text:
As I
read through Extremity Retained,the
excellent collection of Death Metal interviews compiled, edited, and
given context by my friend Jason Netherton, it brings back a lot of
memories and thoughts on the Death Metal scene and my now two-plus
decade long involvement in it (yup, feeling old here!). It's full of
great reminiscences from many of my peers and as well as from guys I
looked up to in the early days of Exhumed. I can't help but feel a bit reflective and look back on the changes and course of the genre in general. The thing that still strikes me the most was the transformation in the sound of the genre between '90 and '95. I thought I'd use my band's blog as a place to spout off a few ideas about how and why the genre went out of fashion in the mid 1990s, much like Thrash Metal did in 1991. I suppose these reflections would have fit in better with my (generously included) contributions in the book, but reading it as a whole kind of spurred me into thinking about all of this and writing this all out.
If you don't have this book yet, fucking buy it!! |
don't remember exactly who I was talking to, but I was looking back
on my days as a rabid Death Metaller from '90-'94 or so, and I was
saying that after around '94 I lost interest in the Death Metal scene
and got heavily into Thrash Metal and Crossover from the '80s. They
responded, with a healthy degree of good natured ribbing, that
'93-'94 was when I "gave up on Death Metal." That sentence kind
of hit me like a glass of cold water in the face. I would say I've
done many things in my life, but one thing I never felt that I did
was "give up on Death Metal." I felt like by '93 and '94 Death
Metal had lost the vast majority of what made it interesting to me.
The bands that intrigued me the most (Carcass,
had either moved on creatively to other styles of music or hadn't
existed for a few years at that point (except for Autopsy,
who were on the verge of splitting up by then).
I felt like Death Metal had given up on me.
With the rise to prominence of Cannibal
(I suppose they had always been prominent), and Suffocation
– who, by '95 represented the last high-speed bands standing
had become quasi-groove metal by the time World Demise hit
and Napalm
was dabbling heavily in industrial metal), the punk-infused, loose
and nasty form of Death Metal was in short supply. Unleashed
Grave had
both slowed their sounds down by the mid-90s, and even Slaughter
of the Soul, one
of my favorite albums of the period, owes more to Dark
Angel than
it does to the obscure Death Metal of the band's earlier period.
Certainly record labels had given up on Death Metal – with the
exception (mostly) of Relapse, but even they were well on their way
to creating an aesthetic that would enable them to sign a band like
Neurosis (which
was sincere, as well as a savvy business move). Not the best time to
be a Massacre and
Necrovore fan.
So, this begs the question – what
happened between '88 and '93 that contributed to the genre's downturn in popularity in the mid '90s and its subsequent stylistic permutations? How did "the end of music as
we know it" become such an over-saturated sub-genre ready to be supplanted as the de rigueur underground Metal style? Like
any question covering an international artistic movement, there are a
lot of answers.
- Part I: The "real musicians"
thing that I think is often ignored, that still grates me to this day
is that around '91-'92, we saw the the introduction of "real
musicians" into the Death Metal genre. In 1988, every guitar nerd
with a flourescent Ibanez guitar with a handle in it was in a Thrash Metal band of some iteration or other - funk-thrash was gaining a lot of traction around '91. Seriously. That was a thing.
When I was growing up, these were very popular rock and metal guitars. Yeah, it's not all "glory days" this and "good old days" that, let me tell you.
Why were they playing Thrash? Because it had
the virtue of being intense and affording musicians more room to show
off their chops but was still comparatively mainstream and had a wide
enough audience that you would be showing off your chops to someone.
and Antrhrax
were selling records by the truck-load and even Coroner,
and Kreator
had videos on MTV.
If you had cable TV and nothing to do on a Saturday night in 1989, you could see this. It was fucking awesome.
But, as with anything, the popularity of Thrash
Metal faded with its novelty – what was innovative in 1983 was
trite by 1989. When Thrash Metal died out in about '91 or so (the
"Clash of the Titans" tour effectively capped the end of the
Thrash Metal era) fans were divided. Of course, some people no longer
cared about music and became accountants that listened to the radio,
but those who continued as members of a "scene" or avid
record-buyers / concert-goes tended to split in two directions.
Firstly, many younger males moved on from Thrash to Death Metal as
Roadrunner and Earache began to gobble up record store rack space
previously occupied by Noise Records and Combat. Older males and
females across the age-spectrum of thrash fandom however, moved
toward grunge – the logical endpoint of crossover. Grunge provided
the volume and bombast of mainstream metal with the simplification
and lack of pretension of punk, and succeeded in becoming a
watered-down, commercially appealing equivalent of both. While Death
Metal absorbed the far smaller portion of recently displaced music
fans, that influx of audience members was a massive growth spurt for
the previously super-underground genre.
Which brings us back to our Funk-Thrashing, Guitar-Center frequenting friends I mentioned earlier, eager for an intense form of music to show off their diligently practiced chops. They were a different breed than the original generation of Death Metal musicians, who never got into the genre with traditional ideas of musical development as instrumentalists, simply because Death Metal was beyond underground, and borderline unacceptable in the mid-80s. People that wanted to pursue "musicality" just weren't into Death Metal. When Death, Massacre, Xecutioner, Morbid Angel, Master, Autopsy, Carcass and Napalm Death were honing their craft, "real musicians" were just beginning to admit that Metallica wasn't a bunch of racket – but the sounds cranked out by the aforementioned bands? That was pure noise, bad comedy. Every Death or Black Metal band from the early 80s (Sodom, Kreator, Possessed, Bathory, Sacrifice, Possessed, et al) moved as quickly towards Thrash Metal as their musical prowess would allow. However, by '91-'92, these legions of Guitar for the Practicing Musician readers were joining, or worse, forming, Death Metal bands. By 1993, Headbanger's Ball (at least in America) was on its way out. But videos from Carcass, Morbid Angel, Death, and Napalm Death were part of its last gasp. So the genre was as close to mass-exposed as it would ever be in the states. The result was very similar to what happened to Thrash Metal around '87 or '88 – there was a glut of extremely competent, utterly uninspiring bands releasing EP's and albums cluttering up the scene. The terrible paradox was that the records were performed more competently than ever, but with very little identity and real passion for the genre.
I can't say Nocturnus wasn't original, but I can say they did not have cool hair. |
many of the members of the innovative Death Metal bands mentioned
above grew to become excellent musicians in their own right – but
the distinction here is that Death
was the primary drive, not showing off their chops. As the '90s wore
on, the speed and "extremity" of Death Metal increasingly
attracted "musician" types who were out to prove that they were
the fastest or most technical - which were substituted for intensity and individuality, spawning legions of extremely skilled and marginally listenable tech-death bands. The musically reckless,
punk-infused side of Death Metal was waning by '93, so I retreated to
pastures that more closely reflected my personal flavor of choice: raw 80s
Metal - be it Death, Thrash, Crossover or just plain Heavy Metal, I
spent the second half of the '90s obsessing over records like
and Money Talks by
Cryptic Slaughter.
As much as I wasn't much of a black metal fan (although there were a
considerable number of those records I liked at the time) I
essentially sympathized with the Black Metal scene's attitude toward
what Death Metal had become by the mid-'90s – safe, sterile,
over-produced and over-saturated.
The classic "Anti-Scott Burns" graphic from Mayhem's Deathcrush EP. Even the catalog number of the release hates Earache Records. |
Interestingly enough, the same bands
that helped to push the genre's musical athleticism to new heights were also
responsible for spawning it's most knuckle-dragger-friendly cliches.
Suffocation balanced incredibly nimble, nuanced guitar-work with
the simplest, heaviest riffing the genre had see with Effigy of
the Forgotten, not only contributing to the
technical prowess of the genre as a whole, but also providing the
seeds for what would become "Slam" - probably the most
rhythmically simplistic form of Death Metal out there, which seems to
be incomprehensibly, yet intrinsically linked to the subject matter of pot-smoking and
pornography. Cannibal Corpse arrived as a musical force with
Tomb of the Mutilated, but simultaneously dragged the genre's obsession
with gore and violence into a brand of petulant misogyny that only
got more embarrassing with their next album, The Bleeding. Luckily, the band has eschewed
that sort of cheap sensationalism as time has progressed and focused
on horror and gore without overtly sexist themes after the departure of original vocalist Chris Barnes.
Although this song is admittedly very fucking badass.
- Part II: The labels
Of course, the host of mediocre,
uninspired and uninspiring musicians playing Death Metal were far
from the only culprits in the demise of the genre's brief commercial
peak. Equally culpable (possibly more so) are record labels, with
Roadrunner and Earache being the most egregious offenders. Labels,
like any other business, were in a race to produce the most
predictable return on their investment – a business practice that
quickly leads to artistic stagnation. Roadrunner seemed eager to give
all of the Death Metal projects to (the admittedly great) engineer /
producer Scott Burns, who faced with decreasing recording artist talent, increasing
workload, and decreasing budgets, spawned the "Morrisound Sound,"
which while it was a good sound (probably because it was a
good sound), was subsequently beaten into the ground. Between Dan
Seagrave's ubiquitous artwork and Scott Burns' increasingly
homogenous production, Death Metal albums were beginning to sound and
look frightfully predictable. Your Monstrosity became not too
unlike your Resurrection which wasn't that different from your
Brutality. The problem with these albums isn't that they're
awful – in fact they're actually pretty decent, and these records
honestly sound better today than they did 20 years ago - simply
because not every new album that you hear sounds like this anymore.
The problem is that these bands simply aren't remarkable. None of
them will ever have a Slowly We Rot or a Symphonies of
Sickness in their catalogs. And in all fairness, I don't know
that my band ever will either. I can live with that, but just
saying... And if my band had gotten signed in 1991, we would have JUMPED at the chance to record at Morrisound and have Dan Seagrave cover art. Which is one of the many reasons we weren't ready to be signed in 1991. Also, we sounded like crap.
Like I said... Pretty much crap.
Exhibits A, B, and C. Not exactly sure what's going on in any of these ambiguously spooky album covers or how they relate to the album titles at all. And 20 years later, I still can't quite muster up the energy to care.
By 1991, even a marginally savvy
record-buyer like myself (age 15/16) could tell that if it was a
Death Metal album on Roadrunner, it would have the same production,
the same artwork and it would be reliably decent. A genre can't grow
and can't remain relevant on "reliably decent." Thrash Metal
lasted nearly 10 years because every year you would get a significant, "future classic" sort of record, Show No Mercy to
The Legacy to ...And Justice For All to Beneath The
Remains (and those are just a few of only the "commercially
successful" thrash classics). Sure, there are tons of clunkers from
tons of bands in the Thrash genre, but many of the best Death Metal
bands with the most to say only made two or three albums in the genre
before abandoning it for something less aesthetically constrictive.
Heartwork is more closely aligned with Kreator or
Megadeth than with Extreme Noise Terror or S.O.B.
Wolverine Blues is I guess, sort of Death Metal? I dunno...
Still on the fence about this album 20 years later.
Equally as damaging was that by '95-'96, Nuclear Blast, Century Media, and Roadrunner had dropped most of their Death Metal bands. As soon as the genre's comparative popularity waned, most of the bands found themselves unsigned very quickly. Roadrunner even dropped Immolation for fuck's sake, so it wasn't just mediocre 2nd and 3rd generation bands getting the axe. Just as Death Metal had gotten musically complacent, the sensationalism of Black Metal came along and grabbed headlines with tales of arson and murder and a different (let's be honest - predominantly way shittier) sound. Soon treble-knob loving Scandinavians made Death Metal obsolete and the '90s iteration of Black Metal became the "extreme metal" of choice of the (truly awful) mid to late '90s, giving fat / really skinny dudes from Orange County a reason to either wear capes and buy drinking horns. That really sucked.
Everybody had THAT friend in 1996. |
- Part III: The inherent limitations
of the Death Metal genre
Which brings us to the third, and
probably most fatal problem preventing Death Metal from having any
breakthrough or sustainable commercial success or aesthetic longevity (as a creative and innovative medium). When your goal is to
put out the most extreme, horrifying and over-the-top record and you
succeed (even if only in your eyes), there's no place to artistically
go from there. You can either a) broaden your style, b) repeat yourself or c) simply
quit, like Repulsion did. When you begin at the musical end of
the line, with no melody, the fastest tempos your musicianship will
allow and the most evil, frightening riffs you can compose, anything
else you do is going to be either a slight variation on a theme or a
watering down of your sound.
The best example of quitting while you're ahead in the history of rock and roll. |
For this reason, to me, Death Metal
represents the ultimate endpoint of the entire genre of Rock Music.
We have to be realistic and concede that Rock and Roll is a 20th
century phenomenon. Lemmy is in his late 60s, and most of the genre's
originators are either dead or old enough to be great-grandparents.
Current successful rock bands do little more than parrot genre
cliches and Death Metal is no different. Taking Heavy Metal and punk
to their logical endpoints of gratuitous volume, speed, and power,
the genre effectively killed underground metal as a marketable
commodity in the United States for decade or more. Certainly its
intensity resonated on a larger scale and paved the way for bands
like Slipknot and Deftones to bring heavier (still extremely shitty if we're being honest) sounds to larger audiences
later on in the 90s, but that's hardly a mark of success. But realistically, Death Metal was never designed to be listenable or
sonically acceptable. In fact, it's just the opposite. Not that it
isn't musical or doesn't require talent (even though it really
doesn't sometimes), but it's supposed to be abrasive,
unlistenable and horrifying. It's fucking Death Metal after all.
That's one of the many reasons I have
a difficult time listening to the "Death Metal" of the late '90s
and beyond. Much of it is simply treading water on innovative ideas that had long
since been thoroughly explored by more inspired practitioners (my band's records probably fall into that category) - or
it's played by capable, well-meaning, but ultimately boring musicians who have
confused "intensity" and "brutality" with the number of beats
per minute in their drummer can quietly double-stroke his kick drums
at or how many riffs they can cram into one "song." Or, even worse, it's played by capable and well-meaning musicians who think that Death Metal would sound better if only it were blended with Jazz/Fusion or polyrhythms or dubstep or video-game sound effects or whatever the fuck kind of stuff musician types like to play.
As far as younger musicians, they have always been competitively minded. Today, we live in a world that, via widely available technology, is more and more quantified and quantifiable. The competitive approach to playing at higher and higher beats-per-minute, does follow a specific type of logic (if a dreadful lack of imagination). In the 21st century, everything has become calculable – from how many people click on the links in your press release and how many fans your band has, to the music itself. Also, everything has become edited - from photo shoots to movies that are more CGI than film, to auto-tune to quantized bass-drum tracks on "death metal" albums. Younger people see the world in more quantified terms, and view and create art with these standards in mind - and rightfully so. They are a new generation that has never experienced life without the internet and cell phones, and they are the youth and should be making youth music. But the way they play "Death Metal" bears little resemblance to albums I grew up with like Consuming Impulse or War Master. Furthermore, is Death Metal or any kind of Rock and Roll really "youth music" at this point? After all, Seven Churches came out in 1985 - almost thirty years ago at this point.
As far as younger musicians, they have always been competitively minded. Today, we live in a world that, via widely available technology, is more and more quantified and quantifiable. The competitive approach to playing at higher and higher beats-per-minute, does follow a specific type of logic (if a dreadful lack of imagination). In the 21st century, everything has become calculable – from how many people click on the links in your press release and how many fans your band has, to the music itself. Also, everything has become edited - from photo shoots to movies that are more CGI than film, to auto-tune to quantized bass-drum tracks on "death metal" albums. Younger people see the world in more quantified terms, and view and create art with these standards in mind - and rightfully so. They are a new generation that has never experienced life without the internet and cell phones, and they are the youth and should be making youth music. But the way they play "Death Metal" bears little resemblance to albums I grew up with like Consuming Impulse or War Master. Furthermore, is Death Metal or any kind of Rock and Roll really "youth music" at this point? After all, Seven Churches came out in 1985 - almost thirty years ago at this point.
Please don't tell me this is "thrash" - it's literally called "Death Metal." How much clearer can it be?? So yeah - roto-toms are Death Metal as fuck.
I'm not saying that's bad, but I'm
saying that it misses out on something intrinsic to the genre as I
know it. That's why a band like Nunslaughter or Asphyx
will always be more Death Metal than a band with tons of super-fast
blast beats or the "lowest" vocals. The quantifying of everything
reduces art to something measurable and cheapens the expression. Of
course, younger people won't see it that way, because they've grown
up with a different set of aesthetic values than I have, and that's
okay. I'm not saying that there's only one "true" way of Death
Metal for everyone, but I know that there is for me. And I'm fine
with that.
However... if there was only one "true" way of Death Metal, this would definitely be it.
- Part IV: "Classic Rock Syndrome"
Which brings me to my last point. If
someone had told me when I was sixteen I would be pushing forty and
still playing in Exhumed and that Morbid Angel
and Carcass would still be touring playing "Chapel of
Ghouls" and "Corporeal Jigsore Quandary" every night, I would
have laughed them out of the room. Because really, how long is any
kind of rock and roll movement supposed to last? The majority of the
punk movement sputtered out within five years, Thrash Metal went from
a regional curiosity in San Francisco, Germany and Los Angeles to a
global phenomenon and then to a virtually dead style within eight
years or so. The New Wave of British Heavy Metal went from about
'77-'82. The superstars of the sixties rock world (Hendrix,
The Beatles, The Doors) became
permanently enshrined precisely because they didn't last.
No reunion tours currently in the works, at least according to Bandsintown. Sorry - too soon? |
And yet here we have Death Metal
bands whose creative peaks are long since behind them trotting out
the hits night after night on the tour circuit. Like all bastard
sons, Death Metal killed its father (or at least gave it the old college try) – mainstream rock and metal –
and then proceeded to take on his most repugnant attributes – greatest
hits tours, creative water-treading and, worst of all, artists
giving the people precisely what they want - whether it's
reunions, creatively stagnant but reliably consistent albums, or just
more Altars of Madness shirts.
I can't wait for the reissue with "40 Years of Madness" on the back.
Ultimately it's bittersweet. Because,
besides playing this music, first and foremost, I'm a fan of the
genre and I enjoy reunion tours and Altars of Madness t-shirts.
Being an optimist, I have to find it encouraging that all of the
hellish racket captured on demo tapes, LPs, 7 inches and CDs in the
80s and 90s has created something that's still with us today. We live
in a capitalist, commercial society, and those avenues ultimately
become the litmus test for an artistic statement's viability. If
there's a market for it, it's still around. And surprisingly enough,
there is still a market for Death Metal, though not as booming or on
the upswing as it was 22 years ago. But it couldn't be any other way.
- Epilog: Is music that big of a deal
anymore anyway?
I'm going to end this on a
question... Certainly in the 80s and early 90s there were large
portions of teenagers that identified specifically as a social group
based around music preferences - metal, goth, punk, rap, whatever. Whether that's the case now, I have
no idea. And if it is the case, does the music mean as much to the
audience when they get it for free from the comfort of their own
computer desk? Or directly to their cell phone? To me – from an old
curmudgeon's point of view – it's difficult to see how a musical
movement can be as personal or mean as much to a teenager today when they haven't
invested nearly as much time, effort and money into finding and
purchasing the music. Or maybe it will mean a lot, but will it mean a
lot for twenty years? They'll never have to ride their bike an extra
five miles because the record store down the street doesn't stock
Napalm Death. They'll never need to make mix-tapes in real
time (they're lucky – that shit is tedious). I don't want to get
into the whole "younger people have shorter attention spans"
bullshit, because every generation says that and I heard it about
Atari 2600 and music videos, so fuck that – but without the effort
of spending your hard-earned money on music, having to actually turn
up to gigs to see bands, needing to memorize information about bands
or hold onto zines and mags, is it really as personal? I hope so, but
the experience is so different today from what I grew up with that I
really don't know.
I'm pretty sure these chicks were feeling it! |
The entire attitude toward music in
our society has shifted. It was always seen as financially tenuous and a bad risk, but now it's degraded to something that's nice, but ultimately valueless. It's
something people give away for free. It's something that is so easy
to steal, it's not even a crime to steal it. I've illegally
downloaded stuff too, so I'm not putting myself above anyone here. I
just think that the way technology has evolved, pop music (which
includes rock, metal, punk, R&B, hip-hop, oldies, country, and
anything else you might hear on FM radio) has become a disposable,
public-domain type commodity. That change may open up a host of new
business opportunities for music to someone far more creative and
foresighted than myself, but as it stands now, it has created a
culture that severely devalues music. Even streaming services like
Pandora and Spotify are struggling from what I've read.
All of that said, one of the greatest
things about being a "genre" fan and musician (it's the same in
film, books, television, probably other arts as well) is that people
who are really into the genre are lifers. Go to any Star Trek
convention or ask a nerd about the Serenity TV show and you will see
a tremendous outpouring of passion. People into metal –
the more underground the truer this holds – have that same kind of
Trekkie-level excitement about stuff like the Thyabhorrent Death
Rides At Dawn 7" EP. They live for this shit and are the reason
that Death Metal has never completely gone away.
Pretty much the same thing.
The fact that Thrash
got pretty damn popular in the 80s (I used to guilt my mom into buying me the magazine Thrash
Metal at the grocery store for
fuck's sake) meant that it's fade from the spotlight in the US was more
pronounced - finding an American High Schooler into Exodus in
1996 was a virtually impossible task. Death Metal's comparative share
of the lime-light was much smaller, so it didn't vanish the same
degree that Thrash's did during the nineties. Instead, it mutated in
different ways, many of which I may not have been too personally
excited about, but at least it was kept alive. And ultimately,
wouldn't it sound weird if the Death Metal of 2002 sounded just like
the Death Metal of 1992, which sounded just like the Death Metal
2012? A genre can't stagnate and survive.
All those retro-thrash kids with puffy white high-tops nailed the color scheme, anyway. |
And now, with our nostalgia-obsessed
and (re)cyclical pop-culture, things have come full-circle. The
summer Metal tour circuit looks more and more like 1992 – Obituary,
Carcass, Morbid Angel and many more (including Exodus, Slayer,
Megadeth, Kreator and their influences like Venom, Angel
Witch, and Motorhead as well as a host of 2nd
and 3rd generation bands influenced by any of the
aforementioned) are on tour and playing to great turnouts. It may
actually be the best time to be a metal fan in the history of the
genre – the originators are still playing, and bands from every
generation and style are active and touring. You can see NWOBHM, Thrash, Death Metal, Black Metal, and
Grindcore at the same festival. With all of that happening,
I can't see how any metal fan isn't excited in 2014. Especially
with 40+ years of history and sub-genres to explore right at their
fingertips. If I could have gotten the Thy Kingdom Come demo
just by typing some shit into a computer when I was a kid, I would
have literally shit my pants with glee. I just hope that in twenty
years, the kids of today will still be as passionate about whatever
shit they're listening to today as I still am about World Without
God by Convulse.
Never, ever gets old.


text:
Metairie, LA – New Orleans Saints quarterback Drew Brees passed a physical and signed his five-year, $100 million contract on Sunday.
Brees and the Saints reached an agreement Friday on the terms of a new deal, which includes an NFL-record $60 million in guaranteed money and a $37 million signing bonus. Brees will make $40 million in the first year of the contract.
"I hope everyone has a great Sunday," Brees tweeted after signing his contract. "Training camp will be here soon. I look forward to seeing the Who Dat Nation in full force."
Brees, who was designated as the team's franchise player this offseason but refused to sign the tender, had not attended any of the Saints' offseason activities while looking for a long-term deal.
Brees, an 11-year veteran, was coming off a record-setting season in which he established new NFL marks for passing yards (5,476), completions (468) and completion percentage (71.2).
He was also named to the NFC Pro Bowl team and led the NFL with 46 touchdown passes and an average of 342 passing yards per game. His 110.6 passer rating ranked second in the NFL.
Brees, who led the Saints to the Super Bowl title after the 2009 season, has thrown for 40,742 yards and 281 touchdowns over 154 career games with the San Diego Chargers and Saints.
The Saints report to training camp on July 24.

subset: commoncrawl


text:
Story highlights
"I will remain a Christian," she told a judge sentencing her to death
Meriam Yehya Ibrahim was sentenced in May to death by hanging for apostasy
An appeals court rules the initial judgment was faulty, her lawyer says
Ibrahim gave birth to a girl in a prison last month
A Sudanese woman has been freed from prison a month after being sentenced to die by hanging for refusing to renounce her Christian faith.
"I am a Christian," Meriam Yehya Ibrahim told the judge at her sentencing hearing in May, "and I will remain a Christian."
An appeals court in Sudan ruled that a lower court's judgment against the 27-year-old was faulty, her lawyer, Mohaned Mustafa El-Nour, said Monday. He declined to elaborate.
An international controversy erupted over Ibraham's conviction in May by a Sudanese court on charges of apostasy, or the renunciation of faith, and adultery. Ibrahim was eight months pregnant when was sentenced to suffer 100 lashes and then be hanged.
"I'm so frustrated. I don't know what to do," her husband, Daniel Wani told CNN in May. "I'm just praying." Wani, uses a wheelchair and "totally depends on her for all details of his life," Ibrahim's lawyer said.
Ibrahim was reunited with her husband after getting out of custody, her lawyer said Monday.
Ibrahim gave birth to a girl in a prison last month, two weeks after she was sentenced. She was in the women's prison with her 20-month-old son, but Sudanese officials said the toddler was free to leave at any time, according to her lawyer.
The criminal complaint filed by a brother, a Muslim, said her family was shocked to find out Ibrahim had married a Christian, U.S. citizen Daniel Wani, after she was missing for several years, according to her lawyer. A Muslim woman's marriage to a Christian man is not considered legal in Sudan, thus the adultery charge.
The apostasy charge came because Ibrahim proclaimed herself to be Christian, not Muslim. Her mother, an Ethiopian Orthodox, was abandoned by her Sudanese Muslim father when Ibrahim was just 6 and she was raised as a Christian, she said.
Sudanese Parliament speaker Fatih Izz Al-Deen defended the conviction last month, insisting that claims that Ibrahim was raised as non-Muslim are untrue. She was raised in an Islamic environment, Al-Deen said.
The lower court had warned Ibrahim to renounce her Christianity by May 15, but she held firm to her beliefs while her lawyer appealed the conviction and sentence.
Her sentence had drawn international condemnation from rights groups and foreign embassies in Khartoum, including those of the United States, United Kingdom and Canada.


text:
Editor's note: This is a repost of a TechCrunch article written by Jon Shieber.
Looking to take on the rental tux market with a higher-quality, lower-priced suit and tie, Black Tux has raised $2.6 million in its first institutional round of funding.
It's the latest brand to come to market with funding led by Lerer Ventures, which has backed everything from health and beauty retailers and eyeglass makers to a company that wants to take everyone to the mattresses.
Lerer isn't the only brand name investor behind The Black Tux, the small early-stage round also picked up commitments from First Round Capital, RRE, Founder Collective, Crosscut, Menlo Ventures, and Raine – the investment fund affiliated with William Morris Endeavor.
"Of all the rounds I have led, there has never been one that has been more oversubscribed," said Ben Lerer, a managing director at the eponymous Lerer Ventures and the Chief Executive of Thrillist Media Group.
The Santa Monica, Calif.-based online tuxedo rental business began as an idea shared by longtime friends Andrew Blackmon and Patrick Coyne.
A little over two years ago Blackmon was trying to select the suits his groomsmen would wear at his wedding. After going with a rental option – and finding the experience "terrible" – the two decided to research the industry.
"We identified four or five things that were wrong with the industry," said Coyne. The suits were ill-fitting, made of cheap material, poorly branded and marketed, and highly overpriced, he said.
So after nearly a year-and-a-half of research, The Black Tux was formed in 2013 and began quietly renting tuxes under its own brand.
There are three tuxedo options and two less-formal options that are available on the company's website. Rentals for a suit or a tux range from $95 to $160 (including shoes and accessories). Clothes are fit based on either a customer's exact measurements, or if those aren't available customers can go to a local tailor and be measured or determined by following a tutorial available on the company's website.
Once an order is placed it arrives within a week and The Black Tux picks up shipping costs for deliveries and returns.
"We've worked with a number of designers and pattern makers for our first five styles," said Coyne. "The idea is to launch [the clothes] under the Black Tux brand, because we're looking to build this brand, but that doesn't mean we wouldn't partner [with existing brands]."
Before raising the institutional round, which closed in December, The Black Tux had already raised $1 million by tapping friends, family and angel investors including Dennis Phelps, of Institutional Venture Partners, and Susan Feldman, the co-founder of One Kings Lane.
The draw for investors is spelled out in the latest Men's Wearhouse quarterly report, which indicated that the company's rental business netted it $142.2 million for the quarter ending November 2, 2013.
"At this point we really want to crush the rental market," Blackmon said. "This is ripe for disruption and there's less satisfaction with incumbents. In the future, if we have a good brand and a huge customer list, we will leverage that into something."
These investments are happening against a backdrop of rising dollar commitments to venture-backed branded businesses, even as the number of those investments declines.
According to data from CrunchBase, 34 consumer-facing branded "fashion" businesses raised roughly $344 million already in the first quarter of 2014. The last time these businesses attracted that much attention was in the third quarter of 2011 when 38 companies raised nearly $370 million


text:
Candystand Debuts Monster Truck Game
Keeping up the action on its Candystand site, WM. Wrigley Jr. Company has released a new advergame created by Stimunation. The game is called Monster Trucks and you get to brand your truck and drive it over all kinds of obstacles and, best of all, crash it. Mmm. Going out to buy some Lifesavers now.


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Pancreatic ductal adenocarcinoma (PDAC) remains a lethal disease. For patients with localized PDAC, surgery is the best option, but with a median survival of less than 2 years and a difficult and prolonged postoperative course for most, there is an urgent need to better identify patients who have the most aggressive disease.
Methods and Findings
We analyzed the gene expression profiles of primary tumors from patients with localized compared to metastatic disease and identified a six-gene signature associated with metastatic disease. We evaluated the prognostic potential of this signature in a training set of 34 patients with localized and resected PDAC and selected a cut-point associated with outcome using X-tile. We then applied this cut-point to an independent test set of 67 patients with localized and resected PDAC and found that our signature was independently predictive of survival and superior to established clinical prognostic factors such as grade, tumor size, and nodal status, with a hazard ratio of 4.1 (95% confidence interval [CI] 1.7–10.0). Patients defined to be high-risk patients by the six-gene signature had a 1-year survival rate of 55% compared to 91% in the low-risk group.
Our six-gene signature may be used to better stage PDAC patients and assist in the difficult treatment decisions of surgery and to select patients whose tumor biology may benefit most from neoadjuvant therapy. The use of this six-gene signature should be investigated in prospective patient cohorts, and if confirmed, in future PDAC clinical trials, its potential as a biomarker should be investigated. Genes in this signature, or the pathways that they fall into, may represent new therapeutic targets.
Citation: Stratford JK, Bentrem DJ, Anderson JM, Fan C, Volmar KA, Marron JS, et al. (2010) A Six-Gene Signature Predicts Survival of Patients with Localized Pancreatic Ductal Adenocarcinoma. PLoS Med 7(7): e1000307. https://doi.org/10.1371/journal.pmed.1000307
Academic Editor: Samir M. Hanash, Fred Hutchinson Cancer Research Center, United States of America
Received: January 4, 2010; Accepted: June 3, 2010; Published: July 13, 2010
Copyright: © 2010 Stratford et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was supported by the Emerald Foundation (JJY), the Kimmel Foundation (JJY), the American College of Surgeons (JJY), the American Surgical Association Foundation (JJY), the North Carolina University Cancer Research Fund (JJY), and the NCI SPORE in Gastrointestinal Cancer P50 CA106991 (jjy, cjd), NCI SPORE in SPORE in Breast Cancer - Core 3 - Biostatistics 5-P50-CA58223-15 (JSM), NIH T32 Cancer Biology Training Grant (JKS), NIH CA106610 (CAI-D). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Abbreviations: DWD, distance weighted discrimination; NEB, University of Nebraska Medical Center Rapid Autopsy Pancreatic Program; PDAC, pancreatic ductal adenocarcinoma; SAM, significance analysis of microarrays; TMA, tissue microarray; TNM, tumor, node, and metastasis; UNC, University of North Carolina at Chapel Hill
Editors' Summary
Pancreatic cancer kills nearly a quarter of a million people every year. It begins when a cell in the pancreas (an organ lying behind the stomach that produces digestive enzymes and hormones such as insulin, which controls blood sugar levels) acquires genetic changes that allow it to grow uncontrollably and to spread around the body (metastasize). Nearly all pancreatic cancers are "pancreatic ductal adenocarcinomas" (PDACs)—tumors that start in the cells that line the tubes in the pancreas that take digestive juices to the gut. Because PDAC rarely causes any symptoms early in its development, it has already metastasized in about half of patients before it is diagnosed. Consequently, the average survival time after a diagnosis of PDAC is only 5–8 months. At present, the only chance for cure is surgical removal (resection) of the tumor, part of the pancreas, and other nearby digestive organs. The operation that is needed for the majority of patients—the Whipple procedure—is only possible in the fifth of patients whose tumor is found when it is small enough to be resectable but even with postoperative chemotherapy, these patients only live for 23 months after surgery on average, possibly because they have micrometastases at the time of their operation.
Why Was This Study Done?
Despite this poor overall outcome, about a quarter of patients with resectable PDAC survive for more than 5 years after surgery. Might some patients, therefore, have a less aggressive form of PDAC determined by the biology of the primary (original) tumor? If this is the case, it would be useful to be able to stratify patients according to the aggressiveness of their disease so that patients with very aggressive disease could be given chemotherapy before surgery (neoadjuvant therapy) to kill any micrometastases. At present neoadjuvant therapy is given to patients with locally advanced, unresectable tumors. In this study, the researchers compare gene expression patterns in primary tumor samples collected from patients with localized PDAC and from patients with metastatic PDAC between 1999 and 2007 to try to identify molecular markers that distinguish between more and less aggressive PDACs.
What Did the Researchers Do and Find?
The researchers identified a six-gene signature that was associated with metastatic disease using a molecular biology approach called microarray hybridization and a statistical method called significance analysis of microarrays to analyze gene expression patterns in primary tumor samples from 15 patients with localized PDAC and 15 patients with metastatic disease. Next, they used a training set of tumor samples from another 34 patients with localized and resected PDAC, microarray hybridization, and a graphical method called X-tile to select a combination of expression levels of the six genes that discriminated optimally between high-risk (aggressive) and low-risk (less aggressive) tumors on the basis of patient survival (a "cut-point"). When the researchers applied this cut-point to an independent set of 67 tumor samples from patients with localized and resected PDAC, they found that 42 patients had high-risk tumors. These patients had an average survival time of 15 months; 55% of them were alive a year after surgery. The remaining 25 patients, who had low-risk tumors, had an average survival time of 49 months and 91% of them were alive a year after resection.
What Do These Findings Mean?
These and other findings identify a six-gene signature that can predict outcomes in patients with localized, resectable PDAC better than, and independently of, established clinical markers of outcome. If the predictive ability of this signature can be confirmed in additional patients, it could be used to help patients make decisions about their treatment. For example, a patient wondering whether to risk the Whipple procedure (2%–6% of patients die during this operation and more than 50% have serious postoperative complications), the knowledge that their tumor was low risk might help them decide to have the operation. Conversely, a patient in poor health with a high-risk tumor might decide to spare themselves the trauma of major surgery. The six-gene signature might also help clinicians decide which patients would benefit most from neoadjuvant therapy. Finally, the genes in this signature, or the biological pathways in which they participate, might represent new therapeutic targets for the treatment of PDAC.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000307.
- The US National Cancer Institute provides information for patients and health professionals about all aspects of pancreatic cancer (in English and Spanish), including a booklet for patients
- The American Cancer Society also provides detailed information about pancreatic cancer
- The UK National Health Service and Cancer Research UK include information for patients on pancreatic cancer on their Web sites
- MedlinePlus provides links to further resources on pancreatic cancer (in English and Spanish)
- Cure Pancreatic Cancer provides information about scientific and medical research related to the diagnosis, treatment, cure, and prevention of pancreatic cancer
- Pancreatic Cancer Action Network is a US organization that supports research, patient support, community outreach, and advocacy for a cure for pancreatic cancer
Pancreatic ductal adenocarcinoma (PDAC), comprising over 90% of all pancreatic cancers, remains a lethal disease with an estimated 232,000 new cases, 227,000 deaths per year worldwide, and a less than 5% 5-y survival rate [1],[2]. Currently the standard of care for the 20% of patients with localized disease is surgery followed by chemotherapy, and in some cases radiation. Unfortunately, despite the use of adjuvant therapy, median survival remains at best 23 mo [3]. It is important to note, however, that up to 27% of patients with resected PDAC can survive for 5 y [4]–[10]. However, in studies examining actual long-term survivors [4]–[10], only two have found that adjuvant therapy was associated with improved survival [9],[10]. In addition, randomized controlled trials of gemcitabine-based chemotherapy demonstrate an improvement in median survival of at best 3 mo [3],[11]. One possible conclusion from these studies is that tumor biology dictates outcome and that our current adjuvant therapy has only a modest impact on altering a patient's course.
Hypothesizing that the dismal outcome of patients with localized disease is due to the presence of micrometastatic disease, current clinical investigation has focused on preoperative or neoadjuvant therapy [12],[13]. This approach, in which patients who cannot tolerate the stress of therapy or who develop metastatic disease during treatment are spared surgery, has demonstrated an overall survival of 34 mo in this highly selected patient population [12],[13]. Therefore the ability to select patients who would most benefit from a neoadjuvant approach may be important. One way to select these individuals is to define a prognostic gene signature that can identify patients with more aggressive tumor biology upfront.
Expression profiling of PDAC has lead to further studies of additional molecular diagnostic and prognostic markers [14]–[19]. However, the search for genes of biological significance in these large datasets continues to be challenging. One approach to identify genes or pathways that are biologically relevant is to study those that are of prognostic significance [20]. Lowe and colleagues found differential gene expression changes associated with nodal status in primary PDAC [21], suggesting that molecular differences in primary PDAC do exist. We hypothesized that by comparing primary PDAC tumors at the extremes of disease, we would identify molecular changes reflective of differences in biology within primary PDAC tumors.
PDAC samples from 15 patients with resected primary PDAC from the University of North Carolina at Chapel Hill (UNC) and 15 patients with metastatic PDAC from the University of Nebraska Medical Center Rapid Autopsy Pancreatic Program (NEB) were used to derive differentially expressed genes associated with metastatic disease. For the NEB samples, human pancreatic tumors from decedents who had previously been diagnosed with PDAC, and who generously consented to post mortem examinations, were obtained from the institutional review board (IRB)-approved NEB Tissue Bank. To ensure minimal degradation of tissue, organs were harvested within 3 h post mortem and the specimens flash frozen in liquid nitrogen.
The training cohort included 34 patients with resected PDAC from Johns Hopkins Medical Institutions (JHMI). The testing or validation cohort included patients from two institutions: 48 from Northwestern Memorial Hospital (NW) and 19 from NorthShore University HealthSystem (NSU). All samples were collected between 1999 and 2007 at the time of operation and flash frozen in liquid nitrogen after approval by each individual IRB. The UNC IRB approved use of all de-identified samples for this study. All available samples were reviewed by a single pathologist (KAV). De-identified data including tumor, node, and metastasis (TNM), grade or differentiation, margin status, and survival were available for the majority of patients.
RNA Isolation and Microarray Hybridization
All RNA isolation and hybridization was performed on Agilent (Agilent Technologies) human whole genome 4×44 K DNA microarrays and at UNC. RNA was extracted from macrodissected snap-frozen tumor samples using Allprep Kits (Qiagen) and quantified using nanodrop spectrophotometry (ThermoScientific). RNA quality was assessed with the use of the Bioanalyzer 2100 (Agilent Technologies). RNA was selected for hybridization using RNA integrity number and by inspection of the 18S and 28S ribosomal RNA. Similar RNA quality was selected across samples. One microgram of RNA was used as a template for DNA preparations and hybridized to Agilent 4×44 K whole human genome arrays (Agilent Technologies). cDNA was labeled with Cy5-dUTP and a reference control (Stratagene) was labeled with Cy3-dUTP using the Agilent (Agilent Technologies) low RNA input linear amplification kit and hybridized overnight at 65°C to Agilent 4×44 K whole human genome arrays (Agilent Technologies). Arrays were washed and scanned using an Agilent scanner (Agilent Technologies). The data are publicly available in Gene Expression Omnibus database (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE21501).
Microarray and Statistical Analysis
All array data were normalized using Lowess normalization. Data were excluded for genes with poor spot quality or genes that did not have mean intensity greater than 10 for one of the two channels (green and red) in at least 70% of the experiments. The log2 ratio of the mean red intensity over mean green intensity was calculated for each gene and went through LOWESS normalization [22]. Missing data were imputed using the k-nearest neighbors imputation (KNN) with k = 10 [23]. A distance weighted discrimination (DWD) was used to detect the systematic biases between the different datasets and then global adjustments made to remove these biases [24]. Genes that were significantly up- or down-regulated were identified using significance analysis of microarrays (SAM) [25]. Two centroids were created using the mean gene expression profile of this significant gene list from the derivation set and used to develop a single sample predictor (SSP, nearest centroid algorithm) [26] for an objective classifier. After DWD, the SSP was applied to a 34-patient training set where any new sample was compared to the resected centroid and assigned by the SSP distance function to the resected centroid using (1 − Pearson correlation coefficient). The X-Tile software program, which assigns a two-population log-rank value to each sample and then determines the best cut-point, was used to determine the best threshold for classifying samples into high- and low-risk categories [27]. X-Tile predicted that the (1− Pearson correlation coefficient) distance of 1 would be the appropriate cut-point to stratify patients into a high- and low-risk group (p = 0.006). A second independent validation cohort was then used as a test set using this predetermined cut-point to evaluate outcome.
Survival analysis was performed using the statistical software programs R, the R-package "survival," and SPSS (SPSS, Inc.). Overall survival (OS) was analyzed using the Kaplan-Meier product-limit method and the significance of our variables was measured by the log-rank test. The Fisher exact test was used to analyze associations between two variables, the Pearson Chi-square test was used to analyze association between more than two variables. Multivariable analysis and analysis of continuous and ordinal variables was performed using the Cox proportional hazards regression method.
Tissue Microarrays
Tissue microarrays (TMAs; UNC2) were prepared from formalin-fixed paraffin-embedded tissue sections using a 2-mm punch. The arrays contained triplicate cores of matched normal and tumor tissue as well as chronic pancreatitis when available, from each patient. We prepared 5-µm sections from each TMA block. Hematoxylin and eosin stained slides from each TMA block were reviewed by a pathologist (KAV) to ensure that tissues were cored accurately.
Slides with 5-µM sections from the paraffin-embedded specimens were deparaffinized and rehydrated. The slides were then subjected to alkaline heat antigen-retrieval using 1% Tris EDTA for 20 min in a steamer. All slides were incubated with 3% H2O2 for 5 min and washed with TBS. The slides were further treated with protein block solution (bovine serum albumin) for 20 min. The sections were incubated with primary KLF6 1∶150 antibody (sc-7158, Santa Cruz Biotechnology) for 60 min at room temperature. Following a TBS wash, the slides were incubated with secondary labeled Polymer-HRP anti-rabbit (Dako K4002) for 30 min. This was followed by a 5-min incubation with the substrate-chromogen, 3,3′-diaminobenzidine (Vector SK-4100). The sections were counterstained with Harris hematoxylin. Positive KLF6 staining was defined as when more than 5% of cells expressed the marker and graded from 0 (no staining) to 4 (strong staining). The results of each protein marker were then expressed as intensity (I) and proportion (P) of positive epithelial cells and the score as the product of I and P [28],[29]. All stained slides were reviewed in a blinded fashion (JMA).
Patient and Tumor Characteristics
In order to study the extremes of PDAC tumor biology, we collected a diverse set of resected PDAC specimens from patients with and without metastases. As the tumor microenvironment is increasingly recognized to play a critical role in tumorigenesis [30]–[33], tissues were macrodissected in order to preserve the normal adjacent tissue and stroma of the tumors. The characteristics of the dataset used to derive the signature (derivation set) comprised 15 primary resected PDAC tumors (UNC1) and 15 primary tumors from patients with metastatic PDAC (NEB). The training set comprised 34 patients with primary PDAC and the independent validation test set comprised 67 patients with primary PDAC (Tables 1 and 2). There were no differences in RNA quality between the decedent and resected PDAC samples. Available treatment data of the patients in the training and test sets are also shown. One of 15 (7%) UNC1 patients received preoperative or neoadjuvant chemotherapy and 11/15 (73%) NEB patients received chemotherapy less than 6 mo prior to death. No patient in the 34-patient training set received neoadjuvant chemotherapy. Only 3% (2/67) of patients in the test set received neoadjuvant chemotherapy and 45% (30/67) of patients received postoperative or adjuvant chemotherapy.
Gene Expression Differences in Nonmetastatic And Metastatic Primary Tumors
We hypothesized that we could enrich for molecular differences in primary PDAC, which may be clinically and biologically relevant, through examining primary tumors representing opposite spectrums of PDAC: early (localized) and late (metastatic) stage. To accomplish this, we compared nonmetastatic (UNC1) with metastatic (NEB) primary PDAC tumors. As the methods of procurement for these tumors differed, we used DWD to identify systematic biases between the two datasets [24]. This method has been used previously to successfully combine three breast cancer datasets across three microarray platforms [26], across species [34], and across multiple datasets [35],[36]. We therefore used DWD to adjust for the systematic biases between the UNC1 and NEB datasets by taking advantage of the fact that each dataset also had 15 normal pancreas samples assayed. In short, we used DWD to adjust these 15 tumor-normal pairs from both datasets to have similar distributions in principal component (PC) 1×PC 2 space. After the DWD adjustment, we used SAM to identify differentially expressed genes [22],[25]. Using a false discovery rate of 5%, we identified six genes that were differentially overexpressed between nonmetastatic and metastatic primary tumors: FBJ murine osteosarcoma viral oncogene homolog B (Fos B), Kruppel-like factor 6 (KLF6), nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, zeta (NFKBIZ, IKBZ, MAIL), ATPase H+/K+ exchanging, alpha polypeptide (ATP4A), germ cell associated 1 (GSG1), and sialic acid binding Ig-like lectin 11 (SIGLEC11) (Figure 1A; Table S1).
Clustering of (A) the six genes defined by SAM evaluation of the metastatic compared to nonmetastatic primary PDAC using a false discovery rate of 5%; (B) patient samples into high- and low-risk groups in a training set of 34 patients with localized and resected PDAC using the X-tile determined cut-point of a Pearson correlation coefficient of zero; (C) patient samples into high- and low-risk groups in an independent test set of 67 patients with localized and resected PDAC using the predetermined cut-point of zero. Kaplan-Meier overall survival of (D) the training set classified into high- and low-risk groups according to the X-tile determined cut-point of a Pearson correlation coefficient of zero; (E) and the independent test set classified into high- and low-risk groups according to the same predetermined cut-point.
Development of a Classifier Using the Six-Gene Signature
We examined the relationship of our six-gene signature to outcome using a training set of 34 patients with localized and resected PDAC. After identifying and adjusting for systematic bias using DWD [24], a resected centroid-based predictor [26] was created using the 30 samples in the derivation dataset. The centroid was then applied to the DWD-adjusted training set of primary PDAC patients to determine the performance of the six-gene signature. X-tile [27] was used to determine the optimal distance function to the centroid cut-point for classifying this training set of patients into high-risk and low-risk groups on the basis of survival (Figure 1B and 1D). The optimal cut-point occurred at a Pearson correlation coefficient of zero (p = 0.006) with patients with Pearson correlation coefficients greater than zero in the low-risk and less than zero in the high-risk groups.
Application of the Six-Gene Signature to an Independent Validation Cohort of 67 Patients
In order to evaluate the performance of the cut-point determined by X-tile [27], we applied the cut-point to an independent validation test set of 67 patients with primary PDAC. Our predetermined Pearson correlation coefficient cut-point of zero distance to the centroid successfully stratified patients into high- (n = 42) and low-risk groups (n = 25) with a median overall survival (OS) of 15 versus 49 mo (p = 0.001) (Figure 1C and 1E). Patients in the high-risk group had 1-, 2-, and 3-y estimated survival rates of 55%, 34%, and 21%, compared to 91%, 64%, and 56% in the low-risk group.
Previous studies in PDAC have found that nodal status is the most predictive of outcome for patients with localized PDAC [37]. We compared our prognostic signature to current clinical prognostic benchmarks. We found that tumors that were node positive (p = 0.091) and grade 2 or 3 trended towards a shorter survival (p = 0.080). Neither T stage (p = 0.977) nor margin status (p = 0.223) were prognostic in this cohort. Treatment with adjuvant chemotherapy (p = 0.699) or with neoadjuvant chemotherapy (p = 0.409) was also not prognostic, although only two patients received neoadjuvant chemotherapy. We found no gene expression changes between the tumors of the two patients who received neoadjuvant chemotherapy and the tumors of patients who received no treatment prior to surgery.
An important feature of any prognostic signature is that it should be independent or additive to currently used clinicopathologic prognostic criteria. We therefore compared the prognostic importance of our molecular signature in the setting of grade (p = 0.417), nodal status (p = 0.381), T stage (p = 0.675), and margin status (p = 0.295). We found that our six-gene signature was the only independent predictor of survival in the 57 patients with complete data, with a hazard ratio of 4.1 (95% confidence interval 1.7–10.0) (Table 3).
We also looked at whether our six-gene signature was confounded by available clinicopathological variables. We found no association between our molecular signature, and tumor size, grade, margin status, nodal status, and neoadjuvant or adjuvant chemotherapy in our independent test set (Table 4).
KLF6 Expression in Primary PDAC
In order to further validate the six-gene signature, we performed immunohistochemical analyses for KLF6, which showed a wide range of expression values between nonmetastatic versus metastatic samples (Figure 1A). To evaluate KLF6 protein expression, we obtained another independent dataset of 50 patients represented on a TMA with matched normal, chronic pancreatitis, and PDAC (UNC2, Table 2). First, using the median score of 1.5 as the cutoff, we found that KLF6 expression was much higher in tumors compared to normal pancreas (p<0.001) (Figure 2A and 2C). KLF6 expression was strong in normal islet cells in agreement with a previous study (Figure 2Ci, white arrowhead) [38]. Second, we found that KLF6 expression with a score greater than 1.5 (high) was associated with a shorter median survival of 11 mo compared to 24 mo for patients with KLF6 expression scores less than 1.5 (low) (p = 0.04) (Figure 2B).
(A) KLF6 staining is significantly higher in PDAC compared to normal adjacent pancreas in an independent dataset of a 50-patient TMA (UNC2) as well as NEB samples used for the original analysis. (B) Kaplan-Meier overall survival of 50 patients classified by high and low KLF6 scores, using the median cutoff score of 1.5. (C) KLF6 immunostaining in the primary tumor of a patient who died of metastatic disease (ii) and in a resected primary tumor (iv). Minimal staining is seen in the matched normal adjacent tissue of both patients (i, iii). KLF6 immunostaining in islet cells (i, white arrowhead). Arrows illustrate normal ductal epithelium. Black arrowheads illustrate tumor.
We profiled and compared nonmetastatic and metastatic primary PDAC tumors and identified a six-gene signature. Although this signature was not derived on the basis of outcomes, we show that it was prognostic in a true test set of resectable PDAC patients. Importantly, our six-gene signature was independently predictive of survival, stratifying patients with median survivals of 15 compared to 49 mo, outperforming current pathological staging criteria, suggesting that our signature will be a powerful prognostic tool for patients with localized PDAC.
PDAC continues to be a devastating disease with few long-term survivors. Surgery remains the standard therapy for patients diagnosed with resectable PDAC [39]. Yet with a median survival only of less than 2 y after surgery, the attendant postoperative mortality rate of 2%–6% [40],[41], and postoperative complication and hospital readmission rates of 59% [41],[42], the decision for surgery should be made cautiously. Therefore, improved patient selection for therapy is necessary. For the majority of patients who cannot undergo surgery, gemcitabine chemotherapy remains the best option, yet only 5%–10% of patients respond to the treatment [43],[44]. Given the current therapeutic limitations, additional prognostic tools are needed to help a patient decide whether to have surgery, and/or neoadjuvant chemotherapy, or when to consider participation in a clinical trial.
Our analysis identified a surprisingly small number of genes with differential expression between early compared to late stage primary PDAC (Table S1). This finding suggests that primary PDAC may be largely homogenous from a global gene expression standpoint. Nonetheless, the differences that we identified appear to be clinically and therefore biologically important. Our findings of molecular differences in resected primary PDAC tumors suggest that there is subtle biological variation in these tumors that influences outcome. A review of previous published studies did not identify differential expression of our six genes [15],[21],[45]–[56]. This finding is not surprising, as previous studies examined differential gene expression changes between either normal pancreas or chronic pancreatitis and PDAC [15],[45]–[56]. Only one study has looked at gene expression changes between PDAC of different stages [21]. Ours was the first, to our knowledge, to study molecular differences between nonmetastatic versus metastatic primary tumors and identify and validate a prognostic signature for PDAC.
Of the six genes identified in this study, most do not have an obvious role in carcinogenesis. Three of the six genes demonstrated significantly higher expression in the poor prognostic groups (SIGLEC11, KLF6, NFKBIZ; Table S2). ATP4A, GSG1, and SIGLEC-11 have not been studied in cancer. SIGLEC-11 is thought to be expressed by tissue macrophages and also the brain microglia [57]. Interestingly, a missense mutation of SIGLEC-11 (S465A) was identified in the mutation discovery screen of the recent genome-wide sequencing of PDAC [58]. NFKBIZ, also called IkappaB zeta, binds to the p50 subunit of nuclear factor (NF)-kappaB and is important for interleukin-6 (IL-6) induction and may be induced by IL-1 receptor and Toll-like receptors [57]. Given the prevalence of chronic pancreatitis and high degree of stromal fibrosis, it is possible that NFKBIZ may play a role in PDAC and inflammation.
KLF6 is a transcription factor and its full length transcript is thought to be a tumor suppressor gene involved in prostate, lung, and ovarian carcinogenesis [59]. However a splice variant KLF6-SV1 has been shown to have oncogenic properties. The oligonucleotide probes used in the Agilent whole human genome array and the antibody against KLF6 did not differentiate between the full-length and splice variant. In agreement with a previous study [38], we found that KLF6 protein expression was higher in tumors than normal pancreas. In addition we found that higher KLF6 expression was associated with worse survival. Hartel et al. further investigated KLF6-SV1 expression in their study using real-time PCR and demonstrated that the higher KLF6 expression seen in tissues was associated with a higher ratio of KLF6-SV1 compared to full-length KLF6. Therefore our findings that KLF6 expression is higher in tumors and is prognostic is likely in agreement with this study.
Only one patient in the UNC1 cohort was treated with neoadjuvant chemotherapy compared to 80% of NEB patients who were treated with palliative chemotherapy. Although there is a possibility that our signature may be reflective of gemcitabine treatment or perhaps resistance, as NEB patients died of metastatic disease despite gemcitabine treatment, the successful application of our six-gene signature on an independent test set of patients where only 3% of patients with localized PDAC were treated with neoadjuvant therapy suggests that it is a rigorous predictor of prognosis in previously untreated patients. We found no association between our six-gene signature and whether a patient received adjuvant chemotherapy. In addition, chemotherapy treatment in this cohort, either pre- or postoperative, did not demonstrate a survival advantage.
Another concern is the validity of our hypothesis that gene expression changes at different stages of primary PDAC development may occur and be important for prognosis. Our study is in agreement with Lowe and colleagues' findings that differential gene expression changes can be identified within primary PDAC [21]. However, they did not address the prognostic value of their findings. Several studies have also suggested that gene expression changes in metastasis may be found in primary tumors. In a study of molecular differences between primary tumors and metastases, Golub and colleagues identified a gene expression signature of metastasis present that could be identified in primary tumors [60]. In addition, studies in melanoma have suggested that metastatic cells may be found in the parent primary tumor [61]. Finally studies in breast cancer have demonstrated that gene expression changes found in breast cancer cells with metastatic potential may be prognostic and predictive of patients who will develop metastasis [62]–[64]. Our study is the first to demonstrate that molecular differences in metastatic PDAC can be identified at earlier stages, and that these differences are predictive of future behavior. Whether these molecular changes are biologically associated with metastatic potential will require further investigation.
We have applied our six-gene signature to an independent dataset of 67 patients, and have validated its prognostic value. In addition, we have validated the protein expression of KLF6 in a 50-patient TMA. Although not nearly as powerful a predictor of prognosis as our six-gene signature, we found that KLF6 expression was prognostic in our 50-patient TMA. Further validation studies will be needed to see if KLF6 alone may be a useful prognostic marker as others have shown [38]. Our findings suggest that the prognostic value of KLF6 is strengthened in evaluating the six genes in their entirety.
Studies of patients with resectable PDAC demonstrate median survivals of up to 22 mo, equivalent to the median survival of patients in our training and testing cohorts [3],[11],[65]. Our finding that our six-gene signature is able to stratify patients, with startling differences in survival, suggests that it may be used to select patients for therapies. For example, for patients who are at high operative risk, knowledge of a median survival of 49 compared to 15 mo, may be helpful in the operative decision-making process. Similarly, patients who have a poor prognosis based on the six-gene signature may be considered for neoadjuvant therapy. Currently, the minority of centers use neoadjuvant therapy as a standard of care, most instead reserve this for patients with locally advanced unresectable or borderline resectable tumors. Therefore the current decision-making process is based on anatomical considerations. Our prognostic signature may refine this paradigm such that neoadjuvant therapy is offered to patients on the basis of biological considerations, regardless of resectability, and may allow us to further study and maximize the benefits of neoadjuvant treatment. In addition, as new therapies are developed, it may help to determine whether patients may require more or less aggressive treatment. Finally, our findings that there are molecular differences associated with late-stage primary tumors, which translate into differences in prognosis, suggest that the six genes in this signature should be further studied for their potential as biomarkers, and some of these genes, or the pathways that they fall into, may represent new therapeutic targets.
Supporting Information
Table S1.
SAM of metastatic compared to localized primary tumors.
Table S2.
Comparison of individual genes in the six-gene signature between the high- and low-risk groups.
JJY thanks Ling Li, the UNC Genomics and Bioinformatics, Translational Pathology, and Tissue Procurement Core Laboratory Facilities for superb technical assistance and Joel Tepper and William Kim for critical review of the manuscript.
Author Contributions
ICMJE criteria for authorship read and met: JKS DJB JMA CF KAV JSM EDR LSC JCS CJD LBT BFC HJK MST CAID MAH CMP JJY. Agree with the manuscript's results and conclusions: JKS DJB JMA CF KAV JSM EDR LSC JCS CJD LBT BFC HJK MST CAID MAH CMP JJY. Designed the experiments/the study: JKS MAH JJY. Analyzed the data: JKS CF JSM CMP JJY. Collected data/did experiments for the study: JKS DJB JMA KAV EDR LSC JCS HJK JJY. Enrolled patients: DJB BFC HJK MST CAID JJY. Wrote the first draft of the paper: JJY. Contributed to the writing of the paper: JKS DJB CF JSM CJD HJK MST MAH CMP JJY. Created figures for the paper: JSM. Responsible for tissue procurement: LBT. Prepared tissue microarray: LBT.
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On Friday, December 6th, from 6:00 – 8:00 pm,
join MAPH students and alumni for ARTBAR, an evening of socializing, drinks, live performance, and art activities at the
Hyde Park Art Center
(5020 S. Cornell Avenue Chicago, IL 60615).
The evening will include:
- Hands on art-making in 2 of the following media: clay, screenprinting, and photography,
- An improv, pop-up, interactive comedy club performance put on by artists exhibiting work in the Michelle Grabner-curated "A Study in Midwestern Appropriation,"
- Drinks, snacks, and socializing, in the spirit of MAPH Social Hour,
- An introduction to the Hyde Park Art Center and its programs for MAPH alumni and students by the Art Center's Marketing & Communications Manager and MAPH alum Brook Rosini,
- DJ and open mic,
- and time to explore the art galleries!
MAPH has covered all the costs for MAPH students and alumni, but please feel free to make additional donations to the Art Center!


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Excited to see opening band Beach Fossils most of all and ended up being blown away by headliner Bear in Heaven last night at The Rickshaw Stop here in San Francisco. Beach Fossils bounced about like a high school version of New Order or Joy Division. I like the music. It sounds familiar and a huge fan of New Order, but it just lacked originality and a spark that I was hoping for. In between the two acts is Twin Sister who would be the musical child of Bjork, Blond Redhead and Jamiroquai, of all bands. Although, I could hear them, I was behind a few too many tall fellas to see anything but the light show. (Hey Rickshaw Stop, raise the stage a foot for your smaller patrons).
When Bear in Heaven went on, something clicked. The sound is thick and full. You know, let's quote Pitchfork as they wrote about Bear in Heaven when they presented the band "Best New Music" award for their album Beast Rest Forth Mouth: Mostly made up of textural, spacious three- to four-minute pop anthems with towering choruses, BRFM is a welcome reminder that an album doesn't have to be bombastic to feel huge and important. Take out the earbuds and let it fill a space: This is music that's bigger than your iPod—music you'll want to feel all around you. Though not quite coming out of nowhere, BRFM seems like a surprise gift—a striking consolidation of the spiky psych-prog tendencies of their debut into a pop framework. -Pitchfork
Hey, Jon Philpot of Bear in Heaven is a Fecal Face fan (bottom right photo)... See them as they are touring the USA and Europe right now. You won't be disappointed -->Check the dates.


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Trent Lott on ImmigrationRepublican Jr Senator (MS) |
Proponents recommend voting YES because:
If we do not legislate now, we will not legislate later this year when our calendar is crowded with Iraq and appropriations bills. We are then an election year, and it will be pushed over to 2009. Circumstances will not be better then, they will be worse.
A vote against cloture is a vote to kill the bill. A Senator may vote for cloture and then express himself in opposition to the bill by voting against the bill.
Opponents recommend voting NO because:
If this bill becomes law, we will see only a 13% reduction in illegal immigration into America, and in the next 20 years we will have another 8.7 million illegals in our country. How can that be reformed? I submit this would be a disaster.
The Congressional telephone systems have shut down because of the mass phone calls Congress is receiving. A decent respect for the views of the American people says let's stop here now. Let's go back to the drawing board and come up with a bill that will work.
The American people get it, and they do have common sense and wisdom on this issue. They know repeating the fundamental mistakes of the 1986 bill, joining a big amnesty with inadequate enforcement, will cause the problem to grow and not diminish. They know promising enforcement after 30 years of broken promises isn't good enough. They know the so-called trigger is a joke because if the trigger is never pulled, the Z visas, the amnesty happens forever.
Proponents recommend voting YES because:
Right now, the polling shows that 91% of the people in America want English as an official language, and 76% of Hispanics believe English should be an official language.
Opponents recommend voting NO because:
I believe the American people understand in order to succeed in our society, immigrants need to learn English. But the amendment would do a number of things that are problematical. The first is that it is contrary to the provisions of law that exist in many States. For example, in New Mexico, you have in their State Constitution, a provision that says that many of the documents within that State have to be provided in both English and Spanish. The same thing is true for the State of Hawaii. I believe this is a States rights issue, and those constitutions of those States ought to be respected. I do not believe it is a matter we ought to be imposing here from Washington DC.
Also, this amendment would undo an executive order conceived by President Bill Clinton and implemented by President George Bush. Both recognized it is important that people who have limited English proficiency receive the kinds of services so they can understand what is going on in terms of the interface between the Government and themselves.
Proponents recommend voting YES because:
This legislation says we wish to add something called guest workers or temporary workers. With guest workers, working Americans would discover there is no opportunity for upward mobility at their job. In fact, every day their employers are trying to find ways to push down wages, eliminate retirement, and eliminate health care. What has happened in this country, with what is called the "new global economy," is dramatic downward pressure on income for American workers. The guest worker program provides that 400,000 people will be able to come in to assume jobs in our country per year--adding to the 12 million illegal immigrants already here.
Opponents recommend voting NO because:
I certainly concur about the need to secure our borders, about the need to have a workable immigration system, and the need for reform that ensures the rule of law is restored in the US. Where I differ is in the belief that we can actually achieve these goals if we have no ability for temporary workers to come to the country. This amendment would eliminate the temporary worker program from this bill.
Now, there are several reasons why a temporary worker program, within certain constraints, is a good idea. The first reason is because it will help to relieve the magnet for illegal immigration. The reason most of the people are crossing our border illegally is to get employment. There are jobs available for them. Some people say this is work Americans will not do. That is actually not true. But there are not enough American citizens to do all of the work that needs to be done. So naturally the law of supply and demand sets in here. People come across the border illegally, and they take that work. What we want to do is both close the border, but also eliminate the magnet for illegal employment here, because the reality is desperate people will always try to find some way to get into the country.
Proponents support voting YES because:
It is obvious there is no more defining issue in our Nation today than stopping illegal immigration. The most basic obligation of any government is to secure the Nation's borders. One issue in which there appears to be a consensus between the Senate and the House is on the issue of building a secure fence. So rather than wait until comprehensive legislation is enacted, we should move forward on targeted legislation which is effective and meaningful. The legislation today provides over 700 miles of Within 18 months, achieves operational control over U.S. land and maritime borders, including:
Proponents support voting YES because:
It is obvious there is no more defining issue in our Nation today than stopping illegal immigration. The most basic obligation of any government is to secure the Nation's borders. One issue in which there appears to be a consensus between the Senate and the House is on the issue of building a secure fence. So rather than wait until comprehensive legislation is enacted, we should move forward on targeted legislation which is effective and meaningful. The legislation today provides over 700 miles of
To reduce document fraud, prevent identity theft, and preserve the integrity of the Social Security system, by ensuring that persons who receive an adjustment of status under this bill are not able to receive Social Security benefits as a result of unlawful activity.
OnTheIssues.org interprets the 2005-2006 USBC scores as follows:
U.S. Border Control, founded in 1988, is a non-profit, tax-exempt, citizen's lobby. USBC is dedicated to ending illegal immigration by securing our nation's borders and reforming our immigration policies. USBC [works with] Congressmen to stop amnesty; seal our borders against terrorism and illegal immigration; and, preserve our nation's language, culture and American way of life for future generations.
Our organization accepts no financial support from any branch of government. All our support comes from concerned citizens who appreciate the work we are doing to seal our borders against drugs, disease, illegal migration and terrorism and wish to preserve our nation's language, culture and heritage for the next generations.


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Rule #1 - Be Patient - Rule #2 - Don't ask when, if you don't contribute - Rule #3 - You have coding skills - LinuxMCE's small brother is available: http://www.agocontrol.com
Does anyone know which is a good nvidia card that does UI2 or UI3? I have a:BFG GeForce 8500 GT - graphics adapter - GF 8500 GT - 512 MBhttp://www.officedepot.com/a/products/468430/BFG-GeForce-8500-GT-graphics-adapter/but for some reason will not get past UI1?
Is the 7150 chip supported?
Quote from: Veidit on April 09, 2008, 04:48:04 pmIs the 7150 chip supported?We have not tested the 7150 yet but would expect it to work fine with the 169.12 driver. However it may also not be detected correctly by the AVwizard as its a new chip. So I think you can assume that it will likely work 'out of the box' but there is a small chance that it may need some modest manual tweaks to get it fully working.


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Just a Bunch of Autonomous Convoys Driving Around an Army Base
A glimpse at the military's future: Fewer soldiers, more autonomous vehicles.
Last month, General Robert Cone, the head of the Army's Training and Doctrine Command, gave a speech that the service's future configuration. In short: fewer soldiers, more "lethality."
How's that? Cone said that in the years and decades ahead, the Army could scale back its brigade combat team—dramatically—from 4,000 to 3,000 soldiers or thereabouts. To make up for the loss in manpower, the service would turn increasingly to robots. Robots could perform many of the support tasks soldiers currently are saddled with, sparing American lives while, as Alexis put it, "giving the Army more killing power per brigade."
Now, a new video from Defense Update provides a glimpse of how that future might look. Recently, the a collaboration between the U.S. Army Tank-Automotive Research, Development and Engineering Center (TARDEC) and Lockheed Martin demonstrated their autonomous systems technology, and how it might be applied in urban environments on a variety of types of vehicles.
The demonstration, Defense Update reports, was a success: "The AMAS CAD hardware and software performed exactly as designed, and dealt successfully with all of the real-world obstacles that a real-world convoy would encounter," David Simon, program manager at Lockheed Martin Missiles and Fire Control for the Autonomous Mobility Appliqué System (AMAS).
The project, Defense Update explains, is "aimed at completely removing the soldier from the cab," leaving only robots on the line. That's the goal: a more lethal force, deadly to somebody else.
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