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Our first Weekend Workshop is being shoved to Saturday (just this time) on top of two other meetups already scheduled for the same day! This is due to Organizer personal schedule (Art must be out of town). The good news is that Tuesday's evening Hack Shack Improvements is also being moved to Monday evening. Why is that good news? Because Tuesday evening is an ARSP special board meeting set to affirm the standing of the Hack Shack, and allow for the possibility of two other volunteers to be able to fully act as event organizers. The primary function of the organizers in this case is to have keys to the main building...and therefore the bathrooms...and therefore must be approved and anointed and background checked etc... by the Board of Directors. We have been trying to get this meeting scheduled for a long time, and finally we are on their agenda. Woo-Hoo!
Apologies to those folks that planned to work on their project on Sunday. You may feel free to come in any day of the week. As for Tuesday's meetup, if you cannot come on Monday, be aware the the Hack Shack is basically open EVERY DAY, though it is best to call ahead to ensure someone is really there.
And now the normal headliner:
A regularly scheduled meetup for folks to work on whatever they like. We are still (now and forever) doing "Hack Shack Improvements" on Sundays, but so many other things happen on Sunday, we might as well make it an official "General Workshop".
This is our space to make, improve, and maintain. Come and help us create a space that suits your needs, we have lots of projects to start & finish.
Meetup members, Log in
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A project of People For the American Way dedicated to monitoring and exposing the activities of the right-wing movement. Learn More >
Garrow: Obama Should Be 'Put Down' Like A 'Rabid Dog'
Submitted by Brian Tashman on Wednesday, 1/29/2014 2:00 pm
Jim Garrow reacted to President Obama's State of the Union by once again calling for the president's death, this time comparing him to a rabid dog who should be "put down."
In a Facebook post today, Garrow suggested that Satan was behind Obama's rise to power and called the president a "quisling agent" who should face a revolution.
The Speech:
"The Boy Who Cried Wolf" is at it again. Perhaps a real wolf will eat him so we don't have to listen to the lies. Rabid dogs are put down for the protection of the innocent and to prevent the spread of disease.
Our "loyal opposition" can't even yell "You lie" without offering an apology later and backing down from speaking the truth. Ted Cruz and Rand Paul made their usual attempt at truth telling but like the Scripture tells us "A prophet is without honor in his own land", and they will be ignored unless it is to hold them up to ridicule on the morning talk shows.
In the meantime the meteor of doom continues on its course with the mad man Obama laughing derisively at the "colonialist empire" he is wreaking havoc on and bringing down. The great Satan allowed its guard to slip and a quisling agent to penetrate. His work of devastation is not done and he has spread his manure of deceit across the land again.
The lonely voices of those not addled into submission to the lies find themselves Alinskied at every turn, browbeaten into conformity, or forced to disappear into obscurity for their audacity in declaring the Emperor to be unclothed, and bare faced in his lies.
Obama is revolting in his prevarication, and our response should be to revolt - period.
- Dr. Jim Garrow -
Filed Under
People:Jim Garrow, Ted Cruz
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subset: commoncrawl


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This HAS to be Kiffin's last big time coaching job. The guy has proved absolutely nothing on the field and does not deserve to be a head coach at a big program. He will either go back to being a coordinator or a head coach at some small school, maybe even in FCS.
well that's just, like, your opinion, man


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Self-reliance and sustainability in the 21st century.
By Alison Rogers
genetic engineering, livestock welfare, food and agricultural policy, industrial agriculture
OK, we know all about the genetically engineered corn, rice and soybeans, but a GE cow? It's true, the FDA is taking public comment on the regulation of altering animal DNA in an attempt to increase their resistance to diseases such as BSE and produce healthier food products, such as meat with increased levels of omega-3 fatty acids. That doesn't sound that bad, does it? But wait, that's not all: Scientists also want to alter animals' genetics to make them more susceptible to diseases that affect humans (such as cancer) for the purpose of research. How about a hypoallergenic pet? That's also on the table. Need an organ transplant? We'll have an animal that's been engineered for that, too. They're even wanting animals to produce human pharmaceuticals such as insulin.
If these animals are approved for the food system (they're not, yet), the FDA states plainly that it will not be required to label the products that contain them.
Read more about the proposal and make your comments here.
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Australia won the toss and chose to bat in the crunch World Cup Pool A game against Sri Lanka at the Sydney Cricket Ground on Sunday.
The 1996 winners Sri Lanka lead the Aussies by one point in the group standings and a win would clinch second spot in the pool behind leaders New Zealand.
Shane Watson returned to Australia's line-up, batting at No.6 for Mitchell Marsh after he was dropped for the last win over Afghanistan, while spinner Xavier Doherty will get his first start in the tournament for paceman Josh Hazlewood.
Doherty's inclusion is an indication that the SCG pitch is expected to favour spin.
Sri Lanka made three changes, with leg-spinner Seekkuge Prasanna, batsman Upul Tharanga and all-rounder Sachithra Senanayake coming in for the injured duo Dimuth Karunaratne and Rangana Herath, with Suranga Lakmal also left out.
It will be the first time all three will feature in the tournament.
Australia: David Warner, Aaron Finch, Steven Smith, Michael Clarke (capt), Glenn Maxwell, Shane Watson, James Faulkner, Brad Haddin (wkt), Mitchell Johnson, Mitchell Starc, Xavier Doherty
Sri Lanka: Lahiru Thirimanne, Tillakaratne Dilshan, Kumar Sangakkara (wkt), Mahela Jayawardene, Angelo Mathews (capt), Dinesh Chandimal, Upul Tharanga, Thisara Perera, Seekkuge Prasanna, Sachithra Senanayake, Lasith Malinga.
Umpires: Ian Gould (ENG), Aleem Dar (PAK)
TV umpire: Richard Illingworth (ENG)
Match referee: Jeff Crowe (NZL)
Weather: Possible shower. Maximum temperature 29 degrees Celsius.


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Medical narratives often depict ordinary people who turn to alternative healing methods when traditional Western health care fails. Seldom can you find families that go to the lengths of Rupert Isaacson and Kristen Neff, who traveled from Austin, Texas, to the steppes of Mongolia with the hopes of improving their son Rowan's autistic condition.
Narrating the documentary The Horse Boy, Isaacson justifies the trip early in the film. At his worst, 5-year-old Rowan's cognitive problems make him the equivalent of "a giant 18-month-old" with poor social skills, incomplete toilet training, and seemingly endless, inexplicable tantrums. Isaacson's research into shamanism and Rowan's affinity for animals, especially horses, inspire the father to see if the two in combination could have therapeutic value. He discovers that Mongolia combines shamanic traditions with horsemanship, so he, Neff and Rowan embark on a journey a world away.
Documentary director Michel Orion Scott crosscuts between the family's travels, expert interviews, and scenes of Rowan's medical treatments as an autistic boy. Rowan makes developmental improvements when, for instance, he plays with the tour guide's son, but also experiences disappointing setbacks. "I've never seen him reject a horse before," Isaacson sighs after one promising ceremony fails to show long-term effects. Isaacson's and Neff's emotional highs and lows on their adventure offer an allegory for raising a special-needs child, which can involve triumphs and disappointments most parents never imagine. In discussing their wishes for the trip, Isaacson hopes Rowan will learn to ride a horse by himself, while Neff simply wants him to start pooping in the toilet. Neff shows more skepticism toward the native spiritualism and suffers more indignities on the trip, including a kick from a horse and some undignified washing rituals.
Given the subject matter, The Horse Boy inevitably sets a somewhat pokey pace and involves plenty of introspective talk from the parents. Rowan, of course, can't really speak for himself. The Mongolian landscapes offer gorgeous vistas (Neff isn't hard on the eyes, either, frankly) and The Horse Boy builds to an inspirational outcome that doesn't gloss over autism's challenges. The Horse Boy doesn't mention that publisher Little, Brown & Co. paid the family a $1 million advance for a book about the experience before they'd even left, but it's difficult to envision Isaacson and Neff as child-exploiters like, say, the Balloon Boy parents. At least they didn't call it The Boy Whisperer.


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South Korea Tackles Multiculturalism
In recent years, the number of rural and low-income South Korean men who have married foreign women has increased dramatically.
The government and civil society have responded by opening schools to help these "marriage migrants" learn to become South Koreans, and to teach South Koreans the value of multiculturalism.
This represents a jarring challenge to the myth South Koreans have been taught from a young age: that all Koreans are descended from a single bloodline, and that their national strength lies in their ethnic homogeneity.
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SkyChart is a software to draw chart of the night sky for the amateur astronomer from a bunch of stars and nebulae catalogs. See main web page for full download. This software is part of a full suite for astronomical observation: https://sourceforge.net/projects/ccdciel/ https://sourceforge.net/projects/indistarter/ https://sourceforge.net/projects/eqmodgui/ Requirement: https://sourceforge.net/projects/libpasastro/ See also: https://sourceforge.net/projects/indi/2,833 weekly downloads
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Software for Moon observation and survey. Let you visualize the real Moon aspect at every time. Also help to study any lunar formations using feature database and pictures library.986 weekly downloads
Scrabble3D is a highly customizable Scrabble game that not only supports Classic Scrabble and Superscrabble but also 3D games and own boards. You can play local against the computer or connect to a game server to find other players.623 weekly downloads
GPAIT is a software asset management and activities IT and Telecom. Written with Lazarus/Free Pascal, GPAIT runs under Linux and Windows OS
kombinatoriC delta library
CAS Algorithms embeded as libraries.
Langage à Objets, Universel et Programmable


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- Financial Times•7 hours ago[$$] UK's FTSE 250 almost erases Brexit plunge
The FTSE 250, the index made up of companies heavily reliant on the state of the UK economy, is within touching distance of erasing its steep losses suffered in the wake of Britain's shock decision to ...
HPE: Accelerating Next
See What HPE Can Do for You. The #1 Company in Hybrid Infrastructure.
- Morningstar•8 hours agoStocks Mixed as Fed Seems Open to September Rate Hike
U.S. stocks were mixed but largely flat Wednesday, as investors digested mixed earnings news and the Federal Reserve's statement on rates. Shares of Apple (AAPL) rose 6.6% Wednesday after the iPhone maker beat expectations despite reporting that profit fell 27% in its fiscal third quarter. Morningstar's director of technology, media, and telecom equity research Brian Colello said he remains confident in our narrow economic moat rating and our long-term thesis that most of Apple's iPhone customers today will continue to stick with the ecosystem (and buy future iPhones) going forward.


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July 30, 2016
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Anus: The opening of the rectum to the outside of the body.
The word "anus" comes straight from the Latin. It referred to the same structure to the Romans. It also meant a "ring" in the sense of an encirclement which was entirely appropriate since the anus encircles the outlet of the bowel.
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Second Edition
The #1 film music text, now with more attention to international films.More
Third Edition
The best way to integrate music theory and aural skills just got better.More
Eighth Edition
A classic music-appreciation text made fresh for today's students.More
Fourth Edition
The book that set the standard for orchestration texts.More
The most comprehensive and integrated package for every music theory classroom.More
The music theory text that students read and understand.More
"Evokes the fire of Redding. . . .
Ribowsky tells the story with nonstop
energy, while always probing for the
larger social and musical pictures."
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"Reads the way Mr. Glass's compositions sound at their best: propulsive, with a surreptitious emotional undertow." —Corinna da Fonseca-Wollheim, New York TimesMore
The classic survey of the field, retooled for a new generation of students.More
An exploration of the unswerving artistic vision underlying Beethoven's
symphonies, from one of the world's leading scholars of the composer's works.More
There's a reason hit songs offer guilty pleasure—they're designed that way.More
"Breezy, opinionated and totally delicious."—David Kirby, Wall Street JournalMore
"The best single volume ever written on the subject, such is its range, authority, and readability."—Times Literary SupplementMore
Brings to life a passionate poet-turned-musician and what compels him and his work.More


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Blockchain offer opportunities for cost reduction and innovation, and some view it as having the potential to become the business equivalent of cloud computing.
Running Windows apps on Linux is achieved mainly by two methods, though there are a number of factors to consider.
Vendors shipped fewer smartwatches as consumers waited to see what the next Apple Watch has in store.
We've worked on Agile practices -- and we think we've succeeded. Kind of.
Comparing Big Data solutions requires first understanding its role in your organization, then breaking down the specific tasks the Big Data solution will perform.


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Quilters' Guild of East Texas
The Hive
meets immediately following the Thursday guild meeting.
July 2016 Newsletter now online
July 14, 2016
Jacquie Gering
Program: Quilting Modern: Honoring Tradition
July 15 2016
Jacquie Gering
Workshop: Creative Quilting with the Walking Foot
August 11 2016
Brenda Jeschke
Program: Machine Embroidery Marries Quilting
August 12 2016
Brenda Jeschke
Workshop: Quilting Using Your Embroidery Machine
The Hive
Meets immediately following the Thursday guild meeting.
General Meeting Information
The Quilters' Guild of East Texas meets on the second Thursday of each month. Fellowship starts with coffee and goodies at 9:30 am. The business meeting and program begins at 10:00 am. Non-members are invited to attend twice before joining.
Our monthly meetings are held at First Christian Church, 4202 South Broadway Avenue, Tyler, TX 75701. The church is located at the intersection of Broadway Avenue and Loop 323 in Tyler, TX. We meet in Disciples' Hall (main building). Workshops meet in the Christian Life Center. Location changes are noted in the newsletter as well as here on the website.
Board meetings are held the Wednesday prior to the guild meeting at 10:00 am, in the Conference Room of the main building of First Christian Church.
Our mailing address is PO Box 130773, Tyler, TX 75703-0773.


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Jen Brea is a phenomenon. After working as a freelance writer in China and Africa, she enrolled for a PhD at Harvard in political science but, four years ago, got sick. She had a fever that lasted ten days.
Discuss the article on the Forums.
Have you been properly tested for Lyme poll?
Discussion in 'Lyme Disease and Co-Infections' started by loayachil, Jan 23, 2013.
Page 2 of 4
Page 2 of 4


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The Eurasian Economic Commission (EEC) has suggested to prepare several pilot digital projects for the industry of the EEU countries, BNews.kz reports [BNews.kz].
12 04 2016 In the ministry of Investment and development of RK was told about the plans on "Digital Kazakhstan-2020" state program creation
The Minister of Investment and Development of RK Asset Issekeshev, Vice-Minister Saken Sarsenov, representatives of "Zerde" NICH" JSC, ICT market and profiled organizations participants participated in presentation of "Digital Kazakhstan-2020" State Program concept.
Kazakhstan is set to enforce a ban on smartphones in the workplace for police and government workers in an effort to prevent information leaks, according to a document that was itself leaked, AFP reports [Tengrinews.kz].
China has built the world's fastest supercomputer using locally made microchips, a survey said Monday, the first time the country has taken the top spot without using US technology, AFP reports [Tengrinews.kz].
Microsoft scientists have demonstrated that by analyzing large samples of search engine queries they may in some cases be able to identify internet users who are suffering from pancreatic cancer, even before they have received a diagnosis of the disease. [hi-tech.mail.ru]
A previously unknown giant planet may have been discovered lurking in the outer reaches of our solar system, US scientists announced on Wednesday, AFP reports.[Tengrinews]
We invite you to participate in a one-day Seminar on the topic: "How to do business in English, so as not "to take English leave»"the foreign partner? (conducts Asel Khamzayeva)
International Informatization Academy presents a unique edition of the book "the Age of the finding of borders", dedicated to the 550th anniversary of the Kazakh Khanate. The book is published in a Deluxe version! The authors of the book of Tompiyev Maral and Uali Murat, published it in two languages, Russian and Kazakh.
08 04 2015 Subscribe to Newsletters
Dear IIA members! In the first quarter of 2015, only 100 members of IIA (from 1476 members) sent their annual reports to the Directorate of our Academy!


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The evacuation of the fairgrounds last year during the 2012 Washington Town and Country Fair due to severe weather prompted emergency personnel to review procedures to determine if there were areas that could be improved.
Although close to 12,000 citizens were evacuated safely that Saturday night with only one injury, due to blowing debris, there was a lot of gridlock trying to get all motorists safely out of the parking lots, and getting the buses to the loading zone.
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kevin harvick won bud shoot out 2010 Who won bud shoot out 2009
kgb answers » News & Current Events » Sports Results » kevin harvick won bud shoot out 2010 Who won bud shoot out 2009
Tags: budweiser shootout, kevin harvick, bud
Wednesday, February 01 2012
Source: http://www.jayski.com/stats/2009/bud2009.htm
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More than halfway through the Sochi Olympics, the IOC's top anti-doping official says he's not surprised there have been no positive tests so far.
Arne Ljungqvist, chairman of the IOC medical commission, says the stringent drug-testing system is working as a deterrent.
He says "it's expected that people don't cheat and those who do are not here.''
As of Friday night, Sochi organizers had conducted 1,799 tests, out of total of 2,453 planned for the games. No positive findings have been reported.
Ljungqvist noted that only one positive test was recorded at the 2010 Vancouver Games.
He says "it shows that the program is pretty efficient and serves as a deterrent.''
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|Publication number
|Publication type
|Application number
|Publication date
|Dec 19, 1989
|Filing date
|Nov 20, 1987
|Priority date
|May 18, 1984
|Fee status
|Also published as
|Publication number
|Jan R. Holmgren, Leif Gustav Lindholm, Lars T. Svennerholm
|Original Assignee
|Holmgren Jan R, Leif Gustav Lindholm, Svennerholm Lars T
|Export Citation
|BiBTeX, EndNote, RefMan
|Patent Citations (3), Non-Patent Citations (2), Referenced by (7), Classifications (43), Legal Events (5)
|External Links: USPTO, USPTO Assignment, Espacenet
This application is a continuation-in-part of U.S. Pat. application Ser. No. 735,324, filed May 17, 1985.
This invention relates to the use of a specific carcinoma associated antigen/hapten of carbohydrate nature, fucosylsialosylgangliotetraose-IV2 Fucα-,II3 NeuAcα-GgOse4 (IUPAC-IUB Lipid Document, 1977) and antibodies against this antigen for diagnostic or therapeutic procedures related to human cancer (e.g. small cell lung carcinomas) with election of Invention II Body treatment with antigens or antibodies.
It is well established that the transformation of normal tissue cells to tumor cells is associated with a change of carbohydrate structures (glycoconjugates) on the cell surface. These new or modified glycoconjugates may serve as antigens and may then represent a type of so-called tumor-associated antigens. The cell surface carbohydrates are linked either to a lipid moiety, in which case they are called glycolipids, or to peptides (proteins), in which case they are called glycopeptides (glycoproteins).
Tumor-associated glycoconjugate antigens are previously known in relation to human cancer disease. In melanomas the carbohydrate structures disialosylgangliotetraose and disialosyllactose have been identified linked to a lipid portion. Two carcinoma associated antigens CEA (carcinoembryonal antigen) and GICA (gastro-intestinal cancer antigen) have been demonstrated particularly in gastrointestinal carcinomas while a third antigen, CA-50, seems to have a more general distribution. All the antigens are shedded from the cell surface or secreted from the tumor cell and can be demonstrated in blood serums by means of immunological methods.
The present invention is based on the discovery that patients with certain forms of lung cancer (small cell carcinomas or oat-cell carcinomas) express in the primary lung tumor and its metastases an acidic glycolipid, which is not expressed in normal lung tissue. This glycolipid antigen is a ganglioside with the complete chemical structure Fucα1-2Galβ1-3GalNAcβ1-4(NeuAcα2-3)Galβ1-4Glc or IV2 Fucα-,II3 NeuAcα-GgOse4 with the short designation Fuc-GM1 (IUPAC-IUB Lipid Document, 1977). This ganglioside was first isolated from bovine brain (Ghidoni et al., J. Neurochem. 27, 511-515, 1976) but indications for its occurrence in other mammalian organs as adipose tissue, spleen and testis have also been presented. Hakomori and co-workers (Baumann et al, Cancer Res. 39, 2637-2643), 1979) isolated from rat hepatomas a ganglioside, which was tentatively identified as Fuc-GM1. A definitive establishment of the chemical structure of this ganglioside was performed by Svennerholm and collaborators (Fredman et al., Eur. J. Biochem. 116, 553-564) on gangliosides isolated from porcine nervous tissue. They also showed that chronic chloroquine treatment of the pig caused an increased lysosomal storage of Fuc-GM1 in nervous tissue (Klinghardt et al., J. Neurochem. 37, 897-908, 1981) but also in several other organs (Fredman et al., Biochem. J. 201, 581-588, 1982). Although this ganglioside has a wide distribution in pig, we have not been able to show its occurrence in normal human lung tissue or in carcinomas from a large number of human organs. In patients, died in lung small cell carcinoma, all lung tumors contained Fuc-GM1 ganglioside, and in other patients Fuc-GM1 was shed to blood serum. With the assay method for Fuc-GM1 developed by us the tumor antigen was detected on the blood serum in patients with lung small cell carcinoma but not in the blood serum of a control population or of patients with other forms of cancer.
Within the scope of the present invention procedures have been elaborated for the isolation of the tumor associated glycolipid, fucosylsialosylgangliotetraosylceramide with the short designation, ganglioside Fuc-GM1, in pure form from human cancer tissue and from animal organ. The purified ganglioside has by a special device obtained an increased immunogenic activity and then been used for the production of monoclonal antibodies. Procedures have, within the scope of the invention, been developed for the identification and quantitative determination in tissues, tissue sections, cytological preparations and various body fluids. All of these methods for diagnostic purposes are based on the fact that the antigen can be detected and quantitatively determined by the reaction with specific antibodies produced against the pure ganglioside antigen, Fuc-GM1.
The following non-limiting examples illustrate the various sources where the ganglioside antigen can be measured: surgical or autopsy material of lung, liver, brain or similar organs, cytological specimens obtained by biopsy of lung or other organs, cytological specimens obtained by biopsy of lung or other organs, where signs of cancer metastases can be suspected, cells, obtained by aspirations of the respiratory tract, expectorations, or by puncture of pleural or abdominal cavity, biological fluids like whole blood, blood plasma or serum, lymph, cerebrospinal fluid, urine, saliva or similar.
The antigen which is used in the present invention is termed, fucosylsialosylgangliotetraose and has the following chemical structure: Fucα1-2Galβ1-3GalNAcβ1-4(NeuAcα2-3)Galβ1-4Glc or IV2 αFucll3 αNeuAcGgOse4 (IUPAC-IUB Lipid Document, 1977). Within the scope of the present invention all antigens, which have been modified by the removal of the terminal glucose moiety or by the substitution of the sialic acid (NeuAc) moiety to the N-acetylgalactosamine (GalNAc) moiety instead of to the galactose (Gal) moiety are covered by this patent application. The monoclonal antibodies referred to in the present invention have all been produced from antigens bound to a lipid group (acylsphingosine) but this claim will also include the binding of the antigenic group to every other compound.
The antigen which has been used in the present invention can be isolated from tumor tissue, obtained by surgery or autopsy of patients with lung small cell carcinoma. The concentration of the antigen in the tumor tissue is in general relatively low, particularly when the patient has been treated with cytostatic drugs, and the isolation of the antigen will then be laborious. We have also found another biological material, which can be used for the isolation of the cancer antigen. When a certain strain of miniature pig is foddered with chloroquine in the diet during 3-6 months, high concentrations of the ganglioside antigen is formed in the pig's central nervous system, particularly in the dorsal root ganglia. The cancer associated ganglioside antigen can then be relatively simply isolated from brain and dorsal root ganglia. By this device one is not limited for the isolation of the antigen to surgery or autopsy material and a large number of practical and ethical difficulties are avoided.
It has previously been found that gangliosides--it means glycolipids containing sialic acid--are poor immunogens and it has been difficult to produce antibodies with high affinity and specificity against them. This difficulty has been circumvented in the present invention by the adsorption of the ganglioside antigen to a bacterial membrane with known high immunogenic activity. By this device a large number of monoclonal antibodies with high specificity and affinity against the cancer antigen have been produced.
The present invention concerns in accordance herewith a procedure for the induction of the cancer associated antigen fucosylsialosylgangliotetraose in the nervous system of a particular type of miniature pig, isolation of the antigen with chromatographical methods and production of monoclonal antibodies against the purified antigen adsorbed to a certain bacterial membrane. The invention includes also the use of the compound fucosylsialosylgangliotetraose and all the derivates of this substance and all types of antibodies directed against them for the diagnosis of different cancer forms, specially certain forms of lung cancer.
It has previously been reported that monoclonal antibodies against certain tumor-associated antigens can suppress tumor development of human tumors implanted in nude mice and clinical studies in patients have also suggested the possibility to suppress or slow down tumor growth in humans (e.g. Herlin, D and Koprowski, H, PNAS (USA), 79:4761-4765, 1982; Adams, D O et al, PNAS (USA) 81:3506-3510, 1984; Sears, H F et al, Lancet I:762-765, 1982). In some of these investigations as well as in other studies, monoclonal antibodies and polyclonal antisers against tumor-associated antigens, in conjunction with macrophages and/or the complement system, have also been found to kill tumor cells in vitro. In no instance, however, has the use of antibodies directed against fucosylsialosylgangliotetraose antigen, which is the subject matter of this invention, been described for any such purposes. Likewise, neither has the fucosylsialosylgangliotetraose antigen been used to induce protective anti-tumor immunity, or antibodies against this antigen been described for detection and localization of tumors using "imaging" techniques which are otherwise obvious possible applications for tumor-associated antigens and tumor-specific antibodies, respectively (e.g. Holmgren J, ed., Tumor marker antigens, Studentlitteratur/Chartwell-Bratt Ltd, Lund, Sweden/Bromley, England, 1985). The present invention also specifically concerns the use of the compound fucosylsialosylgangliotetraose and all the derivatives of this substance and all types of antibodies directed against them for the treatment of small cell lung cancer and other human cancer disease in patients. Such use of the antibodies and antigens in question also extends to the in vivo search for and localization of Fuc-GM1 containing cancers in patients using "imaging" techniques, and the prevention of Fuc-GM1 containing human cancers by stimulating the formation of protective anti-tumor immunity in an individual.
Miniature pigs, type Gottingen, with a weight of 20-30 kg, were given a diet, in which the regular fodder was supplemented with 30 g chloroquine diphosphate per kg fodder. The different ingredients were mixed under the addition of water and after careful mixing the fodder was pelletted and dried. The pigs were given this fodder for 2 months and were then slaughtered (bleeding under narcosis). The whole nervous system was collected, including retina and dorsal root ganglia. Brain and dorsal ganglioa + retina were processed separately, since dorsal ganglia and retina had approx. 20 times higher concentration of Fuc-GM1 than brain.
The tissue was homogenized after the addition of 3 volumes of water to one volume of tissue material. After homogenization with a knife homogenizer at 1500 rpm during 3 min., 10 volumes of methanol was added under continuous stirring. Then 5 volumes of chloroform were added. After extraction for 1 h the clear supernatant was isolated by centrifugation at 2000 rpm. To the supernatant was added water to give a final chloroform-methanol-water ratio 4:8:5.6 (by volume). After mixing in a separatory funnel, two distinct phases appeared. The upper phase was collected and evaporated to dryness after the addition of 0.1 volume of butanol to prevent foaming. The evaporation was performed with a rotaratory evaporator under gentle warming on a water bath, the temperature not exceeding 50� C. The residue was added 0.5 volume methanol per volume original tissue and 0.5 volume of 1.0 M potassium hydroxide and was left overnight at room temperature. The alkaline solution was neutralized to pH 8 with 1.0 M hydrochloric acid and was then allowed to dialyse against running tap water for 48 hours.
The dialysed crude ganglioside fraction was evaporated (lyophilized) and dissolved 1 volume of chloroform-methanol-water with a volume ratio of 60:30:4.5 per volume original tissue. A column (inner diameter 20 mm) was packed with Spherosil-DEAE-dextran, 0.2 volume of resin per volume of original tissue. The dialysed ganglioside extract was added slowly to the column and the column was then eluted with 10 bed volumes of chloroform-methanol-water (60:30:4.5, by volume). The monosialoganglioside fraction was eluted with 10 bed volumes of 0.02 M potassium acetate in methanol. The monosialoganglioside fraction was evaporated and desalted by dialysis against distilled water.
For the chromatography 1 g of silica gel (latrobeads�) was used for each g of original nervous tissue. The gel was suspended in chloroform-methanol (volume ratio 4:1) and poured into a glass column with a sintered glass filter and a diameter of 15-20 mm depending on the amount of gel. The ganglioside fraction was dissolved in 10 ml of chloroform-methanol-water (65:25:4, by volume) and applied to the column. It was eluted first with 15 ml of chloroform-methanol-water (65:25:4, by volume) for each g (weight/volume) of gel, which was collected in one fraction. The elution continued then with chloroform-methanol 2.5 M ammonia (60:40:9, by volume) and 5 ml fractions were sampled on a fraction collector. The elution was monitored by testing 10 μl of each fraction by high performance thin-layer chromatography with the same solvents as used for the column chromatography, chloroformmethanol-2 M ammonia (60:40:9) and the gangliosides were detected with resorcinol reagent. The fractions which contained Fuc-GM1 were pooled and evaporated to dryness.
The final purification of Fuc-GM1 was achieved by preparative thin-layer chromatography. Ganglioside (5 μmoles) was applied on a thin-layer plate (20�20 cm, 0.25 mm thick, Merck, AG., Darmstadt), which was developed for 60 min with chloroform-methanol-2.5 M ammonia at 21� C. After completed chromatography the plate was sprayed with 0.01% bromthymol blue in water and the Fuc-GM1 band was scraped off. The ganglioside was eluted from the gel with chloroform-methanol-water (30:60:20, by volume) and was added one drop of 0.1 M potassium hydroxide dissolved in methanol and evaporated to dryness. The pure ganglioside Fuc-GM1 was kept dry in a vacuum desiccator or was dissolved in a small volume of chloroform-methanol (2:1, by volume) and was kept in a teflon capped tube in the dark at +4� C.
The purified ganglioside Fuc-GM1 from Example 1 was adsorbed to acid-washed Salmonella minnesota bacteria before immunization according to the principle, described by Young, W.W. and collaborators (J. Exp. Med. 150, 1008-1019, 1979).
Balb/c mice, 6-8 weeks old, were immunized intravenously with 5 μg of ganglioside Fuc-GM1, adsorbed to 50 μg acid-washed Salmonella minnesota bacterial membranes, suspended in 100 μl of phosphate-buffered physiological saline, pH 7.4. A new immunization was performed after two weeks with the same dose of immunogen under identical conditions (booster dose).
Three days after the booster dose, the spleen cells taken from the immunized mice were fused with mouse Sp 2/0 myeloma cells. The resulting hybridomas were expanded, tested and cloned according to the protocol, devised by de St. Groth and Scheidegger (J. Immunol. Methods, 1-21, 1980). The culture medium was collected from each microtiter well with growing hybridomas to determine those secreting antibody specific for Fuc-GM1. The determination was performed in an ELISA system according to the following procedure: Fuc-GM1, 50 pmol dissolved in 50 μl of methanol, was added to the wells of a polyvinylmicrotiter plate and evaporated to dryness. The wells were incubated overnight with 100 μl of culture medium diluted 1:2 with 0.01 M phosphate buffered saline (0.14 M) (PBS), pH 7.5. After thorough washing with PBS the wells were incubated for 4 h with 100 μl of peroxydase (HRP)-conjugated rabbit anti-mouse immunoglobulin diluted 1/200 on PBS-1% bovine serum albumin (BSA). The absorbance at 450 nm was determined in a Titertek� microtiter scanner (Flow Laboratories, USA) after incubation for 5 min with 50 μl of substrate (0.1% ortophenyldiamine in 0.1 M citrate buffer, pH 4.5, mixed with 0.3% H2 O2). Hybrids were regarded as positive if the absorbance exceeded that of the mean medium blank by a 2-fold or more. Medium from positive hybrids was collected for further screening and the hybrids were frozen in liquid nitrogen.
Culture medium from hybrids positive in the initial ELISA screening against Fuc-GM1 was tested against normal human lymphocytes for cross-reactivity. Human lymphocytes (HuLy-c) were isolated by centrifugation on Lymphoprep� of blood from five donors of all ABH-blood groups, pooled and used as antigen in an ELISA-test as described by Lindholm et al. (Infect. Immun. 40, 570-576, 1983). Hybrids that produced antibodies cross-reacting with HuLy-c were not further expanded.
The Fuc-GM1positive/HuLy-c negative hybrids were cloned by limited dilution and expanded. The culture medium was collected and used for additional tests without further processing. The isotype of the antibodies produced by each clone was determined by single radial immunodiffusion in agarose containing isotype specific antimouse immunoglobulins.
The Fuc-GM1 positive/HuLy-c negative hybridomas were cloned and screened to determine those secreting antibody specific for Fuc-GM1. The determination was performed in a double antibody solid phase radioimmuno assay. Fuc-GM1 and a large number of different neutral glycolipids and gangliosides were dissolved in methanol and pipetted into the wells of microtiter plates. After evaporation of the solvents the antigen coated wells were incubated with the monoclonal antibodies. Bound antibody was detected with 125 l-labelled antimouse immunoglobulin; 125 l-antimouse lgM or 125 l-antimouse lgaF(ab)2 fragment. Each monoclonal antibody was tested against Fuc-GM1; a standard mixture of human brain gangliosides, normal lung tissue, neutral glycolipids and gangliosides.
The specificity of the monoclonal antibodies were also determined by thin-layer chromatographic immunostaining of the glycolipid antigens. The total neutral and acidic glycolipid fractions from a number of organs were separated on aluminia-backed high performance thin-layer plates (HPTLC) and incubated with the monoclonal antibodies of the Fuc-GM1 positive hybridomas, diluted with Tris buffer-1% BSA (0.05 M Tris, 0.14 M NaCl, pH 7.8, containing 10 g bovine serum albumin/l and 100 mg merthiolate/l). Bound monoclonal antibody was detected with 125 l-labelled antimouse immunoglobulin and then exposing it to X-ray film for 12-24 h. When different monoclonal antibodies were tested on the same HPTLC-plate the antibodies were applied to the plate by soaking cellulose acetate strips in the antibody solution and covering one lane of the HPTLC-plate with the strip.
Only the antibodies which showed an exclusive specificity for Fuc-GM1 have been used in the subsequent studies.
The same principle method was adapted as described in Example 1, but the method has been modified to be optimal for small tissue samples. Tissue, approx. 0.1 g, was homogenized together with 0.5 ml of water in a small conical tube tissue grinder with teflon pestle in an ice bath. After finished homogenization 1.6 ml of methanol and 0.8 ml of chloroform were added. After thorough mixing the tube was centrifuged at 800 xg for 10 min. The clear supernatant was transferred to a Kimax-tube with teflon cap. The sediment was suspended in 0.5 ml of water and then 1.6 ml of methanol and 0.8 ml of chloroform were added. Mixing and centrifugation were performed as before. The two supernatants were combined and water was added to give a final chloroform-methanol-water ratio 4:8:5.6 (by volume). After mixing the tube was centfigued at 100 xg for 5 min. The upper phase was transferred to a small round flask with ground neck and after addition of 0.1 volume of isobutanol, the supernatant was evaporated. The residue was the heated with 0.1 M sodium hydroxide in methanol for 1 h at room temperature.
After finished transesterification 4 ml of chloroform and 1 ml of methanol were added and the content was poured into a small column with 1 g of Sephadex G 25, packed in chloroform-methanol-water 60:30:4.5 (by volume). The eluate was slowly added to a column with 1.0 g of DEAE-Sepharose� (Pharmacia Fine Chemicals, Uppsala, Sweden) in acetate form. After rinsing the column with 10 ml of methanol, the tumor antigen was eluted with 0.02 M potassium acetate in methanol. After evaporation and resolution in chloroform-methanol-water 65:25:4 (by volume) the simple monosialogangliosides were separated from the antigen fraction by elution with 15 column volumes of 65:25:4 (by volume), whereafter the antigen fraction was eluted with 10 volumes of chloroform-methanol-water 50:40:10 (by volume).
A portion of the antigen fraction was dissolved in methanol and 50 μl of extract was pipetted into the wells of a polyvinyl microtiter plate. Standard solutions of 0.5 to 5 pmol of pure Fuc-GM1 in methanol was added to other wells. The solvent was evaporated under a stream of nitrogen. To the unknown samples and standards 10-100 μg of monoclonal antibody, specific for Fuc-GM1 and produced as described in Example 2, dissolved in PBS/BSA was added. The samples were incubated for 1 h at room temperature. The wells were washed 3 times with PBS solution and then 125 l-labelled antimouse-immunoglobulin was added and allowed to react for 3 hours. After repeated washing with PBS the wells with unknowns and standards were cut out from the microtiter plate and counted in the gamma counter. The concentration of fucosylsialosylgangliotetraosyl antigen of the unknowns were calculated from the standard curve of pure Fuc-GM1.
Under the described conditions Fuc-GM1 has been detected in 19/20 lung small cell carcinoma. The antigen has not been identified in other forms of lung carcinomas (squamous cell, large cell or adenocarcinoma) neither in carcinomas of mammary gland, stomach, colorectal mucosa, urinary bladder or uterus. Traces of the antigen has been shown in normal and carcinomatous pancreatic tissue.
The following procedure was used for the demonstration of the fucosylsialosylgangliotetraose antigen in blood serum or plasma. 1.0 ml of serum was slowly dropped into a small test tube with 4 ml of methanol under continuous agitation. Then 2 ml of chloroform was added and the content thoroughly mixed and centrifuged at 800 xg for 10 min. The clear supernatant was transferred to a new tube and the solvent evaporated in a stream of nitrogen under gentle warning on a water bath of 40� C. The residue was dissolved in 5 ml of chloroform-methanol-water 60:25:4 (by volume) and put into a small column (inner diameter 8-10 mm) with 1 g of silica gel (Silica Gel 60, 230-400 mesh, Merck AG, Darmstadt, FRG). The column was eluted with 20 ml of chloroform-methanol-water 65:25:4, (by volume), and then the tumor antigen was eluted with 10 ml of chloroform-methanol-water 50:40:10 (by volume). After evaporation, dialysis for two days against water, and lyophilization, the residue was dissolved into 5 ml of chloroform-methanol-water 60:30:4.5 (by volume) and added slowly to a small column with 1 g of DEAE-Sepharose in acetate form. The column was eluted with 10 ml of methanol and then the tumor antigen was eluted with 10 ml of 0.02 M potassium acetate in methanol. The salt was removed by dialysis and after evaporation the residue was dissolved in a small volume of methanol.
The concentration of tumor antigen was determined with a double solid phase antibody method, at which the antigen was adsorbed to the solid phase and determined with the specific monoclonal antibody (Example 2) and antimouse-immunoglobulin. Fuc-GM1 (20 pmol) and the purified antigen fraction of unknown serum samples were dissolved in methanol and serial dilutions of them (1/2-1/2048) were pipetted in the wells of polyvinyl microtiter plates (Flow Laboratories art.nr. 77-173-05) and were evaporated. Unspecific binding of the wells was blocked with 20 μl of 1% BSA in PBS and then 50 μl of specific monoclonal antibody, diluted in 1% BSA in PBS, was added. After incubation for 4 hours, the wells were rinsed 3 times with 200 μl of PBS. After the rinsing rabbit antimouse immunoglobulin labelled with 125 l, peroxydase or β-galactosidase was added. Measurement of the antigen amount was performed in a gamma counter or after addition of enzyme substrate (ortophenyl diamine, see Example 2), or methylumbelliferyl-β-galactoside in citrate buffer, pH 4.2) reading of the absorbance in a spectrometer or spectrofluorimeter, respectively. The concentration of cancer antigen in blood serum was calculated from the standard curve of Fuc-GM1.
Under the conditions specified above, the antigen was only detected in blood serum of patients with lung small cell carcinoma.
The ability of specific monoclonal antibodies against Fuc-GM1 to kill human tumor cells expressing the Fuc-GM1 antigen was tested in vitro using the antibody-dependent macrophage/monocyte mediated cytotoxicity test (ADMMC).
The specific example described here involved the use of a Fuc-GM1 specific mouse monoclonal antibody (designated F12) prepared as described in Example 2 above, and the Fuc-GM1-containing hepatoma tumor cell line H4-11-E1 (American Type Culture Collection, Rockville, Md) and mouse peritoneal macrophages as target and effector cells, respectively. The F12 monoclonal antibody, prepared and shown to be specific for Fuc-GM1 as described in Example 2 above, was produced for this experiment by injecting F12 hybridoma cells into pristane (2,6,10,14-tetramethylpentadecaene, Aldrich Chemical Co, W Germany) treated normal Balb/c mice. The F12 monoclonal antibody was purified from ascites fluid collected from these mice. After precipitation of ascites fluid with 40% saturated ammonium sulphate, the monoclonal antibody was dialysed against PBS and then adsorbed on a Protein A-Sepharose (Pharmacia AB, Uppsala, Sweden) column and eluted as described by Lindmark (J Immunol Methods, 62:1-13, 1983). Following neutralization with sodium hydroxide (NaOH), the monoclonal antibody was dialysed against PBS, and the immunoglobulin preparation was determined to be pure by agarose gel electrophoresis and quantified by protein determination. The monoclonal antibody was stored at -20� C. until use and was then tested in different concentrations (dilutions prepared in PBS). The hepatoma cell line, H4-11-E1 was cultured in Iscove's medium supplemented with 10% fetal calf serum, and the cells trypsinized, washed and suspended in PBS. This cell line contains large amounts of membrane-associated Fuc-GM1 as determined by the methods described in Example 1 and by immunofluorescence studies using the F12 monoclonal antibody. Mouse peritoneal macrophages were prepared by eliciting peritoneal exudate cells (PEC) by injection of 1.0 ml thioglycollate broth (Difco Laboratories, Detroit, Mi) intraperitoneally into nude mice and collecting the peritoneal cells by peritoneal lavage with 5 ml of sterile sucrose (11.6%) solution 3-4 days later. PEC were washed in PBS and counted in a hemacytometer, and the concentration of cells adjusted to 1�106 /ml. One hundred μl (1�105 cells) of the cell suspension was then aliquoted into 96-well flat-bottom plates (Falcon Plastics, Oxnard, Ca) and incubated for 1-2 h at 37� C. in a CO2 humidified incubator to allow for cell adherence. Non-adherent cells were washed away by aspirating the medium and rinsing each well with PBS 2 times. This procedure yielded a confluent monolayer of adherent cells. Adherent PEC were determined to be 90% macrophage by non-specific esterase staining (kit available from Sigma Diagnostics).
The ADMMC assay was performed in the following way. To each well containing the thioglycollate-elicited macrophages (prepared as described above) were added 4�104 tumor target cells in the presence or absence of purified monoclonal antibody. Serial dilutions of the monoclonal antibody to provide concentrations of 100, 10, 1, 0.1, 0.01, and 0.001 μg/ml of monoclonal antibody, were made in culture medium and added to test wells containing (6-3 H) thymidine (Amersham, England) labelled H4-11-E1 cells and the plates incubated at 37� C. in a CO2 humidified incubator for approx. 40 h. After incubation, tumor cell lysis was measured by release of label into the medium and calculated as follows: Percent cytotoxicity = (experimental release of CPM)--(spontaneous release of CPM) / (maximal release of CPM)--(spontaneous release of CPM)�100. Supernatants were collected from triplicate wells and counted in a β-counter after diluting samples in a scintillation cocktail (Instagel�, Packard, Sweden). Maximum release of label was determined by solubilization of cells in 2% SDS.
Using the ADMMC method and the conditions described the results shown below were obtained in a typical experiment. The data clearly show that a specific monoclonal antibody against Fuc-GM1 was highly efficacious in conjunction with macrophages in killing and lysing Fuc-GM1 containing tumor cells in vitro.
______________________________________F12 monoclonal antibody % tumorconcentration, μg/ml cell lysis______________________________________100 100 10 100 1 86 0.1 45 0.01 28 0.001 33None (medium only) 30100 μg/ml but no macrophages 9______________________________________
We examined the F12 mouse monoclonal antibody against Fuc-GM1, which had shown ability to kill and lyse Fuc-GM1 expressing tumor cells in vitro in conjunction with macrophages as described in Example 5 above for its ability to also suppress tumor development in nude mice in vivo.
The monoclonal antibody F12 was prepared and purified as described in detail in Example 5, and the Fuc-GM1-containing tumor cell line H4-11-E1 was also propagated and cell suspensions prepared as described in Example 5. Thymus-deficient nude mice (nu/nu of C57B1/6 background), 5-8 weeks old, were purchased from Bomholtgaard, Ry, Denmark. Nude mice were housed under pathogen-free conditions in a laminar flow hood in sterilized cages with autoclaved food and water provided ad libitum. All animals used were of the same sex, male.
Tumors were induced by injecting the mice subcutaneously with 2�106 H4-11-E1 cells suspended in in 0.1 ml of PBS. Inoculation of tumor cells was made at 2 opposite localizations on the dorsal hind quarters, and the mice were divided into 3 groups with 10 animals in each group. Mice in 2 of these groups then received daily injections of monoclonal antibody F12 intraperitoneally for 20 days (group A, 0.2 mg monoclonal antibody/injection; and group B, 0.02 mg/injection). The mice of the third group, group C, served as controls of sham-treated tumor growth and were injected daily for 20 days with PBS containing no monoclonal antibody. The incidence of tumor was recorded twice weekly throughout the experiment as the occurrence of tumors at the sites of tumor cell inoculation. Following a 50 day observation period, i.e. 30 days after the last monoclonal antibody or PBS injection, mice were sacrificed.
The figure below summarizes the treatment effects achieved in this experiment. It is evident that with both of the F12 monoclonal antibody treatment dosages tested there was a significant reduction of tumor development as compared to the sham-treated (PBS injected) control group. In fact, with the higher dosage of monoclonal antibody treatment (group A) there was a complete abolition of tumor development. At the time for completion of the experiment the tumor rate (percent palpable tumors out of inoculated tumor sites) in the 3 groups were as follows: Group A, 0%; Group B, 18%; and Group C 55%. ##STR1##
An immunofluorescence method involving a highly specific mouse monoclonal antibody (designated F12) against Fuc-GM1 was used to study the distribution of the Fuc-GM1 antigen in different types of human lung cancer and normal tissues. The monoclonal antibody was prepared as described in Example 2 above. The antibody was concentrated by precipitation of F12 hybridoma culture supernate with 50% saturated ammonium sulphate solution, whereafter the precipitate was redissolved in 1/10 of the starting volume and dialysed against PBS. Tissue specimens obtained at autopsy from patients died from various forms of lung cancer were fixed in 4% formaldehyde in PBS and then frozen in liquid nitrogen and stored at -70� C. Biopsy specimens and some autopsy specimens were directly frozen without previous formaldehyde fixation. Cryostate sections, 4-6 μm thick, were put on glass slides precoated with 0.3% gelatin. After drying by air the cryostate sections were fixed with 5% paraformaldehyde in PBS for 30 min at room temperature followed by treatment with 7.5% sucrose in PBS at 4� C. overnight. The section was then incubated with the F12 Fuc-GM1 specific monoclonal antibody for 30 min at room temperature followed by consecutive incubations for 30 min each with fluoresceine isothiocyanate-conjugated (FITC) rabbit antimouse immunoglobulin (Dako, Dakopatts, Copenhagen, Denmark) and FITC-conjugated swine antirabbit immunoglobulin (Dako), each reagent in a concentration found to be optimal as determined by checker board titrations. Each of the incubation steps during the staining procedure was followed by washing for 15 min with three changes of PBS. Slides were finally mounted with 87% (w/v) glycerol in PBS. The slides were examined for specific fluorescence by microscopy under fluorescent light in a "blinded" fashion.
With this method 19 of 21 cases of small cell lung cancer specimens were specifically stained for Fuc-GM1 with the F12 monoclonal antibody as compared to 2 of 10 cases of squamous epithelial cell lung cancer and 1 of 5 large cell lung cancer specimens. Specimens of lung adenocarcinoma (8 cases) and bronchial carcinoid (3 cases) were all negative, as were 2 examined cases of neuroblastoma. No Fuc-GM1 antigen could be detected by this method in normal lung or bronchial tissues. All other normal tissues tested were also negative except sparsely distributed clusters of stained small round cells in thymus, spleen and lamina propria of the small intestine and intramural ganglionic cells of the small intestine and islet cells of the pancreas. These findings support the view that Fuc-GM1 is highly associated with small cell cancer of the lung and they demonstrate that this tumor-associated antigen can be detected with high sensitivity and specificity with an immuno- fluorescence method based on the use of specific monoclonal antibody against Fuc-GM1.
|Cited Patent
|Filing date
|Publication date
|Jan 29, 1982
|Jun 19, 1984
|Otsuka Pharmaceutical Co., Ltd.
|Process for determining tumor-associated glycolinkage
|May 28, 1983
|Feb 16, 1988
|Otsuka Pharmaceutical Co., Ltd.
|Production of fucosyl antigens and antibodies for recognizing same determination of cancer associated carbohydrate linkage using same and kit for the determination
|May 8, 1986
|Jul 12, 1988
|Dainabot Co., Ltd.
|Method for the detection of cancer
|E. H. Holmes et al., Journ. Biol. Chem., 257, 7698 7703, 1982.
|E. H. Holmes et al., Journ. Biol. Chem., 257, 7698-7703, 1982.
|Citing Patent
|Filing date
|Publication date
|Oct 24, 1986
|Jun 16, 1992
|Research Corporation Limited
|Biochemical reagent
|Feb 7, 1994
|Aug 13, 1996
|Epigen, Inc.
|Human carcinoma antigen (HCA), HCA antibodies, HCA immunoassays and methods of imaging
|Jun 6, 1995
|Dec 2, 1997
|Epigen, Inc.
|Antibodies to human carcinoma antigen
|Jun 6, 1995
|Sep 15, 1998
|Epigen, Inc.
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|Apr 8, 2010
|Jun 24, 2014
|Nederlandse Organisatie Voor Toegepast-Natuurwetenschappelijk Onderzoek Tno
|Assay system for determining binding of hydrophobic drugs
|Apr 8, 2010
|Apr 26, 2012
|Nederlandse Organisatie Voor Toegepast-Natuurwete
|Assay system for determining binding of hydrophobic drugs
|Feb 26, 1991
|Sep 4, 1991
|Sandoz Ltd.
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|U.S. Classification
|435/7.23, 436/64, 436/543, 436/518, 436/813, 435/7.9, 435/960, 435/7.92, 436/548
|International Classification
|Cooperative Classification
|European Classification
|Sep 11, 1989
Owner name: PHARMACIA AB, S-751 82 UPPSALA, SWITZERLAND
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNORS:HOLMGREN, JAN R.;LINDHOLM, LEIF G.;SVENNERHOLM, LARS T.;REEL/FRAME:005140/0352
Effective date: 19890828
|Jun 7, 1993
|Fee payment
Year of fee payment: 4
|Jul 29, 1997
|Maintenance fee reminder mailed
|Dec 21, 1997
|Lapse for failure to pay maintenance fees
|Mar 3, 1998
|Expired due to failure to pay maintenance fee
Effective date: 19971224


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Prestigious Scholarships
If you've been in the scholarship search process for a while, you probably know about the most prestigious scholarships out there. While they are typically more competitive than other awards, the work you put in to the lengthy applications required as part of a submission for these scholarships can pay off if you're chosen as a recipient of one—prestigious scholarships typically have impressive award amounts attached.
Prestigious scholarships are known on a national, and, often, on an international level. Winning one of these could do more for you than help cover college costs, as well, as recipients are then able to boast that they were chosen among thousands of applicants. These awards typically target the best and the brightest among you, and grades, standardized test scores, extracurricular activities and community service will matter. Less tangible criteria will matter as well; scholarship providers for these awards want to see leaders, go-getters, and motivated individuals. Don't let all of this discourage you, though. As long as you're eligible for one of these prestigious scholarships, you may as well apply and put the effort in to apply to the best of your ability. For more information on prestigious scholarships, check out examples of the kinds of awards available below, or conduct a free scholarship search. We'll match you instantly with prestigious scholarships you may be eligible for.
Academic and Merit Scholarships
Most of the prestigious scholarship providers will like to see your academic record, paying attention to your GPA, the kinds of courses you took on in high school, and your level of college preparedness. You may need to be near the top of your class, or have impressive standardized test scores. Most of these awards will spell out in their official rules and requirements the caliber of applicant they'll consider for their scholarship. For example, the Coca-Cola Scholars Program awards 250 scholarships each year ranging from $10,000 to $20,000. Applicants for that award must have at least a 3.0 GPA to be competitive in the pool. The Harry S. Truman Scholarship Program provides up to $30,000 to students in the upper quarter of their junior class. Applicants for this award and many others must also boast an interest in community service and leadership skills, so even if you have a stellar GPA, you may need to get yourself involved in more extracurricular activities to compete for the most prestigious academic and merit scholarships.
Fellowships and Grants
Many of the most prestigious awards come with more than checks sent to your intended college. For example, the more than 100-year-old Rhodes Scholarship offers recipients the opportunity to study at the University of Oxford. About 80 Rhodes Scholars are chosen from a pool of international applicants, with American students typically very well represented among those chosen for the honor. Scholars are chosen based on not only their achievements, but their ability to lead and be involved in a variety of activities. The National Science Foundation offers a Graduate Research Fellowship Program for graduate students pursuing science, technology, engineering, and mathematics. Recipients are expected to contribute to research in their field, as is the requirement for many of the fellowships from research organizations out there. If you're interested in expanding your career opportunities and experiences in your chosen field of study, a fellowship or grant could help you do that.
Prestigious Scholarships for Minorities
Minority scholarships aren't only easy to find due to the large number of awards out there, many of them are also quite prestigious. For example, the Gates Millennium Scholars Program offers low-income minority applicants the opportunity to fund their undergraduate or graduate careers and reach their full potential with a generous aid package and a leadership development component. Scholarship amounts vary for this one, but the program typically covers a winner's unmet need. Those chosen to become Ron Brown Scholars are given $10,000 for four years; at least 10 African-American high school seniors receive the honor annually. Those who do are involved in community service, excel academically, and exhibit leadership potential. As you can see, your funding concerns could be moot if you landed one of these scholarships, so make sure to consider minority scholarships when you're on the hunt for money for college.
Augustana College Distinguished Scholar Competition
Application Deadlines: January 25, Annually
Augustana College invites graduating high school seniors who possess strong records of academic achievement and have demonstrated exceptional leadership to their school and community to participate in the Distinguished Scholars Competition, the College's most prestigious scholarship event. Scholarship awards range from $36,000 to full tuition over four years. In addition, 20 stipends will be [...] More
Catawba College's McCorkle Scholarships
Application Deadlines: February 12, Annually
The McCorkle's Scholarships are the most prestigious scholarship awards at Catawba. Consideration for the McCorkle's Scholarship is by invitation only. In order to be considered for an invitation, students must first apply for admission to Catawba by January of their senior year, and be admitted by February. Qualified students are invited to compete based on high school GPA, coursework intensity, [...] More
Colorado Mesa University's Distinguished Scholar Award
Application Deadlines:
Colorado Mesa University (CMU) offers small class sizes, state-of-the-art facilities, and expert faculty who take an interest in your success. A CMU education is a great value, and we stand by our commitment to keep higher education affordable. Last year, we awarded more than $73 million in financial aid and scholarships to 75 percent of the student body.
Colorado Mesa University's [...] More
David Geffen Medical Scholarship
Application Deadlines:
The David Geffen Medical Scholarship is a prestigious new scholarship that provide four-year financial support to outstanding students entering the David Geffen School of Medicine at UCLA. Mr. Geffen, the world-renowned entertainment executive and philanthropist after whom our medical school is named, has once again made a transformative gift to medical education. This time he has established a [...] More
F. Lammot Belin Arts Scholarships
Application Deadlines: December 15, Annually
The scholarship was endowed with funds provided by the Belin family and has become a prestigious annual award. The scholarship was established to provide financial assistance to artists of outstanding aptitude and promise in the fine arts. It is intended to aid the recipients in their development into professional artists.
The recipient may use the money for formal or informal study or travel [...] More
Gen. Hugh Shelton National Student Leadership Scholarship
Application Deadlines: October 15, Annually
This is one of the USA's most prestigious scholarships for student leaders. It is awarded to an entering freshman, valued at $10,000 per year, renewable upon satisfactory academic progress and leadership involvement.
Selection for this award is based on your leadership experience and potential, personal character and integrity, community service, understanding of and interest in the program, [...] More
Intel Science Talent Search
Application Deadlines: November 11, Annually
The Intel Science Talent Search (Intel STS), a program of Society for Science & the Public, is the nation's oldest and most prestigious pre-college science competition. It honors exceptional high school seniors for their scientific research and their potential as future leaders in the scientific community.
Each year, approximately 1,800 students attending American high schools enter the [...] More
John F. Kennedy Profile in Courage Essay Contest
Application Deadlines: January 06, Annually
The John F. Kennedy Profile in Courage Essay Contest is the nation's most prestigious honor for elected public servants. The Award was created in 1989 by members of President Kennedy's family to honor President John F. Kennedy and recognize and celebrate the quality of political courage that he admired most.
The Profile in Courage Essay Contest invites high school students to consider the [...] More
Levine Scholars Program
Application Deadlines: October 15, Annually
The Levine Scholars Program is UNC Charlotte's most prestigious merit scholarship program that was established in 2009 by benefactors Sandra and Leon Levine. The inaugural class of Levine Scholars entered in the fall semester of 2010 and a new cohort of approximately 20 students is selected to join the program each year. Levine Scholarships are awarded to extraordinary high school seniors based [...] More
Loren L. Zachary Society For The Performing Arts National Vocal Competition for Young Opera Singers
Application Deadlines:
Founded in 1972, by the late Loren L. Zachary and Nedra Zachary, the National Vocal Competition for Young Opera Singers is one of the most prestigious and valuable singing competitions in the world. The competition is open to Singers ages 21 - 35. Singers must be prepared to pursue a professional operatic stage career, be present for all phases of the Competition, and reside in the United States [...] More
McConnell Scholarship
Application Deadlines: December 15, Annually
The prestigious McConnell Scholarships are reserved for 10 Kentucky graduating high school seniors who have demonstrated outstanding leadership potential. Scholarships are renewable for a total of four years.
Scholarship amounts will be determined by the selections committee, but typically will include full tuition and a stipend for books at the University of Louisville. In addition, each [...] More
NDSGC American Indian Scholarship
Application Deadlines:
The recently established prestigious American Indian Scholarships are designed to encourage and support Native American students interesting in pursuing STEM degrees and continuing their education beyond their current enrollment in community college. To assist students in their goals, the North Dakota Space Grant Consortium offers five scholarships, each worth $2,500, to Native American students [...] More
NDSGC Lillian Goettler Scholarship
Application Deadlines: February 12, Annually
The NDSGC has established the prestigious Lillian Goettler Space Grant Award for a female student at North Dakota State University. Applicants will ideally be involved in a research project of NASA relevance. The award, for $2,500 per year, is given to honor the ideals of scholarship as exemplified by Lillian Goettler. Lillian L. Goettler was a distinguished NDSU professor. Awarded a doctorate in [...] More
NDSGC Pearl I. Young Scholarship
Application Deadlines: February 12, Annually
The NDSGC has established the prestigious Pearl I. Young Space Grant Award for a female student at the University of North Dakota. Applicants will ideally be involved in a research project of NASA relevance.
-Must be female
-Must have a minimum 3.5 GPA
American Citizen
-On-campus student majoring in a STEM (science, technology, engineering, or mathematics) field at University [...] More
Oregon Music Hall of Fame Scholarship
Application Deadlines: February 14, Annually
OMHOF awards yearly scholarships to selected graduating Oregon high school seniors who have exhibited serious pursuit and accomplishment in their personal musicianship – and who are college-bound music majors. Recipients are publicly recognized at an award presentation where each performs onstage, demonstrating mastery of his/her instrument.
OMHOF awarded 26 scholarships totaling $35,500. Our [...] More
Overseas Press Club Foundation
Application Deadlines: December 01, Annually
Graduate and undergraduate students, studying at American colleges and universities, or Americans studying abroad, who aspire to become foreign correspondents, are invited to apply for one of fourteen scholarships or internships to be awarded by the Overseas Press Club Foundation.
From among those chosen for OPC Foundation recognition, the Foundation selects up to 11 scholars and pays travel [...] More
Ripon College Knop Science Scholars Program
Application Deadlines: March 01, Annually
The Knop Science Scholarship is a prestigious four-year, full tuition scholarship based on the next academic year's tuition figures. The Ripon College Knop Science Scholars Board convenes each year at the beginning of the second semester. The mission of the board is to identify high-achieving students who show the potential to contribute greatly to the science and mathematics departments at Ripon [...] More
U.S. Stockholm Junior Water Prize
Application Deadlines: April 15, Annually
The Stockholm Junior Water Prize (SJWP) is the world's most prestigious youth award for a water-related science project. The prize taps into the unlimited potential of today's high school students as they seek to address current and future water challenges.
The competition is open to any high school student in grades 9 through 12, and are 15 years of age by August 1st of the competition year. [...] More
University of Georgia/Foundation Fellowships
Application Deadlines: November 04, Annually
The Foundation Fellowship and the Bernard Ramsey Honors Scholarship are the most prestigious undergraduate scholarships at UGA.
The Fellowship provides an annual stipend of $11,072 for in-state students (in addition to the Zell Miller Scholarship, valued at $8,590 per year) and $18,180 for out-of-state students (plus an out-of-state tuition waiver, currently worth $18,210 per year). [...] More
USBC Earl Anthony Memorial Scholarship
Application Deadlines: December 01, Annually
The Earl Anthony Memorial Scholarship annually recognizes a USBC Youth bowler for their community involvement and academic achievements. One winner will be chosen and awarded a $5,000 scholarship. The United States Bowling Congress presents this prestigious scholarship in honor of the late Earl Anthony. Anthony was dedicated to helping youth bowlers and USBC is proud to continue these efforts in [...] More
Vinson & Elkins Scholarship Foundation
Application Deadlines: April 01, Annually
In addition to receiving a $10,000 scholarship, each V&E Scholar is offered summer internships at Vinson & Elkins, mentoring from V&E attorneys (some of whom are themselves V&E Scholars), and reimbursement for an LSAT preparatory course. V&E Scholars have gone on to the nation's most prestigious universities, and many have attended top law schools. Whether our scholars are in law school, the [...] More
Last Edited: February 2016
Prestigious Scholarships
- Augustana College Distinguished Scholar Competition
- Catawba College's McCorkle Scholarships
- Colorado Mesa University's Distinguished Scholar Award
- David Geffen Medical Scholarship
- F. Lammot Belin Arts Scholarships
- Gen. Hugh Shelton National Student Leadership Scholarship
- Intel Science Talent Search
- John F. Kennedy Profile in Courage Essay Contest
- Levine Scholars Program
- Loren L. Zachary Society For The Performing Arts National Vocal Competition for Young Opera Singers
- McConnell Scholarship
- NDSGC American Indian Scholarship
- NDSGC Lillian Goettler Scholarship
- NDSGC Pearl I. Young Scholarship
- Oregon Music Hall of Fame Scholarship
- Overseas Press Club Foundation
- Ripon College Knop Science Scholars Program
- U.S. Stockholm Junior Water Prize
- University of Georgia/Foundation Fellowships
- USBC Earl Anthony Memorial Scholarship
- Vinson & Elkins Scholarship Foundation
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Latest College & Financial Aid News
An Underrepresented, Struggling Minority in Higher Education
July 26, 2016
by Susan DutcaNative American students lag behind their peers from a young age, across almost every measure of student success. From college enrollment, to test scores and on-time graduation, they have the lowest rates of any racial subgroup. They make up a mere 1 percent of the high school and college population and tend to be overlooked when it comes to discussion about the nation's achievement [...]
10 Sweet Scholarships for Being a Man
July 21, 2016
by Susan DutcaColleges and universities across the nation are starting to engage more in discussions regarding what it means to be a man. Masculinity, just like femininity, is celebrated through these gender-specific scholarships. So man-up and check out these scholarship opportunities!: Colored Rocks Contest [...]
College Presidents' High Pay, Short Stay
July 20, 2016
by Susan DutcaPresident Obama gets paid $400,000 per year to serve as President of the United States of America. Many college presidents get paid more for running a school than they would for being the leader of the free world, according to a new report from the Chronicle of Higher Education. Presidents at public universities received a median salary of $431,000 in the 2015 fiscal year, with a 4.3 percent [...]


text: A colorblocked top featuring a contrast chiffon yoke. Round neckline. Short cuffed dolman sleeves. Semi-sheer. Knit. Lightweight.DETAILS: 26" approx. length from high point shoulder to hem, 38" chest, 38" waist, 8" sleeve length from high point shoulderShell: 97% viscose, 3% spandex; Contrast: 100% polyesterHand wash, dry flatImported Product Code : 2037488262


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A la carte Kitchen System
Preparing lunch or a square meal comes naturally with A la carte. This self-contained modular kitchen can be packed up to follow you on the move.
Cedarworks Rhapsody Playbed
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Alexander Girard Purse
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thanks a lot for your software. :)
I'd like to insert audio comments in some videoclips to explain it. Most has no sound at all, then I see that with kdenlive I can add it a music soundtrack and play with volume. Some have ambience sound. But for both, I'd like to have the ability for connect my microphone and add some audio comments as clips plays on.
As an alternative, I can use Audacity to capture my audio comments and later import sound file as a track in kdenlive, but it will be better if I can do it with only one program.
Anyway, thanks again.
Best regards,
Mon, 08/13/2007 - 19:10
I'm not sure if you already do this or not, or if it would work without some fiddling, but have you considered running audacity whilst kdenlive is running?
Then, you could press play on Kdenlive, press record in audactiy, and record a rolling commentary whilst watching kdenlive play back.
Then, you would only need to sync the clip up once inside of kdenlive, rather than once for each soundbyte.
Just a thought!
Thu, 01/07/2010 - 20:32
since I'm faced with exactly the same task over and over again, I'd like to give this issue a push and warm it up for further discussion. I'd love to see audio overdup support in kdenlive.
Would be an outstanding feature.
(Audio overdup: full-duplex recording of audio during playback of existing audio/video on armed tracks-> easy audio comments with full sync to existing video tracks)


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Lenny Lubitz
Investing Strategy
5 ATM Scams That Can Break The BankDon't get scorched by ATM thieves who want to burn a hole in your wallet.
Insurance & Health
Warren Buffett's Best BuysThe Oracle of Omaha's "Rip van Winkle" approach has served him well. Read on to learn more.
Financial Analysis
Carl Icahn's Investing StrategyBuying up failing investments and turning them around helped to create the "Icahn lift" phenomenon.


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Comment Policy: Please read our new comment policy before making a comment. In short, please be respectful of others and do not engage in personal attacks. Otherwise we will revoke your comment privileges.
The Supreme Court is announcing that it will indeed take up the issue of the constitutionality of Obama's despotic executive orders on immigration that allowed children brought into the United States illegally to received "deferred action" on their deportation.
NEW: SCOTUS agrees to review Obama administration's immigration plan.
— ABC News (@ABC) January 19, 2016
Watch below:
Breaking News: SCOTUS to review Obama's orders to shield illegal immigrants from deportation https://t.co/c2vnDcQfPq https://t.co/UpdSYFA8JL
— Fox News (@FoxNews) January 19, 2016
More from ABC News:
The Supreme Court agreed Tuesday to an election-year review of President Barack Obama's executive action to allow up to 5 million immigrants living in the U.S. illegally to "come out of the shadows" and work legally in the United States.
The justices said they will consider undoing lower court orders that blocked the plan from taking effect in the midst of a presidential campaign already roiled by the issue.
The case will be argued in April and decided by late June, about a month before both parties' gather for their nominating conventions.
The immigrants who would benefit from the administration's plan are mainly the parents of U.S. citizens and lawful permanent residents.
Texas is leading 26 mainly Republican-dominated states in challenging the Democratic administration's immigration plan.
So far, the federal courts have sided with the states to keep the administration from issuing work permits and allowing the immigrants to begin receiving some federal benefits.
If the justices eventually side with the administration, that would leave roughly seven months in Obama's presidency to implement his plans. "We are confident that the policies will be upheld as lawful," White House spokeswoman Brandi Hoffine said after the court's action Tuesday.
At issue is the Deferred Action for Parents of Americans program, which Obama said in late 2014 would allow people who have been in the United States more than five years and who have children who are in the country legally to "come out of the shadows and get right with the law."
Texas quickly led a legal challenge to the program and has won every round in court so far. Most recently, in November, the 5th U.S. Circuit Court of Appeals ruled in favor of the states, prompting the appeal to the Supreme Court.
It's almost certainly unconstitutional, but that doesn't mean much to half of the justices on the Supreme Court who rule based on their feelings or skin color or reproductive genitalia instead of the Constitution.


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EU Calls for 'Strong Signal' From ICAO on Carbon Emission
European Union Climate Commissioner Connie Hedegaard called on the United Nations' aviation body to accelerate the design of a global rule to curtail greenhouse-gas emissions from aircraft operators.
The EU, which is seeking to lead the global fight against climate change, included foreign airlines in its emissions-trading market this year after international organizations failed to enact pollution curbs. The UN International Civil Aviation Organization opposes the move, arguing it's in the best position to regulate emissions from carriers.
"There are so many countries saying they want an international regulation," Hedegaard said in an interview during a conference at Bloomberg LP's headquarters in New York today. "The first chance to show that, and also for the ICAO leadership to show that, is at their next meeting in November. There ICAO has the possibility of sending a very strong signal that they really want to work seriously on a global deal."
Hedegaard's comments at a Climate Week NYC event follow an adoption by the U.S. Senate last week of a bill that would effectively shield the country's airlines from participation in the EU emissions trading system, also known as the ETS.
The bill, supported by the airlines, must be reconciled with similar legislation passed by the U.S. House of Representatives last year. Transportation Secretary Ray LaHood has said the Obama administration hasn't taken a position on the bill, and in June said the government "strongly opposes" the EU plan.
European Flights
The expansion of the ETS into flights to and from European airports also triggered opposition from countries including China and Russia, which said Europe should let the ICAO decide on greenhouse-gas limits for the industry.
The EU has repeatedly said that while its law enables the exemption of incoming flights from a country if it implements "equivalent measures" to tackle pollution from aviation, the 27-nation bloc won't give up the inclusion of aviation in its carbon cap-and-trade market.
Under the EU ETS, airlines beginning in 2013 must surrender allowances equal to their emissions in the prior year. The airlines were given free allowances for about 85 percent of their emissions.