FROM C-AMP, as an Immune modulator, TO COMPLEX LYMPHOPROLIFERATIVE DISORDERS

It is well known that cyclins which include the TNF alpha will only have a full effect on inflammatory processes after depletion of c-AMP.  That is for the inflammatory process to reach full effect activations of FRA-1( FosB) and C-Fos that need to occur. The mere stimulation of c-JUN which results from stress at the Receptor is also accompanied by CRE (CRE-tkCAT) increase (through the CRE-binding proteins) which, in a feedback process activates c-AMP to dampen the c-JUN stimulation.  The amount of activity at c-AMP is therefore a clear modulator of  inflammatory processes!
Anti -COX2 which decreases transcription of related genes, will in fact stimulate the C-JUN.
It is important to stress that as c-JUN, JUNB and subsequently c-Fos increase in number, the AP-1 complex is more formed and activated:

"The activator protein 1 (AP-1) is a transcription factor which is a heterodimeric protein composed of proteins belonging to the c-Fos, c-Jun, ATF and JDP families. It regulates gene expression in response to a variety of stimuli, including cytokines, growth factors, stress, and bacterial and viral infections.^[1] AP-1 in turn controls a number of cellular processes including differentiation, proliferation, and apoptosis.^[2]
AP-1 upregulates transcription of genes containing the TPA DNA response element (TRE; 5'-TGAG/CTCA-3').^[1] AP-1 binds to this DNA sequence via a basic amino acid region, while the dimeric structure is formed by a leucine zipper.^[3]　" wikipedia. CBPA, overexpressed in some leukemas, is a leucine Zipper!

In the JDP families is located JDP2, an inhibitor of AP-1.
Interaction of AP-1 through its ATF component will lead to activation of EP300, a gene we talked about, and which leads to cellular differentiation by its contact with the NOTCH, MAML1 and the Merlin, Again here the EP300 binds to the CREB to activate c-AMP, the immune modulator discussed.

"This gene encodes the adenovirus E1A-associated cellular p300 transcriptional co-activator protein.
The protein functions as histone acetyltransferase ^[4] that regulates transcription via chromatin remodeling, and is important in the processes of cell proliferation and differentiation. It mediates cAMP-gene regulation by binding specifically to phosphorylated CREB protein.
This gene has also been identified as a co-activator of HIF1A (hypoxia-inducible factor 1 alpha), and, thus, plays a role in the stimulation of hypoxia-induced genes such as VEGF.<sup>[5] wikipedia



Other virus affect JDP2, Cyclin D, and the Pim</sup>


"E1A binding protein p300 also known as EP300 or p300 is a protein that, in humans, is encoded by the EP300 gene.^[1] This protein regulates the activity of many genes in tissues throughout the body. It plays an essential role in regulating cell growth and division, prompting cells to mature and assume specialized functions (differentiate), and preventing the growth of cancerous tumors. The p300 protein appears to be critical for normal development before and after birth.
The p300 protein carries out its function by activating transcription. To be specific, p300 connects transcription factors, which are proteins that start the transcription process, with the complex of proteins that carry out transcription in the cell's nucleus. On the basis of this function, p300 is called a transcriptional coactivator. The p300 interaction with transcription factors is managed by one or more of p300 domains: the nuclear receptor interaction domain (RID), the CREB and MYB interaction domain (KIX), the cysteine/histidine regions (TAZ1/CH1 and TAZ2/CH3) and the interferon response binding domain (IBiD). The last four domains, KIX, TAZ1, TAZ2 and IBiD of p300, each bind tightly to a sequence spanning both transactivation domains 9aaTADs of transcription factor p53.^[2][3]
The EP300 gene is located on the long (q) arm of the human chromosome 22 at position 13.2.
EP300 is closely related to another gene, CREB binding protein, which is found on human chromosome 16." (wikipedia)

Please note the MYB involvement:
-as it will play a role in hair discoloration,
-is downstream from the PDGF and plays a role in giving longevity to Notch dependent processes
-regulated through the miR155 in CLL
-involve Flavonoids
-involve the Avian Myeloblastosis Virus.

Note also IBiD as it modulates response to Interferon!
Please refuse to see (and I see you resisting) that P53 is engaged by this!
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THIS IS HOW THE CELL GOES FROM A SIMPLE C-AMP TO COMPLEX ACTS OF SURVIVAL VERY RAPIDLY!

ADVANCES IN METASTATIC RENAL CANCER

*IL-2  (High dose) Response rate < 10% but with rare cures
* Medication approved
1. Sunitinib which was compred to Interferon to win approval
2. Avastin in combination to Interferon (not alone) was compared to interferon alone to win approval
3.Pazopanib was compared to placebo to win approval
4.Temsirolimus was compared to Interferon to win approval.
someone thought combining Interferon and Tensirolimus will give a higher response rate, well it did not.  But this bring back the notion that until the MTOR is really amplified, rushing into its inhibition may not bring result.  So timing suggested after failure of VEGF is critical.

5. Pazopanib was compared to Sunitinib, non inferiority proven although Pazopanib had PFS of 8.4 against a 9.5 months accomplished Sutent.  The statical referee came in not statistical difference depite the hair color change of Pazopanib recipient! The hematologic toxicitywere worse with Sutent!

6.New kids on the block (Tivozanib and anti-PD1)
-Tivozanib was compared to Nexavar and came up on top in terms of PFS.  OS not measure because of cross-over

ONE HAS VENTURED TO SUGGEST THAT
START WITH SUTENT
THAN AFINITOR
FOLLOWED BY AXITINIB
THAN ANTI-PD1
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BUT REMEMBER THAT HISTOLOGY MAY FORCE YOU TO SKIP SUNITINIB
AND INTERFERON-BEVACIZUMAB ARE ALSO SOLID OPTIONS, AND SO REMAINS HIGH DOSE IL-2.

7-AXITINIB (AN ANTI-VEGF(s) ) WAS ALSO MATCHED WITH SORAFENIB IN THE HUTSON ET AL STUDY.AND CAME UP ON TOP FOR PFS.  HOWEVER THE OBSERVERS ARE SAYING THAT IN THE LATEST PHASE III STUDY AXITINIB,ALTHOUGH ACTIVE, DID NOT MEET ITS PRIMARY END POINT.

8.EVEROLIMUS AGAINST PLACEBO WON BIG PFS, BUT NO OS!?

NOMENCLATURE OF GENES TO LOOK FOR IN TRIPLE NEGATIVE BREAST CANCER

One may try to determine whether a breast cancer has bad prognosis in order to determine whether chemotherapy should be given (MammaPrint, Oncotypr DX), but more importantly, I believe, is to focus on genes of good prognosis which include driver genes against which we dispose of an answer in our Arsenal.
Currently we dispose of
1. Chemotherapy that attacks DNA and Microfilament/Microtubules,  (first and second law of nature)
2. Immune Modulators such as Interferon
3. Antibody to Membrane Receptor (EGFR/VEGF) Avastin
4.  Inhibitor to T-cell driven immunity (CTLA4)
5.  Inhibitors to sub-membrane or first line driver Mutations KRAS, HRAS, or the RAS family
6.  Inhibitors to 2nd line driver Mutations (anti MEK)
7. Inhibitor to Tertiary line driver Mutations and Mitochondrial level inhibition (MTOR, Metformin)
8. Anti-proteasome or inhibitor to cellular protein degradation (Velcade)
9. Inhibitors at Nuclear lever Include Histone Deacethylator and Acyl transferase inhibitor, check point controller inhibitors,  anti-Centrosome metabolism and inhibitors of various promoters and transcription factors.

Other opportunities not included in this classification go to specific genes of proliferation, Amplification, differentiation and metastasis that have been brought forth as indicator of either response to chemotherapy or simply as "Good prognosis" genes.  These will include the BRCA since a response to PARP inhibitors and Cisplatin based combinations should be anticipated.

Multikinase inhibitors such as Dasatinib (SRC+ BCR/ABL but also STAT5) and Arsenic Trioxide should be included   
LBK1: could predict early disease (inhibitor controlling initiation of metastasis)
DDR2: could predict anti MEK sensitivity
MEKK-1 sensitivity to Cisplatin
TFF1-could predict sensitivity to estrogen despite negative Estrogen
DYRK2, favorable in lung cancer
 
c-JUN amplification and over expression of 8q23-24 could predict  response to interferon/Interleukin
EGFR, VEGF, ALK,  and other Driver Mutations would match those discussed By DR Kris in lung cancer.

(to be continued!)