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Prof Trevor Marshall
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Later today I will be presenting a poster at the Days of Molecular Medicine Conference in Boston. Last year the DMM conference was at Karolinska, this year it is being held at the Mass. General Hospital, part of Harvard.

We haven't said much about Cancer on this study site, as it is such a hot potato for many of you, but I have been working in the background to better understand the disease mechanisms, and to get them to reconcile with the biological 'model' I have built of the Th1 inflammatory processes.

The title of the presentation is "Molecular Static and Dynamic Analyses Reveal Flaw in Murine Model used by US FDA to Detect Drug Carcinogenicity." You can see a PDF copy of the handout at URL
http://autoimmunityresearch.org/dmm2007/dmm2007-handout.pdf

The video associated with the presentation can be seen, in Real Media format, at URL
http://autoimmunityresearch.org/dmm2007/dmm2007.ram

I will be travelling to Boston in the next few hours, but if you have any immediate questions, feel free to ask them, and I will answer when I can.
 

DMiller
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Dr. Marshall,

Maybe while at Mass General you will bump into the folks from CeDAR ( Center for D Activation Research) whose stated mission is "to support research and improve understanding of the widespread biological and clinical consequences related to the activation of the vitamin D receptor". They are affiliated with Mass General.

Prof Trevor Marshall
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Hmm. Their online info doesn't say too much about what they think or do
http://www.massgeneral.org/cedar/ced_about.html
so maybe we will meet up, and I will be able to find out:)

Thanks for the tip
 

tickbite
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it's looking like Dr. Ravi Thadhani has some good impressions......8th slide says "Vitamin D is bad........." I think he also understands more about the whole metabolism picture.....

http://www.massgeneral.org/cedar/ced_lecture1.html

 

wrotek
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I did not know there is a D Activation Center, that is nice.

For convenience



Last edited on Mon May 21st, 2007 12:23 by wrotek

Prof Trevor Marshall
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Thanks for the Flash version of the video, Wrotek.

Well, here I am at Harvard, meeting some very interesting people, and generally trying to learn anything I can learn from the conference attendees.

I can't help but be struck again, as I was at the Salk Institute conference on Diseases of Transcription in January, that nobody else here is using the new molecular tools, that 'wet Biology' is still touted as the standard, and that everybody's research is focused on producing 'the killer drug' rather than defining the cause of a condition. Hmmm...

Anyway, at least everybody agrees that murine models are of limited usefulness, and gene knockout mice are only useful to the extent we are able to define the gene's functions.

I was surpised that the keynote speaker, Ralph Weissleder from Harvard, was absolutely emphatic that research in cell lines can never replace in-vivo data, because the results can be completely different. That was a breath of fresh air.

So I will keep on plugging away... Two more days of presentations still to come...
 

DMiller
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Did you meet anyone from CeDAR? They should be knocking on your door. Who has done more in the area of VDR activation than you?

Ruth Goold
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Hi Trevor,

Very disappointing to hear about the empahsis on 'killer drugs' and lack of interest in the 'cause of condition.'  I have been wondering about the influence of bacterial infections on the role of epigenetic factors (e.g. loss of imprinting - LOI - due to hypo- and hyper-methylation of DNA) that are increasingly being implicated in inflammation and cancer (and of course, aging).  A current review article in Nature highlighted the role of environmental toxins and dietary factors in LOI, but did not mention bacterial infection.  A quick search in PubMed revealed studies implicating  H. pylori infection with the development of gastric (and colon) inflammation and cancer, but little else.  Have you become aware of new research in this area at the meeting?

Ruth 

wrotek
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I hope You are having an interesting time Dr Marshall. Dissapointing to hear that people are not using molecular tools. Maybe it is hard to learn how to operate them, that is what i think :)

tickbite
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HA! Resistance Genes In Our Food Supply

Add that one to the list of reasons bugs are getting ahold of us. This is also a basic concept Dr. M has been telling us: "accumulation over a life time." Furthermore, HGT isn't just allowing abx resistance but virulence genes to mix too.

Prof Trevor Marshall
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DMiller, Nobody from CeDAR is at the conference, nor have any of the delegates mentioned CeDAR to me.  I wil try and make some phone calls this morning.

Ruth, LOI doesn't have to be mysterious when you consider the mutation and expression-changing-ability of the tens of thousands of genes belonging to the pathogens. I doubt that it is as simple as a 'mother' or 'father' imprint, though. Think about how easy it was for Medicine to grasp onto the (IMO faulty) concept of prions, yet how hard it has been for Medicine to recognize that Koch may have been wrong, and that chronic disease is far more complex, and in many ways beyond our control, than the pragma of the past have taught. Most of the people here are interested only in the cycle of applying for grants and then applying for more. Since grants are peer reviewed, you cannot get grants if you are way out in front of your field.

Look for example at Tony Norman's latest work, "IFN-gamma- and TNF-Independent Vitamin D-Inducible Human Suppression of Mycobacteria: The Role of Cathelicidin LL-37."
http://tinyurl.com/22jmqr
and how basic it seems from our vantage point. Indeed, it is basic. Tony; who discovered 1,25-D; has long since failed to lead research in the field, and has no real concept of what we have been doing. I am sure that Tony feels that we are not 'thorough' enough - perception is all a matter of perspective and insight...

Wrotek, Yes, it takes hard work to understand what the molecular software can do, and to get useful results. I have several colleagues, including one from the Gromacs development team, who have helped me with insight from time to time.

Greg, that citation you give is instructive. You see, we are living in real time. In Internet time. If anybody, anywhere in the world, publishes a concept of interest to us we immediately know about it and add its insight  to our pool of knowledge. This conference is co-sponsored by the Journal 'Nature Medicine,' and most of the delegates here are not interested in such 'anecdotal' sources as they rely on 'authority' of 'peer-reviewed literature.' The speakers are selected by Nature Medicine editors.  The speakers for next year's conference have already been (largely) selected. In many ways it is all a lot of self-serving buddy-back-slapping. But our nation continues to pour research monies into the coffers of a system like this, and the nation is living out the results, or lack of results, which come from such poor methodologies.

So in many ways I am a pariah here - how dare I say I have a validated model for chronic disease! I have to seek out the folk who are still relatively untainted by the old-boys-club, such as the younger Nature editors here, and the post-Docs who will shape the next generation of research.

Thanks for all your help as we continue to move forward.
 

wrotek
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I always wondered what kind of brain-maniacs people who develop molecular software, must be :) What kind of people are they.  It is unbelievable .

Last edited on Thu May 24th, 2007 14:36 by wrotek

Prof Trevor Marshall
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Mathematics whizz-kids, I will call them. Conceptual thinkers :)

Ruth Goold
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Dr Trevor Marshall wrote: So in many ways I am a pariah here - how dare I say I have a validated model for chronic disease! I have to seek out the folk who are still relatively untainted by the old-boys-club, such as the younger Nature editors here, and the post-Docs who will shape the next generation of research.
 

Well, maybe Trevor got through to some of those Nature editors with his poster on the differences in the VDR (and consequently inflammatory disease) between mice and men.  Three papers published on-line in Nature Immunology on Aug. 5 highlight differennces between murine and human differentiation of Th-17 (T helper cells important in inflammation and innate immunity).  

jcwat101
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Great!

Would someone mind providing the links for those?

Joyce Waterhouse

Ruth Goold
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Hi Joyce,
They are the first three articles at:
http://www.nature.com/ni/journal/vaop/ncurrent/index.html
Ruth

Ruth Goold
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Joyce,
Another reference you may be interested in:

http://www.jimmunol.org/cgi/content/abstract/179/4/2060

Not an earth shattering revelation for you, but Liu et al. demonstrate that antimicrobial activity is stimulated by 1,25 D  in a human monocyte cell line infected with intracecllular M. tuberculosis.  They identify cathelicidin as the responsible AMP by 'knock-down' of cathlecidin expression with microRNAs.

Ruth




Prof Trevor Marshall
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Ruth,
1. M.tuberculosis uses a different method to evade the immune system than the Th1 pathogens

2. Studies in cell lines have led science on a wild goose chase for a century, they are unreliable as they place too many limitations on the in-vivo experimental  degrees of freedom.

3. Cathelicidin is just one of the 16 families of anti-microbial peptides transcribed by the VDR

Pragma: Only in-vivo and modelling studies have any chance of elucidating Th1 disease mechanisms.

..trevor..

Brenda
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Being a teacher and administrator, this way of thinking does not suprise me.  The students are taught to "get the right answer," not think for themselves nor think outside the box.

This in turn, has taught people to be reactive and not proactive.  (No matter how much they would like to think they are.)  It takes a completely new paradigm to REALLY think outside the box, to really be able to think about the abstract unimaginable, not just the visually concrete.

I hope that enough researchers in my generation will be open enough after going through standard education, will be open to think of different ways of thinking to make new discoveries like Leonardo Da Vinci.

Sincerely,

Brenda

Prof Trevor Marshall
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Brenda,
I am not expecting radical change to occur within the current generation of physicians. Indeed, a significant proportion of them will be struck down by the same Th1 disease they cannot accept as communicable :X It will take another generation to effect radical change, IMO.

I can wait that long ;)

..Trevor..

Ruth Goold
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Trevor,
Do you know which class(es) of AMPs are most effectove against the intracellular Th1 pathogens when the VDR is operating properly?
Ruth

Prof Trevor Marshall
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Ruth,
No, nobody really knows very much about how they work. In particular, some AMPs seem to be able to adapt conformation depending on the organism which is present. "Micro-RNA" loops were being discussed as a possible adaptive mechanism during the conference at Salk on January. I haven't had time to look into this in more detail yet.

 



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