Tamoxifen and Breast Cancer

 
When you get to my age, more and more of your female relatives, friends, and acquaintances will be diagnosed with breast cancer. They will be undergoing more or less radical surgery followed by chemotherapy and/or drug treatment. One of the most common drugs for the treatment of breast cancer is tamoxifen.

Tamoxifen is a chemical that binds to a protein called estrogen (or estradiol) receptor. The estrogen receptor is a protein that binds to DNA to increase (activate) or decrease (repress) gene expression. Its DNA binding properties are influenced by its interaction with the hormone estradiol (estrogen)—a discovery first reported by my friend Keith Yamamoto back in 1972 (Yamamoto and Alberts, 1972).

In normal cells, estrogen can stimulate the growth of tissues by turning on the genes that promote cell division. This is a good thing. However, it turns out that most of the breast cell cancers arise from cells that have estradiol receptors and in that case the presence of estrogen in your blood stream makes the cancer cells grow. These forms of cancer are called estrogen receptor positive (ER+) breast cancers.

That's the bad news. The good news is that such cancers respond well to tamoxifen. The effectiveness of tamoxifen is due to the fact that it binds to the estradiol receptor but doesn't convert it to the active regulator of gene expression.¹ When you take tamoxifen there's so much more of it in your bloodstream that it out-competes all of the estrogen. As a result the cancer cells can't grow, (but neither can any of the other tissues that need estrogen).

Hormone therapy (tamoxifen) is often combined with radiation or chemotherapy to reduce the risk of recurring cancer for women who have undergone surgery to remove tumors. However, if the cancer has not spread to the lymph nodes then hormone therapy by itself is effective against ER+ breast cancer. This is especially true for pre-menopausal women 40 years of age or older where chemotherapy does not add significantly to the effectiveness of tamoxifen [see tamoxifen].

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1. This isn't quite true. Tamoxifen itself doesn't bind to the estradiol receptor protein, instead it is converted inside your body to other chemicals that do bind.

Yamamoto KR, Alberts BM. 1972 In vitro conversion of estradiol-receptor protein to its nuclear form: dependence on hormone and DNA. Proc. Natl. Acad. Sci. USA. 69:2105-2109. [PubMed]

Words That Should Not Be Used Together in the Same Sentence: PETA + Ethics

 

PETA stands for "People for the Ethical Treatment of Animals." Apparently this group is unaware of the fact that human beings are animals because their treatment of humans is far from ethical.

Their latest outrage is a billboard in New Jersey that promotes a link between milk and autism. This is part of their aggressive promotion of vegetarianism. The reasoning—if you stoop to calling it that—is described on their website at Got Autism?.

Orac at Respectful Insolence has taken time off from his campaign against alternative (i.e. non-evidence based) medicine to take a whack at PETA [see PETA: Even more impossible to parody than ever!]. The take-down is impressive. PETA is exposed as bunch of kooks hiding behind the veneer of science in order to promote their special brand of woo. If they harm people by spreading lies, then so much the better, as long as those people are carnivores.

Toward the end of his posting, Orac backs off a little so that he doesn't appear to be too nasty to the PETA fools.

I know, I know. Beating up on PETA is like beating up on a helpless puppy dog, except that puppy dogs are cute and lovable, and PETA is anything but either of the two. It's also too damned easy, leaving me feeling vaguely guilty when I'm done for not going after a more challenging target. I do it anyway because the level of sheer irrationality demonstrated by PETA with each and every one of its campaigns just irritates the hell out of me. I hate having my intelligence insulted in such a manner. Also, the sheer publicity whoring for which PETA is so well known irritates me. It's painfully obvious that PETA doesn't give a rodent's posterior about helping autistic children. It just knows that autism has been in the news a lot lately and decided a good way to get publicity would be to latch onto autism somehow, no matter how tenuous the link they come up with to justify their billboard. Not that it will matter to most PETA supporters or to the "biomedical:" (translation: antivaccinationist) movement. Indeed, this latest campaign is so idiotic that I almost expect to see it touted on autism quackery websites soon.

There, now. I feel better. Slapping down PETA is always a fine diversion when my workload gets too heavy and I need a break. Hopefully, I can pick a more challenging target next time. On the other hand, so much woo is no better than this; so I'm not sure there really is a much more challenging target in that realm.

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Nobel Prize: 2008?

 
Chad Orzel at Uncertain Principles has started a contest to guess this year's Noble Prize winners [Guess the Nobels, Win a Prize]. The Nobel Prize in Physiology or Medicine will be announced next Monday (Oct. 6) and the Nobel Prize in Chemistry will be announced two days later on Wednesday, Oct. 8.

Read the list of blogger nominees from last year and the year before on The Daily Transcript. I'm sticking with Ernest McCulloch and James Till (see photo) for the discovery of stem cells.

Other possibilities include Harry Noller, Tom Steitz (+ other) for the structure of the ribosome and Elizabeth Blackburn, Carol Greider & Jack Szostak for telomeres.

It would be a scandal if Francis Collins and Crag Ventor won for the human genome.

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Canada's Do Not Call List

 
Today is the day Canada's DO NOT CALL (DNCL) list comes into effect. If you register your phone number with the Canadian Radio-television and Telecommunications Commission, telemarketers will not be allowed to call you without breaking the law ($15,000 fine).

Unfortunately there are some notable exceptions ...

There are certain kinds of telemarketing calls and faxes that are exempt from the National DNCL, including those made by or on behalf of:

• registered charities seeking donations
• newspapers looking for subscriptions
• political parties and their candidates, and
• companies with whom you have an existing commercial relationship; for example, if you have done business with a company in the previous 18 months––such as a carpet-cleaning company––that company can call you

Telemarketers making exempt calls must maintain their own do not call lists. If you do not want to be called by these telemarketers, you can ask to be put on their do not call lists. They are obliged to do so within 31 days.

The new legislation that comes into effect today stipulates how telemarketers are supposed to behave when you are called.

Among other things, telemarketers must:

• identify who they are and, upon request, provide you with a fax or telephone number where you can speak to someone about the telemarketing call
• display the telephone number that they are calling from or that you can call to reach them, and
• only call or send faxes between 9:00 a.m. and 9:30 p.m. on weekdays and between 10:00 a.m. and 6:00 p.m. on weekends

Telemarketers must not use Automatic Dialing and Announcing Device (devices that dial telephone numbers automatically and deliver a pre-recorded message). However, these devices can be used by police and fire departments, schools and hospitals, as well as for appointment reminders and thank you calls.

You can put your phone number on the list at DNCL or by calling the toll-free numbers 1-866-580-DNCL (1-866-580-3625) or 1-888-DNCL-TTY (1-888-362-5889).

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Monday's Molecule #90

 
Identify this molecule. You need to describe what you see as accurately as possible and name the species from which this protein was purified. I don't think any of you can do it without a hint so here's a clue.¹

There's a direct connection between today's "molecule" and a Nobel Prize. I'm looking for the person(s) who discovered the molecule as won the Nobel Prize for the discovery.

The first one to correctly identify the molecule and name the Nobel Laureate(s), wins a free lunch at the Faculty Club. Previous winners are ineligible for one month from the time they first collected the prize. There are four ineligible candidates for this week's reward. You know who you are.

THEME:

Nobel Laureates
Send your guess to Sandwalk (sandwalk (at) bioinfo.med.utoronto.ca) and I'll pick the first email message that correctly identifies the "molecule" and names the Nobel Laureate(s). Note that I'm not going to repeat Nobel Laureate(s) so you might want to check the list of previous Sandwalk postings by clicking on the link in the theme box.

Correct responses will be posted tomorrow. I reserve the right to select multiple winners if several people get it right.

Comments will be blocked for 24 hours. Comments are now open.

UPDATE: Alex Ling of University of Toronto is this week's winner. We was able to identify the PDB file as 1whu, part of the structure of polynucleotide phosphorylase from Mus musculis (mouse). Once you've identified the enzyme the Nobel Laureate is obvious: it's Severo Ochoa. Congratulations Alex, I now owe you two lunches.

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1. It is NOT the flying spaghetti monster. GSSGSSGPQKIFTPSAEIVK YTKIIAMEKLYAVFTDYEHD KVSRDEAVNKIRLDTEEHLK EKFPEVDQFEIIESFNIVAK EVFRSIILNEYKRCDGRDSG PSSG

Strategic Voting

 
I probably need to explain strategic voting to those people who don't have the "advantage" of living in a multiparty democracy. Strategic voting is where you deliberately vote for someone who is not your first choice in order to prevent another candidate from winning in your riding.

In the context of the current election, it means that a Liberal could vote for an NDP candidate if it was the NDP candidate who had the best chance of defeating the Conservative candidate in a particular riding. The idea being floated right now is that all Liberal, NDP, and Green Party supporters unite behind the candidate who has the best chance of defeating the Conservative candidate and preventing the Conservatives from getting a majority.

There are many good reasons for opposing strategic voting, not the least of which is that it's fundamentally dishonest.¹ Jennifer Smith of Runesmith's Canadian Content has always been opposed to strategic voting but in today's posting she announces that she's changed her mind [By Any Means Necessary].

My name is Jennifer, and I support strategic voting.

I know other people who are going to hold their nose and vote Liberal even though they are dissatisfied with the Liberal Party and with their leader Stéphane Dion. They realize that by switching their vote to the NDP, Bloc, or Green Party, they will make it more likely that Stephen Harper could remain Primie Minister with a majority government.

I'm not there yet. I want to make absolutely sure that Stéphane Dion gets the message that he should resign on October 15th. I'm not sure he will get the message unless I vote for someone else. On the other hand, a majority Conservative government could be a disaster for Canada.

If a lot of Canadians vote strategically to elect Liberals and prevent a Conservative majority do you think Stéphane Dion will understand what happened and do the right thing?

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1. Everyone with an I.Q. over 50 realizes that we need to change our voting system from first-past-the-post to some sort of proportional system. But that's not going to happen for many years. First, a lot of stupid people have to die. Meanwhile, we're stuck with the debate over strategic voting.

Discussing Junk DNA with an Adaptationist, Again

Nils Reinton is a molecular biologist working in the field of medical diagnostics and he has been challenging the concept of junk DNA in the comment section of a recent posting. The title of that posting, Everything Is There for a Reason?, was direct response to an earlier posting from Nils where he claimed that we shouldn't label DNA as "junk" because it's a science stopper.

During the discussion in the comment to my posting, I challenged Nils to answer a number of questions. He has responded on his blog SciPhu with Hey junk people, I accept your challenge (part I). I resonded to his answers in Discussing Junk DNA with an Adaptationist.

Now Nils has weighed in with Hey junk people, I accept your challenge (part II).

Q: Why is the Fugu genome so much smaller than that of other fish?

and

Q: When two similar species differ in genome size by a factor of two—probably due to an ancient polyploidization—is the majority of DNA in both species functional?

A: His argument is that since the genome size differs between species, much of it must be junk. But, you could easily use the same argument towards a function, by saying that the difference in genome size is a defining (functional) difference between species. We just do not know do we ! And, why does the difference in size not give you reason to speculate on function at least in parts of these regions ? Others have however, speculated far better than me on this topic, and a thorough introduction to such research can be found at junkdna.com and following this link to “The Principle of Recursive Genome Function“.

No, my argument was not that the extra DNA has to be junk just because there are two similar species that differ in the sizes of their genomes.

The question was directed at adaptationists who postulate a function for everything. I wanted to know the adaptationist explanation for those observations. What is it? Following a polyploidization is it possible that most of the DNA in the larger genome becomes non-junk right away?

Incidentally, by linking to the HoloGenomics website (junk.dna), Nils does not enhance his credibility.

Q: In the human lineage there are over one million Alu sequences. They all look like degenerate versions of 7SL RNA. Are all of these sequences functional? If so, what function could they be doing? And why do the human Alus look so different from the mouse ones?

A: I am not saying all Alu-elements are functional. On the “what is junk” scale, one extreme is that everything that hasn’t been ascribed a function is junk (Larry Moran’s position !?) and on the other end is “nothing is junk”. My position is somewhere in the middle: Some of the DNA in our genome is possibly junk. A number of individual Alu-elements will undoubtedly end up in the “junk”-category when more is known about our genome. That said, it has been shown that Alu-elements can constitute (parts of) regulatory and functional elements. It’s rather hard to tell which ones are functional by just looking at them. I therefore refuse to call them “junk” by default, - I strongly feel that the “junk”-label is a dismissal of any possible function(s) and should be used with caution if at all, - even for Alu-elements.

My position is that a huge amount of the DNA in our genomes is junk. That position is based on many different lines of evidence as well as on rational extrapolation from what we know and don't know about molecular biology and evolution.

Nobody is arguing that every single Alu element is junk. That would be stupid because we know for a fact that some of them have secondarily acquired a function. The point is whether most of this repetitive sequence can be reasonably assumed to be functional, and if so, what kind of function does the adaptationist imagine for most of these sequences?

In the absence of any reasonable functional explanation, and in the face of evidence that most Alu elements are degenerate retrotransposons, it is reasonable to adopt the working hypothesis that they are junk. That's not a science stopper. It's just common sense.

Q: Most intron sequences do not seem to have a function. Why does the size of introns in the same gene vary so much in related species and why isn’t the sequence conserved in most cases?

A: This argument is similar to the genome size argument above, and the answers for bullet 5 and 6 are equally valid here. Thus, there may be many reasons for a variation in intron size and this variation is not a very good argument to support the “junk” hypothesis. Also, the intron can contain regulatory elements and the c-gamma example above goes to show that introns can even contain functional (as in transcribed) genetic elements.

The fact that we have a few examples of functional intron sequences is no reason to assume that most of them are functional in the face of abundant evidence that they are not. That's a position that only a confirmed adaptationist would take.

This is a case where the exceptions tend to prove the rule not that the exceptions make a new rule.

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Remembering Paul Newman

 

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Sleepy Hollow

This is a view of the cemetery of the Old Dutch Church of Sleepy Hollow. It was taken by a visitor who posted it on the Friends of the Old Dutch Burying Gorund website.

The church, which you can see in the background of the photo, was built in 1697 in what was then called Phillips Burgh. It is now located in Tarrytown, New York, north of New York City on the east bank of the Hudson river. Sleepy hollow was made famous by Washington Irving, who is buried in this cemetery [The Legend of Sleepy Hollow].

From the listless repose of the place, and the peculiar character of its inhabitants, who are descendants from the original Dutch settlers, this sequestered glen has long been known by the name of SLEEPY HOLLOW, and its rustic lads are called the Sleepy Hollow Boys throughout all the neighboring country. A drowsy, dreamy influence seems to hang over the land, and to pervade the very atmosphere. Some say that the place was bewitched by a high German doctor, during the early days of the settlement; others, that an old Indian chief, the prophet or wizard of his tribe, held his pow-wows there before the country was discovered by Master Hendrick Hudson. Certain it is, the place still continues under the sway of some witching power, that holds a spell over the minds of the good people, causing them to walk in a continual reverie. They are given to all kinds of marvellous beliefs; are subject to trances and visions; and frequently see strange sights, and hear music and voices in the air. The whole neighborhood abounds with local tales, haunted spots, and twilight superstitions; stars shoot and meteors glare oftener across the valley than in any other part of the country, and the nightmare, with her whole nine fold, seems to make it the favorite scene of her gambols.

The dominant spirit, however, that haunts this enchanted region, and seems to be commander-in-chief of all the powers of the air, is the apparition of a figure on horseback without a head.

Phillips Burgh was settled in the late 1600s, mostly by Dutch settlers from New York (New Amsterdam). The original Dutch colony was lost to the English in the Second Anglo-Dutch war, which ended in 1667 and the Dutch territory was permanently ceded to England after the Third Anglo-Dutch war ending in 1674.

One group of settlers were not Dutch but Canadian. The David sibship consisted of Carel David, David David, Angelica David, Mathys David, Margaret David, and Daniel David. They were born in Laval, Quebec (Canada) and moved to New York with their parents Guillaume David and Marie (Armand)¹ David. As the children reached adulthood they migrated north to become farmers in Phillips Burgh and they joined the Dutch Church of Sleepy Hollow.

The David family was originally from France and their ancestors can be traced back to Julien David of St. Etienne who was born about 1200. By the time they emigrated to Canada they were Hugenots.²

I am directly descended from Margaret David who married a French soldier named Pierre Montras (Montrose). They moved to Kingston, New York, just up the river from Phillips Burgh. That's where their daughter Margaret Montras was born in 1691. Pierre died in 1703 leaving Margaret with several children who she farmed out to her brothers and sisters in Phillips Burgh. Many of the Montras (Montrose) children also joined the Dutch Church of Sleepy Hollow.

Margaret Montras was probably living with her uncle Carel Davids (name change) when she met and married Harmen Harmse, the son of the Dutch settler Capt. Jan Harmse and his wife Aeltje (Abrahams) Harmse. Jan Harmse was an elder in the Dutch Church of Sleepy Hollow. We can trace Aeltje Abrahams' ancestors (and mine) back to 1555 in Holland.

When Harman married Margaret Montras he took her name as his surname and became known as Harmen Montras. Their fourth child, Peter (Petrus) Montras, was baptized on March 6, 1715 in the Dutch Church of Sleepy Hollow. He is my great- great- great- great- great- great-grandfather. Peter's descendants changed their last name to Montrose or Montross.

Harmen Montras and his wife Margaret Montras are almost certainly buried in the Old Dutch Church of Sleepy Hollow cemetery in unmarked graves and so are Harmen's parents Jan Harmse and Aeltje. That's four direct ancestors of mine. Part of the house built by Jan Harmse is still standing in Irvington, New York.

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1. The maiden name of Guillaume David's wife Marie is not known for certain. It was probably "Harmens" or some variant of that name. She appears to be from New Holland, possibly Manhattan. She was NOT a french "filles à marier" or a "filles du Roi."

2. There is no evidence to support a connection between Guillaume David and the David line in France. In fact, there's no evidence to support the clam that David was French.

The Oldest Non-Living Things on Earth

 
First we had a link to the oldest living thing on Earth [Botany Photo of the Day and the Oldest Living Organism] and now we link to the oldest thing on Earth [Oldest Rocks on Earth Discovered?].

These rocks are found in the Nuvvuagittuq region of Hudson Bay in Northwestern Quebec (Canada). As part of the Canadian shield they have long been known to be among the oldest rocks on Earth. Some of the rocks from this region have now been reliably dated to 4.28 billion years ago making them the oldest rocks known.

The dating technology is based on the decay of samarium to neodymium-142 and the work is published in this week's Science magazine (O'Neil et al. 2008).

These rocks are not the oldest things, however, because there are zircon inclusions from rocks in Western Australia that date back to 4.38 billion years. The zircon crystals probably formed somewhere else and were incorporated into the Australian rocks.

The Canadian rocks might also be much younger, having incorporated bits of older sediment, but for now, it looks like the Canadian shield may actually have formed over four billion years ago.

One thing is clear, Canada and Australia are the oldest countries in the world, by far.

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J. O'Neil, R. W. Carlson, D. Francis, R. K. Stevenson (2008). Neodymium-142 Evidence for Hadean Mafic Crust Science, 321 (5897), 1828-1831 DOI: 10.1126/science.1161925

Botany Photo of the Day and the Oldest Living Organism

 
The oldest known organism on the planet is about 4,800 years old. Find out what that has to do with the Botany Photo of the Day.

It is often very hard to tell the difference between various species of pine. One of the distinguishing characteristics of this species (left) is that it has five needles per cluster. Other species have one, two, or three. I don't know if there is a species with four needles per cluster, or six.

Here's a question for all the adaptationists, is number of needles per fascicle an adaptation or is it just an allele that was fixed by accident? Is it an example of a morphological characteristic that is not an adaptaion?

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One Hundred Words of Science

 
Check out Biocurious where PhilipJ has posted on One hundred words of science. I've suggested a few changes. Look over the list and see whether you agree.

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Unrealistic Expectations

 
Harold Varmus was in town recently to receive the Henry G. Friesen International Prize in Health Research. He made some interesting comments that were reported in last Thursday's issue of the Globe and Mail [Cancer expert warns of too-great expectations]. Bayman spotted it and reported on Balblab [Varmus on "The Cure" for Cancer].

Here's what Varmus said,

Nobel laureate Harold Varmus, head of New York's Memorial Sloan-Kettering Cancer Center, said one of the inherent difficulties in continuing to raise funds for cancer research is to explain to people how difficult the problems are that still lie ahead.

“These problems are really, really tough, and they're going to be knocked off more or less one by one,” he said in an interview in Toronto, where he received one of Canada's highest-profile medical awards, the Henry G. Friesen International Prize in Health Research.

Unrealistic expectations of an imminent cure for cancer have been around since former U.S. president Richard Nixon declared war on the disease in his 1971 State of the Union address, Dr. Varmus said.

They have been fuelled, he said, by a continuous stream of media articles that trumpet some initiative such as the completion of the genome project and then predict a payoff never matched by reality.

And he argued that the culture of unrealistic expectations is encouraged by the way science is taught in schools, with a focus on outcomes rather than process.

This is part of a growing backlash against hype in the media. I think most of us realize that in the past we exploited the naivety of the media in order to advance our pet projects. As we get older we realize that we were wrong to make this pact with the devil and now we want to turn the clock back and emphasize the purity of science and the search for truth.

We want the general public to understand how science is really done and not how we pretended it was done. One of the reasons for this change in attitude is that science has lost credibility for not living up to the hype. Another reason is that we see the problems with a society that doesn't understand how science really works. It makes fighting creationism and other superstitions much harder.

I hate to bring up framing again but I think these two issues are related. For those of us who want to teach the truth about science, framing sounds too much like the old ways that we are trying to put behind us.

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[Photo Credit: In addition to being a Nobel Laureate and President & Chief Executive of Memorial Sloan-Kettering Cancer Center, Varmus is also Co-founder and Chairman of the Board of PLoS: Public Library of Science.]

Nature's Evolution Question

 
The British science magazine Nature asked the following question of each US Presidential candidate [US election: Questioning the candidates].

Do you believe that evolution by means of natural selection is a sufficient explanation for the variety and complexity of life on Earth?

My answer, of course, is "no"; natural selection is not a sufficient explanation. You also need random genetic drift and a host of other things that are part of evolutionary theory.

How would you answer the question, dear readers?

Both candidates did a pretty good job of answering this question.

Obama: I believe in evolution, and I support the strong consensus of the scientific community that evolution is scientifically validated.

McCain said last year, in a Republican primary debate: "I believe in evolution. But I also believe, when I hike the Grand Canyon and see it at sunset, that the hand of God is there also."

They both avoided answering the direct question. Instead, they interpreted the question to be whether they believe in evolution. They both believe in evolution.

Since this is one of the leading science magazines in the world I'm certain that the question was not about believing in evolution. It was designed to discover whether McCain and Obama were adaptationists. There's no other reasonable explanation since it's impossible that Nature wouldn't know the difference between "evolution" and "natural selection." At least I think it's impossible ...

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Joe Who?

 
According to CBS News,

Washington - Vice presidential candidate Joe Biden says today's leaders should take a lesson from the history books and follow fellow Democrat Franklin D. Roosevelt's response to a financial crisis.

"When the stock market crashed, Franklin D. Roosevelt got on the television and didn't just talk about the, you know, the princes of greed. He said, 'Look, here's what happened,'" Barack Obama's running mate recently told the "CBS Evening News."

Except, Republican Herbert Hoover was in office when the stock market crashed in October 1929. There also was no television at the time; TV wasn't introduced to the public until a decade later, at the 1939 World's Fair.

I would have thought the bloggers would be all over this. Have I been reading the wrong blogs?

Lately I've been wondering what happened to Joe Biden. You don't see much about him on television. Now I know why. Maybe he and Sarah should take a very long trip to Afghanistan and let the big boys run for President.

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