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.

My parents arrived in Florence safe and sound on Tuesday, and we have been catching up since then. Their luggage was filled with the supplements that I will use in my experiments planned for 2007 and 2008. Quite an impressive pile of bottles, I must say. Among other things, including curcumin, of course, they brought me resveratrol, ellagic acid and Scutellaria baicalensis (for my baicalein test). I haven’t had time to do any serious research in the past couple of days. But just this morning a close friend (thanks!) sent me a funny joke, as follows:

The Hikers

One day, Joe, Bob and Dave were hiking in a wilderness area when they came upon a large, raging, violent river. They needed to get to the other side, but had no idea of how to do so. Joe prayed to God, saying, “Please God, give me the strength to cross this river.”Poof! God gave him big arms and strong legs, and he was able to swim across the river in about two hours, although he almost drowned a couple of times.

Seeing this, Dave prayed to God, saying, “Please God, give me the strength and the tools to cross this river.”Poof! God gave him a rowboat and he was able to row across the river in about an hour, after almost capsizing the boat a couple of times.

Bob had seen how this worked out for the other two, so he also prayed to God saying, “Please God, give me the strength and the tools, and the intelligence, to cross this river.”

Poof! God turned him into a woman. She looked at the map, hiked upstream a couple of hundred yards, then walked across the bridge.

I am too excited to do any research this morning, waiting for my parents to arrive from the States. Their plane will land in
Florence in mid afternoon. So, while waiting to go pick them up at the airport, I decided to write about the Palio di Siena, which is a traditional bareback horse race held twice a year (July 2 and August 16) in Siena. It just so happened that yesterday I watched the Palio broadcast live on national TV. I must say, even though I do NOT approve of animal races or anything that puts animals in danger, not at all!, the Palio manages to hold me spellbound, mainly because I don’t want to hear about or see any horses being injured. If any of you has ever seen the Palio, during which ten horses race madly around the dangerous corners of Piazza del Campo (three times), you will know what I mean. Yesterday, though, no horses were seriously injured (one horse was slightly hurt during a trial run, but that’s it), so that was a big relief! (By the way, these are photos I took in 2006 at the Palio of Ferrara, not the Senese one, see below.)

Yesterday’s Palio was interesting because two horses, one from the contrada (city ward) of the Nicchio and the other from the contrada of the Oca, crossed the finish line neck to neck. The judges had difficulty assigning the Palio (a silk banner made specifically for each race), which went first to the Oca, then to the Nicchio, then back to the Oca. The contradaioli, or inhabitants of each contrada, began pulling the silk Palio back and forth above the crowd. The TV commentators said that nothing like that had ever happened before. By the way, for a bit of Palio history, you can check out Wikipedia. I would just like to mention that the Palio probably originated in the Middle Ages; however, the first modern Palio, with horses racing around Piazza del Campo, took place in 1650 ca. (before then, donkeys and even buffalos were used).

There are fierce competitive feelings among the inhabitants of the different Senese contrade, 17 in all (but there used to be 40 or so). Even the children of Siena are brought up in this competitive atmosphere, but for the most part it’s all in good fun. Before yesterday’s race, a husband and wife belonging to two different contrade were interviewed. Their baby girl belongs to the mother’s contrada (but if they have another child, he or she will belong to his father’s contrada). This is a serious matter: every year, on the contrada Saint’s day, all the children born that year are baptized at the fountain of their contrada church. They then become members for life of that particular contrada, and are like brothers and sisters to the other members. It’s okay for two members of opposing contrade to fall in love, but during the days of the Palio they become rivals. In many ways, this ancient tradition adds to the wonder and appeal of this lovely city. However, at the risk of offending any readers from Siena, in my opinion it is time to stop the horse-racing part of the Palio. It is simply too risky for the horses. An example: during the August 16 Palio of 2004, a horse fell and was trampled to death by the other horses. Incredibly, the race was not stopped, even though it could have caused other horses to fall. Any comment would be superfluous.

Traditional Palios held in other Italian cities are not as famous as the one in Siena, but perhaps equally spectacular. Last year, my husband and I spent a long weekend in Ferrara, where the most ancient Palio in the world (dating back to the 13th century) is held. We didn’t go see the horse race, which was just as well, since in 2006 three horses were lamed and had to be killed. We went instead to watch a couple of the magnificent flag-throwing competitions, accompanied by the sound of drums and trumpets played by inhabitants of the contrade dressed in Renaissance costume (see my photo). Absolutely stunning. We couldn’t move because of the huge cheering crowds surrounding us (not my favourite thing, crowds, I confess), but we got caught up in the excitement and began cheering, too. Of course, we cheered everyone, even the few competitors who dropped their flags. But I noticed that, whenever a flag was dropped, the entire crowd would let out a howl of disappointment. That is, there was no cheering from opposite factions. Very nice. The young man who won the single flag-throwing competition was handling and whirling and throwing so many flags that I lost count. And he didn’t drop ONE flag. I can’t tell you how incredible this was. Never seen anything like it. And it goes to show that a Palio can be exciting even without being dangerous both to humans and to animals. So let’s keep the spectacular flag competitions and the magnificent costume pageants and ban the dangerous horse racing.

According to a few herbal websites, rhubarb root has been used for two thousand years as a gentle but effective laxative. It cleanses, and also treats constipation, but €”when taken in smaller doses €”can also relieve diarrhea and hemorrhoids. Quite remarkable. However, a word of caution. I read warnings against munching on or cooking and eating this plant’s leaves, which are extremely toxic. Only the roots and rhizomes are used for medicinal purposes. I thought I should mention this, in case anybody was vaguely thinking of preparing some rhubarb leaf tea. Not a good idea! However, the leaves come in handy if you want to prepare an organic insecticide, for instance to fight those pesky aphids that infest your rose bushes (sigh!). For some useful suggestions, including how to use rhubarb leaves to clean burnt pots and pans (no kidding), go to: http://www.rhubarbinfo.com/rhubarb-uses.html This website also includes a rhubarb tart song and rhubarb limericks. 😉

Other emodin-cancer studies:

1. the previously-mentioned promyeloleukemic HL-60 cell abstract was published in December 2002 in Biochemical Pharmacology : http://tinyurl.com/34xm94
2. another study on HL-60 cells, titled: Aloe-emodin induced in vitro G2/M arrest of cell cycle in human promyelocytic leukemia HL-60 cells (http://tinyurl.com/3xn8fp), was published in 2004 in Food and Chemical Toxicology
3. a study on human oral cancer and emodin was published in Oral Oncology in January 2007: http://tinyurl.com/2mp5rp
4. a hepatocellular carcinoma (HCC) study: http://tinyurl.com/3d6d52, Life Sciences, 2004. This particular study is interesting because it shows that emodin activates the tumor-suppressor p53, also known as tumour protein p53, or TP53, which I have mentioned in previous posts. Go, p53!
5. a study on Merkel cell carcinoma and aloe-emodin: http://tinyurl.com/2p4jj5, published in Oncology Reports in 2004
6. a study titled Emodin Enhances Arsenic Trioxide-Induced Apoptosis via Generation of Reactive Oxygen Species and Inhibition of Survival Signaling (http://tinyurl.com/34ockb), published in Cancer Research in 2004.

Now, since my parents are arriving from the States tomorrow, I have some errands to run. Off I go!

I am posting about two items today. Originally, I was going to post only about Turkey Rhubarb (don’t you love that plant name?). But the “turkey” post brought me to reflect on another topic, i.e., conventional versus alternative approaches to the treatment of MM. First things first, though.

1. Turkey Rhubarb? A friend recently sent me a 2005 study by an MD Anderson research team on plant polyphenols and chemosensitization, which I am going through bit by bit. The bit I looked at yesterday concerns an active component of Turkey Rhubarb (scientific name: Rheum palmatum) called emodin. By the way, the roots and rhizomes of this plant have been used in traditional Chinese and Japanese medicine for centuries. And its extract, emodin, has many medicinal properties; for instance, it is antiaggregant, anti-inflammatory, antimutagenic, antiseptic, antitumour, antiviral, cathartic, cytotoxic, purgative, immunosuppressive, antispasmodic, styptic and viricidal!

The abstract of the above-mentioned MD Anderson study can be seen at: http://tinyurl.com/2k3pea The full study reports that emodin may sensitize cancer cells to chemotherapy, and also kills human promyeloleukemic HL-60 cells in vitro. The MD Anderson researchers examined the effects of emodin on a variety of cancers, from lung to breast cancer, but I found no mention of MM.

So does this extract have any connection to MM? You betcha! 😉 A quick online search took me to the March 2007 issue of Molecular Cancer Therapeutics, which features a study titled: Emodin has a cytotoxic activity against human multiple myeloma as a Janus-activated kinase 2 inhibitor (http://tinyurl.com/38a7om). I wanted to understand what Janus-activated kinase 2, or JAK2, meant, so I looked it up and found the following study: http://tinyurl.com/225l93, according to which IL-6 and the subsequent JAK- dependent signaling pathways are essential for MM cell proliferation. Okay, so anything that inhibits that process is absolutely brilliant! Back to the Molecular Cancer Therapeutics abstract. It concludes that emodin inhibits interleukin-6 €”induced JAK2/STAT3 pathway selectively and induces apoptosis in myeloma cells via down-regulation of Mcl-1, which is a good target for treating myeloma. Taken together, our results show emodin as a new potent anticancer agent for the treatment of multiple myeloma. This all sounds very promising. I just hope more studies are done on this compound, as well as on many others!

2. Conventional/Alternative Food for Thought. However, more importantly, the opening statement of the MD Anderson study abstract provides some serious food for thought: The treatment of cancer with chemotherapeutic agents and radiation has two major problems: time-dependent development of tumor resistance to therapy (chemoresistance and radioresistance) and nonspecific toxicity toward normal cells. Many plant-derived polyphenols have been studied intently for their potential chemopreventive properties and are pharmacologically safe. This is not a new issue for me. I have been thinking along the same lines in recent months. And apparently, I am not the only one, as you will see below

One of the main problems with MM is that eventually the nasty malignant cells become resistant to chemotherapy. Unlike curcumin (just as an example!), conventional treatments do not have the ability to distinguish between normal and cancerous cells. What I hope to achieve with my alternative research is to develop a non toxic but effective alternative protocol that will target only my malignant cells, leaving my normal cells alone.

When I read about what is going on in the conventional MM treatment world, even my non-medical, non-scientific brain is able to figure out that the idea of a multi-pathway attack seems to be the predominant current approach. In other words, conventional chemotherapy drugs are given mainly in combination, not one at a time. And in fact, this morning I read some of the findings of the 11th International Myeloma Workshop just held in Kos, Greece (it ended yesterday). The most effective treatments for patients with relapsed MM, according to the IMF write-up (http://tinyurl.com/3atnmj), are as follows: a. Revlimid plus Dexamethasone; b. Velcade (bortezomib) plus cyclophosphamide and prednisone, and c. Velcade, Revlimid and a steroid. The list of current MM conventional clinical trials (about 300 or so) consists mostly of combinations of various drugs, many of which have been around for some time.

These findings lead me to believe that I am on the right track, except that in my case I want to find a protocol that I can keep modifying, if necessary, in order to keep engaging my MM cells in a sort of battle, but at the same time confounding them–attacking them from different pathways. If my approach works, great. If not, I will find something else (how about that for a positive thought on a sunny Sunday morning?). Only time will tell if my approach is correct, but, as usual, I remain confidently and stubbornly cheerful! Have a great Sunday! 🙂

Now that I have had my June blood tests, I have begun my summer supplement experiment. A few months ago I ordered curcumin capsules without bioperine from a reliable company in Milan. So this summer I want to see if the no-bioperine capsules will work as well as the ones with bioperine that I have been taking since last fall. I won’t change anything else about my intake, which will still include quercetin and oil capsules, and an occasional folic acid pill. A quick note: my Italian curcumin capsules are much smaller than my U.S. ones. I checked their weight (following the example of my friend Don, please see his informative Myeloma Hope blog), and found it to be correct. Why make big capsules if smaller ones work just as well? Smaller capsules are much easier to swallow, so that would be another point in their favour, if they work.

In the fall, I plan to take on a more ambitious project. I have ordered Chinese skullcap capsules (see my Scutellaria Baicalensis page for more information). I will test those for a couple of months and see what happens. When I say test, by the way, I don’t mean that I will stop taking curcumin. Too many potential risks involved (increase in IgG count and so on). Curcumin is to me what a security blanket is to the Peanuts’ character Linus.

Ending on a more personal note. I wish to thank those of you who suggested many wonderful names for our new kitten, who will be joining our merry household on July 10 (more or less). My Mom yesterday suggested Peaches, which I really liked. But last night my husband came up with what I consider to be the best name so far: Peekaboo. We will probably spell it the way it should be pronounced in Italian, that is Pikabu. Our mischievous furry baby loves to play peekaboo, so the name fits perfectly. Is there a cuter kitten in the world? I doubt it! I have no super recent photos, unfortunately; this one was taken about a week ago.

My Dad loves Shakespeare, so when I saw this wonderful list of student essay bloopers from Richard Lederer’s website, I just had to post it as part of my “laughter is good for the immune system” project. 😉 I tried to edit the list, but I was able only to take out a sentence or two. Too funny! The entire list can be read on Lederer’s website: http://www.verbivore.com/adven.htm

Dad, this is for you!

• Shakespeare never made much money and is famous only because of his plays and sonics. He lived at Windsor with his merry wives, writing hysterectomies, tragedies, comedies, and errors. I don’t see why he is so popular when his writing skills are so low. He wrote in Islamic pentameter, and you can’t hardly understand what he is saying.
• In one of Shakespeare’s famous plays, Hamlet rations out his situation by relieving himself in a long soliloquy. A soliloquy is a conversation between one person. Hamlet has an edible complex [ ]. Oedipus and Hamlet really had a lot in common, even if Freud had not yet been invented.
• In Act Five Hamlet talks to Horatio about a skull that has been thrown up. Act Five comes right after Act Four.
• After Macbeth becomes the Thane of Candor, King Duncan wires Macbeth that he will be spending the night at his castle. Then Lady Macbeth tries to convince Macbeth to kill King Duncan by attacking his manhood. All Macbeth does is follow his wife’s odors. He kills the king on page 14. Macbeth and Lady Macbeth then suffer from quilt. In fact, they have so much quilt between them, they can’t sleep at night.
• During the banquet scene, Lady Macbeth is afraid her husband will expose himself in front of his guests. Then Lady Macbeth gets kilt. The proof that the witches in Macbeth were supernatural is that no one could eat what they cooked.
• Romeo and Juliet are an example of a heroic couplet. Romeo and Juliet belonged to the families of the Montages and Copulates, and Lady Copulate disliked Romeo.
• Romeo saw Juliet for the first time at the massacred ball. They tell each other how much they are in love in the baloney scene. After much fighting in the pubic square, Romeo’s last wish is to be laid by Juliet. When Juliet died, they had a funeral in her wedding dress.
• In Julius Caesar, Brutus is a tragic hero despite dying at the end. In Julius Caesar, the toothslayer warned Caesar to beware the March of Dimes. He is murdered by the Ides of March because they think he is ego-testical. Dying, he gasps out the words “Eat you, Brutus!” Then he dies with these immortal words: “Veni, vedi, vici.”
• In The Merchant of Venice, the Rialto is the business part of Venus. Bassanio loved Portia, but he had no money to press his suit. Taming of the Screw is a play about Petruchio, who takes Kate from a bitter screw to an obedient wife. In A Midsummer Night’s Dream, Puck turns Bottom’s head into an ass. The clown in As You Like It is named Touchdown.
• In Anthony and Cleopatra, Cleopatra reclined to become Mark Anthony’s mistress. She took the Roman Empire one man at a time. The barge she shat on, like a burnished throne, glowed on the water. The poop was beaten gold.
• Writing at the same time as Shakespeare was Miguel Cervantes. He wrote Donkey Hote. The next great author was John Milton. Milton wrote Paradise Lost. Then his wife died and he wrote Paradise Regained.