Adverse event: Diarrhea - General Guidelines by Pfizer

Adverse event

Description

General guidelines

Diarrhea

Diarrhea is an abnormal increase in stool liquidity

and frequency (4 to 6 stools or more per day

over baseline) with or without nocturnal bowel

movements and/or moderate abdominal

cramping. Diarrhea is a common side effect of

many cancer regimens. It can cause depletion of

fluids and electrolytes, malnutrition, dehydration,

and hospitalization and therefore can interfere

with cancer treatment, causing dosing delays or

reductions.

1

Patient education strategies

•

Emphasize the importance of maximizing oral

hydration strategies to avoid dehydration and

electrolyte imbalances

2

•

Educate patients about the likelihood that diarrhea

will develop

3-5

Management tips for patients

•

Diarrhea may be managed through diet as well

as pharmacologic treatment when necessary,

based on the clinical judgment of the treating

healthcare provider (HCP).

1,3,4

The first step in

treatment is dietary management

3,5,6

:

–

Yogurt containing probiotics

–

Soluble fiber

–

Small but frequent meals

–

Fluids, such as water, diluted cranberry juice,

broth, decaffeinated tea or coffee

•

Over-the-counter and Rx agents may also be

used, according to labeling

1,3,4

Hypertension

Hypertension is the term used to describe high blood

pressure (BP). In general, hypertension is repeated

BP elevation exceeding 140 mm Hg systolic blood

pressure (SBP) and 90 mm Hg diastolic blood

pressure (DBP).

7

Hypertension is a commonly

reported AE in cancer patients receiving antivascular

endothelial growth factor (VEGF) drugs.

8

Patient education strategies

•

Take antihypertensive medications as prescribed

4

•

Recognize signs of potentially dangerous

high BP (eg, severe headache, shortness of

breath, nosebleeds)

9

•

Follow healthy lifestyle choices: regular exercise,

weight control, moderate alcohol consumption,

sodium restriction

4

Ovarian Cancer

*Researchers who conducted the study who conducted the use of Selumetinib in low grade serous Ovarian cancer were still puzzled because its activity did not follow presence of KRAS or BRAF. They have been wondering if it used another pathway.  But remember MEK is the revolving door to de-differentiation and to the reversal of mesengialization and as such increase tor susceptibility not only to chemotherapy drugs, but also to the secondary angiogenic potentiation of MEK.  That is, with anti-MEK, there is a down regulation of MAPK (as suggested) and therefore  the C-JUN and TGF and cyclins, but also down regulation of the VEGF!

They say " Our results suggest that selumetinib is an active agent, but not necessarily because of BRAF or KRAS mutational activation per se,” the authors concluded.

In an interview, Gershenson said that one reason for the lack of correlation could be biomarker instability. Among the 52 patients, specimens were available for only 40, mutational analysis was done in 34, and in 28 of those the tissue was from the primary therapy and not from the recurrent tumor. “The question arises, are these biomarkers stable over time or do they change, so that what you find in the primary tumor may not be what you find in the recurrent tumor,” he said."   They suggesting here that the lack of correlation could be due to a changing nature of Biomarker.  But the existence of other factors and pathways could not be be excluded!

Gene-Expression Profiling May Help Select Best Drugs for Pancreatic Cancer

Caroline Helwick 

---------------------------------------------------------------------------------------------------

In this study patient with pancreatic cancer had reportedly circulating cell and their genes could predict response to therapy but unfortunately they did not spell out which genes were reviewed.  We will investigate further this article...

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!

MYRISTOYLATION, A TRUE COMMITMENT AT THE CELLULAR MEMBRANE!

Proliferation, growth and spread of cancers is mainly driven by phenomena occurring at the membrane. A Molecular structure called SRC or sarc (for sarcoma) is anchored there,  and Myristoylation is the process that keep it there.  SARC or SRC
Wikipedia suggests:

Src (gene)

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V-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian)
PDB rendering based on 1a07.
Available structures PDB Ortholog search: PDBe, RCSB [show]List of PDB id codes
Identifiers
Symbols	SRC; ASV; SRC1; c-SRC; p60-Src
External IDs	OMIM: 190090 MGI: 98397 HomoloGene: 21120 ChEMBL: 267 GeneCards: SRC Gene
EC number	2.7.10.2
[show]Gene Ontology
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	6714	20779
Ensembl	ENSG00000197122	ENSMUSG00000027646
UniProt	P12931	P05480
RefSeq (mRNA)	NM_005417.3	NM_001025395.2
RefSeq (protein)	NP_005408.1	NP_001020566.1
Location (UCSC)	Chr 20: 35.97 – 36.03 Mb	Chr 2: 157.42 – 157.47 Mb
PubMed search	[1]	[2

Proto-oncogene tyrosine-protein kinase Src is an enzyme that in humans is encoded by the SRC gene.^[1]
Src (pronounced "sarc" as it is short for sarcoma) is a proto-oncogene encoding a tyrosine kinase originally discovered by J. Michael Bishop and Harold E. Varmus, for which they were awarded the 1989 Nobel Prize in Physiology or Medicine.^[2] It belongs to a family of non-receptor tyrosine kinases called Src family kinases. The discovery of Src family proteins has been instrumental to the modern understanding of cancer as a disease where normally healthy cellular signalling has gone awry.
This gene is similar to the v-src gene of Rous sarcoma virus. This proto-oncogene may play a role in the regulation of embryonic development and cell growth. The protein encoded by this gene is a tyrosine-protein kinase whose activity can be inhibited by phosphorylation by c-SRC kinase. Mutations in this gene could be involved in the malignant progression of colon cancer. Two transcript variants encoding the same protein have been found for this gene.<sup>[3]
==============================================================
In fact, SRC gene is at the center of Metastatic process through interaction with cell adhesion molecules, growth factors and many signal transduction pathways:

Wikipedia:</sup>
Interactions
Src (gene) has been shown to interact with

• AR,^[19][20][21]
• ARNT,^[22]
• AHR,^[22]
• ADRBK1,^[23]
• ADRB3,^[24]
• BCAR1,^{[25][26][27][28][29][30]}
• CD44,^[31]
• DAB2,^[32]
• DDEF1,^[33]
• DAG1,^[34]
• EPHB2,^[35][36]
• EGFR,^[37][38][39]
• EPS8,^[40]
• ESR1,^{[19][41][42][43]}
• ESR2,^[19][43]
• GNB2L1,^[44]
• GRB2,^[23][45]
• GRIN2A,^[46][47]
• HNF1A,^[48]
• KHDRBS1,^{[49][50][51][52][53]}
• MT-ND2,^[54]
• MUC1,^[55][56]
• NCOA6,^{[57][58][59][60]}
• PDE6G,^[23]
• PLD2,^[61]
• PRKCZ,^[62]
• PTK2,^{[26][30][63][64][65][66]}
• PTK2B,^[38][67][68]
• RAF1,^[69]
• RASA1,^[70][71]
• RARA,^[42][72]
• RICS,^[73]
• SRF,^[74]
• SHB,^[75]
• STAT1,^[37][76]
• STAT3,^[77] and
• WAS.^[78][79]

Overview of signal transduction pathways involved in apoptosis.

See also

• C-src tyrosine kinase
• Dasatinib
• SU6656
• PP2 (kinase inhibitor)

Genatlas:

• c-SRC is non receptor tyrosine kinase, direct effector of G proteins
• c-SRC plays a role in the regulation of embryonic development and cell growth
• c-SRC has an appreciable role in the organization of the Golgi apparatus, which may be linked to its involvement in protein transport from the Golgi apparatus to the endoplasmic reticulum
• c-SRC has an appreciable role in the organization of the Golgi apparatus, which may be linked to its involvement in protein transport from the Golgi apparatus to the endoplasmic reticulum
• monopalmitoylated SFK required for VEGF mitogenic signaling with SRC and FYN, but maintaining distinct properties in the regulation of VEGF-mediated endothelial cell events (Pubmed 16400523)
• c-SRC regulates Golgi structure and KDELR1-dependent retrograde transport to the endoplasmic reticulum
• c-SRC has a key role in the maintenance of epithelial integrity (Pubmed 18305002)
• c-SRC is crucially involved in the ghrelin-mediated Akt activation (Pubmed 19262695)
• non palmitoylated SFK (Src-family tyrosine kinase), rapidly exchanged between the plasma membrane and late endosomes/lysosomes (suggest that SFK trafficking is specified by the palmitoylation state in the SH4 domain) (Pubmed 19258394)
• major kinase implicated in PTK2 phosphorylation, and is directly translocated from focal adhesions to membrane ruffles, thereby promoting formation of new adhesion complexes (Pubmed 19066724)
• interacting with PDLIM4 and PTPN13 (PDLIM4 suppresses SRC activation through interacting with SRC and PTPN13, allowing PTPN13-dependent dephosphorylation of SRC at the activation loop) (Pubmed 19307596)
• c-SRC inhibits SGK1-mediated phosphorylation hereby restoring the WNK4-mediated inhibition of ROMK channels thus suppressing K secretion) (Pubmed 19706464)
• c-SRC binds DVL2, a key phosphoprotein in Wnt signaling, at two positions: an SH3-binding domain and a C-terminal domain (Pubmed 19920076)
• ----------------------------------------------------------------------------------------------
•  
• THIS  SRC IS PIVOTAL AND CENTER TO ALL ACTIVITY INVOLVING THE SPREAD AND MAINTENANCE OF CANCER.  IT IS SOMEWHAT CELL AND SPECIES SPECIFIC.
• WE PURPOSELY LEFT THE DASATINIB REFERENCE  HERE TO INDICATE THAT SCIENTIST ARE TRYING TO TARGET THIS CROSS ROAD MOLECULAR STRUCTURE.
• IT'S ACTIVITY AT THE MET PROTEIN INSURE CANCER GROWTH AND VASCULARIZATION THROUGH MET EFFECT ON ANGIOGENESIS.
• REMEMBER MET DISTURBANCES ARE PROMINENT  IN PAPILLARY RENAL CELL CANCER.

MYRISTOYLATON, IMPORTANT IN THE ANCHORING OF SRC AT THE MEMBRANE IS AN IRREVERSIBLE EVENT, FRANKLY COMMIT THE PROCESS FORWARD AND MAY COMMIT THE PROCESS TO A CYTOSOLIC PHENOMENA SINCE IT SEEMS TO PRECLUDE MYRISTOYLATED MOLECULES TO HAVE AN EFFECT ON NUCLEAR PROCESSES.

MET ACTIVITY INDUCED BY SRC ACTIVATION BY PHOSPHORYLATION SEEMS TO BE DETERMINED BY THE TYPE OF GROWTH FACTOR INDUCED.  THROUGH HGFR, IT LEADS TO EMBRYONIC DEVELOPMENT IN THE EARLY CELL,  AND TO WOUND HEALING IN RELEVANT TISSUE (SKIN), AND THROUGH HGF, IT LEADS TO MESENCHYMAL DIFFERENTIATION.

THROUGH MET, SRC LEADS TO RAS, PI3K/MAP K AND STAT EFFECTS 

PHENOMENA AT THE MEMBRANE, A TRUE HISTORY, STILL UNFOLDING.

PLEASE ALSO NOTE CONFORMATION RAPPROCHEMENT BETWEEN SRC AND THE C-ABL WHERE IMITIMAB /GLEEVEC ACTS!  SRC, CENTER OF METASTASIS, IS AN INTRODUCTION TO OUR FUTURE DISCUSSIONS.