Thursday, October 31, 2013

CPRIT: GET INVOLVED ! IT'S TOMORROW! Be there...

Email not displaying correctly? View it in your browser.
State of Texas Seal
The CPRIT Oversight Committee meeting this Friday, November 1, 2013 will be broadcast live online. To access the livestream of the meeting, please click here.

Please note, to view the broadcast, you will need to have the basic RealPlayer installed, which can be downloaded for free from: http://www.real.com/realplayer/player-plus

The meeting agenda and supporting materials are available on the CPRIT website.
CPRIT Oversight Committee Meeting
Texas State Capitol Extension

1400 N. Congress Avenue, Austin, Texas 78701

 Room: E1.012


November 1, 2013

9:00 A.M.

ADAPTER GENES

Nothing is simple but yet as determinant as an Adapter gene.
The cell continues to amaze scientists.
When a stimulant attaches to a receptor, the 2, stimulant and receptor, enter the cell in some cases, detaching from the membrane and enter the cell.  Most of the time there is a triggering of main pathways such as the RAS, but sometimes, at the site of attachment, the raw edges of the membrane are not healing and wage their own war...here it is the focal Adhesion kinases that are going to war.  Now, that war is not necessarily random.  Depending on the nature of the stimulant and receptor involved, the FAK can turn to a Gerb2, Lyn or Flyn with a totally new orientation in the metabolism of the cell.  Sometimes the adapter is simply a b-cell linker or it is a T-cell linker and the cell will follow that path or attract these different cells.  It may use RUS1 to block the excited RAS that we spoke about or orient the cell to Rho in order to exacerbate metastasis.  
These linkers are a way to control differentiation, but when erratic, they could compromise the host!  Certain genes are destined to help many proteins such as a portion of an Antibody, imagine them wrongly linked to some other gene leading to unwarranted  multiplication! Things are set for hematologic malignancies!

Preliminary impression:
- Attachment to Lyn- B cell differentiation (some) and if Gerb2 involved, T cell differentiation definitely if the stimulant is TGF alpha!
Flyn- well may be muscle dystrophy, of some form.
Attachment to TBS - mental retardation
Lck-depression such as seen with chronic autoimmune disease (locus Coereleus)

Watch your Adaptor genes carefully!  Otherwise things are going in a direction you may not wish!

Wednesday, October 30, 2013

IN A BIG ANNOUNCEMENT TODAY: CPRIT IS FREE AGAIN! CONGRATULATIONS!

Cancer Prevention and Research Institute of Texas via mail185.atl21.rsgsv.net 
2:24 PM (16 hours ago)
to me
Email not displaying correctly? View it in your browser.
State of Texas Seal
CPRIT has been notified by Governor
Perry, Lt. Governor Dewhurst and
Speaker Straus that the moratorium
  on CPRIT’s grant award processes
has been lifted.

Over the last ten months CPRIT has
taken purposeful strides to strengthen
agency governance and restore trust
in its commitment to the fight against
 cancer in Texas. CPRIT appreciates
the confidence state leadership has
in the agency’s efforts – this action
marks a critical milestone for CPRIT.
We have been working hard in preparation
 for this moment and are ready to move
forward with deliberate purpose,
accountability and transparency to
 serve all Texans.

Staff will contact CPRIT grantees
affected by the moratorium to provide
additional information and next steps
 per this announcement. On November 1, 
2013, the CPRIT Oversight Committee
 will discuss restarting all of CPRIT’s review
processes including resuming review of
applications that have been submitted
and the release of new requests for
applications.

Genetic basis of Autism

The notion that an inflammatory process such as the one induced by an immunization may contribute to children's mental retardation or Autism has fundamental truth when it comes to gene pathways. Indeed, during an acute inflammatory insult, Macrophages that are called to the theater will liberate several cytokines which include TGF alpha.  This cytokine will bind to EGFR receptors while other cytokines induced by the inflammatory process will bind their relevant receptors.  Internalization of these receptors will leave deep edges at the membrane, activating the Focal adhesion molecules of Kinase (FAK ).  The first known gene to react with the FAK gene is the Tuberous sclerosis gene which is known to lead to Autism.  In a forming or developing brain, certain isoforms of this gene may predispose some children to develop autism.   The crux of the problem is to determine which inflammatory process (immunization or other processes) is at the source of the problem!

PTK2 protein tyrosine kinase 2 (PTK2), also known as Focal Adhesion Kinase (FAK), is a protein that, in humans, is encoded by the PTK2 gene.[2] PTK2 is a focal adhesion-associated protein kinase involved in cellular adhesion (how cells stick to each other and their surroundings) and spreading processes (how cells move around).[3] It has been shown that when FAK was blocked, breast cancer cells became less metastatic due to decreased mobility.[4]

 PTK2 has been shown to interact with TSC2, (22 wikipedia)

 Tuberin also known as tuberous sclerosis 2 is a protein that in humans is encoded by the TSC2 gene.
 About 50% of people with TSC have learning difficulties ranging from mild to significant,[2] and studies have reported that between 25% and 61% of affected individuals meet the diagnostic criteria for autism, with an even higher proportion showing features of a broader pervasive developmental disorder.[3] A 2008 study reported self-injurious behavior in 10% of people with TSC.[4] Other conditions, such as ADHD, aggression, behavioral outbursts and OCD (obsessive compulsive disorder) can also occur. Lower IQ is associated with more brain involvement on MRI.(wikipedia)

====================================================
THERE YOU HAVE IT THE FULL STORY!

Tuesday, October 29, 2013

Progress in Genome studies: case in point the DIGITAL PCR.

If what they promise is real, we are entering an important phase where not only we can count mutations,  but can also try to determine levels of gene amplifications  that are secondary, versus those that are in response or a consequence of upstream genes normally amplified or amplified because they are mutated!

" Next-generation sequencing technology has transformed cancer genomics, but faces the challenge of genome and transcriptome heterogeneity inherent to any tumor sample. One strategy for capturing the complex landscape of mutational processes, clonal evolution/amplification and tissue invasion is the application of digital PCR, which enables the identification and precise quantitation of individual mutations - including those present at a very low frequency."(Biomedcentral)

This new technology will open new evaluations of gene quantities as to their meaning and trigger!  It will allow also to detect levels of suppression of a normal gene when it is found in an unexpected amount.  We know for example that in many lung cancers PTEN is suppressed.  Whether  this is a primary happening or secondary can be further debated.  In Ovarian cancer DAB2 is suppressed. ("The down-regulation of DAB2 may play an important role in ovarian carcinogenesis. This gene was initially named DOC2 (for Differentially expressed in Ovarian Cancer) and is distinct from the DOC2A and DOC2B genes (for double C2-like domains, alpha and beta).[3]

 Most of these suppressions are the result of an amplification of an upstream gene or an overexpression of an inhibitory protein.  When it comes to DAB2, it is important to report that this gives the cancerous process some teeth and bad prognosis.  Indeed, the suppression of DOC2 gives the tumor ways of escaping proliferation control by the cancerous cell by activating E3 (removing by unbiquitilation of the inhibitor of the inhibitor of E3).  This new technology will allow direct quantification of the 2 inhibitors or the E3 for that matter.  It may also clarify how Velcade works in relation to the 3 compounds!

Monday, October 28, 2013

COLLABORATION AT CRBCM

A STRONG COLLABORATION BEING BUILT AT CRBCM
KEY MEETING THIS FRIDAY AT UTEP AND TEXAS TECH!

That is great!

I can reserve a small conference room (Bioscience Building Room 3.118) at UTEP. Would you like to give a brief presentation for your current project? If so, I can also prepare a laptop computer and projector.
 

The core of Autoimmune diseases?

TGF alpha WITH ITS CONNECTION TO HLA-DR1 Vs. MIF,
the alpha 4 Beta Integrin WITH THE VASCULITIS!
E3 AND ITS INHIBITORS and the CXCR4 GENES

THAT IS IN THE CORE OF THE BELLY OF THE BEAST!
DO YOU NEED A FULL TEXT, CALL ME,
WANT MORE, HOW ABOUT NCK1? POWERFUL TARGET IN LEUKEMIA!
GO FIGURE!

STILL DON'T BELIEVE
THIS IS THE SUPPORTIVE EVIDENCE

Lupus. 2007;16(8):587-92.

Macrophage activation syndrome in juvenile systemic lupus erythematosus: an under-recognized complication?

Source

Istituto di Ricovero e Cura a Carattere Scientifico Giannina Gaslini, Genova, Italy, Hospital Pedro de Elizalde, Buenos Aires, Argentina.

Abstract

Macrophage activation syndrome (MAS) is a life-threatening complication of rheumatic diseases that is thought to be caused by the activation and uncontrolled proliferation of T lymphocytes and macrophages, leading to widespread haemophagocytosis and cytokine overproduction. It is seen most commonly in systemic juvenile idiopathic arthritis, but is increasingly recognized also in juvenile systemic lupus erythematosus (J-SLE). Recognition of MAS in patients with J-SLE is often challenging because it may mimic the clinical features of the underlying disease or be confused with an infectious complication. This review summarizes the characteristics of patients with J-SLE-associated MAS reported in the literature or seen by the authors and analyses the distinctive clinical, diagnostic and therapeutic issues that the occurrence of MAS may raise in patients with J-SLE.

Sunday, October 27, 2013

WE WENT AND SAW IT!

IT IS THE SAME GAME OVER
WE PLAYED OUR ROLE WHICH IS TO MAKE US PART OF STATISTICS
BUT ONE THING FOR SURE WE HAVE MADE CONTACTS
BUT WE GOT TO BE MOVING FORWARD DESPITE THEM!
FOR THE FIGHT AGAINST THE CURE IS ABOVE POLITICAL GAMES
WILL LOOK TO FOREIGN COUNTRIES FOR HELP IF NEEDED
BECAUSE THERE, LOCAL POLITICS WILL NOT WEIGH IN
ALL WE CARE ABOUT IS KEEPING THE ENGINES WORKING,
THE FIRST SYMPOSIUM LOOKED LIKE OLD DANCE
'CAUSE WE HAVE SEEN IT BEFORE!

Saturday, October 26, 2013

A NEW PLAYER IN TOWN: THE MEDICAL CENTER OF THE AMERICAS.

We are pleased that El Paso can now claim a chance to shine in the area of Biomedical research with the Medical Center of the Americas (MCA).  We don't need to deal only with the stress of ignorance by CPRIT and the lack of interest by the Texan central government.   By the same token, the new shining star (Medical Center of the Americas, with 60 Millions dollars in its war chest ( less than 3 billions being squandered by CPRIT) is in danger of experiencing the same fate as CPRIT- a global takeover by local Universities!
In this town, the drama will unfold just the same unless the leadership shin up and brace from the onslaught which will come from Lubbock the small town that engineered years ago El Paso takeover through Texas Tech University!  Already we are seeing the take over unfold by the prominence of Texas Tech into the activities of the CMAs.    It is surprising that to this day the University of of Texas in El Paso (UTEP) the true local El Paso school has not rise up, as if accepting this dedicated secondary role, as if already prepared to let the takeover unfold!  There is no representative for the private corporations on the MCAs' Board as far as I can tell.  And very soon by the 3rd year of life of the MCAs, the CPRIT story will be lived at El Paso scale!  Unless of course the leardership wakes up early and strategizes a response for prevention!  I met the President of the fundation Ms. Shwartz, she was first to mention the CPRIT story but I am not sure she did realize where the threat to CPRIT came from, Universities' takeover!   Universities in Texas have shown to have the brightest minds but also by being the most expensive and wasteful organizations. Record suggest that only 15-20 percent of money given to them goes to actual research.  The only thing that can change this, the MCA dictates during contract negotiations and follow-ups...
Believe me, when you are the donor, you can stand your ground in defining the rules of engagement.  WILL MCAs STAND ITS GROUND?  WE HAVE YET TO SEE IT!
THE CRBCM CAN HELP, WE WILL CONTINUE THE FIGHT FOR THE CURE UNTIL OUR ENEMIES BECOME IRRELEVANT!

Thursday, October 24, 2013

BY COMMUNITY ONCOLOGIST, THE CRBCM IS CLEARLY NOT INCLUDED! THEY KNOW WHO THEY MEAN!



Community Oncologist Education and Support Systems
Renal Cell Carcinoma and Hematologic Malignancies
Request for Proposals
National Comprehensive Cancer Network and
Pfizer Independent Grants for Learning & Change


Pfizer and National Comprehensive Cancer Network (NCCN) are collaborating
 to offer a new grant opportunity focused on improving care for patients with 
rare types of cancer such as renal cell carcinoma (RCC) and certain hematologic
 malignancies, where treatment options are complex and rapidly advancing.

The mission of Pfizer Independent Grants for Learning & Change (IGL&C) is 
to accelerate the adoption of evidence‐based innovations that align the mutual
 interests of patients, healthcare professionals, and Pfizer, through support 
of independent professional education activities. The term “independent”
 means the initiatives funded by Pfizer are the full responsibility of the
 recipient organization. Pfizer has no influence over any aspect of the initiatives,
 and only asks for reports about the results and impact of the initiatives, 
which it may share publicly.

NCCN, a not‐for‐profit alliance of twenty‐three (23) of the world’s leading
 cancer centers, is dedicated to improving the quality and effectiveness of
 care provided to patients with cancer. Through the leadership and expertise
 of clinical professionals at NCCN Member Institutions, NCCN develops 
resources that present valuable information to the numerous stakeholders
 in the health care delivery system. NCCN has access, through its member
 institutions, to the world’s leading thought leaders in all areas and aspects 
of oncology who are integral to the execution of this program.

This Request for Proposals (RFP) is being issued by both organizations. NCCN is
 the lead organization for review and evaluation of applications. A review
 committee, led by NCCN, will make decisions on which proposals will receive
 funding. Grant funding will be provided by Pfizer. Collectively, up to $2 million 
is available for the program.

Once announced through this distribution list, the RFP will also be 
posted on our website at www.pfizer.com/independentgrants  Please
 refer to the full text of the RFP for various key dates and submission 
instructions.

Clinical Areas:
Category 1: Oncology Communities – RCC
Category 2: Oncology Communities –
 Hematologic Malignancies
LOI Due Date:
December 5, 2013


Please send an email to IGLC@pfizer.com to unsubscribe from this distribution.






Bubbling with excitements!


A Message from Medical Center of the Americas:
Dear BIOMED Registrants:
We look forward to seeing you at the region’s upcoming BIOMED Symposium on October 26, 2013 at the Camino Real Hotel located at 101 South El Paso Street in Downtown El Paso. And, we are excited to announce that we have surpassed our original registration expectation of 150 participants; we are now expecting approximately 350 participants! Thank you for already helping to make this event a success through great participation! We do want to note, however, that this unexpected level of participation may result in a few logistical problems at the events. Furthermore, we will be experimenting with different types of sessions and events to determine what works best. We request that you be patient with us as we work hard to make this first year event successful. We will have evaluation forms available and hope that you provide honest feedback to so that we can improve the event in future years.
Below are a few reminders and updates regarding the Symposium that should help to make things run smoothly over the next couple of days.

OCTOBER 25, 2013: PRE-SYMPOSIUM NETWORKING MIXER INFORMATION
We hope you will consider attending BIOMED’s Pre-Symposium Networking Mixer on October 25, 2013 from 5:30pm-7:30pm at the El Paso Club, 18th floor, Chase Building, 201 East Main Drive, Downtown El Paso. Network with over 200 of the region’s researchers, clinicians and nurses, future leaders and other healthcare professionals. Valet parking is available in the Chase Building garage, accessible via Mesa Street. Simply bring your parking ticket to the El Paso Club for validation. Please RSVP to nsehgal@bmiamericas.org by 5 pm on Thursday, October 24, 2013.
OCTOBER 26: 2013: BIOMED SYMPOSIUM INFORMATION
Symposium Registration
Check-In Table
If you have pre-registered, please come to the Check-In Table on the Mezzanine (2nd Floor). Do not forget to bring your ticket and a form of identification. We will be providing a complimentary drink ticket to the first 180 people for the Collaboration Grant and Networking Reception from 3:30pm-4:30pm in the Ballroom.
Media & VIP Table
If you are affiliated with the Press, please collect your “Press Pass” from the Media & VIP Table on the Mezzanine (2nd Floor).
If you are a VIP (speakers, exhibitors, moderators, judges, elected officials, head of institutions, volunteers, and BMIA or MCA board members), please check-in at the Media & VIP Table on the Mezzanine (2nd Floor).
**Please remember that this is a networking event, so bring lots of your business cards to trade with new contacts you make.
Hotel Accommodations
We have reserved a block of rooms at the Camino Real Hotel located at 101 South El Paso Street and DoubleTree Hotel located at 600 North El Paso Street in Downtown El Paso at a discounted rate. Please make hotel reservations as soon as possible, as we anticipate the hotels will up fast. When you call to make a reservation, please indicate to the hotel clerk that you are making a reservation for the “BIOMED Symposium” so that you receive the discounted rate.

Symposium Parking & Directions
Parking

JUST GO AHEAD AND HELP OUT FOLKS (PHYSICIANS)!

October 16, 2013
Dear Indiana Licensed Controlled Substance Prescribers and Dispensers,
On behalf of the Indiana Professional Licensing Agency, the Indiana State Department of Health, and the Attorney General’s Prescription Drug Abuse Prevention Task Force, we request your assistance in achieving our mutual goals to address the increasing problem of prescription drug addiction in Indiana. 
The survey is completely anonymous, and we will have no ability to track participants’ identities.  The instrument will take approximately 10-15 minutes to complete.
The survey was created in collaboration with the Indiana Professional Licensing Agency, the Center for Health Policy, the Indiana State Department of Health, and the Attorney General’s Prescription Drug Abuse Prevention Task Force.
The survey is being administered through the Center for Health Policy at the IU Richard M. Fairbanks School of Public Health at IUPUI. 
The Center for Health Policy will be solely responsible for analyzing the data and preparing a public report that summarizes the findings from this research.  The final report will be distributed electronically and be available on the Center’s website:  www.healthpolicy.iupui.edu in early 2014.  Their report will be used to improve the INSPECT program and provide better support to healthcare providers.
Please click on the link below for additional details and to begin the survey.
Thank you in advance for your vital assistance with this endeavor!
Sincerely,
Greg Pachmayr
INSPECT Director
Indiana Professional Licensing Agency
402 W Washington St RM W072
Indianapolis, IN 46204

A very important read!

Arkadia Activates Smad3/Smad4-Dependent Transcription by Triggering Signal-Induced SnoN Degradation

  1. Caroline S. Hill1,*
+ Author Affiliations
  1. 1Laboratory of Developmental Signalling, Cancer Research UK London Research Institute, Lincoln's Inn Fields Laboratories, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom
  2. 2Mammalian Neurogenesis, MRC Clinical Sciences Centre, Imperial School of Medicine, Hammersmith Hospital, London W12 0NN, United Kingdom

ABSTRACT

E3 ubiquitin ligases play important roles in regulating transforming growth factor β (TGF-β)/Smad signaling. Screening of an E3 ubiquitin ligase small interfering RNA library, using TGF-β induction of a Smad3/Smad4-dependent luciferase reporter as a readout, revealed that Arkadia is an E3 ubiquitin ligase that is absolutely required for this TGF-β response. Knockdown of Arkadia or overexpression of a dominant-negative mutant completely abolishes transcription from Smad3/Smad4-dependent reporters, but not from Smad1/Smad4-dependent reporters or from reporters driven by Smad2/Smad4/FoxH1 complexes. We show that Arkadia specifically activates transcription via Smad3/Smad4 binding sites by inducing degradation of the transcriptional repressor SnoN. Arkadia is essential for TGF-β-induced SnoN degradation, but it has little effect on SnoN levels in the absence of signal. Arkadia interacts with SnoN and induces its ubiquitination irrespective of TGF-β/Activin signaling, but SnoN is efficiently degraded only when it forms a complex with both Arkadia and phosphorylated Smad2 or Smad3. Finally, we describe an esophageal cancer cell line (SEG-1) that we show has lost Arkadia expression and is deficient for SnoN degradation. Reintroduction of wild-type Arkadia restores TGF-β-induced Smad3/Smad4-dependent transcription and SnoN degradation in these cells, raising the possibility that loss of Arkadia function may be relevant in cancer.

=================================================================

This is very important because,

1. we are not very good at activating genes, so this is one important way.  (all we do is inhibit genes and their protein derivative-that we know!)

2. cancer decreases SMAD to induce lack of proliferation control (through CDK1 for SMAD3 suppression) and disturbance  of Ubiquitilation (E3 for SMAD3).  Increasing SMAD is taking away cancer "aggressiveness"  a new modality of treatment!!   very closely followed at CRBCM-  This is to be proposed in Metastatic prone diseases such as triple negative breast cancer, pancreatic cancer and few others!

Disruption (suppression) at SMADs is a major biomarker of bad Prostate cancers!!!

A dangerous gene PTPRT (PTPrho)

 If you follow our blogs, you will be aware of 3 things about why a gene could be dangerous,
1. Its ability to induce malformation once absent
2. Its interaction with either multiple other genes but particularly its involvement with a "wild gene", genes that are cofactors to anything happening in the cell (Gerb2,FYN) or globally a gene that have just too many interactions with other genes (Androgen related gene).
3.In terms of cancer metastasis and non-curability, the gene involvement with the Wnt (cathenin) and the Notch.  Involvement with the Rho increases the rate of multiplication. 

Based on these criteria, PTPRT (PTPrho) wins the cake!
It is stimulated by Actinin alpha 1
which itself interacts with:


Actinin, alpha 1 has been shown to interact with:
 ===================================================FROM WIKIPEDIA, THIS FOLLOW:"
Receptor-type tyrosine-protein phosphatase T is an enzyme that in humans is encoded by the PTPRT gene.[1][2][3]
PTPRT is also known as PTPrho, PTPρ and human accelerated region 9. The human accelerated regions are 49 regions of the human genome that are conserved among vertebrates, but in humans show significant distinction from other vertebrates. This region may, therefore, have played a key role in differentiating humans from apes.[4]
PTPrho is phosphorylated on tyrosine 912 in the wedge region of its first catalytic domain by Fyn tyrosine kinase. Phosphorylation at this site attenuates synapse formation in cultured neurons. When PTPrho is phosphorylated by Fyn, PTPrho appears to form homophilic multimerizations, likely in cis, which appear to decrease PTPrho association with neuroligins and neurexins. The reduction of cis interactions with neuroligins and neurexons is hypothesized to ultimately lead to the reduction in synapse formation.[12]



Evaluation of the 5’untranslated regions of PTPrho (PTPRT) cDNA indicate a number of transcription factor binding site consensus sequences, including those for AP-2, c-Myb, NF-1, sox-5, and Sp-1, Oct-1, CdxA, C/EBP, En-1, GATA-1, GATA-2, GKLF, HoxA3, Ik-2, Msx-1, Pax-4 and SRY.[5]
(RE1-silencing transcription factor) (REST) is a transcription repressor that binds to REST DNA recognition element (RE-1) in 5’UTRs. A screen of single nucleotide polymorphic genetic changes within the REST binding regions of DNA sequences revealed a polymorphism in the RE-1 of PTPrho (PTPRT). This SNP would result in less REST repressor activity, which could lead to increased expression of PTPrho (PTPRT) in cells that harbored this SNP.[15]
 PTPrho is also upregulated in estrogen receptor alpha positive breast tumor samples versus estrogen receptor alpha negative tumor samples.[18] The authors evaluated 560 selected genes by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) in estrogen receptor alpha positive tissue and compared it to estrogen receptor alpha negative tissue, and found that PTPrho(PTPRT) was upregulated in the estrogen receptor alpha tissue, suggesting a non-tumor suppressor role for PTPrho. [18]"

Wednesday, October 23, 2013

SOME MOVEMENTS FROM CPRIT

Email not displaying correctly? View it in your browser.
State of Texas Seal
CPRIT OVERSIGHT COMMITTEE MEETING
 
Notice of Open Meeting

Texas State Capitol Extension
1400 N. Congress Avenue, Austin, Texas 78701
Room: E1.012

November 1, 2013
9:00 A.M.


Agenda
 


For more information, please call:
(512) 463-3190
 
Please forward this announcement to your networks.

    
http://www.cprit.state.tx.us

Unsubscribe from this list | Forward to a friend| Update your profile
Our mailing address is:
Cancer Prevention and Research Institute of Texas
211 E 7th Street Ste 300
Austin, Texas 78701

Add us to your address book

Copyright (C) 2013 Cancer Prevention and Research Institute of Texas All rights reserved.

our movie project moving forward!


Hi kanko1,
The project you are following "A WHITE WOMAN TO THE CONGO" has reached level 4! Click on the following link to view the latest update of the project now!
http://juntoboxfilms.com/projects/a-white-woman-to-the-congo

join us at the BIOMED RESEARCH CONFERENCE /MEDICAL CENTER OF THE AMERICAS/CRBCM WILL BE PRESENT!


A Message from Medical Center of the Americas:
Dear BIOMED Registrants:
We hope you will consider attending BIOMED’s Pre-Symposium Networking Mixer on October 25, 2013 from 5:30pm-7:30pm at the El Paso Club, 18th floor, Chase Building, 201 East Main Drive, Downtown El Paso. Network with over 200 of the region’s researchers, clinicians and nurses, future leaders and other healthcare professionals. Valet parking is available in the Chase Building garage. Simply bring your parking ticket to the El Paso Club for validation. Please RSVP to nsehgal@bmiamericas.org by 5 pm on Thursday, October 24, 2013.
Sincerely,
Neyha Sehgal
BIOMED Organizer

Imperfection of current tools for genetic evaluations

It is quite evident that despite major advances in genetic studies through the PCR and other sequencing measures, the evaluation of genes and their effects still require highly qualified technicians using sophisticated equipments. One of the implications of this fact is that when one wants to try to look into any scientific fact, a battery of scientists need to be mobilized!

For example, we know that when patients are exposed to a new medication (ie. chemotherapy drug), some patient will have inherent resistance to the drug.  That is they are promptly rejecting the drug, while other will respond first and then develop mechanisms of resistance.  To date, they are no ways of determining which patient is doing what when exposed to the drug!  And this despite our advances in technology.

Our current practice is to give the drug, and wait 3-6 months and check through radiologic and biomarker means  if the tumor grow despite the drug.  During the 3 to 6 months, refractory tumors have time to build in new genetic mutations giving them new mechanisms of escape, defense and otherwise eluding future attacks, and most importantly metastasize to new sites in the host, complicating our battle and making full eradication impossible and dooming our chance for a cure!  Indeed with tumors of "aggressive" tendencies, 6 months is a lifetime of opportunities to settle in and impose a toll of reversible and irreversible disruptions into the host!
This strategy is not good for us.

This is happening despite our knowledge of many facts that could help us avoid this current practice. we know already many pathways and mechanisms of resistance (ie. the MDR gene) but we don't use them for our relevant patients.   We try it on dogs however!
--------------------------------------------------------------------------------------------------------

"Get Your Dog Tested*


Blood sample or cheek swab?

DNA obtained from a dog’s blood is the same DNA that would be obtained from that dog’s cheek cells using a swab. We allow submission of either sample because blood is often the sample preferred by veterinary hospitals while cheek swabs are generally preferred by dog owners."

College of Veterinary Medicine

Veterinary Clinical Pharmacology Lab


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

We know that pathways get underway through consumption of measurable co-factors and obligatory steps that we can promptly measure and determine that the drug is being used or allowed to act at cellular level.   Is it the lack of will, or the sense of desperation because of limitations in our available options that make us afraid to know the truth early.  The point is we cannot go on avoiding to know what is in store for the patients!
Many drugs act through Adenyl Cyclase, many drugs use the Gerb-2, Gab1, etc....why can't we use these available biomarkers of drug actions.   DNMT1 AT EPIGENETIC LEVEL (OR SIMILAR MOLECULES)

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


DNA (cytosine-5)-methyltransferase 1 is an enzyme that in humans is encoded by the DNMT1 gene.[1]
DNA (cytosine-5-)-methyltransferase 1 has a role in the establishment and regulation of tissue-specific patterns of methylated cytosine residues. Aberrant methylation patterns are associated with certain human tumors and developmental abnormalities.[2][3]" wikipedia

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

has been proposed as a way to gauge imprinted information
can we try this as a biomarker of drug effect?

SUFFICE IS TO SAY WE CAN'T GO ON FOOLING OUR PATIENTS INTO INEFFECTIVE DRUG TRIALS! THE TIME TO KNOW IS NOW! AND HERE WE GO AGAIN, A TEAM OF INVESTIGATORS WITH SOPHISTICATED MACHINES NEED TO GO BACK TO WORK AGAIN ON THIS NEW LEAD!  THE ANSWER IN 5 YEARS!


Sunday, October 20, 2013

EVEN HYPERTENSION IS CYTOKINE INDUCED

e-MED:

"Due to investigations into the pathophysiology of hypertension, both in animals and humans, growing evidence suggests that hypertension may have an immunological basis. Studies have revealed that hypertension is associated with renal infiltration of immune cells and that pharmacologic immunosuppression (such as with the drug mycophenolate mofetil) or pathologic immunosuppression (such as occurs with HIV) results in reduced blood pressure in animals and humans. Evidence suggests that T lymphocytes and T-cell derived cytokines (eg, interleukin 17, tumor necrosis factor alpha) play an important role in hypertension. One hypotehesis is that prehypertension results in oxidation and altered mechanical forces that lead to the formation of neoantigens, which are then presented to T cells, leading to T-cell activation and infiltration of critical organs (eg, kidney, vasculature). This results in persistent or severe hypertension and end organ damage. promote T-lymphocyte activation and infiltration and contribute to the pathophysiology of hypertension."

Protease inhibitors could play a role in 2nd line ER positive breast cancer by blocking cytokine formation

"
Researchers are investigating whether protease inhibitors could possibly be used to treat cancer. For example, nelfinavir and atazanavir are able to kill tumor cells in culture (in a Petri dish).[10][11] This effect has not yet been examined in humans; but studies in laboratory mice have shown that nelfinavir is able to suppress the growth of tumors in these animals, which represents a promising lead towards testing this drug in humans as well.[11]
Inhibitors of the proteasome, such as Velcade/Bortezomib are now front-line drugs for the treatment of various cancers, notably Multiple Myeloma." wikipedia

could you imagine blocking formation of undesirable cytokines, you could prevent resistance to to AIs., you could delay resistance to hormone based treatment modalities!

Saturday, October 19, 2013

other puzzling roles of cytokines!

It is not hard to believe that reactivation of TB under Infliximab therapy would be linked to some cytokine or that pain and increased risk of Achille's tendon rupture following chronic use of Ciprofloxacin would be under the doing by cytokines.  And that any disease state associated with the so called "constitutional symptoms would be also a manifestation of Cytokines'effect.  What surprise the most is how little we do ot care to determine exactly which one.  We instead jump to give NSAID and related compound (steroids or Interferons) without further characterization of these cytokine. No wonder why we meet several side effcts that are unforseen such as increase of strokes and cardiovascular disorders or even bleeding!  Cytokines are notorious in inducing vascular disturbances!  Just ask Wegener or Paget for that matter!

Role of Cyclins in ER positive Breast cancers resistance

Now it is increasingly apparent that cyclins may have an increased presumptive role in the resistance to Aromatase inhibitors and hormone driven therapy for ER positive breast cancer. Yes as you apply pressure on the cancer cell by Blocking Receptor ultimately the cell will desensitize  itself from this deadly lack of stimulation. Cancer cells want to survive, Increasing evidences suggest that cell desensitization is by way of   the cytokines.  It is not by mistake that disruption of epigenetic events by Entinostat which ultimately change significantly the profile of cyclins produced by the cell will lead to breaking of cancerous cell resistance to Hormone receptor  driven target therapy.   The cancerous cell uses the NF-kB and c-jun (stress related PI3K/AKT/MTOR) for survival and we know what happens when these pathways reach the epigenetic zone, new cyclins are metabolized to induce resistance.  The proof is in the pudding, only MTOR inhibitors, and anti-CDK break the resistance to AI or SERMs.
Which Cytokines affects induce desensitization is a hot question, and the mechanism trggering the need for desensitization need to be aggressively pursued.  Assumption is that dying cells may through the Wnt and Notch give information that eventually leads to resistance in surviving cells.  How ? when?  remember cell since they are born have the instinctive reflex to survive.  It is their mission, it is their commitment!  Dying cancer cells will have to tell somehow the living cells how and why they are dying for those uninvolved to be prepared and possibly a global cellular desensitization of growth inducing receptor is a reflex.  Indeed it has been shown that cancer cells significantly reduce dependency on growth factor stimulation for an internal "stress" like metabolism.  What trigger this alternative "mode de vie" is in itself a pathway to global resistance to outside stimulation and death inducing external compounds!
On epigenetic level, a switch in transcription, would be enough to alter the cytokines with a resulting resistant change in effects at the receptors!
Here at the CRBCM, work is increasing daily as leads multiply.

The main question is should we incrementally add these agents in a sequential way, or should we give these agents together or all 3 for greater good.   will concurrent use actually disrupt the effect of the other, in other words, should we wait for the resistance to develop in order to add the other mode of of targeting agents when the cancer is counting on it the most?  Adding the MTOR after Avastin failure has proven to be supportive of the sequential  intervention by some reports whereas giving them concurrently may not be additive!  Why? by now receptor site of Avastin is "desensitize" while the surviving cell use the PI3K/MTOR to survive, hit it now with MTOR inhibitor, and Histone deacetylator inhibitor like we are doing now with ER positive breast cancers!

FROM MEDSCAPE

Important Safety Information  |   Full Prescribing Information
KADCYLA showed treatment benefit in HER2+ metastatic breast cancer (MBC) in overall survival (OS) and progression-free survival (PFS) vs lapatinib + capecitabine1
For more details about these and other EMILIA trial endpoints, visit KADCYLA.com.
Indication
KADCYLA® (ado-trastuzumab emtansine), as a single agent, is indicated for the treatment of patients with HER2-positive (HER2+), metastatic breast cancer (MBC) who previously received trastuzumab and a taxane, separately or in combination. Patients should have either:
  • Received prior therapy for metastatic disease, or
  • Developed disease recurrence during or within six months of completing adjuvant therapy
KADCYLA extended median OS by nearly 6 months1
50% improvement in median PFS for KADCYLA vs lapatinib + capecitabine1
  • 9.6 months vs 6.4 months; HR=0.650; 95% CI: 0.549, 0.771; P<0.0001
Important Safety Information
Boxed WARNINGS: HEPATOTOXICITY, CARDIAC TOXICITY, EMBRYO-FETAL TOXICITY
  • Do Not Substitute KADCYLA for or with Trastuzumab
  • Hepatotoxicity: Serious hepatotoxicity has been reported, including liver failure and death in patients treated with KADCYLA. Monitor serum transaminases and bilirubin prior to initiation of KADCYLA treatment and prior to each KADCYLA dose. Reduce dose or discontinue KADCYLA as appropriate in cases of increased serum transaminases or total bilirubin
  • Cardiac Toxicity: KADCYLA administration may lead to reductions in left ventricular ejection fraction (LVEF). Evaluate left ventricular function in all patients prior to and during treatment with KADCYLA. Withhold treatment for clinically significant decrease in left ventricular function
  • Embryo-Fetal Toxicity: Exposure to KADCYLA can result in embryo-fetal death or birth defects. Advise patients of these risks and the need for effective contraception
Additional Important Safety Information
Left Ventricular Dysfunction (LVD)
  • Patients treated with KADCYLA are at increased risk of developing LVD. In EMILIA, LVD occurred in 1.8% of patients in the KADCYLA-treated group and in 3.3% in the comparator group. Permanently discontinue KADCYLA if LVEF has not improved or has declined further
Pregnancy Registry
  • Advise patients to contact their healthcare provider immediately if they suspect they may be pregnant. Encourage women who may be exposed to KADCYLA during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720
Pulmonary Toxicity
  • Cases of interstitial lung disease (ILD), including pneumonitis, some leading to acute respiratory distress syndrome or fatal outcome have been reported in clinical trials with KADCYLA. In EMILIA, the overall frequency of pneumonitis was 1.2%
  • Treatment with KADCYLA should be permanently discontinued in patients diagnosed with ILD or pneumonitis
Infusion-Related Reactions, Hypersensitivity Reactions
  • Treatment with KADCYLA has not been studied in patients who had trastuzumab permanently discontinued due to infusion-related reactions (IRR) and/or hypersensitivity reactions; treatment with KADCYLA is not recommended for these patients. In EMILIA, the overall frequency of IRRs in patients treated with KADCYLA was 1.4%
  • KADCYLA treatment should be interrupted in patients with severe IRR and permanently discontinued in the event of a life-threatening IRR. Patients should be closely monitored for IRR reactions, especially during the first infusion
Thrombocytopenia
  • In EMILIA, the incidence of ≥ Grade 3 thrombocytopenia was 14.5% in the KADCYLA-treated group and 0.4% in the comparator group (overall incidence 31.2% and 3.3%, respectively)
  • Monitor platelet counts prior to initiation of KADCYLA and prior to each KADCYLA dose. Institute dose modifications as appropriate
Neurotoxicity
  • In EMILIA, the incidence of ≥ Grade 3 peripheral neuropathy was 2.2% in the KADCYLA-treated group and 0.2% in the comparator group (overall incidence 21.2% and 13.5%, respectively)
  • Monitor for signs or symptoms of neurotoxicity. KADCYLA should be temporarily discontinued in patients experiencing Grade 3 or 4 peripheral neuropathy until resolution to ≤ Grade 2
HER2 Testing
  • Detection of HER2 protein overexpression or gene amplification is necessary for selection of patients appropriate for KADCYLA. Perform using FDA approved tests by laboratories with demonstrated proficiency
Extravasation
  • In KADCYLA clinical studies, reactions secondary to extravasation have been observed and were generally mild. The infusion site should be closely monitored for possible subcutaneous infiltration during drug administration. Specific treatment for KADCYLA extravasation is unknown
Nursing Mothers
  • Discontinue nursing or discontinue KADCYLA taking into consideration the importance of the drug to the mother
Adverse Reactions
  • The most common ADRs seen with KADCYLA in EMILIA (frequency > 25%) were nausea, fatigue, musculoskeletal pain, thrombocytopenia, increased transaminases, headache, and constipation. The most common NCI-CTCAE (version 3) ≥ Grade 3 ADRs (frequency >2%) were thrombocytopenia, increased transaminases, anemia, hypokalemia, peripheral neuropathy and fatigue
You are encouraged to report side effects to Genentech and the FDA. You may contact Genentech by calling 1-888-835-2555. You may contact the FDA by visiting www.fda.gov/medwatch or calling 1-800-FDA-1088.
Click here for full Prescribing Information for additional important safety information, including Boxed WARNINGS.
Reference: 1. KADCYLA Prescribing Information. Genentech, Inc. May 2013.
© 2013 Genentech USA, Inc. All rights reserved. TDM0001957100
Genentech USA, Inc.
1 DNA Way
South San Francisco, CA
94080-4990

FDA PAGE on scleroderma!

"FDA approves Opsumit to treat pulmonary arterial hypertension
The U.S. Food and Drug Administration today approved Opsumit (macitentan), a new drug to treat adults with pulmonary arterial hypertension (PAH), a chronic, progressive and debilitating disease that can lead to death or the need for lung transplantation.
PAH is high blood pressure that occurs in the arteries that connect the heart to the lungs. It causes the right side of the heart to work harder than normal, which can lead to limitations on exercise ability and shortness of breath. Opsumit belongs to a class of drugs called endothelin receptor blockers, which act to relax the pulmonary arteries, decreasing blood pressure in the lungs.

Opsumit’s safety and effectiveness were established in a long-term clinical trial where 742 participants were randomly assigned to take Opsumit or placebo. The average treatment duration was about two years. In the study, Opsumit was effective in delaying disease progression, a finding that included a decline in exercise ability, worsening symptoms of PAH or need for additional PAH medication.
Similar to other members of its drug class, Opsumit carries a Boxed Warning alerting patients and health care professionals that the drug should not be used in pregnant women because it can harm the developing fetus. Female patients can receive the drug only through the Opsumit Risk Evaluation and Mitigation Strategy (REMS) Program. This restricted-distribution program requires prescribers to be certified by enrolling in the program; all female patients to be enrolled in the program and comply with applicable pregnancy testing and contraception requirements before initiating treatment; and pharmacies to be certified and to dispense Opsumit only to patients who are authorized to receive it.
Common side effects observed in those treated with Opsumit include low red blood cell count (anemia), common cold-like symptoms (nasopharyngitis), sore throat, bronchitis, headache, flu and urinary tract infection.
Opsumit is marketed by San Francisco-based Actelion Pharmaceuticals US, Inc."

GO TO FDA PAGE WHERE THIS NEWS COMES FROM!

speculative gene Biomarkers!

Can amplification of FAK gene predicts for higher risk of Bacterial endocarditis in the right scenario patient?
can FAK level be an important biomarker for healing, senescence monitoring as it could be a result of cytokine effect, of general health status?
DOES FAK EXPRESSION INCREASE BACTERIAL ATTACHMENT OR INCREASE THROMBOTIC STATE?

Friday, October 18, 2013

CYTOKINE STORM!

Now comes an interesting observation, a cytokine storm can be observed when an antibody attacks the CD3 receptor such as achieved by OKT3.  There is a massive cytokine release  leading to fevers,nausea,vomiting severe headche chest pain,dyspnea and even pulmonary edema. and this syndrome is triggered by the engagement by OKT3 of TCR.  Go figure, these Cytokine are really the effectors of disease!  The affect immunity deeply, always give CMV prophylaxis if you go with the OKT3 option!
WHAT IS IT ABOUT CD3 THAT MAKES IT SO SPECIAL IN STORM TRIGERRING, THE COMPANY IT KEEPS?

Thursday, October 17, 2013

THE WORLD OF CYCLINS HAS ABUNDANT INTEREST!

SOME OF THE MANY IMPLICATIONS, /THE IMPACT AND INTEREST BY RESEARCHERS THAT CAUGHT OUR ATTENTION AT CRBCM!

Actions of the chemotactic cytokines MCP-1, MCP-2, MCP-3, RANTES, MIP-1α and MIP-1β on human monocytes

  1. Mariagrazia Uguccioni,
  2. Massimo D'Apuzzo,
  3. Marcel Loetscher,
  4. Beatrice Dewald,
  5. Marco Baggiolini*
The activities of six synthetic CC chemokines, MCP-1, MCP-2, MCP-3, RANTES, MIP-1α and MIP-1β on human blood monocytes were studied. All CC chemokines elicited a bimodal migration response in vitro. Highest numbers of migrating cells were obtained with the monocyte chemotactic proteins (MCP) and RANTES, somewhat lower numbers with MIP-1α, and only weak migration with MIP-1β. The most potent attractants were MCP-1 and MIP-1α which reached maximum efficacy at 0.1 to 1 nM. All CC chemokines also induced the release of N-acetyl-β-D-glucosaminidase from cytochalasin B-pretreated monocytes. The MCP were most effective (MCP-1 > MCP-3 > MCP-2), RANTES and MIP-1α showed moderate (1/3 of MCP-1 activity), and MIP-1β only minimal activity. Cytosolic free Ca2+ changes and exocytosis were used to monitor receptor desensitization. Marked cross-desensitization was observed among MCP-1, MCP-2 and MCP-3 on the one hand, and RANTES, MIP-1α and MIP-1β on the other, indicating receptor sharing within these two subgroups of CC chemokines. The responses to RANTES, MIP-1α and MIP-1β were also moderately to markedly desensitized by pretreatment with MCP-1, MCP-2 or MCP-3, while the responses to the MCP were virtually unaffected by pretreatment with RANTES, MIP-1α and MIP-1β. These results suggest that the MCP also interact with receptors recognized by RANTES, MIP-1α and MIP-1β, but not vice versa. Binding studies were performed with radiolabeled MCP-1 or MIP-1α. All MCP competed readily for labeled MCP-1 yielding a concentration-dependent sigmoidal displacement curve. Displacement with RANTES, MIP-1α and MIP-1β was observed at higher concentrations, but was not complete. Radiolabeled MIP-1α was displaced efficiently by MIP-1α or MIP-1β, but only partially by RANTES. Of the MCP, only MC-3 completely displaced MIP-1α, while only partial displacement was observed with MCP-1 and MCP-2.
---------------------------------------------------------------------

Monocyte chemoattractant protein-1-induced CCR2B receptor desensitization mediated by the G protein-coupled receptor kinase 2

Abstract

Monocyte chemoattractant protein 1 (MCP-1) is a member of the chemokine cytokine family, whose physiological function is mediated by binding to the CCR2 and CCR4 receptors, which are members of the G protein-coupled receptor family. MCP-1 plays a critical role in both activation and migration of leukocytes. Rapid chemokine receptor desensitization is very likely essential for accurate chemotaxis. In this report, we show that MCP-1 binding to the CCR2 receptor in Mono Mac 1 cells promotes the rapid desensitization of MCP-1-induced calcium flux responses. This desensitization correlates with the Ser/Thr phosphorylation of the receptor and with the transient translocation of the G protein-coupled receptor kinase 2 (GRK2, also called β-adrenergic kinase 1 or βARK1) to the membrane. We also demonstrate that GRK2 and the uncoupling protein β-arrestin associate with the receptor, forming a macromolecular complex shortly after MCP-1 binding. Calcium flux responses to MCP-1 in HEK293 cells expressing the CCR2B receptor were also markedly reduced upon cotransfection with GRK2 or the homologous kinase GRK3. Nevertheless, expression of the GRK2 dominant-negative mutant βARK-K220R did not affect the initial calcium response, but favored receptor response to a subsequent challenge by agonists. The modulation of the CCR2B receptor by GRK2 suggests an important role for this kinase in the regulation of monocyte and lymphocyte response to chemokines.

==========================================================

Proteasomal regulation of betac signaling reveals a novel mechanism for cytokine receptor heterotypic desensitization.

Source

Baylor College of Medicine, Departments of Medicine and Immunology, Biology of Inflammation Center, Houston, Texas 77030, USA.

Abstract

IL-5, IL-3, and GM-CSF are hematopoietic cytokines that are key mediators of the allergic inflammatory response. The receptors for these three cytokines consist of a cytokine-specific alpha (Ralpha) chain and a shared common beta (betac) chain. Herein, we demonstrate that agonistic ligation of these receptor subunits rapidly induces proteasomal degradation of the betac, but not the Ralpha, cytoplasmic domain, resulting in termination of signal transduction and yielding a truncated betac isoform ligated to the Ralpha subunit. Proteasomal degradation of the betac cytoplasmic domain was also a prerequisite for endocytosis and lysosomal degradation of the ligated receptor subunits. Moreover, proteasome-dependent termination of signaling induced by one betac-engaging cytokine resulted in cellular desensitization to signal transduction by subsequent stimulation with another betac-engaging cytokine. These data provide the first evidence for ligand-dependent proteasomal degradation of the betac cytoplasmic domain, and they establish a novel mechanism for heterotypic desensitization of shared cytokine receptor signaling.

========================================================

Proteasomal regulation of βc signaling reveals a novel mechanism for cytokine receptor heterotypic desensitization

Abstract

IL-5, IL-3, and GM-CSF are hematopoietic cytokines that are key mediators of the allergic inflammatory response. The receptors for these three cytokines consist of a cytokine-specific α (Rα) chain and a shared common β (βc) chain. Herein, we demonstrate that agonistic ligation of these receptor subunits rapidly induces proteasomal degradation of the βc, but not the Rα, cytoplasmic domain, resulting in termination of signal transduction and yielding a truncated βc isoform ligated to the Rα subunit. Proteasomal degradation of the βc cytoplasmic domain was also a prerequisite for endocytosis and lysosomal degradation of the ligated receptor subunits. Moreover, proteasome-dependent termination of signaling induced by one βc-engaging cytokine resulted in cellular desensitization to signal transduction by subsequent stimulation with another βc-engaging cytokine. These data provide the first evidence for ligand-dependent proteasomal degradation of the βc cytoplasmic domain, and they establish a novel mechanism for heterotypic desensitization of shared cytokine receptor signaling.

Collaborative role of E2F transcriptional activity and G1 cyclindependent kinase activity in the induction of S phase.

Source

Department of Genetics, Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA.

Abstract

A considerable body of evidence points to a role for both cyclin E/cyclin-dependent kinase (cdk)2 activity and E2F transcription activity in the induction of S phase. We show that overexpression of cyclin E/cdk2 in quiescent cells induces S phase, that this coincides with an induction of E2F activity, and that coexpression of E2F enhances the cyclin E/cdk2-mediated induction of S phase. Likewise, E2F overexpression can induce S phase and does so in the apparent absence of cyclin E/cdk2 activity. In addition, although the inhibition of cyclin E/cdk2 activity blocks the induction of S phase after growth stimulation of normal mouse embryo fibroblasts, inhibition of cyclin E/cdk2 does not block S phase induction in Rb-/- cells where E2F activity is deregulated. These results point to the important roles for E2F and cyclin E/cdk2 in the induction of S phase. Moreover, the nature of the E2F targets and the suspected targets for cyclin E/cdk2 suggests a potential molecular mechanism for the collaborative action of cyclin E/cdk2 and E2F in the induction of S phase.