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Shooting the Achilles Heel of Drug-Resistant Cancer

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Cancer cells that develop resistance to drugs, pay a price for this, by simultaneously developing a new vulnerability. If this acquired vulnerability can be identified, it may be exploited clinically. A team of cancer researchers, led by Rene Bernards of the Netherlands Cancer Institute and Oncode Institute, now exposed this acquired vulnerability in melanoma that has developed resistance to a targeted therapy with BRAF-inhibitors. The team then developed a new therapeutic strategy to selectively kill the drug-resistant cancer cells.

Do not fight resistance, but exploit it

One of the greatest obstacles in treating cancer is the rapid emergence of therapy resistance. However, when cancer cells develop drug resistance, they also acquire a new vulnerability, which is, in Darwinian terms, the fitness cost that comes with adapting to a new regime. If this newly acquired vulnerability can be exposed, it may be exploited clinically to keep the cancer at bay for a longer period, according to cancer researcher Rene Bernards.

Professor Bernards: ‘Drug resistance seems inevitable because tumours are constantly adapting. For over 40 years, we have been devising ways to prevent drug resistance in cancer. Now I think: let’s just accept that this is the way it is, and go and see if we can find the new vulnerability associated with resistance. Then we can exploit this sensitivity clinically and keep the cancer under control for a longer time.’

Melanoma

Bernards and his team were able to expose this new vulnerability in melanoma that has developed resistance to treatment with a BRAF inhibitor: a targeted therapy that blocks a signalling pathway in the cancer cell through which it gets the message to keep on dividing. This is due to a mutation in the BRAF gene, which plays an important role in cell division in healthy cells. More than half of all melanoma patients have a mutation in this BRAF gene. For these people, the BRAF-inhibitor does its job and tumour growth stops. But within a few months the tumour cell adapts the original signalling pathway becomes active again, and even hyperactive, so that all lights are green to start growing again.

Reactive oxygen species cause DNA damage

The key question is: what price does melanoma pay for resistance? In the lab, the researchers made melanoma cells resistant to the BRAF inhibitor and saw that the hyperactive resistant melanoma cells produced large amounts of reactive oxygen species. Cancer cells that were still sensitive to the drug did not do this.

Reactive oxygen species are — both in healthy cells and in cancer cells — a double-edged sword. They play an important role in transmitting signals in the cell, but if their concentration becomes too high, they cause DNA damage and the cell may stop dividing. Also in the Bernards experiment, the abundance of free radicals caused the resistant melanoma cells to stop dividing. However: they did not die.

Last push towards cell death

Bernards: ‘Then we thought: suppose we can give those hyperactive resistant tumour cells the last push towards cell death, by allowing them to produce even more free radicals.’ In the lab, this worked perfectly by exposing the cells to a substance that stimulates the production of free oxygen radicals. Only the resistant tumour cells died; tumour cells that were still sensitive to the original drug remained alive.

Tumours shrink

But does this also work in a living organism with melanoma? Bernards tested this on mice with an existing drug, vorinostat, which is known to stimulate the production of free oxygen radicals. Vorinostat has been used in the clinic for 15 years, including for a rare form of lymphoma, and is not very harmful to the patient. In mouse models, the researchers did indeed see tumours shrink under the influence of vorinostat.

Quickly onto a clinical trial

This gave hope, and because it was an approved and safe medicine, Bernards could then, together with physician Jan Schellens and hospital pharmacist Jos Beijnen, quickly start a clinical proof-of-concept trial among a very small number of patients of the Netherlands Cancer Institute. The concept also appeared to work in patients.

One-two punch strategy

This laid the foundation for a new therapeutic strategy. Step one: treat patients with BRAF-mutated melanoma, as usual, with signal pathway inhibitors. Step two: when the tumour has become resistant, stop giving those inhibitors and immediately treat the patients with vorinostat to kill the resistant cancer cells. For boxing enthusiasts: a ‘one-two punch’ approach. A hit from the left, immediately followed by one from the right.

“It is not a combination drug,” emphasizes Bernards, who has made a name for himself with smart combinations of drugs. ‘It is very important that you first stop the signalling pathway inhibitors because they suppress the free radicals and thus eliminate the effects of vorinostat.’

Getting new cancer drugs quickly and cheaply to the clinic

Bernards is happy with his scientific research, which resulted in a well-founded new strategy to treat melanoma that has become resistant. But he is at least as happy with the speed with which a lab study resulted in a clinical trial. ‘It is unique that a clinical trial has already been part of a fundamental scientific publication. This is how we, increasingly, want to do it.’

And moreover, the costing details are favourable. Vorinostat is a notoriously expensive drug, but hospital pharmacist, Beijnen, can make it himself in the pharmacy of Netherlands Cancer Institute. This is permitted for a clinical trial, and there is also no longer a patent on the American medicine. Bernards: ‘That is why this research fits so well with the new Oncode Institute, whose mission it is to bring new treatments to the patient quickly and cheaply.’

Follow-up step 1: nip resistance in the bud

Two follow-up studies are now planned. The first is a clinical follow-up study, under the umbrella of Oncode Institute. Bernards: ‘In our clinical proof-of-concept study, we gave the patients BRAF inhibitors for one year, until the cancer had become resistant. We then exterminated the resistant cells in one month with vorinostat. Now that we know that this principle works, we want to go a step further: we are going to check the patients’ blood every month for mutations in the tumor DNA. As soon as we see a trace of resistance, we briefly treat with vorinostat to nip the resistance in the bud. Then, we again transfer to the BRAF inhibitors, until we see resistance emerge again. With such a pulse-treatment, we think we can keep the cancer under control longer. ‘

Follow-up step 2: find the Achilles heel of other resistant cancers

In addition, Bernards will soon start a major study in which he wants to induce and exploit senescence in cancers other than melanoma. He has just been informed that the European Research Council will invest 2.5 million Euros in this, in the form of an ERC Advanced Grant.

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Parents, Kids Spend More Time Discussing How To Use Mobile Technology Than Talking About Content

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ANN ARBOR—Most parents would agree that one of the of the biggest modern parenting challenges is monitoring a child’s online activity.

A new study appearing in the Journal of Child and Family Studies found that parents spend more time talking with kids about the mechanics of using their mobile devices than they do about what their kids watch and download on those devices.

The findings came from a small, recent study of 75 children and their families, led by researcher Sarah Domoff, then a postdoctoral fellow at University of Michigan Center for Human Growth and Development. The children wore recording devices at home, which recorded talking, conversations or other sounds nearby, as well as audible screen media use.

Domoff, now an assistant professor at Central Michigan University, said the findings revealed some concerning trends in how families and children communicate about media today. Specifically, the researchers observed minimal conversation about the content of programming that children were watching.

Additionally, they learned that other family members appear to play an important role when content is discussed. Children––not parents––initiated most conversations about content, and older siblings played a much bigger role than parents in content mediation for younger siblings. Also, the study found that children as young as toddlers were exposed to multiple media sources at one time, or media multitasking.

Other findings include:

  • Negotiations and conflict are common among parents and children.
  • Parallel family media use is common, meaning different family members use their own devices at the same time.

“One of the most challenging aspects of parenting today is being aware of what children are exposed to online, particularly content delivered via mobile devices,” Domoff said.

“Thus, it is critical that parents utilize privacy settings and restrictions to protect children from certain content. Ideally, this would occur before the child received their own mobile device.”

Domoff recommends developing a family media plan. In 2016, The American Academy of Pediatrics released a tool that helps families set different goals and media use rules based on individual needs, she said.

It’s also troubling that some apps downloaded by children include advertising or request in-app purchases, she said. Parents can identify these apps by using Common Sense Media’s app review.

Parents can also recruit older children to help younger siblings make good content choices.

The study aimed to identify themes of parental mediation and family communication around mobile media devices. There’s a dearth of scientific data in this area compared to television and video games, but studies show that parental mediation leads to better outcomes for children.

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Internet Therapy Apps Reduce Depression Symptoms

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BLOOMINGTON, Ind. — In a sweeping new study, Indiana University psychologists have found that a series of self-guided, internet-based therapy platforms effectively reduce depression.

The work, which reviewed 21 pre-existing studies with a total of 4,781 participants, was published in the November issue of the Journal of Medical Internet Research. The study was led by Lorenzo Lorenzo-Luaces, an assistant professor of clinical psychology in the IU Bloomington College of Arts and Sciences’ Department of Psychological and Brain Sciences.

In the past several years, many internet-based apps and websites have made claims to treat depression. The subjects of the IU study were specifically those applications that provide treatment with cognitive behavioral therapy, a form of psychotherapy that focuses on changing thought patterns and behavior to alleviate symptoms of depression and other mental disorders.

Previous studies had examined the effectiveness of individual internet-based cognitive behavioral therapy apps, or iCBT, using a range of methods. Until this study, however, no review had examined whether the effects of these treatments were inflated by excluding patients with more severe depression or additional conditions such as anxiety or alcohol abuse.

“Before this study, I thought past studies were probably focused on people with very mild depression, those who did not have other mental health problems, and were at low risk for suicide,” Lorenzo-Luaces said.

“To my surprise, that was not the case. The science suggests that these apps and platforms can help a large number of people.”

For Lorenzo-Luaces, internet-based cognitive behavioral therapy apps are an important new tool for addressing a major public health issue: that individuals with mental health disorders like depression far outnumber the mental health providers available to treat them.

“Close to one in four people meet the criteria for major depressive disorder,” he said.

“If you include people with minor depression or who have been depressed for a week or a month with a few symptoms, the number grows, exceeding the number of psychologists who can serve them.”

People with depression are also expensive for the health care system, he added.

“They tend to visit primary-care physicians more often than others,” Lorenzo-Luaces said.

“They have more medical problems, and their depression sometimes gets in the way of their taking their medication for other medical problems.”

By conducting a “meta-regression analysis” of 21 studies, Lorenzo-Luaces and collaborators decisively determined that internet-based therapy platforms effectively alleviate depression. A central question was determining whether previous studies distorted the strength of these systems’ effects by excluding people with severe depression.

The conclusion was that the apps worked in cases of mild, moderate and severe depression.

Many of the studies in the analysis compared use of internet-based cognitive behavioral therapy apps to placement on a wait list for therapy or the use of a “fake app” that made weak recommendations to the user. In these cases, the iCBT apps worked significantly better.

“This is not to say that you should stop taking your medication and go to the nearest app store,” added Lorenzo-Luaces, who said both face-to-face therapy and antidepressants may still prove to be more effective than the iCBT apps alone.

“People tend to do better when they have a little bit of guidance,” he said. But he added that a 10- to 15-minute check-in may be sufficient for many people, freeing health care providers to see more patients.

App-based therapy also has an advantage in situations where access to face-to-face therapy is limited due to logistical barriers, such as long distances in rural areas or inflexible work schedules.

“ICBT apps take the methods we have learned and make them available to the many people who could benefit from them,” Lorenzo-Luaces said.

“It’s an exciting development.”

 

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New Study Finds Employee Incentives Can Lead To Unethical Behavior In The Workplace

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Considering end-of-year bonuses for your employees? Supervisors be forewarned, a new study finds that while incentive rewards can help motivate and increase employee performance it can also lead to unethical behavior in the workplace.

“Goal fixation can have a profound impact on employee behavior, and the damaging effects appear to be growing stronger in today’s competitive business landscape,” says Bill Becker, co-author of the study and associate professor of management in the Pamplin College of Business at Virginia Tech.

The study, “The effects of goals and pay structure on managerial reporting dishonesty,” provides valuable insight into the relationship between pay structures and motivation.

Findings suggest that setting compensation goals can increase dishonesty when managers are also paid a bonus for hitting certain targets.

“These unintended negative consequences can lead to dishonesty, unethical behavior, increased risk-taking, escalation of commitment, and depletion of self-control,” says Becker.

The study points to observations of unethical behaviors in the workplace that include employees falsifying or manipulating financial reporting information as well as time and expense reports.

For example, service professionals such as auditors, contractors, lawyers, and consultants who report hours billed against a target budget is often based on a fixed contract price.

“This causes potential for both under-reporting and over-reporting costs, which can undermine organizational objectives and negatively impact the interest of the firm,” says Becker.

“Using purely monetary incentives is almost always a double edged sword.”

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