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I'm not sure why this is a theme of the blind pumpers and their peanut gallery -- I don't feel threatened. I'm a little innerved by the ignorant assumptions, lack of awareness, and extreme defensiveness, but not threatened. You could say that I'm threatened by the lack of truth or objectivity here, but that's more about principle, not fear.
This isn't about me, and this isn't about you. Maybe we can all just keep it real and have a factual and rational-based discussion. Let's be productive. There is nothing wrong with a little forward looking discussion of the potential -- but don't just dump a load of BS on this board. Let's take some baby steps and ease into the still-wildly-uncertain future. I think the company is probably doing some good things behind the curtains. I look forward to favorable responses from the FDA, Europe/UK, and hopefully positive data from the labs in the foreseeable future...once the regulatory hurdles are cleared. We still have the r/s and financing obligations directly ahead, so don't turn your backs on that either.
There is no doubt...no doubt whatsoever that we will not be delisted. Take it to the bank!
The boys at Nasdaq were told the game plan and the gave us an extension. With the continued progress we would be given another extension if it were needed
But, I am not impressed with misleading information.
Did I miss something? Dern it, those censors irk me.
You can certainly learn about a lot of things by reading the posts on this board
Just sold my lot I purchased at .18 for .265. Let it roll or let if fall...
Continued education material:
https://listingcenter.nasdaqomx.com/Material_Search.aspx?cid=37&mcd=LQ
- What is Nasdaq's compliance process for companies failing to meet the $1.00 minimum bid price requirement?
If a company trades for 30 consecutive business days below the $1.00 minimum closing bid price requirement, Nasdaq will send a deficiency notice to the company, advising that it has been afforded a "compliance period" of 180 calendar days to regain compliance with the applicable requirements.
Thereafter, if such a company does not regain compliance with the bid price requirement a second 180-day compliance period may be available. A company listed on the Nasdaq Capital Market may be eligible for an additional 180-day compliance period if it meets the market value of publicly held shares requirement for continued listing, all other initial inclusion requirements for the Capital Market, except for the bid price requirement, and provides written notice that it intends to regain compliance with the bid price requirement during the second 180-day compliance period, by effecting a reverse stock split if necessary.
Similarly, if a company listed on the Nasdaq Global Select Market or Global Market company is unable to comply with the bid price requirement prior to the expiration of its 180-day compliance period, it may transfer to the Nasdaq Capital Market, so as to take advantage of the additional compliance period offered on that market. Such a company must meet the $1 million market value of publicly held shares requirement for continued listing, and all other requirements for initial listing on the Nasdaq Capital Market (except for the bid price requirement), and provide written notice that it intends to regain compliance with the bid price requirement during the second 180-day compliance period, by effecting a reverse stock split if necessary. If a company does not indicate its intent to cure the deficiency, or if it does not appear to Nasdaq that it is possible for the company to cure the deficiency, the company will not be eligible for the second compliance period.
A Nasdaq Global or Global Select Market company that is in the Hearings Process for the minimum $1.00 bid price requirement can submit a transfer application ONLY if it meets the continued listing requirement for market value of publicly held shares and all other initial listing criteria (except initial bid price) for the Capital Market. If the application is approved, the company's securities will be transferred to the Capital Market. The company will be granted the balance of the second 180-day compliance period to resolve its $1.00 bid price deficiency
- How does a company regain compliance with the minimum bid price requirement?
In order to regain compliance with the minimum bid price requirement, a security must have a closing bid price of $1.00 or more for 10 consecutive business days.
Although an automated computer system tracks each company's bid price on a daily basis, it is suggested that the company contact its Listing Qualifications Analyst via email continuedlisting@nasdaq.com or by phone at +1 301 978 8008 when it believes compliance has been achieved. Nasdaq will provide all compliance determinations, in writing, to the company.
Under certain circumstances, to ensure that the company can sustain long-term compliance, Nasdaq may require the closing bid price to equal or to exceed the $1.00 minimum bid price requirement for more than 10 consecutive business days before determining that a company complies. In determining whether to look beyond the 10 days, Nasdaq will consider, but is not limited to, the following factors:
Margin of compliance (the amount by which the price is above the $1.00 minimum standard);
Trading volume (a lack of trading volume may indicate a lack of bona fide market interest in the security at the posted bid price);
The market maker montage (e.g., if only one of eight market makers is quoting at or above the minimum bid price and the quote is only for 100 shares, then added scrutiny may be appropriate); and
The trend of the stock price (is it up or down?).
- What happens if a company does not regain compliance with the minimum bid price requirement during the compliance period?
If a company is unable to resolve its bid price deficiency during the applicable compliance period, Nasdaq Staff will issue a delisting letter. At that time, the company may request a hearing before a Hearing Panel, which will stay the delisting.
The company will have the opportunity to present its plan to regain compliance to the Panel. This plan of compliance should include implementation of a reverse stock split in the near term. In appropriate cases, and so long as a company commits to implementation of a reverse split within 180 days of the delisting notification, Panels may also consider other factors, such as the company's fundamental financial strengths and weaknesses, the overall market, the company's historical bid price, and impending disclosures, corporate actions and strategic business plans that the company believes may impact its bid price.
You really have no idea what you are talking about. They are not a benevolent organization in a charitable system. It's a highly regulated and standardized business and industry, for crying out loud. There is no 'A' for effort, bonuses for giving it the old college try, etc. I suggest you do more research before posting wild assumptions. Here is some real information for your education:
https://listingcenter.nasdaqomx.com/assets/continuedguide.pdf
Note: The company requested to be moved to the Nasdaq Capital Markets because the listing requirements are lower.
In the face of this sentencing and a mere 3 states away (but a world apart), a big, fat, disparate slap:
http://finance.yahoo.com/news/christie-faces-scrutiny-over-gifts-052600259.html
Christie faces scrutiny over gifts from Cowboys owner
Governor’s aides said gifts acceptable under state policy
The Wall Street Journal By Josh Dawsey, Andrew Tangel and Ted Mann
New Jersey Gov. Chris Christie accepted a plane ride to Dallas and a seat at a Cowboys playoff football game in a luxury suite from team owner Jerry Jones, who has a business relationship with the Port Authority of New York and New Jersey, officials said.
Mr. Christie’s aides said the gifts were acceptable under state policy, which allows the governor to take gifts from “relatives or personal friends that are paid for with personal funds.” Since the governor took office in 2010, Messrs. Christie and Jones have bonded over the governor’s love for the Cowboys, his favorite team since boyhood.
“Governor Christie attended the game [Sunday] night as a guest of Jerry Jones, who provided both the ticket and transportation at no expense to New Jersey taxpayers,” said Kevin Roberts, a spokesman for the governor.
The Cowboys, along with the New York Yankees and Checketts Partners Investment Fund, are owners of Legends Hospitality, the operator of a soon-to-be-opened observatory of the 104-story One World Trade Center—operated by the Port Authority, which Mr. Christie jointly controls with New York Gov. Andrew Cuomo. Financial terms of the deal haven’t been publicly disclosed.
A Port Authority spokeswoman said Legends was selected following a competitive public procurement process in 2013. The observation deck is expected to generate $875 million in revenue over 15 years for the Port Authority through a combination of base rent and shared net income, the authority spokeswoman said.
Randy Levine, president of the Yankees and a board member of Legends, said the bidding process was fair and didn’t involve political or personal favors, and that Messrs. Christie and Cuomo weren’t involved.
“To try and tie one to the other is silly,” he said. Mr. Levine said New York officials at Legends were the primary officials on the bid and that Mr. Jones wasn’t involved, even though his family is a “significant” business owner in the company. He declined to say what percentage.
Mr. Christie’s acceptance of a gift from a business owner with ties to the Port Authority comes amid calls for reform at an agency rocked by the George Washington Bridge scandal and other problems in the past year. Messrs. Christie and Cuomo recently vetoed a legislative overhaul of the authority and instead pushed forward with a set of changes written by a panel that they appointed.
The authority is currently wrestling with how to revise its conflict-of-interest standards for its board of commissioners.
Given the authority’s recent problems, Jameson Doig, an emeritus Princeton University Professor who wrote a book about the Port Authority, said Mr. Christie’s relationship and receiving of gifts from Mr. Jones “sends the wrong signal if Christie or any of his top aides appear to have a conflict of interest in their relationship to the Port Authority.”
“The governor ought to do all he can to avoid that conflict of interest or the appearance of a conflict,” said Mr. Doig, a member of a panel on overhauling the agency’s ethics rules and structure.
Ethics rules differ state by state. Former New York Gov. David Paterson ran into problems when he accepted tickets for the World Series and was fined about $62,000.
Mr. Christie operates under a code of conduct established by executive order by former Gov. James McGreevey. The rules are different for state lawmakers who can’t accept gifts that create a conflict of interest.
The governor’s office didn’t answer questions about who paid for travel for security during the Dallas trip or about how much the gift was worth. Aides said he doesn’t have to disclose personal gifts from friends to the State Ethics Commission, and he never has, according to financial disclosure forms.
Mr. Christie’s love for the Cowboys has drawn attention in recent months as the team has outperformed rivals such as the New York Giants, Philadelphia Eagles and the New York Jets, which have New Jersey fan bases. Mr. Christie has taken to sports radio shows to defend his fandom after critics denounced televised images of his elation at Cowboys’ victories, including Sunday’s 24-20 win over the Detroit Lions.
The trip to Dallas was the latest in a series of excursions with high-profile sports and entertainment figures. He has roamed the sidelines of a Notre Dame University football game and stayed overnight at the Hamptons mansion of rocker Jon Bon Jovi.
Mr. Christie’s aides declined to say whether he paid to attend the Notre Dame game. A spokesman for Notre Dame didn’t know but said he was on the sidelines. Mr. Christie has described himself as a friend of Mr. Bon Jovi.
The state’s ethics laws allow Mr. Christie to take gifts from personal friends, said Susana E. Guerrero, executive director of the state’s ethics commission. There is no explicit definition of what constitutes a personal friend.
“He sort of went as a personal thing,” Ms. Guerrero said. “They can accept gifts from friends.”
Rich Dalrymple, a spokesman for Mr. Jones, said early on Monday that 30 or 40 people attend games in the Cowboys’ owner’s suite, from athletes to entertainers to public officials and that he couldn’t say how much sitting in the box was worth.
Robert Tuchman, who plans luxury getaways for CEOs with his company GoViva, including trips to the Super Bowl, said “people would pay $25,000 to $30,000 per person” for such a trip like Mr. Christie took, including travel.
Mr. Christie said Monday on the radio that he would like to attend the Cowboys playoff game in Green Bay, Wis., this weekend.
try to be a little more positive in the new year. If not, stay away
Not true; you have no clue. eom
First, I would like to apologize for calling you a cheerleader. It was an errant assumption based on your needling into something that didn't involve you. While there are many, many delusional cheerleaders who attack any critical post that doesn't support their fairytale, you are not one of them.
Secondly, I told you I wasn't going to waste my time explaining to you what I opined on regarding another poster. However, having misjudged you, I will retract that. As far as the cutting and pasting comment, someone posted, verbatim, a definition (#msg-109430796) supplied by Wikipedia and made no reference of it. That was it. I was being helpful.
Now, are you challenging me on a source as to another, unrelated post (#msg-109541619), in which I responded "no" to several remarks? If so, I will only say that they are so ridiculous that they don't really need any more explanation. But you want an answer, so here it is. Tissue studies at this stage would be for toxicology...not for efficacy. That should be the end of it. But if I am wrong, and they are looking for inflammation markers to furnish to the FDA for some form of efficacy, a good 'tissue' result would still not virtually mean a successful PhII, nor would it even remotely equate to a drug approval. I feel that, given my prior experience investing in biotech, that that is simple common sense. Finally, as far as them having a partner, would that be a material event? If so, would they be required to announce that? The answers: Yes and Yes.
Regarding your other points: I am not trying to be clever for the sake of being clever; I am not being negative per se -- it is a reaction to the ignorant and misleading posts I sometimes encounter. If I thought those posts were simply innocent but misinformed, I would take a different approach. But there is a cult-like atmosphere of exaggerated, false, and reckless babble, which is both whimsical and deceptive. Therefore, I feel compelled to act. I intend no harm. I'm not sure if the boisterous and blind longs intend harm or not either, but given the steady, withering decline of the stock, it appears to be a consequence. They have no hold on reality of what has been taking place, and what is really at risk.
Sorry coach-if you need me to help you search something as straightforward as that (finding the biotech values board), it isn't worth debating you over anything more challenging. Maybe if you would have taken a more reasonable approach with me, I would have worked with you, but you're obviously too petty and defensive regarding RCPI.
Ps. I am not a believer in censorship, so don't put that on me.
Rock Creek better hurry-up, or their entire platform will be obsolete (of course, I say that in jest -- we know how easy it is to get carried away with new medical approaches and the dreams of wealth that accompany it, don't we?):
http://www.thenewstribune.com/2014/12/22/3534676/early-results-promising-as-a-tacoma.html
Early results for treatment of inflammatory diseases promising for Tacoma-born biotech research company
BY C.R. ROBERTS
Staff writer December 22, 2014
It looks like water, it feels like water and it could change the way medical science attacks disease.
Quietly, slowly, a revolution continues to simmer on the east side of the Thea Foss Waterway at a Tacoma-born biotechnology research firm called Revalesio.
And the world may never be the same.
Founded in 2006 by Tacoma native Eric Russell, the privately held firm has been conducting research into the possibilities offered by bubbles, tiny “nanobubbles” suspended in a saline solution.
Count the several hundred academic papers prepared by researchers worldwide, with 30 to 40 projects being conducted at any one time.
Count the patents so far: 278.
Count the number of diseases that Revalesio’s product, RNS60, might affect: asthma, multiple sclerosis, Parkinson’s disease, dementia, myocardial infarction, endometriosis, eye problems, wound treatment.
And more.
BEGINNINGS
Ten years ago, Eric Russell, grandson of the founder of the investment advisory firm Frank Russell Co., heard of a man in Texas who had developed a process using oxygen-rich bubbles suspended in water with hydroponically grown plants.
Russell secured the rights. The process seemed to increase the yield of vegetables.
But there was something else.
In March 2006, he met with three experts who had inspected his “FoodMachine,” which incorporated the oxygen-bubble technology.
Russell recalls the conversation, when one of the men said the yield increase was amazing, but more significantly there was not just a reduction in plant disease, there was no disease. None.
Russell asked if there might be an effect on human health.
“Nobody in the room had an answer,” he said. “For me, that’s a challenge.”
Within two months, Russell had contacted a Stanford immunologist who tested the water and found it to be, Russell said, “a potent anti-inflammatory.”
“This changed how I thought about what we were dealing with,” Russell said.
BUILDING
Since 2006, Russell and Revalesio have tried to answer three questions:
What is RNS60? What does it do? How does it work?
To help find answers, the company has funded the work of researchers around the world, from the University of Washington in Seattle to the Research School of Physics and Engineering at the Australian National University in Canberra, from Canada to Austria and Switzerland, from Italy to the United Kingdom.
Early animal studies have found RNS60 to be safe, and the most recent results have shown that the product shows promise in treating Alzheimer’s disease and other dementias; multiple sclerosis; Parkinson’s disease; asthma and other inflammatory diseases.
According to the company website, the product has been tested in Phase I trials for asthma, multiple sclerosis and the damage caused by heart attacks. Pre-clinical studies have been conducted for cystic fibrosis, Parkinson’s disease and Alzheimer’s. Phase II studies are in the works for multiple sclerosis and asthma.
Neither the Food and Drug Administration nor the National Institutes of Health would comment on the research, although the FDA, according to Revalesio, has deemed RNS60 to be safe.
The company recently hired a new president, Bert van den Bergh, to move toward commercialization of RNS60 by finding deep-pocket research partners for large Phase III human trials.
Van den Bergh spent 30 years with Eli Lilly & Co. where he served as president of neuroscience products, president of European operations and general manager for the United Kingdom and Germany.
A native of The Netherlands, van den Bergh “was instrumental in the development, commercialization and lifecycle management” of products including Cymbalta, Prozac and Zyprexa, according to a Revalesio news release.
Van den Bergh heard about RNS60 a year ago.
“I had retired from Lilly six years ago,” he said recently at Revalesio headquarters.
“It sounded unbelievable,” he said. “This sounded very fundamental. I had the same skepticism. What are they? How can they alter biology? I got very curious.”
He studied the research, spoke with employees and came away believing that the nanobubbles and their action at the cellular level represent “in a way, new physics. It is novel physics.”
When he told a colleague, a medicinal chemist, that he was moving to Tacoma to work with RNS60, the man scolded, “You’ve gone off the deep end.”
“It’s difficult,” said Russell, “for people to get over the speed bump of ‘What is it?’ The fundamental challenge is that we are physically modifying a fluid and having it do biological work. We’re literally at the leading edge of this new arena of science.”
It’s a place where questions outnumber answers.
“It would be fair to say that when we started in 2004, we had no idea of what we were getting into,” Russell said.
And today, he said, “nobody has clarity on where this will go.”
“Late next year we’ll make a decision on where to focus,” said van den Bergh.
“We’re letting the data drive the map,” said Dr. Richard Watson, chief science officer.
The company is now choosing where to aim its research and resources, whether on dementia, asthma or any of a few other diseases.
“We’ll look at unmet medical needs, the complication of studies, speed of development, market possibilities and regulatory framework,” said van den Bergh.
“Our job is to develop evidence that it works,” said Russell.
OTHER VOICES
The News Tribune contacted two local physicians, both members of the American Academy of Allergy Asthma & Immunology, to review Revalesio data that are publicly available.
Neither was familiar with with RNS60, and both took time to offer an initial reaction.
Dr. Arthur Vegh, in practice for 25 years, serves at Allenmore Medical Center and at a clinic in Federal Way. Along with reading the research, Vegh contacted Revalesio’s Richard Watson for more information.
“It seemed like such a hodgepodge,” Vegh said. “Usually, that makes us think it’s sketchy. But it looks like they’re doing good science.”
“I think it has a chance,” he said. “It sounded like witchcraft, but they’re actually approaching it scientifically. If (proven) safe and effective, it could be a game-changer. This shows some promise biochemically. I still have some of that ‘too good to be true.’ ”
Dr. Kevin Dooms practices at Allergy and Asthma Associates of Bellevue.
“It’s very interesting,” he said after reviewing the data. “I have no idea how it works. It seems to work in a very different way. I’m curious to learn more about it. I’m curious where on the cellular level it makes an effect. This is a novel way of approaching the problem. I’m very excited to see results of Phase II.”
He is excited, he said, “at the opportunity that there may be alternative therapies.”
He manages his patients’ disease, he said, primarily with steroids and albuterol.
“It would be nice to have more tools,” he said.
He said he has seen other new miracle drugs fail to meet expectations.
“We see a lot of it, therapies that look very promising, but they don’t work. One medicine was promising in mice, but when it hit human trials it just fell flat. In the real world, it’s gone nowhere.
“This could be a new way of looking at the cell. On the one hand we’re skeptical, but we’re also very excited that something can come up.”
“Good research and good products don’t go away, but they have their work cut out for them,” he said. “I’d be ecstatic if they were successful.”
IMPLICATIONS
Think of RNS60 as a cellular seltzer with effervescence at the tiniest level. Imagine that those nanobubbles somehow have an inside pressure greater than the pressure exerted by the outside environment. Imagine that those bubbles, surprisingly stable in solution, somehow fortify, protect or nourish cells.
Don’t ask how or why they work. That journey is just beginning.
And don’t look for Revalesio soon to make a splash on “60 Minutes.” It’s too early and the principals at the company are too focused on getting the science right before making claims of cures.
But that hasn’t stopped people from asking for help.
Russell, Watson and van den Bergh regularly hear from people begging to be given the medication for themselves or family members.
“The stories are unbelievable and heartbreaking,” Watson said.
“It gives me a sense of urgency,” said van den Bergh. “You wish you could help.”
“It’s important not to become numb to it,” said Russell.
If all goes better than well, an approved therapy for asthma could be available within five to seven years, he said. Count a dozen years for a dementia therapy.
Russell would not discuss the amount of investment he and his family have made in the company. There have been two outside offerings to investors, from which Revalesio raised $40 million.
The possibilities extend beyond medical applications, Watson said.
“There could be huge implications for sciences in other areas,” he said, naming bioterrorism, chemicals, industrial uses, food production, fermentation, fuel.
He asked, of the medical implications, “Can we generate the environment to germinate the science? We are optimizing, not altering, normal physiology.”
He said the company needs to “get scientists to embrace the questions we’re asking. We want to be the conversation-starter.”
“We have a core technology,” said Russell. “Now we need strategic partners. We see ourselves as stewards of this. Once the evidence and the human studies validate (RNS60), I don’t think we’ll have any trouble getting people’s attention.”
He remains committed to Tacoma, he said, and committed also to a set of core ideals outlined in the company’s statement of its culture, which says in part, “We stand for excellence in all we do and reflect the principles of integrity, compassion and humility.”
The greatest challenge, said van den Bergh, is “translating the story that these little bubbles could have a world-changing impact.”
“Something very unusual is happening in Tacoma,” he said.
It’s something, he said, that can change the way we see physics and biology, and “it’s happening right here. You would expect this in the Bay Area, Boston, Cambridge. That fact is, it’s here.”
“We talk about the story, the journey we’ve been on,” said Russell. “We started with a 10,000-piece puzzle, and we had three pieces. I believe in the end the answers we’ve been pursuing are going to be very elegant and simple.”
Read more here: http://www.thenewstribune.com/2014/12/22/3534676/early-results-promising-as-a-tacoma.html#storylink=cpy
Here's one for you cant (and by the way, it positively references a post you yourself positively responded to 3 days earlier -- [#msg-105497821]):
haysaw Saturday, August 23, 2014 9:24:00 AM
Re: Nomo123 post# 20402 Post # of 21644
#msg-105546097
Yes...useless; ineffectual. Anatabloc does not kill people, and supplements don't kill people (see #msg-105497821 for some history). Therefore your extrapolation is poor. Self-medication, as you call it (even though it may be nothing more than preventative nutrition/supplementation) can help/save people. On the other hand, the FDA's decisions and doctors decisions (or negligence) can kill people too. It helps to have a more reasoned perspective.
Boy, sounds like I'm damned if I don't/damned if I do reply. You're asking me questions, and challenging me not to reply. Hard to take you seriously, not only because of the non-specific questions, but also because of the obvious defensiveness.
Is it that I don't pom-pom like you? Is it because I don't mis-characterize the effectiveness of the compound and create fantasies of all things A-bine? This board is a joke. Not because of the company, but because of all the false-positive attitudes and lack of reasonable opinions. If you want to see how a credible board operates, follow Biotech Values on I-Hub for a little while. You guys would be eaten alive by the informative posters there (but you would also learn quite a bit). One particular series of threads you may want to familiarize yourself with, is those involving newbie biotech investing. Most of the people here are culpable in following those flawed behaviors.
I simply would like for the dialogue here to be respectable, reasonable, objective, etc. If I have something negative to say, it is only to counter the unjustified exuberance, the odd assumptions, and the blatant or naive mischaracterizations certain posters tend to share.
Btw-Please show me where I cut/pasted and didn't provide a source.
If I may, I'd like to make an unprecedented move: by contributing to this board with some real input (lol). If you are expecting news after the bell on Friday, it would not be good. Thus, the bid/ask would not be moving up. The relationship would almost always be an inverse one.
If there was significant after hours volume at higher prices with no news, however, you would most likely see an announcement before the bell on Monday. Of course, if that happened, something leaked early.
Hope that helps.
but i know how to get under your skin
Everyone knows that you are NOMO
the content of my posts scare you
replying to my every post within minutes
Nanobubbles: Potent Potion, or Just Effervescence?
http://www.alzforum.org/news/conference-coverage/nanobubbles-potent-potion-or-just-effervescence
24 Dec 2014
The tinier the bubbles in a glass of champagne, the quicker the booze goes to your head, some say. At the Society for Neuroscience meeting held November 15 to 19 in Washington, D.C., scientists presented surprising findings that suggest the smallest bubbles of all—nanobubbles—may boost cognition and even fight Alzheimer’s disease. The bulk of the data came from Revalesio, a small company based in Tacoma, Washington, and its collaborators.
Nanobubbles are not found in Dom Perignon. In Revalesio’s formulation, they are charged microscopic bubbles filled with oxygen, not carbon dioxide. Researchers have reported that these tiny spheres achieve all manner of cellular heroics, including soothing neuroinflammation, blocking tau phosphorylation, saving neurons from the brink of death, boosting synaptic plasticity, and even rescuing memory deficits in AD mouse models. Clinical trials are already underway to treat multiple sclerosis and asthma, with one for AD on the horizon. Research into the bubbles and their potential applications has taken off recently: A conference devoted to nanobubbles took place in Shanghai last October.
The way these wee bubbles work their magic remains a mystery, and many are still skeptical. However, researchers reported that most of their effects can be explained by activation of phosphatidylinositol-3-kinase (PI3K) and/or a boost in mitochondrial function.
Nanobubbles were discovered serendipitously in the late 1990s by Tony Wood, a then-retired Texas Instruments scientist. In his garage, he tinkered with ways to mix gases and liquids more efficiently. When his mixtures retained dissolved oxygen for longer than expected, Wood discovered that nanobubbles were the reason. He then launched a company aiming to use the bubble formulation for agricultural applications, including improving plants’ resistance to disease. Revalesio later bought Wood’s company and further honed the bubble-creation technique. Currently its researchers generate RNS60, Revalesio's oxygen-filled nanobubble formulation, via a process involving something called Taylor-Couette-Poiseuille (TCP) flow. This is a mixing technique in which a saline solution is whisked rapidly under pressurized oxygen. Wood himself was diagnosed with amyotrophic lateral sclerosis in 2011. In 2012, following Revalesio’s completion of a Phase I safety study in healthy volunteers, Wood started receiving infusions of the bubbles under an FDA compassionate-use protocol. By the start of his treatment, Wood’s condition had already progressed to the point where he relied upon a ventilator, but he has since remained stable throughout nearly three years of treatment. Revalesio cannot conclude whether the plateauing of Wood’s disease is related to the nanobubble infusions.
Revalesio aims to treat people with inflammatory disorders, including multiple sclerosis and asthma, with RNS60. The plans are based on preclinical data suggesting that the bubbles calm microglial responses and boost regulatory T cells, which douse the overeager responses of other T cells that wreak havoc in autoimmune disease (see Khasnavis et al., 2012, and Mondal et al., 2012). Revalesio’s scientists later found that in addition to their effects on inflammation, the bubbles directly protected neurons. At SfN, Avik Roy, a researcher from Kalipada Pahan’s laboratory at Rush University in Chicago, presented a sampling of the data implicating the bubbles in neural regeneration.
Substance Behind the Bubbles
Roy and colleagues chipped away at the mechanism behind the phenomenon. They found that treatment with RNS60 boosted the growth, length, and density of dendritic spines on cultured hippocampal neurons. The treatment also upped the expression of NMDA and AMPA receptor subunits NR2A and GluR1, resulting in an increase in calcium intracellular signaling. In a gene-expression analysis, treatment with RNS60 turned on 62 of 84 genes associated with synaptic plasticity, including CREB; immediate early genes such as ZIF-268, Arc, and c-Fos; synapse-associated genes including PSD-95; and neurotrophic factors such as BDNF. Conversely, RNS60 quenched some genes known to dampen synaptic plasticity. PI3K inhibitors blocked all the gains in synaptic plasticity triggered by the bubbles, suggesting this signaling pathway was central to their broad actions.
The researchers then tried out RNS60 in 5xFAD mice, an aggressive AD model. Compared with those in normal mice, hippocampal neurons in 5xFAD mice had lower levels of key synaptic proteins, and reduced calcium signaling in response to stimulation with neurotransmitters, but two months of daily intraperitoneal injections of RNS60 reversed those effects. The researchers reported these data last July in PLoS One (Roy et al., 2014).
In the August 2 issue of the same journal, the researchers reported that RNS60 treatment rescued deficits in learning and spatial memory in 5xFAD mice (see Modi et al., 2014). RNS60 protected hippocampal neurons in these mice from apoptotic cell death, and shielded cultured neurons from death inflicted by Aß. The bubbles also prevented hyperphosphorylation of tau in vivo in hippocampal neurons from 5xFAD mice, and downregulated the activity of GSK3b, a kinase implicated in phosphorylating tau, in cultured neurons. As with the synaptic plasticity boost, RNS60’s sway over neuronal death, tau phosphorylation, and GSK3b activity depended on the activation of PI3K, which was temporarily buoyed by the bubbles.
Revalesio’s recent findings mesh with those from Rodolfo Llinás’s lab at New York University in New York. An electrophysiologist whose bread and butter for 50 years has been the squid giant synapse, Llinás told Alzforum that he was at first intrigued by (and highly skeptical of) Revalesio’s findings. He decided to test the bubbles for himself. He reported that RNS60 improved synaptic transmission in squid neurons by mobilizing more vesicles to the synapse. Mitochondria in the treated neurons produced more ATP than usual. Llinás and colleagues reported that blocking ATP synthesis abolished all of RNS60’s positive effects (see Choi et al., 2014). Llinás’s lab has since found that RNS60 not only revs up ATP production, but enlarges mitochondria, according to a poster he presented at SfN. Rather than altering the kinetics of synaptic transmission, which could prove harmful, Llinás said that RNS60 simply injects more fuel into the energetically costly process. “I see it as a sort of ‘life optimizer’ rather than a drug,” Llinás said. “It makes everything run as efficiently as possible.” Llinás and colleagues also have a paper in press that reports similar findings in Xenopus giant oocytes.
How does it work? Llinás hypothesizes that the bubbles boost ATP production by delivering oxygen to the mitochondria. Normally, too much oxygen can be harmful, but Llinás said that he and his NYU colleagues Maxim Ivannikov and Mutsuyuki Sugimori have evidence that the bubbles cross the outer cell membrane as well as the mitochondrial membrane, then release the oxygen once inside the powerhouse organelle’s interior. In this way, the bubbles deliver their cargo without creating toxic free radicals in the cell, Llinás said. He thinks a majority of the effects both his lab and Revalesio’s researchers have reported stem from the extra ATP production triggered by this fuel injection.
Revalesio researchers are currently looking into the role of enhanced mitochondrial function in RNS60’s effects. However, for now they say their evidence points to the activation of PI3K as the major event that underlies most of the bubbles’ benefits. “Although it seems like there are various effects of RNS60, it actually has come down so far to a single signaling pathway: PI3K/Akt,” said Supurna Ghosh, Revalesio’s director of neurology research. “All of the effects we have seen so far in T cells, glial cells, or neurons can be abrogated by blocking that pathway.” How would the bubbles activate this pathway? “That’s the key question, and we really do not have an answer for it yet,” Ghosh said. PI3K can be activated from outside the cell via receptors on the cytoplasmic membrane, or from within the cell via other signaling molecules. “It’s possible that the bubbles enter the cell and activate it from inside, or possible that bubbles interfere with other proteins on the cell membrane, in turn activating PI3K,” she said.
Whether the bubbles’ benefits are derived from their physical interactions with proteins or from the way they deliver oxygen to mitochondria, it seems clear from the studies that both the bubble and the oxygen are key, Ghosh said. Control experiments with oxygenated fluids, or bubbles without oxygen, did not produce any of RNS60’s effects. This may dash the hopes of people hoping to glean some of the nanobubbles’ benefits by taking a few hits of oxygen at an oxygen bar (the establishments are growing in popularity and some claim to provide health benefits). Forcing oxygen into tissues by spending time in a hyperbaric chamber may also sound similar, however Watson said he thinks the bubbles’ structure is the key to their effects.
Regardless of exactly how the bubbles work, it seems likely that they are somehow delivered to the CNS, judging by experiments in mice, Ghosh said. Another recent study by the group reported that three hours after of being injected intraperitoneally, nanobubbles activated PI3K in the substantia nigra (see Khasnavis et al., 2014). Currently, there is no way to track the teeny bubbles in vivo, but Richard Watson, Revalesio’s chief scientific officer, said researchers are working on ways to do so by detecting gaseous oxygen. He estimates that the bubbles stick around in the body for about 18 hours before disintegrating.
RNS60 has so far proven safe in Phase 1 trials when injected intravenously or inhaled by healthy people or people with asthma (see clinical trials.gov; clinical trials,gov), and Phase 2 trials for both multiple sclerosis and asthma are about to begin, Watson said (see clinicaltrials.gov). Revalesio is currently devising inclusion criteria for its AD trial, which is expected to begin next year. It plans to enroll people with MCI or in the early stages of AD, and will use a combination of imaging and cognitive measures to monitor effects of RNS60.
At SfN, Watson was enthused by a presentation by Cynthia Lemere of Brigham and Women’s Hospital, Boston, which showcased GE180, a new PET imaging tracer for neuroinflammation (see Part 4 of this series). Watson hopes something like this could be a useful outcome measure in the RNS60 trial.
Lemere and Revalesio are hatching a plan to collaborate. Lemere plans to test RNS60 in AD mouse models, and use the GE180 tracer to measure its effects on neuroinflammation, she told Alzforum. Like most scientists, Lemere had her reservations about the bubbles at first. “It sounds far-fetched and bizarre, but the data looks really good and they’re doing rigorous science,” she said. While Lemere doesn’t believe that any one treatment will be a cure for AD, she said RNS60 could have potential, especially in combination with other therapies. “The fact that this has such broad application is really interesting,” she said. “I believe inflammation plays a big role in disease progression, so if you can quell the inflammation early in that process, you might be able to slow down neurodegeneration.”—Jessica Shugart
Nanobubbles: Potent Potion, or Just Effervescence?
http://www.alzforum.org/news/conference-coverage/nanobubbles-potent-potion-or-just-effervescence
24 Dec 2014
The tinier the bubbles in a glass of champagne, the quicker the booze goes to your head, some say. At the Society for Neuroscience meeting held November 15 to 19 in Washington, D.C., scientists presented surprising findings that suggest the smallest bubbles of all—nanobubbles—may boost cognition and even fight Alzheimer’s disease. The bulk of the data came from Revalesio, a small company based in Tacoma, Washington, and its collaborators.
Nanobubbles are not found in Dom Perignon. In Revalesio’s formulation, they are charged microscopic bubbles filled with oxygen, not carbon dioxide. Researchers have reported that these tiny spheres achieve all manner of cellular heroics, including soothing neuroinflammation, blocking tau phosphorylation, saving neurons from the brink of death, boosting synaptic plasticity, and even rescuing memory deficits in AD mouse models. Clinical trials are already underway to treat multiple sclerosis and asthma, with one for AD on the horizon. Research into the bubbles and their potential applications has taken off recently: A conference devoted to nanobubbles took place in Shanghai last October.
The way these wee bubbles work their magic remains a mystery, and many are still skeptical. However, researchers reported that most of their effects can be explained by activation of phosphatidylinositol-3-kinase (PI3K) and/or a boost in mitochondrial function.
Nanobubbles were discovered serendipitously in the late 1990s by Tony Wood, a then-retired Texas Instruments scientist. In his garage, he tinkered with ways to mix gases and liquids more efficiently. When his mixtures retained dissolved oxygen for longer than expected, Wood discovered that nanobubbles were the reason. He then launched a company aiming to use the bubble formulation for agricultural applications, including improving plants’ resistance to disease. Revalesio later bought Wood’s company and further honed the bubble-creation technique. Currently its researchers generate RNS60, Revalesio's oxygen-filled nanobubble formulation, via a process involving something called Taylor-Couette-Poiseuille (TCP) flow. This is a mixing technique in which a saline solution is whisked rapidly under pressurized oxygen. Wood himself was diagnosed with amyotrophic lateral sclerosis in 2011. In 2012, following Revalesio’s completion of a Phase I safety study in healthy volunteers, Wood started receiving infusions of the bubbles under an FDA compassionate-use protocol. By the start of his treatment, Wood’s condition had already progressed to the point where he relied upon a ventilator, but he has since remained stable throughout nearly three years of treatment. Revalesio cannot conclude whether the plateauing of Wood’s disease is related to the nanobubble infusions.
Revalesio aims to treat people with inflammatory disorders, including multiple sclerosis and asthma, with RNS60. The plans are based on preclinical data suggesting that the bubbles calm microglial responses and boost regulatory T cells, which douse the overeager responses of other T cells that wreak havoc in autoimmune disease (see Khasnavis et al., 2012, and Mondal et al., 2012). Revalesio’s scientists later found that in addition to their effects on inflammation, the bubbles directly protected neurons. At SfN, Avik Roy, a researcher from Kalipada Pahan’s laboratory at Rush University in Chicago, presented a sampling of the data implicating the bubbles in neural regeneration.
Substance Behind the Bubbles
Roy and colleagues chipped away at the mechanism behind the phenomenon. They found that treatment with RNS60 boosted the growth, length, and density of dendritic spines on cultured hippocampal neurons. The treatment also upped the expression of NMDA and AMPA receptor subunits NR2A and GluR1, resulting in an increase in calcium intracellular signaling. In a gene-expression analysis, treatment with RNS60 turned on 62 of 84 genes associated with synaptic plasticity, including CREB; immediate early genes such as ZIF-268, Arc, and c-Fos; synapse-associated genes including PSD-95; and neurotrophic factors such as BDNF. Conversely, RNS60 quenched some genes known to dampen synaptic plasticity. PI3K inhibitors blocked all the gains in synaptic plasticity triggered by the bubbles, suggesting this signaling pathway was central to their broad actions.
The researchers then tried out RNS60 in 5xFAD mice, an aggressive AD model. Compared with those in normal mice, hippocampal neurons in 5xFAD mice had lower levels of key synaptic proteins, and reduced calcium signaling in response to stimulation with neurotransmitters, but two months of daily intraperitoneal injections of RNS60 reversed those effects. The researchers reported these data last July in PLoS One (Roy et al., 2014).
In the August 2 issue of the same journal, the researchers reported that RNS60 treatment rescued deficits in learning and spatial memory in 5xFAD mice (see Modi et al., 2014). RNS60 protected hippocampal neurons in these mice from apoptotic cell death, and shielded cultured neurons from death inflicted by Aß. The bubbles also prevented hyperphosphorylation of tau in vivo in hippocampal neurons from 5xFAD mice, and downregulated the activity of GSK3b, a kinase implicated in phosphorylating tau, in cultured neurons. As with the synaptic plasticity boost, RNS60’s sway over neuronal death, tau phosphorylation, and GSK3b activity depended on the activation of PI3K, which was temporarily buoyed by the bubbles.
Revalesio’s recent findings mesh with those from Rodolfo Llinás’s lab at New York University in New York. An electrophysiologist whose bread and butter for 50 years has been the squid giant synapse, Llinás told Alzforum that he was at first intrigued by (and highly skeptical of) Revalesio’s findings. He decided to test the bubbles for himself. He reported that RNS60 improved synaptic transmission in squid neurons by mobilizing more vesicles to the synapse. Mitochondria in the treated neurons produced more ATP than usual. Llinás and colleagues reported that blocking ATP synthesis abolished all of RNS60’s positive effects (see Choi et al., 2014). Llinás’s lab has since found that RNS60 not only revs up ATP production, but enlarges mitochondria, according to a poster he presented at SfN. Rather than altering the kinetics of synaptic transmission, which could prove harmful, Llinás said that RNS60 simply injects more fuel into the energetically costly process. “I see it as a sort of ‘life optimizer’ rather than a drug,” Llinás said. “It makes everything run as efficiently as possible.” Llinás and colleagues also have a paper in press that reports similar findings in Xenopus giant oocytes.
How does it work? Llinás hypothesizes that the bubbles boost ATP production by delivering oxygen to the mitochondria. Normally, too much oxygen can be harmful, but Llinás said that he and his NYU colleagues Maxim Ivannikov and Mutsuyuki Sugimori have evidence that the bubbles cross the outer cell membrane as well as the mitochondrial membrane, then release the oxygen once inside the powerhouse organelle’s interior. In this way, the bubbles deliver their cargo without creating toxic free radicals in the cell, Llinás said. He thinks a majority of the effects both his lab and Revalesio’s researchers have reported stem from the extra ATP production triggered by this fuel injection.
Revalesio researchers are currently looking into the role of enhanced mitochondrial function in RNS60’s effects. However, for now they say their evidence points to the activation of PI3K as the major event that underlies most of the bubbles’ benefits. “Although it seems like there are various effects of RNS60, it actually has come down so far to a single signaling pathway: PI3K/Akt,” said Supurna Ghosh, Revalesio’s director of neurology research. “All of the effects we have seen so far in T cells, glial cells, or neurons can be abrogated by blocking that pathway.” How would the bubbles activate this pathway? “That’s the key question, and we really do not have an answer for it yet,” Ghosh said. PI3K can be activated from outside the cell via receptors on the cytoplasmic membrane, or from within the cell via other signaling molecules. “It’s possible that the bubbles enter the cell and activate it from inside, or possible that bubbles interfere with other proteins on the cell membrane, in turn activating PI3K,” she said.
Whether the bubbles’ benefits are derived from their physical interactions with proteins or from the way they deliver oxygen to mitochondria, it seems clear from the studies that both the bubble and the oxygen are key, Ghosh said. Control experiments with oxygenated fluids, or bubbles without oxygen, did not produce any of RNS60’s effects. This may dash the hopes of people hoping to glean some of the nanobubbles’ benefits by taking a few hits of oxygen at an oxygen bar (the establishments are growing in popularity and some claim to provide health benefits). Forcing oxygen into tissues by spending time in a hyperbaric chamber may also sound similar, however Watson said he thinks the bubbles’ structure is the key to their effects.
Regardless of exactly how the bubbles work, it seems likely that they are somehow delivered to the CNS, judging by experiments in mice, Ghosh said. Another recent study by the group reported that three hours after of being injected intraperitoneally, nanobubbles activated PI3K in the substantia nigra (see Khasnavis et al., 2014). Currently, there is no way to track the teeny bubbles in vivo, but Richard Watson, Revalesio’s chief scientific officer, said researchers are working on ways to do so by detecting gaseous oxygen. He estimates that the bubbles stick around in the body for about 18 hours before disintegrating.
RNS60 has so far proven safe in Phase 1 trials when injected intravenously or inhaled by healthy people or people with asthma (see clinical trials.gov; clinical trials,gov), and Phase 2 trials for both multiple sclerosis and asthma are about to begin, Watson said (see clinicaltrials.gov). Revalesio is currently devising inclusion criteria for its AD trial, which is expected to begin next year. It plans to enroll people with MCI or in the early stages of AD, and will use a combination of imaging and cognitive measures to monitor effects of RNS60.
At SfN, Watson was enthused by a presentation by Cynthia Lemere of Brigham and Women’s Hospital, Boston, which showcased GE180, a new PET imaging tracer for neuroinflammation (see Part 4 of this series). Watson hopes something like this could be a useful outcome measure in the RNS60 trial.
Lemere and Revalesio are hatching a plan to collaborate. Lemere plans to test RNS60 in AD mouse models, and use the GE180 tracer to measure its effects on neuroinflammation, she told Alzforum. Like most scientists, Lemere had her reservations about the bubbles at first. “It sounds far-fetched and bizarre, but the data looks really good and they’re doing rigorous science,” she said. While Lemere doesn’t believe that any one treatment will be a cure for AD, she said RNS60 could have potential, especially in combination with other therapies. “The fact that this has such broad application is really interesting,” she said. “I believe inflammation plays a big role in disease progression, so if you can quell the inflammation early in that process, you might be able to slow down neurodegeneration.”—Jessica Shugart
As a general rule, when you cut/paste or copy content from somewhere else, you should credit or notate the source.
If the tissue results are reported to be positive it will be concrete proof that it works on humans
Phase 2 results would virtually be a given as would drug approval.
or they have a partner that wants to see the results before funding Phase 2...OR both!!!
The stock will go viral.
The great news is it will be starting very soon.
Try to get out of your own way, and allow a new, better, reasonable sensibility to guide you. I have no obligation or desire to prove anything, nor would such info make a bit of a difference to anything driving this company: it is a complete waste of time, foolish, dumb.Either take my word for it, or don't, my history speaks for itself.
I don't see any likely issue with either IND (FDA or Europe) for Ph1 clinical studies. The timing will be interesting as it relates to the Nasdaq qualifications, and the push for shareholder approval of a potential R/S. In all honesty, the actual confirmation of go ahead for clinical studies doesn't mean much at all, but I guess it does remove some perceived uncertainty.
There is a lot of fortune telling on this board. I reiterate that it is a glaring red flag for this investment. Too much fantasy, not much reality, all drenched in naivety. I should have run when I first started reading all this blind optimism. My bad, but I only have myself to blame. Also telling is the complete absence of expert commentary and rational, balanced, common sense opinions. Yes, the crazies are running the asylum here.
Thanks for the enterainment, and happy holidays.
If only anatabine was a smart drug. You could just eat more onions!
And how's that workin' out for ya'?
it's hard to believe there's no discussion of the announcement.I consider it a small victory, one of the very few in over a year. it should also put to rest the threat of a reverse split for at least 5 months.
Brain inflammation a hallmark of autism, large-scale analysis shows
http://www.eurekalert.org/pub_releases/2014-12/jhm-bia120914.php
Johns Hopkins study is largest so far of gene expression in autism brains
While many different combinations of genetic traits can cause autism, brains affected by autism share a pattern of ramped-up immune responses, an analysis of data from autopsied human brains reveals. The study, a collaborative effort between Johns Hopkins and the University of Alabama at Birmingham, included data from 72 autism and control brains. It will be published online Dec. 10 in the journal Nature Communications.
"There are many different ways of getting autism, but we found that they all have the same downstream effect," says Dan Arking, Ph.D. , an associate professor in the McKusick-Nathans Institute for Genetic Medicine at the Johns Hopkins University School of Medicine. "What we don't know is whether this immune response is making things better in the short term and worse in the long term."
The causes of autism, also known as autistic spectrum disorder, remain largely unknown and are a frequent research topic for geneticists and neuroscientists. But Arking had noticed that for autism, studies of whether and how much genes were being used -- known as gene expression -- had thus far involved too little data to draw many useful conclusions. That's because unlike a genetic test, which can be done using nearly any cells in the body, gene expression testing has to be performed on the specific tissue of interest -- in this case, brains that could only be obtained through autopsies.
To combat this problem, Arking and his colleagues analyzed gene expression in samples from two different tissue banks, comparing gene expression in people with autism to that in controls without the condition. All told, they analyzed data from 104 brain samples from 72 individuals -- the largest data set so far for a study of gene expression in autism.
Previous studies had identified autism-associated abnormalities in cells that support neurons in the brain and spinal cord. In this study, Arking says, the research team was able to narrow in on a specific type of support cell known as a microglial cell, which polices the brain for pathogens and other threats. In the autism brains, the microglia appeared to be perpetually activated, with their genes for inflammation responses turned on. "This type of inflammation is not well understood, but it highlights the lack of current understanding about how innate immunity controls neural circuits," says Andrew West, Ph.D., an associate professor of neurology at the University of Alabama at Birmingham who was involved in the study.
Arking notes that, given the known genetic contributors to autism, inflammation is unlikely to be its root cause. Rather, he says, "This is a downstream consequence of upstream gene mutation." The next step, he says, would be to find out whether treating the inflammation could ameliorate symptoms of autism.
###
Other authors on the study are Simone Gupta, Shannon E. Ellis, Foram N. Ashar, Anna Moes, Joel S. Bader and Jianan Zhan, all of The Johns Hopkins University.
Repeating this over and over does not make this any more of a possibility, nor does the past prove the future. What it amounts to is manipulation, even more so if you have this deleted.
A reasoned person cannot look at that quote and not think it hyperbole, if not total bullshit. So yes, it is interesting, but that is the aim of sensationalism.
I can't wait to here from people when the Rx version is available (time release)
I think that yes is not a question :)
OT-He's the sharpest tool in the drawer...but a tool nonetheless :)
Ot-I know...that's why I put the smile at the end. And yes, DD keeps a very clean house -- he's anal like that :)
Nothing like a sprinkle of salt after a good wound-licking...I'm sure he is ecstatic for you :)
BP doesn't bottom fish. They are more than willing to pay a premium for a company, compound, or platform that has some momentum, or a competitor's interest.
It's doubtful it will help, but it certainly wouldn't hurt.
Rock Creek has to straighten out their regulatory hurdles before anything else. A partnership anytime soon -- at this clinical stage, at these prices -- would have horrendous terms. They need some organically good news, and soon.
Now that the big pharmas know what Rock Creek Pharmaceuticals has discovered