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sexta-feira, 1 de julho de 2011
O presidente da 
O vice-presidente da 
A vice-presidente da 
Ligia Bahia, vice-presidente da 
Pesquisadores do Instituto de Puericultura e Pediatria Martagão Gesteira (
O prazo de envio de resumos de trabalhos para a 10ª Conferência Internacional de Saúde Urbana (
Enzyme Is Important Regulator of Aggressive Breast Cancer Development
ScienceDaily (June 30, 2011) — Researchers at Cold Spring Harbor Laboratory (CSHL) have identified an enzyme that appears to be a significant regulator of breast cancer development. Called PTPN23, the enzyme is a member of a family called protein tyrosine phosphatases, or PTPs, that plays a fundamental role in switching cell signaling on and off.
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When the enzyme PTPN23 is suppressed (top), cancerous breast epithelial cells are able to break free of their moorings and become invasive -- a hallmark of metastasis. Below: similar cells in which PTPN23 is not suppressed; note their regular appearance. |
When the scientists suppressed the expression of PTPN23 in human mammary cells, they noted a cascade of effects that included the cells breaking away from their anchors; their scattering; and their invasion through extracellular matrix (essentially, cells' mooring in tissue). These are the hallmarks of metastasis, the primary cause of mortality in cancer.
PTPs are able to affect cell signaling as a consequence of their very specific biochemical function: they remove phosphate groups from other molecules. Another family of enzymes, called kinases, does precisely the opposite: its members add phosphate groups, and in so doing, work together with the PTPs to regulate cell signaling.
CSHL Professor Nicholas Tonks, who purified the first PTP over 20 years ago, is an authority on phosphatases. He teamed up with CSHL Associate Professor Senthil Muthuswamy, an expert on kinases and breast cancer biology, who is also affiliated with the University of Toronto. They and their colleagues methodically suppressed each of the 105 known PTPs, in a cell culture system constructed to simulate mammary epithelial tissue. The cells were also modified so that the cancer-promoting receptor protein called HER2 (itself a kinase) could be activated selectively. Overabundant HER2 protein (also called ErbB2) is associated with aggressive disease and poor prognosis, and is found in about one-fourth of those who have breast cancer.
To determine the possible impact of PTPs on cancer development in cells expressing activated HER2, the team assembled a library of short-hairpin RNA molecules, or shRNAs, which had the ability to inactivate, one by one, the genes responsible for expressing each PTP. Of the 105 PTPs, they observed that three of them, when suppressed, were associated with increased motility, or the ability of the mammary cells to move freely of one another. The suppression of one of these three -- PTPN23 -- was also observed to cause the cells to become invasive.
Part of what makes this finding intriguing is the fact that the CSHL team was able to trace the cause of these effects to specific elements of a complex signaling cascade. And this, in turn, has led the team to identify a potentially powerful new therapeutic strategy in this aggressive cancer type.
They discovered that PTPN23, under normal conditions, i.e., when not suppressed, recognizes and removes phosphate groups from three molecules important in the signaling cascade in breast epithelial cells. These three molecules are called SRC, E-cadherin and β-catenin. Of the three, the key is SRC: it is a type of kinase that, like HER2, is well known to be a cancer-promoter. SRC-induced anomalies in cell signaling have been linked with breast and other cancer types.
Tonks, Muthuswamy and colleagues demonstrated for the first time that this particular PTP -- PTPN23 -- acts directly on SRC to inhibit its phosphate-adding activity. But when PTPN23 is suppressed, as in the team's experiments, SRC is free to add phosphates to other molecules in the cell, including E-cadherin and β-catenin. Normally, these molecules are important in cell adhesion. But when they are phosphorylated by SRC, their ability to function as the "glue" that holds cells to their anchors in epithelial tissue is impaired, and the cells are able to break free. This adds interest to the observation, made by others, that the gene that expresses PTPN23 is located within a "hotspot" on human chromosome 3 (3p21) that is mutated in breast and other cancers.
"Considering the negative effect of PTPN23 on SRC activity, loss of PTPN23 may promote tumor growth and metastasis in breast tumors that are associated with activation of SRC," the team suggests in a paper on the research published in the journal Genes & Development.
This fine-grained picture of how an absence of PTPN23 can set in motion a chain of events in breast epithelial cells that promotes cancer proliferation in turn suggests the next step in the research. The team tried and was able to reverse the metastatic effects set in train by PTPN23 suppression in these cancer-cell models by introducing a candidate drug molecule called SU6656, which inhibits SRC.
On the theory that PTPN23 regulates the activity of SRC and the phosphorylation status of the E-cadherin/β-catenin signaling complexes to modulate cell motility, invasion and scattering, the team has moved to a new set of experiments in living mice which have been genetically engineered to lack PTPN23. In such animals, they expect aggressive tumors to form. They seek to address these by treating the mice with inhibitors of SRC.
Telomeres: Two Genes Linked to Why They Stretch in Cancer Cells
ScienceDaily (June 30, 2011) — Scientists at Johns Hopkins have provided more clues to one of the least understood phenomena in some cancers: why the "ends caps" of cellular DNA, called telomeres, lengthen instead of shorten.
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This image shows fluorescent staining of abnormal telomere DNA in pancreatic neuroectodermal tumors. |
In a study published online June 30 in Science Express, the Johns Hopkins researchers say they have identified two genes that, when defective, may cause these telomere elongations.
Telomeres contain repeated sequences of DNA that, in normal cells, shorten each time a cell divides. Without telomeres, the cell division-related shortening could snip off a cell's genes and disrupt key cell functions. Most cancer cells, naturally prone to divide rapidly, use high amounts of an enzyme called telomerase to keep their telomeres intact. Yet, some cancer cells are known to maintain their telomere length without help from telomerase.
With no increased production of telomerase, scientists were left to wonder how cancer cells managed to maintain their telomeres, a phenomenon known as "alternative lengthening of telomeres."
"Finding the genes responsible for alternative lengthening of telomeres is the first step in understanding this process and provides opportunities to develop new drug therapies," says Nickolas Papadopoulos, Ph.D., associate professor at the Johns Hopkins Kimmel Cancer Center and director of translational genetics at Johns Hopkins' Ludwig Center.
The first clues to the genes linked to the process came from a study led by Papadopoulos that mapped the genome of pancreatic neuroendocrine tumors, published in the Jan. 20 issue of Science Express. The most prevalent gene alterations in those tumors occurred in genes that include ATRX and DAXX. Proteins made by these genes interact with specific portions of DNA to alter how its chemical letters are read. ATRX and DAXX had also been linked to similar functions in the telomere region, says Alan Meeker, Ph.D., assistant professor of pathology, urology and oncology at Johns Hopkins.
Following a hunch, Meeker and his colleagues took a closer look at the two genes and their specific role in telomere lengthening. With tissue samples from 41 patients with pancreatic neuroendocrine tumors collected during the genome mapping project, the scientists found characteristic signatures of alternative telomere lengthening in 25 of them. Fluorescent dyes targeted specifically to telomeres showed "huge aggregates of telomere DNA" in the 25 samples, with each fluorescent spot holding about 100 times more telomere DNA than normal cells, according to Meeker.
Nineteen of the 25 samples that glowed positive for alternative telomere lengthening had either ATRX or DAXX mutations. Six of those 25 samples did not contain ATRX or DAXX mutations, but the tumor cells showed no expression of these two genes. The remaining 16 samples with no alternative lengthening lacked mutations and had adequate ATRX and DAXX expression.
"We saw a 100 percent correlation between abnormalities in ATRX and DAXX and alternative lengthening of telomeres," says Meeker.
Among 439 other samples of tumors tested by Meeker, Papadopoulos and colleagues, ATRX mutations were found in several brain cancer types, including pediatric and adult glioblastoma samples provided by Hai Yan, M.D., Ph.D., and Darell Bigner, M.D., Ph.D., of Duke University.
Meeker and colleagues tested the telomeres status in glioblastoma samples with tissue available for the assay. All eight glioblastoma tissue samples with ATRX mutations showed the characteristic bright glow of their telomeres, indicative of alternative lengthening, and lack of ATRX expression.
Although the Johns Hopkins team does not yet have an explanation for how the genes do their lengthening work in cancer, Meeker speculates that the mutations alter the way that telomere DNA is packaged, exposing those areas to instability.
Papadopoulos' genome mapping studies showed that patients with pancreatic neuroendocrine tumors containing ATRX/DAXX mutations had better survival than those without the mutations.
"If the correlation holds up, we could use alternative lengthening of telomeres and ATRX/DAXX mutations as a method of determining a patient's prognosis in addition to developing treatments that target these genes," says Meeker.
Funding for the study was provided by the Caring for Carcinoid Foundation, a nonprofit foundation that funds research on carcinoid cancer, pancreatic neuroendocrine cancer, and related neuroendocrine cancers, the Lustgarten Foundation for Pancreatic Cancer Research, the Virginia and D.K. Ludwig Fund for Cancer, National Institutes of Health, the Sol Goldman Pancreatic Cancer Research Center, the American Cancer Society, the Pediatric Brain Tumor Foundation Institute, the Duke Comprehensive Cancer Center Core, the Fundacao de Amparo a Pesquisa do Estado de Sao Paulo, and the Department of Defense Breast Cancer Research Program.
Co-authors of the research include Christopher M Heaphy, Roeland F de Wilde, Yuchen Jiao, Alison P Klein, Barish H Edil, Kenneth W Kinzler, Bert Vogelstein, Ralph H Hruban, Anirban Maitra, Chetan Bettegowda, Fausto J Rodriguez, Charles G Eberhart, and Sachidanand Hebbar from Johns Hopkins; Chanjuan Shi from Vanderbilt University; Johan A Offerhaus from the University Medical Center Utrecht, the Netherlands; Roger McLendon, B. Ahmed Rasheed, Yiping He, Hai Yan, and Darell D. Bigner from Duke University; and Sueli Mieko Oba-Shinjo and Suely Kazue Nagahashi Marie from the University of Sao Paulo, Brazil.
Nanoparticles Disguised as Red Blood Cells to Deliver Cancer-Fighting Drugs
ScienceDaily (June 30, 2011) — Researchers at the University of California, San Diego have developed a novel method of disguising nanoparticles as red blood cells, which will enable them to evade the body's immune system and deliver cancer-fighting drugs straight to a tumor. Their research will be published next week in the online Early Edition of theProceedings of the National Academy of Sciences.
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Scanning fluorescence microscopy image shows the integrity of the RBC-membrane-cloaked polymeric nanoparticles after being taken up by a cancer cell. The RBC membrane was visualized with green dye, polymeric core with red dye, and cancer cell with blue dye. |
"This is the first work that combines the natural cell membrane with a synthetic nanoparticle for drug delivery applications." said Liangfang Zhang, a nanoeningeering professor at the UC San Diego Jacobs School of Engineering and Moores UCSD Cancer Center. "This nanoparticle platform will have little risk of immune response."
The method involves collecting the membrane from a red blood cell and wrapping it like a powerful camouflaging cloak around a biodegradable polymer nanoparticle stuffed with a cocktail of small molecule drugs. Nanoparticles are less than 100 nanometers in size, about the same size as a virus.
Researchers have been working for years on developing drug delivery systems that mimic the body's natural behavior for more effective drug delivery. That means creating vehicles such as nanoparticles that can live and circulate in the body for extended periods without being attacked by the immune system. Red blood cells live in the body for up to 180 days and, as such, are "nature's long-circulation delivery vehicle," said Zhang's student Che-Ming Hu, a UCSD Ph.D. candidate in bioengineering, and first author on the paper.
Stealth nanoparticles are already used successfully in clinical cancer treatment to deliver chemotherapy drugs. They are coated in a synthetic material such as polyethylene glycol that creates a protection layer to suppress the immune system so that the nanoparticle has time to deliver its payload. Zhang said today's stealth nanoparticle drug delivery vehicles can circulate in the body for hours compared to the minutes a nanoparticle might survive without this special coating.
But in Zhang's study, nanoparticles coated in the membranes of red blood cells circulated in the bodies of lab mice for nearly two days. The study was funded through a grant from the National Institute of Health.
A shift towards personalized medicine
Using the body's own red blood cells marks a significant shift in focus and a major breakthrough in the field of personalized drug delivery research. Trying to mimic the most important properties of a red blood cell in a synthetic coating requires an in-depth biological understanding of how all the proteins and lipids function on the surface of a cell so that you know you are mimicking the right properties. Instead, Zhang's team is just taking the whole surface membrane from an actual red blood cell.
"We approached this problem from an engineering point of view and bypassed all of this fundamental biology," said Zhang. "If the red blood cell has such a feature and we know that it has something to do with the membrane -- although we don't fully understand exactly what is going on at the protein level -- we just take the whole membrane. You put the cloak on the nanoparticle, and the nanoparticle looks like a red blood cell."
Using nanoparticles to deliver drugs also reduces the hours it takes to slowly drip chemotherapy drug solutions through an intravenous line to just a few minutes for a single injection of nanoparticle drugs. This significantly improves the patient's experience and compliance with the therapeutic plan. The breakthrough could lead to more personalized drug delivery wherein a small sample of a patient's own blood could produce enough of the essential membrane to disguise the nanoparticle, reducing the risk of immune response to almost nothing.
Zhang said one of the next steps is to develop an approach for large-scale manufacturing of these biomimetic nanoparticles for clinical use, which will be done through funding from the National Science Foundation. Researchers will also add a targeting molecule to the membrane that will enable the particle to seek and bind to cancer cells, and integrate the team's technology for loading drugs into the nanoparticle core so that multiple drugs can be delivered at the same time.
Zhang said being able to deliver multiple drugs in a single nanoparticle is important because cancer cells can develop a resistance to drugs delivered individually. By combining them, and giving the nanoparticle the ability to target cancer cells, the whole cocktail can be dropped like a bomb from within the cancer cell.
Lung Cancer: Study Shows 20 Percent Reduction in Mortality With Low-Dose CT Vs Chest X-Ray
ScienceDaily (June 30, 2011) — Scientists have found a 20 percent reduction in deaths from lung cancer among current or former heavy smokers who were screened with low-dose helical computed tomography (CT) versus those screened by chest X-ray. The primary research results from the National Lung Screening Trial (NLST) were published online in the New England Journal of Medicine.
This article provides a more extensive analysis of the data originally reported in November 2010 while providing additional data to the public and research community without barriers to access. Sponsored by the National Cancer Institute (NCI), part of the National Institutes of Health, the NLST is a nearly decade-long study that establishes low-dose helical CT as the first validated screening test which can reduce mortality due to lung cancer.
"Today's publication gives researchers, policy makers, and the public full access to primary findings from the NLST to guide the use of low-dose helical CT scanning by current and former smokers," said Harold Varmus, M.D., NCI director. "The NCI marshaled the scientific and financial resources required for this expansive study, because only trials such as this allow us to say which methods of screening are effective, and how effective, in defined populations. Having a validated screening test that provides significant, but partial, protection against death from lung cancer complements -- but should not be seen as replacing -- ongoing efforts to control use of tobacco and to find other ways to prevent and treat lung cancer."
The NLST was a randomized national trial involving 53,454 current and former heavy smokers ages 55 to 74. Participants were required to have a smoking history of at least 30 pack-years and were either current or former smokers without signs, symptoms, or history of lung cancer. Pack-years are calculated by multiplying the average number of packs of cigarettes smoked per day by the number of years a person has smoked.
Participants in the NLST were randomly assigned to receive three annual screens with either low-dose helical CT (often referred to as spiral CT) or standard chest X-ray. Helical CT uses X-rays to obtain a multiple-image scan of the entire chest, while a standard chest X-ray produces a single image of the whole chest in which anatomic structures overlie one another.
The paper provides important details about the number of screens that identified abnormalities potentially related to lung cancer (positive screens) and how many of those positive screens turned out to be false positives, meaning that the positive finding did not prove to be lung cancer upon follow-up. On average over the three rounds of screening exams, 24.2 percent of the low-dose helical CT screens were positive and 6.9 percent of the chest X-rays were positive. In both arms of the trial, the majority of positive screens led to additional tests.
Across all three rounds, when a positive screening result was found, 96.4 percent of the low-dose helical CT tests and 94.5 percent of the chest X-ray exams were false positive. The vast majority of false positive results was probably due to the detection of normal lymph nodes or inflamed tissues. False positive results not due to lung cancer were typically confirmed by follow-up CT scans that showed no change in the finding over time.
The published results also provide insight into the type of lung cancers found by screening and the stages at which they were diagnosed. Adenocarcinomas, which begin in cells that line the lungs, and squamous cell carcinomas, which arise from the thin, flat fish-scale-like cells that line passages of the respiratory tract, were detected in the early stages of disease in both arms of the trial. Both types of lung cancer were detected more frequently at the earliest stage by low-dose helical CT compared to chest X-ray. Small-cell lung cancers, which are very aggressive tumors and grow in the tissues of the lung, were infrequently detected at early stages by low-dose helical CT or chest X-ray. Knowing what types of lung cancers are detectable and at what stage they are most detectable by different screening modalities should help researchers refine the use of these tools for future patients.
Additional studies based on the complete NLST data set are ongoing and will include reports on cost-effectiveness of low-dose helical CT as well as the ability to use the data to develop models that may help indicate whether other groups of smokers, such as light smokers or younger smokers, would benefit from screening with low-dose helical CT. Other modeling studies are expected to examine the optimal frequency and duration of screening.
Adverse events, which are harms from the actual screening examinations, were few and relatively minor in the NLST. The rate of complications among people who underwent a diagnostic evaluation prompted by a positive screen was under 2 percent for either type of screening. Among those who did have complications, 16 people screened with low-dose helical CT (10 of whom had lung cancer) and 10 chest X-ray participants (all with lung cancer) died within 60 days of a follow-up invasive diagnostic procedure.
Invasive diagnostic procedures include bronchoscopy, where an instrument is inserted through the nose or mouth into the airways, and percutaneous lung needle biopsy, where a needle is inserted into the lung through the chest to remove a small piece of tissue for examination. While it is not known whether the diagnostic procedures caused these deaths, the low frequency of death within 60 days of an invasive procedure in the NLST suggests that death following evaluation of positive screens occurs rarely.
Radiation exposure associated with low-dose helical CT in the NLST is much lower than that associated with a regular diagnostic chest CT. The authors note any harm from exposure to radiation during the screenings could not be measured directly. Because the effect of such exposure is a long-term outcome, potential harms will need to be modeled in future studies.
It should also be noted that the population enrolled in this study, while ethnically representative of the U.S. population of smokers at high risk for lung cancer, was a highly motivated and primarily urban group that was screened at major medical centers. Thus, these results alone may not accurately predict the effects of recommending low-dose helical CT scanning for other populations.
"These primary findings from the NLST provide a valuable insight into how to potentially decrease death due to lung cancer. But the most important method of decreasing lung cancer rates remains for smokers to quit smoking and for those who don't smoke to continue with their healthy behaviors," said NLST co-investigator, Christine Berg, M.D., of the NCI.
The NLST was conducted by the American College of Radiology Imaging Network, a medical imaging research network focused on the conduct of multi-center imaging clinical trials, and the Lung Screening Study group, which was initially established by the NCI to examine the feasibility of the NLST.
Resistant Mice Provide Clues About Successful Immune Response to Retroviruses
ScienceDaily (June 30, 2011) — Although our body's defense mechanisms are usually capable of detecting and destroying many types of pathogens, some viruses are able to evade the immune system and make us sick. In particular, "retroviruses," such as human immunodeficiency virus (HIV), are notorious for eluding host immune defenses and causing disease.
Now, a new study published by Cell Press online on June 30th in the journal Immunity identifies a key virus-sensing mechanism that is necessary for a successful immune response against infection with this particularly deadly type of virus. The research may help to guide the future design of more effective antiretroviral vaccines.
"The demand for producing highly efficient vaccines against HIV is great and the approaches currently available for making vaccines may not be relevant to retroviruses, as none of the trials conducted to date have been successful," explains the senior study author, Dr. Tatyana V. Golovkina, from the University of Chicago. "It is critical that we achieve a basic understanding of how the immune system detects and responds to retroviruses in order to apply this knowledge to the production of anti-retrovirus vaccines."
To examine exactly what steps in the viral invasion and replication (copying) process are necessary and sufficient to trigger a successful virus-specific immune response in the host, Dr. Golovkina and colleagues used special strains of mice that are resistant to retroviruses. The mice used in the study become infected when exposed to retrovirus, but mount a powerful antivirus immune response that eliminates or controls the virus, making them a superior choice for studies examining successful antiretroviral immunity. The researchers discovered that of all the steps in the viral replication process, the ability to enter the host cell was sufficient to induce successful immune responses. In fact, complete viral replication was dispensable for triggering virus detection. A protein called endosomal Toll-like receptor 7 (TLR7), known for a role in the detection of viral single-chain RNA, was identified as the critical retrovirus-sensing receptor.
Taken together, the findings suggest that an efficient and sustained immune response to retroviruses is induced by sensing of the early stages of retroviral infection. "Although the precise mechanism of retroviral exposure to TLR7 is yet to be identified, our results provide definitive evidence that TLR7-dependent recognition is required for an efficient immune response against retroviruses," concludes Dr. Golovkina. "An understanding of the genetic mechanisms underlying retroviral resistance will help to drive design anti-retroviral vaccines that utilize inactivated viruses combined with targeting the immune pathways employed successfully in resistant organisms."
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