HDAC drugs for autoimmune diseases

Initially it may come as a surprise, but it turns out that some powerful cancer drugs also are useful against autoimmune diseases as well. A good example is the monoclonal antibody rituximab.

In this case the reason is that as a monoclonal antibody, rituximab binds to the protein CD20, which is widely expressed on B cell lymphocytes of the immune system. Once it has bound to the CD20 of a B cell, it may lead to cell death by apoptosis, which is helpful in the case of of B cell cancers such as non-Hodgkin lymphoma and B cell leukemia.

The general pattern here is that some kinds of cancer and some autoimmune diseases both involve the overactivity and proliferation of certain types of immune system cells. A drug that counteracts such pathology may be useful for treating both the associated cancers and autoimmune diseases.

T cells are another large and important class of immune system cells, which we've discussed before (see here). T cells can also be involved in cancer, such as another form of non-Hodgkin lymphoma called cutaneous T cell lymphoma.

There is an FDA-approved drug for this cancer, called vorinostat, also known as suberoylanilide hydroxamic acid (SAHA). We have also mentioned this before, because the compound is a histone deacetylase (HDAC) enzyme inhibitor. HDAC enzymes have the effect of turning off genes, so an inhibitor of a particular HDAC enzyme has the effect of allowing the genes to remain turned on. Some cancers develop because they cause the overexpression of a HDAC enzyme that then turns off genes which would otherwise suppress the cancer. So an inhibitor of the approriate HDAC enzyme boosts the expression of the affected cancer-fighting genes. This is how vorinostat works.

Certain types of T cells can also cause various autoimmune diseases if they get out of control. Normally these T cells should be kept under control by messaging molecules (such as Foxp3) produced by a special type of T cell called a regulatory T cell (T_reg cells). So when a condition develops where there is excessive and harmful activity of T cells, it it may be possible to counteract this by boosting the number or activity of T_reg cells.

And this is precisely what SAHA is apparently able to do – by inhibiting a HDAC enzyme, it raises T_reg cell activity to control the overactivity of other types of T cells, as found in inflammatory bowel disease and various kinds of transplant rejections.

New cancer drugs could help in autoimmune disease

A new class of drugs used to treat cancer might be effective at suppressing overactive immune systems in patients with autoimmune diseases like Crohn's disease, U.S. researchers said on Sunday.

"What we would be proposing would be a therapy that would enhance the body's own immune system's ability to regulate itself," said Wayne Hancock of Children's Hospital of Philadelphia, whose study appears in the journal Nature Medicine.

Hancock said drugs known as histone deacetylases inhibitors, or HDACs, which affect compounds involved in the growth and death of cancer cells, bolstered the production of cells that regulate the immune system in mice.

In one study, the drug helped reverse and prevent inflammatory bowel disease. It also prevented the rejection of heart transplants in other mice. And it stopped rejection of pancreatic cell transplants in other mice.

It's possible that SAHA (i. e. vorinostat, which is distributed commercially by Merck under the name Zolinza) could also work to treat other autoimmune diseases like rheumatoid arthritis. And who knows what other cancer drugs might also have such dual uses?

More: Cancer drugs could fight autoimmune disease

Tags: cancer, autoimmune disease, histone deacetylase enzyme

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Another highly radiation-resistant bacterial species

Perhaps you recall that just about a year ago research identified some of the mechanism by which what was long thought to be unique species of bacterium – Deinococcus radiodurans – managed to survive extremes of exposure to radiation and dessication.

Now it turns out that the species isn't so unique, and a distant relative also has exceptional durability, despite significant genetic differences:

Second Extremely Resistant Bacteria Sequenced Is Surprisingly Different From First

Researchers have completed the whole-genome sequence of Deinococcus geothermalis, which is only the second extremely radiation- and desiccation-resistant bacterium to be sequenced.

The first was for the Guinness World Records-holder Deinococcus radiodurans, which for 50 years has been the subject of extensive investigations aimed at solving the mystery of how this microbe and its close relatives survive immense doses of x-rays and gamma-rays.

Most surprisingly, many of the unique D. radiodurans genes that were strongly implicated in resistance over the last decade have turned out to be unrelated to its survival, and are not present in D. geothermalis.

However, now that complete genome sequences are available, it turns out that the genes they have in common to account for their durability are surprisingly few:

Using computer-based systems to compare the D. geothermalis genome sequence with the sequence of D. radiodurans, a minimal set of genes which encode extreme resistance was defined. Far fewer genes than initially believed appear to be responsible for the extreme resistance trait.

Among other things, this finding apparently rules out one possible source of the durability:

The phenomenal resistance of Deinococcus bacteria has given rise to numerous descriptions of their origin, including that they evolved on Mars under harsh cosmic radiation. The present analysis firmly places the origin of Deinococcus bacteria on Earth, where the evolutionary steps that led to their survival mechanisms clearly occurred in their terrestrial ancestors - most likely in a desert near you.

Tags: microbiology, extremeophiles

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You too can do particle physics

This is just a heads-up for folks who are interested in particle physics and/or highly-distributed computing projects, like the well-known SETI@home.

You too can do particle physics

Public involvement in the Large Hadron Collider, a particle accelerator being built in Switzerland, has received a boost with the relaunch of the LHC@home project, which allows users to donate computer time for LHC computing projects.

Researchers hope the project will help them fine-tune the LHC to shed light on what dark matter is and why particles have mass.

More: here

As most readers undoubtedly know, there are quite a few distributed computing projects of this sort, in which anyone can participate. Examples include projects dealing with climate prediction, gravitational waves, protein folding, and Mersenne primes.

For more information, see the Wikipedia articles on distributed computing and the list of distributed computing projects.

Tags: LHC@home, distributed computing

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Peptide YY and appetite

Just about three months ago we came, briefly, across the peptide called PYY (peptide YY), which has been known, for a few years, to suppress appetite. It has also been known that obese people secrete less PYY than non-obese people. On the other hand, attempts to use PYY directly as a weight-loss drug have not met with much success.

About a year ago, research showed that consumption of protein boosts PYY levels, and in that case there was some benefit to experimental subjects in terms of reducing hunger and promoting weight loss. This would help explain the weight-loss experienced with high-protein diets. Here's a press release on that research:

Eating Protein Boosts Hormone That Staves Off Hunger (9/6/06)

The amount of a hunger-fighting hormone can be increased by eating a higher protein diet, researchers report in the September issue of the journal Cell Metabolism, published by Cell Press. The hormone, known as peptide YY (PYY), was earlier found by the researchers to reduce food intake by a third in both normal-weight and obese people when given by injection.

"We've now found that increasing the protein content of the diet augments the body's own PYY, helping to reduce hunger and aid weight loss," said Medical Research Council clinician scientist Rachel Batterham of University College London, who led the new study.

Scientists have known that high-protein content meals make people feel more full and reduce food intake, resulting in improvements in weight loss and weight loss maintenance. However, the mechanism responsible remained elusive.

In a study in normal-weight and obese people, the researchers now show that enhanced-protein meals stimulate greater release of PYY than either high-fat or high-carbohydrate meals and result in a greater reduction of hunger.

Here's another report on that research: Hello Protein, Goodbye Fat (sub. rqd.) And an earlier article on the PYY controversy: New Data on Appetite-Suppressing Peptide Challenge Critics (sub. rqd.)

Now there are additional findings from the same lab that developed the results of a year ago. The findings indicate that a cortical brain center associated with reward and pleasure (the orbital frontal cortex) responds to PYY:

Brain 'hunger pathways' pinpointed (10/15/07)

The brain circuitry that influences how much food a person will eat – whether they feel starving or full – has been revealed by a new imaging study. The results may help target new treatments against obesity, say researchers.

Rachel Batterham at University College London, UK, and her colleagues have previously shown that a hormone called peptide YY or PYY, which is released by the gut in proportion how many calories we eat, is a powerful appetite suppressant. Previous experiments show that treating normal and obese subjects with intravenous PYY decreases food intake by up to 30%.

Batterham's team used functional magnetic resonance imaging (fMRI) to investigate how PYY affects the brain.

So research findings to date certainly indicate that PYY has very interesting, and quite possibly useful effects. It could be very interesting to watch for further developments involving PYY.

More information:

Appetite 'control centres' found

Gluttons can blame overeating on the brain

Appetite hormone works in two brain areas

Tags: Peptide YY, PYY, appetite, high-protein diet, orbital frontal cortex

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Algebraic number theory - index

This is a list of posts in the algebraic number theory series to date, oldest first.

1. A brief history of algebra

2. Numbers - rational and irrational, real and imaginary

3. Diophantine equations

4. Groups and rings

5. Fields and Galois theory

6. Modular arithmetic

7. Rings of algebraic integers

8. Rings and ideals

9. Uniqueness of factorization

10. Failure of unique factorization

11. Why do we care about unique factorization?

12. More concepts from ring theory

13. Factorization of prime ideals in extension fields

14. Splitting of prime ideals in quadratic extensions of ℚ, part 1

15. Splitting of prime ideals in algebraic number fields

16. Roots of unity and cyclotomic fields

17. Cyclotomic fields, part 2

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Tags: algebraic number theory

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Uniqueness of factorization

Time for another installment of the series on algebraic number theory. Check here for previous articles.

In this installment we're going to look at an important property that some rings (such as ℤ) have, although most rings do not. But it is a useful and important property for proving many number theoretic results, which is why one bothers to consider it. We'll illustrate that soon.

But first we need a little terminology. In any ring, a unit is a ring element that has a multiplicative inverse which is also in the ring. For instance, in ℤ 1 and -1 are units, and they are the only units. Other rings of algebraic integers can have many units, and the set of units of the ring form an abelian group under multiplication. Determining this group of units, in fact, is one of the interesting computational issues in algebraic number theory.

Another important concept is that of a prime element of a ring. A little bit of care is required to define "prime" in a general ring, but essentially a prime element is one that has no factors other than itself and units. As far as divisibility and factors are concerned, units are essentially irrelevant, since they are invertible.

One of the most important properties that the integers have as a ring is unique factorization. That is, for any n∈ℤ, there is a unique way (apart from order and unit factors) to write n as a product of primes.

This fact can be proven using the order properties of ℤ, i. e. for every pair of distinct positive integers a, b, exactly one of a<b, a=b, or a>b is true. To begin with, this implies that for any pair of positive a,b∈ℤ, we can write a=qb+r with 0≤q and 0≤r<b. Reason: you can subtract b from a only a nonnegative but finite number of times (q) before the result is negative. This is because every number in the sequence a, a-b, a-2b, ... is strictly less than its predecessor, and if a is finite, there are only a finite number of distinct positive integers less than a. r is simply the last quantity before you have a negative number, and so 0≤r<b. The numbers q and r are uniquely determined by this procedure, and in fact there is a simple algorithm to find them, as we'll see in a moment.

For any positive integers a,b∈ℤ, we can define the greatest common divisor of the pair as the largest (positive) integer which divides both, written gcd(a,b), or simply (a,b). It may be, of course, that (a,b)=1, in which case we say a and b are relatively prime. As a matter of notation, if one number m divides another n, so that n=mq for some q∈ℤ, we write m|n. If this is not the case, then we write m∤n. (a,b) can be defined by the conditions that (a,b)|a, (a,b)|b, and if both c|a and c|b, then c|(a,b).

The Greek mathematician Euclid, known best for his geometry, was interested in number theory also. In addition to proving that there are infinitely many primes, he also gave a simple algrorithm for computing the greatest common divisior of two integers without explicitly factoring them – since factoring can be a relatively difficult process for large numbers. The algorithm is called, of course, the Euclidean algorithm.

To apply it, assume (without loss of generality) that a>b and write a=q₁b+r₁. Here, q₁>0 and 0≤r₁<b. Provided r₁≠0 we can repeat the procedure and write b=q₂r₁+r₂. We can repeat this procedure as long as the remainder r_k isn't 0. If r_k is the last nonzero remainder, then one notes that (a,b)|r_k, because in fact (a,b) divides all such remainders in the process. But we also have r_k-1=q_k+1r_k, hence r_k|r_k-1 and from r_k-2=q_kr_k-1+r_k, we find r_k|r_k-2 too. If we proceed back all the way we find r_k|b and r_k|a, hence r_k|(a,b). Therefore r_k=(a,b). In other words, (a,b) is the last nonzero remainder in this process.

But even nicer things are true. Go back to a=q₁b+r₁, so that r₁=a-q₁b. Similarly, r₂= b-q₂r₁= b-q₂(a-q₁b)= Ma+Nb for some integers M and N (not necessarily positive). Proceding inductively, we have that (a,b)=Ma+Nb for some M,N∈ℤ. What this says is that a certain Diophantine equation can be solved for unknowns M and N if a, b (and hence (a,b)) are given. Note that if (a,b)>1, the equation d=Ma+Nb could not be solved if 1≤d<(a,b), because a solution would imply (a,b)|d.

We need one more fact about prime numbers. Suppose p is prime, and p|mn for some m,n∈ℤ. So by definition, mn=pq for some q∈ℤ. We claim that p must divide either m or n (perhaps both). For suppose that we don't have p|m, hence (p,m) can't be p. But p is prime, and (p,m)|p, so we must have (p,m)=1. Hence it is possible to write 1=Mp+Nm. Therefore n=n(Mp+Nm)=Mnp+Nmn=Mnp+Npq= p(Mn+Nq). In other words, p|n. This property possessed by primes in ℤ is not shared by "primes" in other rings of algebraic integers, as we shall soon see.

We now have all the facts we need to prove unique factorization in ℤ. The proof is done by supposing factorization isn't unique, and showing this leads to a contradiction. So suppose factorization isn't unique, and for some n there are two different factorizations of n (apart from units ±1). There cannot be any prime which occurs in one factorization but not the other, by the result of the preceding paragraph. Hence the same prime factors occur, but for at least one prime p we have n=Ap^r=Bp^s with 0<r<s, and (A,p)=(B,p)=1. Dividing through by p^r reduces to the case where a prime occurs in one factorization but not the other, which is impossible. The contradiction proves the desired result.

It may seem "obvious" that factorization is unique, because we are so familiar with the fact this is true in ℤ that it is taken for granted. It may therefore be rather surprising that in many (in fact most) rings of algebraic integers, factorization is not unique. Unique factorization is actually a very special and rare occurrence, and a great deal of algebraic number theory is concerned with either trying to compensate for this "problem", or else trying to describe, in some sense, just how badly factorization fails to be unique.

In the next installment we'll explain why unique factorization is a useful property and look at some examples.

Tags: algebraic number theory, unique factorization.

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A fear of pheromones

The following news item has me somewhat steamed:

Ban on Calif. Pesticide Spraying Lifted

The spraying of a pesticide to fight a crop-eating moth can resume after a judge said Friday he was satisfied with a government plan to address environmental and health concerns.

Earlier this month, Judge Robert O'Farrell issued a temporary injunction against the spraying on California's central coast amid concerns over the long-term health effects of CheckMate, which was first dropped in the area last month.

CheckMate is a pheromone spray developed specifically to keep the moth from mating without killing it.

The problem, of course, is that a pheromone is not a pesticide (such as DDT or any other). In common English usage the Latinate suffix "-cide" means killing something or someone. (E. g. "suicide", "genocide", "fratricide".) Pheromones do not kill, either moths or anything else (to the best of anyone's knowledge).

Why is this a problem? Because (in my opinion) it is irresponsible science journalism. And it has consequences. I happen to live in the affected area, and I know there is a lot of heated opposition to this spraying. But I think the opposition is misguided. People are up in arms because they have this general fear of the aerial spraying of strange "chemicals". And it is especially unhelpful for "journalists" and news agencies like the Associated Press, which ought to know better, to be putting out releases that misclassify pheromones as "pesticides".

To be sure, there might still be human or animal health issues associated with the spraying of pheromones. There are certainly some people who are sensitive or allergic to a lot of "chemicals". I do not know for sure whether there are such issues in this case, although it is claimed that "numerous state and federal agencies tested the product and all its ingredients and determined it was safe."

But I do know that the journalism in this case is seriously flawed, and is probably causing a lot of people to worry when they should not need to, simply by calling the pheromones "pesticides", when they are not that at all. Sometimes, not always, chemical sensitivities are psychosomatic. And this is much more likely if the chemicals involved are incorrectly called "pesticides".

Here's a press release from the US Department of Agriculture that says a bit more about the pheromone in question:

New Pheromone Sprayer Leads Amorous Moths Astray

For decades, apple and pear growers have "adorned" their orchards with hundreds of plastic dispensers that emit a chemical sex attractant, or pheromone, to disrupt codling moth mating. Now, thanks to Agricultural Research Service (ARS) studies in Wapato, Wash., growers could soon be spraying the pheromone instead.

Sadly, the Associated Press, even a few days later, was still putting out faulty journalism:

Gov. orders resumption of disputed apple moth pesticide spraying

Something the general population certainly doesn't need is more media confusion about scientific subjects from sources that demonstrate a lack of trustworthiness – and contribute to popular cynicism about journalism in general.

Update (1/18/08): This sort of journalistic malpractice continues: Calif. residents say moth spray dangerous

Residents of Monterey and Santa Cruz counties filed 330 formal complaints to the state related to the light brown apple moth insecticide spraying, and about 300 more complained to doctors or public interest groups, said a report by the California Alliance to stop the Spray, the Santa Cruz (Calif.) Sentinel reported Sunday.

And the same brief article also refers to the pheromone as a "pesticide". Does this sort of incompetence matter? Of course it does. It's quite likely that most of the complainers are reacting to journalistic reports of "pesticides" and "insecticides" rather than what was actually used. Sort of an inverse placebo effect. Misinform people that they've been sprayed with a "poison", and of course some will feel ill. Is it possible there was some real effect? Sure. Whatever substance is involved – including any number that are "organic" or "natural" yet allergenic – there are bound to be at least a few people who might have an adverse reaction. But this can only be greatly magnified by sloppy journalism.

Tags: journalism, pheromones, apple moth, cynicism

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