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Espaço de publicação e discussão sobre oncologia. GBM IMMUNOTHERAPY ONCO-VIRUS ONCOLOGY CANCER CHEMOTHERAPY RADIOTHERAPY



Quarta-feira, 25.02.15

UT Southwestern Researchers Identify Genes Promoting Tumorogenesis

UT Southwestern Researchers Identify Genes Promoting Tumorogenesis

FEBRUARY 23RD, 2015  PATRICIA INACIO, PHD

    

UT Southwestern Medical Center researchers identified a set of genes — MAGE-A3/A6 — that are activated specifically in cancer cells promoting their growth by inhibition of the master regulator of cells’ energy status, the AMP-activated protein kinase (AMPK). The study titled “Degradation of AMPK by a Cancer-Specific Ubiquitin Ligase”was published in the journal Cell and opens new therapeutic avenues for cancer patients.

The AMP-activated protein kinase (AMPK) is a crucial cellular energy sensor, responsible for maintaining a metabolic energy balance within the body. Once activated, AMPK inhibits anabolic metabolism (a process where new molecules are built in a consuming-energy process) to promote catabolic pathways (those that breakdown large molecules, such as nutrients, in an energy-releasing process). In cancer cells derived from different types of cancer, such as lung adenocarcinomas and cervical cancers, AMPK signaling was found to be down-regulated and has been increasingly reported to exhibit tumor-suppressing functions. This anti-tumor activity put AMPK in the spotlight for anti-cancer therapeutics using drugs that stimulate AMPK activity, such as metformin. Currently, multiple clinical trials are testing these types of compounds. In this study, researchers investigated the role of two genes belonging to the melanoma antigen (MAGE) genes, MAGE-A3 and MAGE-A6. Previous work by the team had already identified these genes (whose expression is usually restricted to the testis) are upregulated in cancer cells. However, their role in tumorigenesis was largely unknown.


In this study, the team led by Dr. Ryan Potts discovered that MAGE-A3/A6 downregulates AMPK by promoting its ubiquitination and degradation. MAGE proteins potentiate the activity of specific E3 ubiquitin ligases, enzymes that promote the final step of the ubiquitination cascade, transferring the ubiquitin mark to the target substrate. This process — ubiquitination — promotes the degradation of the targeted protein via the proteasome (a complex inside cells where proteins are degraded). Now, MAGE-A3/6 was found to degrade AMPK via TRIM28 E3 ubiquitin ligase. As a result, the cancer-specific MAGE-A3/6-TRIM28 ubiquitin ligase pathway is able to significantly shut down AMPK signaling and its downstream pathways promoting tumor initiation.

The teams’ findings uncovered a new mechanism of how cancer cells hijack cellular pathways towards tumorogenesis. Ultimately, these results could have important implications for therapeutics, as noted by Dr. Ryan Potts, Assistant Professor of Physiology, Biochemistry, and Pharmacology, and a member of the Harold C. Simmons Comprehensive Cancer Center in a press release. “This is an especially exciting development because there are already FDA-approved drugs, such as metformin, which activate AMPK and are being tested in clinical trials for cancer. We found that the normally testis-restricted MAGE-A3/6 genes are aberrantly expressed in many cancers, including breast, lung, and colon cancers where they promote tumor growth.  Importantly, the expression of these genes is associated with decreased survival for cancer patients. Therefore, these genes are ideal cancer-specific chemotherapy targets.”

 

Newswise — DALLAS – Feb. 17, 2015 – UT Southwestern Medical Center scientists have identified a new biomarker that could help identify patients who are more likely to respond to certain chemotherapies.

UT Southwestern researchers identified how two melanoma antigen genes (MAGE-A3 and MAGE-A6) contribute to tumor growth. Researchers found that these genes have an effect on a protein called AMPK, offering valuable insight that could help identify patients who are most likely to respond to AMPK-directed chemotherapies.

“This is an especially exciting development because there are already FDA-approved drugs, such as metformin, which activate AMPK and are being tested in clinical trials for cancer,” said senior author Dr. Ryan Potts, Assistant Professor of Physiology, Biochemistry, and Pharmacology, and a member of the Harold C. Simmons Comprehensive Cancer Center. “Our study provides a new biomarker, MAGE-A3/6, which can help identify patients who are likely to respond to these treatments.”

The findings are published online in the journal Cell.

The MAGE-A3/6 genes are found on the X chromosome in both men and women. Normally, the function of MAGE-A3/6 is restricted to the production of sperm in men. However, in some situations the genes are abnormally switched on and Dr. Potts and his team discovered that when this happens, normal cells are turned into cancerous cells.

“We found that the normally testis-restricted MAGE-A3/6 genes are aberrantly expressed in many cancers, including breast, lung, and colon cancers where they promote tumor growth.  Importantly, the expression of these genes is associated with decreased survival for cancer patients. Therefore, these genes are ideal cancer-specific chemotherapy targets,” said Dr. Potts, the Michael L. Rosenberg Scholar in Medical Research.

Following further investigation on how MAGE-A3/6 functions to promote cancer, Dr. Potts and his team discovered that the protein − called AMP-activated protein kinase (AMPK) − is inhibited by MAGE-A3/6. AMPK can detect cellular energy levels and controls energy usage in cells. If low energy levels are detected, AMPK switches off energy-consuming pathways (protein and lipid synthesis) and turns on pathways to acquire more energy (cellular breakdown). Additionally, these activities of AMPK can play a role in suppressing the growth of cancerous tumors.

The study used various molecular biological techniques in mouse and human tissues to investigate the mechanisms of interaction between MAGE-A3/6, another protein called TRIM28 and AMPK, and found that MAGE-A3/6 degrades AMPK by working with TRIM28, removing the tumor-suppressive properties and resulting in transformation of normal cells and tumor growth.

Dr. Potts’ lab focuses on understanding the basic molecular, genetic, and cellular events that give rise to cancer. His lab initially defined a novel family of cancer cell-specific proteins, called MAGE proteins, which promote tumor growth, and is now focused on elucidating the biochemical, cellular, and physiological function of individual MAGE proteins.

Dr. Potts was awarded the Sara and Frank McKnight independent postdoctoral fellowship in the Department of Biochemistry at UT Southwestern, was named an Endowed Scholar in Biomedical Research in the Department of Physiology at UT Southwestern, and received a Cancer Prevention and Research Institute of Texas (CPRIT) Scholar in Cancer Research Award.

UT Southwestern’s Harold C. Simmons Comprehensive Cancer Center is one of just 68 NCI-designated cancer centers in the nation. The Simmons Cancer Center includes 13 major cancer care programs with a focus on treating the whole patient with innovative treatments, while fostering groundbreaking basic research that has the potential to improve patient care and prevention of cancer worldwide. In addition, the Center’s education and training programs support and develop the next generation of cancer researchers and clinicians.

In addition, the Simmons Cancer Center is among only 30 U.S. cancer research centers to be named a National Clinical Trials Network Lead Academic Participating Site, a prestigious new designation by the NCI, and the only Cancer Center in North Texas to be so designated. The designation and associated funding is designed to bolster the cancer center’s clinical cancer research for adults and to provide patients access to cancer research trials sponsored by the NCI, where promising new drugs often are tested.

Other UT Southwestern researchers involved in the work include graduate student Carlos T. Pineda; postdoctoral fellow Dr. Saumya Ramanathan; Dr. Klementina Fon Tacer, Instructor in Physiology; graduate student Jenny L. Weon;  Dr. Malia B. Potts, Assistant Instructor of Cell Biology; student Yi-Hung Ou; and Dr. Michael A. White, Professor of Cell Biology and holder of the Grant A. Dove Distinguished Chair for Research in Oncology, and the The Sherry Wigley Crow Cancer Research Endowed Chair in Honor of Robert Lewis Kirby, M.D.

 

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por cyto às 02:24

Sábado, 21.02.15

Targeted MRI-ultrasound is better than standard biopsy at detecting high-risk prostate cancer

Targeted MRI-ultrasound is better than standard biopsy at detecting high-risk prostate cancer

 

Among men undergoing biopsy for suspected prostate cancer, targeted magnetic resonance (MR)/ultrasound fusion biopsy, compared with a standard biopsy technique, was associated with increased detection of high-risk prostate cancer and decreased detection of low-risk prostate cancer, according to a study in JAMA (2015; doi:10.1001/jama.2014.17942).

The current diagnostic procedure for men suspected of prostate cancer is a standard extended-sextant biopsy (ie, standard biopsy). Advances in imaging have led to the development of targeted magnetic resonance (MR)/ultrasound fusion biopsy (ie, targeted biopsy), which has been shown to detect prostate cancer. The implications of targeted biopsy alone compared with standard biopsy or the two methods combined are not well understood, according to background information in the article.

Peter A. Pinto, MD, and M. Minhaj Siddiqui, MD, of the National Cancer Institute (NCI), National Institutes of Health in Bethesda, Maryland, and colleagues examined the outcomes of 1,003 men who underwent an imaging procedure to identify regions of prostate cancer suspicion followed by targeted biopsy and concurrent standard biopsy from 2007 through 2014 at NCI. Patients were referred for elevated level of prostate-specific antigen (PSA) or abnormal digital rectal examination results, often with prior negative biopsy results.

Targeted biopsy diagnosed a similar number of cancer cases (461 patients) to standard biopsy (469 patients). There was exact agreement between targeted and standard biopsy in 690 men (69%) undergoing biopsy. However, the two approaches differed in that targeted biopsy diagnosed 30% more high-risk cancers than standard biopsy (173 vs 122 cases) and 17% fewer low-risk cancers (213 vs 258 cases).

Adding standard biopsy to targeted biopsy lead to 103 more cases of cancer (22%); however, of these, 83% were low risk while only 5% were high risk; 12% were intermediate risk. Thus, the usefulness of combining these methods was found to be limited. The number needed to biopsy by standard biopsy in addition to targeted biopsy to diagnose one additional high-risk tumor was 200 men.

The predictive ability of targeted biopsy for differentiating low-risk from intermediate- and high-risk disease in 170 men with whole-gland pathology after prostatectomy (surgical removal of the prostate gland) was greater than that of standard biopsy or the two approaches combined.

“This study demonstrated that targeted biopsy could significantly change the distribution of risk in men newly diagnosed with prostate cancer toward diagnosis of more high­risk disease,” wrote the authors. “Although these improvements in risk stratification could translate into substantial clinical benefits, it is important to recognize that this study is preliminary with regard to clinical end points such as recurrence of disease and prostate cancer-specific mortality. These findings provide a strong rationale for the conduct of randomized clinical trials to determine the effect of targeted biopsy on clinical outcomes.”

 

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por cyto às 12:16

Sábado, 21.02.15

A*STAR Researchers develop expert systems for identifying treatment targets for cancer and rare diseases

Friday, February 13, 2015
  A*STAR Researchers develop expert systems for identifying treatment targets for cancer and rare diseases

Singapore – In recent months, several national initiatives for personalized medicine have been announced, including the recently launched precision medicine initiative in the US, driven by rapid advances in genomic technologies and with the promise of cheaper and better healthcare. Significant challenges remain, however, in the management and analysis of genetic information and their integration with patient data. The sheer scale and complexity of this data, generated using cutting-edge technologies such as next generation DNA sequencing, requires the development of new computer algorithms and systems that can mine this data to get actionable knowledge.

 

Now, scientists at A*STAR’s Genome Institute of Singapore (GIS) have reported another breakthrough in the development of expert systems that can trawl large datasets, integrating complex disease information to guide doctors in the diagnosis and treatment of diseases. The latest in this series is the development of a system called OncoIMPACT that combines cancer omics data and models learned from hundreds of patients to better sift through genetic mutations and pick potentially causal ones.

 

The lead investigator in this study, Dr Niranjan Nagarajan, Associate Director of Computational and Systems Biology at the GIS, noted, “We are particularly excited about OncoIMPACT’s ability to take into account the unique genetic makeup of each patient to predict treatment targets. It allows us to crunch massive cancer genome datasets in an integrative and model-driven fashion to distill them down to the few key driver mutations.”

 

Assistant Professor Johannes Schumacher from the Institute of Human Genetics at the University of Bonn, added: "The integration of different 'omics' datasets for the identification of cancer driver genes is a challenge. OncoIMPACT fills a gap in integrative analyses and provides the opportunity to revisit large complex datasets for the identification of disease driving genes."

 

The team of researchers at A*STAR have applied OncoIMPACT to more than a thousand cancers such as melanomas, glioblastomas, prostate, bladder and ovarian cancers, and are in the process of building a complete map of driver mutations across cancers. They also demonstrated a proof-of-concept in this study for using driver mutation signatures to predict clinical outcomes for cancer patients. This is an exciting alternative to currently available tests based on RNA and protein levels as DNA can be more reliably assayed, and the team plans to develop this work further.

 

Dr Nagarajan remarked, “Our hope is to create a resource for cancer researchers and clinicians in Singapore and around the world. We envisage a future where expert systems such as OncoIMPACT can leverage genomic data generated worldwide and contribute to personalised and targeted medicine in Singapore.”

 

Dr Gopal Iyer, Principal Investigator of the Cancer Therapeutics Research Laboratory at the National Cancer Centre of Singapore (NCCS) noted, “With the availability of large amounts of genetic data, it is difficult to focus our attention on the real cause and drivers in cancers. There are a number of algorithms that help narrow this search down in groups of cancers. OncoIMPACT, however, is different as it can focus these analyses on a single patient. This is the first step for true treatment individualisation: if we can uncover the drivers behind a tumour in a specific patient, we can ask if this can then be treated with specific drugs.”

 

OncoIMPACT is the latest in the series of expert systems from the GIS and follows the recent publication of Phen-Gen – the first such system to cross-reference patient’s symptoms with genome sequence to detect causal genes for rare diseases. Both methods fall in the emerging area of integrative omics, where complex, multi-dimensional datasets are jointly analysed with sophisticated algorithms to reveal novel biological and medical insights.

 

The development of OncoIMPACT was recently published in the journal Nucleic Acids Research, while Phen-Gen’s development was published in Nature Methods in August 2014. 

 

Notes to Editor:

 

The research findings described in the media release can be found in the Nucleic Acids Researchjournal, under the title, “Patient-specific driver gene prediction and risk assessment through integrated network analysis of cancer omics profiles” by Denis Bertrand1,, Kern Rei Chng1,, Faranak Ghazi Sherbaf2,, Anja Kiesel1, Burton K. H. Chia1, Yee Yen Sia2, Sharon K. Huang3, Dave S.B. Hoon3, Edison T. Liu2,4, Axel Hillmer2 and Niranjan Nagarajan1.

 

1.    Computational and Systems Biology, Genome Institute of Singapore, Singapore 138672, Singapore,

2.    Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore 138672, Singapore,

3.    Department of Molecular Oncology, John Wayne Cancer Institute, Santa Monica, CA 90404, USA and

4.    The Jackson Laboratory for Genomic Medicine, Farmington, CT 06030, USA.

†    These authors contributed equally to the paper as first authors.

 

 

For media queries and clarifications, please contact:

Ms Winnie Lim

Head, Office of Corporate Communications

Genome Institute of Singapore, A*STAR

Tel:      +65 6808 8013

Email: limcp2@gis.a-star.edu.sg

 

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por cyto às 12:11

Sábado, 21.02.15

Lighting up neural stem cells

Lighting up neural stem cells

The screening of thousands of fluorescent molecules has revealed a specific label for neural stem cells

Published online 24 October 2012

In a high-throughput screening of fluorescent molecules, the fluorescent compound CDr3 stained neural stem cells the most brightly and specifically.

© 2012 National Academy of Sciences, USA  (inset, pink); © 2012 A*STAR Singapore Bioimaging Consortium (main image)

Neural stem cells are the precursors of cells in the nervous system. As well as being crucial for early development, they are present throughout life, contributing to flexibility and repair of the nervous system. As such, they can be used to study the brain, and may offer new ways of treating neurological disease.

Current techniques for identifying and labeling live neural stem cells use antibodies to detect specific cell-surface molecules. Small fluorescent molecules, which are commonly used to visualize the locations and movements of molecules and cells, may offer a more convenient and safer alternative.

Young-Tae Chang at the A*STAR Singapore Bioimaging Consortium and co-workers have now identified a fluorescent compound that specifically labels neural stem cells by binding to an intracellular protein1. The molecule, named CDr3, was singled out for its selective labeling of neural stem cells after testing thousands of fluorescent compounds from a 'Diversity Oriented Fluorescence Library’, or DOFL.

“A DOFL is a collection of intrinsically fluorescent low molecular weight compounds which have been synthesized, purified and characterized in our lab,” says co-author Seong-Wook Yun. “We have generated more than 10,000 DOFL compounds so far, each with different chemical and biological properties.”

The researchers narrowed down the number of potentially useful molecules by assessing how strongly they labeled stem cells, and finally determined that CDr3 stained them the most selectively and brightly (see image). They confirmed the specificity of labeling by incubating CDr3 with different cell types and showing that it only stained neural stem cells. Growing stem cells in the presence of CDr3 also showed that it does not affect their survival or division.

A combination of molecular biology techniques revealed that CDr3 labeled the cells by binding to a neural stem cell-specific protein called FABP7. This is found inside the cell, unlike other labeling targets. “Conventionally, live neural stem cells have been identified by detecting cell surface molecules,” explains Yun. “However, these molecules are also highly expressed in other types of cells. FABP7 is a specific intracellular marker of neural stem cells.”

Labeling of neural stem cells with CDr3 not only allowed them to be identified, but also to be separated from other types of cells. According to Yun, this is important for practical applications.

“Detection and isolation of live neural stem cells from heterogeneous cell populations is a key technology, not only for basic research but also for the development of cell-based therapeutics and drug development,” he says.

 

The A*STAR-affiliated researchers contributing to this research are from the Singapore Bioimaging Consortium and the Genome Institute of Singapore

 

Reference

  1. Yun, S.-W., Leong, C., Duanting, Z., Tan, Y. L., Lim, L. et al. Neural stem cell specific fluorescent chemical probe binding to FABP7. Proceedings of the National Academy of Sciences USA 109, 10214–10217 (2012). | article

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por cyto às 12:08

Sábado, 21.02.15

Seeking stem cells

Seeking stem cells

Fluorescent tagging enables scientists to monitor neural stem cells that might help repair neurological damage

Published online 18 February 2015

Stem cells can be specifically distinguished from mature neural cells within a neurosphere using the novel fluorescent label CDy5 (red), with nuclei (blue) and cytosol (green).

© 2015 A*STAR Singapore Bioimaging Consortium

A labeling compound identified at A*STAR that specifically marks neuronal stem cells is not only a useful research tool, but could also assist clinical efforts to repair neurological damage in patients.

Even as adults, we retain reservoirs of neural stem cells that can develop into mature replacements for dead or damaged neurons. However, these reserves are relatively small, and insufficient for repairing severe injuries to the brain or spinal cord. Larger numbers of these stem cells could potentially be grown in culture dishes, but to do so researchers would need to be able to separate them from mature, fully developed neurons that are ineffective for tissue repair.

Young-Tae Chang’s group at the A*STAR Singapore Bioimaging Consortium is looking for a way “to find and isolate neural stem cells using fluorescent dyes, to then grow them in larger numbers to treat neuronal damage or neurodegenerative diseases.”

Chang and Sohail Ahmed of the A*STAR Institute of Medical Biology recently succeeded in identifying such a dye1. One of the challenges in cultivating neural stem cells is that although some will divide ‘symmetrically’ to yield two new stem cells, others divide ‘asymmetrically’ to produce one stem cell and one mature neuron or glial cells.

Reliably identifying true stem cells with existing dyes has proved challenging to date. “These dyes just diffuse out into both cells,” says Chang. He and Ahmed therefore screened a large library of fluorescent chemical compounds in search of a dye that consistently remains stem-cell-specific.

One molecule, which the researchers named CDy5, proved particularly promising. Cultured neural stem cells gradually form structures called neurospheres, composed of both stem cells and neural cells of various stages of maturity. After labeling neurospheres with CDy5, Chang and Ahmed separated out the brightly labeled cells from the dimly labeled ones. Strikingly, cells that were strongly labeled by CDy5 were ten times more likely to form neurospheres (see image). Experiments with single cells showed that this dye remained stem-cell-specific even during asymmetric division, and the researchers subsequently learned that CDy5 forms a strong chemical bond with a protein that is exclusively active in neural stem cells.

Chang intends to use CDy5 to identify culture conditions that either help stem cells maintain their identity or prompt their development into mature nervous tissue. He is also keen to make this tool available to other groups. “I will distribute CDy5 to whoever is interested in using the probe and am excited to see what kinds of new applications or discoveries result,” he says.

 

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por cyto às 12:03

Sábado, 21.02.15

New Insights into Autoimmune Diseases

HHMI Researcher at UTSW Discovers New Insights into Autoimmune Diseases

UTSW’s Zhijian ‘James’ Chen, a Howard Hughes Medical Institute (HHMI) investigator, along with other HHMI researchers have recently published their findings titled “Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation” in the prestigious journal Science

Their study identified the fine-tuned signaling mechanisms underlying the production of interferon in cells, and the common factor between the different interferon-inducing pathways.

The immune system is known to have a delicate balance that needs to be well-kept. Interferon production in particular, a powerful molecule involved in the host’s immune response against pathogens, must be tightly controlled to avoid an attack on the body’s own cells, which occurs in autoimmune diseases.

“Induction of type I interferons has to be tightly regulated, because overproduction can lead to autoimmune diseases like lupus,” said the study’s senior author Dr. Zhijian “James” Chen, an HHMI investigator at the University of Texas Southwestern Medical Center, in a news release. In fact, several autoimmune disorders have been linked to genetic alterations in genes involved in pathways associated with interferon induction. According to Dr. Chen, a better understanding of the signaling pathway underlying the induction of interferon production can aid in the development of therapies for this type of disease.

In humans, three pathways are known to trigger interferon production in response to pathogen infection, and each of these pathways recognizes a different sign of infection. In the case of viral infection, a cytoplasmic sensor named RIG-I is able to identify foreign viral RNA. On the other hand, foreign DNA from bacteria, DNA viruses or retroviruses, is recognized by a cytoplasmic sensor molecule called cGAS.

Toll-like receptors are other type of sensors capable of detecting foreign molecules in cellular compartments, called endosomes. Each receptor interacts with its own adaptor protein (RIG-I with MAVS, cGAS with STING, and Toll-like receptors with TRIF) to deliver the message that a pathogen is present and therefore trigger interferon production. It is thought that all these three adaptor proteins are able to induce interferon production by activation of the same protein – TBK1.

 A graduate student from Dr. Chen’s group – Siqi Liu – found what computational analysis did not: a small motif in the MAVS protein (where a phosphate group is added when the adaptor protein is stimulated) that has similarities to a segment of the STING protein. “If you don’t know what you’re looking for, it’s very hard to find,” noted Dr. Chen. “But Siqi actually recognized it with her eyes.” Interestingly, this same motif was found in MAVS, STING and TRIF adaptor proteins from humans and other mammals. Researchers also identified this motif in IRF3, which is the ultimate factor that leads to interferon production.

Several biochemical studies revealed that once RIG-I, cGAS and Toll-like receptor interact with their corresponding adaptor proteins (MAVS, STING and TRIF, respectively), the motifs identified in these proteins become phosphorylated, which in turn leads to the activation of IRF3 by TBK1. “Basically, phosphorylation of the adaptor protein provides the license for IRF3 to be activated by TBK1,” explained Dr. Chen.

“We have provided a mechanism that explains how this key transcription factor [IRF3] is activated by three distinct pathways known to induce type I interferons,” stated Dr. Chen. The research team aims to further study this mechanism and also develop small molecules that can potentially interfere with these different interactions. “If we can generate inhibitors of these pathways, these molecules might be used as therapeutic agents to treat autoimmune diseases in the future.”

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por cyto às 12:01

Sábado, 21.02.15

Fruits and vegetables have small chemoprotective effect

Fruits and vegetables have small chemoprotective effect, study shows

Increased consumption of fruits and vegetables leads to only a small effect on cancer risk, according to a report published in the Journal of the National Cancer Institute (2010 Apr 6. [Epub ahead of print]).

To clarify the chemopreventive potential of fruits and vegetables, Paolo Boffetta, MD, of Mount Sinai Medical Center in New York City, and colleagues examined the relationship between diet and cancer in 10 Western European countries with widely varying intake of fruits and vegetables.

Researchers found that during a median follow-up of almost 9 years, an increased consumption of 7 ounces of fruits and vegetables reduced cancer risk by only 3%. Additionally, a 3.5-ounce per day increase in total vegetable intake reduced cancer risk by only 2%. However, researchers reported that analysis by gender revealed that women experience a beneficial effect of total vegetable intake.

“Our study supports the notion of a modest cancer preventive effect of high intake of fruits and vegetables, and we can exclude chance as a likely factor,” said the study's authors. “Nevertheless, the observed association of cancer risk overall with vegetable and fruit intake was very weak, and we cannot entirely rule out the possibility of residual confounding by these or other factors.”

According to the press release announcing the study, multiple health organizations worldwide recommend consumption of five servings of fruits and vegetables daily to ward off heart disease, cancer, and other conditions. However, no study has demonstrated conclusively that a high intake of fruits and vegetables reduces the risk of cancer.

 
 
 

 

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por cyto às 11:52

Sábado, 21.02.15

A novel way to get patients to eat their fruits and vegetables: Have them grow their own!

 

A novel way to get patients to eat their fruits and vegetables: Have them grow their own!

 
A novel way to get patients to eat their fruits and vegetables: Have them grow their own!
A novel way to get patients to eat their fruits and vegetables: Have them grow their own!

There are times when a hands-on approach can provide the best results. For example, we know that a diet rich in fruits and vegetables is beneficial in preventing and fighting cancer. Similarly, the health benefits of exercise are indisputable. However, getting survivors and patients with cancer to take advantage of these well-known facts can often prove to be difficult. For Wendy Demark-Wahnefried, PhD, RD, the answer was simple: use the hands-on approach to encourage patients and survivors to start their own vegetable gardens and provide help for them along the way.

HARVEST FOR HEALTH

Demark-Wahnefried and her group call their program Harvest for Health.1 The associate director for cancer prevention and control in the Comprehensive Cancer Center at the University of Alabama at Birmingham (UAB), Demark-Wahnefried is also a professor in the University of Alabama at Birmingham Department of Nutrition Sciences and a registered dietitian.

The Harvest for Health program has several goals. Based on prior studies, the developers of Harvest for Health hypothesized that a gardening intervention would improve a patient's physical activity, quality of life, and physical functioning. The group also theorized that the process of growing fruits and vegetables would increase the patient's consumption of these foods. Prior studies documented that community-based gardening programs can lead to the participants having increased physical activity and functioning, a healthier diet, and improvements in psychosocial well-being and health-related quality of life.2,3

Fresh air, exercise, and the joy of growing what you eat—how could that not make someone feel better? In order to evaluate just how much better, the Harvest for Health team designed a pilot study of a 1-year gardening intervention in 2011. The study was a community-based partnership between UAB and the Alabama Cooperative Extension System. There were eight adults (mean age 56 years) and four children (mean age 10 years) enrolled, with an even distribution of males and females. Their cancers were breast, prostate, or any childhood cancer. Although the children were still being treated, the adults had undergone treatment 2 years earlier. All had permission from their oncologists to take part in the project. The primary caregivers of the children also participated.1

MASTER GARDENERS

For this study, the research team recruited Master Gardeners from the Master Gardener Program. This nationwide program is offered by the National Institute of Food and Agriculture, and is available through each state's Cooperative Extension System. The program recruits and trains volunteers to educate the public about landscaping and gardening. In order to be certified as a Master Gardener, an applicant volunteers for at least 60 hours of instruction and community service, often with an annual follow-up. Demark-Wahnefried's group easily recruited Master Gardeners from nearby localities to work with the patients in 12 one-on-one teams. Each patient and Master Gardener worked together to plan, plant, maintain, and harvest three gardens at the homes of the patients.

A MAJOR SUCCESS

The research team completed physical and psychological assessments of the subjects at baseline, 6 months, and 1 year. After 1 year, 60% of the participants increased their physical activity by more than 30 minutes per week, while 40% increased their fruit and vegetable consumption by at least one serving a day. On study completion the participants exhibited more strength, especially in their hands. They also showed better mobility and were able to get up and down more easily.

The feedback from patients and Master Gardeners alike was extremely positive. Many of the cancer survivors said that gardening encouraged them to eat a healthier diet, especially more vegetables. They all planned to continue gardening, and one participant enrolled in the Master Gardener program so that she could help other cancer survivors, as she was helped. The Master Gardeners who worked on the study were extremely enthusiastic. 

 

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por cyto às 11:48

Sábado, 21.02.15

Cruciferous Vegetables and Cancer Prevention

Cruciferous Vegetables and Cancer Prevention 

Cruciferous Vegetables and Cancer Prevention [Fact Sheet]
Cruciferous Vegetables and Cancer Prevention 

Key Points

• Cruciferous vegetables contain vitamins, minerals, other nutrients, and chemicals known as glucosinolates.

• Glucosinolates break down into several biologically active compounds that are being studied for possible anticancer effects.

• Some of these compounds have shown anticancer effects in cells and animals, but the results of studies with humans have been less clear.

What are cruciferous vegetables?

Cruciferous vegetables are part of the Brassica genus of plants. They include the following vegetables, among others:

  • Arugula
  • Bok choy 
  • Broccoli
  • Brussels sprouts
  • Cabbage
  • Cauliflower
  • Collard greens
  • Horseradish
  • Kale
  • Radishes
  • Rutabaga
  • Turnips
  • Watercress
  • Wasabi

Why are cancer researchers studying cruciferous vegetables?

Cruciferous vegetables are rich in nutrients, including several carotenoids (beta-carotene, lutein, zeaxanthin); vitamins C, E, and K; folate; and minerals. They also are a good fiber source.  

In addition, cruciferous vegetables contain a group of substances known as glucosinolates, which are sulfur-containing chemicals. These chemicals are responsible for the pungent aroma and bitter flavor of cruciferous vegetables.

During food preparation, chewing, and digestion, the glucosinolates in cruciferous vegetables are broken down to form biologically active compounds such as indoles, nitriles, thiocyanates, and isothiocyanates (1). Indole-3-carbinol (an indole) and sulforaphane (an isothiocyanate) have been most frequently examined for their anticancer effects.

Indoles and isothiocyanates have been found to inhibit the development of cancer in several organs in rats and mice, including the bladder, breast, colon, liver, lung, and stomach (2, 3). Studies in animals and experiments with cells grown in the laboratory have identified several potential ways in which these compounds may help prevent cancer:

  • They help protect cells from DNA damage.
  • They help inactivate carcinogens.
  • They have antiviral and antibacterial effects.
  • They have anti-inflammatory effects.
  • They induce cell death (apoptosis).
  • They inhibit tumor blood vessel formation (angiogenesis) and tumor cell migration (needed for metastasis).

Studies in humans, however, have shown mixed results, as described in Question 3.

Is there evidence that cruciferous vegetables can help reduce cancer risk in people?

Researchers have investigated possible associations between intake of cruciferous vegetables and the risk of cancer. The evidence has been reviewed by various experts. Key studies regarding four common forms of cancer are described briefly below.

• Prostate cancer: Cohort studies in the Netherlands (4), United States (5), and Europe (6) have examined a wide range of daily cruciferous vegetable intakes and found little or no association with prostate cancer risk. However, some case-control studies have found that people who ate greater amounts of cruciferous vegetables had a lower risk of prostate cancer (7, 8).

• Colorectal cancer: Cohort studies in the United States and the Netherlands have generally found no association between cruciferous vegetable intake and colorectal cancer risk (9-11). The exception is one study in the Netherlands—the Netherlands Cohort Study on Diet and Cancer—in which women (but not men) who had a high intake of cruciferous vegetables had a reduced risk of colon (but not rectal) cancer (12).

• Lung cancer: Cohort studies in Europe, the Netherlands, and the United States have had varying results (13-15). Most studies have reported little association, but one U.S. analysis—using data from the Nurses' Health Study and the Health Professionals' Follow-up Study—showed that women who ate more than 5 servings of cruciferous vegetables per week had a lower risk of lung cancer (16).

• Breast cancer: One case-control study found that women who ate greater amounts of cruciferous vegetables had a lower risk of breast cancer (17). A meta-analysis of studies conducted in the United States, Canada, Sweden, and the Netherlands found no association between cruciferous vegetable intake and breast cancer risk (18). An additional cohort study of women in the United States similarly showed only a weak association with breast cancer risk (19).

A few studies have shown that the bioactive components of cruciferous vegetables can have beneficial effects on biomarkers of cancer-related processes in people. For example, one study found that indole-3-carbinol was more effective than placebo in reducing the growth of abnormal cells on the surface of the cervix (20).

In addition, several case-control studies have shown that specific forms of the gene that encodes glutathione S-transferase, which is the enzyme that metabolizes and helps eliminate isothiocyanates from the body, may influence the association between cruciferous vegetable intake and human lung and colorectal cancer risk (21-23).

Are cruciferous vegetables part of a healthy diet?

The federal government's Dietary Guidelines for Americans 2010 recommend consuming a variety of vegetables each day. Different vegetables are rich in different nutrients. 

Vegetables are categorized into five subgroups: dark-green, red and orange, beans and peas (legumes), starchy, and other vegetables. Cruciferous vegetables fall into the “dark-green vegetables” category and the “other vegetables” category. More information about vegetables and diet, including how much of these foods should be eaten daily or weekly, is available from the U.S. Department of Agriculture website Choose My Plate. 

Higher consumption of vegetables in general may protect against some diseases, including some types of cancer. However, when researchers try to distinguish cruciferous vegetables from other foods in the diet, it can be challenging to get clear results because study participants may have trouble remembering precisely what they ate. Also, people who eat cruciferous vegetables may be more likely than people who don't to have other healthy behaviors that reduce disease risk. It is also possible that some people, because of their genetic background, metabolize dietary isothiocyanates differently. However, research has not yet revealed a specific group of people who, because of their genetics, benefit more than other people from eating cruciferous vegetables.

Selected References

1. Hayes JD, Kelleher MO, Eggleston IM. The cancer chemopreventive actions of phytochemicals derived from glucosinolates. European Journal of Nutrition 2008;47 Suppl 2:73-88. [PubMed Abstract]

2. Hecht SS. Inhibition of carcinogenesis by isothiocyanates. Drug Metabolism Reviews 2000;32(3-4):395-411. [PubMed Abstract]

3. Murillo G, Mehta RG. Cruciferous vegetables and cancer prevention. Nutrition and Cancer2001;41(1-2):17-28. [PubMed Abstract]

4. Schuurman AG, Goldbohm RA, Dorant E, van den Brandt PA. Vegetable and fruit consumption and prostate cancer risk: a cohort study in The Netherlands. Cancer Epidemiology, Biomarkers & Prevention 1998;7(8):673-680. [PubMed Abstract]

5. Giovannucci E, Rimm EB, Liu Y, Stampfer MJ, Willett WC. A prospective study of cruciferous vegetables and prostate cancer. Cancer Epidemiology, Biomarkers & Prevention2003;12(12):1403-1409. [PubMed Abstract]

6. Key TJ, Allen N, Appleby P, et al. Fruits and vegetables and prostate cancer: no association among 1104 cases in a prospective study of 130544 men in the European Prospective Investigation into Cancer and Nutrition (EPIC). International Journal of Cancer 2004;109(1):119-124. [PubMed Abstract]

7. Kolonel LN, Hankin JH, Whittemore AS, et al. Vegetables, fruits, legumes and prostate cancer: a multiethnic case-control study. Cancer Epidemiology, Biomarkers & Prevention 2000;9(8):795-804. [PubMed Abstract]

8. Jain MG, Hislop GT, Howe GR, Ghadirian P. Plant foods, antioxidants, and prostate cancer risk: findings from case-control studies in Canada. Nutrition and Cancer 1999;34(2):173-184. [PubMed Abstract]

9. McCullough ML, Robertson AS, Chao A, et al. A prospective study of whole grains, fruits, vegetables and colon cancer risk. Cancer Causes & Control 2003;14(10):959-970. [PubMed Abstract]

10. Flood A, Velie EM, Chaterjee N, et al. Fruit and vegetable intakes and the risk of colorectal cancer in the Breast Cancer Detection Demonstration Project follow-up cohort. The American Journal of Clinical Nutrition 2002;75(5):936-943. [PubMed Abstract]

11. Michels KB, Edward Giovannucci, Joshipura KJ, et al. Prospective study of fruit and vegetable consumption and incidence of colon and rectal cancers. Journal of the National Cancer Institute2000;92(21):1740-1752. [PubMed Abstract]

12. Voorrips LE, Goldbohm RA, van Poppel G, et al. Vegetable and fruit consumption and risks of colon and rectal cancer in a prospective cohort study: The Netherlands Cohort Study on Diet and Cancer. American Journal of Epidemiology 2000;152(11):1081-1092. [PubMed Abstract]

13. Neuhouser ML, Patterson RE, Thornquist MD, et al. Fruits and vegetables are associated with lower lung cancer risk only in the placebo arm of the beta-carotene and retinol efficacy trial (CARET). Cancer Epidemiology, Biomarkers & Prevention 2003;12(4):350-358. [PubMed Abstract]

14. Voorrips LE, Goldbohm RA, Verhoeven DT, et al. Vegetable and fruit consumption and lung cancer risk in the Netherlands Cohort Study on diet and cancer. Cancer Causes and Control2000;11(2):101-115. [PubMed Abstract]

15. Chow WH, Schuman LM, McLaughlin JK, et al. A cohort study of tobacco use, diet, occupation, and lung cancer mortality. Cancer Causes and Control 1992;3(3):247-254. [PubMed Abstract]

16. Feskanich D, Ziegler RG, Michaud DS, et al. Prospective study of fruit and vegetable consumption and risk of lung cancer among men and women. Journal of the National Cancer Institute2000;92(22):1812-1823. [PubMed Abstract]

17. Terry P, Wolk A, Persson I, Magnusson C. Brassica vegetables and breast cancer risk. JAMA2001;285(23):2975-2977. [PubMed Abstract]

18. Smith-Warner SA, Spiegelman D, Yaun SS, et al. Intake of fruits and vegetables and risk of breast cancer: a pooled analysis of cohort studies. JAMA 2001;285(6):769-776. [PubMed Abstract]

19. Zhang S, Hunter DJ, Forman MR, et al. Dietary carotenoids and vitamins A, C, and E and risk of breast cancer. Journal of the National Cancer Institute 1999;91(6):547-556. [PubMed Abstract]

20. Bell MC, Crowley-Nowick P, Bradlow HL, et al. Placebo-controlled trial of indole-3-carbinol in the treatment of CIN. Gynecologic Oncology 2000;78(2):123-129. [PubMed Abstract]

21. Epplein M, Wilkens LR, Tiirikainen M, et al. Urinary isothiocyanates; glutathione S-transferase M1, T1, and P1 polymorphisms; and risk of colorectal cancer: the Multiethnic Cohort Study. Cancer Epidemiology, Biomarkers & Prevention 2009;18(1):314-320. [PubMed Abstract]

22. London SJ, Yuan JM, Chung FL, et al. Isothiocyanates, glutathione S-transferase M1 and T1 polymorphisms, and lung-cancer risk: a prospective study of men in Shanghai, China. Lancet2000;356(9231):724-729. [PubMed Abstract]

23. Yang G, Gao YT, Shu XO, et al. Isothiocyanate exposure, glutathione S-transferase polymorphisms, and colorectal cancer risk. American Journal of Clinical Nutrition 2010;91(3):704-711. [PubMed Abstract]

Source: National Cancer Institute

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por cyto às 11:46

Sábado, 21.02.15

Three genes are tied to radiation resistance in recurrent glioblastoma tumors

Three genes are tied to radiation resistance in recurrent glioblastoma tumors

A new study has identified three genes that together enable a lethal form of brain cancer to recur and progress after radiation therapy.

The findings might lead to new therapies that target cancer stem cells, according to researchers at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) in Columbus, who led the study.

The work focused on the brain cancer glioblastoma multiforme (GBM). It investigated a subset of cancer cells within those tumors that behave like stem cells and that sometimes survive radiation therapy. To understand how those cancer stem-like cells survive irradiation, the researchers examined the cancer-related gene EZH2, which is unregulated in GBM and other cancers.

They discovered that in GBM stem-like cells, but not in other tumor cancer cells or in healthy body cells, EZH2 is regulated and controlled by the MELK gene in combination with a second gene,FOXM1. The interaction of the three genes helps the cells survive therapy.

The findings were published in Stem Cell Reports (2015; 10.1016/j.stemcr.2014.12.006).

"Currently, GBM is treated surgically followed by radiation therapy and chemotherapy, but these tumors often recur, and patients generally survive less than 2 years, so we badly need new treatments," said principal investigator Ichiro Nakano, MD, PhD, associate professor in the division of neurological surgery and a researcher in the OSUCCC – James Translational Therapeutics Program.

"Our findings suggest that MELK inhibitors can be applicable to brain and other cancers as a novel cancer stem cell-directed therapy."

In earlier research, Nakano and his colleagues showed that MELK is highly expressed in glioblastoma stem-like cells, and that overexpression is correlated with poor patient survival.

For this study, Nakano and his colleagues used cells dissociated from GBM tumors, a mouse model, and the roundworm Caenorhabditis elegans.

They found that MELK and EZH2 proteins occur together in a subset of tumor cells. Without MELK, GBM cells are more sensitive to irradiation. When MELK is restored, the cells become resistant to radiation.

Recurrent GBM tumors have higher numbers of MELK- and EZH2-positive cells than newly diagnosed tumors. MELK and the oncogenic transcription factor FOXM1 form a complex that drives EZH2 expression.

Of note, the levels of MELK, FOXM1 and EZH2 are strongly linked to patient prognosis.

"Taken together, our data suggest that MELK upregulation after irradiation promotes radiation resistance, and tumor development and progression," Nakano said.

 
 
 

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por cyto às 11:23

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