2 more studies that found, you guessed it, zero XMRV

Dr. Yes

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Hi Hope,

The older "rumor viruses" article by Voisset? that Kurt posted a long time ago talks about this and how it could be an artifact of the techniques or budding endogenous retroviruses (which can happen) rather than a true exogenous virus about to lyse.
However, to date (unless something happened within the last year) no one has proven that any HERV is capable of producing infectious particles. Yet the WPI/NCI study showed that XMRV could infect previously uninfected cells. Some replication-deficient/incomplete HERV particles can bud, but that doesn't explain the infectivity of the WPI samples, nor a number of other findings of that study.

Technically an ultrastructural EM study of the particles in question should be able to make clearer whether they are complete virions or incomplete particles that could be from HERVs. But the stronger argument against contamination stems from a series of findings in the Lombardi study, which relegate the contamination argument to extreme improbability, and for which there has been no explanation offered by those who raise contamination as an issue.
 

Cort

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We are using 'independent' in different ways. They are not 'independent' with regards XMRV unless they use their own samples, their own reagants, etc. Independent basically means having no physical contact with the lab in question.

Its been really clear, anyway, for 8 months that the Research Community does not consider those to be validated studies, hasn't it? The WPI expected other labs to verify their findings - they didn't believe the question was closed because the NCI and Cleveland validated their efforts. They always knew other labs would need to verify their results.

This is why Dr. McClure was wrong about the CDC's three part validation. Yes it was good for both the WPI and the CDC to get backup verification but if the those labs are using the same samples then they aren't completely verifying their results. If the CDC stored the blood wrong then BSRI and the German aren't going to find the virus no matter how hard they look. Ditto in the opposite direction with the labs in the WPI study.
 
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Here is part of the discussion in the related editorial:
"Current Status of Xenotropic Murine Leukemia Virus–Related Retrovirus in Chronic Fatigue Syndrome and Prostate Cancer: Reach for a Scorecard, Not a Prescription Pad"

Mary Kearney and Frank Maldarelli
http://www.journals.uchicago.edu/doi/abs/10.1086/657169

Several factors may contribute to the varied detection of XMRV in different populations, including geographic distribution, patient selection, analyte choice (DNA, RNA, antigen), and detection methodology. Geography may play a pivotal role. Henrich et al [24] studied samples from immunodeficient patients who were well characterized at facilities in Boston and found no evidence of XMRV, whereas Lombardi et al [6] studied similarly affected patients from a distinctly different geographic region and found substantial rates of XMRV. Assay sensitivity and specificity may certainly affect detection. Reports of no XMRV detection, including the 2 in this issue of the Journal have superb sensitivity, generally in the range of 1–10 copies per cells or 10–100 copies/mL plasma. However, viremia may be chronically low (as it is in HTLV), transient, or episodic, complicating detection. XMRV detection is likely to be especially sensitive to potential false positive results by contamination with mouse‐derived material. Many of the hundreds of mouse endogenous retroviruses present in the mouse genome may amplify with XMRV primers; as such, a few copies of the mouse genome may represent a substantial source of contamination.

The new studies in the Journal highlight the following measures needed to resolve conflicting reports on detection of XMRV:
1.

Standardization of detection assays. This aspect is currently being addressed by a consortium of laboratories that will develop clear performance characteristics for testing.
2.

Prospective epidemiologic surveys. In response to the initial identification of XMRV in patients with prostate cancer, the search for XMRV infection was driven by a few clues and the availability of local sample sets. Such “molecular geocaching” is an entirely appropriate first response, but now larger, prospectively designed and appropriately powered epidemiologic studies with longitudinal sampling and standardized sample processing are in order. The data from existing studies, especially power analyses from Henrich et al [24] presented in this issue of the Journal, represent useful starting benchmarks.
3.

Sharing reagents and samples. Because XMRV has been reported in otherwise normal individuals, there are no a priori, gold standard XMRV‐positive or ‐negative populations. A working set of standards will require sharing samples among groups to independently confirm results. This painstaking process will yield a reference panel that would be an invaluable resource to the research community. Researchers have already contributed a number of XMRV molecular biology reagents for general use through the National Institutes of Health AIDS Research and Reference Reagent Program. The establishment of a reference panel will propel research in this field.
4.

Comprehensive and rigorous phylogenetic sequence analysis. Standard phylogenetic analyses established well described lineages for mouse viruses; adding all new sequences to a detailed phylogeny will yield useful observations [25].
5.

Development of tractable animal models, such as macaques [26], will be necessary to dissect XMRV pathogenesis.

Defining any XMRV disease association is a distinct and more challenging prospect. Over the past 40 years, a number of retroviruses have been discovered to be bona fide infections of humans (HTLV‐1–4, HIV‐1, HIV‐2, spumaviruses). Not all infections are associated with disease; no diseases have been unequivocally associated with infection with HTLV‐II or spumaviruses. The XMRV disease association will require “shoe leather” epidemiology, exhaustive molecular biology, and gimlet‐eyed statistical analysis to reach conclusions regarding etiology. As many virologists have long realized, disease association with retroviruses goes beyond traditional Koch’s postulates as benchmarks. As Rowe [27] summarized, Koch’s postulates assume an acute and persistent association of a readily detectable pathogen, criteria that poorly serve investigation of illnesses such as neoplasms and chronically debilitating diseases. The collective experience and utility of retroviruses for these studies [28] will provide invaluable support for XMRV investigations.

Reports of a viral agent in prostate cancer and chronic fatigue syndrome immediately established a new area of research. The XMRV field has strong magnetic properties, attracting basic researchers (particularly old time murine leukemia virus labs), clinicians, patients, and other interested parties to opposing poles regarding etiology, pathogenesis, and therapeutics. With accumulating publications, including those here, there are increasing discussions regarding possibilities for widespread testing and therapeutic intervention. XMRV may be detected using PCR or serologic techniques, and detection technologies are being made commercially available. None of the research or commercial assays has been exhaustively tested, and none is FDA approved. Further research is necessary before any of these tests can be used reliably; at this stage, discussions concerning blood donation deferral for patients with chronic fatigue syndrome are based on the general principle that there might be an infectious etiology, not on specific diagnostic testing. With respect to therapeutics, XMRV is sensitive to some antiretrovirals in vitro [11, 20, 29], and there are calls for use of antiretroviral agents for therapy, even though early observations suggest XMRV replication may be minimal in humans. At this time, such an approach is premature and medically indefensible outside the secure oversight of a well‐controlled clinical trial. “Real world” coping with severe diseases like chronic fatigue syndrome and prostate cancer creates understandable desperation on the part of patients, caregivers, and health care professionals. Such pressures are not justification for testing of therapies in an uncontrolled manner. Indeed, because they are of no help whatsoever to other patients, physicians, pharmaceutical companies, or regulatory agencies, such uncontrolled therapy works directly against the goal of providing effective therapy to the million or more individuals experiencing these serious conditions.
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Anyway, I will echo what I said in another thread. I just can't believe all these scientists don't want to find XMRV or are incompetent. There must be something else going on here. Still have high hopes about XMRV, but the negative studies just keep on piling...
Some groups however are clearly putting more effort into finding it than others - and there are a lot of reasons for this, from funding limitations, researcher biases (eg their PCR is sufficient) etc. The Kimata paper has some interesting discussion with regards to their own difficulties finding the virus.
 

Cort

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Does anyone have the full Tsibris paper? I was struck by this comment in an LA Times article

This week, a group led by Dr. Athe Tsibris of Harvard Medical School reported finding no evidence of XMRV in 32 chronic fatigue syndrome patients, 43 patients with HIV, 97 patients with rheumatoid arthritis, 26 patients who had organ transplants and 95 patients presenting for general care.

"We found nothing," Tsibris said in an interview Wednesday morning. "I would say that is the largest surprise for us. We could not detect XMRV in any sample."

Tsibris said his team replicated the techniques used by Mikovits and her team. "We did exactly what they described and more," he said.
 
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No association between XMRV and autism/prostate cancer (2 studies)

If we already have threads about these two studies please delete.


Mol Autism. 2010 Oct 14
PCR and serology find no association between xenotropic murine leukemia virus-related virus (XMRV) and autism.
Satterfield BC, Garcia RA, Gurrieri F, Schwartz CE.

Cooperative Diagnostics, LLC, Greenwood, SC 29646, USA. brent@codiagnostics.com.
Abstract
ABSTRACT: Xenotropic murine leukemia virus-related virus (XMRV) is a retrovirus implicated in prostate cancer and chronic fatigue syndrome (CFS). Press releases have suggested that it could contribute to autism spectrum disorder (ASD). In this study we used two PCR assays and one antibody assay to screen 25 blood samples from autistic children born to mothers with CFS and from 20 mixed controls including family members of the children assayed, people with fibromyalgia and people with chronic Lyme disease. Using a real-time PCR assay, we screened an additional 48 South Carolina autism disorder samples, 96 Italian ASD samples, 61 South Carolina ASD samples and 184 healthy controls. Despite having the ability to detect low copy number XMRV DNA in a large background of cellular DNA, none of the PCR assays found any evidence of XMRV infection in blood cells from patients or controls. Further, no anti-XMRV antibodies were detected, ruling out possible low level or abortive infections in blood or in other reservoirs. These results imply that XMRV is not associated with autism.

PMID: 20946639 [PubMed - in process]

__________________________________________________


XMRV: A New Virus in Prostate Cancer?
Aloia AL, Sfanos KS, Isaacs WB, Zheng Q, Maldarelli F, De Marzo AM, Rein A.

HIV Drug Resistance Program, National Cancer Institute.
Abstract
Several recent papers have reported the presence of a gammaretrovirus, termed "XMRV" (xenotropic murine leukemia virus-related virus) in prostate cancers (PCa). If confirmed, this could have enormous implications for the detection, prevention, and treatment of PCa. However, other papers report failure to detect XMRV in PCa. We tested nearly 800 PCa samples, using a combination of real-time PCR and immunohistochemistry (IHC). The PCR reactions were simultaneously monitored for amplification of a single-copy human gene, in order to confirm the quality of the sample DNA and its suitability for PCR. Controls demonstrated that the PCR assay could detect the XMRV in a single infected cell, even in the presence of a 10,000-fold excess of uninfected human cells. The IHC used two rabbit polyclonal antisera, each prepared against a purified MLV protein. Both antisera always stained XMRV-infected or -transfected cells, but never stained control cells. No evidence for XMRV in PCa was obtained in these experiments. We discuss possible explanations for the discrepancies in the results from different laboratories. It is possible that XMRV is not actually circulating in the human population; even if it is, the data do not seem to support a causal role for this virus in PCa.

PMID: 20966126 [PubMed - as supplied by publisher]
 

Bob

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Thanks for posting these studies Diesel...
It's interesting to note that they are both zero/zero studies...
I tend to ignore any zero/zero studies these days,
and I think the autism study is especially worthy to be ignored, as Judy Mikovits has already detected XMRV in people with autism, in families with ME.

XMRV: A New Virus in Prostate Cancer?
Aloia AL, Sfanos KS, Isaacs WB, Zheng Q, Maldarelli F, De Marzo AM, Rein A.

HIV Drug Resistance Program, National Cancer Institute.
Abstract

... It is possible that XMRV is not actually circulating in the human population ...
Or maybe it only isn't circulating in your assays due to an ineffectual methodology for reasons soon to be determined by the Blood Working Group!
 

Mark

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I'm pretty sure both of these studies have been posted and discussed before. The Co-operative Diagnostics one certainly has.

Like Bob says, 0/0 studies that fail to mention the possibility that their methodology just can't detect XMRV in blood, do nothing for me except undermine my trust in science and scientists in general. If they can't be honest and accurate in their own conclusions about their own study, and leap straight into wild speculation that is logically unfeasible given other researchers' findings, why should I trust anything else about what they say?
 

redo

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I find it strange that they don't even mention the possibility that their tests doesn't work. I mean, with all which is known about various methods and various results they should at least sqeeze in a sentance about it.
 

garcia

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I find it strange that they don't even mention the possibility that their tests doesn't work. I mean, with all which is known about various methods and various results they should at least sqeeze in a sentance about it.
That would be the honest scientific approach. To consider the very real possibility (some would say extreme likelihood) that their test is dud. Hopefully people are intelligent enough around here to realize that zero/zero means zero.
 

redo

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I am disappointed by that. Mildly put. Before I got ill, I had a great deal of trust into the medical community. But that's gone.

With this publication there are two places where it has gone wrong. First the authors ought to know that there were a possibility (even if they think it's small), and second the medical journal's reviewers should (in decency) point that out to the authors, giving them a chance to include it if they want.

I am not saying that it's impossible that they are right. That their test is showing of the infected ones. Perhaps it is. I am willing to leave that open. But I think it's unscientific for them to leave out the possibility that their tests aren't up to speed. And I think it shows lack of commitment to the case that they don't even bother to send some samples to labs where they have been able to separate healthy from ill (NIH, Harvey Alter or to the WPI). I mean, if they seek the truth, and believe that NIH/WPI are wrong, then why not send them blinded samples. That would clear up a lot of the controversy. But it seems to me that they aren't all that committed to the cause. If they were that should be an obvious and easy thing to do...
 

Bob

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I mean, if they seek the truth, and believe that NIH/WPI are wrong, then why not send them blinded samples.
Yes, it leaves us wondering if they are seeking the truth, or serving their own prejudices or their own careers.

I suppose it would look pretty stupid though, if they write on their own paper that they aren't very clever scientists and don't know how to detect the virus because they haven't developed or tested their methodology adequately!
 

Cort

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That's true but some papers do note areas they have not covered or leave the possibility open that some other test might find otherwise - they basically state the reasons their paper could be wrong. I really think that's considered smart science and good protocol. Not everybody engages in it obviously.

There is a wide variety of styles of writing. Some authors just press their points and ignore conflicting results from other groups. Others do a more professional job and try to sum up the state of the field on their topic - noting conflicting results. I'm surprised that doesn't happen more often actually.

Some papers are almost like press releases for their findings - which is dismaying really.
 

Sean

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As Richard Feynman said, in science you have to bend over backwards to make sure you have covered all the possibilities. The fact that many papers do not do this is very damning.