Genetic basis of Autism

The notion that an inflammatory process such as the one induced by an immunization may contribute to children's mental retardation or Autism has fundamental truth when it comes to gene pathways. Indeed, during an acute inflammatory insult, Macrophages that are called to the theater will liberate several cytokines which include TGF alpha.  This cytokine will bind to EGFR receptors while other cytokines induced by the inflammatory process will bind their relevant receptors.  Internalization of these receptors will leave deep edges at the membrane, activating the Focal adhesion molecules of Kinase (FAK ).  The first known gene to react with the FAK gene is the Tuberous sclerosis gene which is known to lead to Autism.  In a forming or developing brain, certain isoforms of this gene may predispose some children to develop autism.   The crux of the problem is to determine which inflammatory process (immunization or other processes) is at the source of the problem!

PTK2 protein tyrosine kinase 2 (PTK2), also known as Focal Adhesion Kinase (FAK), is a protein that, in humans, is encoded by the PTK2 gene.^[2] PTK2 is a focal adhesion-associated protein kinase involved in cellular adhesion (how cells stick to each other and their surroundings) and spreading processes (how cells move around).^[3] It has been shown that when FAK was blocked, breast cancer cells became less metastatic due to decreased mobility.^[4]

 PTK2 has been shown to interact with TSC2, (22 wikipedia)

 Tuberin also known as tuberous sclerosis 2 is a protein that in humans is encoded by the TSC2 gene.
 About 50% of people with TSC have learning difficulties ranging from mild to significant,^[2] and studies have reported that between 25% and 61% of affected individuals meet the diagnostic criteria for autism, with an even higher proportion showing features of a broader pervasive developmental disorder.^[3] A 2008 study reported self-injurious behavior in 10% of people with TSC.^[4] Other conditions, such as ADHD, aggression, behavioral outbursts and OCD (obsessive compulsive disorder) can also occur. Lower IQ is associated with more brain involvement on MRI.(wikipedia)

====================================================
THERE YOU HAVE IT THE FULL STORY!

MASTERING OF SOME GENES CONTROLLING RECEPTOR FUNCTIONS!

1.SLIT 2    Slit homolog 2 protein is a protein that in humans is encoded by the SLIT2 gene
                SLIT2 has been shown to interact with Glypican 1
 Cell surface heparan sulfate proteoglycans are composed of a membrane-associated protein core substituted with a variable number of heparan sulfate chains. Members of the glypican-related integral membrane proteoglycan family (GRIPS) contain a core protein anchored to the cytoplasmic membrane via a glycosyl phosphatidylinositol linkage. These proteins may play a role in the control of cell division and growth regulation.<sup>[2]  WIKIPEDIA

IF YOU RECALL OUR DISCUSSION  ABOUT RECEPTOR FAILURE, TUMOR GROWTH FACTOR FAILED TO STIMULATE OUR RECEPTOR BECAUSE OF LACK OF DERENGEMENT OF GLYCOSYLATION AND HEPARAN WAS THE FAILURE.  THIS PUT SLIT 2 AT THE RECEPTOR PARTICULARLY IN THE CENTRAL NERVOUS SYSTEM!</sup>
                              
2.MIG6:   The cytoplasmic protein MIG6 (mitogen-induced gene 6; also known as ERRFI1) interacts with and inhibits the kinase domains of EGFR and ERBB2 (refs 3–5). Crystal structures of complexes between the EGFR kinase domain and a fragment of MIG6 show that a 25-residue epitope (segment 1) from MIG6 binds to the distal surface of the C lobe of the kinase domain. Biochemical and cell-based analyses confirm that this interaction contributes to EGFR inhibition by blocking the formation of the activating dimer interface.(ZANG ET AL!)
 MIG-6 Negative regulator of EGFR signaling in skin morphogenesis. Acts as a negative regulator for several EGFR family members, including ERBB2, ERBB3 and ERBB4. Inhibits EGFR catalytic activity by interfering with its dimerization. Inhibits autophosphorylation of EGFR, ERBB2 and ERBB4. Important for normal keratinocyte proliferation and differentiation. Plays a role in modulating the response to steroid hormones in the uterus. Required for normal response to progesterone in the uterus and for fertility. Mediates epithelial estrogen responses in the uterus by regulating ESR1 levels and activation. Important for regulation of endometrium cell proliferation. Important for normal prenatal and perinatal lung development. Interacts with ERBB2. Interacts with EGFR. Levels are very low in quiescent cells. Up-regulated by mitogens. Belongs to the MIG6 family. Note: This description may include information from UniProtKB.

3.  SATB1  HERE BECAUSE OF THE CONNECTION WITH NUCLEAR MATERIAL.  interferon gamma act through here!

4.  SMAD6
Another powerful decoy
" Smad6 specifically competes with Smad4 for binding to receptor-activated Smad1, yielding an apparently inactive Smad1-Smad6 complex. Therefore, Smad6 selectively antagonizes BMP-activated Smad1 by acting as a Smad4 decoy."  Hata et al
 -------------------------------------------------------------------------------------------------
LTB4, because of its interactions with

Peroxisome proliferator-activated receptor gamma has been shown to interact with:

• EDF1^[8][9][10]
• EP300^[11][12]
• HDAC3^[13][11]
• MED1^[12]
• NCOA3^[12]
• NCOA4^[14]
• NCOA2^[12]
• NR0B2^[15]
• PPARGC1A^[16][17]
• RB1.^[11]

Clinical relevance

PPAR-gamma has been implicated in the pathology of numerous diseases including obesity, diabetes, atherosclerosis, and cancer. PPAR-gamma agonists have been used in the treatment of hyperlipidaemia and hyperglycemia.^[18] PPAR-gamma decreases the inflammatory response of many cardiovascular cells, particularly endothelial cells.^[19] PPAR-gamma activates the PON1 gene, increasing synthesis and release of paraoxonase 1 from the liver, reducing atherosclerosis.^[20]
Many insulin sensitizing drugs (namely, the thiazolidinediones) used in the treatment of diabetes target PPARG as a means to lower serum glucose without increasing pancreatic insulin secretion.
A fusion protein of PPAR-γ1 and the thyroid transcription factor PAX8 is present in approximately one-third of follicular thyroid carcinomas, to be specific those cancers with a chromosomal translocation of t(2;3)(q13;p25), which permits juxtaposition of portions of both genes.^{[21] [22]}
Recently pioglitazone, a PPAR-γ agonist has been shown to be effective in reducing inflammation in Parkinson's Disease models. Levels of MMPs and microglia (and therefore TNF-α and other cytokine levels) were found to be reduced. Thus it has been shown to be neuroprotective in MPTP mouse models.

BMP2

The protein encoded by this gene belongs to the transforming growth factor-beta (TGFB) superfamily. The encoded protein acts as a disulfide-linked homodimer and induces bone and cartilage formation. [provided by RefSeq, Jul 2008]

AVASTIN and Blood Vessels

1. Avastin normalizes blood vessel and therefore improves drug delivery
2.Combination with anti-EGFR, shortens PFS
3. Changes endothelium
4. Refractoriness soon develops
5.no cures
6.lack of biomarkers to optimally evaluate,monitor efficacy, and therefore dose optimally
7.Increasing Fibroblast growth factor as a way of dealing with lack of VEGF receptors
?dummy receptor to hijack extracellular - transcription factors increase

A WELL STUDIED MOLECULE!

BUTEIN

1. It is a natural Chalconoid, derived from Toxicodendron Vernicifluum
2. It is inhibitor of EGFR and SRC Tyrosine Kinase, Please give it in all Adenocarcinoma ...(in a trial of course! and at your own expenses and risk!)
3.Inhibitor of c-AMP dependent processes
4. Induce Apoptosis in B16 Melanoma cells and in HL60 Leukemia cells.
5. Anti-inflammatory
6. An Aldolase Reductase
7. An Aromatase inhibitor, please give it in ER positive Breast Cancer
8. a chelator of Iron and Cupper, please give it in Hemosiderosis in a clinical trial
9. Inhibitor of NF-kB and TNF inhibitor, that's how it is an anti-inflammatory
(try it in Sepsis gone overboard-in clinical trial). MD Anderson claimed it does this by Inhibiting IKK, check it out!
10. Activator of Sirtuins, the stuff you give to stop Dementia!  Sirtuins that you take to preserve survival through Telomere protection.  Oh by the way Sirtuins are Histone Deacetylators!  do the math and consequence calculation.  It will add to the MTOR inhibitors!
11, Increase activity of Caspase 3, Increase activity of BAX, and decrease BCL-2 to lead to Apoptosis of cancer cells talked about above!
12. Inhibitor of Glutation reductase

Please I have to stop here,  These are just too much goodies!
I will be taking this Butein myself!
I guess you can relax now!
Believe me, people take Butein to treat their Gastric Cancers even!

NEXT TO THE MTOR,

We are getting closer to the cure every day, we are clearly at the door of the cure acquiring process,
just learning the language spoken by the cell. Already it seems we are overwhelmed by what we find.
There are things we are learning though, and fast:
1. That forces within the cell can be followed through laws of nature, as grouped here:  THAT AMPLIFICATION, PROLIFERATION AND DIFFERENTIATION ARE GOVERNED BY SETS OF GENES AND HAVE VARIOUS LEVELS OF EXPRESSION.
2. That treatment strategies can be made following different steps in pathways
3. That Death traps are located at the membrane, cytoplasm, mitochondria and Nucleus
4. That downstream targets inhibition can overcome resistance to earlier target inhibition
5. That Inactivation and down-regulation of gene expression appears to be more important in Oncogenesis
6. That most of the time MAPK amplification results from the down regulation of PI3K/PTEN
7. That MTOR inhibition is deeper than EGFR/VEGF and PI3k inhibition
8. That VELCADE or antiproteasome will disturb all the pathways of which products need Ubiquitination for degradation
9. That Velcade may worsen VHL depedent syndromes
10. Then, even deeper, that MTOR, are Histone de-acyl- transferases

BUT WHAT WE HAVE NOT TALKED ABOUT ENOUGH IS THE POSSIBILITY OF CURE HIDDEN EVEN DEEPER IN THE DIFFERENTIATION.: HERE ARE HIDDEN THE SO- CALLED "PATHWAYS OF SECONDARY METABOLISM"  AND SURPRISE SURPRISE THAT THE ROLE OF ANTIBIOTICS RE-EMERGES!
HERE, WE LOOK FOR DIMBOA PATHWAYS AND DNA REPLICATION
ASSOCIATION WITH STRESS (FOS, C-JUN)
ASSOCIATION WITH P450
ASSOCIATION WITH UDPG GLUCOSYL TRANSFERASES AND SOME DIOXYGENASE

WE NEED TO EXPLORE ANTIBIOTICS COMING FROM FUNGI.

LET ME COME TO THE CHASE OF BX1, BX2, AS THEY ARE TIED TO U11, U12, AND CHROMOSOME 4.  THIS IS THE NEW BATTLEGROUND!

RESEARCHERS, PLEASE GO BACK TO WORK!

Attended Mark G Kris lecture on Lung Cancer  (KRIS IS FROM MSKCC)

Now genetic sequencing is important

Prescribe the following

1)  EGFR-------------ERLOTINIB, GEFITINIB
2)  ALK-----------------CRIZOTINIB
3) HER-2--------------HERCEPTIN, LAPATINIB
4) BRAF -------------------VEMURAFENIB
5) ROS-1-----------------CRIZOTINIB  (AGAIN)
6) RET--------------------------VANDETANIB  (CABOZANTINIB)
7)MET------------------------CRIZOTINIB (AGAIN)

NICE THE PRESCRIPTION SPELLING OUT ONLY THE GENE SEQUENCING, AND LET YOUR PHARMACIST DO THE REST.
QUESTION: COULD THESE DRIVER GENE ABNORMALITIES BE THE SAME IN TRIPLE NEGATIVE BREAST CANCER?

We believe in the cure for Cancer:

People talk about a cure and skeptics balk!
But the cure is possible and actually exists already in every survivor who had a remote history of cancer.
Remember this, a cancer cell is full of messages encrypted in chemical messages when to grow, when to start aging and when to die.  Yes cancer cells have an internal message when to start apoptosis (self destruction).
It means you could tell it to start apoptosis and kill itself.  Our challenge is to know how to speak to a cell.
Research are starting to learn that language in what is now known as Target Therapy.  Cancer treatment is now becoming a Piano tune.  if you hit the right keys in a song and the cancer cell get it, it will find its way to self destruction.  We are at the early stage of this music, still learning it.  Hitting this key here and seeing what happens.  We are finding out that even tough cancers such as Melanoma, if you hit the BRAF key, things start happening.  In some lung cancers, if you hit the EGFR key, you start getting somewhere.  It is just a matter of time before we start asking to a cell, now time for an increase in BAX or Caspases, and self destruct.  The cell has some redundancy and networking to complicate the road to self destruction, but we still believe that with the right tune, cancer cells will dance to self destruction, and yes cure is within our reach!