THE DESENSITIZATION OF SECONDARY RECEPTORS, A TRAUMATIC PHENOMENON WITH POTENTIALLY NEOPLASTIC CONSEQUENCES   (TO BE CONTINUED)

CANCER CELLS AND THE CURE

A living cell is in constant motion. At any given time, there are periods of chemical reactions unfolding in a living cell. These processes are occurring 24/7. Despite their large number, they are not random, but are coordinated and purposeful. They have one overall objective which is the survival of the cell against all odds. However, when they cannot preserve life, they initiate the programmed cellular death. 
These cellular reactions respect basic chemical laws of ion and atom interactions. However, the general direction from reactions is imposed by the cellular mission which is clearly determined by the location of the cell in a tissue or organ and the expected function to be performed by the organ. At any given point in time, the cell is either in differentiation or proliferation, or changing to adapt to current circumstances of the cell. These functions and adaptations are caused by environmental stimuli reaching the cell.
 These stimuli could be chemical, hormonal, traumatic or electric and they reach receptors which cross the cellular boundaries or membrane, and affect the molecules belonging to a signal transduction pathway. The signal goes on to affect genes in the nucleus of the cell where DNA will be replicated to achieve or respond to the stimuli accordingly. All reactions follow a certain flow to achieve a purpose for the cell. To control the general direction of reaction the cell uses several methods: the first is to silence un-needed genes and to amplify the expression of needed genes that carry the code for the mission to be performed. 
The cell will enter division and proliferation of those genes to impose the general direction or flow of the reaction. The second method used to impose the general direction is the formation of genes that can catalyze or force the reaction to go a certain way: these are called "enzymes" for that particular reaction. If an enzyme is not formed, the reaction is not allowed to progress. Therefore, the control of what is happening is occurring this way. A third way to control the flow of direction is to promote proteins called "regulators". The more the regulators in a reaction, the more likely that regulated reaction can occur in a controlled fashion. The fourth way of controlling reaction is mole fraction which puts together certain regulators and enzymes or proteins in general which are aligned in a chain and forces molecules to go from one protein to another in the mole in a certain direction so that the output is what is needed for the mission. 
These mole-like complexes of proteins are called "core binding factors". Any protein function not needed will not be incorporated in the complex. Genes are silenced by methylation, or simply by being attached to patches of molecules that belong to the histones, the histones that cover genetic material. At any given point, when a gene is needed, the cover can be re-opened or pulled back, which is called "gene remodeling". A cancer cell will tend to move away from the location where it is located not because of its intention to kill the host, but because in that location the nutrients and local conditions will be inadequate eventually to allow further growth. It will seek another location to survive. Before it moves away, it has to take steps to protect its survival. It will break adhesion to surrounding cells; this is mostly achieved by decreasing its surface adhesion molecules. It will secrete proteins that can break fibers on its way in order to get through and detection of these proteins called “metalloproteases” can signal doctors that the disease, the cancer, is on the move. In certain circumstances, it produces a mucus to protect itself against detection by the immune system. 
When it arrives in the new location, the cell will produce a hormone or growth factor which gives itself advantage over the already present cells in that location. This is generally called a “tumor growth factor”. The potential for proliferation, division and growth advantage is driven through the signal transduction pathway inside the cell. This is generally achieved by the expression of a driver gene which is amplified or over-expressed forcing reaction for downstream pathways. This is called a “driver mutation”. 
Experience with chemotherapy which was like a bomb with an indiscriminate effect affecting both good and bad cells of the host has only been able to achieve 20 to 30% of cure. Today, scientists are targeting the driver mutations to stop pathways of growth of cancer cells. We are now getting higher response rates and starting to see response in cancers that were resistant to chemotherapy, e.g. melanoma. People used to talk about cure without believing in their own statement, but with the advance of target therapy, cure is a real possibility. We are just at the beginning of our understanding of the various targets. Cure will be achieved.

FACTORS BEING MONITORED IN THE WELLNESS PROGRAM (part II)

1. AGE
Because with age comes all the trouble.  Age is a relative thing.  At what age do we start monitoring things?
And 40 years of age appears the most thought of in Western Societies.  Mammograms are started and 45 years is a risk factor for men who then ae being monitor for cholesterol.  The natural or true age is linked to genetic and environmental factors.  Age is linked to the length of Telomeres and to Senescence.  Telomeres are these youth protector molecules which keep being clipped and shortened  at each cell cycle until the DNA is exposed to Endonucleases (if you get my drift!).  Sometime we can fool it and make it a variable by exercising, and then it plays catch-up with you later.  Some time, it is not so much of a variable, it is just there to be lived with...Suffice is to say, when you are young you feel invincible, protected.  Being old, well, you have a "Risk factor" .  Cancer does not like to be old, and works hard to preserve or elongate its Telomeres.  This is an area of Target therapy.

2.  Cholesterol, we spoke about yesterday-see WELLNESS PART I

3.  WEIGHT MANAGEMENT WE WILL SPEAK ABOUT NEXT
4.  BLOOD PRESSURE, Hb A1C FOR DIABETIC
5. THYROID FUNCTION (THYROID STIMULATING HORMONE LEVEL)
6. BNP

Brain natriuretic peptide - Wikipedia, the free encyclopedia

en.wikipedia.org/wiki/Brain_natriuretic_peptide

Basic natriuretic peptide (BNP), now known as B-type natriuretic peptide (also BNP) or GC-B, is a 32 amino acid polypeptide secreted by the ventricles of the ...

7.RENAL FUNCTION AND CREATININE
8. HEMOGLOBIN LEVEL
9. C-REACTIVE PROTEIN STATUS    (AND ANTI NUCLEAR ANTIBODY STATUS)
10. FEV 1 (OR WHETHER YOU FEEL TIRED AND SHORT OF BREATH)
11. OXYGEN SATURATION OR SLEEP APNEA PRESENCE
12. ALBUMIN LEVEL  (LOWER THAN 3.5g)
13. MENTAL STATUS / ANXIETY
14. PROTEINURIA
15. ADHESION TO PREVENTION AND IMMUNIZATION
(FLU-SHOT, PNEUMONIA AND NOW SHINGLE SHOT, ANNUAL OPHTHALMO VISIT,MAMMOGRAM,COLONOSCOPY,BONE DENSITY MONITOR, SMOKING CESSATION AND AVOIDANCE OF ALCOHOLI SM)


THESE 15 FACTORS SUM UP YOUR HEALTH.  THIS IS THE REPORT CARD YOU SHOULD GET FROM YOUR DOCTOR WITH EVERY VISIT!

WE WILL DISCUSS THEM AS WE GO ALONG

FOR THE CURE, TIME FOR PARADIGM SHIFT AND A REVOLUTION AGAINST SOME OF OUR LEADERS IN CANCER MEDICINE

Cancer is a disease involving the cell.  Our current understanding is that during the course of our lives, somewhere in our system, a cell's function will be altered enough to transform a normal cell into A CANCER CELL.   Our current understanding is that all cells want to stay alive and for cancer cell multiplication and dissemination it appears to be assurance of a type of cell preservation.  We know that to survive, the cancer cell will escape several mechanisms.  How to stimulate its growth, how to escape detection by the immune system and removal by the Macrophages and related natural measures, how to stay awake by lighting up certain pathways, how to resist against external chemical attacks, how to repair damages caused by attacks, how to survive on their own etc.?

We also know that cancer cells are not the same not only by tissue of origin, but also by pathways driving them.  We know that to escape death, the cancer cell uses redundancies and loopholes in its pathways, that is it may alter or multiply these pathways to overrun incoming inhibitions.  It may amplify measures to block our reach toward programmed death.  The cancer cell knows that once programmed death mechanisms are started, it has to die.  It builds things like Bcl-2 around the Caspase death path.  The cancer cell knows that there are inhibitory forces that need to be altered.  P53 is one of the Major forces. It needs to be altered or mutated.  Flow through a pathway is another force. And altering regulators may be one way to control the flow.  Or leaving a switch on to drive the pathways. etc...

We also know that every major target in pathways has effects downstream toward the nucleus and its DNA, and upstream toward the Membrane.  For some, we have found lateral connections serving as loophole escape.  More than one phenotype of an important Target is meant to provide Resistance to attacks of the main type.
 
With chemotherapy, we have had some success.  Our failures reside in the mechanisms of resistance, in the ability of the cancer cell to repair itself and escape death.  Escaping death appears to be also solely linked to protection against Necrosis and programmed death.

We also know about Driver pathways as well as forces we can use to stop cell migration, division and seeding. We have got to use this knowledge to plan our action for the cure.

The success of target therapy needs to tell us that leaders who continue to push chemotherapy as the only alternative, creating more combinations, need to be more and more left alone, while we switch to Targeting therapy and some combination therapies.

Targeting therapy tells us we got to get better at defining Driver pathways to be effective.  Particularly in solid tumors.  This is the major priority.  HOW DO YOU TELL THIS IS A DRIVER TARGET OR PATHWAY? IS IT BY DOSING REGULATORY MOLECULES, ENZYMES ALONG A PATHWAY, LEVEL OF TRANSCRIPTION GENES, STATUS OF SWITCH TO TARGET MOLECULES, PROMOTER EXPRESSION?  HOW DO YOU SAY THIS IS THE DRIVER PATHWAY?  WITH THIS KNOWLEDGE WE CAN AVOID STUDIES LIKE TAXOTERE & REVLIMID IN PROSTATE CANCER, WHEN TAXOTERE & VELCADE WOULD HAVE BEEN BETTER.

IF WE KNOW HOW TO DO THIS, OUR PATH TO CURE IS ASSURED.

The second question: HOW TO GET THIS CELL TO CASPASE, TO LYSOZOMAL HYDROLASES AND CATHEPSINS, AND OTHER NECROTIC AND AUTOPHAGIC PROCESSES? HOW TO PUSH IT TO PROGRAMMED DEATH?

TIME TO WAKE UP AND SMELL THE COFFEE BEFORE ANOTHER RUN FOR THE CURE!