Tuesday, July 22, 2008

The DNA Network

The DNA Network

A Sizzling Hypocrisy [evolgen]

Posted: 22 Jul 2008 06:30 PM CDT

sizzle.jpg

Randy Olson left a career as a marine biologist (Titleist!) to become a film maker. His first feature project was Flock of Dodos, a movie I enjoyed. His second film is Sizzle, a movie reviewed by lots of ScienceBloggers a couple weeks ago. The gist: a lot of ScienceBloggers didn't like sizzle. Neither did a reviewer for Nature (doi:10.1038/454279a).

I did not request a review copy of the movie because I don't like to diverge much from the main themes of evolgen: evolutionary genetics, manatees, and the douchebag who writes this blog. But some of the recent discussion surrounding Sizzle has caught my attention, and I think it relates to the broader issue of science outreach (that is: communicating science to the general public).

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Company revokes breast cancer gift, freezes puppies [Genetic Future]

Posted: 22 Jul 2008 05:11 PM CDT

Presumably in an attempt to solidify its reputation as the evil corporation du jour, Genetic Technologies has followed up on its decision a fortnight ago to tear back its "gift to the people of Australia and New Zealand" with the purchase of Frozen Puppies Dot Com.

They'll be sorely disappointed when they realise the company actually specialises in "the collection, freezing, exchange and insemination of canine sperm" rather than dunking puppies in liquid nitrogen while cackling evilly.


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Blog Carnivals or Microblogging? [ScienceRoll]

Posted: 22 Jul 2008 03:30 PM CDT


I’ve been the manager of two blog carnivals for almost 2 years now. Gene Genie is about clinical genetics and personalized medicine; while Medicine 2.0 focuses on web 2.0’s impact on medical education and healthcare. It’s extremely hard to find hosts for the editions and to send them enough quality submissions in time.

So I decided to start something different. I beleive Gene Genie still should be a real blog carnival, but Medicine 2.0 should become something innovative. While the pre-scheduled editions will be hosted, I will simultaneously launch a new platform where I can share all the important and interesting posts focusing on medicine 2.0 and health 2.0 with you by using a microblogging service.

Pros:

  • The whole process becomes much faster and more efficient.
  • I don’t need hosts; there are no deadlines.

Cons:

  • Only those who use that specific microblogging service will see the shared items.

There are two possible solutions:

Any suggestion?

The Trip Part V - Iceland [The Daily Transcript]

Posted: 22 Jul 2008 03:18 PM CDT

We were planning to head to Europe so when I discovered that the cheapest tickets were being offered by Icelandair, I jumped on it. Why? I have always wanted to visit this mystic land and Icelandair lets you have a free stopover for up to a week. I highly recommend that you do this once - Iceland was far and away the highlight of our European trip.

Day I - We arrived late in Keflavic where the main international airport is located. This is on the southwest corner of the island and lies right on top of the mid Atlantic ridge in an area known as the Reykjanes. Already you can see that Iceland is not your everyday island. The area west and south of the town are essentially lava fields interrupted by bulges in the earth where gas, superheated water or lava periodically seeps out.

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Although Iceland is cold, I would say that the wind is much more impressive. Looking straight up you could clearly see the clouds zip across the sky. One moment it was sunny, the next rainy, the next foggy, and 5 minutes later the sun came out again. Another nice feature of the country is that it is loaded with geothermal energy sources. Ocean water seeps into cracks between the American and Eurasian plates as they move away from eachother. As the water hits the inner depts on the earth it heats up and boils up to the surface. This is very noticeable in the Reykjanes peninsula, which is full of power plants that convert the hot water into electricity. Another nice feature is that the ample amount of geothermal water means that you can find hot water at any location even the lowliest camp site!

We then arrived at our new home, Alex Camping/Hostel/Motel, a small place that is conveniently located 2 minutes away from the airport. After setting up the tent, we head inside to eat dinner and watch the Spaniards beat the Germans to take the Euro '08 final. Needless to say everyone was cheering for Spain. I should add here that we were able to catch quite a few games over the course of our trip. We saw Turkey make an incredible comeback to beat Croatia with two goals in the last few minutes. In Cancale Brittany we watched Italy beat France while surrounded by angry french partisans . We watched Germany beat Portugal with our Portuguese friends. And finally we watched Germany beat Turkey in Munich - now that was quite an experience! OK lets get back to Iceland ...

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Flies suffer from insomnia too [Bayblab]

Posted: 22 Jul 2008 03:04 PM CDT

On one of my own frequent sleepless nights, I came across a piece in NewScientist about a newly discovered Drosophila gene: Sleepless.

Normal flies sleep away almost half of each day (tell that to the ones in my kitchen). However, flies lacking Sleepless get by on 2 or fewer daily hours of sleep.
The mutation – in a gene that controls how brain cells fire and now dubbed Sleepless – suggests that, at the most basic level, sleep is caused by a slowdown in certain neurons.

An inability to control these neurons might spell a restless night for animals besides flies
As if the fatigue that comes after a sleepless night isn't enough, the authors point out that the mutant flies also have shortened lifespans and impaired co-ordination, underscoring the importance of a good night's rest. Somehow that won't help me sleep any easier.

The research was published in Science.

Medsphere: The Future of Healthcare is Open? [ScienceRoll]

Posted: 22 Jul 2008 02:49 PM CDT


There is a real hype about electronic health records nowadays and Medsphere seems to be an interesting example. Dr. Edmund Billings, Chief Medical Officer for Medsphere and a pioneer in the development of electronic medical records, kindly answered my questions.

Please introduce briefly your service to us. What does Medsphere focus on?

Medsphere offers electronic health record (EHR) through OpenVista, a commercialized open source version of the U.S. Department of Veteran’s Affairs VistA solution.  Most hospital administrators and physicians say the high cost of purchasing traditional systems and equipment is a significant barrier that prevents hospitals from adopting EHR.  Medsphere has incorporated open source technology to revolutionize EHR, making it much more affordable and with less implementation time.  John Halamka, CIO at Harvard Medical School and Beth Israel Deaconess Medical Center in Boston and a Computerworld columnist, recently profiled Medsphere favorably in his blog.

Why open-source?

Medsphere understands that EHR’s are essential to transforming healthcare, but we also appreciate the drawbacks – high cost, long implementation time.  The use of open source helps mitigate both of these main drawbacks – by allowing all groups involved to talk to one another, the old roadblocks are gone and integration is seamless.

There are plenty of EMR systems on the market (EPIC, Cerner, Meditech, Mckesson, Siemens, etc.). Why is Medsphere different or  unique?

The VA system was never designed with a software vendor business model in mind.  It was made to be usable and readily deployable,  much simpler in general.  Over 20 years, it has been deployed in 170 VA facilities and has been used by most residents during their VA rotations.  Its proven and now, its in open source.

Secondly, aside from the introduction of open source into the field of EHRs, Medsphere differs from others on the market in the way that it addresses payment. Rather than a prohibitive up-front cost, they use a subscription-based pricing model that allows for much easier entry into the market.  The subscription covers quality certification, support and all upgrades.

Finally because it is released in open source, it eliminates “vendor lock”  where the customer is locked to their vendor for anything and forever and “vendor fatigue” where everything you ask for costs the customer more.

Do you think patients are ready for this e-health based service?

Patients are not only ready for PHRs, they want them. They realize that there has to be a better way than the old paper and pen method.  They shake their heads when their records are not available or when they are asked over and over again the same questions about their medications, allergies.  We live in an incredibly plugged-in society that does not want to wait for the old paper and pen method to catch up. Even our presidential candidates are jumping on the bandwagon.  The key to broad adoption is that the health information should be a direct by-product of care entered by the patient and the practitioners during the process of care,  not a redundant or strictly patient driven.  Lastly, cellphones and mobile devices are a key form factor particularly in chronic disease e-health management.  Patients can be interacted with in real-time to assess their care and status.

What are your plans for the next months?

Our near-term plan is to further engage and support our customers and community in their open source projects.  We have recently released our source code under the AGPL open source license and are moving to open up more API’s.  We want to provide more opportunities for customers to meet their own needs and to support collaboration across the community.

Intro to Epigenetics [Epigenetics News]

Posted: 22 Jul 2008 02:48 PM CDT

University of Minnesota-Morris biologist PZ Myers has written an introduction to epigenetics at Pharyngula, with some nice illustrations of some of the basic concepts and mechanisms that are generally grouped under the heading of “epigenetics.” It’s a great way to bring yourself up to speed if you don’t know much about epigenetics and want a single article to give you the basics. I’ve come to realize that the majority of the readers here are not in that crowd, as many are working in research labs and companies that have some connection to the area of epigenetics and want to keep up on the very latest developments in epigenetics. So for those are you that are not part of that group, I highly recommend that you head over to this article and read about the basics of epigenetics. Link

One of the questions brought up in the article, which has been covered here before, is what all falls under the umbrella of epigenetics? I think that this is largely an issue of semantics, with some established researchers having an interest in restricting the use of the word in literature, and many others expanding the reach of the word to greater and greater lengths. As I’ve mentioned before, I think this trend is largely a result of the funding opportunities available, and the general trend in recent years as epigenetics becoming one of the “hot new” areas of science.

Increased Coffee Consumption Associated with Lower Risk of Liver Cancer [Highlight HEALTH]

Posted: 22 Jul 2008 12:16 PM CDT

ResearchBlogging.orgHere’s another reason to enjoy your coffee. A recent study in the July edition of the Journal Hepatology found a significant inverse association (meaning opposingly related; an increase in one variable results in a decrease in another) between coffee drinking and the risk of primary liver cancer [1]. The study also found that serum levels of an antioxidant enzyme, elevated in people with low coffee consumption, were associated with an increased risk of developing the disease.

Coffee
Creative Commons License photo credit: Marcelo Alves

Primary liver and bile duct cancers are the sixth most common cause of cancer death in men and the tenth most common cause of cancer death in women [2]. Hepatitis B and C viral infections have been identified as causative factors in greater than 75% of liver cancers worldwide [3]. Interestingly, incidence rates are low in most developed countries except for Japan, where coffee drinking is relatively uncommon. Several studies have also identified an inverse association between coffee consumption and serum levels of gamma-glutamyltransferase (GGT), an enzyme involved in glutathione metabolism [4-5]. Glutathione plays important roles in antioxidant defense, nutrient defense and regulation of a variety of cellular events [6].

Residents of Finland consume more coffee per capita than the Japanese, Americans, Italians and other Europeans. University of Helsinki researchers examined the associations between coffee consumption and serum GGT levels in 60,323 Finnish participants between the ages of 25 and 74 who were cancer-free at the beginning of the study.

Participants were mailed a questionnaire about their medical history, socioeconomic factors, smoking habits and dietary habits. A subset of participants (n = 37,842) had clinical data available, including alcohol consumption and serum levels of GGT. Study participants were divided into five categories based on their response to the question “How many cups of coffee do you drink daily?”:

  • Category 1:   0 — 1 cup
  • Category 2:   2 — 3 cups
  • Category 3:   4 — 5 cups
  • Category 4:   6 — 7 cups
  • Category 5:   8 or more cups per day

During a median follow-up period of 19.3 years, 128 participants were diagnosed with primary liver cancer.

incidence_vs_year_follow-up.pngThe researchers observed that the cumulative incidence curve of liver cancer decreased with increasing amounts of daily coffee consumption (graph). When the analysis was restricted to surveys from participants that had clinical data available, a statistically positive association was found between serum GGT level and liver cancer risk. Joint association of coffee consumption and serum GGT level with liver cancer showed that participants who drank 0 — 1 cups of coffee and were in the top 25% of subjects sampled with respect to serum GGT had about 9.2 times increased risk for liver cancer compared to participants who drank at least 6 cups of coffee daily and were in the bottom 75% of subjects sampled with respect to serum GGT.

The study results are consistent with two meta-analyses published last year demonstrating an inverse relation between coffee consumption and liver cancer [7-8]. While a previous investigation found an inverse association between coffee consumption and serum GGT level, this study is the first large prospective study to suggest that a high level of serum GGT is a risk factor for primary liver cancer. The authors discuss a mechanism for the association between coffee drinking and serum GGT on liver cancer risk [1]:

Several other putative mechanisms behind the association of coffee drinking and serum GGT on liver cancer risk have also been proposed. Coffee contains many compounds, such as chlorogenic acid, which may have the potential to influence glucose metabolism processes to prevent hyperglycemia, and consequently oxidative stress.

Indeed, chlorogenic acid, a chemical largely responsible for coffee’s bitterness, may also be responsible for coffee’s effect on serum GGT level and, ultimately, coffee’s health benefits.

More information and support for patients with “Liver cancer” can be found at Organized Wisdom and MDJunction. Additionally, the American Liver Foundation, the nation’s leading nonprofit organization promoting liver disease prevention and liver wellness, provides research, education and advocacy for those affected by liver-related diseases.

References

  1. Hu et al. Joint effects of coffee consumption and serum gamma-glutamyltransferase on the risk of liver cancer. Hepatology. 2008 Jul;48(1):129-36. DOI: 10.1002/hep.22320
    View abstract

  2. A Snapshot of Liver and Bile Duct Cancers. American Cancer Society. Atlanta, Ga. 2007.
  3. Ferlay et al. GLOBOCAN 2002: Cancer Incidence, Mortality and Prevalence Worldwide. IARC CancerBase No. 5. version 2.0. Lyon, France: International Agency for Cancer Research; 2004.
  4. Casiglia et al. Unexpected effects of coffee consumption on liver enzymes. Eur J Epidemiol 1993;9:293-297.
    View abstract
  5. Tanaka et al. Coffee consumption and decreased serum gamma-glutamyltransferase and aminotransferase activities among male alcohol drinkers. Int J Epidemiol 1998;27:438-443.24.
    View abstract
  6. Wu et al. Glutathione metabolism and its implications for health. J Nutr. 2004 Mar;134(3):489-92.
    View abstract
  7. Larsson and Wolk. Coffee consumption and risk of liver cancer: a meta-analysis. Gastroenterology. 2007 May;132(5):1740-5. Epub 2007 Mar 24.
    View abstract
  8. Bravi et al. Coffee drinking and hepatocellular carcinoma risk: a meta-analysis. Hepatology. 2007 Aug;46(2):430-5.
    View abstract
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This article was published on Highlight HEALTH.

Other Articles You May Like

The Gene Collector: George Church & the Personal Genome Project [Epidemix]

Posted: 22 Jul 2008 11:44 AM CDT

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My latest story in Wired, a profile of geneticist George Church, is in the August issue, now on the stands (and online here).

In some regard, it’s a follow-up to my previous story on personal genomics. But it is really my effort to shine the light on one person who’s doing so much to propell us towards the future of genomics. Church is frighteningly intelligent, yet notably calm and kind (and generous with his time, explaining for me, for instance, the principles of synthetic biology again and again until some of it got through).

It was great fun talking with him and reporting the story. My hope is it helps people understand the ambitions and potential of personal genomics, if pursued on a massive scientific scale.

The Evolution & Medicine Review [evolgen]

Posted: 22 Jul 2008 09:00 AM CDT

doonesbury_evol_medicine_sm.GIF

All good medicine is evidence based -- that is, diagnoses and treatments are developed via the scientific method. Oftentimes, evolutionary biology is employed to understand human health and diseases. This is known as evolutionary medicine.

Evolutionary medicine is a growing field that takes an interdisciplinary approach toward studying human disease. Tools from population ecology, molecular evolution, comparative anatomy, and many other fields are all integrated with clinical medicine to improve our understanding of human disease and develop new treatments. This approach can be applied to infectious diseases, congenital diseases, and acquired diseases.

Despite the rapid growth of this field, there is no central society or journal that deals with these topics. Additionally, because relevant research is often spread across otherwise disparate subdisciplines, people looking for literature on evolutionary medicine must search many different journals. To remedy this problem, a group of researchers working in evolutionary medicine have started an on-line review journal, or Web Based ReView (WeView), called The Evolution & Medicine Review. The creators view it as a sort-of cross between a blog and a review journal, although I'd categorize it as a single topic blog written by experts.

The Evolution & Medicine Review does not publish original research. Instead, the list of contributors produce short reviews on topics that interest them (very bloggy, not that it's a bad thing). You can read more about the EMR on their website.

(Via EvolDir.)

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Index of Suspicion [The Gene Sherpa: Personalized Medicine and You]

Posted: 22 Jul 2008 08:09 AM CDT

There is an age old adage in medicine "You miss 100% of all disease X that you don't look for" It is stolen from an old golf adage that you miss 100% of all putts that you leave short. Big surprise,...

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How to be an Iconoclast in Biology [adaptivecomplexity's column]

Posted: 22 Jul 2008 07:50 AM CDT

Every scientist wants to be an iconoclast, but most end up doing rather conventional work. Understandably, because it takes a special sort of nerve to risk your career and reputation on an idea or approach that could be very, very wrong - so wrong that it would be tough to recover from.

Read More...

GenePartner: Genetic Dating? [ScienceRoll]

Posted: 22 Jul 2008 06:26 AM CDT


Are you kidding me? Do you remember ScientificMatch.com? Now GenePartner just launched its service:

GenePartner is a formula to match men and women by analyzing specific genes in their DNA.

At GenePartner we are dedicated to help you find your ideal life partner. Our formula is based on research on hundreds of couples and analyzes the pattern of genetic combinations found in successful relationships. Using this formula we will determine the probability for a satisfying and long-lasting romantic relationship between two people.

It means you can find your “genetic partner” for $199. They focus on HLA (human leukocyte antigen) genes as:

In collaboration with the Swiss Institute for Behavioural Genetics, we tested a large number of individuals (both romantically involved couples and persons not in a relationship) for their HLA genes.

The GenePartner formula measures the genetic compatibility between two individuals and makes an accurate prediction of the strength of their basis for a long-lasting and fulfilling romantic relationship.

What else can be next in genetics?

More on Techcrunch

Good GM Foods - Bt Corn as an Example [Bitesize Bio]

Posted: 22 Jul 2008 05:47 AM CDT

Last December, I posted a running question - What’s with Europe’s Opposition to GMOs? - and moved on to other topics. This week, I’d like to contrast “good” versus “bad” genetically modified crops. Beginning with the former, a prominent example of a “good” GM crop is Bt corn.

In 2003, PLoS Biology ran an article on Genetically Modified Corn that spent a good deal of time on Bt Corn. The highlights:

Bacillus thuringiensis, a soil bacterium, produces several crystal (Cry) protein toxins that destroy the gut of invading pests, such as larval caterpillars. So far, over 50 cry genes have been identified and found to affect insect orders differently.

Considered safe to humans, mammals, and most insects, Bt has been a popular pesticidal spray since the 1960s because it had little chance of unintended effects. Engineering the gene into corn, however, caused an unexpected public backlash. "We thought it was going to be the greatest thing since sliced bread," says Guy Cardineau, agricultural biotechnologist at Arizona State University. "Here’s a way to withstand insect pressure, eliminate the use of pesticides, and Bt spray was widely used in organic agriculture," he adds. The Bt wrangle illustrates how differently a product and a process can be regarded.

After the expensive development process, today’s concern is that broad-scale planting of Bt corn will render the toxin ineffective over time. Pests can gradually build resistance to any pesticide, and so the United States Environmental Protection Agency (EPA) requires that 20% of Bt field areas be planted to non-Bt corn to avoid such pressures. But humans have to follow the rules. A recent report from the Center for Science in the Public Interest shows that almost 20% of farmers in the United States Corn Belt are violating EPA standards by overplanting Bt corn, causing some to question the regulations and enforcement that will be necessary for certain GM crops.

Now this isn’t my field, I’m just a mild-mannered commentator on what I know about these things from my extra-curricular online reading. I haven’t fact-checked all of that, or the rest of the material from the PLoS Biology paper. That’s what we have peer review of such articles, regulatory agencies and muckrakers for.

So to my understanding, what I keep hearing from such respected sources is that such GM crops improve the way that pesticides and herbicides are used, focus on selective chemical agents, and are already compatible with current standards for organic foods. Leaving very little to complain about. Oh there’s the potential for gene flow into the environment and other potential but probably minor ecological impacts to consider, but the food safety concerns aren’t significant.

As the PLoS Biology article originally pointed out, the *real* concern is overuse, leading to a repeat of antibiotic resistance in crop pests.

The Tenth and Final PGP Volunteer is Revealed! [The Genetic Genealogist]

Posted: 22 Jul 2008 02:01 AM CDT

image Thomas Goetz has written another terrific article about genetic testing and the Personal Genome Project.  This article, entitled “The Gene Collector,” appears in Wired Magazine.  The article provides some new information about the PGP, including some of the incredibly detailed phenotype information that will be collected from the next 100,000 volunteers in the project.

The article also reveals the tenth and final participant of the “First 10″, the original 10 volunteers in the PGP.  I wrote about the first nine volunteers in the PGP almost exactly one year ago and noted that the tenth participant had not yet released his or her name.  The Wired article, however, mentions a number of participants including George Church, Esther Dyson, Rosalynn Gill, John Halamka, and Steven Pinker.  Indeed, a check of the PGP website confirms that Steven Pinker is the last PGP volunteer to be identified.

From the PGP-10 website:

Steven Pinker, Ph.D. is the Johnstone Family Professor of Psychology at Harvard University, and has also taught at Stanford and MIT. His research on visual cognition and the psychology of language has won prizes from the National Academy of Sciences, the Royal Institution of Great Britain, and the American Psychological Association. He has also received five honorary doctorates, several teaching awards, and numerous prizes for his books The Language Instinct, How the Mind Works, and The Blank Slate. He serves on the Usage Panel of the American Heritage Dictionary and many editorial boards, and often writes for Time, The New York Times, The New Republic, and other publications. He has been named Humanist of the Year, and is listed in Foreign Policy and Prospect magazine's "The World's Top 100 Public Intellectuals" and in Time magazine's "The 100 Most Influential People in the World Today." His latest book is The Stuff of Thought: Language as a Window into Human Nature, published by Penguin books in the fall of 2007.”

There is more information at Dr. Pinker’s Harvard website and at Wikipedia.

NY Times Article on Sunscreens for Those Interested in Prevention of Melanoma and Other Skin Cancers [Cancer and Your Genes]

Posted: 22 Jul 2008 01:36 AM CDT

If you have a family history of melanoma or are just interested in doing everything you can to prevent skin cancer, you may be interested in this article by Tara Parker-Pope at the NY Times.

OSCON here I come [business|bytes|genes|molecules]

Posted: 21 Jul 2008 11:29 PM CDT

I am heading to OSCON tomorrow. You are likely to find me somewhere near the AWS booth, or at cloud computing/Ruby talks

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Genetic variant increases triglyceride levels in Asian-Americans [Think Gene]

Posted: 21 Jul 2008 10:42 PM CDT

Josh: While this is certainly an important genetic variation to find, I’m wondering if doctors would be able to use this information if they tested their patients. What could be done differently in treating high levels of triglycerides? This would be much more useful if a drug existed to treat this specific cause of elevated plasma TG levels.

A genetic variant found almost exclusively in individuals of Asian descent increases the risk of elevated triglycerides over four-fold, reports a comprehensive study in the August Journal of Lipid Research. In fact, all 11 subjects who carried both copies of this rare variant for apolipoprotein A-V had extremely high and dangerous triglyceride levels in their blood.

Apolipoprotein A-V is a recently discovered lipid-binding protein that likely plays an important role in metabolizing triglycerides. Some population studies with groups in China and Taiwan indicate that a polymorphism in the APOA5 gene (553 G>T shift) is associated with elevated plasma TG levels, which like cholesterol, increase the risk of heart disease.

To get a broader view of this potentially important gene polymorphism, Clive Pullinger and colleagues examined the frequency and impact of this variant in a population of Chinese-Americans, as well as four other Asian-American populations (Japanese, Korean, Southeast Asian, and Pacific Islander).

The researchers examined 541 individuals and found that 15.1% of Chinese-Americans with high plasma TG (>150 mg/dl) carried at least one copy of the 553T variant, compared with only 3.7% of those with normal TG levels; in non-Chinese Asians these values were 13.7% and 5.4%. When calculated, the 553T variant corresponds to a 4.4 and 2.5 times greater risk of elevated TG in Chinese-Americans and other Asians, respectively.

The frequency became even more prevalent at higher levels; 60% of individuals with TG of >500 mg/dl carried the variant, and at 1000 mg/dl the frequency rose to 80%. And the 11 subjects who had the variant in both copies of their APOA5 gene had an average TG concentration of over 2000 mg/dl, which can pose serious health risks.

This specific genetic change seems restricted to Asians, as the researchers studied 779 non-Asian subjects and found only 3 incidences of the 553T variant (2 Caucasian and 1 Hispanic).

Source: American Society for Biochemistry and Molecular Biology

“An apolipoprotein A-V gene SNP is associated with marked hypertriglyceridemia among Asian-American patients”. Clive R. Pullinger, Bradley E. Aouizerat, Irina Movsesyan, Vincent Durlach, Eric J. Sijbrands, Katsuyuki Nakajima, Annie Poon, Geesje M. Dallinga-Thie, Hiroaki Hattori, Lauri L. Green, Pui-Yan Kwok, Richard J. Havel, Philip H. Frost, Mary J. Malloy and John P. Kane. Journal of Lipid Research, Vol. 49, 1846-1854, August 2008.

The curious case of the proteasome inhibitor Argyrin A [Omics! Omics!]

Posted: 21 Jul 2008 10:03 PM CDT

A burning set of questions in my old shop when I was there, and I have every reason to think is still aflame, is why does Velcade work in some tumors but not others and how could you predict which tumors it will work in. Does the sensitivity of myelomas & certain lymphomas generally (and a seemingly random scatter of solid tumor examples) to proteasome inhibition follow a pattern? And is this pattern a reflection of the inner workings of these cells or more how the drug is distributed throughout the body?

An even broader burning question is whether any other proteasome inhibitor would behave differently at either level. Would a more potent inhibitor of the proteasome have a different spectrum of tumors which it hit?

Now, while Velcade (bortezomib, fka PS) is the only proteasome inhibitor on the market, it will probably not always be that. Indeed, since Velcade has proven the therapeutic utility of proteasome inhibition, other companies and academics have been exploring proteasome inhibitors. The most advanced that I am aware of is a natural product being developed by Nereus Pharmaceuticals, which I will freely confess to not really following.

The featured (and therefore free!) article in July's Cancer Cell describes a new proteasome inhibitor, another natural product. Argyrin A was identified in a screen for compounds which stabilize p27Kip1, an important negative regulator of the cell cycle. Kip1 is one of the a host of proteins reported to be an important protein stabilized by proteasome inhibition (one of duties back on Landsdowne Street was to catalog the literature on such candidates). While there are probably many ways to stabilize p27Kip1, what they reported on is this novel proteasome inhibitor.

By straightforward proteasome assays Argyrin A shows a very similar profile to Velcade. That is, the proteasome has multiple protease activities which can be chemically distinguished, and the pattern of inhibition by the two compounds is very similar. However, by a number of approaches they make the case that there are significant biological differences in the response to Velcade & Argyrin A.

Now there is a whole lot of data in this paper & I won't go into detail on most of it. But I will point out something a bit curious -- very curious. They performed transcriptional profiling (using Affymetrix chips) on samples treated with Velcade, Argyrin A, and siRNA vs an ensemble of proteasome subunits, each at different timepoints. In their analysis they saw lots of genes perturbed by Velcade but a very small set perturbed by Argyrin A and the siRNA. Specifically, they claim 10,500(!) "genes" (probably probesets) for Velcade vs 500 for Argyrin A. That's a huge fraction of the array moving!

Now, I'll confess things are a bit murky. Back at MLNM I would have had the right tools at my disposal & could quickly verify things; now I have to rely on my visual cortex & decaying memory. But when I browse through their lists of genes for Argyrin A in the supplementary data, I don't see a bunch of genes which are a distinct part of the proteasome inhibition signature. At MLNM, huge numbers of proteasome inhibition experiments were done & profiled on arrays, using a number of structurally unrelated proteasome inhibitors in many different cell lines. Not only does a consistent signal emerge, but when an independent group published a signature for proteasome inhibition in Drosophila there was a lot of overlap in their signature & our signature once you mapped the orthologs.

What's the explanation? Well, it could be that I'm not recognizing what is there due to poor memory, though I'm pretty sure. One thing that is worrisome is that the Argyrin A group's data is based on a single profile per drug x timepoint; there are no biological replicates. That's not uncommon due to the expense and challenge of microarray studies, but good experiments are easy. Nor was there any follow-up by another technology (e.g. RT-PCR) to show the effects across biological replicates or other cell lines. Given that these are in tissue culture cells, which can behave screwy if you stare at them the wrong way, that's very unfortunate. Even small differences in the culturing of the cells -- such as edge effects on plates or humidity differences, can lead to huge artifacts.

Another possible explanation is that the Bortezomib cells were watched too late; the first Velcade timepoint is at 14 hours. After 14 hours, the cells are decidedly unhealthy and heading for death. The right times to sample were always a point of contention, but one suggestion that there is an issue is the lack of correlation between the different timepoints for Velcade vs the strong correlation for the other treatments (Figure 7). That works (in my head at least) in reverse too -- it's downright odd that their other treatments are so auto-correlated between 14 and 48 hours with Argyrin A -- if cells are not yet dead at 14 hours but committed to die, one would expect there to be some sort of movement away from the original profile.

One other curiosity. They do report looking for the Unfolded Protein Response (UPR) and report seeing it in the Velcade treated cells but not Argyrin A treated ones. The UPR is the cell's response to misfolded proteins -- and since disposal of misfolded proteins is a role of the proteasome, it has never surprised anyone that the UPR is induced by proteasome inhibitors. Can you really have a proteasome inhibitor that doesn't induce the UPR? If this is truly the case, it is very striking and deserves its own study.

Is the paper wrong? Obviously I can't say, but I really wonder about it. I also wonder if the referees brought up the same questions. Hopefully we'll see some more papers in the future which explore this compound in a wider range of cell lines and with more biological replicates

Nickeleit et al
Argyrin a reveals a critical role for the tumor suppressor protein p27(kip1) in mediating antitumor activities in response to proteasome inhibition.
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UNC, Caltech research finds further evidence for “genetic” contribution to autism [Think Gene]

Posted: 21 Jul 2008 09:46 PM CDT

Josh: The authors of this paper draw a conclusion that this has to be inherited genetically. However, they did not find a gene or set of genes that would be responsible. Perhaps the parents are more “aloof” because they’ve had to adapt and learn to understand their autistic children’s emotional state. I see no reason why this couldn’t be explained by environmental factors, since the children are born into the environment of their parents. The paper is focused on analyzing the phenotypes, which may or may not have genetic causes. Granted, statistics is an area I know little about, but I feel the data to make this conclusion simply isn’t there.

Some parents of children with autism evaluate facial expressions differently than the rest of us – and in a way that is strikingly similar to autistic patients themselves, according to new research by psychiatrist Dr. Joe Piven of the University of North Carolina at Chapel Hill and neuroscientist Ralph Adolphs, Ph.D., of the California Institute of Technology.

Piven, Adolphs and colleague Michael Spezio, Ph.D., formerly of Caltech but now at Scripps College in Claremont, Calif., collaborated to study 42 parents of children with autism, a complex developmental disability that affects an individual’s ability to interact socially and communicate with others. Based on psychological testing, 15 of the parents were classified as being socially aloof.

“This manifests as a tendency not to prefer interactions with others, not to enjoy ’small talk’ for the sake of the social experience and to have few close friendships involving sharing and mutual support,” said Piven, senior author of the study, Sarah Graham Kenan professor of psychiatry in the UNC School of Medicine and director of the newly established Carolina Institute for Developmental Disabilities. “This characteristic is really a variation of normal and not associated with any functional impairment.”

The parents participated in an experiment that measured how they make use of the face to judge emotions. The subjects were shown images depicting facial expressions of emotion that were digitally filtered so that only certain regions of the face were discernible – the left eye, for example, or the mouth. The subjects were then asked to decide as quickly as possible if the emotion depicted was “happy” or “fear.” The part of the face shown and the size of the revealed area randomly varied from trial to trial.

An analysis of the subjects’ correct responses revealed that “aloof” parents relied much more heavily on the mouth to recognize emotion than they did on the eyes, as compared to non-aloof parents and, to a greater extent, to a group of parents of children without autism. Prior studies by Adolphs and his colleagues have shown that humans normally evaluate emotions by looking at the eyes – but studies by Adolphs and Piven have shown that individuals with autism do not.

“We found that some parents who have a child with autism process face information in a subtly but clearly different way from other parents,” Adolphs said. “This is evidence for the hypothesis that the parents with the autistic child have brains that function somewhat differently as well.”

He and other researchers are currently investigating that idea through brain imaging studies. One area of interest is the amygdala, a region located on either side of the brain in the medial temporal lobe that is known to process information about facial emotions and may have abnormal volume in both autistic individuals and their nonautistic siblings.

The finding indicates that certain aspects of autism do run in families. Although such a genetic link was noted in the 1940s in the earliest descriptions of autism, “our study adds considerable specific detail to the story,” Adolphs said.

“Our data strongly suggest that genetic factors make a substantial contribution to autism, but that does not mean that all of the cause of autism is genetic. Together with many other studies, our study argues that genetic factors play a very important role in autism, while leaving open a role for other, environmental factors,” he said.

UNC and Caltech are currently working together to follow up on the finding by looking at the neural circuitry of face processing in parents of autistic individuals, using functional MRI in a National Institutes of Health-funded study.

“We hope that this research contributes towards a cure for autism, even if only indirectly,” Adolphs said. “Once we understand better how people with autism – and their relatives – process social information like information about the faces of other people they look at, we will be in a better position to teach them strategies for social interaction and will be able to explain to them how they differ from neurotypical people.”

Piven said that this approach may disaggregate the phenotype in autism and provide new targets for genetic studies. “In other words, it may lead us to finding genes that are responsible for the face-processing component in autism,” he said.

The researchers noted that an important part of the paper is that it is not claiming all people with autism – or their parents – are ‘impaired’. Instead, they said the study shows that parents who have children with autism – like the autistic subjects themselves – are different and do things differently.

Source: University of North Carolina School of Medicine

Distinct Face-Processing Strategies in Parents of Autistic Children. Ralph Adolphs, Michael L. Spezio, Morgan Parlier, and Joseph Piven. Current Biology. July 22, 2008: 18 (14)

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