1. Identifying best chemotherapy drugs in patients with Mutation in the NOTCH pathway?
Taxotere?
association with Her-2 overexpression and use of Herceptin
NF-kB blocker
or AKT blocker.
Histone de-acetylator
2. Understanding the patterns of Metastasis between epithelial (squamous) (more local recurrence) Vs AdenoCA (more distant recurrence in Esophageal cancer? Genes at play.
Does mesenchymalization dictate or drive long distance metastasis?
3. Mitomycin in NFKB amplification/Mutations
Showing posts with label AKT. Show all posts
Showing posts with label AKT. Show all posts
Tuesday, November 5, 2013
Monday, February 4, 2013
CELLULAR LANGUAGE (II)
In Cellular Language I published recently that we tried to emphasize that big functions of the cell start up with an on-and-off switch. The Tic and The Tan like in MORSE language, the 1and 0 of the computer. While this is true, there are many other simple things at the molecular level that are just as simple, but full of physiologic and scientific implications.
1.ON and OFF switch:
--------------------------
Events that lead to cancer are sometimes an exaggeration of a signal. The K-RAS (there exist many RAS (es) as we discussed in differentiation) has a switch called the Sons of the Sevenless which can stay on, sending signals down the cell continuously. Activated RAS will light on 3 signal pathways:
-MAP kinase (through RAF)--->FOS, JUN (stress), MYC (the dangerous leading to Burkitt)-TF
-RAL/CDC42 (important in the movement of the membrane, Metastasis)
-PI3K (leading to affect on AKT/MTOR) FOXO downstream hiding the PUMA-remember)
Mutations at the RAS itself can also cause it to stay on, as opposed to knocking it out.
Remember, Mutations of RAS occur in 80% of Pancreatic cancers and 50% of colon cancer.
Therefore, a simple switch can kill you with one of the most devastating diseases.
2. Change of shape:
---------------------
To confuse and look smart, your scientist calls this post-translational conformation to emphasize that this change has occurred later because of the nteraction with another molecule (in general).
At the surface of the membrane, there are here and there some Molecules called INTEGRINS; these are of various types and increasing molecular diversity and are best known as Receptors. They are large complexes of molecules gathered in chunks called 'subunits'. They basically cross the thickness of the cellular membrane and, outside the cell, they sense what is going on. Integrins serve many great purposes including cell division, proliferation, migration, adhesion to each either, differentiation, sensing etc. You name it, they do it! Only division of DNA, this, they don't do. But the membrane has to be divided also to make 2 cells in cell divison. Even anti-coagulation happens here. The versatility of the integrins is linked to the variety of subunits it is composed with. Some are nature of cell specific and some are contact specific. By contact specific, I mean what molecule outside the cell it will attach to (ie fibronectin Vs GPIIb).
Suffice is to say that kinking of the Integrins causes exposure of some parts of the Integrin molecule not naturally exposed. If one looks at the skin of the joint at the back of the finger, one will see folded skin. if you forcefully bend your finger, the fold you were looking at will unfold and the bottom of the fold will come out. This is what happen to the integrin when it meets outside the cell another molecule such as TALIN.
That bending triggers the attachment of other molecules or ions (phosphorylation) to the now exposed skin, lighting up the Integrins for the cascade of events which will unfold, including the activation of SRC in Sarcoma.
The shape imposed by the bending is also Molecule specific. Despite the resemblance of SRC with the c-ABL (leukemia), their bending does not offer the same shape, and therefore, different parts of the molecule are exposed and 2 different diseases result.
CELL ADHESION- "join at the hip"
----------------------------------------
At many points the cells are joined to each other at the hips of the Talins. Say, at the hip of the Talin which linked to one Integrin, there is a PLUS SIGN at Cell A, and at the next TALIN attached to the Integrin of cell B, there is a NEGATIVE sign. These 2 integrins will be attached, and cell adhesion is achieved. Simple as that!
Wheels of cellular migration,
-----------------------------,
Cells can roll over other cells by progressively attaching Talin to Talins and breaking the talin-talins (integrin-integrin) behind, engulfing the integrins and using them again in the forthcoming attachment like a wheel touching the ground. The cell is that smart at the membrane.
More simple things to come...
Hiding the PUMA behind the FOXO to have a death TRAP (Apoptsosis) in case the FOXO is compromised!
Just simple, but effective tricks ...
1.ON and OFF switch:
--------------------------
Events that lead to cancer are sometimes an exaggeration of a signal. The K-RAS (there exist many RAS (es) as we discussed in differentiation) has a switch called the Sons of the Sevenless which can stay on, sending signals down the cell continuously. Activated RAS will light on 3 signal pathways:
-MAP kinase (through RAF)--->FOS, JUN (stress), MYC (the dangerous leading to Burkitt)-TF
-RAL/CDC42 (important in the movement of the membrane, Metastasis)
-PI3K (leading to affect on AKT/MTOR) FOXO downstream hiding the PUMA-remember)
Mutations at the RAS itself can also cause it to stay on, as opposed to knocking it out.
Remember, Mutations of RAS occur in 80% of Pancreatic cancers and 50% of colon cancer.
Therefore, a simple switch can kill you with one of the most devastating diseases.
2. Change of shape:
---------------------
To confuse and look smart, your scientist calls this post-translational conformation to emphasize that this change has occurred later because of the nteraction with another molecule (in general).
At the surface of the membrane, there are here and there some Molecules called INTEGRINS; these are of various types and increasing molecular diversity and are best known as Receptors. They are large complexes of molecules gathered in chunks called 'subunits'. They basically cross the thickness of the cellular membrane and, outside the cell, they sense what is going on. Integrins serve many great purposes including cell division, proliferation, migration, adhesion to each either, differentiation, sensing etc. You name it, they do it! Only division of DNA, this, they don't do. But the membrane has to be divided also to make 2 cells in cell divison. Even anti-coagulation happens here. The versatility of the integrins is linked to the variety of subunits it is composed with. Some are nature of cell specific and some are contact specific. By contact specific, I mean what molecule outside the cell it will attach to (ie fibronectin Vs GPIIb).
Suffice is to say that kinking of the Integrins causes exposure of some parts of the Integrin molecule not naturally exposed. If one looks at the skin of the joint at the back of the finger, one will see folded skin. if you forcefully bend your finger, the fold you were looking at will unfold and the bottom of the fold will come out. This is what happen to the integrin when it meets outside the cell another molecule such as TALIN.
That bending triggers the attachment of other molecules or ions (phosphorylation) to the now exposed skin, lighting up the Integrins for the cascade of events which will unfold, including the activation of SRC in Sarcoma.
The shape imposed by the bending is also Molecule specific. Despite the resemblance of SRC with the c-ABL (leukemia), their bending does not offer the same shape, and therefore, different parts of the molecule are exposed and 2 different diseases result.
CELL ADHESION- "join at the hip"
----------------------------------------
At many points the cells are joined to each other at the hips of the Talins. Say, at the hip of the Talin which linked to one Integrin, there is a PLUS SIGN at Cell A, and at the next TALIN attached to the Integrin of cell B, there is a NEGATIVE sign. These 2 integrins will be attached, and cell adhesion is achieved. Simple as that!
Wheels of cellular migration,
-----------------------------,
Cells can roll over other cells by progressively attaching Talin to Talins and breaking the talin-talins (integrin-integrin) behind, engulfing the integrins and using them again in the forthcoming attachment like a wheel touching the ground. The cell is that smart at the membrane.
More simple things to come...
Hiding the PUMA behind the FOXO to have a death TRAP (Apoptsosis) in case the FOXO is compromised!
Just simple, but effective tricks ...
Friday, December 7, 2012
ARSENIC TRIOXIDE COULD SIGNIFICANTLY EXPAND ITS ROLE IN CANCER TREATMENT. AND VITAMIN C AND MICROHYDRIN COULD COME TO THE RESCUE
Cancer cure is through death of the cancer cell. To date, the main way of death for the cancer cell
is through Caspase activation cascade. In most cells, we know how the main way the activation of Caspase occurs. That is Cytochrome C is naturally anchored at the membrane inside the Mitochondria. The Anchor is in fact a chemical bonding or attachment through electrons, like molecules do attach to each other. We believe there, Cytochrome C is attached to a Cardiolipin which is part of the lipids of the membrane. Just imagine another molecule showing up with a free electron, the free electron could attract and pull the one involved in the attachment and break free the Cytochrome C. That Cytochrome C electron no longer attached comes out and activates the Caspase (mostly Caspase 9 which eventually activates members of its family) and there starts the Caspase its work to coagulate DNA and genes start breaking, thus leading to cancer cell death. One of the molecules that produce such disturbing free electrons is Arsenic Trioxide. This delivery of free electrons by arsenic trioxide is not limited to the mitochondria. It occurs through the cytosol (liquid milieu of the cell) disrupting many cellular pathways, delivering global intracellular disruption. ( for those savvy people, do remember that the " breaking" of the anchor could be induced from outside the Mitochondrial membrane through the AKT or Bax effect- this is where Bcl-2 negative effect is the strongest ) arsenic trioxide
This global disruption has been established to treat Acute Promyelocytic Leukemia (APL) (by the way, Chinese researchers lead the way on this one). Frankly speaking, this "Global disruption"can be used in any cancer. The problem is that it can occur in any cell, including our normal cells. Giving caution to the amount you use because of a narrow safety index.
Vitamin C and Microhydrin have also free electron, that is why they can cool down free radicals and therefore are called Anti-Oxydants . The free electrons of these compounds seem to add to those of Arsenic Trioxide to Increase toxicity to the cancer cell. It is worth mentioning that, at the DNA level, these free electron break the strand, triggering our first law (activation of P53 and stoppage of cell cycle).
3 main problems
1. Good and bad pathways are stopped, mitigating the effects of global destruction.
2. (non selectivity) Good and bad cells are killed. This effect is worse in patients with poor reserve of free electron clearing molecules (Gluthatione based, Superoxide based and others). (CAUTION TO EVERYONE)
3. Arsenic is hard to get rid of, and chronic exposure signs will result.
But frankly speaking, you can use this to kill any Cancer. Research will continue at CRBCM no matter what!
Of Note: Use of this information outside of the topic discussed herein, is not endorsed by the CRBCM
is through Caspase activation cascade. In most cells, we know how the main way the activation of Caspase occurs. That is Cytochrome C is naturally anchored at the membrane inside the Mitochondria. The Anchor is in fact a chemical bonding or attachment through electrons, like molecules do attach to each other. We believe there, Cytochrome C is attached to a Cardiolipin which is part of the lipids of the membrane. Just imagine another molecule showing up with a free electron, the free electron could attract and pull the one involved in the attachment and break free the Cytochrome C. That Cytochrome C electron no longer attached comes out and activates the Caspase (mostly Caspase 9 which eventually activates members of its family) and there starts the Caspase its work to coagulate DNA and genes start breaking, thus leading to cancer cell death. One of the molecules that produce such disturbing free electrons is Arsenic Trioxide. This delivery of free electrons by arsenic trioxide is not limited to the mitochondria. It occurs through the cytosol (liquid milieu of the cell) disrupting many cellular pathways, delivering global intracellular disruption. ( for those savvy people, do remember that the " breaking" of the anchor could be induced from outside the Mitochondrial membrane through the AKT or Bax effect- this is where Bcl-2 negative effect is the strongest ) arsenic trioxide
This global disruption has been established to treat Acute Promyelocytic Leukemia (APL) (by the way, Chinese researchers lead the way on this one). Frankly speaking, this "Global disruption"can be used in any cancer. The problem is that it can occur in any cell, including our normal cells. Giving caution to the amount you use because of a narrow safety index.
Vitamin C and Microhydrin have also free electron, that is why they can cool down free radicals and therefore are called Anti-Oxydants . The free electrons of these compounds seem to add to those of Arsenic Trioxide to Increase toxicity to the cancer cell. It is worth mentioning that, at the DNA level, these free electron break the strand, triggering our first law (activation of P53 and stoppage of cell cycle).
3 main problems
1. Good and bad pathways are stopped, mitigating the effects of global destruction.
2. (non selectivity) Good and bad cells are killed. This effect is worse in patients with poor reserve of free electron clearing molecules (Gluthatione based, Superoxide based and others). (CAUTION TO EVERYONE)
3. Arsenic is hard to get rid of, and chronic exposure signs will result.
But frankly speaking, you can use this to kill any Cancer. Research will continue at CRBCM no matter what!
Of Note: Use of this information outside of the topic discussed herein, is not endorsed by the CRBCM
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