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Olympus Image Share for iOS is Back in App Store
By Derrick Story on June 18, 2013 7:11 AM
Fans of the Toshiba FlashAir wireless SD card will be happy to see the Olympus Image Share app back in iTunes for iPhone and iPad.
In my latest book, iPad for Digital Photographers, I recommend Image Share as the easiest way to filter Jpegs from Raws and only upload the Jpegs to your iPad. The app left iTunes for a couple weeks, presumedly while it was being retooled, but now has returned with new features. And most importantly, the old features still work.
If you have an Olympus E-P5, you can now tap the new remote control and geotagging features in the Image Share app. Very nice. Those of us using the FlashAir card don't have access to those features. But we can still wirelessly transfer our photos from the camera to the iOS device.
ShutterSnitch Adds Eye-Fi mobi Support
In related news, the venerable ShutterSnitch app has added support for the Eye-Fi mobi wireless SD card. On first test, I could not get the two talking to each other, even after quitting the Eye-Fi app as instructed by ShutterSnitch. I'll keep testing. Once I get things working, I'll report my findings.
iPad for Digital Photographers
This is the kind of stuff I write about in iPad for Digital Photographers -- now available in print, Kindle, and iBooks format.
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TDS Workshop at the Hot Air Balloon Classic
The Movie Making for Photographers Workshop focused on the Sonoma County Hot Air Balloon Classic for its filmmaking subject. We spent portions of both Saturday and Sunday at Keiser Park in Windsor, CA capturing content for our work in Final Cut Pro X.
Close access to the action provided great content for our filmmaking.
The workshop crew then learned the ins and outs of setting up a project in Final Cut Pro X, organizing the vast library of scenes we had recorded, building an effective storyline, massaging audio, and best practices for outputting our finished product. We also covered how to move Final Cut projects from one drive to another and upgrading existing iMovie work to Final Cut X.
Two professional filmmakers joined us as co-instructors, Louis Ekrem of Laughing Cat Films and Eric Michael Perez of Clicker Video, who shared practical ways to tap the movie making functionality of our DSLRs.
Classroom session of TDS Movie Making Workshop. Photo by Eric Perez.
"I'm never going back to iMovie," remarked Ed Shields, one of the workshop photographers. "Once you get your bearings in Final Cut X, it's actually quite logical," added Craig Tooley, who also joined the group.
Balloon photos by Derrick Story.
Having such intimate access to the action at the Hot Air Balloon Festival was so important for our movie making. We were able to show the details of preparation as well as the sweeping big shots during liftoff. We're planning to do this workshop again next year. If you want to improve your movie making skills and witness firsthand the excitement of a hot air balloon festival, make June 2014 on your calendar.
Join me on my Instagram site as I explore the world of mobile photography.
Flickr for Android Gets Much Needed Facelift
When Yahoo! released Flickr v2 for iOS, iPhone users had a more appealing experience than their Android counterparts. In late May, that discrepancy was diminished... for the most part.
Flickr for Android brings the visual beauty of the iOS version with much, but not all, of its functionality. Since I'm primarily an iOS user, I couldn't tell if the unevenness was my lack of understanding or Flickr's UI. According to others, such as PCMag.com, it's not me; it's the app.
But those few rough spots could be easily ironed out in future updates. And the app itself is beautiful. Like the iOS version, it has reenergized my enthusiasm for mobile Flickr when using Android.
If you haven't done so already, give the new Flickr for Android a try. And while you're at it, join the Digital Story Public Group. We have a talented community there. And selected images from that public group are featured on the TDS Facebook page as the TDS Member Photo of the Day.
If you love mobile photography like I do, then you'll enjoy iPad for Digital Photographers -- now available in print, Kindle, and iBooks versions.
Lowepro Transit Sling 250 - Light, Tight, and Looking Alright
When I'm working in an urban environment, I want to travel light, have fast access to my equipment, and carry a bag that doesn't scream "camera gear." Lately I've been packing my OM-D kit in the Lowepro Transit Sling 250 AW ($99) and feeling great, even during extended shoots.
The Transit sling has fast side-access allowing me to keep the Olympus OM-D tucked away when on the move, then able to grab it quickly when a shot presents itself. I have plenty of room for spare lenses, flash, an extra body, and snacks. There's a dedicated iPad pocket in the back that fits a 10" tablet or iPad mini. If I need a light tripod or monopod, I can use the tuck-away holder on the side of the bag. And just as importantly, I feel like I blend into the environment when working out of the Transit Sling.
Portrait of Alyssa
I used the Olympus OM-D E-M5 with the excellent Panasonic Lumix G X Vario 12-35mm/F2.8 lens to create this portrait of Alyssa in the downtown area of Santa Rosa, CA. With the ISO set to 400, I shot at f/2.8 at 1/800th in Aperture Priority mode, exposure compensation set to -1.3. The focal length was set to 35mm. I then processed the image in Aperture 3.4.
Inside the Transit Sling 250 AW
Inside the Transit Sling I pack the OM-D with grip, Panasonic 12-35mm f/2.8 zoom, Olympus 75mm f/1.8 prime, and the Leica 25mm f/1.4 lens. Also stowed is an Olympus flash, Fujifilm X20 compact camera, filters, cable release, iPad (in the dedicated back pocket) and a snack. In the field, I can upload images directly from the camera to the iPad using a Toshiba FlashAir or Eye-Fi Mobi wireless card.
Regardless if I'm working on location, or processing images on the iPad in a coffee shop, the Tranist Sling 250 protects my gear and doesn't get in the way. I give it a very high nimbleosity rating.
DP Review Gives Canon 40mm Pancake Gold Award
Great minds thinks alike. In this case it's Canon and DP Review. But I like the Canon EF 40mm f/2.8 STM lens too. And DP Review just honored it with Gold Award.
In their review, they write: The EF 40mm f/2.8 STM is a fairly unprepossessing little lens, and its tiny size and relatively low price might make you wonder whether significant compromises have been made in its design and construction. But the moment you start shooting with it and looking at the images it produces, any such thoughts rapidly disappear - it's actually a very fine lens.
And I couldn't agree more. When I'm feeling creative and want to just have fun shooting, the 40mm is one of those lenses I reach for. And for $149, how can you go wrong?
Eye-Fi Mobi Review
The new Eye-Fi Mobi 16GB SDHC Wireless Memory Card does what I've always wanted an Eye-Fi card to do: easily connect my iOS device to my camera regardless of my location.
Once the card and camera are connected, the images flow from the camera to the iOS device, such as an iPad, where you can edit and share the pictures. The process is relatively simple.
Insert the card in the camera and power up.
Download the mobile app at www.eye.fi/mobi and enter the activation code that comes with the card.
Take a picture with your camera to force the card to begin broadcasting.
Open the Settings app on the iPad, tap on WiFi, and choose the Eye-Fi card that's in the list of networks.
Return to the Eye-Fi app and watch the picture being transferred from your camera to the iPad.
In the Eye-Fi app, you can monitor the connection via the status button in the upper left corner. When it's green, the two devices are talking. When it's red, the Eye-Fi card has timed out and stopped broadcasting.
The Eye-Fi app on an iPad mini
This is where the system could use a little refinement. There's no control over how quickly the Eye-Fi card powers down in the camera. As it works out, it's just a couple of minutes. I understand why it does this, to save battery power. But once the card powers down, you have to prod it again to transmit, then go back to Settings on the iPad and log back in to the network.
I would like to have some control over the time period before the card powers down. I found myself having to log in to the card repeatedly, even during a single session of shooting.
Once the images are on the iPad, Eye-Fi creates a Photos Album to manage them. This is very convenient. You can access the Album via the Photos app, iPhoto app, or any other app that can read Albums. I also liked that transfer was swift. My medium-sized Jpegs loaded quickly and were virtually ready for use immediately after capture.
You can set up sharing to Facebook, Twitter, or via email within the Eye-Fi app itself. But since the images are automatically saved to your Camera Roll, you have access to them for publishing using your normal workflow. You can add multiple Eye-Fi Mobi cards to the app, and switch among them as needed. This allows you to have cards in all of your cameras if you wish.
The Eye-Fi Mobi is available in 16 GB ($75) and 8 GB ($50) capacities. Both versions are rated at a speedy Class 10. I anticipate refinements in how we can control the card's power management. But even in this first release, the Mobi is one of the best wireless card options currently available. Both versions are available on Amazon.com
"Samsung Galaxy Camera, Eye-Fi Mobi, Olympus 75mm Lens" - Digital Photography Podcast 379
By Derrick Story on June 10, 2013 7:19 PM
This week on The Digital Story: Samsung Galaxy Camera, Eye-Fi Mobi, and the Olympus 75mm f/1.8 lens. All of this and more on The Digital Story podcast.
Story #1 - Samsung GC110 Galaxy Digital Camera - I've been testing this Android-based (4.1 Jellybean) 16MP camera with 21X optical zoom with 23mm on the wide end.
The Samsung Galaxy also sports a 1.4 GHz quad core processor, giant 4.8" LCD, and WiFi (no cellular with the GC110 model). It's selling on Amazon for $449. That's an investment for a compact camera that's on the large size. So what do you get for your money? I'll go into some detail about that.
Story #2 - The Eye-Fi Mobi 16GB SDHC Class 10 Wireless Memory Card addresses one of my biggest complaints about Eye-Fi cards, lack of easy direct connect. With the Mobi, and the iOS app for my iPad mini, I can shoot with any SD card compatible camera and have the images stream to the iPad.
The Mobi has some nice features that help with energy management and picture organization. The 16 GB SDHC model (class 10) is currently selling on Amazon for $75. I think it's worth it. And I'll discuss why in the second story.
Story #3 - The Olympus 75mm f1.8 Lens is now available in black. Yaay! I've been shooting with this beauty for a week now, and I have first impressions to share.
Reminder! - If you're going to purchase gear through Amazon or B&H Photo, please stop by the TDS home page first. Look for the "Products" box about half way down the page in the second column. There you will see display tiles for Amazon, lynda.com, and B&H Photo, in that order. By entering those sites through those display tiles, you help support The Digital Story.
You can also download the podcast here (32 minutes). Or better yet, subscribe to the podcast in iTunes. You can support this podcast by purchasing the TDS iPhone App for only $2.99 from the Apple App Store.
Monthly Photo Assignment
The June 2013 photo assignment is Stylish.
More Ways to Participate
Want to share photos and talk with other members in our virtual camera club? Check out our Flickr Public Group. And from those images, I choose the TDS Member Photo of the Day.
Podcast Sponsors
Red River Paper -- Keep up with the world of inkjet printing, and win free paper, by liking Red River Paper on Facebook.
Make Your Photos Sizzle with Color! -- SizzlPix is like High Definition TV for your photography.Special Offer! Anyone buying Derrick's new book, iPad for Digital Photographers, even at Amazon's or Barnes And Noble's discount, and putting the password for the Book Owners lounge in the comments space of their SizzlPix! order, will get 10 percent off their entire order -- the equivalent of more than a full refund for the book!
Need a New Photo Bag? Check out the Lowepro Specialty Store on The Digital Story and use discount code LP20 to save 20% at check out.
3 Things I Like About Lightroom 5
Even though there are more than 50 new features in Lightroom 5, there are three in particular that I like. First, we finally have a true full screen preview mode. Now, when I press the "F" key, I get what I've always wanted.
Second, when using the Spot Removal tool, there's an option at the bottom of the screen called Visualize Spots. By checking the box, Lightroom creates a mask that makes it easy to see any flaws that I might want to remove.
Using "Visualize Spots" I can easily see areas that I might want to remove.
And third, the Upright tool, found in the Lens Corrections box, is terrific. It straightens out those lines making the buildings look less distorted. I've tested it with a series of architecture shots, and it has improved the image 9 out of 10 times. More often than not, using Auto mode for Upright is all you need.
Lightroom 5 is available now for download ($79 for upgrade, $149 for new users) and is part of Adobe Creative Cloud.
Apple RAW Compatibility Update 4.06 Supports 9 New Cameras
By Derrick Story on June 8, 2013 12:42 PM
With RAW Compatibility Update 4.06, your Mac (Aperture, iPhoto, and Preview) now supports the following new cameras:
Canon EOS-1D C
Canon EOS Rebel SL1 / 100D / Kiss X7
Canon EOS Rebel T5i / 700D / Kiss X7i
Hasselblad Lunar
Nikon COOLPIX A
Nikon 1 S1
Sony Alpha NEX-3N
The update is for Mountain Lion (Mac OS X 10.8) users.
Use Aperture and iPhoto Together!
To learn about using Aperture and iPhoto together, visit my Using iPhoto and Aperture Together on lynda.com. Also, take a look at our Aperture 3 Learning Center. Tons of free content about how to get the most out of Aperture.
Where's Your Cable Release?
By Derrick Story on June 7, 2013 8:22 AM
They hardly take up any space in your camera bag, yet they're often left behind. The cable release allows you to trip the shutter without jarring the camera, enabling you to capture sharper images.
Nikon "traditional" cable release on a Fujifilm X20
For my Fujifilm X20, I'm using the wonderful (and affordable) Nikon AR-3 Mechanical Release that's 12" long and runs $16.95. For all of my other cameras, I'm using the mandatory electronic releases.
I recommend always having one release for one camera in your bag. For night photography, low-light mood shots, and product work, they really come in handy.
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A number of orchestras and ensembles in the Washington suburbs are looking to graduate from pure local or community status to regional recognition. There's nothing like using one of the biggest pieces of "ear candy" in the classical music repertoire to help move the process along, particularly when you have the right people to pull it off.
On Saturday night the McLean Orchestra opened its season with a program featuring Washington-based piano virtuoso Thomas Pandolfi, who delivered an exhilarating performance of Sergei Rachmaninoff's magnificently tuneful Piano Concerto No. 2 in C minor. Chock full of melodies that are by turn dramatically declarative and achingly evocative, the 1901 "Rachmaninoff Second" is a warhorse of piano competitions that tests the limits of both a pianist's sheer physical prowess and his or her innate musicianship. It features a nearly continuous display of dense writing that requires the pianist to pull each melody out from within a line of notes flying around the keyboard both above and below the melody itself.
What Pandolfi achieved with the McLean Orchestra was a rare mix of technical accuracy and cool confidence that created a masterful path through the concerto, shorn of the nervous tension that often accompanies watching highly "trained" young pianists attempt the most difficult music. Typically Pandolfi would begin a line with a powerful bass pulse that would impel the music forward and finish major passages with an easy flourish worthy of a ragtime or pops performance. Pandolfi and the orchestra's charismatic conductor Miriam Burns also clearly planned major touch points of the Rachmaninoff concerto to preserve its start-to-finish drama rather than produce disjointed pieces of "business" just to display the pianist's chops.
In one notable moment near the end of the concerto's first movement, Pandolfi deftly tucked a four-octave piano countermelody into the full orchestra's restatement of the first half of the concerto's opening theme. On recordings, this moment often features the pianist pounding away at the countermelody in full show-off mode, leading to a delay in the listener's recognition that the orchestra is reprising the main opening theme. With the way Pandolfi and Burns handled it, the orchestra's dramatic presentation of the melody shone through so that when the piano switched from countermelody to take over the second half of the main melody, the effect was seamless, comprehensible and satisfying.
Pandolfi also managed a trick that eludes even some celebrated pianists with Rachmaninoff's music, which is to avoid transferring the power of the concerto's thunderbolt concert-grand bass notes to the top notes, which can lead to harsh pings as lines fly up to the highest of the 88 keys. By gracefully teasing out melodies and countermelodies, as well as luscious rolling chords in a late passage of the concerto's gorgeously lyrical second movement, Pandolfi kept what could otherwise come across as percussive playing within the melodic structure of the full concerto.
Maestra Burns assisted by continually leading the orchestra's brass instruments, especially its French horns, in apt swells and retreats on long notes accompanying some of Pandolfi's most virtuoso passages. When the third and last movement closed on one of classical music's most iconic moments, a monumental final restatement of the Rachmaninoff tune that later in the 20th century became the Frank Sinatra hit "Full Moon and Empty Arms" (later covered by Eddie Fisher, Robert Goulet and Sarah Vaughan), the effect was one of logic and completeness.
The Rachmaninoff piano concerto keynoted a Russian-themed program that also included Tchaikovsky's sixth and last symphony, also known as the "Pathetique" Symphony, and an opera prelude (or overture) by Tchaikovsky's 19th century contemporary Modest Mussorgsky. At the top of the program, Maestra Burns tied the entire program together for the audience, noting some of the distinct personal struggles against which both Tchaikovsky and Rachmaninoff composed some of their most representative music.
She also diplomatically gave the audience some important clues to listening to the program, pointing out that Tchaikovsky's Pathetique Symphony goes from some of the highest highs to the lowest lows of emotional content, poured into an unusual structure where the third of four movements sounds like it ends the entire piece on a triumphant note, only to surrender to a dramatic new theme which pulls the composition into a devastating final movement.
Her commentary paid off as the audience was prepared for the "false ending" of the Tchaikovsky and later waited in hushed silence for about 20 seconds at the actual dying-away end of the piece before surrendering to applause. Along the way were special passages worthy of note by the orchestra's viola and cello sections, some terrific "anchoring" of the brass sections by bass trombonist Dana Landis and tuba player David Porter, and some especially beautiful flourishes by one of the orchestra's most noted members, principal flutist Amy Thomas.
The McLean Orchestra does face a challenge, as it freely admits in the program, with its current performance space at the Oakcrest School in McLean. The unusual, hexagon-shaped stage and semi-circular, wraparound house of Oakcrest's concert hall requires some odd stage set-ups and creates some slightly squirrelly acoustics. In this environment the violin section often does not quite deliver the creamy sound that this Romantic-era and (very) early 20th century music begs for, and the percussion instruments, under the long-time, versatile leadership of Craig Teer, sometimes "pop" too much against the orchestra compared to the orchestra's past venues.
If classical music is going to make it in our area, it will come from young people of moderate means who become fans of the McLean Orchestra and other ambitious groups who are there to hear the music for the first time, not to be upsold to other products. I might suggest to Mr. Frank that while there are plenty of other times and places to do major fundraising, an orchestra's concert evenings should be about the music and not the money – even in McLean, Virginia.
David Rohde is a local pianist, conductor, arranger, vocal teacher and writer who has worked extensively in Washington area musical theater. Most recently he appeared as musical director and conductor of The Arlington Players' April 2014 production of The Most Happy Fella. David particularly enjoys watching musicians and actors he's worked with "make it" when they pursue regional and national performing arts careers. David is a seven-time nominee and two-time recipient of the WATCH Award for Outstanding Musical Direction.
I agree the President's pre-concert remarks were much too long.
In the future, I plan to insert "announcements" in the program book and keep my remarks to welcoming the audience and focusing on the concert at hand.


text:
United States International Trade Commission
The United States International Trade Commission (ITC) is a government body of the USA which can block the importing of goods for various reasons including alleged patent infringement. The law used is section 337 of the Tariff Act of 1930.[1]
Most complaints get rejected, but there are cases where the ITC has banned imports, such as the Broadcom v. Qualcomm case in 2007.[2]
Another possible motivation may be the press coverage. Whether the ITC finally accepts or rejects a request, the media will have, in the mean time, published articles warning that the targeted company may not be able to sell devices in the USA.
About its relation to the courts, an article in Wired wrote:[3]
The ITC is a trade body, not a court, so federal judges can ignore its findings. However, many of them pay attention to what goes on at the ITC.
1 Example cases
2 Banned products
3 Approved for trolls
4 Related pages on en.swpat.org
5.1 News article selection (newest first)
[edit] Example cases
Below are some cases where patent holders have asked the ITC to block imports due to (what might be) software patents. The ITC rejects almost all such requests.
Trend Micro v. Barracuda (2008, USA)[4]
Microsoft v. TomTom (2008, USA)
Nokia v. Apple (2010, USA)
Apple v. HTC (2010, USA)[5]
Elan Microelectronics v. Apple (2010, USA)[6]
Microsoft v. Motorola (2010, USA)[7]
Apple v. Motorola (2010, USA)[8]: Preliminary ruling: rejected.[9]
Samsung v. Apple (2011, USA)[10]
S3 Graphics v. Apple (2011, USA) - rejected in November 2011[11]
[edit] Banned products
Very few complaints actually result in an import ban, but it does happen.
Qualcomm phones[12]
Buffalo's wireless routers
[edit] Approved for trolls
The USITC exists to prevent "unfair" foreign competition entering the US market, so it includes a "domestic industry" requirement.[13] Some thought this could prevent trolls from using the ITC, but this seems to not be the case.
In a decision on 14 April 2010, the ITC rejected a complaint because the patent holder failed to show:
substantial investment in ... exploitation [of the patent], including engineering, research and development, or licensing
This is the decision titled "Certain Coaxial Cable Connectors and Components Thereof and Products Containing Same".[14] "Licensing" can include litigation, but in that case the patent holder:
must show each asserted litigation activity is related to licensing.
However, in a decision on 1 August 2012, a CAFC judge confirmed a decision by the ITC to allow a troll to block imports. CAFC Judge Bryson said:
the domestic industry requirement is satisfied if there is a domestic industry based on "substantial investment in [the patent's] exploitation" where the exploitation is achieved by various means, including "licensing."[15]
[edit] Related pages on en.swpat.org
USA patents courts and appeals
Patent governance
Phone patent litigation - a category of lawsuit that often includes an ITC complaint
[edit] External links
United States International Trade Commission, Wikipedia
[edit] News article selection (newest first)
USITC Asks En Banc Federal Circuit for Power to Block Imports Whose Distribution Induce Infringement in the US, 10 Mar 2014, Patently-O
(This case of induced infringement is about importing hardware which doesn't infringe the patent, but which would when combined with software after being imported)
ITC: How an obscure bureaucracy makes the world safe for patent trolls, 21 Sep 2012, Timothy B. Lee
Non-Practicing Entities at the USITC, 23 Mar 2012, Patently-O
At the ITC, Patent Litigation is Not a Domestic Industry, 16 Apr 2010, LegalTimes (quoted above)
Apple Sued Over Touchpad Technology at ITC, 26 Apr 2010, LegalTimes blog
ITC upholds Qualcomm phone ban, 22 June 2007, The Register - a case where the ITC banned the import of a device
[edit] References
↑ http://www.usitc.gov/press_room/news_release/2007/er1221ee4.htm
↑ http://www.theregister.co.uk/2007/06/22/itc_upholds_qualcomm_phone_ban/
↑ http://www.wired.com/wiredenterprise/2012/03/ms-patent/
↑ http://www.engadget.com/photos/apple-htc-itc-filing-1/#2757943
↑ http://www.bloomberg.com/apps/news?sid=aAUwSSjk1Qjk&pid=20601087
↑ http://www.engadget.com/2010/10/01/microsoft-files-itc-complaint-against-motorola-over-alleged-andr/
↑ http://mediacenter.motorola.com/Press-Releases/Motorola-Mobility-Sues-Apple-for-Patent-Infringement-344d.aspx
↑ http://www.usitc.gov/press_room/documents/337_750_ID.pdf
↑ http://www.bloomberg.com/news/2011-06-29/samsung-files-itc-patent-complaint-against-apple.html
↑ http://usitc.gov/secretary/fed_reg_notices/337/337_724_notice11212011sgl.pdf
↑ http://www.patentlyo.com/patent/2012/08/federal-circuit-again-supports-usitc-jurisdiction-for-pure-enforcement-npes-court-again-splits-on-claim-construction.html
↑ http://legaltimes.typepad.com/blt/2010/04/at-the-itc-patent-litigation-is-not-a-domestic-industry.html
↑ http://www.cafc.uscourts.gov/images/stories/opinions-orders/10-1093.pdf
This wiki is part of the End Software Patents (ESP) campaign (donate). For more information, see:
>> endsoftwarepatents.org (Main ESP website) <<
>> endsoftwarepatents.org/news (News) <<
This wiki is publicly editable. (See: en.swpat.org:About) It's a pool of information, not a statement of ESP's views or policies, so no permission is required. Add your knowledge! (See: Help:How to make a good contribution)
Retrieved from "http://en.swpat.org/wiki?title=United_States_International_Trade_Commission&oldid=35079"

redpajama_set_name: RedPajamaCommonCrawl


text:
Navy Nurse POW, Philippines
The Influenza Epidemic of 1918
Recollections of capture by the Germans, imprisonment, and escape by Lieutenant Edouard Victor Isaacs, U.S.N.
Oral Histories of World War II
83 days on a life raft
Battle of Leyte Gulf, LT Burwell
LT Walter Burwell
Battle of Midway
A doctor remembers the Battle of Midway
John Ford remembers filming Battle of Midway
Recollections of Lieutenant George Gay
Battle of Okinawa
Interrogation of CDR Hashimoto, CO of I-58
Invasion of Normandy - Combat Demolitions Units in Force O
Invasion of Normandy, LT James W. Thompson
Iwo Jima Flag Raising on Mount Suribachi
LT Bell Chaplain on board USS Card
Luzon Operation Lingayen Gulf Landing-LTJG Brown
Navy Flight Surgeon on USS Franklin
Navy Nurse - Philippines, Bataan, Corregidor, & Okinawa
Nurses in support of Normandy Invasion
Oral History - Appendectomy Performed on Fourth War Patrol of USS Seadragon, 1942
Submarine Squadron TWO Report - Appendectomy
Pacific Typhoon, 18 December 1944
Pearl Harbor Attack - Captain Lacouture, USS Blue
Pearl Harbor Attack - LT Ruth Erickson
Pearl Harbor Attack - LT Horace Warden
Pearl Harbor Attack - Pharmacist's Mate Second Class Lee Soucy
Pharmacist's Mate serving with Marines on Guadalcanal
Recollections of Captain Daniel V. Gallery
Recollections of Ensign Leonard W. Tate
Recollections of Lieutenant Commander Dudley S. Knox
Recollections of Lieutenant Commander William Leide
Recollections of Lieutenant Wilton Wenker and Lieutenant Elby
Recollections of Vice Admiral Alan G. Kirk -Rhine River Crossing in 1945
Recollections of the Invation of Normandy
Rescue of Prison Ship Survivors - Recollections of Lieutenant Commander Landon L. Davis, Jr.
Sinking of U-172
Sinking of the USS Indianapolis - Capt Charles McVay
USS Indianapolis - Sinking
War in the Pacific: Actions in the Philippines by Sonarman 1st Class Jack Gebhardt
The Cold War and Vietnam
Operation Crossroads, 1946
Vietnam- Navy Nurse in Saigon, 1963
Navy Combat Field Historian in Vietnam
Some Experiences Reported by the Crew of the USS Pueblo
War Against Terrorism
Emergency Medical Activity after Pentagon Attack, September 11, 2001
2001 to present: USNS Comfort in NYC
U.S. Naval Institute Oral Histories Available in the Navy Department Library
Modern U.S. Navy Strategy and Policy
The Maritime Strategy: Oral History of Captain Peter M. Swartz, USN (Ret.)
The CNO Strategic Studies Group: Oral History of Admiral James R. Hogg, USN (Ret.)
nhhc-topics:women
nhhc-document-types:oral-history
Oral Histories - U.S. Navy Nurse Prisoner of War in the Philippines, 1942-1945
Recollections of LT Dorothy Still Danner, NC, USN, captured by the Japanese in Manila and imprisoned at Santo Thomas and Los Banos in the Philippines
Adapted from: "Dorothy Still Danner: Reminiscences of a Nurse POW." Navy Medicine 83, no. 3 (May-June 1992): 36-40
I never had any childhood dreams of being a nurse. I thought I wanted to be a dress designer, but along came the depression. I became a nurse because my mother liked nursing and the LA County General Hospital paid the nurses a little stipend. She took me there and the next thing I knew I was a student nurse. I really loved nursing and found it a very satisfying profession. That was in 1932 and I was 18 years old.
After graduating from nursing school I worked in two hospitals before joining the Navy in 1937. At that time, there were only 400 nurses in the Navy. I really didn't expect to be hired so I was really surprised when I got my orders to go to the San Diego Naval Hospital for a physical. The next thing I knew I was in the Navy.
My first assignment was at Balboa Hospital in San Diego. Oh, it was beautiful! From the pink building sitting up on the hill, you could look down over the harbor and see all those Navy ships out there and feel very important as part of Uncle Sam's Navy. I spent 1938 and 1939 in San Diego.
In 1939 I was sent to the Canacao Naval Hospital in the Philippines. I traveled across the Pacific on the [transport USS] Henderson [AP-1]. It was a festive trip. We first stopped at Honolulu. I can still see the people on the dock there with their lais and the hula dancers. Then we spent 2 or 3 days going around the islands.
Although the Philippines was not quite as spectacular as Hawaii I became very fond of the base there anyway. The Navy Yard was just across Manila Bay about a half mile away. It was a very active social life. There were always parties and, of course, the nurses got involved along with everybody else.
Our social concerns were put on the back burner when the dependents were sent home around the first of 1941. While we heard about the rape of Nanking, nobody thought the Japs would be silly enough to try and do anything to Uncle Sam.
Pearl Harbor shocked me as it did everyone else. I and the other nurses were awakened in the middle of the night and told that Pearl Harbor had been hit. We were sent to the hospital as soon as we got dressed. Since the hospital was right in the target zone, we sent all the ambulatory patients back to duty and the rest to Manila. Arrangements were made to admit the patients to what had been a dependents ward at the Sternberg Army Hospital.
On Wednesday the 10th, the Navy Yard was bombed. It was wiped out. This raid lasted about an hour. After the raid, we rushed to the hospital, and patients were all over the place. There were Filipino women, children, and men and our own people from the Navy Yard. It was really a shocking scene. The power to the hospital was knocked out. It was a pretty hectic afternoon. Triage was impossible. You just tried to find out which were the worst ones to go to surgery and so on.
Sternberg Hospital too was quickly swamped. The only place that was available was Estado Mayor, an old Army base; we used the barracks as a temporary hospital. In the meantime, they decided to set up joint surgical teams (with Army and Navy Medical Corps) throughout the city. I was with the group assigned to the Jai Alai Club. Our purpose was to care for anyone that was hit - civilian or military - that would come into these emergency centers. We set up a little receiving station near the front of the building, but didn't get any patients.
After spending a few weeks there, we were told to move to the Santa Scholastica school, also in Manila. The Army had already converted it into a hospital. Actually, we had more hospital personnel than patients. On December 31, the Army evacuated al the Army patients on a hospital ship and took them to Australia.
Meanwhile, the Army was retreating toward Bataan to make a stand there. The military declared Manila an open city and retreated, but the medical personnel remained.
On 2 January, the Japanese came into Manila, but didn't come to Santa Scholastica until a few days later. At first the Japanese were not hostile and mostly left us alone. But then they started taking quinine from us. Then they took our beds and mattresses. They also began to slap around and beat up the men. But they ignored us - the nurses.
When the Japanese came they rounded up all the Allied civilians and sent them to the University of Santo Tomas. Although there were some 66 classrooms in the main building, there were still too many people. It was just a mess. The toilet facilities were overwhelmed and sickness began almost overnight. With Japanese permission, the civilians formed an administration committee and appointed a leader. Soon the civilians set up a school for the children, entertainment, and a newsletter, among other things. Santo Tomas was used as a model by the Japanese. They allowed the Swiss delegates to see Santo Tomas, not the POW camps or the other civilian camps.
I was sent to Santo Tomas on March 8, 1942. However, the medical facilities there were still lacking. There was a little hospital set up in what had been a mechanical engineering building. The doctors brought in medicine from their offices. A lot of lab technicians and pharmacists apparently had their own means of bringing drugs in then through Red Cross funds. By the time we got there, they had revamped the rest rooms and had put in showers.
Soon Santo Tomas became too crowded as the Japanese kept bringing people in. They decided to move part of the camp out of Manila. Therefore. they selected a site near the town of Los Banos to house some of the overflow.
"The Country Club"
In May 1943, the Japanese sent 800 men to Los Banos to set up the camp. Two doctors who were going asked our chief nurse if we would go down and help them set up the little hospital. Los Banos was about 60 or 70 kilometers south of Manila. We weren't needed at Santo Tomas anymore due to the influx of Army nurses after the fall of Corregidor.
We went to the agricultural college outside Los Banos which had been a part of the University of the Philippines. The Japanese took a plot of about 55 or 60 acres and put a barbed wire fence around it. Our hospital was a small 25-bed unit. The nurses lived in a dormitory that had plenty of space - two or three nurses in a room.
At Los Banos our first order of business was to get our 25-bed hospital functioning. We initially had two American civilian doctors, but they were repatriated in August 1943. In their place we got another American doctor, Dr. Dana Nance. He was a young fellow, one of those charismatic characters who got out there with the baseball teams and was very concerned about his patients. He was a surgeon and brought his own instruments. Patients who had been sent back to Manila for surgery were now handled in our hospital. We also had a dentist.
Initially, there were only the men and nurses at Los Banos. The dependents were supposed to come in July, but did not arrive until December. When they did, they changed the whole outlook of the camp. They brought touches of civilization with them - tablecloths and salt and pepper shakers, etc. Life itself was not that bad. People had the opportunity to exercise, to go out and cut wood, and do chores that needed to be done to keep the community going. People had recordings they played at the bandstand. And they had baseball games. It was really country club living compared to the other camps.
While food was not plentiful, at least at this time, starvation was not a problem. Since we lived in an old agricultural college we had limited access to meat. We had carabao mainly, and some pigs. We also had a garden in which we grew mostly eggplants and camotes, a sort of sweet potato. Of course, there was rice as usual and mongo beans. Duck eggs were occasionally available.
A Change in Lifestyle
Life began to change in late 1943. when the Japanese military took over the camps. Before, the camps had been run by Japanese civilian administrators. But now there was a supply officer, LT [Sakaadi] Konishi. who had made life miserable for the internees in Santo Tomas - he apparently wanted to starve the internees. He came to Los Banos in 1944 to make life miserable for us too. Moreover, our lifestyle worsened appreciably in early 1944 because the Japanese brought many more civilians into Los Banos. Many of the new civilians - the sick and the elderly - had previously been allowed to stay in their homes in Manila. There were few able-bodied men to take care of this load. Life had really become hard in Santo Tomas.
By March 1944, the whole spirit at Los Banos changed. There was no more country club living. The camp just kind of fell apart and the food situation began to deteriorate. The nurses were moved into a much smaller apartment in tight quarters. However, Eldene Paige and I moved into the barracks across the street from the hospital which gave a little more space.
Living conditions for the others also worsened. The Japanese cut off the south end of the camp and crowded the internees into the remaining portion. By this time, the Americans had invaded the Philippines, so as life got worse for the Japanese, they made life worse for us. We were only getting two meals a day, skimpy meals at that. We mainly had rice, diluted to a pasty lugao. There was practically no meat in the stew; it was very watery. And, of course. we used to have coconut milk, but the coconuts had gotten so expensive they were no longer available. We began to lose weight.
It looked like Christmas 1944 would be very gloomy, but a songfest by the priests and sisters livened things up On Christmas Eve they had a midnight mass and practically the whole camp turned out. It was the most spectacular: mass I've ever seen. There were no gifts involved on Christmas Day, just spirit of friendliness between people. I had more meaning then ever before. It was a beautiful Christmas!
Camp Freedom
On January 9, 1945, American troops landed at Lingayen Gulf. The Japanese awakened us in the middle of the night and told us they were leaving. They turned the camp over to the administrative committee and advised us not to go outside.
The administrative committee then called us to attention: "Today at this time we're announcing you are free. This is Camp Freedom." An American flag was sent up the flagpole and we sang the national anthem. Tears were running down everyone's face. It was a very emotional moment.
Unfortunately, our freedom only lasted a week. Then the Japanese came back. However, MacArthur's troops came down toward Manila and on February 3rd liberated Santo Tomas. After learning about Los Banos, MacArthur assigned the 11th Airborne Division to rescue the in ternees. [MacArthur had good evidence the Japanese would soon execute the Los Banos prisoners.]
The rescue plan was complicated because it was out of the ordinary. Thus far, the Americans had only liberated prisoners in their line of advance. But a Los Banos rescue meant going far behind enemy lines to rescue a little over 3,000 people. Paratroopers themselves were to be dropped over Los Banos and attack in conjunction with infantry who would come ashore in amtracs (amphibious vehicles) from a nearby lake. These amtracs would then evacuate many of the civilians. The raiders already had a map of what the camp was like given to them by an escapee, Pete Miles. Miles and the Filipino guerrillas would act as scouts and guides for the troops. The plan was to sneak up behind all the guard houses in the camp and at the specific moment everything would happen at once.
We didn't know the rescue was going to happen, so we were all feeling pretty low. I was on duty that night. There was a newborn baby and I was trying to feed her with what little powdered milk was left. The mother could hardly nurse the baby. She hadn't had enough nourishment herself. It was just about 7 in the morning [23 Feb. 1945]. 1 had the baby in my arms when I noticed smoke signals going up. Nobody paid any attention to them. Then, all of a sudden we saw a formation of aircraft coming over. As the paratroopers started jumping out, the guerrillas and soldiers around the guard houses began killing the Japanese there. Then the amtracs came in, crashing through the swali-covered fence near the front gate.
I was holding the baby and covering her ears so that the noise wouldn't affect her. An amtrac pulled up in front of the hospital and the American troops jumped out. Oh, we never saw anything so handsome in our lives. These fellows were in camouflage uniforms wearing a new kind of helmet, not those little tin pan things we were used to seeing. And they looked so healthy and so lively.
They were to take the internees out and any that could walk were to go back with troops in the trucks that came overland with the diversionary force. The internees were not military-minded and they just went in all directions. They didn't want to leave anything. The firing was mostly over in about 15 minutes but it took awhile to evacuate the internees. In fact, the American troops actually had to set fire to the barracks to get the internees moving.
Eventually, the troops were able to get about 1,500 people on the amtracs and the rest overland, I left on an amtrac in the second wave. Remarkably, I think there were only two soldiers killed and one internee injured. This whole thing went off with just the most amazing precision that you could imagine. [In retaliation for the raid, the Japanese murdered 1,500 inhabitants of the nearby town of Los Banos. For this and other crimes, LT Konishi was later tried as a war criminal and executed.]
After being liberated from Los Banos, we were flown to Leyte. We were taken to Admiral Kinkaid's [VADM Thomas C. Kinkaid was Commander, 7th Fleet and Southwest Pacific Force] headquarters, where we ate dinner with the Admiral. They served us beautiful steaks, which of course we couldn't eat because our stomachs had shrunk so much.
It was surprising to see how much publicity we got. On Leyte we began to see the flashbulbs going off and then as we got closer to home, more flashbulbs. When we landed in Oakland there was quite a reception for us, including a lot of photographers and media. Then they gave dinners for us. It was quite an affair.
We also had a very thorough examination in Oakland and went on 90-day recuperative leave. My health had been good, but while I was in Los Banos I developed the dry type of beriberi, as had many others. It was very uncomfortable because I ached all over and my knees buckled. There was nothing I could do for it because it was caused by malnutrition. Our diet was not very good, especially during the last few months before our rescue. But I quickly recovered once I was able to eat good food again.
Published: Mon Sep 21 12:35:49 EDT 2015


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Weekly Review 5th – 11th September 2011 "Josip Simunic"
Recovered from that illness on Monday this week, although I still have a cough now triggered from the smoking in the stadium when I saw Hadjuk Split vs Dinamo Zagreb yesterday! It's a big rivalry, the atmosphere was great and the flares and crackers made it crazy! Something you would never see in any other part of the world. Video says it all. The match itself ended 1-1. It was alright, a split player got sent off in the first half an hour, but then split scored! Dinamo equalised later on. When I compare myself to those players that were on the pitch, I thought that I'm not far off (not being cocky), in fact I think I'm just as good as a few of them technically and maybe even smarter! If these teams are the best in Croatia, then I have to be good enough to be a pro. The night before the match, I talked to Josip Simunic because he was staying in our nice hotel, I think they were staying in the luxury suites as well! (footballers lifestyles..). Josip played for Deakin, my old club in Canberra. And actually, another old player from Deakin was playing for Split in the match, Steven Lustica. I told him about my situation, that I am 18, out of school, and trying to find a professional club. I told him that I used to play for Deakin, and asked who my coach was there. He knew exactly who my coach was! He said to me that it's very difficult to make it.. and that's all he kept saying really. But he seemed like a nice guy and I got a photo!
Chris told me this week that he was arranging a trial with a Scottish third division team called Montrose. I basically told him no, I don't want to go live in some place in the middle of nowhere. I did a Google search and looked at maps.. and yeah it's basically a small fishing town. But I've thought about it a bit now.. I guess it depends on where the training ground is, but It's an hours drive away from Aberdeen and Dundee. I guess when I think about that.. it wouldn't be too bad. Hmm.. but Scottish footballers are fucking hard cunts, aren't they? I guess I know for sure I would be faster than alot of them, and probably better technically. Anyway, back to that later.
Jahan gave me the facebook of this guy called John Petter, apparently he's the one who can get me into a club in Holland. But he seems never to answer his facebook messages, so I'm guessing he's a lazy dick with something else going on in his life.
Anyway, with football right now it's about waiting for a desirable city, with an international community, and international student housing for cool social life and great lifestyle. But I guess I can't really wait any longer either.. choices, choices, choices..
So after a long car ride, I'm back in Budapest. I'm starting training with Moses again tomorrow morning. It's midnight now, so It's off to bed.
Missed 3:40 because my priorities were on being with the fam. So roll that on to next week. Approx 3 hrs everyday next week.
Also started the mental training set by athletesaudio.. I've done a few sessions so far, I think all the exercises there are really going to be great help on the pitch.
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In 2009, I was an average soccer player with a dream. I started this blog to document my journey from local underdog to getting offered over $100,000 in soccer scholarships, a contract to play professionally and the experience of playing in Europe.


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Apple's Child Abuse Detection System for Scanning iCloud Photo Libraries
Apple has said that all photo libraries of US iPhone users will be screened for known child abuse images if they are stored on the online iCloud service.
The disclosure came in a series of media briefings in which Apple seeks to dispel alarm over its announcement last week that scan users' phones, tablets and computers for millions of illegal photographs. The company has clarified that it will only apply to photos that are uploaded and stored online.
Apple has been under pressure for the low amount of abuse material it has reported. Credit:Stock Image
While Google, Microsoft, and other tech platforms verify uploaded photos or email attachments against a database of identifiers provided by the National Center for Missing and Exploited Children and other clearinghouses, security experts criticized the Apple's plan as more invasive because the scanning occurs on users' devices. .
Some said they hoped governments would seek to force the iPhone maker to expand the system to search for other material on the devices.
In a post on its website on Sunday, Apple said it would fight such attempts, which can occur in secret courts.
"We have faced lawsuits to build and implement mandatory government changes that degrade user privacy before, and we have strongly rejected those demands," Apple wrote. "We will continue to reject them in the future."
In Monday's briefing, Apple officials said the company's system, which will roll out this year with the release of its iOS 15 operating system, will check existing files on a user's device whether users have those photos. synchronized with the company's storage servers.
The technology will be rolled out first in the United States, with other countries potentially to follow.
Julie Cordua, CEO of Thorn, a group that has developed technology to help law enforcement officials detect sex trafficking, said about half of all child sexual abuse material is in video format.
Rocket League Season 4 Brings Dusty New Deadeye Canyon Arena & More This Week • Eurogamer.net
NSW COVID cases grow, Victoria COVID cases grow, Queensland cases grow, Sydney lockdown continues, Victoria lockdown continues


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Tumor immunology (2)
Innate immunity and inflammation (1)
Solid tumors (1)
Journal of Experimental Medicine (16)
Brief Definitive Report (2)
Nicholas P. Restifo
STING agonist promotes CAR T cell trafficking and persistence in breast cancer
2021: The Year in Experimental Medicine , Innate Immune Signaling in Disease and Homeostasis , JEM Cancer Collection 2021
Nuo Xu, Douglas C. Palmer, Alexander C. Robeson, Peishun Shou, Hemamalini Bommiasamy, Sonia J. Laurie, Caryn Willis, Gianpietro Dotti, Benjamin G. Vincent, Nicholas P. Restifo, Jonathan S. Serody
CAR T therapy targeting solid tumors is restrained by limited infiltration and persistence of those cells in the tumor microenvironment (TME). Here, we developed approaches to enhance the activity of CAR T cells using an orthotopic model of locally advanced breast cancer. CAR T cells generated from Th/Tc17 cells given with the STING agonists DMXAA or cGAMP greatly enhanced tumor control, which was associated with enhanced CAR T cell persistence in the TME. Using single-cell RNA sequencing, we demonstrate that DMXAA promoted CAR T cell trafficking and persistence, supported by the generation of a chemokine milieu that promoted CAR T cell recruitment and modulation of the immunosuppressive TME through alterations in the balance of immune-stimulatory and suppressive myeloid cells. However, sustained tumor regression was accomplished only with the addition of anti–PD-1 and anti–GR-1 mAb to Th/Tc17 CAR T cell therapy given with STING agonists. This study provides new approaches to enhance adoptive T cell therapy in solid tumors.
Host conditioning with IL-1β improves the antitumor function of adoptively transferred T cells
JEM Cancer Collection 2020
Ping-Hsien Lee, Tori N. Yamamoto, Devikala Gurusamy, Madhusudhanan Sukumar, Zhiya Yu, Jane Hu-Li, Takeshi Kawabe, Arunakumar Gangaplara, Rigel J. Kishton, Amanda N. Henning, Suman K. Vodnala, Ronald N. Germain, William E. Paul, Nicholas P. Restifo
J Exp Med (2019) 216 (11): 2619–2634.
Host conditioning has emerged as an important component of effective adoptive cell transfer–based immunotherapy for cancer. High levels of IL-1β are induced by host conditioning, but its impact on the antitumor function of T cells remains unclear. We found that the administration of IL-1β increased the population size and functionality of adoptively transferred T cells within the tumor. Most importantly, IL-1β enhanced the ability of tumor-specific T cells to trigger the regression of large, established B16 melanoma tumors in mice. Mechanistically, we showed that the increase in T cell numbers was associated with superior tissue homing and survival abilities and was largely mediated by IL-1β–stimulated host cells. In addition, IL-1β enhanced T cell functionality indirectly via its actions on radio-resistant host cells in an IL-2– and IL-15–dependent manner. Our findings not only underscore the potential of provoking inflammation to enhance antitumor immunity but also uncover novel host regulations of T cell responses.
Mg2+ regulation of kinase signaling and immune function
Chryssa Kanellopoulou, Alex B. George, Evan Masutani, Jennifer L. Cannons, Juan C. Ravell, Tori N. Yamamoto, Margery G. Smelkinson, Ping Du Jiang, Mami Matsuda-Lennikov, Julie Reilley, Robin Handon, Ping-Hsien Lee, J. Richard Miller, Nicholas P. Restifo, Lixin Zheng, Pamela L. Schwartzberg, Matthew Young, Michael J. Lenardo
J Exp Med (2019) 216 (8): 1828–1842.
Mg2+ is required at micromolar concentrations as a cofactor for ATP, enzymatic reactions, and other biological processes. We show that decreased extracellular Mg2+ reduced intracellular Mg2+ levels and impaired the Ca2+ flux, activation marker up-regulation, and proliferation after T cell receptor (TCR) stimulation. Reduced Mg2+ specifically impairs TCR signal transduction by IL-2–inducible T cell kinase (ITK) due to a requirement for a regulatory Mg2+ in the catalytic pocket of ITK. We also show that altered catalytic efficiency by millimolar changes in free basal Mg2+ is an unrecognized but conserved feature of other serine/threonine and tyrosine kinases, suggesting a Mg2+ regulatory paradigm of kinase function. Finally, a reduced serum Mg2+ concentration in mice causes an impaired CD8+ T cell response to influenza A virus infection, reduces T cell activation, and exacerbates morbidity. Thus, Mg2+ directly regulates the active site of specific kinases during T cell responses, and maintaining a high serum Mg2+ concentration is important for antiviral immunity in otherwise healthy animals.
Cish actively silences TCR signaling in CD8+ T cells to maintain tumor tolerance
Douglas C. Palmer, Geoffrey C. Guittard, Zulmarie Franco, Joseph G. Crompton, Robert L. Eil, Shashank J. Patel, Yun Ji, Nicholas Van Panhuys, Christopher A. Klebanoff, Madhusudhanan Sukumar, David Clever, Anna Chichura, Rahul Roychoudhuri, Rajat Varma, Ena Wang, Luca Gattinoni, Francesco M. Marincola, Lakshmi Balagopalan, Lawrence E. Samelson, Nicholas P. Restifo
Improving the functional avidity of effector T cells is critical in overcoming inhibitory factors within the tumor microenvironment and eliciting tumor regression. We have found that Cish, a member of the suppressor of cytokine signaling (SOCS) family, is induced by TCR stimulation in CD8+ T cells and inhibits their functional avidity against tumors. Genetic deletion of Cish in CD8+ T cells enhances their expansion, functional avidity, and cytokine polyfunctionality, resulting in pronounced and durable regression of established tumors. Although Cish is commonly thought to block STAT5 activation, we found that the primary molecular basis of Cish suppression is through inhibition of TCR signaling. Cish physically interacts with the TCR intermediate PLC-γ1, targeting it for proteasomal degradation after TCR stimulation. These findings establish a novel targetable interaction that regulates the functional avidity of tumor-specific CD8+ T cells and can be manipulated to improve adoptive cancer immunotherapy.
Retinoic acid controls the homeostasis of pre-cDC–derived splenic and intestinal dendritic cells
Christopher A. Klebanoff, Sean P. Spencer, Parizad Torabi-Parizi, John R. Grainger, Rahul Roychoudhuri, Yun Ji, Madhusudhanan Sukumar, Pawel Muranski, Christopher D. Scott, Jason A. Hall, Gabriela A. Ferreyra, Anthony J. Leonardi, Zachary A. Borman, Jinshan Wang, Douglas C. Palmer, Christoph Wilhelm, Rongman Cai, Junfeng Sun, Joseph L. Napoli, Robert L. Danner, Luca Gattinoni, Yasmine Belkaid, Nicholas P. Restifo
Dendritic cells (DCs) comprise distinct populations with specialized immune-regulatory functions. However, the environmental factors that determine the differentiation of these subsets remain poorly defined. Here, we report that retinoic acid (RA), a vitamin A derivative, controls the homeostasis of pre-DC (precursor of DC)–derived splenic CD11b+CD8α−Esamhigh DCs and the developmentally related CD11b+CD103+ subset within the gut. Whereas mice deprived of RA signaling significantly lost both of these populations, neither pre-DC–derived CD11b−CD8α+ and CD11b−CD103+ nor monocyte-derived CD11b+CD8α−Esamlow or CD11b+CD103− DC populations were deficient. In fate-tracking experiments, transfer of pre-DCs into RA-supplemented hosts resulted in near complete conversion of these cells into the CD11b+CD8α− subset, whereas transfer into vitamin A–deficient (VAD) hosts caused diversion to the CD11b−CD8α+ lineage. As vitamin A is an essential nutrient, we evaluated retinoid levels in mice and humans after radiation-induced mucosal injury and found this conditioning led to an acute VAD state. Consequently, radiation led to a selective loss of both RA-dependent DC subsets and impaired class II–restricted auto and antitumor immunity that could be rescued by supplemental RA. These findings establish a critical role for RA in regulating the homeostasis of pre-DC–derived DC subsets and have implications for the management of patients with immune deficiencies resulting from malnutrition and irradiation.
Immune targeting of fibroblast activation protein triggers recognition of multipotent bone marrow stromal cells and cachexia
Eric Tran, Dhanalakshmi Chinnasamy, Zhiya Yu, Richard A. Morgan, Chyi-Chia Richard Lee, Nicholas P. Restifo, Steven A. Rosenberg
Fibroblast activation protein (FAP) is a candidate universal target antigen because it has been reported to be selectively expressed in nearly all solid tumors by a subset of immunosuppressive tumor stromal fibroblasts. We verified that 18/18 human tumors of various histologies contained pronounced stromal elements staining strongly for FAP, and hypothesized that targeting tumor stroma with FAP-reactive T cells would inhibit tumor growth in cancer-bearing hosts. T cells genetically engineered with FAP-reactive chimeric antigen receptors (CARs) specifically degranulated and produced effector cytokines upon stimulation with FAP or FAP-expressing cell lines. However, adoptive transfer of FAP-reactive T cells into mice bearing a variety of subcutaneous tumors mediated limited antitumor effects and induced significant cachexia and lethal bone toxicities in two mouse strains. We found that FAP was robustly expressed on PDGFR-α+, Sca-1+ multipotent bone marrow stromal cells (BMSCs) in mice, as well as on well-characterized, clinical-grade multipotent human BMSCs. Accordingly, both mouse and human multipotent BMSCs were recognized by FAP-reactive T cells. The lethal bone toxicity and cachexia observed after cell-based immunotherapy targeting FAP cautions against its use as a universal target. Moreover, the expression of FAP by multipotent BMSCs may point toward the cellular origins of tumor stromal fibroblasts.
Tumor-reactive CD4+ T cells develop cytotoxic activity and eradicate large established melanoma after transfer into lymphopenic hosts
2018 Nobel Prize Collection
Sergio A. Quezada, Tyler R. Simpson, Karl S. Peggs, Taha Merghoub, Jelena Vider, Xiaozhou Fan, Ronald Blasberg, Hideo Yagita, Pawel Muranski, Paul A. Antony, Nicholas P. Restifo, James P. Allison
Adoptive transfer of large numbers of tumor-reactive CD8+ cytotoxic T lymphocytes (CTLs) expanded and differentiated in vitro has shown promising clinical activity against cancer. However, such protocols are complicated by extensive ex vivo manipulations of tumor-reactive cells and have largely focused on CD8+ CTLs, with much less emphasis on the role and contribution of CD4+ T cells. Using a mouse model of advanced melanoma, we found that transfer of small numbers of naive tumor-reactive CD4+ T cells into lymphopenic recipients induces substantial T cell expansion, differentiation, and regression of large established tumors without the need for in vitro manipulation. Surprisingly, CD4+ T cells developed cytotoxic activity, and tumor rejection was dependent on class II–restricted recognition of tumors by tumor-reactive CD4+ T cells. Furthermore, blockade of the coinhibitory receptor CTL-associated antigen 4 (CTLA-4) on the transferred CD4+ T cells resulted in greater expansion of effector T cells, diminished accumulation of tumor-reactive regulatory T cells, and superior antitumor activity capable of inducing regression of spontaneous mouse melanoma. These findings suggest a novel potential therapeutic role for cytotoxic CD4+ T cells and CTLA-4 blockade in cancer immunotherapy, and demonstrate the potential advantages of differentiating tumor-reactive CD4+ cells in vivo over current protocols favoring in vitro expansion and differentiation.
Naive tumor-specific CD4+ T cells differentiated in vivo eradicate established melanoma
Ying Xie, Akgül Akpinarli, Charles Maris, Edward L. Hipkiss, Malcolm Lane, Eun-Kyung M. Kwon, Pawel Muranski, Nicholas P. Restifo, Paul Andrew Antony
In vitro differentiated CD8+ T cells have been the primary focus of immunotherapy of cancer with little focus on CD4+ T cells. Immunotherapy involving in vitro differentiated T cells given after lymphodepleting regimens significantly augments antitumor immunity in animals and human patients with cancer. However, the mechanisms by which lymphopenia augments adoptive cell therapy and the means of properly differentiating T cells in vitro are still emerging. We demonstrate that naive tumor/self-specific CD4+ T cells naturally differentiated into T helper type 1 cytotoxic T cells in vivo and caused the regression of established tumors and depigmentation in lymphopenic hosts. Therapy was independent of vaccination, exogenous cytokine support, CD8+, B, natural killer (NK), and NKT cells. Proper activation of CD4+ T cells in vivo was important for tumor clearance, as naive tumor-specific CD4+ T cells could not completely treat tumor in lymphopenic common gamma chain (γc)–deficient hosts. γc signaling in the tumor-bearing host was important for survival and proper differentiation of adoptively transferred tumor-specific CD4+ T cells. Thus, these data provide a platform for designing immunotherapies that incorporate tumor/self-reactive CD4+ T cells.
Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8 + T cells
Luca Gattinoni, Steven E. Finkelstein, Christopher A. Klebanoff, Paul A. Antony, Douglas C. Palmer, Paul J. Spiess, Leroy N. Hwang, Zhiya Yu, Claudia Wrzesinski, David M. Heimann, Charles D. Surh, Steven A. Rosenberg, Nicholas P. Restifo
Depletion of immune elements before adoptive cell transfer (ACT) can dramatically improve the antitumor efficacy of transferred CD8 + T cells, but the specific mechanisms that contribute to this enhanced immunity remain poorly defined. Elimination of CD4 + CD25 + regulatory T (T reg) cells has been proposed as a key mechanism by which lymphodepletion augments ACT-based immunotherapy. We found that even in the genetic absence of T reg cells, a nonmyeloablative regimen substantially augmented CD8 + T cell reactivity to self-tissue and tumor. Surprisingly, enhanced antitumor efficacy and autoimmunity was caused by increased function rather than increased numbers of tumor-reactive T cells, as would be expected by homeostatic mechanisms. The γ C cytokines IL-7 and IL-15 were required for augmenting T cell functionality and antitumor activity. Removal of γ C cytokine–responsive endogenous cells using antibody or genetic means resulted in the enhanced antitumor responses similar to those seen after nonmyeloablative conditioning. These data indicate that lymphodepletion removes endogenous cellular elements that act as sinks for cytokines that are capable of augmenting the activity of self/tumor-reactive CD8 + T cells. Thus, the restricted availability of homeostatic cytokines can be a contributing factor to peripheral tolerance, as well as a limiting resource for the effectiveness of tumor-specific T cells.
Synergy of IL-21 and IL-15 in regulating CD8+ T cell expansion and function
Rong Zeng, Rosanne Spolski, Steven E. Finkelstein, SangKon Oh, Panu E. Kovanen, Christian S. Hinrichs, Cynthia A. Pise-Masison, Michael F. Radonovich, John N. Brady, Nicholas P. Restifo, Jay A. Berzofsky, Warren J. Leonard
Interleukin (IL)-21 is the most recently recognized of the cytokines that share the common cytokine receptor γ chain (γc), which is mutated in humans with X-linked severe combined immunodeficiency. We now report that IL-21 synergistically acts with IL-15 to potently promote the proliferation of both memory (CD44high) and naive (CD44low) phenotype CD8+ T cells and augment interferon-γ production in vitro. IL-21 also cooperated, albeit more weakly, with IL-7, but not with IL-2. Correspondingly, the expansion and cytotoxicity of CD8+ T cells were impaired in IL-21R−/− mice. Moreover, in vivo administration of IL-21 in combination with IL-15 boosted antigen-specific CD8+ T cell numbers and resulted in a cooperative effect on tumor regression, with apparent cures of large, established B16 melanomas. Thus, our studies reveal that IL-21 potently regulates CD8+ T cell expansion and effector function, primarily in a synergistic context with IL-15.
Immune Evasion by Murine Melanoma Mediated through CC Chemokine Receptor-10
Takashi Murakami, Adela R. Cardones, Steven E. Finkelstein, Nicholas P. Restifo, Brenda A. Klaunberg, Frank O. Nestle, S. Sianna Castillo, Phillip A. Dennis, Sam T. Hwang
Human melanoma cells frequently express CC chemokine receptor (CCR)10, a receptor whose ligand (CCL27) is constitutively produced by keratinocytes. Compared with B16 murine melanoma, cells rendered more immunogenic via overexpression of luciferase, B16 cells that overexpressed both luciferase and CCR10 resisted host immune responses and readily formed tumors. In vitro, exposure of tumor cells to CCL27 led to rapid activation of Akt, resistance to cell death induced by melanoma antigen-specific cytotoxic T cells, and phosphatidylinositol-3-kinase (PI3K)–dependent protection from apoptosis induced by Fas cross-linking. In vivo, cutaneous injection of neutralizing antibodies to endogenous CCL27 blocked growth of CCR10-expressing melanoma cells. We propose that CCR10 engagement by locally produced CCL27 allows melanoma cells to escape host immune antitumor killing mechanisms (possibly through activation of PI3K/Akt), thereby providing a means for tumor progression.
Tumor Regression and Autoimmunity after Reversal of a Functionally Tolerant State of Self-reactive CD8+ T Cells
Willem W. Overwijk, Marc R. Theoret, Steven E. Finkelstein, Deborah R. Surman, Laurina A. de Jong, Florry A. Vyth-Dreese, Trees A. Dellemijn, Paul A. Antony, Paul J. Spiess, Douglas C. Palmer, David M. Heimann, Christopher A. Klebanoff, Zhiya Yu, Leroy N. Hwang, Lionel Feigenbaum, Ada M. Kruisbeek, Steven A. Rosenberg, Nicholas P. Restifo
Many tumor-associated antigens are derived from nonmutated "self" proteins. T cells infiltrating tumor deposits recognize self-antigens presented by tumor cells and can be expanded in vivo with vaccination. These T cells exist in a functionally tolerant state, as they rarely result in tumor eradication. We found that tumor growth and lethality were unchanged in mice even after adoptive transfer of large numbers of T cells specific for an MHC class I–restricted epitope of the self/tumor antigen gp100. We sought to develop new strategies that would reverse the functionally tolerant state of self/tumor antigen-reactive T cells and enable the destruction of large (with products of perpendicular diameters of >50 mm2), subcutaneous, unmanipulated, poorly immunogenic B16 tumors that were established for up to 14 d before the start of treatment. We have defined three elements that are all strictly necessary to induce tumor regression in this model: (a) adoptive transfer of tumor-specific T cells; (b) T cell stimulation through antigen-specific vaccination with an altered peptide ligand, rather than the native self-peptide; and (c) coadministration of a T cell growth and activation factor. Cells, vaccination, or cyto-kine given alone or any two in combination were insufficient to induce tumor destruction. Autoimmune vitiligo was observed in mice cured of their disease. These findings illustrate that adoptive transfer of T cells and IL-2 can augment the function of a cancer vaccine. Furthermore, these data represent the first demonstration of complete cures of large, established, poorly immunogenic, unmanipulated solid tumors using T cells specific for a true self/tumor antigen and form the basis for a new approach to the treatment of patients with cancer.
Elucidating the Autoimmune and Antitumor Effector Mechanisms of a Treatment Based on Cytotoxic T Lymphocyte Antigen-4 Blockade in Combination with a B16 Melanoma Vaccine: Comparison of Prophylaxis and Therapy
Andrea van Elsas, Roger P.M. Sutmuller, Arthur A. Hurwitz, Jennifer Ziskin, Jennifer Villasenor, Jan-Paul Medema, Willem W. Overwijk, Nicholas P. Restifo, Cornelis J.M. Melief, Rienk Offringa, James P. Allison
DOI: https://doi.org/10.1084/jem.194.4.481
We have previously shown that small B16 melanomas can be successfully treated using a combination of anti–cytotoxic T lymphocyte antigen (CTLA)-4 monoclonal antibody with a granulocyte/macrophage colony-stimulating factor (GM-CSF) producing irradiated tumor cell vaccine. Regression of tumors results in long-lasting immunity and is frequently accompanied by autoimmune depigmentation. Here we examine the cellular and molecular mechanisms of this combined treatment. Histological examination of depigmented lesions revealed infiltration of polymorphonuclear cells and deposition of antibody. The combination therapy also induced tumor rejection and skin depigmentation in B cell–deficient and in CD4+ T cell–depleted mice. Both effects of the treatment absolutely required CD8+ T cells. Analysis of the response in successfully treated mice revealed elevated levels of CD8+ T cells specific for a nonameric peptide consisting of residues 180–188 of the melanocyte differentiation antigen tyrosinase-related protein (TRP)2. There was no evidence of reactivity to the melanocyte antigens gp100, tyrosinase, Mart1/MelanA, or TRP1. Fas–FasL interactions and perforin played a role in mounting the effector response, whereas the tumor necrosis factor pathway was not required. The cellular requirements for tumor rejection in this therapeutic setting were strikingly different from those in a prophylactic setting. In particular, if mice received a prophylactic vaccine consisting of anti–CTLA-4 and B16–GM-CSF before tumor challenge, full protection was obtained even in the absence of CD8+ T cells. Our data demonstrate that therapeutic autoreactive CD8+ T cell responses can effectively be generated in tumor-bearing mice and stresses the value of studying tumor immunity in a therapeutic rather than a prophylactic setting.
Self-Tolerance to the Murine Homologue of a Tyrosinase-Derived Melanoma Antigen: Implications for Tumor Immunotherapy
Teresa A. Colella, Timothy N.J. Bullock, Liane B. Russell, David W. Mullins, Willem W. Overwijk, Chance John Luckey, Richard A. Pierce, Nicholas P. Restifo, Victor H. Engelhard
DOI: https://doi.org/10.1084/jem.191.7.1221
The human tyrosinase-derived peptide Y MDGTMSQV is presented on the surface of human histocompatibility leukocyte antigen (HLA)-A*0201+ melanomas and has been suggested to be a tumor antigen despite the fact that tyrosinase is also expressed in melanocytes. To gain information about immunoreactivity and self-tolerance to this antigen, we established a model using the murine tyrosinase-derived homologue of this peptide F MDGTMSQV, together with transgenic mice expressing the HLA-A*0201 recombinant molecule AAD. The murine peptide was processed and presented by AAD similarly to its human counterpart. After immunization with recombinant vaccinia virus encoding murine tyrosinase, we detected a robust AAD-restricted cytotoxic T lymphocyte (CTL) response to F MDGTMSQV in AAD transgenic mice in which the entire tyrosinase gene had been deleted by a radiation-induced mutation. A residual response was observed in the AAD+tyrosinase+ mice after activation under certain conditions. At least some of these residual CTLs in AAD+tyrosinase+ mice were of high avidity and induced vitiligo upon adoptive transfer into AAD+tyrosinase+ hosts. Collectively, these data suggest that F MDGTMSQV is naturally processed and presented in vivo, and that this presentation leads to substantial but incomplete self-tolerance. The relevance of this model to an understanding of the human immune response to tyrosinase is discussed.
Predominant Role for Directly Transfected Dendritic Cells in Antigen Presentation to CD8+ T Cells after Gene Gun Immunization
Angel Porgador, Kari R. Irvine, Akiko Iwasaki, Brian H. Barber, Nicholas P. Restifo, Ronald N. Germain
Cutaneous gene (DNA) bombardment results in substantial expression of the encoded antigen in the epidermal layer as well as detectable expression in dendritic cells (DC) in draining lymph nodes (LNs). Under these conditions, two possible modes of DC antigen presentation to naive CD8+ T cells might exist: (a) presentation directly by gene-transfected DC trafficking to local lymph nodes, and (b) cross-presentation by untransfected DC of antigen released from or associated with transfected epidermal cells. The relative contributions of these distinct modes of antigen presentation to priming for cytotoxic T cell (CTL) responses have not been clearly established. Here we show that LN cells directly expressing the DNA-encoded antigen are rare; 24 h after five abdominal skin bombardments, the number of these cells does not exceed 50–100 cells in an individual draining LN. However, over this same time period, the total number of CD11c+ DC increases more than twofold, by an average of 20,000–30,000 DC per major draining node. This augmentation is due to gold bombardment and is independent of the presence of plasmid DNA. Most antigen-bearing cells in the LNs draining the site of DNA delivery appear to be DC and can be depleted by antibodies to an intact surface protein encoded by cotransfected DNA. This finding of predominant antigen presentation by directly transfected cells is also consistent with data from studies on cotransfection with antigen and CD86-encoding DNA, showing that priming of anti-mutant influenza nucleoprotein CTLs with a single immunization is dependent upon coexpression of the DNAs encoding nucleoprotein and B7.2 in the same cells. These observations provide insight into the relative roles of direct gene expression and cross-presentation in CD8+ T cell priming using gene gun immunization, and indicate that augmentation of direct DC gene expression may enhance such priming.
gp100/pmel 17 Is a Murine Tumor Rejection Antigen: Induction of "Self"-reactive, Tumoricidal T Cells Using High-affinity, Altered Peptide Ligand
Willem W. Overwijk, Allan Tsung, Kari R. Irvine, Maria R. Parkhurst, Theresa J. Goletz, Kangla Tsung, Miles W. Carroll, Chunlei Liu, Bernard Moss, Steven A. Rosenberg, Nicholas P. Restifo
Many tumor-associated antigens are nonmutated, poorly immunogenic tissue differentiation antigens. Their weak immunogenicity may be due to "self"-tolerance. To induce autoreactive T cells, we studied immune responses to gp100/pmel 17, an antigen naturally expressed by both normal melanocytes and melanoma cells. Although a recombinant vaccinia virus (rVV) encoding the mouse homologue of gp100 was nonimmunogenic, immunization of normal C57BL/6 mice with the rVV encoding the human gp100 elicited a specific CD8+ T cell response. These lymphocytes were cross-reactive with mgp100 in vitro and treated established B16 melanoma upon adoptive transfer. To understand the mechanism of the greater immunogenicity of the human version of gp100, we characterized a 9-amino acid (AA) epitope, restricted by H-2Db, that was recognized by the T cells. The ability to induce specific T cells with human but not mouse gp100 resulted from differences within the major histocompatibility complex (MHC) class I–restricted epitope and not from differences elsewhere in the molecule, as was evidenced by experiments in which mice were immunized with rVV containing minigenes encoding these epitopes. Although the human (hgp10025–33) and mouse (mgp10025–33) epitopes were homologous, differences in the three NH2-terminal AAs resulted in a 2-log increase in the ability of the human peptide to stabilize "empty" Db on RMA-S cells and a 3-log increase in its ability to trigger interferon γ release by T cells. Thus, the fortuitous existence of a peptide homologue with significantly greater avidity for MHC class I resulted in the generation of self-reactive T cells. High-affinity, altered peptide ligands might be useful in the rational design of recombinant and synthetic vaccines that target tissue differentiation antigens expressed by tumors.