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Posted by Derek
Remember back when Sanofi-Aventis submitted Acomplia (rimonabant) to the FDA? Remember when the FDA told them that they needed more data before it would be approved? That's been over a year ago now - time flies - and now they're saying that another hearing with the agency is scheduled for June 13.
There was an excellent summary of the whole situation by Jeanne Whalen in the Wall Street Journal the other day, which subscribers will already have seen. Here's the article for free access in the Arizona Republic for everyone else. This will take you through the whole story, from the hype of 2004 to the. . .well, uncertainly today.
What's worth thinking about are the (in retrospect, rash) statement of Sanofi's people back then about the huge blockbuster potential of the drug, and the (in retrospect, clueless) statements of various analysts back a year ago. "A brief delay" was one phrase that turned up several times, along with predictions of approval by the middle of 2006. . .make the the end of the year. . .OK, first quarter of 2007. . .fine, fine, by the end of '07.
And what's continued to amaze me is the ability of the S-A management to give no details about what's going on with the drug. A year ago, I thought they'd be forced to talk shortly by investor pressure, but I'm clearly a bit clueless myself. . .
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+ TrackBacks (0) | Category: Diabetes and Obesity
Quite a while ago (sheesh, five years - this is an old blog, as these things go!), I wrote about a "Chemical Wish List". There are a lot of elements and functional groups that nature has not provided us with, and we could really use them. The earlier post was a request for something the size of fluorine that's electron-donating instead of electron-withdrawing, but today I have another one for the list.
I want a nitro group, or something a lot like it, that's metabolically stable. Nitro's an odd duck, as the structure in its brief Wikipedia entry will show. That drawing is a compromise attempt to represent reality (dotted lines in chemical structures are a giveaway for that). You can draw other resonance structures, all of which approach the truth to greater or (mostly) lesser degrees. Basically, the two oxygens have more electon density on them that usual, and the nitrogen has less. Neither oxygen has a full negative charge on it, but they're closer to it than usual.
And that's what makes nitro interesting. It's quite a polar functional group, and compounds that contain it reflect that. Take a look at the simplest organonitro compound, nitromethane. It dissolves freely in water, and boils at nearly the same temperature, 100 degrees C. Boiling point is a fairly good surrogate for polarity, other things being equal, since it's measuring how well the molecules prefer each other's company in the liquid state, as opposed to flying off on their own in the gas phase. For comparison, methanol (CH3OH) boils at about 65 degrees C, and methylamine is wimpy indeed, fizzing away at about minus 6. Now, there are some molecular weight differences in there which can't be totally ignored, but there's no doubt that nitro is one polar group.
We need polar groups in medicinal chemistry. Those, along with the general shape of the molecule, are the biggest parts of binding energies to our in vivo protein targets. Nitro groups uniquely offer a positive charge right next to a forked arrangement of partial negatives, and I'm sure we could do a lot with that - if the darn things didn't get chewed up in living systems. That nitrogen is nearly as oxidized as it can get (well, there's nitrate anion, true), and there are plenty of systems in the body ready to bring it back down.
That's where the trouble starts. If you go all the way down from nitro, you end up with an amine (NH2). But the intermediates along the way - hydroxylamines, nitrosos, all that kind of thing - are rather reactive and nasty. Those are what give nitro groups their bad reputation in medicinal chemistry - too many of them, especially the ones where the nitro is on an aromatic ring, are experimental (or, gulp, real-world) carcinogens because of those metabolites. The same thing happens to aryl amines, too, because other enzyme systems can oxidize them up to the nasty middle steps. I don't think that they make it all the way up to nitro in vivo, but more perverse things than that happen in biochemistry all the time. For those who don't know this stuff and would like to know more, here's a nice presentation on the basics of drug metabolism - navigate down to #88 in the frame to get to the nitro section.
Now, it's not like there are no nitro-containing drugs. Putting the group on a five-membered heterocyclic ring is often a tolerable move, and there are plenty of examples of that working out. But there's always going to be some suspicion attached to the group, and you're never sure that things are going to work out, since human metabolism can differ from your animal models. Most medicinal chemists opt for caution, and don't put nitro groups on any of their aromatic rings to avoid heartbreak later on. (And of course, there are aliphatic nitros, but those have their own problems).
No, what I want is something that's the size, shape, and polarity of a nitro group, but is rock-solid to metabolism. Sort of a trifluoromethyl group with lots of charge on it. We could certainly have a good time with one of those. . .
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+ TrackBacks (0) | Category: Life in the Drug Labs
The semi-annual American Chemical Society meeting is underway in Chicago this week. I'm not there, since duty calls here at Stately Pipeline Manor. (At one point a few months ago, I'd been invited to participate in a symposium that was later dropped. Little did I know that no one would still be employed at the Wonder Drug Factory by the time the meeting rolled around)! C&E News has a blog covering the meeting, and Chemistry World is doing the same.
I haven't actually been to an ACS national meeting in quite some time. They're pretty good-sized affairs, with several thousand attendees, although the size can vary significantly depending on where the meeting is held. There are, naturally, only a certain number of cities that can handle conventions of this size easily - we're not going to be seeing one in Bozeman, Montana or Fort Smith, Arkansas any time soon, although some people might prefer either of those to some of the cities where the meetings are actually held.
A glance at the past meeting calendar shows some locations that come up regularly, and others that pop up for reasons unknown. Boston (site of the next one in August), San Diego, Washington, and New Orleans are regular stops in recent years. Chicago, New York, Philadelphia, and Anaheim make multiple appearances, too. The venues are planned out to 2012, and those stalwarts make up most of the list, with San Antonio and Salt Lake City as outliers. Other places I can remember national meetings showing up are Las Vegas, Atlanta, Miami (not for a while, though, I think) and Dallas.
If anyone has particular nominations for best and worst places to attend one, I'd be glad (and other readers might be as well) to hear them. I'd also be interested in cities off the usual circuit where you'd like to see a meeting take place - yeah, I know, Shanghai, Pune, and Bangalore, but try to think of some others. I've heard the most gripes about Anaheim, personally, for lack of interesting sights, general character, etc., but complaints about facilities, food, and accommodations will also be welcomed. We'll get that Fort Smith booking yet.
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+ TrackBacks (0) | Category: Chemical News
Amgen served up a nasty surprise on Friday with the results of a trial they're running on their Vectibix (panitumumab) cancer therapy. It's an EGFR inhibitor (same space as Imclone's Erbitux) and this trial was the first to test a "dual biologics" approach to colon cancer. One group got the standard of care (oxaliplatin and irinotecan chemotherapy, plus Genentech's Avastin VEGF inhibitor), and other other got that plus Vectibix.
Unfortunately, in one of those unexpected results that cancer trials are always delivering, the two-protein-therapeutics group actually showed slightly worse survival data than did the standard-of-care group, and that takes care of that. By itself, this result isn't enough to call Vectibix a failure by any means. But its expected rise to overshadow Erbitux has clearly been delayed.
Imclone's stock price reflects this. Does it ever - my modest short position in their stock is now underwater good and proper. Their stock's up 45% so far this year, with a lot of that in just the last two weeks. But these are early days (he said to himself abstractedly, looking out the window with his brokerage statement in his lap). Both drugs are in similar Phase III trials against colorectal cancer (as that first link, to Bioworld Today, details) and eventually we're going to have about as good a head-to-head comparison as you can expect in this area. Whether that'll be enough to decide anything, well. . .
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+ TrackBacks (0) | Category: Business and Markets | Cancer | Clinical Trials
If you want to get a feel for chemistry, one way might be to wander through the periodic table, picking one particular type of compound and seeing how things change as you go from element to element. (That's a good part of how Mendeleev figured the whole thing out, actually). But you'll want to pick carefully. Chlorides, for example, are rabble, as Primo Levi put it memorably. He was right: one chloride is often very much like another, even when the elements involved are very different - it's as if they've been pulled down to a lowest common denominator. I make some exception for the beautiful green of nickel (II) chloride, or the startling metallic purple of the anhydrous chromium (III) salt, but really, if you can't get something neat looking from the nickel or chromium compounds, you're really in a bad way. Most other chlorides are nondescript white powders. Boring!
Pick hydride instead. Hydrides are, if anything, a bit too exciting sometimes, since they tend to be rather reactive. With water, the usual reaction of a metal hydride is to strip off a proton immediately, giving you the hydroxide of the metal and plenty of lively hydrogen gas bubbling off. Sometimes the whole process is joyful enough for the whole mess to burst into flame.
That'll happen to you with the alkali metal hydrides, over on the left-hand side of the table. Organic chemists the world over know sodium hydride the best. It's a fine strong base - kinetically rather slow, but it deprotonates and spares not. By contrast, you hardly ever see much lithium hydride around. Potassium hydride makes an appearance every so often, though, to muttered curses, since it's usually stored as a slurried suspension in mineral oil and is correspondingly painful to weigh and dispense. It's lively stuff, too, and will set things on fire for you with great thoroughness. The higher alkali hydrides are things I've never seen, and I have no desire to, if their ferocity steps up like potassium does versus sodium.
The next row over (the alkaline earths) feature a compound that gets used every so often in the lab, calcium hydride. It's a good drying agent, because of that water reactivity, and solvents are distilled from a spoonful or two of it to make them anhydrous. But has anyone ever seen or handled magnesium hydride? I sure haven't. It's one of the things that the hydrogen-storage people mess around with, apparently, but you just don't come across it in an organic chemistry lab. Ditto for the other alkaline earths: barium hydride? Never seen it or even thought about it. I don't have access to Scifinder for the time being, since I have no desire for a second mortgage on my house just now, but I see from the web that apparently some people are using the stuff. Maybe it has a great future in organic synthesis, but it sure has no past.
This same pattern holds as you go across the elements. You come across some things that are used all the time (boron hydride, better known as borane), and some that are encountered once in a while (aluminum hydride, copper hydride). There are some well-studied chemicals that are just too reactive and nasty for most people, like phosphine or stannane, and some that are too reactive and nasty for any sane person at all, like mercuric hydride. Some of the nasty ones that are used much more outside of organic chemistry. People who do semiconductor work, for example, know all about the arsenic and germanium hydrides, for example, while few organic chemists have ever touched them.
And then there are some that I'm not sure anyone ever messes with at all. They don't seem to be particularly worse than their neighbors; they just sort of seem to be overlooked. Chemists in the audience - ever thought about titanium hydride? Me neither. Chromium hydride? Never once, until this evening (I wonder what color it is?) These are simple compounds, but even among the simple ones you keep finding all these streets that no one ever walks down. . .
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+ TrackBacks (0) | Category:
There's an unusual article in Nature that several folks have e-mailed me about. It's unusual for several reasons. For one thing, it's synthetic organic chemistry, and there's not much of that in Nature at all - it's an interesting choice of journal on the part of the authors, Phil Baran of Scripps and two of his students, Thomas Maimone and Jeremy Richter. The title also gives away the other odd feature (as a title should): "Total Synthesis of Marine Natural Products Without Using Protecting Groups".
I was talking about protecting groups here just a couple of months ago. In synthesizing complex molecules, they're often necessary, because there will often be several similarly reactive groups exposed at the same time, and you need to be able to distinguish them. Or you'll need to do something severe to another end of the molecule-in-progress, which an amine or alcohol somewhere either won't let you do or won't survive if you try.
The trouble, as any synthetic chemist can tell you, is that protecting groups introduce their own complexities. Ideally, you want to be able to put them on and remove them with no loss of material, but that's impossible. Ideally, you'd want each one to be removable under conditions that won't disturb any of the others, or anything else in your molecule, but that can be a tall order too as they start to add up. And ideally, you'd want all of them to be able to stand up to anything else you'd like to do, until it's time for them to leave, but that's not available in the real world, either. Sometimes a big part of the work (mental and physical) that goes into a total synthesis is figuring out how to manage all the protecting groups.
Baran makes the case that this has gone too far. He's made several complex molecules without protecting anything at all. There's a price to be paid, of course - some of the steps along the way have not-so-impressive yields because of the bareback conditions. But the counterargument is that the overall yield of the synthesis is often higher in spite of this, because there are so fewer steps, and the cost and complexity are cut similarly.
Of course, you can't do this by just plowing ahead with the same reactions that a protecting-group-laden synthesis would use. They're on there for a reason, and that method would send you right into the ditch. Baran tries instead to mimic the biochemical synthesis of these molecules as much as possible, since after all, cells don't use protecting group chemistry, either.
This is an idea with a long and honorable history in organic chemistry, starting with Sir Robert Robinson's startling one-pot synthesis of tropinone back in the 1917. That one is usually taken as the father of all biomimetic syntheses, although it's been pointed out (by no less an authority than Arthur Birch) that this is partly a legend. But it's a legend that has performed function of its reality, leading to a whole series of biologically-inspired syntheses. This latest paper is a call to make biomimetic synthesis the centerpiece of the field again.
I'm sympathetic to that view, but it's not going to be easy. Read closely, the paper shows that this kind of work can be very difficult indeed, even when the biogenic pathways to your target molecules have been studied (which isn't always the case). There are a lot of steps here that required careful coaxing to work in reasonable yields, or at all - no one should confuse the lack of protecting groups with a savings in time. And these difficulties also undermine the claim of reduced cost and complexity a bit, since they represent plenty of time and effort - and if they aren't synonymous with cost and complexity, I don't know what is. Academia may obscure this a bit, since we're only talking graduate student labor here, but it's a real issue.
Where I see this making an impact industrially is in process chemistry. Many times companies work out several parallel routes to an important drug substance, looking for the lowest overall cost. That's where attention to no-protecting-group methods could pay off. Process groups already try to avoid these steps anyway, for the same reasons.
But for the most part, drug substances aren't so complex that they need lots of protecting group manipulation. We could always try to get into more complicated structures through these routes, but this leads to a chicken-and-egg problem. The medicinal chemists generally don't have the time to investigate the picky conditions needed to make no-protection chemistry work, so they're not going to have access to the shorter, higher-yielding syntheses needed to do analoging work. (And there's the real problem that these analogs might need complete re-optimization of the trickier steps each time, which would be a real nightmare). The process chemists would have the time and mandate to work out the no-protection stuff, on the other hand, but if med-chem can't deliver a good drug candidate, then they have nothing to optimize.
The Nature link above is subscriber-only, but you can read the supporting information with all its synthetic details here if you like. It's a pretty big PDF file, though, so be warned. I'd be interested to hear what readers, both academic and industrial, think about this one.
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+ TrackBacks (0) | Category: Academia (vs. Industry) | Drug Development | General Scientific News
Jim Hu has a good post on some proposed new FDA rules for its advisory panel members. Some sort of changes have been coming for a while now - here's an op-ed that I wrote on the subject back in 2005. I argued that many of the best scientists and clinicians in a given field already work with the industry (which isn't such a bad thing when you think about it), and that restrictive requirements for serving on advisory panels could do more harm than good.
Well, here's the new proposal: the cutoff is $50,000 in the previous 12 months. At that or above, you won't be allowed on the panel. Between $1 (presumably) and $50,000, you can sit on the panel, but won't be allowed to vote. My guess is that that's going to have a pretty big impact if it goes through, and that we're going to see some very different committee rosters.
Or, of course, maybe we're going to see some new forms of relationships between drug companies and their consultants. That's what happens whenever efforts are made to regulate money in the political world, and it wouldn't surprise me a bit here. There are two ways to look at this: if you're suspicious of the FDA's motives (like, say, Rep. Maurice Hinchley of New York, who has a bill mandating these changes and more coming along), then you'll probably see the whole process as a form of organized bribery, wheel-greasing to get defective drugs past the regulatory authorities. Another way to look at it, though, is that outside experts have something that the drug companies need (expertise, and more importantly, expertise from another point of view than the one from inside the company), and that they're willing to pay for it. This may seem odd, but these consultants don't always tell us what we want to hear.
The tough part is when a drug is on the edge of getting approved or not - it has some good points, some bad ones, and the decision could go either way. That's when suspicions are raised that an extra $50,000 here and there is what tipped things over to approval. I don't see that happening, myself (although readers are invited to submit counterexamples). Many approvals can be honestly argued either way, because these medical questions are inherently one big grey area.
The media reaction to this story is rather more toward the former point of view, though. The Washington Post's take on the story is that ". . .the new guidelines implicitly acknowledge what critics have long said -- that it is possible to find enough qualified experts who do not have ties to drug and device manufacturers." And Gardiner Harris in the New York Times gives one sentence to someone at the American Enterprise Institute, while leaving plenty of space for words from Rep. Hinchley and my own representative, Rosa DeLauro, both of whom are good places to go for "corporate poisoners" quotes.
Well, this is the first act of a rather long session of political theatre. There are 60 days of public comment on this proposal, then more wrangling comes along after that. Then there are the bills in the House, which if things go on long enough will get thrown into the next election cycle, and on it goes. It's worth watching, but be ready for a protracted show.
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+ TrackBacks (0) | Category: Clinical Trials | Drug Development | Press Coverage | The Dark Side | Why Everyone Loves Us
Pfizer's enormous torcetrapib failure last fall wasn't the only time a company has come to grief in the cardiovascular area, and it's not going to be the last one, either. That's been proven this week by a much smaller company, Atherogenics, and their lead drug, AGI-1067 (partnered with AstraZeneca).
The company is targeting expression of the VCAM-1 protein in blood vessels. That's an immunoglobin that seems to be involved in the adhesion of various blood cell types to the vessel walls, and as such is considered a very interesting target for atherosclerosis. AtheroGenics has been working on a series of drug candidates that interfere with the expression of VCAM-1 (through blocking an oxidative pathway in the endothelial cells) and could thus slow the development of arterial plaques (or reduce the size of plaques that had already formed).
Such is the hope, anyway. AGI-1067 behaved well in animal models, and went through numerous Phase I trials in combination with other cardiovascular agents. That link will also take you through the Phase IIa and IIb trials, which showed some real effects in reduction of plaque volume. Those results led to this Phase III trial (with the acronymn ARISE), which expanded the number and variety of patients while looking at real-world endpoints.
That's just how things should work. You see if the drug is tolerated, alone and with the therapies it's going to be given with. Then you check some primary endpoints, to see if the mechanism you're targeting is really being affected. Finally, you see if that's actually going to do a real number of patients any good: I, II, and III. And, unfortunately, III is where the Atherogenics drug ran into trouble.
They missed their primary endpoint, which was a composite score of cardiovascular adverse events - death, heart attack, stroke, angina, etc. Overall, AGI-1067 was no better than placebo when given along with the standard drugs for this patient population. There's no way to call that good news, and no one's even trying. At the same time, though, the company claims to have seen positive effects in some disease states. What subgroups those are, and how positive those effects were, won't be known until next week's meeting of the American College of Cardiology in New Orleans. It's impossible to say if this is just wishful thinking, or a drug worth salvaging.
That's just what the people at AstraZeneca have to decide. The company's pipeline could use some help (not that this distinguishes them very much these days), so they don't want to walk away from something promising. At the same time, they can't afford to throw good development money after bad, either. But the stakes are much, much higher for AtheroGenics, since this physiological pathway is basically the platform for the entire company. There are doubtless some very difficult and unpleasant meetings in progress, not the tiniest bit of fun for anyone involved. My. . .well, heart, goes out to everyone involved. . .
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+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Drug Development
Missed a day or two there - my apologies to the readership. I was out of town, up in Boston/Cambridge (and just in time for a fine March snowstorm). Every time I'm up there, I remember the first time I visited Cambridge, some years ago. I was walking along near Kendall Square and I began to notice that the visible number of thoughtful-looking bearded guys wearing oxford-cloth button-down shirts with the sleeves rolled up and khaki trousers (that is, to a first approximation looking exactly like me) had reached a level unknown to my experience.
It was a strange moment. I'm used to feeling a bit removed from my environment, so to suddenly blend in so thoroughly was a bit of a shock. The same feeling has hit me in just a few other places, mostly around large well-respected universities, and there have been a few isolated incidents elsewhere. I still recall talking with some other chemists at a conference once when one of the group made what is still the only casual conversational reference to Kurt Goedel I've ever encountered (well, other than the ones I've made myself, and I don't trot 'em out too often, for a lot of good reasons).
It can even happen at a distance. When my wife and I were watching the coverage of the first Mars Rover landing, broadcast from JPL in Pasadena, the way the people there talked about the project and the looks on their faces as they awaited word of a successful landing made me realize again that I am in fact part of a tribe, and that these people were members of it, too. We're scattered all over the world, but we know each other when we meet.
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+ TrackBacks (0) | Category: Who Discovers and Why
Here's a quick synthetic question for the lab jockeys in the audience: is there a name reaction that has never, ever worked well for you? The Skraup synthesis has a bad reputation, for example - I've never had the pleasure, but I've heard many stories of splattering dark crud and 20% yields.
I suppose we should distinguish between reactions that are supposed to work well and don't, and reactions that no one has ever claimed are nice (like the Skraup). There's a whole category of reactions that will give you 40 per cent yields when other methods will give you 90, but will also give you 40 per cent when everything else gives you zero. I can't say anything bad about those; they are what they are.
On the other hand, even more most reliable transformations can turn on you. I once had a primary alcohol that I just could not protect with a TBDMS group, a difficulty that made me feel like a complete hack until a disgusted colleague or two had to try it on the same substrate and I was vindicated. But silyl groups are usually pretty friendly. For now, let's take nominations for Least Reliable/Most Overrated Reaction. I'm curious to see what makes the list. . .
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+ TrackBacks (0) | Category: Life in the Drug Labs
Schering-Plough woke everyone up with a large surprise bid for Organon, the long-suffering pharmaceutical arm of Akzo Nobel. Many people are spinning this as a good deal for everyone involved, and that may be. But then again, people always seem to say that about mergers and buyouts, and they're not always right, are they?
Organon has strengths in endocrinology and CNS, two areas where Schering-Plough has never had much of a presence (despite a number of shots on goal in the latter one). The problem is, even the companies that have had success in CNS have had to take a lot of shots, because it's that kind of field. No one really understands antipsychotic and antidepressant drugs, for example, and thinking that you do has been a recipe for trouble. The biggest prospect in Organon's portfolio is asenapine, an antipsychotic, which Schering-Plough seems to have their eye on. But that's a drug that Pfizer walked away from last year, citing "a commercial analysis of the compound". It was my impression that that commercial analysis took place after Pfizer got a look at some of the clinical data, though, and I see that I'm not alone in thinking that way (nor alone in my worries about betting big money on drugs in this area).
There's also the question of how much Schering-Plough is paying. When Bayer bought up German Schering (no relation!), they paid around eight times earnings (and that was already more than they wanted to spend, thanks to Merck-Darmstadt). Schering-Plough is paying around 14 times earnings for Organon. As pointed out here, Akzo Nobel was hoping to raise 9 billion by spinning Organon off, and estimates were that an outside buyer might be willing to go as high as 10. Schering-Plough offered 14.5, which news seems to have been greeting by incredulous delight over in Holland, as well it might. Words like "phenomenal" have been used.
There's no word yet (that I've seen) on what will happen to various sites and divisions of the two companies after the buyout goes through. You'd have to assume that there will be some real cuts - that's the only way to make that price work out - and I'd guess that it'll be more on the Organon side. Most of the press coverage has been about how Schering-Plough is picking up all these late-stage drugs, with nothing about the earlier research at all. (Of course, my assumptions about where a drug company will make cuts in research has already been shown to be imperfect, so keep that in mind. . .)
Well, Fred Hassan is a dealmaker, no doubt about it. And it's true that you have to take risks to make it in the drug industry. As (disclosure!) someone who still holds a reasonable amount of Schering-Plough stock, I hope this one works out for him. It'll be interesting to watch.
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+ TrackBacks (0) | Category: Business and Markets | The Central Nervous System
I wanted to link tonight to the "Milkshake Manifesto" over at OrgPrep Daily. It's a set of rules for med-chem, and looking them over, I agree with them pretty much across the board. There's a general theme in them of getting as close to the real system as you can, which is a theme I've sounded many times.
That applies to things like "Rule of Five" approximations and docking scores - useful, perhaps if you're sorting through a huge pile of compounds that you have to prioritize, not so useful if you've already got animal data.
He also takes a shot at Caco-2 cells and other such approximations to figure out membrane and tissue penetration. I've never yet seen an in vitro assay for permeability that I would trust - it's just too complicated, and it may never yield to a reductionist approach.
I'm a big fan of reductionism, don't get me wrong, but it's not the tool for every job. Living systems are especially tricky to pare down, and you can simplify yourself right out of any useful data if you're not very careful. The closer to the real world, the better off you are. It isn't easy, and it isn't cheap, but nothing good ever came easy or cheap, did it?
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+ TrackBacks (0) | Category: Drug Assays | Drug Development | In Silico
Back in November, I announced the impending closure of the Wonder Drug Factory, and there were plenty of people who responded with news of open positions. My colleagues and I really appreciated it - a number of interviews (and some placements) resulted.
Since then, many of the folks I worked with have found a place to land. That said, there are still a number of us who are looking, and one common factor has been length of experience. Among my med-chem colleagues, the ease of re-employment has been pretty closely correlated with job level. Associates have been largely snapped up. Less-experienced PhDs have had a harder time, but are gradually finding positions. "And then," he said, "there are people like me. . ."
Well, I do have some possible prospects, but some of them aren't going to be resolved for a while yet, so there's nothing concrete yet. I would, in these circumstances, be very glad to hear of positions that I've missed, both for my own use and for my former co-workers. The people that I know are still looking are experienced med-chem project and group leaders, higher-level people in HTS and assay development, and some experienced pharmacology/biology lab heads. They're all worth talking to if your company has a need - just send along an email and we'll take it from there.
There are a number of companies with advertised positions at these levels (Biogen/Idec, Sepracor, AstraZeneca, Wyeth, Novartis, and others). Of course, when these things are listed, everyone knows what kind of slushy tidal wave of applications hits the HR offices. Any readers at such places who believe that they might be able to help out from the inside (making sure that CVs get to the right hands, etc.) are also welcome to write. Big Pharma, Small Pharma, Biotech - everyone's welcome. And thanks (again) to everyone who's written so far. We'll get everybody employed yet.
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+ TrackBacks (0) | Category: Closing Time
Man, have things changed since I was in grad school. We used to pour all kinds of horrible things down the drain - mind you, this was a good twenty years ago. But you can't do that now, can you?
A respected University of Washington pharmacology professor became a felon Wednesday when he acknowledged dumping a flammable substance down a laboratory sink and then trying to conceal his actions.
Daniel Storm, 62, pleaded guilty in federal court to violating the Resource Conservation and Recovery Act by flushing about four liters of the solvent ethyl ether. He faces a maximum five years in prison and a $250,000 fine when sentenced June 18, although prosecutors have recommended probation under the terms of a plea agreement.
Well, everywhere I've worked, the safety officers have tried to put the fear of RCRA ("rick-rah") into us, and by gosh, it looks like they may have had a point. Turns out that Prof. Storm's lab had several elderly containers of ether which turned up in a lab inspection, and he decided to get out of paying the $15,000 hazardous waste disposal bill. So he decided to take matters into his own hands.
And how: he went after the metal ether cans with an ax, which means that he was lucky not to blow himself up. (A stray spark from the metal could have done the trick, and who knows how much peroxide was in the stuff, for that matter). Why the Monty Python lumberjack routine? Well, the lids were too tight, and according to Prof. Strong, the ax just happened to be handy. (How many times have the police heard that old excuse, eh?) Yep, you can't pour ether down the sink like we used to, and you can't chop open the stuff with an ax like we. . .well, actually, we never used to do that. No one ever has, most likely.
What really ripped it was when he went on to fake paperwork from a nonexistant waste disposal company to make it look as if the ether had been properly hauled away. No, if you haven't clicked on that link yet, you'll have to take my word that I'm not making this up as I go along. But you get the impression that Professor Strong sure was. Makes you wonder if he had been exposed to too many fumes. A spokeswoman for the school says that she's unware of any similar incidents there, and I'll bet she's telling the truth. No, I've seen some stupid things done with diethyl ether, but this one threatens to retire the trophy.
Comments (27)
+ TrackBacks (0) | Category: How Not to Do It
The grad-school advice topic from the other day got me to thinking about another issue in that line. Everyone knows about how hot all the mixed chemistry-biology stuff is (and has been). Chemical biology, biological chemistry - call it what you like, a lot of people are doing it (and a lot of people are getting funded for it).
That's fine with me. I find a lot of the work very interesting (though not invariably), and some of it looks like it could lead to useful and important things. My worry, though, is: what happens to the grad students who do this stuff? They run the risk of spending too much time on biology to be completely competent chemists, and vice versa. Instead of being seen as well-rounded modern scientists, ready to take on the blurred boundaries of the new research, they might end up unacceptable to their potential colleagues in any given discipline.
I'm sure these fears have come up every time a new field of research opens up. ("Organometallics, you say? So, are you an organic chemist or an inorganic one, hey?") They've taken care of themselves in the past, and they probably will this time, too - eventually. But I'd have to think that there's going to be a lag time, which we're surely still in, during which the people who've done hybrid projects are going to have a hard time proving themselves in the traditional categories.
I should qualify that to the traditional industrial categories. Academia, following the hot topics and following the grant money, is surely more more hospitable to the new breed. But many of the tools of chemical biology are still a bit blue-sky for use in the drug industry (or are seen to be), and even the ones that are already in use tend to be used by people who are more easily classified. Probably the smaller companies are out in front on this, having less invested in the standard organizational charts and often being closer to the academic worldview anyway. Thoughts?
Comments (17)
+ TrackBacks (0) | Category: Graduate School | How To Get a Pharma Job
Failure's an orphan, sure enough. We get to hear about the really big clinical failures in the drug industry, the Vanlevs and the torcetrapibs, because they hit the greasy chute just when they're bounding up on the stage, while all the spotlights are on them. But there are plenty of other projects that just sort of evaporate, with no one wishing to call attention to them.
That's well illustrated in the recent case of GlaxoSmithKline. The company updated its research pipeline in its annual report last week, and analysts noticed that eleven drugs had disappeared from clinical trials since the last listing. No press releases were sent out at the time, no conference calls were made. None of the drugs were, individually, expected to be huge parts of GSK's future by themselves - but losing nearly a dozen compounds from the clinic has to hurt.
Among them were a beta-3 agonist for diabetes (solabegron) and a glycoside-based thrombin inhibitor (odiparcil). I wouldn't have been putting a lot of money down on either of them, myself - not that I have any information about the compounds in particular, just that those mechanisms have been graveyards for drug development. Counting the number of beta-3 agonists or thrombin inhibitor projects that have been reported over the years would be a nasty job, and none of them (so far) have made it to market.
There were also several oncology compounds missing, and that's no huge surprise, either. Cancer drugs have the highest failure rates in the clinic - the last estimate I saw was around 95%, which is the sort of number that makes you want to thoughtfully look out the window for a while.
I almost wish that more were made of these failures. It would be painful for the companies involved, but it would give people a better idea of how painful drug discovery can be. I had a friend who was always worried about flying anywhere, and I kept wanting to pop in every few seconds, all day long, with news of yet another plane that had landed safely in Chicago, Atlanta, LAX or wherever, just to get the point across. In the drug industry, though, we have the reverse situation - almost everything we try to put into the air crashes. There should be some way to get the point across that most of our drug candidates never make it, taking all their development money down with them.
Comments (21)
+ TrackBacks (0) | Category: Drug Development
I've had an e-mail from someone going off to grad school in chemistry. He wants to eventually do drug discovery work, and is wondering which way to go:
I have it narrowed down to two departments. One is a large, well funded and well respected university with a specific research advisor that is actively recruiting me for his lab. He is a leader in his field and my place in the lab would be in the capacity of synthetic chemist (making various inhibitors). Although his lab is in the chemistry dept it is more on the bio-organic side. My other choice is a smaller less well respected school with fewer resources (lots of TAing) but I could do total synthesis. I would like to join the first group but obviously I want to be able to get a job. If I joined the first group, would I be unemployable in pharma? With a post doc heavy in synthesis would I be able to get a job?
My answer to him was that I'd go with the first lab. A larger school with a more well-known advisor is worth more than the chance to do total synthesis for a PhD - and just as he mentioned, he can do a synthesis-heavy postdoc if need be. Connections mean a lot - ask someone who's job hunting! - and a PhD advisor is generally the first major source of them at the start of a career. The work described is definitely not so far afield that it's going to mess up later job-hunting.
I told him, though, to be sure to get a varied chemistry background in whichever group he joins. You don't want to get too specialized - for future med-chem employment, that can be a killer. A seminar full of same reaction (or class of reactions) over and over isn't going to impress anyone later on - you need to show that you can pick up new chemistry and get it to work, and that you've had to deal with the things that didn't.
One of the reasons that we like total synthesis people is because they've had a wide range of experience, as well as practice with overcoming difficulties. Total synthesis is probably the most efficient way of getting a wide background in synthetic problem-solving in the shortest amount of time. Admittedly, it doesn't always seem like the shortest amount of time while you're doing it, but you can't have everything.
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+ TrackBacks (0) | Category: Graduate School | How To Get a Pharma Job
We've had a hundred years or so of nonstop love directed toward organomagnesium compounds (from Victor Grignard, patron saint of getting the reaction named after you and not your supervisor, right on down). So I've always found it interesting that there weren't more organocalciums out there.
Calcium is probably (from an organic chemist's viewpoint) one of the more underused elements in the first few rows of the periodic table. It's always overshadowed by its neighbors. I've never even seen pure calcium metal, as far as I can remember. OK, people distill some organic solvents from calcium hydride to dry them - at least they do in grad school, 'cause in many industrial labs no one distills solvents at all. And there's calcium sulfate as a drying agent (Drierite, by trade name), but people mostly use that for gas drying (calcium chloride, too, although I haven't seen a good old calcium chloride drying tube in a while). For drying liquids, a higher-volume trade, people reach for sodium or magnesium sulfate instead.
And while that's about as high-profile as calcium gets in many labs, those kinds of uses aren't exactly in the center ring. I recall seeing some old work with calcium metal in liquid ammonia, doing Birch chemistry, but I've never heard of anyone actually doing any of it. As far as real organocalcium compounds, the literature is mighty thin. One problem seems to be that the metal itself (unlike magnesium) doesn't just up and react with organic halides very well. Some Grignards, once they get going, have to be beaten down with frantic bucket runs to the ice machine, but not so with calcium.
Chemist Rueben Rieke has gotten around this problem in his usual fashion, by making insanely reactive calcium metal. His calcium work is about ten years old now, but I haven't seen too much follow-up. (One reason might be that Rieke's conditions can be rather painful to use, which difficulty he wisely exploited by forming his own company to do the stuff for other people). But I see that the latest Angewandte Chemie has an organocalcium article from a group of enterprising Germans, so perhaps this stuff might be working its way into the mainstream.
Once people have a reasonable way to get to these compounds, the hard part can begin: finding out what on earth they're good for. You'd have to think that there are interesting reactions and catalysts which can be prepared from calcium derivatives, since they're bound to have their own character. But where to start? An obscure element needs a champion. Boron had H. C. Brown, and Sharpless brought vanadium into vogue for a few years. A host of people lifted palladium from the back shelves to indispensability. Who speaks for calcium?
Comments (7)
+ TrackBacks (0) | Category: Chemical News
Over here at scenic Lowe Manor (otherwise known as the House that Pharma Has Paid And Will, With Any Luck, Continue Paying For), the dinner table conversation sometimes runs to things like the proper handling of flaming t-butyllithium. Well, OK, the conversation is a bit one-sided, since I'm the only one in the house who's used the darn stuff. My wife has done a lot of bacteriology and molecular biology, fields that don't find much use for pyrophoric organometallics, and I'll keep my kids a good distance from any bottles of butyllithium, thanks.
But I was speaking to the them the other night about the value of experience. Tertiary butyllithium catches on fire, and there's nothing you can do about it. Your best course is to be aware of that, and to expect it. That way, you won't be shocked when you put your syringe into a bottle of the stuff and withdraw it only to find a merry orange flame burning from the tip of the needle. That's a good sign - it shows that your bottle of butyllithium is still good, as opposed to the cloudy, wimpy, hydrolyzed stuff that you should carefully leave sitting in someone else's hood when they're not around.
This pilot light will do you no harm, and will extinguish itself once you put your syringe needle through the next rubber septum. But if you're not expecting it, the sight can come as a bit of a jolt. The consequences are generally not good. There's almost always a tensing of the hand and arm muscles, which tends to depress the syringe plunger a bit, and whooomph: instant flamethrower. I've heard of several completely needless fires that started this way, invariably at the hands of someone who wasn't psychologically prepared to wield some (temporarily) flaming lab equipment with the needed aplomb.
As I mentioned here before, I've had still more practice with fiery glassware. I can attest that a butyllithium flame from the pure substance has a more noble purple color to it than the common orange of the commercial hexane solutions. That magenta hue is from the emission spectrum of lithium itself, and (at least in my case) it did not have a calming effect.
There are, regrettably, even more stupid things to be done with t-BuLi. I'm not sure if I've told this one here before - it's not in the archives at right, so here goes: a friend of mine in grad school was showing a summer undergrad student (hear the chairs of the experienced chemists draw closer) how to do cannula transfers of air-sensitive materials. (This involves hooking up a hose system with needles and tubing, with dry nitrogen or argon gas bled in at the front end of the system to force the stuff over into another waiting flask). There was a double manifold set up in the hood, as usual, to allow a vacuum pump out to remove air from reaction flasks and let nitrogen in to replace it. Somehow, this summer student got the vacuum and nitrogen setting all hosed around when trying to cannulate a whacking load of t-BuLi, and reported back a few minutes later that (although everything was set up perfectly) no butyllithium was appearing.
Feeling the hair raise up on his arms, my friend came to look things over, and saw that indeed, no t-BuLi was showing up in the receiving flask. But there was nitrogen pressure going in, so surely something had to be going somewhere, right? He looked up. . .and realized with a sinking heart that the vacuum manifold at the top of the hood was inexorably filling with the stuff. Now what? I always think in that kind of situation that it's time for lunch, no matter what the clock says.
Comments (26)
+ TrackBacks (0) | Category: How Not to Do It
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- Northern New York Newspapers
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WARRANT - POTSDAM - St. Lawrence County Sheriffs Department deputies picked up Amy I. Fields, 39, of 334 County Route 28A, Ogdensburg, Friday on a bench warrant issued by the town of Oswegatchie Court. Deputies said they observed Fields operating a vehicle in the village of Potsdam, and shewas taken into custody without incident. Fields was additionally charged with second-degree aggravated unl�censed operation of a motor vehicle. She was arraigned in town of Oswegatchie Court and released on her own recognizance. She was released to appear March 15 in Potsdam Village Court on the aggravated unlicensed operation charge.
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Dr. Ira Spinner's Ratings
After 2 injections and medication, my foot hurts more than ever. I was away for 6 weeks and was in great pain. I left 2 messages wit his staff asking that Dr. Spinned call me back. He never called me back. Needless to say, I'm looking for another podiatrist!
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Dr Spinner and his staff are extremely professional and pay so much attention to each patient. I could not believe how much time, patience and selflessness they showed when they explained each procedure and diagnosis I had. They were so caring. I highly recommend them to all my friends and family!
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Best experience I've had in a Dr's office. I wasn't just another number at the bakery counter. Dr. Spinner took his time to talk to me as patient and a person. .He diagnosed my condition and cured it in 2 visits. I'm back to running thanks to his treatment and the unbelievable arch supports he made me.
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Dr Spinner is probably the BEST doctor I have ever been to. The most caring and professional person you will ever meet. I am so happy I have him for my Podiatrist. You don't find service like this anywhere else !
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Staff was professional and cortious. Dr was knowledgable spent time with to insure i understood my diagnosis and treatment
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Dr. Spinner is an excellent doctor and I highly recommend him.
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Highly knowledgable. Felt Like I was a member of his family. Was to 3 prior podiatrist before Dr. S. I wish I would have came to his office first.
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42 U.S. Code § 15406 - Requirement for public notice and comment
For purposes of section 15401 (a)(1)(C) [1] of this title, a State plan meets the public notice and comment requirements of this section if—
(1) not later than 30 days prior to the submission of the plan, the State made a preliminary version of the plan available for public inspection and comment;
(3) the State took the public comments made regarding the preliminary version of the plan into account in preparing the plan which was filed with the Commission.
[1] See References in Text note below.
Source(Pub. L. 107–252, title II, § 256,Oct. 29, 2002, 116 Stat. 1697.)
References in Text
Section 15401 (a)(1)(C) of this title, referred to in text, probably should be a reference to section 15403 (b)(1)(C) of this title because there is no subsec. (a)(1)(C) in section 15401 andsubsec. (b)(1)(C) ofsection 15403 relates to public notice and comment requirements of section 15406 of this title.
LII has no control over and does not endorse any external Internet site that contains links to or references LII.


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A recap of how the past three ICC World Twenty20s were won by India, Pakistan and England respectively.
As the 2012 ICC World Twenty20 looms, a look back at how the past three editions were won.
ICC World Twenty20 2007-08 in South Africa
Winner: India
Runners up: Pakistan
Venues: Cape Town, Durban, Johannesburg
Most runs: 265 - Mathew Hayden
Most Wickets: 13 - Umar Gul
Player of the Final: Irfan Pathan
Player of the Series: Shahid Afridi
The inaugural ICC World Twenty20 was staged in South Africa from September 11-24, 2007. The 12 participating teams were divided into four groups of three each. India was in Group D along with Pakistan and Scotland and under the inspirational captaincy of MS Dhoni, trounced Pakistan in a thrilling and unforgettable final at The Wanderers.
As per the tournament rules, the top two teams from each group went through to the second stage of the tournament, the Super Eights. India stormed into the next round after beating Pakistan in a dramatic bowl-out 3-0 and Scotland. In the Super Eights, they beat England and South Africa and in the semi-finals held their nerves to defeat Australia by 15 runs and set up a mouth-watering final against Pakistan.
In Johannesburg, Dhoni won the toss and opted to bat. India's was a stop-start innings, with Gautam Gambhir leading the way with a 54-ball 75 and Rohit Sharam injecting crucial runs with an unbeaten 30 off 16. As he had been during the tournament, Umar Gul was on the ball and collected the prized wickets of Yuvraj Singh and Dhoni as India finished on 157 for 5.
In the second innings, Pakistan faltered until Misbah-ul-Haq struck three sixes off Harbhajan Singh in the 17th over. Pakistan needed 13 from the final over, and after much deliberation Dhoni decided to give the ball to Joginder Sharma who had bowled an ice-cool two-wicket final over against Australia in the previous game.
A wrong call by the captain would have cost India the trophy. Joginder started with a wide delivery, then a dot. He bowled a full toss next, and Misbah hit him for a six. Six runs off
4 balls was a simple situation for Pakistan, but Joginder's magic worked for Dhoni. On the very next ball, Misbah went for a scoop which landed safely in Sreesanth's hands at short fine leg to crown India Twenty20 champions. Irfan Pathan, who scalped three wickets, was adjudged Man of the Match. Joginder never played another match for India.
ICC World Twenty20 2009 in England
Winner: Pakistan
Runners up: Sri Lanka
Venues: Lord's, The Oval, Trent Bridge
Most runs: 265 - Mathew Hayden
Most Wickets: 13 - Umar Gul
Player of the Final: Shahid Afridi
Player of the Series: Tillakaratne Dilshan
Most Runs: 317 - Tillakratane Dilshan
Most Wickets: 13 - Umar Gul
Just months after the attack on the visiting Sri Lankan team in Lahore that resulted in Pakistan losing the right to host international cricket, a Younis Khan-led outfit beat Sri Lanka to win the title at Lord's. It was Pakistan's first major trophy in 17 years.
Pakistan peaked at the right moment, overcoming a poor start, which included a defeat to England in its opening game and a thrashing to Sri Lanka in the Super Eights. Riding on a superb 54 off 52 balls from Shahid Afridi, Pakistan pummeled Sri Lanka, who had been unbeaten in the tournament, at Lord's on June 21.
Sri Lanka won the toss and elected to bat, with skipper Kumar Sangakkara holding the innings together after the side lost four wickets inside the Poweplay. Playing cautiously, Sangakkara scored 64 off 52 balls and struck seven boundaries in his innings to take the score to 138 for 6. In reply, Pakistan's openers Kamran Akmal and Shahzaib Hasan provided a 48-run start. Afridi then displayed commendable composure in guiding Pakistan to an eight-wicket win with eight balls remaining. His match analysis of 1 for 20 and 54 off 40 balls clinched him the Man-of-the-Match award. Tillakaratne Dilshan was declared Man of the Series for his 317 runs at an average of 63.40.
ICC World Twenty20 2010 in the West Indies
Winner: England
Runners up: Australia
Venues: St Lucia, Barbados, Guyana
Player of the Final: Craig Kieswetter
Player of the Series: Kevin Pietersen
Most Runs: 317 – 302 – Mahela Jayawardene
Most Wickets: 13 – Dirk Nannes
Under Paul Collingwood, England clinched the 2010 World Twenty20 in spectacular fashion by trouncing Australia to win their first major trophy in international cricket.
England didn't had a good start in the tournament as they lost their opening game to West Indies by eight wickets before the second clash against Ireland was abandoned due to heavy downpour. A tense six-wicket win over defending champions Pakistan gave Collingwood's team the much-needed momentum, and from there they pressed on to beat South Africa by 39 runs and New Zealand by three wickets. A seven-wicket win over Sri Lanka in the semi-finals set up a clash with Australia at Bridgetown on May 16.
Batting first, Australia – who had not lost a single match in the tournament – were kept to 147 for 6 with David Hussey top-scoring with 59 off 54 balls after the team collapsed to 8 for 3. In defense of that middling total, Australia struck an early blow but a match-winning stand between Kevin Pietersen (47) and Craig Keiswetter (63) swung the match away.


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I think this song is easily the best song written by avenged sevenfold. From the amazing lyrics to the crazy drumming and of course the unbelievable guitar parts. I love the huge solos that they play and how amazing they play it live. This song should be on top of this list.
I didn't expect for this song to be at the top, but seeing it so low on this list depresses the hell out of me. I can say with utmost confidence that half of the people who voted for Afterlife don't even know any songs from Avenged Sevenfold's best album, City of Evil.
I'm surprised this song isn't rated higher. This is one of the better war songs out there, since it covers life after a war, making it unique. The guitar riffs and solos absolutely rule, and M. Shadows voice versatility is on full display. Have to love this song if you are a fan of A7X!
No no no! The last time I was on this sight, the amazing MIA was in the top ten, its rightful place, this is ridiculous, get some votes in now because this song is far to epic to be so poorly credited as this ranking suggests.
Ok I am a die hard Avenged Sevenfold fan and everyone of their songs are great. Everyone says that every band has a best song but I think every song is the best for Avenged m/. But if I really had to pick one song to be my favorite its definitely this song. It's an utter masterpiece. The power of his voice during Staring at the carnage... (the second time) it is unbelievable.
This song absolutely should be number one. I fall in love with this song because its Patriotic, the sacrifice and war. I love the part when M. Shadows sang the slow part. And the part Synyster solo himself, The Rev playing amazingly! AWESOME!
This is quite possibly their best song ever! Just listen to the songs first before you vote! Nothing is quite like this song, its like heaven and hell meeting or something
The best a7x song I ever heard... Awesome..
Why the song was rarely played during the live show?
Such a great song... Love it very much..
Why? This is a great song should be in the top 5,10 or number 1 instead. This song have what it takes. My top ten list is.1.M.I. A 2. Afterlife 3. So Far Away 4. Almost easy 5. Seize The Day 6. Dear God 7. Hail To The King 8. A Little Piece of Heaven 9. Buried Alive 10. Bat Country. Somtimes I sing all of this songs especially M.I. A and I say VOTE! VOTE! VOTE!
Great song. Starts mellow, so some might pass over it, but it has a great meaning, and DOES get harder. One of their best, I would say. Top ten at least, maybe top 5. Not number one though.
This is such and underrated song its crazy. This should EASILY be at least number 2 or 3. It might even be a bit better than afterlife but probably not.
Well this is the perfect song.. And the guitar works are also one of my favorites.. I think this should be their number 1 song..
This song is an epic and emotional song, I don't really see why it is so low in the list. It ends with a nice mellow ending too that gives it a nice touch.
Although it is very long I never get bored of it
Just awesome!
Good lyrics and totally the best for sevenfold
This song starts off slow then goes into a sick hard rock song. The riffs are amazing and the lyrics own your face!
A fitting end to Avenged Sevenfold's best album in my opinion. Won't crack the Top 10 because it's populated mostly by singles...
I love A7x, and this song is one of a kind. Its really great, not that those above aren't
This song is so amazing, please listen to this song and see its lyrics before voting for other songs
What.. The best song of Avenged Sevenfold falls so much back. Why the people had became crazy?
One of the best guitar solos I've ever heard Synyster Gates RULES!
Calm parts, hardcore metal parts, this song has it all. Easily my favorite A7X song ever!
This song has an amazing solo, great lyrics and great melody. Deserves a better place
What a great way to end City Of Evil. I think this song is 10 times better than Afterlife.
One of the best musical piece for soldiers fighting in faraway lands
This song should be in the top ten with second heartbeat. A little piece of heaven and dear god in my opinion should be out of the ten songs. Listen the solo and read the texte. They are great


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Groucho Marx Turns 120
What can I say about comic legend Groucho Marx that he didn't say better? In honor of Groucho's birthday on October 2nd, I bring to you some of his finest one-liners:
"I don't want to belong to any club that will accept people like me as a member."
"I was married by a judge. I should have asked for a jury."
"I married your mother because I wanted children. Imagine my disappointment when you came along."
"I never forget a face, but in your case I'll be glad to make an exception."
"Don't look now, but there's one too many in this room and I think it's you."
The AADL owns several Marx Brothers films, including those that many consider their three best: Duck Soup, Horse Feathers, and Animal Crackers. Check out the cigar smoking, fake mustache wearing, joke a minute Groucho Marx today from your local library.


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KUSA - Are you the person always sneaking up on your friends and family to see if you can give them a good scare? A Denver company is looking to hire you for its upcoming Halloween season.
Getscared.com is hosting an open audition for 150 performers who wish to join the team.
Auditions will take place on Saturday from 10 a.m. to 4 p.m. at the 13th Floor located at 4120 Brighton Blvd., C2 (a couple blocks south of the Denver Coliseum.)
Performer candidates must be age 16 or older. Those interested in auditioning are asked to fill out an application available at http://getscared.com/contact.html to set up an audition time in advance or must fill out an application on the day of auditions and wait for the next available audition time.
The 13th Floor will be open from Sept. 13 to Nov. 2 and the Asylum will be open from Sept. 27 to Nov. 2.


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- Infowars - http://www.infowars.com -
Mark Dice protests Super Bowl: We know more about football than politics
Posted By aaron On February 2, 2010 @ 5:32 pm In constitution,Old Infowars Posts Style | Comments Disabled
You Tube
February 2, 2010
CBS 4 in Florida mentions Mark Dice's protest of the Super Bowl. Why? Because Americans have been consumed with entertainment and sports that they forgot about issues that really matter– our Constitution, politics and so much more.
See the full "rant" below, or at Mark Dice's website: TheResistanceManifesto.com
Mark Dice: The Super Bowl has been CANCELED!!
Article printed from Infowars: http://www.infowars.com
URL to article: http://www.infowars.com/mark-dice-protests-super-bowl-we-know-more-about-football-than-politics/
Click here to print.
Copyright © 2015 Infowars. All rights reserved.


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Naturopathy incorporates a wide range of natural therapies and treatments – including
nutrition, herbalism and massage therapy – that provide tools to help you achieve
better health.
Your health and well-being are looked at holistically – your eating habits, exercise,
work, relaxation and other lifestyle factors are all part of the equation.
Most chronic illnesses respond to naturopathy, as do many digestive problems.
Naturopathy helps with depression, anxiety and stress-related conditions.
You're able to take control of your own health and well-being.
Paula is so relaxed and easy to communicate with. She totally focuses on me and
is so genuinely keen to help with practical advice that is easy to understand and
use in normal daily life.
- Dale


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Shareholders in US satellite broadcaster SiriusXM are moving to get a Delaware Chancery Court judge to investigate an agreement in 2009 that led to Liberty Media taking control of the company.
The full article is available to our subscribers only.
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Couric not sure she's happy with the way her show is now
CBS Evening News anchor Katie Couric says that she's not sure she would have made the move from NBC if she knew she'd be doing the type of show she is doing right now.
In a New York interview, Couric says that understands that viewers hate change and that they tried to change too many things in the first couple of months that she was there, but that she's not sure she would have taken the gig if she knew it would end up as the same traditional network news show. She says there are days she wishes she hadn't taken it. She even hints that if it doesn't turn out to be the job for her, "I'll do something else that's really exciting and fulfilling for me."
I bet her CBS bosses are thrilled with those type of comments.


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We encourage employers to contact the Career Services Associate, Lindsey Riley, with any questions you may have at (314) 977-7100.
Posting a Position
The Career Services Office now utilizes Symplicity to manage job postings, recruiting programs, job fairs, employer profiles, and more. For more information on Symplicity, please visit the Symplicity page. To login or register for an account, please use this link: https://law-slu-csm.symplicity.com/employers/


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PvP in the zombie apocalypse. Limited resources. Endless zombies. Last team alive wins.
This one looks really good!
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my favorite
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'Jurassic Park 4′ Reveals a First Look at the New Raptors!
Yes, that is the head of an animatronic velociraptor that will appear in 'Jurassic Park 4,' giving us our first direct look at a dinosaur from the highly anticipated film. It turns out that director Colin Trevorrow wasn't lying or exaggerating when he promised that his sequel would feature practical effects ... and we love him for it.
Weekend Box Office Report: 'Tammy' and the Transformers Battle it Out
'Star Wars: Episode 7′ Casts Carrie Fisher's Daughter as a Young Princess Leia
We knew that 'Star Wars: Episode 7' was going to be a little nostalgia-heavy with the return of the original trilogy's stars to the franchise, but it turns out that it goes even deeper than that...
Weekend Box Office Report: 'Transformers: Age of Extinction' Makes About as Much Money as You'd Expect
Look, everyone knows that it's your obligation as a human being to go see a new 'Transfomrers' movie when it comes out whether you want to or not. It's the only explanation for the success of the past three films (since no one actually likes them) and it's the only explanation for the massive first weekend of 'Transformers: Age of Extinction,' which had the biggest opening of 2014 so far.
'24: Live Another Day' Review: "7:00 P.M. — 8:00 P.M."
Weekend Box Office Report: 'Think Like a Man Too' Soundly Defeats 'Jersey Boys'
Unless your movie was named 'Jersey Boys,' this was a pretty excellent weekend at the box office for all parties involved. A new film opened big in the number one spot, last week's champions held on strong, and others continued to perform well further down the charts. But boy, it really kinda' sucks to be 'Jersey Boys.'
'Star Wars: Episode 7′ Ankle Watch: Harrison Ford Sidelined for Two Months
Last week, the internet couldn't stop talking about Harrison Ford's 'Star Wars: Episode 7' injury. Oh, the jokes! Oh, the memes! There's a certain amount of comedy to be found in an elderly Han Solo injuring his ankle thanks to the door of the Millennium Falcon. But now is the time to quit with the laughter: Ford's injury, while certainly not life-threatening, is bad enough that he won't be able to return to the set for eight weeks.
Weekend Box Office Report: '22 Jump Street' Takes 'How to Train Your Dragon 2′ to School
Everyone expected '22 Jump Street' and 'How to Train Your Dragon 2' to open well, but you won't find many people who expected the raunchy R-rated comedy to open bigger than the family friendly animated adventure. But here we are! Both films opened well, but '22 Jump Street,' like the first film, is has taken a hammer to all expectations.
'Dumb and Dumber 2′ Poster: Cinema's Biggest Idiots (and Their Stupid Car) Are Back!
The first 'Dumb and Dumber 2' trailer will officially arrive with '22 Jump Street' next week, but you don't have to wait until then to get a new look at Harry and Lloyd's grand return. A new poster debuted online and it showcases the return of a major character from the original film -- yes, we're talking about the stupid car shaped like a dog.


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Common Oak
Latin name: Quercus robur
Native words: Old Irish (duir) Scots Gaelic (darach) Old English (ac) Welsh (derwen) eastern Celtic (derva)
Ogham sign: D
Height when mature: 30 -40m 100 ft
Height after 10 years:
Oak botanical description:
There are 2 native British oak tree species; Common, or Pedunculate oak (Q. robur) and Sessile Oak (Q.petraea). Sessile oak was the first to arrive in the British isles, and grows naturally in upland areas; Q. robur prefers lower regions. There are 2 key distinguishing features between sessile and pedunculate oak. The first is the acorn. On pedunculate oak they are borne on stalks (or 'peduncles'), sessile acorns are not. Secondly, in winter if you look at the dead leaves remaining on the tree, you will see that the leaf stalks on pedunculate oak are very short. In late winter and spring, light brown buds which look like small nuts are arranged spirally around outer twigs and are clustered at the twig tips. The leaves emerge between mid April and Mid May. Oak does flower, with the male flowers appearing as slender pale green catkins and the female flowers on spiked stalks behind them. The male catkins appear with the first leaves. Oak leaves are quite distinctive, having 3-6 unequal 'thumb' shaped lobes on either side of the leaf, which gives it a wavy edged look. Often tiny discs appear on the underside which are made by insects and called galls, but do not seriously affect the tree. Leaf fall occurs in October and November. The green acorns develop during the summer and sit in a small cup. Oaks do not necessarily produce acorns every year. When they do, the acorns fall usually leaving the cup behind and turn brown as they lie on the ground. Once they have fallen, an acorns first task is to send out a red shoot which roots in the ground and becomes the main tap root. This descends deeply seeking out water. The next spring a main shoot appears and two opposed leaves, recognisably oak, develop Left to their own devices, mature Oaks can have a massive spread to them and are often as wide as they are tall, which increase the sense of grandeur when one regards them. Outer branches regularly die and fall, leaving decaying or dead stumps which are a common feature of the tree. After a while the oak starts to undergo a process known as 'crown death' which is a natural part of its life cycle. As the name suggests, the highest branches start to die back first. The heart wood of the main trunk will also die and rot without killing the tree, so that oaks often have the appearance of being three quarters dead, and yet they are still healthy.
Oak natural history and ancient wisdom:
Oak trees can live up to 1000 years old but are generally mature at 75, and live on average 150-250 years. Today they are the commonest British native tree met with in woods and hedgerows. Their great utility for man has meant no other tree has played such an important role or been so valued by humans, even to the extent of being an object of worship and veneration. Many of the most ancient oaks in the British Isles are pollarded trees. Oaks were pollarded for a variety of reasons. It was mainly undertaken to encourage the growth of large branches at the crown which could be used for building timber. Oak wood is so durable and strong it was prized for roof timbers in great medieval grain barns and churches, such as Lincoln Cathedral. Green oak (that is unseasoned) was invaluable for shipbuilding. Great warships such as Henry VIII's Mary Rose and Grace a Dieu were built almost entirely out of oak, as were nearly all ships before the construction of the iron 'Great Britain'; 2000 mature oak trees were used to build one ship in 1812. Whole forests of pollarded oak were reserved for naval shipyards and some still survive. Oaks other great asset was its seed, better known as acorns. From ancient times and throughout the medieval period, pigs were moved into pasture woodland to feed on acorns in autumn. In the Domesday Book many woods were calculated in value according to the number of swine they would support, which indicates oak was the commonest tree. The right to graze pigs known as "pannage" was often keenly disputed and jealously guarded. It meant that large oak forests were maintained because of their acorn crop. So valuable and significant to communities was this function that it entered mythology of early societies: In Irish myth, Fer Caille ("Man of the Wood") is a semi divine figure who appears as a swineherd with one eye who carries a black pig. He is clearly derived from a woodland deity. The sinister gargoyle still to be seen in the roof or pillars of many English churches surrounded by oak leaves known as Jack in the Green or the Green Man has a similar ancestry. Oak leaves around the Green Man in churches reflected the survival of a strong association between oak and sacred spaces from pagan belief into Christianity. The sacred oak of Ireland was at Dunmanogoe while the earliest Christian synod in England met at St Augustine's oak in Herefordshire. The Kings of Tara in Ireland met under Oaks. Ironically, this role of oaks as sacred meeting places was transferred from pagan religions. The presence of sacred oak groves where Celtic people worshipped was well known in classical times and commented on by writers such as Strabo and Pliny. The survival of giant oaks which had lasted generations probably lies behind why certain trees became sacred. This was a tree which probably started as a recognisable way marker in forest and a communal meeting place because they were so massive and old, and became well known over time, respected for their longevity and role in pannage existing as part of the community. As they became associated with sites of power such as moots, religious authorities would have sought to access the power space oaks represented. Others who wanted to break that power recognised the potential of oaks. The Romans undertook a wholesale felling of sacred groves upon their conquest of England; from now on people would not look to the oak as gathering places or places where power was held and distributed. But the survival of oak as the symbol of strength and landscape heritage (the National Trusts symbol is oak leaf and acorns!) shows they did not succeed!
Oak place names:
There are thousands of place names derived from oak. This is a testimony to the intimate relationship between this tree and the peoples of the British Isles. As well as village names there are many individual farm and field names of ancient heritage reflecting an association with oak trees. Look at an Ordnance Survey map and find the Broad Oak or Great Oak farms and lanes that point to where ancient trees grew (and sometimes still do!). Anywhere that begins with 'Ac': - Acton Bridge (Cheshire) 'settlement by a bridge where oaks grew' Acle (Norfolk) 'oak wood' Acrise (Kent) 'oak copse' Accrington (Lancashire) 'settlement where acorns are found' Aqualate Mere (Staffordshire) 'oak glade mere' Oakenshaw (West Yorkshire) 'Oak wood' Oakleigh (Kent) 'in the lee of the oak wood' Hatfield Broad Oak (Essex) 'heath where the big oak grew' Copdock ( Suffolk) 'coppiced oak' or 'oak rising to a summit' In Ireland 'derry' means an oak wood. Kildare means "Church of the Oak". The old Celtic word 'derva' appears in the place name derwent as in the river Derwent and Derwentwater (Cumbria). It means river or lake by which oaks grow.
Oak wildlife rating:
Excellent. 284 insect species have been found living in oaks. Jays and Squirrels, which both feed on them, spread the acorn by carrying them away and burying them in the ground. The Purple Hairstreak and Purple Emperor butterflies rely on oak. Most British bats roost in the crevices and hollows, and Great Spotted Woodpeckers, Spotted Flycatchers, Nuthatches and Treecreepers find food and nest holes on oaks. Wild Primroses, Bluebells and wild garlic and wild violets all rely on the rich soil beneath oaks to thrive. Some ecologists argue individual oaks should be designated nature reserves in their own right!
Common Oak trees good points/ bad points:
Only suitable for large gardens, but excellent for filling gaps in hedgerows or native woodland, as they survive well. Oaks require substantial amounts of water and will send out extensive and deep roots in search of it. Mature oak trees will draw up large quantities from a garden, rapidly removing water and nutrients from other plants. Many woodland and shade loving plants such as wood anemones and aconites will do well under oaks. In the last 5 years a new disease of oaks known as "Sudden oak death" or Phytophthora ramorum has struck native oaks. P. ramorum invades plants through the bark and cuts off the flow of food from the leaves to the roots. Eventually the roots die, causing the upper tree and limbs to die from lack of water. The trees must be felled.


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A look back with Alexander Payne and Jim Taylor
George Eastman House, "Rochester's Home," is also home to the legacy of George Eastman and the arts he made possible. As such, it attracts many of Hollywood's finest filmmakers, including Oscar nominees Alexander Payne and Jim Taylor.
Payne has been nominated for three more Academy Awards this year, for producing, directing and writing THE DESCENDANTS (2010). Jim Taylor, his frequent collaborator, was also nominated this year for his work co-producing the film. This is their fifth feature film but the first time they have not shared a writing credit.
Payne and Taylor were invited by Assistant Curator Jim Healy to introduce a screening of their second film, ELECTION (1999) in July 2006, and participated in a Q&A after the film. Payne returned in December of that year to host a screening of one of his many favorite films, Richard Fleischer's THE GIRL IN THE RED VELVET SWING (1955). [Fleischer himself was a guest of GEH ]. Once he arrived a good relationship was established between our archive and the filmmaker. During both visits, Payne spent a few days at GEH, mostly watching many private screenings of films from our archive in the Dryden Theatre. He's a real cinephile – but not the kind who slavishly repackages his influences in his own movies. They're best classified not as comedies or dramas but as Alexander Payne films.
(l to r) Jim Talylor, Jim Healy and Alexander Payne
Healy, in his introduction to ELECTION, called Payne and Taylor "contemporary descendants to great filmmakers like Frank Tashlin, Michael Ritchie, Hal Ashby and the pioneers of film satire – Billy Wilder and Preston Sturges." Healy called their films "exquisitely written and profoundly funny." He praised their "great taste in cinema and their expansive knowledge of film history and a deep understanding of essential film grammar – the cinematic language laid out by their predecessors."
Of the four films that he has written and directed, when asked why he chose to screen ELECTION for the Rochester audience Payne said that it tends to be the "favorite of film nerds. And it is Cinemascope. And can I brag and say that both Barack Obama and Richard Holbrooke have told me that it's their favorite political movie?"
The following are some of the highlights from both of Alexander Payne's visits to George Eastman House.
Payne: "Casting is Job 1. The old cliché that 90% of directing is casting is really true. Even though I spend a lot of time complaining about working with the studio, [we] deal with who the top two or three actors are then after that it's completely mine."
"I shot [ELECTION] soon after CASINO (1995) had come out. It kind of quietly had an influence on the style of the film. It's one of the few American films that I've seen with multiple voiceovers. [It is] moving and cutting quickly to constantly changing music cues which [Scorsese] began in GOODFELLAS (1990). I think CASINO is kind of a masterpiece."
In response to a question about how they met, Jim Taylor said "[In 1989] Alexander had a room that was for rent. He had a two bedroom apartment. We were just acquaintances but I moved into that room and we became friends and started writing together."
Payne, Taylor and Healy on the Dryden Theatre stage.
George Eastman House: "Your first film was in '96. How many scripts did you guys work on together before you hit on one that got made?"
Payne: "Actually in '91 we wrote and I directed two shorts for the Playboy Channel called INSIDE OUT – an anthology series. The producer Alan Poul, who later produced SIX FEET UNDER, did that show. He tried to get who at the time he thought were cutting edge and non-DGA directors."
Audience member: "Has SIDEWAYS brought you a lot of freedom? Do you have a narrow window of opportunity? How secure do you feel?"
Jim Taylor: "We're doing really well. But we don't want to feel to secure. That could be a problem."
Payne: "But I think filmmakers should act as though they have complete freedom. Especially when we're writing, we're pretending we have a billion dollar budget. Let restrictions come later."
Payne on classic Hollywood cinema: "The more I learn as a film director, the more I learn about technique, the more I see the huge achievement of the classical Hollywood film style. No matter how they are made or under what conditions, a director is always thinking about how to make the actors move and where to put the camera. Whether you're Godard or Michael Curtiz, it's the same problem. Where do I put my actors and how do I move my camera. I see the elegance and practicality and efficiency and economy with which classical Hollywood film directors worked. And it's astonishing. Young film school kids in love with the French New Wave, or now they talk about Korean cinema or something like that, they might [minimize] the film that they've seen the most, like CASABLANCA (1942). I say go try to make a CASABLANCA. Making something like that is going to be harder than trying to emulate any of these other films."
Because it is my blog I can close with my favorite part of the evening. Jim reminded the audience that "we should remember the Stanley Kubrick quote that 'the only person in the world who has final cut is the projectionist'. So kudos to Ben Tucker up there in the booth."
Payne: "Thank you, Ben."
Those moments make it fun to work at George Eastman House.
We wish Alexander Payne and Jim Taylor the best of luck on Oscar night.
Payne with audience members after the screening.
Ben Tucker is the Processing Technician in the Motion Picture Department. He has been employed by George Eastman House since 2003.


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We have included all charges provided to us by this hotel. However, charges can vary, for example, based on length of stay or the room you book.


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Your first look at what's happening around Milwaukee. All of the latest events you can't miss in the city.
On Tap Today: Day of the Dead, Halloween holdovers, Ricky Skaggs, Katt Williams
Halloween seems so yesterday. But the action isn't letting up.
Dia de los Muertos. Milwaukee's celebration really gets going with a parade in Walker's Point starting at 5 p.m. in Walker Square Park.
But if you still can't let go of Halloween, there's a Haunted Brewery Bash at Best Place at the former Pabst Brewery site and Highbury Pub's video-game-themed costume party tonight.
Ricky Skaggs and Bruce Hornsby, who joined forces recently to create a pretty interesting album, are at Potawatomi Bingo Casino's Northern Lights Theater tonight at 8.
Comedian Katt Williams brings a new attitude, or so he says, when he plays the U.S. Cellular Arena at 8 tonight.
Comments »
Read and share your thoughts on this story.


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The Seattle Seahawks continued to talk to Vincent Jackson's representatives on Saturday, but "the price was too high," according to a source familiar with the dealings.
That is, the price Jackson was asking was still too high.
I don't know exactly what that price is, but Clark Judge from CBSSports.com talked to one NFC general manager who indicated it was darn near the price reported two weeks ago that was a week later disputed by one of Jackson's agents.
Judge cites the unnamed G.M. saying the Chargers started by asking for the same thing they'd essentially been asking for all offseason — first-round and third-round picks — but that price dropped to "almost anything."
The Chargers placed a first-and-third tender on Jackson back in March. That gave Jackson a $3.268 million one-year deal with the Chargers and the right to negotiate with other teams. Had another team signed Jackson, it would have also had to give the Chargers those two draft picks (or another negotiated price).
That did not happen, and Jackson and left tackle Marcus McNeill, also unhappy with his contract status, had their tenders reduced on June 15 by more than $2.5 million. Both are believed to be willing to sit out the season.
Tags: 5 Million, Chargers, Contract Status, Draft Picks, nfc, SEATTLE SEAHAWKS, Sit, Tenders, vincent jackson
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