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Sirolimus seems to lower the cancer risk in some transplant patients.
Sirolimus was shown to inhibit the progression of dermal Kaposi's sarcoma in patients with renal transplants.
Other mTOR inhibitors, such as temsirolimus (CCI-779) or everolimus (RAD001), are being tested for use in cancers such as glioblastoma multiforme and mantle cell lymphoma.
However, these drugs have a higher rate of fatal adverse events in cancer patients than control drugs.
A combination therapy of doxorubicin and sirolimus has been shown to drive AKT-positive lymphomas into remission in mice.
Akt signalling promotes cell survival in Akt-positive lymphomas and acts to prevent the cytotoxic effects of chemotherapy drugs, such as doxorubicin or cyclophosphamide.
Sirolimus blocks Akt signalling and the cells lose their resistance to the chemotherapy.
Bcl-2-positive lymphomas were completely resistant to the therapy; eIF4E-expressing lymphomas are not sensitive to sirolimus.
Sirolimus also shows promise in treating tuberous sclerosis complex (TSC), a congenital disorder that leaves sufferers prone to benign tumor growth in the brain, heart, kidneys, skin, and other organs.
After several studies conclusively linked mTOR inhibitors to remission in TSC tumors, specifically subependymal giant-cell astrocytomas in children and angiomyolipomas in adults, many US doctors began prescribing sirolimus (Wyeth's Rapamune) and everolimus (Novartis's RAD001) to TSC patients off-label.
Numerous clinical trials using both rapamycin analogs, involving both children and adults with TSC, are underway in the United States.
Most studies thus far have noted that tumors often regrew when treatment stopped.
Facial angiofibromas occur in 80% of patients with TSC, and the condition is very disfiguring.
A retrospective review of English-language medical publications reporting on topical sirolimus treatment of facial angiofibromas found sixteen separate studies with positive patient outcomes after using the drug.
The reports involved a total of 84 patients, and improvement was observed in 94% of subjects, especially if treatment began during the early stages of the disease.
Sirolimus treatment was applied in several different formulations (ointment, gel, solution, and cream), ranging from 0.003 to 1% concentrations.
Reported adverse effects included one case of perioral dermatitis, one case of cephalea, and four cases of irritation.
mTOR, specifically mTOR1, was first shown to be important in aging in 2003, in a study on worms; sirolimus was shown to inhibit and slow aging in worms, yeast, and flies, and then to improve the condition of mouse models of various diseases of aging.
Sirolimus was first shown to extend lifespan in wild-type mice in a study published by NIH investigators in 2009; the studies have been replicated in mice of many different genetic backgrounds.
The results are further supported by the finding that genetically modified mice with impaired mTOR1 signalling live longer.
The known adverse effects caused by sirolimus and marketed analogs at the doses used in transplant regimens, especially the increased risk of infection due to immunosuppression, as well as dose-dependent metabolic impairment, make it unlikely that chronic, long-term treatment with sirolimus could become a widely used anti-aging agent.
Among the effective strategies that have been explored to minimize such side effects are intermittent treatment regimens and combinations with insulin sensitizers (rosiglitazone) or antidiabetics (metformin) to prevent metabolic dysfunction.
As many of these side effects are believed to result not from inhibition of mTORC1, but instead from off-target inhibition of a second mTOR complex, mTORC2, there have been efforts to develop rapamycin analogs that are more specific for mTORC1; these compounds show reduced side effects in vivo.
In contrast to the immunosuppressive effects found in long-term high dosing, a study combining low-dose Everolimus (a rapamycin analog) and Dactolisib for a single 6 week course followed by influenza vaccination in healthy elderly patients (>65 years of age) found that this combination significantly reduced the number of infections reported by participants relative to placebo (from 2.41 to 1.49 infections per person per year), increased the serological response by more than 20%, did not produce any excess events of hyperglycemia or hypercholesteremia (associated with mTORC2 inhibition) and was generally well tolerated.
Rapamycin has complex effects on the immune system—while IL-12 goes up and IL-10 decreases, which suggests an immunostimulatory response, TNF and IL-6 are decreased, which suggests an immunosuppressive response.
The duration of the inhibition and the exact extent to which mTORC1 and mTORC2 are inhibited play a role, but are not yet well understood.
As of 2016 studies in cells, animals, and humans have suggested that mTOR activation as process underlying systemic lupus erythematosus and that inhibiting mTOR with rapamycin may be a disease-modifying treatment.
As of 2016 rapamycin had been tested in small clinical trials in people with lupus.
Lymphatic malformation is either a superficial, deep or mixed growth of lymphatic vessels.
Treatment is limited to removal or destruction, however, the rate of recurrence is high.
García M et al.
made a topical formulation of rapamycin, and conducted a small case series, involving 11 patients with superficial lymphatic malformations.
The clinical appearance improved in all 11, and symptoms improved in 9 of the 11.
The average follow-up time was 16.1 months, indicating that topical rapamycin, ranging from .4-1.0% is promising for management of superficial lymphatic malformations.
Rapamycin is used in biology research as an agent for chemically induced dimerization.
In this application, rapamycin is added to cells expressing two fusion constructs, one of which contains the rapamycin-binding FRB domain from mTOR and the other of which contains an FKBP domain.
Each fusion protein also contains additional domains that are brought into proximity when rapamycin induces binding of FRB and FKBP.
In this way, rapamycin can be used to control and study protein localization and interactions.
Ascension
Ascension or ascending may refer to:
CNA
CNA may be an acronym or abbreviation for any of the following:
Chronic fatigue
Chronic fatigue may refer to:
but is distinct from:
St. Marys River (Florida–Georgia)
The St. Marys River (named Saint Marys River by the USGS, and sometimes misspelled as "St. Mary's River") is a river in the southeastern United States.
From near its source in the Okefenokee Swamp, to its mouth at the Atlantic Ocean, it forms a portion of the border between the U.S. states of Georgia and Florida.
The river also serves as the southernmost point in the state of Georgia.
The St. Marys River rises as a tiny stream, River Styx, flowing from the western edge of Trail Ridge, the geological relic of a barrier island/dune system, and into the southeastern Okefenokee Swamp.
Arching to the northwest, it loses its channel within the swamp, then turns back to the southwest and reforms a stream, at which point it becomes the St. Marys River.
Joined by another stream, Moccasin Creek, the river emerges from Okefenokee Swamp at Baxter, Florida/Moniac, Georgia.
It then flows south, then east, then north, then east-southeast, finally emptying its waters into the Atlantic, near St. Marys, Georgia and Fernandina Beach, Florida.
On 6 July 1805 Lieutenant Robert Pigot of arrived off the harbour in the French privateer schooner "Matilda", which the British had captured three days earlier.
On 7 July Pigot took "Matilda" twelve miles up the St Marys River to attack three vessels reported to be there.
Along the way militia and riflemen fired on "Matilda".
Eventually the British reached the three vessels, which were lashed in a line across the river.
They consisted of a Spanish privateer schooner and her two British prizes, the ship and the brig "Ceres", which the Spanish privateer had captured some two months earlier.
The Spaniards had armed "Golden Grove" with eight 6-pounder guns and six swivels, and given her a crew of 50 men.
The brig too was armed with swivels and small arms.
The Spanish schooner carried six guns and a crew of 70 men.
Pigot engaged the vessels for an hour, and then after "Matilda" had grounded, took his crew in her boats and captured "Golden Grove".
The British then captured the other two vessels.
Lastly, Pigot fired on a group of 100 militia, with a field gun, dispersing them.
The British had two men killed, and 14 wounded, including Pigot, who had received two bullet wounds to head and one to a leg.
A crowd of Americans on the Georgia side of the river watched the entire battle.
See Battle of Fort Peter
Martin, Charles.
"Where the River Ends".
New York, Broadway Books, 2008. .
An artist and his dying wife fulfill her wish of one last canoe ride from the headwaters of the St. Marys to the sea.
Taking Tiger Mountain (By Strategy)
Taking Tiger Mountain (By Strategy) is the second solo album by English musician Brian Eno (credited simply as "Eno"), released in November 1974 by Island Records.
Unlike his debut album "Here Come the Warm Jets", Eno's second album used a core band of five instrumentalists--keyboardist, guitarist, bassist, drummer and percussionist--and used fewer guest musicians.
Also participating was guitarist and co-writer Phil Manzanera, who had played with Eno in Roxy Music.
To help guide the production of the album, Eno and Peter Schmidt developed instruction cards called Oblique Strategies to facilitate the making of the album.
"Taking Tiger Mountain (By Strategy)" is a loose concept album that addresses a variety of subjects that range from espionage to the Chinese Communist revolution.
The album alludes to pop-song structures, but Eno's lyrics play with themes of geopolitical intrigue.
It did not chart in the United Kingdom or the United States, but it got good reviews from critics.
Since its release, the album has received even more critical attention, with varying opinions on its quality.
The album was inspired by a series of postcards depicting a Chinese revolutionary opera titled "Taking Tiger Mountain by Strategy".
Eno described his understanding of the title as referring to "the dichotomy between the archaic and the progressive.
Half Taking Tiger Mountain – that Middle Ages physical feel of storming a military position – and half (By Strategy) – that very, very 20th-century mental concept of a tactical interaction of systems."
To further explore the possibilities of the studio setting, Eno and his friend Peter Schmidt developed instruction cards, called Oblique Strategies.
During the recording sessions, he would allow the cards to dictate the next unconsidered action in the recording process.
Describing the words on the album as an expression of "idiot glee", Eno and Schmidt eventually expanded the Oblique Strategies set to over 100 "worthwhile dilemmas", which would be used in nearly all his future recordings and productions.
Schmidt also designed the album cover, which consists of four prints from an edition of fifteen hundred of his unique lithographs, as well as Polaroids of Eno, credited on the album sleeve to Lorenz Zatecky.
Manzanera spoke positively about the recording experience.
He described it as:
...just doing anything we felt like doing at the time.
The engineer we used, Rhett Davies, also did "Diamond Head" and "801 Live" and Quiet Sun, so it was like family.
There was a lot of experimenting and a lot of hours spent with Brian Eno, me, and Rhett in the control room doing all the things that eventually evolved into those cards, the Oblique Strategies, and it was just a lot of fun.
Eno's group on "Taking Tiger Mountain" included Brian Turrington and Freddie Smith of The Winkies, along with Wyatt and Manzanera.
Other musicians played on the album.
These included Andy Mackay of Roxy Music, along with the Portsmouth Sinfonia, an orchestra in which Eno had once played clarinet.
The Portsmouth Sinfonia allowed anybody to join as long as they had no experience with the instrument they would play in the orchestra.
For guest drummer Phil Collins, Eno called in a favor from Collins' group Genesis.
After Eno had helped with the production of Genesis' album "The Lamb Lies Down on Broadway", Genesis front man Peter Gabriel asked how they could reciprocate.
Collins played drums on "Mother Whale Eyeless".
The sound of "Taking Tiger Mountain (By Strategy)" has been described as more upbeat than Eno's previous solo album, while the lyrics have darker themes and subject matter.