Month: April 2006

When Clinical Trials Go Wrong

The journal Nature reports on a novel theory as to why trials of monoclonal antibody drug TGN1412 went badly wrong and left six men critically ill with massive organ failure and inflammation in March.

As Sciencebase has already reported, it seems there is no evidence of drug contamination, dosing problems, meaning the devastating effects were almost certainly caused by TGN1412 itself. So, why didn’t this show up in the preclinical animal trials?
Antibodies to be used as drugs are modified to have the same overall structure as a human antibody. The CD28 antibody receptor — which switches on immune cells, and was targeted by TGN1412 — is identical in humans and monkeys, so researchers thought that the drug would have comparable effects in the two species.

But crucially, the antibody’s ‘tail’, at the opposite end of the molecule from the CD28-binding site, may not be the same. Antibody tails are known to undergo a phenomenon called ‘crosslinking’, in which they bind to other antibodies and amplify the immune response. Some researchers believe this could have caused the human volunteers’ immune system to release a massive flood of inflammatory molecules called a ‘cytokine storm’, causing their organs to shut down within hours of taking the drug.

Thomas Hünig, co-founder of the company TeGenero, which developed the drug, told Nature that he agrees this could be what happened. The idea is supported by research on another super-antibody that activates the immune system in a similar way. Early tests in mice triggered an uncontrolled immune response. But tweaks to the antibody’s tail solved the problem, and the drug has now been approved for patients taking immunosuppressive drugs.

Nature

Alcoholic and Astronomic

A vast cloud of methyl alcohol, spanning some 463 billion kilometres and wrapped around a stellar nursery could help astronomers explain the formation of some of the most massive stars in our galaxy. Lisa Harvey-Smith revealed details of the observations at the Royal Astronomical Society’s National Astronomy Meeting on 4th April.

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David Bradley turns the spotlight on the astronomical revelations in this month’s Spotlight physical sciences webzine

Bird Flu Poll

H5N1 at last reached British shores this month and now both the Eastern and Western seaboards of the USA are on tenterhooks. In the spirit of serious scientific debate, I’ve posted a poll all about avian influenza on the SciScoop Science Forum.

So, are we all doomed to be tarred and feathered or is it just a load of media fluff and feathers? You decide.Meanwhile, check out SciScoop regular contributor Chad’s excellent ongoing posting on the bird flu story on SciScoop.

ET on the Other Hand

US researchers are hoping to develop a simple analytical technique that could be used on future space missions to probe for signs of life. The technique will seek out signs of extraterrestrial chirality.

Some molecules exist in handed, or chiral, forms. A left-handed form and a right-handed form. The building blocks of proteins, the amino acids, for instance, are chiral, as too are the proteins they form and even the genetic material, DNA, that codes for the proteins. Chiral molecules can also be made synthetically, several drugs are produced in just the left or right-handed form for improved efficacy and to reduce side-effects.

Life elsewhere in the solar system could reveal itself through its chiral activities. Find out more in the April issue of David Bradley’s Spotlight on PSIgate the physical sciences site.

Salmonella Shows its Mettle

Salmonella bacteria use RNA to assess and adjust magnesium levels, according to researchers at the Washington University School of Medicine in St. Louis. Eduardo Groisman and colleagues at WUSTL have added a new gene to the bacterium via a mechanism known as the riboswitch.

Riboswitches were first identified in 2002 and sense when a protein is needed and stop the creation of the protein if it isn’t. A riboswitch, does not rely on anything binding to DNA; instead, the switch is incorporated into messages for construction of proteins. These messages are protein-building instructions copied from DNA into strands of RNA. The riboswitch is a sensor within the RNA that can twist it into different configurations that block or facilitate the production of the protein encoded in the message.

Previously identified riboswitches respond to organic compounds such as nucleotides and sugars. The Salmonella riboswitch, reported on Friday in Cell, responds to magnesium ions, key elements in the stability of cell membranes and reactants in an energy-making process that fuels most cells.

“Magnesium ions are essential to the stability of several different critical processes and structures in the cell, so there has to be a fairly intricate set of regulators to maintain consistent levels of it,” says senior investigator Groisman, “To approach such a complex system, we study it in a simpler organism, the Salmonella bacterium.”

Groisman and his colleagues uncovered the magnesium riboswitch while they were investigating the MgtA gene, which is controlled by the major regulator of Salmonella virulence, the phoP/phoQ system. The MgtA gene codes for a protein that can transport magnesium across the bacterium’s cell membrane. Groisman’s group showed 10 years ago that the phoP/phoQ system controls when Salmonella makes MgtA.

You can read more about the work at the WUSTL site.

Blogging Tag Cloud

This post is no longer relevant as I switched tag cloud systems.

One aspect of the Sciencebase science blog that seems to be of perennial interest to regular visitors is the cloud of keywords to the right of the page. This tag cloud changes continually as new posts appear in the blog, shifting the emphasis on that part of the page between the various categories and subject areas that I cover.

So, how does it work, that’s the usual question from visitors. Well, it’s presumably obvious insofar as the size and shade of each keyword in the cloud reflects the number of posts associated with a particular tag. size and shade of each word reflects how many entries there are in my blog with a particular tag. Hence, chemistry is big and black because I’ve posted lots of chemistry entries whereas the word worm is small and so faintly gray as to be almost invisible as there are only very few entries with that tag. This particular post is in “Geek”, so it will have added a small amount of extra weight to that keyword in the cloud. Mouseover each tag in the cloud to see how many articles are available under that tag (I’ve not tagged up all articles though, so those are only numbers for those posts that have appeared since the switch to WordPress).

Anyway, lots of blogging software has plugins or builtin functionality to create such a tag cloud, so search the web for that phrase (tag cloud) together with the name of your blogger to find out how to add it. The Sciencebase blog uses the amazing Ultimate Tag Warrior together with a clever bit of extra coding in the template file to create this ephemeral and ever-changing menu.

September 2008 update: Sharp-eyed readers will have noticed the tag cloud has been missing for a while now. I disabled UTW some time ago and am now using Simple Tags and working my way through 1500 posts on Sciencebase to add useful tags and to resurrect the tag cloud at a later date. Watch this space.

Cat Flu Among the Pigeons

Dodgy mixed metaphors in Nature press releases aside, an important paper published this week and leaked by the media ahead of embargo expiration (tut, tut) reports how the first case of a domestic cat dying from the avian influenza H5N1 virus in Thailand in 2004 hit the airwaves.

Since then, numerous cases have emerged globally, including the death and euthanasia of 147 captive tigers fed virus-infected chicken carcasses. As feline fatalities increase scientists are now urging that the role cats might play in spreading avian influenza and the evolution of the virus ought to be reconsidered.

Albert Osterhaus and colleagues at Erasmus University in the Netherlands discuss the latest reports and experimental studies that underline the vulnerability of cats to H5N1 virus infection and the risks that cats pose to agencies fighting its global spread. They emphasise how cats can be infected with the virus through contact with domestic and wild birds, and then excrete the virus from the respiratory and digestive tract, sometimes transmitting infection to other cats. They also note that cats fed virus-infected chickens can be infected directly through the gut. This worryingly novel route for influenza transmission in mammals could be a serious cause for concern.

Despite this evidence, the authors argue that the impact of cats on the epidemiology of the avian influenza virus is still being overlooked by key organizations such as the World Health Organization (WHO).

The authors conclude that they cannot rule out the possibility of the virus mutating into a more dangerous strain in feline and other mammalian hosts, and suggest increased surveillance and precautions to be taken to prevent the virus leaping to humans.

More information in Nature this week.

Phishing attack or dodgy marketing

I just received an email purportedly from an academic publisher offering me the chance to win an iPod simply for taking part in a survey of my usage of their products. Fair enough.

But, when I click the survey link, the anti-phishing filter in my email program is tripped revealing the message to be a potential security risk. The reason? When one clicks the link to the survey, the link is apparently to “xyz321.con”, but the actual link is pointed to “uvw123.nob”. In other words, they don’t match, a discrepancy that is usually indicative of an internet fraud. Similar things happen with those “Validate your account” messages that appear to be from your bank, eBay, or Paypal, viz, click on something that looks like www.paypal.com and end up at a phishing page on www.abcxyz123.info or whatever.

To an inexperienced user, there is no quick and easy way to validate that the Springer email is genuine, so most would, I’d hope, follow their IT deparments didacts and simply delete the message as a phish.

If I were running such a marketing mail out, then I’d ensure the URL and anchor pointed to the same domain, in this case it would look far “safer” if both pointed to “publishersite.com” rather than some other obscure domain that is unrelated to the company’s genuine domain. This looks and is much safer for the end users and so would ensure a much high percentage take-up of the offer.

For more information on phishing and other computer security issues, I’d recommend you check out http://www.sciencetext.com where I host a stack of tech and security tips, just in case you haven’t got an IT department to offer the software and knowledge to back up those didacts.

Tuberculosis Waste Disposal Defeats Immune System

The first detailed structure of a crucial protein-cleaving component, the proteasome, commonly known as the cellular waste disposal unit, of the tuberculosis bacterium has been obtained by US researchers. The existence of a proteasome in this microbe, only hinted at previously, could offer new targets for drug research to treat the disease.

Read on…

For more science news with a spectral angle visit my spectroscopy news page.

Testing the Substitutes

Substituted pyridines are the starting materials in the manufacture of a wide range of chemical products from agrochemicals to pharmaceuticals.

As such, understanding the fundamentals of their structures is important in developing synthetic schemes for new compounds containing this component. Now, Indian chemists have used sophisticated analytical techniques to study the vibrational spectra of these compounds and have revealed nuances of the dynamics of such molecules for the first time.

Read the full story in SpectroscopyNOW.com