Yes, don't forget the TELOMERES!

• October 2013
• > Vannier et al., 342 (6155): 239-242

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RTEL1 Is a Replisome-Associated Helicase That Promotes Telomere and Genome-Wide Replication

1. Jean-Baptiste Vannier¹,*,
2. Sumit Sandhu²,*,
3. Mark IR. Petalcorin¹,
4. Xiaoli Wu²,
5. Zinnatun Nabi²,
6. Hao Ding²,³,^†,
7. Simon J. Boulton¹,^†

+ Author Affiliations

1. ¹DNA Damage Response laboratory, London Research Institute, Cancer Research UK, Clare Hall, South Mimms EN6 3LD, UK.
2. ²Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba R3E 3J7, Canada.
3. ³Manitoba Institute of Child Health, Winnipeg, Manitoba, R3E 3P4, Canada.

1. ↵†Corresponding author. E-mail: dingh@cc.umanitoba.ca (H.D.); simon.boulton@cancer.org.uk (S.J.B.)

1. ↵* These authors contributed equally to this work.

• Abstract
• Editor's Summary

Regulator of telomere length 1 (RTEL1) is an essential DNA helicase that disassembles telomere loops (T loops) and suppresses telomere fragility to maintain the integrity of chromosome ends. We established that RTEL1 also associates with the replisome through binding to proliferating cell nuclear antigen (PCNA). Mouse cells disrupted for the RTEL1-PCNA interaction (PIP mutant) exhibited accelerated senescence, replication fork instability, reduced replication fork extension rates, and increased origin usage. Although T-loop disassembly at telomeres was unaffected in the mutant cells, telomere replication was compromised, leading to fragile sites at telomeres. RTEL1-PIP mutant mice were viable, but loss of the RTEL1-PCNA interaction accelerated the onset of tumorigenesis in p53-deficient mice. We propose that RTEL1 plays a critical role in both telomere and genome-wide replication, which is crucial for genetic stability and tumor avoidance.
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PLEASE GO TO THE FULL ARTICLE,
GOOD JOB FOR THESE SCIENTISTS!

Until we can talk to the CBX, the piccolo, and the IKAROS, Brain tumors and certain Leukemia will remain elusive!

It is striking what similarities exist between brain tissue function and white blood cell function at the molecular level.  When it comes to Neoplasia, Medulloblastoma is linked to hematologic neoplasm!
And any therapeutic intervention against blood cell proliferative disorders may have Neurologic side effects, and it is important that Phase 1 studies be conducted in centers that can handle seizures and accurately evaluate mental status changes (Leucodystrophic Encephalopathy)!  The similarities are not only found at the membrane where the frizzled and the Lck, and Merlin (Neurofibromatosis) are located, but deep inside the cells at the Nuclear/Chromatin level where the Ikoros and CBX5 are plenty at play!
It is evident that the CBXs and the Ikoros are epigenetic and this is where Leukemia and most malignant Brain tumors come to hide their source and powers.  And guess who is following them, the triple negative breast cancers!  It is actually amazing that this last disease may be more likely Cytokine driven given its selective appearance in certain groups of our population (HLADRs implicated).
The CRBCM continues its unfettered progress, not distracted by belligerent political forces, but tracking down this disease from the Wnt, Notch, Wisp3, non expressed Hormone Receptors, to the STAT5, SMADs, and now to the SUV39H1-CBX, Ikoros, Piccolo,Tousled, a Ku70, and to chromatin modulation.
Progress is slow but deliberate.  It is surprising that even deep here, through the FADD-MBD4, the Caspases can help achieve Apoptosis...there is hope for the cure!

Real clinical questions

1. Identifying best chemotherapy drugs in patients with Mutation in the NOTCH pathway?
Taxotere?
association with Her-2 overexpression and use of Herceptin
NF-kB blocker
or AKT blocker.
Histone de-acetylator

2. Understanding the patterns of Metastasis between epithelial (squamous) (more local recurrence)  Vs AdenoCA (more distant recurrence in Esophageal cancer? Genes at play.
Does mesenchymalization dictate or drive long distance metastasis?

3. Mitomycin in NFKB amplification/Mutations

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CPRIT’s Oversight Committee met November 1 for the first time since February beginning a new era for the agency – one with a higher level of transparency, improved processes and strengthened accountability to the taxpayers of Texas. As I reported to the Oversight Committee, in addition to provisions in SB 149 which modified CPRIT’s enabling legislation, the agency has taken action to implement all 41 of the State Auditor’s January 2013 recommendations. We accomplished a number of important items at the meeting that will allow CPRIT’s work to move forward. We also began our commitment to transparency by holding the meeting at the State Capitol and streaming the meeting live over the web – a first for CPRIT. Within days, we’ll post a video of the proceedings to our website as well. Major actions of the Oversight Committee include: Adopting new bylaws for how the Oversight Committee will operate as a governing body, including an updated code of conduct. These bylaws indicate the Oversight Committee commitment to operating with the highest level of integrity; Posting revised administrative rules to the Texas Register for public comment. The rules expanded from 40 to over 120 pages, and implement many of the State Auditor’s recommendations as well as other process and accountability improvements; Restarting our grantmaking process, including the approval of Scientific Review Council appointees. This action allows CPRIT to resume review of grants and enable healthcare and medical professionals to apply for new grants. We expect additional steps at the next Oversight Committee meeting scheduled for November 22, 2013. At that session, I anticipate discussion about research and prevention program priorities, and a number of other actions important to our continuing operations. I want to express my gratitude to the members of the 83rd Legislature and their staffs, state leadership offices and CPRIT staff for getting us to November 1. The new Oversight Committee came to the meeting well-prepared and eager to resume the important responsibilities assigned to CPRIT by the citizens of Texas. It’s nice to be back at work! Regards, Wayne R. Roberts Interim Executive Director Cancer Prevention & Research Institute of Texas P.O. Box 12097 Austin, Texas 78711

Digging deeper ! Chromatin remodeling

As we are progressing  deeper into our understanding of disease pathophysiology, we are discovering that some of the cancers are caused or exacerbated by abnormalities of cyclin pathways (Triple negative breast cancers).  There are disturbances at Cyclins and Hormone Receptors at the membranes.  But deeper into the cells, there is disturbance at the Histones (epigenetic zone) where modulation is needed for transcriptions factors to be formed and unleashed.  Here, the dance is governed by the PRBM1, BAFs, PBAF, BRDs, RSC, ARIDs and SWI/SNF (Chromatin remodeling).  This is where BRAC-1 also plays its main function. Indeed some of the Adaptors or cofactor fail the BRCA-1 to continue to repair DNAs!  And some cytokines fail here!  we are working deeper!

Marching on toward future therapies in Cancer Medicine

Most cancers result from a disturbance of our genes.  The disturbance could be functional or simply a change in the nature of genes called Mutations.  Mutations that are deleterious are those that stop or otherwise alter the fundamental function of the gene.  Genes can initiate, regulate, facilitate or simply hook to other genes.  Hooking (Adapter) to other genes has a strong impact because it can change the direction of the pathways, or give a gene the powers of the gene it is now hooked onto!  There are those who simply allow hooking to membranes as in Anchor genes that sometimes allow trans-membrane transport, sometime just providing a substrate from other reactions to occur. 
Hooks can also connect several molecules (Homeobox).

Suffice is to say that if a gene is broken, let's introduce a new gene.

The challenge is: how do we get a new gene in there?
Here we are looking at Nanotechnology to achieve this challenge!

The true role of E-Cadherin Vs the ASSASSIN (destructors)

One of the main activities of cancer cells to complete their "criminal enterprise" is to escape proliferation control, and cancer cells have known this and have mastered the way to achieve this very efficiently through the Cadherins.  Though it is emphasized that the cancer cells reduce E-cadherin expression to free themselves from their neighbors by reducing Adhesion molecules, the truth is that there is a more ominous enterprise going on.  Degradation of E-cadherin through Ubiquitilation consumes or distracts E3 from its main job which is to remove some of the Inhibitors to CDK, LEAVING THE CELL WITH UNCHECKED CELL DIVISION.

Occupying the HAKAI  (ASSASSIN) would be helpful in achieving control of the process.

The E3 ubiquitin-protein ligase Hakai (HAKAI) also known as Casitas B-lineage lymphoma-transforming sequence-like protein 1 (CBLL1) is an enzyme that in humans is encoded by the CBLL1 gene.^[1] This gene encodes an E3 ubiquitin ligase for the E-cadherin complex and mediates its ubiquitination, endocytosis, and degradation in the lysosomes. The encoded protein contains a RING-finger domain and is also thought to have a role in control of cell proliferation.

BASIC SCIENCE QUESTIONS

Should patients with lymphoproliferative disorders avoid Alcohol since LMRP positivity suggests COOH  involvement?
Can pain at lymph nodes in Hodgkin disease after ingestion OF ALCOHOL or pruritus predict the presence of LMRP mutation?
Is the pruritus in Hodgkin disease linked to the presence of COOH at the nerve terminal?
Should we treat lymphoproliferative disorders with LRMP expression with Cisplatin etoposide based therapy?

Interleukin-4 is the best protective Interleukin of all, I wonder if we should be measuring it as a prognosis factor in  Lymphoproliferative disorders? Is overexpression of HGAL or GCET2 a corollary indication of IL-4 activity?

Critical importance of the Notch1

TSG1, HGS, and STAM2 appear critical in the importance of the NOTCH1.

We have stressed the importance of the NOTCH in cancer and wanted to provide some of the proof for the supportive evidence found in the literature.  The Notch through its interaction with MAML1, easily affects EP300 leading to activation of TSG, a critical gene in the action of P53.  Indeed P53 acts by activating TSG which leads to an increasing inhibitory activity of p21 on CDKs, blocking as a result cell division and therefore proliferation.
Inhibition at the NOTCH will therefore remove breaks to cell division and will mark a significant tendency to cancer incurability!
And I wish things stop there, but they don't:
The Activation of TSG will disturb the resting HSG which bothers the Merlin and blocks NF2 leading to the loss of growth control by contact of surrounding cells, the cell losing control of its growth...Hyperplasia can easily ensue!
The HSG now excited, engages the STAM2 and 3 things:

1. Interaction with JAK1 leading to metastasis

" Expression of JAK1 in cancer cells enables individual cells to contract, potentially allowing them to escape their tumor and metastasize to other parts of the body (wikipedia)"
the involvement of JAK-1 multiply the worsening of the situation because it will excite: PTPN11

" PTPN11 is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation." 
and with the ELP gene, the process will affect the SMAD3 leading to loss of control of proliferation and normal ubiquitylation of inhibitory proteins.

2.S TAM2 will engage Cytokin Receptors  (Cullins)

3. STAM2 will engage the tract to E3.

But the engagement of the Notch does still not stop there...

the GSK3B comes into play! and ....

PONATINIB: ARIAD ASKED TO STOP PRODUCTION !

THROMBOTIC EVENTS AND POSSIBLE VASCULOPATHY MAY HAVE LED TO THE FDA ORDER TO SUSPEND REPORTEDLY THE PRODUCTION OF PONATINIB A DRUG JUST RECENTLY APPROVED IN THE TREATMENT OF CHRONIC MYELOID LEUKEMIA

Ponatinib (Iclusig, previously AP24534) is an Food and Drug Administration approved oral drug candidate developed by ARIAD Pharmaceuticals for the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL). It is a multi-targeted tyrosine-kinase inhibitor.^[1] Some forms of CML, those that have the T315I mutation, are resistant to current therapies such as imatinib. Ponatinib has been designed to be effective against these types of tumors.^[2]
Oncologists have complained, however, that many patients can not afford the "astronomical" cost of $138,000 a year, which makes it one of the most expensive drugs in medicine, and far more expensive than what is needed to pay the development costs.<sup>[3][4] WIKIPIDIA

THE THROMBOTIC COMPLICATION WAS NOT NEW HOWEVER, IT IS UNCLEAR WHY THE FDA MOVED TO ORDER ARIAD TO STOP THE PRODUCTION.</sup>  


"The United States Food and Drug Administration issued a partial clinical hold on new trial enrollment for Iclusig on 9 October 2013 due to an increased number of blood clots observed in patients taking the drug.^[6] The EPIC trial was later cancelled on 18 October.^{[7]"WIKIPEDIA}

NOW THE STOP ORDER IS IN EFFECT REPORTEDLY!

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

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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!

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. 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!

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!

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?

Pringe A, Trail L, Ruperto N, Buoncompagni A, Loy A, Breda L, Martini A, Ravelli A.

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.

IT IS ALL ABOUT THE CYTOKINES!

The discovery of DNA and nuclear material has led to the emphasis on the alteration of Nuclear functions to fight cancer, indeed most of the original chemotherapy drugs had mechanisms of action centered on breaking or somehow impairing DNA.  This focus to a certain extent affected our judgement in the evaluation of certain drugs.  We are now finding out that the strength of certain drug  (and weakness /susceptibility to resistance) is not really due to their main effect on DNA (ie. epigenetic disturbances induced by  Etoposide).  The discovery that BCL-2 has a mechanism of resistance to certain drugs is point in case that nuclear material induced disturbances have significant limitations that occur away from the nucleus (at the Mitochondria).  Anti-proliferative chemotherapies have now shown their limits and scientists have kept this in our panoply of options against cancer.

Scientists have long been fascinated by the laws of nature, these driving forces that drive in certain ways or directions the chains of chemical reactions within the cells.  From Glycogenolysis to the Krebs' cycle, to the cellular pathways, role of enzymes these catalysts of chemical reaction and gene regulators, our focus has been progressively shifting.   The maximal effect of standard chemotherapy having been realized, the shift now has gone to driver Mutations, blocking pathways and modulating reactions etc.   But beyond the mutation, gene alterations and so forth, one thing that make a cancer spread like a wild fire is its stimulation by a growth factor, or its self dependence in achieving survival most of the time at very different levels of energy expenditure!  This role squarely falls into the area of epigenetics which is the critical area of Cytokine production determination.  Now, once produced, Cytokines, to be effective, must connect to their receptors!  This is where the wheels rub the asphalt to speed up the chemical reactions!

One of the mechanisms of increased cytokine production, aside from their gene amplification, is failure at the receptor.  Indeed, when a receptor fails, the normal reaction (law of nature) is to concur the resistance by sending more of the same cytokine.  While this increase could be partially succesful in restoring homeostasis depending on the level of abnormality at the receptor, the relative increase has other side effects due to the non specificity of receptors.  Co-receptors or other receptors susceptible to the same cytokine find themselves super excited and are driving downstream reactions at higher rates.  A SIGNIFICANT PHENOMENON NEEDS TO OCCUR AT THIS POINT, THAT IS THE DESENSITIZATION OF SECONDARY RECEPTORS, A TRAUMATIC PHENOMENON WITH POTENTIALLY NEOPLASTIC CONSEQUENCES   (TO BE CONTINUED)

Interesting aspects of Herpetic Infections

No infection is as intriguing as the Herpetic infection.  Its interest lays in several facts
1. The mere fact that a Third of the US population may be involved makes this disease one of the most prevalent ones,  but it is also feared.  Whether the fear is justified or not remains a question.
2. Certainly it has something to do with horrific stories of potential recurrence of horrific burning neuropathic pains that we have heard about. Science does not know for sure whether only specific viral serotypes lead to this or whether certain hosts genes isoforms or inflammatory reactions  may be contributing to this presentation.
3. The outbreak is accompanied with guilt and sense of guiltiness that is mostly unjustified...many questions arise after the realization that those painful skin or otherwise lesions could be herpetic...that a partner you have gave this to you and that you may give this to a new partner?  Those questions are valid but with the prominence of the prevalence of this disease in the US, who and when one got exposed to Herpes is one of the great mysteries in herpetic disease.  Herpes 1 has been linked to Over crowding, and Herpes 2 is the one with a sexual connotation.  But one should remember that the Herpetic Virus will invade teguments (particularly abrasions) when contact happens, sexual or not!  And very often this happens in our tender ages of infancy.  Remember the infection can be symptomatic, but most of the time completely without any clinical manifestations. And enters quietly a dormancy.
4. The dormancy itself is quite a puzzling event!  All we know is that the capsule to this double stranded DNA viral particule is from the host!  This may help it to be "tolerated " by the host.  We can speculate that class I MHC will not be bothered. Only the class II may note the invader most likely and provide the Antibody that we can measure!
5. The exacerbation of the herpetic infection is also puzzling in many ways
-It happens when we are under stress (menstruation and exposure to UV light), pregnancy state and post chemotherapy, the so called state of "when the immune system" is down!
-To the writer this is a state of activity of the c-JUN and Fos, the NF-kB and full epigenetic phenomena as if cyclines and TNF, TGFs are in full swing!  Epigenetic events seem to free or unleash genes (regulators or not) that will reactivate the Virus.
-How and where these events occur (Golgi, Nucleus, or cytosolic) remains to be clarified.

 (Let raise the eyelid of this dormant disease and look at it through its eyes/pupils without awakening it!)

6. The bad exacerbation could be virally induced or it could be in fact a reaction of the Host  (Neutrophilic Grazymes) or Cyclin effects.  ie. In post Brain trauma injury (TBI) we know that post synaptic nerve death is due to  Cytokins that kill post synaptic nerve, is it the same in this herpetic disease?And if it is, what would be the therapeutic implications?!

*A new prognosis factor added to Metastatic Colon Cancer, STROMAL PARTICIPATION IN THE HISTOLOGY OF THE CANCER.  STRONG STROMAL PRESENCE OR INFILTRATION IMPLYING INTERCELLULAR EXCHANGE WITH THE STROMAL TISSUE, AND IS OF POORER PROGNOSIS.  THIS HAS BEEN REPORTEDLY VALIDATED.

This is an official CDC HEALTH UPDATE

 

Distributed via the CDC Health Alert Network March 4, 2013, 16:30 ET (4:30 PM ET) CDCHAN-00342

 

Notice to Clinicians: Continued Vigilance Urged for

Fungal Infections among Patients Who Received

Contaminated Steroid Injections

  Summary
CDC continues to receive new reports of fungal infection among patients who were given injections of contaminated methylprednisolone acetate (MPA¹) from the New England Compounding Center (NECC) in Framingham, Mass.   Most of these recent cases have been localized spinal or paraspinal infections (e.g., epidural abscesses) in patients, although new cases of meningitis or arachnoiditis also have been reported. Because many of these new cases are among patients with minimal symptoms, CDC is re-emphasizing the recommendation for clinicians to remain vigilant for fungal infections, especially in patients with mild or even baseline symptoms, and consider evaluation with magnetic resonance imaging (MRI) if clinically warranted. This Health Alert Network (HAN) notice provides the following:

·         Information about the current status of the outbreak;

·         Recommendations for clinical management and follow-up of exposed patients;

·         Information about new revisions to web-based interim clinical guidance (http://www.cdc.gov/hai/outbreaks/clinicians/guidance_cns.html); and

·         Notice of an upcoming CDC conference call to provide clinicians with additional diagnostic and treatment information.

 

Status of Fungal Disease Outbreak
As of March 4, 2013, a total of 720 cases, which includes 48 deaths, have been reported in 20 states. Current information about the outbreak, including case counts and distribution by state, and clinician and patient guidance, is available online at http://www.cdc.gov/hai/outbreaks/meningitis.html.

Fungal meningitis, often with a mild clinical presentation, was the predominant clinical syndrome reported among case-patients during the first several weeks of the outbreak (figure). Over the past several months, there has been a marked decrease in reports of fungal meningitis, but CDC continues to receive reports of localized spinal and paraspinal infections, which include epidural abscess, phlegmon, arachnoiditis, and discitis.  Additionally, some of these newly identified case-patients had initially tested negative for signs of a fungal infection (either by lumbar puncture or MRI) and have subsequently developed fungal infection, indicating a prolonged incubation period.

 

After the recall of NECC steroid medications on September 26, state and local health departments identified almost 14,000 people in 23 states who were potentially exposed to the implicated MPA; of these, an estimated 11,000 individuals received spinal or paraspinal injections. Through active notification by clinics with assistance from states and CDC in early October, nearly all of these exposed persons were contacted at least once and informed of their risk for fungal infection as a result of receiving injections with contaminated medication.

Despite this and subsequent patient outreach efforts, CDC and public health partners remain concerned   about the potential for some exposed patients to have localized fungal infections that have gone unrecognized. These infections may be unrecognized because some patients have not continued to receive close clinical follow-up or because they have not recognized symptoms suggestive of a localized infection, which may be difficult to distinguish from their baseline chronic pain. 

As described in CDC’s HAN update on December 20 (http://emergency.cdc.gov/HAN/han00338.asp), MRI testing was done on 128 patients in Michigan, Tennessee, and North Carolina who had no previous evidence of infection and had new or worsening symptoms at or near the site of their spinal or paraspinal injection. Of these, 67 (52%) had findings suggestive of localized infection.  In addition, of 109 different patients reporting persistent but baseline symptoms at or near the site of their spinal or paraspinal injection, 15 (14%) also had abnormal MRI findings suggestive of infection, and 27 (25%) had non-specific enhancement of soft tissue or other paraspinal structures.  The clinical significance of these findings is unclear; however, there is a theoretical risk that failure to diagnose these infections in a timely fashion could result in poor outcomes for patients (e.g., neurologic compromise, osteomyelitis, or progression to meningitis

Patient and Clinician Recommendations

Early in the outbreak, CDC advised clinicians to closely monitor and evaluate patients who received injections of implicated MPA. Additional guidance was provided in HAN updates issued on November 20 (http://emergency.cdc.gov/HAN/han00335.asp) and December 20 (http://emergency.cdc.gov/HAN/han00338.asp). Because of the possibility that some patients may have unrecognized, localized fungal infections, CDC is re-emphasizing the following recommendations for patients who received a spinal or paraspinal injection with implicated MPA: 

 

Patients

Patients who received an injection in or near their spine from one of the three implicated lots of MPA¹ and who have any symptoms at or near the site of their injection should seek evaluation by their medical provider for the possibility of a localized infection, such as an epidural abscess.  This includes patients who initially received steroid injections for pain and continue to have persistent baseline pain. 

 

Clinicians

As a part of continued monitoring of patients who received an injection with implicated MPA, clinicians should consider re-evaluating patients who received a spinal or paraspinal injection with implicated MPA for signs and symptoms suggestive of infection, including any symptoms at or near the site of their injection.  Because of the prolonged incubation period for these infections, this guidance pertains both to patients who have not been previously evaluated and to those who have already had a prior negative evaluation (e.g., normal cerebrospinal fluid profile, normal findings on MRI) but continue to have complaints:

 

-          In patients with new or worsening symptoms at or near the site of their injection, clinicians should obtain an MRI with contrast of the symptomatic area(s).

-          In patients with persistent but baseline symptoms, clinicians should consider obtaining an MRI with contrast of the symptomatic area(s) because the presentation of spinal or paraspinal infections can be subtle, and may be difficult to distinguish from a patient’s baseline chronic pain.

-          In some cases, radiologic evidence of abscess or phlegmon has become apparent on repeat MRI studies performed subsequent to an initially normal imaging procedure. Clinicians should therefore have a low threshold for repeat MRI studies in patients who continue to have symptoms localizing to the site of injection, even after a normal study. However, the optimal duration between MRI studies is unknown.

-          Clinicians should also consider reviewing MRI results with a neuroradiologist because of potential difficulties in interpreting imaging results for these patients.

 

Revised Clinical Guidance and Clinician Information Call

In response to input from expert consultants on fungal disease and physicians who have been treating patients affected by this outbreak, CDC has revised its Interim Treatment and Diagnostic Guidance for Central Nervous System and Parameningeal Infections Associated with Injection of Contaminated Steroid Products (http://www.cdc.gov/hai/outbreaks/clinicians/guidance_cns.html). The revisions include addition of new information on several topics, including:

 

-          Surgical management of parameningeal disease

-          Duration of antifungal treatment

-          Monitoring clinical status after cessation of antifungal treatment

-          Information on non-first-line medications (e.g., posaconazole or itraconazole)

 

A conference call for clinicians interested in obtaining additional information about the management and treatment of patients with fungal illness associated with this outbreak has been scheduled for March 13 at 5:00 p.m.  The presenter will be Tom Chiller, M.D., medical officer, CDC. Registration and call-in information and other details about the conference call will be available on CDC’s website http://www.cdc.gov/hai/outbreaks/clinicians/index.html.

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¹NECC lots of methylprednisolone acetate (PF) 80mg/ml:

Methylprednisolone Acetate (PF) 80 mg/ml Injection, Lot #05212012@68, BUD 11/17/2012
Methylprednisolone Acetate (PF) 80 mg/ml Injection, Lot #06292012@26, BUD 12/26/2012
Methylprednisolone Acetate (PF) 80 mg/ml Injection, Lot #08102012@51, BUD 2/6/2013

 

The Centers for Disease Control and Prevention (CDC) protects people's health and safety by preventing and controlling diseases and injuries; enhances health decisions by providing credible information on critical health issues; and promotes healthy living through strong partnerships with local, national, and international organizations.

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