The NCF has identified an important cancer process that plays a critical role in CFIDS/ME. This process revolves around STAT1, a protein previously identified to be abnormal in CFIDS/ME patients. A research grant awarded to Donald Carrigan, Ph.D. and Konstance Knox, Ph.D., by the NCF, confirmed this abnormality and the scientists subsequently reported their findings at an AACFS/IACFS conference meeting in 2004 [1,2]. The NCF's STAT1 research had been based on a prior discovery made by Kenny DeMeirleir, M.D. [3,4]. In addition, the NCF had contacted Robert Suhadolnik, Ph.D., from Temple University, who conducted STAT1 lab tests on behalf of the NCF. Dr. Suhadolnik was able to provide additional confirmation of this abnormality from NIH blood samples obtained from patients who had been diagnosed with CFIDS/ME by NIH staff physicians [5].

Patients may recall that the NCF published an "Investigational Report" based on the role of STAT1 in patient blood samples back in 2003 [6,7]. Here was the brief synopsis from that report:

* STAT1 deficiency identified in CFIDS/ME patients

* p53 deficiency identified in CFIDS/ME patients

The scientific interpretation was as follows:

* Loss of STAT1 constitutes a serious illness that may ultimately be fatal because the cells are unresponsive to interferon leaving them unable to adequately defend against

infections.

* Loss of p53 constitutes a pre-malignant state because surveillance against DNA mutations, protein alterations, and unregulated cell growth/division are left unguarded.

* Loss of these proteins assists in immune deficiency and dysregulation

Thus, STAT1 negatively regulates cell proliferation and angiogenesis and thereby inhibits tumor formation. Consistent with its tumor suppressive properties, STAT1 and its downstream targets have been shown to be reduced in a variety of human tumors. As a result, STAT1 deficientmice are highly susceptible to tumor formation [8].

Now, new research has implicated STAT1 in the cancer process [9]. In this report, Joan Durbin, Ph.D. and colleagues provide direct evidence for STAT1 in Ras oncogenicity. This finding is of critical importance because the Ras oncogene is implicated in 30% of all human cancers [10].

What is Ras you might ask? In molecular biology, Ras is the name of a protein, the gene that encodes it, and the family and superfamily of proteins to which it belongs. The Ras oncogene is a signal transduction protein, which means that it communicates signals from outside the cell to the nucleus. Sometimes a DNA mutation turns the signal permanently on, which leads to unlimited cell growth and ultimately to cancer [11].

How does Ras do this? Ras proteins function as binary molecular switches that control intracellular signaling networks. Ras-regulated signal pathways control such processes as actin cytoskeletal integrity, proliferation, differentiation, cell adhesion, apoptosis, and cell migration.Ras and Ras-related proteins are often deregulated in cancers. This dysregulation leads to decreased cell apoptosis along with increased cell invasion and metastasis.

The Ras genes were first identified as the transforming oncogenes, responsible for the cancer-causing activities of the Harvey (the HRas oncogene) and Kirsten (KRas) sarcoma viruses, by Edward M. Scolnick and colleagues at the National Institutes of Health (NIH). These viruses were discovered originally in rats during the 1960's by Jennifer Harvey and Werner Kirsten, respectively. In 1982, activated and transforming human Ras genes were discovered in human cancer cells by Geoffrey M. Cooper at Harvard, Mariano Barbacid and Stuart A. Aaronson at the NIH and by Robert A.Weinberg of MIT. Subsequent studies identified a third human Ras gene, designated NRas, for its initial identification in human neuroblastoma cells [12].

Dr. Durbin had first been contacted by the NCF in 2003 because she was a world expert on STAT1. In fact, she helped to create the animal model for STAT1 deficiencies [13]. Fortunately for the NCF, she suggested a new research direction for our grant program to pursue and this subsequently led to the NCF's funding of Knox and Carrigan's STAT1 research in CFIDS/ME.

The finding of Ras involvement in CFIDS/ME provides yet another important step in our understanding of why some patients may develop cancer during this disease process. Ras oncogenicity would perhaps provide credence to earlier investigations as to whether or not CFIDS/ME was a prelude to cancer [14].

Fortunately for the NCF, we already have gained valuable experience working with various Ras-based inhibitors both in-vitro and in-vivo thanks to the kind assistance from several forward-thinking scientific groups from around the globe.

As 2008 comes to a close, the NCF continues to be highly optimistic as we move selective medical research forward towards appropriate CFIDS/ME therapies that will be based on sound medical science. To date, the NCF has provided scientists over $600,000 to fund very selective CFIDS/ME research. With continued support and donations from the patient community, the NCF will "stay the course" to complete its medical mission to greatly impact patient lives worldwide.

References:

1. Potential Role of STAT1 in the Pathogenesis of Chronic Fatigue

Syndrome; Knox KK,

Carrigan DR; NCF Research Grant, awarded 2003

2. Deficiency in the Expression of STAT1 Protein in a Subpopulation of

Patients with Chronic

Fatigue Syndrome (CFS); Knox KK, Cocchetto A, Jordan E, Leech D,

Carrigan DR; AACFS/

IACFS Conference, 2004

3. Chronic Fatigue Syndrome: A Biological Approach; Englebienne P,

DeMeirleir K; CRC

Press, 2002

4. US Patent Application # 20030077674; published April 24, 2003; filed

June 17, 2002;

titled Methods for diagnosis and treatment of chronic immune

diseases; Inventors:

Fremont M, Englebienne P, Herst CVT

5. NCF Personal Communications; Suhadolnik R, 2003

6. Part One - Unmasked Research: STAT1-alpha and p53 Deficiencies are

Found in Patients

with Chronic Fatigue Syndrome; The National CFIDS Foundation

Responds by Funding

Several New Research Initiatives; 2003

7. Part Two - Total Exposure: Expanded Model for RNase L Fragmentation

in CFS Uncovered;

The National CFIDS Foundation Announces the Use of Elastase

Inhibitors as a Potential

Treatment for CFS Patients; 2003

8. Signal transducers and activators of transcription (STATs): Novel

targets of chemopreventive

and chemotherapeutic drugs; Klampfer L; Curr Cancer Drug Targets,

Mar 6(2):107-21, 2006

9. Stat1 phosphorylation determines Ras oncogenicity by regulating p27

kip1; Wang S, Raven

JF, Durbin JE, Koromilas AE; PLoS ONE. 3(10):e3476. Epub 2008 Oct

22, 2008

10. Somatic activation of the K-ras oncogene causes early onset lung

cancer in mice; Johnson L,

Mercer K, Greenbaum D, Bronson RT, Crowley D, Tuveson DA, Jacks

T; Nature Apr

26;410(6832):1111-6; 2001

11. The molecular perspective: the ras oncogene; Goodsell DS;

Oncologist 4(3):263-4; 1999

12. Wikipedia; http://en.wikipedia.org/wiki/Ras_oncogene

13. Targeted disruption of the mouse STAT1 gene results in compromised

innate immunity to

viral disease; Durbin JE, Hackenmiller R, Simon MC, Levy DE; Cell

84(3): 443-450; 1996

14. Cancer and a fatiguing illness in Northern Nevada--a causal

hypothesis; Levine PH, Fears

TR, Cummings P, Hoover RN; Ann Epidemiol. May;8(4):245-9; 1998