Thursday, January 31, 2013

CELLULAR LANGUAGE

The challenge brought to us by the need of a cure and failure of destructive conventional chemotherapy have proven to human being that there is the need to understand better cellular function. Our learning has led to discover that the Cell has many properties and can do many things on its own including dying on its own or cell programmed death. Yes, coordinated Changes within the cell based on its age, position and state of independence or loss of input from other cell can trigger cell death. These coordinated changes are indeed a language that one must talk to send a message to the cell that it is time to die. And it is now apparent to scientists that brutalizing and violence to a cell through chemotherapy and Radiation will never be sufficient to accomplish a cure. Cells are ready for a violent attack. You need to convince the cell to die. You need to target functions of the cell and already tough to conquer cancer start listening. By targeting therapy we learn that cutting a signal could lead to death of a cell. like a battery, there is a positive and negative. in the cell, there switches which are on or off. In a computer there 1 and zero. What a computer can do with these 1 basic things is anybodies guess. The Morse language had only 2 signal Tic and Tan. (Tic Tan Tic, Tan TAN tic!)
Through an ON and OFF switch, through a positive and negative electrical charge, the cell transfer an input that will lead to extensive result.
While empirically we tend to believe that more is better, it it the OFF signal that is the most full off consequences.

AT CELLULAR LEVEL, LACK OF INPUT IS THE MOST FULL OF CONSEQUENCE AND CAN LEAD TO DEATH IF SPOKEN AT THE RIGHT PLACE AND THE RIGHT TIME.

1. If a cell is left alone. lack of environment talking to it (ie. IN MYELOMA), lack of sister cell talking to it, lack of positive excitatory stimulation, will kill it . We have called this ANOIKIS.

2.Target Therapy works because it BLOCKS the excitatory stimulation.

3. A post synaptic neuron will die if the pre-synaptic neuron stops sending excitatory input.

4. Muscle death or Atrophy will occur if synaptic input cease or desist.
5. Necrosis will occur if Oxygen ceases
6. Acid from Lysosome will kill the cell if it seeps in the Cytosol that is relatively basic

BASICALLY, IT 'S AGAIN IT'S ON OR OFF, TIC OR TAN, NEGATIVE POSITIVE, ONE OR ZERO EVEN AT CELLULAR LEVEL.

IF YOU GET THIS, THE YOU WILL ALSO UNDERSTAND THAT
AT GENE LEVEL, IT IS THE DECREASE OF GENE THAT IS MORE IMPORTANT THEN AMPLIFICATION

1. Suppression of PTEN in sarcoma or lung cancer will act on PI3K/MTOR
2. decrease or suppression of STAT1 will be present in triple negative Breast cancer
3. P53 silencing mutation
4. MDM2 silencing Mutation
5. gene deletion or silencing
6.

Oncogene. 2005 Sep 15;24(41):6269-80.

The polycomb group protein enhancer of zeste homolog 2 (EZH 2) is an oncogene that influences myeloma cell growth and the mutant ras phenotype.

Croonquist PA, Van Ness B.

Source

The Graduate Program in Molecular, Cellular, Developmental Biology, and Genetics, University of Minnesota, Minneapolis, MN 55455, USA.

Abstract

Three distinct proliferative signals for multiple myeloma (MM) cell lines induce enhancer of zeste homolog 2 (ezh 2) transcript expression. EZH 2 is a polycomb group protein that mediates repression of gene transcription at the chromatin level through its methyltransferase activity. Normal bone marrow plasma cells do not express ezh2; however, gene expression is induced and correlates with tumor burden during progression of this disease. We therefore investigated how EZH 2 expression is deregulated in MM cell lines and determined the consequence of this activity on proliferation and transformation. We found that EZH 2 protein expression is induced by interleukin 6 (IL-6) in growth factor-dependent cell lines and is constitutive in IL-6-independent cell lines. Furthermore, EZH 2 expression correlates with proliferation and B-cell terminal differentiation. Significantly, EZH 2 protein inhibition by short interference RNA treatment results in MM cell growth arrest. Conversely, EZH 2 ectopic overexpression induces growth factor independence. We found that the growth factor-independent proliferative phenotype in MM cell lines harboring a mutant N- or K-ras gene requires EZH 2 activity. Finally, this is the first report to demonstrate that EZH 2 has oncogenic activity in vivo, and that cell transformation and tumor formation require histone methyltransferase activity.
Oncogene (2005) 24, 6269-6280.

7.NME1/NM23

NME1

From Wikipedia, the free encyclopedia

Jump to: navigation, search

NME/NM23 nucleoside diphosphate kinase 1

PDB rendering based on 1be4.

Available structures

PDB

Ortholog search: PDBe, RCSB

[show]List of PDB id codes

Identifiers

Symbols

NME1; AWD; GAAD; NB; NBS; NDKA; NDPK-A; NDPKA; NM23; NM23-H1

External IDs

OMIM: 156490 MGI: 97355 HomoloGene: 128514 ChEMBL: 2159 GeneCards: NME1 Gene

EC number

2.7.4.6

[show]Gene Ontology

Orthologs

Species

Human

Mouse

RefSeq (mRNA)

RefSeq (protein)

Location (UCSC)

Chr 17:
49.23 – 49.24 Mb

Chr 11:
93.96 – 93.97 Mb

PubMed search

[1]

[2]

Nucleoside diphosphate kinase A is an enzyme that in humans is encoded by the NME1 gene.^[1] It is thought to be a metastasis suppressor.
This gene (NME1) was identified because of its reduced mRNA transcript levels in highly metastatic cells. Nucleoside diphosphate kinase (NDK) exists as a hexamer composed of 'A' (encoded by this gene) and 'B' (encoded by NME2) isoforms. Mutations in this gene have been identified in aggressive neuroblastomas. Two transcript variants encoding different isoforms have been found for this gene. Co-transcription of this gene and the neighboring downstream gene (NME2) generates naturally-occurring transcripts (NME1-NME2), which encodes a fusion protein consisting of sequence sharing identity with each individual gene product.^[2]

Interactions

NME1 has been shown to interact with Aurora A kinase,^[3] NME3,^[4]^[5] Protein SET,^[6] RAR-related orphan receptor alpha,^[7] TERF1,^[8] CD29^[9] and RAR-related orphan receptor beta.^[7]

^{------------------------------------------------------------------------------------------------------}
^{8 IN SARCOMA, DELETION OF CDKN2A}
^{--------------------------------------------------------------------------------------------------------}
^{9. DECREASE IN E-CADHERIN IN METASTATIC DISEASE}
^{AND EARLY TRANSFORMATION}
^{-------------------------------------------------------------------------------}

^{AND THE LIST OF TUMOR SUPPRESSION GENE GOES ON.}

^{SO IN GENERAL CANCER IS CAUSED BY NEGATIVE. LACK OR SUPPRESSION OF A GENE}
^{SO ANYTIME THAT YOU ARE LOOKING FOR CAUSE OF CANCER, PAY MORE ATTENTION TO THE SUPPRESSION NOT THE HYPERACTIVITY!}
^{LET SUPPRESS FOXO3 TO TELL CANCER TO DIE! LET'S CONTINUE TO SUPPRESS GROWTH FACTORSAND THE CURE WILL BE OUR TO REACH!}

Wednesday, January 30, 2013

State audit calls for extensive reforms of Texas’ cancer-fighting agency

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comments (2)

By James Drew
jdrew@dallasnews.com
11:03 am on January 28, 2013 | Permalink

State Auditor John Keel (File photo)

Update at 2:25 p.m. by Daniel Lathrop: Now you can read the audit for yourself.
AUSTIN – Legislators should consider several changes in state law to make Texas’ cancer-fighting agency more accountable and transparent to taxpayers, according to a state audit obtained Monday by The Dallas Morning News.
The audit lists problems in seven major areas, from how the Cancer Prevention and Research Institute of Texas makes grant decisions to how it monitors how public dollars are spent.
“Weaknesses in CPRIT’s processes reduce its ability to properly award and effectively monitor its grants,” state Auditor John Keel concludes in the report.
The audit calls on the state agency, which is under criminal and civil investigations, to ensure that all decisions are free from real or apparent conflict of interest.
The report says CPRIT’s management “generally agreed” with the audit’s dozens of recommendations.
Bill Gimson, who resigned last month as CPRIT’s executive director, discussed grant recommendations with some members of the agency’s Oversight Committee before presenting recommendations to the 11-member panel. The audit, as is typical with its practices, does not identify the Oversight Committee members involved.
Also, auditors identified two members of CPRIT’s commercialization review council who had financial and personal interests in certain grant recipients. The audit also does not identify them.
One review council member also was a member of the board of directors for a grantee that received a $25.2 million research award, a nonprofit called the Statewide Clinical Trials Network of Texas, or CTNeT, which has offices in Dallas and Houston.
Another member of the review council worked as a consultant for two applicants applying for “incubator” grants. Incubators are designed to link research and business opportunities.
The person, however, was not listed as taking part in the review of incubator grant applications and neither applicant ultimately submitted a formal request for funding, the audit says.
The state auditor says CPRIT reports it does not receive final information about donors to the CPRIT Foundation – a nonprofit group formed to supplement funding for the state agency — or the donation amounts. But CPRIT has no assurances that it is not awarding grants to donors, which would create a conflict of interest, the audit says.
“CPRIT’s lack of controls for ensuring there are not any business or professional relationships between its peer reviewers and grantees impairs CPRIT’s ability to ensure the public that its award decisions are not improperly influenced,” according to the audit.
The audit notes two controversies revealed last year: the $20 million grant to a Houston area incubator in 2012 without a science review, and the $11 million award in 2010 to a Dallas-based biotechnology firm, Peloton Therapeutics, without both scientific and business reviews.
Keel adds a third grant with problems.
CPRIT awarded $25.2 million, its largest grant, in 2010 even though the recipient, a nonprofit group, did not exist at the time.
The grant originally went to the University of Texas-M.D. Anderson Cancer Center. It is unclear what allowed CPRIT to transfer the award from M.D. Anderson to the newly-formed CTNeT nonprofit group, the audit says.
“CPRIT also did not have documentation to support that the scientific review council recommended the original application for a grant,’ the audit says.
The audit also says:
* CTNeT’s grant application did not receive a favorable peer review
score. CPRIT evaluated grant applications on a scale of 1 to 9, with 1
being the highest. The CTNeT grant application received a peer review
score of 4.64. Auditors reviewed the peer review scores for 44 other
applications and identified 9 applications that were not awarded grants
that received peer review scores ranging from 3.93 to 4.40.
* CPRIT has a role in CTNeT’s business operations.
Without using names, the audit says Jimmy Mansour, chairman of CPRIT’s oversight committee chair; vice chair Dr. Joseph Bailes, and Gimson interviewed and
hired CTNeT’s chief operating officer, Patricia Winger, before the contract was executed.
In addition, Gimson, former chief scientific officer Dr. Alfred Gilman, and a
member of CPRIT’s commercialization review council were members of
CTNeT’s board of directors.
* CPRIT made $6.8 million in advance payments to CTNeT even though its
grant agreement with CTNeT allowed only reimbursement payments.
* CTNeT did not comply with matching funds requirements and annual
progress reporting requirements.
* CPRIT’s relationship with CTNeT and its lack of enforcing contract
requirements impair CPRIT’s ability to ensure that CTNeT is properly
using grant funds and complying with grant requirements.

7 37

Parkland Memorial cuts a $500,000 deal to enlist lobbying powerhouse for regulatory issues as fate rests with regulators

At a time Parkland Memorial Hospital needs a critical blessing from federal regulators to avoid a shutdown, its officials have...

OPINION ON GENETIC TESTING

As our knowledge keep expanding, it is fair to suggest that Knowledge of Driver Mutation makes a difference in our patients particularly in instances where we have an effective inhibitor. The frequency of the Mutation has been a frustrating basis for intervention since the high rate of an eventual mutation could be linked to its early occurrence in the cancerous transformation. Giving a value in early detection with no effect on the outcome.
Dividing genetic abnormality in those of proliferation, those involved in amplification, and those of differentiation, those pointing to metastasis and finally those for survival, could prove useful.
It is not enough to know that P53 is amplified if it is not mutated. The reason for the amplification needs to be clarified by a comprehensive view of the ensemble of genetic change panel.

In many instances, our view of the events in a cell is frustratingly narrow. Reading on Uterine cancer today I found out that Uterine cancer is divided in endometrioid and non Endometrioid. I learned that 83% of endometrioid cancer have a PTEN depression or mutation abnormality. This is thought to be an early event. Meaning it may not matter that much in the outcome of our patient and MTOR inhibition turned out to have a mild effect. On the non endometrioid cancer very little is said. We know it is most of the time coming from an Atrophic mucosa, what this means at molecular level, lack of stimulation by Estrogen, Receptor insensitivity, a panoramic gene testing is needed to find a useful answer. So it seems to us that any genetic testing report should tell us the state of gene alteration in each group of cellular functions to be useful.

In some tissue such has sarcoma, brain, (Melanoma) knowing the EGFR or VGEF amplification only appears a partial issue. What is the status of gene of differentiation, and other genes. Until we have a comprehensive panel for each cell type, our effort will not progress for the cure. The flurry of progress in lung cancer came from a consistent panel reporting of genes mutation and drivers at one Institution (Harvard). This is the way to go! WE GOT TO RAISE THE BAR.

UTERINE OR ENDOMETRIAL CANCER

WITH INCREASE OF OBESITY RATE, THIS CANCER IS ONE OF THOSE ON THE RISE
AFFECTING 46000 WOMEN A YEAR
WITH 8000 DYING EVERY YEAR

4 TYPES

1-ENDOMETRIOID (80%)

2.1-SEROUS
2.2-CLEAR CELL
2.3-MUCINOUS
2.4-MIXED

The Endometrioid type is preceded by Hyperplasia and is genErally localized and of good prognosis.
The serous type is preceded by atrophy and is of worse prognosis.

Of those with uterine inner third involvement,
-----------------------------------------------
55% of Serous will have spread of disease
17% with Endometrioid will have spread of disease
Median survival is 12 months in metastatic disease

11 genetic alterations described:
==========================

1,loss of function of PTEN: An early event see in 83 % of Endometriod cancer.
opening the door to MTOR inhibitor use
metformin seems to potentiate effect of Taxol through modulation of MTOR.

INHIBITION OF PTEN MAY PREDICT SENSITIVITY TO PARP INHIBITORS, SO OLAPARIB HAS BEEN TRIED. PARP INHIBITOR TRIED IN THOSE POSITIVE FOR BRCA 1,2

2.PIK3CA Mutation

3.AKT mutation
4.Microsattelite instability
5.KRas Mutation : 26% of endometrioid cancer (MEK Inhibition by Selumetinib trial)
6.Overexpression of EGFR (Avastin and Decoy Aflibercept with minimum response from Sutent, NEXAVAR, AND THALIDOMID) Tarceva, Iressa,Erbitux

In non-endometrioid cancer, existence of ERBB2 poto-ocnocgen has led to trial of Trastuzumab, Lapatinib with minimal response
7.P53 mutation
8.Nuclear B Catenin
9.Her-2/Neu amplification
10.FGFR PRESENCE HAS LED TO TRIAL WITH DOVITINIB
11.P16 inactivation

Tuesday, January 29, 2013

COMPLICATIONS ENCOUNTERED AT DEFINING GENE AMPLIFICATION.

As we dig deeper into the 4th law of nature, we quickly encountered difficulty in defining primary and secondary amplification.

Primary gene Amplification:
---------------------------
It is now evident that an amplified gene could be the result of the effect of a growth factor or cyclins acting on a receptor at membrane level and into the Cytosol. This is a secondary gene amplification.
Once a cell has chosen a specific orientation, that is it has chosen between proliferation or differentiation, that orientation will be the focus of gene Amplification. This amplification is generally non specific and is our definition of Primary Amplification. This general amplification is generally mild like in a buzz. when found, it is low level amplification. the gene is found generally in less than 10 percent of cells... Most of the time around 4-5% of cells. It is a tone. Our research locate this Amplification in the MLL and MYC genes and in the Histone Acetyl transferase and related molecules (PCAF, P300). Sometime, this basic amplification and a secondary amplification can double up in the same gene, leading to an exacerbated amplification such as it occurs in Burkitt lymphoma. This will prompt us to look into difference of Expression of MYC in Ovarian cancer Vs Myc expression the Burkitt lymphoma. There must be a big difference, may be in the level of Cyclins. we will investigate.

Suffice is to say the real reason of the Amplification to be in the MYC and Histone Acetyl transferase, is that both have regulatory powers on the P53 which needs to be downregulated to allow proliferation to continue in cancer. So aside from the Regular MDM2 which the principal regulator, Histone acetyl transferase which MYC promotes, is the second main P53 regulator. In our previous blog, we had discussed the interactions of P53 with upstream structure toward the membrane.

Secondary gene Amplification.
-------------------------------
Secondary gene Anplification is the result of the action of proliferation genes, Amplification gene and oncogenic driver and non driver Mutations.
This Amplification targets
1. Membrane receptors (EGFR, FGFR-1, Her-2,)
2. RAS and GTPases (ie. RAp1GTPase, Hras)
3. growth factors and CYCLINS (CCND1,FGFR and its related HST-1,c-MET)
4. Signal trasduction pathways (AKT/MTOR)
5. Regulators of pathways (TSG with impact on the AKT)
6.Transcription Factors (MLL, a regulator of transcription factor with activity on the TSG in the AKT/MTOR pathway
7. Histones and epigenetic triggers
8. DNA proper (Ki 67 seen only in dividing cells, CDKs, it may acts also on genes of differentiation such Myo, RET, TRK, int-1, hst-1 )
Secondary amplification double up on the primary to multiply itself.

Some other Amplifier are downregulated for action to be unveiled (PTEN and its increase of AKT)
SECONDARY GENE AMPLIFICATION WILL TEND TO BE WITH HIGHER PERCENTAGE THAN 10%

A note to make before
Downstream from MTOR is located a key to Apoptosis by the name of FOXO, check it out! THE FOX HIDE THE PUMA GENE!

Monday, January 28, 2013

Travis County DA: “The CPRIT investigation is ongoing and aggressive”

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comments (0)

By James Drew
jdrew@dallasnews.com
5:17 pm on January 23, 2013 | Permalink

AUSTIN – The Travis County district attorney said Wednesday afternoon that her office’s investigation into Texas’ cancer-fighting agency is “very serious and we are far from finished in our efforts.”
“The CPRIT investigation is ongoing and aggressive,” said Rosemary Lehmberg.
Lehmberg’s six-line statement came a day after Jimmy Mansour, chairman of the Oversight Committee of the Cancer Prevention and Research Institute of Texas, released his own through Bill Miller, a powerful Austin lobbyist and political consultant.
Miller’s statement said Mansour met with the district attorney’s office last week and was assured that he and all other current board members “are free from suspicion in the ongoing CPRIT investigation.”
“Mr. Mansour is pleased that the cloud has lifted,” Miller said in his statement.
Reached for comment, Gregg Cox, director of the district attorney’s Public Integrity Unit, replied in an email that Mr. Mansour is cooperating in the investigation.
He said the Jan. 18 interview of Mansour focused on two topics – the divestment of stock that Mansour owned when he was appointed by Lt. Gov. David Dewhurst to serve on CPRIT’s Oversight Committee, and the committee’s awarding of a grant to Peloton Therapeutics.
“His statement is accurate with respect to those areas,” Cox wrote.
The Dallas Morning News reported in November that companies run by Dallas businessman David Shanahan got $12.8 million in CPRIT grants after Shanahan and his associates gave $90,000 to the campaigns of Gov.Rick Perry and Dewhurst.
One of those companies was Gradalis Inc., a biotechnology firm based in Carrollton, and one of those associates was Mansour, who had contributed $40,500 to Dewhurst in the eight years leading to his appointment to CPRIT.
Mansour, through spokesman Miller, told the newspaper that he invested in Gradalis in 2006 and became a board member. Mansour said he was advised that as a member of the Oversight Committee, he could hold investments in companies that received awards, and in which his ownership was no more than 5 percent of the firm. He said that was the case with the stock he owned in Gradalis, which he decided to sell.
Mansour said the sale of the Gradalis stock that he owned personally and through a limited partnership ended in what he called a “substantial loss” in 2009.
The following year, the Oversight Committee members, including Mansour, ratified a $748,905 award to Gradalis, as part of a much larger grant.
Also last November, CPRIT confirmed that an $11 million award to Peloton Therapeutics, a company on the campus of the UT Southwestern Medical Center, did not receive required commercial or scientific review.
Shortly after that news broke, theTravis County district attorney’s office said it had opened a criminal investigation into how CPRIT awards grants.
In her statement Wednesday, Lehmberg wrote: “Let me emphasize the investigation is very serious and we are far from finished in our efforts.”
CPRIT head resigns as Travis County DA confirms investigation of agency
Pressing CPRIT for answers after it awarded $11 million to Dallas’ Peloton Therapeutics without the required review
==============================================================

At CRBCM we now believe that if criminal activity is not found.
the competency of people in charge of the investigation needs further reevaluation, or the same network involved with CPRIT management is at work and stole the verdict. With the extent of misrepresentation and conflict of interest unveiled at CPRIT, It will be a Blasphemy and misconduct of justice if no soul is held accountable! Or at least indicted! This is a fair prediction.
When a non existing company is given a grant. I do not need a law degree to see a wrong-doing!
When people call this the "CPRIT CON", These prosecutors need to deliver. After this audit, the chance of no prosecution in our view is zero! The bet is on.

The malice at CPRIT has been deliberate, ostentatious and, at time pugnacious. What a sad day it will be if our prosecutors came back empty handed. What a sad day it will be. We will know the network got to them! I agree with the auditors, prosecutor should not be part of the Oversight committee. They become witnesses for the true prosecutors!

What a mess this is. It will go in history! let's write it right!

CPRIT AUDIT REPORT IS ON THE LEVEL.
==================================
The CRBCM would like to commend the Audit team for a job that is at the level within the time constraint. The report, although partial, reveals that auditors intended to do a good job and the mess at CPRIT was blatant. There is no aspect you could look at CPRIT to not find fault. From cavalier rejection of applications, to payment of cronies, everything was there for the auditors to see. Abduction of the system by universities which created phony companies (one such company got a grant before its existence), What reviews were completed and non compliance with their own standards. More than a messy company, CPRIT did not have a soul. Basically, CPRIT as described, was hijacked by bandits and conspirators, people were so full of their powers, they were day and night imagining ways to detour the money.
With just 10% of projects reviewed at least 4 projects did not meet the requirements created by CPRIT.
Should time be given to the auditors to complete their work, we project that 40 or more projects will not have met CPRIT's own standards. And that is being kind and conservative!

Basically, CPRIT was a mess, the leadership a joke, and plenty of politics and conspiracy were the rule.
CPRIT needs a soul and a vision. Cure needs to be imagined, and steps to reach it carefully planned.

With 42% of funds going to the MD Anderson, and 15% to Baylor, the statewide vision was non-existent at CPRIT. Zero percent went to El Paso. Basically while all resident of Houston could feel the money. I was in Houston, I could see many new shiny Buildings own and being built by Bio-tech companies. Tax-payers in El Paso paid for nothing! Basically, the rest of Texas is paying bonds for the good of Houston. On top of this, Applicants companies are now paying friends of CPRIT. Bio-alliance is getting $1000 per application. Why. Tax payers have already paid for this service, this is another tax on businesses trying to pull pieces of meat from within the jaw of the MD Anderson. Bio-alliance may be a MD Anderson derivative. With the complexity of the corrupt network put in place. It is hard to determine anymore.

With half of the Money going to Houston, we are being robbed to feed the beast that is Houston. Can CPRIT come back to its mission? If the changes suggested are allowed to be put in place by the same team members. I really doubt it. The legislature need to place a visionary at the head with muscle to replace contaminated apples in the bag! It takes one rotten element to spoil the entire mission.

What is described by auditors is so bad that an outsider is needed with a big broom for a complete clean up. For the sanity of the mission this is what should come!

CPRIT need a vision, fairness, a soul, and backbone to stand against big Universities! CPRIT needs someone who believes CPRIT is an autonomous organization with answer to the people of Texas, not just the MD Anderson!

I was reading a commentary by a regional journalist who was trying to explain why El Paso was not getting any research fund. "There is no institution in El Paso with matching fund available" he claimed being the reason. Now we know this to be a pretext! The MD Anderson could just write it has the money and CPRIT would comply. This is what is defined as cavalier... and I don't make this stuff up! Read the report and we can talk!

CPRIT HAS BEEN AUDITED

An Audit Report on Grant Management at the Cancer Prevention and Research Institute of Texas and Selected Grantees

January 2013

Report Number 13-018

Overall Conclusion

The Cancer Prevention and Research Institute of Texas (CPRIT) should significantly improve the transparency and accountability of its grant management processes. Weaknesses in CPRIT's processes reduce its ability to properly award and effectively monitor its grants. Specifically, CPRIT should address deficiencies in the following areas:

- Making award decisions.

- Evaluating grant applications.

- Verifying compliance with matching funds requirements.

- Processing payments to grantees.

- Monitoring grantees' expenditures.

- Assessing and measuring research progress.

- Managing contract agreements with grantees.

Making Award Decisions

CPRIT should ensure that all award decisions are free from real or apparent conflicts of interest. The executive director discussed award recommendations with certain members of the oversight committee prior to presenting the recommendations to the full oversight committee. Also, CPRIT’s chief scientific officer, chief commercialization officer, and director of scientific review had office locations on the campuses of higher education institutions that received CPRIT awards. The chief scientific officer, the chief commercialization officer, and the director of scientific review are responsible for managing the peer review process for grant applications in their respective areas. In addition, auditors identified two members of CPRIT's commercialization review council with financial and personal interests in certain grantees. Specifically:

- One member of the commercialization review council was also a member of the board of directors for a grantee that received a $25.2 million research award from CPRIT. According to CPRIT's records, that individual did not participate in the review of the grant application for that grantee.

- Another member of the commercialization review council provided consulting services to two applicants applying for Texas life sciences incubator commercialization grants. That individual was not listed as participating in the review of grant applications for incubator grants, and neither applicant ultimately submitted a formal application for an incubator grant.

CPRIT also reported that it does not receive financial information about donors to the CPRIT Foundation or the amounts of the donations. Without that information, CPRIT has no assurances that it is not awarding grants to the CPRIT Foundation donors, which could create a conflict of interest. The General Appropriations Acts (81st and 82nd Legislatures) state that an individual; an organization; or an employee, officer, or director of an organization that makes a contribution to the CPRIT Foundation, or a person who has second-degree consanguinity or affinity to an employee of CPRIT, is not eligible to receive grants from CPRIT.

CPRIT's lack of controls for ensuring there are not any business and professional relationships between its peer reviewers and grantees impairs CPRIT's ability to assure the public that its award decisions are not improperly influenced.

Evaluating Grant Applications

CPRIT should ensure that its policies and procedures for evaluating grant applications are up to date and consistently followed. In addition, CPRIT should maintain records of all reviews that are performed.

Auditors could not verify that CPRIT consistently followed its process for withdrawing grant applications from the peer review process. CPRIT did not have reliable data to support grant applications that were withdrawn (see Chapter 1-B for more information).

Auditors identified the following significant issues for three grant applications tested:

- The Statewide Clinical Trials Network of Texas (CTNeT) received a $25.2 million research grant from CPRIT even though CTNeT did not exist at the time the grant was awarded. The CTNeT grant was the largest single grant that CPRIT had awarded as of June 2012. CPRIT originally awarded the grant to the University of Texas M.D. Anderson Cancer Center in June 2010. Subsequent to the award, CTNeT was formed and registered to become a Texas-based non-profit company in August 2010 and CPRIT executed a grant agreement with CTNeT in September 2010. It is unclear what allowed CPRIT to transfer the award from the University of Texas M.D. Anderson Cancer Center to CTNeT. CPRIT also did not have documentation to support that the scientific review council recommended the original application for a grant.

- CPRIT awarded a $20.0 million commercialization grant to the Houston-Area Translational Research Consortium (HATRC) and the Institute for Applied Cancer Science (IACS). Neither the HATRC grant application nor the IACS research proposal received scientific, due diligence, or intellectual property reviews. CPRIT reported that it rescinded the award in May 2012 after IACS requested to resubmit its research proposal for commercialization and scientific reviews.

- CPRIT awarded an $11.0 million commercialization grant to Peloton Therapeutics Inc. (Peloton, formerly Damascus Pharmaceuticals), whose application did not receive scientific, commercialization, due diligence, or intellectual property reviews.

Auditors reviewed the peer review scores for 218 (5.9 percent) of the 3,698 grant applications CPRIT reported receiving from September 2009 through June 2012 through the CPRIT Application Receipt System. Auditors identified four applications for which the peer review scores were not consistent with receiving a grant recommendation. CPRIT also did not have documentation to support the factors that peer reviewers used in making grant recommendations to CPRIT's executive director.

In addition, CPRIT did not document its review of recruitment grant applications or maintain records of those reviews in its Peer Review Management Information System. Recruitment grants are for the recruitment of investigators with the ability to make outstanding contributions to the field of cancer research, promote inquiry into new areas, foster collaboration, and stimulate growth in the field. Select scientific review council members manually review the recruitment grant applications; however, the only documentation maintained was a one-page summary statement that recommends the award of a recruitment grant. As of August 2012, CPRIT had awarded 60 recruitment grants totaling $184.9 million.

By not ensuring that all grant applications are properly evaluated and documented, CPRIT weakens its ability to ensure that its award decisions best align with the agency's mission.

Verifying Compliance with Matching Funds Requirements

CPRIT should verify the accuracy and availability of the matching funds its grantees report. The Texas Constitution, Article III, Section 67 (a)(3)(i), requires that before CPRIT awards a grant, the grantee must have funds equal to one-half the amount of the grant dedicated to the research that is the subject of the grant. CPRIT requires grantees to certify the amount of matching funds available for research at (1) the time of contract execution and (2) on an annual basis thereafter. However, CPRIT did not verify the accuracy and availability of the matching funds reported. In addition, during site visits to five grantees, auditors identified two methodologies, permitted by CPRIT, that allow a grantee to report funds that were not used on a CPRIT-funded research project as matching funds. Specifically:

- During interviews with auditors, staff at the University of Texas M.D. Anderson Cancer Center, the University of Texas Southwestern Medical Center, and the Baylor College of Medicine reported that the matching funds those institutions reported to CPRIT were based on the total amount of funding available to them for cancer research, excluding CPRIT funding. However, those reported matching funds were not dedicated to CPRIT-funded research projects. As of August 2012, those three institutions had received a combined 331 awards totaling $402.4 million.

- CTNeT, which received a $25.2 million research grant, did not dedicate $12.6 million in matching funds as required. Instead, CPRIT accepted certifications that the University of Texas M.D. Anderson Cancer Center and the Baylor College of Medicine would fulfill CTNeT's matching funds requirements for the first and second year of the grant agreement term, respectively. However, CTNeT did not receive those reported matching funds. For the first year of the CTNeT grant, CTNeT reported that the CPRIT grant accounted for 98.0 percent of its total revenue.

Processing Payments to Grantees

CPRIT should establish requirements to help ensure the appropriateness of advance payments and reimbursements it makes to grantees. Specifically:

- Advance payments. CPRIT's policies and procedures specify that CPRIT will distribute funds on a reimbursement basis. However, it made advance payments that totaled $40.2 million to 10 grantees from September 2008 through August 2012.

- Reimbursements. CPRIT relies on quarterly financial status reports and supporting documentation that grantees submit for reimbursement payments. However, CPRIT did not always obtain sufficient documentation from grantees to support the appropriateness of the reported expenditures. For 85 (84.1 percent) of the 101 reimbursements tested, or $9.4 million in reimbursements, CPRIT did not obtain documentation such as time sheets, invoices, contracts, and bill records to support the reimbursed expenditures. For those 85 reimbursements, grantees typically provided CPRIT with spreadsheets that summarized the expenditures.

Monitoring Grantees' Expenditures

CPRIT should improve its processes for monitoring grantee expenditures. CPRIT requires grantees to submit quarterly financial reports on research expenditures associated with awarded grants. In addition, CPRIT established a desk review process to assess grantees’ financial controls and reported expenditures. However, CPRIT did not ensure that all grantees submitted financial reports in a timely manner, did not maintain a complete record of all the financial reports it received from grantees, and had not performed any desk reviews of 487 grants totaling approximately $683 million as of June 2012.

Assessing and Measuring Research Progress and Compliance with Grant Milestones

CPRIT should ensure that grantees submit all required annual progress reports by required due dates, and it should review those reports and document those reviews. While CPRIT developed monitoring tools for tracking the due dates and submissions of annual progress reports, CPRIT lacked documentation to support that it followed up with grantees for past due reports. For a sample of 20 grant agreements that auditors reviewed, CPRIT had not received 12 (60 percent) of 20 annual progress reports that were due from September 2011 through June 2012. CPRIT's records indicated that it had started following up with grantees about past due reports beginning in May 2012. In addition, CPRIT has not developed review criteria for evaluating and measuring a grantee's reported progress. Although CPRIT used its peer reviewers to evaluate the eight annual progress reports it received, the peer reviewers did not document whether a grantee's reported progress met grant milestones or whether any problems had been identified that could affect the grantee's ability to complete the research project. CPRIT reported that it received emails from the peer reviewers indicating that a review was complete and that no issues had been reported by reviewers.

CPRIT should improve its management of the CTNeT research grant and other administrative practices.

Auditors identified significant weaknesses in CPRIT's award decision and management of the $25.2 million research grant to CTNeT (see Chapter 3 for more information about this grant). Specifically:

- CTNeT's grant application did not receive a favorable peer review score. CPRIT evaluated grant applications on a scale of 1 to 9, with 1 being the highest. The CTNeT grant application received a peer review score of 4.64. Auditors reviewed the peer review scores for 44 other applications and identified 9 applications that were not awarded grants that received peer review scores ranging from 3.93 to 4.40.

- CPRIT has a role in CTNeT's business operations. CPRIT’s oversight committee chair, vice-chair, and executive director interviewed and hired CTNeT's chief operating officer before the contract was executed. In addition, CPRIT's executive director, chief scientific officer, and a member of CPRIT's commercialization review council are members of CTNeT's board of directors.

- CPRIT made $6.8 million in advance payments to CTNeT even though its grant agreement with CTNeT allowed only reimbursement payments.

- CTNeT did not comply with matching funds requirements and annual progress reporting requirements.

CPRIT’s relationship with CTNeT and its lack of enforcing contract requirements impair CPRIT's ability to ensure that CTNeT is properly using grant funds and complying with grant requirements.

CPRIT also should improve certain procurement and payment practices for vendors and other professional services.

CPRIT should strengthen its vendor procurement and payment practices to ensure that the services and costs for grant management services and virtual management company services are reasonable and necessary. Specifically:

- The costs for a five-year contract for grant management services increased from $15.7 million to $21.2 million (35.2 percent) within the first three years of the contract. The cost increases were based on amendments to the contract that increased the workload of the grant management services contractor and the development of a grant management system.

- The costs for the first two years of a four-year contract for virtual management company services increased from $1.5 million to $4 million, approximately 166.7 percent. The cost increases were based on amendments to include services management, an entrepreneur-in-residence program, salaries for additional executive positions that were added to the contractor's staff, and other direct costs.

CPRIT also did not consistently obtain sufficient documentation to support the appropriateness of honorarium payments it made to its peer reviewers. From September 2009 through June 2012, honorarium payments to peer reviewers were approximately $6.7 million. In addition, CPRIT lacked documentation to justify increases in honorarium payments to officers of its peer review committees. Also, auditors identified honorarium payment amounts for certain peer reviewers that may be significantly higher than the payment amounts that the National Cancer Institute pays its peer reviewers.

Auditors communicated other, less significant issues to CPRIT's management separately in writing. Those issues were related to administrative reporting discrepancies, the forms grantees use for reporting, reporting practices for certain grantees' payment practices, performance feedback to grantees, executing grant agreements, and management of peer reviewer rosters.

The Legislature should consider amending statutory requirements to improve the transparency and accountability of CPRIT.

The Legislature should consider statutory requirements to:

- Allow peer reviewers to provide their grant recommendations to the executive director and members of the CPRIT oversight committee at the same time.

- Clarify what funds can be used and the intended use of matching funds reported by grantees.

- Clarify whether contributions made by non-profit foundations affiliated with grantees are appropriate.

- Prohibit an interlocking directorate between CPRIT and the CPRIT Foundation.

- Prohibit CPRIT employees from serving on a grantee's board of directors and related foundations.

- Clarify the positions of the oversight committee's presiding officer and other officers, including the responsibilities and specific term of service for those positions.

- Allow members of the oversight committee to affirmatively vote to approve the executive director's recommendations.

- Remove the Attorney General and the Comptroller of Public Accounts from CPRIT's oversight committee so that their statutory duties and responsibilities would not be impaired.

- Allow the executive director to provide CPRIT's oversight committee, along with grant recommendations, documentation of the other factors that the executive director considered when making grant recommendations.

- Require the CPRIT Foundation to make its records, books, and reports available to the public.

Contact the SAO about this report.

Download the Acrobat version of this report. (.pdf)

ASCO GI: Phase III Bevacizumab Results of the AVEX and TRIBE Trials

Plus: Avastin gets new indication from FDA for second-line treatment

By Anna Azvolinsky, PhD¹ | January 28, 2013

¹Freelance Science Writer and Cancer Network Contributor. Follow Her on Twitter

The same week that bevacizumab (Avastin) received a new indication for the treatment of metastatic colorectal cancer, results from two phase III trials involving the drug were presented at the American Society of Clinical Oncology 2013 Gastrointestinal Cancers Symposium (ASCO GI) held January 24–26 in San Francisco.

TRIBE Trial Results at ASCO GI 2013

Results of the phase III TRIBE trial—comparing bevacizumab plus FOLFOXIRI with bevacizumab plus FOLFIRI—for metastatic colorectal cancer patients who have not been previously treated with chemotherapy were presented at ASCO GI (abstract #336). First-line FOLFOXIRI combined with bevacizumab showed better efficacy compared with the combination with FOLFIRI. A phase II trial had initially showed promise of this combination.

Among 35 Italian centers, 508 patients were randomized one to one to either arm, which both included up to 12 cycles of 5 mg/kg bevacizumab followed by bevacizumab plus fluorouracil as a maintenance therapy.
The study met its primary endpoint—a median progression-free survival of 11.9 months was seen in the FOLFOXIRI arm compared with 9.5 months in the FOLFIRI arm (hazard ratio [HR] = 0.72; P = .001). Response rates were also higher for the FOLFOXIRI combination—64% compared with 53% in the FOLFIRI group (P = .015). Toxicities were as expected and comparable in the two groups.

AVEX Trial Results at ASCO GI 2013

Another bevacizumab phase III trial reported at the meeting was the AVEX trial of elderly metastatic colorectal cancer patients. The AVEX trial compared bevacizumab in combination with capecitabine or capecitabine alone in previously untreated patients 70 years or older (abstract #337).
According to the study researchers, this is the first randomized, prospective trial that has analyzed the benefit of bevacizumab specifically in elderly patients. The results show the combination may be a better treatment that improves elderly patient outcomes. The results validate the use of bevacizumab with capecitabine, a fluoropyrimidine, in elderly patients.
“[These results] confirm a benefit with increased response and tumor control,” said David Cunningham, MD, head of the gastrointestinal unit at the Royal Marsden Hospital in the United Kingdom, and the presenter of the study.
The open-label trial administered bevacizumab to one half of the patients at a 7.5 mg/kg dose every 3 weeks. A total of 280 patients (median age of 76) in 10 countries were part of the trial, which showed the combination prolonged progression-free survival compared with chemotherapy alone. Progression-free survival was 9.1 months for patients taking the combination compared with 5.1 months in the chemotherapy alone arm (HR = 0.53; P < .001).
Overall survival was also improved, but the difference between the two arms was not statistically significant—median overall survival was 20.7 months in the combination arm compared with 16.8 months for the capecitabine arm (HR = 0.79; P = .182). Grade 3 and higher adverse events were more frequent in the combination arm, but researchers said the regimen was generally well tolerated. Grade 3 or higher toxicities were seen in 59% of patients taking bevacizumab plus capecitabine compared with 44.1% of patients taking capecitabine alone.
“This trial result emphasizes that with appropriate selection, patients with advanced colorectal cancer, regardless of age, may benefit from chemotherapy and that the combination of capecitabine and bevacizumab represents a good option that has a favorable balance between efficacy against side effects,” said Cunningham.

Avastin Gets New FDA Indication for Second-Line Treatment

The US Food and Drug Administration (FDA) approved the use of bevacizumab (Avastin) as part of a new combination treatment for the second-line treatment of metastatic colorectal cancer. The drug is now approved in combination with a fluoropyrimidine-based irinotecan or oxaliplatin chemotherapy for metastatic colorectal cancer patients whose cancer has progressed after first-line treatment with a regimen that contains bevacizumab (ie, second-line treatment of bevacizumab/oxaliplatin for patients who received prior therapy of bevacizumab/irinotecan and vice versa).
Patients receiving the combination lived longer compared with those who switched to chemotherapy alone as a second-line treatment. Results showed a 19% risk of death reduction for patients on the combination therapy compared with standard chemotherapy alone (HR = 0.81; P = .0057) in the phase III ML18147 trial. The median overall survival was 11.2 months compared with 9.8 months. The results are published in the Lancet Oncology.
Bevacizumab is already approved in combination with chemotherapy as a first-line therapy for metastatic colorectal cancer patients and also as a second-line treatment in combination with FOLFOX4 (5-fluorouracil, leucovorin, and oxaliplatin).

DIET FAILURES

With any kind of diet, by the time you reach the 6-12 week mark, the selected strategy has given you its maximum benefit. Hopefully, by then you will have achieved the 10% reduction of your total weight which is the realistic goal to pursue. If you did it right, 1-2 pound per week of weight loss, you would have lost at least 10 pound by now. After this, maintenance is the challenge and your body's response is even more of a challenge.
The body wants to get back to the size it knows you can achieve. Make no mistake, size is the major killer. Just look at the tumor, when it gets too big, areas of necrosis soon happen because some areas will suffer ischemia.

Your body will start asking for food, will try to tell you that just this small thing will not be harmful, and it will tell this throughout the day. TIMING, WHEN YOU CAN AFFORD TO EAT SOMETHING IS AN IMPORTANT STRATEGY TO PUT IN PLACE. KEEP CONTROL OVER THIS. REMEMBER ONE THING IS FOR SURE: BY THIS TIME, GROWTH HAS STOPPED AND THAT THIS IS ALREADY A GREAT GOAL ACHIEVED. KEEP IT THERE.

To go further down, avoid staying home near the refrigerator. Go out, walk at the mall without money, just your ID! Or best go to the gym or call your support buddy. When the diet effect is maximized, that is when you need to exercise the most, and that's when you need Calorie control the most, and your vitamins. Whatever you do, do not increase your Carbohydrate intake, or any excess calories. Remember, you will not increase your weight doing this. The body will fight back, trying to use what you have given it to its maximum advantage, using everything to its advantage, constipation will set in to prolong intestinal absorption and reduce stool size, but work on staying "regular". Constipation is a proven risk of Colon cancer. Take it out. At this stage, it also is hard to exercise. Your body will tell your brain not to exercise. Any excuses will come to mind. Double down and keep exercising. A walk will be good any time. Remember, staying home with the refrigerator in the house is one of the brain challenges. If you do reach for the refrigerator, have safe options. Very cold water, sweet non sugary options or a fruit. Dried vegetable chips or low calorie nuts. Here, frequency to the refrigerator needs to be controlled by a schedule.

So, schedule or time your eating, when you reach to eating, find options that are safe, and keep on moving or exercising; this should be your strategy. And remember, if you do not increase your weight, that's an objective success already. We will keep trying to find more and let you know!

Sunday, January 27, 2013

OVEREXPRESSION OF SQLE GENE ON CHROMOSOME 8, MARKER OF PROLIFERATION?

One of the gene marked as proliferation genes is the SQLE, This gene located at 8q24 was puzzling to me because it has a role in Sterol Biosynthesis. I wonder why this gene was in the proliferation section. Then it occurs to me that new cells need new cellular membranes. Of course, you need to over-express this.
I should confess that sterol biosynthesis is a tremendous opportunity for cancer cure because research is advanced in this area. I know the Trypanosome has been fought through this media. Silencing SQLE. Who would have thought....!

SPEAKING SLEEPING SICKNESS, MEDICATIONS USED TO TREAT THIS DISEASE INCLUDE ARSENIC DERIVATIVES. IN AN EFFORT TO POTENTIATE THE ARSENICALS, COMBINATION WITH DFMO HAD BEEN TRIED, I WONDER IF ONE CAN USE THIS COMBINATION FOR TREATMENT IN ACUTE PROMYELOCYTIC LEUKEMIA? WILL LOOK INTO THIS!

NOMENCLATURE OF THE GENES OF PROLIFERATION, STILL THE 3RD LAW,

1. ZWINT:

During cell division, separation of chromosome or chromosome movement is not random, and follows microtubule tracks through an attachment at the Kinetochore. Kinetochore attaches the chromosome at its inner section, and the micotubule at the outer section. protein components of the the Kinetochore include Dynein, a cytoplasmic protein that need to be recruited (phosphorylated) to the Kinetochore. The ZWINT (at 10q21)with its interactor ZW10, serves as a substrate to AURORA B, helps globally with the Dynein recruitment at the Kinetochore. Disruption at the Kinetochore will foil cell division.
Expression of the ZWINT marks a proliferative phase in the cancerous process.

2. TTK
CANNOT DESCRIBE IT BETTER
"

This gene encodes a dual specificity protein kinase with the ability to phosphorylate tyrosine, serine and threonine. Associated with cell proliferation, this protein is essential for chromosome alignment at the centromere during mitosis and is required for centrosome duplication. It has been found to be a critical mitotic checkpoint protein for accurate segregation of chromosomes during mitosis. Tumorigenesis may occur when this protein fails to degrade and produces excess centrosomes resulting in aberrant mitotic spindles. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2009]

Genomic context

Location :: 6q13-q21"; SOURCE NCBI; ------------------------------; RELATED GENES : THE CYCLIN DEPENDENT KINASE AND PLK-1; RELATED PATHWAY pRb PATHWAY.; THIS IS PROLIFERATION AT IT BEST, CANCER MUTATES THESE TO ESCAPE PROLIFERATION CONTROL

Can Metastasis of Triple-Negative Breast Cancer Be Thwarted?

By Anna Azvolinsky, PhD¹ | January 24, 2013

¹Freelance Science Writer and Cancer Network Contributor. Follow Her on Twitter

Researchers have demonstrated how a particularly aggressive type of breast cancer, triple-negative disease, spreads to other parts of the body. The results may lead to new therapies that could treat metastatic breast cancer. The findings are published in Cancer Cell.

Breast cancer cells; H&E stain

Triple-negative breast cancer (TNBC) readily spreads to other parts of the body and has few treatment options—there are currently no therapies specifically for TNBC approved by the US Food and Drug Administration. Approximately 15% to 25% of all breast cancers are TNBC.

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Researchers at the Weill Cornell Medical College of Cornell University in New York and colleagues have identified a microRNA (miRNA), the small RNA molecules that regulate gene expression, called miR-708 that is repressed in metastatic breast cancer. Expression of the miRNA in breast cancer mouse models specifically blocked metastasis, but did not affect primary tumor growth. The study shows that miR-708 normally functions as a metastatic tumor inhibitor.
“These studies suggest that miR-708 has the potential in the treatment of extraordinarily high-risk breast cancer patients,” said lead study author Vivek Mittal, PhD, associate professor of cell and developmental biology at Weill Cornell Medical College, referring to patients with TNBC whose cancer has metastasized. “TNBC is almost like a death sentence for these patients.”
The study of the miRNA also presents a theory for why TNBC is more malignant compared with other breast cancer types. Using primary and metastatic breast cancer patient tumor samples, Mittal and colleagues showed that miR-708 is present in all types of primary breast tumors, but is not expressed in metastatic breast tumors. However, miR-708 was downregulated (expressed less) in TNBC compared with other breast cancer types. “We think that TNBC is the most metastatic because the primary tumor itself may contain more metastatic, stem-like cells.” Earlier studies have suggested this to be the case.
MiR-708 normally functions to decrease intracellular calcium levels, resulting in activation of the ERK/FAK pathway that impairs the ability of cells to migrate and, therefore, metastasize. When miR-708 is inhibited, the cells can readily migrate and invade other organs. Higher calcium levels trigger migratory pathways that help cancer cells travel to other organs and can lead to metastasis.
When the researchers delivered synthetically made miR-708 to mice with primary TNBC tumors, the miRNA was able to block metastasis development of the TNBC tumor cells in the lungs of the mice.
“The surprising part is that miR-708 does not affect primary tumor growth, but impacts metastasis alone, suggesting its exclusive role in later metastasis pathways,” said Mittal.
The study also identified the protein complex that inhibits expression of miR-708. The complex works to remodel proteins to epigenetically silence certain genes.
“Our finding is significant,” said Mittal. “Since previously discovered breast cancer miRNAs targeted primary tumor growth by affecting proliferation and apoptosis, it was difficult to discern their role following metastatic dissemination.”
According to Mittal, two approaches to target the miR-708 miRNA are ongoing. One is using an epigenetic therapeutic approach by inhibiting one of the complexes that silences miR-708. Another is directly adding back miR-708 miRNA using either liposomes or nanoparticles for delivery.
If targeted agents against miR-708 are developed, they would be among the first that would restore the normal function of an miRNA and the first to specifically target cancer metastasis.
The current study identified miR-708 using a next-generation miRNA sequencing approach. Had a microarray approach been used, the miR-708 miRNA would not have been identified, as it was not available on any of the microarray platforms, said Mittal. “MiRNA sequencing is powerful and allows discovery of known and novel miRNAs.” Whether miR-708 also has a role in metastasis in other cancers has yet to be addressed.

UPDATE ON TREATMENTS OF PERIPHERAL T CELL LYMPHOMA

3 AGGRESSIVE TYPES:
==================
1. PTLC- NOS
2. AITL: AngioImmunoblastic
3ALCL (Anaplastic large cell (ALK +) 6% AND alk NEGATIVE
CD30 , t(2,5)(p23,q25)
---------------------------------------------------------------------------------
1 Peripheral T cell lymphoma not otherwise specified
-PET
-Gene Profiling
treat it with EPOCH (CHOEP) or Etoposide based regimen followed by transplant
consider Romidepsin (upfront in Europe)
followed by Gemcitabine, Navelbine (Doxil)

Europeans give ACVBP +/- Romidepsin (Vindesin not available in the US)

refractory disease" FDA has released 3 drugs, their role and position is being evaluated"
=============
Romidepsin
Pralatrexate
CD30 positive - BRENTUXIMAB VEDOITIN
----------------------------------------------------------------------------------------------
2. some T cell lymphoma are clearly Indolent i.e Mycosis Fungoides (MF)
-------------------------------------------------------------------------------
3. Anaplastic Large cell Lymphoma
ALK negative
for Europeans ACVBP followed by transplant

USA, same paradigm as in PTCL NOS

FOR ALK POSITIVE -- CHOP ALONE IS THE BEST NO TRANSPLANT (NO ETOPOSIDE NEEDED) (THE GERMAN STUDY WAS RETROSPECTIVE )
CRIZOTINIB

PRALATREXATE AND ROMIDEPSIN HAVE BEEN USED IN CLINICAL TRIAL
---------------------------------------------------------------------------------------------------------
4. ANGIOIMMUNOBLASTIC

STEROIDS
SOME CLAIM CYCLOSPORINE (PARTICULARLY WHEN HEMOLYTIC ANEMIA)

IN EUROPE CHOP-ROMIDEPSIN

IN USA, GEMZAR
FOR THOSE WITH A COMPONENT OF CD20 POSITIVE, RITUXAN +STEROID

WHATEVER YOU DO, DON'T GIVE ADRIAMYCIN!

sCD163 and sTARC are disease response biomarkers for Hodgkin's lymphoma

As published in Clinical Cancer Research, combined sCD163 and sTARC are better markers of disease response in patients with Hodgkin's lymphoma undergoing first-line therapy than either marker alone. sCD163 reflected tumor burden during treatment, while sTARC was more significant upon completion of therapy.

Read the article summary now:
http://www.mdlinx.com/oncology/news-article.cfm/4317702/?utm_source=in-house-msg&utm_medium=message&utm_campaign=reactiv-scott

GENETIC MUTATIONS GIVING FURTHER INSIGHT INTO HEMATOLOGIC MALIGNANCIES, POINTING OUT WHERE ABNORMALITIES ARE WHICH WHICH WILL IMPACT SIGNIFICANTLY RESEARCH FOR THERAPY.

While Multiple Myeloma seems to result from amplification of major pathways with Ubiquitinated molecule persistence being one of the major therapeutic interventions (as a result of proteasome inhibitors), most likely by feedback blockage of major pathways and mitotic check point arrests, Myelodysplasia and Leukemia are going purely NUCLEAR. SF3B1 mutation now associated with Refractory Anemia with ring Sideroblasts and cases of Chronic lymphocytic leukemia, putw us square and fair into the realm of m-RNA splicing. The new interest in SETBP1 ties some case of mental retardation to elevated risk of Anemia. (Schinzel-Giedion Syndrome). But remember, the elevated risk of AML in Down Syndrome-Coincidence or similarity, is the question!

Finding abnormality in the PRPF8 gene in dysplasia and leukemia brings back and re-enforces that splicing abnormality may be a significant driver in these conditions. These findings cast doubt that researchers pushing drugs treating myeloma in Leukemia treatment may meet disappointment. It is another animal all around!

Abnormality in CSMD1 gene (regulator in the complement system) caught our attention. Is this an insight into immunodeficiency in Dysplastic syndrome...? we will follow-up!

Another gene PPFIA2 is down regulated by Androgen therapy in prostate cancer, if it is significant, can we use this as predictive indicator in a therapeutic strategy?

We can't seriously finish without talking about the RUNX-1: what a major target since differentiation lays here. But is differentiation a meaningful target? Remember, allowing these cells to fully mature may lead them to Apoptosis... so let's weigh this one!

The future is exciting in Research!

Saturday, January 26, 2013

Adrenaline Funk by Clement Albert on Ubetoo

by Clement Albert
Adrenaline rushing in my veins

http://www.ubetoo.com/clementalbert/54807#.UQQiUGhzo7o.email
copy the link if it does not work!
---
This message was sent by drkcancerclinic@GMAIL.CON via http://addthis.com. Please note that AddThis does not verify email addresses.

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A little music for relaxation can only do good!

PRELIMINARY DISCUSSION ON THE 4TH LAW. THE 4TH LAW IS BEST UNDERSTOOD AS THE SET OF FORCES THAT DRIVE THE CELL FUNCTIONS IN A PARTICULAR ELECTED DIRECTION.

THE 4TH LAW IS BEST UNDERSTOOD AS THE SET OF FORCES THAT DRIVE THE CELL FUNCTIONS IN A PARTICULAR ELECTED DIRECTION.
At molecular level, this is enforced by GENE AMPLIFICATION. That is if the cell is going toward differentiation, the cell will make cellular processes to direct all the cellular function to that aim. for specific cancer this equivalent to the notion of DRIVER Mutation. Cellular functions are not totally random and living things do not stay still! life is always on the go, and on the go for survival. And once it has chosen a direction, it direct its functions toward an overall goal which at cellular level is to ensure survival. The drive, the stamina, the direction is battery powered and purposeful!
In the cell that drive is powered and to ensure that it has direction, AMPLIFICATION GENES go to work.

One good example of this is what happens with some Viruses. A number of viruses when the enter the host cell, will incorporate their viral genome into the genome of the host to manage to use the host survival machinery to their advantage. Insertion in the genome of the host sometimes is not enough to trigger the use of the Viral genome in the host machinery, the Virus has to recruit a "growth factor" most of the time called FACTOR-1 to ensure amplification of its genetic material. (this is known for HIV infection)

In cancer cells, there are amplification genes toward the completion and survival of the cancerous process.
In lung and thyroid cancers, TTF-1 represent such a gene. found amplified in about 10 % of tumors. Scientist have had trouble defining its role. But they know its AMPLIFICATION is bad news for the host. It is a driver gene for the cancerous process. In the cell, there are several levels of GENE AMPLIFICATIONS.

The first level is mission driven. If the mission is to differentiate, this 4th law push to achieve the mission.
if the mission is to grow a cancer, the cell uses all its resources to make a "perfect cancer." This means, tolerate error in the DNA multiplication, down-regulate the repair mechanism, down-regulate or mutate the regulator of P53, MDM2. Amplify VGEF so that the tumor has plenty of good blood vessels.

The second level of amplification is actually originating from the stimulus, the cause of the transformation. the cause could be a change in Oxygen level, a break of shorten Telomerase tail, Tumor growth factor (FGF-1), Cyclins, or an oncogenic mutation or break of DNA strands. This will ultimately stimulate receptors with subsequent signal transduction pathways flow that could be amplified by way of intensity of the signals, but also enzymatic up-regulation and nuclear transcription amplification. Amplification can be then cancerous based, but also stimuli caused.

the 3rd amplification is what occurs at the DRIVER Mutation due to growth factors or increased catalytic rate from related enzymes.

It is hard to measure cancer driven gene Amplification. Most of the study keeps taking Metothrexate and its mechanism of Resistance because amplification of Dehydrofolate Reductase is the mechanism of resistance. every body focus on this enzyme to measure resistance. But when you look at amplification at this various levels, it is not hard to see that these measurements are missing the point or are just misleading.

We will discuss the relevant Genes under the section or Rubric "NOMENCLATURE". Frankly speaking, we have not finished yet the genes for the 3rd law.

We are working hard at CRBCM!

Coalition for the Reversal of Breast Cancer Mortality in African American Women

Thursday, January 31, 2013

The polycomb group protein enhancer of zeste homolog 2 (EZH 2) is an oncogene that influences myeloma cell growth and the mutant ras phenotype.

Source

Abstract

NME1

Interactions

Wednesday, January 30, 2013

More in Open government, The Business of Government

Parkland Memorial cuts a $500,000 deal to enlist lobbying powerhouse for regulatory issues as fate rests with regulators

Tuesday, January 29, 2013

Monday, January 28, 2013

Travis County DA: “The CPRIT investigation is ongoing and aggressive”

CPRIT HAS BEEN AUDITED

An Audit Report on Grant Management at the Cancer Prevention and Research Institute of Texas and Selected Grantees

Overall Conclusion

Contact the SAO about this report.

ASCO GI: Phase III Bevacizumab Results of the AVEX and TRIBE Trials

ASCO GI: Phase III Bevacizumab Results of the AVEX and TRIBE Trials

Plus: Avastin gets new indication from FDA for second-line treatment

TRIBE Trial Results at ASCO GI 2013

AVEX Trial Results at ASCO GI 2013

Avastin Gets New FDA Indication for Second-Line Treatment

DIET FAILURES

Sunday, January 27, 2013

Genomic context

Saturday, January 26, 2013

Adrenaline Funk by Clement Albert on Ubetoo

PRELIMINARY DISCUSSION ON THE 4TH LAW. THE 4TH LAW IS BEST UNDERSTOOD AS THE SET OF FORCES THAT DRIVE THE CELL FUNCTIONS IN A PARTICULAR ELECTED DIRECTION.

Contact::