Being thankful for things that…didn’t happen…

March 6, 2008 / / 1 Comment

The other day I was reading bits and pieces from “The uncollected Wodehouse” when I came across a gem that I thought I would write about today. P.G. Wodehouse, by the way, is best known for his Jeeves (the brainy butler) character. If you have never read the Jeeves and Wooster books and need a laugh, rush over to the library and borrow some. And if you have never seen the TV series, rent it immediately: the one with Stephen Fry magnificently portraying Jeeves and an equally magnificent Hugh Laurie (yes, Dr. House) playing the part of Bertie Wooster, the scatterbrained aristocrat. But this is neither here nor there.

Point is, I read a two-page story titled “The secret pleasures of Reginald.” This long (sorry!) excerpt (I took parts of it out, so as to shorten it, but you can read the entire story here: http://tinyurl.com/yw43js) illustrates Reggie’s “thankful…not” theory:

I found Reggie in the club one Saturday afternoon. He was reclining in a long chair, motionless, his eyes fixed glassily on the ceiling. He frowned a little when I spoke. "You don’t seem to be doing anything," I said.

"It’s not what I’m doing, it’s what I am not doing that matters."

It sounded like an epigram, but epigrams are so little associated with Reggie that I ventured to ask what he meant.

He sighed. "Ah well," he said. "I suppose the sooner I tell you, the sooner you’ll go. Do you know Bodfish?"

I shuddered. "Wilkinson Bodfish? I do."

"Have you ever spent a weekend at Bodfish’s place in the country?"

I shuddered again. "I have."

"Well, I’m not spending the weekend at Bodfish’s place in the country."

"I see you’re not. But — "

"You don’t understand. I do not mean that I am simply absent from Bodfish’s place in the country. I mean that I am deliberately not spending the weekend there. When you interrupted me just now, I was not strolling down to Bodfish’s garage, listening to his prattle about his new car." […]

I got his true meaning. "I see. You mean that you will be thanking your stars that you aren’t with Bodfish."

"That is it, put crudely. But I go further. I don’t indulge in a mere momentary self-congratulation, I do the thing thoroughly. If I were weekending at Bodfish’s, I should have arrived there just half an hour ago. I therefore selected that moment for beginning not to weekend with Bodfish. I settled myself in this chair and I did not have my back slapped at the station. A few minutes later I was not whirling along the country roads, trying to balance the car with my legs and an elbow. Time passed, and I was not shaking hands with Mrs. Bodfish. I have just had the most corking half-hour, and shortly – when you have remembered an appointment – I shall go on having it. What I am really looking forward to is the happy time after dinner. I shall pass it in not playing bridge with Bodfish, Mrs. Bodfish, and a neighbor. Sunday morning is the best part of the whole weekend, though. That is when I shall most enjoy myself. Do you know a man named Pringle? Next Saturday I am not going to stay with Pringle. I forget who is not to be my host the Saturday after that. I have so many engagements of this kind that I lose track of them."

"But, Reggie, this is genius. You have hit on the greatest idea of the age. You might extend this system of yours."

This is genius, indeed. We normally use the adjective “thankful” to express appreciation for a positive experience or whatnot. But how about being thankful for things that did NOT happen? In fact, I can think of a number of things for which I am thankful…not.

For instance, I am thankful that I did NOT accept a teaching position at a university in Canada many years ago, before I was awarded my Ph.D. I love Canada, loved living there, don’t get me wrong, but for some reason, when I was offered this job on a silver platter, something that I can best describe as a gut feeling induced me to decline. It was as though I KNEW that I had to leave for Italy that fall. Now, for someone in my position, i.e., a jobless Ph.D. candidate, it was a crazy thing to do (what was I thinking?!)–but I listened to my gut feeling and flew to Italy.

And I met Stefano. If I hadn’t turned down the teaching job, we wouldn’t be together today. Yes, there are indeed worse things than spending a weekend with Bodfish.

Heaven and hell…

March 5, 2008 / / 2 Comments

While walking down the street one day a U.S. senator is hit by a bus and dies. His soul arrives in heaven and is met by St. Peter at the entrance.

"Welcome to heaven," says St. Peter. "Before you settle in, it seems there is a problem. We seldom see a high official around these parts, you see, so we’re not sure what to do with you."

"No problem, just let me in," says the man.

"Well, I’d like to, but I have orders from higher up. What we’ll do is have you spend one day in hell and one in heaven. Then you can choose where to spend eternity."

"Really, I’ve made up my mind. I want to be in heaven," the senator protests.

"I’m sorry, but we have our rules."

And with that, St. Peter escorts him to the elevator and he goes down, down, down to hell. The doors open and he finds himself in the middle of a green golf course. In the distance is a clubhouse and standing in front of it are all his friends and other politicians who had worked with him.

Everyone is very happy and in evening dress. They run to greet him, shake his hand, and reminisce about the good times they had while getting rich at the expense of the people. They play a friendly game of golf and then dine on lobster, caviar and champagne.

Also present is the devil, who really is a very friendly guy who has a good time dancing and telling jokes. They are having such a good time that before he realizes it, it is time to go. Everyone gives him a hearty farewell and waves while the elevator rises…The elevator goes up, up, up and the door reopens on heaven where St. Peter is waiting for him.

"Now it’s time to visit heaven."

So, 24 hours pass with the senator joining a group of contented souls moving from cloud to cloud, playing the harp and singing. They have a good time and, before he realizes it, the 24 hours have gone by, and St. Peter returns.

"Well, then, you’ve spent a day in hell and another in heaven. Now choose your eternity."

The senator reflects for a minute, then he answers: "Well, I would never have said it before, I mean heaven has been delightful, but I think I would be better off in hell."

So St. Peter escorts him to the elevator and he goes down, down, down to hell. Now the doors of the elevator open and he’s in the middle of a barren land covered with waste and garbage. He sees all his friends, dressed in rags, picking up the trash and putting it in black bags as more trash falls from above.

The devil comes over to him and puts his arm around his shoulder. "I don’t understand," stammers the senator. "Yesterday I was here and there was a golf course and clubhouse, and we ate lobster and caviar, drank champagne, and danced and had a great time. Now there’s just a wasteland full of garbage and my friends look miserable. What happened?"

The devil looks at him, smiles and says, "Yesterday we were campaigning. Today you voted."

Avastin: a tale of appalling approval

March 4, 2008 / / 3 Comments

I love the idea of starving a tumour to death by cutting off its blood supply. That is what anti-angiogenic drugs are supposed to do. But first, what exactly is angiogenesis? I have mentioned this process here and there but don’t think I really have dealt with it in much depth. So yesterday and then today, after getting home from work, I looked it up.

From a previous post we know that tumours cannot grow beyond a certain size (the size of a sesame seed, I read!) because of a lack of oxygen and nutrients. But, unfortunately for us, tumours are very adaptable, so instead of kicking the bucket they start secreting a horde of growth factors (e.g., the infamous VEGF, or vascular endothelial growth factor) which induce angiogenesis, or blood vessel growth. The tumour is thus able to receive a constant supply of nutrients and can grow inside of us like a nasty weed. Without the process of angiogenesis, tumours wouldn’t be able to grow or spread.

In 2004, an anti-angiogenic drug called bevacizumab (trade name: Avastin) was approved by the FDA “for use in combination with standard chemotherapy in the treatment of metastatic colon cancer and most forms of metastatic non-small cell lung cancer. In 2008, it was approved by the FDA for use in breast cancer, against the advice of its advisory panel.” (source: Wikipedia) Say WHAT??? Against the advice of its own advisory panel???

How could something so bizarre happen? I went to read the February 22 2008 New York Times article (http://tinyurl.com/yu3xx5) dealing with this subject (notice that it’s printed in the “Business” section of the paper…this will make sense as you read on…). An excerpt: “FDA approval for late-stage cancer treatments is usually contingent upon data showing a drug extended, or improved the quality of, patients’ lives. Avastin showed neither in a study, according to Genentech’s application.” NEITHER? Ehhhh?

Genentech, the pharmaceutical company that produces Avastin, showed that this drug “slowed tumor growth, without actually increasing life expectancy.” Contrary to what we read in this particular New York Times article, however, the FDA decision has a lot of breast cancer advocates and organizations very worried. And with good reason. Take a look at this February 16 2008 Science Daily article: http://tinyurl.com/2a33u7 Fatal seizures? Brain swelling? If you aren’t convinced yet, read this NY Times August 24 2007 article: http://tinyurl.com/yvuozf The news is sobering indeed. I wouldn’t go anywhere near Avastin.

Why am I suddenly interested in this drug? Well, I became concerned after reading a few Science Daily articles about it. It is also being discussed by myeloma patients right now. So today I checked to see if there were any clinical trials, and yes, there are currently seven trials testing bevacizumab on myeloma patients (relapsed and refractory…), mostly in combination with other drugs (bortezomib and so on). And there are 96 breast cancer and Avastin clinical trials. 96? Oh yes, I admit to being concerned, not for myself but for all the patients who are in clinical trials testing drugs with unknown side effects in the long run. And the short-term side effects are scary enough, as we have learned from the Science Daily articles.

A recent Ralph Moss report focused on the Avastin issue: http://tinyurl.com/2edftu An excerpt (but please go read the full report, it’s excellent on many MANY levels): “On Friday, Feb. 22, 2008, top administrators of the Food and Drug Administration (FDA) approved the drug Avastin for the treatment of advanced breast cancer. Avastin, which has already been approved for colon and lung cancer, is controversial because it has never been shown to extend overall survival (OS) in breast cancer patients. It has been shown to improve disease-free survival (DFS) by as much as 5.5 months, but disease-free survival is not by any means the same thing as overall survival. A patient receiving Avastin may have a 5.5 month improvement in disease-free survival yet still die at approximately the same time as someone who did not receive the drug.”

Need I mention that Genentech’s stock, which had been declining, according to a February 23 2008 New York Times article (http://tinyurl.com/26zts4), after the FDA approval…all of a sudden rose more than 8 percent? Money, profit, and more money…but who CARES about the patients??? Certainly not the CEOs whose pockets are being lined with blood money.

Ralph Moss ends his report attacking the FDA’s double standards: on the one hand, this agency is always ready to squash any promising CAM (complementary and alternative medicine) treatments, on the other, it gives a “free pass” to a big pharma company “for a drug that has yet to be proven to do anything significant for breast cancer patients.”

In Moss’ words, the “FDA has once again significantly lowered its standards for drug approval. If it proposed doing so across the board, including taking a more even-handed approach to CAM treatment, that would be the basis for an interesting discussion. But what FDA is doing is permitting a lower standard for the expensive products of Big Pharma, while remaining wary of all non-toxic or non-patentable agents. So, whatever happened to the level playing field that a former director of the National Institutes of Health (NIH) promised the CAM movement back in 1992? Gone with the wind.”

But wait, it isn’t all doom and gloom out there. Curcumin inhibits angiogenesis. No kidding. There are 85 studies in PubMed dealing with this topic. Not one. Eighty-five. I have read a few of them, myself. Oh, and so does resveratrol. But this is material for at least another post. I will leave it at that…for now.

Concluding thought: do we really need to strangle a tumour with drugs that are toxic, potentially fatal (some women have already died from Avastin) and outrageously expensive?

Need an excuse to drink coffee?

March 2, 2008 / / 5 Comments

Thanks to Sherlock, who sent me the full study that I will be discussing today, and to a Grouppe Kurosawa mailing, I found out something that I had not previously known about coffee. As it did for yours truly, the following should put a smile on the faces of coffee drinkers. This was meant to be a simple brief discussion of a study on caffeine, but it turned into a huge time-consuming bit of research. One thing led to another…I did my best not to go overboard!

An Italian study (see abstract: http://tinyurl.com/3862f5) published in May 2007 in “Molecular Pharmacology” states that caffeine inhibits VEGF and IL-8 (interleukin-8) in human colon cancer cells. Specifically, it inhibits HIF-1 alpha, or “hypoxia-inducible factor alpha.” Let’s take a closer look at HIF-1 alpha before proceeding.

I read that solid tumours are unable to grow beyond a certain size because of hypoxia, which means "insufficient oxygen." What happens is that, as tumours grow, they need more and more nutrients and oxygen. At a certain point, though. the tumour microenvironment just can’t deal with this constant demand (if I got that right…) and becomes hypoxic. Under hypoxic conditions (less than 6% oxygen, I read), HIF-1 alpha, a transcription factor, becomes activated, and it in turn activates genes, dozens of them!, that keep tumours alive and well, via angiogenesis, glucose transport and whatnot. So tumour progression goes hand in hand with the increased activity of HIF-1 alpha.

Is this bothersome transcription factor present in myeloma, I wondered for just a split second? I really didn’t need to do a search to answer that question.

But I did do a search, and, quelle surprise!, it turns out that HIF-1 alpha is involved in myeloma angiogenesis as well. See this Italian study: http://tinyurl.com/36eywf. And see also this very colourful PDF presentation prepared by an Italian team for the 10^th International Myeloma Workshop (Sydney, 2005): http://tinyurl.com/ytwej8 It also shows the involvement of HIF-1 alpha in myeloma angiogenesis.

Back to the Italian study on caffeine (see abstract): “Pretreatment of cells with caffeine significantly reduces adenosine-induced VEGF promoter activity and VEGF and IL-8 expression.” (Wait…adenosine? Uffa, another thing to look up…) Here we go: simply put, adenosine is a natural chemical, a neurotransmitter, released by brain cells to make us sleepy. The more we stay awake, the more adenosine gets released. But I should point out that adenosine is present also in all cells of the body, and, aha!, has the function of protecting cells from damage under conditions of hypoxia. And it protects solid tumours from the attacks of NK cells and T-lymphocytes, as can be seen in this abstract (“International Journal of Oncology,” March 2008): http://tinyurl.com/yu7o72. It seems to be involved in a lot of mischief! Well, ok, not all the time!, for instance it mediates the damage caused by strokes…

Enough. You can read more about the importance of adenosine on the Grouppe Kurosawa public blog (February 29 post): http://tinyurl.com/23fbgo. The main thing we need to know is that, when adenosine is released, HIF-1 alpha and VEGF, the very best friends of cancer cells, are activated.

I started going through the Italian caffeine study with my usual (exaggerated!) attention to detail, then I decided that that didn’t make any sense. Do we really care that much about how this all works? Naaah. The important thing is the study’s clear message (well, to me, a morning coffee drinker, at least!): DRINK COFFEE! (yes, yes, YES…!).

Okay, just a few points (can’t help it, sorry!

Hypoxic tumour cells are resistant to chemotherapy and radiotherapy. Eh!
Hypoxia stimulates IL-8, which is involved with cancer progression (including myeloma progression, as we know from a previous post).
HIF-1 “contributes to tumor progression and metastasis.”

This, according to the authors, “is the first report examining the in vitro effect of caffeine on hypoxic cancer cells.” Their “data suggest three potential chemopreventive targets for caffeine: 1) HIF; 2) VEGF and IL-8; and 3) cell migration.” They add: “our results indicate that, in tumor colon hypoxic cells, adenosine increases VEGF promoter activity via the HIF-1 pathway and that caffeine is able to block this effect.”

Now, while the cancer cells studied here were not myeloma ones, there is quite a bit of common ground, as we have seen (VEGF, IL-8 etc.). So I will be interested to read future studies on this topic. In the meantime, I will enjoy my usual morning homemade cappuccino with much more gusto!

Oh, I just can’t resist adding this lovely titbit at the end.

Guess what other substance inhibits HIF-1 alpha? Any ideas? Yes! CURCUMIN! (I always check…). See this abstract, published in “Oncology Reports” in 2006: http://tinyurl.com/2aooud It suggests that “curcumin may play pivotal roles in tumor suppression via the inhibition of HIF-1 alpha-mediated angiogenesis.” And a “Molecular Pharmacology” 2006 study (full text: http://tinyurl.com/27q93o) also suggests that curcumin inhibits tumour growth by targeting this transcription factor.

HAH! Now I have TWO good reasons to be happy today!

Making bread

March 1, 2008 / / 6 Comments

I made my first bread yesterday. Italian bread, what else?

Well, to tell the truth, years ago, when I was in my early 20s, I did occasionally make a sort of Wonder Bread…without the chemicals (see cartoon on the left), but the bread I made yesterday was entirely different: it wasn’t put in a mould of any shape or size but shaped by (my) hand and placed on a cookie sheet.

I followed a recipe, and, about halfway through, thought I had made a crucial mistake at each step: the dough ended up being too sticky, more like cake batter than pliable dough; I had to add about 200 extra (!) grams of flour to get it to the kneading point; the dough didn’t rise because my kitchen (so I thought) was too cold; enfin, the dough looked nothing like the photo in the book (I have one of those gorgeous step-by-step recipe books with colour illustrations).

Okay, Margaret, don’t panic. It’s only BREAD. No big deal.

But panic I did. I called one of my best friends, a fabulous cook and also a bread-making goddess. Horrified, she exclaimed, “You tried making WHAT? Have you lost your mind? It’s extremely difficult to make that kind of bread, blablabla. For one thing, you need a wood-burning oven! Why didn’t you just try making loaf bread?” (Well, what she really said was: hai fatto COSA? Ma che ti sei impazzita? Ma chi te l’ha detto di fare quel pane lì? Il pane normale è difficilissimo da fare, eppoi va cotto in un forno a legna, blablabla. Ma perché non hai fatto il pane in cassetta, che è facilissimo, invece?)

I looked around my kitchen: no wood-burning oven in sight, just my electric one. I thanked her and hung up. Sob!

I began to tremble. It wasn’t bad enough that my sticky dough wasn’t rising properly, now I didn’t have the right kind of oven. Urgh. I called Stefano at work to let him know that he’d better stop at the supermarket on his way home to buy some proper bread. Mine, I told him, was going to be a terrible-tasting tooth-breaking flat focaccia, at best. (For the record: he actually did buy some bread…hmmm, could this be considered grounds for divorce? ).

The misshapen hand-shaped dough that I managed, eventually, to pop in my preheated oven didn’t look anything like the photo in the bread book. Sigh.

I have vowed NEVER EVER to buy another step-by-step cookbook with colour illustrations, things like that just make you feel totally inept. Because guess WHAT?

My bread turned out to be the best bread we have ever tasted! The best bread in the entire WORLD! Stefano pronounced it “delicious!” (which, I am quick to point out, he almost never does, except when I make NY cheesecake or apple pie). He said I should start selling it. This morning, first thing, before even having his usual cup of espresso, the man who never ever eats breakfast (ever!) made himself two salami sandwiches with my bread! Hah! Triumph! Well, I may not be the bread-making goddess, but I am definitely (now) the bread-making QUEEN!

This photo shows all that is left this morning of my, as it turned out, gorgeous bread, crunchy on the outside, soft and moist on the inside!

Margaret's Corner

Month: March 2008