Tag Archives: cancer

Rotating night shift work can be hazardous to your health

Possible increase in cardiovascular disease and lung cancer mortality observed in nurses working rotating night shifts, according to report in the American Journal of Preventive Medicine

ELSEVIER HEALTH SCIENCES


Night shift work has been consistently associated with higher risk for cardiovascular disease (CVD) and cancer. In 2007 the World Health Organization classified night shift work as a probable carcinogen due to circadian disruption. In a study in the current issue of the American Journal of Preventive Medicine, researchers found that women working rotating night shifts for five or more years appeared to have a modest increase in all-cause and CVD mortality and those working 15 or more years of rotating night shift work appeared to have a modest increase in lung cancer mortality. These results add to prior evidence of a potentially detrimental effect of rotating night shift work on health and longevity.

Sleep and the circadian system play an important role in cardiovascular health and antitumor activity. There is substantial biological evidence that night shift work enhances the development of cancer and CVD, and contributes to higher mortality.

An international team of researchers investigated possible links between rotating night shift work and all-cause, CVD, and cancer mortality in a study of almost 75,000 registered U.S. nurses. Using data from the Nurses’ Health Study (NHS), the authors analyzed 22 years of follow-up and found that working rotating night shifts for more than five years was associated with an increase in all-cause and CVD mortality. Mortality from all causes appeared to be 11% higher for women with 6-14 or ?15 years of rotating night shift work. CVD mortality appeared to be 19% and 23% higher for those groups, respectively. There was no association between rotating shift work and any cancer mortality, except for lung cancer in those who worked shift work for 15 or more years (25% higher risk).

The NHS, which is based at Brigham and Women’s Hospital, began in 1976, with 121,700 U.S. female nurses aged 30-55 years, who have been followed up with biennial questionnaires. Night shift information was collected in 1988, at which time 85,197 nurses responded. After excluding women with pre-existing CVD or other than non-melanoma skin cancer, 74,862 women were included in this analysis. Defining rotating shift work as working at least three nights per month in addition to days or evenings in that month, respondents were asked how many years they had worked in this way. The prespecified categories were never, 1-2, 3-5, 6-9, 10-14, 15-19, 20-29, and ?30 years.

According to Eva S. Schernhammer, MD, DrPH, currently Associate Professor of Medicine, Harvard Medical School, and Associate Epidemiologist, Department of Medicine, Brigham and Women’s Hospital, Boston, this study “is one of the largest prospective cohort studies worldwide with a high proportion of rotating night shift workers and long follow-up time. A single occupation (nursing) provides more internal validity than a range of different occupational groups, where the association between shift work and disease outcomes could be confounded by occupational differences.”

Comparing this work with previous studies, she continues, “These results add to prior evidence of a potentially detrimental relation of rotating night shift work and health and longevity…To derive practical implications for shift workers and their health, the role of duration and intensity of rotating night shift work and the interplay of shift schedules with individual traits (e.g., chronotype) warrant further exploration.”

Source: American Journal of Preventive Medicine via EurekAlert

Musashi proteins, stained red, appear in the cell cytoplasm, outside the nucleus. At right, the cell nucleus is stained blue.
Image Credit: Yarden Katz/MIT

Proteins drive cancer cells to change states

When RNA-binding proteins are turned on, cancer cells get locked in a proliferative state.

 By Anne Trafton


 

A new study from MIT implicates a family of RNA-binding proteins in the regulation of cancer, particularly in a subtype of breast cancer. These proteins, known as Musashi proteins, can force cells into a state associated with increased proliferation.

Biologists have previously found that this kind of transformation, which often occurs in cancer cells as well as during embryonic development, is controlled by transcription factors — proteins that turn genes on and off. However, the new MIT research reveals that RNA-binding proteins also play an important role. Human cells have about 500 different RNA-binding proteins, which influence gene expression by regulating messenger RNA, the molecule that carries DNA’s instructions to the rest of the cell.

“Recent discoveries show that there’s a lot of RNA-processing that happens in human cells and mammalian cells in general,” says Yarden Katz, a recent MIT PhD recipient and one of the lead authors of the new paper. “RNA is processed at several points within the cell, and this gives opportunities for RNA-binding proteins to regulate RNA at each point. We’re very interested in trying to understand this unexplored class of RNA-binding proteins and how they regulate cell-state transitions.”

Feifei Li of China Agricultural University is also a lead author of the paper, which appears in the journal eLife on Dec. 15. Senior authors of the paper are MIT biology professors Christopher Burge and Rudolf Jaenisch, and Zhengquan Yu of China Agricultural University.

Controlling cell states

Until this study, scientists knew very little about the functions of Musashi proteins. These RNA-binding proteins have traditionally been used to identify neural stem cells, in which they are very abundant. They have also been found in tumors, including in glioblastoma, a very aggressive form of brain cancer.

“Normally they’re marking stem and progenitor cells, but they get turned on in cancers. That was intriguing to us because it suggested they might impose a more undifferentiated state on cancer cells,” Katz says.

To study this possibility, Katz manipulated the levels of Musashi proteins in neural stem cells and measured the effects on other genes. He found that genes affected by Musashi proteins were related to the epithelial-to-mesenchymal transition (EMT), a process by which cells lose their ability to stick together and begin invading other tissues.

EMT has been shown to be important in breast cancer, prompting the team to look into Musashi proteins in cancers of non-neural tissue. They found that Musashi proteins are most highly expressed in a type of breast tumors called luminal B tumors, which are not metastatic but are aggressive and fast-growing.

When the researchers knocked down Musashi proteins in breast cancer cells grown in the lab, the cells were forced out of the epithelial state. Also, if the proteins were artificially boosted in mesenchymal cells, the cells transitioned to an epithelial state. This suggests that Musashi proteins are responsible for maintaining cancer cells in a proliferative, epithelial state.

“These proteins seem to really be regulating this cell-state transition, which we know from other studies is very important, especially in breast cancer,” Katz says.

Musashi proteins, stained red, appear in the cell cytoplasm, outside the nucleus. At right, the cell nucleus is stained blue. Image Credit: Yarden Katz/MIT
Musashi proteins, stained red, appear in the cell cytoplasm, outside the nucleus. At right, the cell nucleus is stained blue.
Image Credit: Yarden Katz , MIT

 

The researchers found that Musashi proteins repress a gene called Jagged1, which in turn regulates the Notch signaling pathway. Notch signaling promotes cell division in neurons during embryonic development and also plays a major role in cancer.

When Jagged1 is repressed, cells are locked in an epithelial state and are much less motile. The researchers found that Musashi proteins also repress Jagged1 during normal mammary-gland development, not just in cancer. When these proteins were overexpressed in normal mammary glands, cells were less able to undergo the type of healthy EMT required for mammary tissue development.

Brenton Graveley, a professor of genetics and developmental biology at the University of Connecticut, says he was surprised to see how much influence Musashi proteins can have by controlling a relatively small number of genes in a cell. “Musashi proteins have been known to be interesting for many years, but until now nobody has really figured out exactly what they’re doing, especially on a genome-wide scale,” he says.

The researchers are now trying to figure out how Musashi proteins, which are normally turned off after embryonic development, get turned back on in cancer cells. “We’ve studied what this protein does, but we know very little about how it’s regulated,” Katz says.

He says it is too early to know if the Musashi proteins might make good targets for cancer drugs, but they could make a good diagnostic marker for what state a cancer cell is in. “It’s more about understanding the cell states of cancer at this stage, and diagnosing them, rather than treating them,” he says.

The research was funded by the National Institutes of Health.

Source : MIT News Office

In a paper appearing in the Nov. 18 issue of Nature Communications, the researchers demonstrate the use of the particles, which carry distinct sensors for fluorescence and MRI, to track vitamin C in mice. Wherever there is a high concentration of vitamin C, the particles show a strong fluorescent signal but little MRI contrast. If there is not much vitamin C, a stronger MRI signal is visible but fluorescence is very weak.

Illustration: Christine Daniloff/MIT

Two sensors in one

Nanoparticles that enable both MRI and fluorescent imaging could monitor cancer, other diseases.

By Anne Trafton


 

MIT chemists have developed new nanoparticles that can simultaneously perform magnetic resonance imaging (MRI) and fluorescent imaging in living animals. Such particles could help scientists to track specific molecules produced in the body, monitor a tumor’s environment, or determine whether drugs have successfully reached their targets.

 

In a paper appearing in the Nov. 18 issue of Nature Communications, the researchers demonstrate the use of the particles, which carry distinct sensors for fluorescence and MRI, to track vitamin C in mice. Wherever there is a high concentration of vitamin C, the particles show a strong fluorescent signal but little MRI contrast. If there is not much vitamin C, a stronger MRI signal is visible but fluorescence is very weak.

In a paper appearing in the Nov. 18 issue of Nature Communications, the researchers demonstrate the use of the particles, which carry distinct sensors for fluorescence and MRI, to track vitamin C in mice. Wherever there is a high concentration of vitamin C, the particles show a strong fluorescent signal but little MRI contrast. If there is not much vitamin C, a stronger MRI signal is visible but fluorescence is very weak. Illustration: Christine Daniloff/MIT
In a paper appearing in the Nov. 18 issue of Nature Communications, the researchers demonstrate the use of the particles, which carry distinct sensors for fluorescence and MRI, to track vitamin C in mice. Wherever there is a high concentration of vitamin C, the particles show a strong fluorescent signal but little MRI contrast. If there is not much vitamin C, a stronger MRI signal is visible but fluorescence is very weak.
Illustration: Christine Daniloff/MIT

 

Future versions of the particles could be designed to detect reactive oxygen species that often correlate with disease, says Jeremiah Johnson, an assistant professor of chemistry at MIT and senior author of the study. They could also be tailored to detect more than one molecule at a time.

 

“You may be able to learn more about how diseases progress if you have imaging probes that can sense specific biomolecules,” Johnson says.

 

Dual action

 

Johnson and his colleagues designed the particles so they can be assembled from building blocks made of polymer chains carrying either an organic MRI contrast agent called a nitroxide or a fluorescent molecule called Cy5.5.

 

When mixed together in a desired ratio, these building blocks join to form a specific nanosized structure the authors call a branched bottlebrush polymer. For this study, they created particles in which 99 percent of the chains carry nitroxides, and 1 percent carry Cy5.5.

 

Nitroxides are reactive molecules that contain a nitrogen atom bound to an oxygen atom with an unpaired electron. Nitroxides suppress Cy5.5’s fluorescence, but when the nitroxides encounter a molecule such as vitamin C from which they can grab electrons, they become inactive and Cy5.5 fluoresces.

 

Nitroxides typically have a very short half-life in living systems, but University of Nebraska chemistry professor Andrzej Rajca, who is also an author of the new Nature Communications paper, recently discovered that their half-life can be extended by attaching two bulky structures to them.  Furthermore, the authors of the Nature Communications paper show that incorporation of Rajca’s nitroxide in Johnson’s branched bottlebrush polymer architectures leads to even greater improvements in the nitroxide lifetime. With these modifications, nitroxides can circulate for several hours in a mouse’s bloodstream — long enough to obtain useful MRI images.

 

The researchers found that their imaging particles accumulated in the liver, as nanoparticles usually do. The mouse liver produces vitamin C, so once the particles reached the liver, they grabbed electrons from vitamin C, turning off the MRI signal and boosting fluorescence. They also found no MRI signal but a small amount of fluorescence in the brain, which is a destination for much of the vitamin C produced in the liver. In contrast, in the blood and kidneys, where the concentration of vitamin C is low, the MRI contrast was maximal.

 

Mixing and matching

 

The researchers are now working to enhance the signal differences that they get when the sensor encounters a target molecule such as vitamin C. They have also created nanoparticles carrying the fluorescent agent plus up to three different drugs. This allows them to track whether the nanoparticles are delivered to their targeted locations.

 

“That’s the advantage of our platform — we can mix and match and add almost anything we want,” Johnson says.

 

These particles could also be used to evaluate the level of oxygen radicals in a patient’s tumor, which can reveal valuable information about how aggressive the tumor is.

 

“We think we may be able to reveal information about the tumor environment with these kinds of probes, if we can get them there,” Johnson says. “Someday you might be able to inject this in a patient and obtain real-time biochemical information about disease sites and also healthy tissues, which is not always straightforward.”

 

Steven Bottle, a professor of nanotechnology and molecular science at Queensland University of Technology, says the most impressive element of the study is the combination of two powerful imaging techniques into one nanomaterial.

 

“I believe this should deliver a very powerful, metabolically linked, multi-combination imaging modality which should provide a highly useful diagnostic tool with real potential to follow disease progression in vivo,” says Bottle, who was not involved in the study.

 

The research was funded by the National Institutes of Health, the Department of Defense, the National Science Foundation, and the Koch Institute for Integrative Cancer Research.

Source: MIT News