Friday, February 1, 2013

DIFFERENTIATION AND THE CURE.
5TH LAW OF NATURE

Although it would have been nice if there were clear cut cross-road between DIFFERENTIATION and PROLIFERATION. Nature has understood that most tissues will need to be repaired particularly when it comes to the skin. Therefore some differentiated cells could trigger de-defferentiation when repair is needed. The question is then how could the shift occur. What makes a hyperdifferentaiated cell shift gears and enter proliferation.
Stimuli from outside the cells including local specific growth factors (TGF Beta, nerve growth factor,Epidermal growth factor, Epiregulin, transforming Growth factor, Platelet derived GF, and so on) attach to its cellular receptor, and trigger N,H,C, K -RAS. and depending on the type of RAS, differentiation will be directed. There are other point of tissue specificity but the family of RAS is one area of folk differentiation.

One other location of folk differentiation is at the level of transcription genes and at genetic plicing (PRPF8,
U2AF2 (keep an eye on this one), WT-1 (looks like EGFR), PUF60, ASF/SF2,WDR,EFTUD2, PPFIA-down regulates androgen for differentiation, SF3B1 etc...

Researchers looking at NRAS and KRAS function were manipulating a Colon cancer cell when the find themself with a cell with putative stem cell features indicating that whatever stimuli being applied reversed the cell to open up totipotential characteristic. We know that cell from skin would repair wound through proliferative process. Increase in TNF and Interferons would yield fibrotic tissue. After a trauma,These growth factors will direct efforts to another type of RAS. The RAS stimulation follow the MEK transduction signal to lead to appropriate transcription and splicing factors for relevant nuclear events globally!

The thing is the more complete the differentiation, the less the proliferative potential.

This beg a question that investigators have been struggling, forcing full differentiation by maximizing differentiation a viable strategy for cure by silencing proliferation. One thing is for sure, high dose interferon disrupts growth factor effects and had been for a while the only treatment for Melanoma until BRAF was interfered with and now regulation of the MEK/MAP kinase has also been inhibited. Disruption of growth factors at the membrane leads to expression of molecules and disruption of Glycocalyx susceptible to recruit
immune cells.

THIS SAME MECHANISM would more likely lead to cirrhosis in the liver where injury lead to change of growth factors leading to preponderance of fibrous tissue and new nodules. This is differentiation challenged by "trauma" to the liver tissue!

GENE PROFILING, P53 STORY

P53
---------------
At least half of the Sarcomas will show activity at P53, the cellular Molecule of the year in 1993,
in up to 10% of cases, the P53 will actually be mutated. It is either overexpressed or suppressed in the rest of the cases of Sarcoma. The P53 is suppressed if repression occurs at P14 or at CDKN2A or if MDM2 is overexpressed. P14 shield P53 from the effect of MDM2. P53 is also overexpressed if its degradation is stopped at the proteasome.

At the nuclear level, Acetylated P53 combines to P300 and promote P21 and Puma leading to Apoptosis. This effect can be blocked by Fusion protein EWS-Fli1 in Ewing Sarcoma, and by upregulation of Histone DE-Acelase 1 which effectively blocks down transcription effect of P53.

If you count right, there are 6 potential targets of interaction with P53, if you include upstream toward the membranes...calling for Multitarget therapy in those conditions where wild type P53 is overexpressed!

GENE PROFILING IS A MUST STEP IN CANCER TREATMENT!

LOOPHOLE EXISTS WHEN p53 IS BLOCKED DOWNSTREAM THOUGH,
BLOCKAGE OF p53 IN THE NUCLEAR, TRIGGERS EXPRESSION OF JAG1, HEY1 WHICH INTENSIFY NOTCH3 AND STILL LEAD TO CELL CYCLE ARREST.

MARTA Q LACY.
Professor of Medicine
Division of Hematology
Mayo Clinic College of Medicine
Rochester, Minnesota

Relapse remains a significant clinical problem for multiple myeloma. Nearly all patients eventually relapse, and, although survival rates are improving and treatment options continue to grow, the move to upfront combination therapy does limit options in relapse. FDA approved options for relapsed multiple myeloma include the immunomodulatory agents thalidomide and lenalidomide and the proteasome inhibitors, bortezomib and carfilzomib (for patients who have received at least 2 prior therapies including treatment with bortezomib and an immunomodulatory agent).

For patients not resistant or refractory to immunomodulatory agents and proteasome inhibitors, there are effective choices. However, for patients who have failed thalidomide, lenalidomide, and bortezomib survival is low.¹ Disease-, regimen-, and patient-related factors contribute to therapy selection in relapse. Disease-related factors include risk as assessed by FISH and cytogenetics and duration of response to initial therapy. Patient-related factors include comorbidities, age, and performance status. Regimen-related factors include prior drug exposure, toxicity of the regimen, the mode of administration, and whether the patient has had a previous stem cell transplant. These factors should be carefully weighed when making treatment decisions for relapsed myeloma patients.

At diagnosis, Mr Johnson had no high-risk molecular markers and excellent renal function. In this setting, at Mayo, we prefer to start with lenalidomide and dexamethasone because it has high remission rates, is oral, well tolerated, and unlikely to induce peripheral neuropathy. When using lenalidomide in patients with no personal history of VTE, we favor prophylaxis with aspirin at 325 mg daily. We would use IV bisphosphonates monthly for 12 months and quarterly for 1 additional year. In patients with low-risk disease, we consider risks and benefits of maintenance therapy. If maintenance therapy is chosen, consider limiting the duration to 12-24 months.

At relapse, if our patient had a good response and a long duration of remission (> 12 months), we favor re-introduction of the initial regimen. If the patient has suboptimal response or a short remission duration, we would change the class of drug used (eg, if initially treated with an immunomodulatory agent [thalidomide, lenalidomide], we would switch to proteasome inhibitor [bortezomib, carfilzomib]. If initially treated with a proteasome inhibitor, we would switch to an immunomodulatory agent). In this particular case, we would need to factor in that the patient now has renal failure and a new bone lesion. We generally re-introduce bisphosphonates quarterly at relapse in patients with new bone lesions. However, since this patient has renal failure, we would wait for renal improvement and favor pamidronate over zoledronic acid with a reduced dose of 30 mg (from 90 mg).¹ Also due to the renal status of this patient, full-dose lenalidomide should not be used. I would favor switching to bortezomib because it can be used at full dose. However, dose-adjusted lenalidomide is also an option.² A second ASCT may also be considered, especially if the initial remission was extremely long (eg, > 4 years).

Thomas G. Martin III, MD
Clinical Professor of Medicine
Multiple Myeloma Translational Initiative
UCSF Medical Center, University of California, San Francisco
San Francisco, California

Mr Johnson's presentation was fairly typical and consistent with standard risk myeloma. At UCSF, we would consider this young (< 60 years), standard risk patient to be an excellent candidate for autologous transplantation at presentation. Therefore, we would avoid melphalan containing therapy and limit upfront lenalidomide therapy to 4-6 cycles thus allowing ample marrow reserve for stem cell collection. Lenalidomide/dexamethasone, bortezomib/dexamethasone, and/or lenalidomide with bortezomib would all be considered excellent upfront therapy options. Appropriate supportive care measures would be oral calcium and vitamin D and IV bisphosphonates. Patients receiving proteasome inhibition should receive anti-viral prophylaxis to prevent zoster reactivation and patients receiving immunomodulatory agents should receive venous thromboembolism (VTE) prophylaxis. Patients at increased risk for VTE should receive therapeutic warfarin, while low-risk patients, such as this one, can receive aspirin (325 mg) daily. In patients treated with autologous transplantation, we favor lenalidomide maintenance based on the CALGB 100104 and French randomized post-transplantation maintenance trials.^1,2 The median time to progression in the CALGB study was almost double for the lenalidomide arm (46 months) versus the placebo arm (27 months). The optimal duration of maintenance therapy remains unclear but we attempt to continue maintenance in this setting for at least 1 year and often for 2-3 years depending on tolerability and count suppression.

At relapse, Mr Johnson has developed significant renal insufficiency and this prevents the use of full-dose lenalidomide, as lenalidomide clearance is primarily renal. Since Mr Johnson's remission lasted 24 months, one could choose to use either dose-reduced lenalidomide, or a bortezomib-containing regimen. There are a number of reports describing improved renal function in patients receiving early bortezomib administration and no increased toxicity. Consequently, we would likely recommend a bortezomib-based regimen, like cyclophosphamide, bortezomib, and dexamethasone (CyBorD) in this case. One should consider re-instituting bisphosphonate therapy once the renal function improves (unless the renal insufficiency is due to hypercalcemia for which bisphosphonates should be used right away). At relapse, one always needs to consider toxicity from prior therapy. Since the patient has a history of neuropathy, we would choose to administer bortezomib at weekly intervals and by subcutaneous injection. If the neuropathy increases, option would include switching to carfilzomib or lenalidomide-based therapy.

Katherine Sanvidge Shah, PharmD, BCOP
Hematology/Oncology Pharmacy Specialist
Emory University Hospital
Winship Cancer Institute
Atlanta, Georgia

I agree with holding off on bisphosphonate therapy until Mr Johnson's renal function improves. One exception would be if he were hypercalcemic at relapse. In this case, we would give full-dose therapy x 1 dose (for hypercalcemia of malignancy). If the renal function does not improve, we would consider dose-reduced zoledronic acid or pamidronate for the treatment of his lytic disease. At first relapse for this patient, we would also favor adding bortezomib into the treatment regimen of this patient as he has not previously received a proteasome inhibitor as dose reductions are not required with renal insufficiency (ie, exhibits good renal data), though we likely would have used bortezomib in the upfront setting.

Monitoring

Martha Q. Lacy, MD

For patients like Mr Johnson who achieve a CR, what do you monitor and how often?

Thomas G. Martin III, MD

Once a patient has achieved remission following upfront therapy, it is important to follow their myeloma for evidence of relapse. Early recognition of disease relapse often can prevent morbid complications including hypercalcemia, compression fractures, and renal failure. For patients on maintenance therapy, we will follow their CBC including neutrophil and platelet counts every 4-6 weeks and adjust dosing accordingly. A history and physical exam and laboratories including serum protein electrophoresis, quantitative immunoglobulins, serum immunofixation electrophoresis, and serum free light chains can be followed every 12 weeks. We will follow 24-hour urine tests (TP, UPEP, UIFE) every 12 weeks if a patient has had disease that is only assessable by urine tests (this is rare). We perform bone marrow biopsies every 12-18 months unless the patient has truly nonsecretory disease for which BMB exams are performed every 3-6 months. We rarely performed routine skeletal surveys but prefer PET/CT or total body MRI exams, every 12-18 months.

Elizabeth Bilotti, MSN, RN, APN

For patients who have achieved a CR post-transplant, we would follow every 3 months or as clinically indicated for reported symptoms, with a change in the frequency of assessments at the time signs of relapse became present. Evaluation would include full laboratory assessment (CBC, chemistry panel, quantitative immunoglobulins, SPEP, free light chain analysis, serum immunofixation with 24-hour urine analysis as appropriate ‒ UTP, UPEP, and urine immunofixation on a 24-hour urine). Radiographic imaging and BM biopsy would be determined based upon medical necessity and only used routinely in patients with non-secretory disease.

Thursday, January 31, 2013

Dear Komen friends,

We are less than three weeks away from Race for the Cure! I hope you will consider joining me at Cohen Stadium on Sunday, February 17 for the 21^st Annual Komen El Paso Race for the Cure. Thousands of women in El Paso rely on Komen funds for screening mammograms, treatment assistance, and wigs/prosthesis during treatment. Breast cancer services provided through Komen funds help diagnose breast cancer early when it is most treatable and save lives right here in El Paso. We need YOUR support in order to continue Komen El Paso’s work in our community.
You can join Team Suzy NOW and receive $5 off your registration fee. Register online for before 11:00 pm MST tomorrow, January 31 using Discount Code 2013RETURNINGCAPTAIN (case sensitive), and receive $5 off your Non-Competitive, Competitive, or Sleep in for the Cure registration!
But you may say, Stephanie, I will be out of town OR I don’t even live in El Paso. It doesn’t matter! With Sleep in for the Cure, you can show your support and don’t even need to get out of bed. I will not love you less if you choose this option : )
You can also join me in the fight by donating in support of my participation in the Race. My goal is to raise $1,000 this year. Please help me reach that goal with your financial support. Online donations are simple, and the site is secure. If you would prefer, you can also send me your tax-deductible contribution written out to Komen Race for the Cure.
Any amount that you can give will help! I truly appreciate your support and hope to see you Sunday, February 17 bright and early!

ACTIVITY AT CRBCM

WE HAVE NOW APPLIED FOR PROJECTS WITH THE DEPARTMENT OF DEFENSE
ON RESEARCH ON TRAUMATIC BRAIN INJURY; OF COURSE, CHANCES OF SUCCESS APPEAR SLIM TO NONE. MOTHER OF ALL POLITICS THERE. BUT IT IS AN EXERCISE PREPARING US FOR BETTER.

WE HAVE NOW INITIATED EFFECTIVE CONTACT WITH OUR LOCAL UNIVERSITY - UTEP. WILL MEET DR RENATO J. AGUILERA ON MONDAY FOR CONSULTATION AND HAVE SUBMITTED FOR EXERCISE PURPOSE 2 LETTERS OF INTENT TO PARTICIPATE IN THE RESEARCH ACTIVITIES OF THE "BORDER BIOMEDICAL RESEARCH CENTER (BBRC)"- EXPECTATION AGAIN LOW. WE WILL LEARN FROM WHAT THEIR CRITICISM WILL BE.

PLAN 2 GRANTS APPLICATIONS AT NIH AND 2 FOR ASCO THIS YEAR.
IF YOU THINK CPRIT IS A POLITICAL FARCE AND GIMMICK, THINK AGAIN WHEN YOU REACH ASCO AND THE OTHER REAL DEALS.

THE POINT IS THAT WE CANNOT BE FAULTED FOR TRYING. WE ARE NOT THE MD ANDERSON WITH 42% SUCCESS RATE AT CPRIT, BETTER THAN MOST TARGET THERAPY RESULTS! THE JOKE IS ON US WHO INNOCENTLY APPLIED BELIEVING IN A POTENTIAL FAIR SYSTEM THAT WAS A JOKE UNDER THE OLD LEADERSHIP AT CPRIT. WE ARE EAGER TO SEE WHAT COMES OUT OF THE REFORMED CPRIT, IF ANY! EVERY SESSION WAS AN OPPORTUNITY TO FUNNEL MORE MONEY TO MD ANDERSON AND BAYLOR, NO WONDER THE ENTIRE CPRIT SHIP WENT DOWN LIKE THE TITANIC, HOUSTON IS NOT TEXAS PEOPLE, WAKE UP!

HERE HOWEVER, THE NEED OF US IN THE MARKET IS PROPULSING US TO STAY ALIVE. EL PASO IS AN UNDERSERVED AREA. WE ARE NEEDED, SO DOORS ARE OPENING DESPITE NORMAL RESISTANCE...SO CRBCM IS ADVANCING EVEN IN TROUBLED WATERS...WE WILL BE HERE UNTIL WE ARE HEARD. THE IRS WAS A SURPRISE OPPONENT, YOU WOULD THINK THAT THE GOVERNMENT WOULD BE THERE TO HELP SMALL BUSINESSES AND NON PROFIT ORGANIZATIONS. NO, THEY ARE SITTING ON OUR FILE. WE JUST LOST 60,000 DOLLARS THAT COULD HAVE HELPED THE PEOPLE OF EL PASO THROUGH OUR PROGRAM BECAUSE OF FAILURE OF IRS TO GRANT US THE NON PROFIT STATUS. A COALITION IS NON PROFIT PAR-EXCELLENCE PEOPLE! WAKE UP. EVEN THE IRS COMMISSIONER IS OUT TO LUNCH. WE WROTE TO HIM. NO RESPONSE. HE SEEMS MORE BUSY WORKING TO STAY IN POWER TO DO NOTHING! SOUNDS FAMILIAR. PEOPLE WHO INDULGE IN POLITICS SOMETIME WORK SO HARD POLITICKING THAT THEY FORGET THEIR PRIMARY JOB!

WELL, WE ARE NOT DEAD YET; THE CRBCM WILL KEEP UP THE FIGHT!
LET'S GET READY, RACE FOR THE CURE IS COMING UP ON FEBRUARY 17TH.
GET THOSE SNEAKERS AND RUNNERS OUT AND GET INTO YOUR BEST SHAPE EVER!
=====================================================================

Dear Komen friends,

TEMPLATE FOR HEPATOCELLULAR CARCINOMA FOLLOW-UP:

DOES THE PATIENT HAVE
- JAUNDICE OR ELEVATED LFT(S) FOR USE OF DOXORUBICIN
- POOR APPETITE
- ASCITES (?THROMBUS AT HEPATIC VEIN)
- ABDOMINAL PAIN
- NAUSEA ALREADY
- WEIGHT LOSS

HX OF DM-ROLE OF INSULIN
HX OF HEPATITIS B OR C
HX OF CIRRHOSIS (LOCAL INTERVENTION)
HX OF HEMOCHROMATOSIS

LAB
- ALPHA FETOPROTEIN LEVEL
- ? DES-GAMMA-CARBOXYPROTHROMBIN
- U/S FOR DETECTION
- CT FOR MEASUREMT OF LESIONS,
- MRI FOR EXISTENCE OF CAPSULE AND PERIPHERAL INVASION, EXACT NUMBER OF LESIONS,
- PET FOR METASTATIC LESIONS AND RESPONSE TO THERAPY

TYPE OF HISTOLOGY
- FIBROLAMELLAR
- PSEUDOGLANDULAR
- PLEIOMORPHIC (GIANT CELL)
- CLEAR CELL
- ANAPLASTIC

CANDIDATE FOR
- SANDOSTATIN
- TAMOXIFEN
- ORAL SYNTHETIC RETINOIDS
- GALLIUM

P53 STATUS, MICROSATELLITE INSTABILITY, MDR,
TO PREDICT RESPONSE TO DAORUBICIN, PLATINUM, 5-FU, INTERFERON, EPIRUBICIN, TAXOL,

SORAFENIB (FATIGUE,RASH,DIARRHEA,HYPERTENSION.HAND FOOT SYNDROME)
- EGFR,VEGF

CANDIDATE
- TRANSPLANT
- PERCUTANEOUS ETHANOL
- TACE (WATCH FOR TUMOR >8CM, PORTAL VEIN THROMBUS,LFT-BILURIBIN LEVEL, SHUNT)
- RADIOFREQUENCY ABLATION (TUMOR <5CM)
- STEREOTACTIC RT
- SIRT

WHAT ABOUT IMMUNEPHERESIS AND PEXA-VEC?????

MUTATIONS IN HEPATOMA? (CONTINUE REVIEWING LITERATURE OF COURSE I DID NOT INVENT THIS)

NOMENCLATURE OF GENES IN SARCOMA (TO BE FURTHER DEVELOPED)

1.ALT REPAIR GENE: British researcher have suggested that this gene of Mesenchymal origin
is one of the 2 mechanism of control of cell mortality at Telomere level. At this level, life of the cell which is linked to length of the Telomere tail can by activation of Telomere which release the ALT network of genes which in turn stop immortality. Mesenchymal Cancers to keep living will desactivate this process by Mutation here. Opening up a target therapy option.
This Alternative lengthening of Telomere function is related to and work in conjunction with repair mechanisms at Nuclear DNA (ERCC-1, which impart susceptibility to Cisplatin), at transcription gene level (CSA, CSB) and at the level of the double strand DNA (ATM, Ku80, PKC, BRCA, RAD 50). We should stress the inter-relation between Telomerase activity with both the failure of DNA repair which lead to aging, and the proliferative inputs from NSUN5 and MYEOF (Myeloma)... DSC54 and WNT54 are related gene.
British investigator suggest these changes to be seen in MFH, Liposarcoma, GBM, Osteosarcoma, and Ewing sarcoma. We should stress the inter-relation between Histone and Telomerase activation which is mostly repressive of negative, Mutation of in the histone is needed to unveil Telomerate amplification.

2. P53
---------------
At least half of the Sarcoma will show activity at P53, the cellular Molecule of the year in 1993,
in up to 10% of cases, the P53 will actually be mutated. It is either overexpressed or suppressed in the rest of the cases of Sarcoma. The P53 is suppressed if repression occur at P14 or at CDKN2A or if MDM2 is overexpressed. P14 shield P53 from the effect of MDM2. P53 is also over expressed if its degradation is stopped at the proteasome.

At nuclear level, Acetylated P53 combines to P300 and promote P21 and Puma leading to Apoptosis. This effect can be blocked by Fusion protein EWS-Fli1 in Ewing Sarcoma, and by upregulation of Histone DE-Acelase 1 which effectively block down transcription effect of P53.

if you count right, there are 6 potential target of interaction with P53, if you include upstream toward the membranes...calling for Multitarget therapy in those condition where wild type P53 is overexpressed!

GENE PROFILING IS A MUST STEP IN CANCER TREATMENT!

MDM2
KRAS
BRAF
ETV3
EAT2
TGFBR
CDKN2A
FLI 1
ERG
EWSR
MIC (CD99)
EA1F
PI3K
(LY29004)
EWS-ATF
MAP KINASE
KIT
PDGFR
PAX3-FKHR
EWS
TLS-CHOP
TAF2N
FACTOR 1 PROMOTER
ERB-2
HSP
PPAR
CDK
EGFR
PTEN
P21
RB
TELOMERE--LACK OF TRF-2
================================================
BASAL CELL
CK 5
CK 15
================================================
NG2 BRAIN NEUROGLIA 2

CHECK 185 DEL aG-1
6174DEL IT-2
5382 InS C
=============================
REGULATOR OF CELL CYCLE
CDK, CCNB, CENPE, AURORA KB, PLK1

ALSO CHECK MAD2,POLE2,CDC2,TOPK,GMNN
GPS,
======================================
BREAST CANCER
KI-67
=======================================
EGFR IN MESOTHELIOMA
===================================

WE ARE WORKING HARD AT CRBCM

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

7 37

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.

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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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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!

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