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Posts Tagged ‘Proceedings of the National Academy of Sciences of the United States of America’

Today’s fundamental challenge in Prostate cancer screening

Posted in Imaging-based Cancer Patient Management, tagged biopsies, breast cancer, Cancer - General, cancer grade, cancer management, Clinical trial, Conditions and Diseases, costs of procedure, environment, FDA, Food and Drug Administration, health, Health care, medicine, mortality, Mortality rate, National Institutes of Health, New England Journal of Medicine, over-treatment, Proceedings of the National Academy of Sciences of the United States of America, prostat cancer screening, PSA, research, science, screening, transrectal, TRUS, United States on September 2, 2012| 12 Comments »

Today’s fundamental challenge in Prostate cancer screening

Author and Curator: Dror Nir, PhD

The management of men with prostate cancer is becoming one of the most challenging public health issues in the Western world. It is characterized by: over-diagnosis; over-treatment; low treatment efficacy; treatment related toxicity; escalating cost; and unsustainability [Bangma et al, 2007; Esserman et al, 2009]. How come? Well, everyone accepts that most prostate cancers are clinically insignificant. It is well known that all men above 65 harbor some sort of prostate cancer. Due to the current aggressive PSA-based screening, one in six men will be diagnosed with prostate cancer. Yet, the lifetime risk of dying of prostate cancer is only 3%. The problem is that, once diagnosed with prostate cancer, there is no accurate tool to identify those men that will die of the disease (in my previous post I mentioned 1:37). Currently, screening practices for prostate cancer are relying on the very unspecific prostate-specific-antigen (PSA) bio-marker test to determine which men are at higher risk of harboring prostate cancer and therefore need a biopsy. The existing diagnostic test is a transrectal ultrasound (TRUS) guided prostate biopsy aimed at extracting representative tissue from areas where cancer usually resides. This procedure suffers from several obvious faults:

1. Since the imaging tool used (B-mode ultrasound) is poor at detecting malignancies in the prostate, the probability of hitting a clinically significant cancer or missing a clinically insignificant cancer is subject to random error.

2. TRUS biopsy is also subjected to systematic error as it misses large parts of the prostate which might harbor cancer (e.g. apex and anterior zones).
3. TRUS guided biopsies are often unrepresentative of the true burden of cancer as either the volume or grade of cancer can be underestimated.

In the last ten years I was leading the development of an innovative ultrasound-based technology, HistoScanningTM, aimed at improving the aforementioned faults;

Among the other most popular imaging modalities aimed at better prostate cancer detection in routine use are: MRI, Elastography, Contrast Enhanced Ultrasound etc…

In my future posts I will go into more detail on how these imaging modalities fit into routine workflow, how much they stay within budget constraints and what level of promise they bear for promoting personalized medicine. Stay tuned… Footnote: According to the final report by an advisory panel to the USA government: Doctors should no longer offer the PSA prostate cancer screening test to healthy men because they’re more likely to be harmed by the blood draw, and the chain of medical interventions that often follows than be helped; (http://www.usatoday.com/news/health/story/2012-05-21/prostate-cancer-screening-test-harmful/55118036/1) But then; what should be offered instead?

Biologists create first predictive computational model of gene networks

Posted in Biological Networks, Gene Regulation and Evolution, Cell Biology, Signaling & Cell Circuits, Computational Biology/Systems and Bioinformatics, tagged Biologist, California Institute of Technology, Computational model, embryo, gene, Gene regulatory network, Proceedings of the National Academy of Sciences of the United States of America, Sea urchin on August 30, 2012| 1 Comment »

Reported by: Dr. Venkat S. Karra, Ph.D.

Biologists create first predictive computational model of gene networks

Biologists at the California Institute of Technology (Caltech) have spent the last decade or so detailing how these gene networks control development in sea-urchin embryos. Now, for the first time, they have built a computational model of one of these networks.

This model, the scientists say, does a remarkably good job of calculating what these networks do to control the fates of different cells in the early stages of sea-urchin development—confirming that the interactions among a few dozen genes suffice to tell an embryo how to start the development of different body parts in their respective spatial locations. The model is also a powerful tool for understanding gene regulatory networks in a way not previously possible, allowing scientists to better study the genetic bases of both development and evolution.

The researchers described their computer model in a paper in the Proceedings of the National Academy of Sciences.

The model encompasses the gene regulatory network that controls the first 30 hours of the development of endomesoderm cells, which eventually form the embryo’s gut, skeleton, muscles, and immune system. This network—so far the most extensively analyzed developmental gene regulatory network of any animal organism—consists of about 50 regulatory genes that turn one another on and off.

To create the model, the researchers distilled everything they knew about the network into a series of logical statements that a computer could understand.

By computing the results of each sequence hour by hour, the model determines when and where in the embryo each gene is on and off. Comparing the computed results with experiments, the researchers found that the model reproduced the data almost exactly. “It works surprisingly well,” the researchers say.

The Incentive for “Imaging based cancer patient’ management”

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biomarkers & Medical Diagnostics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, FDA Regulatory Affairs, Health Economics and Outcomes Research, HealthCare IT, Imaging-based Cancer Patient Management, International Global Work in Pharmaceutical, Medical Devices R&D Investment, Personalized and Precision Medicine & Genomic Research, Pharmaceutical R&D Investment, Population Health Management, Genetics & Pharmaceutical, Scientist: Career considerations, Statistical Methods for Research Evaluation, Technology Transfer: Biotech and Pharmaceutical, tagged breast cancer, breast cancer mortality, breast cancer screening, breast thermography, Cancer - General, Cancer screening, cancer tumours, Cardiac surgery, Chemotherapy, Clinical trial, Conditions and Diseases, costs of treatment, Diagnosis, early diagnosis, elastography, evidence based medicine, health, health economics, histoscanning, imaging based cancer detection, imaging ultrasound, innovations in cancer detection, Magnetic resonance imaging, mammography, medicine, National Institutes of Health, New England Journal of Medicine, new methods for cancer detection, Proceedings of the National Academy of Sciences of the United States of America, Prostate cancer, Prostate cancer screening, research, science, smart imaging, tissue characterisation, ultrasound based cancer detection, United States on August 27, 2012| 15 Comments »

The Incentive for “Imaging based cancer patient’ management”

Author and Curator: Dror Nir, PhD

Article 11.1 Introduction by Dror Nir PhD

Image taken from http://www.breastthermography.com/breast_thermography_mf.htm

It is generally agreed by radiologists and oncologists that in order to provide a comprehensive work-flow that complies with the principles of personalized medicine, future cancer patients’ management will heavily rely on “smart imaging” applications. These could be accompanied by highly sensitive and specific bio-markers, which are expected to be delivered by pharmaceutical companies in the upcoming decade. In the context of this post, smart imaging refers to imaging systems that are enhanced with tissue characterization and computerized image interpretation applications. It is expected that such systems will enable gathering of comprehensive clinical information on cancer tumors, such as location, size and rate of growth.

What is the main incentive for promoting cancer patients’ management based on smart imaging?

It promises to enable personalized cancer patient management by providing the medical practitioner with a non-invasive and non-destructive tool to detect, stage and follow up cancer tumors in a standardized and reproducible manner. Furthermore, applying smart imaging that provides valuable disease-related information throughout the management pathway of cancer patient will eventually result in reducing the growing burden of health-care costs related to cancer patients’ treatment.

Let’s briefly review the segments that are common to all cancer patients’ pathway: screening, treatment and costs.

Screening for cancer: It is well known that one of the important factors in cancer treatment success is the specific disease staging. Often this is dependent on when the patient is diagnosed as a cancer patient. In order to detect cancer as early as possible, i.e. before any symptoms appear, leaders in cancer patients’ management came up with the idea of screening. To date, two screening programs are the most spoken of: the “officially approved and budgeted” breast cancer screening; and the unofficial, but still extremely costly, prostate cancer screening. After 20 years of practice, both are causing serious controversies:

In trend analysis of WHO mortality data base [1], the authors, Autier P, Boniol M, Gavin A and Vatten LJ, argue that breast cancer mortality in neighboring European countries with different levels of screening but similar access to treatment is the same: “The contrast between the time differences in implementation of mammography screening and the similarity in reductions in mortality between the country pairs suggest that screening did not play a direct part in the reductions in breast cancer mortality”.

In prostate cancer mortality at 11 years of follow-up [2], the authors,Schröder FH et. al. argue regarding prostate cancer patients’ overdiagnosis and overtreatment: “To prevent one death from prostate cancer at 11 years of follow-up, 1055 men would need to be invited for screening and 37 cancers would need to be detected”.

The lobbying campaign (see picture below) that AdmeTech (http://www.admetech.org/) is conducting in order to raise the USA administration’s awareness and get funding to improve prostate cancer treatment is a tribute to patients’ and practitioners’ frustration.

Treatment: Current state of the art in oncology is characterized by a shift in the decision-making process from an evidence-based guidelines approach toward personalized medicine. Information gathered from large clinical trials with regard to individual biological cancer characteristics leads to a more comprehensive understanding of cancer.

Quoting from the National cancer institute (http://www.cancer.gov/) website: “Advances accrued over the past decade of cancer research have fundamentally changed the conversations that Americans can have about cancer. Although many still think of a single disease affecting different parts of the body, research tells us through new tools and technologies, massive computing power, and new insights from other fields that cancer is, in fact, a collection of many diseases whose ultimate number, causes, and treatment represent a challenging biomedical puzzle. Yet cancer’s complexity also provides a range of opportunities to confront its many incarnations”.

Personalized medicine, whether it uses cytostatics, hormones, growth inhibitors, monoclonal antibodies, and loco-regional medical devices, proves more efficient, less toxic, less expensive, and creates new opportunities for cancer patients and health care providers, including the medical industry.

To date, at least 50 types of systemic oncological treatments can be offered with much more quality and efficiency through patient selection and treatment outcome prediction.

Figure taken from presentation given by Prof. Jaak Janssens at the INTERVENTIONAL ONCOLOGY SOCIETY meeting held in Brussels in October 2011

For oncologists, recent technological developments in medical imaging-guided tissue acquisition technology (biopsy) create opportunities to provide representative fresh biological materials in a large enough quantity for all kinds of diagnostic tests.

Health-care economics: We are living in an era where life expectancy is increasing while national treasuries are over their limits in supporting health care costs. In the USA, of the nation’s 10 most expensive medical conditions, cancer has the highest cost per person. The total cost of treating cancer in the U.S. rose from about $95.5 billion in 2000 to $124.6 billion in 2010, the National Cancer Institute (www.camcer.gov) estimates. The true sum is probably higher as this estimate is based on average costs from 2001-2006, before many expensive treatments came out; quoting from www.usatoday.com : “new drugs often cost $100,000 or more a year. Patients are being put on them sooner in the course of their illness and for a longer time, sometimes for the rest of their lives.”

With such high costs at stake, solutions to reduce the overall cost of cancer patients’ management should be considered. My experience is that introducing smart imaging applications into routine use could contribute to significant savings in the overall cost of cancer patients’ management, by enabling personalized treatment choice and timely monitoring of tumors’ response to treatment.

References

1. BMJ. 2011 Jul 28;343:d4411. doi: 10.1136/bmj.d4411
2. (N Engl J Med. 2012 Mar 15;366(11):981-90):

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Artificial Vision: Cornell and Stanford Researchers crack Retinal Code

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biomarkers & Medical Diagnostics, Cell Biology, Signaling & Cell Circuits, Chemical Genetics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Medical Devices R&D Investment, Stem Cells for Regenerative Medicine, tagged Blade Runner, Cornell University, Ganglion cell, Proceedings of the National Academy of Sciences of the United States of America, Retina, Sheila Nirenberg, Stanford University, Visual acuity on August 15, 2012| 5 Comments »

Researchers crack retinal code to deliver artificial vision

Reporter: Aviva Lev-Ari, PhD, RN

Getty Images/Flickr RF

Cornell University researchers have devised a new method for restoring human vision by looking into the way retinal cells communicate with the brain and each other. The result, they claim, is an enormous leap in quality over existing visual prosthetics.

Artificial vision may seem like science fiction, and it’s true that the kind you see in “Star Trek” or “Blade Runner” still is, but there are projects all over the world that are successfully giving back partial vision to to blind patients. There are, however, a number of obstacles: the size of the microelectrodes, the way of powering the device, the type of blindness the person has and other factors prevent current treatments from doing much more than letting patients see a few monochrome blobs.

That’s enough to safely navigate a room or street (no small improvement), but what about recognizing faces and objects, or reading signs and symbols? New research by Dr Sheila Nirenberg at Cornell and Chethan Pandarinath at Stanford University claims to make such levels of acuity possible.

Their method doesn’t rely on just making electrodes smaller or increasing the size of the image sensor. Instead, they looked at how the healthy retina communicates with the brain and tried to emulate that.

T. Anderson, D. Benson via The Cell

A rat neuron, illustrating the level of interconnection common in such cells

The retina is a complicated, multi-layered web of cells that are networked together and constantly communicating. Some forms of blindness result from a degeneration of the light-sensitive cells (rods and cones) while the rest of the neural circuitry remains in place. Loss of any entire cell type would cause blindness as well, but when this particular type happens, that means that the ganglion cells, which collect information from multiple rods and cones and collate it, are intact and could still potentially send signals to the brain.

It’s as if two people were talking on the telephone: the conversation will end either if the line itself is disrupted, or if one of the people hangs up. In this type of blindness, the line is fine and the brain is still listening, but no one is talking on the other end. And as it turns out, the replacement signals sent by existing retinal implants have been extremely garbled. What the researchers did was to find out how to send a signal that is much more easily understood.

By studying ganglion cells closely, Nirenberg arrived at a sort of algorithm that describes how the ganglion cells expect to be fed information from the rods and cones. By taking the normal image signal and passing it through an “encoder” running this algorithm, their device can send that image to ganglion cells in such a way that a much clearer image is sent to the brain. You can see the differences in this diagram:

Sheila Nirenberg / Cornell University

The technique, which they call “optogenic stimulation,” works like this: the digital image, provided by a camera or image sensor in the eye, is sent to the encoder, which then sends the special encoded image to a microscopic projector. The projector shines onto the ganglion cells, which have received gene therapy so that they respond to light somewhat in the way the missing cells would have. And then the ganglion cells send that image along.

With it, they claim that 9,800 ganglion cells, properly treated and exposed with the device, will be able to “bring prosthetic capabilities into the realm of normal image representation.” That is to say, a grid of 100-by-100 of them would give enough visual information that a person would have a serious semblance or real vision.

The experiments thus far, successful as they have been, were all performed on mouse retinas. But the researchers see no reason why it should not be attempted for humans as well; Nirenberg says that the gene therapy portion is the most important thing to test thoroughly, though similar techniques have already been used in the retina for other diseases.

Nirenberg and Pandarinath’s paper, “Retinal prosthetic strategy with the capacity to restore normal vision,” was published recently in the Proceedings of the National Academy of Sciences.

Devin Coldewey is a contributing writer for NBC News Digital. His personal website is coldewey.cc.

http://www.futureoftech.msnbc.msn.com/technology/futureoftech/researchers-crack-retinal-code-deliver-artificial-vision-942282

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Copper and its role on “progressive neurodegeneration” and death

Posted in Alzheimer's Disease, Innovations in Neurophysiology & Neuropsychology, tagged Bovine spongiform encephalopathy, Bruce Beutler, New Guinea, PRNP, Proceedings of the National Academy of Sciences of the United States of America, Scripps Research, Scripps Research Institute, Transmissible spongiform encephalopathy on August 14, 2012| 2 Comments »

Reported by: Dr. Venkat S. Karra, Ph.D.

Many of us are familiar with prion disease from its most startling and unusual incarnations—the outbreaks of “mad cow” disease (bovine spongiform encephalopathy) that created a crisis in the global beef industry. Or the strange story of Kuru, a fatal illness affecting a tribe in Papua New Guinea known for its cannibalism. Both are forms of prion disease, caused by the abnormal folding of a protein and resulting in progressive neurodegeneration and death.

While exactly how the protein malfunctions has been shrouded in mystery, scientists at The Scripps Research Institute now report in the journal Proceedings of the National Academy of Sciences (PNAS) that reducing copper in the body delays the onset of disease. Mice lacking a copper-transport gene lived significantly longer when infected with a prion disease than did normal mice.

“This conclusively shows that copper plays a role in the misfolding of the protein, but is not essential to that misfolding,” said Scripps Research Professor Michael Oldstone, who led the new study.

“We’ve known for many years that prion proteins bind copper,” said Scripps Research graduate student Owen Siggs, first author of the paper with former Oldstone lab member Justin Cruite. “But what scientists couldn’t agree on was whether this was a good thing or a bad thing during prion disease. By creating a mutation in mice that lowers the amount of circulating copper by 60%, we’ve shown that reducing copper can delay the onset of prion disease.”

Zombie Proteins
Unlike most infections, which are caused by bacteria, viruses, or parasites, prion disease stems from the dysfunction of a naturally occurring protein.

“We all contain a normal prion protein, and when that’s converted to an abnormal prion protein, you get a chronic nervous system disease,” said Oldstone. “That occurs genetically (spontaneously in some people) or is acquired by passage of infectious prions. Passage can occur by eating infected meat; in the past, by cannibalism in the Fore population in New Guinea through the ingestion or smearing of infectious brains; or by introduction of infectious prions on surgical instruments or with medical products made from infected individuals.”

When introduced into the body, the abnormal prion protein causes the misfolding of other, normal prion proteins, which then aggregate into plaques in the brain and nervous system, causing tremors, agitation, and failure of motor function, and leads invariably to death.

A Delicate Balance
The role of copper in prion disease had previously been studied using chelating drugs, which strip the metals from the body—an imprecise technique. The new study, however, turned to animal models engineered in the lab of Nobel laureate Bruce Beutler while at The Scripps Research Institute. (Beutler is currently director of the Center for the Genetics of Host Defense at UT Southwestern.)

The Beutler lab had found mice with mutations disrupting copper-transporting enzyme ATP7A. The most copper-deficient mice died in utero or soon after birth, but those with milder deficiency were able to live normally.

“Copper is something we can’t live without,” said Siggs. “Like iron, zinc, and other metals, our bodies can’t produce copper, so we absorb small amounts of it from our diet. Too little copper prevents these enzymes from working, but too much copper can also be toxic, so our body needs to maintain a fine balance. Genetic mutations like the one we describe here can disrupt this balance.”

Death Delayed
In the new study, both mutant and normal mice were infected with Rocky Mountain Laboratory mouse scrapie, which causes a spongiform encephalopathy similar to mad cow disease. The control mice developed illness in about 160 days, while the mutant mice, lacking the copper-carrying gene, developed the disease later at 180 days.

Researchers also found less abnormal prion protein in the brains of mutant mice than in control mice, indicating that copper contributed to the conversion of the normal prion protein to the abnormal disease form. However, all the mice eventually died from disease.

Oldstone and Siggs note the study does not advocate for copper depletion as a therapy, at least not on its own. However, the work does pave the way for learning more about copper function in the body and the biochemical workings of prion disease.

source:

http://www.dddmag.com/news/2012/08/copper-facilitates-prion-disease?et_cid=2794933&et_rid=45527476&linkid=http%3a%2f%2fwww.dddmag.com%2fnews%2f2012%2f08%2fcopper-facilitates-prion-disease

Like a prion, Alzheimer’s protein seeds itself in the brain (sciencenews.org)
New compounds inhibit prion infection (sciencedaily.com)

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Stem cells create new heart cells in baby mice, but not in adults, study shows

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biomarkers & Medical Diagnostics, Cardiac & Vascular Repair Tools Subsegment, Cardiovascular Pharmacogenomics, Cell Biology, Signaling & Cell Circuits, Chemical Genetics, Computational Biology/Systems and Bioinformatics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, tagged Cornell University, Cornell University College of Veterinary Medicine, Kotlikoff, National Institutes of Health, Proceedings of the National Academy of Sciences of the United States of America, Stem cell, University of Bonn on August 3, 2012| 5 Comments »

Reporter: Aviva Lev-Ari, PhD, RN

Stem cells create new heart cells in baby mice, but not in adults, study shows

Kotlikoff Lab

The picture on the left shows green c-kit+ precursor stem cells within an infarct (lower right) in a three-day old mouse. These cells are becoming new myocytes and also new vessels. On the right is another image of a heart taken after three months showing a small residual scar (on bottom) remaining from what was an infarct, and new myocytes (red areas) throughout the region.

By Krishna Ramanujan

http://www.news.cornell.edu/stories/July12/HeartStemCells.html

In a two-day-old mouse, a heart attack causes active stem cells to grow new heart cells; a few months later, the heart is mostly repaired. But in an adult mouse, recovery from such an attack leads to classic after-effects: scar tissue, permanent loss of function and life-threatening arrhythmias.

A new study by Cornell and University of Bonn researchers found that stem cells did not create new heart cells in adult mice after a heart attack, settling a decades-old controversy about whether stem cells play a role in the recovery of the adult mammalian heart following infarction — the leading cause of sudden death in the developed world — where heart tissue dies due to artery blockage.

“If you did have fully capable stem cells in adults, why are there no new heart cells after an infarct? And is this due to the lack of stem cells or due to something special about the infarct that inhibits stem cells from forming new heart cells?” asked Michael Kotlikoff, the Austin O. Hooey Dean of Cornell’s College of Veterinary Medicine, and senior author of the paper appearing Aug. 29 in the Proceedings of the National Academy of Sciences.

Beating heart cells

This movie shows beating heart cells in culture that originated as stem cells (look closely around the center of the frame). The researchers used a mouse model where heart cells fluoresced red and undifferentiated stem cells fluoresced green. All of the cells shown in the movie were green at the time of culture and they turn red after they become heart cells. There were no red cells to start, indicating that the origin of the beating red cells was green stem cells. Watch video

Co-author Michelle Steffey, a small-animal surgeon in Cornell’s veterinary college, developed a procedure to infarct a neonatal mouse heart that is only one-tenth-of-an-inch wide. “It was a tour-de-force technically to infarct and recover those baby mice,” said Kotlikoff.

The baby mice grew new heart cells and almost completely recovered from infarction, proving that the infarction did not inhibit stem cells from growing new heart cells. The same procedure was carried out on adult mice and no new heart cells formed, confirming that adults do not have the requisite stem cells to create new heart cells, called myocytes, though new blood vessel cells were created.

To track the stem cells, Kotlikoff and colleagues used a mouse model they developed in which cells fluoresce green when the stem cell marker c-kit is present. In the experiment, after infarction, cells with the c-kit marker fluoresced green in neonatal and adult mice.

“In looking at the adult responses, we were able to prove that the c-kit-marked cells do not form heart cells, but form all of the new blood vessels within the infarct,” said Kotlikoff. The stem cells found in the adult heart “have lost the ability to become heart cells,” he said. It is known that developmentally single stem cells differentiate into all tissues at the start of life, but over time these cells become “developmentally restricted” or specialized to form only certain tissues, he added.

The study also showed for the first time that vessel stem cells in the adult heart originate there and are not recruited from bone marrow, as has been reported. Those reports have justified a controversial procedure in which bone marrow cells are injected into patients with infarctions.

Finally, the study settles the question of whether new heart cells in a neonatal mouse come from undifferentiated stem cells or from pre-existing heart cells that divide. To answer the question, the researchers used another mouse model where heart cells fluoresced red and undifferentiated stem cells fluoresced green. These two cell types were separated. The researchers found that the green stem cells that had moved into the infarct formed beating red heart cells in culture, proving that the stem cells had become heart cells.

Sophie Jesty, an associate professor and resident in cardiology at Cornell’s College of Veterinary Medicine, is the paper’s lead author. Researchers at the University of Bonn analyzed the mice to understand and quantify new myocyte formation.

The study was funded by the National Institutes of Health, New York State Stem Cell Science and the European Union Seventh Framework Programme.

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Protein Folding may lead to better FLU Vaccine

Posted in Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Genome Biology, Health Economics and Outcomes Research, Infectious Disease & New Antibiotic Targets, Personalized and Precision Medicine & Genomic Research, Population Health Management, Genetics & Pharmaceutical, Proteomics, tagged Biology, HA's structure (folding), hemagglutinin (HA), Infectious Diseases, influenza A virus, Messenger RNA, National Institutes of Health, Peptide, Proceedings of the National Academy of Sciences of the United States of America, Protein folding, Ribosome on July 25, 2012| 2 Comments »

Reporter: Aviva Lev-Ari, PhD, RN

July 25, 2012

Insights into protein folding may lead to better flu vaccine

S.B. Qian

This image shows shows mRNA (purple) with ribosomes (beige) bearing nascent protein chains (pink) in different stages of folding.

By Krishna Ramanujan

A new method for looking at how proteins fold inside mammal cells could one day lead to better flu vaccines, among other practical applications, say Cornell researchers.

The method, described online in the Proceedings of the National Academy of Sciences July 16, allows researchers to take snapshots of the cell’s protein-making machinery — called ribosomes — in various stages of protein production. The scientists then pieced together the snapshots to reconstruct how proteins fold during their synthesis.

Proteins are made up of long chains of amino acids called polypeptides, and folding gives each protein its characteristic structure, which determines its function. Though researchers have used synthetic and purified proteins to study protein folding, this study looks at proteins from their inception, providing a truer picture for how partially synthesized polypeptides can fold in cells.

Proteins fold so quickly — in microseconds — that it has been a longtime mystery just how polypeptide chains fold to create the protein’s structure.

“The speed is very fast, so it’s very hard to capture certain steps, but our approach can look at protein folding at the same time as it is being synthesized by the ribosomes,” said Shu-Bing Qian, assistant professor of nutritional sciences and the corresponding author on the paper. Yan Han, a postdoctoral associate in Qian’s lab, is the paper’s first author.

In a nutshell, messenger RNA (mRNA) carries the coding information for proteins from the DNA to ribosomes, which translate those codes into chains of amino acids that make up proteins. Previously, other researchers had developed a technique to localize the exact position of the ribosomes on the mRNA. Qian and colleagues further advanced this technique to selectively enrich only a certain portion of the protein-making machinery, basically taking snapshots of different stages of the protein synthesis process.

“Like a magnifier, we enrich a small pool from the bigger ocean and then paint a picture from early to late stages of the process,” Qian said.

In the paper, the researchers also describe applying this technique to better understanding a protein called hemagglutinin (HA), located on the surface of the influenza A virus; HA’s structure (folding) allows it to infect the cell.

Flu vaccines are based on antibodies that recognize such proteins as HA. But viruses have high mutation rates to escape antibody detection. Often, flu vaccines lose their effectiveness because surface proteins on the virus mutate. HA, for example, has the highest mutation rate of the flu virus’ surface proteins.

The researchers proved that their technique can identify how the folding process changes when HA mutates.

“If people know the folding picture of how a mutation changes, it will be helpful for designing a better vaccine,” Qian said.

“Folding is a very fundamental issue in biology,” Qian added. “It’s been a long-term mystery how the cell achieves this folding successfully, with such speed and with such a great success rate.”

Co-authors include researchers at the National Institute of Allergy and Infectious Diseases.

The research was funded by the National Institute of Allergy and Infectious Diseases Division of Intramural Research, National Institutes of Health Grant, Ellison Medical Foundation Grant and U.S. Department of Defense Exploration-Hypothesis Development Award.

http://www.news.cornell.edu/stories/July12/ProteinFoldingQian.html

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Engineered Microvessels Provide a 3-D Test Bed for Human Diseases

Posted in Biological Networks, Gene Regulation and Evolution, Cell Biology, Signaling & Cell Circuits, Disease Biology, Small Molecules in Development of Therapeutic Drugs, tagged Blood, Blood vessel, Circulatory system, Cornell University, Endothelium, Proceedings of the National Academy of Sciences of the United States of America, Qin Shi Huang, University of Washington on May 30, 2012| Leave a Comment »

Reporter: Prabodh Kandala, PhD

Mice and monkeys don’t develop diseases in the same way that humans do. Nevertheless, after medical researchers have studied human cells in a Petri dish, they have little choice but to move on to study mice and primates.

University of Washington bioengineers have developed the first structure to grow small human blood vessels, creating a 3-D test bed that offers a better way to study disease, test drugs and perhaps someday grow human tissues for transplant.

The findings are published this week in the Proceedings of the National Academy of Sciences.

“In clinical research you just draw a blood sample,” said first author Ying Zheng, a UW research assistant professor of bioengineering. “But with this, we can really dissect what happens at the interface between the blood and the tissue. We can start to look at how these diseases start to progress and develop efficient therapies.”

Zheng first built the structure out of the body’s most abundant protein, collagen, while working as a postdoctoral researcher at Cornell University. She created tiny channels and injected this honeycomb with human endothelial cells, which line human blood vessels.

During a period of two weeks, the endothelial cells grew throughout the structure and formed tubes through the mold’s rectangular channels, just as they do in the human body.

When brain cells were injected into the surrounding gel, the cells released chemicals that prompted the engineered vessels to sprout new branches, extending the network. A similar system could supply blood to engineered tissue before transplant into the body.

After joining the UW last year, Zheng collaborated with the Puget Sound Blood Center to see how this research platform would work to transport real blood.

The engineered vessels could transport human blood smoothly, even around corners. And when treated with an inflammatory compound the vessels developed clots, similar to what real vessels do when they become inflamed.

The system also shows promise as a model for tumor progression. Cancer begins as a hard tumor but secretes chemicals that cause nearby vessels to bulge and then sprout. Eventually tumor cells use these blood vessels to penetrate the bloodstream and colonize new parts of the body.

When the researchers added to their system a signaling protein for vessel growth that’s overabundant in cancer and other diseases, new blood vessels sprouted from the originals. These new vessels were leaky, just as they are in human cancers.

“With this system we can dissect out each component or we can put them together to look at a complex problem. That’s a nice thing — we can isolate the biophysical, biochemical or cellular components. How do endothelial cells respond to blood flow or to different chemicals, how do the endothelial cells interact with their surroundings, and how do these interactions affect the vessels’ barrier function? We have a lot of degrees of freedom,” Zheng said.

The system could also be used to study malaria, which becomes fatal when diseased blood cells stick to the vessel walls and block small openings, cutting off blood supply to the brain, placenta or other vital organs.

“I think this is a tremendous system for studying how blood clots form on vessels walls, how the vessel responds to shear stress and other mechanical and chemical factors, and for studying the many diseases that affect small blood vessels,” said co-author Dr. José López, a professor of biochemistry and hematology at UW Medicine and chief scientific officer at the Puget Sound Blood Center.

Future work will use the system to further explore blood vessel interactions that involve inflammation and clotting. Zheng is also pursuing tissue engineering as a member of the UW’s Center for Cardiovascular Biology and the Institute for Stem Cell and Regenerative Medicine.

Ref: http://www.sciencedaily.com/releases/2012/05/120528154907.htm