Protein that makes local bladder cancer invasive found

May 15, 2010 By Leave a Comment

Washington, May 15 (ANI): Researchers at the Kimmel Cancer Center at Jefferson have identified a protein, which, according to them, is involved in pushing tumours to become invasive – and deadly.

It is known that bladder cancer often becomes aggressive and spreads in patients despite treatment.

“We have found that IGF-IR is a critical regulator of motility and invasion of bladder cancer cells, and this could offer us a novel molecular target to treat patients with this cancer in order to prevent metastasis,” said the lead investigator, Dr. Andrea Morrione, a research associate professor of Urology at Jefferson Medical College.

The researchers claim that the finding is promising because there are about a dozen agents targeted against the protein, the insulin-like growth factor receptor I (IGF-IR), that are now undergoing clinical testing to treat a variety of patient tumours.

“Testing presence of the protein could also serve as a novel tumour biomarker for diagnosis, and possibly prognosis of bladder tumours,” he added.

Although bladder cancer is common, the molecular mechanisms that push the cancer to become invasive and to spread are still poorly understood, say the researchers.

Although most bladder cancers are caught early and treated, they often come back and become aggressive, despite subsequent therapy with surgery, chemotherapy, or immunotherapy.

In the study, the researchers looked at the role of the protein receptor for the growth factor IGF-I, an important modulator of cell proliferation in bladder cancer cells.

They found that although activation of IGF-IR did not affect growth of bladder cancer cells, it did promote the migration and invasion of these cells.

The researchers showed that IGF-IR activated other molecules in cancer-promoting pathways (Akt and MAPK) that allow cancer cells to break its bond with other cells in a tumor in order to travel to others sites in the body.

“These data seem to indicate that this protein receptor may play a more prominent role in later stages of bladder cancer, not in the initiation of the cancer,” said Morrione.

Additional work is needed to validate the role of IGF-IR in pushing bladder cancer into an invasive form, but if the results continue to be promising, it might be possible to test anti IGF-IR therapies in bladder cancer and to see how effective a test for these proteins in bladder tumor biopsies might predict cancer spread, the researchers say.

The study has been published in the June issue of American Journal of Pathology. (ANI)

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Proteins key for normal-sized brains found

May 13, 2010 By Leave a Comment

Washington, May 13 (ANI): In a new study, boffins at MIT”s Picower Institute for Learning and Memory have analyzed the interaction of two proteins key to brain development.

The work may one day correct or prevent genetic conditions tied to smaller-than-normal brains and shed light on the evolution of human head size.

Neurogenesis is the process through which neurons are created during prenatal development to populate the growing brain.

Li-Huei Tsai, director of the Picower Institute and Picower Professor of Neuroscience, found that two proteins–Cdk5rap2 and pericentrin—work together to regulate neural growth in the developing brain. Loss of function of these proteins results in human disorders such as primary autosomal recessive microcephaly (MCPH) and Majewski osteodysplastic primordial dwarfism, type II (MOPDII), genetic conditions characterized in part by abnormally small head circumference.

An understanding of these rare genetic disorders may offer insight into one of the most striking differences between us and our closest living relatives: brain size and cognitive ability.

The researchers show that Cdk5rap2 and pericentrin interact with one another to regulate proliferation of neural progenitor cells that give rise to the brain layer called the neocortex. Pericentrin recruits Cdk5rap2 to structures within the neural progenitor cells, and loss of Cdk5rap2 results in decreased cell proliferation.

“Given the link between head circumference, intelligence deficits and psychiatric disorders, these findings have implications for our understanding of how abnormalities in brain development can play a role in a number of diseases,” said Tsai, a Howard Hughes Medical Institute investigator and the director of the neurobiology program at the Broad Institute”s Stanley Center for Psychiatric Research. In addition to leading to potential treatments for MCPH and MOPDII, the work may also shed light on the increase in brain size during human evolution. (ANI)

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Artificial human skin created

April 21, 2010 By Leave a Comment

Washington, Apr 21 (ANI): University of Granada researchers have created artificial human skin by tissular engineering basing on agarose-fibrin biomaterial.

The artificial skin was grafted onto mice, and optimal development, maturation and functionality results were obtained. This pioneering finding will allow the clinical use of human skin and its use in many laboratory tests on biological tissues –which, additionally, would avoid the use of laboratory animals. Further, this finding could be useful in developing new treatment approaches for dermatological pathologies.

This research was conducted by José María Jiménez Rodríguez, from the Tissular Engineering Research group of the Department of Histology of the University of Granada, and coordinated by professors Miguel Alaminos Mingorance, Antonio Campos Muñoz and José Miguel Labrador Molina.

Researchers from the University of Granada firstly selected the cells that would be employed in generating artificial skin. Then, they analysed the evolution of the in-vitro culture and, finally, they performed a quality control of the tissues grafted onto nude mice. To this purpose, several inmunofluorescence microscopy techniques had to be developed. These techniques allowed researchers to evaluate such factors as cell proliferation, the presence of differentiating morphological markers, the expression of cytokeratin, involucrine and filaggrin, angiogenesis and artificial skin development into the recipient organism.

To make this assay, researchers obtained human skin from small biopsies belonging to patients following surgery at the Plastic Surgery Service of the University Hospital Virgen de las Nieves in Granada.

To create artificial human skin, human fibrin from plasma of healthy donors was used. Researchers then added tranexamic acid –to prevent fibrinolysis–, and calcium chloride to precipitate fibrin coagulation, and 0.1 percent aragose. These artificial-skin substitutes were grafted on the back of the nude mice, with the purpose of observing its evolution in vivo. The equivalent skin substitutes were analysed by transmission and scanning light and electron microscopy and inmunofluorescence.

The skin created in the laboratory showed adequate biocompatibility rates with the recipient and no rejection, dehiscence or infection was registered. Additionally, the skin of all animals used in the study started to show granulation after six days from implantation. Within the following twenty days, cicatrization was complete. (ANI)

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Protein that tells the heart when it”s big enough identified

March 26, 2010 By Leave a Comment

Washington, Mar 26 (ANI): Researchers at Johns Hopkins have found the secret behind how the human heart and other organs automatically “right size” themselves— a protein discovered in fruit fly eyes.

The protein, named Kibra, is linked to a relay of chemical signals responsible for shaping and sizing tissue growth by coordinating control of cell proliferation and death.

The discovery could hold clues to controlling cancer.

In a series of experiments, the scientists manipulated Kibra”s role in a signalling network called the Hippo pathway, which consists of several proteins working together as a braking system.

Counterparts of the components in the Hippo pathway in flies are found in most animals, suggesting that this pathway may act as a “global regulator” of organ size control, said Dr. Duojia Pan.

“People have always been curious about what makes a hippopotamus grow so much bigger than a mouse. As well as how our two hands, which develop independently, get to very similar sizes. Our studies show that Kibra regulates Hippo, which keeps organs characteristically sized, preventing my heart or your liver from becoming as hefty as those befitting a large African amphibious mammal,” said Pan.

The researchers identified the gene they named Hippo in 2003, showing that an abnormal copy of it led to an unusually large eye in a developing fruit fly.

Pan said that the new experiments moved the investigation “slowly and methodically upstream” to find Hippo”s trigger, where “the key to size-control lies.”

Pan added that the Hippo-Kibra link could be a key to understanding and treating cancer because cancer is literally a disease of uncontrolled growth.

The Johns Hopkins and Florida State teams discovered Kibra by studying ovarian cells from adult flies and by using a gene-controlling technique called RNA interference (RNAi) to systematically turn off each of the approximately 14,000 genes in the fly genome, one at a time, in cultured fly cells.

They then analysed the function of Kibra in the developing fly larvae.

They found that the Hippo pathway was not active in the absence Kibra.

Further studies on human cells measured the activity of the Hippo pathway while manipulating human Kibra and showed that like its fruit fly counterpart, human Kibra acts as a tumour suppressor protein that regulates Hippo signalling.

“The discovery of Kibra moves us an important step closer to identifying the initial signal that triggers Hippo”s activation. We”re making progress along the Hippo pathway, heading toward the cell surface, and believe we will find that elusive signal en route,” said Pan.

The study has been published in Developmental Cell. (ANI)

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Zebrafish study may shed light on cell regeneration in human heart

March 25, 2010 By Leave a Comment

London, March 25 (ANI): A new Spanish study has found that cardiac muscle cells known as cardiomyocytes carry out repair in an injured zebrafish heart – a finding that could provide insight into how human hearts could be made to repair themselves after a heart attack.

The research, conducted by Juan Carlos Izpisúa Belmonte and his colleagues at the Salk Institute for Biological Studies and the Center of Regenerative Medicine in Barcelona (CMRB), found that these cellular grown-ups outperform stem cells in cardiac repair.

Izpisúa Belmonte, professor in the Gene Expression Laboratory, said: “What the results of our study show is that mother nature utilizes other ways besides going all the way back to pluripotent stem cells to regenerate tissues and organs.”

Izpisúa Belmonte also noted, that at least in fish, the body may have evolved surprising repair strategies driven by cell types more seasoned than stem cells.

To identify which cells actually filled in excised zebrafish heart muscle, the researchers first used some genetic engineering to only make cardiomyocytes “transgenic” by inserting into them a tracer gene that made them glow green under a microscope.

Thereafter, they chopped off about 20 per cent of each fish ventricle and waited a couple of weeks for the hearts to regenerate: if regenerated heart muscle didn”t glow, it would mean that cells other than cardiomyocytes, such as a cardiac stem cell population, had replaced the damaged muscle.

However, all regenerated heart muscle cells glowed green, indicating that well established cardiomyocytes remaining after injury had likely regressed to a more “youthful” state, started dividing again to replenish lost cells, and then matured a second time into new heart muscle.

The team also demonstrated that cardiomyocytes recaptured lost youth in part by re-activating the production of proteins associated with cell proliferation, factors typically expressed in immature progenitors.

Human hearts cannot undergo these types of regenerative changes on their own. When damaged by heart attack, our heart muscle is replaced by scar tissue incapable of contracting. However, prior to heart failure, damaged mammalian heart muscle cells enter a save-yourself state known as “hibernation,” in which they cease contracting in an effort to survive.

Chris Jopling, a postdoctoral fellow of Izpisúa Belmonte”s at CMRB and first author of the study, believes human heart “hibernation” is significant.

He said: “During heart regeneration in the zebrafish we found that cardiomyocytes displayed structural changes similar to those observed in hibernating cardiomyocytes.

“Because of these similarities, we hypothesize that hibernating mammalian cardiomyocytes may represent cells that are attempting to proliferate.”

Thus, it can be said that mammalian hearts can undergo a kind of metabolic “downsizing” that is a prelude to cell division.

Jopling said: “This idea fits nicely with the findings from a number of groups — that forced expression of cell cycle regulators can induce cardiomyocyte proliferation in mammals.

“Maybe all they need is a bit of a push in the right direction.”

Izpisúa Belmonte added: “We can no longer view differentiated cells as being a static endpoint of the differentiation process.

“If we could mimic in mammalian cells what happens in zebrafish, perhaps we could be in a position to understand why regeneration does not occur in humans.”

The study has appeared in the March 25, 2010 issue of Nature. (ANI)

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Scientists isolate liver cancer stem cells prior to tumour formation

September 19, 2009 By Leave a Comment

Washington, September 18 (ANI): US researchers may have moved a step further towards gaining a deeper understanding of the role of stem cells in liver cancer.

A team of experts from Penn State College of Medicine and the University of Southern California used a unique approach that involves study of individual cells, and became the first ever researchers to show a population of cancer stem cells in the liver prior to tumour formation.

Writing about their work in the journal Stem Cells, the researchers say that their findings suggest a potential link between liver stem cells and liver cancer.

Lead researcher C. Bart Rountree and colleagues have revealed that they used a liver-specific PTEN (phosphatase and tensin homolog deleted on chromosome 10) mouse model to study the microenvironment of the liver.

“The PTEN knock-out mouse is one model of chronic liver injury that ultimately leads to liver cancer. During chronic injury, liver stem cells proliferate, and at times of healthy liver, the liver stem cells are very rare. We were initially looking for what is driving liver stem cell proliferation during chronic liver injury,” Rountree said.

“We started investigating liver stem cells in many different liver injury models with the idea we may be able to help people with liver disease, but we discovered that some cells we isolated were malignant. It was quite a surprise for us because there were not any tumors in the mice when we isolated the cells,” Rountree said.

The liver is the only organ in the body that is able to fully regenerate itself. Its cells, including hepatocytes and cholangiocytes, can divide and repopulate themselves.

In cases of chronic liver injury, including by a virus or alcoholism, the hepatocytes lose the ability to make more of themselves. In such settings, liver stem cells proliferate and can make either of the cell types.

However, patients with chronic injury also develop liver cancer, opening the possibility that the stem cells are involved in tumour formation.

“There’s been a groundswell of interest in understanding the role of specific stem cells in the development of liver cancer. There is a cancer stem cell lurking out there that may be very bad. It has stem cell properties and is malignant, resistant to chemotherapy. These properties make it harder to treat these cancers,” Rountree said.

“What we ended up doing was shifting our understanding of liver stem cells and their role in malignancy. All work previously done was looking at patients, animal models or cell lines after the tumor already developed. What we did was identify malignant stem cells before there is evidence of the primary tumor. This gave us a new perspective on not only what the potential of stem cells for therapy is, but also in terms of what’s driving cancer formation. Imagine treating a cancer before a primary malignancy forms,” Rountree added.

For their study, the researchers created ten cell lines to study using a single-cell isolation technique. They separated cells that make a unique surface protein called CD133 by placing them in a liquid medium, and running through a flow cytometer.

Once identified, a robot took a single CD133-positive cell and placed it in a single drop into one well of a culture dish. Doing that several hundred times, the cell lines were established.

The researchers said that, when expanded up, the single cells were found to have stem cell characteristics, having markers of both hepatocytes and cholangiocytes.

When the researchers injected the lines into a mouse with a deficient immune system, the tumours then formed.

According to Rountree, there is interest in targeting these stem cells with malignant potential.

“Can we target these cells in patients with hepatitis B or C, either before or after their cancer forms? The broader implication is very powerful. If you look at a patient with chronic injury and find a way to specifically target cells with malignant potential, you may be able to prevent liver cancer in the first place,” Rountree said. (ANI)

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Single gene offers promising approach to treat both ebola and anthrax infections

August 21, 2009 By Leave a Comment

Washington, August 21 (ANI): A minor reduction in levels of a gene called CD45 may provide protection against the virus that causes Ebola hemorrhagic fever and the bacterium that causes anthrax, according to a study.

Published in the online issue of Cell Host and Microbe, the study on mice was led by scientists at the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID).

The researchers say that their findings suggest a common host restriction factor as well as a promising approach to drug development for treating two completely different infections.

During the study, the researchers observed that the mice that expressed reduced levels of CD45-between 11 and 77 percent-were protected against Ebola virus.

Besides an overall survival rate of 90 to 100 percent, the mice were also found to have reduced levels of virus load in the major organs.

The researchers said that the experimental mice had completely cleared the virus 10 days after challenge.

On the other hand, they added, the mice that had naturally occurring levels of CD45-or none at all- failed to clear the virus, and succumbed to infection within 7 to 8 days following challenge.

The protein encoded by CD45 is a member of the protein tyrosine phosphatase (PTP) family, known to be signalling molecules that regulate a variety of cellular processes, including cell growth, cell division, and the development of malignancies that can lead to tumour formation.

The researchers created various “knockdown” mice, which expressed reduced levels of CD45, to determine how those changes may alter the body’s immune response to microbial pathogens such as Ebola virus.

They say that the “knockdown” mice retained greater control of gene expression and immune cell proliferation following Ebola virus infection, the factors that contributed to enhanced viral clearance, increased protection against the virus, and a reduction in cell death.

Based on the study’s findings, the authors came to the conclusion that host susceptibility to Ebola virus is dependent on the delicate balance of the body’s natural immune system, which can be determined by the levels of a single regulator gene.

The study built upon a related study, published in the Journal of Biological Chemistry in May this year, which showed that CD45 also plays a role in protection from Bacillus anthracis, the causative agent of anthrax.

The next step for the researchers is to look at the mechanism of action to better understand how reduced expression of this gene regulates the pathogenesis of both diseases, as that information may one day lead to the identification and discovery of additional promising compounds for treating Ebola and anthrax infections. (ANI)

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Aspirin ‘cuts colorectal cancer death risk’

August 12, 2009 By Leave a Comment

Washington, Aug 12 (ANI): Taking aspirin on a regular basis after being diagnosed with colon cancer has been found to reduce the chances of dying from the disease, reveals a new study.

Numerous prospective, observational studies have shown that regular aspirin use is linked to a lower risk of colorectal adenoma (a benign tumour) or cancer.

However, the influence of aspirin on survival after diagnosis of colorectal cancer has been unknown.

Dr. Andrew Chan of Massachusetts General Hospital and Harvard Medical School in Boston and colleagues studied aspirin use in 1,279 men and women with colorectal cancer that had not spread to other parts of the body.

They found that people who took aspirin regularly after their diagnosis were nearly 29 percent less likely to die from their cancer than people who did not take aspirin. These people also were 21 percent less likely to die for any reason while they were in the study lasting more than two decades.

“These results suggest that aspirin may influence the biology of established colorectal tumours in addition to preventing their occurrence,” Chan said.

Aspirin is likely, at least in part, to prevent colorectal neoplasia (tumour growth) through inhibition of cyclooxygenase-2 (COX-2; an enzyme), which promotes inflammation and cell proliferation, and is overexpressed in the majority of human colorectal cancers, according to background information in the article.

The study has been published in the August 12 issue of JAMA. (ANI)

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Mouse model may pave way for better anti-depressant treatments

May 28, 2009 By Leave a Comment

Washington, May 28 (ANI): Using a new experimental mouse model of depression/anxiety, scientists have found that the anti-depressant effects of drugs like Prozac involve both neurogenesis-dependent and -independent mechanisms.

The finding could lead to development of better treatments for depression and anxiety.

The mouse model is the first to permit simultaneous examination of multiple effects of antidepressant treatment in the same animal.

Not much is known about the specific molecular influences of selective serotonin reuptake inhibitors (SSRIs) and other types of antidepressants commonly prescribed for treatment of depression and anxiety disorders.

“Recently, compelling work in rodents has suggested that SSRIs may stimulate changes in a brain region called the hippocampus as well as other brain structures. For example, anxiety/depression-like changes in behavior have been linked with a decrease in cell proliferation in the hippocampus, a change that is reversed by antidepressants,” said study author Dr. Denis J. David from the University of Paris-Sud.

Previous studies have already confirmed that long-term exposure to glucocorticoids induces anxiety and a depressive-like state in rodents. Elevated glucocorticoid levels have been linked with depression and anxiety in humans.

“We developed an anxiety/depression-like model based on elevation of glucocorticoid levels that offered an easy and reliable alternative to existing models,” said David.

Chronic anti-depressant treatment reversed the behavioural dysfunctions and inhibition of hippocampal neurogenesis observed in the experimental mice.

They observed that when hippocampal neurogenesis was prevented, the efficacy of Prozac was blocked in some but not all of the behavioural paradigms.

The researchers could identify candidate genes whose expression was decreased in a brain region called the hypothalamus and normalized by Prozac.

Mice deficient in one of these genes, beta-arrestin 2, displayed a reduced response to Prozac in multiple behavioural tasks.

This indicated that beta-arrestin signalling is necessary for the antidepressant effects of Prozac.

The finding suggested that both neurogenesis-dependent and – independent mechanisms underlie antidepressant actions.

The study has been published in the latest issue of the journal Neuron. (ANI)

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Scientists shed new light into primate eye evolution

May 19, 2009 By Leave a Comment

Washington, May 19 (ANI): A recent study has provided a new insight into the evolution of the eyes of primates, taking the example of the nocturnal owl monkey.

Researchers comparing the fetal development of the eye of the owl monkey with that of the capuchin monkey have found that only a minor difference in the timing of cell proliferation can explain the multiple anatomical differences in the two kinds of eyes.

The findings help scientists understand how a structure as complex as the eye could change gradually through evolution, yet remain functional.

The findings also offer a lesson in how seemingly simple genetic changes in the brain and nervous system could produce the multiple evolutionary changes seen in more advanced brains, without compromising function.

Analysis for this study was performed at St. Jude Children’s Research Hospital in the US.

“The molecular, cellular and genetic pathways that coordinate proliferation during development have been fine-tuned since the first multicellular organisms emerged millions of years ago,” said Michael Dyer, member of St. Jude Developmental Neurobiology.

“When these pathways are deregulated during human development, one of the consequences is childhood cancer. Therefore, by studying how changes in the regulation of proliferation during development can lead to dramatic changes in form and function during evolution, we can gain a deeper understanding of these ancient pathways that lie at the heart of many pediatric cancers,” he added.

The owl monkey’s eye has numerous adaptations to make it effective for nocturnal function.

For example, it has a greater number of rod photoreceptor cells than the capuchin monkey, which is diurnal (active during the day).

Rod cells are the most light-sensitive cells in the retina making them effective for nighttime vision.

The owl monkey’s nocturnal retina is also larger and lacks a fovea, the central region of high-density cone photoreceptors that gives the diurnal eye high acuity and daytime color vision.

For both owl and capuchin monkeys, the specialized cell types in the eye all develop in the growing embryo from a single type of immature cell, called a retinal progenitor cell.

“These two species evolved about 15 million years ago from a common ancestor that had a diurnal eye,” Dyer said.

“So, we believe that comparing how their eyes develop during embryonic growth could help us understand what evolutionary changes would be required to evolve from a diurnal to a nocturnal eye,” he added. (ANI)

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New insights into cancer progression

April 23, 2009 By Leave a Comment

Washington, Apr 22 (ANI): A University of Leicester researcher has made some significant advancements on the causes of cancer, which can lead to improved and effective therapies.

Professor Andrew Fry, of the Department of Biochemistry aims to understand the molecular control of cell division and as a result identify proteins, which can be targeted in specific tumours, leaving other cells unharmed.

Many current cancer treatments act by killing all dividing cells and are not necessarily specific for the cancer cells, hence the severe side effects.

While studying how cancer cells divide and spread in the body, Fry has got significant insights on the causes of many human diseases, including cancer, and has identified a number of new targets for cancer treatment.

“An adult human being contains millions of cells that all arise following the fertilization of an egg cell by a sperm cell,” said Fry.

“Human development therefore requires cells to divide again and again to create the tissues and organs of our body.

“Cell division is a complex mechanical process that not only leads to the production of new cells but ensures that each one maintains the right genetic content required to sustain life.

“Loss of control over cell proliferation and the development of genetic and chromosomal abnormalities are classic hallmarks of cancer,” Fry added.

He studied a family of proteins that play a role in cell division and cilia organization, which makes them attractive targets for the development of new anti-cancer drugs.

Fry looked at a particular structure that lies at the heart of each and every cell, called the centrosome (standing for “central body”), and how centrosome defects contribute to cancer progression. (ANI)

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