Factor X have we finally found the fountain of Youth?

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kurt9
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Re: Factor X have we finally found the fountain of Youth?

Postby kurt9 » Thu Oct 25, 2018 3:02 am

The reason I went with 700mg for a body weight of around 70Kg is that a smaller dose will not produce the desired effect. So, you really are looking at 100mg for each 10 Kg of body weight. In any case, it is very benevolent, unlike Dasatinib, which can really harm you if used improperly.

The article posted is rather hype. I view senolytics as a crucial step, but one of several for life extension.

I will play around with purported Lipofuscin removal agents early next year. I want to do this one step at a time in order to make it easy for my liver. Good liver health is something to be jealously guarded.

williatw
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Re: Factor X have we finally found the fountain of Youth?

Postby williatw » Thu Oct 25, 2018 3:42 am

kurt9 wrote:The reason I went with 700mg for a body weight of around 70Kg is that a smaller dose will not produce the desired effect. So, you really are looking at 100mg for each 10 Kg of body weight. In any case, it is very benevolent, unlike Dasatinib, which can really harm you if used improperly.


Well I am about 91kg body weight so for me the equivalent dosage would be 900mg/day. Understand you don't do it long term; that is you do it for some period of time say 2 weeks and then lay off? How often do you need to repeat the procedure for best results?


kurt9 wrote:The article posted is rather hype. I view senolytics as a crucial step, but one of several for life extension.




The primary value of the senolytic therapy is that it would be a critical present day proof-of-concept for the life extension of humans developing technology. Even if the results of say metformin/rapamycin therapy for instance produce only modest life extension in humans say 5-15% (on ave.) it would energize the whole movement. There are likely tens if not hundreds of billions of dollars worth of venture capital funding waiting on the sidelines that would swoop in once they were convinced that the life extension movement isn't hype/snake oil.
Last edited by williatw on Fri Oct 26, 2018 12:46 am, edited 2 times in total.

williatw
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Re: Factor X have we finally found the fountain of Youth?

Postby williatw » Thu Oct 25, 2018 5:11 am

Fisetin—a new senolytic


Senolytic drugs have been the most promising near-term anti-aging therapy since the ground-breaking paper by van Deursen of Mayo Clinic published in 2011. The body accumulates senescent cells as we age, damaged cells that send out signal molecules that in turn modify our biochemistry in a toxic, pro-inflammatory direction. Though the number of such cells is small, the damage they do is great. Van Deursen showed that just getting rid of these cells could increase lifespan of mice by ~25%. But he did it with a trick, using genetically engineered mice in which the senescent cells had a built-in self-destruct switch.

After that, the race was on to find chemical agents that would do the same thing without the genetically engineered self-destruct. They must selectively kill senescent cells, while leaving all other cells unharmed. It’s a tall order, because even a little residual toxicity to normal cells can be quite damaging. Before last week, the two best candidates were FOXO4-DRI and a combination of quercetin with dasatinib.


I’ve written in the past (here and here) that senolytic drugs are our best prospect for a near-term lift on the road to anti-aging medicine.

Last week, a large research group affiliated with the original May Clinic team published findings about fisetin, the latest and greatest candidate for a senolitic pill, another flavenoid, very close in structure to quercetin.

Image

They grew senescent and normal cells in a test tube, then tested 11 different plant-derived chemicals for power to kill the one while leaving the other unharmed. The winner was fisetin.


Image

(MEF stands for Mouse Embryonic Fybroblast, the cells that were cultured in the screening experiment.)

Fisetin is especially interesting because it is cheap, easily available, widely-regarded as safe, but not nearly as well studied as quercetin.

They took the winner, fisetin, and subjected it to a series of tests. They began with in vitro (cell culture) tests and proceeded to in vivo tests with live animals, culminating with an impressive life span assay in mice.

(The runner-up was curcumin, less interesting perhaps only because it has already been extensively studied. The curcumin molecule is unrelated to quercetin or fisetin, and is not a flavenoid. I can’t help but wonder if they had subjected curcumin to the same thorough testing that they reserved for fisetin, how would curcumin have fared?)

Image


The paper’s principal findings were:
◾Fisetin has lower liver toxicity (at equivalent doses for senolytic benefit) than any of the other senolytics tested so far.
◾Fisetin reduces pro-inflammatory signaling in a short course given to mice and in long-term experiments where fisetin was added to the mouse chow.
◾Fisetin reduces number of senescent fat cells in a short course given to mice.
◾Mice fed fisetin for long periods had much more glutathione than control mice. (Glutathione is one of very few marker molecules that seems to be wholly beneficial.)
◾Most impressively, mice fed fisetin late in life lived 10-15% longer than control mice. This represents a 50% increase in the remaining lifespan after the intervention.



Image

What we know and what we’d really like to know

We’d like to know, do humans who take large doses of fisetin live longer? Do they have toxic side-effects? These questions require decades to answer.

Does fisetin reduce age markers in humans, especially methylation age? This is a feasible study, since the test is mature and safety of fisetin is fairly well established for short courses. Perhaps this experiment is being considered; I’ve written to the corresponding authors of the most recent study, in case they haven’t already thought of it. This test would not be definitive because we know that methylation age is not perfectly correlated with biological age; but if positive it would confirm both that fisetin is accomplishing epigenetic rejuvenation and that methylation tests were correctly informing us of this; a negative result would be ambiguous.

Episodic Dosing

It makes sense that senolytics should be taken periodically, not continuously. A high dose can be toxic to existing senescent cells, and then getting out of the way, it can allow normal cells to recover from any damage. This sounds like good theory, but different dosing regimens have not been tested experimentally. In fact, the new paper reports positive results from both high episodic dosing and lower everyday dosing.

The Mayo group had previously tested fisetin, and found it effective in killing some kinds of human senescent cells but not others. In previous tests, fisetin was found to be effective in senescent fat cells (pre-adipocyte, white adipose tissue), and that is where it was primarily tested in the new studies.

Authors’ comments

They note that the episodic treatment and short half-life suggest that the benefits of fisetin come from its senolytic action, rather than other actions as an antioxidant and signal molecule. They emphasize that clearing senescent white blood cells and making room for new, active white blood cells are activities that enhance the benefits of fisetin, since white blood cells contribute to clearing the remaining senescent cells.

Fisetin has previously been shown to have anti-cancer activity and to inhibit inflammatory signals directly. Here is a review of benefits of fisetin from three years ago. Drugage lists just two previous lifespan studies with fisetin, with encouraging results from yeast and fruitflies.

The Bottom Line

If we choose to take fisetin at this stage in the science, we are early adopters, and our main concern ought to be safety. There is little doubt that killing senescent cells will be beneficial. But what is the toxic burden of fisetin, and what dosage can we safely take without risk of damage to normal cells? The current study covers a lot of ground but doesn’t answer this question, apparently because they are convinced that fisetin is quite safe.

Strawberries, apples, grapes, and onions all contain fisetin, but at low levels compared to a senolytic dose. For example, the highest food concentration, 160 ppm, is found in strawberries. A half pound of strawberries yields 36 mg of fisetin. We’re still guessing at the therapeutic dose, based on mouse studies, and the experimental dosage in human trials is about 1,000 to 1,500 mg (based on this clinical trial), the content to 30-40 pounds of strawberries on each of two consecutive days.
In the best cases, fisetin was shown to reduce senescent cell burden by 50% and up to 75% in cell cultures. This is a good start, and encourages us to think we can do better by combining fisetin with other agents, or perhaps with fasting.


Also reported today,

Clearing Senescent Cells From The Brain In Mice Preserves Cognition

It sounds impressive, but I’m not impressed. First, mouse models of Alzheimer’s have been discredited repeatedly. Mice don’t naturally get AD, so they have to be genetically engineered to do so, and the genetically modified mice don’t share the deep causes of human AD. Time and again, treatments have been found effective in the mouse model that fail to translate to humans. Second, the treatment used in the study to kill senescent brain cells also relied on another genetic modification, and would not be applicable to humans.

My guess is that effective senolytic agents for humans will be available within a few years, and that they will decrease risk of all age-related disease, including Alzheimer’s. But this study does little to advance us toward that goal.





https://joshmitteldorf.scienceblog.com/ ... /#comments

kurt9
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Re: Factor X have we finally found the fountain of Youth?

Postby kurt9 » Thu Oct 25, 2018 3:03 pm

williatw wrote:
Well I am about 91kg body weight so for me the equivalent dosage would be 900mg/day. Understand you don't do it long term; that is you do it for some period of time say 2 weeks and then lay off? How often do you need to repeat the procedure for best results?


I did it only 4 times (4 days in a row). The experiments I read about it suggested trying it from one to five times. I would not do it more than 5 times. I plan to repeat maybe a year from now.

williatw
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Re: Factor X have we finally found the fountain of Youth?

Postby williatw » Tue Oct 30, 2018 11:24 pm

'Spectacular' diabetes treatment could end daily insulin injections

Hour-long procedure that stabilises blood sugar levels of sufferers of type 2 diabetes is still effective one year on, study shows


Image
Woman self-administering insulin with a hypodermic syringe. Photograph: Ian Hooton/Getty Images/Science Photo Library RF


A potential medical breakthrough that could put an end to the daily insulin injections endured by people living with diabetes has been unveiled by Dutch scientists.

By destroying the mucous membrane in the small intestine and causing a new one to develop, scientists stabilised the blood sugar levels of people with type 2 diabetes. The results have been described as “spectacular” – albeit unexpected – by the chief researchers involved.

In the hourlong procedure, trialled on 50 patients in Amsterdam, a tube with a small balloon in its end is inserted through the mouth of the patient down to the small intestine. The balloon is inflated with hot water and the mucous membrane burned away by the heat. Within two weeks a new membrane develops, leading to an improvement in the patient’s health.

Even a year after the treatment, the disease was found to be stable in 90% of those treated. It is believed there is a link between nutrient absorption by the mucus membrane in the small intestine and the development of insulin resistance among people with type 2 diabetes.

Jacques Bergman, a professor of gastroenterology at Amsterdam UMC, said: “Because of this treatment the use of insulin can be postponed or perhaps prevented. That is promising.”

Bergman added of the procedure that it was “amazing that people suffer very little from this”.

He told the Dutch broadcaster Nederlandse Omroep Stichting: “With those people we see a spectacular improvement in blood sugar levels one day after the operation, before they even lose one kilo, which has put us on the track.

“Because the question now is whether this is a permanent treatment, or whether it is something that you have to keep repeating – something that in theory should be possible. We looked at whether we could stop their insulin, which is still ongoing, but the first results are truly spectacular, with the lion’s share of patients no longer using insulin after this treatment.”

The new discovery initially seems most suitable for borderline patients who already take pills but whose blood sugar level is high enough for doctors to advise that they inject insulin in the short term.

Apart from dispensing with insulin injections, researchers claim that those treated could benefit from a lower risk of cardiovascular disease, kidney failure, blindness and numbness in the hands and feet. Scientists from Amsterdam UMC who presented their study at a conference in Vienna this week were said to be cautious but “jubilant” about the initial results.

People with type 2 diabetes aged between 28 and 75 are now being recruited for a larger study of 100 people.

Almost 3.7 million people in the UK live with a diagnosis of type 1 or 2 diabetes, an increase of 1.9 million since 1998. Type 1 diabetes is where the level of sugar in the blood is too high because the pancreas does not produce insulin.

Those with type 2 diabetes are not producing enough insulin. The impact can be controlled by changes to diet, but it is a progressive disease. Most people will need to take tablets or inject insulin after living with it for five to 10 years.

Nine out of 10 people diagnosed with diabetes have type 2. It is estimated that there are nearly 1 million people currently living with the condition who have yet to be diagnosed and that 12.3 million people are at an increased risk due high levels of sugar in their blood.



https://www.theguardian.com/society/201 ... injections

williatw
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Re: Factor X have we finally found the fountain of Youth?

Postby williatw » Tue Oct 30, 2018 11:37 pm

No shit:



Sloppy science bears substantial blame for Americans' bad eating habits


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Brian Wansink poses for a photo in a food lab at Cornell University in Ithaca, N.Y. on Dec. 6, 2016.



A spectacular case of sloppy science came crashing to a close last month. Cornell University’s Brian Wansink, a world-renowned scientist who seized headlines with his research on American eating habits, had many of his papers retracted and resigned from his professorship. Wansink’s fall is not just the tale of a single scientist gone astray. It is, instead, an indictment of an entire type of nutrition science that has led to mistaken dietary advice dispensed to Americans for decades.

Wansink’s misdeeds played out in Cornell classrooms and nutrition journals and, as crucially, around American dinner tables. He had a central role in all our diets. From 2007 to 2010, he served as executive director of the U.S. government’s Dietary Guidelines, which set the standard for healthy eating for the nation. Under Wansink, the guidelines shifted to be ever-more based on the same type of easily manipulated, weak observational data he produced in his lab. A new iteration of the guidelines, under a different director, was issued in 2015, yet the reliance on weak data has remained the same.
Wansink’s research depended on observational studies, which can yield only associations, such as “coffee is associated with cancer.” These are at best suggestions of hypotheses, and they nearly always fall far short of demonstrating cause and effect. To show causation — that coffee causes cancer, for example — a real experiment, or clinical trial, is needed. For nutrition policy, however, we have rarely required that caliber of research.

Worse, the associational data in nutrition studies are particularly unreliable because the studies depend upon self-reported answers on dietary questionnaires with such queries as: How many cups of pasta did you consume weekly for the last six months? Or, how much did you enjoy that last slice of pizza? Studies have long shown that people misrepresent what they eat — or they simply can’t remember.

John Ioannidis, a Stanford University professor and evidence-based medicine expert, recently wrote that, given all of the problems with this kind of nutrition research, “Reform has long been due.” The claims of this weak science, when tested properly by rigorous clinical trials, have been shown in two analyses to be correct only 0% to 20% of the time. This means that 80% to100% of the time, they're wrong.

These kinds of odds may be relatively harmless when it comes to studying our intake and enjoyment of pizza, as Wansink did. Yet for the Dietary Guidelines, much more is at stake. Mistakes of the past, such as the now-jettisoned caps on dietary cholesterol and total fat, show the harm of rushing to create policy based on weak science.

The guidelines are surprisingly powerful: They drive choices for school lunches, feeding programs for the elderly, hospital food and military rations, as well as influencing the advice dispensed by doctors, nurses, dieticians and nutritionists. If the guidelines are off or downright wrong, the potential impact on our epidemics of obesity, diabetes and neurological diseases is devastating.


Critics have argued that the guidelines, launched in 1980, were based on shaky science before Wansink got involved, but his guidance arguably drove them off the rails. His 2010 guidelines turned the recommendations away from a focus on food groups and toward dietary patterns. This sounds reasonable enough, yet the fundamental flaw lies in the evidence base for the patterns.

I examined each study cited by the guidelines’ advisory committee to support the recommendations, and the results, published in a science journal in 2015, were astonishing. The government’s three recommended Food Patterns — “U.S.-Style,” “Mediterranean” and “Healthy Vegetarian”— were supported by fewer than a handful of truly rigorous trials. Even the government’s expert panel noted the deficiencies.

A single Mediterranean-diet trial, on only 180 people, was cited to demonstrate that any of these patterns could produce significant weight loss. The advisory committee deemed there was “limited” or “insufficient” evidence to show that the diets could combat diabetes. And the support for claims that the diets could prevent heart disease was ambiguous at best (blood pressure was the only risk factor that improved in quite a few studies, and in others, both “bad” and “good” cholesterol dropped, implying mixed outcomes overall).


The key, large clinical trial cited to claim cardiovascular benefits for the Mediterranean diet was recently retracted and reissued, raising serious doubts about its basic reliability. Meanwhile, the government’s review of the Healthy Vegetarian diet concluded that the evidence for any disease-fighting powers of this diet was “limited”— the lowest rank given for available data.

The lack of rigorous experimentation is matched by the data’s lack of transparency. In retracting Wansink’s papers, the editors of the Journal of the American Medical Assn. said their primary reason was that the data could not be confirmed because the original dietary surveys had been thrown out. Much the same problem dogs the country’s largest observational nutrition study, funded by the National Institutes of Health and run by Harvard’s T.H. Chan School of Public Health. Its findings are among the most highly cited in the Dietary Guidelines’ evidence base, yet Harvard does not publicly disclose its data, making those findings also impossible to confirm.

Defenders of the current guidelines’ argue that the urgency of our obesity and diabetes epidemics virtually demands that we march forward with recommendations based even on imperfect data. Yet mistakes of the past, such as the now-jettisoned caps on dietary cholesterol and total fat, show the real harm of rushing to create policy based on weak science. Most people still don’t even know about these reversals in our dietary guidelines — that the weight of evidence has now shifted to sugars and refined carbohydrates as the more likely dietary culprits. However, un-learning diet rules once they have been learned proves to be extremely difficult.

Wansink’s downfall reveals the corrosive powers perpetually undermining good science in nutrition. Observational studies are supposed to be exploratory work, hardly ready for prime time. Yet the pressure to publish, the reality that media coverage drives grant making, and that these both drive the professional trajectory of researchers, push scientists like Wansink and others to oversell their results.

When imperfect data shape headlines, and the entire Dietary Guidelines, the losers are science itself and, quite clearly, the public health.




http://www.latimes.com/opinion/op-ed/la ... story.html


Defenders of the current guidelines’ argue that the urgency of our obesity and diabetes epidemics virtually demands that we march forward with recommendations based even on imperfect data.


Gee...that sounds like the arguments trotted out for dare I say it, Climate Science; the parallels are interesting.

williatw
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Re: Factor X have we finally found the fountain of Youth?

Postby williatw » Tue Nov 06, 2018 9:09 am

The Observer Cancer research


A cure for cancer: how to kill a killer




Revolutionary work on the body’s immune system and a host of new drug trials mean that beating cancer may be achievable



Image
A transparent tumour tomography showing T-cells attacking a tumour following treatment.

In December 2015, the second generation of checkpoint inhibitors (called anti-PD-1 or anti-PD-L1, depending on whether they’re blocking the T-cell or tumour side of the handshake) was used to unleash the immune system of Jimmy Carter and clear an aggressive cancer from his liver and brain. The news of the 91-year-old’s miraculous recovery surprised everyone, including the former president himself.


Last month, the Nobel prize in medicine was awarded for two breakthrough scientific discoveries heralded as having “revolutionised cancer treatment”, and “fundamentally changed the way we view how cancer can be managed”. One of them went to a charismatic, harmonica-playing Texan named Jim Allison for his breakthrough advances in cancer immunotherapy. His discovery had resulted in transformative outcomes for cancer patients and a radical new direction for cancer research.

And yet many cancer patients, and even some doctors, have hardly heard of cancer immunotherapy or refuse to believe it. Those who have struggle to make sense of the new menu of options and sort reasonable hope from overblown hype.


“The emergence of cancer immunotherapy has occurred so quickly, it’s hard for scientists, let alone physicians and patients, to keep track of it all,” explains Dr Daniel Chen, a Stanford oncologist and researcher who helped bring some of the new cancer breakthroughs from lab to clinic. “The tidal wave of data is still teaching us fundamental concepts about the interaction of the human immune system and human cancer.” It’s also bringing us important new approaches to the treatment – and possibly the cure – of cancer. “So, this data needs to be disseminated as quickly as possible.”

It’s estimated that nearly 40% of us will be diagnosed with cancer in our lifetimes and, until very recently, we’ve had three basic options for dealing with that news. We’ve had surgery for at least 3,000 years. We added radiation therapy in 1896. Then in 1946, chemical warfare research led to the use of a mustard gas derivative to poison cancer cells and the advent of chemotherapy. More recently, we also started poisoning cancer through drugs that attempt to starve tumours of nutrients or blood supply.

Those traditional “cut, burn and poison” techniques are effective in about half of cases. It’s a laudable medical accomplishment that also leaves behind the other half of cancer patients. According to the World Health Organisation’s international agency for research on cancer, that translates to 9,055,027 deaths worldwide in 2018 alone.

Our usual defence against disease is our immune system. It does an excellent job of sorting out what doesn’t belong in the body and attacking it – except when it comes to cancer. For 100 years, the reasons behind that apparent failure were a mystery. Jim Allison’s breakthrough was the realisation that the immune system wasn’t ignoring cancer. Instead, cancer was taking advantage of tricks that shut down the immune system. But what if you could block those tricks and unleash the immune system’s killer T-cells against the disease?

The trick Allison’s immunology lab at the University of California, Berkeley, found involved a protein on the T-cell called CTLA-4. When stimulated, CTLA-4 acted like a circuit breaker on immune response. These brakes, which he called checkpoints, kept the cell killers from going out of control and trashing healthy body cells. Cancer took advantage of those brakes to survive and thrive.

In 1994, the lab developed an antibody that blocked CTLA-4. “Roughly, it’s like taking a brick and jamming it behind the T-cell brake pedal,” explains Dr Max Krummel, immunologist who had worked with Allison on CTLA-4. When they injected it into cancerous mice, the antibody jammed behind CTLA-4’s brake pedal and prevented the T-cell attack from being stopped. Instead, the T-cells destroyed the tumours and cured the cancer.

The immune system is the deep ocean ecosystem of the human body. We’ve barely begun to plumb its depths


What they had found would eventually win the Nobel. It would also fly in the face of what every practising oncologist had been taught about cancer and how to fight it. It took 15 years, says Krummel, before they could finally test whether what worked in mice would translate to people.

Blocking the brakes on the immune system turned out to cause serious toxicities in some patients. “We learned pretty quickly that immunotherapy was not a free ride,” explains Dr Jedd Wolchok, a cancer immunotherapist and one of the primary investigators in the clinical trials for Allison’s anti-CTLA-4 drug. “But we were also seeing some remarkable things.” For some of the metastatic melanoma patients in the study, even terminal stage 4 patients only days away from hospice, the drug effectively cured their cancer.

“You never forget that,” Wolchok explains. “And at the time, we really had nothing that would work for metastatic melanoma.” In 2011, that anti-CTLA-4 drug would gain approval as ipilimumab (trade name Yervoy) for use treating melanoma; it has since been approved to treat kidney and colorectal cancer. As a drug, it has saved many thousands of lives. But as a proof of concept, the success of ipilimumab proved that the immune system could, in fact, be weaponised against cancer. It also kicked off the search for newer, better immune checkpoints.


The first to be discovered was called PD-1. Its discoverer, Dr Tasuku Honjo of Kyoto University, shares this year’s Nobel in medicine. PD-1 is part of a sort of secret handshake that body cells give a T-cell, telling it: “I’m one of you, don’t attack.” Cancers co-opted this secret handshake, tricking T-cells into believing they were normal, healthy body cells. But that handshake could be blocked, creating a more precise cancer-killing machine with far fewer toxic side-effects than blocking CTLA-4.

In December 2015, the second generation of checkpoint inhibitors (called anti-PD-1 or anti-PD-L1, depending on whether they’re blocking the T-cell or tumour side of the handshake) was used to unleash the immune system of Jimmy Carter and clear an aggressive cancer from his liver and brain. The news of the 91-year-old’s miraculous recovery surprised everyone, including the former president himself.

Image
Groundbreaking work: Nobel prize-winning immunologist Jim Allison.

For many people, “that Jimmy Carter drug”, the anti-PD-1 drug pembrolizumab, approved last year and sold as Keytruda, was the first and only thing they’d heard about cancer immunotherapy. Keytruda is currently one of the most widely used of the new class of drugs, approved for use against nine different types of cancer in the US, and a smaller number in the UK, and that list is growing rapidly, as is the number of acronyms for the dozens of new checkpoints being tested. The immune system remains the deep ocean ecosystem of the human body. We’ve barely begun to plumb its depths.


For researchers such as Chen and others, this is our penicillin moment in the war on cancer. As a drug, penicillin cut infection rates, cured some bacterial diseases and saved millions of lives. But as a scientific breakthrough, it redefined the possible and opened a fertile new frontier for generations of researchers. Nearly 100 years after the discovery of that one simple drug, antibiotics are an entire class of medicines with a global impact so profound that we take them for granted. Invisible terrors that plagued and poisoned mankind for millennia are now casually vanquished at a high street chemist. “We’ve only just discovered the checkpoint inhibitors,” Chen says. “So it’s the breakthrough – we’ve just discovered our penicillin.”

https://interactive.guim.co.uk/uploader ... Jepxam9f8/


Seven years after the approval of that first checkpoint inhibitor, there are reportedly 940 “new” cancer immunotherapeutic drugs being tested in the clinic by more than half-a-million cancer patients in more than 3,000 clinical trials, with over 1,000 more in the preclinical phase.



Those numbers are dwarfed by the number of trials testing immunotherapy combinations or using them in concert with chemotherapy or radiation, which, Allison notes, essentially turn the dead tumour into a cancer vaccine. It’s hoped that, with checkpoint inhibitors releasing the brakes, the immune system can effectively finish up what the chemotherapy starts. There are so many ongoing trials it’s impossible to typify their stages or results, but several have been positive. The European Society for Medical Oncology recently announced the first modest immunotherapy success against triple negative breast cancer, a horribly aggressive disease found primarily in younger women, which has stubbornly resisted previous treatment options.

Nor are checkpoint inhibitors the only immunotherapy of cancer. There are currently numerous clinical trials involving bespoke vaccines, customised to a patient’s individual cancer. Another promising technique, known as adoptive cell transfer, fertilises a clone army of extracted T-cells, then reinjects them into the patient to chase down each cell; another called chimeric T-cell therapy, or CAR-T, reengineers a patient’s killer T-cell into a sort of robocop cancer killer, creating a startlingly powerful living drug capable of adapting to match cancer for a lifetime. CAR-T has already wiped out certain forms of childhood leukaemia. These are claims that simple cancer drugs can’t make.

The patients who respond to these drugs go into remissions measured not in extra weeks or months of life, but lifetimes
“The word cure can now be used in oncology,” says Dr Axel Hoos, an immunologist and former global medical lead for the Bristol-Myers Squibb immune-oncology programme. “It’s no longer fantasy or a cruel promise that you can’t fulfil. We don’t yet know who will be the lucky patients who will be cured, but we have seen cures already.”

Hype can be dangerous, just as false hope can be cruel. There’s a natural tendency to invest too much hope in a new science, especially one that promises to turn the tables on a disease that has, in some way, touched everyone’s life, and sober caution is required. Right now, there are only handful of immunotherapies available. The majority of patients respond partially or not at all and some even develop and acquire resistance to the disease. But the minority of cancer patients who have been shown to respond to these drugs experience remissions measured not in extra weeks or months of life, but in lifetimes. “Such transformative, durable responses are the unique value proposition of the cancer immunotherapeutic approach,” Chen says. But it’s important to note that that potential is different from a guarantee of any one outcome for any individual patient.

https://interactive.guim.co.uk/uploader ... bbI77EQH7/

And as Wolchok told me: “Immunotherapy is not a free ride.” There are the toxicities that occur when a T-cell response in unleashed. There is also the “economic toxicity” of bespoke cancer treatments that bring about durable remission but cost upwards of $1m. A third concern, especially in rural or underserved sectors, is access to both information and the drugs and drug trials themselves. They’re out there but patients and physicians need to be empowered to ask questions and understand their choices. Several doctors tell me that the goal of treatment, if a cure isn’t possible, is holding on for the next breakthrough. If and when it comes, patients and doctors need to be ready to understand it. “After all,” says Chen, “there’s nothing more useless than therapeutic breakthroughs against cancer that people don’t know about.”






https://www.theguardian.com/science/201 ... unotherapy

Aero
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Re: Factor X have we finally found the fountain of Youth?

Postby Aero » Thu Nov 15, 2018 12:43 am

Aero wrote:I don't know about telomeres but for health extension, Crispr Pharmaceuticals has something that's pretty sure. It is a targeted and programmable gene editing methodology. It has been approved for human trials. It very specifically targets the programmed gene in the dna strand, snips it out and replaces it, as programmed. The company CEO says that programming the system will be big business for those who can do it. In particular, once a specific gene is programmed, cancer gene, for example, a serum is injected and the system snips out and replaces all of those genes in the body. The cancer is cured because the cells no longer reproduce cancer cells. That part is not a lot different than what has been tried for many years, it is the specificity of gene targeting that is the new breakthrough. Oh, and Crispr Pharmaceuticals is attracting $billions in partnerships and licensing from the major drug companies.

The stock market is still waiting for the cures to be demonstrated and reproduced, it seems.


Pardon me for quoting myself but I made a mistake today, I've been thinking! If the above works out as claimed, do you foresee any of the following?

1- Complete identity change by modifying one's DNA so that it wouldn't match police records? Or crime scene evidence?
2- "Doctors" claiming a brand new discovery of the "longevity gene" and treatment only costs $***.***? Just give it time, about 3 months, to work (and for me to get out of town).
3- People who want to change the color of their hair and eyes?
4- Other?

I was just thinking that some of the social side effects could be interesting. Is muscle strength genetic? Can one's height be changed genetically? Body odor? Body "parts?"
Aero

Betruger
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Re: Factor X have we finally found the fountain of Youth?

Postby Betruger » Sun Dec 09, 2018 10:35 pm

People are already amputating themselves as a form of body modification. You think >CRISPR level DIY body mod toolbox is going to make it less popular?
You can do anything you want with laws except make Americans obey them. | What I want to do is to look up S. . . . I call him the Schadenfreudean Man.

williatw
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Re: Factor X have we finally found the fountain of Youth?

Postby williatw » Mon Dec 17, 2018 1:34 am

An Interview with Reason – Near-Term Life Extension Therapies

Tam Hunt December 12, 2018


What are the most promising near-term therapies that may actually turn back the clock on biological aging?

Senolytic treatment, obviously, is the one that is here already and is presently available. It is fortunate that some of the first drugs identified to have this effect are, to a significant degree, already widely used and cheap. The animal results are far better in terms of robustness and reproducibility than any of the calorie restriction mimetic and other stress response tinkering work. The first human data from formal trials will arrive late this year or in early 2019. These first-generation approaches are killing only about half of the senescent cells at best (and far fewer than that in some tissues) but are nonetheless very effective in comparison to any other approach to age-related inflammatory disease.


The next approach to arrive that will likely have a similar character and size of effect is breaking of glucosepane cross-links, but since that involves a completely new enzyme-based therapy, we're unlikely to see it in people any sooner than a decade from now. If there is interest in that field, someone might uncover a useful small molecule prior to then, but it seems unlikely.

Other than that, over that same timeframe: (a) advances in stem cell medicine, moving beyond the simple transplantation therapies that do little other than suppress inflammation towards ways to actually replace damaged populations and have them get to work; (b) removal of amyloids through means other than the immunotherapies that are the present staple of that field; (c) forms of immune system restoration, such as via thymic regrowth, replacement or enhancement of hematopoietic stem cells, and clearance of problem immune cells.

I'm not convinced that there is an enormous benefit to be realized from approaches to enhance mitochondrial function, such as NAD+ precursors and mitochondrially targeted antioxidants, that get a lot of hype and attention. They may have a small positive effect on metabolism in later life, which would make them worth taking when cheap and safe. They are not in any way reversing aging - they are forcing a damaged machine to work harder without addressing any of the causes of failure. One can paint the same picture when discussing ways to enhance stem cell function without addressing the underlying damage, such as telomerase therapies and the use of signaling molecules. It may meet the cost-benefit equation, but it also may not, since these are much more expensive propositions.

Why is breaking extracellular crosslinks so important?

This is important because cross-links cause stiffening of tissues. The stiffening of blood vessels is the cause of hypertension, and hypertension is (like inflammation) a major way in which low-level biochemical damage is translated into many different forms of structural damage: pressure damage to delicate tissues; rupture of capillaries in the brain; remodeling and weakening of the heart; increased risk of atherosclerotic lesions causing stroke or heart attack. High blood pressure is very damaging. It is so harmful that ways to reduce blood pressure that work by overriding signaling systems - which do absolutely nothing to eliminate the root cause, the biochemical damage of aging - can still produce large reductions in mortality risk.

All of that can be greatly reduced by cross-link breaking, and there is only one major class of cross-links in humans that needs targeting to obtain that benefit: those involving glucosepane. Thus, like senolytics, once there is some motion towards achieving this end, we should see a very rapid expansion of the industry and delivery of benefits to patients. Glucosepane is hard to work with, so very few groups have done anything meaningful - the first big advance that the SENS Research Foundation achieved in this field was to fund the creation of the tools needed to move forward at all in this part of the field. Even now, there is really only one group working earnestly on it that I know of, David Spiegel's team at Yale, with a couple of others doing some investigative work around the edges of the challenge. The Spiegel approach is to mine the bacterial world for enzymes that degrade glucosepane and then refine the successes into therapeutic drugs. His team is a fair way along, and work is progressing in a funded startup company at this point.


https://www.leafscience.org/an-intervie ... therapies/

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Re: Factor X have we finally found the fountain of Youth?

Postby williatw » Tue Jan 29, 2019 8:00 pm

This is probably Bulls!&t but here goes:


A cure for cancer? Israeli scientists say they think they found one

“We believe we will offer in a year's time a complete cure for cancer."

By Maayan Jaffe-Hoffman




Image


A small team of Israeli scientists think they might have found the first complete cure for cancer.

“We believe we will offer in a year’s time a complete cure for cancer,” said Dan Aridor, of a new treatment being developed by his company, Accelerated Evolution Biotechnologies Ltd. (AEBi), which was founded in 2000 in the ITEK incubator in the Weizmann Science Park. AEBi developed the SoAP platform, which provides functional leads to very difficult targets.

“Our cancer cure will be effective from day one, will last a duration of a few weeks and will have no or minimal side-effects at a much lower cost than most other treatments on the market,” Aridor said. “Our solution will be both generic and personal.”

Image



It sounds fantastical, especially considering that an estimated 18.1 million new cancer cases are diagnosed worldwide each year, according to reports by the International Agency for Research on Cancer. Further, every sixth death in the world is due to cancer, making it the second leading cause of death (second only to cardiovascular disease).

Aridor, chairman of the board of AEBi and CEO Dr. Ilan Morad, say their treatment, which they call MuTaTo (multi-target toxin) is essentially on the scale of a cancer antibiotic – a disruption technology of the highest order.

The potentially game-changing anti-cancer drug is based on SoAP technology, which belongs to the phage display group of technologies. It involves the introduction of DNA coding for a protein, such as an antibody, into a bacteriophage – a virus that infects bacteria. That protein is then displayed on the surface of the phage. Researchers can use these protein-displaying phages to screen for interactions with other proteins, DNA sequences and small molecules.

In 2018, a team of scientists won the Nobel Prize for their work on phage display in the directed evolution of new proteins – in particular, for the production of antibody therapeutics.

AEBi is doing something similar but with peptides, compounds of two or more amino acids linked in a chain. According to Morad, peptides have several advantages over antibodies, including that they are smaller, cheaper, and easier to produce and regulate.

When the company first started, Morad said, “We were doing what everyone else was doing, trying to discover individual novel peptides for specific cancers.” But shortly thereafter, Morad and his colleague, Dr. Hanan Itzhaki, decided they wanted to do something bigger.

To get started, Morad said they had to identify why other cancer-killing drugs and treatments don’t work or eventually fail. Then, they found a way to counter that effect.

For starters, most anti-cancer drugs attack a specific target on or in the cancer cell, he explained. Inhibiting the target usually affects a physiological pathway that promotes cancer. Mutations in the targets – or downstream in their physiological pathways – could make the targets not relevant to the cancer nature of the cell, and hence the drug attacking it is rendered ineffective.

In contrast, MuTaTo is using a combination of several cancer-targeting peptides for each cancer cell at the same time, combined with a strong peptide toxin that would kill cancer cells specifically. By using at least three targeting peptides on the same structure with a strong toxin, Morad said, “we made sure that the treatment will not be affected by mutations; cancer cells can mutate in such a way that targeted receptors are dropped by the cancer.”

“The probability of having multiple mutations that would modify all targeted receptors simultaneously decreases dramatically with the number of targets used,” Morad continued. “Instead of attacking receptors one at a time, we attack receptors three at a time – not even cancer can mutate three receptors at the same time.”

Furthermore, many cancer cells activate detoxification mechanisms when in stress from drugs. The cells pump out the drugs or modify them to be non-functional. But Morad said detoxification takes time. When the toxin is strong, it has a high probability of killing the cancer cell before detoxification occurs, which is what he is banking on.



Many cytotoxic anticancer treatments aim at fast-growing cells. But cancer stem cells are not fast growing, and they can escape these treatments. Then, when the treatment is over, they can generate cancer again.

“If it does not completely annihilate the cancer, the remaining cells can start to get mutations again, and then the cancer comes back, but this time it is drug resistant,” Morad said.

He explained that because cancer cells are born out of mutations that occur in cancer stem cells, most of the overexpressed proteins which are targeted on the cancer cell exist in the cancer stem cells. MuTaTo’s multiple-target attack ensures that they will be destroyed as well.

Finally, some cancer tumors erect shields which create access problems to large molecules, such as antibodies. MuTaTo acts like an octopus or a piece of spaghetti and can sneak into places where other large molecules cannot reach. Morad said the peptide parts of MuTaTo are very small (12 amino acids long) and lack a rigid structure.

“This should make the whole molecule non-immunogenic in most cases and would enable repeated administration of the drug,” he said.

Morad said their discovery could also reduce the sickening side-effects of most cancer treatments, which stem from drug treatments interacting with the wrong or additional targets, or the correct targets but on non-cancerous cells. He said MuTaTo’s having a combination of several highly specific cancer-targeting peptides on one scaffold for each type of cancer cell would increase the specificity to the cancer cell due to the avidity effect. In addition, in most cases, the non-cancer cells that have a protein in common with the cancer cells do not overexpress it.

“This makes a great difference between the two kinds of cells and should decrease the side effects dramatically,” Morad said.

He equated the concept of MuTaTo to the triple drug cocktail that has helped change AIDS from being an automatic death sentence to a chronic – but often manageable – disease.

Today, AIDS patients take protease inhibitors in combination with two other drugs called reverse transcriptase inhibitors. The drug combination disrupts HIV at different stages in its replication, restrains an enzyme crucial to an early stage of HIV duplication and holds back another enzyme that functions near the end of the HIV replication process.

“We used to give AIDS patients several drugs, but we would administer them one at a time,” Morad explained. “During the course of treatment, the virus mutated, and the AIDS started attacking again. Only when patients started using a cocktail, were they able to stop the disease.”

Now, he said, people with AIDS are HIV carriers, but they are not sick anymore.

The MuTaTo cancer treatment will eventually be personalized. Each patient will provide a piece of his biopsy to the lab, which would then analyze it to know which receptors are overexpressed. The individual would then be administered exactly the molecule cocktail needed to cure his disease.
However, unlike in the case of AIDS, where patients must take the cocktail throughout their lives, in the case of MuTaTo, the cells would be killed, and the patient could likely stop treatment after only a few weeks.

The company is now writing patents on specific peptides, which will be a large bank of targeting toxin peptides wholly owned and hard to break, said Aridor.

Morad said that so far, the company has concluded its first exploratory mice experiment, which inhibited human cancer cell growth and had no effect at all on healthy mice cells, in addition to several in-vitro trials. AEBi is on the cusp of beginning a round of clinical trials which could be completed within a few years and would make the treatment available in specific cases.
Aridor added: “Our results are consistent and repeatable.”



https://www.jpost.com/HEALTH-SCIENCE/A- ... one-578939

williatw
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Re: Factor X have we finally found the fountain of Youth?

Postby williatw » Wed Jan 30, 2019 6:35 pm

Or not:

"More likely, this claim is yet another in a long line of spurious, irresponsible and ultimately cruel false promises for cancer patients."
— Dr. Ben Neel


But Dr. Ben Neel, director of Perlmutter Cancer Center at NYU Langone Health, is skeptical, telling Fox News via email: "Of course, curing cancer is the goal of everyone who comes to work every day at a cancer center — and if this company does, in fact, cure cancer, they will have my congratulations and thanks. But cancer is multiple diseases, and it is highly unlikely that this company has found a 'cure' for cancer, anymore than there is a single cure for infections."


This admittedly doesn't exactly inspire confidence:

The treatment has not been tested in humans yet, although Aridor said it has shown success in mice and is nearing the clinical trial stage.


https://www.foxnews.com/health/cure-for ... evelopment

williatw
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Re: Factor X have we finally found the fountain of Youth?

Postby williatw » Sat Feb 09, 2019 11:26 pm

Reporting on the Longevity Leaders Conference




Dr. Aubrey de Grey was in fine form as usual during the keynote panel discussion at the start of the event, just as he was when, later that day, I had the opportunity to interview him about progress with SENS. While we will be publishing the interview I did with Aubrey later, it's a good time to share the interesting concept of damage crosstalk now. It turns out that Aubrey has become more optimistic about the medical control of age-related damage and has moved his prediction of longevity escape velocity down from 20 years to 18. Quite simply, there is increasing evidence that the different aging processes have a lot more influence and interaction with each other (crosstalk) than previously thought.



https://www.fightaging.org/archives/201 ... /#comments

williatw
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Re: Factor X have we finally found the fountain of Youth?

Postby williatw » Fri Feb 22, 2019 11:53 pm

CRISPR Gene Editing Makes Stem Cells ‘Invisible’ to Immune System



Technique Prevents Transplant Rejection in the Lab, a Major Advance for Stem Cell Therapies

Image
Human heart muscle cells derived from triple-engineered stem cells that are “invisible” to the immune system. The red is troponin, a protein that participates in cardiac muscle contraction. The blue is the cell’s nucleus. Researchers hope cells like these will eventually be used to treat heart failure. Credit: Xiaomeng Hu.

UC San Francisco scientists have used the CRISPR-Cas9 gene-editing system to create the first pluripotent stem cells that are functionally “invisible” to the immune system, a feat of biological engineering that, in laboratory studies, prevented rejection of stem cell transplants. Because these “universal” stem cells can be manufactured more efficiently than stem cells tailor-made for each patient – the individualized approach that dominated earlier efforts – they bring the promise of regenerative medicine a step closer to reality.

“Scientists often tout the therapeutic potential of pluripotent stem cells, which can mature into any adult tissue, but the immune system has been a major impediment to safe and effective stem cell therapies,” said Tobias Deuse, MD, the Julien I.E. Hoffman, MD, Endowed Chair in Cardiac Surgery at UCSF and lead author of the new study, published Feb. 18 in the journal Nature Biotechnology.

The immune system is unforgiving. It’s programmed to eradicate anything it perceives as alien, which protects the body against infectious agents and other invaders that could wreak havoc if given free rein. But this also means that transplanted organs, tissues or cells are seen as a potentially dangerous foreign incursion, which invariably provokes a vigorous immune response leading to transplant rejection. When this occurs, donor and recipient are said to be – in medical parlance – “histocompatibility mismatched.”
Sonja Schrepfer, MD, PhD and Tobias Deuse, MD in the lab.
“We can administer drugs that suppress immune activity and make rejection less likely. Unfortunately, these immunosuppressants leave patients more susceptible to infection and cancer,” explained Professor of Surgery Sonja Schrepfer, MD, PhD, the study’s senior author and director of the UCSF Transplant and Stem Cell Immunobiology (TSI) Lab at the time of the study.

ImageSonja Schrepfer, MD, PhD and Tobias Deuse, MD in the lab.

In the realm of stem cell transplants, scientists once thought the rejection problem was solved by induced pluripotent stem cells (iPSCs), which are created from fully-mature cells – like skin or fat cells – that are reprogrammed in ways that allow them to develop into any of the myriad cells that comprise the body’s tissues and organs. If cells derived from iPSCs were transplanted into the same patient who donated the original cells, the thinking went, the body would see the transplanted cells as “self,” and would not mount an immune attack.

But in practice, clinical use of iPSCs has proven difficult. For reasons not yet understood, many patients’ cells prove unreceptive to reprogramming. Plus, it’s expensive and time-consuming to produce iPSCs for every patient who would benefit from stem cell therapy.

“There are many issues with iPSC technology, but the biggest hurdles are quality control and reproducibility. We don’t know what makes some cells amenable to reprogramming, but most scientists agree it can’t yet be reliably done,” Deuse said. “Most approaches to individualized iPSC therapies have been abandoned because of this.”

Deuse and Schrepfer wondered whether it might be possible to sidestep these challenges by creating “universal” iPSCs that could be used in any patient who needed them. In their new paper, they describe how after the activity of just three genes was altered, iPSCs were able to avoid rejection after being transplanted into histocompatibility-mismatched recipients with fully functional immune systems.

“This is the first time anyone has engineered cells that can be universally transplanted and can survive in immunocompetent recipients without eliciting an immune response,” Deuse said.

The researchers first used CRISPR to delete two genes that are essential for the proper functioning of a family of proteins known as major histocompatibility complex (MHC) class I and II. MHC proteins sit on the surface of almost all cells and display molecular signals that help the immune system distinguish an interloper from a native. Cells that are missing MHC genes don’t present these signals, so they don’t register as foreign. However, cells that are missing MHC proteins become targets of immune cells known as natural killer (NK) cells.
Lewis Lanier, PhD, study co-author.Lewis Lanier, PhD, study co-author.
Working with professor Lewis Lanier, PhD – study co-author, chair of UCSF’s Department of Microbiology and Immunology, and an expert in the signals that activate and inhibit NK cell activity – Schrepfer’s team found that CD47, a cell surface protein that acts as a “do not eat me” signal against immune cells called macrophages, also has a strong inhibitory effect on NK cells.

Believing that CD47 might hold the key to completely shutting down rejection, the researchers loaded the CD47 gene into a virus, which delivered extra copies of the gene into mouse and human stem cells in which the MHC proteins had been knocked out.

Image
Lewis Lanier, PhD, study co-author

CD47 indeed proved to be the missing piece of the puzzle. When the researchers transplanted their triple-engineered mouse stem cells into mismatched mice with normal immune systems, they observed no rejection. They then transplanted similarly engineered human stem cells into so-called humanized mice – mice whose immune systems have been replaced with components of the human immune system to mimic human immunity – and once again observed no rejection.

Additionally, the researchers derived various types of human heart cells from these triple-engineered stem cells, which they again transplanted into humanized mice. The stem cell-derived cardiac cells were able to achieve long-term survival and even began forming rudimentary blood vessels and heart muscle, raising the possibility that triple-engineered stem cells may one day be used to repair failing hearts.

“Our technique solves the problem of rejection of stem cells and stem cell-derived tissues, and represents a major advance for the stem cell therapy field,” Deuse said. “Our technique can benefit a wider range of people with production costs that are far lower than any individualized approach. We only need to manufacture our cells one time and we’re left with a product that can be applied universally.”

Authors: Additional authors on the paper include Xiaomeng Hu (co-first author), Alessia Gravina, Dong Wang and Grigol Tediashvili of UCSF, University Heart Center Hamburg, Cardiovascular Research Center Hamburg and the German Center for Cardiovascular Research; Victor J. Garcia of the University of North Carolina School of Medicine; and Mark M. Davis of Stanford University and the Howard Hughes Medical Institute. Lewis Lanier is the American Cancer Society Professor and Chair in the Department of Microbiology and Immunology; the J. Michael Bishop, MD, Distinguished Professor in Microbiology and Immunology; and director of the Parker Institute for Cancer Immunotherapy at UCSF.


Addendum:
They then transplanted similarly engineered human stem cells into so-called humanized mice – mice whose immune systems have been replaced with components of the human immune system to mimic human immunity – and once again observed no rejection.
Additionally, the researchers derived various types of human heart cells from these triple-engineered stem cells, which they again transplanted into humanized mice.


So once more it hasn't been tried with humans yet so no way to know if it will even work (in people).




https://www.ucsf.edu/news/2019/02/41331 ... une-system

Diogenes
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Re: Factor X have we finally found the fountain of Youth?

Postby Diogenes » Thu Feb 28, 2019 10:49 pm

I just wish to say I appreciate your effort in posting this information in here.
‘What all the wise men promised has not happened, and what all the damned fools said would happen has come to pass.’
— Lord Melbourne —


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