Wisconsin scientists grow functional vocal cord tissue in the lab

Author: press release

Madison, Wisconsin – University of Wisconsin scientists have succeeded in growing functional vocal-cord tissue in the laboratory, a major step toward restoring a voice to people who have lost their vocal cords to cancer surgery or other injuries.

Dr. Nathan Welham, a speech-language pathologist, and colleagues from several disciplines, were able to bioengineer vocal-cord tissue able to transmit sound, they reported in a study published today in the journal Science Translational Medicine.

About 20 million Americans suffer from voice impairments, and many have damage to the vocal-cord mucosae, the specialized tissues that vibrate as air moves over them, giving rise to voice.

While injections of collagen and other materials can help some in the short term, Welham says not much can be done for people who have had larger areas of their vocal cords damaged or removed.

“Voice is a pretty amazing thing, yet we don’t give it much thought until something goes wrong,” says Welham, an associate professor of surgery in the UW School of Medicine and Public Health. “Our vocal cords are made up of special tissue that has to be flexible enough to vibrate, yet strong enough to bang together hundreds of times per second. It’s an exquisite system and a hard thing to replicate.”

Welham and colleagues began with vocal-cord tissue from a cadaver and four patients who had their larynxes removed but did not have cancer. They isolated, purified and grew the cells from the mucosa, then applied them to a 3-D collagen scaffold, similar to a system used to grow artificial skin in the laboratory.

In about two weeks, the cells grew together to form a tissue with a pliable but strong connective tissue beneath, and layered epithelial cells on top. Proteomic analysis showed the cells produced many of the same proteins as normal vocal cord cells. Physical testing showed that the epithelial cells had also begun to form an immature basement membrane which helps create a barrier against pathogens and irritants in the airway.

Welham says the lab-grown tissue “felt like vocal-cord tissue,” and materials testing showed that it had qualities of viscosity and elasticity similar to normal tissue.

To see if it could transmit sound, the researchers transplanted the bioengineered tissue onto one side of larynges that had been removed from cadaver dogs. The larynges were attached to artificial wind pipes and warm, humidified air was blown through them. Not only did the tissue produce sound, but high-speed digital imaging showed the engineered mucosa vibrating like the native tissue on the opposing side. Acoustic analysis also showed the two types of tissue had similar sound characteristics.

Finally, the researchers wanted to see if the tissue would be rejected or accepted by mice that had been engineered to have human immune systems. The tissue grew and was not rejected, performing equally well in mice that had the larynx-cell donor’s immune system (created via a blood donation from the larynx-cell donors) and mice with different human immune systems.

“It seems like the engineered vocal cord tissue may be like cornea tissue in that it is immunoprivileged, meaning that it doesn’t set off a host immune reaction,” Welham says, adding that earlier studies had also suggested this.

In one way, the tissue was not as good as the real thing: its fiber structure was less complex than adult vocal cords, but the authors said this was not surprising because human vocal cords continue to develop for at least 13 years after birth.

Welham says that vocal-cord tissue that is free of cancer is a rare commodity, so clinical applications will either require banking and expansion of human cells, or the use of stem cells derived from bone marrow or other tissues. Stem cells could be primed to differentiate into vocal-cord cells by exposing them to vibration and tensile forces in a “laryngeal bioreactor.” Such work is being pursued by other laboratories, including here at Wisconsin.

Clinical applications are still years away, but Welham says this proof-of-principle study is a “robust benchmark” along the route to replacement vocal-cord tissue. Moving this promising work forward requires more testing of safety and long-term function.

The lead researcher on the paper was associate scientist Changying Ling, a member of Welham’s lab in the division of otolaryngology in the UW School of Medicine and Public Health Department of Surgery. Other team members include:
Immunology expert Dr. Will Burlingham and graduate student Matthew Brown of the transplant division
Materials expert Dr. Sundaram Gunasekaran of the Department of Biological Systems Engineering
Proteomics expert Dr. Lloyd Smith and associate scientist Dr. Brian Frey of the Department of Chemistry
This work was supported by grants R01 DC004428 and R01 DC010777 from the National Institute on Deafness and Other Communication Disorders (NIDCD) and grant R01 AI066219 from the National Institute of Allergy and Infectious Diseases. M.E.B. was supported by training grant T32 GM081061 from the National Institute of General Medical Sciences; E.E.D. was supported by training grant T32 AQ10 DC009401 from the NIDCD. Flow cytometry was performed in the Flow Cytometry Laboratory of the University of Wisconsin Carbone Cancer Center, which is supported by grant P30 CA014520 from the National Cancer Institute.

November, 2015|Oral Cancer News|

Number of immune cells in tumors could soon help predict and treat cancers

Authors: Emma King, University of Southampton and Christian Ottensmeier, University of Southampton

Immune cells in the blood primarily defend us against infection. But we’re now learning that these cells can also keep us free from cancer. Patients with less efficient immune systems such as organ transplant recipients or those with untreated HIV, for example, are more susceptible to cancers. It is also becoming increasingly apparent that we can use immune cells to predict survival in people who do develop cancer. And that, in fact, there are immune cells within cancers.

Head and neck cancer underway

Head and neck cancer underway

The number of immune cells inside a tumor can hugely vary: some patients have vast numbers while some have very few. In a recent study, we showed that in head and neck cancers, the survival of a patient depends on how many immune cells are within the tumor. This could be a valuable way of individualizing cancer treatments.

Patients with lots of immune cells, for example, could be offered less toxic cancer treatment while those with few immune cells may need more aggressive treatment to improve their chances of survival.

Not all immune cells within the tumor are able to “attack” the cancer. By looking at specific cell markers – proteins on the cell exterior that allow us to see whether, for example, cells are exhausted – we can determine which individual immune cells in the tumor will be effective in tackling the cancer, or if they are exhausted and not able to perform any useful function. It’s possible that these exhausted cells could be reinvigorated to become useful again with targeted immunotherapy treatments currently in development.

These include vaccines, so if a cancer has been caused by a virus, we can vaccinate the patient with a short segment of the same virus to encourage the immune system to react to it. Around 30% of head and neck cancers, for example, are the result of human papillomavirus (HPV). There has been a 225% increase in these types of cancers over the past 15-20 years and in the US, HPV will cause more of these cancers than cervical ones. In these cases, cancer cells continue to express part of the HPV on their surface. The hope is that following vaccination, immune cells will be better able to identify these HPV cancer cells and kill them.

For people who simply don’t have many immune cells in tumors, specific, targeted immunotherapy could be one option. But also broader “brush stroke” treatments. These broader treatments cover all immunotherapies that encourage a patient’s immune system in a fairly non-specific way. Our immune cells are normally very tightly regulated and include many fail-safe systems to prevent them from over-reacting primarily to infections. General immunotherapy takes the brakes off and allows the immune cells to react to the cancer cells.

It may be that a combination of specific vaccine and non-specific immune treatments could be enough in combination to tip the balance in favor of the patient’s immune system so that it is able to overcome the cancer.

We’re going to further investigate how immune cells might help us to fight cancer and two head and neck cancer immunotherapy trials are due to start at the University of Southampton in the next six months.

One of these trials will look at a HPV cancer vaccine, while the other will investigate a non-specific immunotherapy molecule for those 70% of patients that develop head and neck cancer independent of HPV. Our hope is that within five years the results of these trials could influence the way we treat cancers.The Conversation

Note: This article was originally published on The Conversation.

September, 2014|Oral Cancer News|

Study reveals genetic diversity within tumors predicts outcome in head and neck cancer


Researchers at the Massachusetts General Hospital (MGH) and Massachusetts Eye and Ear Infirmary have developed a new way to predict the survival rate of patients who have squamous cell carcinoma of the head and neck, thanks to a study partially funded by a CPRIT grant. One of the problems with treating cancer is the degree of genetic heterogeneity within a tumor. What this means is that there are sub populations of tumor cells within a given tumor that have different mutations. This makes the cancer difficult to treat because some cells due to their different mutations will be resistant to the same treatment. According to Edmund Mroz, PhD at the MGH center for Cancer Research (lead author of a report in Cancer on May 20, 2013), this new method of measuring genetic heterogeneity can be applied to a wide range of cancers. (Additional co-authors included Curtis Pickering, PhD, and Jeffrey Myers, MD, PhD, both from the University of Texas M.D. Anderson Cancer Center.)


Prior to this study, genes and proteins that are involved with treatment resistance have been identified, however, there has been no way to measure tumor heterogeneity to predict patient survival. Mroz and his group of researchers working in the lab of James Rocco, MD, PhD at MGH developed this new measure by looking at advanced gene sequencing data to calculate a number that indicates the genetic variance found in sub populations of cells within a tumor. They dubbed this new procedure as the mutant-allele tumor heterogeneity (MATH). This measure of heterogeneity has the ability to predict not only the number of mutations present but how widely the particular mutations are shared within different sub populations of tumor cells. This research was published in Oral Oncology (March 2013) and was only able to demonstrate that patients with known factors predicting poor outcomes had lower survival rates or what is known as high MATH scores. So, further research was needed.

Mzor and colleagues have now looked at the tumors from 74 patients that had squamous cell head and neck cancer and analyzed their genetic data. These patients had completed their treatment and researchers had the outcome data as well. The MATH measure was applied and these researchers found that higher MATH scores were correlated with shorter survival and with patients who had genetic heterogeneity. This demonstrates that the MATH scores were well correlated with outcomes more so than earlier predictions based on what was known at the time as identifiable risk factors.

At the moment, the take home message is that MATH values along with clinical findings can help predict survivability based on tumor cell heterogeneity. Furthermore, MATH may be able to determine what type of therapy the patient is best suited for. For example, if their MATH score is high, this calls for therapies that are more aggressive to ensure tumor cell resistance doesn’t occur. On the hand, patients who have low MATH scores, need less aggressive therapeutic approaches.

Rating HPV biomarkers in head, neck cancers


Not all head and neck cancers are created equal. Those started by infection with the human papillomavirus are less often fatal than those with other causes, such as smoking. Detection of a reliable fingerprint for HPV could help patients avoid unnecessarily harsh treatment. A new study finds that while one popular biomarker for HPV is not a reliable predictor of mortality from the cancers alone, combinations of some biomarkers showed much more promise.

“Everybody who has studied it has shown that people with virally associated disease do better,” said Karl Kelsey, aprofessor of epidemiology and pathology and laboratory medicine at Brown University, and corresponding author of the study in Cancer Research. “There are now clinical trials underway to determine if they should be treated differently. The problem is that you need to appropriately diagnose virally related disease, and our data suggests that people need to take a close look at that.”

In the study, Kelsey and his multi-institutional team of co-authors measured the ability of a variety of biomarkers to predict mortality from head and neck squamous cell carcinoma (HNSCC). Their data came from hundreds of adult head and neck cancer patients in the Boston area that they have been tracking since late 1999. As part of that data set, they were able to look at blood serology and tumor tissue samples, and they interviewed participants about risk behaviors such as smoking and drinking.

DNA alone not reliable
One of the most important findings of the study, Kelsey said, is that extracting and amplifying the DNA of HPV in tumors, a popular notion among doctors given its success in confirming HPV’s role in cervical cancers, is not particularly helpful in predicting eventual mortality from head and neck cancer.

For example, among 94 patients for whom the researchers could assess the predictive value of all the biomarkers in the study, HPV DNA was present in tumors of 59 patients and absent in 35. Among the 59 who had the DNA, 23 of them, or 39 percent, had died. Among the 35 without the DNA, 13 of them, or 37 percent had died.

“You can’t just do PCR [a DNA amplification technique] of the virus in the tumor and assume it means much,” Kelsey said.

More promising combinations
Among several other potential HPV biomarkers in patients, the most reliable predictors of mortality turned out to be certain combinations of them, particularly antibodies to the E6 and E7 proteins that are expressed by the virus and have the effect of turning off cells’ ability to suppress tumors.

Kelsey and his colleagues found that measuring blood serum levels of antibodies that respond to E6 and E7 helped to assign meaning to measures of HPV DNA in tumors. Among people who had both HPV DNA and E6/E7 measurements, those with HPV DNA in tumors who were E6/E7 negative died in 30 of 56 cases, while those with HPV DNA in tumors who were E6/E7 positive died in only eight of 55 cases.

Levels of E6 and E7 antibodies in blood also proved telling in combination with staining tumors to detect the p16 protein, which indicates that tumor-suppression has been inactivated. Among patients in whom both those tests were both run, those with p16 overexpression who were E6/E7 negative had a much higher rate of death (11 in 17 cases) than people who did not overexpress p16 and were E6/E7 positive (3 in 9 cases) or those who overexpressed p16 and who were also E6/E7 positive (6 in 37 cases).

“Our study strongly suggests that the combination of detection of HPV 16 DNA in HNSCC tumors or p16 immunostaining with E6/E7 antibodies represents the most clinically valuable surrogate markers for the identification of patients with HNSCC who have a better prognosis,” Kelsey and his co-authors concluded.

In a companion paper published simultaneously in Cancer Research another team found that measuring viral load and patterns of viral gene expression were also useful markers.

Source: Brown University

September, 2012|Oral Cancer News|

Demystifying the immortality of cancer cells


In cancer cells, normal mechanisms governing the cellular life cycle have gone haywire. Cancer cells continue to divide indefinitely, without ever dying off, thus creating rapidly growing tumors. Swiss scientists have discovered a protein complex involved this deregulated process, and hope to be able to exploit it to stop tumor formation in its tracks.

The telomeres can be seen as white dots on these chromosomes © National Institute of Health

All our cells come equipped with an automatic self-destruct mechanism; they are programmed to die after a certain number of divisions. This internal clock is of great interest to cancer researchers, because most forms of cancer exhibit a defect in this innate timing mechanism. Cancer cells continue to divide indefinitely, long past the moment at which a normal cell would self-destruct. A team of researchers from professor Joachim Lingner’s laboratory at EPFL has learned how this defect is regulated in a tumor. Post-doctoral researcher Liuh-Yow Chen led the team in publishing an article appearing in the journal Nature on the 4th of July 2012. Their hope is that the discovery will provide new targets for drug therapies to combat the deadly disease.

Cellular immortality, which is responsible for cancer formation, hearkens back to a critical function of the cells of the developing embryo. At the ends of every chromosome there is a special sequence of DNA known as a telomere, whose length is governed by the telomerase enzyme. This sequence represents the lifespan of the cell. Every time the cell divides, it is shortened, and when the telomere finally runs out, the cell dies. This reserve allows most cells to divide about 60 times – sufficient for the cell to play its given role in the organism, without succumbing to inevitable genetic mutation.

Cellular immortality, cancer’s common denominator
Normally, once the embryonic stage is completed, our cells stop producing telomerase – with the notable exception of somatic stem cells. But occasionally, a cell will mutate and reactivate production of the enzyme, so that when the cell divides, the telomere gets longer instead of shorter. This is what gives cancer cells their immortality.

“This mutation, on its own, is not enough to cause cancer,” explains Joachim Lingner, co-author and head of the lab. “But cellular immortality is a critical element in tumor formation in 90% of known cancers.” Researchers the world over hope to be able to stop the runaway growth of cancer cells by targeting this mechanism with drug therapy.

But interestingly enough, even in a cancer cell the telomere doesn’t grow indefinitely long. With each cell division it loses some 60 nucleotides, like most cells, but then the activated telomerase causes it to gain just as many back. The internal clock is reset to zero, and the cell becomes immortal. But there’s one interesting question here: What is stopping the telomere from getting indefinitely long?

Stopping the clock with three proteins
The EPFL team was able to provide an answer to this question; they identified three proteins that join together and then attach themselves to the telomere. A bit like a lid on a pot, this protein complex prevents telomerase from acting on the telomere. But in the cancer cell, their timing is off – their involvement takes place too late.

“If we could cause these proteins to act earlier, or if we could recreate a similar mechanism, the cancer cell would no longer be immortal,” explains Ligner. The cancer cells would die a normal death. Clinical applications are still a long way off, however, he insists. “Our discovery may allow us to identify potential targets – for example, a secondary protein to which these three proteins also attach. But right now our work is still in the basic research stages.”

Source: Cancer July 5, 2012

A spitting image of health

Author: Susan Galdos

Rinse and spit.

Someday soon, doctors may join dentists in issuing these simple instructions. And before leaving the office, you might know whether you’re at risk for oral cancer. Additional tests on that same ptui may reveal whether you show signs of certain other cancers or diseases such as diabetes and Alzheimer’s.

Saliva — the frothy fluid that helps clean the mouth, digest food and fight tooth decay — carries many of the same proteins and other molecules found in blood and urine. Scientists have long been interested in mining a person’s mix of these compounds for clues to diagnosing diseases. Three years ago, these efforts got a boost when researchers completed a preliminary master list of the proteins found in spit — 1,166 of them.

Since then, scientists have nearly doubled the length of the protein list, while identifying changes in the salivary protein profile that are linked to disease. Other labs are delving into genetic material found in human saliva, looking for variations in gene activity that might signal disease risk.

Already, studies show that diseases such as breast cancer, type 2 diabetes and Alzheimer’s leave specific and identifiable signatures in saliva. Such biomarkers have also been found for Sjögren syndrome, an autoimmune condition that affects production of tears and saliva. And proteins known to be related to heart activity, including a handful whose levels are elevated during a heart attack, have also shown up in spittle.

Such findings — combined with the fact that saliva is quick, easy and painless to collect — may make spit the body fluid of choice to get an inside view of health, says David Wong, a dental expert at the University of California, Los Angeles who helped lead efforts to catalog spit’s proteins. “As a screening test, saliva is a latecomer,” Wong says. “But it’s catching up. The science is maturing and developing.”

Currently, most medical diagnoses are based on blood samples. That’s because serum, the clear part of blood, contains high amounts of proteins, genetic material and other molecules of interest. A bevy of studies have linked certain genes and proteins found in blood to specific diseases. But drawing blood requires trained clinicians and special equipment to handle and store the samples. Blood tests also mean frightening needles and long waits for test results.

Spit collection, on the other hand, is simple, if not glamorous. To get a sample, patients just drool into a vial or swipe a swab across their gums. Efforts are now under way to develop real-time detectors to diagnose disease from just a few drops of the slaver. Such test kits could be used in a dental office or emergency room and be carried onboard emergency response vehicles.

“The concept is that there are going to be various devices and capabilities that doctors, nurses and dentists — or patients themselves — can use to monitor health,” Wong says.

To make that happen, researchers are working to validate the biomarkers they’ve already discovered and to test tools that can be used on the fly.

SALIVA'S SOURCEGlands on the bottom of the mouth and sides of the cheeks make saliva and empty it into the mouth via ducts. Within the glands, networks of capillaries take up proteins and other molecules from the blood, adding them to the gland-derived fluid. - Nicole Ranger Fuller

What’s in there

Saliva is mostly water, but its fluid content doesn’t come from the cola or the coffee that you drink. Instead, it comes from three major salivary glands located on the bottom of the mouth and sides of the cheeks, as well as smaller glands elsewhere in the mouth and throat. Within these glands, networks of capillaries surround the ducts that carry saliva to the mouth. As blood filters through the capillaries, specialized cells take up water, proteins and other molecules. This chemical brew gets mixed with the fluid produced by the glands, creating spit.

In 2004, Wong’s team at UCLA, along with groups at the University of California, San Francisco and the Scripps Research Institute in La Jolla, received funding from the National Institute of Dental and Craniofacial Research to find out what is in saliva. The list of ingredients includes more than 2,200 proteins, collectively called the “salivary proteome.”

About two-thirds of the proteins come from the salivary glands themselves. Some serve as protectors, Wong says, warding off microbes and other invaders that come into contact with the mouth. Other gland-produced proteins work to digest food, heal wounds or control the teeming hordes of bacteria residing in the mouth.

The remaining proteins come from other parts of the body, such as the liver, muscles or heart, and filter in through the blood. Though these proteins probably serve no specific role in the mouth, researchers can pick up on them to find out what’s going on in other parts of the body.

With that in mind, Timothy Griffin, a biochemist at the University of Minnesota’s Twin Cities campus, is looking to see how saliva proteins differ between healthy people and those with cancer. Studies have shown that saliva in patients with cancer may contain unexpected proteins. Other times, a protein may change in its abundance, showing up in fewer or greater numbers as the illness progresses, or it might get chemically modified, changing in shape or function.

Protein changes associated with a particular disease can serve as biomarkers for that disease, Griffin says. For the last three years, his group has been working to suss out protein biomarkers for oral cancer, collecting saliva samples not only from patients already diagnosed with the disease, but also from people who face an elevated risk, such as those with an oral lesion in a precancerous state.

Griffin says the idea is to identify subtle shifts in the molecular makeup of saliva that signal the transformation from a premalignant state to full-blown cancer.

Last year, his group reported in PLoS ONE that changes in the abundance of two proteins — myosin and actin — occur during this transformation. The scientists are now gathering more samples to see if the differences hold true for large numbers of people.

Such early markers are crucial in diseases such as oral cancer, where progression occurs in only a small percentage of cases, Griffin says. “Doctors could continue to watch a premalignant lesion to see if it’s at risk for transformation, and know when to intervene.”

A dollop of saliva on a chip like this one can be analyzed for disease-related proteins by a portable detector. Credit: Rice Univ.

Beyond the mouth

Griffin’s group is also looking at ways to better analyze saliva proteins that originate outside of the mouth to see what’s going on elsewhere in the body. The problem is, proteins that originate outside the mouth appear in saliva in quantities so small that searching for them becomes the equivalent of looking for a needle in a wet, stringy haystack.

In a study published in March in the Journal of Proteome Research, Griffin and colleagues used a technology called dynamic range compression, or DRC, to sort through the content of saliva samples collected from women who had breast cancer, looking for low-abundance proteins associated with the disease.

DRC employs various biomolecules to bind to the different proteins found in saliva. Proteins that bind remain in the sample, and those that don’t are washed away. Because proteins appearing in high numbers quickly saturate their binding baits, a large number are removed from the sample. Low-abundance proteins, though, bind fully to the bait and remain in the sample, boosting their proportion in the contents to be analyzed.

In the study, Griffin’s group collected saliva samples from 10 healthy women and 10 women with metastatic breast cancer. A portion of the samples from each group were left untreated and analyzed for their protein content; the rest were analyzed using DRC. The researchers identified twice as many different low-abundance proteins in the DRC–treated samples.

Among those proteins, Griffin’s group found a handful of biomarkers known from blood to be associated with metastatic breast cancer. “We knew that there were proteins in the blood that are diagnostic of these breast cancer patients,” he says. “But we wanted to see if we could see them in saliva.”

Griffin says the study serves as a proof of principle that saliva tests can detect proteins that change as a result of cancers in parts of the body besides the mouth. Such tests might someday be paired with other diagnostic measures, such as mammograms, to monitor women at high risk of breast cancer.

Saliva-based tests also hold promise as a screening tool for hard-to-diagnose diseases such as Alzheimer’s. Last year, scientists at the Neurodegenerative Diseases Biomedical Research Center in Madrid, Spain, found increased levels of a protein known to form the toxic brain plaques associated with Alzheimer’s in the saliva of Alzheimer’s patients. The protein may help diagnose the disease at early stages, when therapies are more effective, the team noted in BMC Neurology.

Wong’s lab is looking past proteins to ask what else in spit can be diagnostic. In recent years, the group has studied distinct bits of the genetic material messenger RNA in saliva. By focusing on this material, which carries the blueprints for protein synthesis, the scientists hope to determine when and where genes are turned on or off in various types of cells and tissues, and then relate this information to disease. So far, results show mRNA signatures for pancreatic cancer and breast cancer, as well as oral cancer and Sjögren syndrome.

Wong’s team is also looking at ways to diagnose disease by picking up on changes in the presence of microbial organisms that invade the mouth.

“Not every disease will reflect itself through the proteins, and not every disease will reflect itself through RNA,” Wong says. “If you want to look for biomarkers, the more targets you look at the better off you’ll be finding those targets that will be of interest.”

Levels of the protein A2MG differ among people without diabetes, with impaired glucose tolerance (IGT) and with diabetes (graph). Additional molecules (right) also show concentration increases with disease progression. Credit: P. Rao et al/Journal of Proteome Research 2009

Tools of the trade

With numerous signatures of disease now under study, scientists are working to develop instruments to detect and analyze the molecules found in saliva.

Wong’s group has designed a desktop device capable of simultaneously analyzing the protein and mRNA content of a sample within minutes. In a clinical trial, the device successfully detected both levels of interleukin-8, a protein associated with tumor growth and cell movement in numerous cancers, and levels of the mRNA that carries the blueprints for that protein. The study compared spit samples from 28 patients who had oral cancer with samples from 28 healthy people. Scientists could correctly identify patients with oral cancer based on elevated levels of these two biomarkers with 90 percent accuracy, findings published in 2009 in Clinical Cancer Research showed.

A dentist himself, Wong says that in the future dental offices might be equipped with such diagnostic devices, making dentists primary health-care providers. When patients come into a dentist’s office, in addition to getting a teeth cleaning or denture adjustment, they could be evaluated for diseases such as osteoporosis or cancer, he says. No needle pricks or embarrassing urine cups needed.

Other groups are developing devices that can be used on the go. Chemist John McDevitt of Rice University in Houston has developed a device, called a bioto­meter, that analyzes saliva samples, as well as other body fluids, on board emergency vehicles. Like programmers developing apps for an iPhone, McDevitt’s team has individual test cards customized for specific health conditions. Each card can look for multiple biomarkers associated with that condition.

The battery-operated analyzer weighs in at just under five kilograms, making it light enough to transport from place to place. Working like an ATM machine, the device reads information on the disposable test cards inserted into it. Each card contains a series of wells packed with tiny detection beads that act as microsponges to collect the biomarkers of interest.

McDevitt and his colleagues are already using the device to analyze spit samples to find out whether patients with chest pain are suffering a heart attack. A drop of saliva obtained from a gum swab goes onto the appropriate test card and is placed in the analyzer. If the saliva sample contains troponin T, a protein characteristic of a heart attack (it is released into the blood when heart cells die), the detection beads will emit a fluorescent color. The analyzer spots that color glow in the beads and indicates that the patient is indeed experiencing a heart attack.

McDevitt says he hopes saliva-based tests can detect heart attacks faster and more accurately than traditional methods. Of the millions of patients who visit emergency rooms with chest pain each year, only about half of those suffering a heart attack are immediately diagnosed using the electrocardiogram. The others must undergo additional testing, which can take anywhere from 90 minutes to several hours to process.

With the biotometer, clinicians could make a diagnosis within minutes instead of hours, McDevitt says.

The device is now being tested in a clinical trial in Houston, directed by Baylor College of Medicine cardiologists, to see how spit samples work in conjunction with the EKG to diagnose cardiac arrest patients. A second study is in progress on emergency vehicles in San Antonio.

Within spitting distance

Currently being manufactured by Force Diagnostics, a biotechnology firm in Chicago, McDevitt’s device will be made available for real-world applications within the next few months. The first units will be deployed for blood-based testing, targeting HIV infection in Africa. A 12-minute field test will replace a two-hour lab version, McDevitt says.

Initial applications for spit-based tests using the biotometer and other devices may appear within two to three years. Oral disease and gum disease tests will probably come online first. Widespread screening for conditions such as pancreatic cancer, breast cancer or heart attack may occur within five years.

These developments and other findings from various labs are laying the groundwork for a dramatic change in disease treatment, McDevitt says, allowing clinicians to move from reactive to preventive medicine.

As part of the heart attack trial, for example, his group is collecting information on protein changes associated with the risk of future heart attacks. Current diagnostic methods can’t easily detect the earliest stages of cardiac disease, he says, so the findings open up the possibility of using the biomarkers in saliva, or other body fluids, to detect health risks months or years before they become full-blown problems.

“I think we actually have a way to do it,” McDevitt says. “We’re seeing this in our trials right now.”

His optimism is supported by a study published in the Oct. 25 Journal of the American College of Cardiology. It showed that adjusting therapy to control levels of the protein NT-proBNP in the blood of heart patients could lower the rates of arrhythmias, stroke and heart attack. NT-proBNP is a known marker of cardiac distress, and is already detectable in spit. Because spit tests are cheaper and easier to administer than blood tests, clinicians might someday use them to monitor such patients.

But first, saliva-based biomarkers have to undergo vigorous tests to prove their reliability. That will require large-scale trials involving thousands of patients. Such trials are already evaluating markers associated with oral cancer, heart attack and Sjögren syndrome.

Obtaining scientific credibility is not the only hurdle to making saliva tests a clinical reality. If scientists can’t address some social stigmas, they may as well be spitting into the wind.

Spit doesn’t seem to have the respect of other body fluids, Wong says. “To say ‘I spit on your grave’ is considered a very negative statement.”

He hopes the saliva-based medical tests will help others see the value of this slippery fluid.

November, 2011|Oral Cancer News|

SIBLING proteins may predict oral cancer

Author: Medical College of Georgia

The presence of certain proteins in premalignant oral lesions may predict oral cancer development, Medical College of Georgia researchers said.

SIBLINGs, or Small Integrin-Binding Ligand N-linked Glycoproteins, are a family of five proteins that help mineralize bone but can also spread cancer. SIBLINGs have been found in cancers including breast, lung, colon and prostate.

“Several years ago we discovered that three SIBLINGs — osteopontin, bone sialoprotein and dentin sialophosphoprotein — were expressed at significantly high levels in oral cancers,” said Dr. Kalu Ogbureke, an oral and maxillofacial pathologist in the MCG School of Dentistry. “Following that discovery, we began to research the potential role of SIBLINGs in oral lesions before they become invasive cancers.”

The study, published online in the journal Cancer, examined 60 archived surgical biopsies of precancerous lesions sent to MCG for diagnosis and the patients’ subsequent health information. Eighty-seven percent of the biopsies were positive for at least one SIBLING protein — which the researchers discovered can be good or bad, depending on the protein. For instance, they found that the protein, dentin sialophosphoprotein, increases oral cancer risk fourfold, while bone sialoprotein significantly decreases the risk.

“The proteins could be used as biomarkers to predict [the potential of a lesion to become cancerous],” said Dr. Ogbureke, the study’s lead author. “That is very significant, because we would then be in a position to modify treatment for the individual patient’s need in the near future.”

Precancerous oral lesions, which can develop in the cheek, tongue, gums and floor and roof of the mouth, are risk factors for oral squamous cell carcinoma, which accounts for over 95 percent of all oral and pharyngeal cancers. Oral cancer, the sixth most common cancer in the world, kills about 8,000 Americans annually, Dr. Ogbureke said.

Treatment has been stymied up to this point because of clinicians’ inability to predict which lesions will become cancerous. Surgery is standard for oral cancer, but treatment methods vary for precancerous lesions.

“When we treat these lesions now, there’s an implied risk of under- or over-treating patients,” Dr. Ogbureke said. “For example, should the entire lesion be surgically removed before we know its potential to become cancer, or should we wait and see if it becomes cancer before intervening?”

Further complicating the matter is that the severity of dysplasia, or abnormal cell growth, in a lesion can be totally unrelated to cancer risk. Some mild dysplasias can turn cancerous quickly while certain severe dysplasias can remain harmless indefinitely. The protein findings, which help eliminate the guesswork in such cases, “are fundamental,” Dr. Ogbureke said. “If we’re able to recognize these lesions early and biopsy them to determine their SIBLING profile, then oral cancer could be preventable and treatable very early.”

Dr. Ogbureke’s next step is to design a multi-center study that incorporates oral cancer risk factors, such as smoking and alcohol consumption, to further investigate their relationship with SIBLING protein expression.

Medical College of Georgia (2010, March 5). SIBLING proteins may predict oral cancer. ScienceDaily. Retrieved September 21, 2010,

September, 2010|Oral Cancer News|

Researchers: B6 may cut cancer risk for smokers by 50%

Author: staff

People who smoke and have a high level of vitamin B6 and other essential proteins and vitamins in their body will cut their chance of contracting lung cancer by fifty percent.

According to a study by scientist at the International Agency for Research on Cancer, cigarette smoking causes many kinds of diseases like heart attack, throat cancer and so on.

However, the major disease caused by smoking is lung cancer.This disease is very common and is seen in non-smokers. Deficiency in vitamin B6 and methionine is the major cause for lung cancer. Over 1.2 million people fatally fall victim to lung cancer every year. Vitamin B6 is very prevalent in vegetables, meat, nuts, and other high protein nutrient foods.

Thus, taking in more vitamins and proteins daily will lessen the chance for smokers to develop lung cancer. Eighty percent of all lung cancer diagnoses are related to smoking cigarettes.

UConn scientist may have way to detect pre-tumor cancer

Author: staff

A University of Connecticut researcher thinks he might have found a way to find cancer even before it reveals itself in a tumor or other symptoms. Jim Rusling, professor of chemistry and cell biology at the UConn Health Center, has been working with colleagues at the National Institutes of Health to detect specific proteins found in the blood of those with prostate or oral cancer.

These biomarker proteins are detectable in early stages of these cancers, so the researchers believe they can be used for earlier detection and prevention than is now possible.

Rusling noted that the approach has an advantage over genetic testing, because that can only assess the risk of getting the disease, whereas measuring biomarkers can reveal the actual presence cancer. He described the project, funded by a $1.5 million NIH grant, in a recent issue of Analytical Chemistry.

New biomarker technique could provide early detection for cancer

Author: press release provided by University of Connecticut

Modern genetic testing can predict your risk of contracting particular diseases based on predispositions discovered in your DNA. But what if similar biotechnology could tell you that you’ve got a disease before you notice any symptoms? What if it could even tell you, before any signs of a tumor, that you have cancer?

Jim Rusling, professor of chemistry at UConn and professor of cell biology at the UConn Health Center, ponders these questions on a daily basis. Since 2006, he and colleagues at the University and the National Institutes of Health (NIH) have been developing techniques to detect biomarker proteins – the physiological traits that indicate that a person has a specific disease – for prostate and oral cancer. Because these biomarkers are often present in the blood in a disease’s early stages, they can be used for early detection and prevention.

“DNA predicts which proteins can be made, but it can’t predict which proteins are actively expressed,” Rusling says. “It only assesses the risk of a disease. There’s a big push now to measure proteins as biomarkers.”

In a recent publication in the journal Analytical Chemistry, Rusling and his colleagues describe a system they developed to detect with record sensitivity the bloodstream levels of a protein associated with several types of oral cancer, including head and neck squamous cell carcinomas. The project was funded by a $1.5 million grant from the National Institute of Environmental Health Sciences at NIH.

The protein, called interleukin-6 or IL-6, is normally present in very low levels in the bloodstream – so low that previous biomarker sensors might not be able to detect it. This and other biomarkers are signaling molecules, which can instruct cells that have become cancerous to grow faster. Their levels can increase even before tumors begin to form, enabling early detection that might head off the formation of cancerous growths.