Showing posts with label epigenetics. Show all posts
Showing posts with label epigenetics. Show all posts
Sunday, June 16, 2013
Regarding changing genes: this is what I do, in induced pluripotent stem
cells by gene targeting/genome editing, but all this is not, and will
not be for a while, available for human clinical treatments. Concerning
epigenetics: yes there are some studies on nutrition and epigentics but
I am not that sure how would these apply to your case. In general
epigenetics is a more an in vitro dicipline connected to chromatin
modification analysis and whole organisms in vivo studies on epigenetics
are not the rule.
expression of SPP1 is regulated epigenetically in GISTs, and high expression of SPP1 is a novel and independent prognostic parameter in GISTs.
My understanding is the expression of SPP1 is regulated epigenetically in GISTs, and high expression of SPP1 is a novel and independent prognostic parameter in GISTs.
Epigenetic regulation of Secreted Phosphoprotein 1 (SPP1) expression was analysed at mRNA and protein levels in GIST882 and GIST48b cells after treatment with a demethylating agent. Impacts on tumorigenesis-related signalling pathways were analysed by Western Blot after stimulation of GIST cell lines with SPP1.
Conclusion
The expression of SPP1 is regulated epigenetically in GISTs, and high expression of SPP1 is a novel and independent prognostic parameter in GISTs.
http://c953383.r83.cf2.rackcdn.com/file_attachment/attachments/8876/originalcfd8084a371c346654a98fd5c586daaf.html?1330573778
http://www.wikigenes.org/e/gene/e/6696.html
RELATION WITH MERCURY? Unknown.
BREAST CANCER LINK.
Moreover, Spp1 expression correlates with disease prognosis for numerous cancers including breast cancer where it is associated with disease progression and metastasis.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2665764/
. http://en.wikipedia.org/wiki/Osteopontin#Potential_clinical_application "The fact that OPN interacts with multiple cell surface receptors which are ubiquitously expressed makes it an active player in many physiological and pathological processes including wound healing, bone turnover, tumorigenesis, inflammation, ischemia and immune responses1. Therefore, manipulation of plasma OPN levels may be useful in the treatment of autoimmune diseases, cancer metastasis, osteoporosis and some forms of stress.[2]"
Ssecreted phosphoprotein 1 (SPP1) OR Osteopontin (OPN), also known as bone sialoprotein I (BSP-1 or BNSP), early T-lymphocyte activation (ETA-1), secreted phosphoprotein 1 (SPP1), 2ar and Rickettsia resistance (Ric), is a human gene product,[1] which is also conserved in other species. Osteopontin is a SIBLING glycoprotein that was first identified in 1986 in osteoblasts.
Potential clinical application
The fact that OPN interacts with multiple cell surface receptors which are ubiquitously expressed makes it an active player in many physiological and pathological processes including wound healing, bone turnover, tumorigenesis, inflammation, ischemia and immune responses1. Therefore, manipulation of plasma OPN levels may be useful in the treatment of autoimmune diseases, cancer metastasis, osteoporosis and some forms of stress.[2]Role in autoimmune diseases
OPN has been implicated in pathogenesis of rheumatoid arthritis. For instance, researchers found that OPN-R, the thrombin-cleaved form of OPN, was elevated in the rheumatoid arthritis joint. However, the role of OPN in rheumatoid arthritis is still unclear. One group found that OPN knock-out mice were protected against arthritis.[47] while others were not able to reproduce this observation.[48] OPN has been found to play a role in other autoimmune diseases including autoimmune hepatitis, allergic airway disease, and multiple sclerosis.[49]Role in cancers and inflammatory diseases
It has been shown that OPN drives IL-17 production;[50] OPN is overexpressed in a variety of cancers, including lung cancer, breast cancer, colorectal cancer, stomach cancer, ovarian cancer, papillary thyroid carcinoma, melanoma and pleural mesothelioma; OPN contributes both glomerulonephritis and tubulointerstitial nephritis; and OPN is found in atheromatous plaques within arteries. Thus, manipulation of plasma OPN levels may be useful in the treatment of autoimmune diseases, cancer metastasis, osteoporosis and some forms of stress.[2]Research has implicated osteopontin in excessive scar-forming and a gel has been developed to inhibit its effect.[51]
Role in allergy and asthma
Osteopontin has recently been associated with allergic inflammation and asthma. Using a murine model of allergic inflammation, it was demonstrated that OPN-s, the secreted form of OPN, exerts opposing effects on mouse Th2 effector responses and subsequent allergic airway disease: pro-inflammatory at primary systemic sensitization, and anti-inflammatory during secondary pulmonary antigenic challenge, mainly through the regulation of different dendritic cell subsets.[52] OPN deficiency was also reported to protect against remodeling and bronchial hyperresponsiveness (BHR), again using a chronic allergen-challenge model of airway remodeling.[53] Furthermore, it was recently demonstrated that OPN expression is upregulated in human asthma, is associated with remodeling changes and its subepithelial expression correlates to disease severity.[54] OPN has also been reported to be increased in the sputum supernatant of smoking asthmatics,[55] as well as the BALF and bronchial tissue of smoking controls and asthmatics.[56]Role in muscle disease and injury
Evidence is accumulating that suggests that osteopontin plays a number of roles in diseases of skeletal muscle, such as Duchenne muscular dystrophy. Osteopontin has been described as a component of the inflammatory environment of dystrophic and injured muscles,[22][57][58][59] and has also been shown to increase scarring of diaphragm muscles of aged dystrophic mice.[60] A recent study has identified osteopontin as a determinant of disease severity in patients with Duchenne muscular dystrophy.[61] This study found that a mutation in the osteopontin gene promoter, known to cause low levels of osteopontin expression, is associated with a decrease in age to loss of ambulation and muscle strength in patients with Duchenne muscular dystrophy.MANIPULATION OF OSTEOPONTIN/SPP1
The Dietary Supplement Protandim® Decreases Plasma Osteopontin and Improves Markers of Oxidative Stress in Muscular Dystrophy Mdx Mice
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2926985/
The nutritional supplement Protandim® has been shown to reduce plasma TBARS by approximately 40% in healthy human subjects after 4 months of treatment, with significant inductions of the antioxidant enzymes superoxide dismutase and catalase
Our data demonstrate a remarkably similar finding in mdx mice with a reduction in plasma TBARS of approximately 48% after 6 months of treatment. Our plasma TBARS result suggests that induction of antioxidant enzymes by a combination of phytochemicals reduces oxidative stress in mdx mice.
- which is nearly equivalent to the manufacturers recommended human dose of 675 mg per day for a 60 kg adult, or 422 mg/m2.
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Abstract
Osteopontin (OPN) is a secreted, integrin-binding matrix phosphorylated glycoprotein that is overexpressed in many advanced cancers. However, the functional mechanisms by which OPN contributes to gastric cancer development are poorly understood. Here, we report that curcumin inhibited the growth of SGC7901 cell and induced apoptosis in a concentration- and time-dependent manner, while the acquired expression of OPN in SGC7901 cells dramatically promoted cell survival under serum depletion and prevented curcumin-induced apoptosis. Furthermore, PI3-K inhibitor LY294002 attenuated OPN-mediated Akt activation. Moreover, inhibiting the binding of OPN to αvβ3 integrins reduced activation of Akt. Taken together, these results demonstrate that the pro-survival and anti-apoptosis activities of OPN in gastric cancer cells are mediated in part through PI3-K/Akt pathway via αvβ3 integrins.
Therapeutic effects of epigallocatechin gallate on streptozotocin-induced diabetic nephropathy in mice.
http://www.krcp-ksn.com/article/S2211-9132%2812%2900472-X/abstract
Diabetic nephropathy is one of the most serious complications in diabetes mellitus and has been the most common cause of end-stage renal disease. Green tea extracts have antioxidant properties, and (-)-epigallocatechin 3-O-gallate (EGCG) is known to be the most abundant in green tea. Osteopontin (OPN) is a large phosphoglycoprotein adhesion molecule, and has emerged as a potentially key pathophysiologic contributor in diabetic nephropathy. We examined whether EGCG could amelliorate the development of diabetic nephropathy and its role of OPN. The mice (n=28) were divided into 3 groups. Control group (n=7) was intraperitoneal (IP) injected 0.9% saline, Streptozotocin (STZ) group (n=7) was IP injected STZ 200
mg/Kg and induced diabetic nephropathy. After a 8weeks, EGCG groups (n=7/each group) were received EGCG 50mg/kg and 100mg/kg
body weight by subcutaneous injection. Serum glucose, blood urea
nitrogen, serum creatinine, urine volume and urine protein amounts were
measured. Western blot assay of OPN was compared for the different
groups. Histopathologic examination and immunohistochemical staining of
mice kidney were performed. Compared with control group, STZ-group
showed an increase in blood glucose, blood urea nitrogen, creatinine
levels and urine protein amounts, and a decrease in body weight. All the
above parameters were significantly reversed with EGCG treatment. After
STZ injection, there were an diabetic glomerulosclerosis with increased
renal OPN accumulation and its protein expression in the kidney cortex.
EGCG-treated mice kidney showed a reduced expression of above
parameters and an reserved pathologic findings. These results suggest
that EGCG ameliorates STZ-induced diabetic nephropathy by OPN
suppression. The potential use of EGCG in the treatment of diabetic
nephropathy should be further explored.
Hello, I'm new here. Doctors found a partially calcified 6cm GIST outside of the stomach. What causes this?
- Erin Parker likes this.
Beverly Shirts Surgery is your best bet for a cure. Here is some good information for you. I'm running out now but will check with you later. http://www.gistsupport.org/for-new-gist-patients.php If you only have one tumor and it's removed completely, you may not need chemo drugs at all.
www.gistsupport.org
Newly diagnosed GIST patients learn here what to ask your doctor, about pathology reports and tissue samples, finding good care for GIST cancer.
Brown Rice Thanks. From the site: "Random genetic mutations are the apparent cause of GISTs." I doubt surgery cures genetic mutations. If you remove it, won't it simply return if the cause isn't addressed? What causes those mutations in the first place?
Cathy Freeman I've been down this road and am still in the midsts of all the information . . . Do you have a genetic mutation. Mine is SDHB and the meds to date aren't known to be effective on SDHB mutations. I'm going to the NCI in a few weeks for their annual Pediatric Gist Clinic as well as a Paraganglioma Clinic which is the rare tumors my father and aunt died of (and what I inherited). I'll be talking to head doctors but from my knowledge to date surgery is my best option. I had 1/3rd of my stomach removed 5 years ago and 2/3rds of my liver last year (which grew back). The next set of tumors, for me, could appear anywhere in the torso or head. I don't think in my case there is a medication that has proven itself thus I take it one day at a time with some emotional issues hanging around the curtain edges. My genetic mutation wasn't random. It was inherited from my father and his sister also had it (all the children in his family and his sister didn't have chlldren). For me surgery was my best bet and gave me a few years between tumors.- Beverly Shirts Mine has never returned, and I've never been on Gleevec or any other drug. 12 1/2 cm stomach primary tumor, 5 per 50 mitotic rate. My only surgery was in August of 2000.
Michele Arsenault I honestly can't think of anyone who has not treated their GIST (or any other cancer) without surgery, medication or a combination of both sucessfully.
- Brown Rice Help me understand the cause: Tumors are caused by genetic mutations, which is different than DNA damage. Is that correct? What causes these random or inherited mutations? And shouldn't DNA repair genes have the ability to correct mutations and maintain genomic integrity?
- Beverly Shirts Mandi Lobisser I'm at yearly scans right now, but mostly to monitor two other issues, completely non GIST related. I'm deciding now about continuing them. Brown Rice no one knows what causes most cancers. Please check on our site for all of the genetic "what causes this" science information, written by scientists who explain it well. I'll also put out the bat signal for Marina Symcox, a PhD in such things, and a GIST patient as well. She's in Oklahoma though, so I am not sure if she has power. Start here and follow the links. You can also type in search words, such as "causes" or "mutations" etc. on that site to bring up more info. http://www.gistsupport.org/for-new-gist-patients.php If your tumor is smallish, and yours is, and the mutation rate is low, surgery has a very good chance of curing you. Where are you being seen?
www.gistsupport.org
Newly diagnosed GIST patients learn here what to ask your doctor, about pathology reports and tissue samples, finding good care for GIST cancer. - Brown Rice Beverly Shirts thanks, but I couldn't find it on that site. But I found on genetics.Utah.edu that genetic mutations are caused by chemicals, radiation, and errors when the DNA is replicated. The cause of these errors are caused by DNA damage during cell division. Basically, it comes down to DNA damage? If so, what would repair DNA damage and correct mutations? I'd love to hear from Marina Symcox !
- Beverly Shirts She will check in. http://www.gistsupport.org/about-gist/what-is-gist.php?searchresult=1&sstring=what+causes+gist%3F#wb_98 I just typed in "what causes GIST?" on our site and SEVERAL links came up. This is one.
www.gistsupport.org
Gastrointestinal stromal tumor (GIST) is a very rare cancer affecting the digest...See More - Beverly Shirts There is much more at that link, but here is one part. What causes GIST?
There are no known environmental or behavioral risk factors contributing to GIST. Therefore, patients should not worry that their diet or lifestyle choices contributed to GIST. Random genetic mutations are the apparent cause of GISTs. The majority of GISTs show identified mutations in cell-surface proteins called tyrosine kinase receptors. These mutations are discussed further in the pages on Diagnosis and Pathology Results as well as Mutation Analysis. Most GISTs show mutations in a gene that produces a growth factor receptor called KIT. A few GISTs show mutations in the gene for a closely related receptor for platelet derived growth factor receptor alpha (PDGFR a or PDGFRA). A few GISTs are normal or “wildtype” for both these genes, and the causal mutations or these GISTs have not been identified. Almost all GISTs are sporadic, meaning that the mutations are random occurrences affecting a single individual. However, there are rare examples of GIST running in families due to an inheritable germline mutation (see Familial GIST page). In addition, people affected by neurofibromatosis type 1 (NF1) have an increased chance of developing GIST (see our page GIST in NF1). - Brown Rice Yeah, that's what I found earlier and quoted from the site: "Random genetic mutations are the apparent cause of GISTs. " but no information on what causes genetic mutations, specifically.
- Beverly Shirts This is a good fact sheet. http://www.genetics.edu.au/Information/Genetics-Fact-Sheets/Changes-to-the-Genetic-Code-FS4
- Brown Rice Thanks! I also found this helpful http://learn.genetics.utah.edu/archive/sloozeworm/mutationbg.html and http://en.wikipedia.org/wiki/Mutation#Harmful_mutations
learn.genetics.utah.edu
Ultraviolet light, nuclear radiation, and certain chemicals can damage DNA by altering nucleotide bases so that they look like other nucleotide bases. - Beverly Shirts It's kind of a s*** happens thing really. What causes gene mutations?
Chemicals and radiation can damage genes. However, most mutations occur when the cell makes errors as it copies its genes. Ge...See More
- Brown Rice "A DNA damage can cause an error when the DNA is replicated, and this error of replication can cause a gene mutation that, in turn, could cause a genetic disorder. DNA damages are repaired by the DNA repair system of the cell.
Because DNA can be damaged in many ways, the process of DNA repair is an important way in which the body protects itself from disease.' http://en.wikipedia.org/wiki/Mutation#Harmful_mutations
en.wikipedia.org
Changes in DNA caused by mutation can cause errors in protein sequence, creating partially or completely non-functional proteins. Each cell, in order to function correctly, depends on thousands of proteins to function in the right places at the right times. When a mutation alters a protein that play... - Brown Rice Is it caused by an impaired DNA repair system?
In my case, 'chemicals/radiation' exposure, would probably be the main cause of DNA damage. I was tested with high mercury and arsenic levels. - Brown Rice Please correct me if I'm wrong. So in conclusion, GIST is caused by random or inherited genetic mutations caused by errors in DNA replication from DNA damage either by radiation, chemicals, or "many other factors" that should be repaired by our DNA repair system, unless that system is also damaged.
- Beverly Shirts I'll leave it for Marina Symcox, she is wonderful at explaining complicated science in understandable terms. As the first sentence says on our site, no known cause exists for GIST. As it says on those pages above and on our site, it's random, and most are born with some kind of defect, and defects are also the way species evolve. Radiation and chemical exposure, as far as I know, has no known correlation to GIST.
- Beverly Shirts You may find something here as well. http://gistsupport.medshelf.org/Marina_Sez
gistsupport.medshelf.org
Marina Symcox, PhD is a born teacher. Trained in biochemistry, she turned her co...See More - Beverly Shirts http://gistsupport.medshelf.org/Marina_Continues..Born_With_or_Acquiring_Mutations
gistsupport.medshelf.org
We can categorize cancer causing defects into two categories: 1) Broken brakes o...See More - Brown Rice That's a bit more helpful, but still doesn't explain what causes these mutations? And what is the role of epigenetics in turning on or silencing these mutations? "The genome dynamically responds to the environment. Stress, diet, behavior, toxins and other factors activate chemical switches that regulate gene expression." http://learn.genetics.utah.edu/content/epigenetics/
Marina Symcox Tumors can partially calcify. Laying down calcium deposits is the way the body sequesters off dead tissue. Even growing tumors may develop dead zones that show signs of calicification. A tumor that has been treated well with Gleevec may show much calcification over the course of years as the tumor remains under control.- Marina Symcox DNA damage can lead to mutations, just like stumbling around with your fingers on a keyboard can lead to typographical errors. While the cells have mechanisms to repair damaged DNA, sometimes the repair does not happen, and at some point both strands of the DNA are compatible with the change, and it becomes heritable to all the daughter cells. The mutations in GIST are not usually heritable, and are not passed down through a family. Instead they are accidental mishaps in one cell, and all of the daughter cells from that one cell will carry the mutation. The rest of the cells in the body will not have that mutation. Very rarely there are heritable mutations in GIST (egg and sperm carry them and all the cells in the body have the mutation.) This is extremely rare, only a handful of families in the entire world have heritable GIST.
- Marina Symcox You will never know what caused the mutation that lead to your GIST. While we can blame toxins in the enviroment, the oxygen that we breathe to live also has the capacity to damage DNA. The role of epigenetics in cancer is important, but not as well delineated as the role of DNA mutations. The GIST that forms in young women seems to be driven not by mutations but by epigenetic siliencing of key genes. For now, adult GIST is mostly considered in terms of mutations and not epigenetics, but epigenetics has a role in all types of cancer.
- Brown Rice Thanks Marina Symcox! Can you expand on this statement: "The GIST that forms in young women seems to be driven not by mutations but by epigenetic siliencing of key genes. " What key genes are silenced and where are the studies on this? I see a study here for example on how certain epigenetic changes predict GIST behavior http://meeting.ascopubs.org/cgi/content/abstract/24/18_suppl/9542
meeting.ascopubs.org
Instituto Nacional de Cancer, Rio de Janeiro, Brazil; Consultoria em Patologia, Botucatu, Brazil; Novartis Oncology, São Paulo, Brazil - Brown Rice Given that epigenetic changes predict GIST behaviour, does that mean that they can be 'turned off' or 'turned on'? My understanding of epigenetics is 'harmful' mutations (whatever the cause may be -environmental toxins or oxygen) can be silenced or activated by histone inhibitors for example, is that correct?
"Inappropriate epigenetic activity plays a significant role in cancer development but, unlike DNA mutations, which are permanent, epigenetic changes can be reversed. This means that it may be possible to find a way to regulate inappropriate epigenetic activity or to get a gene that is inappropriately expressed due to epigenetic changes to begin functioning normally again. The team is using a combination of two drugs (a DNA-demethylating agent, and a histone deacetylase inhibitor) to reverse the epigenetic modifications that inappropriately turned genes on or off in cancer cells. " http://www.aacr.org/home/public--media/stand-up-to-cancer/su2c-dream-teams/bringing-epigenetic-therapy-to-the-forefront-of-cancer-management.aspx
I understand that histone deacetylase inhibitors has been used as a therapeutic strategy for GISTs.
http://carcin.oxfordjournals.org/content/33/9/1674.abstract
www.aacr.org
Researchers have discovered that there are additional layers of material outside...See More - Marina Symcox While there are drugs that can affect the epigenetic or gene silencing aspect of DNA, these drugs are not specific for what is wrong in your GIST. HDACi are a class of such drugs.
- Brown Rice Marina Symcox What I'm trying to understand is can the genes involved GIST be silenced or activated? You mentioned earlier that "The GIST that forms in young women seems to be driven not by mutations but by epigenetic siliencing of key gene." Does that mean they can be 'turned on/off' in epigenetic terms? Sorry for all the questions, I appreciate this dialogue and it has helped me gain a better understanding.
- Marina Symcox I don't think there are any drugs that offer a fine level of control for turning off or on aspecific "GIST genes." GIST that develops in young females primarily involves a loss of function of the succinate dehydrogenase gene, and it seems that a build up of the metabolic products caused by this defect will impact the proteins that regulate the methylation level of DNA...so over time the cells have too much gene silencing of tumor suppressor genes.
- Brown Rice Hi Marina Symcox, I contacted Dr Kondo, a Japanese researcher who conducted, for the first time, genome-wide DNA methylation analysis in GISTs. Their extensive analyses revealed that DNA methylation accumulates on a genome-wide basis during tumor progression. He explains that: "KIT or PDGFRA mutations may initiate the start of GIST. Epigenetic changes, which sometimes may be affected by environmental factors, could activate the KIT or PDGFRA mutated cells to be more aggressive GISTs. " http://gut.bmj.com/content/early/2011/06/26/gut.2011.241034.abstractgut.bmj.comFrom trainee to consultant, BMJ Group offers doctors around the world tailored i...See More
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