Posts Tagged ‘state’

Sorting cells with sound waves

Separating cells with sound offers a gentler alternative to existing cell-sorting technologies, which require tagging the cells with chemicals or exposing them to stronger mechanical forces that may damage them.

“Acoustic pressure is very mild and much smaller in terms of forces and disturbance to the cell. This is a most gentle way to separate cells, and there’s no artificial labeling necessary,” says Ming Dao, a principal research scientist in MIT’s Department of Materials Science and Engineering and one of the senior authors of the paper, which appears this week in the Proceedings of the National Academy of Sciences.

Subra Suresh, president of Carnegie Mellon, the Vannevar Bush Professor of Engineering Emeritus, and a former dean of engineering at MIT, and Tony Jun Huang, a professor of engineering science and mechanics at Penn State, are also senior authors of the paper. Lead authors are MIT postdoc Xiaoyun Ding and Zhangli Peng, a former MIT postdoc who is now an assistant professor at the University of Notre Dame.

The researchers have filed for a patent on the device, the technology of which they have demonstrated can be used to separate rare circulating cancer cells from white blood cells.

To sort cells using sound waves, scientists have previously built microfluidic devices with two acoustic transducers, which produce sound waves on either side of a microchannel. When the two waves meet, they combine to form a standing wave (a wave that remains in constant position). This wave produces a pressure node, or line of low pressure, running parallel to the direction of cell flow. Cells that encounter this node are pushed to the side of the channel; the distance of cell movement depends on their size and other properties such as compressibility.

However, these existing devices are inefficient: Because there is only one pressure node, cells can be pushed aside only short distances.

The new device overcomes that obstacle by tilting the sound waves so they run across the microchannel at an angle — meaning that each cell encounters several pressure nodes as it flows through the channel. Each time it encounters a node, the pressure guides the cell a little further off center, making it easier to capture cells of different sizes by the time they reach the end of the channel.

This simple modification dramatically boosts the efficiency of such devices, says Taher Saif, a professor of mechanical science and engineering at the University of Illinois at Urbana-Champaign. “That is just enough to make cells of different sizes and properties separate from each other without causing any damage or harm to them,” says Saif, who was not involved in this work.

In this study, the researchers first tested the system with plastic beads, finding that it could separate beads with diameters of 9.9 and 7.3 microns (thousandths of a millimeter) with about 97 percent accuracy. They also devised a computer simulation that can predict a cell’s trajectory through the channel based on its size, density, and compressibility, as well as the angle of the sound waves, allowing them to customize the device to separate different types of cells.

To test whether the device could be useful for detecting circulating tumor cells, the researchers tried to separate breast cancer cells known as MCF-7 cells from white blood cells. These two cell types differ in size (20 microns in diameter for MCF-7 and 12 microns for white blood cells), as well as density and compressibility. The device successfully recovered about 71 percent of the cancer cells; the researchers plan to test it with blood samples from cancer patients to see how well it can detect circulating tumor cells in clinical settings. Such cells are very rare: A 1-milliliter sample of blood may contain only a few tumor cells.

“If you can detect these rare circulating tumor cells, it’s a good way to study cancer biology and diagnose whether the primary cancer has moved to a new site to generate metastatic tumors,” Dao says. “This method is a step forward for detection of circulating tumor cells in the body. It has the potential to offer a safe and effective new tool for cancer researchers, clinicians and patients,” Suresh says.

The research was funded by the National Institutes of Health and the National Science Foundation.

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Medicaid reimbursements may affect cancer screening rates among beneficiaries

Although Medicaid is a joint state-federal government health insurance program, each state sets the policies for its own Medicaid program within requirements set by the federal government. This includes setting how much providers are paid for health care services and who is allowed to enroll in Medicaid. To determine whether state Medicaid eligibility and reimbursement policies affect receipt of breast, cervical, and colorectal cancer screening among Medicaid beneficiaries, Michael Halpern, MD, PhD, MPH, of RTI International, and his colleagues analyzed 2007 Medicaid data from 46 states and Washington DC.

“Few studies have examined how state-specific differences in Medicaid policies might affect use of preventive care services, particularly for early detection of cancer,” said Dr. Halpern. “Our study was able to compare differences in cancer screening for Medicaid beneficiaries in almost all states, providing a broad, national picture of the effects of state-level Medicaid policies on receipt of these critical medical care services among a large group of underserved individuals.”

The researchers found that in states with higher payments for office visits, Medicaid beneficiaries were more likely to receive recommended screenings for early detection of all three types of cancer. In contrast, higher payments for cancer screening tests (such as colonoscopy, mammography, and Pap tests) were not always linked with increased screenings among Medicaid beneficiaries. The team also found that Medicaid beneficiaries in states that had an “asset test” (which considers an individual’s savings, property, or other items of worth to determine whether he or she could enroll in Medicaid) were less likely to be screened for cancer.

The association between higher Medicaid reimbursements for office visits and increased likelihood of receiving cancer screenings may reflect barriers in access to primary care physicians and other providers for Medicaid enrollees in states with lower reimbursements. Increasing reimbursements for office visits may facilitate access to primary care among Medicaid beneficiaries, and thereby increase the likelihood of receiving appropriate cancer screening tests. On the other hand, raising reimbursement for the screening tests themselves may be a less effective policy tool for increasing use of recommended screenings. The results also indicate that eliminating asset tests may increase the likelihood of receiving cancer screenings by helping low-income individuals remain enrolled in Medicaid.

“Due to multiple factors, including Health Care Reform and decreased state budgets, many states are changing their Medicaid policies, including how much health care providers are paid and who is allowed to enroll,” said Dr. Halpern. “Our findings can help state health care decision makers and policy leaders to develop new Medicaid policies that aid low income individuals in receiving recommended cancer screenings.”

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Crucial step in DNA repair identified by researchers

Such disorders are caused by faulty DNA repair systems that increase the risk for cancer and other conditions.

The findings are published in this week’s Proceedings of the National Academy of Sciences. The study was funded by the National Institute of Environmental Health Sciences.

Regents Professor Michael Smerdon and post-doctoral researcher Peng Mao found that when DNA is damaged, a specific protein must first be “unbuckled” to allow easy access for the DNA “repair crew.” Without this unbuckling, entry to the damaged site is hampered by the compact arrangement of genes and protein in chromosomes called chromatin.

Smerdon and Mao’s finding is one of the first to document details of how this repair process takes place in chromatin.

Daily demands for DNA repair

Each human cell sustains a range of assaults that can create up to 100,000 DNA injuries every day, said Smerdon. The cells must repair this damage by continually — and quickly — producing replacement DNA and proteins.

Like a tiny locomotive, an enzyme called RNA polymerase runs up and down the DNA copying genetic information. When it comes to a gene whose protein is needed by the cell, it stops and unwinds the double-stranded DNA, copies one strand and sends it off to machinery to manufacture the new protein. And all is well.

But when DNA is damaged by UV radiation or harmful substances, it forms an impenetrable mass that stalls the RNA polymerase, said Smerdon. Like a boulder on the railroad tracks, the lifeless lump blocks all protein production from that gene. Unless quickly repaired, the cell could die.

In healthy people, an enzyme repair crew travels along with the RNA polymerase and instantly rushes in to excise the damage and clear the tracks. This is called transcription-coupled repair, or TCR, an aspect of one of four known DNA repair systems. Smerdon said that even a partial deficiency in any of the repair systems could lead to life-threatening disorders.

Children of the moon

Smerdon’s laboratory studies repair deficiency diseases like xeroderma pigmentosum or XP, first identified as a possible hereditary disorder in 1874. Known as children of the moon, XP patients lack the enzymes to cut out damaged DNA and are so sensitive to UV light that even fluorescent lights can blister their skin.

Their skin cancer rates are 2,000 times higher than in people without the disorder. They can safely venture outside only at night.

Smerdon and his colleagues also study Cockayne Syndrome, a TCR deficiency disease that causes extreme sun sensitivity, nervous system degeneration and premature aging.

Other DNA repair deficits can cause a range of diseases such as leukemia, breast cancer and hereditary non-polyposis colorectal cancer, a common cause of colon cancer in Western nations.

Loosening the belt

Using yeast and human cells, Smerdon, Mao and their team discovered that there are two steps to the normal TCR repair process and that a protein in the chromatin, called H2B, is critically involved in the first step.

To help the repair enzymes gain entry to heavily shielded DNA, H2B first unbuckles a smaller protein. Like loosening your belt after a big dinner, this allows the strands of DNA to relax and move apart. As the strands open, the repair crew has room to come in and clear the damage.

This unbuckling of the smaller protein, ubiquitin, is saddled with a jawbreaker term called deubiquitylation, but Smerdon and Mao say it makes DNA repair more efficient and that without it repair would be next to impossible.

Their finding sets the stage for future investigations into the largely uncharted arena of DNA repair in chromatin. The goal is to better understand how this process works in humans.

Gene therapy

“Even at a basic fundamental level, I have not lost sight of what you hope this research could ultimately do in terms of human health,” said Smerdon.

“One of the treatments under development is targeted gene therapy,” he said. “If a patient has a mutation in a specific gene, it would be a way of giving them a normal copy to try to correct that gene. Though it has been done successfully in some diseases, it is still being investigated in repair deficit cases.”

Mao speculates that in the future, people with DNA repair problems might be given a drug that could boost the activity of repair enzymes. But there are no clinical trials at this point.

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