Medical, 'Hi-JAK-ing' Cancer

'Hi-JAK-ing' Cancer

Author	Message
ironjustic #1 / 8	'Hi-JAK-ing' Cancer Paper highlight: 'Hi-JAK-ing' cancer by inhibiting Jak2 September 13, 2010 Myeloproliferative neoplasms (MPN) comprise a family of {filter} cancers characterized by clonal expansion of a single {filter} cell type. Untreated, these cancers can progress to bone marrow failure and acute myeloid leukemia. Several groups have identified activating mutations in the JAK2 gene as associated with MPN; JAK2 inhibition has therefore emerged as approach to MPN therapy. Thus far, however, JAK2 inhibition strategies have had limited efficacy and have been accompanied by significant toxicity. In this paper, Ross Levine and his group at the Memorial Sloane Kettering Cancer Center, New York, describe an indirect approach to reducing JAK2 activity by pharmacologically targeting HSP90, a protein that stabilizes JAK2. Inhibiting HSP90 normalized {filter} counts and improved survival in two mouse models of MPN, and the treatment promoted JAK2 degradation in samples from MPN patients. The authors believe that targeting HSP90, perhaps in combination with JAK2 inhibition, may be the way forward in the treatment of patients with MPN. More information: HSP90 is a therapeutic target in JAK2-dependent myeloproliferative neoplasms in mice and humans: http://www.**.com/ 4ce9ffed3af0 Provided by Journal of Clinical Investigation -------------------- Resveratrol induces apoptosis in K562 (chronic myelogenous leukemia) cells by targeting a key survival protein, heat shock protein 70 Authors: Chakraborty, Prabir K.1; Mustafi, Soumyajit Banerjee1; Ganguly, Sudipto2; Chatterjee, Mitali2; Raha, Sanghamitra Source: Cancer Science, Volume 99, Number 6, June 2008 , pp. 1109-1116(8) Publisher: Blackwell Publishing Abstract: Chronic myelogenous leukemia (CML) is a myeloproliferative disease associated with a characteristic chromosomal translocation called the Philadelphia chromosome. This results in the expression of the Bcr-Abl fusion protein, a constitutively active protein tyrosine kinase. Although there are a few treatment options with Bcr-Abl kinase inhibitors, drug resistance is often encountered. One of the major obstacles in overcoming drug resistance in CML is the high endogenous levels of heat shock protein 70 (Hsp70). Resveratrol is a phytoalexin produced by several plants. We studied the chemotherapeutic effects and mode of action of resveratrol on K562 (CML) cells. Resveratrol induced apoptosis in K562 cells in a time-dependent manner. This was established by increased annexin V binding, corroborated with an enhanced caspase-3 activity and a rise in the sub-G0/G1 population. Resveratrol treatment also caused suppression of Hsp70 both in mRNA and protein levels. The downregulation of Hsp70 by resveratrol exposure was correlated with a diminished presence of heat shock factor 1 (HSF1) in the nucleus, and the downregulation of transcriptional activity of HSF1. High endogenous levels of Hsp70 have been found to be a deterrent for sensitivity to chemotherapy. We show here that resveratrol could considerably enhance the apoptosis induction in K562 cells by 17-allylamino-17-demethoxygeldanamycin, an anticancer agent that inhibits Hsp90 but augments Hsp70 levels. We conclude that resveratrol significantly downregulated Hsp70 levels through inhibition of HSF1 transcriptional activity and appreciably augmented the pro-apoptotic effects of 17-allylamino-17- demethoxygeldanamycin. (Cancer Sci 2008; 99: 1109-1116) Document Type: Research article DOI: 10.1111/j.1349-7006.2008.00809.x Affiliations: 1: Crystallography and Molecular Biology Division, Saha Institute of Nuclear Physics, 1/AF Bidhan Nagar, Kolkata-700064; 2: Department of Pharmacology, Institute of Post Graduate Medical Education and Research, 244B Acharya JC Bose Road, Kolkata-700020, India ----------------- Researchers Show Resveratrol Works In The Brain By Metal Chelating Effects Researchers now convincingly show that, via its iron-chelating effects, resveratrol is able to cross barriers that protect the brain from entry of toxins ({filter}/brain barrier) and reduce oxidation (spoilage) of fats and increase the activity of protective antioxidant enzymes in the brain of healthy rodents. The research has application for age-related brain disorders such as Alzheimer's and Parkinson's disease. Resveratrol decreased malondialdehyde (an end product of oxidation of fats) in brain tissues by -300%. Doses ranging (in human equivalents) from 87.5 to 875 milligrams were effective in this regard. Higher doses were not more effective. Resveratrol also significantly increased the activity of antioxidant enzymes superoxide di{filter}ase, catalase and peroxidase by 160%, 270% and 210% (see above chart). The forms of most of these protective enzymes were iron-controlling proteins, confirming that resveratrol's primary action is via its ability to control metallic metals. Loose (free) iron causes tissue damage in all forms of age-related brain disease. While a relatively high dose of resveratrol was shown to be most effective (875 milligrams human equivalent dose), this was only a 7-day study. It is expected that a life-long accumulation of iron in brain tissues will require a high loading dose and a lower maintenance dose. The current fad of ultra-high dose resveratrol supplementation may be beneficial initially, but lead to anemias over longer term use. -Resveratrol News April 2007 http://www..com/ Who loves ya. Tom Jesus Was A Vegetarian! http://www..com/ Man Is A Herbivore! http://www..com/ DEAD PEOPLE WALKING http://www.*.com/
Sat, 02 Mar 2013 20:54:09 GMT

#2 / 8	'Hi-JAK-ing' Cancer
Fri, 19 Jun 1992 00:00:00 GMT

Ken #3 / 8	'Hi-JAK-ing' Cancer No one cares Rusty ya half-witted Canuck Spammer
Sat, 02 Mar 2013 23:15:13 GMT

#4 / 8	'Hi-JAK-ing' Cancer
Fri, 19 Jun 1992 00:00:00 GMT

ironjustic #5 / 8	'Hi-JAK-ing' Cancer Paper highlight: 'Hi-JAK-ing' cancer by inhibiting Jak2 << "The drug worked whether they had the mutation or not" "Can lead to low {filter} counts" "Main side effect is lowered {filter} cell counts in some patients" JAK inhibitor provides rapid, durable relief for myelofibrosis patients September 15, 2010 An {filter}medication produces significant and lasting relief for patients with myelofibrosis, a debilitating and lethal bone marrow disorder, researchers at The University of Texas MD Anderson Cancer Center report in the Sept. 16 New England Journal of Medicine. Myelofibrosis is caused by the accumulation of malignant bone marrow cells that trigger an inflammatory response, scarring the bone marrow and limiting its ability to produce {filter}, causing anemia. "The problem with myelofibrosis is the lack of available therapies for patients - there are none approved for this disease today," said principal investigator Srdan Verstovsek, M.D., Ph.D., associate professor in M. D. Anderson's Department of Leukemia. Average life expectancy for people with this disease is 5 to 7 years. Available therapies approved for other diseases provide little response and are mainly palliative. "This experimental drug is the first to target one of the underlying abnormalities in the malignant cells that cause myelofibrosis," Verstovsek said. "It provides unprecedented reduction of enlarged spleens that are a central characteristic of the disease, and relieves pain, fatigue and other symptoms, improving quality of life." Swollen spleens cause pain, malnutrition "Interestingly, other organs, mainly the spleen, attempt to take over the production of {filter} cells. Bone marrow forms in the spleen," Verstovsek said. Malignant cells also accumulate there. "The growing spleen causes significant problems for the patient, and not just because it's painful. It compresses the stomach and bowels, so patients suffer malnutrition and lose weight. The ability to walk and to bend is affected, and the body deteriorates overall." End-stage patients resemble the severely malnourished, with bloated abdomens and thin limbs. Patients on the study gained weight while on the medication. The phase I/II clinical trial of INCB018424, a JAK1 and JAK2 inhibitor developed by Incyte Corp., established maximum tolerated doses and then optimal dosing regimens for the drug, which targets abnormal signaling caused by a specific mutation in the JAK2 gene that was discovered in 2005 in patients with myelofibrosis. The clinical trial began in June 2007 at MD Anderson and the Mayo Clinic and enrolled 153 patients, all of whom had either advanced disease or were newly diagnosed with high intermediate- or high-risk myelofibrosis. Clinical responses have been maintained and 115 patients (75 percent) remain on the trial. Most patients benefited, with those on optimal doses experiencing: A median reduction in spleen volume, as measured by magnetic resonance imaging, of 33 percent at six months, with 48 percent enjoying reductions of 35 percent or higher. This equals a median reduction of 52 percent in the length of the spleen below the ribcage, measured by palpation, which is how spleen size is typically measured in clinical practice. Swift and lasting spleen reduction; 70 percent to 82 percent of patients on the three optimal dosing regimens had spleen reduction of at least 25 percent that occurred within the first two months of therapy and lasted beyond a year. Rapid and lasting improvement in symptom score, with 51 percent of patients achieving a 50 percent reduction at one month, and 58 percent maintaining that reduction at six months. Greater exercise capacity as measured in a six-minute walk. Patients increased their distance by a median of 34 meters at one month and 71 meters at six months. Median weight gain ranging from 14.5 pounds to 20.6 lbs after one year. Symptom improvement coincided with a quick and sustained reduction in a variety of inflammatory cytokines involved in disease biology. The main side effect is lowered {filter} cell counts in some patients, which can be remedied by lower doses or temporarily halting therapy. "The JAK2V617F mutation is one of several involved in myelofibrosis. It's the most prevalent, found in about half of patients. But it's not the sole cause of the disease," Verstovsek noted. "Myelofibrosis is too complex to be eliminated by a single drug. It will probably take combination therapies to cure it." Normally, JAK2 is turned on by various growth factors to make new {filter} cells as needed. The JAK2V617F mutation leaves the JAK2 enzyme permanently turned on, which causes the overgrowth of bone marrow cells at the heart of myelofibrosis. While the JAK2 inhibitor was expected to help patients with JAK2 mutations, the drug worked whether they had the mutation or not. "This suggests that patients who do not have specific mutations still have a very active JAK signaling pathway and can benefit from JAK inhibition," Verstovsek said. "However, because the drug also inhibits normal JAK2, it can lead to low {filter} counts that can limit dosing." Provided by University of Texas M. D. Anderson Cancer Center Who loves ya. Tom Jesus Was A Vegetarian! http://www.*.com/ Man Is A Herbivore! http://www..com/ DEAD PEOPLE WALKING http://www.*.com/ Quote: > September 13, 2010 Myeloproliferative neoplasms (MPN) comprise a > family of {filter} cancers characterized by clonal expansion of a single > {filter} cell type. > Untreated, these cancers can progress to bone marrow failure and acute > myeloid leukemia. > Several groups have identified activating mutations in the JAK2 gene > as associated with MPN; JAK2 inhibition has therefore emerged as > approach to MPN therapy. Thus far, however, JAK2 inhibition strategies > have had limited efficacy and have been accompanied by significant > toxicity. > In this paper, Ross Levine and his group at the Memorial Sloane > Kettering Cancer Center, New York, describe an indirect approach to > reducing JAK2 activity by pharmacologically targeting HSP90, a protein > that stabilizes JAK2. > Inhibiting HSP90 normalized {filter} counts and improved survival in two > mouse models of MPN, and the treatment promoted JAK2 degradation in > samples from MPN patients. > The authors believe that targeting HSP90, perhaps in combination with > JAK2 inhibition, may be the way forward in the treatment of patients > with MPN. > More information: HSP90 is a therapeutic target in JAK2-dependent > myeloproliferative neoplasms in mice and humans: http://www.*.com/ > 4ce9ffed3af0 > Provided by Journal of Clinical Investigation > -------------------- > Resveratrol induces apoptosis in K562 (chronic myelogenous leukemia) > cells by targeting a key survival protein, heat shock protein 70 > Authors: Chakraborty, Prabir K.1; Mustafi, Soumyajit Banerjee1; > Ganguly, Sudipto2; Chatterjee, Mitali2; Raha, Sanghamitra > Source: Cancer Science, Volume 99, Number 6, June 2008 , pp. > 1109-1116(8) > Publisher: Blackwell Publishing > Abstract: > Chronic myelogenous leukemia (CML) is a myeloproliferative disease > associated with a characteristic chromosomal translocation called the > Philadelphia chromosome. > This results in the expression of the Bcr-Abl fusion protein, a > constitutively active protein tyrosine kinase. > Although there are a few treatment options with Bcr-Abl kinase > inhibitors, drug resistance is often encountered. > One of the major obstacles in overcoming drug resistance in CML is the > high endogenous levels of heat shock protein 70 (Hsp70). Resveratrol > is a phytoalexin produced by several plants. > We studied the chemotherapeutic effects and mode of action of > resveratrol on K562 (CML) cells. > Resveratrol induced apoptosis in K562 cells in a time-dependent > manner. > This was established by increased annexin V binding, corroborated with > an enhanced caspase-3 activity and a rise in the sub-G0/G1 > population. > Resveratrol treatment also caused suppression of Hsp70 both in mRNA > and protein levels. > The downregulation of Hsp70 by resveratrol exposure was correlated > with a diminished presence of heat shock factor 1 (HSF1) in the > nucleus, and the downregulation of transcriptional activity of HSF1. > High endogenous levels of Hsp70 have been found to be a deterrent for > sensitivity to chemotherapy. > We show here that resveratrol could considerably enhance the apoptosis > induction in K562 cells by 17-allylamino-17-demethoxygeldanamycin, an > anticancer agent that inhibits Hsp90 but augments Hsp70 levels. > We conclude that resveratrol significantly downregulated Hsp70 levels > through inhibition of HSF1 transcriptional activity and appreciably > augmented the pro-apoptotic effects of 17-allylamino-17- > demethoxygeldanamycin. (Cancer Sci 2008; 99: 1109-1116) > Document Type: Research article > DOI: 10.1111/j.1349-7006.2008.00809.x > Affiliations: 1: Crystallography and Molecular Biology Division, Saha > Institute of Nuclear Physics, 1/AF Bidhan Nagar, Kolkata-700064; 2: > Department of Pharmacology, Institute of Post Graduate Medical > Education and Research, 244B Acharya JC Bose Road, Kolkata-700020, > India > ----------------- > Researchers Show Resveratrol > Works In The Brain By Metal Chelating Effects > Researchers now convincingly show that, via its iron-chelating > effects, resveratrol is able to cross barriers that protect the brain > from entry of toxins ({filter}/brain barrier) and reduce oxidation > (spoilage) of fats and increase the activity of protective > antioxidant > enzymes in the brain of healthy rodents. > The research has application for age-related brain disorders such as > Alzheimer's and Parkinson's disease. > Resveratrol decreased malondialdehyde (an end product of oxidation of > fats) in brain tissues by -300%. Doses ranging (in human equivalents) > from 87.5 to 875 ... read more »*
Mon, 04 Mar 2013 08:09:36 GMT

ironjustic #6 / 8	'Hi-JAK-ing' Cancer Paper highlight: 'Hi-JAK-ing' cancer by inhibiting Jak2 "The drug worked whether they had the mutation or not" "Can lead to low {filter} counts" "Main side effect is lowered {filter} cell counts in some patients" << Soooo since Jak2 causes increased red {filter} cell count / polycythemia and polycythemia MUST be treated with {filter}letting .. one might wonder why {filter}letting isn't being used as opposed to these massively expensive {filter}. It even works when there is no mutation means even though there is no 'human model of Jak2 muation' which CAUSES coincidentally polycythemia the drug STILL works. So meaning there is an increased red {filter} cell INFLUENCE simpy because by lowering Jak2 in a NORMAL cancer stricken person THEY TOO get .. better. You see how that works do ya .. Just let me know if you don't .. {filter}letting for the polycythemia in leukemia .. http://www.**.com/ What Causes Polycythemia Vera? Polycythemia vera (PV) also is known as primary polycythemia. A mutation, or change, in the body's JAK2 gene is the main cause of PV. The JAK2 gene makes an important protein that helps the body produce {filter} cells. What causes the change in the JAK2 gene isn't known. PV generally isn't passed from parent to child. However, in some families, the JAK2 gene may have a tendency to mutate. Other, unknown genetic factors also may play a role in causing PV. Who loves ya. Tom Jesus Was A Vegetarian! http://www..com/ Man Is A Herbivore! http://www..com/ DEAD PEOPLE WALKING http://www.*.com/ Quote: > JAK inhibitor provides rapid, durable relief for myelofibrosis > patients > September 15, 2010 An {filter}medication produces significant and lasting > relief for patients with myelofibrosis, a debilitating and lethal bone > marrow disorder, researchers at The University of Texas MD Anderson > Cancer Center report in the Sept. 16 New England Journal of Medicine. > Myelofibrosis is caused by the accumulation of malignant bone marrow > cells that trigger an inflammatory response, scarring the bone marrow > and limiting its ability to produce {filter}, causing anemia. > "The problem with myelofibrosis is the lack of available therapies for > patients - there are none approved for this disease today," said > principal investigator Srdan Verstovsek, M.D., Ph.D., associate > professor in M. D. Anderson's Department of Leukemia. Average life > expectancy for people with this disease is 5 to 7 years. Available > therapies approved for other diseases provide little response and are > mainly palliative. > "This experimental drug is the first to target one of the underlying > abnormalities in the malignant cells that cause myelofibrosis," > Verstovsek said. "It provides unprecedented reduction of enlarged > spleens that are a central characteristic of the disease, and relieves > pain, fatigue and other symptoms, improving quality of life." > Swollen spleens cause pain, malnutrition > "Interestingly, other organs, mainly the spleen, attempt to take over > the production of {filter} cells. Bone marrow forms in the spleen," > Verstovsek said. Malignant cells also accumulate there. "The growing > spleen causes significant problems for the patient, and not just > because it's painful. It compresses the stomach and bowels, so > patients suffer malnutrition and lose weight. The ability to walk and > to bend is affected, and the body deteriorates overall." > End-stage patients resemble the severely malnourished, with bloated > abdomens and thin limbs. Patients on the study gained weight while on > the medication. > The phase I/II clinical trial of INCB018424, a JAK1 and JAK2 inhibitor > developed by Incyte Corp., established maximum tolerated doses and > then optimal dosing regimens for the drug, which targets abnormal > signaling caused by a specific mutation in the JAK2 gene that was > discovered in 2005 in patients with myelofibrosis. > The clinical trial began in June 2007 at MD Anderson and the Mayo > Clinic and enrolled 153 patients, all of whom had either advanced > disease or were newly diagnosed with high intermediate- or high-risk > myelofibrosis. Clinical responses have been maintained and 115 > patients (75 percent) remain on the trial. > Most patients benefited, with those on optimal doses experiencing: > A median reduction in spleen volume, as measured by magnetic resonance > imaging, of 33 percent at six months, with 48 percent enjoying > reductions of 35 percent or higher. This equals a median reduction of > 52 percent in the length of the spleen below the ribcage, measured by > palpation, which is how spleen size is typically measured in clinical > practice. > Swift and lasting spleen reduction; 70 percent to 82 percent of > patients on the three optimal dosing regimens had spleen reduction of > at least 25 percent that occurred within the first two months of > therapy and lasted beyond a year. > Rapid and lasting improvement in symptom score, with 51 percent of > patients achieving a 50 percent reduction at one month, and 58 percent > maintaining that reduction at six months. > Greater exercise capacity as measured in a six-minute walk. Patients > increased their distance by a median of 34 meters at one month and 71 > meters at six months. > Median weight gain ranging from 14.5 pounds to 20.6 lbs after one > year. > Symptom improvement coincided with a quick and sustained reduction in > a variety of inflammatory cytokines involved in disease biology. > The main side effect is lowered {filter} cell counts in some patients, > which can be remedied by lower doses or temporarily halting therapy. > "The JAK2V617F mutation is one of several involved in myelofibrosis. > It's the most prevalent, found in about half of patients. But it's not > the sole cause of the disease," Verstovsek noted. "Myelofibrosis is > too complex to be eliminated by a single drug. It will probably take > combination therapies to cure it." > Normally, JAK2 is turned on by various growth factors to make new > {filter} cells as needed. The JAK2V617F mutation leaves the JAK2 enzyme > permanently turned on, which causes the overgrowth of bone marrow > cells at the heart of myelofibrosis. > While the JAK2 inhibitor was expected to help patients with JAK2 > mutations, the drug worked whether they had the mutation or not. "This > suggests that patients who do not have specific mutations still have a > very active JAK signaling pathway and can benefit from JAK > inhibition," Verstovsek said. "However, because the drug also inhibits > normal JAK2, it can lead to low {filter} counts that can limit dosing." > Provided by University of Texas M. D. Anderson Cancer Center > Who loves ya. > Tom > Jesus Was A Vegetarian! http://www..com/ > Man Is A Herbivore! http://www..com/ > DEAD PEOPLE WALKING http://www.*.com/ > > September 13, 2010 Myeloproliferative neoplasms (MPN) comprise a > > family of {filter} cancers characterized by clonal expansion of a single > > {filter} cell type. > > Untreated, these cancers can progress to bone marrow failure and acute > > myeloid leukemia. > > Several groups have identified activating mutations in the JAK2 gene > > as associated with MPN; JAK2 inhibition has therefore emerged as > > approach to MPN therapy. Thus far, however, JAK2 inhibition strategies > > have had limited efficacy and have been accompanied by significant > > toxicity. > > In this paper, Ross Levine and his group at the Memorial Sloane > > Kettering Cancer Center, New York, describe an indirect approach to > > reducing JAK2 activity by pharmacologically targeting HSP90, a protein > > that stabilizes JAK2. > > Inhibiting HSP90 normalized {filter} counts and improved survival in two > > mouse models of MPN, and the treatment promoted JAK2 degradation in > > samples from MPN patients. > > The authors believe that targeting HSP90, perhaps in combination with > > JAK2 inhibition, may be the way forward in the treatment of patients > > with MPN. > > More information: HSP90 is a therapeutic target in JAK2-dependent > > myeloproliferative neoplasms in mice and humans: http://www..com/ > > 4ce9ffed3af0 > > Provided by Journal of Clinical Investigation > > -------------------- > > Resveratrol induces apoptosis in K562 (chronic myelogenous leukemia) > > cells by targeting a key survival protein, heat shock protein 70 > > Authors: Chakraborty, Prabir K.1; Mustafi, Soumyajit Banerjee1; > > Ganguly, Sudipto2; Chatterjee, Mitali2; Raha, Sanghamitra > > Source: Cancer Science, Volume 99, Number 6, June 2008 , pp. > > 1109-1116(8) > > Publisher: Blackwell Publishing > > Abstract: > > Chronic myelogenous leukemia (CML) is a myeloproliferative disease > > associated with a characteristic chromosomal translocation called the > > Philadelphia chromosome. > > This results in the expression of the Bcr-Abl fusion protein, a > > constitutively active protein tyrosine kinase. > > Although there are a few treatment options with Bcr-Abl kinase > > inhibitors, drug resistance is often encountered. > > One of the major obstacles in overcoming drug resistance in CML is the > > high endogenous levels of heat shock protein 70 (Hsp70). Resveratrol > > is a phytoalexin produced by several plants. > > We studied the chemotherapeutic effects and mode of action of > > resveratrol on K562 (CML) cells. > > Resveratrol induced apoptosis in K562 cells in a time-dependent > > manner. > > This was established by increased annexin V binding, corroborated with > > an enhanced caspase-3 activity and a rise in the sub-G0/G1 > > population. > > Resveratrol treatment also caused suppression of Hsp70 both in mRNA > > and protein levels. > > The downregulation of Hsp70 by resveratrol exposure was correlated > > with a diminished presence of ... read more »**
Mon, 04 Mar 2013 08:46:15 GMT

#7 / 8	'Hi-JAK-ing' Cancer
Fri, 19 Jun 1992 00:00:00 GMT

Ken #8 / 8	'Hi-JAK-ing' Cancer Quote: > No one cares Rusty ya half-witted Canuck Spammer Still----no one cares ya spamming{filter}wadd
Mon, 04 Mar 2013 10:30:34 GMT

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