by CharlesC
Posted by Christina
News Article:Health Day (Apr 26, 2007)"Scientists spot mechanism behind lung cancer drug resistance.
"Primary Scientific News Article:Science (May18, 2007) Vol.316.no.5827,pp1039-1043
Posted by cadeta
News Article:Impaired gene helps non-small cell lung cancer resist drug, Biotech Business Week 2006.
Primary ArticleFunctional characterization of the candidate tumor suppressor gene NPRL2/G21 located in 3p21.C3. Cancer research 64, 438-6433, September 15, 2004. American Association for Cancer Research.
After reviewing everyone blogs i noticed a similarity between cell proliferation and the discovery of a new therapuetic drug being studied for a particular type of cancer . But their were two articles in the blog that caught my attention . One was titled "Drug Resistant Lung Cancer" by Christina and the other "Genes give clue to lung Cancer" by cadeta. Instead of stating that reaserchers are coming up with a development for a therapuetic drug on cancer, this article discusses how a drug to treat lung cancer can be resistant. In the blog written by christina, it states how researchers developed to understand that a MET amplification was found in lung cancer patients that had developed a drug resistance to the two growth factor receptor kinase inhibitors. These kinase inhibitors have shown in recent studies that they may help with the treatment in lung cancer.
The common molecular event occurs in "Genes give a clue to lung cancer". just like how reaserachers found MET amplification in patients with EGFR, which are becoming resistant to growth factor receptor Kinases inhibitors, the occurance of cell amplification, and resistance to a drug for the treatment in lung cancer but was found in genes. Both of the articles discussses the cell proliferation within tumor supressor genes and the effect on how growth factor receptors play a key role on how the treatment for cancer responds to to them.
After the discovery of a certain gene like NPRL2 having to do with the resistant to lung cancer therapy, will this help with other cancer treatments?
Are their particular growth factor kinases inhibitors, like the ones Gefitinib and erlotinib naturally found in most diagnosed with cancer?
Tuesday, February 19, 2008
Monday, February 18, 2008
BLOG COMPARISONS
Blog Post1:
IKBKE gene amplification is seen loud and clear in breast cancer tumors!
Primary Article:
Boehm, Jesse S. et. al (2007). Integrative Genomic Approaches Identify IKBKE as a Breast Cancer Oncogene. Cell Press Vol. 129, pp. 1065-1079
Blog Post 2:
Can we finally stop breast cancer from spreading?!
Primary Article:
Xiaoming Ju, Sanjay Katiyar, Chenguang Wang, Manran Liu, Xuanmao Jiao, Shengwen Li, Jie Zhou, Jacob Turner, Michael P. Lisanti, Robert G. Russell, Susette C. Mueller, John Ojeifo, William S. Chen, Nissim Hay, and Richard G. Pestell. (2007, May). Akt1 Governs Breast Cancer Progression In Vivo. Proceedings of the National Academy of Sciences, 104: 7438 – 7443.
Summary:
These two blog posts stood out to me the most because of the way they were so closely related. When I was reading the summaries it seemed as if the two articles could have both sited the other article as a secondary source. The first blog post talks about breast cancer and how the survival of breast cancer was due to the mutation of the gene IKBE. It describes the experiment that the researchers conducted to search the pathway of the IKBE gene and find out where the mutation occurs that leads to the vitality of breast cancer in general.
The second blog post talks about there ever being a cure for cancer. It mainly discussed the fact that researchers found that AKT1 which is involved in the pathway of IKBE was the key to finding a way to sustain breast cancer so that not as may women were dying from the disease. It also talks about how breast cancer is one of leading cancers in America which is also true. It was basically extremely interesting to me how the two articles went hand in hand with one another.
Questions:
1. Did these two articles ever site each other as sources?
2. What new research is being done in breast cancer research?
3. What is the connection between IKBE and AKT1?
IKBKE gene amplification is seen loud and clear in breast cancer tumors!
Primary Article:
Boehm, Jesse S. et. al (2007). Integrative Genomic Approaches Identify IKBKE as a Breast Cancer Oncogene. Cell Press Vol. 129, pp. 1065-1079
Blog Post 2:
Can we finally stop breast cancer from spreading?!
Primary Article:
Xiaoming Ju, Sanjay Katiyar, Chenguang Wang, Manran Liu, Xuanmao Jiao, Shengwen Li, Jie Zhou, Jacob Turner, Michael P. Lisanti, Robert G. Russell, Susette C. Mueller, John Ojeifo, William S. Chen, Nissim Hay, and Richard G. Pestell. (2007, May). Akt1 Governs Breast Cancer Progression In Vivo. Proceedings of the National Academy of Sciences, 104: 7438 – 7443.
Summary:
These two blog posts stood out to me the most because of the way they were so closely related. When I was reading the summaries it seemed as if the two articles could have both sited the other article as a secondary source. The first blog post talks about breast cancer and how the survival of breast cancer was due to the mutation of the gene IKBE. It describes the experiment that the researchers conducted to search the pathway of the IKBE gene and find out where the mutation occurs that leads to the vitality of breast cancer in general.
The second blog post talks about there ever being a cure for cancer. It mainly discussed the fact that researchers found that AKT1 which is involved in the pathway of IKBE was the key to finding a way to sustain breast cancer so that not as may women were dying from the disease. It also talks about how breast cancer is one of leading cancers in America which is also true. It was basically extremely interesting to me how the two articles went hand in hand with one another.
Questions:
1. Did these two articles ever site each other as sources?
2. What new research is being done in breast cancer research?
3. What is the connection between IKBE and AKT1?
Oncogenes at it Again
Posts:
IKBKE gene amplification is seen loud and clear in breast cancer tumors!
Primary paper:
Boehm, Jesse S. et al (2007). Integrative Genomic Approaches Identify IKBKE as a Breast Cancer Oncogene. Cell Press Vol.129, pp.1065-1079
Leukemia Patients with KIT-D816 Mutations.
Primary Paper:
Schnittger, S. et al (2006). KIT-D816 Mutations in AML1-ETO-Positive AML are associated with impaired event-free and overall survival.
At face value, what sparked the interest on reflecting on these two articles was the fact that they are both not only caused by mutations, which we know is what gives rise to cancer, but they both can be linked to specific oncogenes. These particular mutations give rise to types of breast cancer and acute myeloid leukemia that can be categorized as “gain-of-function” mutations as opposed to “loss-of-function” which is the category that for instance a tumor suppressor gene would fall under because the gene can no longer suppress the growth or development of tumors. In studying any type of cancer it is important to maybe make this a primary distinction in order to conduct more focused research.
The mutation being examined in breast cancer occurs in the IKBKE caused by gene amplification leading it to function as an oncogene. In terms of acute myeloid leukemia, KIT is a proto-oncogene that when converted causes the D816 which becomes KIT –D816. It is important to note that both IKBKE and KIT-D816 starts off as normal genes. Mutations cause for these once normal genes to become oncogenes which are directly linked to development of any type of cancer. This is one of the first points emphasized in Cancer Biology.
After reading both these blogs a few questions did rise such as if these mutations are only specific to specific forms of breast cancer and leukemia? This then leads me to wonder how many types of these cancers exist. Are there any studies that are looking at the factors that contribute to the occurrence of these mutations; are they environmental or genetic or both?
IKBKE gene amplification is seen loud and clear in breast cancer tumors!
Primary paper:
Boehm, Jesse S. et al (2007). Integrative Genomic Approaches Identify IKBKE as a Breast Cancer Oncogene. Cell Press Vol.129, pp.1065-1079
Leukemia Patients with KIT-D816 Mutations.
Primary Paper:
Schnittger, S. et al (2006). KIT-D816 Mutations in AML1-ETO-Positive AML are associated with impaired event-free and overall survival.
At face value, what sparked the interest on reflecting on these two articles was the fact that they are both not only caused by mutations, which we know is what gives rise to cancer, but they both can be linked to specific oncogenes. These particular mutations give rise to types of breast cancer and acute myeloid leukemia that can be categorized as “gain-of-function” mutations as opposed to “loss-of-function” which is the category that for instance a tumor suppressor gene would fall under because the gene can no longer suppress the growth or development of tumors. In studying any type of cancer it is important to maybe make this a primary distinction in order to conduct more focused research.
The mutation being examined in breast cancer occurs in the IKBKE caused by gene amplification leading it to function as an oncogene. In terms of acute myeloid leukemia, KIT is a proto-oncogene that when converted causes the D816 which becomes KIT –D816. It is important to note that both IKBKE and KIT-D816 starts off as normal genes. Mutations cause for these once normal genes to become oncogenes which are directly linked to development of any type of cancer. This is one of the first points emphasized in Cancer Biology.
After reading both these blogs a few questions did rise such as if these mutations are only specific to specific forms of breast cancer and leukemia? This then leads me to wonder how many types of these cancers exist. Are there any studies that are looking at the factors that contribute to the occurrence of these mutations; are they environmental or genetic or both?
WNT signaling pathway
Posted By: Minerva B
Primary Scientific Article:
Gumz, M.L. et al. (2007) Secreted Frizzled-Related Protein 1 Loss Contributes to Tumor Phenotype of Clear Cell Renal Cell Carcinoma. Clinical Cancer Research; 13(16)
Gumz, M.L. et al. (2007) Secreted Frizzled-Related Protein 1 Loss Contributes to Tumor Phenotype of Clear Cell Renal Cell Carcinoma. Clinical Cancer Research; 13(16)
Blog Post #2 GPRC5A Can Be the Key to Lung Cancer
Posted By: MON
Primary Scientific Article:
Primary scientific article:Tao, Q., Fujimoto, J., Men, T., Ye, X., Deng, J., Lacroix, L. & et al. (2007, November 13 ). Identification of the Retinoic Acid – Inducible Gprc5aAs a New Lung Tumor Suppressor Gene. Journal of the National Cancer Institute, 99(22), 1668-1682.
Blog Comments
From a molecular biology standpoint, the blog that I particularly find to be interesting is Minerva B’s blog on clear cell renal carcinoma (ccRCC). I decided to comment on this blog because ccRCC is a cancer located in the kidney’s that’s on the rise. Like Minerva said in her blog, it has resistance to radiation and chemotherapy which makes it very expensive and difficult to treat. It’s a challenge to conduct studies and tests on difficult cancers like ccRCC. This post explains the studies that researchers conducted and the results that they were able to prove about the sFrP1 (Secreted Frizzled-Related Protein 1), which is a tumor suppressor gene. What I found interesting is that when the gene is turned off transcription factors are blocked. Scientist made the educated guess that if the sFRP1 gene activated by turning it on. Activating it will lessen the growth of the tumor and can even get rid of it. I find that to be a tremendous discovery, thats one of the cancers that we can possibly treat if detected early.
Primary scientific article:Tao, Q., Fujimoto, J., Men, T., Ye, X., Deng, J., Lacroix, L. & et al. (2007, November 13 ). Identification of the Retinoic Acid – Inducible Gprc5aAs a New Lung Tumor Suppressor Gene. Journal of the National Cancer Institute, 99(22), 1668-1682.
Blog Comments
From a molecular biology standpoint, the blog that I particularly find to be interesting is Minerva B’s blog on clear cell renal carcinoma (ccRCC). I decided to comment on this blog because ccRCC is a cancer located in the kidney’s that’s on the rise. Like Minerva said in her blog, it has resistance to radiation and chemotherapy which makes it very expensive and difficult to treat. It’s a challenge to conduct studies and tests on difficult cancers like ccRCC. This post explains the studies that researchers conducted and the results that they were able to prove about the sFrP1 (Secreted Frizzled-Related Protein 1), which is a tumor suppressor gene. What I found interesting is that when the gene is turned off transcription factors are blocked. Scientist made the educated guess that if the sFRP1 gene activated by turning it on. Activating it will lessen the growth of the tumor and can even get rid of it. I find that to be a tremendous discovery, thats one of the cancers that we can possibly treat if detected early.
As I red up on other blog posts, there was a common thread between Kidney Cancer Caused by "Sleeping Gene"? Rise and Shine!!!! Posted by: MinervaB and GPRC5A Can Be the Key to Lung Cancer Posted by: MON. Both of the post were written and researched by using primary articles pertaining to these cancers and their tumor suppressor gene’s. The genes that are involved are GPRC5A and sFRP1. sFRP1 functions as a tumor suppressor gene and GPRc5A is a gene is that is key to developing cancer. Both of these genes, Inhibit uncontrolled proliferation by affecting WNT, which is a signaling pathway. So far in my senior semior seminar class we have studied signaling pathways and tsg's. The common thread I see in both blogs is the signaling pathways and the tsg's that supress or inhibit uncontrolled cell proliferation.
Remaining Questions:
1.)In what way moelcularly does both tsg inhibit proiferation by affecting WNT?
2.)Sine I found a common relationship between the two blogs. Does the primary articles cite one another?
Now the metastasize of cancers can be prevented!!!
Can we finally stop breast cancer from spreading?! Blog by Kaz Ju, X., Katiyar, S., Wang, C., Liu, M., Jiao, X., Li, S., et al. (2007, May). Akt1 Governs Breast Cancer Progression In Vivo. Proceedings of the National Academy of Sciences, 104: 7438 – 7443.
“What’s the Bladder? A Look into Bladder Cancer and the Tumor Suppressor Gene RhoGD12” blog by PattyP13 Titus, B., Frierson, H.F., Conaway, M., Ching, K., Guise, T., Chirgwin, J., Hampton, G., Theodorescu, D. (2005). Endothelin Axis Is a Target of the Lung Metastasis Suppressor Gene Rho GD12. Clinical Cancer Research 65, (16).
Breast cancer is one of the most common cancers in women living in the United States. As years go by, researchers are trying their best to fine a cure for breast cancer. They are trying to find the cause of breast cancer as well as a therapeutic drug to block the cancer from traveling through the other parts of the body a process called metastasis. Instead of just removing a women’s breast, medical researchers are trying to figure out a way to just stop the cancer from metastasizing through the body. Since nowadays the researchers are getting closer and closer to find the cure for breast cancer fewer women are dying from this cancer each year. I found the article by Ju, X., Katiyar, S., Wang, C., Liu, M., Jiao, X., Li, S., et al.to be very important because the result the scientist discovered pave the way for a new therapeutic drug for breast cancer. The drug that the scientists are studying is an anti-Akt which would be a good treatment for women who are at the earlier stage of breast cancer. I was amazed when I discovered that the researcher had found the protein that enables the breast cancer to proliferate. The mice that did not have two copies of the Akt1gene did not develop cancer, but the mice that had one copy had a small tumor which was growing slowly. The mice who had two copies of Akt1 had the cancer, which grew extremely fast. This article is novel because researchers are getting closer in finding what causes breast cancer. They are also trying to find a new drug that can block breast cancer metastasizing throughout the body or a treatment for it. The scientist found the protein that helped beast cancer to spread all over the body.
The two article I have chosen to comment on are Can we finally stop breast cancer from spreading by Kaz B and “What’s the Bladder? A Look into Bladder Cancer and the Tumor Suppressor Gene RhoGD12 by PattyP3.
The two articles did not have any molecular event in common expect they both are trying to prevent proliferation of cancer cells. The articles were related to what I have studied in class so far: a cell that has the ability to metastasize is a cell that is not functioning properly and has a mutation in its DNA. In class I studied that an ocogene is a mutated or abnormal form of proto-ocongene. In class I have learned that Akt1 is a kinase (adding of phosphate groups) that takes parts in normal pro-growth signaling pathways in the cell and it encodes for proteins.
As I was reading and learning about my classmate’s blog, the two articles that I choose to comment on are Kaz and Patty. I found these two blogs to be very significant because both of these articles explain how it is important for scientist to come up with a new strategy to prevent the spreading of cancer in other part of the body, and how to stop it from the first place that it began. On Kaz’s article the scientist were trying to find the protein that helps with the spreading of tumor cells in breast cancer. During the research in both article the scientist used mice to perform their experiment. On Kaz’s article the researcher raised a few mice that had no Akt1 gene with other mice with ErbB2 onocogen. After the experiment was done the researchers found the protein in some of the mice. The mice that did not have two copy of Akt1 gene did not develop cancer.
The other mice that had one copy of the gene had a small tumor that was slow growing. The mice with two copy of the gene had cancer that was spreading fast. Patty’s article it emphasized that patients that had late stage bladder cancer relapse with fatal lung cancer. RhoGD12 gene is a tumor suppressor gene that is found in bladder cancers, whenever the RhoGd12 expression is not working, the genes ET-1 is present which encodes for endotheline and is controlled by RhoGd12. When the gene RhoGD12 is present, ET-1 turns “off”. Endothelin which is an amino acid helps tumor cells metastasize, the gene RhoGD12 make ET-1 stay of so the cancer will not proliferate.
The research did a DNA microarrays and an RNA isolation they study a metastasis and a non-metastasis bladder cancer cells. They gave a group of mice ET-1 suppress in the mice’s drinking water this would of give them the role of ET-1 cancer metastasis. They watch the mice for twelve weeks and while the cancer spread through their lungs. The mice that were DNA microarray had many genes including RhoGD12 that were not express.
Questions
1. When a gene loses its function is it possible for it to regain?
2. Why did the researchers do a DNA microarray and an RNA islocation?
“What’s the Bladder? A Look into Bladder Cancer and the Tumor Suppressor Gene RhoGD12” blog by PattyP13 Titus, B., Frierson, H.F., Conaway, M., Ching, K., Guise, T., Chirgwin, J., Hampton, G., Theodorescu, D. (2005). Endothelin Axis Is a Target of the Lung Metastasis Suppressor Gene Rho GD12. Clinical Cancer Research 65, (16).
Breast cancer is one of the most common cancers in women living in the United States. As years go by, researchers are trying their best to fine a cure for breast cancer. They are trying to find the cause of breast cancer as well as a therapeutic drug to block the cancer from traveling through the other parts of the body a process called metastasis. Instead of just removing a women’s breast, medical researchers are trying to figure out a way to just stop the cancer from metastasizing through the body. Since nowadays the researchers are getting closer and closer to find the cure for breast cancer fewer women are dying from this cancer each year. I found the article by Ju, X., Katiyar, S., Wang, C., Liu, M., Jiao, X., Li, S., et al.to be very important because the result the scientist discovered pave the way for a new therapeutic drug for breast cancer. The drug that the scientists are studying is an anti-Akt which would be a good treatment for women who are at the earlier stage of breast cancer. I was amazed when I discovered that the researcher had found the protein that enables the breast cancer to proliferate. The mice that did not have two copies of the Akt1gene did not develop cancer, but the mice that had one copy had a small tumor which was growing slowly. The mice who had two copies of Akt1 had the cancer, which grew extremely fast. This article is novel because researchers are getting closer in finding what causes breast cancer. They are also trying to find a new drug that can block breast cancer metastasizing throughout the body or a treatment for it. The scientist found the protein that helped beast cancer to spread all over the body.
The two article I have chosen to comment on are Can we finally stop breast cancer from spreading by Kaz B and “What’s the Bladder? A Look into Bladder Cancer and the Tumor Suppressor Gene RhoGD12 by PattyP3.
The two articles did not have any molecular event in common expect they both are trying to prevent proliferation of cancer cells. The articles were related to what I have studied in class so far: a cell that has the ability to metastasize is a cell that is not functioning properly and has a mutation in its DNA. In class I studied that an ocogene is a mutated or abnormal form of proto-ocongene. In class I have learned that Akt1 is a kinase (adding of phosphate groups) that takes parts in normal pro-growth signaling pathways in the cell and it encodes for proteins.
As I was reading and learning about my classmate’s blog, the two articles that I choose to comment on are Kaz and Patty. I found these two blogs to be very significant because both of these articles explain how it is important for scientist to come up with a new strategy to prevent the spreading of cancer in other part of the body, and how to stop it from the first place that it began. On Kaz’s article the scientist were trying to find the protein that helps with the spreading of tumor cells in breast cancer. During the research in both article the scientist used mice to perform their experiment. On Kaz’s article the researcher raised a few mice that had no Akt1 gene with other mice with ErbB2 onocogen. After the experiment was done the researchers found the protein in some of the mice. The mice that did not have two copy of Akt1 gene did not develop cancer.
The other mice that had one copy of the gene had a small tumor that was slow growing. The mice with two copy of the gene had cancer that was spreading fast. Patty’s article it emphasized that patients that had late stage bladder cancer relapse with fatal lung cancer. RhoGD12 gene is a tumor suppressor gene that is found in bladder cancers, whenever the RhoGd12 expression is not working, the genes ET-1 is present which encodes for endotheline and is controlled by RhoGd12. When the gene RhoGD12 is present, ET-1 turns “off”. Endothelin which is an amino acid helps tumor cells metastasize, the gene RhoGD12 make ET-1 stay of so the cancer will not proliferate.
The research did a DNA microarrays and an RNA isolation they study a metastasis and a non-metastasis bladder cancer cells. They gave a group of mice ET-1 suppress in the mice’s drinking water this would of give them the role of ET-1 cancer metastasis. They watch the mice for twelve weeks and while the cancer spread through their lungs. The mice that were DNA microarray had many genes including RhoGD12 that were not express.
Questions
1. When a gene loses its function is it possible for it to regain?
2. Why did the researchers do a DNA microarray and an RNA islocation?
Oncogenes at it Again
Posts:
IKBKE gene amplification is seen loud and clear in breast cancer tumors!
Primary paper:
Boehm, Jesse S. et al (2007). Integrative Genomic Approaches Identify IKBKE as a Breast Cancer Oncogene. Cell Press Vol.129, pp.1065-1079
Leukemia Patients with KIT-D816 Mutations.
Primary Paper:
Schnittger, S. et al (2006). KIT-D816 Mutations in AML1-ETO-Positive AML are associated with impaired event-free and overall survival.
At face value, what sparked the interest on reflecting on these two articles was the fact that they are both not only caused by mutations, which we know is what gives rise to cancer, but they both can be linked to specific oncogenes. These particular mutations give rise to types of breast cancer and acute myeloid leukemia that can be categorized as “gain-of-function” mutations as opposed to “loss-of-function” which is the category that for instance a tumor suppressor gene would fall under because the gene can no longer suppress the growth or development of tumors. In studying any type of cancer it is important to maybe make this a primary distinction in order to conduct more focused research.
The mutation being examined in breast cancer occurs in the IKBKE caused by gene amplification leading it to function as an oncogene. In terms of acute myeloid leukemia, KIT is a proto-oncogene that when converted causes the D816 which becomes KIT –D816. It is important to note that both IKBKE and KIT-D816 starts off as normal genes. Mutations cause for these once normal genes to become oncogenes which are directly linked to development of any type of cancer. This is one of the first points emphasized in Cancer Biology.
After reading both these blogs a few questions did rise such as if these mutations are only specific to specific forms of breast cancer and leukemia? This then leads me to wonder how many types of these cancers exist. Are there any studies that are looking at the factors that contribute to the occurrence of these mutations; are they environmental or genetic or both?
IKBKE gene amplification is seen loud and clear in breast cancer tumors!
Primary paper:
Boehm, Jesse S. et al (2007). Integrative Genomic Approaches Identify IKBKE as a Breast Cancer Oncogene. Cell Press Vol.129, pp.1065-1079
Leukemia Patients with KIT-D816 Mutations.
Primary Paper:
Schnittger, S. et al (2006). KIT-D816 Mutations in AML1-ETO-Positive AML are associated with impaired event-free and overall survival.
At face value, what sparked the interest on reflecting on these two articles was the fact that they are both not only caused by mutations, which we know is what gives rise to cancer, but they both can be linked to specific oncogenes. These particular mutations give rise to types of breast cancer and acute myeloid leukemia that can be categorized as “gain-of-function” mutations as opposed to “loss-of-function” which is the category that for instance a tumor suppressor gene would fall under because the gene can no longer suppress the growth or development of tumors. In studying any type of cancer it is important to maybe make this a primary distinction in order to conduct more focused research.
The mutation being examined in breast cancer occurs in the IKBKE caused by gene amplification leading it to function as an oncogene. In terms of acute myeloid leukemia, KIT is a proto-oncogene that when converted causes the D816 which becomes KIT –D816. It is important to note that both IKBKE and KIT-D816 starts off as normal genes. Mutations cause for these once normal genes to become oncogenes which are directly linked to development of any type of cancer. This is one of the first points emphasized in Cancer Biology.
After reading both these blogs a few questions did rise such as if these mutations are only specific to specific forms of breast cancer and leukemia? This then leads me to wonder how many types of these cancers exist. Are there any studies that are looking at the factors that contribute to the occurrence of these mutations; are they environmental or genetic or both?
What can a mutation in the BRAF protein do to me????
Possible Cure for Skin Cancer????? Blog by Charlene C.
Futreal, Andy. June 10. 2002. “ British Scientist Identify Skin Cancer Gene”. The New York Times. June11.2002. http://ww.nytimes.com/
Turn off the switch for thyroid papillary carcinoma cancer!!! Blog by Tanya M.
Cohen,Y., Xing, M., Mambo, E., Guo., Z., Wu. G., Trink, B., et al. (2003 April) BRAF mutation in papillary thyroid carcinoma. Journal of the National Cancer Institute, vol. 95, No.8.
I believe that developing a possible cure for skin cancer is vital because this disease is very common; everybody who is exposed to UV light is at risk of getting skin cancer. Although skin cancer may be dormant for years, one has to remember that cancer is a work in progress, which means it takes time for symptoms to occur. Finding a drug that could inhibit the mutant BRAF in cancer cells would save lives; that way, we can at least stop the tumor cells from proliferating. When BRAF proto-oncoprotein is constantly activated that leads to uncontrollable growth. BRAF protein is similar to RAF which is in the RAS-MAPK pathway. BRAF is activated when an adaptor protein helped Ras become activated by binding GTP to it instead of GDP, then activated Ras would then bind BRAF, which would become phosphorylated, and it would become active. BRAF is a kinase (an enzyme that catalyzes protein phosphorylation), and when it is active, it phosphorylates other proteins, like MEK and MAPK and then pass on the pro-growth signal to the nucleus. This article is extremely important because not only did the results of the experiment pave the way for future research about skin cancer, they also discovered a way to create an inhibitor that slowed down the kinase for a similar protein to BRAF called the ABL protein. ABL protein acts as a proto-oncoprotein in most normal cells. However, the finding states that ABL was present in patients diagnosed with leukemia. It is unknown to me whether what the researchers found in the patient diagnosed with leukemia was a mass of ABL protein or a mutated ABL protein.
While reading these fascinating blogs, I discovered a common molecular event between these two articles: Possible Cure for Skin Cancer????? and Turn off the switch for thyroid papillary carcinoma cancer!!! discussed by Charlene C. and Tanya M. I found these two articles interesting because they both examine the relationship between BRAF in cancer; in fact the research in Charlene C’s article was the basis for the scientists to see if the mutated gene BRAF was present in papillary thyroid cancer. Both papers explored the BRAF gene which is found in normal cell types as well as cancerous cell types. What is fascinating is that Cohen et al knew that BRAF mutation was involved in thyroid cancer and that BRAF has a connection with melanoma through the experiment that they did in June2002. Therefore, with this knowledge they were able to make new hypothesis and did further experiment. The result of their new experiment showed that there was a mutation in the BRAF gene (T1796A) in 69% of papillary thyroid cancers. They discovered that nucleotide 1796 in BRAF was changed from thymine (T) to adenine (A), and this single change was enough to contribute to BRAF always being “on” which then causes the thyroid cells to proliferate and then eventually become cancer cells. Both these findings may pave the way for chemotherapy to deactivate the mutated BRAF protein. While reading these articles, I noticed a lot of similarity to what we have learned in class especially knowing that when something that should not always be turned on is on. We know that then chaos will happen; there will be uncontrollable growth which in turn becomes malignant tumor. The similar research Cohen et al did was that even though they knew that a mutation in BRAF can be labeled as an oncogene in cancer patients, they could not identify the specific point mutation in the most malignant melanomas. The scientists then created a study in which they can separate the normal cells from the tumor cells and did an experiment to figure out in which cell types BRAF is most active and found that BRAF was present in the patient’s DNA who had cancer. They screened the BRAF gene mutation in different type of cancers. There were no differences in the results described about the on and off switch.
I have several questions I would like to pose regarding this information: besides the spontaneous changes that can happen within the cells when proliferating and mutation, what is the main thing that can distract a gene which stops it from doing what it’s supposed to do? For example, why would the BRAF gene in T1796A change T to A? How do these genes get activated? In addition, I am curious about environmental triggers: can the environment cause the mutations to be turned on? Or can an individual’s life style such as obesity set off the gene?
Futreal, Andy. June 10. 2002. “ British Scientist Identify Skin Cancer Gene”. The New York Times. June11.2002. http://ww.nytimes.com/
Turn off the switch for thyroid papillary carcinoma cancer!!! Blog by Tanya M.
Cohen,Y., Xing, M., Mambo, E., Guo., Z., Wu. G., Trink, B., et al. (2003 April) BRAF mutation in papillary thyroid carcinoma. Journal of the National Cancer Institute, vol. 95, No.8.
I believe that developing a possible cure for skin cancer is vital because this disease is very common; everybody who is exposed to UV light is at risk of getting skin cancer. Although skin cancer may be dormant for years, one has to remember that cancer is a work in progress, which means it takes time for symptoms to occur. Finding a drug that could inhibit the mutant BRAF in cancer cells would save lives; that way, we can at least stop the tumor cells from proliferating. When BRAF proto-oncoprotein is constantly activated that leads to uncontrollable growth. BRAF protein is similar to RAF which is in the RAS-MAPK pathway. BRAF is activated when an adaptor protein helped Ras become activated by binding GTP to it instead of GDP, then activated Ras would then bind BRAF, which would become phosphorylated, and it would become active. BRAF is a kinase (an enzyme that catalyzes protein phosphorylation), and when it is active, it phosphorylates other proteins, like MEK and MAPK and then pass on the pro-growth signal to the nucleus. This article is extremely important because not only did the results of the experiment pave the way for future research about skin cancer, they also discovered a way to create an inhibitor that slowed down the kinase for a similar protein to BRAF called the ABL protein. ABL protein acts as a proto-oncoprotein in most normal cells. However, the finding states that ABL was present in patients diagnosed with leukemia. It is unknown to me whether what the researchers found in the patient diagnosed with leukemia was a mass of ABL protein or a mutated ABL protein.
While reading these fascinating blogs, I discovered a common molecular event between these two articles: Possible Cure for Skin Cancer????? and Turn off the switch for thyroid papillary carcinoma cancer!!! discussed by Charlene C. and Tanya M. I found these two articles interesting because they both examine the relationship between BRAF in cancer; in fact the research in Charlene C’s article was the basis for the scientists to see if the mutated gene BRAF was present in papillary thyroid cancer. Both papers explored the BRAF gene which is found in normal cell types as well as cancerous cell types. What is fascinating is that Cohen et al knew that BRAF mutation was involved in thyroid cancer and that BRAF has a connection with melanoma through the experiment that they did in June2002. Therefore, with this knowledge they were able to make new hypothesis and did further experiment. The result of their new experiment showed that there was a mutation in the BRAF gene (T1796A) in 69% of papillary thyroid cancers. They discovered that nucleotide 1796 in BRAF was changed from thymine (T) to adenine (A), and this single change was enough to contribute to BRAF always being “on” which then causes the thyroid cells to proliferate and then eventually become cancer cells. Both these findings may pave the way for chemotherapy to deactivate the mutated BRAF protein. While reading these articles, I noticed a lot of similarity to what we have learned in class especially knowing that when something that should not always be turned on is on. We know that then chaos will happen; there will be uncontrollable growth which in turn becomes malignant tumor. The similar research Cohen et al did was that even though they knew that a mutation in BRAF can be labeled as an oncogene in cancer patients, they could not identify the specific point mutation in the most malignant melanomas. The scientists then created a study in which they can separate the normal cells from the tumor cells and did an experiment to figure out in which cell types BRAF is most active and found that BRAF was present in the patient’s DNA who had cancer. They screened the BRAF gene mutation in different type of cancers. There were no differences in the results described about the on and off switch.
I have several questions I would like to pose regarding this information: besides the spontaneous changes that can happen within the cells when proliferating and mutation, what is the main thing that can distract a gene which stops it from doing what it’s supposed to do? For example, why would the BRAF gene in T1796A change T to A? How do these genes get activated? In addition, I am curious about environmental triggers: can the environment cause the mutations to be turned on? Or can an individual’s life style such as obesity set off the gene?
Pee Worried and What's the Bladder
Post 1: Pee Worried!!!
News Article:Drug Week Editors (February 11, 2005) “Fragile histidine triad gene inactivation supports bladder cancer formation.”
Primary Article:Vaccine, A., Sevignani C. , Giarnieri, E. (2004, November 15) Inactivation of the FHIT Gene Favors Bladder Cancer Development. Clinical Cancer Research Vol. 10, 7607-7612
Cited Article:Ishii, H., Mimori, K., Inoue, H. (2006, December 6) Fhit Modulates the DNA Damage Checkpoint Response. Cancer Research 66, 11287-11292
Post 2: “What’s the Bladder? A Look into Bladder Cancer and the Tumor Suppressor Gene RhoGD12”
Bladder Cancer; Endothelin axis is a target of the lung metastasis Suppressor Gene RhoGD12. (2005, October 7). NewsRx.com, p. 72.Primary Research Article
Titus, B., Frierson, H.F., Conaway, M., Ching, K., Guise, T., Chirgwin, J., Hampton, G., Theodorescu, D. (2005). Endothelin Axis Is a Target of the Lung Metastasis Suppressor Gene Rho GD12. Clinical Cancer Research 65, (16). Retrieved February 11, 2008, from https://mail2.pmc.edu/exchweb/bin/redir.asp?URL=http://cancerres.aacrjournals.org/cgi/reprint/65/16/7320.
Both Posts 1 and 2 discuss bladder cancer and two different genes involved in its formation. I find both articles noteworthy because bladder cancer isn’t one of the cancers that we think of being one of the important ones. In the article entitled “Pee Worthy” it discusses how the discovery of the FHIT gene may have a large role in bladder cancer formation and how they will continue to explore possible gene therapy. Blog 2, “What’s the Bladder? A look into bladder cancer and the tumor suppressor gene RhoGD12 was an interesting find because it linked bladder cancer to lung cancer through a tumor suppressor gene known as RhoGD12, which occurred in late stage bladder cancer.
Both posts have a common event which is bladder cancer. Post 1 discusses a main gene involved and post 2 discusses bladder cancer at its end stages and what other genes may play a role. This relates back to many discussions in class on how a mutation of a gene at any point in the cell cycle may cause a mutation. Also how one cancer may lead to another due to metastasis?
There wasn’t much in common between the two blogs except they discuss the same type of cancer and they both involve a gene mutation. Both articles are doing continued research to treat the cancers.
Some questions that still remain regarding both articles are
1. How will gene therapy to the RhogD12 and the FHIT gene help in treating bladder cancer
2. What other cancers may be caused by the metastasis of bladder cancer other than lung cancer.
News Article:Drug Week Editors (February 11, 2005) “Fragile histidine triad gene inactivation supports bladder cancer formation.”
Primary Article:Vaccine, A., Sevignani C. , Giarnieri, E. (2004, November 15) Inactivation of the FHIT Gene Favors Bladder Cancer Development. Clinical Cancer Research Vol. 10, 7607-7612
Cited Article:Ishii, H., Mimori, K., Inoue, H. (2006, December 6) Fhit Modulates the DNA Damage Checkpoint Response. Cancer Research 66, 11287-11292
Post 2: “What’s the Bladder? A Look into Bladder Cancer and the Tumor Suppressor Gene RhoGD12”
Bladder Cancer; Endothelin axis is a target of the lung metastasis Suppressor Gene RhoGD12. (2005, October 7). NewsRx.com, p. 72.Primary Research Article
Titus, B., Frierson, H.F., Conaway, M., Ching, K., Guise, T., Chirgwin, J., Hampton, G., Theodorescu, D. (2005). Endothelin Axis Is a Target of the Lung Metastasis Suppressor Gene Rho GD12. Clinical Cancer Research 65, (16). Retrieved February 11, 2008, from https://mail2.pmc.edu/exchweb/bin/redir.asp?URL=http://cancerres.aacrjournals.org/cgi/reprint/65/16/7320.
Both Posts 1 and 2 discuss bladder cancer and two different genes involved in its formation. I find both articles noteworthy because bladder cancer isn’t one of the cancers that we think of being one of the important ones. In the article entitled “Pee Worthy” it discusses how the discovery of the FHIT gene may have a large role in bladder cancer formation and how they will continue to explore possible gene therapy. Blog 2, “What’s the Bladder? A look into bladder cancer and the tumor suppressor gene RhoGD12 was an interesting find because it linked bladder cancer to lung cancer through a tumor suppressor gene known as RhoGD12, which occurred in late stage bladder cancer.
Both posts have a common event which is bladder cancer. Post 1 discusses a main gene involved and post 2 discusses bladder cancer at its end stages and what other genes may play a role. This relates back to many discussions in class on how a mutation of a gene at any point in the cell cycle may cause a mutation. Also how one cancer may lead to another due to metastasis?
There wasn’t much in common between the two blogs except they discuss the same type of cancer and they both involve a gene mutation. Both articles are doing continued research to treat the cancers.
Some questions that still remain regarding both articles are
1. How will gene therapy to the RhogD12 and the FHIT gene help in treating bladder cancer
2. What other cancers may be caused by the metastasis of bladder cancer other than lung cancer.
BRAF Mutation in Skin Cancer and Thyroid Papillary Carcinoma
Post:
Possible Cure for Skin Cancer?????
Primary Research:
Davies, Helen (2002). Mutations of the BRAF gene in human cancer. The Journal Nature. www.nature.com/nature.
Post Sharing a Common Thread:
Turn off the Switch for Thyroid Papillary Carcinoma Cancer!!!
Primary Research:
Cohen, Y. et. al ( 2003). BRAF Mutation in Papillary Thyroid Carcinoma. Journal of the National Cancer Institute, Vol. 95, No. 8.
The, Possible Cure for Skin Cancer blog, posted by Charles C., caught my attention because, it is interesting how exposure to the environment (such as UV light from the sun) and other things, can cause someone to suddenly be at risk for having skin cancer. Sometimes people don’t tend to think twice about any random mark that might develop on there skin since it might be so small at the time, because of this lack of care many people don’t realize that it can actually be a sign of skin cancer until it gets bigger and out of controlled. Skin Cancer is also one of the most common cancers around, it is important for me to understand why it is so common and what can we do to cure it. This article suggested that researchers discovered the mutation of a gene known as BRAF a couple of years ago, that is seen in skin cancer patient’s malignant melanomas and even in normal cell patients. Malignant Melanomas is usually linked with skin cancer and it derives from a melanocyte, which can be a dark-pigmented benign tumor or malignant which metastasizes rapidly.
Another blog, Turn off the Switch for Thyroid Papillary Carcinoma Cancer, posted by Tanya M. also mentions a BRAF mutation and it’s involvement in papillary thyroid cancer and melanoma. The primary article for this research explains the large amount of mutations in BRAF that occurs in both melanoma and papillary thyroid carcinoma and it also describes how the RAF kinase inhibitor (12) can be a new way that they can try to treat these tumors. In, A Possible Cure for Skin Cancer, researchers also came to the conclusion that there might be a kinase inhibitor drug out there that they might be able to use to inhibit activity for the BRAF protein. Although, this article does not talk about papillary thyroid carcinoma cancer, it focuses on malignant melanomas and how they were also able to find a point mutation which causes the proteins to phosphorylate. These articles are similar to the discussions my classmates and I had in our classroom because, it brings up cell proliferation, point mutations, and even cell death. It also goes into detail about kinase activity and the serine and threonine kinase (that was also talked about in class), which is what the BRAF protein is.
The questions that remain with me regarding the information I had analyzed are:
1) Since the BRAF protein is also in normal cells, according to the Possible Cure for Cancer blog, is this why skin cancer is more common in humans than other cancers?
2) If researchers come up with a drug that will somehow treat these mutations, will it affect normal cells in any way?
3) How exactly does BRAF cause mutations in papillary thyroid cancer and where is it located?
Possible Cure for Skin Cancer?????
Primary Research:
Davies, Helen (2002). Mutations of the BRAF gene in human cancer. The Journal Nature. www.nature.com/nature.
Post Sharing a Common Thread:
Turn off the Switch for Thyroid Papillary Carcinoma Cancer!!!
Primary Research:
Cohen, Y. et. al ( 2003). BRAF Mutation in Papillary Thyroid Carcinoma. Journal of the National Cancer Institute, Vol. 95, No. 8.
The, Possible Cure for Skin Cancer blog, posted by Charles C., caught my attention because, it is interesting how exposure to the environment (such as UV light from the sun) and other things, can cause someone to suddenly be at risk for having skin cancer. Sometimes people don’t tend to think twice about any random mark that might develop on there skin since it might be so small at the time, because of this lack of care many people don’t realize that it can actually be a sign of skin cancer until it gets bigger and out of controlled. Skin Cancer is also one of the most common cancers around, it is important for me to understand why it is so common and what can we do to cure it. This article suggested that researchers discovered the mutation of a gene known as BRAF a couple of years ago, that is seen in skin cancer patient’s malignant melanomas and even in normal cell patients. Malignant Melanomas is usually linked with skin cancer and it derives from a melanocyte, which can be a dark-pigmented benign tumor or malignant which metastasizes rapidly.
Another blog, Turn off the Switch for Thyroid Papillary Carcinoma Cancer, posted by Tanya M. also mentions a BRAF mutation and it’s involvement in papillary thyroid cancer and melanoma. The primary article for this research explains the large amount of mutations in BRAF that occurs in both melanoma and papillary thyroid carcinoma and it also describes how the RAF kinase inhibitor (12) can be a new way that they can try to treat these tumors. In, A Possible Cure for Skin Cancer, researchers also came to the conclusion that there might be a kinase inhibitor drug out there that they might be able to use to inhibit activity for the BRAF protein. Although, this article does not talk about papillary thyroid carcinoma cancer, it focuses on malignant melanomas and how they were also able to find a point mutation which causes the proteins to phosphorylate. These articles are similar to the discussions my classmates and I had in our classroom because, it brings up cell proliferation, point mutations, and even cell death. It also goes into detail about kinase activity and the serine and threonine kinase (that was also talked about in class), which is what the BRAF protein is.
The questions that remain with me regarding the information I had analyzed are:
1) Since the BRAF protein is also in normal cells, according to the Possible Cure for Cancer blog, is this why skin cancer is more common in humans than other cancers?
2) If researchers come up with a drug that will somehow treat these mutations, will it affect normal cells in any way?
3) How exactly does BRAF cause mutations in papillary thyroid cancer and where is it located?
Soft Tissue Sarcoma vs. Estrogen Receptors Beta
Stopping The Spread of Soft Tissue Sarcoma: Is it Possible?
Chen, C., Cen, L., Chan, C., Hsieh, F., Chen, G., et al. (2007 June 28). Signal transducer and activator of transcription factor 3 is involved in cell growth and survival of human rhabdomyosarcoma and osteosarcoma cells. BMC Cancer, (7) 111.
Does the Estrogen Receptors Beta have an Influential Role in inhibiting the Effects of Ovarian Cancer?
Lazennec, Gwendal (2004). Involvement of Estrogen Receptor β in Ovarian Cancinogenesis. Cancer Research, 64, 5861-5869. Retrieved February 12, 2008, from the World Wide Web:
The article on soft tissue sarcoma was one of the articles that grabbed my attention. I was particularly interested in this article because I was unaware on how Stat3 was involved in tissue. The article described by the soft tissue sarcoma post, illustrates the effect Stat3 has on osteosarcomas, rhabdyomaosarcomas, and other soft tissue sarcoma. It goes on and demonstrates that Stat3 is a proto-oncogene that is highly regulated, meaning that it not always active and knows when to turn on and off. However, when there is a mutation in its pathway it can lead to constant activation, which then causes uncontrolled cell division. Once this happens the cancer develops. Another article that I enjoyed reading was “Does the Estrogen Receptor βeta have an Influential Role in inhibiting the Effects of Ovarian Cancer”? The post on ErbB in ovarian cancer describes how ErbB receptors have a great effect on cancer cells. It continues by describing the difference between ErbB and ErbA receptors. The researchers wanted to know if the two receptors had a different effect on cancer proliferation; in order to find out if both receptors had an effect the researchers introduced both ErbA and ErbB receptors to the infected cells. Once the receptors were added they noticed that ErbA had little effect on cell proliferation, on the other hand ErbB had a great effect on cell proliferation. This proves that ErbB receptors are inhibitors of cancer cells.
In comparing these two posts I think that both bloggers did an excellent job, and they both provided immensive information. The common events discussed in both post was how signal transduction played a vital role in the signal pathway. To illustrate, in the research discussed in the sarcoma post it was found that if there is a mutation that occurs in Stat3 then it will have a massive of uncontrolled cell division. However in the ovarian article it states that the ErbB receptors are inhibitors of cancer cells and slows down cell proliferation. This relates back to what my classmates and I have learned in class, since one of the effects of cancer is due to an effect in signaling pathways “on/off” together these posts prove the importance of careful regulation of signaling pathways in cancer.
The two questions that are still in mind after reading and analyzing both posts are, Does ErbB receptors have an effect on any other type of cancers? and
What is the next step a patient takes if they realize they have sarcoma?
Chen, C., Cen, L., Chan, C., Hsieh, F., Chen, G., et al. (2007 June 28). Signal transducer and activator of transcription factor 3 is involved in cell growth and survival of human rhabdomyosarcoma and osteosarcoma cells. BMC Cancer, (7) 111.
Does the Estrogen Receptors Beta have an Influential Role in inhibiting the Effects of Ovarian Cancer?
Lazennec, Gwendal (2004). Involvement of Estrogen Receptor β in Ovarian Cancinogenesis. Cancer Research, 64, 5861-5869. Retrieved February 12, 2008, from the World Wide Web:
The article on soft tissue sarcoma was one of the articles that grabbed my attention. I was particularly interested in this article because I was unaware on how Stat3 was involved in tissue. The article described by the soft tissue sarcoma post, illustrates the effect Stat3 has on osteosarcomas, rhabdyomaosarcomas, and other soft tissue sarcoma. It goes on and demonstrates that Stat3 is a proto-oncogene that is highly regulated, meaning that it not always active and knows when to turn on and off. However, when there is a mutation in its pathway it can lead to constant activation, which then causes uncontrolled cell division. Once this happens the cancer develops. Another article that I enjoyed reading was “Does the Estrogen Receptor βeta have an Influential Role in inhibiting the Effects of Ovarian Cancer”? The post on ErbB in ovarian cancer describes how ErbB receptors have a great effect on cancer cells. It continues by describing the difference between ErbB and ErbA receptors. The researchers wanted to know if the two receptors had a different effect on cancer proliferation; in order to find out if both receptors had an effect the researchers introduced both ErbA and ErbB receptors to the infected cells. Once the receptors were added they noticed that ErbA had little effect on cell proliferation, on the other hand ErbB had a great effect on cell proliferation. This proves that ErbB receptors are inhibitors of cancer cells.
In comparing these two posts I think that both bloggers did an excellent job, and they both provided immensive information. The common events discussed in both post was how signal transduction played a vital role in the signal pathway. To illustrate, in the research discussed in the sarcoma post it was found that if there is a mutation that occurs in Stat3 then it will have a massive of uncontrolled cell division. However in the ovarian article it states that the ErbB receptors are inhibitors of cancer cells and slows down cell proliferation. This relates back to what my classmates and I have learned in class, since one of the effects of cancer is due to an effect in signaling pathways “on/off” together these posts prove the importance of careful regulation of signaling pathways in cancer.
The two questions that are still in mind after reading and analyzing both posts are, Does ErbB receptors have an effect on any other type of cancers? and
What is the next step a patient takes if they realize they have sarcoma?
Cancer Post Comparison
The two blog posts that I found particularly interesting are:
"Possible Cure for Skin Cancer?????"
Davies, Helen (2002). Mutations of the BRAF gene in human cancers. The Journal Nature. Retrieved February 2008, from the World Wide Web: http://www.nature.com\nature
"Drug Resistant Lung Cancer"
Science (May 18, 2007) vol.316.no.5827, pp 1039-1043
The information that is presented in both of these summaries is noteworthy because both skin cancer and lung cancers are common cancers that affect millions of people. Researchers have discovered what is the cause of these cancers. Both cancers arise do to the disfunction of a specific receptor. Before these new found discoveries there was no effective treatment for these cancers. Now that researchers have "pin pointed" the cause for these cancers there is hope that there will be development of new cancer treatment that will effectively treat these cancers.
The commonalities between the posts are that both cancers effect organs one being the skin and the other is the lungs. Also the type of mutation in which the cancer arises from is a point mutation that occurs on a receptor of a certain gene. The genes that are involved are BRAF for skin cancer and EGFR for lung cancer. These mutaions relate to BI490 lectures because there are different things that can occur when there is a point mutation of a recptor. In the case of BRAF it normally acts as a proto-oncogene but when mutaion occurs it transforms in to an oncogene. As learned in class a proto-oncogene is a normally acting gene and an oncogene is the mutated form of a proto-oncogene. Proto-oncogenes regulate cell proliferation. Oncogenes allow uncontrollable cell proliferation. EGFR is a kinase. Kinases induce phosphorylation. During phosphorylation ATP phosphorylates a receptor by donating two phosphates; which causes ATP to convert in ADP. The process of phosphorylation causes cell proliferation. Normally ATP has to be present in order for phosporylation to occur. Only ATP is capable of donating the two phosphates. When a mutation occurs on the EGFR receptor it changes the structure of the receptor. Now phosphorylation can occur even if only ADP is present. The similar research that is present in both posts is that there is not any very effective treatment for BRAF skin cancer nor EGFR lung cancer.
Questions that are unanswerer after reading both articles is are researchers using these very same studies to test on a broader population in order to see in they recieve the same results? Do they plan to expand the time period in which the studies were conducted to see if that has an effect on there data? Specifically how do they plan to use these discoveries to make new drig treatment for these specific types of cancers?
"Possible Cure for Skin Cancer?????"
Davies, Helen (2002). Mutations of the BRAF gene in human cancers. The Journal Nature. Retrieved February 2008, from the World Wide Web: http://www.nature.com\nature
"Drug Resistant Lung Cancer"
Science (May 18, 2007) vol.316.no.5827, pp 1039-1043
The information that is presented in both of these summaries is noteworthy because both skin cancer and lung cancers are common cancers that affect millions of people. Researchers have discovered what is the cause of these cancers. Both cancers arise do to the disfunction of a specific receptor. Before these new found discoveries there was no effective treatment for these cancers. Now that researchers have "pin pointed" the cause for these cancers there is hope that there will be development of new cancer treatment that will effectively treat these cancers.
The commonalities between the posts are that both cancers effect organs one being the skin and the other is the lungs. Also the type of mutation in which the cancer arises from is a point mutation that occurs on a receptor of a certain gene. The genes that are involved are BRAF for skin cancer and EGFR for lung cancer. These mutaions relate to BI490 lectures because there are different things that can occur when there is a point mutation of a recptor. In the case of BRAF it normally acts as a proto-oncogene but when mutaion occurs it transforms in to an oncogene. As learned in class a proto-oncogene is a normally acting gene and an oncogene is the mutated form of a proto-oncogene. Proto-oncogenes regulate cell proliferation. Oncogenes allow uncontrollable cell proliferation. EGFR is a kinase. Kinases induce phosphorylation. During phosphorylation ATP phosphorylates a receptor by donating two phosphates; which causes ATP to convert in ADP. The process of phosphorylation causes cell proliferation. Normally ATP has to be present in order for phosporylation to occur. Only ATP is capable of donating the two phosphates. When a mutation occurs on the EGFR receptor it changes the structure of the receptor. Now phosphorylation can occur even if only ADP is present. The similar research that is present in both posts is that there is not any very effective treatment for BRAF skin cancer nor EGFR lung cancer.
Questions that are unanswerer after reading both articles is are researchers using these very same studies to test on a broader population in order to see in they recieve the same results? Do they plan to expand the time period in which the studies were conducted to see if that has an effect on there data? Specifically how do they plan to use these discoveries to make new drig treatment for these specific types of cancers?
From the Peanut Gallery...
I have always been interested in sports medicine and studying how certain conditions would affect an athlete on the molecular level. I am particularly attracted to any research on muscles and any other soft tissue in the body. This is why I found the blog on soft tissue sarcoma interesting titled, “Stopping the Spread of Soft Tissue Sarcoma: Is It Possible?”. In the study it was found that there was elevated STAT3 phosphorylation in rhabdomyosarcoma and this novel finding might just be the key to stopping it. The blog and the primary article both hint to a way to slow the spread of soft tissue sarcoma through the regulation of the STAT3 transcription factor (which allows for the producing of a protein) in cells. But is there a deeper cause? In actuality the STAT3 factor is supposed to be regulated by the SH2 domain, protein inhibitors of activated STATs and cytosine signaling protein suppressors. Through an imbalance in the pathway stems the problem. If researchers could find a way to return balance to the pathway then the sarcoma would cease or at the very least be slowed.
This similar imbalance also occurs in Neuroblastoma. In the blog titled: “Stopping Neuroblastoma Before It Kills!!!” based on the primary article by A. Gupta and others, we find that another protein is always activated in these cells. We find that an acid binding protein called CRABP II is always left activated due to the MycN transcription factor which is directly responsible for the proliferation of a neuroblastoma tumor. The common theme amongst both of these cancers is the signaling pathway. There is always an imbalance that leads to the over expression of something which then eventually leads to the formation of diseased cells. Soft tissue sarcoma and neuroblastoma do not involve the exact same pathway or even the same genes but they do exhibit a similar mechanism of onset. Something is always left on. This correlates with what we have learned so far because one of the main themes of cancer is its longevity and ability to leave something permanently “on” or “off”. Also, in order to determine what proteins were involved both studies examined either the tissue being affected or specifically the protein and its transduction ability. Both methods were able to tell researchers which proteins were responsible for the proliferation of the cancers. However, in the sarcoma study researchers used the western blot analysis to discover which protein was affecting the diseased tissue while the neuroblastoma study used a two dimensional gel to find out how CRABP II was communicating with other proteins to determine the frequency of attachment to it. From this they determined that CRABP II expression was elevated.
Based on the two blogs results, I only have two questions. The first is how many cell pathways are present in a cell and are the same pathways present in every cell? The second question is, is neuroblastoma a common childhood cancer for the same reason that retinoblastoma is a common childhood cancer?
“Stopping the Spread of Soft Tissue Sarcoma: Is It Possible?”: Primary Article
Chen, C., Cen, L., Chan, C., Hsieh, F., Chen, G., et al. (2007 June 28). Signal transducer and activator of transcription factor 3 is involved in cell growth and survival of human rhabdomyosarcoma and osteosarcoma cells. BMC Cancer, (7) 111.
“Stopping Neuroblastoma Before It Kills!!!”: Primary Article
Gupta A., Williams B.R., Hannash S.M., and Rawwas J. (2006, August 15). Cellular Retinoic Acid-Binding Protein II Is a Direct Transcriptional Target of MycN in Neuroblastoma. Cancer research, 66, 8100-8108.
This similar imbalance also occurs in Neuroblastoma. In the blog titled: “Stopping Neuroblastoma Before It Kills!!!” based on the primary article by A. Gupta and others, we find that another protein is always activated in these cells. We find that an acid binding protein called CRABP II is always left activated due to the MycN transcription factor which is directly responsible for the proliferation of a neuroblastoma tumor. The common theme amongst both of these cancers is the signaling pathway. There is always an imbalance that leads to the over expression of something which then eventually leads to the formation of diseased cells. Soft tissue sarcoma and neuroblastoma do not involve the exact same pathway or even the same genes but they do exhibit a similar mechanism of onset. Something is always left on. This correlates with what we have learned so far because one of the main themes of cancer is its longevity and ability to leave something permanently “on” or “off”. Also, in order to determine what proteins were involved both studies examined either the tissue being affected or specifically the protein and its transduction ability. Both methods were able to tell researchers which proteins were responsible for the proliferation of the cancers. However, in the sarcoma study researchers used the western blot analysis to discover which protein was affecting the diseased tissue while the neuroblastoma study used a two dimensional gel to find out how CRABP II was communicating with other proteins to determine the frequency of attachment to it. From this they determined that CRABP II expression was elevated.
Based on the two blogs results, I only have two questions. The first is how many cell pathways are present in a cell and are the same pathways present in every cell? The second question is, is neuroblastoma a common childhood cancer for the same reason that retinoblastoma is a common childhood cancer?
“Stopping the Spread of Soft Tissue Sarcoma: Is It Possible?”: Primary Article
Chen, C., Cen, L., Chan, C., Hsieh, F., Chen, G., et al. (2007 June 28). Signal transducer and activator of transcription factor 3 is involved in cell growth and survival of human rhabdomyosarcoma and osteosarcoma cells. BMC Cancer, (7) 111.
“Stopping Neuroblastoma Before It Kills!!!”: Primary Article
Gupta A., Williams B.R., Hannash S.M., and Rawwas J. (2006, August 15). Cellular Retinoic Acid-Binding Protein II Is a Direct Transcriptional Target of MycN in Neuroblastoma. Cancer research, 66, 8100-8108.
Drug Resistance!
Blog Post #1:
Cancer Degrading Drug!!!
Primary Article:
Sambol, E. et. al (2006). Flavopiridol Targets c-KIT Transcription and Induces Apoptosis in Gastrointestinal Stromal Tumor Cells. Cancer Research, Vol.66, pp. 5858-5866.
Blog Post #2:
Drug Resistant Lung Cancer
Posted by christina
Primary article:
Science (May18, 2007) Vol.316.no.5827,pp1039-1043
Summary:
Blog post #1 “Drug Resistant Lung Cancer” and Blog Post #2 “Cancer Degrading Drug” both discuss how the amplification of specific genes can result in drug resistance to tyrosine kinase inhibitors that are usually effective in the treatment of cancer. It is important to note that the tyrosine kinase inhibitors discussed in both of these articles are pharmaceutical agents/drugs not the natural tyrosine kinase inhibitors that are naturally present in the body. The genes and pathways discussed as well as the type of cancer being researched, however, are different in both articles.
The post entitled “Cancer Degrading Drug”, portrays how a mutation in cKIT, results in KIT amplification, and the resistance of GIST cells to the tyrosine kinase inhibitor known as imatinib mesyrate. Imatinib mesyrate normally regulates cellular development and functioning by preventing mutated forms of KIT from binding to bcr-abl receptors. Cellular resistance to imatinib mesyrate leads to increased cellular proliferation of GIST cells via continuous binding and transduction of cellular signals that activate GIST growth and division.
The post entitled “Drug resistant lung cancer”, states how a cellular mutation, results in MET amplification, and the resistance of epidermal growth factor receptors to gefitinib a type of tyrosine kinase inhibitor. Gefitinib normally functions to regulate the growth and proliferation of epidermal cells. Cellular resistance to gefitinib leads to increased cell proliferation of epidermal cells via continuous signaling of ERBB3.
The information found in these articles reinforces the idea we have frequently discussed in class, which is that cancer is the accumulation of several mutations that results in unregulated, uncontrolled cell proliferation. One of these mutations could result in gene amplification that results in cellular resistance to a specific tyrosine kinase inhibitor; current cancer drugs. The research presented within these articles, however, could pave the way to new, more effective cancer drug therapies.
Questions:
How do drugs function as tyrosine kinase inhibitors?
Is cellular resistance of specific tyrosine kinase inhibitors common in cancer?
Cancer Degrading Drug!!!
Primary Article:
Sambol, E. et. al (2006). Flavopiridol Targets c-KIT Transcription and Induces Apoptosis in Gastrointestinal Stromal Tumor Cells. Cancer Research, Vol.66, pp. 5858-5866.
Blog Post #2:
Drug Resistant Lung Cancer
Posted by christina
Primary article:
Science (May18, 2007) Vol.316.no.5827,pp1039-1043
Summary:
Blog post #1 “Drug Resistant Lung Cancer” and Blog Post #2 “Cancer Degrading Drug” both discuss how the amplification of specific genes can result in drug resistance to tyrosine kinase inhibitors that are usually effective in the treatment of cancer. It is important to note that the tyrosine kinase inhibitors discussed in both of these articles are pharmaceutical agents/drugs not the natural tyrosine kinase inhibitors that are naturally present in the body. The genes and pathways discussed as well as the type of cancer being researched, however, are different in both articles.
The post entitled “Cancer Degrading Drug”, portrays how a mutation in cKIT, results in KIT amplification, and the resistance of GIST cells to the tyrosine kinase inhibitor known as imatinib mesyrate. Imatinib mesyrate normally regulates cellular development and functioning by preventing mutated forms of KIT from binding to bcr-abl receptors. Cellular resistance to imatinib mesyrate leads to increased cellular proliferation of GIST cells via continuous binding and transduction of cellular signals that activate GIST growth and division.
The post entitled “Drug resistant lung cancer”, states how a cellular mutation, results in MET amplification, and the resistance of epidermal growth factor receptors to gefitinib a type of tyrosine kinase inhibitor. Gefitinib normally functions to regulate the growth and proliferation of epidermal cells. Cellular resistance to gefitinib leads to increased cell proliferation of epidermal cells via continuous signaling of ERBB3.
The information found in these articles reinforces the idea we have frequently discussed in class, which is that cancer is the accumulation of several mutations that results in unregulated, uncontrolled cell proliferation. One of these mutations could result in gene amplification that results in cellular resistance to a specific tyrosine kinase inhibitor; current cancer drugs. The research presented within these articles, however, could pave the way to new, more effective cancer drug therapies.
Questions:
How do drugs function as tyrosine kinase inhibitors?
Is cellular resistance of specific tyrosine kinase inhibitors common in cancer?
Sunday, February 17, 2008
Cancer Degrading Drug!!!
News Article:
Drug Week (2006). Gastrointestinal Stromal Tumor; Gastrointestinal stromal tumor apoptosis induced by flavopiridol.
Primary research article:
Sambol, E. et. al (2006). Flavopiridol Targets c-KIT Transcription and Induces Apoptosis in Gastrointestinal Stromal Tumor Cells. Cancer Research, Vol.66, pp. 5858-5866.
Articles citing primary article:
Fornier, M.N. et. al (2007). Phase I Dose- Finding Study of Weekly Docetaxel Followed by Flavopiridol for Patients with Advanced Solid Tumors. Clinical cancer Research 13(19), pp. 5841-5846.
Guo, T. et. al (2007). Sorafenib Inhibits the Imatinib- Resistant KITT670I Gatekeeper Mutation in Gastrointestinal Stromal Tumor. Clinical Cancer Research 13(16), pp. 4874-4881.
Liu, Y. et. al (2007). Histone H2AX Is a Mediator of Gastrointestinal Stromal Tumor Cell Apoptosis following Treatment with Imatinib Mesylate. Cancer Research 67(6), pp. 2685-2692.
Mutation in the cKIT gene results in germ cell tumors, mastocytosis, small cell lung cancers, breast cancers and gastrointestinal stromal tumors. Imatinib mesylate is a tyrosine kinase inhibitor, which blocks the active mutated forms of KIT, bcr- abl receptors. Imatinib mesylate inhibits KIT kinase activity; and is highly active in KIT dependent GIST cell lines. Resistance of GIST cells to imatinib mesylate is hypothesized to occur because of amplification of KIT, secondary mutations cKIT gene product is a 145 kDa transmembrane protein. cKIT belongs to the type III receptor tyrosine kinase family.
Because GIST cells require the constant signaling of KIT. Researches wanted to know if flavopiridol could be an effective alternate to imatinib mesylate by inducing transcriptional suppression of the KIT receptor. Flavopridol is a cylin dependent kinase inhibitor. To evaluate the antiproliferative effect of drug exposure on GIST cells, the cells were plated in 96-well plates of a density of 2 X 10Ù4 cells per well and allowed to adhere overnight at 37 degrees Celsius. The cells were incubated with CyQuant dye and lysed. The cells were treated with varying concentrations of flavopiridol or imatinib mesylate. A DNA fragment of the human cKIT promoter was prepared by PCR amplification.
150 n/mol/L Flavopiridol had no effect on GIST cells at 24 and 48 hours. With 300nmol/L of flavopiridol there was an increase in apoptosis within 42% and 58% Annexin V staining at 24 and 48 hrs. The induction of apoptosis did not seem to increase with imatinib mesylate concentrations up to 10 u mol/L. activity, which was evidenced by the significant increase in cleaved product using a fluorescence based assay. KIT protein remained stable until 24 hours, and then it stared to reduce significantly. Because KIT down regulation occurred with apoptosis suggested that the down regulation of KIT may be required for cell death.
The primary article gives a lot of information. It discusses the methods on how the experiment was done, what the results of the experiment are, the secondary article is quoting the primary research. I trust both sources equally, because the secondary article is quoting directly from the primary article.
Of all the other cancer drugs out there why did they choose flavorpiridol to test on mutated KIT kinase?
Is there a drug other than flavorpiridol that causes the same effect on cKIT kinase?
Drug Week (2006). Gastrointestinal Stromal Tumor; Gastrointestinal stromal tumor apoptosis induced by flavopiridol.
Primary research article:
Sambol, E. et. al (2006). Flavopiridol Targets c-KIT Transcription and Induces Apoptosis in Gastrointestinal Stromal Tumor Cells. Cancer Research, Vol.66, pp. 5858-5866.
Articles citing primary article:
Fornier, M.N. et. al (2007). Phase I Dose- Finding Study of Weekly Docetaxel Followed by Flavopiridol for Patients with Advanced Solid Tumors. Clinical cancer Research 13(19), pp. 5841-5846.
Guo, T. et. al (2007). Sorafenib Inhibits the Imatinib- Resistant KITT670I Gatekeeper Mutation in Gastrointestinal Stromal Tumor. Clinical Cancer Research 13(16), pp. 4874-4881.
Liu, Y. et. al (2007). Histone H2AX Is a Mediator of Gastrointestinal Stromal Tumor Cell Apoptosis following Treatment with Imatinib Mesylate. Cancer Research 67(6), pp. 2685-2692.
Mutation in the cKIT gene results in germ cell tumors, mastocytosis, small cell lung cancers, breast cancers and gastrointestinal stromal tumors. Imatinib mesylate is a tyrosine kinase inhibitor, which blocks the active mutated forms of KIT, bcr- abl receptors. Imatinib mesylate inhibits KIT kinase activity; and is highly active in KIT dependent GIST cell lines. Resistance of GIST cells to imatinib mesylate is hypothesized to occur because of amplification of KIT, secondary mutations cKIT gene product is a 145 kDa transmembrane protein. cKIT belongs to the type III receptor tyrosine kinase family.
Because GIST cells require the constant signaling of KIT. Researches wanted to know if flavopiridol could be an effective alternate to imatinib mesylate by inducing transcriptional suppression of the KIT receptor. Flavopridol is a cylin dependent kinase inhibitor. To evaluate the antiproliferative effect of drug exposure on GIST cells, the cells were plated in 96-well plates of a density of 2 X 10Ù4 cells per well and allowed to adhere overnight at 37 degrees Celsius. The cells were incubated with CyQuant dye and lysed. The cells were treated with varying concentrations of flavopiridol or imatinib mesylate. A DNA fragment of the human cKIT promoter was prepared by PCR amplification.
150 n/mol/L Flavopiridol had no effect on GIST cells at 24 and 48 hours. With 300nmol/L of flavopiridol there was an increase in apoptosis within 42% and 58% Annexin V staining at 24 and 48 hrs. The induction of apoptosis did not seem to increase with imatinib mesylate concentrations up to 10 u mol/L. activity, which was evidenced by the significant increase in cleaved product using a fluorescence based assay. KIT protein remained stable until 24 hours, and then it stared to reduce significantly. Because KIT down regulation occurred with apoptosis suggested that the down regulation of KIT may be required for cell death.
The primary article gives a lot of information. It discusses the methods on how the experiment was done, what the results of the experiment are, the secondary article is quoting the primary research. I trust both sources equally, because the secondary article is quoting directly from the primary article.
Of all the other cancer drugs out there why did they choose flavorpiridol to test on mutated KIT kinase?
Is there a drug other than flavorpiridol that causes the same effect on cKIT kinase?
wow
Hello PMC Senior Seminar Students:
I am reading the blogs posted and must say I am learning a lot. The first thing I notice is enticing titles! They make a person want to read more. However, what I am most impressed by are the summaries of the primary literature. For your first experience at reading and extracting the messages from primary literature, this is an impressive start. It is fortunate for you that this semester you are learning about the way scientists do research and publish their findings. You are also learning about the most recent advances in cancer research. While all of this is new to you, it is obvious that by stretching, you are gaining alot.
My congratulations to you all, and I am looking forward to reading the blogs as they get better and more involved.
dr.b
I am reading the blogs posted and must say I am learning a lot. The first thing I notice is enticing titles! They make a person want to read more. However, what I am most impressed by are the summaries of the primary literature. For your first experience at reading and extracting the messages from primary literature, this is an impressive start. It is fortunate for you that this semester you are learning about the way scientists do research and publish their findings. You are also learning about the most recent advances in cancer research. While all of this is new to you, it is obvious that by stretching, you are gaining alot.
My congratulations to you all, and I am looking forward to reading the blogs as they get better and more involved.
dr.b
Saturday, February 16, 2008
Wnt pathway
Posts sharing a common thread:
Post #1: "Kidney Cancer Caused by "Sleeping Gene"? Rise and Shine!!!!"
Primary research:
Gumz, M.L. et al. (2007) Secreted Frizzled-Related Protein 1 Loss Contributes to Tumor Phenotype of Clear Cell Renal Cell Carcinoma. Clinical Cancer Research; 13(16)
Post #2: "GPRC5A Can be the Key to Lung Cancer"
Primary research:
"Tao, Q., Fujimoto, J., Men, T., Ye, X., Deng, J., Lacroix, L. & et al. (2007, November 13 ). Identification of the Retinoic Acid – Inducible Gprc5a As a New Lung Tumor Suppressor Gene. Journal of the National Cancer Institute, 99(22), 1668-1682."
The “Sleeping Gene” post and the “GPRC5A Can be the Key to Lung Cancer” post discuss tumor suppressor genes that affect the Wnt signaling pathway, which controls cell proliferation. The articles mention that either sFRP1 or GPRC5A suppress or inhibit proliferation in cancer by affecting the Wnt signaling pathway. Both sFRP1 and GPRC5A are identified as tumor suppressor genes because they both suppress cell proliferation and cell survival. The normal Wnt signaling system involves the following pathways.
When Wnt is present:
GSK3 is inhibited and cannot destroy beta-catenin
beta-catenin can enter nucleus and activate other proteins
expression of cell proliferation genes turned on
When Wnt is absent:
GSK3 binds with beta-catenin
beta-catenin is target for degradation
Post #2: "GPRC5A Can be the Key to Lung Cancer"
Primary research:
"Tao, Q., Fujimoto, J., Men, T., Ye, X., Deng, J., Lacroix, L. & et al. (2007, November 13 ). Identification of the Retinoic Acid – Inducible Gprc5a As a New Lung Tumor Suppressor Gene. Journal of the National Cancer Institute, 99(22), 1668-1682."
The blog entitled "GPRC5A Can Be the Key to Lung Cancer" mentions GPRC5A is a protein-coupled receptor that is deleted in the lung cancer. SFRP1 means Secreted Frizzled-Related Protein 1. In kidney cancer cells, SFRP1 is missing when tumors are present. The blog post "Sleeping Gene" says that sFRP1 (Secreted Frizzled-Related Protein 1) functions in the Wnt signaling pathway to prevent tumor growth and metastisis. immediately referred to “GPRC5A Can be the Key to Lung Cancer” that GPRC5A may inhibit, the Wnt pathway by acting in the noncanoical Wnt pathway which caught my attention. The noncanonical Wnt pathway is connected to the Wnt pathway, but it functions against the Wnt signaling. When Wnt is around, cells usually proliferate. These noncanonical pathways try to stop Wnt signaling. They suppress, or inhibit, normal canonical Wnt signaling. Both articles mention sFRP1 and GPRC5A normally may (they don't know for sure about GPRC5A) suppress or inhibit proliferation by their effects on the Wnt signaling pathway. Both sFRP1 and GPRC5A are identified as tumor suppressor genes and both are deleted in the tumor cells. The primary source “Identification of the Retinoic Acid – Inducible Gprc5a As a New Lung Tumor Suppressor Gene” stated in the discussion that GPRC5A receptor binds to the seven - transmembrane frizzled receptor that may activate the noncanonical Wnt signaling. Another thing that triggers my interest is sFRP1 could be the frizzled receptor that is mentioned in the second article, “Secreted Frizzled-Related Protein 1 Loss Contributes to Tumor Phenotype of Clear Cell Renal Cell Carcinoma”.
The blog post, "Sleeping Gene." mentions that many renal cell carcinomas are resistant to chemotherapy and radiation treatments. "GPRC5A" mentionsthat the researchers still do not know what is the ligand for GPRC5A receptor and still wondered whether or not it functions in the noncanonical Wnt system. The blog entitled "Sleeping Gene" mentions sFRP1 stops signaling from causing uncontrollable proliferation and metastasis through the Wnt pathway.Since beta-catenin in the Wnt pathway is the key to proliferation, can researchers make a drug targeting beta-catenin to cure the cancers? Would researchers link these two tumor suppressor genes together further studies?
Wednesday, February 13, 2008
Possible Cure for Skin Cancer?????
Charles C.
Citation-
Futreal, Andy. June 10. 2002. “ British Scientist Identify Skin Cancer Gene”. The New York Times. June11.2002. http://ww.nytimes.com/
Davies,Helen. June 27.2002. “Mutations of the BRAF gene in human cancer”. The Journal Nature. www.nature.com/nature
“Researchers discover a mutation of BRAF gene in skin cancer patients”
Scientist located in the UK and united States have come to a conclusion of identifying a specific protein that can be mutated in people diagnosed with cancer. Even though the gene called b-raf is found in normal cell types or cancerous cell types, Researchers discovered the gene b-raf being present in the most malignant melanomas. They discovered that BRAF can actually be labeled as an oncogene in cancer patients. In the primary article it lists other types of cancers that also have the same mutation, such as colorectal cancer and borderline ovarian cancer.
Before the research was constructed, scientist and researchers could not identify the specific point mutation that was occurring in patients with malignant melanoma. Throughout the experiment researchers created a study first by observing and designing a graph with examples of DNA sequences from patients diagnosed with cancer. Located in the primary source figure 1 divides the caner patients by labeling one with the tumor cells and the other is from normal cells in the body. As a result the tumor cell patients proved that the gene BRAF was occurring as a point mutation in these particular cancer DNA sequences. Researchers came to the conclusion that there might be a study to create an inhibitor drug that inhibits the kinases activity of the protein BRAF. Since today researchers have found out how to create an inhibitor that inhibits the kinases for a similar structure to BRAF called the ABL proteins. ABL is found in individuals diagnosed with leukemia. With this discovery, we might have a good chance of doing the same with the protein BRAF.
In human cancers the point mutations in BRAF activates the kinases which makes the proteins phosphorylate. Researchers took the amino acid V599E which changed the BRAF protein into a BRAF mutation in the DNA. They discovered that when the amino acid is mutated to BRAF it not only converts it to a BRAF mutation but it reacts more actively to kinases.
To compare the articles they both mention that the specific gene mutation in malignant melanoma is BRAF. They also both state that with this discovery there may be a chance to develop an inhibitor to stop the activity of BRAF. In the primary source it states that BRAF mutation occurs in precisely 66% of patients with malignant melanoma. In contrast the secondary source states that the gene is found in around 70% of malignant melanoma patients. Even though the primary source is more enhanced with information about the particular gene and is more precise with their calculations, the secondary source was easier to read for the greater public to understand. Given that the primary source explains in detail what exactly occurs in the gene b-raf and displays graphs explaining the effects of the different amino acids being mutated to BRAF. I would most likely trust the information given in the primary source. The secondary source mainly distributes the name of the gene and statements from the director and the author of the article making it a more opinionated article about the discovery.
Questions:
1. Will this identification in the skin cancer gene help lead to identifying other point mutations in other caner genes?
2. If they do create a therapeutic drug for malignant melanoma, will people who at first find out that they are diagnosed with the specific cancer have the same effect on the drug as if a person who has known they have been diagnosed with the skin cancer for a certain amount of time?
Citation-
Futreal, Andy. June 10. 2002. “ British Scientist Identify Skin Cancer Gene”. The New York Times. June11.2002. http://ww.nytimes.com/
Davies,Helen. June 27.2002. “Mutations of the BRAF gene in human cancer”. The Journal Nature. www.nature.com/nature
“Researchers discover a mutation of BRAF gene in skin cancer patients”
Scientist located in the UK and united States have come to a conclusion of identifying a specific protein that can be mutated in people diagnosed with cancer. Even though the gene called b-raf is found in normal cell types or cancerous cell types, Researchers discovered the gene b-raf being present in the most malignant melanomas. They discovered that BRAF can actually be labeled as an oncogene in cancer patients. In the primary article it lists other types of cancers that also have the same mutation, such as colorectal cancer and borderline ovarian cancer.
Before the research was constructed, scientist and researchers could not identify the specific point mutation that was occurring in patients with malignant melanoma. Throughout the experiment researchers created a study first by observing and designing a graph with examples of DNA sequences from patients diagnosed with cancer. Located in the primary source figure 1 divides the caner patients by labeling one with the tumor cells and the other is from normal cells in the body. As a result the tumor cell patients proved that the gene BRAF was occurring as a point mutation in these particular cancer DNA sequences. Researchers came to the conclusion that there might be a study to create an inhibitor drug that inhibits the kinases activity of the protein BRAF. Since today researchers have found out how to create an inhibitor that inhibits the kinases for a similar structure to BRAF called the ABL proteins. ABL is found in individuals diagnosed with leukemia. With this discovery, we might have a good chance of doing the same with the protein BRAF.
In human cancers the point mutations in BRAF activates the kinases which makes the proteins phosphorylate. Researchers took the amino acid V599E which changed the BRAF protein into a BRAF mutation in the DNA. They discovered that when the amino acid is mutated to BRAF it not only converts it to a BRAF mutation but it reacts more actively to kinases.
To compare the articles they both mention that the specific gene mutation in malignant melanoma is BRAF. They also both state that with this discovery there may be a chance to develop an inhibitor to stop the activity of BRAF. In the primary source it states that BRAF mutation occurs in precisely 66% of patients with malignant melanoma. In contrast the secondary source states that the gene is found in around 70% of malignant melanoma patients. Even though the primary source is more enhanced with information about the particular gene and is more precise with their calculations, the secondary source was easier to read for the greater public to understand. Given that the primary source explains in detail what exactly occurs in the gene b-raf and displays graphs explaining the effects of the different amino acids being mutated to BRAF. I would most likely trust the information given in the primary source. The secondary source mainly distributes the name of the gene and statements from the director and the author of the article making it a more opinionated article about the discovery.
Questions:
1. Will this identification in the skin cancer gene help lead to identifying other point mutations in other caner genes?
2. If they do create a therapeutic drug for malignant melanoma, will people who at first find out that they are diagnosed with the specific cancer have the same effect on the drug as if a person who has known they have been diagnosed with the skin cancer for a certain amount of time?
Gene Gives Clue to Lung Cancer
News Article:
Impaired gene helps non-small cell lung cancer resist drug, Biotech Business Week 2006.
Primary Article
Functional characterization of the candidate tumor suppressor gene NPRL2/G21 located in 3p21.C3. Cancer research 64, 438-6433, September 15, 2004. American Association for Cancer Research.
Lung cancer is the killer of over a million people world wide; it can develop in changes in oncogenes and TSG’s. But after recent research it was found that these cancer cells that are mutated are highly resistant to the drug that is used today.
Researchers have identified NPRL2 a TSG (tumor suppressor gene) located on chromosome 3 as a possible cause of non-small lung cancer. According to this article on tumor biology that analyzed 4 genes to report its functional characterization, NPRL2 is a homozygous deletion on the 3p21 gene that inhibits cell growth by apoptosis and alters the cell cycle.
In an experiment to analyze the gene expression of NPRL2 they found that it was resistant to Cisplatin, which is a ,platinum containing cancer drug used in treating cancers that has already metasisized.
After redoing the experiment the results were different, the resistant cisplatin cells had limited proliferation and increased the chances of apoptosis.
Both articles raised the question, “How will the NPRL2 gene change the way we look at lung cancer”
Impaired gene helps non-small cell lung cancer resist drug, Biotech Business Week 2006.
Primary Article
Functional characterization of the candidate tumor suppressor gene NPRL2/G21 located in 3p21.C3. Cancer research 64, 438-6433, September 15, 2004. American Association for Cancer Research.
Lung cancer is the killer of over a million people world wide; it can develop in changes in oncogenes and TSG’s. But after recent research it was found that these cancer cells that are mutated are highly resistant to the drug that is used today.
Researchers have identified NPRL2 a TSG (tumor suppressor gene) located on chromosome 3 as a possible cause of non-small lung cancer. According to this article on tumor biology that analyzed 4 genes to report its functional characterization, NPRL2 is a homozygous deletion on the 3p21 gene that inhibits cell growth by apoptosis and alters the cell cycle.
In an experiment to analyze the gene expression of NPRL2 they found that it was resistant to Cisplatin, which is a ,platinum containing cancer drug used in treating cancers that has already metasisized.
After redoing the experiment the results were different, the resistant cisplatin cells had limited proliferation and increased the chances of apoptosis.
Both articles raised the question, “How will the NPRL2 gene change the way we look at lung cancer”
STOPPING THE SPREAD OF SOFT TISSUE SARCOMA: IS IT POSSIBLE??
SOFT TISSSUE SARCOMA; Study data from Ohio State University provide new insights into soft tissue sarcoma. (2007, December 3). Biotech Business Week, 1033.
Chen, C., Cen, L., Chan, C., Hsieh, F., Chen, G., et al. (2007 June 28). Signal transducer and activator of transcription factor 3 is involved in cell growth and survival of human rhabdomyosarcoma and osteosarcoma cells. BMC Cancer, (7) 111.
The articles address certain types of soft tissue sarcomas. Soft tissue sarcomas are malignant tumors that can develop from fat, muscle, nerve, fibrous tissues surrounding joints, blood vessel, or deep skin tissues. They can develop in any part of the body. They include oesteosarcomas (ca. of the bone); rhabdomyosarcomas (ca. of the voluntary muscles) which includes alveolar and embryonal; and also leiomyosarcoma cell lines which is soft tissue cancer of the smooth or involuntary muscles.
Stat3 is a proto-oncogene that is highly regulated; therefore it is not always turned on. However, a mutation in its pathway can lead to its constant activation, which then contributes to uncontrolled cell proliferation and cancer. Researchers noticed the constitutively activation of Stat3 in cancer cells.
However, they did not know if the signaling pathway of constitutive Stat 3 plays any role in the survival and growth of osteosarcomas, rhabdomyosarcomas, and other soft tissue sarcomas. In order to find out if constitutive Stat3 was activated, in the cancers listed above, researchers examined sarcoma tissues and sarcoma cell lines using immunohistochemistry and western blot analysis with a specific phosphor-Stat3 antibody. Through studies, researchers found that the activated Stat3 pathway is important for cell growth and survival of human sarcoma cells; the study also showed that Stat3 phosphorylation is elevated in human rhabdomyosarcoma, osteosarcoma and other soft tissue sarcomas.
My summary article is from Biotech Business Week, Dec. 3, 2007. This summary is not a typical newspaper article because it contains mostly direct quotes from the abstract of the primary article. The words are those of the principal researchers. Therefore, because nothing has been reworded, trust is not an issue; however the article does not provide complete data. The complete article was easier to understand because it provided extensive background information and gave details on the methods. Because the secondary article summarizes the basic information in only two paragraphs, some important findings were left out. For example, in the primary study, the authors stated that further research must be done to determine the mechanism of the constitutive Stat3 phosphorylation; the study showed mainly the relationship, but not the mechanism. Furthermore the discussion section mentions that the activated Stat 3 pathway could be useful in developing new chemotherapy drugs because blocking Stat 3 signaling in sarcoma cells induces apoptosis, which can stop growth. I checked Google Scholar and Highwire Press, and this article has not yet been cited.
My reaction to the two articles was that the primary source was clearer and gave more substantial information. I enjoyed seeing the charts and being able to understand them and think about the implications as described in the Discussion section. The primary article motivated me into wanting to know more about the constitutive Stat3 and find out more about their future research. The two questions I have remaining are: have researchers made any progress to developing chemotherapy agents and how many subjects were involved in the study and how old were they?
Chen, C., Cen, L., Chan, C., Hsieh, F., Chen, G., et al. (2007 June 28). Signal transducer and activator of transcription factor 3 is involved in cell growth and survival of human rhabdomyosarcoma and osteosarcoma cells. BMC Cancer, (7) 111.
The articles address certain types of soft tissue sarcomas. Soft tissue sarcomas are malignant tumors that can develop from fat, muscle, nerve, fibrous tissues surrounding joints, blood vessel, or deep skin tissues. They can develop in any part of the body. They include oesteosarcomas (ca. of the bone); rhabdomyosarcomas (ca. of the voluntary muscles) which includes alveolar and embryonal; and also leiomyosarcoma cell lines which is soft tissue cancer of the smooth or involuntary muscles.
Stat3 is a proto-oncogene that is highly regulated; therefore it is not always turned on. However, a mutation in its pathway can lead to its constant activation, which then contributes to uncontrolled cell proliferation and cancer. Researchers noticed the constitutively activation of Stat3 in cancer cells.
However, they did not know if the signaling pathway of constitutive Stat 3 plays any role in the survival and growth of osteosarcomas, rhabdomyosarcomas, and other soft tissue sarcomas. In order to find out if constitutive Stat3 was activated, in the cancers listed above, researchers examined sarcoma tissues and sarcoma cell lines using immunohistochemistry and western blot analysis with a specific phosphor-Stat3 antibody. Through studies, researchers found that the activated Stat3 pathway is important for cell growth and survival of human sarcoma cells; the study also showed that Stat3 phosphorylation is elevated in human rhabdomyosarcoma, osteosarcoma and other soft tissue sarcomas.
My summary article is from Biotech Business Week, Dec. 3, 2007. This summary is not a typical newspaper article because it contains mostly direct quotes from the abstract of the primary article. The words are those of the principal researchers. Therefore, because nothing has been reworded, trust is not an issue; however the article does not provide complete data. The complete article was easier to understand because it provided extensive background information and gave details on the methods. Because the secondary article summarizes the basic information in only two paragraphs, some important findings were left out. For example, in the primary study, the authors stated that further research must be done to determine the mechanism of the constitutive Stat3 phosphorylation; the study showed mainly the relationship, but not the mechanism. Furthermore the discussion section mentions that the activated Stat 3 pathway could be useful in developing new chemotherapy drugs because blocking Stat 3 signaling in sarcoma cells induces apoptosis, which can stop growth. I checked Google Scholar and Highwire Press, and this article has not yet been cited.
My reaction to the two articles was that the primary source was clearer and gave more substantial information. I enjoyed seeing the charts and being able to understand them and think about the implications as described in the Discussion section. The primary article motivated me into wanting to know more about the constitutive Stat3 and find out more about their future research. The two questions I have remaining are: have researchers made any progress to developing chemotherapy agents and how many subjects were involved in the study and how old were they?
Turn off the switch for thyroid papillary carcinoma cancer!!!
Primary article:
Cohen,Y., Xing, M., Mambo, E., Guo., Z., Wu. G., Trink, B., et al. (2003 April) BRAF mutation in papillary thyroid carcinoma. Journal of the National Cancer Institute, vol. 95, No.8.
News article:
Szabo, L. (2004, Nov.9). Taking on thyroid cancer. USA Today 11D
The scientific article (Cohen et al., 2003) has been cited in other primary scientific articles. The most recent three are the following;
Kambara, T., Simms, L., Whitehall, V., Spring, K., Wynter, C., Walsh, M., et al. (2004). Colorectal cancer: BRAF mutation is associtated with DNA methylation in serrated polyps and cancers of the colorectum. Gut 53, 1137-1144
He, H., Jazdzewski, K., Li, W., Liyanarachchi, S., Nagy, R., Volinia, S. (2005). The role of microRNA genes in papillary thyroid carcinoma. PNAS 102, 19075-19080
Xing, M. (2005). BRAF mutation in thyroid cancer. Endocr.Relat.Cancer 12, 245-262
The type of cancer that the articles address is papillary thyroid carcinoma, the most common form of thyroid cancer; and anaplastic thyroid cancer which; is most often fast growing and fatal. The other cancers mentioned are melanoma; lung, head and neck cancers; as well as other less common thyroid cancers.
Carcinoma- “An invasive malignant tumor derived from epithelial tissue that tends to metastasize to other areas of the body”. http://dictionary.reference.com/browse/carcinoma%
Melanoma- A dark-pigmented benign or malignant tumor that arises from a melanocyte and occurs most commonly in the skin. Malignant melanoma metastasizes quickly and is associated with sun exposure. http://dictionary.reference.com/browse/melanoma
Summary:
The new research that is described in the primary study is that the BRAF mutation is involved in papillary thyroid cancer. The study was done at Johns Hopkins University School of Medicine. The researchers already knew that BRAF was linked to melanoma, and that there must have been a genetic mutation in papillary thyroid cancers. Thus they tested for it in thyroid cancer as well as the other cancers mention above.
The researchers did a test on 476 tumors, for 214 lungs, 126 head and neck, 54 thyroids, 27 bladder, 38 cervical, and 17 prostate cancers for BRAF T1796A mutation by polymerase chain reaction. These samples were taken from the patients and were kept in the tissue bank.
Through their experiments, Cohen et al found a mutation in the BRAF T1796A gene in 69% of papillary thyroid cancers. They discovered that there was a misinterpretation in the chemical bases in the following amino acid (adenine, thymine, cytosine, and guanine that help build up DNA. In the BRAF gene in the nucleotide 1796 it changed (T) thymine to (A) adenine. The researchers discovered that a single coding mistake in more than 2000 in the nucleotides in gene made it stay on the “on” position, causing thyroid cells to proliferate and divide into a cancer. They screened for the BRAF gene mutation in different types of cancers and thyroid tumors. They did not find any mutation in the biopsy samples of the 20 sample of benign thyroid, 13 of the patients had follicular, and 3 with medullary thyroid carcinoma and Hurthle cell carcinoma. This was not found in some other thyroid cancers, nor in cervical, prostate, or bladder cancers.
The primary scientific article describes in great detail the BRAF mutation, its role in malignant melanoma, and how it could relate to papillary thyroid cancer. The researchers explained their methods, using scientific terms for cell lines, mutations, and genes. On the other hand, the USA Today article talks about other thyroid cancers, and mentions there are many new studies all over the country, not just at Johns Hopkins. However, the articles give in the same information about one finding, but in very different languages. The primary article states that “The high frequency of BRAF mutations in melanoma and papillary thyroid carcinoma suggests that inhibition of BRAF activity by the newly developed RAF kinase inhibitors (12) may offer a new strategy in the treatment of these tumors.” On the other hand, the secondary article states “the gene, called BRAF, acts as an on/off switch for cell growth. In tumors with the mutation, this switch gets stuck in the “on” position.” Most readers without a scientific background can understand about an on/off switch, but not about RAF kinase inhibitors.
My reaction to the information provided in the primary article is that it is very helpful for people who are interested in doing research. There were a few charts and tables that helped me to understand the results of the research, and what was the researchers purpose. The secondary article was extremely simple to understand the audience does not have to be scientists or a science majors to understand; what was being done. I trust the primary article more because it has more reliable information and it is written in a way that you know a scientist or a researchers who knew what they were doing or talking about wrote the article. However, the secondary article does quote scientists from notable research centers, including David Sidransky, who was one of the researchers in the primary article (et al.!) and is the director of the Johns Hopkins University School of Medicine.
Question
why does chemo and radiation therapy only shrink the anaplsatic tumor for a short period of time?
Why is the activation of BRA mutations is so important in development of papillary thyroid cancer?
Cohen,Y., Xing, M., Mambo, E., Guo., Z., Wu. G., Trink, B., et al. (2003 April) BRAF mutation in papillary thyroid carcinoma. Journal of the National Cancer Institute, vol. 95, No.8.
News article:
Szabo, L. (2004, Nov.9). Taking on thyroid cancer. USA Today 11D
The scientific article (Cohen et al., 2003) has been cited in other primary scientific articles. The most recent three are the following;
Kambara, T., Simms, L., Whitehall, V., Spring, K., Wynter, C., Walsh, M., et al. (2004). Colorectal cancer: BRAF mutation is associtated with DNA methylation in serrated polyps and cancers of the colorectum. Gut 53, 1137-1144
He, H., Jazdzewski, K., Li, W., Liyanarachchi, S., Nagy, R., Volinia, S. (2005). The role of microRNA genes in papillary thyroid carcinoma. PNAS 102, 19075-19080
Xing, M. (2005). BRAF mutation in thyroid cancer. Endocr.Relat.Cancer 12, 245-262
The type of cancer that the articles address is papillary thyroid carcinoma, the most common form of thyroid cancer; and anaplastic thyroid cancer which; is most often fast growing and fatal. The other cancers mentioned are melanoma; lung, head and neck cancers; as well as other less common thyroid cancers.
Carcinoma- “An invasive malignant tumor derived from epithelial tissue that tends to metastasize to other areas of the body”. http://dictionary.reference.com/browse/carcinoma%
Melanoma- A dark-pigmented benign or malignant tumor that arises from a melanocyte and occurs most commonly in the skin. Malignant melanoma metastasizes quickly and is associated with sun exposure. http://dictionary.reference.com/browse/melanoma
Summary:
The new research that is described in the primary study is that the BRAF mutation is involved in papillary thyroid cancer. The study was done at Johns Hopkins University School of Medicine. The researchers already knew that BRAF was linked to melanoma, and that there must have been a genetic mutation in papillary thyroid cancers. Thus they tested for it in thyroid cancer as well as the other cancers mention above.
The researchers did a test on 476 tumors, for 214 lungs, 126 head and neck, 54 thyroids, 27 bladder, 38 cervical, and 17 prostate cancers for BRAF T1796A mutation by polymerase chain reaction. These samples were taken from the patients and were kept in the tissue bank.
Through their experiments, Cohen et al found a mutation in the BRAF T1796A gene in 69% of papillary thyroid cancers. They discovered that there was a misinterpretation in the chemical bases in the following amino acid (adenine, thymine, cytosine, and guanine that help build up DNA. In the BRAF gene in the nucleotide 1796 it changed (T) thymine to (A) adenine. The researchers discovered that a single coding mistake in more than 2000 in the nucleotides in gene made it stay on the “on” position, causing thyroid cells to proliferate and divide into a cancer. They screened for the BRAF gene mutation in different types of cancers and thyroid tumors. They did not find any mutation in the biopsy samples of the 20 sample of benign thyroid, 13 of the patients had follicular, and 3 with medullary thyroid carcinoma and Hurthle cell carcinoma. This was not found in some other thyroid cancers, nor in cervical, prostate, or bladder cancers.
The primary scientific article describes in great detail the BRAF mutation, its role in malignant melanoma, and how it could relate to papillary thyroid cancer. The researchers explained their methods, using scientific terms for cell lines, mutations, and genes. On the other hand, the USA Today article talks about other thyroid cancers, and mentions there are many new studies all over the country, not just at Johns Hopkins. However, the articles give in the same information about one finding, but in very different languages. The primary article states that “The high frequency of BRAF mutations in melanoma and papillary thyroid carcinoma suggests that inhibition of BRAF activity by the newly developed RAF kinase inhibitors (12) may offer a new strategy in the treatment of these tumors.” On the other hand, the secondary article states “the gene, called BRAF, acts as an on/off switch for cell growth. In tumors with the mutation, this switch gets stuck in the “on” position.” Most readers without a scientific background can understand about an on/off switch, but not about RAF kinase inhibitors.
My reaction to the information provided in the primary article is that it is very helpful for people who are interested in doing research. There were a few charts and tables that helped me to understand the results of the research, and what was the researchers purpose. The secondary article was extremely simple to understand the audience does not have to be scientists or a science majors to understand; what was being done. I trust the primary article more because it has more reliable information and it is written in a way that you know a scientist or a researchers who knew what they were doing or talking about wrote the article. However, the secondary article does quote scientists from notable research centers, including David Sidransky, who was one of the researchers in the primary article (et al.!) and is the director of the Johns Hopkins University School of Medicine.
Question
why does chemo and radiation therapy only shrink the anaplsatic tumor for a short period of time?
Why is the activation of BRA mutations is so important in development of papillary thyroid cancer?
Pee Worried!!!
News Article:
Drug Week Editors (February 11, 2005) “Fragile histidine triad gene inactivation supports bladder cancer formation.”
Primary Article:
Vecchione, A., Sevignani C. , Giarnieri, E. (2004, Novemer 15) Inactivation of the FHIT Gene Favors Bladder Cancer Development. Clinical Cancer Research Vol. 10, 7607-7612
Cited Article:
Ishii, H., Mimori, K., Inoue, H. (2006, December 6) Fhit Modulates the DNA Damage Checkpoint Response. Cancer Research 66, 11287-11292
The cancer being addressed in these articles is bladder cancer. New research being described in the articles is exploring the possibility of a FHIT-based gene therapy for bladder cancer. Researchers have studied and found that the fragile histidine triad (FHIT) gene inactivation supports bladder cancer formation. They have found that the "FHIT gene located on chromosome 3p14.2 is frequently deleted in human tumors". Researchers studied the effects of "restored Fhit protein expression on cell proliferation, cell kinetics, and tumorigenicity in BALB/c nude mice, with human SW780 Fhit-null transitional carcinoma derived cells". Researchers found that “in-vitro transduction of SW780 Fhit-negative cells with adenoviral-FHIT inhibited cell growth, increased apoptotic cell population, and suppressed subcutaenoustumor growth in nude mice”. Scientist’s findings suggested that the “important role of Fhit in bladder cancer development and support the effort to additionally investigate a FHIT-based gene therapy”.
Both articles discuss the main point of the research. They give the same information but the same details. The news article and primary article both discussed the FHIT gene and its location, the role of FHIT alteration in the development of bladder cancer. Both articles discussed the experiments done to explore the possibility of FHIT gene therapy for bladder cancer.
Although both articles discussed the same points and described the findings of the research, the news article provided the information in a better read. The news article did not provide much of the results and discussion in a scientific read. They did not get specific and go into detail. The primary article stated all the research done and described in detail the findings. Each result had a discussion explaining the results.
My reactions to the articles are positive. Reading about the experiments done and their findings helps me to understand what research is being done on bladder cancer. I trust both sources and do not find any to be misleading. Both sources were informational but the primary article provided more experiments and results than the news article. The questions I have for researchers are: How early on can bladder cancer be detected? and How soon will a FHIT-based gene therapy be available for patients?
Drug Week Editors (February 11, 2005) “Fragile histidine triad gene inactivation supports bladder cancer formation.”
Primary Article:
Vecchione, A., Sevignani C. , Giarnieri, E. (2004, Novemer 15) Inactivation of the FHIT Gene Favors Bladder Cancer Development. Clinical Cancer Research Vol. 10, 7607-7612
Cited Article:
Ishii, H., Mimori, K., Inoue, H. (2006, December 6) Fhit Modulates the DNA Damage Checkpoint Response. Cancer Research 66, 11287-11292
The cancer being addressed in these articles is bladder cancer. New research being described in the articles is exploring the possibility of a FHIT-based gene therapy for bladder cancer. Researchers have studied and found that the fragile histidine triad (FHIT) gene inactivation supports bladder cancer formation. They have found that the "FHIT gene located on chromosome 3p14.2 is frequently deleted in human tumors". Researchers studied the effects of "restored Fhit protein expression on cell proliferation, cell kinetics, and tumorigenicity in BALB/c nude mice, with human SW780 Fhit-null transitional carcinoma derived cells". Researchers found that “in-vitro transduction of SW780 Fhit-negative cells with adenoviral-FHIT inhibited cell growth, increased apoptotic cell population, and suppressed subcutaenoustumor growth in nude mice”. Scientist’s findings suggested that the “important role of Fhit in bladder cancer development and support the effort to additionally investigate a FHIT-based gene therapy”.
Both articles discuss the main point of the research. They give the same information but the same details. The news article and primary article both discussed the FHIT gene and its location, the role of FHIT alteration in the development of bladder cancer. Both articles discussed the experiments done to explore the possibility of FHIT gene therapy for bladder cancer.
Although both articles discussed the same points and described the findings of the research, the news article provided the information in a better read. The news article did not provide much of the results and discussion in a scientific read. They did not get specific and go into detail. The primary article stated all the research done and described in detail the findings. Each result had a discussion explaining the results.
My reactions to the articles are positive. Reading about the experiments done and their findings helps me to understand what research is being done on bladder cancer. I trust both sources and do not find any to be misleading. Both sources were informational but the primary article provided more experiments and results than the news article. The questions I have for researchers are: How early on can bladder cancer be detected? and How soon will a FHIT-based gene therapy be available for patients?
Does the Estrogen Receptor βeta have an Influential Role in inhibiting the Effects of Ovarian Cancer?
Lazennec, Gwendal (2004). Involvement of Estrogen Receptor β in Ovarian Cancinogenesis. Cancer Research, 64, 5861-5869. Retrieved February 12, 2008, from the World Wide Web:
http://cancerres.aacrjournals.org/cgi/content/abstract/64/16/5861
Lazennec, Gwendal (2004). Ovarian Cancer; Reduced ER beta in cancer cells loss in tumor-suppressing ability. Drug Week, 493. Retrieved February 12, 2008, from the World Wide Web:
http://www.newsrx.com/
L. Albanito, A. Madeo, R. Lappano, A. Vivacqua, V. Rago, A. Carpino, T. I. Oprea, E. R. Prossnitz, A. M. Musti, S. Ando, et al. (2007). G Protein-Coupled Receptor 30 (GPR30) mediates Gene Expression Changes and Growth Response to 17 {beta}-Estradiol and Selective GPR30 Ligand G-1 in Ovarian Cancer Cells. Cancer Research, 67(4), 1859-1866. Retrieved February 12, 2008, from the World Wide Web:
http://cancerres.aacrjournals.org/cgi/content/abstract/64/16/5861
D. Alvaro, B. Barbaro, A. Franchitto, P. Onori, S. S. Glaser, G. Alpini, H. Francis, L. Marucci, P. Sterpetti, S. Ginanni-Corradini, et al. (2006). Estrogens and Insulin-Like Growth Factor 1 Modulate Neoplastic Cell Growth in Human Cholangiocarinoma. The American Journal of Pathology, 169(3), 877-888. Retrieved February 12, 2008, from the World Wide Web:
http://cancerres.aacrjournals.org/cgi/content/abstract/64/16/5861
A. J O’Donell, K. G Macleod, D. J Burns, J. F Smyth, and S. P Langdon (2005). Estrogen receptor-{alpha} mediates gen expression changes and growth response in ovarian cancer cells exposed to estrogen. Endocrine-Related Cancer, 12(4), 851-866. Retrieved February 12, 2008, from the World Wide Web:
http://cancerres.aacrjournals.org/cgi/content/abstract/64/16/5861
Does the Estrogen Receptor βeta have an Influential Role in inhibiting the Effects of Ovarian Cancer?
Early discoveries showed evidence of the estrogen hormone playing a role in cancer. Although researchers knew that estrogen has an effect on cancer their knowledge of its specific role was vague. Researchers limited knowledge and urge to learn more was what lead to further studies about estrogen. The reason why an estrogen ovarian cancer study was conducted is that ovarian cancer is very common amongst women and has a high mortality rate. Also, estrogen has a correlation with ovarian cancer and a study would determine the exact correlation between estrogen and ovarian cancer. The results of a successful study would lead to future drugs for treatment of ovarian cancer and other cancers.
The study was conducted with approximately four dozen test subjects. The subjects were women who had ovarian cancer. Ovarian cysts and tumors were extracted from the patients in order to be used as test material. Normal ovaries were used as the control. The cysts and tumors were tested to see if they showed signs of for ERα and or ERβ receptors. The researchers wanted to see if these two receptors of the same family had a different effect on cancer proliferation.
The tests on the cyst and tumors showed that both ERα and ERβ receptors were present in the infected cells. The ERβ receptors were depleted in number compared to the number of receptors present in a healthy individual. The roles of the receptors were also very much different in how the effected the progression of cancer. The ERα receptors had little effect on inhibiting cell growth. The ERβ receptors seem to have an inhibitory effect on cell growth and mobility.
Later in the study the normal ovaries were study in order to confirm the researchers’ suspicions. The normal ovaries were infected with various viruses that would make the normal ovaries become cancerous. After a 24hr span the ovaries were attempted to be treated by the researchers. The researchers introduced ERα and ERβ receptors to the infected cells. The ERα receptors did not have much of an inhibitory effect on cancer cell proliferation. On the other hand the ERβ receptors had a great inhibitory effect on the cancer cells proliferation and mobility. ERβ receptors slowed cell proliferation and mobility by over 50% which confirmed the researchers’ suspicions that ERβ receptors are inhibitors of cancer cells.
The two articles that I used to gather information on the studied topic were both beneficial. Both articles gave the same information. The only differences between the articles is that the secondary source was a condense version of the primary source; and that the primary source was just more in depth about numerical data and included charts. The overall content of both articles were the same in regards of being equally informative. I believe that the articles are a huge break through for future cancer treatment. Both articles are equally beneficial. Although, the primary source is more in depth with its data, the secondary source is easier to be understood by some one who does not have a strong science background.
Some additional questions are:
1.What are scientists going to do with this new found information?
2.Will more studies be conducted to see how ERβ receptors affect other types of cancers?
Can we finally stop breast cancer from spreading?!
News Article:
Thomas Jefferson University (2007, April 11). Scientists Identify Protein Key To Breast Cancer Spread, Potential New Drug Target. ScienceDaily. Retrieved February 13, 2008, from
http://www.sciencedaily.com /releases/2007/04/070409181641.htm
Primary Scientific Article:
Xiaoming Ju, Sanjay Katiyar, Chenguang Wang, Manran Liu, Xuanmao Jiao, Shengwen Li, Jie Zhou, Jacob Turner, Michael P. Lisanti, Robert G. Russell, Susette C. Mueller, John Ojeifo, William S. Chen, Nissim Hay, and Richard G. Pestell. (2007, May). Akt1 Governs Breast Cancer Progression In Vivo. Proceedings of the National Academy of Sciences, 104: 7438 – 7443.
Article Citing Primary Article:
Margit Hagel, Elizabeth L. George, Ann Kim, Rulla Tamimi, Sarah L. Opitz, Christopher E. Turner, Akira Imamoto, and Sheila M. Thomas (2002, Feb.). The Adaptor Protein Paxillin Is Essential for Normal Development in the Mouse and Is a Critical Transducer of Fibronectin Signaling. Proceedings of the National Academy of Sciences, 22: 901 - 915.
Xiao-ding Peng, Pei-Zhang Xu, Mei-Ling Chen, Annett Hahn-Windgassen, Jennifer Skeen, Joel Jacobs, Deepa Sundararajan, William S. Chen, Susan E. Crawford, Kevin G. Coleman, and Nissim Hay (2003, June). Dwarfism, Impaired Skin Development, Skeletal Muscle Atrophy, Delayed Bone Development, and Impeded Adipogenesis in Mice Lacking Akt1 and Akt2.Genes & Dev, 17: 1352 - 1365.
Manuel Morales-Ruiz, David Fulton, Grzegorz Sowa, Lucia R. Languino, Yasushi Fujio, Kenneth Walsh, and William C. Sessa (2000, Apr.). Vascular Endothelial Growth Factor–Stimulated Actin Reorganization and Migration of Endothelial Cells Is Regulated via the Serine/Threonine Kinase Akt. Circ. Res, 86: 892 - 896.
Summary:
Year after year, thousands of women are continuously being diagnosis with breast cancer and dying from this deadly disease as well. After skin cancer, breast cancer is the most common type of cancer that of woman in the United States today. As the years go on, researchers are getting closer and closer to discovering the causes of breast cancer and working on new drugs to block it from traveling all over the body and even help treat the disease all together.
Although more women are being diagnosed with it, fewer women are dying. Breast cancer tends to be more popular in women age 40 and up then the young. It is said that women should give there self monthly breast screening tests, clinical breast exams, and even yearly mammograms searching for any bumps, lumps, or other abnormalities, just in case cancer forms, so it can quickly be treated in it’s early stages.
Like many other cancers, breast cancer is said to be found best in its early stage. This is because if it is caught during this time, most likely it is not spread throughout the body as much as it could have been. The ScienceDaily article mentioned that any of the anti-Akt drugs that they are working on will work better on earlier cancers than the later ones, which is something that we already knew about. What the researchers for this study did, in order to find the protein that helps with the spreading of breast cancer, was changed the inheritance of the mice so they will lack Akt1. The way they did this was by raising the mice that was missing the Akt1 gene with other mice that held the ErbB2 oncogene. Once this part was done, researchers examined carefully looked at the role that Akt played.
In the end of there experiments, researchers came across the protein itself that helps spread breast cancer. They found that mice who didn’t have two copies of the gene said to produce Akt1 didn’t really get any tumors but, the ones that had one copy of it developed more tumors that where very small and grew in very slow. And mice that had both copies of Akt1 developed cancer very fast. This showed them that Akt1 is a gene that they should look into that can be a main cause of ErbB2 breast cancer development.
The primary scientific article and ScienceDaily have very similar information but, the primary scientific article gives more detail on there study, how they went about it, and more findings. Due to similar information that was found in the news article, I trust it’s findings but the primary scientific article is just a little bit more trustworthy due to the details and the information is coming directly from those who did the research. The question that is left for researchers is whether or not the patient’s samples that they were looking at is important in promoting metastasis breast cancer of other types? What I do wonder about as well, is how long did it take the researchers to actually do this study since they had to bread mice to come to the conclusions that they had? And why do patients who use Herceptin, a treatment for ErbB2-positive breast cancer, end up relapsing.
Kidney Cancer Caused by "Sleeping Gene"? Rise and Shine!!!!
News Article:
Mayo Clinic (2007). Reactivating a Critical Gene Lost in Kidney Cancer Reduces Tumor Growth. Retrieved from http://www.sciencedaily.com/releases/2007/08/070815120439.htm
Primary Scientific Article:
Gumz, M.L. et al. (2007) Secreted Frizzled-Related Protein 1 Loss Contributes to Tumor Phenotype of Clear Cell Renal Cell Carcinoma. Clinical Cancer Research; 13(16)
This article has been cited by:
Morris, M.R. et al. (2008) Fundamental Epigenomics Approach to Identify Methylated Candidate Tumor Suppressor Genes in Renal Cell Carcinoma. British Journal of Cancer 98, 496-501
Rubin, J.S., Bottaro, D.P. (2007) Loss of Secreted Frizzled-Related Protein-1 Expression in renal Cell Carcinoma Reveals a Critical Tumor Suppressor Function. Clinical Cancer Research 13; 4660-4663
Could this be? Is the idea of having a “sleeping” gene a true one? Well in short the answer is yes. Secreted Frizzled-Related Protein 1, more commonly known as sFRP1, is a critical protein that has been found dormant or silent in clear cell renal carcinoma. Clear cell renal carcinoma or ccRCC is the most frequently occurring form of kidney cancer and the occurrences are increasing each year. Not only is it a common kidney cancer, but it has shown a resistance to radiation and chemotherapy therefore making it extremely difficult to treat. Obviously this called for a close examination of the molecular activity taking place in this type of cancer. This is what led researchers at the Mayo Clinic in Florida to conduct a study on the topic.
Normally, sFRP1 functions as a tumor suppressor gene that stops the WNT signaling pathway, which in turn would prevent an oncogenic signal chain from continuing uncontrollably. This would also prevent tumor growth and metastisis, which would occur due to the invasive nature of cancer cells. Unfortunately, through a process called methylation, proteins and transcription factors are blocked and unable to activate genes. This is to say that sFRP was never “turned on”. Therefore, in discovering the inactivity of sFRP1 in ccRCC scientists hypothesized a causational relationship between the protein inactivity and tumor growth. Furthermore, this would mean that reactivating sFRP1 would stop tumors from growing and even eliminate existing ones.
Were researchers able to prove this? The answer is yes. Researchers transfected the sFRP1 gene into human renal cancer cells. This allowed them to reactivate sFRP1 in human, animals, and tumors did in fact stop growing. Science Daily offered a brief yet accurate synopsis of the major findings by the research done at the Mayo Clinic. Basically they pointed out a few methods used to examine levels of sFRP1 from patient samples. Researchers found with one sample that the gene expression of sFRP1 was low. In another sample they saw low levels of sFRP1 mRNA, which is needed for the production of sFRP1. Lastly they point out that there was a comparison made between normal and cancerous cells. The vast majority of these cancerous samples exhibited a loss of sFRP1.
On the other hand, what is better than getting the information directly from the people who conducted the research? The researchers offer a detailed and concise step by step portrayal of the study and the findings. It is so detailed that the study can be duplicated just from reading the article. This is in fact the most trustworthy source for information on the issue. These findings open the door for treatment development for ccRCC and maybe other cancers. They may also lead to further research to answer questions about preventative measures and in which stages of the disease will reactivating sFRP1 be effective.
Mayo Clinic (2007). Reactivating a Critical Gene Lost in Kidney Cancer Reduces Tumor Growth. Retrieved from http://www.sciencedaily.com/releases/2007/08/070815120439.htm
Primary Scientific Article:
Gumz, M.L. et al. (2007) Secreted Frizzled-Related Protein 1 Loss Contributes to Tumor Phenotype of Clear Cell Renal Cell Carcinoma. Clinical Cancer Research; 13(16)
This article has been cited by:
Morris, M.R. et al. (2008) Fundamental Epigenomics Approach to Identify Methylated Candidate Tumor Suppressor Genes in Renal Cell Carcinoma. British Journal of Cancer 98, 496-501
Rubin, J.S., Bottaro, D.P. (2007) Loss of Secreted Frizzled-Related Protein-1 Expression in renal Cell Carcinoma Reveals a Critical Tumor Suppressor Function. Clinical Cancer Research 13; 4660-4663
Could this be? Is the idea of having a “sleeping” gene a true one? Well in short the answer is yes. Secreted Frizzled-Related Protein 1, more commonly known as sFRP1, is a critical protein that has been found dormant or silent in clear cell renal carcinoma. Clear cell renal carcinoma or ccRCC is the most frequently occurring form of kidney cancer and the occurrences are increasing each year. Not only is it a common kidney cancer, but it has shown a resistance to radiation and chemotherapy therefore making it extremely difficult to treat. Obviously this called for a close examination of the molecular activity taking place in this type of cancer. This is what led researchers at the Mayo Clinic in Florida to conduct a study on the topic.
Normally, sFRP1 functions as a tumor suppressor gene that stops the WNT signaling pathway, which in turn would prevent an oncogenic signal chain from continuing uncontrollably. This would also prevent tumor growth and metastisis, which would occur due to the invasive nature of cancer cells. Unfortunately, through a process called methylation, proteins and transcription factors are blocked and unable to activate genes. This is to say that sFRP was never “turned on”. Therefore, in discovering the inactivity of sFRP1 in ccRCC scientists hypothesized a causational relationship between the protein inactivity and tumor growth. Furthermore, this would mean that reactivating sFRP1 would stop tumors from growing and even eliminate existing ones.
Were researchers able to prove this? The answer is yes. Researchers transfected the sFRP1 gene into human renal cancer cells. This allowed them to reactivate sFRP1 in human, animals, and tumors did in fact stop growing. Science Daily offered a brief yet accurate synopsis of the major findings by the research done at the Mayo Clinic. Basically they pointed out a few methods used to examine levels of sFRP1 from patient samples. Researchers found with one sample that the gene expression of sFRP1 was low. In another sample they saw low levels of sFRP1 mRNA, which is needed for the production of sFRP1. Lastly they point out that there was a comparison made between normal and cancerous cells. The vast majority of these cancerous samples exhibited a loss of sFRP1.
On the other hand, what is better than getting the information directly from the people who conducted the research? The researchers offer a detailed and concise step by step portrayal of the study and the findings. It is so detailed that the study can be duplicated just from reading the article. This is in fact the most trustworthy source for information on the issue. These findings open the door for treatment development for ccRCC and maybe other cancers. They may also lead to further research to answer questions about preventative measures and in which stages of the disease will reactivating sFRP1 be effective.
IKBKE gene amplification is seen loud and clear in breast cancer tumors!
News Article:
Kirkley, Sharon. (2007, June 15). Cancer fight may have key gene to target; Breast Cancer Research. National Post Canada.
Primary Scientific Article:
Boehm, Jesse S. et. al (2007). Integrative Genomic Approaches Identify IKBKE as a Breast Cancer Oncogene. Cell Press Vol. 129, pp. 1065-1079
Articles citing primary article:
1. Adelaide, Jose. et. al (2007). Integrated Profiling of Basal and Luminal Breast Cancers. Cancer Research Vol. 67, pp. 11565-11575
2. Liu, Dingxie, Liu Zhi, Jiang David, Dackiw, Alan P., and Xing Mingzhao. et. al (2007). Inhibitory Effects of the Mitogen-Activated Protein Kinase Kinase Inhibitor CI-1040 on the Proliferation and Tumor Growth of Thyroid Cancer Cells with BRAF or RAS Mutations. Journal of Clinical Endocrinology & Metabolism Vol. 92, pp. 4686-4695
Summary:
Researchers found that the onset and survival of breast cancer cells is in part due to a mutation in IKBKE that resulted in gene amplification. Mutated IKBKE is an oncogene that results in uncontrolled cell proliferation. Prior to this research little was known in regards to how IKBKE could cause cancer or why the over activation of NFkB pathways seemed to be a common characteristic of breast cancer. The discovery found in the article is important because it could potentially lead to effective breast cancer drugs and therapies. Breast cancer is the most common form of cancer found in women.
The researchers used a combination of various techniques to find and isolate the gene that was causing cancer. Their initial goal was unrelated to the study of IKBKE. They first set out to study if two pathways commonly associated with normal cell cycle control and cancer RAS-MAPK and P13K-AKT could be hyper activated resulting in uncontrolled cell proliferation without there being a mutation in RAS. RAS is a proto-oncogene that activates both pathways. In order to study this the scientists created sixteen cell lines expressing all possible combinations of the three mutations, other then that of RAS, that were known to cause problems in the cell signaling pathways of MAPK and P13K. Scientists closely monitored the number of initial mutations and copies of those mutations so that all cell cultures would be alike with the exception of the initial mutation they had been given. Results showed that tumor growth would appear when both RAS-MAPK and the P13K- AKT pathways were over activated and communicated with each other. This activity would occur via co-expression of MEK that would activate the MAPK pathway and myr-AKT expression that would activate the P13K pathway. Since both pathways generate signals that produce transcription factors via a signal cascade due to phosphorylation, the scientists then set out to find out what kinases would have the ability to affect signal transduction in one or both pathways and possibly contribute in the aforementioned co-expression. In order to pinpoint kinases scientists then created cell lines that expressed MEK and myr-AKT kinases to ORF’s, open reading frames to see if they would induce cancer. As a result of this experiment four kinases were identified. Unfortunately, with the results of this experiment another question emerged. Were any if not all of these kinases over expressed in human cancers?
In order to test whether or not any or all of these kinases were over expressed in human cancers, regions of cancer cell tumors that presented single nucleotide polymorphisms that may have resulted in a mutation that encoded, for more kinases then it should have, were examined. One hundred seventy nine cell lines were examined in total and from all of those the only gene that was amplified was IKBKE. In order to narrow IKBKE relationship to cancer in general and be able to draw conclusions between the IKBKE mutation and specific cancers, a CGH was performed on 30 breast tumors of different stages to see if a mutation in IKBKE could be a specific cause of breast cancer. The procedure CGH simply involves screening tumor samples for genetic changes showing patterns of copy number changes i.e. gene amplification. This procedure found a mutation on chromosome 1q32. Unfortunately, however, these results only led to the emergence of another question. Could increased levels of IKBKE by itself cause cancer? What would happen to the cell if IKBKE was under expressed i.e. suppressed?
The scientists chose to create cell lines that expressed gene amplification of IKBKE wild type to test whether or not increased levels of IKBKE alone was enough to cause cancer. Upon observation of theses cell lines the researchers noted that an increase in levels of IKBKE led to an increase in transcription via activation of the NFkB pathway that resulted in an increase in protein levels that promoted cell proliferation. When IKBKE was inactivated within the same cell lines breast cancer cells were unable to proliferate. In order to further test if the activation of NFkB was necessary in cell transformation, the scientists mutated the NFkB pathway so that it would be unable to phosphorylate and initiate internal signals. These cell lines when compared to those with increased levels of IKBKE and a functioning NFkB pathway experienced much less cancer formation. Therefore IKBKE normally functions as a kinase but when expressed in high levels within cells it can function as an oncogene that promotes cell proliferation via activation and communication of the NFkB pathway.
The primary article as to be expected provides more information and details about the approaches and methods the researchers used to discover that the presence of IKBKE in excess within cells had the capability of inducing cellular transformation resulting in cancer. While the news article simply provides readers with basic information regarding the fact that the scientists were studying kinases to see if the presence of any in excess could be attributed to cancer and discovered that IKBKE seemed to present in high amounts amongst the breast cancer tumors they examined. Utilizing this comparison it is obvious that the primary article is more trustworthy. Both articles, however, due a good job in describing how the discovery could in the near future lead to more effective breast cancer treatments and therapies thereby improving the lives of thousands of women. In this way both articles make me feel hopeful about the future of cancer research.
Questions:
How would researchers go about trying to produce a drug that triggers the mutation that produces excess IKBKE?
How many other kinases are known to play a part in cellular transformation?
Kirkley, Sharon. (2007, June 15). Cancer fight may have key gene to target; Breast Cancer Research. National Post Canada.
Primary Scientific Article:
Boehm, Jesse S. et. al (2007). Integrative Genomic Approaches Identify IKBKE as a Breast Cancer Oncogene. Cell Press Vol. 129, pp. 1065-1079
Articles citing primary article:
1. Adelaide, Jose. et. al (2007). Integrated Profiling of Basal and Luminal Breast Cancers. Cancer Research Vol. 67, pp. 11565-11575
2. Liu, Dingxie, Liu Zhi, Jiang David, Dackiw, Alan P., and Xing Mingzhao. et. al (2007). Inhibitory Effects of the Mitogen-Activated Protein Kinase Kinase Inhibitor CI-1040 on the Proliferation and Tumor Growth of Thyroid Cancer Cells with BRAF or RAS Mutations. Journal of Clinical Endocrinology & Metabolism Vol. 92, pp. 4686-4695
Summary:
Researchers found that the onset and survival of breast cancer cells is in part due to a mutation in IKBKE that resulted in gene amplification. Mutated IKBKE is an oncogene that results in uncontrolled cell proliferation. Prior to this research little was known in regards to how IKBKE could cause cancer or why the over activation of NFkB pathways seemed to be a common characteristic of breast cancer. The discovery found in the article is important because it could potentially lead to effective breast cancer drugs and therapies. Breast cancer is the most common form of cancer found in women.
The researchers used a combination of various techniques to find and isolate the gene that was causing cancer. Their initial goal was unrelated to the study of IKBKE. They first set out to study if two pathways commonly associated with normal cell cycle control and cancer RAS-MAPK and P13K-AKT could be hyper activated resulting in uncontrolled cell proliferation without there being a mutation in RAS. RAS is a proto-oncogene that activates both pathways. In order to study this the scientists created sixteen cell lines expressing all possible combinations of the three mutations, other then that of RAS, that were known to cause problems in the cell signaling pathways of MAPK and P13K. Scientists closely monitored the number of initial mutations and copies of those mutations so that all cell cultures would be alike with the exception of the initial mutation they had been given. Results showed that tumor growth would appear when both RAS-MAPK and the P13K- AKT pathways were over activated and communicated with each other. This activity would occur via co-expression of MEK that would activate the MAPK pathway and myr-AKT expression that would activate the P13K pathway. Since both pathways generate signals that produce transcription factors via a signal cascade due to phosphorylation, the scientists then set out to find out what kinases would have the ability to affect signal transduction in one or both pathways and possibly contribute in the aforementioned co-expression. In order to pinpoint kinases scientists then created cell lines that expressed MEK and myr-AKT kinases to ORF’s, open reading frames to see if they would induce cancer. As a result of this experiment four kinases were identified. Unfortunately, with the results of this experiment another question emerged. Were any if not all of these kinases over expressed in human cancers?
In order to test whether or not any or all of these kinases were over expressed in human cancers, regions of cancer cell tumors that presented single nucleotide polymorphisms that may have resulted in a mutation that encoded, for more kinases then it should have, were examined. One hundred seventy nine cell lines were examined in total and from all of those the only gene that was amplified was IKBKE. In order to narrow IKBKE relationship to cancer in general and be able to draw conclusions between the IKBKE mutation and specific cancers, a CGH was performed on 30 breast tumors of different stages to see if a mutation in IKBKE could be a specific cause of breast cancer. The procedure CGH simply involves screening tumor samples for genetic changes showing patterns of copy number changes i.e. gene amplification. This procedure found a mutation on chromosome 1q32. Unfortunately, however, these results only led to the emergence of another question. Could increased levels of IKBKE by itself cause cancer? What would happen to the cell if IKBKE was under expressed i.e. suppressed?
The scientists chose to create cell lines that expressed gene amplification of IKBKE wild type to test whether or not increased levels of IKBKE alone was enough to cause cancer. Upon observation of theses cell lines the researchers noted that an increase in levels of IKBKE led to an increase in transcription via activation of the NFkB pathway that resulted in an increase in protein levels that promoted cell proliferation. When IKBKE was inactivated within the same cell lines breast cancer cells were unable to proliferate. In order to further test if the activation of NFkB was necessary in cell transformation, the scientists mutated the NFkB pathway so that it would be unable to phosphorylate and initiate internal signals. These cell lines when compared to those with increased levels of IKBKE and a functioning NFkB pathway experienced much less cancer formation. Therefore IKBKE normally functions as a kinase but when expressed in high levels within cells it can function as an oncogene that promotes cell proliferation via activation and communication of the NFkB pathway.
The primary article as to be expected provides more information and details about the approaches and methods the researchers used to discover that the presence of IKBKE in excess within cells had the capability of inducing cellular transformation resulting in cancer. While the news article simply provides readers with basic information regarding the fact that the scientists were studying kinases to see if the presence of any in excess could be attributed to cancer and discovered that IKBKE seemed to present in high amounts amongst the breast cancer tumors they examined. Utilizing this comparison it is obvious that the primary article is more trustworthy. Both articles, however, due a good job in describing how the discovery could in the near future lead to more effective breast cancer treatments and therapies thereby improving the lives of thousands of women. In this way both articles make me feel hopeful about the future of cancer research.
Questions:
How would researchers go about trying to produce a drug that triggers the mutation that produces excess IKBKE?
How many other kinases are known to play a part in cellular transformation?
Evidence of RTK Co Activation for GBM Tumors!!!!!
News article:
(2007, October 5). Study Suggest Brain Tumors Need Treatment With Multiple ‘Targeted’ Drugs. Drug Week, p. 76
Primary scientific article:
Stommel, J.M. et al. (2007). Co activation of Receptor Tyrosine Kinases Affects the Response of Tumor Cells to Targeted Therapies
Articles citing primary article:
Weil R.J (2008). Incorporating Molecular Tools into Early-Stage Clinical Trials. PLoS Med 5(1): e21
Doi:10.1371/journal.pmed.050021
Guo A. (2008, January 7). Signaling networks assembled by oncogenic EGFR and c-Met. The National Academy of Sciences of the USA
Guirgis H.M (2007). A perspective on tyrosine kinase inhibitors in gastrointestinal stromal tumors and cancer: past and present with emphasis on future and cost. Cancer Therapy Vol 5
Summary:
The primary and secondary article focuses on the study of glioblastoma multiforme (GBM). GBM is an aggressive brain tumor that is nearly always fatal. It’s the most prevalent and highest malignant tumor in the central nervous system of human adults and also the most lethal of many cancers.
What is already known is that receptor tyrosine kinase (RTK) is located on the surface of both normal and cancerous cells and receive signals from the cells location. The signals are chemical “growth factors” directing the cells to divide and grow. Launch of PI3K pathway components appears to be universal in GBM. Activation and signaling received by RTK are transmitted to the cells nucleus by PI3K and behaves abnormally in cancer cells. An epidermal growth factor receptor (EGFR) is a key pathogenic event, with amplification of mutation has been implicated in GBM. Making it a forceful target for therapeutic inhibition. Other RTK’s have been reported to be misrepresented in GBM. Researchers evaluated and sought data that several PI3k activators coexist in glioma cell lines.
The goal of the study is to define the compendium of co activated RTKs in GBM, by using an antibody array technique that will allow simultaneous assessment of the phosphorylation status of 45 RTKs at one time. This test was determined by consequent incubation. Researchers incubated 20 glioma cell lines LN382, SF763, LN18 and HS683 on RTK antibody arrays. Phosphorylations were determined by incubation with horse radish peroxidase. In 19 of the 20 cell lines, three or more RTKs were activated at the same time sending abnormal growth signals to the nucleus. Researchers also explored the therapeutic implications of RTK co activation. By using U87MG glioma cells that constitutively expressed a kinase-dead EGFR vIII (growth factor receptors) at levels comparable to those observed in primary GBMs.
Researchers found that most activated RTKs remained phosphorylated under serum deficiency and in tumor cells. Demonstrating that the RTK activation in the altered cells, is not due to ligands in serum-containing culture media’s. The findings of the study explained clinical responses to RTK-inhibitor monotherapy for many tumor types and look forward to constructive outcomes by combinations of drugs alongside different activated RTKs. The study provided proof for ultimate accomplishment of a therapeutic pattern in human cancer.
(2007, October 5). Study Suggest Brain Tumors Need Treatment With Multiple ‘Targeted’ Drugs. Drug Week, p. 76
Primary scientific article:
Stommel, J.M. et al. (2007). Co activation of Receptor Tyrosine Kinases Affects the Response of Tumor Cells to Targeted Therapies
Articles citing primary article:
Weil R.J (2008). Incorporating Molecular Tools into Early-Stage Clinical Trials. PLoS Med 5(1): e21
Doi:10.1371/journal.pmed.050021
Guo A. (2008, January 7). Signaling networks assembled by oncogenic EGFR and c-Met. The National Academy of Sciences of the USA
Guirgis H.M (2007). A perspective on tyrosine kinase inhibitors in gastrointestinal stromal tumors and cancer: past and present with emphasis on future and cost. Cancer Therapy Vol 5
Summary:
The primary and secondary article focuses on the study of glioblastoma multiforme (GBM). GBM is an aggressive brain tumor that is nearly always fatal. It’s the most prevalent and highest malignant tumor in the central nervous system of human adults and also the most lethal of many cancers.
What is already known is that receptor tyrosine kinase (RTK) is located on the surface of both normal and cancerous cells and receive signals from the cells location. The signals are chemical “growth factors” directing the cells to divide and grow. Launch of PI3K pathway components appears to be universal in GBM. Activation and signaling received by RTK are transmitted to the cells nucleus by PI3K and behaves abnormally in cancer cells. An epidermal growth factor receptor (EGFR) is a key pathogenic event, with amplification of mutation has been implicated in GBM. Making it a forceful target for therapeutic inhibition. Other RTK’s have been reported to be misrepresented in GBM. Researchers evaluated and sought data that several PI3k activators coexist in glioma cell lines.
The goal of the study is to define the compendium of co activated RTKs in GBM, by using an antibody array technique that will allow simultaneous assessment of the phosphorylation status of 45 RTKs at one time. This test was determined by consequent incubation. Researchers incubated 20 glioma cell lines LN382, SF763, LN18 and HS683 on RTK antibody arrays. Phosphorylations were determined by incubation with horse radish peroxidase. In 19 of the 20 cell lines, three or more RTKs were activated at the same time sending abnormal growth signals to the nucleus. Researchers also explored the therapeutic implications of RTK co activation. By using U87MG glioma cells that constitutively expressed a kinase-dead EGFR vIII (growth factor receptors) at levels comparable to those observed in primary GBMs.
Researchers found that most activated RTKs remained phosphorylated under serum deficiency and in tumor cells. Demonstrating that the RTK activation in the altered cells, is not due to ligands in serum-containing culture media’s. The findings of the study explained clinical responses to RTK-inhibitor monotherapy for many tumor types and look forward to constructive outcomes by combinations of drugs alongside different activated RTKs. The study provided proof for ultimate accomplishment of a therapeutic pattern in human cancer.
While reading both the Primary and Secondary article, I noticed that they both had the same content. The secondary article was obviously easier to to read because it was basically a summary of the primary article, and didn’t have as many pages as the primary article. The primary article on the second hand was very difficult to understand. I had to take notes and read over the data several times to finally understand the study that was being held. I prefer the primary article because it had more facts and had figures of the studies and outcomes that were held. When I first read the secondary article I was totally lost. Reading the primary article actually made me understand the secondary article more; giving me the conclusion that both articles are the same. The primary just has more concrete proof about the co activation of RTK and the effects of responses of the tumor cells.
My additional questions are:
1.) Since RTK inhibitors are given to patients with solid tumors how is combination therapy yielding better results?
2.) What are the numbers? Of patients yielding better results?
3.) Could this prolong the life of people with GBM since that type of cancer is so lethal?
Stopping Neuroblastma Before it Kills!!!
Gupta A., Williams B.R., Hannash S.M., and Rawwas J. (2006, August 15). Cellular Retinoic Acid-Binding Protein II Is a Direct Transcriptional Target of MycN in Neuroblastoma. Cancer research, 66, 8100-8108.
Drug Week (2006, October 27). Neuroblastoma therapeutic target in cellular retinoic acid-binding protein II found.
Both the primary and secondary article describes the knowledge about Neuroblastoma. Neuroblastoma is the most common cancer during childhood, which forms in the nerve tissue. Neuroblastoma is a heterogeneous disease that involves MycN ocogene. MycN is a transcription factor that regulates the number of proteins in neuroblastoma. The researchers already knew that once the acid binding protein II called CRABP II is turned on, there is a rapid development of neuroblastoma tumor. Thus the researchers wanted to determine why CRABP II has an effect on the proliferation of neuroblastoma.
Gupta et al. hypothesized that if MycN activates CRABP II to always stay on, this will cause a more rapid development of the nueroblastoma tumor. To illustrate they decided to do an experiment using a two dimensional gel. They took varying amounts of protein and placed them into the gel; the proteins traveled freely throughout the gel. Once a protein connected to CRABP II the device would light up, informing that CRABP II was present. As they repeated this experiment they realized the frequency that the different proteins would attach to CRABP II.
Analyzing the results the researchers noticed that CRABP II expression was observed in nine of the fourteen gels, indicating that the MycN tumor showed a high CRABP II expression. They concluded that CRABP II is expressed at high levels in MycN neuroblastoma tumor.
The summary article found in drug week is mainly a direct quotation from the abstract of the primary article; therefore, that section is identical. The secondary article includes the contact information incase the reader wants to access the full primary article. However the primary study describes the method, results, and full detail explanation of the research on the relationship among CRABP II, MycN and neuroblastoma.
I don’t mistrust the secondary article because it presents the goals and the result of the experiment; this article is probably intended for scientific readers who wish to learn more about neuroblastoma. After reading both articles I was more interested in the primary study because I felt more involved throughout the process and had a better and clear understand of the effect MycN and CRABP II have on neuroblastoma.
Questions:
Once a patient realize that they have neuroblastma what is the next step?
How long will the treatment take for the neuroblastma tumor to be removed or cured?
Articles that have been cited:
Ishola T.A, Chung D.H, (2007). Neuroblastoma. Surgical Oncology, 209-310.
Wang J.X, Chen J., Wang D, (2007) Expression and functional analysis of cellular retinoic acid binding protein from silkworm pupae. Journal of cellular biochemistry.
Drug Week (2006, October 27). Neuroblastoma therapeutic target in cellular retinoic acid-binding protein II found.
Both the primary and secondary article describes the knowledge about Neuroblastoma. Neuroblastoma is the most common cancer during childhood, which forms in the nerve tissue. Neuroblastoma is a heterogeneous disease that involves MycN ocogene. MycN is a transcription factor that regulates the number of proteins in neuroblastoma. The researchers already knew that once the acid binding protein II called CRABP II is turned on, there is a rapid development of neuroblastoma tumor. Thus the researchers wanted to determine why CRABP II has an effect on the proliferation of neuroblastoma.
Gupta et al. hypothesized that if MycN activates CRABP II to always stay on, this will cause a more rapid development of the nueroblastoma tumor. To illustrate they decided to do an experiment using a two dimensional gel. They took varying amounts of protein and placed them into the gel; the proteins traveled freely throughout the gel. Once a protein connected to CRABP II the device would light up, informing that CRABP II was present. As they repeated this experiment they realized the frequency that the different proteins would attach to CRABP II.
Analyzing the results the researchers noticed that CRABP II expression was observed in nine of the fourteen gels, indicating that the MycN tumor showed a high CRABP II expression. They concluded that CRABP II is expressed at high levels in MycN neuroblastoma tumor.
The summary article found in drug week is mainly a direct quotation from the abstract of the primary article; therefore, that section is identical. The secondary article includes the contact information incase the reader wants to access the full primary article. However the primary study describes the method, results, and full detail explanation of the research on the relationship among CRABP II, MycN and neuroblastoma.
I don’t mistrust the secondary article because it presents the goals and the result of the experiment; this article is probably intended for scientific readers who wish to learn more about neuroblastoma. After reading both articles I was more interested in the primary study because I felt more involved throughout the process and had a better and clear understand of the effect MycN and CRABP II have on neuroblastoma.
Questions:
Once a patient realize that they have neuroblastma what is the next step?
How long will the treatment take for the neuroblastma tumor to be removed or cured?
Articles that have been cited:
Ishola T.A, Chung D.H, (2007). Neuroblastoma. Surgical Oncology, 209-310.
Wang J.X, Chen J., Wang D, (2007) Expression and functional analysis of cellular retinoic acid binding protein from silkworm pupae. Journal of cellular biochemistry.
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