Immunology

Surprising discovery could mean one-size-fits-all cancer treatment; researcher says nobody believed this c – OregonLive

Not so long ago, people had trouble even saying the word. They whispered it, with a shudder, or simply called it the C-word.

Treatments have come a long way from the days when a cancer diagnosis was a near-certain death sentence. Survival rates have dramatically increased in recent decades for many types of the disease.

Still, cancer remains fearsome and has resisted all attempts to eradicate it.

Now researchers at Waless Cardiff University have made a surprising discovery about the immune system they believe could lead to a pan-cancer cure. Their work indicates that a newly identified T-cell in the blood can be genetically modified, or reprogrammed, to kill a large variety of cancers without harming healthy tissue.

As the researchers put it in a peer-reviewed paper in Nature Immunology: the targeting of cancer cells would allow immune destruction of malignancies in all individuals.

Thats right -- all individuals.

It raises the prospect of a one-size-fits-all cancer treatment, a single type of T-cell that could be capable of destroying many different types of cancers across the population, Cardiff University professor and lead author Andrew Sewell said in a university statement this week.

He added:

Previously nobody believed this could be possible.

Cancer experts not involved in the research say this is indeed an exciting development, with one calling it a transformative new finding. But they caution its early days. The process has been tested in the laboratory and in animals but not yet in humans.

At the moment, University of Manchester immunology professor Daniel Davis told the BBC, this is very basic research and not close to actual medicines for patients.

Whats unique about this newly discovered T-cell, Cardiff University said in a statement about the research, is that it sports a receptor that can recognize many types of cancer through a molecule called MR1 that, unlike previously known cell-surface molecules, does not vary in the human population -- meaning it is a hugely attractive new target for immunotherapies.

Sewell acknowledges there are plenty of hurdles to overcome, but he says the T-cell discovery opens up an exciting new frontier in the fight against cancer.

Read the research in Immunology Nature.

-- Douglas Perry

@douglasmperry

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Surprising discovery could mean one-size-fits-all cancer treatment; researcher says nobody believed this c - OregonLive

Immunology

Antiviral treatments inspire new kind of cancer drug | Stanford News – Stanford University News

Stanford virologist Jeffrey Glenn did not set out to tackle cancer. For years, he and his lab have worked to develop new ways of battling viruses like the ones that cause hepatitis delta and the common cold but the lessons theyve learned fighting viruses has led to a new kind of drug that has been effective at treating cancer in mice.

Jeffrey Glenn, professor of medicine and of microbiology and immunology, has spent years developing new ways to disrupt normal cellular processes in viruses. This work has led to drugs that can shrink and prevent the spread of tumors in mice. (Image credit: Courtesy of Stanford Medicine)

The underlying idea, Glenn said, is to disrupt otherwise normal cellular processes that both viruses and some cancer cells rely on to grow and spread. Now, tests in mice show that drugs based on that idea can shrink tumors and prevent their spread. The scientists from Stanford, the University of Texas, Baylor College of Medicine and the University of California, San Francisco, published their findings Jan. 22 in Science Translational Medicine.

Finding the new drug could not have happened without an unusual series of events and collaborations that spanned several academic disciplines, said Glenn, professor of medicine and of microbiology and immunology, whose lab developed the compounds with the assistance of Stanford ChEM-Hs Medicinal Chemistry Knowledge Center and support from ViRx@Stanford, an NIH-sponsored Center of Excellence for Translational Research led by Glenn.

Weve been working for many years on potent drugs that we had shown were important for viruses, said Glenn, who is also a member of Stanford Bio-X, the Maternal & Child Health Research Institute and ChEM-H. This is just an important target that hasnt really been appreciated in cancer, and we had the perfect drugs to get this started.

Originally, when they were looking for new ways to stop viruses such as hepatitis delta, Glenn and colleagues thought they might try a sort of end run around the virus and target cell functions that viruses hijack to replicate and spread. That way, even if a virus does infect a cell, thats more or less the end of it.

Glenns approach worked. In 2015, he and colleagues at the National Institutes of Health showed that the new approach prevented hepatitis delta from replicating and releasing new copies of the virus in patients. Later, they modified their strategy to attack enterovirus 71, which is best known for causing hand, foot and mouth disease but can also lead to devastating polio-like paralysis symptoms in children.

Glenn and his lab have continued to develop antiviral drugs, but their focus changed somewhat when their antiviral efforts caught the attention of Jonathan Kurie, a professor of thoracic/head and neck medical oncology at the University of Texas MD Anderson Cancer Center. Kurie had learned that the same cellular processes Glenn and colleagues had successfully shut down was also involved in metastasis. After reading a paper describing the earliest compounds Glenn and his colleagues had developed, he wrote Glenn asking for some of the drug.

I told him we had much better molecules now, and we have known for a long time that they would also work in cancer, Glenn said, and he sent along two new compounds that he had developed with Mark Smith, who heads the Medicinal Chemistry Knowledge Center.

In the new paper, the team shows that their hunch was correct the same drugs Glenn, Smith and colleagues were developing to treat enterovirus can also treat certain kinds of cancers, at least in mice and human cancer cells in a lab dish.

In mouse studies, a drug the team tested reduced how often a human cancer implanted into the mouse in one lung spread to the second lung. With another compound, there were no detectable metastases at all, and both drugs reduced the size of tumors in the first lung. Human breast cancers growing in mice also shrunk in half after just one week of treatment.

The team also looked at an earlier drug developed in collaboration with Kevan Shokat, a professor of cellular and molecular pharmacology at the University of California, San Francisco, and a professor of chemistry at the University of California, Berkeley. That drug, they found, also curbed cell growth in human lung cancer cell lines. The team also gained some insight into which mice and one day, they hope, humans might benefit the most from the new drugs. They found that mice with extra copies of a particular gene responded much better to the drugs.

Now, Glenn said, My goal is to take this all the way to the clinic.

Glenn said the teams success is due in part to a significant shift in the last few years in what his lab does, building on an infectious brew of researchers from a range of academic disciplines.

I think thats the secret thing, having chemists physically in the lab with biologists, virologists and physician-scientists, Glenn said. Weve leveraged the special enabling environment of Stanford to create a unique group that has never existed before here or in academia. Its allowed things to happen that just wouldnt have happened otherwise.

That team is also starting to think about new ways to use their drugs, for example in combination with existing therapies to make them better against drug-resistant tumors, which might be susceptible to a new approach. Weve shown a proof of concept, and I think this could be useful in many cancers.

Additional Stanford authors are Edward Pham, a postdoctoral fellow in Glenns lab and a ChEM-H Physician-Scientist Research Fellow; Kaustabh Basu, a graduate student in chemistry; and research associates Khanh Nguyen and Grace Lam. Researchers from Baylor College of Medicine, the University of California, San Francisco, the University of Texas MD Anderson Cancer Center and the University of Texas Medical Branch contributed to the study.

The research was supported by grants from the National Institutes of Health, the Lung Cancer Research Foundation and the Department of Defense.

To read all stories about Stanford science, subscribe to the biweekly Stanford Science Digest.

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Antiviral treatments inspire new kind of cancer drug | Stanford News - Stanford University News

Immunology

supported scientists reverse HIV and SIV latency in two animal models – National Institutes of Health

News Release

Wednesday, January 22, 2020

Findings represent progress toward an HIV cure.

In a range of experiments, scientists have reactivated resting immune cells that were latently infected with HIV or its monkey relative, SIV, in cells in the bloodstream and a variety of tissues in animals. As a result, the cells started making copies of the viruses, which could potentially be neutralized by anti-HIV drugs and the immune system. This advance, published today in two papers in the journal Nature, marks progress toward a widely accessible cure for HIV.

The new research was conducted by investigators from the Collaboratory of AIDS Researchers for Eradication (CARE) based at the University of North Carolina at Chapel Hill and from the Emory Consortium for Innovative AIDS Research (E-CIAR) in Nonhuman Primates, both funded by the National Institutes of Health. Scientists from ViiV Healthcare and Qura Therapeutics collaborated on the research. CARE is part of the Martin Delaney Collaboratories for HIV Cure Research, the flagship NIH-supported HIV cure research program. The joint efforts of scientists from a variety of specialties made the new findings possible.

A simple, safe and scalable cure for HIV is an aspirational goal that, if achieved, would accelerate progress toward ending the HIV pandemic, said Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases, part of NIH. These new findings help sustain our cautious optimism that an HIV cure is possible.

While consistent antiretroviral therapy (ART) maintains the health of people living with HIV and prevents transmission of the virus, it is not a cure. Developing an HIV cure has been extremely difficult due to the persistence of viral reservoirs, where the virus hides from the immune system. These reservoirs consist of HIV-infected cells containing HIV genetic material that can generate new virus particles if a persons treatment is interrupted. The cells have entered a resting state that they maintain until they are activated to produce the virus. The immune system cannot recognize and kill HIV-infected cells in a resting state, and ART has no effect on them.

Consequently, scientists have been attempting to activate the HIV reservoir so therapeutic agents or an enhanced immune system can recognize and kill the infected cells, eliminating HIV. This strategy is often called kick and kill. Previous attempts to reactivate or kick the HIV reservoir worked well in the laboratory but were either ineffective or too toxic when tested in animals and people.

One of todays reports describes the testing of a compound called AZD5582, which belongs to a class of molecules that have proven safe as experimental cancer therapeutics.

CARE scientists obtained 20 mice with human immune systems, infected the animals with HIV, and then gave them ART that suppressed the virus. Next, the scientists injected AZD5582 into 10 of the mice and a placebo into the other 10.

Within 48 hours, high levels of HIV RNA were detected in the blood of six of the AZD5582-treated mice. HIV RNA levels in resting immune cells of the bone marrow, thymic organoid, lymph node, spleen, liver and lung were up to 24-fold higher in the AZD5582-treated mice than in the controls. This indicated that AZD5582 had activated resting cells in the HIV reservoir throughout the treated mice. The compound did not cause toxicity in the mice or activate their immune systems.

The E-CIAR and CARE investigators also obtained 21 rhesus macaques, infected them with SIV and gave them suppressive ART. More than a year after the monkeys began ART, the scientists gave 12 of them weekly intravenous infusions of AZD5582 for either three or 10 weeks.

The level of SIV increased in the blood of five of the nine monkeys (55%) that received 10 doses of AZD5582 and in none of the three monkeys that received fewer doses. Thus, SIV levels increased in five of 12 monkeys (42%) overall, even as they remained on ART. SIV RNA levels in resting immune cells from the monkeys lymph nodes were significantly higher in animals treated with 10 doses of AZD5582 than in the nine monkeys that did not receive the compound. The investigators found AZD5582 treatment to be safe for most of the monkeys. The scientists did not detect a consistent reduction in the size of SIV reservoir in the AZD5582-treated monkeys, however, suggesting that it may be necessary to pair the compound with another agent to kill activated reservoir cells.

The researchers have begun additional animal studies to determine the best dose and timing of treatment and to be sure AZD5582 activates the reservoirs of many different HIV and SIV strains. It also will be important to test other compounds in the same class as AZD5582 to determine which might work best in humans, according to the scientists. If the results of these follow-up studies are successful, a preliminary clinical trial of treatment with AZD5582 or a related compound in people living with HIV may follow.

This study was led by J. Victor Garcia, Ph.D., Ann Chahroudi, M.D., Ph.D., and Richard Dunham, Ph.D. Dr. Garcia is director of the International Center for the Advancement of Translational Science, an Oliver Smithies Investigator and a professor of medicine, microbiology and immunology at University of North Carolina at Chapel Hill. Dr. Chahroudi is an associate professor of pediatrics in the division of pediatric infectious diseases at Emory University School of Medicineand director of the Emory + Children's Center for Childhood Infections and Vaccines. Dr. Dunham is a director at ViiV Healthcare and an adjunct assistant professor at University of North Carolina at Chapel Hill.

The other new report published today describes how a combination of two agents strongly activated the SIV reservoir in ART-treated rhesus macaques and the HIV reservoir in ART-treated mice with human immune systems. One agent, an antibody called MT807R1, depletes the body of immune cells called CD8+ T cells. The other agent is an engineered protein complex called N-803, a more powerful version of a naturally occurring molecule that activates certain immune cells to fight pathogens.

E-CIAR scientists obtained 35 rhesus macaques, infected them with SIV and gave them ART, which suppressed the virus in 33 of the animals. At least a year after ART began, the scientists gave seven monkeys N-803 alone, 14 monkeys MT807R1 alone, and 14 monkeys both MT807R1 and N-803.

N-803 alone had no impact on the SIV reservoir. MT807R1 alone led to a moderate but significant increase in the level of SIV in the animals blood (their viral load). But the combination of MT807R1 plus N-803 led to a robust and persistent increase in the SIV viral load of all 14 animals even the six in which fewer than three copies of SIV were detected before the experimental treatment began.

CARE scientists at UNC replicated these outcomes in 23 mice that had been given human immune systems, infected with HIV and given suppressive ART.

In addition, investigators demonstrated in cell culture that N-803 could reactivate human immune cells latently infected with HIV, but that adding CD8+ T cells to the culture suppressed the latency-reversing activity of N-803.

Taken together, the findings illustrate that CD8+ T cells play a role in maintaining the SIV reservoir in monkeys. The scientists hope to clarify exactly how CD8+ T cells do this so they can develop a latency-reversing strategy that does not require eliminating all CD8+ T cells and is thus gentler on the body.

This research was led by Guido Silvestri, M.D. Dr. Silvestri is the Georgia Research Alliance Eminent Scholar in comparative pathology, professor and interim chair of the department of pathology and laboratory medicine at Emory University School of Medicine, and chief of the division of microbiology & immunology at Yerkes National Primate Research Center.

CARE is funded by NIAID with additional support from the National Institute on Drug Abuse, the National Institute of Mental Health and the National Institute of Neurological Disorders and Stroke, all part of NIH. E-CIAR is also funded by NIAID with additional support from the NIH Office of Research Infrastructure Programs.

NIAID conducts and supports research at NIH, throughout the United States, and worldwide to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID website.

About the National Institutes of Health (NIH):NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

NIHTurning Discovery Into Health

CC Nixon, M Mavigner et al. Systemic HIV and SIV latency reversal via non-canonical NF-B signalling in vivo. Nature DOI: 10.1038/s41586-020-1951-3 (2020).

JB McBrien et al. Robust and persistent reactivation of SIV and HIV by N-803 and depletion of CD8+ cells. Nature DOI: 10.1038/s41586-020-1946-0 (2020).

###

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supported scientists reverse HIV and SIV latency in two animal models - National Institutes of Health

Immunology

Therapeutic Potential of Dupilumab in the Treatment of Chronic Rhinosi | TCRM – Dove Medical Press

Jean Kim,1,2 Robert Naclerio1

1Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 2Department of Medicine: Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

Correspondence: Jean KimJohns Hopkins Bayview Medical Center, 4940 Eastern Ave, Suite A102B, Baltimore, MD 21224, USATel +1 410-550-0460Fax +1 410-550-2871Email jeankim@jhmi.edu

Abstract: Chronic rhinosinusitis with nasal polyposis (CRSwNP) is one of the most severe forms of chronic rhinosinusitis. CRSwNP is characterized by nasal and facial congestion, loss of sense of smell, rhinorrhea, and post-nasal drip. Treatments have been ineffective at controlling disease recurrence, despite multiple courses of medical and surgical therapies. Oral glucocorticoid therapy is often used to control exacerbations leaving the patient exposed to steroid-induced adverse effects. Thus, there is a clear unmet need for new treatments to achieve better control of the disease. Advances in understanding Type 2 inflammatory processes that occur in about 80% of the Western world patients with CRSwNP have resulted in new avenues for disease control. Biologics in the form of monoclonal antibodies, which target Type 2 inflammation, have helped control the severest forms of atopic dermatitis and asthma. Treatment regimes for CRSwNP now include biologics. In July 2019, dupilumab was the first monoclonal antibody to gain FDA approval for the treatment of CRSwNP. In this review, we summarize the proof of concept clinical trials and Phase 3 trials leading to approval of dupilumab, an anti-IL4 alpha receptor antagonist that blocks the actions of both IL4 and IL13. These studies show that dupilumab is a proven treatment option to control disease. Collective studies demonstrate a high safety profile. Questions arise as to the best use of dupilumab in the context of current treatment paradigms, and for which sub-population of the varied heterogeneous endotypes of CRSwNP patients. Recognizing the high cost of biologics forces the need for cost-effectiveness analysis.

Keywords: chronic rhinosinusitis, nasal polyps, Type 2 inflammation, dupilumab

This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License.By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.

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Therapeutic Potential of Dupilumab in the Treatment of Chronic Rhinosi | TCRM - Dove Medical Press

Immunology

Johns Hopkins Researchers: Climate Change Threatens to Unlock New Microbes and Increase Heat-Related Illness and Death – Newswise

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Newswise The Journal of Clinical Investigation (JCI) recently published Viewpoint articles by Johns Hopkins University School of Medicine professors who warn that global climate change is likely to unlock dangerous new microbes, as well as threaten humans ability to regulate body temperature.

Johns Hopkins Bloomberg Distinguished Professors Rexford Ahima, M.D., Ph.D., and Arturo Casadevall, M.D., Ph.D., M.S., along with William Dietz, M.D., Ph.D., director of the George Washington Universitys Sumner M. Redstone Global Center for Prevention and Wellness, and Susan Pacheco, M.D., associate professor in the Department of Pediatrics at the University of Texas Health Science Center at Houston, authored journal articles relevant to their fields that detail how rising temperatures around the world pose dangerous threats to humanity.

Ahima, director of Johns Hopkins Division of Endocrinology, Diabetes and Metabolism, wrote in the journal that global warming threatens human thermoregulation and survival.

Ahima explains that people generate body heat and have the capacity to regulate their temperature within a few degrees. But as heat waves become more common, more severe, and longer, we expect to see more heat-related illnesses and deaths, he writes.

Ahima cites a recent study that examined global heat-related mortality, pointing out that tropical and subtropical countries and regions will experience the sharpest surge in illness and death stemming from higher temperatures, while the United States and Europe can also expect increases.

Casadevalls article explores the specter of new infectious diseases as a result of the changing climate.

Given that microbes can adapt to higher temperatures, writes the professor of molecular microbiology and immunology, and infectious diseases, at Johns Hopkins schools of medicine and public health, there is concern that global warming will select for microbes with higher heat tolerance that can defeat our endothermy defenses and bring new infectious diseases.

Endothermy allows humans and other warm-blooded mammals to maintain high temperatures that can protect against infectious diseases by inhibiting many types of microbes.

Casadevall cites a particular climate threat from the fungal kingdom.

We have proposed that global warming will lead many fungal species to adapt to higher temperatures, he writes, and some with pathogenic potential for humans will break through the defensive barrier provided by endothermy.

As an example, Casadevall points to the rise of Candida auris, a species of fungus identified in 2009 and called a catastrophic threat by the U.S. Centers for Disease Control and Prevention in 2017.

The nearly simultaneous emergence of Candida auris on three continents, an event proposed to result from global warming, has raised the specter that increased warmth by itself will trigger adaptations on certain microbes to make them pathogenic for humans.

Casadevall says that, while fungi present the most immediate threat, other microbes also adapt to evolving conditions such as temperature. He writes that the conceptual threat originally identified with fungi, and exemplified by C. auris as the canary in the coal mine, applies across the microbial world.

Dietzs article addresses climate change and malnutrition, calling obesity, undernutrition and climate change a syndemic, or multiple epidemics that interact and share common underlying social or economic determinants and policy drivers. In her article, Pacheco discusses climate changes adverse consequences regarding pregnancy and maternal, fetal and child health.

In all four JCI Viewpoint articles, long-term strategies are urged to reduce greenhouse gas emissions and slow the trend of rising temperatures.

SEE ORIGINAL STUDY

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Johns Hopkins Researchers: Climate Change Threatens to Unlock New Microbes and Increase Heat-Related Illness and Death - Newswise

Anatomy

How Greys Anatomy and Station 19 Will Sync Up for Its 2020 Crossover – Variety

Nearly a year after Greys Anatomy made television history by becoming the longest-running primetime medical drama, the ABC series is taking on a new challenge on Thursday, Jan. 23: becoming more immersed with its spinoff, Station 19, for a more unified two-hour weekly block.

But while there are natural ties between the two dramas, trying to line up storylines, share casts who film on different lots and find the right balance for the shows is a constant juggle.

It was for sure the greatest challenge of my career and everyone around me has been saying the same thing, Krista Vernoff, who runs both shows, tells Variety. [Station 19 director/executive producer] Paris Barclays walking around saying, I dont know why we dont have documentary crews rolling. This is crazy what were doing.

Here, Vernoff breaks down how the worlds of Station 19 and Greys Anatomy will collide.

Syncing the Shows

Much like the first Greys Antomy spinoff, Private Practice, which ran from 2007-2013, Station 19 was launched as backdoor pilot on the mothership in 2018. Though there was an obvious overlap Greys Anatomys Ben (Jason George) became a firefighter and moved to Station 19 but remained married to Greys Anatomys Bailey (Chandra Wilson) the two shows remained fairly separate.

But with the request for Greys Anatomys 16th season and Station 19s third year to be more interconnected, Vernoff started from the ground up.

My top priority was character work and finding stories that excited me, she says. So I had to start at the beginning, which is falling in love with the world of first responders, the characters, figuring out what I still wanted to know about them and what I wanted to discover.

And once those things made themselves known, she realized that the relationships, both platonic and romantic, would help serve to unite the shows. Thats where you start in Shondaland, she says.

Complicating matters was an avalanche of insanity: although the shows needed to be on the same timeline, Station 19 was held until midseason. That meant Greys Antomy was tasked with setting up new relationships, like the unexpected romance between Station 19s Vic (Barrett Doss) and Greys Anatomys Jackson (Jesse Williams), while not completely spoiling Station 19s cliffhangers.

Production-wise, Station 19 was a few weeks behind the mothership in episode number, but the Greys Anatomy hours were airing much sooner which meant the actors on Station 19 were filming far ahead on relationships that had just begun to develop on Greys.

[Doss and Williams] were playing scenes on Station 19 without knowing what happened really between them on Greys Anatomy the eight episodes prior, Vernoff recalls. Theyre calling me and going, Were having this fight, but what has happened? How close are we? How long have we been together? And the two writers rooms, side by side, have some answers to those questions.

The unusual schedule meant that the writers arced out Greys Anatomy significantly deeper into the season than they normally would, Vernoff says. And its made negotiating crossover guest stars and their schedules more complex than years past.

When we book a guest star for Station 19, we have to pin those guest stars and make sure theyll still stay available for the episode of Greys Anatomy that wont shoot for two months, Vernoff explains. And they cant change their hair [in between]!

Though a number of other series share combined universes including the CWs Arrowverse and NBCs trio of Chicago shows from Dick Wolf the sheer scope of connectivity has made this process an unparalleled challenge. For guidance, Vernoff has leaned on her former Shameless colleague John Wells and Greys Anatomy creator Shonda Rhimes.

John Wells, who has sort of seen and done everything, just has a way of helping me remember that its not brain surgery, Vernoff says. It just quiets me down a little internally. Shonda just laughs and thinks this is delightful to watch me go through [this].

Vernoff was a long-time producer on Greys Anatomy before she took the reins as showrunner, but her tenure on Station 19 is newer. The show itself is still in its early stage, and this is her first time running it.

Theres not a model for it because of the particular set of circumstances, she says. Its a new showrunner [for Station 19] in Season 3 and because of the amount of merging of the two worlds that weve been asked to do. What I do is marvel at the way the cast, crews, producers and writers have risen to this extraordinary task. The fact is that weve sort of been asked to accomplish the impossible and we feel like were pulling it off.

Combining the Worlds

When it came time to craft the major crossover that kicks off with Station 19s season premiere, Vernoff was faced with creating a story that would simultaneously resolve Greys Anatomys fall finale cliffhanger and Station 19s second season finale cliffhanger, introduce potential new viewers to the world of Station 19, and move the story ahead to match the timeline of the mothership.

The challenge was to honor and respect the fans whove been watching for the first two seasons [of Station 19], Vernoff says. Re-piloting would be easy. If Id been able to bring Station 19 back simultaneous to Greys Anatomy, I wouldnt also be faced with bridging the nine-week timeline. So it was a challenge; it was daunting.

But, Vernoff says she is excited by where it landed.

I feel like we I feel like we touched on almost every cliffhanger that the show left in in season two, she continues. We went deeper into some of those cliffhangers; we handled some of the others in one line of dialogue. And we created an exciting hour of TV, where you meet these firefighters doing what they do. What they do is thrilling and completely different than what surgeons do. I wanted to invite you into a world to have you meet these people fresh, if you were fresh, and be excited to see them again if you werent.

Ending Greys Anatomys 2019 run with a car crashing through Joes (Steven W. Bailey) bar also served as a natural bridge into Station 19.

The executives at ABC were so excited when we pitched the car through the wall, Vernoff says. They understood instantly what that did: It very organically asked people to come watch the other show to see our [Greys] people get rescued. And they were so excited by that concept.

The scribe also praised executives for not artificially forcing storylines or actors to appear on either show that dont genuinely fit in with the plot the writers are trying to tell. The network has been extremely supportive and extremely respectful, she says. They understood the size of this challenge. There has not been a lot of pressure to force dynamics.

With network production schedules a whirlwind under the best of circumstances, the shows werent able to add days to their calendar to allow for more wiggle room for series regulars to hop between shows. (Though, with a number of series regulars from each show recurring on their sister series, the producers were granted a little bit of extra financial support to help accommodate that burden.) Vernoff credits the Greys Anatomy and Station 19 line producers with keeping the shows schedules running smooth amidst the madness.

New Players, New Rules

Although the Shondaland universe has been very good about going back to actors they liked Joshua Malina, Katie Lowes, George Newbern and Bellamy Young appeared on both Greys Anatomy and Private Practice, while Scott Foley and Jeff Perry had big arcs on Greys, prior to starring on Scandal the new combined universe means fresh ground rules for guest stars.

I discussed with Linda Lowy and her extraordinary casting teams that if theyve appeared on Greys Anatomy in the last two seasons, if theyre [going to be] on Station 19, they have to be playing the same character, Vernoff says. I checked that with Shonda because I was like, What are we doing here [with rules]? And Shonda basically said, You see the same actors over and over on Law & Order playing different characters, it is what it is. Weve been on the air for 16 years, weve used every actor in Hollywood, let the actors work.

However, as interconnected as the shows are, they still have to be created for a viewer of either drama to be able to have a complete story if they choose to just watch a single show per week.

The best experience is going to be to watch both, Vernoff notes. Youre going feel like you got more stories if youre watching both like you have a more complete world. But heres another angle to this challenge: These shows only air together on ABC on Thursday nights. When you stream them, youre not watching them this way. Overseas Greys Anatomy is in a lot of markets that Station 19 isnt [in yet].

This means that each hour of each show needs to be a whole story [by] itself, she continues. And when merged with the other show, when there are crossover elements, it needs to feel like, Oh, thats a bigger movie. So I had to make two-hour movies, [but] if you only watched [either the first or last] hour, you felt totally satisfied.

Ongoing Effects

Crossovers will continue throughout the season, though on a much smaller scale.

Shifting Greys Anatomy from its Thursdays at 8 p.m. time slot to 9 p.m. also allowed for Station 19 (which now airs at 8 p.m.) to introduce characters who will go on to be patients either the same night or sometimes the following week, Vernoff says.

Weve got an episode [of Station 19] where weve got a camping trip and theres an incident, Vernoff previews. And the whole hour of TV is this really fun, funny, delightful episode of Station 19 that culminates with a patient who we care about and will follow through on [over at] Greys Anatomy.

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How Greys Anatomy and Station 19 Will Sync Up for Its 2020 Crossover - Variety

Anatomy

BNI Shoreline Jan. 28th Meeting Presentation Anatomy of a Divorce – Zip06.com

Date: Tuesday morning, January 28, 2020 @ 7:15amTopic: The Anatomy of a Divorce: Review of Court File Speaker: Divorce Attorney Cynthia Sheppard of Riccio & Beletsky, LLCAttorney Sheppard will access online a divorce matter shes handling and will go through the following pleadings and motions available for public access: 1) Divorce complaint including summons and automatic orders2) Pendente Lite motions3) Divorce judgment and incorporated Separation Agreement4) Post-Judgment MotionsFREE! Visitors welcome as guests of a member. To be invited, contact BNI PR at BNI.Clinton.PR@gmail.com or BNI.Clinton@gmail.comBNI Business Network International is the worlds leading business networking and referral organization. BNI Shoreline (Clinton) Chapter meets every Tuesday morning from 7:15am to 9am.Any of our professionals will speak, free of charge, to civic, philanthropic and/or affinity groups. For more information or a list of topics, please contact BNI PR at BNI.Clinton.PR@gmail.com

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BNI Shoreline Jan. 28th Meeting Presentation Anatomy of a Divorce - Zip06.com

Anatomy

Stars Who Almost Played Other TV Roles on Grey’s Anatomy, NCIS, Lost, Gilmore Girls, Friends and Other Shows – TVLine

Somewhere, theres an alternate universe where Rob Lowe practiced medicine not on Code Black, but as Greys Anatomys McDreamy. Where Katie Holmes played Orange Is the New Blacks Piper Chapman. And where Game of Thrones Iwan Rheon almost played Game of Thrones Jon Snow?!

The TV landscape is littered withalmost-casting stories the many cases in which a major small-screen role was nearly filled by someone else. If some of them had come to fruition, we could have seen Houses Lisa Edelstein slipping into Carrie Bradshaws Manolo Blahniks, orParks and Recreations Chris Pratt sporting a Buy More name tag.

In some cases, actors didnt land the lead roles for which they originally auditioned, but they did pop up as other characters on those same shows. Such was the case for Smallvilles Jensen Ackles,Arrows Anna Hopkins andThe Affairs Colin Donnell, to name a few.

In the attached photo gallery, weve gathered more than 20 almost-casting stories from TV shows past and present, all of which got us wondering about how those series would play out with different stars. (Note: We of course havent included every case of an actor missing out on a certain role, but simply a selection that struck us as particularly fun or curious. Admit it: You want to know what True Blood would be like with Benedict Cumberbatch as Bill, right?)

Scroll through the attached gallery or click here for direct access to see the aforementioned almost-castings and many more, then drop a comment with the stories that intrigue you most!

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Stars Who Almost Played Other TV Roles on Grey's Anatomy, NCIS, Lost, Gilmore Girls, Friends and Other Shows - TVLine

Anatomy

You’ll Worry About Everyone in ‘Station 19’-‘Grey’s Anatomy’ Crossover – TVInsider

Regarding the cliff-hanging return of Grey's Anatomy: "Watch with a whole box of tissues!" So says showrunner Krista Vernoff, who now holds the same job on companion series Station 19.

The Grey's fall finale closed with a car crashing through the wall of Joe's Bar, the watering hole frequented by staff from both Grey Sloan Memorial Hospital and the firehouse three blocks away. When Thursday's crossover kicks off on the new season of Station 19 (the Seattle-set shows have switched timeslots), there's a very real danger the building will collapse.

The firefighters hustle to save team members Ben Warren (Jason George) and retired captain Pruitt Herrera (Miguel Sandoval), along with a batch of doctors including Jackson Avery (Jesse Williams), Levi Schmitt (Jake Borelli), and an injured Taryn Helm (Jaicy Elliot), who are all trapped inside.

"The bar is underground, and the structure is unstable," Vernoff notes. "Arguably, we could worry about everyone [in there] which includes the responding [firefighters]."

(ABC/Eric McCandless)

You might also worry about someone outside. When we last saw Miranda Bailey (Chandra Wilson, above), the surgery chief and wife of Ben had suffered a miscarriage. Now she waits to see if she will lose her husband as well.

Looking ahead on Station 19, Vernoff says to expect a darker, grittier tone, "with more death and chaos." She also promises flashbacks illuminating who these heroes are "and what makes them want to run toward fire."

Station 19, Season Premiere, Thursday, January 23, 8/7c, ABC

Grey's Anatomy, Thursdays, 9/8c, ABC

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You'll Worry About Everyone in 'Station 19'-'Grey's Anatomy' Crossover - TVInsider

Anatomy

Anatomy of an advertisement: The story behind Greenpeace’s terrifying turtle extermination – gotech daily

After the impact of the rank tan palm oil campaign, Aardman and Greenpeace unveiled Turtle Journey last week a heartbreaking stop-motion animation that encourages people to take action against the maritime crisis.

The campaign brought together Greenpeaces strength as an activist with the famous creative from Aardman Animations, the creators of Wallace and Gromit and famous voices such as Olivia Colman, Dame Helen Mirren and David Harbor from Stranger Things.

The drum went behind the scenes to find out how the major project came about.

One of Greenpeaces main concerns has been to raise public awareness of the problems the worlds oceans face as a result of climate change. What started as a Twitter joke in 2018 led David Harbor from Stranger Things to dance with penguins in Antarctica to raise awareness of their plight.

https://t.co/29mTHvLYOA

Here is a petition to create the largest protected area in the world. @ Greenpeace has 1 million characters.

Lets give them 1.8.

1.8 million.

1 for each square kilometer proposed

for the guins.

here i dance with them,

as promised.

they have no netflix. @ greenpeace? pic.twitter.com/jjLBk2XOIr

David Harbor (@DavidKHarbour), February 20, 2018

The same year, Radiohead singer and environmental activist Thom Yorke released a single in support of Greenpeaces mission to protect the Antarctic Ocean from the effects of climate change, commercial fishing and human interference. The message of the ominous instrumental was broadcast on the London Marble Arch.

To celebrate World Ocean Day 2018, people from 25 countries and all seven continents have painted blue and made waves of people to demonstrate their support for the protection of the oceans.

Happy World Oceans Day! Together we are committed to a rescue plan for the oceans that would create huge new marine reserves around the world. If it

Despite all the steps Greenpeace has taken to bring this message home, Chris Till, deputy director of fundraising at Greenpeace, admitted that it was not as effective as it would have liked.

If you spoke to most people, you would have no idea that the United Nations (UN) is in the process of negotiating a major new global ocean treaty, he said on Earth.

The Greenpeace team recognized that it needed to do something to break out of its support bubble and spread its message across the world.

Ahead of the UN negotiations on the World Ocean Treaty in March, Greenpeace wanted to draw up an action plan and file a petition to ensure that the treaty was brought to life.

Greenpeace also fought peoples resistance to shocking shots. For decades, bodies like Comic Relief and Children in Need have relied on painful footage to get people to donate. However, recent reports claim that hearts are persistent against excruciating content.

In preparing this campaign, Greenpeace quickly came to the conclusion that emotional animation would be a more effective tactic.

As a society, we quickly get used to pictures that used to be shocking, Till admitted. Animation can be different because it enables people to connect emotionally. You can see yourself in history as it is difficult in the real world.

The team had also learned a lesson from its highly successful rank tan campaign. Greenpeaces emotional story with actress Emma Thompson, who has summed up the harsh reality of palm oil and the effects of its cultivation on Earth.

(embed) https://www.youtube.com/watch?v=TQQXstNh45g (/ embed)

With the help of Iceland, which converted the video for its Christmas advertising, the film brought the topic of palm oil into the popular mindset. This in turn encouraged more people to take this into account when buying food and products.

It really put it in the public eye, said Till. And we knew we had to do something similar in our next campaign to really get people talking and take action against the maritime crisis.

Around the time Greenpeace was designing this campaign, Aardman Animation contacted the company to let them know that it was interested in working with the organization.

It just felt perfect, said Till. We were looking for something that would create a strong connection with our audience, and Aardman is brilliant at it. Since we are both familiar names, it would help to get the word out.

After market tests for more extensive ocean communication, the study convinced the team to focus on turtles. Till argued that while Greenpeace talks about whales, they are received differently around the world. In contrast, turtles have a universal appeal.

The Greenpeace team then talked to the Aardman producers about what they wanted to get out of the film, what reaction they wanted, and soon they started working on a job.

This was then used to reach Aardmans director network, which asked 12 questions about what this film could look like. They were brilliant and varied and offered many different ways of dealing with a potentially very difficult topic, said Till.

We knew we wanted the animation to be instantly recognizable as Aardman, he said of Greenpeaces creative vision. We wanted something that was immediately accessible and that took people on a real emotional journey.

Till explained that emotional shock was a phrase that kept popping up in their discussions, as Greenpeace knew that while it is good to provide facts and figures, it is not always enough to clarify the case or that To get people to prioritize the problem .

According to Till, the decision for the director was a fun, if painful, decision-making process, in which the team refined and restricted ideas until they chose Gavin Strange.

Just hearing Gav talk about his vision showed that he really got to the heart of the problem, said Till. He not only understood it intellectually, but also had a strong emotional connection to history. As an added extra, Strange read it to boost its pitch, along with a real musical mood.

With the first premise agreed in mid-September, Aardman started animation while Greenpeace stayed in close contact all the time, with Till admitting that the main producer was his primary speed dial.

We had to do it right because its a big story to tell in a short video, he said. Due to the process of stop motion animation, the script, sentence and characters had to be signed off before the start of the filming, since all changes become more difficult, so to speak, once they have been set in sound. When you go back and revive, you lose days and a lot of effort.

Due to the nature of the stop motion function, the team used an animated storyboard instead of a script. In this way, they were able to calculate the timing of each shot to a fraction of a second.

One problem was how the characters should be presented, since they had to agree on the exact type of turtle to focus on the color of the shell. And this had to be reconciled with the story itself to ensure that each character was scientifically correct, with clear distinctions and personalities.

The team then had to keep to a tight schedule to ensure that it was ready by January to have enough airtime to make waves before the final outcome of the United Nations maritime treaty in March was known.

To manage the team. Aardman, who worked individually on recordings, attached boards with pictures of the individual recordings on the walls so that they could move between the studios to show how it worked.

In total, the stop motion recording took six weeks a tedious process, considering that the total length of the film is just under two minutes.

(embed) https://www.youtube.com/watch?v=kVDciiQT4c4 (/ embed)

Well-known voices include Olivia Colman, Dame Helen Mirren and David Harbor as well as Bella Ramsey from Game of Thrones, Jim Carter from Downton Abbey and the comedian Ahir Shah.

In addition to the scientific data and facts, Greenpeace also has an extensive telephone directory of famous stars who want to support their campaigns.

Colman really did everything, said Till of the Oscar winners performance. She took the time to take the latest The Crown recordings and deliver them in less than an hour. She just got it.

Till said he was in Harbors ear while he was recording when the actor was working remotely in New York. He said the whole process was interesting to experience as each famous voice approached the shoot in different ways.

We dont want to be accused of being hyperbolic, Till explained why, alongside the video, a report was released about the threats that tortoises face in the real world. We know that as a lobby and science organization, it is vital for us to show that science is there to underpin this story.

Turtles Under Threat reports that six out of seven sea turtles are on the Red List of the International Union for Nature Conservation and are threatened with extinction, even though the creature has crossed the worlds oceans for more than 100 million years.

Unfortunately, our film is a fiction, but what happens to our turtle family in this film unfortunately happens to real turtles around the world, said Till dejectedly.

The campaign has not yet started last week. But Greenpeace said it had already collected over 280,000 signatures not far from its 300,000 goal.

(embed) https://www.youtube.com/watch?v=cQB4RAZVMf4 (/ embed)

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Anatomy of an advertisement: The story behind Greenpeace's terrifying turtle extermination - gotech daily