text:
|Publication number
|Publication type
|Application number
|Publication date
|Oct 18, 1988
|Filing date
|Apr 20, 1987
|Priority date
|Apr 20, 1987
|Fee status
|Publication number
|John S. Stupakis
|Original Assignee
|Jss Scientific Corporation
|Export Citation
|BiBTeX, EndNote, RefMan
|Patent Citations (16), Referenced by (41), Classifications (19), Legal Events (4)
|External Links: USPTO, USPTO Assignment, Espacenet
The background of the invention will be discussed in two parts.
This invention relates to dental chairs, and more particularly to a lightweight, transportable dental chair, collapsible into the size of a suitcase.
Dental chairs are typically huge, bulky mechanized arrangements, requiring electrical machine driven sources of air or hydraulics for operation. In many environments, such as for field military use, or in remote locations in third world countries, medical and dental supplies and equipment have to be transported in wheeled vehicles or airplanes, and sometimes on foot or by pack animals. In such instances space and weight requirements dictate against the use of such conventional dental chairs.
A prior art folding dental chair is shown and described in U.S. Pat. No. 271,596, issued to Browne on Feb. 6, 1883, the chair being formed of interconnected pivotably attached barshaped members supporting a seat, back and footrest, with ratchet bars on the base portion for providing height adjustment.
A "Collapsible Seat" is disclosed in U.S. Pat. No. 3,419,309, which issued to Smith on Dec. 31, 1968, the seat being configured as a suitcase enclosure, with inflatable cushion members therein.
Another such suitcase apparatus is disclosed in U.S. Pat. No. 3,179,465, "Convertible Beach Chair-Suit case Combination", such patent issuing on Apr. 20, 1965 to Roberts. The suitcase is configured for enclosing therein tubular rigid frame members pivotally attached to the interior of the suit case structure.
An "Elevator Chair" is disclosed in U.S. Pat. No. 4,538,854, which issued to Wilson on Sept. 3, 1985, such patent disclosing a chair having a seat portion with an inflatable bag under the seat portion, with a vacuum device housed within the inflatable bag for providing air to the interior thereof. Sliding support members are provided at the corners of the seat.
Inflatable devices are shown and described in U.S. Pat. No. 3,112,956, entitled "Inflatable Seat and Back Rest", which issued to Schick et al on December 3, 1963; and U.S. Patent No. 4,504,989, entitled "Inflatable Support Arrangement", which issued to Maltz on Mar. 19, 1985.
In accordance with an aspect of the invention, it is accordingly an object of the invention to provide a new and improved lightweight dental chair comprised of rigid and inflatable parts, and which may be collapsed into a suitcase size.
The foregoing and other objects of the invention are accomplished by providing afield portable dental chair, which, in its collapsed position, is configured as a suitcase with a handle for portability. The base portion of the suitcase is generally rigid and is provided on the bottom exterior with pivotable outriggers for support, while the box-like interior forms a compartment for housing a bellows arrangement for raising and lowering the chair, with a telescopic internal structure for stabilization. A seat and seat back are hingedly coupled, and have generally rigid tray-shaped configurations to form an enclosure with an inflatable cushion contained therein, inflation of which provides support for the head, back, seat and legs of a patient.
Other objects, features and advantages of the invention will become readily apparent from a reading of the specification, when taken in conjunction with the drawings, in which like reference numerals refer to like elements in the several views.
FIG. 1 is a perspective view of the dental chair apparatus according to the invention, set up, inflated and ready for use;
FIG. 2 a side elevational view of the dental chair apparatus of FIG. 1, partially broken away and partially in cross-section;
FIG. 3 is a partial side elevational view, similar to FIG. 3, with the inflatable portions deflated;
FIG. 4 is a perspective view of the dental chair apparatus of FIG. 1 shown collapsed in its suitcase sized portable position; and
FIG. 5 is a bottom plan view of the dental chair apparatus in its collapsed position shown in FIG. 4.
Referring now to the drawings, and particularly to FIGS. 1 and 2, there is shown a dental chair apparatus, generally designated 10, which generally includes a base assembly 12, an accordion pleated bellows 14, a generally rigid seat member 18, a generally rigid seat back member 20 interconnected therewith, and inflatable cushion members 21-24, for the support of the head, back, seat and legs, respectively, of an occupant of the chair 10. Attached to the base assembly 12, for introducing air into the bellows 14, is a foot pump 25; and for releasing air from the bellows 14, a foot operated air-release control 26.
As will be described, and referring also to FIG. 4, the seat member 18 and the seat back member 20 are configured as generally square shallow trays, with the base 12 configured as a somewhat deeper tray, the parts being so dimensioned, arranged and configured, to form, on collapsing or folding, a structurally rigid generally rectangular box-like or suitcase-sized package, generally designated 10' (See FIG. 4), of predetermined dimensions, wherein the planar surface of the reverse side of the seat back member 20 is one side of the suitcase thus formed, with the bottom of the base 12 being the opposing side. A suitable handle 11 is affixed to a side wall of the base 12 to facilitate carrying. As will be described, the parts are so formed that the inflatable cushion members 21-24 (in a deflated condition), the bellows 12 (in a deflated condition), and an internal structural support arrangement, are contained within the dimensions of the suitcase 10' thus formed.
Referring to FIGS. 1 and 2, and also to FIG. 5, the base 12 is generally square in bottom plan elevation, and is formed to provide an enclosure or a tray-shaped compartment 30 on the interior thereof, with a peripheral recess on the bottom exterior of the compartment 30. On the underside, the base 12 is configured for receiving, and has attached thereto, a plurality of generally bar-shaped pivotable outrigger members, or feet, 31-38. In the folded or retracted position, the undersides of the feet 31-38 form a plane, along with the generally planar undersurface of the central compartment 30, and four corner legs 39-42. The feet 31-38 are pivoted about pivot pins 31a-38a positioned in proximity to the legs 39-42. In the retracted position, the outer edges of the legs 31-38 are coextensive with the outer walls 44-47 of the base 12. In the extended position shown in FIGS. 1 and 2, the feet 31-39 extend (as shown also in dotted lines in FIG. 5) in a direction ninety degrees to the folded position, and serve as outrigger support members, or stabilizers for the weight of the occupant or person in the chair. To facilitate pivoting, the undersurface of the legs 31-38 may be provided with finger gripping recesses 31b-38b. The corner leg members 39-42 may be formed as solid block members to provide four-corner vertical weight support for the chair 10.
The seat member 18 and the seat back member 20 are generally identically configured with generally square generally rigid plate-shaped portions 18a and 20a, with peripheral side walls 18b-18e and 20b-20e (not all of which are shown), respectively, with the open part of each of the members in facing relation to form an enclosure for receiving therein the deflated inflatable cushion members 21-24. The seat member 18 and seat back member 20 are hingedly coupled by a suitable hinge member 48. The adjacent sides 18b and 20b of seat member 18 and seat back member 20, respectively, are interconnected by a pivotably coupled support arm set 50 including arms 50a and 50b. An identical support arm set 52 arrangement is included on the opposite side with arms 52a and 52b interconnecting adjacent sides 18d and 20d of seat member 18 and seat back member 20, respectively. Referring also to FIG. 6, the arms 50a and 50b are formed of metal bar or strap material, with arm 50a slightly longer than arm 50b. They are pivotably coupled together, such as by a rivet 51 passing through adjacent abutting ends thereof, with a portion of arm 50a extending beyond the so-coupled end. This portion has an outwardly extending stop member 50c at a position for coaction with the adjacent edge of the arm 50b in the pivoted position shown. The opposite end of each arm is pivotally coupled, such as by use of a rivet or screw to the walls 18b and 20b, of seat member 18 and seat back member 20, respectively, with the arm sets 50 and 52 thus providing the necessary support for maintaining the seat member 18 at a given angle to the seat back member 20.
The inflatable cushion members 21-24 may be formed of a suitable plastic material as a unit, that is of one-piece construction similar to an air mattress, with the facing layers of plastic about the edges and along certain lines suitably bonded to form a plurality of air-receiving pockets. A single air valve 19 may be provided for the entire inflatable cushion structure, or individual air valves may be provided for each cushion 21-24 to provide for different amounts of air in each section, and consequently, differing amounts of stiffness or inflexibility for each section. In any event, the rearward surface of the cushion member 22, and the rearward surface of the cushion member 23 are secured, such as by adhesive to the adjacent surface 20a and 18a, of the seat back member 20 and the seat member 18, respectively. In this manner, as shown in FIG. 3, when the seat back member 20 is opened, or pivoted clockwise as viewed in the drawing relative to the seat member 18, the head cushion 21 is unfolded clockwise, and the leg support cushion 24 portion is unfolded counterclockwise, after which the cushions may be inflated.
Referring now to FIGS. 1 and 2, the means for raising and lowering the seat 18 relative to the base 12 will be described. As will be described, the portion of the chair 10 between the undersurface of the planar portion 18a of seat member 18 and the open end of base 21 forms a compartment or enclosure, for receiving a bellows 14, which is attached at its upper end to the undersurface of the seat member 18. At the lower end, the bellows has the lower peripheral edge thereof attached within the compartment 30 to the base 12, in airtight relation, and in a manner to be suitably contained, when collapsed, within the side walls 44-47, that is, the diameter of the bellows 14 is slightly less than the distance between the inner surfaces of an opposing set of walls.
Secured on the interior of the bellows 14, there is a structural support system, generally designated 58, which includes a plurality of telescopically interconnected members 58a-58h, of stepped dimension, each of which has an inwardly extending peripheral flange at the upper end thereof, and an outwardly extending peripheral flange at the lower end thereof, to permit the members to be received within one another in telescopic relation. The lowermost member 58a is generally cup-shaped, and the botom thereof may conveniently serve as the lower surface of the base 12. The uppermost member 58h is of an inverted cup-shaped configuration with the base thereof suitably secured, such as by bolts 57, to the undersurface of plate-shaped portion 18a of the seat member 18. The members 58a-58h may be cylindrical or rectangular in cross-section, and are fabricated to close tolerances to provide a backbone of vertical support for the chair apparatus 10, that is, the outer dimension of the lower flange portion is closely matched to the inner dimension of the member to which it is connected. Correspondingly, the inner dimension of the upper flange closely corresponds to the outer dimension of the cylinder to which it is connected. In order to prelude rotation of the seat 18, the members 58a-58h are preferably square in cross-section, in which event, the members are self-keyed to one another. Alternatively, the members 58a-58h may be cylindrical, with suitable keying means (not shown) formed at the periphery, such as a vertical slot in one member, with a rib or shaft member coacting within the slot to limit the movement of the members relative to one another to a vertical direction. To provide the tightness of fit, while permitting ease of movement in the vertical direction, the cylinders may be conveniently formed of a suitable self-lubricating plastic material, such as Teflon, or Delrin material. In addition, such materials offer lightness of weight. To further facilitate upward and downward movement, some, or all of the members 58a-58f may be provided with venting apertures 59, or one way air valves, not shown, arranged to permit ease of raising the seat 18, with slight resistance to downward movement without the chair 10 being occupied.
For purposes of filling of the bellows 14 with air, a foot operated pump 25 is provided, interconnected through tubing 25a to a valve arrangement 27a which passes through the wall 44 into communication with the interior of the bellows 14. A foot-operated air release control 26 is connected through tubing 26a to a valve 27b passing through wall 44. Conveniently, the pump 25 and the control 26 would be on a common plate for ease of use by the dentist. Of, course, the pump 25 may also be used to inflate the cushion members 21-24.
The material used to make the rigid members 12, 18, 20, and 31-38 may be any suitable lightweight material, such as fiberglass, high impact plastics, plywood or any combination thereof. Similarly, molded lightweight metal parts of aluminum or magnesium may be judiciously used, in part, with the overall selection of materials thus providing a high strength lightweight, field portable dental chair 10, which may be readily erected for use, and readily disassembled and folded for transport, all in a suitcase size, such as eighteen inches square by seven inches deep.
Thus it may be seen that the construction, configuration, dimensions, and arrangement of the various components of the chair 10 provide first and second compartments, or enclosures, bounded by generally rigid members, for completely receiving and enclosing therein the flexible or inflatable portions of the chair 10, along with the flexible bellows 14 being configured for housing the telescopic structural support system 58 on the interior thereof. While there has been shown and described a preferred embodiment, it is to be understood that various other adaptations and modifications may be made within the spirit and scope of the invention.
|Cited Patent
|Filing date
|Publication date
|Jul 31, 1882
|Feb 6, 1883
|Apr 29, 1920
|Mar 29, 1921
|King William A
|Collapsible seat
|Jan 12, 1942
|Apr 2, 1946
|Coleman Lamp & Stove Co
|Portable stove
|Jun 1, 1951
|Jan 24, 1956
|Edward P Bishop
|Air mattress
|Aug 30, 1961
|Dec 3, 1963
|Schick Melvin Edward
|Inflatable seat and back rest
|Sep 25, 1962
|Apr 20, 1965
|Roberts Arthur H
|Convertible beach chair-suit case combination
|Jul 20, 1967
|Dec 31, 1968
|Ving Smith
|Collapsible seat
|Aug 14, 1970
|Aug 8, 1972
|Daybrook Ottawa Corp
|Seat suspension system
|Mar 5, 1974
|Sep 30, 1975
|Michael J Johnson
|Portable collapsible high chair
|Jun 27, 1983
|Mar 19, 1985
|Maltz Dean I
|Inflatable support arrangement
|Dec 13, 1982
|Sep 3, 1985
|Morette's Limited
|Elevator chair
|Title not available
|May 19, 1981
|Dec 16, 1982
|Harry Apprich
|Height-adjustable seat
|Title not available
|Title not available
|Title not available
|Citing Patent
|Filing date
|Publication date
|Aug 28, 1989
|Sep 11, 1990
|Wickes Manufacturing Company
|Automobile foot rest
|Sep 27, 1988
|Sep 18, 1990
|Ikeda Bussan Co., Ltd.
|Lumbar support device
|Nov 26, 1990
|Jan 5, 1993
|Christine Canet
|Portable case which can be converted into a chair
|Nov 22, 1993
|Aug 9, 1994
|Telescope Casual Furniture Co.
|Collapsible chair
|Jun 30, 1995
|Nov 26, 1996
|Global Upholstery Company
|Seat height adjustment mechanism for a chair
|Jan 11, 1996
|Oct 6, 1998
|Davidson Textron, Inc.
|Adjustable resting surfaces for automotive interior trim
|Aug 23, 1995
|May 4, 1999
|Global Upholstery Company
|Control mechanism for a chair
|Sep 17, 1998
|Jul 13, 1999
|Davidson Textron Inc.
|Adjustable resting surfaces for automotive interior trim
|Mar 10, 1999
|Feb 1, 2000
|Global Upholstery Company
|Control mechanism for a chair
|Jan 23, 1997
|Mar 14, 2000
|Lear Corporation
|Vehicle seat assembly incorporating a one-piece shell as seat back and lower seat support
|Jul 28, 1998
|Jun 12, 2001
|Jeff Wilson
|Front wheel suspension fork for two wheeled vehicles and method
|Nov 21, 2000
|Jun 18, 2002
|Bell Dental Products, Llc
|Self contained dental chair with integrated compressor and vacuum pump and methods
|Sep 16, 2002
|Apr 13, 2004
|Activar, Inc.
|Shock and vibration isolation apparatus for motor vehicles seats
|May 19, 2003
|Aug 24, 2004
|Addie Sanders
|Portable patient transfer assist system
|Aug 1, 2002
|Mar 29, 2005
|Seminar Components (Uk) Limited.
|Adjustable chairs and beds
|Mar 4, 2005
|Apr 18, 2006
|Seminar Components (Uk) Limited
|Adjustable chairs and beds
|Nov 7, 2005
|Aug 21, 2007
|Wornie Smith
|Portable chair and method of use thereof
|Jul 6, 2007
|Apr 20, 2010
|Airbus Deutschland Gmbh
|Installable reclining device for emergency medical aid of patients
|Jul 10, 2007
|May 25, 2010
|Global Total Office An Ontario Limited Partnership Having Global Upholstery Co.Inc. As Its General Partner
|Method for replacing a telescoping cylinder in a reconfigurable chair
|Mar 22, 2011
|Caterpillar Inc.
|Independent height adjustment system for a seat assembly and machine using same
|May 8, 2009
|Aug 30, 2011
|Ergoergo, Inc.
|Exercise device
|Apr 17, 2012
|Hni Technologies Inc.
|Chair back rest with improved resilience and support
|Oct 21, 2005
|Sep 18, 2012
|Fetisoff Valentine A
|Portable self-contained pneumatic lift chair
|Sep 16, 2011
|Nov 19, 2013
|Atwood Mobile Products Llc
|Air ride seat pedestal with independent height adjustment
|Sep 29, 2005
|May 13, 2014
|Robert B. Chaffee
|Membrane deflation in combination with rigid surfaces
|Feb 3, 2010
|May 20, 2014
|Salvatore Matteo
|Convertible workstation
|May 29, 2012
|May 27, 2014
|Stanley W. Widmer
|Lightweight chair
|Jul 11, 2013
|Feb 3, 2015
|Carol D. Miller
|Portable lift facilitating assembly
|Aug 1, 2002
|Oct 28, 2004
|Hale Richard John
|Adjustable chairs and beds
|Dec 30, 2003
|Jul 7, 2005
|Machael Jay R.
|Chair back rest with improved resilience and support
|Mar 4, 2005
|Jul 14, 2005
|Seminar Components (Uk) Limited
|Adjustable chairs and beds
|Sep 29, 2005
|Feb 16, 2006
|Chaffee Robert B
|Membrane deflation in combination with rigid surfaces
|Oct 21, 2005
|May 10, 2007
|Fetisoff Valentine A
|Portable self-contained pneumatic lift chair
|Oct 25, 2005
|May 10, 2007
|GLOBAL TOTAL OFFICE an Ontario limited partnership having GLOBAL UPHOLSTERY CO.
|Adjustment mechanism for a chair and method for replacing a telescoping cylinder in a reconfigurable chair
|Nov 7, 2005
|May 17, 2007
|Wornie Smith
|Portable chair and method of use thereof
|Jul 6, 2007
|Jan 10, 2008
|Joerg Cremers
|Installable reclining device for emergency medical aid of patients
|Jul 10, 2007
|Jan 17, 2008
|Global Total Office an Ontario Limited Partership having Global Upholstery Co. Inc. as its General
|Method for replacing a telescoping cylinder in a reconfigurable chair
|May 20, 2008
|Nov 26, 2009
|Caterpillar Inc.
|Independent height adjustment system for a seat assembly and machine using same
|Nov 19, 2008
|May 20, 2010
|Martin Lin
|Inflatable sofa set
|Nov 11, 2010
|Alan Heller
|Exercise device
|Nov 5, 1990
|Aug 22, 1991
|David Levy Menaged
|Inflatable reading stand
|U.S. Classification
|International Classification
|Cooperative Classification
|European Classification
|Jun 22, 1987
Owner name: JSS SCIENTIFIC CORPORATION, 25 EAST HUNTINGTON DR.
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNOR:STUPAKIS, JOHN S.;REEL/FRAME:004726/0222
Effective date: 19870414
|May 20, 1992
|Maintenance fee reminder mailed
|Oct 18, 1992
|Lapse for failure to pay maintenance fees
|Dec 22, 1992
|Expired due to failure to pay maintenance fee
Effective date: 19921018


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September 14, 2012
Long time Rochester resident and even longer time movie fan, especially Indie and Art House variety. Visit the Little fairly frequently. Got a thing for horror films too, (Zombies, not Vampires.) Looking forward to some good discussions.
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BNSF C44-9W 4416 leads a land barge eastward on the Hi Line, battling the strong winds just east of Cutbank, MT.
BNSF isn't messing around with this Z train! 5 units hustle this priority traffic west on the Glasgow Sub doing every bit of the 70mph speed limit.
BNSF ES44C4 8339 leads a stack train east on the Hi Line Sub towards a crew change and fuel at Havre, MT.
Amtrak's Empire Builder is well ahead of schedule stopped at the station in Shelby, MT about 20 minutes early... much to the dismay of the crew on CREX 1327 east who has to wait for their departur... (more)
BNSF ES44AC 6174 leads a Superior, WI bound coal train east on the Staples Sub.
BNSF ES44C4 6553 and 3 sisters lead a long stack train downhill into Chester for a meet with the Havre local.
CREX ES44AC 1327 leads an empty crude oil train eastward on BNSF's Hi Line Sub, destined for another load at Epping, ND.
BNSF ES44C4 8339 leads a stack train past an old elevator near Burnham, MT on the Hi Line Sub.
BNSF C44-9W 5280 and SD70ACe 9006 have no issues getting their Havre-Minot manifest up to 60 per, just moments after leaving the yard at Havre.
Operating a day early (!), BNSF's Havre, MT - Minot, ND manifest gets rolling on the Milk River Sub, minutes after departing its origin yard.
BNSF ES44DC 7414 rips down the main at Culbertson at 70mph with a hot Chicago-Portland Z train in tow.
BNSF ES44DC 7414 teams up with 4 other various GEs, ripping through Williston, ND at 50mph with a hot Z train.
CSXT AC4400CWs 64, 70 and CREX ES44AC 1407 are staged with an empty crude oil train in the new yard just east of Epping on BNSF's Glasgow Sub. They are 3rd in line to load, with two trains already... (more)
BNSF's Montana Division #835 local (Stanley-Williston turn) works some customers at Tioga, ND with a nice consist, including a GP60B.
A BNSF Dilworth, MN - Portland, OR vehicle train holds tight at Mile 36 of the Jamestown sub waiting for a fleet of eastbounds to come off of the single track at Magnolia.


text:
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Reader Contributions Are Encouraged So We...
Researchers Now Have a Myriad of...
Co-Sourcing Improves Pharmaceutical Laboratory Productivity
Keep the Opportunities, Lose the Opportunists
Evotec is purchasing a 70% stake in India-based drug discovery services company Research Support International (RSIPL) for €2.8 million (about $4.02 million) in cash. The deal also gives Evotec a call option for the future purchase of the remaining 30 percent in the event of a change-of-control. RSIPL was established in 2004 as a wholly owned subsidiary of DIL (formerly Duphar-Interfran; www.dil.net) and currently has about 160 employees. Completion of the transaction will see RSIPL operate as Evotec India. The new site will complement the company's existing facilities in Hamburg and Abingdon, U.K. Evotec says that the Indian company will provide both important capacity expansion and complementary drug discovery and chemistry capabilities to its existing discovery platform in a cost-effective location. During May Evotec paid £0.5 million ($0.84 million) in cash for Summit's zebrafish screening business including operations in Abingdon and Singapore. The company says that despite this and the €2.8 million payout for the RSIPL stake, it should still have over €65 million ($93.41 million) in liquid funds by the end of 2009.
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MDMA (commonly known as the empathogen "ecstasy") is classified as a Schedule 1 drug, which is reserved for compounds with no accepted medical use and a high abuse potential. Two researchers from Stanford, however, call for a rigorous scientific exploration of MDMA's effects to identify precisely how the drug works, the data from which could be used to develop therapeutic compounds.Do you agree that ecstasy should be studied for its potential therapeutic benefits?
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Game! What's missing from this picture? (Our shower has been broken and we asked landlord to fix...Please Note: Shower is ONLY THING still intact in bathroom)
(photo by Vicky) Roommate woke up to find our toliet, sink, and medicine cabinet missing, and no one working. It was like the creepiest thief ever! Supposedly we don't get a toliet again until tomorrow night. I'm crossing my legs until then.
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Spending time with friends or researching. There is quite a bit that I'm interested in at any given time and I enjoy pursuing those interests wherever they lead. At least every other week I go out with friends or host small parties. I prefer cozy conversations over drinks to the...
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All Rise...
Judge Roman Martel found out what happens when Uwe Boll tries to make a serious film about global issues.
The Charge
"We'll make sure the world knows your story."
Opening Statement
I've watched Dr. Boll's films before. They were his video game based work, and I agree with most critics, they were pretty bad. A little research shows that Boll has started making serious dramatic films about the Vietnam war, prison and rampaging gunmen. Now we have a movie with Darfur in the title. I think Dr. Boll wants to be taken seriously. Will Attack on Darfur do the trick?
Facts of the Case
A group of journalists and a trio of African Union peacekeepers travels from a military base in Sudan into a small village in the Darfur region. In the village they take pictures, interview folks and film documentary footage. They are troubled and disturbed by the stories they hear dealing with the Janjaweed marauders decimating whole villages. The journalists are determined to make a difference with the information they have.
As they leave they see a convoy of Janjaweed raiders heading toward the village. They know that those people will suffer, but there might be a slim chance that the Janjaweed will not harm the people if they know Western journalists are present. They decide to go back to the village and do their best to prevent a massacre. This sets in motion a series of gruesome events that will change their lives forever.
The Evidence
Subtlety thy name isn't Uwe Boll.
As I watched Attack on Darfur, I marveled how a toning down of certain elements would have made this a really good and affecting movie. But time and again Uwe refuses to guide the viewer and instead grabs their head, wrenches it in the direction he wants them to look and shouts at the top of his lungs—THIS IS IMPORTANT!
Let's start with basic story construction. The idea is to play up the contrasts between the peaceful happy life of the villagers to the absolute terror of the marauder's raid. To do this we get montages, lots of them. Montages of happy smiling villagers living so simply, so peacefully, the lovely score by Jessica de Rooij carries us along. It just keeps going and going, until you want have your teeth checked because all the sweetness and love might cause a cavity.
When the horrors come, Boll does the same thing: montages of death, rape, shooting, infanticide, more rape, dismemberment, more shooting, more children getting murdered and more rape. Its all very graphic and disturbing, as it was meant to be. But it is also so manipulative and obvious that it made me angry at the movie.
A note about the violence: it's brutal stuff. I know that Boll wanted to shock his audience into action, he wanted to show it like it is. But violence can be just as effective or more effective if you leave things to the imagination. This type of violence is so harsh it borders on exploitative, and that's going to turn viewers against the film.
To put the viewer into the action, Boll decided to film everything with hand held cameras. This could have been an effective choice, one that would work wonderfully during the onslaught on the village. There's just one small problem. Not content to allow the handheld footage to be organic, Boll makes sure you know its hand held by non-stop shaking, vibrating and flailing during the entire film! Dialogue scene, driving scene, vicious death scene or touching scene of despair…the cameraman is having convulsions. This does not draw the viewer in. It makes them motion sick or painfully aware that someone is shooting this way on purpose.
Finally, there is the lightening quick editing. Regardless of the type of scene we are watching, no shot lasts much longer than 40 seconds. Maybe this was done to tone down the handheld motion sickness, maybe it was to create the feel of an action film. Maybe it was just for kicks. Who knows. But it does more harm than good. Long steady shots during the first half of the film could have provided a startling contrast to a more brutal and choppy second half of the film. In fact the fast editing works well during the massacre, but to have it during driving and dialogue scenes was distracting.
Dr. Boll provides a commentary that is a double edged sword. On the positive side, he describes the shooting process of the film and it actually gave me a greater appreciation of the set construction and the acting. On the negative side, he spends a huge amount of time talking about politics, comparing his film to Hotel Rwanda, and stroking his ego.
The DVD cover is hilarious. This looks like an action packed thriller with Billy Zane blowing away bad guys in helicopters. The back of the case even labels the film genre as "action." Um, no. The violence here is ugly and disturbing, not thrilling and fun. This is violent drama about the horrors in Darfur. I feel bad for the poor renter who picks this up thinking he's getting a fun straight to video action flick.
The Rebuttal Witnesses
The location shooting in South Africa is gorgeous, and when the camera isn't shaking around like a kid hopped up on sugar cubes, you get some great shots of the surrounding countryside. The fact the entire village was actually constructed out of real mud bricks and using materials actually found in the area added to the authenticity of the set.
The cast was uniformly good. The actors playing the journalists don't have too much to work with. They were improvising a lot of their dialogue, but they did a good job. Hakeem Kae-Kazim as the African Union Captain assigned to accompany the journalists is the best of the professionals. He has a world weariness to his performance that is perfect for his character, and when he makes the decision to do what he can to help the villagers his eyes tell you he believes he's a dead man.
The cast playing the villagers are actual Sudanese refugees who escaped to South Africa. Boll asked them to play themselves and it was a great idea. These people have been through hell and you can see it in their faces and eyes. When they are telling their stories to the journalists it feels real, because it is.
I also want to throw in another set of kudos to composer Jessica de Rooij. Her score is excellent and really helps the movie. This gal needs to score a high profile project, because she's got talent.
The DVD itself is a good product. The picture was clear and sharp. The 5.1 Surround was utilized well. The only extra is the commentary.
Closing Statement
This is such an important topic that I feel bad for coming down hard on it. But Attack on Darfur did not meet its goals. I was angry at the movie—not at the situation in Sudan. I don't like feeling like I'm being manipulated, made motion sick and annoyed all at the same time. I understand the what Dr. Boll was trying to do. But he needed to trust the stories the people were telling, trust the audience to feel compassion, and trust his crew to capture these elements.
The Verdict
Guilty of trying too hard.
Give us your feedback!
Did we give Attack On Darfur a fair trial? yes / no
What's "fair"? Whether positive or negative, our reviews should be unbiased, informative, and critique the material on its own merits.
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Review content copyright © 2010 Roman Martel; Site design and review layout copyright © 2016 Verdict Partners LLC. All rights reserved.


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Rebecca Plevin Health Reporter
Rebecca Plevin is a health reporter at KPCC. She also writes KPCC's consumer health blog, Impatient.
Prior to working at KPCC, Rebecca spent five years covering health news in California's Central Valley, first for the bilingual paper Vida en el Valle, and then for Fresno-based Valley Public Radio. She was also a lead reporter on The Reporting on Health Collaborative's groundbreaking series of stories about valley fever.
Rebecca's work has appeared on Morning Edition, All Things Considered, Marketplace, The California Report, Latino USA, and Capital Public Radio's health documentary series, The View From Here. For her work at KPCC, Rebecca has earned an LA Press Club Award for best blog and was a finalist for a Gerald Loeb award. As a newspaper reporter, she twice earned the George Gruner Award for Meritorious Public Service in Journalism, as well as top honors from the California Newspaper Publishers Association and the National Association of Hispanic Journalists.Rebecca grew up in the Washington, D.C. area and is a graduate of Northwestern University's Medill School of Journalism. She's also a fluent Spanish speaker, an avid rock climber and an acro yoga fanatic.
Stories by Rebecca Plevin
A cautionary tale: Vicodin sparks an ex-addict's relapse
In the first installment of a periodic series on dealing with pain, "Mary" tells how her doctor prescribed her the powerful opioid despite her concerns about a relapse.
LA County works on meningitis vaccination campaign
Public health officials say meningitis has disproportionally effected gay men. But improving immunization levels could be challenging.
Black Lives Matter rally blocks 405 Freeway in Inglewood
The violence of the past week, involving the deaths of five police officers and two black men, was on a lot of people's minds at rallies across L.A. Sunday.
Experts unsure why gay men at higher risk for meningitis
Twelve L.A. County residents have contracted meningitis in the past two months; seven of them have been gay or bisexual men.
Blood banks' new summer challenges: Zika, donor iron levels
The summer is always tough for blood banks. But new rules regarding Zika virus and male hemoglobin levels are aggravating a blood supply shortage.
FAQ: How California's new vaccination law works
This year, for the first some, some parents will no longer be able to skip vaccinating their kids based on their personal beliefs.
SoCal trauma centers: No surge in July 4th fireworks injuries
At least three Southern Californians suffered severe hand injuries, but several regional trauma centers saw just a handful of people hurt by fireworks.
Fight against opioid abuse spreads to LA urgent care clinics
Eighty clinics adopt opioid prescribing guidelines, following the lead of L.A. County's emergency departments. Officials plan to reach out to dentists next.
Meningitis outbreak prompts LA clinics to offer free vaccine
The AIDS Healthcare Foundation and AIDS Project Los Angeles are now offering the meningitis vaccine for free. It's recommended for gay men and those with HIV.
Water polo a big concussion risk, according to survey
In a UC Irvine survey of about 1,500 water polo players, just over one out of three reported getting at least one concussion while playing the sport.
2 LA sheriff's deputies shot, suspect in custody
A man who shot two deputies Thursday night in Bellflower, leaving them critically wounded, has been caught and is now in custody, sheriff's officials said Friday.
San Gabriel Complex: Some residents returning home; winds still a threat
Some Duarte residents were being allowed to return to their homes Wednesday, but many evacuations remain in place. Firefighters face another day of strong winds.
It's mosquito season: Who should use insect repellent, and when
L.A. and Orange County health officials recommend using mosquito repellent when going outside at dawn and dusk. Their main concern is West Nile virus, not Zika.
San Gabriel Complex: Firefighters brace to protect homes; Residents prep to evacuate
Firefighters have been hampered by extremely dry and rocky terrain, sporadic wind gusts and thin staffing, as nearby crews work to extinguish wildfires throughout SoCal.
Lawmakers renew push to block surprise medical bills
A new bill would protect people from paying surprise medical bills for out-of-network charges. It's an updated version of a proposal that stalled last year.


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Zumba at Albuquerque Little Theatre!!!
Led by Instructor Debbie Thomas ***YOUR FIRST CLASS IS FREE*** Wednesdays at 4:30 PM All classes will take place at Albuquerque Little Theatre in the rehearsal hall. CLICK HERE FOR MORE INFORMATION
We're Having a Blockbuster Summer at ALT! Join us!
We've got a Blockbuster Summer happening at ALT! Education classes are in full swing and we still have availability for our next 3 sessions (see our web site for details!)… we've got a FUNdraiser happening this Sunday the 14th at B2B (Bistronomy Beers to Burgers) on Central Ave. in Nob Hill — come by from … Continue reading
The Producers has wrapped… The Vivian Awards have been given… you may be thinking to yourself, "The folks at ALT must be so bored with nothing to do…" NOT! We've got lots happening in the next month! And one VERY cool and important thing requires YOUR help! On Sunday, July 14th, we're having a … Continue reading
ALT Announces Auditions for "YOUNG FRANKENSTEIN"
Announcing Auditions for YOUNG FRANKENSTEIN… YOUNG FRANKENSTEIN Book by Mel Brooks and Thomas Meehan; Music and Lyrics by Mel Brooks Directed by Henry Avery; musical direction by HB & William W. Williams *Saturday, July 13, 2013: Vocal auditions–11 am – 3 pm, by appointment* Dance auditions–3:30 pm – 5 pm *Sunday, July … Continue reading


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Photos: A bully parade in downtown Littleton
Breed-specific legislation might be a hot-button issue in the metro area, but that didn't stop local American pit bull terrier advocates and their canine best friends from proudly walking down Main Street in Littleton on Saturday to promote positive awareness of the breed. As costumed bullies and other breeds marched in the third annual Colorado Pit Bull Parade, photographer Darian Simon was there to record the whole dog party. Here's a photo preview; see the full slide show here.
See also: Photos: Pit bull lovers show off their pets during author/advocate Ken Foster's Denver stop
Continue reading for more pit bull photos.
Now see the full Colorado Pit Bull Parade slide show.
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20580 Rankings
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Breast cancer is the most common cancer in women in developed countries and has a well-established genetic component. Germline mutations in a network of genes encoding BRCA1, BRCA2, and their interacting partners confer hereditary susceptibility to breast cancer. Abraxas directly interacts with the BRCA1 BRCT (BRCA1 carboxyl-terminal) repeats and contributes to BRCA1-dependent DNA damage responses, making Abraxas a candidate for yet unexplained disease susceptibility. Here, we have screened 125 Northern Finnish breast cancer families for coding region and splice-site Abraxas mutations and genotyped three tagging single-nucleotide polymorphisms within the gene from 991 unselected breast cancer cases and 868 female controls for common cancer-associated variants. A novel heterozygous alteration, c.1082G>A (Arg361Gln), that results in abrogated nuclear localization and DNA response activities was identified in three breast cancer families and in one additional familial case from an unselected breast cancer cohort, but not in healthy controls (P = 0.002). On the basis of its exclusive occurrence in familial cancers, disease cosegregation, evolutionary conservation, and disruption of critical BRCA1 functions, the recurrent Abraxas c.1082G>A mutation connects to cancer predisposition. These findings contribute to the concept of a BRCA-centered tumor suppressor network and provide the identity of Abraxas as a new breast cancer susceptibility gene.
Breast cancer is the most common malignancy affecting women. The presence of a family history is the most important single risk factor, with the first-degree relatives having about a twofold increased risk over the general population. BRCA1 and BRCA2 are the two most important susceptibility genes in hereditary predisposition to breast and ovarian cancer. However, germline mutations in these tumor suppressors account for no more than 20% of the familial breast cancer cases worldwide (1). Most of the remaining cancer cases are predicted to involve mutations in moderate- and low-penetrance susceptibility genes together with influence from environmental factors, although the data from large multiple-case families strongly suggest that there might still be additional high-penetrance genes to be identified (2, 3). Improved knowledge on the functions of BRCA1 and BRCA2 in the DNA damage response pathway has been instrumental in the identification of a number of breast cancer susceptibility genes including PALB2, BRIP1, ATM, and CHEK2, all with protein products interacting directly or indirectly with BRCA1 and BRCA2 (4, 5).
BRCA1 plays multifaceted roles as a gatekeeper of genomic integrity. It is essential for efficient DNA repair by homologous recombination and execution of cell cycle checkpoints activated by DNA damage (6). The C-terminal region of BRCA1 contains two BRCT (BRCA1 C-terminal) repeats that are critical for its tumor suppressor function. These BRCA1 BRCT motifs are the most common site of clinical mis-sense mutations, which invariably disrupt phosphorylation-dependent interactions with direct binding partners (7, 8).
Abraxas (ABRA1, CCDC98, or FAM175A) serves as a central organizer of a large BRCA1 holoenzyme complex, directly binding via its phosphorylated C terminus to the BRCA1 BRCT motifs (9–11). This interaction links BRCA1 to a core protein complex dedicated to ubiquitin chain recognition and hydrolysis at DNA double-strand breaks (DSBs) (9, 12–16). Abraxas and the other members of this complex [RAP80, BRCC36, MERIT40/NBA1 (HUGO name BABAM1), and BRCC45] are required for DNA damage checkpoints and cellular resistance to ionizing radiation (IR).
A deleterious germline RAP80 variant (del81E) that abrogates ubiquitin binding, DSB targeting, and genome integrity has been reported in two breast cancer patients (17). Additionally, a recent genome-wide linkage consortium study suggested an association between the rare allele of single-nucleotide polymorphism (SNP) rs8170 in MERIT40/NBA1 and an increased propensity for hormone receptor–negative breast cancer, both in the general population and in BRCA1 mutation carriers (18). The same SNP has also been associated with susceptibility to serous epithelial ovarian cancer (19). These findings suggest that BRCA1, in association with the core Abraxas complex, has tumor-suppressive function in humans. Here, we provide evidence in support of this hypothesis by identifying a novel germline mutation in Abraxas that exclusively associates with familial cancer and abrogates BRCA1-dependent DNA repair function.
We screened 125 affected index patients of Northern Finnish breast cancer families for germline mutations in the Abraxas gene, revealing four intronic and six exonic variants (Table 1). Together, five of the changes have not been reported either in the National Center for Bio-technology Information (NCBI) SNP database (http://www.ncbi.nlm.nih.gov/SNP/) or by previous studies (20, 21). A computer simulation analysis using PolyPhen software indicated that of the observed changes, only c.1082G>A was likely to result in functional changes in the protein. ESEfinder 2.0 and NNSplice software analysis did not reveal any likely abnormalities. Alteration c.1082G>A results in Arg361Gln (R361Q), which changes the last residue of a putative bipartite nuclear localization signal (NLS) (Fig. 1A) (10). Both Abraxas protein and mRNA sequence alignments revealed absolute evolutionary conservation among vertebrates at the site of the wild-type sequence (Fig. 1B). None of the studied common SNPs within Abraxas showed a statistically significant association with cancer susceptibility (table S1).
Abraxas c.1082G>A alteration was observed in 3 of 125 studied breast cancer families (2.4%) but was absent from 868 healthy female control individuals. The mutant allele was also identified in 1 of 991 breast cancer cases unselected for a family history of the disease (Table 1). The prevalence of c.1082G>A in familial compared with control cases, and also in familial compared with unselected breast cancer cases, was found to be significantly different (P = 0.002 and 0.005, respectively), which suggests that this variant is disease-associated and specifically correlated with familial cancer. In agreement, the only mutation-positive breast cancer patient in the unselected cohort also proved to have a familial cancer background (Fig. 1C, Family BR-0194).
Segregation analysis was performed in two of the mutation-positive families (BR-0194 and 96-653, Fig. 1C), showing cosegregation between Abraxas c.1082G>A and cancer phenotype. Because of a lack of suitable DNA samples, segregation analysis was not possible for the two remaining Abraxas mutation–positive breast cancer families (BR-02101 and 98-063). Of these, the index case of Family BR-02101 was diagnosed with both breast and endometrial cancer at the age of 37 and 49 years, respectively. She had a family history notable for stomach, lung, and prostate cancer, in addition to two maternal female cousins diagnosed with breast cancer at 48 and 54 years of age, respectively. The index case in the fourth family (98-063) was diagnosed with two ipsilateral primary breast tumors of different morphology (lobular and mucinous) at the age of 49 years. Her deceased sister displayed bilateral breast cancer at 53 and 71 years of age. The index patients of all four Abraxas mutation–positive breast cancer families tested negative for mutations in BRCA1, BRCA2, TP53, CDH1, and PALB2. The average age of disease onset of the confirmed five Abraxas mutation–positive breast cancer cases was 46 years (variation, 35 to 53 years), similar to those with Finnish BRCA1 (46 years; variation, 32 to 57 years) and BRCA2 (48 years; variation, 45 to 67 years) mutations (22). For comparison, the mean age of onset for the recurrent Finnish PALB2 c.1592delT was found to be 52.9 years (variation, 39 to 73 years), and the average age of onset for the unselected breast cancer cases was 57.9 years (variation, 23 to 92) (23).
Morphology studies of R361Q-positive breast cancers (Table 2) revealed a lobular phenotype in four of the five tumors (80%). A second primary disease of mucinous morphology was observed in one of the patients who initially presented with lobular disease. This was in marked contrast to the single case (20%) of the ductal phenotype, which is typically seen in about 75% of breast cancer cases (24). Immunohistochemistry was performed on sections from the same breast cancer cases noted above, and all four of the informative tumors revealed strong expression of both the estrogen receptor (ER) and the progesterone receptor (PR), as well as total absence of human epidermal growth factor receptor 2 (HER2) expression (Table 2). These phenotypic observations suggest that Abraxas mutation–positive breast cancer cases can deviate from the pattern of hormone receptor and HER2 negativity associated with BRCA1 tumors (25). Tumors from patients with mutations in BRCA2 and PALB2, which, like Abraxas, encode BRCA1-associated proteins, also frequently show hormone receptor positivity (23, 26).
BRCA1 and BRCA2 mutated cancers often display loss of heterozygosity (LOH), whereas loss of the wild-type allele at other BRCA-associated breast cancer susceptibility genes is less common (27, 28). To test whether LOH had occurred in tumors of individuals heterozygous for the Abraxas mutation (a total of six R361Q-positive tumors), we extracted genomic DNA from pure or highly enriched tumor cell populations obtained by laser-capture microdissection from formalin-fixed, paraffin-embedded tumor tissue sections, and we amplified and sequenced an Abraxas gene segment surrounding the c.1082G>A mutation by polymerase chain reaction (PCR). The existence of the c.1082G>A mutation was confirmed in all studied tumors, whereas no evidence of loss of the wild-type allele was ever seen (table S2).
To assess the impact of R361Q on Abraxas subcellular localization, we stably expressed epitope-tagged wild-type or R361Q mutant Abraxas in three different cell lines at near-endogenous levels and examined subcellular localization by immunofluorescence (IF). Wild-type Abraxas demonstrated predominantly nuclear localization by IF, whereas Abraxas R361Q was primarily cytoplasmic (Fig. 2, A and B). Coimmunoprecipitation experiments revealed that R361Q maintained interactions with BRCA1 and other core components of the holoenzyme complex (Fig. 2C). Notably, Abraxas R361Q preferentially immunoprecipitated with BRCA1 and other interacting partners in the cytoplasm, whereas wild-type Abraxas primarily displayed these interactions in the nucleus (Fig. 2D and fig. S1).
To determine the impact of R361Q on DNA damage response functions, we examined recruitment of wild-type Abraxas or R361Q to DSBs. R361Q recruitment to a specific site of nuclease-induced DSBs (29) was strongly reduced in comparison to wild-type Abraxas, suggesting deficiency in DNA damage response functions due to impaired nuclear accumulation (fig. S2A). Similar results were observed at IR-induced foci (IRIF) in three different cell types (Fig. 3, A and B). Consistent with a dominant-negative activity, R361Q expression significantly reduced both BRCA1 and RAP80 IRIF formation and resulted in IR hypersensitivity in three different cell lines (Fig. 3, A to C, and fig. S2, C and D). In addition, R361Q expression partially disrupted the G2 checkpoint in response to IR and reduced the efficiency of homology-directed DSB repair (Fig. 3, D and E). These results suggest that reduced nuclear accumulation by Abraxas R361Q negatively affects DSB localization of its interacting partners. In support of this concept, inhibition of nuclear export by leptomycin B treatment increased nuclear Abraxas R361Q and restored IRIF for Abraxas R361Q, BRCA1, and RAP80 (fig. S3, A and B). Conversely, Abraxas R361Q expression did not aberrantly affect subcellular localization of β-catenin, further emphasizing the specificity for its impact on BRCA1 and RAP80 (fig. S4). Abraxas, in addition to BRIP1 (FANCJ) and RAP80 (17, 27, 30), is now the third BRCA1 BRCT–interacting partner with germline human breast cancer–associated mutations shown to exert dominant-negative effects on BRCA1 DNA repair function. These findings suggest that the nature of the Abraxas R361Q mutation may obviate the need for LOH in tumors from affected patients.
Here, we report the identity of a novel, recurrent, constitutional mutation in the Abraxas gene in familial breast cancer. Abraxas R361Q demonstrated exclusive association with cancer, segregation with disease within families, and loss of biological function in the DNA damage response. The impaired DNA damage response function extends beyond Abraxas itself, because Abraxas R361Q exerted a dominant-negative influence on BRCA1 and RAP80 by diminishing their accumulation at IR-induced DNA damage foci. In light of this finding, it is interesting that breast cancer–associated mutation RAP80delE81 displayed similar dominant-negative properties with respect to BRCA1 localization to IR-induced foci (17).
These observations complement existing knowledge of breast cancer–associated mutations within genes encoding proteins present in other BRCA1-containing protein complexes, reinforcing the concept of a BRCA-centered tumor suppressor network dedicated to the maintenance of genomic integrity (4, 31). Moreover, they establish ubiquitin recognition at DNA damage sites as a bona fide tumor suppression function of BRCA1-associated protein complexes. The BRCA1 protein complex containing Abraxas and RAP80 is unique in comparison to BRCA1 complexes that contain breast cancer suppressors PALB2, BRCA2, and BRIP1. RAP80 targets BRCA1 and Abraxas to ubiquitinated chromatin extending for a distance away from DSBs, whereas BRCA1 complexes containing BRCA2 and PALB2 or BRIP1 are thought to directly interact with DNA intermediates during homologous recombination–dependent DNA repair (32). Mutation in any of these genes results in severely reduced homologous recombination, whereas cells deficient for Abraxas or RAP80 display elevated use of homology-directed DNA repair mechanisms (33, 34). Abraxas R361Q cells displayed slightly reduced homology-directed repair of a nuclease-induced DSB (Fig. 3E), suggesting that Abraxas R361Q expression impairs BRCA1-dependent DNA repair differently than would an Abraxas-null allele. It is also unclear whether the IR hypersensitivity displayed in three different Abraxas R361Q–expressing cell lines was a result of the slight reduction in homology-directed DNA repair or alternatively due to defective G2 checkpoint signaling (Fig. 3D). Therefore, it would be interesting to determine whether cancers expressing Abraxas or RAP80 dominant-negative mutant alleles would exhibit similar responses to chemotherapy regimens as tumors harboring mutations in other genes within the BRCA network. The development of various Abraxas- or RAP80-deficient tumor models will be important to test such predictions.
In addition to breast cancer, Abraxas R361Q families displayed some relatively rare cancer types. Recently, a genome-wide association study associated a novel variant, rs1494961, located near Abraxas, with genetic susceptibility to upper aero-digestive tract cancers (35). In our current study, both lung and lip cancer and lymphoma of the throat occurred in the two Abraxas c.1082G>A families shown in Fig. 1C. In addition, Family BR-0194 had a case of neuroblastoma; mutations in anotherBRCA1-associatedgene, BARD1, have recently been connected to this disease (36).
In conclusion, we have identified a coding variant of the Abraxas gene with a significantly different distribution in the familial cancer cases compared to the studied controls. This alteration is found in 2.4% of the studied Northern Finnish familial breast cancer cases and predominantly associates to a lobular tumor phenotype. On the basis of its exclusive occurrence in familial cancer cases, disease cosegregation, evolutionary conservation, and disruption of critical BRCA1 DNA damage response functions, the recurrent mutation connects to cancer predisposition. Similar to BRCA1 and BRCA2, mutations in Abraxas appear to be involved in susceptibility to certain other malignancy types beyond breast cancer. The present results warrant investigation of Abraxas as a new cancer susceptibility gene in other populations as well. The identification of additional Abraxas mutation–positive families would provide the means for more reliable cancer risk assessments and evaluation of the potential use of Abraxas mutation testing in clinical diagnostics.
Mutation screening of Abraxas was performed on blood DNA samples obtained from 125 breast and breast-ovarian cancer families originating from Northern Finland (23). One index patient from each family was chosen according to the youngest age of breast cancer onset. Inclusion criteria for the 73 high-risk families were as follows: (i) three or more cases of breast cancer, potentially in combination with single ovarian cancer in first- or second-degree relatives, or (ii) two cases of breast or breast and ovarian cancer in first- or second-degree relatives, of which at least one with early disease onset (<35 years), bilateral breast cancer, or multiple primary tumors including breast or ovarian cancer in the same individual. The remaining 52 families were indicative of moderate disease susceptibility, presenting either two cases of breast cancer in first- or second-degree relatives, or breast cancer under the age of 35 (2 cases). Together, 15 of the studied index cases had previously been tested positive for known breast cancer–associated germline mutations in BRCA1 or BRCA2 (11 cases), TP53 (1 case), and PALB2 (3 cases). All of the biological specimens and clinical information of the familial breast cancer cases investigated were collected at the Oulu University Hospital, with the informed consent of the patients.
For the Abraxas c.1082G>A genotyping and tagging SNP (tagSNP) analysis, DNAs from an unselected cohort of breast cancer patients (n = 991) were collected without selection for a family history of breast cancer. This sample set consisted of 544 Northern Finnish cases operated at the Oulu University Hospital during the years 2000 to 2007 and 447 patients with invasive breast cancer from the Kuopio Breast Cancer Project (KBCP), originating from the province of Northern Savo in Eastern Finland and diagnosed at the Kuopio University Hospital between 1990 and 1995 (37).
Informed consent to participate in the study has been obtained from each patient, and the studies have been approved by the Finnish Ministry of Social Affairs and Health, and appropriate ethical committees of each of the participating University Hospitals.
Together, 868 Finnish female control cases were used for genotyping and tagSNP analysis. The Northern Finnish control samples (where the number of studied individuals varied between 88 and 506, depending on the specific analysis) derived from anonymous cancer-free Finnish Red Cross blood donors (age ≥45 years) originating from the same geographical region as the studied cancer patient cohort. The age- and area of residence–matched KBCP cohort consisted of DNA from 362 control subjects selected from the National Population Register during the same time period as the unselected breast cancer patients (37). All control individuals were cancer-free at the time of donation of the blood sample. There was no follow-up on donor health status.
The entire coding region and exon-intron boundaries of the Abraxas gene were screened for germline mutations either by conformation-sensitive gel electrophoresis (CSGE, exons 2 to 8) or by direct sequencing (exons 1 and 9). Samples with deviating CSGE patterns or those directly sequenced were analyzed with the Li-Cor IR2 4200-S DNA Analysis system (Li-Cor Inc.) using the SequiTherm EXEL II DNA Sequencing Kit-LC (Epicentre Technologies) or with ABI3730 (ABI Perkin Elmer) using the BigDye Terminator v3.1 Cycle Sequencing Kit (Applied Biosystems). Oligonucleotides were designed with Primer3 software (http://frodo.wi.mit.edu/cgi-bin/primer3/primer3_www.cgi, table S3).
Genotyping of Abraxas c.1082G>A and tagSNPs rs12499395, rs12649417, and rs13125836 was done with MassARRAY mass spectrometer (Sequenom Inc.) and iPLEX Gold (Sequenom) on 384-well plate format (used primers in table S4). TagSNPs were selected with the HapMap Genome Browser release 2 (Phase 3, NCBI build 36, bdSNP b126) as of 23 February 2010 (http://hapmap.ncbi.nlm.nih.gov/cgi-perl/gbrowse/hapmap3r2_B36/). TagSNPs for region chr4:84593218-84633217 were picked out for the CEU population with the Tagger multimarker algorithm with r2 cutoff at 0.8 and minor allele frequency (MAF) cutoff at 0.05. MassARRAY was used for spectra acquisitions from the SpectroCHIP (Sequenom). Data analysis and genotype calling were done with Typer Analyzer software version 220.127.116.11 (Sequenom). Each 384-well plate contained a minimum of eight nontemplate controls. For the c.1082G>A mutation, DNAs from three heterozygous mutation carriers were used as positive controls on each plate. For quality control, duplicate analysis was done for 6.5% of the samples from Oulu and for 6.7% of the samples from Kuopio.
Carrier frequencies between patients and healthy controls were compared with Pearson χ2 or Fisher's exact test (two-sided, SPSS version 17.0 for Windows). All alterations were checked with NNSplice software for potential effects on splicing (http://www.fruitfly.org/seq_tools/splice.html). Arg361Gln was tested for possible pathogenicity with PolyPhen software (http://genetics.bwh.harvard.edu/pph). For tagSNP data, the overall association as well as the Hardy-Weinberg equilibrium, allele-specific P, odds ratio, and confidence interval were computed with Cochran-Armitage trend test.
Formalin-fixed, paraffin-embedded tissue sections (4 μm) were de-paraffinized and rehydrated in graded alcohols. Heat-induced epitope retrieval was performed with a digital pressure cooker in citrate buffer (pH 6.0) before application of the appropriate polyclonal (or monoclonal) antibody. The primary antibody was detected with the Envision+ system (K4011, DakoCytomation) that uses horseradish peroxidase–labeled polymer conjugated to goat anti-rabbit immuno-globulin antibodies. The immune complexes were identified using a peroxidase reaction with 3,3′-diaminobenzidine-plus as chromogen. Slides were counterstained with Mayer's hematoxylin. Antibodies against ER (monoclonal, clone 1D5), PR (monoclonal, clone PgR636), and HER2 (polyclonal) were all purchased from Dako and used at 1:100, 1:200, and 1:1000, respectively.
BRCA1 was detected by immunoblotting (IB) with mouse monoclonal antibody MS110 at a 1:10 dilution, and by IF with a rabbit polyclonal antibody 07-434 (Millipore) at 1:500. A RAP80 rabbit polyclonal antibody was used for IB at 1:500 and IF at 1:100 dilutions. BRCC36 was detected by IB with a rabbit polyclonal antibody (12). MERIT40 was detected by IB at 1:1000 with a rabbit polyclonal antibody (14). Hemagglutinin (HA)–tagged proteins were detected by IB at 1:1000 and for IF at 1:1000 dilutions with mouse monoclonal antibody HA.11 (Covance).
HeLa, 293T, MCF10A, and U2OS cells were cultured in Dulbecco's modified Eagle's medium (Gibco) with 10% calf serum. Transient transfections were performed with LipoD293 (SignaGen Laboratories) according to the manufacturer's protocols.
293T cells were lysed in NETN-150 buffer [150 mM tris-HCl (pH 7.4), 1 mM EDTA, 0.05% Nonidet P-40, 0.5 mM phenylmethylsulfonyl fluoride, and 5 mM β-mercaptoethanol] for the production of whole-cell extracts. Nuclear and cytoplasmic fractions were obtained from cells by Dounce homogenization of cells treated with hypotonic buffer [10 mM KCl, 10 mM tris-HCl (pH 7.4), 1.5 mM MgCl2]. Nuclei were lysed in NETN-150 buffer at 4°C for 45 min. All subsequent steps were performed in NETN-150 buffer. The quality of our fractionation was evaluated by the detection of specific markers: γ-tubulin for the cytoplasmic fraction and proliferating cell nuclear antigen for the nuclear compartment.
All radiation exposures were performed with a Gammacell 40 irradiator (Nordion International), which used cesium-137 as the radiation source.
U2OS cells were cultured on glass coverslips and transiently transfected with LipoD293 (SignaGen Laboratories) according to the manufacturer's protocols. Cells were treated with 10 Gy IR and allowed to recover for the indicated times in a 37°C incubator. Cells were washed with phosphate-buffered saline (PBS) and then fixed in 3% paraformaldehyde/2% sucrose containing solution for 10 min at room temperature. Cells were subsequently permeabilized with 0.5% Triton solution for 5 min at 4°C and then incubated with the appropriate primary antibody for 20 min at 37°C. Cells were then washed with PBST (PBS–Tween 20) and incubated with secondary antibody for 20 min at 37°C. Nuclei were then stained by incubating the cells in a PBS solution containing Hoechst 33258 dye (1 μg/ml). After four washes in PBST, coverslips were mounted onto glass slides with Vectashield mounting media (Vector Labs) and visualized with a Nikon Eclipse 80i fluorescence microscope.
The G2 checkpoint assay was performed by assessing the percentage of mitotic cells at 0 Gy and at 1 hour after 2 Gy IR as previously described (14). A rabbit polyclonal antibody against phosphorylated histone H3 (Upstate Biotechnology) was used to detect mitotic cells.
Homology-directed DNA repair assay was performed as described (34). U2OS cells containing stable integration of the direct repeat green fluorescent protein (DR-GFP) reporter locus were transiently transfected with I-SceI and Abraxas plasmids and then scored for homology-directed DNA repair by fluorescence-activated cell sorting (FACS) for GFP-positive cells 72 hours after transfection.
The FLAG-HA–tagged version of Abraxas R361Q was created from Addgene vector 27495.
Table S1. Association analysis of three Abraxas tagSNPs with breast cancer.
Table S2. LOH analysis of laser-capture microdissected tumor cell DNA of Abraxas c.1082G>A germline mutation carriers.
Table S3. Abraxas primers and PCR amplicon details.
Table S4. iPLEX primers used for Abraxas c.1082G>A and tagSNP genotyping.
Fig. S1. Abraxas R361Q is preferentially immunoprecipitated with its interacting partners in the cytoplasm.
Fig. S2. Expression of Abraxas R361Q affects DNA damage response.
Fig. S3. Nuclear retention of Abraxas R361Q restores localization and recruitment to DSB.
Fig. S4. Cytoplasmic localization of Abraxas R361Q does not aberrantly activate β-catenin.
We thank A. Mustonen, A. Jukkola-Vuorinen, M. Grip, V. Kataja, and nurses K. Mononen and O. Kajula for their help in sample and data collection and in patient contacts. The contribution of H. Erkko and technical assistance by M. Otsukka, H. Konola, R. Vuento, and E. Myöhänen are gratefully acknowledged. We thank all the patients and their family members for volunteering to participate in these studies, as well as the Finnish Red Cross Blood Service for help with collection of population control blood samples. We are also grateful to M. Jasin (Memorial Sloan-Kettering Cancer Center) for providing the DR-GFP cell line and I-SceI expression plasmid.
Funding: R.W. gratefully acknowledges the financial support from the Finnish Cancer Foundation, the Academy of Finland (grant number 122715 and Center of Excellence grant number 251314), CIMO, the University of Oulu, the Oulu University Hospital, the Cancer Fund of Northern Finland, the Sigrid Jusélius Foundation, the Cancer Fund of Savo, the Ida Montini Foundation, and the Tyyni Tani Foundation. The Kuopio group acknowledges the support from the Finnish Cancer Society, the Academy of Finland (grant number 127220), the special Government Funding (EVO) of Kuopio University Hospital (grant numbers 5654112 and 5501), and the strategic funding of the University of Eastern Finland. R.A.G. gratefully acknowledges funding from the National Cancer Institute (1R01CA138835-01), an American Cancer Society Research Scholar Grant, and funds from the Abramson Family Cancer Research Institute. J.P.-F. was supported in part by a Doctoral Research Award from the Canadian Institutes for Health Research.
Author contributions: R.W. and R.A.G. designed and oversaw the study with helpful input from K.P. S.S. performed the mutation analysis and the statistical and bioinformatic assessment of the initial genetic findings obtained from the familial and unselected breast cancer cohorts and controls from Oulu. K.P. was responsible for the sequencing and loss of heterozygosity analysis on archival patient tissue material, with some early-phase mutation analysis help from S.S. J.M.H., A.M., and V.-M.K. contributed with the KBCP cohort, and J.M.H. and A.M. performed the tagSNP association and haplotype analysis as well as iPLEX c.1082G (a mutation testing in both unselected cases and controls from Kuopio). A.M., K.P., and J.M.H. performed the statistical analysis of the obtained tagSNP data. R.W. gathered the extended genealogy and cancer registry data for the mutation-positive families, and S.K. was responsible for obtaining suitable archival tissue samples as well as laser-capture dissection of tumor material for the LOH analysis and for getting detailed clinicopathology data of the studied cancer cases. J.P.-F. and B.A. performed the functional studies. S.S. prepared the initial manuscript draft with critical input from K.P., R.W., and R.A.G. R.W., R.A.G., K.P., B.A., S.S., and J.P.-F. prepared the advanced manuscript, and all authors contributed to critical review of the paper.
Competing interests: The authors declare that they have no competing interests.
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Hi all - If you missed last month's session where Niels from Magnetic presented on their use of MongoDB, we will be hosting a webinar tomorrow on this topic. Details are below. http://www.10gen.... Wednesday, August 10th @ 1:00pm ET The Magnetic data marketplace empowers advertisers and publishers to use search data as the key indicator of intent and retarget campaigns to the most relevant audience online. With more than 270 million search profiles, Magnetic significantly lifts the value of media and improves campaign performance. This webinar will examine how Magnetic uses MongoDB for their online advertising platform. Mark Weiss, the Senior Director of Engineering at Magnetic, will discuss how the company drastically simplified its architecture by taking advantage of MongoDB's rich combination of features. Topics will include: How Magnetic takes advantage of MongoDB's flexible data model Leveraging atomic counters for real-time analytics on impression counts and frequency caps Using map/reduce to offer a new tier of near-real-time reporting Hope you can join. Cheers, Meghan
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Bored with Chrome OS? GalliumOS is a specialized Linux distribution based on Ubuntu for Chromebooks only. Is it worth using? Let's find out!
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Like a lot of 23-year-olds, Andrea "Annie" Damiano is a big Eagles and Phillies fan, and she follows the Olympics closely.
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Bergholt Stuttley Johnson wrote:What like a STD?
Bergholt Stuttley Johnson wrote:cant, I have no experiance of either
const string Name = "Jason Cantrell";
const string Location = "New Orleans";
Prosecutor p = People.GetPerson(Name, Location, true) as Prosecutor;
if(p != null)
p.IQ = -1;
Zac Greve wrote: It is either that or my installation of the VS2012 SDK that fixed the issue.
Chris Maunder wrote:Helloooo overage charges!
ChrisElston wrote:I really don't want to know what sort of stuff you're searching for.
Chris Maunder wrote:I finally upgraded my cracked, slow, creaking iPhone 3G to a 5
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