The MDM2 amplification/Mutation was the highest finding and remain persistently present through the various stages of lung cancers making it the strongest predictor of the tested genes. We are now conducting studies to see its presence in nearby tissues or normal tissues of same patients in order to see if there is a baseline MDM2 amplification to be compared to levels of MDM2 in diseased tissues. I should also stress that among the tested tissues, some were from treated patients. Even treatment did not affect Much the MDM2 mutation/amplification expression. A follow-up study may indicate if this affect long term recurrence.
In the ERA of testing post adjuvant therapy, corollary question will be whether a treatment that affect the MDM2 should be included to improve the cure or whether fixing the MDM2 would be crucial in achieving cure or prolonging progression free survival. Could some of patients who achieve a cure, still display an MDM2 Mutation? what is the outcome and response rate on cancers with NO MDM-2 mutation. To what therapy they respond to....and therefore what therapy should be included in MDM-2 positive patients. Is there a P53 Mutation, These are relevent questions in this era of target therapy!
and when you think LIKE WIKIPEDIA
" Mdm2 achieves this repression by binding to and blocking the N-terminal
trans-activation domain of p53. Mdm2 is a p53 responsive gene—that is,
its transcription can be activated by p53. Thus when p53 is stabilized,
the transcription of Mdm2 is also induced, resulting in higher Mdm2
protein levels." Mdm2 is capable of auto-polyubiquitination, and in complex with p300, a cooperating E3 ubiquitin ligase,
is capable of polyubiquitinating p53. In this manner, Mdm2 and p53 are
the members of a negative feedback control loop that keeps the level of
p53 low in the absence of p53-stabilizing signals. This loop can be
interfered with by kinases and genes like p14arf when p53 activation signals, including DNA damage, are high."
IS THE MDM-2 A TRUE DRIVER MUTATION WHEN IT IS PRESENT GIVEN THE POSSIBILITY OF AUTO-UBUQUITINATION
WE THANK MDHONORS FOR THEIR SUPPORT!
Friday, February 28, 2014
Work still to be done in survivors
One of the aspect of cancer treatment that remains to be clearly categorized in most cancers including our focus:Breast cancers, is how to best monitor survivors and separate them early in high risk for recurrence versus those who should expect longer remission. So far we have concentrated purposely on monitoring recurrence by Xrays or checking bio-markers in the blood. But genetic work could also help predict recurrence and may be suggest target therapy to be envisioned early. ie OLOPADE et al: "A new model of ovarian cancer tumor progression implicates aberrant
FANCF promoter methylation that is associated with gene silencing and
disruption of the Fanconi-anemia-BRCA pathway. Disruption of the pathway
occurs de novo in ovarian cancers and may contribute to selective
sensitivity to platinum salts." (BRING BACK TO YOUR INTELLIGENCE THAT MANY DRUGS WORKS THROUGH EPIGENETIC EFFECTS AND NOT DNA CROSS-LINKING)
Although the disease can recur locally by increase of the original tumor size, most of the time the disease return in a metastatic fashion. And when this occurs, there are many implications to be drawn.
Neoplastic transformation assumes acquisition of new functions to the cell. One of the critical function is ability to metastasize, acquisition of MET1 amplification, activity at the Rho gene/RHOA/ROCK but also activity at Vimentin are important processes the cell has to go through to acquire these new functions. These are just some of the aspects.....
===============================================
Detection of cancer recurrence is as complex as the nature of the Neoplastic process itself!
1. There are activity at promoter genes, most of there activity are silencing of certain promoter genes through methylation. see implications of Methylation of such gene as TGF Beta, SMAD4 and even FBXO32, Cyclin D, 14.3.3. etc (Aberrant Methylation)
2. Suppression of E-Cadherin which for some poise the cell for Migration. If this occur through MSK1, it may also impact p38MAPK and restart tumor induced by the MAPK pathway amplification, and inducing VEGF induced migration of cells. This phenomena could be worse in these disease when Anti-VEGF is not usually used (since we use Anti-VEGF only in certain diseases--if we continue to use clinical trial as our basis foe adoption of a treatment)
3.Coming back to methylation, it has been stricking that certain genes are not remarkably expressed in certain cancer cells. ie. "
"DAB2 mRNA is expressed in normal ovarian epithelial cells but is down-regulated or absent from ovarian carcinoma cell lines."wikipedia This seems to involve somehow the SMAD
do remember "DAB2 has been shown to interact with C-src tyrosine kinase,[4] Cdk1,[5] Src,[4] LRP2,[6] DVL3,[7] PIN1,[5] MYO6,[8][9] DVL2,[7] DAB2IP,[10] Mothers against decapentaplegic homolog 3[11] and Mothers against decapentaplegic homolog 2.[11]" wikipedia
note many things please
attachment opportunity offered by C-Src
involvement of Cdk1 affecting cell proliferation and of course SMAD.... Terget therapy in mind!
ALSO
4. FOR RECURRENT DISEASE, PERSISTENCE OF CERTAIN INDUCERS (G-PROTEINS) PROPPING PUSH TO REESTABLISH A TUMOR PROCESS, OR LACK OF CERTAIN INHIBITORS TO GERB2 INVOLVEMENT SUCH AS SPRY-2. (MARKING AMPLIFICATION OF GERB2 IN SURVIVOR MONITORING!)
WILSON ET AL "HER-2 overexpression in the context of the mesenchymal MDA-MB-231 breast cell line potentiated the TGF-beta induced pro-invasive and pro-metastatic gene signature." MARKING THE IMPORTANCE OF TGF IN HER-2 POSITIVE CANCERS!
5.In BRCA-1 pt
we have already stress the importance of following PTPN2 as it impacts TGF, Paxillin, and mainly SHC1, the regulator of Apoptosis!
6. And if you are following Vimentin, weel check the AXL, decrease of RAB25, and the Integrin Beta subunit, these to gauge Epithelia-mesothelial transformation, an important step to acquisition of metastatic potential
well I stop here, survivors are deemed expensive because of this complexity and gene monitoring, weel we are not up to it yet, we chose head in the sand...And I am not talking yet about persistant of viral compounds that may also be important in metastatic potential in survivors. What we need is a better organization of pouring info coming to us ...."sparsely-disconnected" .
Although the disease can recur locally by increase of the original tumor size, most of the time the disease return in a metastatic fashion. And when this occurs, there are many implications to be drawn.
Neoplastic transformation assumes acquisition of new functions to the cell. One of the critical function is ability to metastasize, acquisition of MET1 amplification, activity at the Rho gene/RHOA/ROCK but also activity at Vimentin are important processes the cell has to go through to acquire these new functions. These are just some of the aspects.....
===============================================
Detection of cancer recurrence is as complex as the nature of the Neoplastic process itself!
1. There are activity at promoter genes, most of there activity are silencing of certain promoter genes through methylation. see implications of Methylation of such gene as TGF Beta, SMAD4 and even FBXO32, Cyclin D, 14.3.3. etc (Aberrant Methylation)
2. Suppression of E-Cadherin which for some poise the cell for Migration. If this occur through MSK1, it may also impact p38MAPK and restart tumor induced by the MAPK pathway amplification, and inducing VEGF induced migration of cells. This phenomena could be worse in these disease when Anti-VEGF is not usually used (since we use Anti-VEGF only in certain diseases--if we continue to use clinical trial as our basis foe adoption of a treatment)
3.Coming back to methylation, it has been stricking that certain genes are not remarkably expressed in certain cancer cells. ie. "
"DAB2 mRNA is expressed in normal ovarian epithelial cells but is down-regulated or absent from ovarian carcinoma cell lines."wikipedia This seems to involve somehow the SMAD
do remember "DAB2 has been shown to interact with C-src tyrosine kinase,[4] Cdk1,[5] Src,[4] LRP2,[6] DVL3,[7] PIN1,[5] MYO6,[8][9] DVL2,[7] DAB2IP,[10] Mothers against decapentaplegic homolog 3[11] and Mothers against decapentaplegic homolog 2.[11]" wikipedia
note many things please
attachment opportunity offered by C-Src
involvement of Cdk1 affecting cell proliferation and of course SMAD.... Terget therapy in mind!
ALSO
Decreased expression of 14-3-3 sigma is associated with advanced disease in human epithelial ovarian cancer: its correlation with aberrant DNA methylation.
Akahira J1, Sugihashi Y (READ THE ARTICLE)4. FOR RECURRENT DISEASE, PERSISTENCE OF CERTAIN INDUCERS (G-PROTEINS) PROPPING PUSH TO REESTABLISH A TUMOR PROCESS, OR LACK OF CERTAIN INHIBITORS TO GERB2 INVOLVEMENT SUCH AS SPRY-2. (MARKING AMPLIFICATION OF GERB2 IN SURVIVOR MONITORING!)
WILSON ET AL "HER-2 overexpression in the context of the mesenchymal MDA-MB-231 breast cell line potentiated the TGF-beta induced pro-invasive and pro-metastatic gene signature." MARKING THE IMPORTANCE OF TGF IN HER-2 POSITIVE CANCERS!
5.In BRCA-1 pt
we have already stress the importance of following PTPN2 as it impacts TGF, Paxillin, and mainly SHC1, the regulator of Apoptosis!
6. And if you are following Vimentin, weel check the AXL, decrease of RAB25, and the Integrin Beta subunit, these to gauge Epithelia-mesothelial transformation, an important step to acquisition of metastatic potential
well I stop here, survivors are deemed expensive because of this complexity and gene monitoring, weel we are not up to it yet, we chose head in the sand...And I am not talking yet about persistant of viral compounds that may also be important in metastatic potential in survivors. What we need is a better organization of pouring info coming to us ...."sparsely-disconnected" .
Wednesday, February 26, 2014
AND IT KEEPS HAPPENING FOR THE" WONDER" DRUG
FROM MEDSCAPE:
"The FDA has given accelerated approval to ibrutinib (Imbruvica) for treating CLL in patients who have undergone at least 1 previous therapy. Approval was granted based on the findings of a clinical study of 48 previously treated patients who were diagnosed with CLL, on average, 6.7 years before the study. The patients had an overall response rate of nearly 58%, with a duration of response from 5.6 to 24.2 months. The most common adverse effects observed in the study included thrombocytopenia, diarrhea, bruising, neutropenia, anemia, and upper respiratory tract infection. Ibrutinib was also approved for treating mantle cell lymphoma in 2013."
================================THIS DRUG IS JUST WONDERFUL, ATTESTING TO THE STRENGTH AND IMPORTANCE OF THIS RECEPTOR IN LYMPHOCYTE RELATED PROLIFERATIONS.....=================
"The FDA has given accelerated approval to ibrutinib (Imbruvica) for treating CLL in patients who have undergone at least 1 previous therapy. Approval was granted based on the findings of a clinical study of 48 previously treated patients who were diagnosed with CLL, on average, 6.7 years before the study. The patients had an overall response rate of nearly 58%, with a duration of response from 5.6 to 24.2 months. The most common adverse effects observed in the study included thrombocytopenia, diarrhea, bruising, neutropenia, anemia, and upper respiratory tract infection. Ibrutinib was also approved for treating mantle cell lymphoma in 2013."
================================THIS DRUG IS JUST WONDERFUL, ATTESTING TO THE STRENGTH AND IMPORTANCE OF THIS RECEPTOR IN LYMPHOCYTE RELATED PROLIFERATIONS.....=================
CAN YOU PLEASE GET ME TO MELBOURNE, SCIENCE WILL ACTUALLY OCCUR THERE!
"The
2014 meeting of the International Cytokine and Interferon Society is to
be held in Melbourne, Australia, during October 26-29, at the
state-of-the-art Melbourne Convention Centre. The meeting will provide
an outstanding forum for basic science and clinical researchers to
present their latest data and exchange ideas relating to the broad role
of cytokines and interferons in human disease, and applications to
therapies." FROM THEIR SITE!
DO YOU WANT ME TO REPORT TO YOU OR WHAT!?
CYTOKINE IS THE ANSWER, FROM TRAUMATIC BRAIN INJURY TO DIABETES
BUT YOU STILL NEED THE CRBCM ANGLE !? HOW CAN WE GET THERE?...CALL 915-307-3354 IF YOU COME UP WITH SOMETHING!
DO YOU WANT ME TO REPORT TO YOU OR WHAT!?
CYTOKINE IS THE ANSWER, FROM TRAUMATIC BRAIN INJURY TO DIABETES
BUT YOU STILL NEED THE CRBCM ANGLE !? HOW CAN WE GET THERE?...CALL 915-307-3354 IF YOU COME UP WITH SOMETHING!
INSTEAD OF TORTURING PATIENT WITH NODE DISSECTION, HOW ABOUT SIMPLY TESTING FOR VGEF-D
IN BREAST CANCER, AND MELANOMA
OBTAINING SENTINEL NODE HAS BECOME A PREOCUPATION
UNLESS WE REALLY NEED TO (SUCH AS CHECKING FOR MORE ABNORMAL GENE) can we just check VGEF D.
(rattling the cage at CRBCM)
can't make up this stuff:
"
Tumor metastasis to lymph nodes:
Lymph node metastasis is very often associated with several types of human malignancies. Cancer cells’ journey to lymph node takes place largely through lymphatic tunnel located in and around of primary tumor. VEGF-D’s interactions with VEGFR-3 predominantly expressed in lymphatic vessels plays a key role in restructuring lymphatic channel and, hence, able to alter its functions related to fluid and cell transport along the conduits. VEGF-D has been established to be over-expressed in both tumor tissues and patients’ serum samples in several types of human cancer. In addition, VEGF-D expression has been implicated with increased incidence of regional lymph node metastasis. In experimental mice study, genetically modified tumor cell that was forced to produce VEGF-D protein have been established to boost up regional lymph nodes metastases.[2]" wikipedia
and instead of the c-FOS, dose the FIGF,
INSTED OF .....DON'T LET ME STARTED NOW, GO WITH WHAT YOU KNOW!
OBTAINING SENTINEL NODE HAS BECOME A PREOCUPATION
UNLESS WE REALLY NEED TO (SUCH AS CHECKING FOR MORE ABNORMAL GENE) can we just check VGEF D.
(rattling the cage at CRBCM)
can't make up this stuff:
"
Tumor metastasis to lymph nodes:
Lymph node metastasis is very often associated with several types of human malignancies. Cancer cells’ journey to lymph node takes place largely through lymphatic tunnel located in and around of primary tumor. VEGF-D’s interactions with VEGFR-3 predominantly expressed in lymphatic vessels plays a key role in restructuring lymphatic channel and, hence, able to alter its functions related to fluid and cell transport along the conduits. VEGF-D has been established to be over-expressed in both tumor tissues and patients’ serum samples in several types of human cancer. In addition, VEGF-D expression has been implicated with increased incidence of regional lymph node metastasis. In experimental mice study, genetically modified tumor cell that was forced to produce VEGF-D protein have been established to boost up regional lymph nodes metastases.[2]" wikipedia
and instead of the c-FOS, dose the FIGF,
INSTED OF .....DON'T LET ME STARTED NOW, GO WITH WHAT YOU KNOW!
CSK random phosphorylation/related clinical questions
FYN
LCK
LYN
YES-1
HCK
Src
FRG
BLK
FRK
1.ATRA combined to Geevec as a way to break gleevec resistance?
2.disease with PDGF with STATs amplification could benefit from Gleevec if inhibition of Src is promoted
3.Could ATRA or the Piperazines (Gleevec) disrupt enough deployment of signal pathways to slow down a Cytokine storm (and TBI).
4.Could dampening of CRKL be used as a marker in CML
5.can ADAMs 17 be a biomarker of CML response or Myeloma response
6"PDGFR-beta is a key marker of hepatic stellate cell activation in the process of fibrogenesis."wikipedia
level of PDGFR in hepatoma?or Glioblastoma/ Nexavar activity linked to effect on PDGFR?
JUST WATCH OUT WITH THESE Random PHOSPHORYLATION, IT IS HOW CASEIN INDUCES TRIPLE NEGATIVE
BREAST CANCERS.
JUST REMEMBER Src INFLUENCES PDGF INDUCED PHOSPHORYLATION OF STATs.
LCK
LYN
YES-1
HCK
Src
FRG
BLK
FRK
1.ATRA combined to Geevec as a way to break gleevec resistance?
2.disease with PDGF with STATs amplification could benefit from Gleevec if inhibition of Src is promoted
3.Could ATRA or the Piperazines (Gleevec) disrupt enough deployment of signal pathways to slow down a Cytokine storm (and TBI).
4.Could dampening of CRKL be used as a marker in CML
5.can ADAMs 17 be a biomarker of CML response or Myeloma response
6"PDGFR-beta is a key marker of hepatic stellate cell activation in the process of fibrogenesis."wikipedia
level of PDGFR in hepatoma?or Glioblastoma/ Nexavar activity linked to effect on PDGFR?
JUST WATCH OUT WITH THESE Random PHOSPHORYLATION, IT IS HOW CASEIN INDUCES TRIPLE NEGATIVE
BREAST CANCERS.
JUST REMEMBER Src INFLUENCES PDGF INDUCED PHOSPHORYLATION OF STATs.
vain attempt but we keep dancing!
Dear Peggy;
You have been successfully registered for the following training event.
------------------------------
Title: SBA Lending Fair
Location: 9050 Viscount Blvd. , ASC "A" Bldg. (Auditorium), El Paso, TX 79925
Date(s): 2/27/2014
Time(s): 5:30pm to 7:30pm
Description:
Instructions:
------------------------------
Thank you for your participation!
Best regards,
C.G.
El Paso Community College SBDC
You have been successfully registered for the following training event.
------------------------------
Title: SBA Lending Fair
Location: 9050 Viscount Blvd. , ASC "A" Bldg. (Auditorium), El Paso, TX 79925
Date(s): 2/27/2014
Time(s): 5:30pm to 7:30pm
Description:
Instructions:
------------------------------
Thank you for your participation!
Best regards,
C.G.
El Paso Community College SBDC
Good News at CRBCM
It is official,
DR kankonde became Iterim Director of El Paso 4 Griffols/Talecris Plasma Center starting 03/01/2014.
He is also the full time Center Medical Director of El Paso 2 since 8/15/2013.
we keep progressing slowly but surely!
DR kankonde became Iterim Director of El Paso 4 Griffols/Talecris Plasma Center starting 03/01/2014.
He is also the full time Center Medical Director of El Paso 2 since 8/15/2013.
we keep progressing slowly but surely!
Pick into the cure!
Cytokines that can induce cellular stress, may also exacerbate P53 induced apoptosis through release of its regulators. Indeed P53 regulators include
Tomasini et al
" that TP53INP1s, in association with HIPK2, regulate p53 transcriptional activity on p21, mdm2, pig3, and bax promoters. Furthermore, TP53INP1s overexpression induces G1 arrest and increases p53-mediated apoptosis. Although a TP53INP1s and HIPK2 additive effect was observed on apoptosis, G1 arrest was weaker when HIPK2 was transfected together with TP53INP1. These results indicate that TP53INP1s and HIPK2 could be partners in regulating p53 activity."
the role of TGF on these regulators needs further scrutiny since it it such an important growth factor in breast cancer
could blockage of the Cutlins help?
Blocking these regulator could decrease cancer dependance on rescue measure and restore the effectiveness of Hypoxic apoptosis?
GO TO ARTICLE!
Tomasini et al
" that TP53INP1s, in association with HIPK2, regulate p53 transcriptional activity on p21, mdm2, pig3, and bax promoters. Furthermore, TP53INP1s overexpression induces G1 arrest and increases p53-mediated apoptosis. Although a TP53INP1s and HIPK2 additive effect was observed on apoptosis, G1 arrest was weaker when HIPK2 was transfected together with TP53INP1. These results indicate that TP53INP1s and HIPK2 could be partners in regulating p53 activity."
the role of TGF on these regulators needs further scrutiny since it it such an important growth factor in breast cancer
could blockage of the Cutlins help?
Blocking these regulator could decrease cancer dependance on rescue measure and restore the effectiveness of Hypoxic apoptosis?
GO TO ARTICLE!
TP53INP1s and Homeodomain-interacting Protein Kinase-2 (HIPK2) Are Partners in Regulating p53 Activity*
Richard Tomasiniठet al!Tuesday, February 25, 2014
new NF1 case stumbled upon!
As if things were not enough today a case of metastatic Head and neck cancer with vertebral involvement showed up, the interest in abnormality in G-proteins and may be the SProuty2 may be growing.
what does the NF-1 gene has to do with these propensity to Neoplasm. The patient had severe bipolar syndrome!
Its mutation release cell control through removal of RAS regulation, growth becomes uncontrolled.
Its ATPase shape affects deeply activity of the G-proteins.
Mutation in NF1 seems to be a trigger to EGFR expression (and erbB2) and may contribute to mass formation, in other words, recuperation of some embryonal fucntion is at the basis of tumor formation
?those with NF-1 Mutation becomes sensitive to anti-EGFR inhibition?
NF-1 mutation is also cause for over expression of Insulin Growth Factor Receptor and associated EMA/GLUT-1, and CD34 particularly on Fibroblasts, and S-100. (identifying several bio-markers and detection, may be prognosis in several research pertaining to NF-1)
other genes involved
Snx5
MIB-1
Neur2
Zath1
E2, DPK and DIP
Delta and the Notch
reference
====================================
and into the details of negative activity
all these identify new targets?
what does the NF-1 gene has to do with these propensity to Neoplasm. The patient had severe bipolar syndrome!
Its mutation release cell control through removal of RAS regulation, growth becomes uncontrolled.
Its ATPase shape affects deeply activity of the G-proteins.
Mutation in NF1 seems to be a trigger to EGFR expression (and erbB2) and may contribute to mass formation, in other words, recuperation of some embryonal fucntion is at the basis of tumor formation
?those with NF-1 Mutation becomes sensitive to anti-EGFR inhibition?
NF-1 mutation is also cause for over expression of Insulin Growth Factor Receptor and associated EMA/GLUT-1, and CD34 particularly on Fibroblasts, and S-100. (identifying several bio-markers and detection, may be prognosis in several research pertaining to NF-1)
other genes involved
Snx5
MIB-1
Neur2
Zath1
E2, DPK and DIP
Delta and the Notch
reference
Mind Bomb Is a Ubiquitin Ligase that Is Essential for Efficient Activation of Notch Signaling by Delta
Motoyuki Itoh1, Ch====================================
and into the details of negative activity
The mechanism of growth-inhibitory effect of DOC-2/DAB2 in prostate cancer. Characterization of a novel GTPase-activating protein associated with N-terminal domain of DOC-2/DAB2.
Wang Z1,all these identify new targets?
And now it comes
In sarcoma particularly GIST
people seems to try Pazopanib added to Gleevec!
and Panobinostat seems the selected HDAC inhibitor of choice!
"
Panobinostat (LBH-589) is an experimental drug developed by Novartis for the treatment of various cancers. It is a hydroxamic acid[1] and acts as a non-selective histone deacetylase inhibitor (HDAC inhibitor)." wikipedia
In Gist, a sudden interest in the SRC gene! more work for CRBCM, will look into this!
people seems to try Pazopanib added to Gleevec!
and Panobinostat seems the selected HDAC inhibitor of choice!
"
Panobinostat (LBH-589) is an experimental drug developed by Novartis for the treatment of various cancers. It is a hydroxamic acid[1] and acts as a non-selective histone deacetylase inhibitor (HDAC inhibitor)." wikipedia
In Gist, a sudden interest in the SRC gene! more work for CRBCM, will look into this!
and questions keep ringing the deep senses!
Does random phosphorylation induced by Casein and related decrease of AP-1 critical to Breast cancer (TNBC) development
can we equate or parallel depression of PTEN under HIF influence to Casein phosphorylation induced depression of AP-1 in inducing cancers?
The same phosphorylation affect the RELA causing cross talking of the NOTCH and Catenins
all this putting center epigenetic phenomena to Neoplastic transformation
does this justify the cancer preventive force of certain anti-inflamatory drugs
can the effect of neoplastic prevention be linked to expression of c-fos
how does BCL-2 expression linked to c-fos
As easy at it sound, only certain facts leads to c-Fos expression...suggestion is overexpression of c-fos indicates that certain condition in the cell have been satisfied!
Are we in the belly of the beast when it comes to Breast and Pancreatic cancers, Are we at the bottom of the GTX combination used in Pancreatic cancer ?(the founders was talking of enzyme limiting activities and saturation?
check it out!
can we equate or parallel depression of PTEN under HIF influence to Casein phosphorylation induced depression of AP-1 in inducing cancers?
The same phosphorylation affect the RELA causing cross talking of the NOTCH and Catenins
all this putting center epigenetic phenomena to Neoplastic transformation
does this justify the cancer preventive force of certain anti-inflamatory drugs
can the effect of neoplastic prevention be linked to expression of c-fos
how does BCL-2 expression linked to c-fos
As easy at it sound, only certain facts leads to c-Fos expression...suggestion is overexpression of c-fos indicates that certain condition in the cell have been satisfied!
Are we in the belly of the beast when it comes to Breast and Pancreatic cancers, Are we at the bottom of the GTX combination used in Pancreatic cancer ?(the founders was talking of enzyme limiting activities and saturation?
check it out!
Casein kinase II is a negative regulator of c-Jun DNA binding and AP-1 activity
Monday, February 24, 2014
Role of the RELA gene in Triple negative Breast cancer
Is it the best biomarker
Is it the gene at play?
Is it the sign of Involvement of the epigenetic Zone
Is it a sign of Etoposide activity
Is it at play in hair discoloration
Is RELA sufficiently connected to be an adaptor gene, a wild gene? could it be a driver gene through autophosphorylation?
Pivotal role of the RELA in Breast Cancer though cross talking with the NOTCH, the steroidsand the Catenins?
Is RELA's role underestimated in Breast Cancer (TNBC)?
These are just some of the questions that the RELA gene raises !
Is it the gene at play?
Is it the sign of Involvement of the epigenetic Zone
Is it a sign of Etoposide activity
Is it at play in hair discoloration
Is RELA sufficiently connected to be an adaptor gene, a wild gene? could it be a driver gene through autophosphorylation?
Pivotal role of the RELA in Breast Cancer though cross talking with the NOTCH, the steroidsand the Catenins?
Is RELA's role underestimated in Breast Cancer (TNBC)?
These are just some of the questions that the RELA gene raises !
Sunday, February 23, 2014
An interesting clinical case, A CLASSIC CASE OF GENE INTERFERENCE
a 49 year hispanic woman passed out while taking a shower, she was taken to the ER, further work-up revealed a 6.4 mass in the in her stomach which passed the physical wall of the and into the peritoneal wall. The mass turned up to be A GIST (Gastrointestinal stromal Tumor). An interesting finding by itself since it twist positively the prognosis and raise considerable interest for surgical Intervention.
The internet and the American cancer society suggest "
from the same sources
"
What makes this case even more interesting are 2 additional informations (and believe me I would not bring forth this case if there are no more twists), few months back the dermatologist had seen the same patient for Neurofibromatosis. Indeed she has disseminated on her skin "NEVI" like lesions typical of this disease. NOT ONLY SHE HAS THE NF-1 RELATED GENE, BUT SHE ALSO HAVE "CAFE AU LAIT " SPOTS
--------------------------------------------------------------------------------------------------
RAISING THE POSSIBILITY :" Mutations in the NF1 gene have been linked to NF-1, Juvenile myelomonocytic leukemia and Watson syndrome. A condition with a separate gene mutation but similar Café au lait spots is Legius syndrome which has a mutation on the SPRED1 gene.Patients without Neurofibromin 1 or SPRED1 mutations may have SPRED2, SPRED3 or SPRY1, SPRY2, SPRY3 or SPRY4 mutations.[5]...." WIKIPEDIA
and
(raising the possibility of anti-EFR in this disease)
AND A NEW CULPRIT IS BORN: ANDERSON ET AL.
"
Sprouty (Spry) proteins modulate the actions of receptor tyrosine kinases during development and tumorigenesis. Decreases in cellular levels of Spry, especially Sprouty2 (Spry2), have been implicated in the growth and progression of tumors of the breast, prostate, lung, and liver. During development and tumor growth, cells experience hypoxia. Therefore, we investigated how hypoxia modulates the levels of Spry proteins. Hypoxia elevated the levels of all four expressed Spry isoforms in HeLa cells."
PLEASE INTERFERE WITH SPROUTY ABSOLUTELY......
AND THIS INCREASES THE ROLE OF THE RAS AMPLIFICATION IN THIS DISEASE, AND MAKES ANTI-MEK EVEN MORE IMPRORTANT....AS A POTENTIAL AMPLIFIER DOWNSTREAM!
CAN SPROUTY EXPRESSION BE A BIOMARKER IN THIS DISEASE?
====================================================
Just as you start to get comfortable with the case
let me bring up yet another twist to this genetic rich case,
as I examine the patient, I find out quickly she has been unable to raise her hands for years and has been told to be ANA antibody positive....Now if you have been a careful reader, you may have noted that Juvenile Myelomonocytic Leukemia is part of this syndrome, pointing to a potential disruption of Monocyte which are incriminated in autoimmune diseases. Polymyositis came to mind as I examine the woman
" Another important event in the pathogenesis of Polymyositis is the increased expression of MHC proteins by m/s cells. Auto-Ag is presented in association with MHC-I molecules on the surface of Myocytes and is recognized by CD8 cytotoxic T cells that subsequently initiate m/s destruction."wikipedia
Pachman et al!
" It is our premise that JDMS is a distinct disease entity and that the increase in HLA-B8 and -DR3 in JDMS places this disease in the company of other immunopathic disorders. There are conflicting data concerning immunological abnormalities in JDMS , but there appears to be impairment of natural killing and evidence of complement activation. The frequent positive ANA in JDMS raises the speculation of its relationship to the antinuclear antibody, Jo-1, found in some adults with PM, which has specificity for tRNAHis. Most newly diagnosed JDMS patients have antibodies to Coxsackie B which may be related to the pathogenesis of this disease. Specific pathological findings of endothelial cells containing reticulotubular inclusions are associated with vessel occlusion, subsequent obliteration and increased Factor VIII levels in clinically active disease."
SHOULD I TEST FOR COXSACKIE, WHO IS GOING TO PAY!
THE LADY WAS FOUND WITH A PULMONARY EMBOLUS
AND COULD NOT BE ANTICOAGULATED AND A FILTER WAS PLACED
SHE HAS AN HARDENED RIGHT THIGH
AND TO CONCLUDE, HER FATHER DIED OF PANCREATIC CANCER
AND SHE HAS AN INQUISITIVE DAUGHTER WHOM I MAY BE FORCED TO TEST ALSO AS TO HER PREDISPOSITION TO THIS CALAMITY SYNDROME!
The internet and the American cancer society suggest "
"Based on people treated between 1992 and
2000, the overall relative 5-year survival rate of people diagnosed with
a malignant GIST was estimated to be about 45%.
- If the tumor was confined to the organ where it started, the 5-year relative survival was 64%.
- If it had grown into nearby tissue when it was first diagnosed, the 5-year relative survival was around 30%.
- If it had spread to distant sites when it was first diagnosed, the 5-year relative survival was 13%. "
from the same sources
"
A few families have gastrointestinal stromal
tumors (GISTs) caused by a DNA mutation passed down from parent to
child. But most DNA mutations related to GISTs are not inherited. These
changes occur for no apparent reason, and are called acquired or sporadic.
The cancer cells of most patients with GIST have a change in an oncogene called c-kit. The c-kit
gene is found in all cells of the body. It directs the cell to make a
protein called KIT, which causes the cell to grow and divide. Usually
the c-kit gene is inactive. It is only active if there is a need for more interstitial cells of Cajal (ICCs). In most GISTs the c-kit
gene is mutated and is always active. This may explain why the cancer
forms. The cells are always growing and dividing. In some families that
have many members with GISTs, doctors have found inherited mutations of
the c-kit gene.
In about 5% to 10% of GISTs, the cancer cells have mutation in a different gene called PDGFRA,
which causes the cell to make too much of a different protein (also
called PDGFRA). This has the same effect on the cell as does KIT.
Most GISTs have changes in either the c-kit or the PDGFRA
gene, but not both. A small number of GISTs do not have changes in
either of these genes. Researchers are still trying to determine what
gene changes lead to these cancers."
Most of these stromal tumors stained positively for CD34 (Miettinen et al 1995). The KIT protein is a transmembrane receptor for stem cell factor. The
intracytoplasmic portion of this receptor functions as a tyrosine
kinase. The availability of the immunohistochemical marker, CD117, to
the KIT protein, has revolutionized the diagnosis of GIST, by
identifying a treatment target. Approximately 95% of GISTs stain
positive for CD117, making it a very useful marker for diagnosis (Miettinen and Lasota 2001). This has led to the development of the targeted therapy imatinib mesylate (STI-571; Glivec®,
Novartis, Basel, Switzerland). This drug inhibits several tyrosine
kinase receptors with varying affinity, including KIT, the BCR-ABL
fusion protein, and the platelet derived growth factor receptor (PDGFR) (Heinrich et al 2000, De Giorgi and Verweij 2005). DIN et al
The surgeon have discussed the case and referred the case for Neoadjuvant Gleevec.
-------------------------------------------------------------------------------------------------------------------
"As imatinib targets the ATP (adenosine triphosphate) binding site of the KIT receptor (encoded by exon 11), tumors with exon 11 mutations treated with imatinib have a significantly better partial response rate, event free and overall survival compared to exon 9 or no detectable mutation. A partial response rate of up to 83% has been achieved, showing how sensitive these tumors can be (Heinrich et al 2003a; Corless et al 2004; Debiec-Rychter et al 2006)."DIN
(DO PATIENT NEEDS TO REDUCE ATP PRODUCING MOLECULES IN THIS DISEASE ?)
(HOW DOES CAJAL CELL ACTIVITY LINKED TO TUMOR PROGRESSION/PRODUCTION)
(IS IT CRITICAL TO KNOW WHICH GENE IS AFFECTED IN AN INDIVIDUAL PATIENT)
DON'T GET EXCITED WE KNOW THE ROLE OF EXON 11.
and like any good thing, Gleevec comes with a word of caution per DIN et al:
--------------------------------------------------------------------------------------------------------
" The main circulating metabolite is an N-demethylated piperazine derivative which accounts for 16% of the AUC (area under the curve) for imatinib. This, with imatinib accounts for most of the activity, but there are a number of smaller metabolites. CYP3A4 is the major cytochrome P450 involved in imatinib metabolism. Thus, drugs that are co-administered may alter the pharmacokinetics. Erythromycin, fluconazole, and rifampicin have shown inhibition of imatinib metabolism. Imatinib increases exposure to simvastatin. Alprazolam, caffeine, clindamycin, clonazepam, cortisol, ethinyl oestradiol, and verapamil may cause toxic effects when given with imatinib. St. John’s wort increases imatinib clearance by 43%. Patients should avoid excessive amounts of paracetamol as both are metabolized by CYP3A4 (D’Amato et al 2005; Novartis 2005).
-------------------------------------------------------------------------------------------------------------------
"As imatinib targets the ATP (adenosine triphosphate) binding site of the KIT receptor (encoded by exon 11), tumors with exon 11 mutations treated with imatinib have a significantly better partial response rate, event free and overall survival compared to exon 9 or no detectable mutation. A partial response rate of up to 83% has been achieved, showing how sensitive these tumors can be (Heinrich et al 2003a; Corless et al 2004; Debiec-Rychter et al 2006)."DIN
(DO PATIENT NEEDS TO REDUCE ATP PRODUCING MOLECULES IN THIS DISEASE ?)
(HOW DOES CAJAL CELL ACTIVITY LINKED TO TUMOR PROGRESSION/PRODUCTION)
(IS IT CRITICAL TO KNOW WHICH GENE IS AFFECTED IN AN INDIVIDUAL PATIENT)
DON'T GET EXCITED WE KNOW THE ROLE OF EXON 11.
and like any good thing, Gleevec comes with a word of caution per DIN et al:
--------------------------------------------------------------------------------------------------------
" The main circulating metabolite is an N-demethylated piperazine derivative which accounts for 16% of the AUC (area under the curve) for imatinib. This, with imatinib accounts for most of the activity, but there are a number of smaller metabolites. CYP3A4 is the major cytochrome P450 involved in imatinib metabolism. Thus, drugs that are co-administered may alter the pharmacokinetics. Erythromycin, fluconazole, and rifampicin have shown inhibition of imatinib metabolism. Imatinib increases exposure to simvastatin. Alprazolam, caffeine, clindamycin, clonazepam, cortisol, ethinyl oestradiol, and verapamil may cause toxic effects when given with imatinib. St. John’s wort increases imatinib clearance by 43%. Patients should avoid excessive amounts of paracetamol as both are metabolized by CYP3A4 (D’Amato et al 2005; Novartis 2005).
What makes this case even more interesting are 2 additional informations (and believe me I would not bring forth this case if there are no more twists), few months back the dermatologist had seen the same patient for Neurofibromatosis. Indeed she has disseminated on her skin "NEVI" like lesions typical of this disease. NOT ONLY SHE HAS THE NF-1 RELATED GENE, BUT SHE ALSO HAVE "CAFE AU LAIT " SPOTS
--------------------------------------------------------------------------------------------------
RAISING THE POSSIBILITY :" Mutations in the NF1 gene have been linked to NF-1, Juvenile myelomonocytic leukemia and Watson syndrome. A condition with a separate gene mutation but similar Café au lait spots is Legius syndrome which has a mutation on the SPRED1 gene.Patients without Neurofibromin 1 or SPRED1 mutations may have SPRED2, SPRED3 or SPRY1, SPRY2, SPRY3 or SPRY4 mutations.[5]...." WIKIPEDIA
and
Sprouty2 acts at the Cbl/CIN85 interface to inhibit epidermal growth factor receptor downregulation
Kaisa Haglund,"(raising the possibility of anti-EFR in this disease)
AND A NEW CULPRIT IS BORN: ANDERSON ET AL.
"
Sprouty (Spry) proteins modulate the actions of receptor tyrosine kinases during development and tumorigenesis. Decreases in cellular levels of Spry, especially Sprouty2 (Spry2), have been implicated in the growth and progression of tumors of the breast, prostate, lung, and liver. During development and tumor growth, cells experience hypoxia. Therefore, we investigated how hypoxia modulates the levels of Spry proteins. Hypoxia elevated the levels of all four expressed Spry isoforms in HeLa cells."
PLEASE INTERFERE WITH SPROUTY ABSOLUTELY......
AND THIS INCREASES THE ROLE OF THE RAS AMPLIFICATION IN THIS DISEASE, AND MAKES ANTI-MEK EVEN MORE IMPRORTANT....AS A POTENTIAL AMPLIFIER DOWNSTREAM!
CAN SPROUTY EXPRESSION BE A BIOMARKER IN THIS DISEASE?
====================================================
Just as you start to get comfortable with the case
let me bring up yet another twist to this genetic rich case,
as I examine the patient, I find out quickly she has been unable to raise her hands for years and has been told to be ANA antibody positive....Now if you have been a careful reader, you may have noted that Juvenile Myelomonocytic Leukemia is part of this syndrome, pointing to a potential disruption of Monocyte which are incriminated in autoimmune diseases. Polymyositis came to mind as I examine the woman
" Another important event in the pathogenesis of Polymyositis is the increased expression of MHC proteins by m/s cells. Auto-Ag is presented in association with MHC-I molecules on the surface of Myocytes and is recognized by CD8 cytotoxic T cells that subsequently initiate m/s destruction."wikipedia
Pachman et al!
" It is our premise that JDMS is a distinct disease entity and that the increase in HLA-B8 and -DR3 in JDMS places this disease in the company of other immunopathic disorders. There are conflicting data concerning immunological abnormalities in JDMS , but there appears to be impairment of natural killing and evidence of complement activation. The frequent positive ANA in JDMS raises the speculation of its relationship to the antinuclear antibody, Jo-1, found in some adults with PM, which has specificity for tRNAHis. Most newly diagnosed JDMS patients have antibodies to Coxsackie B which may be related to the pathogenesis of this disease. Specific pathological findings of endothelial cells containing reticulotubular inclusions are associated with vessel occlusion, subsequent obliteration and increased Factor VIII levels in clinically active disease."
SHOULD I TEST FOR COXSACKIE, WHO IS GOING TO PAY!
THE LADY WAS FOUND WITH A PULMONARY EMBOLUS
AND COULD NOT BE ANTICOAGULATED AND A FILTER WAS PLACED
SHE HAS AN HARDENED RIGHT THIGH
AND TO CONCLUDE, HER FATHER DIED OF PANCREATIC CANCER
AND SHE HAS AN INQUISITIVE DAUGHTER WHOM I MAY BE FORCED TO TEST ALSO AS TO HER PREDISPOSITION TO THIS CALAMITY SYNDROME!
Friday, February 21, 2014
Side effects at the cellular level
The development of unintended consequences is one of the most significant events full of duplicity. It leads to unplanned events that could unravel the whole experiment. The cell knows it is not perfect and has prepared itself to a world of various stimulants that scientists around the world and nature keep creating. The cell keeps its options open, ready to adapt. Its flexibility to conversion expands its potential to undergo unplanned events or side effects. Some of the side effects are favorable, other neutral, but still some have deleterious effects.
1. One such example are Reuptake inhibitors:
----------------------------------------------
Whether it is a serotonin or Dopamine, inhibitor or reuptake, it results in increased extracellular concentrations of the targeted compound. Now it is always of use to remind ourselves that not all compounds are target specific and that certain compounds can stimulate several receptors, therefore raising the possibility of creating unintended consequences that we can call "side effects".
2.Co-stimulation of several Receptors Versus Co-binding of several Receptors.
----------------------------------------------------------------------------------
Multikinases have the advantage of blocking several of their targets, and may shutdown or activate several pathways. Generally, this is a positive thing. Side effects come along when some receptors blocked in the process lead to obligatory vital pathways or processes that are also shutdown or impacted, leading to miserable consequences. One of the things most researchers fear is the distant presence of an unplanned receptor in the Brain! You give a medication planned to act on a Muscle or a white cell, and you get a significant seizure side effect (real case).
Some Multikinases are so effective that they shut down the effect of other therapeutic interventions (don't try anti-VEGF and M-TOR inhibitor concurrently until you are sure of your purpose).
3.Adaptor genes:
---------------------
The cell is a master of giving directions to cellular reactions. To achieve this it put stogether "Core Binding Factors" (term used here loosely to make a point) or a congregate of various molecules that may come together to master, interact and shape sometimes one molecule (give this molecule a specific post-translational modification) into a new molecule that will achieve a specific purpose...like a factory would! ie. check the prognosis of CBF presence in Leukemias!
Certain genes, however, orient squarely a molecule to some clear purpose, if a molecule A attaches to the LYN gene Vs Gerb2, consequences are drastically different....Whether a solid tumor or a hematologic disease results could be a matter of which Adaptor gene was used!
4. Co-binding of Receptor
5. Lack of Inhibitors
6. Non specificity, sing the common pathways and possibility of saturation
7. Secondary liberation and release of "second messenger"
8. Unique localization of certain common receptors
9. Susceptibilty of certain Heterogeneic genes
10. The G proteins
etc.; all these could be expanded to justify why side effects develop, like it or not, in cellular life...No wonder we have to give "consents" for clinical trials....
AND GUESS HOW LONG THIS ARTICLE COULD BECOME IF MEATS AND BONES WERE ADDED! A BOOK WOULD NOT CUT IT!
1. One such example are Reuptake inhibitors:
----------------------------------------------
Whether it is a serotonin or Dopamine, inhibitor or reuptake, it results in increased extracellular concentrations of the targeted compound. Now it is always of use to remind ourselves that not all compounds are target specific and that certain compounds can stimulate several receptors, therefore raising the possibility of creating unintended consequences that we can call "side effects".
2.Co-stimulation of several Receptors Versus Co-binding of several Receptors.
----------------------------------------------------------------------------------
Multikinases have the advantage of blocking several of their targets, and may shutdown or activate several pathways. Generally, this is a positive thing. Side effects come along when some receptors blocked in the process lead to obligatory vital pathways or processes that are also shutdown or impacted, leading to miserable consequences. One of the things most researchers fear is the distant presence of an unplanned receptor in the Brain! You give a medication planned to act on a Muscle or a white cell, and you get a significant seizure side effect (real case).
Some Multikinases are so effective that they shut down the effect of other therapeutic interventions (don't try anti-VEGF and M-TOR inhibitor concurrently until you are sure of your purpose).
3.Adaptor genes:
---------------------
The cell is a master of giving directions to cellular reactions. To achieve this it put stogether "Core Binding Factors" (term used here loosely to make a point) or a congregate of various molecules that may come together to master, interact and shape sometimes one molecule (give this molecule a specific post-translational modification) into a new molecule that will achieve a specific purpose...like a factory would! ie. check the prognosis of CBF presence in Leukemias!
Certain genes, however, orient squarely a molecule to some clear purpose, if a molecule A attaches to the LYN gene Vs Gerb2, consequences are drastically different....Whether a solid tumor or a hematologic disease results could be a matter of which Adaptor gene was used!
4. Co-binding of Receptor
5. Lack of Inhibitors
6. Non specificity, sing the common pathways and possibility of saturation
7. Secondary liberation and release of "second messenger"
8. Unique localization of certain common receptors
9. Susceptibilty of certain Heterogeneic genes
10. The G proteins
etc.; all these could be expanded to justify why side effects develop, like it or not, in cellular life...No wonder we have to give "consents" for clinical trials....
AND GUESS HOW LONG THIS ARTICLE COULD BECOME IF MEATS AND BONES WERE ADDED! A BOOK WOULD NOT CUT IT!
Thursday, February 20, 2014
Still today: Minorities experience longer delays between cancer diagnosis and treatment !
1. Prostate Cancer:
Among men with prostate cancer, African Americans experience longer treatment delays after being diagnosed than Caucasians. That is the finding of an analysis published early online in Cancer, a peer-reviewed journal of the American Cancer Society. The study suggests that efforts are needed to reduce racial disparities in prostate cancer care in order to provide earlier treatment for African Americans.
2. Breast Cancer:
Breast cancer in women between the ages of 15 and 39 years (adolescents and young adults [AYAs]) constitutes 5% to 6% of all breast cancer cases in the United States. Breast cancer in AYA women has a worse prognosis than in older women. Five-year survival rates are lowest for AYA women, and only a few studies have examined the impact of delay in treatment, race/ethnicity, and other socioeconomic factors on survival in AYA women.
3. Effects of Health Insurance and Race on Early Detection of Cancer
Richard G. Roetzheim,
Naazneen Pal, Colleen Tennant,
Lydia Voti,
John Z. Ayanian,
Annette Schwabe and
Jeffrey P. Krischer
+ Author Affiliations
Affiliations of authors: R. G. Roetzheim, University of South Florida Department of Family Medicine, and Division of Cancer Control, H. Lee Moffitt Cancer Center and Research Institute, Tampa; N. Pal, C. Tennant, University of South Florida Department of Family Medicine; L. Voti, Florida Cancer Data System, Sylvester Comprehensive Cancer Center, University of Miami, FL; J. Z. Ayanian, Division of General Medicine, Department of Medicine, Brigham and Women's Hospital, and Department of Health Care Policy, Harvard Medical School, Boston, MA; A. Schwabe, Department of Chronic Disease Epidemiology, Florida Department of Health, Tallahassee; J. P. Krischer, H. Lee Moffitt Cancer Center and Research Institute.
Correspondence to: Richard G. Roetzheim, M.D., M.S.P.H., University of South Florida Department of Family Medicine, 12901 Bruce B. Downs Blvd., MDC 13, Tampa, FL 33612 (e-mail: rroetzhe@com1.med.usf.edu).
Among men with prostate cancer, African Americans experience longer treatment delays after being diagnosed than Caucasians. That is the finding of an analysis published early online in Cancer, a peer-reviewed journal of the American Cancer Society. The study suggests that efforts are needed to reduce racial disparities in prostate cancer care in order to provide earlier treatment for African Americans.
African-Americans experience longer delays between diagnosis and treatment of prostate cancer
Date: May 28, 2013, Source: Wiley2. Breast Cancer:
Breast cancer in women between the ages of 15 and 39 years (adolescents and young adults [AYAs]) constitutes 5% to 6% of all breast cancer cases in the United States. Breast cancer in AYA women has a worse prognosis than in older women. Five-year survival rates are lowest for AYA women, and only a few studies have examined the impact of delay in treatment, race/ethnicity, and other socioeconomic factors on survival in AYA women.
CONCLUSIONS AND RELEVANCE: Young women with breast cancer with a longer TDT have significantly decreased survival time compared with those with a shorter TDT. This adverse impact on survival was more pronounced in African American women, those with public or no insurance, and those with low SES.
JAMA Surg. 2013 Jun;148(6):516-23. doi: 10.1001/jamasurg.2013.1680.
Delay in surgical treatment and survival after breast cancer diagnosis in young women by race/ethnicity.3. Effects of Health Insurance and Race on Early Detection of Cancer
Our final study population consisted of the 28 237 Florida residents diagnosed with colorectal cancer, breast cancer, melanoma, or prostate cancer in 1994, for whom information was available on both stage and insurance payer (Table 1⇔). Most patients were older than 65 years of age, and Medicare was the most common type of insurance. Table 2⇔ presents the proportion of patients who were diagnosed at a late stage of cancer for each category of insurance payer and race. The insurance payer was statistically significantly associated with stage at diagnosis for each of the four cancers examined. Patients insured by Medicaid and patients who were uninsured were at greater risk for late stage disease. Non-Hispanic African-Americans were at a greater risk of a late stage diagnosis for breast and prostate cancers.
Effects of Health Insurance and Race on Early Detection of Cancer
Richard G. Roetzheim,
Naazneen Pal, Colleen Tennant,
Lydia Voti,
John Z. Ayanian,
Annette Schwabe and
Jeffrey P. Krischer
+ Author Affiliations
Affiliations of authors: R. G. Roetzheim, University of South Florida Department of Family Medicine, and Division of Cancer Control, H. Lee Moffitt Cancer Center and Research Institute, Tampa; N. Pal, C. Tennant, University of South Florida Department of Family Medicine; L. Voti, Florida Cancer Data System, Sylvester Comprehensive Cancer Center, University of Miami, FL; J. Z. Ayanian, Division of General Medicine, Department of Medicine, Brigham and Women's Hospital, and Department of Health Care Policy, Harvard Medical School, Boston, MA; A. Schwabe, Department of Chronic Disease Epidemiology, Florida Department of Health, Tallahassee; J. P. Krischer, H. Lee Moffitt Cancer Center and Research Institute.
Correspondence to: Richard G. Roetzheim, M.D., M.S.P.H., University of South Florida Department of Family Medicine, 12901 Bruce B. Downs Blvd., MDC 13, Tampa, FL 33612 (e-mail: rroetzhe@com1.med.usf.edu).
Wednesday, February 19, 2014
A fast-paced life-style induces 'doc-shopping' with unforeseeable consequences...
In the search of perfect health and instant relief from any noticeable sign from the body, some individuals shop and hop from one doctor's office to the other, often without any measurable relief from the perceptions that the body keeps sending - signs of aliveness, wakefulness, tiredness, excitement, fullness after a great meal, shivers from a fright....
A president-like appointment schedule involving 10 or more specialists charts the course of the week, the daily medical trips are punctuated by the ingestion of up to 36 different medications at meticulously recorded times and separated from or taken during meal times as advised...
Over a few innocent weeks and month, unobtrusively, life is turned into a full-time state of disease that demands constant attention, worry, discussion, opposition and scrutiny that ends up creating anxiety not only in the patient, but also in each and every one of his or her family members as they shiver in dark anticipation with every sigh, hiccups, burp and yawn.
The outcry: "Oh well, I don't know what is wrong with me, really!" leads to ever more head scratching... maybe soon these doctors will loose their hair over the puzzling case !
by PK
A president-like appointment schedule involving 10 or more specialists charts the course of the week, the daily medical trips are punctuated by the ingestion of up to 36 different medications at meticulously recorded times and separated from or taken during meal times as advised...
Over a few innocent weeks and month, unobtrusively, life is turned into a full-time state of disease that demands constant attention, worry, discussion, opposition and scrutiny that ends up creating anxiety not only in the patient, but also in each and every one of his or her family members as they shiver in dark anticipation with every sigh, hiccups, burp and yawn.
The outcry: "Oh well, I don't know what is wrong with me, really!" leads to ever more head scratching... maybe soon these doctors will loose their hair over the puzzling case !
by PK
Help us fund the Testing of Biomarkers to define, monitor and better address OBESITY, A CONDITION OF PROFOUND ENDOCRINE AND CYTOKINE DISTURBANCES, a true state of DISEASE!
Testing Biomarkers to
define, monitor and better address OBESITY, A CONDITION OF PROFOUND ENDOCRINE AND CYTOKINE
DISTURBANCES, a true disease state
We want to establish
new guidelines for monitoring obesity by finding specific biomarkers.
Following BMI, lipid profile and pushing diet and physical activity is clearly
insufficient. Blocking the central nervous system to force mental rejection
of food is not the answer, either.
Obesity becomes a
disease because of its high inflammatory state, determined by a relatively
high level of Growth factor and Cytokines inducing major deleterious
consequences on the muscle skeletal system through the activated NF-KB.
In morbid obesity,
RIP140 levels are down-regulated in visceral adipose tissue. The RIP 140 (also
known as NRIP1) interacts with DAX1 which involves the COPS2, SREBF1 (the bone modulator) and SF1
("feminization" of obese individuals). (see literature) In breast cancer, RIP140
is involved in regulation of E2F1, an oncogene which discriminates between luminal
and basal tumor types. RIP140 influences cancer phenotype and prognosis.. "In
addition, RIP140 has a role in inflammation, since it acts as a coactivator for
NFkappaB/RelA-dependent cytokine gene expression. Lack of RIP140 leads to an inhibition of
proinflammatory pathways in macrophages and RIP-140 modulation is part of cachexia induced by
Tumors.
Also,
in a state of obesity, even outside the cell, there is a relatively large
number of insulin molecules."Without receptors to stimulate, they will go downstream and stimulate MAPK AND STRESS LIKE c-JUN/fos, LEADING TO INCREASED CYTOKINES with Interferons and interleukins leading to diseases caused by obesity.
HONESTLY
AS WE PROGRESS IN CANCER SCIENCE, THE TIME FOR DIAGNOSIS OF CANCER WITHOUT GENETIC RECIPE AT THE BASIS OF THE DISEASE IS QUITE PASSED! GIVING OLD CHEMOTHERAPY SHOULD ONLY BE ALLOWED IN REFRACTORY DISEASES...BUT HERE WE ARE, WITH LEADERS DISTRACTED DRIVING US BACKWARDS.... RESARCHERS ARE LEFT FIGHTING OVER WHETHER TO TEST THE DNA, THE RNA OR SIMPLY THE RELATED PROTEIN, AN EXTRA $2000 WOULD HAVE ALLOWED TO PURCHASE THE 50 ELISA KITS, BUT ALL IS FALLING SHORT BECAUSE OF THAT AMOUNT! IF THIS IS HAPPENING HERE...WHAT ABOUT...? SHOULD WE REALLY BE DISCUSSING THIS NOW?
Tuesday, February 18, 2014
The Combination of Etoposide and Histone Deacetylases applied to Cancers with high levels of c-MYC and c-FOS gene expression
The
Combination of Etoposide and Histone Deacetylases applied to Cancers with high
levels of c-MYC and c-FOS gene expression:
This research
project investigates the possibility of combining Etoposide with Histone
Deacetylases in the treatment of cancers that display a significant expression
of te c-Myc and c-Fos gene. The drugs
proposed for this trial are Etoposide and Histone Deacetylases.
Etoposide was
first synthesized in 1966 and is a drug widely used in chemotherapy since 1983
when it obtained FDA approval. Etoposide
forms a ternary complex with DNA and the topoisomerase II enzyme which
participates in the unwinding of DNA, hence prevents the rwligation of the DNA
strands, and by doing so causes DNA strands to break. This action then leads to DNA synthesis errors and
subsequently to cell death. Etoposide has, however, some reported side effects
such as low blood pressure, hair loss, pain or burning at the injection site .
Histone
deacetylation has been an effective treatment for various types of cancers. By
the removal of acetyl groups from histones, histone deacetylases create a
non-permissive chromatin conformation that prevents the transcription of genes
that regulate the expression of proteins involved in tumor development such as
c-FOS. In addition to histones, histone deacetylases deacetylate a variety of
other proteins including transcription factors and other abundant cellular
proteins involved in the regulation of
cell growth, differentiation and cell death. Histone Deacetylases are among the
most promising therapeutic targets for cancer treatment, and they have inspired
researchers to study and develop HDAC inhibitors worldwide.
The present
research project consists in computerized and laboratory testing of the
efficacy of combining these two treatments in cases of observed overexpression
of both the c-MYC and c-FOS gene.
Although the two drugs already exist and are used in cancer therapy, the
interaction of the two drugs when used
in combination needs to be examined. This can be achieved by using a mouse
model bearing specified tumors to be done at the University of Texas at El Paso
(UTEP). Preliminary testing should be conducted by implanting cancer cells in
the skin of mice. The combined treatment should then be applied
indiscriminately to mice presenting high expression of c-Myc and c-FOS, and to
those with low expression of these genes. The response to the treatment will be
monitored to evaluate the efficacy of the treatment in mice with high c-Myc and
c-FOS expression as compared to the control group with low c-Myc and low c-FOS
expression. In a later phase, testing would be conducted in cancer patients presenting high expression
of c-Myc and c-FOS, especially for patients treated for triple negative breast
cancer, but also for ovarian cancer and other types of cancer with an
overexpression of c-MYC.
The
combination of Etoposide with Histone Deacetylases represents de facto a
novelty in cancer treatment, especially in the case of triple negative breast
cancer that is until today associated with a worse prognosis than other breast
cancer types. It has a characteristic recurrence pattern with the peak risk of
recurrence and the majority of deaths occurring in the first 3 and 5 years
after the initial treatment, respectively.
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