Margaret’s Corner

I have been super busy with work commitments in the past few days and haven’t had the time to do any research or write any posts. The company where I teach English, you see, had an important health and safety audit, and since the common language was English (the auditors were French and knew no Italian) I was asked to be the official interpreter.

There were some amusing moments, I have to admit (during which I couldn’t even crack a smile, of course), such as when we were in the company lab and one of the auditors remarked to the chemist in charge of the lab: So, you are responsible for the dangerous substances in the company. You are a professional, you are a chemical…  I just love it when things like this happen (oh, and by the way, over lunch I tried my rusty French on the auditors and made a few mistakes, perhaps even funnier than this one…yes, we had a few good laughs there…).

Getting to the less interesting business of my MRI results, I just wanted to say that they turned out fine. I have a few small hernias here and there and some age-related arthritis. Nothing new.

And in fact there have been “no substantial changes” since May of 2005, the date of my last spinal MRI. I am pleased.

I am also pleased to report that I have a new car. It’s a yellow FIAT Panda (see photo; it is parked in front of our house). I loved my old Mazda, too, but the brakes were beginning to…go. The FIAT dealership gave us a zero interest financial plan (can’t beat that!), which is the main reason we decided to go ahead and buy this car. Its colour, by the way, is “optimistic yellow.” Absolutely purrrfect for moi!

I’m thrilled to bits. I already adore my Panda. What a great car!

According to a recent Science Daily article (see: http://tinyurl.com/5v6xxo), researchers at Brigham and Women’s Hospital and Harvard Med School have discovered a molecule called resolvin E1 (RvE1) produced by the body from omega-3 fatty acids that helps resolve and prevent respiratory distress in laboratory mice. This molecule is found in cold-water fish (salmon, mackerel and, ugh, anchovies) and is produced by the body in response to the onset of inflammation. The abstract can be read here: http://xrl.us/kj8qf.

The experts still do not completely understand why fish oil is so effective against inflammation: increased levels of omega-3 fatty acids are associated with lower asthma prevalence in people, but the mechanisms to support that observation are poorly understood.

But the main thing is: omega-3 fatty oils are effective against asthma.

One thing led to another, and I found myself involved in a bit of research that I hadn’t intended to do (happens a lot to me…). Completely by chance, in fact, I came upon a study by a team of Japanese researchers on the same topic–asthma, mice and RvE1–a study published in March 2008 (see: http://tinyurl.com/6xaddo), that is, a few months before the publication of the study reported in Science Daily. The Japanese researchers discovered the exact same thing about RvE1.

So, just for the heck of it, I did a search on PubMed for RvE1 and asthma, and found another study (full version available for free here: http://tinyurl.com/5d64sa) published back in 2005 (!!!) on the protective anti-inflammatory effect of this molecule, and on the role it has in preventing (drum roll!) osteoclast-mediated bone destruction in periodontitis (= a severe form of gum disease).

Osteoclasts? Why, those are the hyperactive bone-destroyers in multiple myeloma…! At that point, I had a look at the full study, where I read that bone loss in periodontitis is caused by osteoclast activity. The researchers discovered that the animals (sigh) with periodontitis that were treated with RvE1 had only a few osteoclasts compared to the untreated ones. Conclusion: RvE1 inhibits osteoclasts. Well, well! (I just hope that the “animals” involved in this study were tiger mosquitoes…)

Another excerpt tells us that periodontitis has pathogenic features similar to those observed in other inflammatory diseases such as arthritis. And read this: Resolvins are a new family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammatory signals. Because it is now increasingly apparent that local inflammation plays a critical role in many diseases, including cardiovascular disease, atherosclerosis, and asthma, experiments were undertaken to evaluate the actions of the newly described EPA-derived Resolvin E1 (RvE1) in regulation of neutrophil tissue destruction and resolution of inflammation. The results were that RvE1, used as a topical pharmacologic agent, was found to prevent the progression of tissue destruction. 

Treatment with RvE1 was more effective and less damaging than the chronic use of antibiotics. Interesting. The researchers propose that regulating inflammation with molecules such as RvE1 is a rational new therapeutic approach to the treatment of osteoclast-mediated bone disease. Aha!!!

It turns out that there are 32 studies in PubMed on RvE1. The earliest study dealing with the specific anti-inflammatory activity of these so-called resolvins, as far as I can tell, dates to 2004. But the above-mentioned Science Daily article led me to believe that RvE1 was a startling NEW discovery. Why would that be? Well, I have learned my lesson. From now on, whenever I see exclamations such as “exciting new discovery…,” I will do a background check. There just might be a less publicized precedent…as happened with the IRF4 studies…

Now for my own personal experience. I have suffered from asthma for years. I know the main source of my trouble: cats. I am very allergic to cats, but I am also a huge cat-lover (life is unfair, sometimes…!) and now have four cats. When Stefano and I went to Northumberland in April I didn’t have one asthma attack, not even with all the walking we did. I didn’t use my cortisone inhaler or my Ventolin. Why? No cats. Simple.

My non-cat loving friends think I’m nuts. They don’t understand that the benefits of having cats in my life far outweigh the inconvenience of having to use a cortisone inhaler once a day (I would like to mention that in the pre-curcumin period I was much worse off, and used cortisone and Ventolin quite a lot).

Recently, though, I haven’t needed to use my inhaler. As for Ventolin, well, I haven’t used it in a long time. Is it a coincidence that I have started taking a fish oil supplement in recent months? After reading about RvE1, I think the answer to that question is ”no.” 

So my fish oil intake is probably inhibiting my overly eager osteoclasts…and it has gotten rid of my asthma…at least for now…

Hey, that means I can adopt another cat! Hehe…just kidding! (or am I?)

For an introduction to IRF4 please see my June 27^th post. Now, let’s see, the full “Nature” study starts with a discussion of a genetic method to identify therapeutic targets in cancer in which small hairpin RNAs (shRNAs) that mediate RNA interference are screened for their ability to block cancer cell proliferation and/or survival. The researchers used myeloma cells lines from three molecular subtypes.

Hairpin whaaats? Molecular subwhaaaats? I had to look up all this stuff even though I suspected that the latter had to do with all the different types of myeloma (truth be told, I didn’t find out that there were different types of myeloma until quite recently…in fact, before my diagnosis, I used to think that leukaemia was just one type of cancer…who’d ever heard of Hairy Cell Leukemia, Acute Myelogenous Leukemia or Acute Megakaryocytic Leukemia? Indeed, come to think of it, who’d ever heard of…Multiple Myeloma??? Ahhh, how things change…). Anyway, I found a lot of information about different myeloma subtypes online. I am not going to bother with small RNA hairpins…I never use hairpins anyway…well, okay, I used ‘em on my wedding day, nine years ago…but that is IT!

Myeloma subtypes. A UAMS communication (http://tinyurl.com/ssheh) tells us that in 2006 seven genetic subtypes of myeloma were identified among 414 myeloma patients. Of those seven subtypes, four were associated with better patient outcomes following high-dose chemotherapy and a stem cell transplantation. Ok, but what happened to the other three? I am curious. At some point I really should take a look at the full study, which is available for free online: http://tinyurl.com/3eqm6l

I also read the presentation (see: http://tinyurl.com/3efgjp) given by Dr. Rafael Fonseca at the island of Kos 2007 International Myeloma Workshop. Myeloma, he says, is not a homogenous type of cancer, but many well defined variants exist. And these variants can best be examined by looking at genetic/cytogenetic markers. The idea is that genetic testing should be useful in figuring out what kind of treatment would be the best for a particular subtype. Targeted treatment, in other words. Interesting concept…that we will come across again later…

Back to the IRF4 study. It is very technical, and I confess that I got lost at times among the various translocations and missense substitutions and fourth introns and coding regions…but a few things were clear, such as the following: The knockdown of IRF4 killed ten myeloma cell lines, but had a minimal effect on five lymphoma cell lines. Knockdown, by the way, is simply a technique used to reduce the expression of one of more genes. For instance, remember the mutant tumour-suppressor p53? Well, when this evil mutant form is “knocked down,” cancer cells become less aggressive. Anyway, the upshot is that ten myeloma cell lines were annihilated when IRF4 was knocked down. Excellent!

The researchers point out that the myeloma cell lines they tested bear many of the recurrent genetic aberrations typical of this cancer, including genetic abnormalities that activate the NF-kB pathway. Ah. So here we have another thing that triggers the infamous NF-kB…good to know, I suppose (sigh). Reading this study made me wish to have more genetic testing…this may be another matter I will discuss with my haematologist this fall (as much as I hate BMBs, it might be worth having another one…).

Back to the study. The myeloma lines tested were like drug addicts badly in need of a fix, which was provided by a perfectly normal (not aberrant, that is) IRF4. The researchers wanted to understand the molecular basis for this dependence, so they looked at genetic changes in the myeloma lines after IRF4 was knocked down. They noticed that 308 genes became down-regulated (down-regulation is the process whereby a response to a stimulus is reduced or suppressed. For instance, curcumin down-regulates the hyperactive transcription factor NF-kappaB in cancer cells).

The researchers then examined normal haematopoietic (= blood or blood-forming) cells that require high IRF4 expression, including plasma cells […] and dendritic cells, and found that IRF4 regulates a broader set of genes in myeloma than in individual haematopoietic subsets. So myeloma gives IRF4 the chance to expand its standard genetic network. And Mr. Normal Nice Guy IRF4 thus becomes Mr. Normal But Not So Nice Guy IRF4.

The paragraph continues: Roughly one-quarter of the IRF4 target genes in myeloma were upregulated in activated B cells but not plasma cells, including genes known to be important in cellular growth and proliferation, such as MYC. I looked up MYC on Wikipedia and discovered that the mutated or over-expressed form of this gene can cause cancer. 

I also found the following: Myc is activated upon various mitogenic signals such as Wnt, Shh […]. Activated by Wnt and Shh…wait a sec, those are signaling pathways that are crucial for the survival of cancer stem cells! Could cancer stem cells somehow be involved, here? There is no mention of cancer stem cells in the study so I have no way of answering that question. The more I think about it, the more it seems doubtful…oh well.

Anyway, according to the IRF4 study, MYC has a prominent role in the pathogenesis of myeloma. But when the activity of IRF4 was reduced, the levels of MYC mRNA also decreased by more than twofold in myeloma cell lines and caused MYC DNA-binding activity to decrease in nuclear extracts of myeloma cells. So it would seem that if you block IRF4 you also block MYC (and vice versa), and this process will eventually lead to the death of myeloma cells.

The researchers also discovered that IRF4 and MYC are co-dependent: Our data suggest that the oncogenic activation of MYC in myeloma upregulates IRF4, which in turn drives expression of MYC and other IRF4 target genes. A vicious cycle, in other words. Probably not an easy cycle to interrupt, I would imagine.

Another interesting sentence: […] the dependency of myeloma on IRF4 may be best described as ‘non-oncogene addiction’; that is, the aberrant function of a normal cellular protein that is required for cancer cell proliferation or survival. The loss of IRF4, they add, results in ‘death by a thousand cuts’. I like the sound of those last five words!

Another important observation: the reduction of the activity of IRF4 by only 50% (!!!) is enough to kill myeloma cells without harming healthy cells: a ~50% knockdown of IRF4 mRNA and protein was sufficient to kill myeloma cell lines. Wow.

The researchers are optimistic. At the end of the study they speculate that an IRF4-directed therapy might kill myeloma cells while sparing normal cells, and hope that IRF4 can be exploited as an Achilles’ heel of multiple myeloma. Too early to tell…but interesting.

Cancer symposium. It just so happened that yesterday an international symposium on cancer genotypes and phenotypes (see: http://tinyurl.com/6dxpnv) took place right here in Florence. Today is the second (final) day of the symposium. I found out too late to attend the session that was open to the public yesterday afternoon but watched a local news report last night indicating that the current tendency in oncology is to move away from toxic treatments in favour of targeted treatments based on a molecular approach (aha!). You can read the symposium program here (circadian rhythms were also discussed!): http://tinyurl.com/6hv2oz

Exciting times…!

I am going through the full IRF4 myeloma study for the umptieth time, but it has been sizzling hot in Florence today, and I confess that I have not felt inspired (to revise my IRF4 draft etc.). Today the heat wave that has been plaguing Florence for way too long reached the level of Red Alert or Stage 3 (again!). Ah yes, it’s HOT. Hot and damp. We are lucky to live in a green area of Florence, but even so we are not happy campers. My cats are even less happy, even though Peekaboo looks quite perky in this photo that I took of her yesterday.

Well, life goes on…in spite of the heat.

Yesterday afternoon I went to a downtown clinic to have an MRI of my spine. Unlike last time (2005), though, I didn’t fall asleep only to be startled awake at a certain point by a rather loud snort…well, ok, by my very own loud snort, hehe! I mean, REALLY, Margaret…snoring inside the MRI machine…!

No, this time I was slid inside a different machine. Unlike the 2005 MRI machine that was open at the sides, this was a closed machine that looked like a slender and long space capsule (I have read that the results from an open MRI are less accurate, by the way).

I didn’t mind the fact that it was closed. What I did mind was the tremendous NOISE: it was like being right on the stage of a very loud punk rock/heavy metal concert…not my favourite kind of music, either…boomboomboom! I wore ear mufflers provided by the very considerate MRI technician who also put a cushion under my legs so I would be more comfortable. But even with the mufflers, the noise was deafening.

When the noise began, I thought I might have to keep calm by doing some deep abdominal breathing but, as it turned out, I was quite relaxed through the entire procedure, which took about 40 minutes. To distract myself from being bored to bits, from the noise and also from the heat that I started feeling under my back (heat generated by the machine, not the weather this time…), I visited a few of the “happy places” in my mind. In other words, I meditated.

At the top of my “happy place” list is definitely Farne Island, Northumberland, UK. That’s where Stefano and I went last April mainly to see the puffins (see my blog header photo of a puffin; I took that photo, btw). That is where I experienced something that I can only attempt to portray as pure happiness…standing in the middle of the island with puffins whizzing all around and above me. Yes, pure bliss. The feelings I experienced on Farne Island were and are beyond description. And ever since then, whenever I meditate and decide to “visit” a happy place in my mind, that happy place is always Farne Island.

Anyway, mainly thanks to the powers of meditation, the MRI was no big deal. As I mentioned, perhaps a bit on the boring side (now, why can’t DVD players be installed inside those things? I wouldn’t have minded watching a bit of the BBC “Pride and Prejudice” series again…or of “Chocolat”…or even listening to some soothing classical music…).

MRI results next week. No worries!

Off and on during the past few months, there has been a bit of discussion on the MMA listserv about a cancer treatment (considered by some to be controversial) developed by a team led by Zheng Cui, Ph.D., at the Wake Forest University Baptist Medical Center. This treatment came up again as a topic in the past few days, too, and it just so happens that yesterday morning I read a pertinent Science Daily article (http://tinyurl.com/5qzdo6) and today decided to write a post about it even though I don’t have much time.

The following explains the procedure in a nutshell: The treatment will involve transfusing specific white blood cells, called granulocytes, from select donors, into patients with advanced forms of cancer. A similar treatment using white blood cells from cancer-resistant mice has previously been highly successful, curing 100 percent of lab mice afflicted with advanced malignancies. Curing? One hundred percent? Advanced malignancies?

A bit of background (http://tinyurl.com/4hysuz). In 1999, Dr. Cui and his team of researchers discovered by chance, it seems, a cancer-resistant mouse. This mouse remained healthy even when repeatedly injected with a particularly lethal form of cancer. The wonder mouse’s cancer-resistant trait was inherited by its babies, too. How about that for a shocker?!

Another shocker: the Wake Forest team subsequently determined that the mouse’s white cells cured, I repeat, cured advanced cancers in other lab mice. Yes indeed, this cancer-killing ability can be transferred from one mouse to another.

Well, it turns out that a similar cancer-killing activity, or CKA, is also present in the white blood cells of some human beings. That would explain why some people exposed to toxic crud of all sorts (surprisingly) don’t ever develop cancer, whereas people living the healthiest lifestyles possible do. The researchers postulate that some people may have a diminished activity of cancer resistance…an activity that could possibly be restored. Restored? Wow!

The team has already tested different groups of human beings and discovered that there exist different CKA levels. As expected, people with cancer have lower CKA levels than healthy people. The levels decrease with age, during the winter and in stressful periods (another good reason to avoid stress and, I suppose, to be happy, sigh!, about the horrendous heat wave that has hit Florence these days…).

Anyway, Wake Forest is getting ready to conduct a human clinical trial titled “Leukocyte Infusion Therapy Clinical Trial,” or LIFT for short. The idea is to inject cancer patients with white cells taken from healthy folks whose white cells possess sky-high CKA levels (lucky dudes!).

On the Wake Forest website (http://www1.wfubmc.edu/LIFT) you will be able to read more details, such as the background scientific research and the call for cancer patients/healthy volunteers to participate in the upcoming clinical trial.

I had a question in my mind about graft-versus-host disease, and found out that this issue will be addressed during the clinical trial: Donor granulocytes per se are not known to produce TA-GVHD.  However, granulocytes collected via apheresis may contain with some donor T-lymphocytes that in some rare occasions can produce various degrees of TA-GVHD in some individuals, especially the recipients with immune suppression. Well, that would seem to exclude us myeloma folks from being able to try this procedure, eh…

But hey, it is too early to reach any conclusions. I really hope that the results of the human trial will be the same, or even better!, than the mice experiments. And that there will be no hint of GVHD! Yeah!

Cancer-resistant humans, who would ever have thought that possible, except in a science fiction movie? Remarkable, simply remarkable…

In my June 11 post I mentioned reading about two compounds that effectively eradicate AML at the bulk, progenitor and stem level: celastrol and 4-hydroxy-2-nonenal or HNE (AML stands for acute myelogenous leukaemia, by the way). Well, thanks to Sherlock , I was able to read the whole University of Rochester/University of Pennsylvania study. The abstract can be seen here: http://tinyurl.com/6ltvw5

The full study begins with an acknowledgment of the importance of cancer stem cells, or CSCs, for studies of basic tumor biology and the development of improved therapies. Like normal stem cells, CSCs are thought to reside at the apex of a developmental hierarchy and are responsible for the continued growth and expansion of bulk tumor populations. Consequently, the biological activity of CSCs may contribute to initiation, maintenance, and relapse of at least some forms of cancer. Yes, this sounds all too familiar…

The researchers further comment that several studies have shown that AML stem cells (AML-SCs) are refractory to commonly used clinical agents such as cytarabine and anthracyclines, thereby further supporting the hypothesis that malignant stem cells represent a probable reservoir from which disease relapse may occur. In vitro studies, they continue, have shown that the combination of the chemotherapeutic drug idarubicin and the proteasome inhibitor MG-132 can effectively eradicate leukemia stem cells via a mechanism involving concomitant inhibition of nuclear factor-kB (NF-kB)–mediated survival signals and induction of oxidative stress.

Then they discuss parthenolide (PTL), a substance that can ablate AML-SCs as a single agent. As a single agent, mind you! Impressive. They add that the SC-killing mechanism is similar to the one used by the idarubicin and MG-132 mixture, and that is: combined inhibition of NF-kB and induction of oxidative stress, thus indicating that common biological principles underlie the anti–AML-SC effects of these agents despite their chemical diversity.

The researchers decided to explore other AML stem cell killing possibilities using gene expression signatures. They examined the natural antileukemia characteristics of PTL, which has been shown to induce very potent and specific effects, mediating rapid death of AML-SCs, but not normal hematopoietic stem and progenitor cells, looking for other substances that provoke a similar response in cancer stem cells. They then tested those compounds against AML stem cells.

For this purpose, they used the GEO or Gene Expression Omnibus, a sort of humongous gene expression warehouse. To their surprise, they found a recurring and chemically diverse group of compounds that mimic the PTL gene expression pattern and, like PTL, are capable of ablating AML cells at the bulk, progenitor, and stem-cell level. The sentence that follows is also important: As with PTL, the mechanism of action for these new compounds involves concomitant inhibition of the NF-kB survival signal and induction of oxidative stress, suggesting their general importance in targeting AML stem cells. Sorry to keep repeating “NF-kB plus oxidative stress,” but this is a crucial point, methinks.

The researchers identified and tested four compounds, including the two that I mentioned the other day and that inhibit NF-kB and proteasomes. These two were found to have molecular characteristics comparable to those of PTL. I should note that these compounds, while known for their anticancer activity and for their ability to inhibit NF-kB, had never before been tested for their specific ability to target leukemic stem cells.

By the way, the other two compounds, gedunin and hemin, did not target the AML stem cells and were therefore discarded.

In conclusion, this study is remarkable not only because of the discovery of two new compounds that exterminate AML stem cells, but also because a gene expression database was used to identify potentially useful compounds. Very very interesting approach…

The multiple myeloma patient support list (MMSupport) has been buzzing with a bit of news that you can read about on the National Cancer Institute website: http://tinyurl.com/6rwjx8

In a nutshell, our myeloma cells rely on the activity of a single protein, IRF4, for the activation of a wide range of genes responsible for cell survival and spread. Blocking the production of this protein can be strikingly effective in eliminating cancer cells in laboratory models of multiple myeloma. “These findings reveal a hitherto unknown and, for myeloma cells, critical network of gene activity centered on this one protein,” said Louis M. Staudt, M.D., Ph.D., deputy chief of the Metabolism Branch at NCI’s Center for Cancer Research. “What we have now is a new window of opportunity for therapeutic development in multiple myeloma.”  The abstract of the June 22^nd “Nature” study can be read here: http://tinyurl.com/47ay24

IRF4 is not a mutant form, by the way, but its ability to activate normally inactive genetic programs inappropriately is crucial for the survival of myeloma cells. So, by blocking IRF4, we should be able to kill our myeloma cells. Would this include our myeloma stem cells? Well, that is not clear in the news release. Perhaps there is a mention of this in the full study.

Speaking of which, my dear Sherlock sent me the full study, but I haven’t had time to read it yet. I will print it out and read it at some point tomorrow and then post about anything of interest, ah, but not until Sunday at least, since tomorrow my brilliant husband is going to check my computer and almost certainly take it apart in order to change or fix a few components that have been misbehaving recently. This means, by the way, that I will be offline (e-mail included) for most if not the entire weekend.

Anyway, I also wanted to mention that the IRF4-myeloma connection does not really appear to be a “new” discovery. There may, of course, be some new findings (I won’t know until I read the full 2008 study), but if you search PubMed you will find an IRF4-myeloma study (see: http://tinyurl.com/5cwqzv) published in “Nature Genetics”…in 1997. More than ten years ago, that is…no comment…

Now I just have to do some research to find a natural inhibitor of IRF4. By the way, if anyone finds out something in this sense, please let me know. Thanks! Oh, have a great weekend, everyone!

Last year I found a mouth-watering recipe for chocolate mousse on Debra Fioritto Weber’s Guide to French Cuisine website. I have tried this recipe again and again on friends and family members, and “first-timers” have always been completely taken aback when I inform them that the mousse has no added sugar. I repeat, no added sugar. The only sugar in this recipe is contained in the type of chocolate that you use. Therefore, the darker the chocolate, the better. And by omitting sugar, you can enjoy this mousse without worrying about feeding your myeloma or cancer cells. All you need for the recipe is: fresh whipping/heavy cream, good quality dark chocolate, a bit of salt (a bit of salt enhances the flavour of the chocolate) and a teaspoon of liquid vanilla or a liqueur of your choice.

The following will make enough (?) mousse for four people:

1. Heat 1/3 cup of whipping/heavy cream over high(ish) heat until it (almost) boils.

Finely chop 5 oz. (150 grams) of bittersweet or semi-sweet chocolate. I use very dark chocolate to minimize the sugar content.

Now, Debra tells us to pour the hot cream over the chopped chocolate and whisk until the chocolate is completely melted and smooth, and I know this is a common method used by patisserie chefs, but when I am in a hurry I just add the chopped chocolate to the cream heating up on the stove. I haven’t found that it makes a huge difference in terms of taste and consistency. Just make sure that you end up with a smooth and shiny mixture. Important: allow the chocolate cream to cool.

2. Once cooled, add 1/8 of a teaspoon of salt  and also a teaspoon of vanilla extract (or a liqueur of your choice, just to give it a nice aftertaste). I make my own vanilla since it’s not a typical Italian sweet flavouring (not in liquid form, anyway).

3. Beat one cup of whipping/heavy cream (if you want a less solid mousse, use slightly more cream) until stiff peaks form. Add the cooled chocolate mixture slowly and beat on low speed until the mixture forms soft peaks. This will take a few seconds. Don’t overbeat, or the mousse will be too firm.

Pour the mixture into a pretty bowl or whatnot and chill until ready to serve. You can garnish the mousse with shaved chocolate curls, raspberries, mint leaves and so on. I suppose I should have thought of taking a photo of the mousse that I prepared yesterday, but my girlfriends came over to play cards after dinner, and between a laugh and a giggle we managed to polish off most of it. Oops!

Anyway, enjoy! And please send me feedback if you try this recipe. Thanks!

I receive all sorts of daily alerts and newsletters. Frequently I am simply overwhelmed with too much information and don’t have the time, unfortunately, to examine it all. Including, I regret to say, some of my blog readers’ links. Well, I do my best! If only I could teach my cats to use Internet…!

Anyway, yesterday was the birthday of Florence’s patron saint, St. John the Baptist, so I didn’t go to work (in fact, the company was closed on Monday as well, which made this a four-day holiday, hurray). Since Florence is one of the hottest cities in Italy this week (yesterday we had a Stage 3 heat wave alert, and I think we are still in the red zone today…feels like it, at any rate!), I was happy to stay inside under my ceiling fan and do some catching up, reading and writing. So glad I am NOT a tourist in Florence today…

Curcumin, obesity and diabetes. One of the items I read was a Eureka alert (http://tinyurl.com/4qzjre) on curcumin and diabetes. A group of Columbia University Medical Center scientists lead by Dr. Drew Tortoriello, an endocrinologist, discovered that turmeric-treated mice were less susceptible to developing Type 2 diabetes, based on their blood glucose levels, and glucose and insulin tolerance tests. They also discovered that turmeric-fed obese mice showed significantly reduced inflammation in fat tissue and liver compared to controls. They speculate that curcumin, the anti-inflammatory, anti-oxidant ingredient in turmeric, lessens insulin resistance and prevents Type 2 diabetes in these mouse models by dampening the inflammatory response provoked by obesity. I am now curious to read their results, to be published soon in “Endocrinology.”

Very interesting topic. My glucose levels are perfect, but they have always been within the normal range, so I can’t say that I have noticed a huge difference. Yes, a bit lower compared to before, but I doubt there is much statistical significance.

And the link between inflammation and obesity is also interesting: Curcumin administration was also associated with a small but significant decline in body weight and fat content, despite level or higher calorie consumption, suggesting that curcumin beneficially influences body composition.

I am going to try to keep an eye on the work of these scientists because they are exploring novel methods of curcumin administration to increase its absorption, and are also interested in identifying novel anti-inflammatory processes invoked by curcumin and in adapting those processes in the development of more potent curcumin analogues. Yeah!

Drink coffee! Another item of interest to those of us, especially women!, who drink coffee is that apparently we will live longer. Have a look at this HealthDay article: http://tinyurl.com/3kojwq Okay, you may well object that this holds true probably only for healthy folks since all the Spanish study participants were free of heart disease and cancer, but hey, every little bit counts. And besides, I will never tire of repeating this!, caffeine inhibits angiogenesis, an important tumour-feeding process.

Another bit of recent research shows that drinking coffee lowers your risk of developing type 2 diabetes.

Okay, so myeloma may kill me in the end, but these studies indicate that thanks to my coffee and curcumin intake I will die without a trace of diabetes and probably with a healthy heart. Small consolation, perhaps…but after all, chi s’accontenta, gode (I found a not-very-good English translation of that Italian saying: there’s no point in complaining…). Eh!

Sherlock (grazie!) came across and sent me a study by Carol Ann Huff and William Matsui recently published in the “Journal of Clinical Oncology” (June 10 2008) and titled “Multiple myeloma cancer stem cells.”. The abstract can be viewed here: http://tinyurl.com/4yx38s

The full study tells us that most myeloma cells are mature and quiescent and lack the ability to clone themselves. The fact that the majority of plasma cells are quiescent suggests that tumor growth is restricted to a specialized cell population.

A bit of history. In the 1970s Salmon and Hamburger showed that more than 86% of tumor samples from patients with multiple myeloma were capable of colony formation, and clonogenic growth occurred at a frequency of 1 in 100 to 100,000 cells. This could be explained by one of the following hypotheses: 1. only a small, functionally unique, subset of cancer cells was able to clone itself or 2. all myeloma cells can clone themselves, but only a few express this property at any point in time.

From what I wrote in my second paragraph, we can figure out that Huff and Matsui believe that hypothesis 1 is correct. Based on scientific data, they suggest that myeloma stem cells are clonotypic B cells: The ability of clonotypic B cells to recapitulate multiple myeloma in immunodeficient mice suggests that these cells represent the cancer stem cell in multiple myeloma. This part wasn’t easy to follow, but basically some features of clonotypic B cells are similar to those of healthy adult stem cells, such as resistance to toxic injury, and the continual risk of relapse among patients treated with standard therapies suggest that myeloma stem cells should also be relatively drug resistant. They can also self-renew and give rise to differentiated effectors (ie, plasma cells).

The scientists tested various novel chemotherapy drugs recently approved for the treatment of myeloma. The myeloma cancer stem cells were relatively resistant to both standard cytotoxic compounds and novel agents in vitro compared with the myeloma plasma cells. This suggests that these drugs work against the bigger population of myeloma cells, the ones that don’t have a cloning ability, but have no effect on the smaller population of stem cells. Nothing new here.

For the more scientifically-minded, here are a few comparisons between myeloma stem cells and normal ones: it appears that myeloma stem cells display properties common to normal stem cells, such as expression of membrane-bound drug transporters, intracellular detoxification enzymes, and quiescence. Thus, the chemoresistance of cancer stem cells may be mediated by multiple processes similar to those that protect normal stem cells.

The paragraphs that follow deal with therapeutic ways to target myeloma stem cells. For instance, as we know, the aberrant functioning of the Notch, Wnt and Hedgehog pathways is fundamental for the well-being of myeloma stem cells. These pathways therefore represent a good target. Let me add that we have non toxic ways to affect these pathways: curcumin, cyclopamine (by the way, I just read that a new water-soluble form has been developed!), zerumbone, DMAPT…

Then we are immersed in a discussion concerning telomerase activity…mamma mia, I confess I had to resort to parts of my brain that I never thought I possessed (!) in order to attempt to understand this section…not easy stuff! But, in essence, telomerase activity is an important process in myeloma, and its inhibition means that myeloma stem cells end up not being able to clone themselves. So, telomerase becomes another target.

Another promising target seems to be SOX2 (I wrote a post and page about SOX2 a while ago, by the way), an embryonic transcription factor that is normally turned off after embryonic stem cells differentiate; however, in both MGUS and myeloma patients it becomes reactivated (hah! Figures…).

Anyway, even if you don’t understand what this all means (as I don’t, to be honest), the point is this: SOX2 antibodies are present in folks with MGUS but not in those with myeloma. If you are lucky enough to possess those antibodies, you are less likely to develop myeloma. So targeting SOX2 could be another way to injure the myeloma stem cells, since, as Huff and Matsui write, SOX2 is a feature of clonogenic myeloma cells, and stimulation of anti-SOX2 immunity could limit clonogenic tumor growth of primary samples in vitro.

The development of new evil-stem-cell-focused treatments won’t happen overnight. That much is clear. New trial designs that incorporate novel end points will be needed to study myeloma stem-cell–targeted therapies. One potential strategy is to incorporate these approaches with existing therapies to determine whether they prevent tumor regrowth and prolong the duration of remissions after cytoreduction with chemotherapeutic or novel agents.

The researchers admit that the exact phenotype of the clonogenic cell has not been definitively established and controversy remains. Resolution of the controversy will probably depend on how well patients respond to stem-targeted treatments (read: on long-term outcomes…). Time…time…

The study ends as follows: growing knowledge regarding the basic biology of multiple myeloma, such as the identification of prognostic categories based on cytogenetic alterations or transcriptional profiling may allow multiple myeloma to serve as a model system to address general questions regarding cancer stem-cell biology.

As a myeloma patient, I confess that I (selfishly) don’t care that much about setting up a model system. I care much more about getting the promising, non toxic, stem-cell-targeting treatments into clinical trials as soon as possible. I’m ready and willing to try them!

So, where do I sign?!!!