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Comments On Aug 14, 2014:Works great. Easy install. Motor has smooth power now. Better traction.
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Comments On Aug 13, 2014:This was the first modification that I made. I knew right away that for trail riding the bike stalled way too easily when lugging the motor. This lets you lug the hell out of it and use that torque! This coupled with going up 2 teeth on the rear sprocket have made this a trail conquering machine.
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Comments On Mar 04, 2014:WHEN I RECEIVED MY KIT, THE EPOXY THAT STEAHLY REQUIRES WAS EXPIRED BY OVER 5 MONTHS. STEAHLY WILL NOT WARRANTY THE PRODUCT IF EXPIRED EPOXY IS USED. CONTACTED ROCKY MOUNTAIN, AND THEY COULD NOT GIVE ME AN ESTIMATED TIME IN WHICH I WOULD RECEIVE MY WARRANTIED EPOXY KIT. TECH NOTE: THESE KITS HAVE BEEN CHECKED AND WILL BE MONITORED FOR EXPIRATION DATES.
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Comments On Mar 06, 2014:Adding the flywheel weight has made a noticeable different in the deliver of power. I believe its been a good addition to my bike.
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Comments On Feb 06, 2014:These are worth their weight in gold in nasty off road situations, great way to get a feel of more torque and to smooth the hit on a peaked out powerband.
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Comments On Jan 26, 2014:In my experiences with Steahly, their products have always been high quality. This FWW is no different. Comes with a tool to install the weight it takes roughly 20 minutes. Ive had it on for about 40 hours and check it often(as recommended) and so far set screws have stayed tight. As far as performance it did not necessarily take anything away from the hit but it did help prevent stalling and no other changes needed to be made to the bike.
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Comments On Dec 10, 2013:Made the bike track better, less stalling, and overall better riding experience. I went with a 13oz weight.
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Comments On Dec 04, 2013:Easy to install and works awesome! I got the 12oz and it didn't rob any power just made the power easier to get traction. Sweet!
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Comments On Oct 21, 2013:Used on 2004 CR250R. 10 oz. weight. Completely changes power characteristics. With 13/51 gearing this bike climbs as good as any 450 4 stroke now. On acceleration the front tire tends to come off the ground easier, sometimes unexpectedly, due to better rear wheel hook up. Don't need flywheel puller for this bike, engine lock up tool is very handy though. Can have this weight on or off in under 10 minutes. Highly recommended for 2 strokes in the Utah deserts.
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Comments On Jun 10, 2013:made a big difference before and after. Really helped me out since I'm just a beginner.
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Ubisoft Confirms Controversial New DRM System Being Used for Splinter Cell: Conviction on PCBy Garnett Lee, Feb 26, 2010 1:20pm PST Softpedia reports that the upcoming Splinter Cell: Conviction was on a list of titles planned to use Ubisoft's controversial new PC DRM system given to PC Gamer by a company representative. Also appearing there are Silent Hunter 5: Battle of the Atlantic, Prince of Persia: The Forgotten Sands, and the all new Ghost Recon game in development.
With Assassin's Creed 2 and Settler 7 already known to be using the system as well, Ubisoft appears resolute in its adoption of the new DRM for all PC projects going forward. As part of the comment, the Ubisoft representative said, "it's hard for us to say, yes, from now until the day that we all die all of our games are going to include this but most will."
At the heart of the matter is the requirement of an active connection to the internet, without which the game will not work at all. Serious as the threat piracy poses is, the deluge of responses indicate that such draconian measures miss the mark on two counts. Potential customers put off by the restriction may choose not to buy a game they might otherwise have and hackers inevitably find ways around the protections to steal the game anyway -- a point even the Ubisoft representative was resigned to.[thanks Shacker retarded talking dinosaur for the tip]
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By: JackAxe x Show Full PostAnyone else notice that UbiSoft is now charging $60 for a PC game? Oh well, I gave up on this company a couple of years back and at that time I never imagined they'd paint themselves into a corner.Feb 26, 2010 10:14pm PSTAnyone else notice that UbiSoft is now charging $60 for a PC game? Oh well, I gave up on this company a c... : JackAxe
By: darthfusion x Show Full PostD.R.M....
One of the biggest problems with Anti-Piracy Measures such as DRM, is that they hurt those of us that would have actually bought the game as well.
Safedisc, SecuRom, DRM. Things that get in the way even if you legitimately go out and buy the game. Safedisc and SecuRom for example prevent games from working if you have Emulation Software AT ALL on your PC. The only way to get around it, is to crack (essentially hack) the game. (Star Wars Battlefront II was a prime example of this).
And now we're seeing DRM that REQUIRES you to be connected to the internet to play a SINGLE PLAYER only game...
A lot of people buy single player games on PC because they don't have a solid (or stable) internet connection...
If you like Single Player games for your laptop this one's not for you :P
The Result = Sadly, if You want to play games with these kind of Anti-Piracy Measures without issues... You're better off downloading a pirated ALREADY cracked version of the game, that will work efficiently, (because you're going to have to find the crack to get it to work anyway).Apr 07, 2010 5:30pm PDT
By: kodt x Show Full PostI was wondering, if DRM is mostly there to prevent 0-day pirating. And to make sure the initial launch isn't undermined by DRM. Why not have this restrictive DRM (which may take some time to pirate) in place at first but promise all legitimate buyers that a patch to remove all DRM will be released in 3-6 months or so.
The truth is I don't think most people will be negatively affected by the DRM, but they see potential for it down the road. If the game was sure to be DRM free down the road we would not feel bad buying it with DRM up front.
Also it seems like pirates could just wait for the DRM free version without any worry of Trojans being packed in with the cracks.Feb 27, 2010 10:06pm PSTI was wondering, if DRM is mostly there to prevent 0-day pirating. And to make sure the initial launch is... : kodt
By: alllivestaken x Show Full PostDidn't everyone say the same thing about MW2 and not having dedicated servers, different controversy but people still bought it anyway. Plus I'm sure it won't be as bad as people think.Feb 26, 2010 5:05pm PSTDidn't everyone say the same thing about MW2 and not having dedicated servers, different controversy but ... : alllivestaken
Thread Truncated. Click to see all 10 replies.
P.S> the DRM is the worst Idea ever though! : alllivestaken
i would have bought MW2 if it had dedicated servers, because it doesnt, i didnt buy it : landaishan
By: Sewje x Show Full PostWell it's this or do a Microsoft and take it out of the PC platform completely. There must be money coming in some way if they can do this and make money. I guess the ones who complain DON'T make any difference to their bottem line :) Hate to say it so harshly but they don't give a shit about you!
Well we'll see soon enough!Feb 28, 2010 4:51pm PSTWell it's this or do a Microsoft and take it out of the PC platform completely. There must be money comin... : Sewje
By: Dr_Cube x Show Full PostAgain, I don't hold it against them from trying to protect their product but this is going to gut what remains of their PC sales. If there's going to be DRM it's got to be provided by the platform (i.e. Steam or Games for Windows Live) simply for usability reasons. Publisher specific DRM layered on top, especially when it requires yet another account to manage and a password to remember, just becomes another bother.
Also, as many others have already said, this is going to be a support nightmare for Ubisoft when it goes live.Feb 26, 2010 2:38pm PSTAgain, I don't hold it against them from trying to protect their product but this is going to gut what re... : Dr_Cube
By: Jess Horton x Show Full PostSo ... while I think this DRM sucks balls I can understand that for every action there is a reaction. Piracy is fine with me but how can you expect them to just sit idle? The only thing I find ironic is the people who are in disgust with the implementation and therefor point their fingers in the wrong direction. Is it really Ubisoft's fault that they have to try something ... not at all. If someone keeps stealing your wallet ... eventually you'll put a chain on it.Feb 26, 2010 2:28pm PSTSo ... while I think this DRM sucks balls I can understand that for every action there is a reaction. Pir... : Jess Horton
Thread Truncated. Click to see all 14 replies.
And as consumers we have a right to show our displeasure with their product by not purchasing it and voic... : capt tripps
Very true. I mean don't get the wrong impression ... this is bullshit in my eyes. I'm not buying a game t... : Jess Horton
By: bloodypalace x Show Full PostAnti-piracy is just a sad joke!
It only affects the legitimate buyers....Feb 26, 2010 1:51pm PST
Thread Truncated. Click to see all 19 replies.
Remove the anti. Without piracy there would be no anti-piracy therefore alleviating the problem we are no... : Jess Horton
This doesn't change the fact that a company has a choice when it comes to anti-piracy measures. Piracy i... : Lucien Irenicus
there aren't any legitimate buyers left anymore, or at least to make a difference. pc retail sales have ... : isildur21367
What gokwyjibo said^^ I haven't bought a single retail game in 4 years. Steam ftw! : bloodypalace
I've bought over 8 games in the past 2 years alone, all through Steam, and have over 80 pc games total. S... : Epsilon Sector
By: azuvatar x Show Full PostAu revoir, monsieur FisherFeb 27, 2010 4:12pm PSTAu revoir, monsieur Fisher : azuvatar
By: kikinchaz x Show Full PostAll console ports (excluding Settlers) so meh to be honest. That said, I hope the PC gamers who don't have access to these titles on a console speak with their wallets and don't buy the games. This DRM is pathetic, especially for Singleplayer games/Feb 26, 2010 4:52pm PSTAll console ports (excluding Settlers) so meh to be honest. That said, I hope the PC gamers who don't hav... : kikinchaz
By: Xulu x Show Full Posthoho here we go again.
learned my lesson with chaos theory, a game I'll never be able to play ever again.Feb 26, 2010 9:19pm PSThoho here we go again. learned my lesson with chaos theory, a game I'll never be able to play ever aga... : Xulu
By: Frush81 x Show Full Postya fuck those drm just stop supporting pc that will fix itFeb 27, 2010 6:04am PST
By: cell9song x Show Full PostYou would think with the immensely negative response to their DRM announcement, they'd sit down and think it through a little more.
This is exactly the same childish, petulant actions that is killing off the music labels. You have to wonder how these guys got into the positions they occupy (upper management)Feb 26, 2010 1:49pm PSTYou would think with the immensely negative response to their DRM announcement, they'd sit down and think... : cell9song
By: A Trusted Friend x Show Full PostWhen they remove it, I'll consider purchasing it as it looks interesting.
Until then,
no.Feb 26, 2010 5:32pm PSTWhen they remove it, I'll consider purchasing it as it looks interesting. Until then, no. : A Trusted Friend
By: Lukiopimp x Show Full PostPredictably, this will not bring in more money, it will give your shareholders a happyslappy face. Furthermore please cut out the dramatization "...until the day that we all die...". Shareholders do not buy your product, your customers do (or better did). Ubifail.Feb 27, 2010 4:05am PST
By: valcan_s x Show Full PostCould you not do the following instead?
* I am trying to make my system as anti piracy as possible but also gamer friendly *
- Make the user logon to the Internet and unlock there game - check
- Write to memory a encrypted key that you successfully unlocked your game - check
- Boot up game with no Internet, game checks for key in system memory - check
- Play your game
* My rule as long as you want to play you essentially have to make one call to a server and the app writes to system memory a key *
* Valcan_s fail safes *
- try to read this key in mem other than the game.exe the game instantly terminates
- try to modify this key in mem the game instantly terminates
- note - make sure you do not run your virus scan software while playing it would kill your game for it breaks my rule
Personally this new shit where you have to be on-line 24 7 sucks balls, yet I understand why they do it. Still there has to be a better way isn' t there?
I am sure a above means is possible and you guys and my self would tolerate it way more.
No? Any thoughts?
Feb 26, 2010 2:10pm PSTCould you not do the following instead? * I am trying to make my system as anti piracy as possible bu... : valcan_s
Thread Truncated. Click to see all 14 replies.
you'd be surprised how many people are vehemently against install online activation. : dahanese
I hate it my self, but it beats online 24 - 7 1000% I would take that model any day over have to be on... : valcan_s
By: darksied x Show Full PostAgain, all people can do is bash them on trying something new to help stop piracy. Yeah, I don't like it either; even though I like assassin's creed, if I was to get 2 on the PC my connection goes down every now and then for a second and I don't want to get kicked out, BUT... two things here:
1. They have to try something new. If this works, they will know for a fact that every sale was a legitimate one and it will be a milestone in its own right (stopping piracy, which has never been done). If this happens, EVERYONE is going to adopt this method (i.e. the guild wars type, where you're always connected or you don't play).
2. I have a feeling at the moment they don't really give a crap if no one buys the PC versions of these games. The console games sell a ton already, and I'm sure they don't even get 10% of their sales from PC.
But if this whole system works and stops people from illegally downloading them, then they will focus more on PC games, which is a better thing for everyone. I, along with everyone else, hates how people do crappy ports and shoddy attempts at PC versions of good console games, and that's because they're not even expecting any return on their work in a piracy-saturated market. Maybe a successful DRM solution will give them more incentive to work harder at those PC versions. Of course, that's just me hoping, but if this takes off, and PC games from Ubisoft get the same attention as console games, then I can see myself eventually trying this out.Feb 26, 2010 2:00pm PSTAgain, all people can do is bash them on trying something new to help stop piracy. Yeah, I don't like it ... : darksied
Thread Truncated. Click to see all 9 replies.
You can't "stop" piracy. It *will* be cracked. As long as it's not cracked in the first few but critical ... : BornAcorn
By: Unkei x Show Full Posti'll buy it on Steam on xmas sales for 7 euros tyvmFeb 27, 2010 1:16am PST
By: GoldfishInAJarOfPickles x Show Full PostThis is essentially steam (with no offline mode), stop whining. I will continue to buy Ubisoft games through steam.Feb 26, 2010 3:11pm PSTThis is essentially steam (with no offline mode), stop whining. I will continue to buy Ubisoft games thro... : GoldfishInAJarOfPickles
By: MeestaNob x Show Full PostMeestaNob Confirms Controversial New Purchasing Policy for Ubisoft Games: [b]He ain't buying one ever again.[b]Feb 26, 2010 6:10pm PST
By: Damarius101 x Show Full PostHAha! Stupid Ubisoft. Wait till their sales get buttfucked. Then theyll see.Feb 26, 2010 2:39pm PST
By: UMG x Show Full PostHow shocking! They want to protect their property against theft! Alert the Press. :/Feb 26, 2010 4:40pm PST
Thread Truncated. Click to see all 4 replies.
By: Physick1 x Show Full PostWhat a shitload of fuck!
This is just a way to get out of PC gaming all together. Sales will be shit due to the DRM but Ubisoft will spin it around saying sales where down on PC due to pirates. It will be their way out of pc gaming as it seems that's what they wanted all along.Feb 26, 2010 2:25pm PSTWhat a shitload of fuck! This is just a way to get out of PC gaming all together. Sales will be shit... : Physick1
By: scary_monster x Show Full PostNOOOOO not Price of Persia!!! FFFUUU
I hope you go bankrupt you bastards!!Feb 26, 2010 4:43pm PST
By: vertdang x Show Full PostStupid-assed Ubisoft. This just became an instant non-purchase.
I refuse to support this kind of Draconian DRM.Feb 26, 2010 4:20pm PST
By: Pneum0 x Show Full PostMy cables been down off and on all week. I won't support this type of drm, for one simple reason. The time I play sp player titles is when my internet goes down. It pry's me away from tf2/quakelive/bf long enough so I get sucked into the sp adventure.Feb 26, 2010 4:13pm PST
By: bullbear73 x Show Full PostBooo ubisoft. Definitely going to avoid titles with their crazy new DRM. Way to force people to pirate a game that they would've paid for just so they can get the functionality it should've included in the first place. I've never pirated a game and don't plan to do so to play these, but I do see it as a way to increase piracy. It's a good way to punish people who actually want to buy their product.Feb 26, 2010 3:21pm PSTBooo ubisoft. Definitely going to avoid titles with their crazy new DRM. Way to force people to pirate a ... : bullbear73
By: Zerbyte x Show Full PostI wasnt buying it, at least to start, since they are pricing the PC version as much as the consoles.Feb 26, 2010 3:11pm PST
By: Johnnsen x Show Full PostCool, another game I won't get! Planned on this, AC2 and the Settlers (if it would have gotten good reviews). But like this, no chance.Feb 26, 2010 2:48pm PST
By: sinclair4217 x Show Full PostOn the face of it, this seems so nonsensical that I cannot help going down the tinfoil hat road and wondering if this isn't actually a roundabout way of justifying dropping PC releases all together when sales plummet into the abyss.
Feb 26, 2010 1:53pm PSTOn the face of it, this seems so nonsensical that I cannot help going down the tinfoil hat road and wonde... : sinclair4217
By: at0micgarden x Show Full PostEvery time I read news like this, a little piece of me dies.Feb 26, 2010 2:36pm PST
By: bob3578 x Show Full Post1 of 2 things is going to happen here. 1) Ubisoft is gonna bow to the overwhelming negative press from this and make it better by making the DRM less... inhuman? or 2) They will do nothing and the ridiculous drop in sales will make people lose their jobs until it stops.
Have fun Ubisoft, you're now officially fucked.Feb 26, 2010 2:32pm PST
By: fix-cz x Show Full PostIt's not "controversial", it's totally wrong and unacceptable!Feb 26, 2010 2:26pm PST
By: sinclair4217 x Show Full PostThey better it make it damned clear on the box that this these releases requires an always on connection or they will end up with a another class action lawsuit on their hands like they did with using Starforce DRM.
They dropped Starforce as a result of that.
http://consumerist.com/2006/04/ubisoft-dumps-starforce-like-hermaphrodite-girlfriend.htmlFeb 26, 2010 2:17pm PST
By: ElArabDeMagnifico x Show Full PostUsually I'd be waving my torch and pitchfork but as of now, I'm just glad Ubi is confirming what games will be using this because now I won't be that guy who had no idea what he was getting into. I know exactly what to avoid now.
Sadly I can't just play the console version of this, the only other console I have is a PS3.Feb 26, 2010 2:02pm PST
By: megreedy x Show Full Post... so i go to vacation to a remote island with my laptop.... and there is no internet service... i can't enjoy my game!!!!!! RAGEFeb 26, 2010 2:00pm PST
By: MoG_Sheba x Show Full PostThey just do not get it. This only hurts those people that have bought the game. Just like with requiring the CD to be in the drive to play. *sigh* Doing this only fuels the torrents and code breakers to do what they would already to faster. Not sure why they support torrents and illegal copies by doing such things like this. There are other ways, which this one is clearly not the way to go. It does not really stop me from buying a game, just like with the need to have a CD in the drive, but it only makes the experience from a legal owner to not be a pleasant one. There is a way around everything and that can not be stopped, but putting things in place like will only make this game even more distributed illegally than it would had been without.Feb 26, 2010 1:44pm PSTThey just do not get it. This only hurts those people that have bought the game. Just like with requiri... : MoG_Sheba
By: Tech T x Show Full PostPotential customer confirms: Not going to buy any Ubisoft PC games.Feb 26, 2010 1:50pm PST
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Online Classes
City College of San Francisco offers online classes using the learning management system called Insight. Information about online classes is found in the class schedule. Some classes require on-campus meetings. Check the instructor's website for specific class informaiton. For information about accessing online classes go to insight.ccsf.edu. Class login information wil be sent to your CCSFmail address. Click here for more info about CCSFmail.
CCSF online classes are all credit degree applicable classes with the exception of DSPS-P and DSPS-S.
Online classes provide students an opportunity to learn in an environment that is physically remote from instructors and classmates, and at the same time close and personal. Online classes open the classroom to a world of dynamic, diverse content.
Current Online Classes
To see descriptions of all Spring 2014 online courses, go to CCSF 2014 Spring Class Schedule Listings.
Becoming an Online Student
Online classes are not for everyone. To succeed, you have to be self-motivated, possess good study skills, and be an independent learner. Online classes are as challenging as on-campus courses. Online classes are not self-paced. Course assignments, quizzes and exams have deadlines. Some courses have an on-campus component.
Tips for Success
1. Take a short self evaluation to help you decide if online classes are right for you.
2. Check to make sure the computer you will be using meets the minimum hardware and software requirements.
3. Enroll in LERN 55. This one unit course introduces technology and study skills necessary to succeed in online courses. Includes online course navigation, course-related computer competency, self-directed learning, online communications, and study skills for online learning. Especially useful for students new to online study and students who have been unsuccessful in online courses in the past.
4. Talk with your Counselor about what courses work with your educaiton plan.
All Online Classes are Different...Just Like
Face-to-face Classes!
Online classes at CCSF are not-self paced classes. Classes require online tools such as forums, assignments and testing along with regular effective contact between the instructor and student.
Just as all face to face classes have different deadlines and requirements, so do online classes. Some have due dates on a Monday while others have due dates on a Thursday. Some online classes require no orientation while others require a mandatory orientation. Some online classes offer only one orientation and others offer several options.
It is important that students check the faculty member's website for class details. It is the student's responsibility to meet individual online class requirements including required orientations, scheduled meetings, and course work.
Computer Requirements
A computer with internet capability is the primary tool used for online courses. Students are strongly encouraged to have some basic computer experience and regular access to a computer with internet capabilities. The computer will need to meet certain hardware and software reequirements. Check System Requirements to find out if your computer meets the requirements for an online class.
Student may use the open access computer labs on the Ocean Campus and CCSF Sites with a valid current semester CCSF ID with a barcode. More info is found here.


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I have an appt. with my RE on the 27th! Looking to hopefully start meds early Dec. with the IUI probably being a few days before Christmas. I hope this is a VERY Merry Christmas!!
I sure hope it works...the triplets have over heard Jason and I talking and to say they are on board with a new baby would be an understatement. They have even been telling their teachers that they are getting a baby girl. Yikes...LOL.
Here is hoping we have a good crop of September babies coming! Good luck ladies!


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The Qingdao Administration Centre of Sailing Sport was founded in 2010 to develop the 'Sailing City' and get more Chinese involved in sailing. This year will be Qingdao's fifth time participating in the race.
Qingdao is excited to be taking part in this year's race after some very successful times in the last four editions of the race as a Team Sponsor and Host Port.
The reputation of Qingdao has been enhanced, a number of ordinary people have gained round the world race experiences, sharing experiences and knowledge of sailing to more people.
This year, the team sponsors aim to have a top three podium finish, increase Qingdao's international influence and get more attention worldwide by showcasing Qingdao as the 'Sailing City' as well as a Chinese developed seashore city.
Located in the core area of the eastern coast of the city, Qingdao Olympic Sailing Centre was the venue for the 2008 Olympic and Paralympic Games events. The century-old Olympics joined hands with century-old Qingdao, injecting new vitality into the beautiful port city and taking this popular tourist destination on another journey as the 'sailing capital' of China.
Now, the sailing centre is a comprehensive function area combining sports, tourism, entertainment and food. The welcome and prize giving ceremonies for the Clipper Race crews will be held here again this year.
Meet in Qingdao and sail with passion. The beautiful sailing capital of China is awaiting your arrival!
After skippering New York during the Clipper 11-12 Race, I just have to race and be apart of it again especially with the new bigger faster Clipper Race fleet.


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Holiday office party etiquette
Published On: Dec 01 2011 09:58:16 PM ESTSorry, Flash is not supported.
Updated On: Dec 04 2013 10:05:27 AM EST
Updated On: Dec 04 2013 10:05:27 AM EST
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Hi Els - here is my 'queen' layout :)
Queen of Roses
Thanks for another great challenge.
Lovely Layout and beautiful photos!
Thanks for joining the ABC challenge this month ;-)
Here is my layout
River Fun
~Holli~ Mommy of two special angels
My very grumpy little boy who didn't like his hat.
Last edited by Els AW; 06-18-2013 at 09:41 PM.
Ive called my Q&R Alphabet Challenge LO Quick Response and havent I just the right photo for it??? I used the kit I feel Poorly by Danas Footprint Digital Design
link to gallery http://www.godigitalscrapbooking.com...0077&nocache=1
My LO @:
Mary Anne
This is a lovely page Mary Ann, just like a fairytale!
Thanks for playing the ABC challenge this month ;-)


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@ The Elbow Room, 605 N. Pennsylvania St., Indianapolis, IN 46204
The cost: For members of the Section, one new pair of mittens and one hat or scarf for a child (to be donated). For your generous donations, you will be given 2 drink tickets and hors d'oeuvres. Guests are welcome for an additional $15.
We have a lot to celebrate this year! Join us!


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Two women, believed to be behind an East Texas bank robbery, have been caught in Mississippi.
Mississippi police say the mother and daughter robbed a bank in Mississippi, and may be the same women who robbed the Citizen's National Bank in Henderson last month.
On February 28, a woman walked into the Citizen's National Bank, walked up to the counter, and showed a clerk a handgun.
Around the same time, another woman who authorities believe was the get-away driver, walked into this convenience store next door.
According to officials, these two women could be the same women arrested in Mississippi, who are mother and daughter.
"In Henderson, I haven't seen it, we've had other bank robbers, but not female, and certainly not mother,daughter," said Lieutenant Sweeney with the Henderson Police Department.
Evie Mearlene Herrin, 57, and Amelia Darci Crew, 30, are both from Cleveland, Texas.
Authorities say they've managed to rob four different banks; in Texas, Louisiana, and now Mississippi.
Sweeney said they are waiting for a confirmation from the FBI that these are the same women involved in the bank robbery here in East Texas, but he feels certain that it is.
"I don't know what was found at the scene; I would imagine at some point in time, somebody would go to where these people live, and see if there's any evidence there," said Sweeney.
Whether it's the face mask, the gun, the clothing, or the purse, Sweeney hopes the FBI will find something to confirm it's the same women in all four bank robberies.
"One could assume that they do look like what we've seen at the various robberies, especially the one in Sulphur, Louisiana, where the woman's face is seen," said Sweeney.
Henderson police will continue with their investigation, and are working with the FBI to check all evidence that is available.
Both the mother and daughter are in a Mississippi jail on bonds totaling $200,000.
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Musicacristiana2.com is at the age of #4. Alexa ranks on #11,649,162 in the world ranking. This site's Pagerank value is (0/10). This site service in United States. It has 36 category. Its IP address is 126.96.36.199. Last updated on Tuesday, 01 July 2014.
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Traffic Rank Graph
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On the first episode of Making Matilda, book writer Dennis Kelly reveals his "reckless" approach to writing a musical, Matilda's "strong sense of justice" and the difference between childish and child-like.
Scenes from the well-loved musical, now playing at the Minskoff Theatre.March 18, 2010
If/Then headliner Idina Menzel reveals the strange things that can happen in a New York minute in this final installment of our special series with the stars of the new musical.July 17, 2014
See clips of Denzel Washington in August Wilson's 'Fences'April 26, 2010
The upcoming star of the Broadway's Les Miserables, Ramin Karimloo, sang with his idol, original Jean Valjean Colm Wilkinson, at a special charity event in Toronto.January 16, 2014
Get a sneak peek of the national tour of Wicked.January 1, 2013
Surprise! Wicked star Lindsay Mendez is back for a very special episode of Fly Girl! Paty down with the green girl as she celebrates the holidays with all your favorite people. Merry everything!December 19, 2013
The nekkid guys come back to the New York stage.April 5, 2012
Get a sneak peek of Newsies.November 29, 2013
As the shaman Rafiki, Tshidi Manye kicks off The Lion King with the signature song "Circle of Life." Hear how the South African actress prepares before each show and how the role is a connection to her culture.November 12, 2012
"Dancing Queen" from the smash hit Broadway musical "Mamma Mia!"January 25, 2010


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Exercise Electrocardiogram
Test Overview
An exercise electrocardiogram (EKG or ECG) is a test that checks for changes in your heart while you exercise. Sometimes EKG abnormalities can be seen only during exercise or while symptoms are present. This test is sometimes called a "stress test" or a "treadmill test." During an exercise EKG, you may either walk on a motor-driven treadmill or pedal a stationary bicycle.
The heart is a muscular pump made up of four chambers. The two upper chambers are called atria, and the two lower chambers are called ventricles. A natural electrical system causes the heart muscle to contract and pump blood through the heart to the lungs and the rest of the body. See a picture of the heart and its electrical system.
An exercise EKG translates the heart's electrical activity into line tracings on paper. The spikes and dips in the line tracings are called waves. See a picture of the EKG components and intervals.
A resting EKG is always done before an exercise EKG test, and results of the resting EKG are compared to the results of the exercise EKG. A resting EKG may also show a heart problem that would make an exercise EKG unsafe.
Why It Is Done
An exercise electrocardiogram is done to:
Experts disagree about the use of an exercise EKG to test people who do not have symptoms of heart disease.
How To Prepare
Tell your doctor if you:
Talk to your doctor about any concerns you have regarding the need for the test, its risks, how it will be done, or what the results will mean. To help you understand the importance of this test, fill out the medical test information form(What is a PDF document?).
Your doctor may recommend how you should eat before the test. For example, your doctor may suggest you only eat a light breakfast before your test.
An exercise EKG may be dangerous and should not be done in some situations. Be sure to tell your doctor if you:
Remove all jewelry from your neck, arms, and wrists. Wear flat, comfortable shoes (no bedroom slippers) and loose, lightweight shorts or sweat pants. Men are usually bare-chested during the test. Women often wear a bra, T-shirt, or hospital gown. Avoid wearing any restrictive clothing other than a bra.
You may want to stretch your arm and leg muscles before beginning an exercise EKG.
How It Is Done
An exercise electrocardiogram (EKG or ECG) is usually done in a doctor's office, clinic, or hospital lab by a health professional or doctor. The test results are evaluated by an internist, family medicine doctor, or cardiologist.
Before the test
During the test
For exercise, you will either walk on a treadmill or pedal on a stationary bicycle while being monitored by an EKG machine. Your EKG will be monitored on screen, and paper copies will be printed out for later review before you start the exercise, at the end of each section of exercise, and while you are recovering.
The test is usually performed in a series of stages, each lasting 3 minutes. After each 3-minute stage, the resistance or speed of the treadmill or bicycle is increased.
After the test
When the exercise phase is completed:
The entire test usually takes 15 to 30 minutes.
How It Feels
The electrodes may feel cool when they are put on your chest. If you have a lot of hair on your chest, a small area under each electrode may need to be shaved. When the electrodes are taken off, they may pull your skin a little.
The room where the exercise electrocardiogram is done may be kept cool for comfort, since you will warm up rapidly when you begin to exercise.
The blood pressure cuff on your arm will be inflated every few minutes. This will squeeze your arm and feel tight. Tell your health professional if this is painful.
While exercising, you may have leg cramps or soreness; feel tired, short of breath, or lightheaded; have a dry mouth; and sweat. You might even have some mild chest pain. Tell the health professional or doctor if you have these symptoms.
An exercise electrocardiogram is generally safe. Emergency equipment will be available in the testing area. Risks include:
The electrodes are used to transfer an image of the electrical activity of your heart to tracing on paper. No electricity passes through your body from the machine, and there is no danger of getting an electrical shock.
An exercise electrocardiogram (EKG or ECG) is a test that checks for changes in your heart while you exercise. Your doctor may be able to talk to you about your results right after the test. But complete test results may take several days.
Your doctor will look at the pattern of spikes and dips on your electrocardiogram to check the electrical activity in different parts of your heart. The spikes and dips are grouped into different sections that show how your heart is working. See a picture that explains the EKG components and intervals.
What Affects the Test
You may not be able to have the test or the results may not be accurate if:
What To Think About
An exercise EKG is not always accurate. The test results from an exercise EKG are always evaluated along with other information, such as your symptoms and other risk factors.
Other Places To Get Help
Related Information
eMedicineHealth Medical Reference from Healthwise
This information does not replace the advice of a doctor. Healthwise disclaims any warranty or liability for your use of this information. Your use of this information means that you agree to the Terms of Use. How this information was developed to help you make better health decisions.
To learn more visit Healthwise.org
© 1995-2012 Healthwise, Incorporated. Healthwise, Healthwise for every health decision, and the Healthwise logo are trademarks of Healthwise, Incorporated.


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Cave Aged
Quick View
Regular Price: $21.99/EA
Special Price: $17.99/EAYou may not know it, but Époisses is actually a French word meaning "completely worth the effort"—either that or "stinky but incredibly loveable" because the end result, a custardy bacon bomb, is oh-so-worth-it. One slurp of the intensely creamy paste of this French classic, and you'll know why we go to such lengths to ensure that this unctuous pasteurized cow's milk round, made in Burgundy, France, is so delightfully decadent. After near extinction in France during the World Wars, Époisses de Bourgogne was resurrected in the 1950s by our beloved M. Berthaut. After being carefully hand-ladled into forms and dry-salted, each wheel takes a turn in French cave. Tucked into a clever wooden box meant to ease transport to our fair shores, serving Époisses isn't nearly as difficult as aging it—slice a crusty baguette and dunk away, adding a glass of Burgundian white for terroir-driven perfection. Read More
Quick View
Tete de MoineIf you have a Girolle, you too can shave ''the monk's head.'' A strong raw cow's milk cheese from the Jura Mountains, assertively fruity and full-bodied. Read More


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By Taryn AsherFox 2 NewsHOLLY, Mich. (WJBK) -- A woman who wishes to remain antonymous has worked at a few nursing homes over the last 30 years, but claims she has never seen such poor patient care as she did at Oakland County's Holly Convalescent Center."It should be shut down. No one is safe there," she said.On December 12, the certified nurses assistant filed a complaint with the state claiming two patients over the last year chocked to death and that nurses on duty didn't follow the proper protocol for resuscitation -- performing the Heimlich, but refusing to do CPR or call 9-1-1."She did nothing. Matter of fact, she told me, 'You can stop. She's gone.' I thought it was horrible, and I've been haunted by this. She died in my arms."To this day, she says the patients' families believe their loved ones died from a heart attack and the nursing home covered up the fact that nurses neglected to seek medical help."When [she] died and we put her back in the bed, they had me finish digging out the sandwich out of her throat and told me to be careful not to cut her throat with my nails so there wouldn't be any tears in her throat or any bleeding."This woman no longer works at the nursing home. Although paperwork shows she received stellar reviews, she says she was fired for willful neglect just days after she complained about the neglect of another patient and told administrators she wouldn't lie about what happened."I have to pay my bills. I have kids to support. I'm a single mom. I needed a job, but when you have someone die in your arms, that doesn't go away."She struggled about coming forward, but now she is glad she did. The state is investigating. Based on interviews and records, the Department of Health and Human Services says the facility failed to provide necessary care and services that led to their deaths.The state's investigation determined two out of six patients at the Holly Convalescent Center were in immediate jeopardy. According to the report, the facility made changes right away to change its status, but the state still says it's not in compliance.I spoke to the owner for the for-profit nursing home, David Hainey, by phone, who turned down an interview.Online records show the nursing home has a history of below average reviews and has been cited over the years for a number of deficiencies.The Department of Licensing and Regulatory Affairs says this case is still under review and a final report has yet to be released.
35 Skyline DriveLake Mary, FL 32746
Phone: (407) 644-3535News Tips: (866) 55-FOX35


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Health Literacy
Primary tabs
Last Date:
Tuesday, November 26, 2013 - 1 p.m.
Learn to find and assess quality online health information (2.5 hours). Seats will be filled on a first-come, space-available basis.
Instructors: A. Muhammad, PIA International, Inc.
Computer Lab, Room 311
Required Skills: The ability to read and comprehend English well, and the skills acquired in PC Basics, Word I Basics and Web I Basics.
You will learn to:
- Navigate medical websites.
- Evaluate medical websites for updates and active links.
- Research personal health issues.
- Make informed health decisions based on information retrieved from credible health websites.
Sponsored by the National Library of Medicine of the National Institutes of Health and the D.C. Department of Health's HIV/AIDS Administration. Presented by the Project for Intermediate Advocates.
Bring your own flash drive to save class documents, or send them to your email account.


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We want you to be happy with your decision, so look for an email soon to Customize Your Experience!
When we combine individual strengths, unite toward a common goal, and collaborate to get results, we all get to share in the success! Thanks for making our team work.
Create custom gifts by adding your logo or artwork to hundreds
of Baudville products. You'll work with a talented graphic artist
to easily create a one-of-a-kind custom item that is also


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Slide 1
What Is the Human Genome?
The complete supply of DNA--all the genes and spaces in between--in all the chromosomes of a species is called its genome. Except for red blood cells, which have no nucleus, the human genome is located in the nucleus of every cell in the body. There it is organized into 46 very large molecules called chromosomes; 44 are called autosomes and 2 are called the sex chromosomes.
An international collaboration known as the Human Genome Project has identified every chemical base in the human genome and has discovered that there are about 25,000 genes present.
Slide 2
Cancer Genomics
Cancer genomics is the study of the human cancer genome. It is a search within "cancer families" and patients for the full collection of genes and mutations--both inherited and sporadic--that contribute to the development of a cancer cell and its progression from a localized cancer to one that grows uncontrolled and metastasizes (spreads throughout the body).
Slide 3
A Sample Human Genome
A human karyotype is a display of its genome. It shows all the chromosomes present in an individual after they have been stained and arranged in pairs called homologs. This is a male karyotype because there is an X and a Y chromosome present.
The centromere of a chromosome is the region that separates the two arms. The arm above the centromere, which is shorter, is called the p arm, while the longer arm is the q arm.
Slide 4
Genes: Keepers of the Code
The 25,000 genes scattered throughout the human chromosomes comprise only about 3 percent of the total genome. These genes hold information critical to all human life. While all the component bases in a gene are copied as information leaves the nucleus, not all this information is kept. This is because within a gene there are both coding and noncoding stretches of bases. For example, in split genes, coding sections called exons supply the genetic instructions that are copied to direct protein building. These sections are preserved, but other noncoding sections within the gene, called introns, are rapidly removed and degraded.
Close to each gene is a "regulatory" sequence of DNA, which is able to turn the gene "on" or "off." Farther away, there are enhancer regions, which can speed up a gene's activity.
Slide 5
Noncoding Regions
The massive DNA molecules known as chromosomes also have many noncoding regions located outside the genes. These contain large stretches of repetitive sequences. Some of the sequences in these locations are involved in the regulation of gene expression, and others simply act as spacers. Still other regions have functions as yet undiscovered.
Slide 6
Genes to mRNA to Proteins
When a gene "switches on," it eventually makes a protein, but it does not do so directly. First, the gene codes an intermediary molecule called mRNA. To transfer a gene's information from DNA to mRNA, base pairing is used. However, there is one change: An adenine base (A) in the DNA matches with a new base called uracil (U) in the mRNA. This difference helps to distinguish mRNA from DNA.
mRNA travels from the nucleus into the cytoplasm to cell organelles called ribosomes. There it directs the assembly of amino acids that fold into a unique protein.
Slide 7
RNA Processing Before Translation
Before mRNA leaves the nucleus, it undergoes further processing. The regions not involved in building proteins, called introns, are cut out of the message. The mature RNA that arrives at a ribosome contains only exons that will be used to build a protein in a process called translation.
Slide 8
Triplet Code
The translation of base sequences from DNA to protein is dependent on the nucleotide triplet in mRNA. Each mRNA triplet of nucleotides, called a codon, codes for a single amino acid, and, ultimately, a string of amino acids makes up a protein. Since the complementary DNA that specifies a particular mRNA has only four nucleotide bases in a gene, 64 (4X4X4) possible combinations of codons are available to code for 20 amino acids. So there is great redundancy. There are 60 mRNA triplets for 19 amino acids, 3 triplets for "stop," and 1 triplet to call for methionine, the 20th amino acid that signals "start." Most amino acids are coded for by more than one triplet codon. However, each triplet is linked to only one amino acid. (For more information on how genes build proteins, please see Genetic Variation.)
Slide 9
All mutations are changes in the normal base sequence of DNA. These changes may occur in either coding or noncoding regions. Mutations may be silent and have no effect on the resulting protein. This is especially true if they occur in noncoding regions of the DNA. But even base pair changes in the coding region may be silent because of the redundancy of the code. For example, a mutation within a codon may occur, yet still call for the same amino acid as was called for earlier.
Mutations may involve a single base change--called a point mutation--or may involve larger sections of DNA through deletions, insertions, or translocations.
Slide 10
Mutations: Somatic and Germline
Most cancers arise from several genetic mutations that accumulate in cells of the body over a person's lifespan. These are called somatic mutations, and the genes involved are usually located on autosomes (non-sex chromosomes). Cancer may also have a germline mutation component, meaning that they occur in germ cells, better known as the ovum or sperm. Germline mutations may occur de novo (for the first time) or be inherited from parents' germ cells. An example of germline mutations linked to cancer are the ones that occur in cancer susceptibility genes, increasing a person's risk for the disease.
Slide 11
Tumors Are Clonal
Each cell, when it divides, generates two identical new ones. So, when a cell acquires a mutation, it passes that mutation on to its progeny during cell growth and division. Because cells with cancer-linked mutations tend to proliferate more than normal cells, cellular candidates for additional mutations grow in number. Mutations continue to accumulate and are copied to descendant cells. If one cell finally acquires enough mutations to become cancerous, subsequent cancer cells will be derived from that one single transformed cell. So all tumors are clonal, which means that they originate from a single parent cell, whether that first mutant cell was of germline or somatic origin.
Slide 12
Somatic Mutations
The majority of human cancers result from an accumulation of somatic mutations. Somatic mutations are not passed on to the next generation. An 80-year cancer-free lifespan is no small accomplishment. It requires as many as 10 million billion body cells to copy themselves correctly. It is easy to see how random errors can occur. These changes are acquired during a person's lifetime from exposures to carcinogens and other mutagens, or from random unrepaired errors that occur during routine cell growth and division. Occasionally, one of these somatic mutations alters the function of some critical genes, providing a growth advantage to the cell in which it has occurred. A clone then arises from that single cell.
Slide 13
Mitosis and Somatic Mutations
Normal human cells with a nucleus having 23 pairs of chromosomes are called diploid or 2N to indicate these homolog pairs. During the cell growth cycle for body (somatic) cells, the DNA of all 23 pairs--46 chromosomes--copies itself (4N). When the cell next divides by a process called mitosis, each daughter cell ends up with 23 pairs or 2N, a complete set of chromosomes. If a mutation occurs during the process of mitosis, only the offspring of the mutated somatic cell will have the alteration present.
Slide 14
Meiosis and Germline Mutations
Unlike other human body cells, maturing germ cells, like ova or sperm, must cut their chromosome number from 46 to 23, from 2N to N. They do this through two specialized cell divisions in a process called meiosis. After meiosis is complete, each germ cell has only one-half of the 44 original body chromosomes (or autosomes) plus either an X or a Y sex chromosome.
Slide 15
Recombination: Crossing Over
Early in meiosis, each chromosome pair copies itself. These homologs are all attached at the centromere and are wound very tightly around one another. Right before duplicate sets of homologs pull apart and move toward a different end of the cell to complete the first division, recombination can occur, as the intertwined genetic material separates. Then, later in meiosis, a second division occurs, and even the chromosomes within a homolog move apart, leaving only a haploid number (n) in each ovum or sperm. If mutations occur during meiosis, either in the ova or sperm, these will be germline mutations.
If mutated ova or sperm then go on to fertilization, their germline mutations will pass to every somatic cell in the new individual.
Slide 16
De Novo Mutations
Inherited mutations had to start somewhere, and that somewhere is a de novo mutation. A de novo mutation is a new mutation that occurs in a germ cell and is then passed on to an offspring. All germline mutations started as a de novo mutation in some ancestor. De novo mutations are common in a few inherited cancer susceptibility syndromes.
Slide 17
Point Mutations
Point mutations, single base changes in DNA sequences, are the most common type of alteration in DNA. They can have varying effects on the resulting protein.
A missense point mutation substitutes one nucleotide for a different one, but leaves the rest of the code intact. The impact of these point mutations depends on the specific amino acid that is changed and the protein sequence that results. If the change is critical to the protein's catalytic site or to its folding, damage may be severe.
Nonsense mutations are point mutations that change an amino acid codon to one of the three stop codons, which results in premature termination of the protein. Nonsense mutations may be caused by single base pair substitutions or by frameshift mutations.
Slide 18
Frameshift Mutations
Another type of mutation that can occur is a frameshift mutation. When a gene is copied, the action begins in the nucleus. There an mRNA strand copies the DNA strand exactly. It codes for a protein precisely, leaving no gaps or spaces separating the triplets. This set of connected triplets is called the reading frame. A frameshift mutation is caused by the addition or loss of a nucleotide, or nucleotides. This alters the content of every triplet codon that follows in a reading frame. Frameshift mutations usually result in a shortened abnormal or nonfunctional protein, and they can create an early STOP codon downstream. If the number of added or missing base pairs is a multiple of three, the resulting protein may be drastically altered, and its function will depend on the extent of these alterations.
Slide 19
Splice-Site Mutations
Splice-site mutations occur within genes in the noncoding regions (introns) just next to the coding regions (exons). They can have profound effects on the resulting protein, which may lead to disease. Before mRNA leaves the nucleus, the introns are removed and the exons are joined together. This process is called splicing. Splicing is controlled by specific intron sequences, called splice-donor and splice-acceptor sequences, which flank the exons. Mutations in these sequences may lead to retention of large segments of intronic DNA by the mRNA, or to entire exons being spliced out of the mRNA. These changes could result in production of a nonfunctional protein.
Slide 20
Regulatory Mutations
Although mutations in the noncoding region are generally silent, that is not always the case. Some of the most important regulatory regions are in the 5' noncoding flanking region of the gene. Promoter sequences that regulate the gene are located there. Also, enhancer sequences that regulate the rate of gene activity are in noncoding regions a considerable distance from the gene. And gene repressor regions, which negatively regulate gene activity, also exist. Mutations in any of these regions can change the rate of protein production.
Her2 protein expression is a good example of how gene amplification can have a regulatory impact upon a tumor's growth. In breast cancer, overexpression of Her2 protein results from gene amplification in chromosome 17. This increase in production of growth-signaling molecules speeds up the rate of the cancer's progress.
Slide 21
SNPs: Frequently Occurring Genetic Variants
There are over a million single nucleotide polymorphisms (SNPs) in the human genome. SNPs are specific sites within a human genome at which some individuals will have one nucleotide present while other individuals will have a different one. SNPs begin their existence as point mutations, and they eventually become established in a population. This substitution must occur in a significant proportion (more than 1 percent) of a large population for it to be called a SNP. Here is an example: In the DNA sequence TAGC, a SNP occurs when the G base changes to a C, and the sequence becomes TACC. When SNPs occur within a gene, the protein that results usually remains somewhat functional.
Slide 22
Large Deletions or Insertions
Large deletions or insertions in a chromosome also may lead to cancer. These may occur during mitosis or during recombination in meiosis. Translocations occur when segments of one chromosome break off and fuse to a different chromosome, without any loss of genetic material. Many of these have been found to enable tumor development. Inversions are mutations that arise when two breaks occur in a chromosome and the piece is reinserted in reversed order. Other chromosomal abnormalities include nondisjunction, the failure of the homologs (chromosome pairs) to separate as new cells divide. Source: Ried Lab, NCI
Slide 23
Example: Translocation of Bcr-Abl Genes
In chronic myelogenous leukemia, a translocation occurs between chromosomes 9 and 22. This rearrangement of genomic material creates a fusion gene call Bcr-Abl that produces a protein (tyrosine kinase) thought to promote the development of leukemia. The drug Gleevec blocks the activation of the Bcr-Abl protein.
Slide 24
Cancer-Associated Mutations
Cancer-associated mutations, whether somatic or germline, whether point mutations or large deletions, alter key proteins and their functions in the human biosystem. A wide variety of mutations seems to be involved. Even mutations in noncoding regions, such as in promoters, enhancers, or negative regulatory regions, can result in under- or overexpression of proteins needed for normalcy. Other mutations may cause production of important checkpoint proteins to malfunction. Collectively, these mutations conspire to change a genome from normal to cancerous.
Slide 25
Genotypes and Phenotypes
Cancer may start as a new genotype, that is, as a change in the genetic makeup of a person, but it ultimately produces a new phenotype as well. A phenotype is the physical manifestation of a genotype in the form of a trait or disease. Cancer is known for its ever-changing genotypes and phenotypes.
Slide 26
All genotypes are not created equal in their influence on phenotype. Genes come in many varieties called alleles, and some are more dominant than others. In a pair of alleles, the effect of a dominant allele prevails over the effect of a recessive allele. And the effects of a recessive allele become apparent only if the dominant allele becomes inactivated or lost.
Slide 27
Same Allele, Different Locus, Different Phenotype
Different mutations in the same gene can result in different phenotypes. A good example is the RET proto-oncogene. Germline mutations of RET lead to multiple endocrine neoplasia (MEN) type 2. The disease produced varies depending on where in the RET gene the germline mutation sits, so the phenotype may be MEN-2A, MEN-2B, or familial medullary thyroid cancer.
Slide 28
Different Locus, Different Allele, Same Phenotype
Many cancer susceptibility syndromes are genetically heterogeneous (a mixture), which means that different mutations (genotypes) can be expressed as the same phenotype (e.g., cancer). These different mutations may be located within the same gene but at different locations (locus heterogeneity) or on different genes altogether (allelic heterogeneity). For example, hereditary breast and ovarian cancer susceptibility has both locus and allelic heterogeneity. More than 500 different mutations have been identified that can occur in the BRCA1 gene on chromosome 17 and increase a woman's risk for breast cancer. And more than 300 mutations scattered throughout the BRCA2 gene on chromosome 13 are associated with hereditary breast and ovarian cancer susceptibility.
Slide 29
Sometimes one person with a dominant allele will express a trait, yet that same genotype in another person will remain silent. This is an example of differences in penetrance. In classic Mendelian genetics, if an individual carries a dominant allele, the trait will be expressed (genotype = phenotype). However, if all carriers of a certain dominant allele in a population do not express the trait (same genotypes/different phenotypes), the gene is said to have incomplete penetrance.
Slide 30
Factors Influencing Penetrance
Modifier genes affect the expression of some alleles, which may increase or decrease the penetrance of a germline mutation such as an altered cancer susceptibility allele. Penetrance may also be affected by mutations in DNA damage response genes, whose normal function is to recognize and repair genetic damage. If repair malfunctions, mutations may accumulate in other genes, increasing the likelihood that a given cell will progress to cancer.
Slide 31
Age-Related Penetrance
Penetrance is usually age related, meaning that the trait is not expressed in most carriers at birth but occurs with increased frequency as the carriers get older. For example, germline mutations in mismatch repair genes associated with hereditary nonpolyposis colorectal cancer (HNPCC) are incompletely penetrant. So not all individuals who carry these mutations will get colorectal cancer, but the risk increases as individuals age. About 20 percent of carriers will never develop colorectal cancer.
Slide 32
Epigenetic Factors and Penetrance
Epigenetic factors are mechanisms outside the gene such as a cell's exposure to carcinogens or hormones, or genetic variations that modify a gene or its protein by methylation, demethylation, phosphorylation, or dephosphorylation. These factors can alter what is ultimately expressed; they can change a phenotype. For example, hormone and reproductive factors may influence the penetrance of certain cancer-linked mutations. Breast and ovarian cancer are more likely to occur in women with early menarche, late menopause, and a first child after age 30 (or no children at all). These factors are believed to be linked to a woman's exposure to estrogen and progesterone and their effects on cell differentiation in the breast that occur during pregnancy.
In cancer, both the genotype and the phenotype change over time. Epigenetic factors play a key role in these changes.
Slide 33
Epigenetic Example: Methylation Alters Gene Expression
Methylation of the genome can render areas silent. There are two types of methylation that occur. Maintenance methylation adds methyl groups to newly synthesized strands of DNA at spots opposite methylated sites on the parent strand. This activity makes sure that daughter molecules of DNA maintain a methylation pattern after cell division. There is also de novo methylation, which can add methyl groups to totally new positions and change the pattern in a localized region of the genome.
Genes that must be expressed in all tissues have unmethylated regions, called CpG islands, located upstream. On the other hand, genes that must be turned off in differentiated tissues have these islands methylated. This allows a histone deacetylase complex nicknamed HDAC to bind, compress the shape of the genomic material, and inactivate the gene.
Slide 34
Imprinting Alters Gene Expression
Genomic imprinting is an uncommon event in human genomes that occurs when only one of a pair of genes present on homologous chromosomes is expressed because the other has been silenced by methylation. Thirty genes in humans display such imprinting. Curiously, for specific genes, the maternal copy is the one chosen to be silenced; for others, the paternal copy is selected.
Slide 35
Carrier Frequency
Carrier frequency describes the prevalence in a given population of germline mutations in a specific gene. A mutation carrier is sometimes called a heterozygote because two different alleles are present at a given locus--one with a germline mutation and one normal allele. Here, 2 out of 10 individuals carry a mutated allele at a particular gene locus, so the carrier frequency is 20 percent.
Slide 36
Prevalence and Founder Effect
Some populations have a higher prevalence of specific cancer-associated alleles than others. This may result from a founder effect, which occurs when a population undergoes rapid shrinkage and then expansion in an isolated setting. In a population that is geographically or reproductively isolated, an individual called a founder carries or develops a germline mutation that is rare in the general population.
Slide 37
Example: Founder Effect in Ashkenazi Jewish Population
Because of reproductive isolation, later generations of an isolated population will have a higher frequency of a mutation than the original population. For example, Ashkenazi Jews were segregated from the rest of the population and lived in separate communities for hundreds of years. Today, one percent of the Ashkenazi Jewish population--one person in 40--carries a 185delAG mutation in BRCA1, which places them at higher than the average risk for breast and ovarian cancer.
Slide 38
Mutations in Cancer Susceptibility Genes: BRCA1
Here is an example of the mutations seen in the BRCA1 breast cancer susceptibility gene.
Individuals who inherit these cancer-predisposing germline mutations carry their mutated alleles in every cell in their bodies.
Slide 39
Mutations in Cancer Susceptibility Genes: BRCA2
Here is an example of the mutations seen in the BRCA2 breast cancer susceptibility gene.
Inheriting these mutated alleles greatly increases a person's lifetime risk for developing cancer. This may explain why cancers linked to germline mutations in susceptibility genes often occur at an earlier age and in multiple sites.
Slide 40
Autosomal Dominant Inheritance
Most hereditary cancer syndromes are inherited in autosomal dominant fashion.
Dominant inheritance occurs when only one copy of an allele is required for a particular trait to be expressed (phenotype). In autosomal dominant inheritance, multiple generations express the traits, with no skipped generations (assuming complete penetrance).
Slide 41
Examples of Dominantly Inherited Cancer Syndromes
Hereditary cancer syndromes are relatively uncommon, accounting for only about 5 to 10 percent of all cancers. Nevetheless, as many as 50,000 cancers newly diagnosed in the U.S. each year are associated with a hereditary syndrome.
Slide 42
Cancer Susceptibility: Incomplete Penetrance and Phenocopies
Individuals who inherit cancer susceptibility mutations inherit a predisposition to cancer, not cancer itself. Some mutation carriers inherit their predisposing genotypes in an autosomal dominant fashion, yet they do not develop cancer, indicating that their altered genes are incompletely penetrant. A somatic mutation in a second allele is required for cancer to develop.
Further confusing the situation is the fact that sporadic forms of cancer may also occur in families along with a hereditary cancer syndrome. These cases of sporadic cancer are called phenocopies because their phenotype is similar to that of the affected mutation carriers, but their genotype is different. Genetic testing may determine if the cancer is hereditary or sporadic in nature.
Slide 43
Example: BRCA1-Linked Hereditary Breast and Ovarian Cancer
In this pedigree of a family with a BRCA1 mutation, numbers below each person indicate age at first cancer diagnosis, if affected; age at death, if deceased; and age at interview, if alive. This family exemplifies several hallmarks of hereditary breast and ovarian cancer. The fact that the mutation is passed on by autosomal dominant transmission is evident in that approximately 50 percent of family members in each generation carry the mutation. Notice that an unaffected father passes the mutation to his affected daughter, showing that transmission of the BRCA1 mutation can occur through either parent. Note the high penetrance of the disease and early age at onset. The penetration is incomplete, though high, as shown by one female carrier who lives to age 86 and another who lives to age 92 without a diagnosis of breast or ovarian cancer.
Slide 44
Example: BRCA2-Linked Hereditary Breast Cancer
In this pedigree, it again becomes clear that most mutations in cancer susceptibility genes are germline and pass as dominant traits with incomplete penetrance. Note the female carrier who lives to age 83 and dies of natural causes even though her mother was affected by breast cancer and died at age 48. Also note two males: one diagnosed with breast cancer and the other with prostate cancer. Men who inherit an abnormal BRCA2 gene have an increased risk (80 times the lifetime risk of men without the mutation) for male breast cancer. They also are three to seven times more likely than men without the mutation to develop prostate cancer.
Slide 45
Autosomal Recessive Inheritance
In autosomal recessive inheritance, two copies of the allele are required for the trait to be expressed. Carriers of one disease allele will not develop the illness, and several generations may be unaffected, leading to the appearance of skipped generations. Males and females are equally affected. If both parents carry one copy of the recessive allele, one in four offspring, on average, will express the trait.
Slide 47
X-Linked Inheritance
In X-linked inheritance, the gene of interest is on the X chromosome, not on an autosome. Because females have 2 X chromosomes, they must inherit two copies of the disease allele to express the disease phenotype. Females with only one mutated allele are carriers.
Males are more frequently affected because they only have one X chromosome and need only one allele mutated to express a disease phenotype. All males who inherit a copy of the abnormal X chromosome are affected by the disease (assuming 100 percent penetrance).
Slide 48
Other Genetic Conditions Linked to Increased Cancer Risk
Hereditary susceptibility to breast cancer occurs in several other rare genetic conditions. Breast cancer is the most common adult manifestation of Li-Fraumeni syndrome, a multiple cancer syndrome caused by germline mutations in the TP53 gene. Breast cancer also is the most frequent malignancy diagnosed in Cowden syndrome, a condition with germline mutations in the PTEN gene. Both benign and malignant breast tumors occur in Muir-Torre syndrome, a condition related to hereditary nonpolyposis colon cancer (HNPCC), characterized by germline mutations in the DNA mismatch repair genes MSH2 and MLH1. Patients with Peutz-Jeghers syndrome display abnormal pigmentation, gastrointestinal polyps, and, if they are women, they are at increased risk for breast cancer and they experience early onset bilateral disease.
Slide 49
Normal Cell Growth: The Cell Cycle
The cell cycle is a critical process that a cell undergoes in order to copy itself exactly. Most cancers have mutations in the signals that regulate the cell's cycle of growth and division. Normal cell division is required for the generation of new cells during development and for the replacement of old cells as they die.
Most cells remain in interphase, the period between cell divisions, for at least 90 percent of the cell cycle. The first part of the interphase is called G1 (for first gap), followed by the S phase (for DNA synthesis), then G2 (for second gap). During G1, there is rapid growth and metabolic activity, including synthesis of RNA and proteins. Cell growth continues during the S phase, and DNA is replicated. In G2, the cell continues to grow and prepares for cell division. Cell division (mitosis) is referred to as the M phase. Cells that do not divide for long periods do not replicate their DNA and are considered to be in G0.
In normal cells, tumor suppressor genes act as braking signals during G1 to stop or slow the cell cycle before S phase. DNA repair genes are active throughout the cell cycle, particularly during G2 after DNA replication and before the chromosomes prepare for mitosis.
Slide 50
Abnormal Cell Growth: Oncogenes
Most cancers have mutations in proto-oncogenes, the normal genes involved in the regulation of controlled cell growth. These genes encode proteins that function as growth factors, growth factor receptors, signal-relaying molecules, and nuclear transcription factors (proteins that bind to genes to start transcription). When the proto-oncogene is mutated or overregulated, it is called an oncogene and results in unregulated cell growth and transformation. At the cellular level, only one mutation in a single allele is enough to trigger an oncogenic role in cancer development. The chance that such a mutation will occur increases as a person ages.
Slide 51
Tumor Suppressor Genes
Most cancer susceptibility genes are tumor suppressor genes. Tumor suppressor genes are just one type of the many genes malfunctioning in cancer. These genes, under normal circumstances, suppress cell growth. Some do so by encoding transcription factors for other genes needed to slow growth. For example, the protein product of the suppressor gene TP53 is called p53 protein. It binds directly to DNA and leads to the expression of genes that inhibit cell growth or trigger cell death. Other tumor suppressor genes code for proteins that help control the cell cycle.
Slide 52
Mutations in Tumor Suppressor Genes
Both copies of a tumor suppressor gene must be lost or mutated for cancer to occur. A person who carries a germline mutation in a tumor suppressor gene has only one functional copy of the gene in all cells. For this person, loss or mutation of the second copy of the gene in any of these cells can lead to cancer.
Slide 53
Two-Hit Hypothesis
In 1971, Dr. Alfred Knudson proposed the two-hit hypothesis to explain the early onset at multiple sites in the body of an inherited form of cancer called hereditary retinoblastoma. Inheriting one germline copy of a damaged gene present in every cell in the body was not sufficient to enable this cancer to develop. A second hit (or loss) to the good copy in the gene pair could occur somatically, though, producing cancer. This hypothesis predicted that the chances for a germline mutation carrier to get a second somatic mutation at any of multiple sites in his/her body cells was much greater than the chances for a noncarrier to get two hits in the same cell.
Tumor suppressors act recessive at the phenotypic level (both alleles must be mutated/lost for cancer to develop), but the "first hit" germline mutation at the genotypic level is actually inherited in an autosomal dominant fashion.
Slide 54
Loss of Heterozygosity
In hereditary cancer syndromes, individuals are called heterozygous (having one or more dissimilar gene pairs) because they start life with a germline mutation in one of the alleles linked to cancer susceptibility, but it is balanced by a normal counterpart. These individuals are predisposed to cancer because all their cells have already sustained the first hit to cancer-linked genes. If the critically needed normal suppressor gene that balances this germline mutation is lost at some time during an individual's life, a condition called loss of heterozygosity (LOH) occurs.
Slide 55
Heterozygous Condition
There are several ways a cell can suffer loss of heterozygosity. An entire chromosome containing a normal allele may be lost due to failure of the chromosomes to segregate properly at mitosis (nondisjunction). Alternatively, an unbalanced exchange of genetic material can occur in a process called translocation, resulting in loss of a chromosomal region containing the normal gene. Sometimes when a normal gene is lost, a reduplication of the remaining chromosome with an abnormal gene occurs, leaving the cell with two abnormal gene copies. Normal genes may also be lost during normal mitotic recombination events or as a consequence of a point mutation in the second allele, leading to inactivation of the normal counterpart.
Slide 56
Repair Failure
Some mutations linked to cancer appear to involve a failure of one or many of the cell's repair systems. One example of such error involves DNA mismatch repair. After DNA copies itself, proteins from mismatch repair genes act as proofreaders to identify and correct mismatches. If a loss or mutation occurs in the mismatch repair genes, sporadic mutations will more likely accumulate. Other errors in repair may involve incorrect cutting out of bases--or whole nucleotides--as repair proteins try to fix DNA after bulky molecules, such as the carcinogens in cigarettes, have attached. This is faulty excision repair. Sometimes both strands of DNA suffer breaks at the same time, and faulty recombinational repair occurs. Any of these mistakes may enable mutations to persist, get copied, and eventually contribute to cancer's development.
Slide 57
Cancer Susceptibility: Much Still Unknown
Much remains elusive in our understanding of cancer susceptibility. Breast cancer is a good example of how incomplete a picture we have.
Most women with a family history of breast cancer DO NOT carry germline mutations in the single highly penetrant cancer susceptibility genes, yet familial clusters continue to appear with each new generation.
About 5 to 10 percent of breast cancer cases are linked to germline mutations in single, highly penetrant cancer susceptibility genes such as BRCA1 and BRCA2. Strong genetic predisposition and cancer susceptibility in these families is passed down in an autosomal dominant fashion.
Another 15 to 20 percent of breast cancers, however, are associated with some family history but no evidence of such autosomal dominant transmission. These cases are not well understood. Possibly environmental or multiple gene interactions contribute to very low penetrance of susceptibility genes, or possibly yet undiscovered mutations are involved.
Slide 58
Epigenetic Changes: Much Still Unknown
Much remains unknown about the role of epigenetic factors and cancer. Epigenetic changes are reversible modifications to genes or proteins that occur in the tumor and its microenvironment. Epigenetic modifier molecules have been observed making tumor-friendly, nonmutational changes in an already confused biosystem. For example, by heavily methylating genes or promoter regions, gene activity critical to counteract a tumor's drive toward metastasis gets turned off. Or noncoding ribonucleic acids meddle in epigenetic fashion, interfering with a cell's regulation of growth or attempt to repair damage.
Slide 59
Other Cancer-Associated Mutations: Much Still Unknown
In addition to oncogenes and tumor suppressor genes, most cancers acquire several other key mutations that enable cancer to progress. While researchers don't yet know all the mutations involved, they have organized them in terms of their activities in support of tumor growth and metastasis. In addition to the contributions of oncogenes and mutated suppressor genes, additional genomic mutations enable the invasion of neighboring tissue, evasion of immune system detection, recruitment of a new blood supply, dissemination and targeting of new sites, and the penetration and reinvasion through new blood and tissue layers. Over time, successful metastasis occurs.
Slide 61
A Daunting Challenge
A comprehensive analysis of the cancer genome remains a daunting challenge. There is no single technology at present that will detect all the types of abnormality--deletions, rearrangements, point mutations, frameshift insertions, amplifications, imprinting, and epigenetic changes--implicated in cancer. Microarrays and gene chip analysis, however, are beginning to unveil some key genomic drivers. (Please see Molecular Diagnostics for more information.)
Many clinical trials now include genomic profiles of cancer patients as prognostic and diagnostic indicators. Genomic profiles are even used to monitor where and how the cancer genome has been hit during molecularly targeted therapies. Mining and sharing all this data should eventually help oncologists to better integrate the genotypic and phenotypic changes that occur in a biosystem during cancer's progression. This knowledge will be used to bring earlier and better interventions to cancer patients.


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