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Protein Discovery May Explain Why Patients Develop Resistance To New Anti-Cancer Drugs

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A team of researchers at the University of Cambridge has identified a protein complex that might explain why some cancer patients treated with the revolutionary new anti-cancer drugs known as PARP inhibitors develop resistance to their medication.

In a study published in Nature Cell Biology, the team from the Wellcome/Cancer Research UK Gurdon Institute show that Shieldin — so-called because it shields the ends of broken DNA — regulates DNA repair and could be a useful marker for identifying which patients are likely to respond poorly to PARP inhibitors.

The DNA in our cells is susceptible to damage caused by external factors such as sunlight or smoking, or internal factors including our genetics. One form of damage is when both strands of the DNA double helix break — this can lead to cell death, so cells have various repair mechanisms to fix the damage.

The simplest mechanism for repairing DNA breaks is known as ‘non-homologous end-joining’ (NHEJ). This mechanism essentially ‘sticks together’ the broken DNA strands, but it is imperfect and can result in deletions of segments of DNA.

A more accurate repair mechanism is ‘homologous recombination’ (HR). This mechanism uses a copy of our DNA as a reference text to fill in any missing gaps. However, NHEJ and HR work in competition against each other: if the balance is tipped in favour of HR, then cells will use this mechanism to repair the DNA damage.

Among the proteins involved in HR is BRCA1. However, some people carry a ‘bad’ BRCA1 mutation, which makes them more susceptible to cancer. Normal cells in these people have one ‘bad’ copy of the BRCA1 gene, but still have one ‘good’ copy, meaning that they can still carry out HR — and hence are still able to carry out vital DNA repair; however, their cancer cells have lost the good copy of BRCA1 and are no longer able to carry out homologous recombination.

Professor Steve Jackson and colleagues at the Gurdon Institute previously exploited this weakness to develop PARP-inhibitor drugs, which cause a double-strand DNA break that can only be repaired by homologous recombination: so, BRCA1-negative cancer cells die, while surrounding healthy cells survive.

However, some patients taking PARP inhibitors develop resistance to the drugs — and some patients do not even respond from the outset. To understand why this should be the case, Professor Steve Jackson and colleagues used cutting-edge CRISPR-Cas 9 gene editing techniques to screen breast cancer cells with the BRCA1 mutation and identify which genes drive resistance.

They identified two genes that produce a protein complex now referred to as Shieldin. From this they were able to show that Shieldin plays an important role in NHEJ, binding at the site of the broken strands of DNA. It is this complex that appears to be the key to patients responding to PARP inhibitors.

The balancing act between NHEJ and HR should mean that the cells of people with the BRCA1 mutation cannot perform homologous recombination — hence PARP inhibitors are able to kill the cells. But when Shieldin levels are depleted — which may arise from spontaneous mutations in tumour cells — the balance changes and the patient’s tumour cells regain the ability to perform homologous recombination — and hence, PARP inhibitors are no longer effective.

Professor Jackson, whose group led the research, said: “There is a balancing act within our cells — a tug of war between proteins such as BRCA1 and Shieldin. Who wins determines whether the cell carries out error-free, albeit slower DNA repair, or faster, error-prone repair.”

The study’s lead author, Wellcome Clinical Fellow Dr Harveer Dev, explained:

“In BRCA1 mutated cells, it appears as though the persistence of the Shieldin complex at DNA breaks renders these cells sensitive to PARP inhibitors. This explains why these drugs are normally effective in patients with BRCA1 mutations. But when Shieldin levels are low, patients can develop resistance to these drugs.”

To confirm their results, the researchers took breast cancer biopsies from patients with the BRCA1 mutation and transplanted them into mice. They found that mice that had low levels of Shieldin from the outset did not respond to the PARP inhibitors, and mice that evolved resistance to the drugs had tumours with low levels of Shieldin. They also went on to show that resistance to PARP inhibitors can lead the same cancer cells to develop vulnerabilities to alternative cancer treatments, such as radiotherapy or platinum-based chemotherapy.

Professor Jackson concluded:

“As we improve our understanding of these DNA repair networks and how they interact, we should be able to better predict the responsiveness of an individual patient’s tumour to specific therapies like PARP inhibitors, and ultimately personalise cancer therapy to achieve the maximum benefit.”

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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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