That’s one of my favourite movies. Yesterday I discovered that, in addition to being an organic farm with 300 hectares of land and 20,000 olive trees (!), the former convent where we took my parents for lunch yesterday has been the set for many films, including Room with a View ! Fancy that. This huge complex is located on a hill above Florence, only a 10-minute drive from our house, yet we have never been or even eaten there. Yes, we have passed it a number of times on our way to Fiesole, but never stopped to check it out. Then, just a few days ago, we read a write-up about it in an Italian gourmet magazine and thought it would be a good place to have a birthday celebration. And it was! Well, well. I still have a lot to discover about my own city, it would seem!

The food was quite decent, but the best parts were:

1. the view of the hills from the loggia where we ate, and

2. the sight of two pairs of swallows busily and oh so quickly! feeding their hungry offspring in two different nests. One nest (the one in the photos) had been built under the rafters, the other was sitting right on the alarm system box over in a corner of the loggia. (I hope that alarm never has cause to go off!) These photos give an idea of what the little birds looked like right before and after a feeding. I just love the facial expressions! I was totally mesmerized, and almost didn’t eat my lunch!

After lunch, my Mom and I took a look at the 15th century cloister, and came upon a fresco, the Madonna della Misericordia, by Spinello Aretino. The icing on the cake! Okay, I have some research to do, so, ciao a tutti!

Today is my Mom’s birthday. We have made lunch reservations in a country trattoria–a small family-owned restaurant–which has a loggia overlooking fields and hills (your typical lovely Tuscan scenery) and, in the distance, Florence. It’s our birthday surprise for her. I don’t have much time for research today and wasn’t actually going to post anything, but a close friend (thank you!) sent me this joke, which has an excellent food-for-thought message, so here goes:

A man and his dog were walking along a road. The man was enjoying the scenery, when it suddenly occurred to him that he was dead. He remembered dying, and that the dog walking beside him had been dead for years. He wondered where the road was leading them. After a while, they came to a high, white stone wall along one side of the road. It looked like fine marble. At the top of a long hill, it was broken by a tall arch that glowed in the sunlight. When he was standing before it he saw a magnificent gate in the arch that looked like mother-of-pearl, and the street that led to the gate looked like pure gold. He and the dog walked toward the gate, and, as he got closer, he noticed a man sitting at a desk off to one side.

When he was close enough, he called out, “Excuse me, where are we?”

“This is Heaven, sir,” the man answered.

“Wow! Would you happen to have some water?” the man asked.

“Of course, sir. Come right in, and I’ll have some ice water brought right up.” The man gestured, and the gate began to open.

“Can my friend,” gesturing toward his dog, “come in, too?” the traveller asked.

“I’m sorry, sir, but we don’t accept pets.”

The man thought a moment and then turned back toward the road and continued the way he had been going with his dog. After another long walk, and at the top of another steep hill, he came to a dirt road leading through a farm gate that looked as if it had never been closed. There was no fence. As he approached the gate, he saw a man inside, leaning against a tree and reading a book.“Excuse me!” he called to the man. “Do you have any water?”

“Yeah, sure, there’s a pump over there, come on in.”

“How about my friend here?” the traveller gestured to the dog.

“There should be a bowl by the pump.”

They went through the gate, and sure enough, there was an old-fashioned hand pump with a bowl beside it. The traveller filled the water bowl and took a long drink, then gave some to the dog. After they had both quenched their thirst, they walked back toward the man who was standing by the tree.

“What do you call this place?” the traveller asked.

“This is Heaven,” he answered.

“Well, that’s confusing,” the traveller said. “The man down the road said that was Heaven, too.”

“Oh, you mean the place with the gold street and pearly gates? Nope. That’s Hell.”

“Doesn’t it make you mad for them to use your name like that?”

“No, we’re just happy that they screen out the folks who would leave their best friends behind.”

Soooo…Sometimes we wonder why friends keep forwarding jokes to us without writing a word. Maybe this will explain. When you are very busy, but still want to keep in touch, guess what you do? You forward jokes.When you have nothing to say, but still want to keep contact, you forward jokes.

When you have something to say, but don’t know what and don’t know how, you forward jokes.

Also, to let you know that you are still remembered, you are still important, you are still loved, you are still cared for, guess what you get? A forwarded joke.

So, the next time you receive a joke, don’t think that you’ve been sent just another forwarded joke, but that you’ve been thought of today, and your friend on the other end of your computer wanted to send you a smile.

You are all welcome @ my water bowl anytime.

It turns out that I had miscalculated Peekaboo’s age, so we have to wait for another week to bring her into our household. Kittens should not be taken away from their mothers until they are at least 2 months old. So, we wait patiently for Monday, July 23.

On the subject of cats: I was looking through my photos the other day and found this one, which reminded me of the trip we took to Rome in April 2006. My husband had never been to Rome (fancy that!), and I hadn’t been there since I was in high school (an Italian liceo in Florence), so this was a particularly enchanting trip. Practically a new experience for both of us. But almost the best part of our trip was when we came upon Torre Argentina, a square that hosts the remains of four Roman temples and Pompey’s Theatre. Extraordinary. At one point, though, we began rubbing our eyes after seeing strange-looking little dots moving around among the ruins. The dots turned out to be cats. Cats everywhere, sleeping, walking, playing among the ruins. Upon closer inspection, on one side of the ruins, we found the Torre Argentina Cat Sanctuary, a shelter for homeless cats. Women called “gattare,” or “cat-ladies,” have been taking care of these cats since 1929. We walked down a few steps and then into the shelter, which is located inside a sort of low-ceilinged cave. We were very impressed with what we saw and with the stories we were told by the really friendly volunteers who run the shelter, and who feed and take care of all the cats. Sick cats are kept inside large cages, treated, then released. There is also a gift shop. Of course, I bought cat calendars (the photos are of these cats among the ancient Torre Argentina ruins) and T-shirts and left a donation. Have a look at the Wikipedia write-up on Torre Argentina, which also mentions the sanctuary: http://tinyurl.com/yo44vq. By the way, according to tradition, Julius Caesar was assassinated right here in this square. Cat-lovers who know Italian can check out: http://www.romancats.de/romancats/index_it.php My final advice is, if you are a cat-lover and are on holiday in gorgeous Rome, please stop by this cat sanctuary (after or before eating a meal at Giggetto al Portico d’Ottavia, of course! 😉 ). You won’t regret it!

Quercetin. Okay, so this is nothing new: organic vegetables are better for us than non organic vegetables. I eat only organic vegetables and fruit, and in summer we grow our own tomatoes, arugula, eggplant as well as several different varieties of herbs, plus we have a fig tree, an apple tree, a strawberry plant and a monster raspberry plant (which is attempting to take over our entire back yard at the moment!), which periodically explodes with fruit between May and October and, if we are quick enough, we get to eat some of it before the bugs polish off everything. I also juice only organic vegetables and fruit, since I also use the peels and rinds. Anyway, this is neither here nor there.

My point is, I found a recently published University of California-Davis study (http://tinyurl.com/3dbb7d) particularly interesting because it compared the amounts of two flavonoids, quercetin and kaempferol (the latter is extracted from tea, broccoli and grapefruit, e.g.), in dried tomato samples that had been collected between 1994 and 2004 as part of a long-term study on agricultural methods. Researchers compared organic versus non-organic tomatoes. And, quelle surprise!, the organic samples had higher levels of both compounds, respectively 79% and 97%, than the non-organic ones. Science may finally be catching up to plain common sense.

According to the Times UK July 5 online edition (http://tinyurl.com/2pu5zq), these researchers believe that the different levels of flavonoids in tomatoes are due to the absence of fertilisers in organic farming. Plants produce flavonoids as a defence mechanism; they are triggered by nutrient deficiency. Feeding a plant with too many nutrients, such as inorganic nitrogen commonly found in conventional fertiliser, curbs the development of flavonoids. The lower levels of flavonoids in conventional tomatoes were caused by over-fertilisation , the research team concluded. So a rich soil may actually not be such a good thing to have in our vegetable garden, after all! Interesting.

Honey Bee Epidemic. I reported in an earlier post about honey bees dying all over the world (by the way, please switch off your cell phones!). This horrifying phenomenon has reached such serious proportions that there is a name for it: Colony Collapse Disorder, or CCD, a term coined in late 2006. I don’t want to go overboard on this issue, but I do have an update. A couple of days ago, just by chance, I came across some news about organic honey bees. Apparently, organic bees are NOT dying. That caught my attention, so I did a bit of research into the matter, thinking of my little honey bee friend (whom I saw on my raspberry plant the other day, so he at least is in good health!). Sharon Labchuk, an organic beekeeper from Prince Edward Island, reports that organic beekeepers have experienced no problems with CCD. She says that The problem with commercial operations is pesticides used in hives to fumigate for varroa mites and antibiotics are fed to the bees to prevent disease. Hives are hauled long distances by truck, often several times during the growing season, to provide pollination services to industrial agriculture crops, which further stresses the colonies and exposes them to agricultural pesticides and GMOs. Speaking of trucking bees all around the country, I read that, in order to pollinate the half million acres of almond trees in California, one million “rented” hives are driven there from 40 U.S. States. Talk about stressing out those poor little creatures! No wonder that since October 2006 billions of U.S. bees have disappeared. Billions! Another problem I read about is that bees are being bred to be larger than normal. And, apparently, bigger bees do not do as well as natural-sized bees. Michael Bush is a beekeeper who addresses some of these issues on his website: http://www.bushfarms.com/bees.htm

It all boils down to being sensible. If you use pesticides and other poisons or try to create a super-bee variety, i.e., if you tamper too much with Nature, eventually you will run into huge problems. And the finished product €”tomatoes, apples, honey, whatever €”may well be toxic and won’t taste as good, either. Need I say more? Organic is the only way to go. Of course, this is just my opinion!

Here we go again. I recently came across another natural substance that has been used to treat various ailments for hundreds of years in traditional medicine throughout the world, from North America to Russia and Japan. It is called betulinic acid, or BA, and is extracted from the white birch tree (Betula Alba), as well as from other plant species found mainly in tropical areas. Ralph Moss (http://tinyurl.com/25g8sv) informs us that traditional medicine has used it to treat diarrhea, dysentery, cholera, and all diseases of the alimentary tract. It is said to be a good “blood cleanser.” Blood cleanser, huh? Sounds good to me!

Of course I did an online search, et voilà , there it was!, a study mentioning birch tree extract and MM cells in the same breath, a study (http://tinyurl.com/2room7) published in 2006, informing us that BA possesses antiviral, antiparasitic, antibacterial and anti-inflammatory activities, including, from what I read elsewhere, the ability to inhibit both Staphylococcus aureus and Escherichia coli. But most importantly, BA can inhibit the growth of cancer cells: In this study, we demonstrated a remarkable antiproliferative effect of BA in all tested tumor cell cultures including neuroblastoma, rabdomyosarcoma-medulloblastoma, glioma, thyroid, breast, lung and colon carcinoma, leukemia and multiple myeloma, as well as in primary cultures isolated from ovarian carcinoma, cervical carcinoma and glioblastoma multiforme.

That BA could kill cancer cells is not such a recent discovery. A University of Illinois study on BA and melanoma cells was published in 1995: http://tinyurl.com/29j76f Melanoma tumour growth was completely inhibited without toxicity. A follow-up study (http://tinyurl.com/235mag) was published in 2003. Another 2003 study showed for the first time that BA induces apoptosis in head and neck cancer cells. See: http://tinyurl.com/28hm27 And yet another 2003 study (full study: http://tinyurl.com/39tdwk) published in the Journal of Immunology examines the anti-cancer properties of BA and also mentions its anti-HIV effects. BA was found to suppress the activation of NF-kappa B in different cancer cell lines €”colon and lung, for instance. The researchers found that BA is a very potent inhibitor of TNF-induced NF-kB activation. This is important because TNF, or tumour necrosis factor, is very much involved in cancer growth and metastasis. BA was also found to induce apoptosis in brain tumour cells. The study ends: overall our results suggest that BA may have applications for various diseases mediated through NF-kB activation, including cancer, inflammation, and AIDS.

A July 2007 study (http://tinyurl.com/2fclmz) published in Molecular Cancer Therapeutics points out that, while BA is not toxic even at a high dosage, it is not very potent. These researchers examine the purportedly stronger effects of six BA analogues, notably CBA-Im [1-(2-cyano-3-oxolupa-1,20(29)-dien-28-oyl)imidazole] (how’s that for a mouthful?). Another 2007 study (http://tinyurl.com/24aumm) published in Cancer Letters states that Treatment with BA was shown to protect mice against transplanted human melanoma and led to tumor regression. In contrast, cells from healthy tissues were resistant to BA and toxic side-effects in animals were absent. This is important. Like curcumin and many other non toxic compounds, BA leaves healthy cells alone. Those are five key words I seek in a study: It Leaves Healthy Cells Alone. These researchers tested cells from five high mortality cancers €”lung, colorectal, breast, prostate and cervical €”and discovered that, after 48 hours, almost equal amounts of BA inhibited their proliferation.

A clinical trial (see: http://tinyurl.com/23fqjp) is currently examining the effects of betulinic acid (a 20% betulinic acid ointment) on melanoma. I hope BA will soon be tested in a clinical trial setting with MM patients, which is the same wish I have expressed concerning so many other plant extracts with anti-MM effects in vitro.

I would like to end by quoting the final passages of Robert Frost’s poem “Birches”:

It’s when I’m weary of considerations,
And life is too much like a pathless wood
Where your face burns and tickles with the cobwebs
Broken across it, and one eye is weeping
From a twig’s having lashed across it open.
I’d like to get away from earth awhile
And then come back to it and begin over.
May no fate willfully misunderstand me
And half grant what I wish and snatch me away
Not to return. Earth’s the right place for love:
I don’t know where it’s likely to go better.
I’d like to go by climbing a birch tree,
And climb black branches up a snow-white trunk
Toward heaven, till the tree could bear no more,
But dipped its top and set me down again.
That would be good both going and coming back.
One could do worse than be a swinger of birches.

My computer has the flu today. My display suddenly goes dark, then my computer reboots for no apparent reason. I have lost a few online searches (a slight annoyance…), so I have finally decided to give my computer some aspirin and tuck it into bed for the rest of the day, until the household technical genius (my husband) gets home from work.

However, I am on another hot trail, so stay tuned. 😉

P.S. Before I go, though, if any cat-lovers out there can give me an idea on how to give an antibiotic to a cat, please please please drop me a line. Puzzola, our eldest cat, has a urinary tract infection, but she is more cunning than a fox and can “smell” that pill miles away. We have tried everything, even grinding it up and hiding it inside her favorite food (a bit of chicken). Nothing works! So now it takes three of us to hold her, throw the pill down her throat, clamp her mouth shut, tickle her throat and wait for her to swallow the bloody pill. Such an indignity for our queen! Any ideas? Thank you! Okay, I’d better post this before my computer sneezes again!

A friend (thank you!) sent me an MD Anderson study published in Blood (see abstract: http://tinyurl.com/2l4hb3) in July 2007. The study informs us that Salinosporamide A, a powerful proteasome inhibitor extracted from a marine bacterium, Salinispora tropica, also suppresses NF-kappa B, inhibits RANKL-induced osteoclastogenesis, and can overcome MM cell resistance to bortezomib (Velcade). The latter process, by the way, according to these researchers, would indicate that these two proteasome inhibitors have different mechanisms of action; therefore, when administered together, their effect would be synergistically stronger. Salinosporamide A also enhances the cytotoxicity of thalidomide, and inhibits the expression of the infamous COX-2 mentioned in previous posts. Among other things.

This extract, which was renamed NPI-0052, is currently being tested in a Phase I clinical trial for relapsed and relapsed/refractory MM patients in various locations throughout the U.S. (see: http://tinyurl.com/2klq9c) The April 2007 press release informing of the clinical trial can be read here: http://tinyurl.com/3832rf

In 2005, the Dana-Farber Cancer Institute published a study (abstract: http://tinyurl.com/2odmp4; full study: http://tinyurl.com/2qo9aj), which examines the synergism of the combination bortezomib- NPI-0052. However, since this particular study is available online, I won’t add anything else, but urge those interested to go have a look.

Back to the 2007 MD Anderson study. Researchers found that NPI-0052 was a more potent proteasome inhibitor than bortezomib but, they caution, this does not necessarily mean that it will be more effective than Velcade in clinical testing. The study ends: Overall, this study showed for the first time that the antiproliferative, proapoptotic, anti-osteoclastogenic, and anti-invasive effects of NPI-0052 might be mediated through the suppression of NF-kB and NF-kB-regulated gene products. Together, these findings provide a novel opportunity to exploit NPI-0052 proteasome inhibitor, not only in the treatment of cancer through the modulation of NF-kB activation pathway. Thus, use of NPI-0052 might provide a novel approach to the treatment of myeloid leukemia and potentially other types of cancers that are resistant of chemotherapy and radiotherapy. This study also informs us that NPI-0052 was first discovered during the fermentation of Salinispora tropica, a new seawater-requiring actinomycete found in marine sediments in the Bahamas.

How about that? An extract from a bacterium living in ocean sediment can induce apoptosis of multiple myeloma cells, colon cancer cells, chronic lymphocytic leukemia, acute lymphocytic leukemia and acute myeloid leukaemia. And I have written at least one post against…bacteria (well, germs!)! I (almost) stand corrected! 

Reading through the recently-mentioned MD Anderson 2005 study on plant polyphenols and chemosensitization (abstract: http://tinyurl.com/2k3pea), I came upon piperine, and it seemed a good time to write a post about this spicy alkaloid ingredient of black pepper which enhances the bioavailability of many compounds, including my beloved curcumin. I should mention once again that curcumin, from all accounts, is poorly bioavailable. There are quite a few studies on this topic. One of them, a 2002 study (http://tinyurl.com/2y8gp6), concludes that curcumin is avidly metabolized by human intestinal tissue. And this could be a major reason for its poor systemic availability. And a 2005 study (http://tinyurl.com/2tlgwm) on curcumin and colorectal cancer patients states the following: Taken together, the results presented here and elsewhere suggest that whilst orally ingested curcumin has low systemic availability, it furnishes sufficient levels in the human intestinal tract to cause pharmacodynamic changes commensurate with intestinal chemoprevention. The low systemic availability of curcumin might be considered a disadvantage because it precludes the use of curcumin as a chemopreventive agent for target organs distant from the gastrointestinal tract. Note: these cancer patients were given three different doses amounting to less than 4 grams a day, which is less than half the amount of curcumin I am taking, AND this particular experiment lasted only one week. But even a dose of 3,600 mg was found to have positive effects in the colorectum.

I found a not-too-technical explanation for what happens to curcumin once it is ingested in an article written by Dr. Richard Beliveau and published in the London Free Press in March 2007: as soon as it enters the intestine, the molecule is quickly modified by an enzyme called UDP-glucuronosyltransferase, which triggers its elimination, without it having had the chance to exert its numerous anti-cancerous and anti-inflammatory effects. In the presence of pepper however (and therefore, of piperine), the UDP-glucuronosyltransferase activity is blocked, which allows the turmeric to be better absorbed. This effect of piperine is quite remarkable because it increases by almost 2,000 per cent the concentration of curcumin in the blood, thus allowing it to reach sufficient concentrations to produce its effects. [ ]

Piperine and bioavailability. A study published in 1985 (http://tinyurl.com/3dpp53) concludes that piperine is a potent inhibitor of drug metabolism. A 1998 study (http://tinyurl.com/329d2d) examines the bioavailability of curcumin in animals and humans, and concludes that piperine enhances the serum concentration, extent of absorption and bioavailability of curcumin in both rats and humans with no adverse effects. But an even more interesting study (http://tinyurl.com/2zz8mm), published in 1997 on oral drug bioavailability in humans, reminds us that one of the factors involved in the first-pass effect is food, which can inhibit or enhance the absorption of drugs. I confess that I had to look up first-pass effect (or first-pass metabolism ), which simply means that after a drug is swallowed it is absorbed by our digestive system and goes into the liver, which may metabolize it and change it to the point that only a small unchanged amount will be bioavailable (which is apparently what happens to curcumin). This study gives us a list of some inhibiting foods, such as smoked foods or cruciferous vegetables. Hmmm. Interesting. Garlic instead seems to have no effect on drug metabolism. But, and this was the most interesting bit for me, the study brings up something I already knew, but only vaguely: Constituents of grapefruit juice also result in reduced first-pass metabolism, especially for drugs that are CYP3A substrates. Again, this dietary effect is more pronounced in the intestinal epithelium than the liver. A similar, but more generalized, phenomenon also appears to be associated with eating piperine- and capsaicin-containing spices. In fact, some time ago I read that MM patients doing chemotherapy should avoid eating grapefruit. But, in the case of curcumin-takers, reducing the first-pass effect with grapefruit might work quite well. So, how about swallowing curcumin with a big glass of grapefruit juice? I have actually done this in the past, whenever I have been able to buy organic grapefruit. A 2004 study (http://tinyurl.com/2z8bjg) shows that piperine enhances the bioavailability of EGCG in mice by inhibiting glucuronidation and gastrointestinal transit. Glucuronidation, by the way, is a chemical process used by the body to expel a variety of molecules, including drugs and pollutants, as well as substances like curcumin and EGCG. Therefore, inhibiting this process means that these compounds are better absorbed. So far, so good. The study concludes that piperine inhibits small intestinal glucuronidation of EGCG, which may result in increased absorption, and that piperine may also slow the GI transit of EGCG, thus increasing residence time in the intestine and allowing for greater absorption. […] The increase in plasma bioavailability for EGCG may improve its cancer preventive activity in vivo.

Piperine and cancer. Piperine doesn’t merely increase the bioavailability of some compounds, but also seems to have some anti-cancer activity of its own. I will cite a few studies, including one (http://tinyurl.com/ypn47e) published in 2005 on lung cancer and piperine, which concludes: Our present results explain the understanding of unique association between anti-peroxidative effect of piperine and ultimately the capability of piperine to prevent cancer. It has anti-cancer properties also in the case of melanoma, according to this 2004 study in which (by the way) one of the inhibited cytokines was the infamous IL-6: http://tinyurl.com/37sl4b

Final considerations. The use of the conditional tense may result may improve in the above-mentioned 2004 piperine-EGCG study is interesting, and brings me to ask a few final questions, undoubtedly dictated by my ignorance and my non-scientific brain (so please forgive me!). What if it doesn’t matter if curcumin stays in the serum for an extended period of time? In other words, what if at least some of the anti-cancer effects of curcumin have little to do with its presence in the serum? If curcumin is so poorly bioavailable, how can one explain my test results, as well as those of other successful curcumin-takers? Another question: I have a MM listserv friend who is taking 12 grams of curcumin and discovering yellow stains €”corresponding to the head and trunk areas of her body €”on her sheets every morning. So, if curcumin is seeping out of her pores to the point of staining her sheets, what is going on? I have a lot of questions, but very few answers. However, I do have an update on my summer experiment with curcumin capsules without bioperine, which I began taking on June 28. I have noticed a change that might mean something or not. In the past couple of days, I have been awakened in the morning by peripheral neuropathy (PN, as we MMers call it) in both hands. This hasn’t happened in months. Could it be caused by the absence of piperine, i.e., I am not absorbing enough curcumin? Is it the summer heat? The stress of my new job? No idea. I even considered ending the experiment, but I want to persevere until the beginning of September, unless the PN gets a lot worse. I can be quite stubborn at times! 🙂

A new listserv friend (thank you!) just sent me this flight story to add to my funny pages for the immune system, as follows:

My son and I were flying back to Arizona from Nevada on a Southwest Airlines flight. There was a storm and it was very turbulent. The pilot came on and announced that he was changing altitudes to try to avoid the turbulence. He did this twice, but it didn’t help. Finally he came on and made this announcement after telling us to buckle our safety belts and having the flight attendants check to see that we had done so:

“Attention passengers, we are climbing from 25,000 feet to 30,000 feet. We have never done this before, so uh, sit tight.” Good one! 🙂

Yesterday afternoon I went to visit our new kitten, Peekaboo!, and took about a million photos of her and her two equally adorable siblings, since I won’t see them until next week when I will go to pick her up and bring her over to our house. Can’t wait, even though she is definitely going to be a handful. While I was visiting, she was like a little ping pong ball, boing boing boing all over my neighbours’ yard, hiding behind their bushes and jumping out suddenly to grab my toes. Clearly, Peekaboo is a fitting name for this tiny creature. Such a cutie!

I am doing research in bits and pieces, but please bear with me for a couple of days since my parents have just arrived from the States, and I haven’t seen them in months. Lots of catching up to do. However, I do have a couple of half-finished posts that I will finish and put up in the next couple of days.