Saturday, July 6, 2013

Differential Androgen Deprivation Therapies with Anti-androgens ...

  1. Chawnshang Chang?,?1
  1. From the ?George Whipple Laboratory for Cancer Research, Departments of Pathology, Urology, and Radiation Oncology, and the Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York 14642,
  2. the ?Chawnshang Chang Sex Hormone Research Center, Tianjin Institute of Urology, Tianjin Medical University, Tianjin 300211, China, and
  3. the ?Sex Hormone Research Center, China Medical University and Hospital, Taichung 404, Taiwan
  1. ?1 To whom correspondence should be addressed. E-mail: chang{at}urmc.rochester.edu.

Background: Androgen deprivation therapy (ADT) suppresses prostate cancer (PCa) growth, yet its effects on PCa metastasis remain unclear.

Results: ADT with MDV3100/enzalutamide or Casodex/bicalutamide versus ASC-J9? led to enhanced versus suppressed PCa metastasis.

Conclusion: Casodex/MDV3100 induces PCa metastasis via modulation of TGF-?1/Smad3/MMP9 signaling.

Significance: Targeting androgen receptor with ASC-J9? is better than targeting androgens with Casodex/MDV3100 to better battle PCa metastasis.

Abstract

Despite the fact that androgen deprivation therapy (ADT) can effectively reduce prostate cancer (PCa) size, its effect on PCa metastasis remains unclear. We examined the existing data on PCa patients treated with ADT plus anti-androgens to analyze ADT effects on primary tumor size, prostate-specific antigen (PSA) values, and metastatic incidence. We found that the current ADT with anti-androgens might lead to primary tumor reduction, with PSA decreased yet metastases increased in some PCa patients. Using in vitro and in vivo metastasis models with four human PCa cell lines, we evaluated the effects of the currently used anti-androgens, Casodex/bicalutamide and MDV3100/enzalutamide, and the newly developed anti-AR compounds, ASC-J9? and cryptotanshinone, on PCa cell growth and invasion. In vitro results showed that 10 ?m Casodex or MDV3100 treatments suppressed PCa cell growth and reduced PSA level yet significantly enhanced PCa cell invasion. In vivo mice studies using an orthotopic xenograft mouse model also confirmed these results. In contrast, ASC-J9? led to suppressed PCa cell growth and cell invasion in in vitro and in vivo models. Mechanism dissection indicated these Casodex/MDV3100 treatments enhanced the TGF-?1/Smad3/MMP9 pathway, but ASC-J9? and cryptotanshinone showed promising anti-invasion effects via down-regulation of MMP9 expression. These findings suggest the potential risks of using anti-androgens and provide a potential new therapy using ASC-J9? to battle PCa metastasis at the castration-resistant stage.

Footnotes

  • ?* This work was supported, in whole or in part, by National Institutes of Health Grant CA156700. This work was also supported by the George Whipple Professorship Endowment and Taiwan Department of Health Clinical Trial and Research Center of Excellence Grant DOH99-TD-B-111-004. ASC-J9? was patented by the University of Rochester, University of North Carolina, and AndroScience and then licensed to AndroScience. Both the University of Rochester and C. Chang own royalties and equity in AndroScience.

  • ?Graphic This article contains supplemental Materials and Methods.

  • Received April 12, 2013.
  • Revision received May 14, 2013.

Source: http://www.jbc.org/content/288/27/19359.abstract

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Long day for a loss

Diamondbacks outlast Mets 5-4 in 15 innings

(AP Photo/Frank Franklin II)

By MIKE FITZPATRICK

AP Sports Writer

NEW YORK (AP) Even at the end of an exhausting series, the Arizona Diamondbacks are a determined bunch in extra innings.

Cliff Pennington hit an RBI single with two outs in the 15th and the Diamondbacks, boosted early by Gerardo Parra's bunt double, finally outlasted the New York Mets 5-4 in a back-and-forth classic Thursday to split a draining four-game set at Citi Field.

Arizona scored in the final three innings but couldn't close out the feisty Mets until Brad Ziegler retired Kirk Nieuwenhuis on an easy grounder with runners at second and third to finish a game that lasted 5 hours, 46 minutes.

"It's a grind, but if we want to win a world championship, we're going to have to endure a lot worse than that," Diamondbacks manager Kirk Gibson said.

Anthony Recker and Nieuwenhuis hit tying homers in consecutive extra innings for New York, making its final home appearance before hosting the All-Star game July 16.

Meanwhile, the NL West-leading Diamondbacks improved to 10-3 in extra innings, the most such wins in the majors.

"There's no question this team will fight to the end of the game," Ziegler said. "It's just two really competitive teams going out and putting on a show on a holiday."

In a span of four days, the clubs played a 13-inning game, a 15-inning marathon and two others delayed by rain for a total of 3 1/2 hours. The 16 hours, 40 minutes worth of baseball marked the second-longest four-game series in the majors since 1987, according to STATS. The Dodgers and Astros played 11 more minutes inside the Houston Astrodome back in 1989.

So it was only fitting that the finale Thursday went on and on throughout a humid afternoon as kids who lined up beyond the outfield wall in the eighth inning waited patiently to run the bases after the final out.

"It felt like a marathon tennis match, to be honest with you," Nieuwenhuis said. "It's tough not to come up on top there at the end, but it's a 162-game season and we've got to bring it tomorrow."

Cody Ross drew a bases-loaded walk from New York reliever David Aardsma in the 13th, but the Diamondbacks squandered a great chance to add on. And of course, with two outs in the bottom half, Recker homered off Heath Bell to tie it again.

Arizona pushed across another run in the 14th on Martin Prado's bloop RBI single off Brandon Lyon with two outs.

Moments later, Nieuwenhuis sent a one-out liner barely over the left-center fence off Chaz Roe (1-0), who made his major league debut in the series opener Monday.

Recker and Nieuwenhuis were both batting .167 when they connected. The Mets said the last time a team hit two tying homers in extra innings was 1998, when Ray Lankford and Eli Marrero did it for the Cardinals.

"At first, you get disappointed. You've got the lead, they hit the home run. And it's disappointing when you have to reload and understand what's ahead of you," Gibson said. "Then, they hit the second one and you've just got to tell yourself, `You can take it.' You learn a lot about yourself in series like this and days like this."

Scott Rice (3-5) retired his first two batters in the 15th before Parra singled. Wil Nieves followed with a single for his fourth hit and Pennington lined a single to left to make it 5-4.

Pennington is 8 for 11 with three RBIs in extra innings this season.

Ziegler walked two in the bottom half but hung on for his first save since 2011 with Oakland.

And at last, it was over.

"This is one of the good signs for this club: We're really good in close games," Gibson said. "A good character check today. They all stepped up."

The Mets are no strangers to long games themselves- especially on July 4. They lost a 20-inning marathon at home to Miami last month, won a 20-inning game in St. Louis three years ago and came out on top in an Independence Day thriller at Atlanta in 1985.

That rain-delayed 16-13 victory is best remembered for Braves pitcher Rick Camp's tying homer with two outs in the 18th and the postgame fireworks that went off around 4 a.m.

By pulling out this test of endurance, the Diamondbacks finished 3-7 on a long road trip against three NL East teams.

"It was exhausting, especially when we got the lead twice and we kept losing it," said Nieves, who had a teddy bear in his bag to bring home to his daughter.

Wearing alternate caps on the Fourth of July, the teams were back at it in 87-degree heat and humidity less than 13 hours after their rain-delayed game ended Wednesday night. Arizona put the leadoff batter on six times in the first eight innings but managed only Nieves' two-run single in the fifth.

Mets starter Dillon Gee and counterpart Ian Kennedy, who matched a season high with eight strikeouts, kept the sluggish offenses in check for seven innings each.

Gee, who entered with a .126 career batting average, lashed a two-out RBI single that tied it at 2 in the fifth.

Ross drew a leadoff walk in the fifth and Parra dragged a hard bunt through the right side. With second baseman Daniel Murphy cheating toward the middle and first baseman Josh Satin breaking back to the bag, the ball rolled into shallow right field before Murphy could retrieve it.

Ross scampered to third and Parra slid into second easily. Nieves smacked the next pitch for a two-run single.

David Wright doubled in the Mets fourth and advanced on Kennedy's wild pitch before scoring on a groundout by Marlon Byrd.

NOTES: For the first time since 1973, the Mets have played three games that lasted at least 15 innings. They've lost all of them. ... Arizona will recall top prospect Tyler Skaggs from Triple-A Reno to start Friday night against Colorado in place of injured RHP Trevor Cahill (bruised right hip). The 21-year-old lefty went 1-1 with a 5.40 ERA in three starts for the Diamondbacks earlier this season. He was optioned to Reno on June 10. "He went back down there and got some more starts. He'll have a better understanding of what he's up against," Gibson said. ... Parra returned to the lineup in RF after sitting out two games. He was shaken up trying to make a diving catch on the warning track Monday, leaving him with scrapes and bruises on his face and arm. ... After the game, the Mets designated Lyon for assignment. They will recall reliever Greg Burke from Triple-A Las Vegas before Friday night's game in Milwaukee. ... Mets RHP Zack Wheeler (1-1, 5.06 ERA) makes his fourth major league start Friday night. ... New York pinch hitter John Buck was ejected in the 12th by first base umpire Mike Everitt for protesting a checked-swing third strike.

Updated July 4, 2013

Source: http://scores.nbcsports.msnbc.com/mlb/recap.asp?g=330704121

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Friday, July 5, 2013

Microsoft Develops Stereo-3D Display with Haptic Feedback Technology

Microsoft Research has developed a stereoscopic 3D monitor with haptic technology which simulates the sense of touch through tactile feedback mechanisms. In case the prototype device becomes a commercial product, it can revolutionize personal computers, interactivity of communication with people and things as well as many industries.

But how can a user touch and feel objects inside the virtual world? Can a flat touchscreen convey depth, weight, movement, and shape? Yes, say scientists in the natural interaction research group at Microsoft Research Redmond. Mike Sinclair, Michel Pahud, and Hrvoje Benko mounted a multitouch, stereo-vision 3D monitor on a robot arm to study how the kinesthetic haptic sense, which relates to motion rather than tactile touch, can augment touchscreen interactions.

The result is Actuated 3D Display with haptic feedback, a project that features a haptic device that provides 3D physical simulation with force feedback. The system consists of a touchscreen with a robot arm, engineered for instant, sensitive responsiveness, smooth forward and backward movement, and applications that support multitouch screen interactions, force sensing, 3D visualizations, and depth movement. By moving a finger on the screen, the user can interact with on-screen 3D objects and experience different force responses that correspond to the physical simulation.


Objects that can be touched and manipulated with the Actuated 3-D Display.

The Power of One Dimension

?I had been interested in the notion of putting a robot behind something you could touch. Originally, I had wanted a robot arm with many degrees of freedom. But complexity, costs, and safety issues narrowed down the options to one dimension of movement. At that point, I was sure that others must have already looked into this scenario, but after looking at the literature, it turned out no one had done this,? said Mr. Sinclair.

It also turned out that being limited to a robot armature with one dimension of movement ? the Z-axis of the applications ? provided valuable insights into how much or how little data humans need to detect the shape and type of object being touched.

?Contour detection was a major component of the project. The question was, by using your normal haptic sense, could you actually identify the type of object you were touching, even though it?s being presented by a fairly crude device consisting of a 2D touch screen and a robot arm that moves only in one dimension, forward and back along a track,? said Mr. Pahud.

To determine whether the device could simulate contours convincingly, an application presents the user with two rigid shapes of different depths, a cup and a ball. By changing the depth of the screen according to the user?s touch input, the team was able to simulate the surface contour of the 3D object. In contrast to the force-feedback behavior, this mode of operation can be thought of as setting the screen position with infinite resistance so that the user ?feels? the contour of the 3D object by tracing a finger along its surface.

?Your finger is always aware of motion. As your finger pushes on the touchscreen and the senses merge with stereo vision, if we do the convergence correctly and update the visuals constantly so that they correspond to your finger?s depth perception, this is enough for your brain to accept the virtual world as real,? said Mr. Pahud.

Taking this experiment a step further, the team ?blindfolded? subjects by making the screen blank. The goal was to see whether users could identify shapes by touch alone.

?They could not see anything, and the shapes were simple objects. We knew beforehand that complicated objects wouldn?t work, but some of the objects were reasonably sophisticated ? a pyramid, a wedge, a cylinder. But I would say these results were the biggest and most pleasant surprise of the project,? claimed Mr. Sinclair.

The project proved that with just a low-bandwidth data channel ? the finger ? it is possible to model surface contours. The low bandwidth is simply a function of the fact that, with a finger, the user only touches one point at a time, yet with sufficient haptic feedback as the finger moves, there is enough information to identify shapes.

Idle Forces at Work

One feature of the Actuated 3D Display with haptic feedback project that users might not notice but was essential to its function was implementation of a constant idle force.

?It is a very lightweight force that pushes back to follow the finger and maintain constant contact. At first, it feels as though you are touching a hard wall that?s easy to push, but you get used to it very quickly because it supplies only a few ounces of force against the finger. Since touchscreen interactions require the user?s finger to remain in contact with the surface, the main challenge of the idle mode is to ensure that the screen remains in contact with the fingertip regardless of the direction that the fingertip is moving, either away or toward the user,? explained Mr. Sinclair.

Thanks to this small idle force, the screen can follow the user?s finger in depth excursions, both positive and negative, until a haptic force beyond the idle force is commanded, such as when touching and interacting with an object.

The team also implemented four additional command modes: force, velocity, position, and detent, where additional forces are added to the idle force depending on the position of the finger and the application requirements. Detent mode, for example, specifies a fixed-position command to the controller, which makes the screen remain exactly at a desired position, effectively canceling the idle force. This adds a brief resistance that creates a haptic signal for the user, analogous to the sensory click of a radio dial when turned off. The detent mode proved extremely useful for exploring volumetric data.

Exploring Data Through Touch

From the first discussion about this work, Pahud envisioned a 3D image of a brain, built from volumetric data.

?I could see an image of the front of a brain and pushing a finger through the layers of the brain to travel through the data. I could imagine receiving haptic feedback when you encountered an anomaly, such as a tumor, because we can change the haptic response based on what you touch. You could have different responses for when you touch soft tissue versus hard tissue, which makes for a very rich experience,? he said.

In contrast to other project applications that apply to 3D scenes, the volumetric-data-exploration application shows how movement and haptics can enhance interactions with 2D data. Mr. Pahud implemented a volumetric medical-image browser that shows the MRI-scanned data of a human brain. By gently pushing on the screen, the user can explore the data using touch and view different image slices of the brain. ?The brain browser is not just for exploring data through touch. The prototype is meant to demonstrate how touch interactions can be deployed for meaningful work.


Brain Explorer. The interface provides a method to mark and save depth investigations of interest.

To facilitate search and retrieval of annotated slices, the project implements a haptic detent to mark that slice. Thus, when the user?s finger moves past an annotated slice, either coming or going, the detent provides tactile resistance to alert the user of an annotated slice. The user may continue on and push past the detent, but the detent has done its job by making it easier to find annotations through touch, unaided by visuals.

There is no doubt that the kinesthetic approach creates a productive new paradigm that augments touchscreen interactions. Mr. Pahud and Mr. Sinclair see many opportunities for this type of haptic device.

?There?s always 3D gaming. but also 3D modeling, education, and medical. We anticipate improving the experience with crisper, more detailed feedback, such as texture,? concluded Mr. Sinclair.

Tags: Microsoft, Stereo 3D, Haptic Feedback

Source: http://www.xbitlabs.com/news/monitors/display/20130705135016_Microsoft_Develops_Stereo_3D_Display_with_Haptic_Technology.html

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Da Vinci-code, bird-style: Cockatoos can solve complex puzzles

Ten untrained Goffin's cockatoos were able to complete a series of complex sequential tasks to access a nut reward.

By Elizabeth Barber,?Contributor / July 5, 2013

In a recent study, 10 cockatoos were able to solve a complex puzzle that involved a series of steps.

University of Oxford

Enlarge

In an experiment, ten untrained Goffin's cockatoos were presented with a complex device that, if a series of steps were completed, would proffer up a quarter of a cashew: first, the birds must remove a pin, then a screw, then a bolt; then turn a wheel 90 degrees and then a latch sideways.

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It took one of the birds, Pipin, less than two hours to finish the process unassisted in five different sessions. Other birds finished the puzzle with some help, after being offered either?the series of locks incrementally or after watching a bird partner do the task.

Except for work with chimpanzees, a nonhuman animal successfully completing more than three, novel, sequential steps without prior training has not been previously documented in scientific literature. Most similar studies test the animal?s ability to learn through reinforcement a set of behaviors. But this study was more interested in the cockatoo?s capacity to innovate: Could this Indonesian bird develop solutions to a problem not present in its natural environment? Did it understand the logic of working toward a series of tasks sequentially?

?Our aim was to investigate?innovative problem solving under controlled conditions, to explore the mechanism of learning, and to advance towards identifying what it is that animals learn when they master a complex new sequential task,? write the scientists in the paper, published in PLOS ONE.

To complete the puzzle, the birds had to understand the necessity of completing each step in sequence. Because there was only one reward at the end of the puzzle, that means that the birds had to complete the first four steps with only the promise of another step. And to test whether or not the birds both understood the underlying problem of the sequential tasks and had to innovate in each round, rather than simply having learned through reinforcement how to undo each lock, the scientists reordered the locks, removed a step, or changed the locks? functionality in each of the five sessions.

?We cannot prove that the birds understand the physical structure of the problem as an adult human would, but we can infer from their behaviour that they are sensitive to how objects act on each other, and that they can learn to progress towards a distant goal without being rewarded step by step,? said Alex Kacelnik, a professor at Oxford University's Department of Zoology and a co-author of the study, in a press release.

In addition to appearing to understand the general concept of sequential task doing, the birds also seemed to demonstrate what is known as the ?cognitive ratchet? process: once the birds learned to solve one lock, they seldom struggled with future locks of the same type.

?The birds' sudden and often errorless improvement and response to changes indicates pronounced behavioural plasticity and practical memory,? said Auguste von Bayern, also of Oxford University and a co-author.

Goffin's cockatoos - small and white - are a uniquely curious and not-easily-discouraged species, eager to explore their world with their tongues, beaks, and claws, and the scientists say that that the birds' intrepidness and fascination with their surroundings was a critical factor in their success.

?We believe that they are aided by species characteristics such as?intense curiosity, tactile exploration techniques and persistence," said Dr. von Bayern.

Source: http://rss.csmonitor.com/~r/feeds/csm/~3/8hxAEr6jsuQ/Da-Vinci-code-bird-style-Cockatoos-can-solve-complex-puzzles

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Internet big boys concerned over rules for news sites

Global firms request two changes to licensing regulation

FIVE major Internet and technology companies have expressed concern over new government licensing rules for online news sites, calling them "unwarranted and excessive".

They also warned that the new licensing framework could affect Singapore's business-friendly image and hamper innovation.

The companies - Facebook, Google, eBay, Yahoo and cloud computing corporation Salesforce - also urged the Government to ease up on the rules, which look set to spark a lively debate in Parliament next Monday.

The five are members of the Asia Internet Coalition (AIC), an industry association they had formed to represent their interests in Internet policy issues in the region.

Earlier this year, the five were among hundreds of companies, groups and individuals that objected to government legislation in the United States.

They said its Stop Online Piracy Act and Protect IP Act, which aimed to address copyright infringement, would clamp down on free speech, innovation and the development of the Internet.

In Singapore, the new licensing regime affects only one of them: Yahoo. Its website Yahoo Singapore is among 10 sites that must have an individual licence.

Under the new framework, which kicked in on June 1, an individual licence is a must for websites with more than 50,000 Singapore visitors a month and which carry more than one news story about Singapore a week.

The licence entails putting up a $50,000 performance bond. Also, if or when told by the Government to take down prohibited content, the websites must comply in 24 hours.

Said the AIC: "This new regulation - and the regulatory trend that this may be indicative of - could unintentionally hamper Singapore's ability to continue to drive innovation, develop key industries in the technology space and attract investment in this key sector.

"We also believe the scope of the regulation and manner in which it was introduced have negatively impacted Singapore's global image as an open and business-friendly country."

The AIC made two requests.

One is for the regulation to include a statement that the websites will not be liable for content posted by users. To proactively police content is an "untenable position", the AIC said, noting that online platforms have "incentives" to address misuse of their services.

The second is for websites to be given a "reasonable timeframe" to comply, instead of up to 24 hours. The AIC said 24 hours was particularly difficult for international companies, which have to negotiate across time zones.

It also took issue with the $50,000 bond, saying it would be a "financial risk" to start-ups.

"It sends a very strong wrong message to the Internet community in and beyond Singapore that these changes could presage a more restrictive attitude to the Internet.

"It could also set a precedent for more restrictive regimes around the region," the AIC said in its three-page June 14 letter that was addressed to Minister for Communications and Information Yaacob Ibrahim.

The Ministry of Communications and Information said yesterday that it told the AIC that Singapore adopts a "light touch approach" in Internet regulations and the licensing framework has not changed this approach.

It reiterated that the new regulations are for greater parity for news providers on traditional and online media platforms. The content standards that sites have to adhere to have also "not resulted in the stifling of online discourse, nor have they prevented netizens from commenting on government policies".

On the 24-hour window requirement, the ministry said it is "important" in managing false news that may cause mass panic as information can spread quickly on the Internet.

As for the bond, it is to ensure websites remove prohibited content "quickly" and when directed to do so by the Government.

The ministry added that the Media Development Authority (MDA) met the AIC early last month to provide clarifications and invited it to take part in an upcoming public consultation on amendments to the Broadcasting Act next year.

The three firms providing the 10 licensed sites - Yahoo, Singapore Press Holdings and MediaCorp - have given their feedback on the new licensing framework, which the MDA is reviewing, said the ministry. "The engagement process with the licensees is ongoing," said a ministry spokesman yesterday.

twong@sph.com.sg


Background Story

NEGATIVE IMPACT

...the scope of the regulation and manner in which it was introduced have negatively impacted Singapore's global image as an open and business- friendly country.

- The Asia Internet Coalition

Source: Straits Times ? Singapore Press Holdings Ltd. Permission required for reproduction.

Source: http://www.singaporelawwatch.sg/slw/headlinesnews/27239-internet-big-boys-concerned-over-rules-for-news-sites.html

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Thursday, July 4, 2013

Founder Stories: Swell's Ram Ramkumar On Transitioning From CTO To CEO

Screen Shot 2013-07-03 at 12.22.43 PMFor today's Founder Stories, I met with Ram Ramkumar, co-founder and new CEO of Concept.io, which last week launched Swell, an adaptive mobile app that streams audio news content. Ram explains how, as CEO, he has to focus on usability and design, which is in contrast to his experience running a technical team at Snaptell.

Source: http://feedproxy.google.com/~r/Techcrunch/~3/4i5hYlPqxrM/

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Yahoo Acquires Xobni

Screen Shot 2013-07-03 at 1.16.26 PMYahoo has just announced that they've acquired Xobni, the startup that tries to make your inbox and contacts list less terrible by focusing on the people you communicate with most.

Source: http://feedproxy.google.com/~r/Techcrunch/~3/BUF_b1pMbxw/

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