GET A LITTLE DIRTY MAY BE GOOD FOR YOU!
I know coming from a health professional it is somewhat surprising or even shocking, but take a moment and read about this statement!
ALLERGIES ARE ON THE RISE!
"The increase in allergic diseases noted in the last 2 decades is thought to result from better hygiene conditions, decreases in infant and childhood infections,and an increasingly sedentary and indoor lifestyles." (Wasserman)
yes the less you have been exposed to antigen the more likely you could become allergic. You have not challenged your innate immune system enough. The author suggest that this fact somehow "alters the protective maturation of the acquired immune system". Now this statement is heavy in implications! It implies that the development of class II Major Histocompatibility (MHC) is some what influenced in their development by class I Antigen? or am I over-reaching?
Innate immune system is Tolerance of self Antigens? Acquired Immunity is the stuff mostly class II antigens deal with!
Challenging this statement, will need to read more about this! At CRBCM, we like this form of challenge! keeps one with sharp mind!
This is germaine to genetics because its throws you next into methylation of genes involved in immunity!
Indeed the "Hygiene Hypothesis" suggested switch off of T2H was not fully completed in favor of T1H...Methylation could have been the silencing mechanism!? check this out!
Friday, June 14, 2013
IN OTHER SAD NEWS AND REMINDER!
"
A state audit in January revealed that three grants totaling nearly $60 million were awarded without going through proper review channels. The audit stated Bill Gimson, the executive director of CPRIT at the time, recommended the three grants for approval even though the peer review councils did not recommend them for approval.
Gimson resigned in December."
THE HOUSTON CHRONICLE
"Grand jury hearing evidence on CPRIT grant to Dallas company"-GO TO ARTICLE IN THE DALLAS NEWS!
BAYAN RAJI REPORTED"
A state audit in January revealed that three grants totaling nearly $60 million were awarded without going through proper review channels. The audit stated Bill Gimson, the executive director of CPRIT at the time, recommended the three grants for approval even though the peer review councils did not recommend them for approval.
Gimson resigned in December."
THE HOUSTON CHRONICLE
CPRIT reform bill heads to governor's desk
By Todd Ackerman, Eric Berger | May 24, 2013 | Updated: May 25, 2013 2:59pm
-----------------------------------------------------------------------------------------------------AND IT'S STILL THERE LAST WE HEARD CAUGHT UP IN A DRINKING INCIDENT
" The news that Gov. Rick Perry is pressuring Travis County District Attorney Rosemary Lehmberg to resign in the wake of her DWI conviction has some Texas liberals seeing a hidden agenda: that the governor wants to short circuit a criminal investigation into the Cancer Prevention and Research Institute of Texas."(THE CHRONICLE)
AND I HAVE TOLD YOU THAT THE CURE IS WITHIN REACH BUT THE HUMAN COMPONENT MAKES IT HARDER TO REACH BEACAUSE HUMANS ARE BEING HUMANS!
THANKS TO MEDSCAPE
"In an highly anticipated decision, the Supreme Court has effectively invalidated the patents held by Myriad Genetics for the BRCA1 and BRCA2 genes.
However, the ruling is not all bad news for Myriad.
The Court unanimously ruled that although naturally isolated DNA is not patentable, synthetically created exon-only strands of nucleotides — complementary (c)DNA — is patentable.
In essence, the Court ruled that 5 of Myriad's claims covering isolated DNA are not eligible for patents. But according to Myriad, the company holds more than "500 valid and enforceable claims in 24 different patents conferring strong patent protection for its BRACAnalysis test."
The ruling was written by Justice Thomas, who was joined by Chief Justice Roberts and Justices Kennedy, Ginsberg, Breyer, Alito, Sotomayor, and Kagan; Justice Scalia concurred in part. The Court held that "a naturally occurring DNA segment is a product of nature and not patent eligible merely because it has been isolated, but cDNA is patent eligible because it is not naturally occurring."
It notes that "Myriad's principal contribution was uncovering the precise location and genetic sequence of the BRCA1 and BRCA2 genes." Although this was an important contribution, "Myriad did not create or alter either the genetic information encoded in the BCRA1 and BCRA2 genes or the genetic structure of the DNA."
In the decision, Justice Thomas notes that Myriad's claims were not "saved by the fact that isolating DNA from the human genome severs chemical bonds and thereby creates a non-naturally occurring molecule." This is because the claims are "simply not expressed in terms of chemical composition, nor do they rely in any way on the chemical changes that result from the isolation of a particular section of DNA."
However, the decision leaves the door somewhat open on gene patenting because it distinguishes natural from synthetic DNA. The Court noted that "cDNA does not present the same obstacles to patentability as naturally occurring, isolated DNA segments."
More specifically, Justice Thomas points out that "cDNA retains the naturally occurring exons of DNA, but it is distinct from the DNA from which it was derived." Thus, this form of DNA is "not a 'product of nature' and is patent eligible under §101."
Long and Convoluted Journey
Today's decision puts an end to what has been a long and protracted case. Myriad acquired patents on the 2 genes in the mid-1990s. Since that time, it has become the sole commercial provider of testing services for BRCA1 and BRCA2 in the United States.
On May 12, 2009, the American Civil Liberties Union and the Public Patent Foundation filed a lawsuit against the US Patent and Trademark Office, Myriad Genetics, and the University of Utah Research Foundation, which hold the patents on the BRCA1 and BRCA2 genes. It charged that patents on human genes violate the First Amendment and patent law because genes are "products of nature," and therefore cannot be patented.
The coplaintiffs in the case, including several medical organizations, physicians, academic researchers, cancer survivors, and patient advocates, represented 150,000 geneticists, pathologists, and laboratory professionals.
On March 29, 2010, a New York federal court ruled against Myriad, finding that patents on the BRCA1 and BRCA2 genes were invalid. Myriad appealed the case, and it was heard by the US Court of Appeals for the Federal Circuit in April 2011. Three months later, the appeals court ruled in Myriad's favor, finding that companies can obtain patents on specific genes.
In March 2012, the US Supreme Court instructed the appeals court to reconsider the case after a unanimous ruling invalidated 2 patents on a blood test that determines drug dosages, which had been licensed to Prometheus Laboratories.
In August 2012, a divided federal appeals court (2 to 1) ruled in favor of Myriad and gene patents in general. However, the Court invalidated patents on methods used to compare gene sequences. A month later, the plaintiffs once again asked the Supreme Court to hear the challenge to Myriad's patents. In November 2012, the Supreme Court agreed to hear it.
Today's decision is likely to have far-reaching implications for the biotechnology industry, and will undoubtedly raise questions about the validity of thousands of other patents that are currently in force.
Victory for Both Sides?
Both sides of the court battle see the ruling as a victory. The American Society for Clinical Pathology (ASCP) and Breast Cancer Action, both plaintiffs in the case, have expressed satisfaction with the ruling in press releases.
"Isolated DNA is a product and law of nature, not an invention, so it is not open to patent protection," said Steve Kroft, MD, FASCP, president-elect of the ASCP, in a statement. "Gene patents hinder advances in patient care and make the process slower and more expensive for women to find out if they have certain gene mutations that could adversely affect their health."
According to the ASCP, the cost of BRCA testing will be considerably lower without patent protection, and laboratories nationwide will be able to conduct the tests. In addition, patients will be able to obtain a second opinion, which Myriad Genetics has not allowed.
Breast Cancer Action, a nonprofit advocacy group, called the decision
a "tremendous win for women's health — and for all our health!" They
echoed the sentiments of the ASCP, in that "Myriad's monopoly is broken
and other labs can conduct testing, perform vital research, and develop
treatments using the human BRCA1 and 2 genes."
Myriad also claimed victory because the Court upheld its claims on cDNA, and pointed out that the Court noted that many of Myriad's unchallenged claims are method claims applying knowledge about the BRCA1 and BRCA2 genes.
"We believe the Court appropriately upheld our claims on cDNA, and underscored the patent eligibility of our method claims, ensuring strong intellectual property protection for our BRACAnalysis test moving forward," said Peter D. Meldrum, president and CEO of Myriad. "More than 250,000 patients rely on our BRACAnalysis test annually, and we remain focused on saving and improving peoples' lives and lowering overall healthcare costs.
However, the ruling is not all bad news for Myriad.
The Court unanimously ruled that although naturally isolated DNA is not patentable, synthetically created exon-only strands of nucleotides — complementary (c)DNA — is patentable.
In essence, the Court ruled that 5 of Myriad's claims covering isolated DNA are not eligible for patents. But according to Myriad, the company holds more than "500 valid and enforceable claims in 24 different patents conferring strong patent protection for its BRACAnalysis test."
The ruling was written by Justice Thomas, who was joined by Chief Justice Roberts and Justices Kennedy, Ginsberg, Breyer, Alito, Sotomayor, and Kagan; Justice Scalia concurred in part. The Court held that "a naturally occurring DNA segment is a product of nature and not patent eligible merely because it has been isolated, but cDNA is patent eligible because it is not naturally occurring."
It notes that "Myriad's principal contribution was uncovering the precise location and genetic sequence of the BRCA1 and BRCA2 genes." Although this was an important contribution, "Myriad did not create or alter either the genetic information encoded in the BCRA1 and BCRA2 genes or the genetic structure of the DNA."
In the decision, Justice Thomas notes that Myriad's claims were not "saved by the fact that isolating DNA from the human genome severs chemical bonds and thereby creates a non-naturally occurring molecule." This is because the claims are "simply not expressed in terms of chemical composition, nor do they rely in any way on the chemical changes that result from the isolation of a particular section of DNA."
However, the decision leaves the door somewhat open on gene patenting because it distinguishes natural from synthetic DNA. The Court noted that "cDNA does not present the same obstacles to patentability as naturally occurring, isolated DNA segments."
More specifically, Justice Thomas points out that "cDNA retains the naturally occurring exons of DNA, but it is distinct from the DNA from which it was derived." Thus, this form of DNA is "not a 'product of nature' and is patent eligible under §101."
Long and Convoluted Journey
Today's decision puts an end to what has been a long and protracted case. Myriad acquired patents on the 2 genes in the mid-1990s. Since that time, it has become the sole commercial provider of testing services for BRCA1 and BRCA2 in the United States.
On May 12, 2009, the American Civil Liberties Union and the Public Patent Foundation filed a lawsuit against the US Patent and Trademark Office, Myriad Genetics, and the University of Utah Research Foundation, which hold the patents on the BRCA1 and BRCA2 genes. It charged that patents on human genes violate the First Amendment and patent law because genes are "products of nature," and therefore cannot be patented.
The coplaintiffs in the case, including several medical organizations, physicians, academic researchers, cancer survivors, and patient advocates, represented 150,000 geneticists, pathologists, and laboratory professionals.
On March 29, 2010, a New York federal court ruled against Myriad, finding that patents on the BRCA1 and BRCA2 genes were invalid. Myriad appealed the case, and it was heard by the US Court of Appeals for the Federal Circuit in April 2011. Three months later, the appeals court ruled in Myriad's favor, finding that companies can obtain patents on specific genes.
In March 2012, the US Supreme Court instructed the appeals court to reconsider the case after a unanimous ruling invalidated 2 patents on a blood test that determines drug dosages, which had been licensed to Prometheus Laboratories.
In August 2012, a divided federal appeals court (2 to 1) ruled in favor of Myriad and gene patents in general. However, the Court invalidated patents on methods used to compare gene sequences. A month later, the plaintiffs once again asked the Supreme Court to hear the challenge to Myriad's patents. In November 2012, the Supreme Court agreed to hear it.
Today's decision is likely to have far-reaching implications for the biotechnology industry, and will undoubtedly raise questions about the validity of thousands of other patents that are currently in force.
Victory for Both Sides?
Both sides of the court battle see the ruling as a victory. The American Society for Clinical Pathology (ASCP) and Breast Cancer Action, both plaintiffs in the case, have expressed satisfaction with the ruling in press releases.
"Isolated DNA is a product and law of nature, not an invention, so it is not open to patent protection," said Steve Kroft, MD, FASCP, president-elect of the ASCP, in a statement. "Gene patents hinder advances in patient care and make the process slower and more expensive for women to find out if they have certain gene mutations that could adversely affect their health."
According to the ASCP, the cost of BRCA testing will be considerably lower without patent protection, and laboratories nationwide will be able to conduct the tests. In addition, patients will be able to obtain a second opinion, which Myriad Genetics has not allowed.
Information from Industry
Myriad also claimed victory because the Court upheld its claims on cDNA, and pointed out that the Court noted that many of Myriad's unchallenged claims are method claims applying knowledge about the BRCA1 and BRCA2 genes.
"We believe the Court appropriately upheld our claims on cDNA, and underscored the patent eligibility of our method claims, ensuring strong intellectual property protection for our BRACAnalysis test moving forward," said Peter D. Meldrum, president and CEO of Myriad. "More than 250,000 patients rely on our BRACAnalysis test annually, and we remain focused on saving and improving peoples' lives and lowering overall healthcare costs.
"
Thursday, June 13, 2013
A NICE EXAMPLE OF TARGETING THERAPY,
While one will quickly think of CML and the Gleevec story as a hit and run case (I really meant Home Run case) of successful targeting therapy, there is a forgotten case. Secretly but concretly established is the case of the GIANT CELL TUMOR OF THE BONE. The condition is rare but can be a pain in the neck if you pardon my french! In one percent of cases, it can even Metastasize! Go figure! for what is described a "benign" disease
It is cause by the RANKL, those receptor that call the Osteoclast like cells to come in the theater and destroy the bone! well we found DENOSUMAB, and it gave us 80% response rate. nothing to be ashamed about. DENOSUMAB A GOOD TARGET THERAPY!
AND LIKE IN GOOD COMMERCIAL, THEY GIVE YOU IN SMALL PRINTS (yes but watch for headache,nausea,,hypocalcemia, hypophosphatemia and osteonecrosis of the jaw) AND HOPE YOU DID NOT SEE IT!
While one will quickly think of CML and the Gleevec story as a hit and run case (I really meant Home Run case) of successful targeting therapy, there is a forgotten case. Secretly but concretly established is the case of the GIANT CELL TUMOR OF THE BONE. The condition is rare but can be a pain in the neck if you pardon my french! In one percent of cases, it can even Metastasize! Go figure! for what is described a "benign" disease
It is cause by the RANKL, those receptor that call the Osteoclast like cells to come in the theater and destroy the bone! well we found DENOSUMAB, and it gave us 80% response rate. nothing to be ashamed about. DENOSUMAB A GOOD TARGET THERAPY!
AND LIKE IN GOOD COMMERCIAL, THEY GIVE YOU IN SMALL PRINTS (yes but watch for headache,nausea,,hypocalcemia, hypophosphatemia and osteonecrosis of the jaw) AND HOPE YOU DID NOT SEE IT!
GENES IN SARCOMA (CONTINUE)
GNAS-1
This is the perfect example that intermediaries in a pathways can be critical
when a receptor is linked to its ligand, the chemical reaction goes nowhere without some G-protein taking the flash and transmitting this spark to Adenylate Cyclase. When you see danger, you stand to fight back or run to safety because of GNAS gene. Believe Me Adrenaline rush will no do you a thing without GNAS, the Gene is so important they gave a Nobel Prize to the guy who found it.
" . A Nobel Prize was awarded to Earl Sutherland in 1971 for discovering the key role of AC-III in human liver, where adrenaline indirectly stimulates AC to mobilize stored energy in the "fight or flight" response. The effect of adrenaline is via a G protein signaling cascade, which transmits chemical signals from outside the cell across the membrane to the inside of the cell (cytoplasm). The outside signal (in this case, adrenaline) binds to a receptor, which transmits a signal to the G protein, which transmits a signal to adenylate cyclase, which transmits a signal by converting adenosine triphosphate to cyclic adenosine monophosphate (cAMP). cAMP is known as a second messenger.[1]wikipedia"
-----------------------------
And I have mentioned that any important gene give a deformity if missing, this one does. The name of the deformity
GNAS-1
This is the perfect example that intermediaries in a pathways can be critical
when a receptor is linked to its ligand, the chemical reaction goes nowhere without some G-protein taking the flash and transmitting this spark to Adenylate Cyclase. When you see danger, you stand to fight back or run to safety because of GNAS gene. Believe Me Adrenaline rush will no do you a thing without GNAS, the Gene is so important they gave a Nobel Prize to the guy who found it.
" . A Nobel Prize was awarded to Earl Sutherland in 1971 for discovering the key role of AC-III in human liver, where adrenaline indirectly stimulates AC to mobilize stored energy in the "fight or flight" response. The effect of adrenaline is via a G protein signaling cascade, which transmits chemical signals from outside the cell across the membrane to the inside of the cell (cytoplasm). The outside signal (in this case, adrenaline) binds to a receptor, which transmits a signal to the G protein, which transmits a signal to adenylate cyclase, which transmits a signal by converting adenosine triphosphate to cyclic adenosine monophosphate (cAMP). cAMP is known as a second messenger.[1]wikipedia"
-----------------------------
And I have mentioned that any important gene give a deformity if missing, this one does. The name of the deformity
Polyostotic fibrous dysplasia, look it up!
In the brain GNAS-1 dances with important people such as RIC8 which has a nice name to fool you Synembryn-A,
mess with Synembryn A and brace yourself to deal with DGK-1, and EGL-30
to know more ask Klattenhoff!
Klattenhoff C, Montecino M, Soto X, et al.
(2003). "Human brain synembryn interacts with Gsalpha and Gqalpha and
is translocated to the plasma membrane in response to isoproterenol and
carbachol.". J. Cell. Physiol. 195 (2): 151–7.
That is the pattern of cellular events, "start small and keep amplifying"
----------------------------------------another intermediary we spoke about was GNA12
there we discussed already the role of anti-CD44 and anti-P110 alpha
and its link to HSP90.
Puzzled? go to article-blog!
PONDERING ABOUT SARCOMA
GENETIC SYNDROMES ASSOCIATED WITH SARCOMA
1. LI FREUMANI ASSOCIATED WITH P 53
2. RETINOBLASTOMA ASSOCIATED WITH Rb 1 DELETION
3. NEUROFIBROMATOSIS TYPE 1, WELL EASY NF-1 MUTATION
4. GARDNER SNDROME ASSOCIATED WITH APC MUTATION
5. McCUNE ALBRIGHT SYNDROME ASSOCIATED WITH GNAS-1 MUTATION
6. BLOOM, ROTHMUND THOMPSON &WERNER ASSOCIATED WITH LOSS OF HELICASE FUNCTION
ALSO
WELL DIFFERENTIATED LIPOSARCOMA IS LINKED TO AMPLIFICATION OF MDM2, MUTATION IN CDK4 (AMPLIFICATION MEANS A CLEAR DRIVER GENE, REPRESSING THIS MAY HAVE AN EFFECT AS A THERAPEUTIC INTERVENTION, TRY IT!)
DID YOU KNOW THAT IN OSTEOSARCOMA, METASTASIS TO LYMPH NODES IS SO RARE THE DISEASE IS STAGE IV WHEN THIS HAPPEN? CONVERSELY, LUNG METS CAN BE REMOVED AND SOME PEOPLE BELIEVE IT IS NOT STAGE IV (THAT'S WHAT HAPPEN WHEN POLITICIANS GETS INVOLVED IN SCIENCE!) BUT THIS IS TRUE BELIEVE ME, CHECK IT OUT!
WITH THE HELICASE! YOU'RE TALKING THE HELIX OF DNA
THERE IS THE SCIENCE IN DEPTH !
"Many cellular processes, such as DNA replication, transcription, translation, recombination, DNA repair, and ribosome biogenesis involve the separation of nucleic acid strands that necessitates the use of helicases."WIKIPEDIA
WHEN SOMEONE IS TALIKNG HELICASE, DROP EVERYTHING AND LOOK AT HIM
HE IS TALKING DNA SCIENCE! AND THIS IS SERIOUS BECAUSE SO MANY GENES ARE INVOLVED, BRAIN MALFORMATION AND MALFUNCTION ARE INVOLVED, AND MORE IMPORTANTLY APOPTOSIS (THE CURE) IS NOT FAR AWAY!
" These functions assist in prevention of apoptosis, resulting in cortical size regulation, as well as a contribution to the survival of hippocampal and cortical structures, affecting memory and learning.[26] This helicase is located on the X chromosome (Xq13.1-q21.1)" GENES ? A SLEW INVOLVED!
GENETIC SYNDROMES ASSOCIATED WITH SARCOMA
1. LI FREUMANI ASSOCIATED WITH P 53
2. RETINOBLASTOMA ASSOCIATED WITH Rb 1 DELETION
3. NEUROFIBROMATOSIS TYPE 1, WELL EASY NF-1 MUTATION
4. GARDNER SNDROME ASSOCIATED WITH APC MUTATION
5. McCUNE ALBRIGHT SYNDROME ASSOCIATED WITH GNAS-1 MUTATION
6. BLOOM, ROTHMUND THOMPSON &WERNER ASSOCIATED WITH LOSS OF HELICASE FUNCTION
ALSO
WELL DIFFERENTIATED LIPOSARCOMA IS LINKED TO AMPLIFICATION OF MDM2, MUTATION IN CDK4 (AMPLIFICATION MEANS A CLEAR DRIVER GENE, REPRESSING THIS MAY HAVE AN EFFECT AS A THERAPEUTIC INTERVENTION, TRY IT!)
DID YOU KNOW THAT IN OSTEOSARCOMA, METASTASIS TO LYMPH NODES IS SO RARE THE DISEASE IS STAGE IV WHEN THIS HAPPEN? CONVERSELY, LUNG METS CAN BE REMOVED AND SOME PEOPLE BELIEVE IT IS NOT STAGE IV (THAT'S WHAT HAPPEN WHEN POLITICIANS GETS INVOLVED IN SCIENCE!) BUT THIS IS TRUE BELIEVE ME, CHECK IT OUT!
WITH THE HELICASE! YOU'RE TALKING THE HELIX OF DNA
THERE IS THE SCIENCE IN DEPTH !
"Many cellular processes, such as DNA replication, transcription, translation, recombination, DNA repair, and ribosome biogenesis involve the separation of nucleic acid strands that necessitates the use of helicases."WIKIPEDIA
WHEN SOMEONE IS TALIKNG HELICASE, DROP EVERYTHING AND LOOK AT HIM
HE IS TALKING DNA SCIENCE! AND THIS IS SERIOUS BECAUSE SO MANY GENES ARE INVOLVED, BRAIN MALFORMATION AND MALFUNCTION ARE INVOLVED, AND MORE IMPORTANTLY APOPTOSIS (THE CURE) IS NOT FAR AWAY!
" These functions assist in prevention of apoptosis, resulting in cortical size regulation, as well as a contribution to the survival of hippocampal and cortical structures, affecting memory and learning.[26] This helicase is located on the X chromosome (Xq13.1-q21.1)" GENES ? A SLEW INVOLVED!
Wednesday, June 12, 2013
Dear Colleagues:
On
May 7, 2013, Governor Pence signed Senate Bill 415 mandating that on
July 1, 2015, a provider that is licensed under Indiana Code 25 and who
is authorized within the
provider’s scope of practice to administer immunizations shall
electronically provide immunization data to the immunization data
registry for all immunizations administered to individuals who are less
than nineteen (19) years of age. This important legislative
mandate will move Indiana closer to the Healthy People 2020 goal of
properly immunizing children by creating a comprehensive immunization
record of all administered vaccines.
Please see the attached memo for additional information.
William C. VanNess II, MD
State Health Commissioner
HINTS OF TARGET THERAPY! JUST DO IT AND THANK ME LATER!
Proposed cytosine cycle.
" Five-hydromethylcytosine (hmC) is generated from 5-methylcytosine (mC) through oxidation catalyzed by the TET family of oxygenases. HmC may then be deaminated by members of the AID/APOBEC family and the resulting 5-hydroxymethyluracyl (hmU) is excised by thymine–DNA glycosylase (TDG), or another DNA glycosylase. This initiates the base excision repair process (BER), leading to replacement of hmU by an unmethylated cytosine. Further oxidation of hmC by TET enzymes may lead to 5-formylcytosine (fC) or 5-carboxylcytosine (caC). These modified cytosines may be specifically recognized and excised by TDG, leading to subsequent BER activity. CaC may also be converted to cytosine by a not yet identified decarboxylase. Oxidation of mC may also impair their recognition by maintenance methyltransferase DNMT1 and allow replication-dependent demethylation. A: abasic (apurinic/apyrimidinic) site."(Mercher et al)
-----------------------------------------------------------------------------
Disruptive antibody
PDZK1 is a scaffold protein that connects plasma membrane proteins and regulatory components, regulating their surface expression in epithelial cells apical domains. It may be involved in the coordination of a diverse range of regulatory processes for ion transport and second messenger cascades. In complex with SLC9A3R1, it may cluster proteins that are functionally dependent in a mutual fashion and modulate the trafficking and the activity of the associated membrane proteins. It may also play a role in the cellular mechanisms associated with multidrug resistance through its interaction with ABCC2 and PDZK1IP1. May potentiate the CFTR chloride channel activity. PDZK1 functions to connect SCARB1 with the cellular machineries for intracellular cholesterol transport and/or metabolism and may be involved in the regulation of proximal tubular Na(+)-dependent inorganic phosphate cotransport therefore playing an important role in tubule function (life science research)
-------------------------------------------------------------------------------------------
IDAX gene blocks the devil (Dvl) and therefore the Wnt, and through Caspase 3, regulate the TET2.
Block the PDZ locus on the Devil and you can get Leukemia under control!
=====================================================
FOR ANGIOSARCOMA , GO TO YOUNG'S NOTE
Proposed cytosine cycle.
" Five-hydromethylcytosine (hmC) is generated from 5-methylcytosine (mC) through oxidation catalyzed by the TET family of oxygenases. HmC may then be deaminated by members of the AID/APOBEC family and the resulting 5-hydroxymethyluracyl (hmU) is excised by thymine–DNA glycosylase (TDG), or another DNA glycosylase. This initiates the base excision repair process (BER), leading to replacement of hmU by an unmethylated cytosine. Further oxidation of hmC by TET enzymes may lead to 5-formylcytosine (fC) or 5-carboxylcytosine (caC). These modified cytosines may be specifically recognized and excised by TDG, leading to subsequent BER activity. CaC may also be converted to cytosine by a not yet identified decarboxylase. Oxidation of mC may also impair their recognition by maintenance methyltransferase DNMT1 and allow replication-dependent demethylation. A: abasic (apurinic/apyrimidinic) site."(Mercher et al)
-----------------------------------------------------------------------------
Disruptive antibody
PDZK1 is a scaffold protein that connects plasma membrane proteins and regulatory components, regulating their surface expression in epithelial cells apical domains. It may be involved in the coordination of a diverse range of regulatory processes for ion transport and second messenger cascades. In complex with SLC9A3R1, it may cluster proteins that are functionally dependent in a mutual fashion and modulate the trafficking and the activity of the associated membrane proteins. It may also play a role in the cellular mechanisms associated with multidrug resistance through its interaction with ABCC2 and PDZK1IP1. May potentiate the CFTR chloride channel activity. PDZK1 functions to connect SCARB1 with the cellular machineries for intracellular cholesterol transport and/or metabolism and may be involved in the regulation of proximal tubular Na(+)-dependent inorganic phosphate cotransport therefore playing an important role in tubule function (life science research)
-------------------------------------------------------------------------------------------
IDAX gene blocks the devil (Dvl) and therefore the Wnt, and through Caspase 3, regulate the TET2.
Block the PDZ locus on the Devil and you can get Leukemia under control!
=====================================================
FOR ANGIOSARCOMA , GO TO YOUNG'S NOTE
II
Abstract
Background:
Angiogenesis is the process of new blood vessel formation
,
and is regulated by angiogenic growth factors
including vascular endothelial growth factor (VEGF)
.
Angiosarcomas are rare, aggressive vascular tumours
.
Studies were performed to investigate the expression of angiogenicgrowth factors in angiosarcoma
,
and to assess vascular targeted agents for the treatment of angiosarcoma
.
Methods:
In vitro studies compared
two human cutaneous angiosarcoma cell lines (ASM and ISO-HAS) with human dermal microvascular endothelial cells (HuD MECs).
The cell lines were compared in functional assays
,
including cell viability, cell differentiaiton and cell migration assays, and protein expression profiled using antibody arrays. Cell responses to vascular targeted agents were compared including response to bevacizumab an anti-VEGF antibody, axitinib a VEGFreceptor (VEGFR) tyrosine
kinase inhibitor
,
selumetinib a MEK inhibitor and DMXAA a vascular disrupting agent.'
Tuesday, June 11, 2013
CXCR4, THE CRBCM IS LOOKING INTO THIS!JUST GO AHEAD AND BRUSH UP WITH ME!
WIKIPEDIA!
'CXCR-4 is an alpha-chemokine receptor specific for stromal-derived-factor-1 (SDF-1 also called CXCL12), a molecule endowed with potent chemotactic activity for lymphocytes. This receptor is one of several chemokine receptors that HIV can use to infect CD4+ T cells. HIV isolates that use CXCR4 are traditionally known as T-cell tropic isolates. Typically, these viruses are found late in infection. It is unclear as to whether the emergence of CXCR4-using HIV is a consequence or a cause of immunodeficiency.
CXCR4 is upregulated during the implantation window in natural and hormone replacement therapy cycles in the endometrium, producing, in presence of a human blastocyst, a surface polarization of the CXCR4 receptors suggesting that this receptor is implicated in the adhesion phase of human implantation.
CXCR4's ligand SDF-1 is known to be important in hematopoietic stem cell homing to the bone marrow and in hematopoietic stem cell quiescence. Until recently, SDF-1 and CXCR4 were believed to be a relatively "monogamous" ligand-receptor pair (other chemokines tend to use several different chemokine receptors in a fairly "promiscuous" manner). Recent evidence demonstrates ubiquitin is also a natural ligand of CXCR4.[3] Ubiquitin is a small (76-amino acid) protein highly conserved among eukaryotic cells. It is best known for its intracellular role in targeting ubiquitylated proteins for degradation via the ubiquitin proteasome system. Evidence in numerous animal models suggests ubiquitin is anti-inflammatory immune modulator and endogenous opponent of proinflammatory damage associated molecular pattern molecules.[4] It is speculated this interaction may be through CXCR4 mediated signalling pathways.
It has been associated with WHIM syndrome.[6]
While CXCR4’s expression is low or absent in many healthy tissues, it was demonstrated to be expressed in over 23 types of cancer, including breast cancer, ovarian cancer, melanoma, and prostate cancer. Expression of this receptor in cancer cells has been linked to metastasis to tissues containing a high concentration of CXCL12, such as lungs, liver and bone marrow.[7][8] However, in breast cancer where SDF1/CXCL12 is also expressed by the cancer cells themselves along with CXCR4, CXCL12 expression is positively correlated with disease free (metastasis free) survival. CXCL12 (over-)expressing cancers might not sense the CXCL12 gradient released form the metastasis target tissues since the receptor, CXCR4, is saturated with the ligand produced in an autocrine manner.[9] Another explanation of this observation is provided by a study that shows the ability of CXCL12 (and CCL2) producing tumors to entrain neutrophils that inhibit seeding of tumor cells in the lung.[10]
===========================================================
AND WHY? READ THIS
IS THERE A RELATION WITH TRIPLE NEGATIVE BREAST CANCER?
HOW DOES STIMULATION OF CXR4 LINKED TO INTERFERON?
IS THERE CORRELATION WITH PSORIASIS? (PRSOS1?) THESE ARE THE QUESTIONS WE ARE STRUGGLING WITH?
WIKIPEDIA!
'CXCR-4 is an alpha-chemokine receptor specific for stromal-derived-factor-1 (SDF-1 also called CXCL12), a molecule endowed with potent chemotactic activity for lymphocytes. This receptor is one of several chemokine receptors that HIV can use to infect CD4+ T cells. HIV isolates that use CXCR4 are traditionally known as T-cell tropic isolates. Typically, these viruses are found late in infection. It is unclear as to whether the emergence of CXCR4-using HIV is a consequence or a cause of immunodeficiency.
CXCR4 is upregulated during the implantation window in natural and hormone replacement therapy cycles in the endometrium, producing, in presence of a human blastocyst, a surface polarization of the CXCR4 receptors suggesting that this receptor is implicated in the adhesion phase of human implantation.
CXCR4's ligand SDF-1 is known to be important in hematopoietic stem cell homing to the bone marrow and in hematopoietic stem cell quiescence. Until recently, SDF-1 and CXCR4 were believed to be a relatively "monogamous" ligand-receptor pair (other chemokines tend to use several different chemokine receptors in a fairly "promiscuous" manner). Recent evidence demonstrates ubiquitin is also a natural ligand of CXCR4.[3] Ubiquitin is a small (76-amino acid) protein highly conserved among eukaryotic cells. It is best known for its intracellular role in targeting ubiquitylated proteins for degradation via the ubiquitin proteasome system. Evidence in numerous animal models suggests ubiquitin is anti-inflammatory immune modulator and endogenous opponent of proinflammatory damage associated molecular pattern molecules.[4] It is speculated this interaction may be through CXCR4 mediated signalling pathways.
Clinical significance
Drugs that block the CXCR4 receptor appear to be capable of "mobilizing" hematopoietic stem cells into the bloodstream as peripheral blood stem cells. Peripheral blood stem cell mobilization is very important in hematopoietic stem cell transplantation (as a recent alternative to transplantation of surgically harvested bone marrow) and is currently performed using drugs such as G-CSF. G-CSF is a growth factor for neutrophils (a common type of white blood cells), and may act by increasing the activity of neutrophil-derived proteases such as neutrophil elastase in the bone marrow leading to proteolytic degradation of SDF-1. Plerixafor (AMD3100) is a drug, recently approved for routine clinical use,[5] which directly blocks the CXCR4 receptor. It is a very efficient inducer of hematopoietic stem cell mobilization in animal and human studies.It has been associated with WHIM syndrome.[6]
While CXCR4’s expression is low or absent in many healthy tissues, it was demonstrated to be expressed in over 23 types of cancer, including breast cancer, ovarian cancer, melanoma, and prostate cancer. Expression of this receptor in cancer cells has been linked to metastasis to tissues containing a high concentration of CXCL12, such as lungs, liver and bone marrow.[7][8] However, in breast cancer where SDF1/CXCL12 is also expressed by the cancer cells themselves along with CXCR4, CXCL12 expression is positively correlated with disease free (metastasis free) survival. CXCL12 (over-)expressing cancers might not sense the CXCL12 gradient released form the metastasis target tissues since the receptor, CXCR4, is saturated with the ligand produced in an autocrine manner.[9] Another explanation of this observation is provided by a study that shows the ability of CXCL12 (and CCL2) producing tumors to entrain neutrophils that inhibit seeding of tumor cells in the lung.[10]
Drug response
Chronic exposure to THC increased T lymphocyte CXCR4 expression on both CD4+ and CD8+ T lymphocytes. [11]Interactions
CXCR4 has been shown to interact with USP14.[12]"===========================================================
AND WHY? READ THIS
IS THERE A RELATION WITH TRIPLE NEGATIVE BREAST CANCER?
HOW DOES STIMULATION OF CXR4 LINKED TO INTERFERON?
IS THERE CORRELATION WITH PSORIASIS? (PRSOS1?) THESE ARE THE QUESTIONS WE ARE STRUGGLING WITH?
PATIENTS WITH EARLY STAGE BREAST CANCER RECEIVE AC FOLLOWED BY TAXOL ON AN EVERY 2 WEEKS BASES. NOW IT IS REPORTED THAT THE TAXOL PORTION CAN BE GIVEN WEEKLY WITH LESS TOXICITY AND WITHOUT NEED FOR GROWTH FACTOR AND FOR SAME EFFICACY...TRY IT!
READ:""ONLINE FIRST: Early Breast Cancer: Less Toxicity, Similar Efficacy with Weekly Paclitaxel vs. Every-Two Week Regimen
READ:""ONLINE FIRST: Early Breast Cancer: Less Toxicity, Similar Efficacy with Weekly Paclitaxel vs. Every-Two Week Regimen
BY RABIYA S. TUMA, PHD"(ONCOLOGY TIMES)
*FDA HAS APPROVED LENALINOMIDE FOR REFRACTORY MANTLE CELL LUMPHOMA
"Out of 133 patients who were evaluable for efficacy: 26% had an overall response; 7% achieved a complete response or an unconfirmed complete response; and 19% achieved a partial response. Median duration of response for the patients who achieved a complete, an unconfirmed complete, or a partial response was 16.6 months." PER ONCOLOGY TIME.
*AS THE INCIDENCE OF MELANOMA IS INCREASING, IT IS WELCOME NEWS THAT THERE IS PROGRESS IN THE MANAGEMENT OF THIS DISEASE, AND THE INTRODUCTION OF IPILIMUMAB AND VEMURAFENIB HAVE CHANGED NCCN GUIDELINES.
YET THE REPORTED 20 YEAR SURVIVAL IS STILL REPORTED AS
STAGE I 90% WITH 10% OF PEOPLE DYING WITH THIS DISEASE
STAGE II 50% WITH HALF OF THESE PATIENTS DYING OF MELANOMA
STAGE III 40% WITH 60% DYING OF THE DISEASE
STAGE IV 5-10% WITH 90-95 % DYING.
FOR A WHILE THERE, THERE WAS NO CHANGE OF SURVIVAL IN STAGE IV UNTIL THE ARRIVAL OF IPILIMUMAB, A T CELL ACTIVITY MODULATOR.
AND FOR THOSE BRAF POSITIVE, VEMURAFENIB IS AN OPTION. REISTANCE TO BRAF CAN BE EXPECTED IF GENES DOWN STREAM ARE OVEREXPRESS. THIS IS WHERE MEK IS LOCATED, AND ADDING ANTI MEK (TRAMETINIB) TO ANTI-BRAF (DABRAFENIB) HAS BEEN SHOWN TO INCREASE RESPONSE RATE. NOTABLY THE COMBINATION HAS LESS SKIN TOXICITY. BUT GET READY TO FIGHT PYREXIA IF YOU GO THIS WAY!
CONSIDER SENTINEL NODE DISSECTION IN PATIENT WHO'S LESION THICKNESS IS GREATER THAN 0.75mm.
"Out of 133 patients who were evaluable for efficacy: 26% had an overall response; 7% achieved a complete response or an unconfirmed complete response; and 19% achieved a partial response. Median duration of response for the patients who achieved a complete, an unconfirmed complete, or a partial response was 16.6 months." PER ONCOLOGY TIME.
*AS THE INCIDENCE OF MELANOMA IS INCREASING, IT IS WELCOME NEWS THAT THERE IS PROGRESS IN THE MANAGEMENT OF THIS DISEASE, AND THE INTRODUCTION OF IPILIMUMAB AND VEMURAFENIB HAVE CHANGED NCCN GUIDELINES.
YET THE REPORTED 20 YEAR SURVIVAL IS STILL REPORTED AS
STAGE I 90% WITH 10% OF PEOPLE DYING WITH THIS DISEASE
STAGE II 50% WITH HALF OF THESE PATIENTS DYING OF MELANOMA
STAGE III 40% WITH 60% DYING OF THE DISEASE
STAGE IV 5-10% WITH 90-95 % DYING.
FOR A WHILE THERE, THERE WAS NO CHANGE OF SURVIVAL IN STAGE IV UNTIL THE ARRIVAL OF IPILIMUMAB, A T CELL ACTIVITY MODULATOR.
AND FOR THOSE BRAF POSITIVE, VEMURAFENIB IS AN OPTION. REISTANCE TO BRAF CAN BE EXPECTED IF GENES DOWN STREAM ARE OVEREXPRESS. THIS IS WHERE MEK IS LOCATED, AND ADDING ANTI MEK (TRAMETINIB) TO ANTI-BRAF (DABRAFENIB) HAS BEEN SHOWN TO INCREASE RESPONSE RATE. NOTABLY THE COMBINATION HAS LESS SKIN TOXICITY. BUT GET READY TO FIGHT PYREXIA IF YOU GO THIS WAY!
CONSIDER SENTINEL NODE DISSECTION IN PATIENT WHO'S LESION THICKNESS IS GREATER THAN 0.75mm.
MORE ABOUT 5-AZACITIDINE
Be careful though, when you give an hypomethylating agent, do not expect that the agent is de-methylating everywhere, some molecule end up being methylated, this is called Reverse Methylation. There seem to me a random (or not) reorganization of the methylation.
Moreau
"Exposure of cells to histone deacetylase inhibitors, or to the demethylating agent 5-aza-2′-deoxycytidine, revealed that HLA-G gene transcription is inhibited by DNA methylation. Reversal of methylation-mediated repression may directly induce HLA-G cell-surface expression, supporting the idea that HLA-G might be activated by such a mechanism during malignancy, inflammation, and allogenic reactions"
what is the meaning of this
is this point to limitation of this drug activity
should we be checking for HLA-G
more work is ahead I guess!
Be careful though, when you give an hypomethylating agent, do not expect that the agent is de-methylating everywhere, some molecule end up being methylated, this is called Reverse Methylation. There seem to me a random (or not) reorganization of the methylation.
Moreau
"Exposure of cells to histone deacetylase inhibitors, or to the demethylating agent 5-aza-2′-deoxycytidine, revealed that HLA-G gene transcription is inhibited by DNA methylation. Reversal of methylation-mediated repression may directly induce HLA-G cell-surface expression, supporting the idea that HLA-G might be activated by such a mechanism during malignancy, inflammation, and allogenic reactions"
what is the meaning of this
is this point to limitation of this drug activity
should we be checking for HLA-G
more work is ahead I guess!
Monday, June 10, 2013
HEIGHTS OF SPECULATIONS
It is generally said that infiltration of Lymphocytes in the tumor points to an immune response against the tumor and therefore imparts a good prognosis, and we did mention this earlier. But now comes the mitigation to this message, when those lymphocytes are TREG cells the picture is not so clear any more...
"In cancer such as Breast Cancer, there are data that intratumoral Treg cells confer poorer prognosis, in colorectal cancer, Treg cells convey a better prognosis."(Clurman) Just take a note of this!
Remember Treg are T cell regulators that "maintain tolerance by suppressing expansion of effector cells directed against self Antigen". If tumors comes from you, than they can have "self Antigen" and will get away with it! and attack you, protected by these Treg cells! Looking under these perspectives, it now becomes critical to know what Lymphocyte is in the tumor. A Treg T cell or a true Activated T cell. let's work at discerning these things before we comment on prognosis!
This point is very emphasized in clinical practice by the example of Ipilimumab. It is said that its effect resides in the removal of (check point) inhibitory effects of a T cell Regulator (such as the Treg discussed here) CTLA4. Removing these inhibitory influences unleashes the full might of the Activated T cell against the cancer. But the side effect to this is that tolerance of normal tissue is low leading to immune attack of even normal tissue. Cases of Colitis,dermatitis hepatitis, thyroid dysfunction and Stevens Johnson syndrome have been reported, so help you God, Colonic perforation even have been reported. But yes it is one of the only drug which in recent years or decades, has improved survival in Melanoma, and that is a big first.
It is generally said that infiltration of Lymphocytes in the tumor points to an immune response against the tumor and therefore imparts a good prognosis, and we did mention this earlier. But now comes the mitigation to this message, when those lymphocytes are TREG cells the picture is not so clear any more...
"In cancer such as Breast Cancer, there are data that intratumoral Treg cells confer poorer prognosis, in colorectal cancer, Treg cells convey a better prognosis."(Clurman) Just take a note of this!
Remember Treg are T cell regulators that "maintain tolerance by suppressing expansion of effector cells directed against self Antigen". If tumors comes from you, than they can have "self Antigen" and will get away with it! and attack you, protected by these Treg cells! Looking under these perspectives, it now becomes critical to know what Lymphocyte is in the tumor. A Treg T cell or a true Activated T cell. let's work at discerning these things before we comment on prognosis!
This point is very emphasized in clinical practice by the example of Ipilimumab. It is said that its effect resides in the removal of (check point) inhibitory effects of a T cell Regulator (such as the Treg discussed here) CTLA4. Removing these inhibitory influences unleashes the full might of the Activated T cell against the cancer. But the side effect to this is that tolerance of normal tissue is low leading to immune attack of even normal tissue. Cases of Colitis,dermatitis hepatitis, thyroid dysfunction and Stevens Johnson syndrome have been reported, so help you God, Colonic perforation even have been reported. But yes it is one of the only drug which in recent years or decades, has improved survival in Melanoma, and that is a big first.
Sunday, June 9, 2013
INTERESTING OBSERVATIONS
?Is it true that Azacitine will work better in warm conditions.
?will Azacidine work better in DNMT1 mutated cells
?is DNMT1 critical to the Polycomb/trithorax complex function
De-methylating without disabling this polycomb function mitigates the impact of demethylation because of memory issues! The cell seems to remember its status before de-methylation, you need to knock down DNMT1to potentiate the effect of 5-Azacitidine! May be adding Retinoic Acid?
COMBINATION OF ATRA WITH 5-AZACITIDINE?
?
KIM " This activity was augmented by histone deacetylase inhibition. These findings provide evidence of epigenetic dysregulation of estrogen receptor beta in atherosclerosis and vascular aging. We suggest that focal epigenetic changes in estrogen receptor beta contribute to the development of atherosclerosis and vascular aging."
POST MENOPAUSAL WOMEN SEE A DROP OF ESTROGEN, A METHYLATION OR THE GENE MAKING THE ESTROGEN RECEPTOR IS A PROGRAMMED EVENT, WILL DYSREGULATION OF THE POLYCOMB CHANGE THAT? OR IS-IT MUTATION OF THE DNMT1 AGAIN ENOUGH?
WHY LUPUS IS ACTIVE IN WOMEN AGE 15-44
IT HAS TO DO WITH THIS!
CESCHIN ET AL
"Multiple signaling pathways ultimately modulate the epigenetic information embedded in the chromatin of gene promoters by recruiting epigenetic enzymes. We found that, in estrogen-regulated gene programming, the acetyltransferase CREB-binding protein (CBP) is specifically and exclusively methylated by the coactivator-associated arginine methyltransferase (CARM1) in vivo. CARM1-dependent CBP methylation and p160 coactivators were required for estrogen-induced recruitment to chromatin targets. Notably, methylation increased the histone acetyltransferase (HAT) activity of CBP and stimulated its autoacetylation. Comparative genome-wide chromatin immunoprecipitation sequencing (ChIP-seq) studies revealed a variety of patterns by which p160, CBP, and methyl-CBP (meCBP) are recruited (or not) by estrogen to chromatin targets. Moreover, significant target gene-specific variation in the recruitment of (1) the p160 RAC3 protein, (2) the fraction of a given meCBP species within the total CBP, and (3) the relative recruitment of different meCBP species suggests the existence of a target gene-specific “fingerprint” for coregulator recruitment."
BELIEVE ME, ESTROGEN INCREASES GENE METHYLATION
PEGGY SUGGESTED OOPHORECTOMY AS MEANS TO CONTROL BAD LUPUS IN WOMEN OF REPRODUCTIVE AGE WHO HAVE HAD THEIR CHILDREN !? WHAT DO YOU THINK?
?Is it true that Azacitine will work better in warm conditions.
?will Azacidine work better in DNMT1 mutated cells
?is DNMT1 critical to the Polycomb/trithorax complex function
De-methylating without disabling this polycomb function mitigates the impact of demethylation because of memory issues! The cell seems to remember its status before de-methylation, you need to knock down DNMT1to potentiate the effect of 5-Azacitidine! May be adding Retinoic Acid?
COMBINATION OF ATRA WITH 5-AZACITIDINE?
?
Methylation of the estrogen receptor gene is associated with aging and atherosclerosis in the cardiovascular system.
Post WSKIM " This activity was augmented by histone deacetylase inhibition. These findings provide evidence of epigenetic dysregulation of estrogen receptor beta in atherosclerosis and vascular aging. We suggest that focal epigenetic changes in estrogen receptor beta contribute to the development of atherosclerosis and vascular aging."
POST MENOPAUSAL WOMEN SEE A DROP OF ESTROGEN, A METHYLATION OR THE GENE MAKING THE ESTROGEN RECEPTOR IS A PROGRAMMED EVENT, WILL DYSREGULATION OF THE POLYCOMB CHANGE THAT? OR IS-IT MUTATION OF THE DNMT1 AGAIN ENOUGH?
MicroRNA-152 mediates DNMT1-regulated DNA methylation in the estrogen receptor α gene.
Wang Y ET ALWHY LUPUS IS ACTIVE IN WOMEN AGE 15-44
IT HAS TO DO WITH THIS!
CESCHIN ET AL
"Multiple signaling pathways ultimately modulate the epigenetic information embedded in the chromatin of gene promoters by recruiting epigenetic enzymes. We found that, in estrogen-regulated gene programming, the acetyltransferase CREB-binding protein (CBP) is specifically and exclusively methylated by the coactivator-associated arginine methyltransferase (CARM1) in vivo. CARM1-dependent CBP methylation and p160 coactivators were required for estrogen-induced recruitment to chromatin targets. Notably, methylation increased the histone acetyltransferase (HAT) activity of CBP and stimulated its autoacetylation. Comparative genome-wide chromatin immunoprecipitation sequencing (ChIP-seq) studies revealed a variety of patterns by which p160, CBP, and methyl-CBP (meCBP) are recruited (or not) by estrogen to chromatin targets. Moreover, significant target gene-specific variation in the recruitment of (1) the p160 RAC3 protein, (2) the fraction of a given meCBP species within the total CBP, and (3) the relative recruitment of different meCBP species suggests the existence of a target gene-specific “fingerprint” for coregulator recruitment."
BELIEVE ME, ESTROGEN INCREASES GENE METHYLATION
PEGGY SUGGESTED OOPHORECTOMY AS MEANS TO CONTROL BAD LUPUS IN WOMEN OF REPRODUCTIVE AGE WHO HAVE HAD THEIR CHILDREN !? WHAT DO YOU THINK?
INTERESTING ASSUMPTION!
The observation that Systemic Lupus Erythematosus occurs mostly in female patients to a rate of 8-9:1 over males, and mostly between the age 15 to 44 points to the female reproductive years. These years are characterized by the reign of Estrogen and its potential suppression of class I Antigen (HLA Antigens) to protect the child from rejection. We are suggesting that Estrogen would somehow increase epigenic events through Methylation most likely, affects type I Interferon, the destroyer in Lupus, and causes exacerbation of Lupus!
If methylation is that important, Azacytidine could be important in the treatment of Lupus particularly those patient with TET2 Mutation positive ???LET'S GO TO WORK
THE NEW KNOWLEDGE THAT AZACITIDINE HAS IMMUNE IMPLICATION FURTHER SUPPORTS THESE ASSUMPTIONS!
The observation that Systemic Lupus Erythematosus occurs mostly in female patients to a rate of 8-9:1 over males, and mostly between the age 15 to 44 points to the female reproductive years. These years are characterized by the reign of Estrogen and its potential suppression of class I Antigen (HLA Antigens) to protect the child from rejection. We are suggesting that Estrogen would somehow increase epigenic events through Methylation most likely, affects type I Interferon, the destroyer in Lupus, and causes exacerbation of Lupus!
If methylation is that important, Azacytidine could be important in the treatment of Lupus particularly those patient with TET2 Mutation positive ???LET'S GO TO WORK
THE NEW KNOWLEDGE THAT AZACITIDINE HAS IMMUNE IMPLICATION FURTHER SUPPORTS THESE ASSUMPTIONS!
REASON FOR OUR COALITION: THE BREAST CANCER PARADOX
RACIAL DISPARITIES IN INCIDENCE AND MORTALITY OF BREAST CANCER.
=============================================================
Population based research have indeed pointed out unique racial disparities into the prevalence and mortality of breast cancers in the United States. These disparities have been CONSISTENTLY occurring without being met effectively because of lack of political will by mostly white leaders, and a weak misrepresented minority populations (Hispanic and black population appear equally affected) which has not grasp the extent of this problem! And the fact that it represents the LARGEST OPPORTUNITY to curb mortality for this particular disease. (after Mammogram, hormone treatment, the BRCA discovery, are just some of the major interventions that curbed Mortality of Breast Cancer)
As stated above, these disparity have been consistently occurring years after years and grown into a sad phenomena well coined "The Breast Cancer Paradox". People (researchers) have taken the time to coin it but relatively nothing is being done about it! THE PARADOX IS FOUND IN THE FACT THAT THE INCIDENCE OF BREAST CANCER IN HISPANIC AND AFRICAN AMERICAN POPULATIONS IS LOW (YES LOW LOW LOW) AS IT COMPARES TO THE WHITE POPULATION. BUT DID YOU KNOW THAT THE MORTALITY IN THE MINORITY POPULATION IS HIGHER (YES HIGH, HIGH, HIGH!). BASICALLY MANY PEOPLE (3000 (OUT OF 6000) AFRICAN AMERICAN WOMEN ALONE DIE A YEAR FROM BREAST CANCER FOR LACK OF INTERVENTION).
This fact has been described time and time again, it has been coined "Breast cancer Paradox", it has been looked at and ponder on, BUT NO EMERGENCY HAS BEEN DECLARED IN OUR TRILLION DOLLAR ECONOMY, NO PRIORITY HAS BEEN DECLARED, NO-ONE REALLY CARE ENOUGH TO RAISE THE ISSUE THE WAY IT SHOULD BE !
YET! The dichotomy has been observed years after years, and suscitated some comments some interest as a social curiosity can, or a scientific oberservation would. But nothing comprehensive has been declared. Our attempt to involve CPRIT has fallen in political quagmire and died with the CPRIT debacle. The COALITION will bring back the fore front! It is a shame for this great nation to fail to recognize what is really happening with unchanged deaths in its minority population!
OF EVEN GREATER INTEREST IS THE OBSERVATION THAT:
-------------------------------------------------------------------------
This Unique and deadly Breast cancer has unique charasteristics that strengthen the notion that it is genetic based. Indeed the Breast cancers involving minorities, are mostly triple negative therefore cannot benefit meaningfully from 2 major therapeutic interventions: Hormonal treatment and Herceptin and related drugs that seems the focus of our new drug developments. Research seems to look the other way all together folks!
Furthermore and to re-enforce the monolytic and genetic basis of the Breast cancer observed in blacks and Hispanics, up to 70% in some areas of these triple negative cases, have the unique Basal cell like morphology WELL DESCRIBED AGAIN. THE UNIQUENESS OF THIS PATHOLOGY SHOULD IN NORMAL CIRCUMSTANCES BEG AND CALL FOR IMMEDIATE INVESTIGATIONS WITH THE MEANS WE HAVE TODAY. BUT SILENCE IS WHAT WE HAVE TODAY!
WE HAD HOPED THAT THE DISCOVERY OF THE HUMAN GENOME WILL BRING CLEAR ANSWERS. BUT YES THEY DECODED THE GENOME OF THE TRIPLE NEGATIVE BREAST CANCER. BUT ALL WE GOT IS THAT IT LOOKS LIKE OVARIAN CANCERS. THAT IS DRUGS USED IN THAT DISEASE (TAXANE, PLATINUM) CAN BE USED IN THIS TRIPLE NEGATIVE BREAST CANCER, THIS WAS ALREADY IN PRACTICE, NO ADVANCEMENT THERE. SO WHERE DO WE GO FROM HERE. FOLKS ARE STILL DYING!
CRBCM HAS BEEN PUSHING FOR A COMPREHENSIVE - PRIORITY BASED PROGRAM BUT OUR EFFORTS ARE DYING IN DEATH EARS, NO POLITICIAN IS FULLY EMBRACING THE CAUSE! CRBCM EARLY CONCERNS WERE SURVIVAL OF THE ORGANIZATION, NOW THAT GREATER EAST CANCER CENTER, THE PARENT ORGANIZATION, IS OF FIRM GROUNDS, AND WE ARE NOT GOING ANYWHERE, WE ARE LAUNCHING A SECOND WIND OF CONSCIENCE-RAISING-ACTIVITIES TO ADDRESS THIS DISPARITY IN CANCER RESEARCH.
CRBCM IS DEDICATED TO OPEN THE DOOR TO THIS EMERGENCY! AND YOU CAN HELP!
RACIAL DISPARITIES IN INCIDENCE AND MORTALITY OF BREAST CANCER.
=============================================================
Population based research have indeed pointed out unique racial disparities into the prevalence and mortality of breast cancers in the United States. These disparities have been CONSISTENTLY occurring without being met effectively because of lack of political will by mostly white leaders, and a weak misrepresented minority populations (Hispanic and black population appear equally affected) which has not grasp the extent of this problem! And the fact that it represents the LARGEST OPPORTUNITY to curb mortality for this particular disease. (after Mammogram, hormone treatment, the BRCA discovery, are just some of the major interventions that curbed Mortality of Breast Cancer)
As stated above, these disparity have been consistently occurring years after years and grown into a sad phenomena well coined "The Breast Cancer Paradox". People (researchers) have taken the time to coin it but relatively nothing is being done about it! THE PARADOX IS FOUND IN THE FACT THAT THE INCIDENCE OF BREAST CANCER IN HISPANIC AND AFRICAN AMERICAN POPULATIONS IS LOW (YES LOW LOW LOW) AS IT COMPARES TO THE WHITE POPULATION. BUT DID YOU KNOW THAT THE MORTALITY IN THE MINORITY POPULATION IS HIGHER (YES HIGH, HIGH, HIGH!). BASICALLY MANY PEOPLE (3000 (OUT OF 6000) AFRICAN AMERICAN WOMEN ALONE DIE A YEAR FROM BREAST CANCER FOR LACK OF INTERVENTION).
This fact has been described time and time again, it has been coined "Breast cancer Paradox", it has been looked at and ponder on, BUT NO EMERGENCY HAS BEEN DECLARED IN OUR TRILLION DOLLAR ECONOMY, NO PRIORITY HAS BEEN DECLARED, NO-ONE REALLY CARE ENOUGH TO RAISE THE ISSUE THE WAY IT SHOULD BE !
YET! The dichotomy has been observed years after years, and suscitated some comments some interest as a social curiosity can, or a scientific oberservation would. But nothing comprehensive has been declared. Our attempt to involve CPRIT has fallen in political quagmire and died with the CPRIT debacle. The COALITION will bring back the fore front! It is a shame for this great nation to fail to recognize what is really happening with unchanged deaths in its minority population!
OF EVEN GREATER INTEREST IS THE OBSERVATION THAT:
-------------------------------------------------------------------------
This Unique and deadly Breast cancer has unique charasteristics that strengthen the notion that it is genetic based. Indeed the Breast cancers involving minorities, are mostly triple negative therefore cannot benefit meaningfully from 2 major therapeutic interventions: Hormonal treatment and Herceptin and related drugs that seems the focus of our new drug developments. Research seems to look the other way all together folks!
Furthermore and to re-enforce the monolytic and genetic basis of the Breast cancer observed in blacks and Hispanics, up to 70% in some areas of these triple negative cases, have the unique Basal cell like morphology WELL DESCRIBED AGAIN. THE UNIQUENESS OF THIS PATHOLOGY SHOULD IN NORMAL CIRCUMSTANCES BEG AND CALL FOR IMMEDIATE INVESTIGATIONS WITH THE MEANS WE HAVE TODAY. BUT SILENCE IS WHAT WE HAVE TODAY!
WE HAD HOPED THAT THE DISCOVERY OF THE HUMAN GENOME WILL BRING CLEAR ANSWERS. BUT YES THEY DECODED THE GENOME OF THE TRIPLE NEGATIVE BREAST CANCER. BUT ALL WE GOT IS THAT IT LOOKS LIKE OVARIAN CANCERS. THAT IS DRUGS USED IN THAT DISEASE (TAXANE, PLATINUM) CAN BE USED IN THIS TRIPLE NEGATIVE BREAST CANCER, THIS WAS ALREADY IN PRACTICE, NO ADVANCEMENT THERE. SO WHERE DO WE GO FROM HERE. FOLKS ARE STILL DYING!
CRBCM HAS BEEN PUSHING FOR A COMPREHENSIVE - PRIORITY BASED PROGRAM BUT OUR EFFORTS ARE DYING IN DEATH EARS, NO POLITICIAN IS FULLY EMBRACING THE CAUSE! CRBCM EARLY CONCERNS WERE SURVIVAL OF THE ORGANIZATION, NOW THAT GREATER EAST CANCER CENTER, THE PARENT ORGANIZATION, IS OF FIRM GROUNDS, AND WE ARE NOT GOING ANYWHERE, WE ARE LAUNCHING A SECOND WIND OF CONSCIENCE-RAISING-ACTIVITIES TO ADDRESS THIS DISPARITY IN CANCER RESEARCH.
CRBCM IS DEDICATED TO OPEN THE DOOR TO THIS EMERGENCY! AND YOU CAN HELP!
Friday, June 7, 2013
MUTATIONS AT THE TET2 GENE, LET'S STOP THE NOISE!
==============================================
WE HAVE EXPLAINED THAT DURING CELL DEVELOPMENT, AND DEPENDING ON LOCATION AND FUNCTION, SOME GENES WILL BE SILENCED. AND ONE OF THE WAY THE GENE ARE SILENCED IS THROUGH A CERTAIN LEVEL OF METHYLATION. ONE OF THE REGULATOR THAT CHECK LEVEL OF METHYLATION IN HEMATOPOIETIC LINEAGE IS TET2.
IT APPEARS THAT MUTATION OF TET2 HAPPENS AS A RESULT OF NEOPLASTIC TRANSFORMATION THAT TRIGGERS DEMETHYLATION (DE-SILENCING) OF GENES OF PROLIFERATION,PUSHING UNCONTROLLED GROWTH.
THAT WHAT'S MUTATION OF TET2 MEANS (READ CAREFULLY DR GRANT COMMENTS)
ONCE THE DEMETHYLATION HAS OCCURRED LOGICALLY THE PRESENCE OF TET2 MUTATIONS SHOULD BE MINIMAL. ITS PRESENCE MEANS NEW GENES ARE BEING DEMETHYLATED AND MAY EITHER PORTEND TO PERSISTENCE OF PROLIFERATIVE GENES AND THEREFORE ATTEST TO THE NEED OF FURTHER DE- METHYLATING AGENTS. HYPOMETHYLATING AGENTS SEEMS TO AFFECT METHYLATON OR DISORGANIZE METHYLATION OF PROLIFERATIVE GENES.
LOGICALLY AT THE END OF THE PLANNED CYCLES OF AZACITIDINE OR DECITABINE, TET2 GENE MUTATION PERSISTENCE SHOULD MILITATE AGAINST STOPPING TREATMENT.
HYPOTHETICALLY, TET2 MUTATION MARKS THE FACTS THAT METHYLATION AND THE PROLIFERATIVE PROCESS HAVE BEGUN OR CONTINUE (THE MYELOPROLIFERATIVE PROCESS HAS STARTED), ITS PERSISTENCE POINT TO NEW METHYLATION OCCURING AND THAT THERAPY WITH THESE AGENTS IS NEEDED STILL.
IN AML OF THE ELDERLY, IT WILL REENFORCE THE NEED FOR THE DECITABINE OPTION OR THAT DECITABINE OR AZACITIDINE SHOULD BE ADDED TO THE REGIMEN IN MAINTENANCE SETTING.
LET'S GO OUT THERE AND VERIFY THIS ASSUMPTION IN PRACTICE
OR CONTINUE THE FOLLOWING NOISE!
=========================================================================
SMITH ET AL
The encoded protein is involved in myelopoiesis, and defects in this gene have been associated with several myeloproliferative disorders. (GENE RESOURCES)
TET2(mut) were identified in 7.6% of younger adult patients with AML and did not impact the response to therapy and survival. Mutations were mutually exclusive with IDH(mut), which supported recent data on a common mechanism of action that might obscure the impact of TET2(mut) if compared against all other patients with AML.(GAITZIK ET AL)
Tet2 deficiency led to decreased genomic levels of 5hmC and augmented the size of the hematopoietic stem/progenitor cell pool in a cell-autonomous manner.
There was no difference in the frequency of genome-wide aberrations, TET2 expression, or the JAK2V617F 46/1 haplotype between TET2-mutated and nonmutated patients. There was no significant prognostic association between TET2 mutations and World Health Organization subtypes, International Prognostic Scoring System score, cytogenetic status, or transformation to acute myeloid leukemia.
Italian researchers recently determined that mutations in the TET2 gene do not negatively influence the response of patients with myelodysplastic syndromes to treatment with Vidaza. However, they also found that certain modifications to the BCL2L10 gene negatively impacted outcomes following Vidaza treatment.
“TET2 mutations [...] were associated with higher response rates to [Vidaza]. This might help to identify patients at higher probability of response to [Vidaza] and avoid unnecessary burden to unresponsive patients,” said the study’s lead author, Dr. Maria Teresa Voso of the Università Cattolica del Sacro Cuore in Rome, Italy.(LANGHOLTZ)
Our data indicate that Tet2 has a critical role in regulating the expansion and function of HSCs, presumably by controlling 5hmC levels at genes important for the self-renewal, proliferation, and differentiation of HSCs.(RAO)
Indeed, while according to the authors TET2 mutations might be involved in the negative regulation of monocyte lineage determination, neither TET2 nor ASXL1 mutations are possibly sufficient in determining the disease establishment. A further interesting observation reported in this paper is that among 14 CMML patients who were tested after progression to acute leukemia (i.e. marrow blasts >20%), only 2 had a TET2 mutation, raising the question as to whether TET2 mutation, when present at diagnosis, might be lost upon leukemic transformation.(ONIDA)
Dr. Grant indicated no relevant conflicts of interest.
Aberrant methylation of DNA, particularly hypermethylation of tumor suppressor genes, occurs frequently in many cancers, including hematopoietic malignancies. This has prompted the development of agents capable of reversing hypermethylation, such as DNA methyltransferase inhibitors. These agents have yielded encouraging results both alone and in combination with other epigenetic agents (e.g., histone deacetlyase inhibitors) in patients with myelodysplastic syndrome (MDS) and some acute leukemias. However, the endogenous factors regulating the hypermethylated state have not been fully elucidated.
The protein encoded by this gene is a methylcytosine dioxygenase that catalyzes the conversion of methylcytosine to 5-
==============================================
WE HAVE EXPLAINED THAT DURING CELL DEVELOPMENT, AND DEPENDING ON LOCATION AND FUNCTION, SOME GENES WILL BE SILENCED. AND ONE OF THE WAY THE GENE ARE SILENCED IS THROUGH A CERTAIN LEVEL OF METHYLATION. ONE OF THE REGULATOR THAT CHECK LEVEL OF METHYLATION IN HEMATOPOIETIC LINEAGE IS TET2.
IT APPEARS THAT MUTATION OF TET2 HAPPENS AS A RESULT OF NEOPLASTIC TRANSFORMATION THAT TRIGGERS DEMETHYLATION (DE-SILENCING) OF GENES OF PROLIFERATION,PUSHING UNCONTROLLED GROWTH.
THAT WHAT'S MUTATION OF TET2 MEANS (READ CAREFULLY DR GRANT COMMENTS)
ONCE THE DEMETHYLATION HAS OCCURRED LOGICALLY THE PRESENCE OF TET2 MUTATIONS SHOULD BE MINIMAL. ITS PRESENCE MEANS NEW GENES ARE BEING DEMETHYLATED AND MAY EITHER PORTEND TO PERSISTENCE OF PROLIFERATIVE GENES AND THEREFORE ATTEST TO THE NEED OF FURTHER DE- METHYLATING AGENTS. HYPOMETHYLATING AGENTS SEEMS TO AFFECT METHYLATON OR DISORGANIZE METHYLATION OF PROLIFERATIVE GENES.
LOGICALLY AT THE END OF THE PLANNED CYCLES OF AZACITIDINE OR DECITABINE, TET2 GENE MUTATION PERSISTENCE SHOULD MILITATE AGAINST STOPPING TREATMENT.
HYPOTHETICALLY, TET2 MUTATION MARKS THE FACTS THAT METHYLATION AND THE PROLIFERATIVE PROCESS HAVE BEGUN OR CONTINUE (THE MYELOPROLIFERATIVE PROCESS HAS STARTED), ITS PERSISTENCE POINT TO NEW METHYLATION OCCURING AND THAT THERAPY WITH THESE AGENTS IS NEEDED STILL.
IN AML OF THE ELDERLY, IT WILL REENFORCE THE NEED FOR THE DECITABINE OPTION OR THAT DECITABINE OR AZACITIDINE SHOULD BE ADDED TO THE REGIMEN IN MAINTENANCE SETTING.
LET'S GO OUT THERE AND VERIFY THIS ASSUMPTION IN PRACTICE
OR CONTINUE THE FOLLOWING NOISE!
=========================================================================
SMITH ET AL
The encoded protein is involved in myelopoiesis, and defects in this gene have been associated with several myeloproliferative disorders. (GENE RESOURCES)
TET2(mut) were identified in 7.6% of younger adult patients with AML and did not impact the response to therapy and survival. Mutations were mutually exclusive with IDH(mut), which supported recent data on a common mechanism of action that might obscure the impact of TET2(mut) if compared against all other patients with AML.(GAITZIK ET AL)
Tet2 deficiency led to decreased genomic levels of 5hmC and augmented the size of the hematopoietic stem/progenitor cell pool in a cell-autonomous manner.
There was no difference in the frequency of genome-wide aberrations, TET2 expression, or the JAK2V617F 46/1 haplotype between TET2-mutated and nonmutated patients. There was no significant prognostic association between TET2 mutations and World Health Organization subtypes, International Prognostic Scoring System score, cytogenetic status, or transformation to acute myeloid leukemia.
Italian researchers recently determined that mutations in the TET2 gene do not negatively influence the response of patients with myelodysplastic syndromes to treatment with Vidaza. However, they also found that certain modifications to the BCL2L10 gene negatively impacted outcomes following Vidaza treatment.
“TET2 mutations [...] were associated with higher response rates to [Vidaza]. This might help to identify patients at higher probability of response to [Vidaza] and avoid unnecessary burden to unresponsive patients,” said the study’s lead author, Dr. Maria Teresa Voso of the Università Cattolica del Sacro Cuore in Rome, Italy.(LANGHOLTZ)
Our data indicate that Tet2 has a critical role in regulating the expansion and function of HSCs, presumably by controlling 5hmC levels at genes important for the self-renewal, proliferation, and differentiation of HSCs.(RAO)
Indeed, while according to the authors TET2 mutations might be involved in the negative regulation of monocyte lineage determination, neither TET2 nor ASXL1 mutations are possibly sufficient in determining the disease establishment. A further interesting observation reported in this paper is that among 14 CMML patients who were tested after progression to acute leukemia (i.e. marrow blasts >20%), only 2 had a TET2 mutation, raising the question as to whether TET2 mutation, when present at diagnosis, might be lost upon leukemic transformation.(ONIDA)
Dr. Grant indicated no relevant conflicts of interest.
Aberrant methylation of DNA, particularly hypermethylation of tumor suppressor genes, occurs frequently in many cancers, including hematopoietic malignancies. This has prompted the development of agents capable of reversing hypermethylation, such as DNA methyltransferase inhibitors. These agents have yielded encouraging results both alone and in combination with other epigenetic agents (e.g., histone deacetlyase inhibitors) in patients with myelodysplastic syndrome (MDS) and some acute leukemias. However, the endogenous factors regulating the hypermethylated state have not been fully elucidated.
The protein encoded by this gene is a methylcytosine dioxygenase that catalyzes the conversion of methylcytosine to 5-
| TET2 gene alterations are more frequent in chronic myelomonocytic leukemia than in other subgroups of hematopoietic diseases studied so far and could negatively affect the patients’ outcome. The striking association between TET2 gene alterations and monocytosis, already observed in patients with systemic mastocytosis, could indicate a negative role of TET2 in the control of monocytic lineage determination.KOSMIDER ET AL. |
PROGRESS IN CANCER CURE FIGHT!
Progress in the search for cancer cure is slowed not only by the true challenge posed by this disease, but also and mainly by politicians at various levels. Some politicians speculate with funding levels, some are discontent with distribution of funding, some don't like who is asking for funding. These political concerns have a heavy burden on the search for a cure of which difficulties they compound.
In El Paso,TX, universities which have the the expertise and public funded facilities resist to help us in the completion of funded projects of public health importance. Now we have to fight a political fight rather than progressing in our search for the cure. WHAT PEOPLE FORGET IS THAT WE ARE A "COALITION" WHICH BY DEFINITION MEAN GROUP DESTINED TO FIGHT FOR A CAUSE. AND WE ARE READY!
Progress in the search for cancer cure is slowed not only by the true challenge posed by this disease, but also and mainly by politicians at various levels. Some politicians speculate with funding levels, some are discontent with distribution of funding, some don't like who is asking for funding. These political concerns have a heavy burden on the search for a cure of which difficulties they compound.
In El Paso,TX, universities which have the the expertise and public funded facilities resist to help us in the completion of funded projects of public health importance. Now we have to fight a political fight rather than progressing in our search for the cure. WHAT PEOPLE FORGET IS THAT WE ARE A "COALITION" WHICH BY DEFINITION MEAN GROUP DESTINED TO FIGHT FOR A CAUSE. AND WE ARE READY!
NEW RANDOM NEWS
*5 POWERFUL DRUG RECOGNIZED BY THE FDA, CHECK THEM OUT
1--DARATUMUMAB FOR MYELOMA
2--PALBOCICLIB FOR BREAST CANCER
3--LDK 378 FOR LUNG CANCER
4--LAMBROLIZUMAB FOR MELANOMA
5--IBRUTINIB FOR A SLEW OF HEMATOLOGIC MALIGNANCY CLL,MANTLE CELL LYMPHOMA AND WALDENSTROM MACROGLOBULINEMIA
*HAPPY ANNIVERSARY TO 85 YEAR OLD DR JAMES D.WATSON, NOBEL LAUREATE FOR HIS DISCOVERY AND CHARACTERIZATION OF THE DOUBLE HELIX DNA 60 YEARS AGO!
HE IS STILL LIVING IN NEW YORK! SALUTE!
*HYPEREOSINOPHILIC SYNDROME TREATED WITH CAMPATH, AN ANTI-CD52
EOSINOPHIL REPORTEDLY DO EXPRESS CD52
10 OUT OF 12 PATIENT HAD SYMPTOMS RELIEVED, AND RESPONSE TO THERAPY. PROOF IS IN THE PUDDING (SEE THE FULL ARTICLE BY PAOLO STRATI ET AL!
*5 POWERFUL DRUG RECOGNIZED BY THE FDA, CHECK THEM OUT
1--DARATUMUMAB FOR MYELOMA
2--PALBOCICLIB FOR BREAST CANCER
3--LDK 378 FOR LUNG CANCER
4--LAMBROLIZUMAB FOR MELANOMA
5--IBRUTINIB FOR A SLEW OF HEMATOLOGIC MALIGNANCY CLL,MANTLE CELL LYMPHOMA AND WALDENSTROM MACROGLOBULINEMIA
*HAPPY ANNIVERSARY TO 85 YEAR OLD DR JAMES D.WATSON, NOBEL LAUREATE FOR HIS DISCOVERY AND CHARACTERIZATION OF THE DOUBLE HELIX DNA 60 YEARS AGO!
HE IS STILL LIVING IN NEW YORK! SALUTE!
*HYPEREOSINOPHILIC SYNDROME TREATED WITH CAMPATH, AN ANTI-CD52
EOSINOPHIL REPORTEDLY DO EXPRESS CD52
10 OUT OF 12 PATIENT HAD SYMPTOMS RELIEVED, AND RESPONSE TO THERAPY. PROOF IS IN THE PUDDING (SEE THE FULL ARTICLE BY PAOLO STRATI ET AL!
Thursday, June 6, 2013
INSUFFICIENCY OF IMMUNOTHERAPY IN MUCINOUS CANCERS.
Interesting this case in point by Baretta et al. published in Clinical Breast Cancer:
"RESISTANCE TO TRASTUZUMAB IN HER-2 POSITIVE MUCINOUS INVASIVE DUCTAL BREAST CARCINOMA"
BRAVO! For addressing this topic. Yes indeed, while it is obvious that if a tumor is Her-2 positive it would more likely respond to Herceptin, their 2 cases demonstrate the power of Mucin into shielding these receptors from their Agonist Herceptin. They specify that to be consider Mucinous, the tumor should have a greater than 50% Mucinous component (you figure it out or just wait for the pathologist to call it). the other component is "ductal" of course. And as a matter of proportion, a "Mixed" type could be defined!
And yes the authors believed that "Mucin acted as a barrier against Trastuzumab". They went on to comment that "Mucins has a central role in maintaining homeostasis and protecting the luminal surfaces of epithelium-lined ducts in the human body." They went on to conclude that appreciating the peculiarity of Mucin presence should allow a early change in therapy! And Bravo again to the team!
Several other aspect of immunothereapy were discussed by RUDY, a fellow in Oncology,
She suggested in a comprehensive review that infiltration of the lymphocyte in the tumor was a good prognosis (our pathologists need to report this to us) and the bad role of TWIST gene,
" Twist was a tumor-associated antigen recognized by tumor-specific CD8+ T cells; thus, this study provided a rationale for further exploration of immunotherapy using the pTw9 epitope. Additional animal studies must be done before human studies to determine the value of targeting Twist in the adjuvant setting may begin. Investigators hope to find out whether targeting Twist may prevent gross metastasis of breast cancer in patients with Twist-positive micrometastatic disease." RUDY ET AL
Interesting this case in point by Baretta et al. published in Clinical Breast Cancer:
"RESISTANCE TO TRASTUZUMAB IN HER-2 POSITIVE MUCINOUS INVASIVE DUCTAL BREAST CARCINOMA"
BRAVO! For addressing this topic. Yes indeed, while it is obvious that if a tumor is Her-2 positive it would more likely respond to Herceptin, their 2 cases demonstrate the power of Mucin into shielding these receptors from their Agonist Herceptin. They specify that to be consider Mucinous, the tumor should have a greater than 50% Mucinous component (you figure it out or just wait for the pathologist to call it). the other component is "ductal" of course. And as a matter of proportion, a "Mixed" type could be defined!
And yes the authors believed that "Mucin acted as a barrier against Trastuzumab". They went on to comment that "Mucins has a central role in maintaining homeostasis and protecting the luminal surfaces of epithelium-lined ducts in the human body." They went on to conclude that appreciating the peculiarity of Mucin presence should allow a early change in therapy! And Bravo again to the team!
Several other aspect of immunothereapy were discussed by RUDY, a fellow in Oncology,
She suggested in a comprehensive review that infiltration of the lymphocyte in the tumor was a good prognosis (our pathologists need to report this to us) and the bad role of TWIST gene,
" Twist was a tumor-associated antigen recognized by tumor-specific CD8+ T cells; thus, this study provided a rationale for further exploration of immunotherapy using the pTw9 epitope. Additional animal studies must be done before human studies to determine the value of targeting Twist in the adjuvant setting may begin. Investigators hope to find out whether targeting Twist may prevent gross metastasis of breast cancer in patients with Twist-positive micrometastatic disease." RUDY ET AL
ACTIVITY AT CRBCM
(AS OF 6/62013)
WE THANK VISITORS OF OUR BLOG, WE HAVE CROSSED THE 20,000 REVIEWS, POINTING TO THE INTENSITY AND ORIGINALITY OF OUR WORK, THE CRBCM FOOT PRINT IS RAPIDLY INCREASING. THANK YOU FOR VISITING!
(AS OF 6/62013)
WE THANK VISITORS OF OUR BLOG, WE HAVE CROSSED THE 20,000 REVIEWS, POINTING TO THE INTENSITY AND ORIGINALITY OF OUR WORK, THE CRBCM FOOT PRINT IS RAPIDLY INCREASING. THANK YOU FOR VISITING!
OTHER COUNTRIES HAVE LOWER NUMBERS
|
AGE RELATED EXPRESSION OF DEFICIENT GENE
Although one may have deficient gene,death from its consequences varies based on how critical lack of expression is to the body. Lack of function in a critical tissue leads rapidly to death. Expression of a deficient gene depends on whether it it dominant or recessive, and whether one is homo or heterozygotic as related to the gene in question. many diseases of genetic basis express themselves at a letter stage in life. Polycystic Kidney disease for example gives its full blown syndrome only after 30 years of age, and starts worsening to finally take the life of the bearesr in their 5th ot sixth decade of life. Althto though one cannot say for sure what intervened with age for the syndrome to fully express, we know that immune and hormonal developments contribute significantly to this unfortunate unfolding.
We know that in infectious processes we encounter as we age, there is disturbances of Interferons levels, and if one has an autoimmune disease, these interferon levelsare somewhat permanent or constant. Interferon activate T cell and boost Immunity but also secondarily immune system surveillance of cancer occurrence. This interferon seems linked to Class I histocompatibilty HLA-A,B,C.
In Women however, as they age and enter reproductive age, there is need to suppress class I HLAin order to "tolerate" a child/fetus. It is assumed that a vague of hormone driven gene methylation seems to be the mechanism. Gene methylation will silence many genes and could potentially silence normal genes that where conterbalancing the gene defect. Defectuous genes will this way get there chance to finally express themselves and cause progression of syndromes thay can cause. Androgenic development in males achieves the same deterioration. Giving Azacytidine had reversed these methylation by the way although clinical trials are still ongoing on whetehr it can meaningfully change the course of these gene based diseases.That is before irreversible tissue damage sets in.
Although one may have deficient gene,death from its consequences varies based on how critical lack of expression is to the body. Lack of function in a critical tissue leads rapidly to death. Expression of a deficient gene depends on whether it it dominant or recessive, and whether one is homo or heterozygotic as related to the gene in question. many diseases of genetic basis express themselves at a letter stage in life. Polycystic Kidney disease for example gives its full blown syndrome only after 30 years of age, and starts worsening to finally take the life of the bearesr in their 5th ot sixth decade of life. Althto though one cannot say for sure what intervened with age for the syndrome to fully express, we know that immune and hormonal developments contribute significantly to this unfortunate unfolding.
We know that in infectious processes we encounter as we age, there is disturbances of Interferons levels, and if one has an autoimmune disease, these interferon levelsare somewhat permanent or constant. Interferon activate T cell and boost Immunity but also secondarily immune system surveillance of cancer occurrence. This interferon seems linked to Class I histocompatibilty HLA-A,B,C.
In Women however, as they age and enter reproductive age, there is need to suppress class I HLAin order to "tolerate" a child/fetus. It is assumed that a vague of hormone driven gene methylation seems to be the mechanism. Gene methylation will silence many genes and could potentially silence normal genes that where conterbalancing the gene defect. Defectuous genes will this way get there chance to finally express themselves and cause progression of syndromes thay can cause. Androgenic development in males achieves the same deterioration. Giving Azacytidine had reversed these methylation by the way although clinical trials are still ongoing on whetehr it can meaningfully change the course of these gene based diseases.That is before irreversible tissue damage sets in.
Wednesday, June 5, 2013
CRK GENE
It is a co-factor to many Kinases, and sometime act as a regulator
CRK (gene) has been shown to interact with:
It is a co-factor to many Kinases, and sometime act as a regulator
CRK (gene) has been shown to interact with:
- BCAR1,[7][8][9][10][11][12][13][14][15]
- Cbl gene,[16][17]
- Dock180,[18][9][10][19][20]
- EPS15,[21]
- Epidermal growth factor receptor,[22][23]
- Grb2,[24][18][25] (A WILD WILD GENE)
The focal adhesion kinase (FAK), a protein-tyrosine kinase (PTK), associates with integrin receptors and is activated by cell binding to extracellular matrix proteins, such as fibronectin (FN). FAK autophosphorylation at Tyr-397 promotes Src homology 2 (SH2) domain binding of Src family PTKs, and c-Src phosphorylation of FAK at Tyr-925 creates an SH2 binding site for the Grb2 SH2-SH3 adaptor protein. FN-stimulated Grb2 binding to FAK may facilitate intracellular signaling to targets such as ERK2-mitogen-activated protein kinase. We examined FN-stimulated signaling to ERK2 and found that ERK2 activation was reduced 10-fold in Src- fibroblasts, compared to that of Src- fibroblasts stably reexpressing wild-type c-Src. FN-stimulated FAK phosphotyrosine (P.Tyr) and Grb2 binding to FAK were reduced, whereas the tyrosine phosphorylation of another signaling protein, p130cas, was not detected in the Src- cells. - IRS4,[26][27]
- MAP4K1,[28][29][30]
- MAPK8,[31]
- NEDD9,[32][33]
- PDGFRA,[34][35]
- PDGFRB,[34]
- PTK2,[9][12]
- Paxillin[12][36]
- RAPGEF1,[37]
- RICS,[38][39]
- SH3KBP1,[40] and
- SOS1.[25]wikipedia
- Crk together with CrkL participates in the Reelin signaling cascade downstream of DAB1.[2][3]
- We could get your attention that REELIN defect leads to brain MALFORMATION, POINTING TO CRK AND DAB1 AS IMPORTANT TARGET GENES IN SARCOMA!
-
Reelin is a large secreted extracellular matrix glycoprotein that helps regulate processes of neuronal migration and positioning in the developing brain by controlling cell–cell interactions. Besides this important role in early development, reelin continues to work in the adult brain. It modulates synaptic plasticity by enhancing the induction and maintenance of long-term potentiation.[2][3] It also stimulates dendrite[4] and dendritic spine[5] development and regulates the continuing migration of neuroblasts generated in adult neurogenesis sites like subventricular and subgranular zones. It is found not only in the brain, but also in the spinal cord, blood, and other body organs and tissues.
Reelin has been suggested to be implicated in pathogenesis of several brain diseases. The expression of the protein has been found to be significantly lower in schizophrenia and psychotic bipolar disorder, but the cause of this observation remains uncertain as studies show that psychotropic medication itself affects reelin expression. Moreover, the epigenetic hypothesis aimed at explaining the changed levels[6] has received some contradictory evidence.[7][8] Total lack of reelin causes a form of lissencephaly. Reelin may also play a role in Alzheimer's disease, temporal lobe epilepsy and autism.(WIKIPEDIA)
Reelin takes part in the developmental change of NMDA receptor configuration, increasing mobility of NR2B-containing receptors and thus decreasing the time they spend at the synapse.[53][dead link][54][55] It has been hypothesized that this may be a part of the mechanism behind the "NR2B-NR2A switch" that is observed in the brain during its postnatal development.[56] Ongoing reelin secretion by GABAergic hippocampal neurons is necessary to keep NR2B-containing NMDA receptors at a low level.[52]
The Disabled-1 (Dab1) gene encodes a key regulator of Reelin signaling. Reelin is a large glycoprotein secreted by neurons of the developing brain, particularly Cajal-Retzius cells. DAB1 functions downstream of Reln in a signaling pathway that controls cell positioning in the developing brain and during adult neurogenesis
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