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Knocking out DNA repair system could boost chemo’s kick

Futurity.org - Sun, 2017-11-12 19:37

Cells have a way of sensing the damage that certain chemotherapy drugs induce, researchers report. This finding could have important implications for treating cancer.

The busy world inside a cell is directed by its DNA blueprint. When the blueprints change, cells can sicken, die, or become cancerous. To keep DNA in working order, cells have ways to detect and mend damaged DNA.

“Blocking this pathway could be a way to make resistant tumors sensitive again.”

Some of the oldest chemotherapy drugs are known as alkylating agents because they kill cancer cells by adding groups of carbon and hydrogen atoms to—or alkylating—DNA. The extent of the alkylation damage overwhelms the cells’ ability to heal themselves via their DNA repair pathways. And some tumors are abnormally dependent on proteins involved in DNA repair, such that knocking out those proteins kills the tumor cells.

“We found that human cells can sense alkylation damage and mobilize a repair complex specifically suited to repair this kind of injury,” says senior author Nima Mosammaparast, an assistant professor of pathology and immunology, and co-leader of the DNA Metabolism and Repair Working Group at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine.

“Knocking out this complex may be a way to increase the potency of certain chemotherapy drugs, or to specifically target tumor cells that have become dependent on the repair complex,” she says.

Chemo and DNA repair

Alkylation can happen naturally, which is why cells have this repair system in the first place. Also, certain chemotherapy drugs force it to happen.

Busulfan, used to treat leukemia, and temozolomide, prescribed for brain tumors, alkylate many spots along DNA. It is difficult for the genetic blueprint to be copied accurately where DNA has been alkylated, so such alkylation damage kills the cells.

Studying cells treated with alkylating chemotherapy drugs or with drugs that lead to other kinds of DNA damage, the researchers determined how cells try to mend DNA damage caused specifically by alkylating agents.

They identified a group of proteins that clustered near the spots on the DNA that had been alkylated. Cells that lacked a key member of this protein complex were more likely to die if researchers treated them with alkylating drugs than cells that had the protein, indicating the importance of the protein complex in repairing DNA. Lacking the key protein made no difference when the DNA was damaged in other ways.

These findings suggest that sensing alkylation damage is a major primary defense against chemotherapy drugs such as busulfan and other alkylating agents.

Interfering with this repair complex could amplify the killing power of such drugs and potentially even avert or undermine drug resistance. After a successful course of chemotherapy, tumors sometimes recur tougher than before, having become resistant to the drugs from the first round of treatment.

How some breast cancer cells return after chemo

“There’s some evidence now that overexpressing components of this signaling pathway may be how some tumors become resistant to chemotherapy,” Mosammaparast says. “Blocking this pathway could be a way to make resistant tumors sensitive again.”

A silver lining

Recurrent tumors are not the only ones that may have high levels of DNA repair proteins. Some tumors that have never encountered alkylating chemotherapy drugs have high levels of key alkylation-repair proteins. And when they do, it portends poorly for the patients.

“In some kinds of pancreatic, prostate, and lung cancer, overexpressing components of this pathway indicates a significantly worse prognosis,” Mosammaparast says.

There is a possible silver lining, though.

Tumors that have high levels of key alkylation repair proteins are often dependent on them, meaning that if those proteins were somehow inhibited, the cells would die. Normal cells are not dependent on this alkylation repair pathway to the same degree. Other repair systems can handle the level of alkylating DNA damage a healthy cell typically encounters.

“That could be an opening for a chemotherapy drug,” Mosammaparast says. “We may be able to design a drug that is toxic to tumors but not to normal cells by targeting this alkylation repair pathway.”

The drug olaparib, approved in 2014 to treat hereditary ovarian cancer, exploits a similar vulnerability. It targets tumors that are unusually dependent on a repair pathway that stitches DNA back together after it has been cut into pieces. Olaparib blocks that pathway, and without it, the cancerous cells die.

Biomaterial package delivers chemo and fights resistance

The researchers report their findings in the journal Nature.

The National Institutes of Health (NIH); American Cancer Society; Alvin Siteman Cancer Research Fund; the Siteman Investment Program; and the Children’s Discovery Institute of St. Louis Children’s Hospital funded the work.

Source: Washington University in St. Louis

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Can tumor-cell ‘spheroids’ beat ovarian cancer?

Futurity.org - Sun, 2017-11-12 19:17

Honeycomb-like arrays of tiny, lab-grown cancers could one day help doctors zero in on individualized treatments for ovarian cancer, an unpredictable disease that kills more than 14,000 women each year in the United States alone.

A new process can grow hundreds of cultured cell masses, called spheroids, from just a few tumor cells derived from a patient. Grown in a structure called a 384-hanging drop array, each spheroid is encased in a tiny droplet of a special culturing medium. The 3D method yields cells that grow and multiply just as they would inside the body.

Eventually, those spheroids could serve as a testing ground where doctors could quickly try out a variety of different medications to find the best combination for an individual patient and adjust on the fly as the disease evolves, helping to stay one step ahead of tumor cells.

Ovarian cancer’s free-floating spheroids shuttle cancer through the abdomen with the ability to form new tumors wherever they go.

“Today we’re limited to two-dimensional cells grown in bovine serum that’s derived from cows. Cells grown this way often don’t respond to medication the same way as ovarian cancer cells inside the body,” says Geeta Mehta, assistant professor of materials science and engineering at the University of Michigan.

“Three-dimensional cultured spheroids provide a much more predictive way to test many different medications, and a way to grow many cultured cells from just a few of the patient-derived cells.”

Researchers administered cancer drugs to the cultured cancer spheroids and compared their response to that of ovarian cancer cells that had been removed from the same patient and implanted into mice. The response of the cultured spheroids accurately mirrored that of the natural implanted cells. The findings appear in Clinical Cancer Research.

Even among cancers, ovarian cancer is particularly menacing, Mehta says. Its free-floating spheroids shuttle cancer through the abdomen with the ability to form new tumors wherever they go—the liver, the intestines, the abdominal wall. And the cells within those spheroids mutate often and unpredictably, quickly developing new strains that resist chemotherapy drugs.

Ovarian cancer’s deadly adaptability contributes to a 70-percent relapse rate among patients who have had surgery to remove a tumor. It’s these patients who Mehta believes may one day benefit from the new technique.

The hanging drop array’s hundreds of individual compartments make it possible to grow many spheroids at once and quickly gather data about multiple drugs. This is key, as chemotherapy treatment often requires complex cocktails of multiple drugs administered together. The cells could provide a way to test many cocktails simultaneously.

“…understanding why something doesn’t work can be extremely useful as a way of developing better treatments or treatment combinations.”

While widespread clinical use is likely years off, Mehta says the team now plans to do more extensive testing, culturing cells from patients who are undergoing chemotherapy, then administering the same chemotherapy drugs to the cultured cells and measuring their response.

“This is a really important step to expedite personalized medicine for cancer patients,” says senior coauthor Ronald Buckanovich, professor of medicine at the University of Pittsburgh.

“The ability to take patients’ samples, rapidly grow them in a more physiologic manner and study their response to therapy, without using mice, will be a faster, cheaper, and more humane way to rapidly test a patient’s response to dozens of therapeutics”

The team also plans to expand testing of the treatment beyond cancer stem cells to other cell types with the goal of gaining a broader understanding of the role each cell type plays in building resistance to chemotherapy.

Most ovarian cancers get their start in fallopian tubes

“This gets us closer to an understanding of what treatment options work best, but it also gives us a way to study exactly what happens when a treatment fails,” says coauthor Karen McLean, assistant professor of gynecologic oncology at the University of Michigan.

“And understanding why something doesn’t work can be extremely useful as a way of developing better treatments or treatment combinations.”

The Department of Defense Ovarian Cancer Research Program Early Career Investigator Awards and the National Cancer Institute of the National Institutes of Health supported the work.

Source: University of Michigan

The post Can tumor-cell ‘spheroids’ beat ovarian cancer? appeared first on Futurity.

Axing protection for undersea monuments could spell disaster

Futurity.org - Sun, 2017-11-12 19:08

The Trump administration is considering rolling back federal protections for a number of national monuments, a move many marine experts disagree with.

While most monuments are on land and relatively accessible, three are deep below the ocean’s surface and many miles from the mainland: the Pacific Remote Islands Marine National Monument and the Rose Atoll Marine National Monument, both in the central Pacific Ocean, and the Northeast Canyons and Seamounts Marine National Monument off the coast of New England.

Most people will never explore the canyons and reefs of these watery realms, but their value is hard to overestimate, according to scientists with years of experience exploring and studying these and adjacent areas.

Biology graduate student Tim White and and Kosta Stamoulis of the University of Hawaii track a gray reef shark within the Pacific Remote Islands Marine National Monument. (Credit: Palmyra Atoll Research Consortium via Stanford)

The Stanford Woods Institute for the Environment spoke with marine experts Rob Dunbar, Fiorenza Micheli, Stephen Palumbi, and Tim White about potential impacts from a loss of protections, including the resumption of commercial fishing in currently off-limits areas. Dunbar is a professor in the School of Earth, Energy & Environmental Sciences at Stanford University. Micheli and Palumbi are both professors of marine science at the university’s Hopkins Marine Station. White is a doctoral student in biology.

The post Axing protection for undersea monuments could spell disaster appeared first on Futurity.

Face transplant recipient meets donor family

CNN - Sun, 2017-11-12 19:00
Andy Sandness received a face transplant and now he's meeting the donor's family for the first time. If you or someone you know is showing warning signs of suicide, contact the National Suicide Prevention Lifeline at 800-273-TALK.

New York Times photographer tweets ‘photo’ of black box to protest White House coverage blackout

Washington Post - Sun, 2017-11-12 19:00
The White House faced criticism over limited access for reporters during Trump's Asia trip.

Op-Ed Contributor: Yes, the G.O.P. Can Block Roy Moore

NY Times - Sun, 2017-11-12 18:59
The Republicans aren’t powerless to prevent Alabama from sending him to the Senate.

First look inside Texas church after shooting

CNN - Sun, 2017-11-12 18:53
A memorial inside the Texas church where 26 people were shot and killed includes chairs placed where each victim was found and audio recordings of the victims' voices. CNN's Kaylee Hartung describes the scene.

How enzymes direct ‘traffic’ inside cells

Futurity.org - Sun, 2017-11-12 18:51

Protein “motors” inside cells act like trucks on tiny cellular highways to deliver life-sustaining cargo. Researchers now know how cells deploy enzymes to place traffic control and “roadway under construction” signs along those highways.

The findings could lead to new therapies for spinal cord and nerve injuries and neurodegenerative diseases.

“To stay alive and function, every cell in our body needs to transport cargoes to the place they’re needed inside the cell, in the right amount, and at the right time,” says Robert O’Hagan, assistant research professor of genetics at Rutgers University-New Brunswick and the Human Genetics Institute of New Jersey. “So there has to be a lot of organization in how transport inside the cell is regulated, and now we know a lot more about how that happens.”

The highways inside cells are called microtubules. Proteins called kinesins and dyneins act like motors—and are essentially the cargo trucks in cells. The motor proteins drive cargo around microtubule highways.

A central question in cell biology is how intracellular transport and the highway systems are organized. How do the motor proteins know where to go and how fast they need to be?

As reported in Current Biology, researchers looked at C. elegans, a microscopic roundworm, and looked at microtubules in cilia—hair-like organelles that protrude from cells and perform sensory tasks.

They found that TTLL-11 is an enzyme that puts traffic signs composed of the amino acid glutamate on the microtubule highways to regulate the speed of the protein cargo trucks. CCPP-1 is an enzyme that takes down these glutamate traffic signs when there are too many of them.

“Working together, they seem to regulate the speed of the motors that move cargoes on the microtubular highways,” O’Hagan says.

The scientists also found that the glutamates can also act as a “roadway under construction” sign, changing the highways’ structure.

Intriguingly, these enzymes are involved in degenerating cells that are crucial for vision, as well as neurons. The findings suggest that future therapies targeting these enzymes might counter neurodegenerative diseases or nerve damage, including spinal cord injuries, O’Hagan says.

How spinal cord neurons know where to reach

“The picture that’s emerging from our and other labs’ research is that, for neurons to regenerate after injury or to survive in the brain, they need to be able to reorganize their microtubular highways and their cargo trucks in order to bring the right cargoes around to rebuild or maintain the cell.

“There’s a lot more to be discovered. Our next step is to see how this works in the spinal cord in mammals, so we’ve started studies of rat spinal cord neurons.”

The National Institutes of Health and the New Jersey Commission on Spinal Cord Research supported the work.

Source: Rutgers University

The post How enzymes direct ‘traffic’ inside cells appeared first on Futurity.

Witness films moment of quake

CNN - Sun, 2017-11-12 18:50
A 7.3 magnitude earthquake on the Iraq-Iran border has killed dozens of people. CNN's Amara Walker and Julie Martin have the latest on this disaster.

Security Breach and Spilled Secrets Have Shaken the N.S.A. to Its Core

NY Times - Sun, 2017-11-12 18:48
A serial leak of the agency’s cyberweapons has damaged morale, slowed intelligence operations and resulted in hacking attacks on businesses and civilians worldwide.

The Neediest Cases Fund: Her Secret to a Long Life? ‘It’s Good to Work a Lot’

NY Times - Sun, 2017-11-12 18:45
As a teenager, Bella Pevzner fled Belarus after the Nazi invasion. She worked well into her 70s, and at 89, she is applying her dogged work ethic to her paintings.

In ‘Watershed Moment,’ YouTube Blocks Extremist Cleric’s Message

NY Times - Sun, 2017-11-12 18:30
The site has largely removed videos of Anwar al-Awlaki, Al Qaeda’s leading voice in English before his death by drone — and after, when he became a jihadist hero.

Trump says U.S. won't be 'taken advantage of anymore.' Hours later, Pacific Rim nations reach deal on trade without America.

Washington Post - Sun, 2017-11-12 18:30
The agreement represents a rebuke of the president, coming near the end of his 12-day swing through Asia.

Ex-CIA chief: Russia threat is obvious

CNN - Sun, 2017-11-12 18:10
Former CIA Director John Brennan and former Director of National Intelligence James Clapper respond to President Trump, who suggested he's done confronting Russian President Vladimir Putin over his country's election meddling and is taking Putin at his word that Russia did not seek to interfere in the 2016 election.

First service at Texas church since massacre

CNN - Sun, 2017-11-12 18:06
The congregation of First Baptist Church of Sutherland Springs held a service on Sunday, one week after a gunman opened fire in the church, killing 25 people and an unborn child in the deadliest mass shooting in Texas history.

Silence Lifts in Statehouses as Harassment Scandals Bring Swift Penalties

NY Times - Sun, 2017-11-12 18:02
The cascade of allegations has prompted broad disavowals and public calls for resignations in male-dominated legislatures.

EPA is taking more advice from industry — and ignoring its own scientists

Washington Post - Sun, 2017-11-12 18:00
Under Scott Pruitt, the agency has reassessed its data and analyses at the prompting of corporations.

In New Film, 'My Friend Dahmer' Author Portrays Serial Killer As Sympathetic Outcast

NPR All Things Considered - Sun, 2017-11-12 17:51

My Friend Dahmer, based on the best-selling graphic novel by John Backderf, tells a story of serial killer Jeffrey Dahmer's high school years and the kids who knew him, including Backderf.

New Exhibit Shows Off Special Effects Pioneer Ray Harryhausen's Lasting Works

NPR All Things Considered - Sun, 2017-11-12 17:51

A new exhibition in Oklahoma City presents the work of pioneering stop-motion animator Ray Harryhausen. In an age of CGI and 3-D animation, his work still influences and delights.

In D.C., Brain Science Meets Behavioral Science To Shed Light On Mental Disorders

NPR All Things Considered - Sun, 2017-11-12 17:51

The Society for Neuroscience meeting is taking place in Washington, D.C., this weekend. Researchers there are focusing on how to find the biological underpinnings of mental disorders.

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