2 miRNAs found to correlate with survival in urinary bladder cancer

Main Category: Urology / Nephrology
Also Included In: Cancer / Oncology
Article Date: 19 Aug 2013 - 1:00 PDT Current ratings for:
2 miRNAs found to correlate with survival in urinary bladder cancer

German researchers have identified four biomarkers that correctly determine malignancy of urinary bladder cancers and contribute to the accurate prediction of patient outcomes. Their results are published in the September issue of The Journal of Molecular Diagnostics.

Current prognosticators of bladder cancer, such as tumor grade, stage, size, and number of foci, have limited usefulness for clinicians since they do not accurately reflect clinical outcomes. Therefore, investigators have been searching for new biomarkers with better diagnostic and prognostic capabilities. Focusing on the role of microRNAs (miRNAs), small non-coding RNAs, researchers have identified four miRNAs that together perfectly discriminated between nonmalignant and malignant tissue, including one alone that classified 81% of the samples correctly. Levels of two miRNAs correlated with overall survival time.

Urinary bladder cancer is the fourth most common cancer in the West. According to the National Cancer Institute, it is estimated that in the United States 72,570 individuals will be diagnosed with and 15,210 will die of cancer of the urinary bladder in 2013. At presentation, in 75% of patients the cancers are confined to the mucosa or submucosa (known as non-muscle invasive bladder cancer, NMIBC), whereas in 25% of cases the cancers have already invaded nearby muscle (muscle-invasive bladder cancer, MIBC).

In a series of experiments, investigators analyzed bladder tissue from patients with NMIBC, MIBC, and nonmalignant bladders. After screening 723 miRNAs by microarray, they selected a subset of 15 distinctively deregulated miRNAs for further validation by real-time quantitative PCR. Seven miRNAs were found to be up-regulated, and eight were down-regulated in malignant bladder tissue samples compared to healthy tissue. Four miRNAs were expressed differently in bladder cancers that invaded muscle compared to those that did not. With one exception, no correlation was found between tumor stage and miRNA levels.

When all 15 of the selected miRNAs were considered together, they correctly classified 100% of tissues as either normal or malignant. Further analysis identified four miRNAs that led to 100% correct classification, and one miRNA (miR-130b) that by itself had an 81% accuracy rate. "These results underline the great potential of miRNAs to serve as diagnostic markers, as previously noted for other urological tumors," says lead investigator Klaus Jung, MD, the Department of Urology at the University Hospital Charité, Berlin and the Berlin Institute for Urologic Research.

The investigators found that tumor grading could not be correlated with overall survival. Yet, they were able to find two miRNAs that significantly correlated with survival: miR-141 and miR-205. miR-141 showed a trend (P=0.08) of being able to stratify patients with muscle-invasive tumors into two groups with different overall survival times. "This finding could be of clinical importance, but these results must be interpreted cautiously," says Dr. Jung. "However, previously published studies underline the possible prognostic potential of miRNAs to predict progression and disease-specific or overall survival in bladder cancer patients."

miRNAs are small non-coding RNAs that contain between 19 and 24 nucleotides. miRNAs regulate gene expression by degrading messenger RNAs or impairing their translation. In recent years there has been a growing interest in miRNAs as potential diagnostic and/or prognostic biomarkers in cancers and other diseases.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our urology / nephrology section for the latest news on this subject.

miRNA Profiling Identifies Candidate miRNAs for Bladder Cancer Diagnosis and Clinical Outcome

Nadine Ratert , Hellmuth-Alexander Meyer , Monika Jung , Poline Lioudmer , Hans-Joachim Mollenkopf , Ina Wagner , Kurt Miller , Ergin Kilic , Andreas Erbersdobler , Steffen Weikert , Klaus Jung; doi:10.1016/j.jmoldx.2013.05.008

Elsevier Health Sciences

Please use one of the following formats to cite this article in your essay, paper or report:

MLA

Sciences, Elsevier Health. "2 miRNAs found to correlate with survival in urinary bladder cancer." Medical News Today. MediLexicon, Intl., 19 Aug. 2013. Web.
19 Aug. 2013. APA

Please note: If no author information is provided, the source is cited instead.

'2 miRNAs found to correlate with survival in urinary bladder cancer'

Please note that we publish your name, but we do not publish your email address. It is only used to let you know when your message is published. We do not use it for any other purpose. Please see our privacy policy for more information.

If you write about specific medications or operations, please do not name health care professionals by name.

All opinions are moderated before being included (to stop spam). We reserve the right to amend opinions where we deem necessary.

Contact Our News Editors

For any corrections of factual information, or to contact the editors please use our feedback form.

Please send any medical news or health news press releases to:

Note: Any medical information published on this website is not intended as a substitute for informed medical advice and you should not take any action before consulting with a health care professional. For more information, please read our terms and conditions.

View the original article here

Scientists unravel cancers linked to herbal remedies containing Aristolochic Acid, a natural compound found in Aristolochia plants

Main Category: Cancer / Oncology
Also Included In: Complementary Medicine / Alternative Medicine;  Liver Disease / Hepatitis
Article Date: 14 Aug 2013 - 0:00 PDT Current ratings for:
Scientists unravel cancers linked to herbal remedies containing Aristolochic Acid, a natural compound found in Aristolochia plants

A team of scientists from the National Cancer Centre Singapore, Duke-NUS Graduate Medical School Singapore, and Taiwan's Chang Gung Memorial Hospital, LinKou, have made a breakthrough in understanding the cancer-promoting action of Aristolochic Acid (AA), a natural product of Aristolochia plants traditionally used in some Asian herbal remedies for weight loss and slimming. Using advanced DNA sequencing technologies, the team, led by Professors Teh Bin Tean, See-Tong Pang, Patrick Tan and Steve Rozen discovered that AA is the most potent carcinogen identified to date, causing more DNA mutations than cigarette smoke or ultraviolent light. The team also discovered that besides its previously known contribution to kidney failure and a form of kidney cancer, AA may also contribute to liver cancer. The team identified a "genetic fingerprint" of AA exposure that may pave the way to new approaches to detect AA presence in humans and the environment. The group is also affiliated with the Cancer Science Institute in Singapore, and the Genome Institute of Singapore.

AA is a natural compound found in Aristolochia plants commonly used in traditional herbal preparations for various health problems such as weight-loss, menstrual symptoms and rheumatism. It was officially banned in Europe and North America since 2001 and in Asia since 2003. However, its long-term impact is still being felt as patients with associated kidney failure and cancer are still being diagnosed, especially in Taiwan. In addition, certain AA-containing products are still permitted under supervision and products containing AA are still easily available worldwide, including over the internet.

The potent cancer-promoting activity of AA strongly warrants efforts to restrict the use of AA containing products, including health supplements. "We would like to call for greater public awareness on the adverse health effects of AA. It is therefore important to know the contents of herbal products before one consumes them." said Prof Pang. Reassuringly, in Singapore there is no cause for worry as under the Poisons Act since 1 January 2004, products and herbs sold and supplied in Singapore are not allowed to contain AA and the toxic constituents of Aristolochia herbs.

The Singapore-Taiwan study also reports that carcinogens can leave tell-tale "genetic fingerprints" of their exposure in the DNA of cancer cells, and provides a valuable demonstration of how such fingerprints can be used to identify other cancers not previously associated with that carcinogen. Dr Poon Song Ling, the lead author of the study, said: "AA's contributions to kidney failure and cancer have been documented, but AA's possible role in other cancer types was unknown. In this study, we found that the AA-related DNA fingerprint could be used to screen for the potential involvement of AA in other cancers, such as liver cancer." Such findings could lead to a new wave of DNA-based detection systems for monitoring carcinogen exposures in humans and the environment.

This breakthrough came after 1.5 years of intensive research and was recently published online in Science Translational Medicine, a publication that focuses on practical medical advances that result from all stages of translational medicine.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our cancer / oncology section for the latest news on this subject.

The research was supported by grants from the Singapore National Medical Research Council, the Singapore Millennium Foundation, the Lee Foundation, the National Cancer Centre Research Fund, The Verdant Foundation, the Duke-NUS Graduate Medical School Singapore, the Cancer Science Institute of Singapore, the Chang Gung Memorial Hospital, LinKou, the Taiwan National Science Council, and the Wellcome Trust.

Mutational Signature of Aristolochic Acid Exposure as Revealed by Whole-Exome Sequencing

Margaret L. Hoang, Chung-Hsin Chen, Viktoriya S. Sidorenko, Jian He, Kathleen G. Dickman, Byeong Hwa Yun, Masaaki Moriya, Noushin Niknafs, Christopher Douville, Rachel Karchin, Robert J. Turesky, Yeong-Shiau Pu, Bert Vogelstein, Nickolas Papadopoulos, Arthur P. Grollman, Kenneth W. Kinzler, and Thomas A. Rosenquist. Sci Transl Med 7 August 2013 5:197ra102. DOI:10.1126/scitranslmed.3006200

SingHealth

Please use one of the following formats to cite this article in your essay, paper or report:

MLA

SingHealth. "Scientists unravel cancers linked to herbal remedies containing Aristolochic Acid, a natural compound found in Aristolochia plants." Medical News Today. MediLexicon, Intl., 14 Aug. 2013. Web.
14 Aug. 2013. APA

Please note: If no author information is provided, the source is cited instead.

'Scientists unravel cancers linked to herbal remedies containing Aristolochic Acid, a natural compound found in Aristolochia plants'

Please note that we publish your name, but we do not publish your email address. It is only used to let you know when your message is published. We do not use it for any other purpose. Please see our privacy policy for more information.

If you write about specific medications or operations, please do not name health care professionals by name.

All opinions are moderated before being included (to stop spam). We reserve the right to amend opinions where we deem necessary.

Contact Our News Editors

For any corrections of factual information, or to contact the editors please use our feedback form.

Please send any medical news or health news press releases to:

Note: Any medical information published on this website is not intended as a substitute for informed medical advice and you should not take any action before consulting with a health care professional. For more information, please read our terms and conditions.

View the original article here

Targeted therapy identified for protein that protects and nourishes cancer - inhibitor found that blocks Skp2

Main Category: Cancer / Oncology
Article Date: 05 Aug 2013 - 1:00 PDT Current ratings for:
Targeted therapy identified for protein that protects and nourishes cancer - inhibitor found that blocks Skp2

Scientists at The University of Texas MD Anderson who identified a protein's dual role in cancer promotion have discovered a way to shut it down, opening a potential new avenue for cancer treatment.

Reporting this week in the journal Cell, the researchers describe the first compound that directly binds to and blocks Skp2, a protein they previously showed both turns off a cellular defense against cancer and switches on a cancer-feeding metabolic pathway.

"The beauty of this study is we identified an inhibitor and showed how it functions to block Skp2. Inhibitors often are discovered without an initial understanding of how they work," said co-senior author Hui-Kuan Lin, Ph.D., associate professor of Cellular and Molecular Oncology at MD Anderson.

Lin teamed with co-senior author Shuxing Zhang, Ph.D., assistant professor of Experimental Therapeutics and head of the Integrated Molecular Discovery Laboratory at MD Anderson, to identify and characterize the drug.

"There are many more chemical compounds available than there are estimated stars in the universe," Zhang said. "We have a database with 10 million compounds, but our prescreening analysis narrowed our computerized search to 120,000 and then further to find small-molecule candidates that inhibit Skp2."

Their inhibitor plugs critical binding sites on Skp2, preventing it from connecting to Skp1 to form a complex, which is the first step in its two cancer-promoting functions, Lin said.

Compound hits prostate, lung tumors

"This compound has a high degree of specificity ?" our tests in prostate and lung cancer show it preferentially targets the cancer cells but not the normal cells," Lin said. Steps remain to define the drug's potential off-target effects before it can advance to human clinical trials, Lin said.

The researchers also found that the inhibitor suppresses prostate cancer stem cells, which play a role in cancer initiation, progression and resistance to chemotherapy.

Normally, Skp2 E3 ligase binds to and tags other proteins with molecules called ubiquitins, which can serve as activation signals or as targets marking the protein for destruction. Skp2 is overexpressed in numerous cancers and plays a critical role in cell cycle progression leading to cell division, metabolism and dormancy, as well as cancer progression and metastasis.

Lin and colleagues previously showed that Skp2 promotes cancer by:

Marking for destruction a cancer-stifling protein called p27 that renders cells senescent, or incapable of dividing. Firing up a signaling pathway that activates glucose metabolism (glycolysis), which cancer cells primarily rely upon to grow and survive. They also showed that the glycolysis pathway contributes to Herceptin resistance and shorter survival among breast cancer patients whose tumors heavily express the HER2 protein.

By analyzing the connection between Skp2 and Skp1, Zhang's group identified two pocket-like regions on Skp2 where the proteins connect.

Skp2 has been a logical target for cancer therapy, Zhang said, but presented two major obstacles.

Targeting protein-protein interactions is already difficult and Skp2 has a huge area where it interfaces with other proteins, making it hard to find one small molecule to completely block that surface.

"To begin such a search, to rationally design a drug, you must first understand the target's biology and then look at its structure and fully comprehend its complex interactions and how disrupting those will help treat the disease," Zhang said. "Once you understand those, you're ready to screen using computer models."

Virtual screening of the 120,000 compounds with a program developed by Zhang revealed 25 candidates that bind to either or both pockets. Additional analyses showed that Compound #25, also known as SZL-P1-41, effectively disrupted Skp1-Skp2 interactions.

Subsequent experiments showed Compound #25 suppresses Skp2-related tagging and destruction of the cell dormancy protein p27, restoring its expression in prostate cancer cells, and also stifles Skp2 signaling that activates the cancer-feeding glycolysis pathway.

Detailed experiments showed the drug's effect is achieved by binding specifically to one of the pockets on Skp2 to disrupt formation of the Skp2-Skp1 complex.

Initial cell line experiments showed Compound #25 selectively destroyed prostate cancer cells with minimal effects on normal tissue. The drug's effects were confirmed in two lung cancer cell lines and in liver and osteocarcinoma cell lines.

Underlying mechanisms for the drug's effect on prostate cancer cells proved to be cellular senescence initiation and glycolysis suppression.

Recent research indicates that glycolysis is important to cancer stem cell formation and that senescence through telomere shortening restrains cancer stem cell growth.

Since Compound #25 blocks glycolysis and promotes senescence, the team tested its effect on prostate cancer stem cells.

Treatment stymies cancer stem cell formation, shrinks tumors

Treating prostate cancer cells with the compound reduced the population of cancer stem cells in a dose-dependent manner. The drug didn't work at all in cancer cells where Skp2 had been silenced.

Because cancer stem cells are a major cause of chemotherapy resistance, the researchers treated cell lines with Compound #25 and either of the chemotherapies doxorubicin or cyclophosphamide. Combining the new drug tripled the cancer cell growth inhibition of doxorubicin and doubled that of cyclophosphamide.

Finally, evasion of cellular senescence and promotion of glycolysis are hallmarks of cancer progression and drug resistance. The team tested its drug in mice with prostate and lung tumors. In both cases, treated mice had tumors about a quarter of the size of those in mice injected with a control agent.

Lin, Zhang and MD Anderson have filed for patent protection of this work.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our cancer / oncology section for the latest news on this subject.

Co-authors and funding

Co-authors include first author Chia-Hsin Chan, Ph.D., Yuan Gao, Guoxiang Jin, Ph.D., Asad Moten, Zhen Cai, Ph.D., Dazhi Xu, Ph.D., and Mien-Chie Hung, Ph.D., of MD Anderson's Department of Molecular and Cellular Oncology; John Kenneth Morrow of Experimental Therapeutics; Loren Stagg, Ph.D., and John Ladbury, Ph.D., of Biochemistry and Molecular Biology; Christopher Logothetis, M.D., of Genitourinary Medical Oncology; and Chien-Feng Li, M.D., Ph.D., Chi-Mei Foundational Medical Center and the National Institute of Cancer Research, Taiwan.

Gao and Morrow are students in The University of Texas Graduate School of Biomedical Sciences at Houston, a joint program of MD Anderson and The University of Texas Health Science Center at Houston.

This research was funded by the MD Anderson Trust Scholar Award, MD Anderson's Prostate SPORE grant from the National Cancer Institute of the National Institutes of Health (P50 CA140388) and its NCI Cancer Center Support Grant (CA 016672), a grant from the American Cancer Society, an MD Anderson Center for Targeted Therapy-University of Texas at Austin Texas Institute for Drug and Diagnostics Development joint grant; and also a career development award from MD Anderson's NCI Breast Cancer SPORE and a Susan G Komen Foundation Postdoctoral Fellowship Award to Chan.

University of Texas M. D. Anderson Cancer Center

Please use one of the following formats to cite this article in your essay, paper or report:

MLA

University of Texas M. D. Anderson Cancer Center. "Targeted therapy identified for protein that protects and nourishes cancer - inhibitor found that blocks Skp2." Medical News Today. MediLexicon, Intl., 5 Aug. 2013. Web.
5 Aug. 2013. APA
University of Texas M. D. Anderson Cancer Center. (2013, August 5). "Targeted therapy identified for protein that protects and nourishes cancer - inhibitor found that blocks Skp2." Medical News Today. Retrieved from
http://www.medicalnewstoday.com/releases/264317.php.

Please note: If no author information is provided, the source is cited instead.

'Targeted therapy identified for protein that protects and nourishes cancer - inhibitor found that blocks Skp2'

Please note that we publish your name, but we do not publish your email address. It is only used to let you know when your message is published. We do not use it for any other purpose. Please see our privacy policy for more information.

If you write about specific medications or operations, please do not name health care professionals by name.

All opinions are moderated before being included (to stop spam). We reserve the right to amend opinions where we deem necessary.

Contact Our News Editors

For any corrections of factual information, or to contact the editors please use our feedback form.

Please send any medical news or health news press releases to:

Note: Any medical information published on this website is not intended as a substitute for informed medical advice and you should not take any action before consulting with a health care professional. For more information, please read our terms and conditions.

View the original article here

Essential clue to Huntington's disease solution found by McMaster researchers

Main Category: Huntingtons Disease
Article Date: 31 Jul 2013 - 1:00 PDT Current ratings for:
Essential clue to Huntington's disease solution found by McMaster researchers

Researchers at McMaster University have discovered a solution to a long-standing medical mystery in Huntington's disease (HD).

HD is a brain disease that can affect 1 in about 7,000 people in mid-life, causing an increasing loss of brain cells at the centre of the brain. HD researchers have known what the exact DNA change is that causes Huntington's disease since 1993, but what is typically seen in patients does not lead to disease in animal models. This has made drug discovery difficult.

In this week's issue of the science journal, the Proceedings of the National Academy of Sciences, professor Ray Truant's laboratory at McMaster University's Department of Biochemistry and Biomedical Sciences of the Michael G. DeGroote School of Medicine reveal how they developed a way to measure the shape of the huntingtin protein, inside of cell, while still alive. They then discovered was that the mutant huntingtin protein that causes disease was changing shape. This is the first time anyone has been able to see differences in normal and disease huntingtin with DNA defects that are typical in HD patients.

They went on to show that they can measure this shape change in cells derived from the skin cells of living Huntington's disease patients.

"With mouse models, we know that some drugs can stop, and even reverse Huntington's disease, but now we know exactly why," said Truant. "The huntingtin protein has to take on a precise shape, in order to do its job in the cell. In Huntington's disease, the right parts of the protein can't line up to work properly. It's like trying to use a paperclip after someone has bent it out of shape."

The research also shows that the shape of disease huntingtin protein can be changed back to normal with chemicals that are in development as drugs for HD.

"We can refold the paper clip," said Truant.

The methods they developed have been scaled up and used for large scale robotic drug screening, which is now ongoing with a pharmaceutical company. They are looking for drugs that can enter the brain more easily. Furthermore, they can tell if the shape of huntingtin has been corrected in patients undergoing drug trials, without relying on years to know if the HD is affected yet.

This research was a concerted effort from many sources: funding from the Canadian Foundation Institute and the Ontario Innovation Trust for an $11M microscopy centre at McMaster in 2006, ongoing support from the Canadian Institutes of Health Research, and important funding from the Toronto-based Krembil Foundation. The project was initiated with charity grant support from the Huntington Society of Canada, which allowed them to show this method was promising for further support.

The last piece of the puzzle was from the Huntington's disease patient community, with skin cell donations from living patients and unaffected spouses that allowed the team to look at real human disease.

There are eight other diseases that have a similar DNA defects as Huntington's disease, Truant's group is now using similar tools to develop assays to measure shape changes in those diseases, to see if this shapeshifting is common in other diseases.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our huntingtons disease section for the latest news on this subject.

Polyglutamine domain flexibility mediates the proximity between flanking sequences in huntingtin, Nicholas Stephane Caron, Carly Robyn Desmond, Jianrun Xia, and Ray Truant, doi: 10.1073/pnas.1301342110 PNAS July 29, 2013

McMaster University

Please use one of the following formats to cite this article in your essay, paper or report:

MLA

University, McMaster. "Essential clue to Huntington's disease solution found by McMaster researchers." Medical News Today. MediLexicon, Intl., 31 Jul. 2013. Web.
31 Jul. 2013. APA

Please note: If no author information is provided, the source is cited instead.

'Essential clue to Huntington's disease solution found by McMaster researchers'

Please note that we publish your name, but we do not publish your email address. It is only used to let you know when your message is published. We do not use it for any other purpose. Please see our privacy policy for more information.

If you write about specific medications or operations, please do not name health care professionals by name.

All opinions are moderated before being included (to stop spam). We reserve the right to amend opinions where we deem necessary.

Contact Our News Editors

For any corrections of factual information, or to contact the editors please use our feedback form.

Please send any medical news or health news press releases to:

Note: Any medical information published on this website is not intended as a substitute for informed medical advice and you should not take any action before consulting with a health care professional. For more information, please read our terms and conditions.

View the original article here