Rock Creek Pharmaceuticals Inc (fka RCPIQ)

[prov719]

TTT (TNFa-Targeted Therapies) and Breast Cancer. This is a must read:Origins and Actions of Tumor Necrosis Factor a in Postmenopausal Breast Cancer. Just out today. (NO MENTION OF VITAMIN C, although I won't dispute that Vitamin C has positive affects on the human body, it simply has nothing to do with Anatabine.)

It discusses TNFa relative to breast cancer and TNFa in general. It also discusses current TNFa targeted treatments and their side affects. If Anatabloc does not have these side affects, then it will be extremely desired by big pharma because I believe Anatabloc sets up a blockade of TNFa action without compromising its critical immune function. (someone correct me if I am wrong).

TNFa?...Remember this journal release....

Amelioration of Experimental Autoimmune Encephalomyelitis by Anatabine

http://www.plosone.org/article/info:doi/10.1371/journal.pone.0055392

A significant decrease in TNF-a (Mann-Whitney U = 22, Z = -3.622, P<0.001), IL-1ß (Mann-Whitney U = 9, Z = -4.19, P<0.001) and IL-17 (Mann-Whitney U = 55, Z = -1.976, P<0.05) was observed in the spleen of anatabine treated EAE mice compared to placebo EAE mice. (* P<0.05 for EAE placebo mice vs control non-immunized mice; ¤ P<0.05 for EAE placebo mice vs EAE anatabine treated mice).

It is all about allowing TNFa to do its normal job and keep NF-kB from protecting bad/rouge cells. If you do that WITHOUT WEAKENING THE IMMUNE SYSTEM RESPONSE, $$$$$....

Published today and available for a fee.... from

http://online.liebertpub.com/doi/abs/10.1089/jir.2012.0155?ai=skui=26eh2af=T#utm_source=ETOCutm_medium=emailutm_campaign=jir

Clinical Associations Between TNFa and Breast Cancer Risk
Advanced age and TNFa

Advanced age is a major risk factor in the development of breast cancer. Approximately 70% of postmenopausal cases are diagnosed as ER+ tumors, suggesting that processes within the postmenopausal endocrine system are altered as such that peripheral estrogens, particularly those in the breast, are being upregulated. Increased levels of plasma TNFa in older individuals may help to provide an explanation.
As well as being a critical pro-inflammatory immune cytokine, TNFa is also implicated in a number of disease pathologies. These include rheumatoid arthritis (Maini and Taylor 2000), inflammatory bowel disease (Bruin and others 1995), osteoporosis (Fujita and others 1990), and atherosclerosis (Fukuo and others 1997). Most of these conditions affect older individuals, suggesting that increasing concentrations of TNFa in those with advanced age contribute to common diseases associated with aging.[color=red][/color] Breast cancer could be one other such disease. Animal models were initially investigated to establish a link between aging and increasing TNFa levels. Aged mice and rats show a significantly increased secretion of cytokines from the T-helper cells of their immune systems, and this is likely to account for the increased peripheral estrogen synthesis also observed (Chorinchath and others 1996; Morin and others 1997). A number of studies have since examined this association in a large human cohort and uncovered similar associations between increasing age and higher levels of measured serum TNFa (Paolisso and others 1998).
Obesity and TNFa
In addition to advanced age, rates of breast cancer occurrence are significantly higher in obese women, with increased weight strongly associated with a higher risk of developing not only breast but many other forms of cancer (Basen-Engquist and Chang 2011). Obese breast cancer patients also show higher mortality rates, greater metastasis to distal sites, larger tumor mass, and overall poorer prognosis when compared to non-obese breast cancer patients (Maruthur and others 2009; Hauner and others 2011). Again, strong associations between TNFa and obesity may help to provide an explanation.
In addition to being produced by cells of the immune system, TNFa is also produced in adipose tissue, including mature adipocytes, stromal-vascular cells, and preadipocytes (Hube and others 1999; Weisberg and others 2003; Fain and others 2004). Initially shown in animal models (Hotamisligil and others 1993), TNFa levels are also markedly increased in the adipose tissue of obese individuals (Hotamisligil and others 1995). This has been shown clinically as obese patients record a higher serum concentration of TNFa than age-matched healthy weight individuals. This effect was decreased upon surgery-mediated weight loss (Hotamisligil and others 1995). TNFa may indeed be one of the driving forces behind obesity and insulin resistance, as mice lacking a functional TNFa protein or receptor are protected from diet-induced obesity and insulin resistance (Schreyer and others 1998; Nieto-Vazquez and others 2008). The mechanism resulting in increased TNFa production in states of obesity is, however, undefined, and this knowledge may help explain why obese individuals are at higher risk of breast cancer. It has been recently been shown that TNFa positively regulates its own transcription and secretion in adipose tissues, perhaps explaining how high levels of the cytokine are maintained in obesity (Neels and others 2006).
Significantly, adipose tissue is also the major site of estrogen conversion in postmenopausal women, highlighting a link between increased TNFa and estrogen production. The increased risk of developing breast-cancer in obese women may therefore not only be associated with the increased estrogen production from the higher volume of fat cells, but also with the increased production of TNFa which may further drive estrogen production. Studies in mice have shown that obesity is associated with increased aromatase activity and TNFa expression in the mammary gland (Subbaramaiah and others 2011), supporting this hypothesis.

The Potential for TNFa-Targeted Breast Cancer Therapies
Given its important role in many facets of breast cancer development, progression, and maintenance, TNFa represents an attractive yet challenging therapeutic target.

A review on the relationship of TNFa & NF-kB can be found here (it is very enlightening on whats going on at the nucleus level):

http://www.nature.com/onc/journal/v22/n13/full/1206262a.html

Tumor necrosis factor (TNF ) is a potent pro-inflammatory cytokine with important roles in control of immune and inflammatory responses as well as cell cycle proliferation and apoptosis (Tracey and Cerami, 1993). TNF stimulation can result in the activation of a caspase cascade leading to apoptosis (Chang and Yang, 2000), but more commonly causes activation of two major groups of transcription factors, activator protein-1 (AP-1) and nuclear factor B (NF- B) (Barnes, 1997; Karin et al., 1997). The genes induced by AP-1 and NF- B, such as IL-6, Rantes, 12-lipoxygenase, and IL-8, are involved in chronic and acute inflammatory responses, but some, such as cIAP2, Bcl-xL, and 14-3-3 , also act to suppress TNF -induced apoptosis (Leong and Karsan, 2000; Manos and Jones, 2001). These data are in accord with studies demonstrating that inhibition of NF- B potentiates the cytotoxicity of TNF . Transfection of several human tumor lines with a dominant-negative form of the NF- B inhibitor I B rendered them each more susceptible to the apoptotic effects of TNF (Van Antwerp et al., 1996; Wang et al., 1996). In addition, sulindac, an NSAID inhibitor of NF- B activation, was shown to enhance significantly TNF -mediated apoptosis of several lung cancer cell lines (Berman et al., 2002). Since a number of standard chemotherapy agents act like TNF to both promote apoptosis and activate NF- B, understanding the role of NF- B in suppressing apoptosis may have significant clinical applications.
TNF , an inflammatory cytokine with cytotoxic properties, acts like many standard chemotherapeutic agents to both promote apoptosis and activate the transcription factor NF- B. Since several studies have shown that inhibition of NF- B potentiates the cytotoxicity of TNF , understanding the mechanism by which NF- B carries out this function may be of clinical significance. If specific downstream targets of NF- B were identified that were critical for its antiapoptotic effects, specific chemotherapeutic agents that targeted these genes could be given in concert with standard agents for more effective induction of apoptosis in the tumor.
This was interesting:
Overall, the results obtained in this study are twofold. First, this study systematically screened TNF -induced genes using cDNA microarrays, and confirmed, using real-time PCR, 16 genes including three novel targets that are upregulated following TNF stimulation. A number of genes identified here agree with the results of a recent study examining TNF -induced genes in human vein endothelial cells (Murakami et al., 2000), including A20, B94, I B, and members of the GRO and interleukin families. Second, by using siRNA directed against p65, the dependence of these genes on the transcription factor NF- B after TNF induction was investigated. The results correlated well with the existence of NF- B binding sites in the promoter regions of these genes. As both pro- and antiapoptotic genes are regulated by NF- B, these studies demonstrate that targeting specific downstream genes of NF- B may be more effective than targeting NF- B itself for augmenting apoptosis in response to TNF .
Makes me wonder if Anatabloc works on several downstream genes or just NF-kB itself?

If the peer reviews that are forth coming do not show a statistically significant increase in the number of infections in the trial group, then Anatabloc is indeed a remarkable candidate for TNFa-Targeted Therapies. JMHO.

YES, I HAVE A LONG POSITION IN STSI…. Because I believe!!!! I also believe in Vitamin C :)