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sandratayler July 26 2014, 04:11

Unwinding the Stress

I came out of the theater happy even though I wasn’t certain I’d enjoyed the movie. The summer air was warm even at 1am and the world had that quiet feeling it gets when most of the people in the city have already gone to bed. We weren’t alone at that late night showing, but people dispersed quickly afterward. I felt light and free. The movie (Lucy) wasn’t my favorite, but it had many things to discuss, praise, and rant about, which made it a great movie for Howard and I. We love to dissect movies after we’ve seen them. Howard held my hand as we walked to the car. We’ve been married twenty years. We share four kids, a household, and a business. We slip into business conversations without even thinking about it. Yet sometimes we can shed all of that and just be Howard and Sandra. I wanted to stay out in the summer air and just twirl around in that freedom.

Instead I got to dash back to the theater because I’d felt so free that I’d forgotten to pick up my purse when exiting. I got it back without trouble. Even the dash back to the theater felt exhilarating, not worrisome. It was exactly what I needed after a day which had been filled with flashes of random stress and anxiety. We didn’t linger, we went home and to bed like responsible adults who like their jobs and know they get to do them again in the morning. I suppose in my case it helped that my job for the morning was to take the kids to the water park.

Public places like water parks can be highly stressful. For most of my parenting years they were exactly that. Then the kids got older and we became familiar enough with the park that the whole experience was more predictable. I’ve often heard it said that humans seek out novel experiences. Our family does too, but we like the new things to be structured around predictable things. If I have too many variables to track, then I experience stress rather than relaxation. There are times when the stress of new experiences is good. What I wanted and needed was to extend the relaxation which began with the late night movie. So I swam with the kids and felt the sun dry me off. I got just a little bit sunburned in the places that I missed with the sunscreen. We came home ready for a slow afternoon.

I still had things to do, of course. I’d earned a slower day by working frantically earlier in the week, but there were some things that needed to be complete before the weekend. Those things fit into the afternoon between the water park and the church picnic.

Tables were set up in a cul de sac. Some of the men had pulled out their grills and were cooking hamburgers. The members of the congregation had brought their chairs and were mingling around the tables of food and across the lawns. I thought that I probably ought to be reaching out and reconnecting to the many people that I care about who were present. Instead I found myself a quiet spot where I could watch. I wanted to be there, but I had low social energy. I caught up with some friends who came to sit with me. I was glad of that. I also loved watching the multi-generational crowd as they ate and played with the dunk tank set up in front of one of the houses. I’ve lived in this neighborhood long enough to watch some kids grow up and have kids of their own. I loved that I could be part of it, even when I mostly sat and watched.

I walked home in the cooler air of the evening. Our back lawn was soft under my feet. I paused a moment to survey the spot where our deck used to be. I like it better without the deck there. It feels more open. I’ll like it even better when the space is something lovelier than a patch of dirt. Yet it is nice to have a project that can wait until later, when we’re not in high summer. We’ve only a few more weeks of hot summer left.

I’ve been watching the end of July come closer. As soon as we hit August, we’re in the last slide toward the school year. I’ll have to pull out the letters from the school and figure out what they hoped I’d do with the kids over the summer. We’ll have only bare reading logs when the first day of school arrived. The kid read plenty over the summer, but I excused them and myself from tracking or measuring any of it. Today I managed to do the same for myself and it was good.

Comments are open on the original post at onecobble.com.

kayre July 26 2014, 01:50

So....

I was waiting in line for a haircut this morning. I had already turned my phone down, so after a bit I checked it, and there was a voicemail message from my contact at Just Right Presby. There was still someone ahead of me so I slipped out and returned his call. After the opening greetings, he said "I'd like to offer you a job!" I said "oh, please do!" and he laid out the details-- about 20% more than I'm making now, 5 Sundays off per year. I accepted on the spot, having already decided that this was best for me and my family.

Things that make me especially happy:

Being a Presbyterian again, after 30 years a Methodist and nearly 6 years serving Lutherans.
Pipes!
A genuine choir, a dozen folk capable of singing in 4 parts, even willing to attempt a cappella.
12 hours later, I've gotten 'hello' emails from the pastor and 2 committee heads.
The title is Minister of Music-- a title I've actually never held.

I've emailed Too Big Lutheran telling them I'm withdrawing my application, and phoned Too Small Methodist. That was hard; they don't have another candidate, and there's a lot I found appealing about them. In fact, I even said that if there's any way I can help with some of the outreach ideas Rev. P. has without stepping on the toes of whoever they hire, I would love to do so.
hrrunka July 25 2014, 21:04

Museums...

Sunday last, I didn't do much, apart from replace the two remaining small guy-line stakes for my mast with new larger ones. That was a tiring exercise involving quite a bit of hammering.

Monday I spent a while trying to sort a few things out, and made a trip to the shops mid-to-late afternoon. While walking home from the shops I heard Colin calling on VHF, but was unable to get back to him on the hand-held. The rather more powerful rig at home did manage to get through, but by that stage he wasn't that far away. In the evening we went along to one of my radio clubs. It was an informal fix-it and chat evening, and that gave Colin a chance to demonstrate his MTR.

Tuesday morning we headed for the recently re-opened Imperial War Museum. On the way in we were handed timed tickets for the new World War One gallery, but once we got inside it became fairly obvious that the queue was long. Rather than stand around for an hour or more, we instead went and had a look at some of the other galleries. The new layout suffered somewhat from a labelling scheme that often puts the explanations for exhibits some distance from the exhibits themselves. The most informative gallery we visited, the Ashcroft Gallery, was also the only one in which exhibits and explanations were one beside the other. At lunchtime we took a look at the eateries in the IWM (and the queues and prices in them) and decided we'd seen enough there for one day. We bought a snack from Tescos along the way, and headed across to H.M.S. Belfast. Unfortunately (but rather as we'd expected), nobody was in the Bridge Wireless Office, but we spent at least a couple of hours looking round the old ship, and headed home just as the evening rush was beginning. In the evening we went out to take advantage of Wetherspoons Steak Club, and made up for the light lunchtime snack we'd had earlier.

On Wednesday morning, after a brief geocache hunt, Colin headed home. I think I spent much of the rest of the day doing very little.

Thursday morning's Morse practice was both better and worse than last week's. My overall accuracy at 12 words-per-minute was down on last week, but the longest single stretch of error-free reception was rather better. In the evening there was an entertaining talk at the local astronomical society meeting.

Today I've been to the shops, and to try to sort out a problem with a friend's doorbell, and done not much else. There have been a couple of nearby thunderstorms, but neither of them dropped much rain here. They were, however, near enough for me to decide to unplug antennas and do something not directly radio-related. This evening's been a quiet one, with no gaming. There was a pretty sunset.
mizkit July 25 2014, 16:59

Recent Reads/GGK Book Club: A Song for Arbonne

I just finished A SONG FOR ARBONNE, which was May’s GGK Book Club book. (I’m working on catching up! I bet I’ll be almost caught up by the end of the year! :))

I’ve been kind of interested in re-reading SONG, because I’ve only read it once and it didn’t, er, sing to me, as it were. It’s the one GGK book I’ve never had any particular interest *in* re-reading, which, in the end, caused me to be interested in re-reading it. I was wondering if it was my callow youth that caused it to not click, or if it was the book itself, or, well, what.

It’s the book.

SONG’s real problem for me—and I can remember, however vaguely, that this was its essential problem 20+ years ago as well—is that it is not TIGANA. Now, this is frankly an unfair assessment, because I don’t like to, and try not to, judge books for not being what I want them to be. Especially when the book it’s failing to be is my favourite book, full stop.

The thing is, I feel like SONG wants to be TIGANA. It has so many of the same themes: love of (complicated) family, love of country, love of music, and all the costs therein. It’s not the same story, not even vaguely, but to me, as a reader, it just feels like thematically it’s already been done, and done more powerfully, in TIGANA.

Maybe I’m reading it as the wrong kind of song. Maybe it’s a ballad to TIGANA’s overture, I don’t know, but it just doesn’t work for me the way TIGANA does. I can even see moments in it where I feel like it *should*, but it doesn’t reach the heights (or the depths). I kind of wish I could step back and read SONG first, just to see if, delivered outside of TIGANA’s shadow, it would hit me more powerfully.

There was also—noticeably to me now—the attitude of the main character, Blaise, toward women. It was progressive for his people, but Arbonne’s society is modeled on Eleanor of Aquitaine’s Court of Love, and is ruled by a woman, which Blaise doesn’t start out thinking very highly of. I suspect that my distaste for his distaste may have colored my reading back then; it *certainly* did this time. (He comes around, and does so in a way and a timeline appropriate to both himself and the book, but starting where he does kind of makes me want to smack him around. Again, not a really fair assessment, but there you go.)

Even so, I think I liked it better this time: I wasn’t so much expecting it to be TIGANA, maybe. It was in most ways a total revelation, as I remembered exactly one thing (the big secret revealed at the end) and it turned out I’d entirely forgotten all the particulars (indeed, remembering the big secret caused me to completely incorrectly assign the secret to someone and I was actually surprised when I turned out to be wrong), so it was a pretty satisfying read in most regards.

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(x-posted from The Essential Kit)

inthepipeline July 25 2014, 13:45

The Antibiotic Gap: It's All of the Above

http://pipeline.corante.com/archives/2014/07/25/the_antibiotic_gap_its_all_of_the_above.php

Here's a business-section column at the New York Times on the problem of antibiotic drug discovery. To those of us following the industry, the problems of antibiotic drug discovery are big pieces of furniture that we've lived with all our lives; we hardly even notice if we bump into them again. You'd think that readers of the Times or other such outlets would have come across the topic a few times before, too, but there must always be a group for which it's new, no matter how many books and newspaper articles and magazine covers and TV segments are done on it. It's certainly important enough - there's no doubt that we really are going to be in big trouble if we don't keep up the arms race against the bacteria.

This piece takes the tack of "If drug discovery is actually doing OK, where are the new antibiotics?" Here's a key section:

Antibiotics face a daunting proposition. They are not only becoming more difficult to develop, but they are also not obviously profitable. Unlike, say, cancer drugs, which can be spectacularly expensive and may need to be taken for life, antibiotics do not command top dollar from hospitals. What’s more, they tend to be prescribed for only short periods of time.

Importantly, any new breakthrough antibiotic is likely to be jealously guarded by doctors and health officials for as long as possible, and used only as a drug of last resort to prevent bacteria from developing resistance. By the time it became a mass-market drug, companies fear, it could be already off patent and subject to competition from generics that would drive its price down.

Antibiotics are not the only drugs getting the cold shoulder, however. Research on treatments to combat H.I.V./AIDS is also drying up, according to the research at Yale, mostly because the cost and time required for development are increasing. Research into new cardiovascular therapies has mostly stuck to less risky “me too” drugs.

This mixes several different issues, unfortunately, and if a reader doesn't follow the drug industry (or medical research in general), then they may well not realize this. (And that's the most likely sort of reader for this article - people who do follow such things have heard all of this before). The reason that cardiovascular drug research seems to have waned is that we already have a pretty good arsenal of drugs for the most common cardiovascular conditions. There are a huge number of options for managing high blood pressure, for example, and they're mostly generic drugs by now. The same goes for lowering LDL: it's going to be hard to beat the statins, especially generic Lipitor. But there is a new class coming along targeting PCSK9 that is going to try to do just that. This is a very hot area of drug development (as the author of the Times column could have found without much effort), although the only reason it's so big is that PCSK9 is the only pathway known that could actually be more effective at lowering LDL than the statins. (How well it does that in the long term, and what the accompanying safety profile might be, are the subject of ongoing billion-dollar efforts). The point is, the barriers to entry in cardiovascular are, by now, rather high: a lot of good drugs are known that address a lot of the common problems. If you want to go after a new drug in the space, you need a new mechanism, like PCSK9 (and those are thin on the ground), or you need to find something that works against some of the unmet needs that people have already tried to fix and failed (such as stroke, a notorious swamp of drug development which has swallowed many large expeditions without a trace).

To be honest, HIV is a smaller-scale version of the same thing. The existing suite of therapies is large and diverse, and keeps the disease in check in huge numbers of patients. All sorts of other mechanisms have been tried as well, and found wanting in the development stage. If you want to find a new drug for HIV, you have a very high entry barrier again, because pretty most of the reasonable ways to attack the problem have already been tried. The focus now is on trying to "flush out" latent HIV from cells, which might actually lead to a cure. But no one knows yet if that's feasible, how well it will work when it's tried, or what the best way to do it might be. There were headlines on this just the other day.

The barriers to entry in the antibiotic field area similarly high, and that's what this article seems to have missed completely. All the known reasonable routes of antibiotic action have been thoroughly worked over by now. As mentioned here the other day, if you just start screening your million-compound libraries against bacteria to see what kills them, you will find a vast pile of stuff that will kill your own cells, too, which is not what you want, and once you've cleared those out, you will find a still-pretty-vast pile of compounds that work through mechanisms that we already have antibiotics targeting. Needles in haystacks have nothing on this.

In fact, a lot of not-so-reasonable routes have been worked over, too. I keep sending people to this article, which is now seven years old and talks about research efforts even older than that. It's the story of GlaxoSmithKline's exhaustive antibiotics research efforts, and it also tells you how many drugs they got out of it all in the end: zip. Not a thing. From what I can see, the folks who worked on this over the last fifteen or twenty years at AstraZeneca could easily write the same sort of article - they've published all kinds of things against a wide variety of bacterial targets, and I don't think any of it has led to an actual drug.

This brings up another thing mentioned in the Times column. Here's the quote:

This is particularly striking at a time when the pharmaceutical industry is unusually optimistic about the future of medical innovation. Dr. Mikael Dolsten, who oversees worldwide research and development at Pfizer, points out that if progress in the 15 years until 2010 or so looked sluggish, it was just because it takes time to figure out how to turn breakthroughs like the map of the human genome into new drugs.

Ah, but bacterial genomes were sequenced before the human one was (and they're more simple, at that). Keep in mind also that proof-of-concept for new targets can be easier to obtain in bacteria (if you manage to find any chemical matter, that is). I well recall talking with a bunch of people in 1997 who were poring over the sequence data for a human pathogen, fresh off the presses, and their optimism about all the targets that they were going to find in there, and the great new approaches they were going to be able to take. They tried it. None of it worked. Over and over, none of it worked. People had a head start in this area, genomically speaking, with an easier development path than many other therapeutic areas, and still nothing worked.

So while many large drug companies have exited antibiotic research over the years, not all of them did. But the ones that stayed have poured effort and money, over and over, down a large drain. Nothing has come out of the work. There are a number of smaller companies in the space as well, for whom even a small success would mean a lot, but they haven't been having an easy time of it, either.

Now, one thing the Times article gets right is that the financial incentives for new antibiotics are a different thing entirely than the rest of the drug discovery world. Getting one of these new approaches in LDL or HIV to work would at least be highly profitable - the PCSK9 competitors certainly are working on that basis. Alzheimer's is another good example of an area that has yielded no useful drugs whatsoever despite ferocious amounts of effort, but people keep at it because the first company to find a real Alzheimer's drug will be very well rewarded indeed. (The Times article says that this hasn't been researched enough, either, which makes me wonder what areas have been). But any great new antibiotic would be shelved for emergencies, and rightly so.

But that by itself is not enough to explain the shortage of those great new antibiotics. It's everything at once: the traditional approaches are played out and the genomic-revolution stuff has been tried, so the unpromising economics makes the search for yet another approach that much harder.

Note: be sure to see the comments for perspectives from others who've also done antibiotic research, including some who disagree. I don't think we'll find anyone who says it's easy, though, but you never know.

jhetley July 25 2014, 11:33

And another Friday

Air temperature 54 F for the newspaper walk, dew point 49, light west wind, scattered clouds.  Also, for some reason, a light plane circling over the neighborhood to the north.  Fairly low, probably at the minimum altitude.

Speaking of light aircraft, Wife and I stirred up a group of crow-sized pointy-winged birds over at the park yesterday evening.  One of them went "ki-ki-ki" when it vanished into a tree.  I think we have a family of Cooper's hawks, who are welcome to all the starlings they can eat.  And then some.
jhetley July 24 2014, 16:47

Thursday floral report

Either field thistle or pasture thistle has joined the Canada thistle on the roadsides.  Can't tell the difference between the first two on bicycle botany.  Maybe both.  Meanwhile, tansy, goatsbeard, birdsfoot trefoil, and goldenrod are battling for roadside yellow supremacy.

No fresh roadkill.  A red squirrel attempted suicide near the golf course, but turned back at the last second.  And something has been working on that small raccoon, dragging it to the edge of the asphalt.  I suspect crows -- coyote or fox would have hauled it into the woods.

Cooler, dryer, but windy.  Got out on the bike, added miles, did not die.

15.29 miles, 1:11:43
inthepipeline July 24 2014, 14:28

Phenotypic Assays in Cancer Drug Discovery

http://pipeline.corante.com/archives/2014/07/24/phenotypic_assays_in_cancer_drug_discovery.php

The topic of phenotypic screening has come up around here many times, as indeed it comes up very often in drug discovery. Give your compounds to cells or to animals and look for the effect you want: what could be simpler? Well, a lot of things could, as anyone who's actually done this sort of screening will be glad to tell you, but done right, it's a very powerful technique.

It's also true that a huge amount of industrial effort is going into cancer drug discovery, so you'd think that there would be a natural overlap between these: see if your compounds kill or slow cancer cells, or tumors in an animal, and you're on track, right? But there's a huge disconnect here, and that's the subject of a new paper in Nature Reviews Drug Discovery. (Full disclosure: one of the authors is a former colleague, and I had a chance to look over the manuscript while it was being prepared). Here's the hard part:

Among the factors contributing to the growing interest in phenotypic screening in drug discovery in general is the perception that, by avoiding oversimplified reductionist assumptions regarding molecular targets and instead focusing on functional effects, compounds that are discovered in phenotypic assays may be more likely to show clinical efficacy. However, cancer presents a challenge to this perception as the cell-based models that are typically used in cancer drug discovery are poor surrogates of the actual disease. The definitive test of both target hypotheses and phenotypic models can only be carried out in the clinic. The challenge of cancer drug discovery is to maximize the probability that drugs discovered by either biochemical or phenotypic methods will translate into clinical efficacy and improved disease control.

Good models in living systems, which are vital to any phenotypic drug discovery effort, are very much lacking in oncology. It's not that you can't get plenty of cancer cells to grow in a dish - they'll take over your other cell cultures if they get a chance. But those aren't the cells that you're going to be dealing with in vivo, not any more. Cancer cells tend to be genetically unstable, constantly throwing off mutations, and the in vitro lines are adapted to living in cull culture. That's true even if you implant them back into immune-compromised mice (the xenograft models). The number of drugs that look great in xenograft models and failed out in the real world is too large to count.

So doing pure phenotypic drug discovery against cancer is very difficult - you go down a lot of blind alleys, which is what phenotypic screening is supposed to prevent. The explosion of knowledge about cellular pathways in tumor cells has led to uncountable numbers of target-driven approaches instead, but (as everyone has had a chance to find out), it's rare to find a real-world cancer patient who can be helped by a single-target drug. Gleevec is the example that everyone thinks of, but the cruel truth is that it's the exceptional exception. All those newspaper articles ten years ago that heralded a wonderful era of targeted wonder drugs for cancer? They were wrong.

So what to do? This paper suggests that the answer is a hybrid approach:

For the purpose of this article, we consider ‘pure’ phenotypic screening to be a discovery process that identifies chemical entities that have desirable biological (phenotypic) effects on cells or organisms without having prior knowledge of their biochemical activity or mode of action against a specific molecular target or targets. However, in practice, many phenotypically driven discovery projects are not target-agnostic; conversely, effective target-based discovery relies heavily on phenotypic assays. Determining the causal relationships between target inhibition and phenotypic effects may well open up new and unexpected avenues of cancer biology.

In light of these considerations, we propose that in practice a considerable proportion of cancer drug discovery falls between pure PDD and TDD, in a category that we term ‘mechanism-informed phenotypic drug discovery’ (MIPDD). This category includes inhibitors of known or hypothesized molecular targets that are identified and/or optimized by assessing their effects on a therapeutically relevant phenotype, as well as drug candidates that are identified by their effect on a mechanistically defined phenotype or phenotypic marker and subsequently optimized for a specific target-engagement MOA.

I've heard these referred to as "directed phenotypic screens", and while challenging, it can be a very fruitful way to go. Balancing the two ways of working is the tricky part: you don't want to slack up on the model just so it'll give you results, if those results aren't going to be meaningful. And you don't want to be so dogmatic about your target ideas that you walk away from something that could be useful, but doesn't fit your scheme. If you can keep all these factors in line, you're a real drug discovery scientist, and no mistake.

How hard this is can be seen from the paper's Table 1, where they look over the oncology approvals since 1999, and classify them by what approaches were used for lead discovery and lead optimization. There's a pile of 21 kinase inhibitors (and eight other compounds) over in the box where both phases were driven by inhibition of a known target. And there are ten compounds whose origins were in straight phenotypic screening, with various paths forward after that. But the "mechanism-informed phenotypic screen" category is the shortest list of the three lead discovery approaches: seven compounds, optimized in various ways. (The authors are upfront about the difficulties of assembling this sort of overview - it can be hard to say just what really happened during discovery and development, and we don't have the data on the failures).

Of those 29 pure-target-based drugs, 18 were follow-ons to mechanisms that had already been developed. At this point, you'd expect to hear that the phenotypic assays, by contrast, delivered a lot more new mechanisms. But this isn't the case: 14 follow-ons versus five first-in-class. This really isn't what phenotypic screening is supposed to deliver (and has delivered in the past), and I agree with the paper that this shows how difficult it has been to do real phenotypic discovery in this field. The few assays that translate to the clinic tend to keep discovering the same sorts of things. (And once again, the analogy to antibacterials comes to mind, because that's exactly what happens if you do a straight phenotypic screen for antibacterials. You find the same old stuff. That field, too, has been moving toward hybrid target/phenotypic approaches).

The situation might be changing a bit. If you look at the drugs in the clinic (Phase II and Phase III), as opposed to the older ones that have made it all the way through, there are still a vast pile of target-driven ones (mostly kinase inhibitors). But you can find more examples of phenotypic candidates, and among them an unusually high proportion of outright no-mechanism-known compounds. Those are tricky to develop in this field:

In cases where the efficacy arises from the engagement of a cryptic target (or mechanism) other than the nominally identified one, there is potential for substan- tial downside. One of the driving rationales of targeted discovery in cancer is that patients can be selected by pre- dictive biomarkers. Therefore, if the nominal target is not responsible for the actions of the drug, an incorrect diagnostic hypothesis may result in the selection of patients who will — at best — not derive benefit. For example, multiple clinical trials of the nominal RAF inhibitor sorafenib in melanoma showed no benefit, regardless of the BRAF mutation status. This is consistent with the evidence that the primary target and pharmacodynamic driver of efficacy for sorafenib is actually VEGFR2. The more recent clinical success of the bona fide BRAF inhibitor vemurafenib in melanoma demonstrates that the target hypothesis of BRAF for melanoma was valid.

So, if you're going to do this mechanism-informed phenotypic screening, just how do you go about it? High-content screening techniques are one approach: get as much data as possible about the effects of your compounds, both at the molecular and cellular level (the latter by imaging). Using better cell assays is crucial: make them as realistic as you can (three-dimensional culture, co-culture with other cell types, etc.), and go for cells that are as close to primary tissue as possible. None of this is easy, or cheap, but the engineer's triangle is always in effect ("Fast, Cheap, Good: Pick Any Two").

jhetley July 24 2014, 11:49

Drizzle-gray

Damp but not actually raining, managed to walk for the newspaper.  Air temperature 64 F, dew point 57, wind NNE at 12 mph.  There is a non-zero chance of a bike ride later.

So far, no retaliation from the local avians for my removal of that dead rowan.  I'd be more worried if it had been a favored mockingbird perch -- they remember faces, and can be vindictive.  Sparrows don't seem to carry grudges.  And the tree was really too small for crows to grow fond of it.

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