HAPPY BIRTHDAY, MOM!!!

 

80 (today) and still going strong…!!!

 

I love you!!!

 

Un bacione!!!

This morning I have a cat story to tell. About a month ago, I heard the unmistakable, heart-chilling sound of desperate kittens crying. The noise was coming from my next door neighbour’s terrace. I peeked over the wall and saw my neighbour, a very sweet elderly lady, wringing her hands in distress. With tears in her eyes, she told me that a young mother cat had brought her six kittens there a few days earlier but had not been near them since the day before. The kittens were about ten days old. My neighbour didn’t know what to do. Well, at that late hour, neither did I.

 

I spent a nightmare-ridden night, tossing and turning, worrying about those kittens.

 

Early the next morning, after visiting the kittens and making sure that they had indeed been abandoned by the mother (there are signs you have to look for: for instance, if they are dirty and smelly it means that the mother hasn’t been cleaning them, etc.). No doubt about it. They had definitely been abandoned. No time to be wasted.

 

I confess that I have never nursed any kittens. Before being abandoned, even my tiny Priscilla was already more or less weaned. How could I possibly manage to nurse SIX kittens with no previous nursing experience?

 

So I got on the phone. I called every single Florentine animal protection agency I could find in the phonebook and online. I called all the cat and dog kennels. Almost everyone was sympathetic but couldn’t help me. The only advice I got was that if I wanted to save those kittens I would have to nurse them myself (that would have been my last resort, by the way; I would simply have taken time off work).

 

Well, I was determined to save those kittens. I called my vet who told me to get in touch with the National Association for the Protection of Animals (ENPA)…the man who answered the ENPA phone told me very sternly that according to Italian law those kittens could N-O-T be moved. Under any circumstances. They had to stay right where the mother had left them.

 

“So wait, I have to let them die of starvation, is that it?” I retorted angrily. “There is nothing else you can do. The kittens cannot be moved, period. It’s the law, signora,” he told me. What kind of cruel law is that??? And this is supposed to be an animal protection agency??? But I didn’t have the time to argue with this guy.

 

Time was running out.

 

I hung up and finally got in touch with the “gattare,” who are mainly female volunteers that take care and feed the stray cat “colonies” in Florence. The very kind gattara I spoke with told me that she had a volunteer who just might agree to take on so many kittens. This was someone, she reassured me, who had already successfully nursed kittens that young. The gattara called me back within a few minutes, telling me that this woman, whom I will name Gianna, had said yes. Joy!

 

My very distraught neighbour was thrilled to hear this bit of news. Like me, she has never had to deal with kittens abandoned this early by their mother (my neighbour has eight adult cats of her own, by the way).

 

A word or two in the mother cat’s defence: I don’t think she had enough milk for all those babies. I read online that sometimes mother cats, especially inexperienced ones like this one, are overwhelmed by large litters and can abandon them. Nature is cruel, but there you go.

 

Anyway, Gianna, who lives with five cats, all saved from a cruel fate, arrived here soon after we spoke by phone and took the kittens home. During the first few critical days, she kept them wrapped up in a shawl and slept with them to keep them warm. She fed them every 3-4 hours and also treated them for intestinal parasites.

 

I am thrilled to report that they all survived.

 

Gianna has fallen in love with all the kittens, but mainly with the smallest and weakest one, a little white and orange tabby that she barely managed to save. She is going to adopt him and has found excellent homes for the others among her family and friends.

 

Gianna and I have been in touch by phone almost daily, and I am going to visit her and the kittens on Monday (I hope I remember to take my camera!). Oh, I have asked her to teach me how to nurse and wean kittens. She has enthusiastically agreed, so that if something like this happens again I will be equipped and prepared to take care of the kittens myself.

 

This is a case of abandonment by an inexperienced mother cat. I started to add a few paragraphs about the cruel but unfortunately common practice of abandoning pets before the summer holiday season, but I decided that this should be a celebratory post…so I want to end on a positive note, which is that the six kittens are alive and already doing what kittens do, playing and being mischievous and whatnot.

 

My heartfelt thanks to all the magnificent Giannas in the world!

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!