Genes, environment and schizophrenia—new study finds placenta is missing link

Hiding in plain sight, new research shines a spotlight on the placenta’s critical role in the nature versus nurture debate and how it confers risk for schizophrenia and likely other neurodevelopmental disorders including ADHD, autism, and Tourette syndrome. This new scientific frontier, with far-reaching implications for maternal and child health, creates the possibility that scientists can more accurately predict who is at risk of mental illness, and develop strategies to prevent or lessen their occurrence by increasing the resiliency and health of the placenta.

The study, “Convergence of placenta biology and genetic risk for schizophrenia,” was led by researchers at the Lieber Institute for Brain Development and published in Nature Medicine. “For the first time, we have found an explanation for the connection between early life complications, genetic risk, and their impact on mental illness and it all converges on the placenta,” said Daniel R. Weinberger, who led the team of investigators on the study and is CEO of the Lieber Institute for Brain Development (LIBD).

In contrast to prior studies that focused on how genes related to behavioral disorders directly alter prenatal brain development, this novel research found that many genes associated with risk for schizophrenia appear to alter early brain development indirectly, by influencing the health of the placenta. The research showed that these genes are “turned on” in the placenta during complicated pregnancies and signal a placenta under duress.

While the subject of myth and ritual in many cultures, the placenta remains a scientifically neglected human organ, despite its essential role for supplying nutrients and chemicals critical for normal prenatal development. Indeed, the placenta is the only organ removed from a human body that is not routinely sent to the laboratory for examination.

For over a quarter of a century, brain development during pregnancy and shortly after birth has remained central to a hypothesis that schizophrenia is a neurodevelopment disorder. However, the biological mechanisms involved were poorly understood. Previous studies have shown that genetic variants alone increase the odds of developing schizophrenia by only a fraction, while early life complications during pregnancy and labor can increase risk by up to 2-fold. The Lieber Institute investigators studied over 2800 adult individuals, 2038 of whom had schizophrenia, of various ethnic backgrounds from four countries, including the USA, Europe and Asia. All had undergone genetic testing and were surveyed for obstetrical history information.

Researchers found a prominent interaction between genes associated with risk for schizophrenia and a history of a potentially serious pregnancy complication. Individuals having high genetic risk and serious early life complications have at least a fivefold greater likelihood of developing schizophrenia in comparison to individuals with similarly high genetic risk but no history of serious obstetrical complications. This led to a series of analyses of gene expression in multiple placenta tissue samples, including samples of placenta from complicated pregnancies that include preeclampsia and intrauterine growth restriction. The results showed a striking and consistent turning on of the schizophrenia genes in these placentae and the more they were turned on, the more the placenta showed other signs of being under stress, for example, being more inflamed.

A Clue to Higher Male Risk for Schizophrenia

One of the many mysteries of developmental behavioral disorders, including schizophrenia, autism, ADHD, dyslexia, and Tourette Syndrome is why their incidence is 2-4 times greater in males than in females. The Lieber Institute team findings may shed light on this mystery. They found that the schizophrenia genes turned on in the placenta from complicated pregnancies were dramatically more abundant in placentas from male compared with female offspring. The placenta appears to be at least part of the explanation for the sex bias associated with these disorders.

“The surprising results of this study make the placenta the centerpiece of a new realm of biological investigation related to how genes and the environment interact to alter the trajectory of human brain development,” said Weinberger.

Further research into this emerging frontier of clinical medicine will advance the understanding of the biological interplay between placental health and neurodevelopment. There is a potential to discover novel approaches to therapeutic treatments and prevention strategies, and ultimately reduce the incidence of neurodevelopmental behavior disorders.

 Explore further: Assisted reproduction may up risk of placental anomalies

More information: Gianluca Ursini et al, Convergence of placenta biology and genetic risk for schizophrenia, Nature Medicine (2018). DOI: 10.1038/s41591-018-0021-y

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‘Exergaming’ a Good Workout for Less-Active Heart Failure Patients

When patients regularly included simulated sports activities using a video-game console into their daily routine in a randomized trial, overall their self-perception of well-being improved along with functional capacity.

But not every patient with heart failure who exercised using the Wii Sports(Nintendo) gaming console reaped the benefits. Some defied expectations that high adherence would translate to bigger gains.

Those assigned to use the gaming console showed better improvements in 6-minute walk distance over 3 months compared with patients given “motivational support” to increase their activity levels. But there wasn’t a strong correlation between gaming time and functional response.

That might have something to say about how an “exergaming” strategy in patients with heart failure in practice might or might not effectively complement more traditional approaches to promoting exercise, researchers speculate.

The primary finding of the HF-Wii study, reported at the European Society of Cardiology 2017 Congress, showed that patients assigned to exergaming had better 6-minute walk test (6MWT) results than the control group.

The new findings of improved self-perceived well-being as well as the unexpected relationship between exergaming adherence and functional outcomes were reported here this week at the European Society of Cardiology (ESC HF) Heart Failure 2018 by principal investigator Tiny Jaarsma, PhD, of Linköping University, Sweden.

Exergaming as done in the trial “requires rigorous physical exercise” and consists of simulated sports activities like golfing, bowling, or playing tennis by the patient, alone or with other participants, said Jaarsma during her presentation.

Addressing those audience members who seemed unfamiliar with Wii Sports and exergaming in general, Jaarsma explained, “It’s not doing a Sudoku on your phone, it is really being physically active and intended as a workout.”

Experience in patients with heart failure, she said, suggests that “it increases motivation, increases activity, promotes better health behaviors, and improves exercise capacity and health.”

In 2010, the American Heart Association (AHA) controversially entered a partnership with Nintendo in which the company donated $1.5 million to the organization, which for its part allowed its “heart check” emblem to be displayed on the packaging of Wii exergaming systems. The emblem was in use to identify consumer products the AHA certified as healthy lifestyle choices.

To be sure, the benefits of increased activity levels in heart failure are well recognized; often the challenges are patient engagement in and continued adherence to an exercise program. Exergaming seems to meet those challenges in various ways, Jaarsma pointed out for theheart.org | Medscape Cardiology. Most of the patients had fun playing the simulated sports, which can be done conveniently at home.

Also, exergaming can be performed alone or as a family activity, the latter of which was a big draw for some patients. “When we did a pilot study several years ago, we saw that the amount of time playing was related to having grandchildren,” Jaarsma said. Their support and participation, it was thought, helped encourage the grandparents with heart failure to use the gaming device more often.

HF-Wii assigned 605 patients with heart failure to a recommendation to use the Wii Sport console for at least 30 minutes a day or to receive “motivational support only” and standard advice about exercise.

Wii consoles were provided to patients and installed in their homes for free. Patients received introductory lessons on their use and were given continued access to technical support, Jaarsma said.

There were no requirements for study entry based on NYHA functional class or left-ventricular ejection fraction. The patients were primarily in Sweden but also the Netherlands, Germany, Italy, Israel, and the United States.

Adherence to the exergaming time recommendation varied. Just over a third of patients, 34.8%, achieved more than 90% of the prescribed usage time. About half, 49.5%, fulfilled more than 60% of the exergaming prescription.

But a surprisingly large 17% of the exergaming group never used the console. They showed significantly less 6MWT improvement over 3 months compared with either the control group or those who actually used the Wii console regardless of adherence level.

Otherwise, there was no observed dose-response effect; those achieving all or nearly 100% of the recommended usage showed about as much 6MWT improvement as users with lower adherence.

“Those people who were really highly adherent, they were of course the people who had already been exercising — younger, fitter — so they could easily do 80%” of the recommended level, Jaarsma said. Put another way, she said, patients who used the Wii system the most were those with the least to gain from it.

Pointing in part to the 17% of patients in the exergaming group who didn’t use the system, Christopher M. O’Connor, MD, of the Inova Heart & Vascular Institute, Falls Church, Virginia, said he’d been hoping that adherence in the trial would be “a little bit better, because adherence is the big thing with exercise.”

Patients in the HF-ACTION trial adhered to their exercise protocol at about the same level that HF-Wii patients adhered to their exergaming recommendation, O’Connor told theheart.org | Medscape Cardiology. That’s “curious” because in the earlier trial, “we were asking people to exercise on a treadmill 200 minutes a week for two-and-a-half years.”

O’Connor isn’t involved in HF-Wii but co-chaired HF-ACTION, which had randomly assigned about 2300 patients with heart failure to usual care with or without supervised exercise-training sessions plus a home-based exercise regimen. Patients in the intervention group showed dose-response relationships between exercise and functional capacity, quality of life, and 90-day survival.

If exergaming could be shown to produce gains like those seen in HF-ACTION, he said, it could be recommended as offering benefits similar to those from conventional exercise. It could then serve as one exercise option among many for individual patients, and choice itself, O’Connor said, might improve compliance.

As assigned discussant following Jaarsma’s presentation, Loreena M. Hill, PhD, of Queen’s University Belfast, UK, said the study “really demonstrates very positive results” and shows that the exergaming option is acceptable to patients. But it would be prudent to explore its long-term impact, she said, before exergaming should be recommended in clinical practice.

The previously reported functional benefits from exergaming in the trial included a 33-meter longer 6MWT distance (P = .002) at 3 months compared with the control group.

Table. Mean Current and Expected Well-Being Scores^a at 3 Months in HF-Wii

ENDPOINTS	EXERGAME GROUP	CONTROL GROUP	P
Current well-being	6.6	6.2	< .05
Expected well-being	7.6	7.4	< .05

a. Cantril Ladder of Life scales ranging from 1 to 10.

In the new HF-Wii secondary analysis, patients in the exergaming group compared with controls showed significantly better responses from baseline to 3 months on Cantril Ladder of Life scales for current and expected well-being.

But there were no significant differences in responses based on the Hospital Anxiety and Depression Scale or in quality of life by the Minnesota Living With Heart Failure Questionnaire.

Jaarsma agreed that exergaming would likely serve as one exercise option among many for most patients, but it likely won’t provide substantial functional gains for heart failure patients who are already active. If they walk a dog three times a week or bike for an hour, for example, “the Wii won’t add to that.”

Nintendo did not provide Wii systems or other support for the trial. Jaarsma and Hill have reported no relevant financial relationships. O’Connor discloses consulting fees from Novella and Amgen; ownership or partnership or being a principal in BisCardia; and research support from Otsuka, Roche Diagnostics, BG Medicine, Critical Diagnostics, Astellas, Gilead, GE Healthcare, and ResMed.

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4 Potential Takeout Candidates In The Marijuana Sector

A consolidation wave is sweeping across the marijuana industry, as companies aim to improve their competitive positioning and market share in an industry which offers a lot a promise.

Aurora Cannabis Inc ACBFF 3.43% recently announced a deal to buyMedReleaf Corp MEDFF 3.42% in an all-cash transaction valued at C$3.2 billion.

The proposed combination would mean a total funded capacity of over 570,000 kg per year of high-quality facilities in Canada and Denmark.

Recent Deals In The Space

Aurora itself has been on a buying spree, having bought CanniMed Therapeutics in a C$1.2 billion deal and taken a majority interest in Green Organic Dutchman.

Aphria Inc APHQF 3.26% announced a deal in January to acquire Nuuvera, which works with partners in Germany, Italy and Israel, for C$826 million in cash and stock. Aphria also boughtVancouver Island-based cannabis producer Coast Cannabis for C$230 million in cash and stock earlier this year.

In an interesting turn, Constellation Brands, Inc. STZ 0.07% announced last October its intention to pick up a minority stake in Canopy Growth for C$245 million.

Why This Frenetic Deal Pace

M&A activity has perked up in the space in the last couple of years following the widespread legalizing of medical marijuana. To top it, Canada is poised to make the selling of recreational marijuana legal this year.

Sales of recreational marijuana may fetch Canada $5 billion per year to start with, according to estimates by Deloitte. This number goes up to $8.7 billion, if people who are likely to consume are also accounted.

“I think we’re going to continue to see a lot more (consolidation),” Alan Brochstein, a cannabis industry analyst and founder of 420 Investor, was quoted as saying to Marijuana Business Daily.

In Canada, there could be continued consolidation among licensed producers, Matthew Karnes, Founder and Managing Partner at GreenWave Advisors, an independent cannabis research and financial analysis firm, told Benzinga.

Karnes sees big alcohol companies picking up financial stakes in marijuana companies, with pharma companies waiting on the sidelines.

The momentum in pot stocks is so strong that Canopy Growth is seeking to list its shares on the NYSE under the ticker symbol CGC before the end of May. The company also announced an agreement to buy the 33 percent stake it doesn’t already own in its BC Tweed Joint Venture.

“Continued M&A activity and the billions invested in cannabis companies this year signal a maturation of capital market activity in the cannabis sector,” said Javier Hasse, Benzinga cannabis reporter and author of “Start Your Own Cannabis Business: Your Step-By-Step Guide to the Marijuana Industry.”

“The high level of investments also comes with better conditions to raise money and more comfort among investors,” said Hasse.

4 Potential Targets

Maricann Group Inc MRRCF

Maricann Group, which recently picked up Malta’s Medican Holdings, a licensed operator, has been discussed as a takeout target for quiet some time now. A March 19 article in Deep Divepointed to comments by CEO Ben Ward about a potential interest by an undisclosed party, and the appointment of M&A lawyer Clay Horner as counsel to the special committee of Maricann. The company recently announced a foray into the European market through its deal to buy Haxxon AG, a producer of feminized high CBD cannabis plants. In late December, it stitched up a deal to supply cannabis to Canadian pharmacy chain Lovell Drugs.

Emblem Corp EMMBF 0.85%

Licensed Canadian marijuana producer Emblem that focuses on edible oil and smokeless products could be a viable acquisition target, according to Technical420.com. The reason? Attractive valuation and focus on expansion and cannabis oil.

OrganiGram Holdings Inc OGRMF 1.42%

The company’s recently reported Q1 results showed a record revenue of C$2.4 million and the recent cultivation license expansion it received from Health Canada, which triples its production to 16,000 kg per annum.

Hiku Brands Company Ltd. DJACF 1.11%

The vertically integrated company formed following the merger of DOJA Cannabis Company and Tokyo Smoke has been on a bulking up spree. It recently announced an agreement to buy WeedMD. There have been whispers that Hiku is also being sought out.

Growing Market

The focus of companies operating out of North America could shift to potential targets in South American countries such as Columbia and Uruguay, according to Hasse. The rationale – license holders will be sought out, as these licenses are limited and have already been handed out.

With the imminent Canadian approval of recreational marijuana and more and more U.S. states legalizing marijuana, the prospects for the industry appears bright.

“In the US, we expect 2018 retail sales of $12.2B up from $8.2B in 2016 and reaching $35B by 2022 based on the expectation that every state will be medical only or fully Legal,” said Karnes.

https://bit.ly/2JgTKTr

Aimmune announces new clinical data on AR101 for Peanut Allergy

Aimmune Therapeutics reported additional results from its pivotal Phase 3 PALISADE trial of AR101 for the treatment of peanut allergy at the Congress of the European Academy of Allergy, Asthma, and Immunology 2018 in Munich. Aimmune previously announced that the trial met its primary and secondary efficacy endpoints in the pre-specified primary analysis of the 4-17 age cohort. Additional analyses including adults treated in the study were presented at EAACI. PALISADE enrolled a total of 554 patients ages 4-55. After approximately one year of treatment, clinical reactivity to peanut protein was assessed in an exit double-blind, placebo-controlled food challenge. The trial met its primary endpoint as 67% of AR101 patients ages 4-17 tolerated at least a 600-mg dose of peanut protein in the exit DBPCFC, compared to 4% of placebo patients. The lower-bound of the 95% confidence interval of the difference between treatment arms at the primary endpoint was 53%, greatly exceeding the pre-specified threshold of 15%. Based on these results, Aimmune plans to submit a Biologics License Application for AR101 to the U.S. Food and Drug Administration by the end of 2018, followed by a Marketing Authorisation Application to the European Medicines Agency in the first half of 2019. In the U.S., AR101 has FDA Fast Track Designation, as well as FDA Breakthrough Therapy Designation for peanut-allergic patients ages 4-17

https://bit.ly/2KZiufZ

Myriad Genetics signs definitive agreement to acquire Counsyl

Myriad Genetics announced that it has signed a definitive agreement to acquire Counsyl, a pioneer in expanded carrier screening and non-invasive prenatal screening for $375M through a combination of cash and Myriad common stock. On completion of the transaction, which is expected to close in Myriad’s fiscal first quarter 2019, Counsyl will become a wholly owned subsidiary of Myriad. Myriad estimates that approximately 900,000 carrier screening tests and approximately 1.3M non-invasive prenatal screening tests will be performed in the U.S. during its fiscal year 2018. The company believes these markets will grow at a double-digit rate with approximately 3.5M total reproductive genetic tests performed in the U.S. in fiscal year 2023, representing a market of more than $1.5B.

https://bit.ly/2kxuyK0

How age-enhanced photos of missing children are created

It happens everyday on Facebook, Instagram and in real life—that moment when you see someone you haven’t seen in years. Maybe they’ve gone gray or gained a few pounds, but there’s no doubt you’re looking at that friend from high school or the cousin who moved away when you were both 10 years old. You see the boy you once rode bikes with in the face of the man or the girl who taught you how to French-braid your hair in the eyes of the woman.

Those moments can be both exhilarating and nostalgic. You’re happy to see a person who played an important role in your life but wistful over the time together that’s been lost.

For parents of missing children, a photo of their child as he or she might look today can call up multiple emotions—sadness, anguish, frustration and anger to name a few. But for many, they also bring hope.

Colin McNally, supervisor of the Forensic Imaging Unit at The National Center for Missing and Exploited Children in Alexandria, Va., and three forensic artists on staff, have been tasked with creating age-enhanced photos of missing children. The photos can provide essential information in finding missing individuals.

“It’s a way to bridge a gap in time,” says McNally. “The missing child isn’t going to be just the 4-year-old boy in the photo. He’s going to be 10 years old—maybe 16 years old. He’s going to age and we do everything we can to make that aging appear as authentic as possible.”

Once a parent agrees to the process, McNally’s team tries to gather as many photos and as much information as possible before creating the age-enhanced image.

“Photos and videos of relatives when they were the current age of the missing child are really helpful,” McNally says. “They can help us determine what someone might look like today—the shape of the nose, the skin tone, the hairline. We don’t necessarily take all the traits from the mother or the father and incorporate them into the image. Instead, we try to be as logical as possible. If there are brothers or sisters, who do they look like? If there’s an aunt or uncle who looked like the child when they were young, we take that into account. We try to be as thorough as possible.”

In some cases, though, the source material is limited.

“We may only have one or two photos to use, maybe just of the child, so we have to work with what we have,” says McNally. “We’ll use what we know about general growth principles—wrinkles, sagging eyelids—to age them so it can be more difficult but it’s still possible.”

Once the source material is collected, the forensic artists use a high-resolution photo of the missing child as the base of their image or start from scratch. McNally’s team works on drawing tablets and iMacs, using Adobe Photoshop to create and enhance their work.

“We do color corrections and a few other Photoshop tasks but the majority of our work is actual drawing and digital painting,” says McNally. “It’s a very hands-on process.”

That process—nearly a pencil-to-paper approach—helps humanize the subjects and can keep the artists grounded in their work. “We have an amazing staff who put so much of their own selves into these images,” McNally says. “These are artists with a deep connection to their subjects.”

Before the images are finalized, the forensic artists show them to the child’s parents for their approval.

“They’re the experts on their child,” he says. “They may point something out that we missed, like a small scar or attached earlobes, or they’ll say something about a hairstyle or clothing.”

Once the photo is approved, it’s distributed to the FBI, thousands of law enforcement agencies and numerous private agencies. Since the program’s inception in 1989, NCMEC’s forensic artists have used age-enhancement techniques on more than 6,500 images of missing children and created more than 500 facial reconstructions for unidentified deceased children. Photos of the missing children are updated every two years until the child turns 18, then every five years. McNally says that some of the missing children have had their photos age-enhanced 12 times.

That commitment to the program is reflective of the importance McNally and others place on their profession. “It’s a huge responsibility,” says McNally.

And one that’s essential to NCMEC’s mission. “Any given day staff at the Missing Children Division are working on 5,000 to 6,000 active missing children reports—many of these are considered long-term cases—and the work our Forensic Imaging Team does to age progress long-term missing children is invaluable to our ability in finding these children,” says Robert Lowery, vice president of the NCMEC’s Missing Children’s Division. “It allows us to continually place in front of the public renderings of what we believe the child looks like in a present day setting and ask for their help in reporting any sightings. These images also serve as a reminder to the public that we are still looking for these children and will not stop until they are found.”

Given the difficult nature of searching for missing children, McNally says the challenge in aging someone isn’t just a matter of gray hair and added weight.

“We want to make sure that we’re really capturing the unique characteristics of the child, those little things that might make them recognizable to someone, like the way they smile—do they show their teeth? – or how they position their head—is their face at a slight angle when they speak?” he says. “If we’re right, someone will be able to look at someone who’s in 40s or 50s and see the person they knew when they were in their teens. We’re not just trying to capture what they look like; we want to show who they are. It’s not always possible but sometimes, we can find a small trait that can make all the difference.”

 Explore further: Abducted children: Conventional photos alone don’t aid the search

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Genome’s dark matter offers clues to major challenge in prostate cancer

The dark matter of the human genome may shed light on how the hormone androgen impacts prostate cancer.

Researchers at the University of Michigan Rogel Cancer Center identified a novel gene they named ARLNC1 that controls signals from the androgen receptor, a key player in prostate cancer. Knocking down this long non-coding RNA in mice led to cancer cell death, suggesting this may be a key target for future therapies. The study is published in Nature Genetics.

Current prostate cancer treatments aim to block the androgen receptor to stop cancer growth. But most patients become resistance to androgen-specific therapies, developing a challenging form of the disease called metastatic castration-resistant prostate cancer.

“The androgen receptor is an important target in prostate cancer. Understanding that target is important. This study identifies a feedback loop that we could potentially disrupt as an alternative to blocking the androgen receptor directly,” says study senior author Arul Chinnaiyan, M.D., Ph.D., director of the Michigan Center for Translational Pathology.

Chinnaiyan’s lab identified thousands of lncRNAs in a 2015 paper. Long non-coding RNAs are considered the dark matter of the genome because so little is known about them.

While searching for lncRNAs that might play a role in prostate cancer, the team discovered that ARLNC1 is elevated in prostate cancer relative to benign prostate tissue, which suggests a role in cancer development. And it was associated with androgen receptor signaling, which made it more intriguing.

The researchers found that the androgen receptor actually induces ARLNC1 expression. Then ARLNC1 binds to the androgen receptor messenger RNA transcript. This stabilizes the level of androgen receptor, which then feeds back to sustain ARLNC1.

“At the end of the day, you’re creating or stabilizing more androgen receptor signaling in general and driving this oncogenic pathway forward. We’re envisioning a potential therapy against ARLNC1 in combination with therapy to block the androgen receptor—which would hit the target and also this positive feedback loop,” Chinnaiyan says.

When researchers blocked ARLNC1 in cell lines expressing androgen receptor, it led to cancer cell death and prevented tumor growth. In mouse models, elevating ARLNC1 caused large tumors to form. Knocking down ARLNC1 in mice caused tumors to shrink.

Researchers plan to continue studying the biology of ARLNC1 to understand how it’s involved in prostate cancer progression and androgen receptor signaling.

“We want to further characterize the dark matter of the genome,” Chinnaiyan says. “There are a number of these lncRNAs that we don’t understand how they functionally work. Some of them will certainly be very useful as cancer biomarkers and we think a subset are important in biological processes.”

More information: Yajia Zhang et al, Analysis of the androgen receptor–regulated lncRNA landscape identifies a role for ARLNC1 in prostate cancer progression, Nature Genetics (2018). DOI: 10.1038/s41588-018-0120-1

https://bit.ly/2GWq7RW