text:
Star Wars: The Mandalorian
Star Wars Stories
Original Trilogy
Live-Action Television
Rogue One Prequel
Star Wars: Underworld
Galaxy's Edge
Blue Harvest
First Order Transmissions
Idiot's Array
Live Podcasts
MSW Presents
Now This Is Podcasting!
Podcast 2187
Rebel Grrrl
Rogue Won
Steele Wars
Tarkins Top Shelf
The Cargo Hold
The Sith List
Kessel Toy Run
THE SITH LIST -Episode 153- Far From Home spoilery review, Episode IX, The Eternals, MCU and more.
Blue Harvest Episode 209: Seeing Red
Did Somebody Say "SITH TROOPERS"?
Tarkin's Top Shelf #71: A Heart-To-Heart with Padmé Amidala @cattaber
Rogue Won: Episode 169: Jason 'THE' Ward dishes on his LAST THREE articles detailing massive HYPE for #TheRiseofSkywalker
The red Stormtroopers from Star Wars: The Rise of Skywalker are in fact Sith Troopers!
Kessel Run Radio Episode 10: Ranking The Disney Era Star Wars Films! w/ Ken Napzok
Jason Ward (EIC) July 10, 2015
Colin Trevorrow is likely to be Star Wars: Episode IX director?
Umberto Gonzalez of Heroic Hollywood is reporting Colin Trevorrow has locked 2019's Star Wars: Episode IX as the film he'll direct after Book…
Guest Poster July 9, 2015
Star Wars: Dark Disciple by Christie Golden – Saf's Review
Christie Golden's Dark Disciple is the latest addition to the new Star Wars canon, a breath of fresh air for…
Jason Ward (EIC) July 9, 2015
Star Wars: The Force Awakens: The Resistance and the Legend of Luke Skwalker!
SPOILERS THAT PERTAIN TO THE CLIMATE OF STAR WARS: THE FORCE AWAKENS BELOW: If you're like me, you watch…
Ron July 9, 2015
Iconic Random House Little Golden Books Line Retells Star Wars Films for the First Time
It's funny the things that you remember from your childhood. Some things just leave an impression on you for various…
Amanda Ward July 9, 2015
Petco Star Wars Pet Fans Collection at Comic Con
Hold on to your butts, Star Wars pet owners! Petco is debuting an all-new selection of awesome pet gear and toys…
On Star Wars: The Force Awakens' General Organa and Poe!
POTENTIAL SPOILERS FOR STAR WARS: THE FORCE AWAKENS BELOW! Hello from SDCC! I will leave a lot of the speculation…
Meet Star Wars: The Force Awakens' new female hotshot pilot!
SPOILERS BELOW FOR STAR WARS: THE FORCE AWAKENS! In Star Wars: The Force Awakens we're going to meet a new…
San Diego Comic-Con: Hasbro First Order Stormtrooper Preview
San Diego Comic-Con is finally here and there is no doubt that Star Wars will have a substantial impact on…
Johnamarie July 8, 2015
Journey to 'The Force Awakens': Book Covers and Descriptions Revealed
Later this fall, Star Wars fans everywhere will embark on an incredible journey that will lead up to the premiere of…
Disney Infinity 3.0 Star Wars Play Set Release Date Confirmed
Today, Disney Interactive announced that the Disney Infinity 3.0 Edition Starter Pack, featuring the Star Wars "Twilight of the Republic"…
Star Wars: Rogue One to feature some classic bounty hunters?
There are spoilers below if they pan out for Star Wars: Anthology – Rogue One. If you recall, back in May…
Concept: Star Wars: The Force Awakens – Supreme Leader Snoke!
I have seen a concept piece for "Uber" who is Supreme Leader Snoke in Star Wars: The Force Awakens. I can't say…
Rumor: Photo leaks with all Star Wars films due out until 2020.
This is very interesting if true but it's also very fishy. Our friends at Indie Revolver have come across a…
Disney Blog hints Han Solo film linked to third anthology film!
The Disney Blog has hinted that the Han Solo film will have a connection to the Anthology film Josh Trank…
It is official! Star Wars: Anthology – Han Solo written by Lawrence Kasdan and Son!
It's official! Lawrence Kasdan and his son Jon Kasdan will be writing Star Wars: Anthology – Han Solo! The Lego…
Christopher Miller and Phil Lord will be directing Star Wars: Anthology – Han Solo!?
The Hollywood Reporter is saying that Christopher Miller and Phil Lord will be directing Star Wars: Anthology – Han Solo!…
Star Wars: Uprising Gameplay Preview Video
The Star Wars Twitter just posted this awesome video that gives a peek at gameplay footage from upcoming mobile RPG…
Star Wars: The Force Awakens' First Order Stormtrooper in Magazine Ad!
The ad is pretty confusing as to what it pertains to as it has no logo or text indicating…
Jesse Tschopp July 7, 2015
Star Wars: Dark Disciple by Christie Golden – Jesse's Slightly Spoilery Review
WARNING: There are some slight spoilers in this review. For those unaware, Dark Disciple by Christie Golden is a novelization…
No Star Wars: The Force Awakens trailer at SDCC but here are seven things we might see to be excited about.
EW confirmed there won't be a trailer at Star Wars: The Force Awakens' panel at San Diego Comic Con this Friday. Exclusive:…
Randy Lo Gudice (Editor) July 5, 2015
Episode 85! MakingStarWars.net's Now, This Is Podcasting!
It's the 4th of July episode! Jason, Randy, Johna and Jeremy and gathered once again to bring you this week's…
Donny Yen cast in Star Wars: Episode VIII?
Our friend Eric Tan has let us know that Apple Daily, a Hong Kong newspaper, has written: Donny Yen (Yen…
Star Wars and Indy are about to have a bigger role at Disney's Hollywood Studios!
As a Southern California resident with a Disneyland annual pass, I perk up every time something Star Wars –related is…
Is this piece of concept art what Maz Kanata looks like in Star Wars: The Force Awakens?
SPOILERS BELOW! DON'T READ ON IF YOU DON'T WANT TO KNOW DETAILS ABOUT STAR WARS: THE FORCE AWAKENS! In Star Wars:…
Filming on Star Wars: Anthology – Rogue One has begun!
UPDATE: While filming has begun on Rogue One, principal photography officially begins August 3rd, 2015. The majority of filming has…
Now, This is Podcasting!
Star Wars: The Rise of Skywalker concept art, a game of pareidolia, and Black Park!
Star Wars: The Rise of Skywalker Pickups are happening and the X-wings have returned.
Rumors & Speculation: Star Wars: Episode IX and the threat of The Knights of Ren!
Archives Select Month July 2019 June 2019 May 2019 April 2019 March 2019 February 2019 January 2019 December 2018 November 2018 October 2018 September 2018 August 2018 July 2018 June 2018 May 2018 April 2018 March 2018 February 2018 January 2018 December 2017 November 2017 October 2017 September 2017 August 2017 July 2017 June 2017 May 2017 April 2017 March 2017 February 2017 January 2017 December 2016 November 2016 October 2016 September 2016 August 2016 July 2016 June 2016 May 2016 April 2016 March 2016 February 2016 January 2016 December 2015 November 2015 October 2015 September 2015 August 2015 July 2015 June 2015 May 2015 April 2015 March 2015 February 2015 January 2015 December 2014 November 2014 October 2014 September 2014 August 2014 July 2014 June 2014 May 2014 April 2014 March 2014 February 2014 January 2014 December 2013 November 2013 October 2013 September 2013 August 2013 July 2013
© Copyright 2019, Making Star Wars. All Rights Reserved.
MakingIndy.net
Covering the upcoming Indiana Jones 5 film production and everything about the future of Indiana Jones. Featuring MakingIndy.net's Keeping Up With the Joneses podcast.
Visit MakingIndy.net
Recent Posts: Making Indiana Jones
Mark Your Journals: Disney Says Indiana Jones V to Premiere in 2021
Indiana Jones 5 will not make the set release date and may be written by Jon Kasdan.
Fingered Podcast
Fingered by Randy & Jason has it's pulse on the finger of pop culture! New podcasts 5 days a week cover news, movies, TV, music, technology, and weird and bizarre.
Get Fingered!
Recent Posts: Fingered Podcast
Facebook Cringe: Bhrandhey is a one year old newborn.
Decisiones: Milf Versus Daughter in a love off! A Spanish TV group watch!


text:
Taisho Mebiusline Review (non-spoiler)
It took me quite a while to finish Taisho Mebiusline by Love Delivery. But that's partly thanks to me being distracted by other games and I don't want to discourage anyone with this. In fact, Taisho Mebiusline is very worth the time. Do note that this is a R-18 BL game so there is mature content. This will be a non-spoiler review, and only CGs I'll show are featured on the official website already. The rest are random screenshots of the OP, background.
The official website's synopsis already gives you a clue on what to expect from the game – supernatural elements as our protagonist, Hiiragi Kyouichirou, is able to see spirits after he recovered from an illness which threatened his life; some amounts of politics as the army plans to make use of those same dead spirits to counter the threats from abroad. The character relationship chart shown also gives a basic presentation of each characters' stake. Kyouichirou encounters Shigure running away from the pursuits of Tatebayashi Kai and his team – only to personally witness the latter call upon a dead being to fight. Misaki, a mysterious stranger, helps Kyouichirou out time after time but he also constantly warns Kyouichirou not to get further involved in the messy affairs of the army and spirits. Having heard reports about Kyouichirou and Misaki, Senge Iori starts to develop a keen interest in the former. While both of them serve the army and make use of the dead, Kyouichirou observes that there's a tension between Senge and Tatebayashi. However, all of which I've just described is really just the tip of the iceberg.
Ise Kaoru, Ise Kahoru
The thing that stood out for me is that no matter which route you delve further into, the remaining key characters still continue on with each of their goals – in other words, they don't become static and are not abandoned just like that. The best example is Senge as even if you go and do the other 3 routes, he does continue to pursue Kyouichirou when given the chance. The only exception is probably Misaki as he doesn't appear as much in 2 routes, though one may argue that he has his own special circumstances too. Also, the fact that the Happy Ends are not 100% perfect in a sense as they don't force for one. Another thing I have to commend on are the sub-characters. I was surprised at how much development some of them got, in particular Tatebayashi's team (and his butler) – I even joke that the Ise twins stole the spotlight at one point. Maybe it's not a joke.
Anyway, let me now review in a more systematic way. Plot: while it's for certain that Misaki's route reveals the most (since his contains the True End), each route still does have substantial plot. I personally played in the order of Tatebayashi, Shigure, Senge, Misaki, True End as recommended by a friend. I have seen others recommend playing Shigure first – I think it's up to you on whether you'd like to start with Tatebayashi or Shigure as both of them have entirely different focuses. However, I strongly recommend on leaving Senge, Misaki, True End for last. Going back to the plot, it is nice to see that every route actually drops little hints on what the True End is all about – at the same time, while the True End makes references to the revelations from all the previous routes it doesn't necessarily explain everything. In other words, all the routes are worth your playing time.
Individually: Tatebayashi's route is more driven by all the different ongoing plots and awesome sub-characters so his route has a lack of romance. But as a first route it managed to capture my interest enough. Shigure's route was the biggest and most pleasant surprise for me as I didn't expect to love him and the couple so so much. My first impression of him was the weakest among all the characters, but his route did him every justice he deserved – plot, character + relationship development, humour, sad scenes.
Ise Kaoru, Hiiragi Kyouichirou, Shigure
Senge's route…Senge Senge Senge simply put, is painfully good. From the start, I expected his route to be interesting since he's always at opposite ends with all the other characters, including Kyouichirou. As such, I enjoyed how they handled Kyouichirou here – you can see him trying to resist, struggle, and (re)negotiate with himself and Senge. And Senge is easily the most complex and well-developed character in the game for me, and maybe that's why I found his route to contain the most amazing writing, imagery, chemistry and dialogue. That being said, I did mention the word "painful" too so you should mentally prepare yourself. Misaki's route definitely reveals the most revelations and I was pleased with how mythology was tied together with some of them. Those mainly focus on Kyouichirou and Misaki though. The True End picks up after this and is in my opinion, the near-perfect end as everything gets tied together to the bigger plot that occurred in the shadows all this time. It is up to the person to decide on whether this bigger plot was anti-climatic or not – but I think that all the previous clues was certainly leading up to this direction and so I was satisfied.
Characters: My favourites ended up being Kyouichirou, Shigure and the Ise twins it's a coincidence that all the CGs feature them. That being said, I really did end up liking pretty much everyone (even though I enjoy making fun of Senge). Kyouichirou retains his characteristic traits in each route – a strong and stubborn sense of his form of justice, loyalty to his country; and once he gets himself into something it is very, very difficult to keep him at bay. Oh, can't forget about his adorable love for senbei too! The same about characteristic traits can be said for the other characters, but it's up to Kyouichirou on how much he can change/support him – with the exception being Senge in certain Ends in my opinion 'cos it's probably too late in the game to change him significantly and that's what made his route painfully interesting but anyway I'm ranting.
Interface/Art/Music/Extras: The interface pretty standard though I really loved the fact that if you mouseover the top of the game screen, only then does the menu drop down – it's a cute and appreciated touch. And though it's a limited amount of space, they also allowed you to "save" your favourite game lines. The art is lovely though slightly inconsistent at times in terms of the CG art. Also, it's worth noting that you have the option of CG animations and while it is a bit awkward at points to see only certain elements animated – routes like Shigure's really made full use of those animations. The background art is decent enough. The music is amazing and is certainly one of the highlights of the game. You unlock the standard CG gallery, scene replay gallery, music section – and when you fully complete the game you can access the theme songs and ED songs.
Bad Ends: Yes, I played every one of them. It is interesting to note that only Tatebayashi's has CG (scenes), oh and one of Shigure's. The rest are mostly dead ends in a sense Amnesia so they do not give much insight, except maybe for Misaki's which teases you with little hints on what Misaki's true identity might be. The only bad end which I was impressed by was the last one for Tatebayashi's, as it's pretty much a "what-if" situation and it really highlights the depth of Tatebayashi's loyalty.
Voice-acting: I would love to say that everyone did a fantastic job – but I have to admit that I giggled at a few of Misaki's lines for uh, certain reasons. But other than that, amazing effort to everyone – in particular to the voices behind Kyouichirou, Shigure, Ise twins, Senge. Bias, what bias?
Language: The language is heavy, I won't lie. Terms you're used to reading in hiragana/katakana – they use kanji. Simpler terms you're used to reading – they use fancier/more difficult ones. There's quite a bit of terminology too. Despite all of this though, I still think that it's worth the effort.
All in all, I really enjoyed Taisho Mebiusline. While the game does have its light-hearted moments, it is probably best to expect a heavier game in general. I mean, it's quite telling when the first game choice you've to make for Kyouichirou is how he feels with regards to the military expansion and growth for the country at the cost of its other people. Oh, and for people wondering about the meaning behind the game title – while they do provide you several interpretations on what メビウス can mean, the True End does explain the full title. I do recommend this game, and I hope that this review has given some insight on what you can expect from it.
Posted in: BL, Game, PC, Review, Taisho Mebiusline | Tagged: bl game, love delivery, taisho mebiusline
Amnesia Crowd: Working, Orion & Concluding Thoughts
DRAMAtical Murder re:connect: Koujaku's Route
17 thoughts on "Taisho Mebiusline Review (non-spoiler)"
Pingback: Taishou Mebiusline – Misaki & True End – Bishie Holic
Pingback: Taishou Mebiusline – Misaki & True End – VN Cafe
I started playing this on the side while playing Hakuoki, and gosh it discouraged me! The words used made me want to hit my head on a desk wwww. Thank goodness Kyou is voiced or I'd be ??? all the time lmao. I imagine I'd play this a lot slower but the art/animation is beautiful so I don't think I mind. (Also why do I keep on falling for historical stories even if they fry my brain orz)
Ahhhh I'm so happy that you started it!!! Yes it's hard to pick up the words at first but it will be worth it, I promise! I may not remember as well but let me know if you need to confirm anything ♡ can't wait to see who ends up being your bias 😀
It seems that I forgot to save the other night so I had to redo from the start lmao. It has gotten quite easier? (or I got familiar with the words lol) But I'll still take you up on that 😀
I'm pretty sure you put your recommended order on your post, and I just can't seem to find it atm ~_~. Should I go for Shigure or Tatebayashi first? :O
Oops www
Yup I put: Tatebayashi or Shigure, Senge, Misaki, True End. 🙂
Umm usually people recommend Shigure's first because the plot is less heavy and it is more balanced (with very cool animation). Tatebayashi's route is plot-heavy and it took me a while to get into it – but once I saw the deeper plot I got quite engrossed haha.
I guess if you want to start with a more balanced route – go for Shigure. If you're curious about the deeper plot and wanna be spoiled a bit – go for Tatebayashi.
Additional opinion: the romance in Shigure's route is sooo cute (also I'm weak to his voice). The romance in Tatebayashi's route is very shoujo haha.
–now i'm even more torn ahaha. I guess since I liked Tatebayashi's character design more, I'll go for Shigure's first. :3
Speaking of voices, can I just gush how I love Kyou's voice. It sounds so smoooth! I want to listen to his voice for a looong time. www
Heheheh yay I get to see your reactions to Shigure first then!
Yes I like Kyou's voice a lot too! ♡ i like it when the characters chant the norito too – especially Misaki and Shigure.
Pingback: Taisho Mebiusline Teito Bibouroku Review (non-spoiler) – chocolatemix
Therapii says:
I don't quite recall the 'Mebuisline" really explains at the True End. I only remembered that it appeared several times on Senge' and Misaki' routes during "that" time =_=;
In Senge and Misaki's routes, there are a few interpretations on what メビウス can mean. But first, it obviously(please highlight)
makes a reference to the Möbius strip/band. It goes in one full circle despite the twist. So an interpretation of メビウス in the game is that it's never-ending. But in Senge/Misaki's routes, it is never linked up with Taisho (Mebiusline). It does in the True End 'cos it's only there that we learn the motive of the mastermind. During the so-called last boss scene (aka when the Queen goes to open the door to the other world to get her husband), Kyouichirou tries to talk her out of it but clearly his words fall on deaf ears. Shigure remarks that she's gone mad. At this moment, we have this monologue by Kyouichirou:
狂人と話しているような堂々巡り。
始点からぐるりと回って、いつしかまた始点に戻っている。
不可能図形の環のように。
昴后はおそらく、狂気の環の中で同じ事を繰り返す。
陰宮に国巫が宿ったとして、陰宮の肉体が老いて死ねば
また新たな憑代を用いて復活を企むだろう。
大正は永遠に終わらない。
It's the last line which prompts me to see Taisho Mebiusline = Taisho never ends. The Queen is stuck in her own (mad) loop of thought (to be together with her loved one). She wants to revive him through her child, and even if her child's body ages and passes away she'll certainly want to revive her loved one again. Taisho era will never end since the Emperor will never 'die' as long as this Queen keeps doing this. On the flipside, once they acknowledge that the Emperor has indeed passed away and Tenshi inherits the throne – it states that Taisho era has ended and a new era (Showa) has started.
Sorry for the rant, but I'm just going through the thought process I went through on how I came to understand "Taisho Mebiusline". I hope this clears up your doubt!
Damn! That's pretty deep thought I must say. Thanks! Now I understand the game much clearer with knowing the meaning of the title again. When I think again, Senge said that their relationship will go in Mebiusline or something along the line, so it makes perfect sense after reading your explanation.
You're welcome! Yup I think so. O:
yaoidaisuki says:
My friend played this game and she loved. I was about to play it, but she said the same thing "the language is heavy" so I decided to play another time ;P
Thanks for the review!! ;D
I really like games like that, with this theme hehehe =3
Ohh glad to hear that your friend loved it! ❤ Haha, maybe if you encounter any difficulties you can ask her to clarify what happened too. /o\
You're welcome! Hope that you can play it for yourself soon. ^^
ETf says:
Shigure ended up surprising everyone, didn't he? He's one of the least popular characters before the game shipped, and a week after that he's everybody's favourite. I also find Kyouichirou to be a breath of fresh air—-sure, he's probably not as *badass* as popular BL protag trends seem to be, but the way he processes his situation and reacts to them is more manly than most, in the traditional Japanese sense of manly.
My favourite is Kyouichirou = Shigure > Senge > Misaki > Tatebayashi = Ise Twins, but I love everyone to ridiculous levels. I think the difficult language actually helps the game, in the end—-you get this certain *feel* for the period and its way of thinking that I simply have never ran into in other works set in the same era but using more modern language. (I'm a fan of the period.) And considering what it's about, it really is imperative that you know why the characters think what they think. The writer is a fan of old literature and etymology, and it shows.
OH, and that last picture. I think I saw some liner notes that said 'the most important part of the title picture is that they are looking different ways, because they all dream of a different future'. That's a neat touch, to me.
I think based on character design alone, Shigure didn't look as attractive as the rest so yeah. X'D I don't play BL games as extensively as other people but indeed, Kyouichirou was such a joy to be with. To be honest, he said some of the most manly lines in the game – like his resolution to Senge.
I do agree that the language does add to the atmosphere of the game – even if every scene with the royal family made me play slower (lol).
Oh yes, I recall reading the notes on that illustration – said that it was chosen among all the other drafts 'cos of everyone facing different directions. 😀

redpajama_set_name: RedPajamaCommonCrawl


text:
Molecular and Cellular Pathobiology
19p13.1 Is a Triple-Negative–Specific Breast Cancer Susceptibility Locus
Kristen N. Stevens, Zachary Fredericksen, Celine M. Vachon, Xianshu Wang, Sara Margolin, Annika Lindblom, Heli Nevanlinna, Dario Greco, Kristiina Aittomäki, Carl Blomqvist, Jenny Chang-Claude, Alina Vrieling, Dieter Flesch-Janys, Hans-Peter Sinn, Shan Wang-Gohrke, Stefan Nickels, Hiltrud Brauch, Yon-Dschun Ko, Hans-Peter Fischer, Rita K. Schmutzler, Alfons Meindl, Claus R. Bartram, Sarah Schott, Christoph Engel, Andrew K. Godwin, JoEllen Weaver, Harsh B. Pathak, Priyanka Sharma, Hermann Brenner, Heiko Müller, Volker Arndt, Christa Stegmaier, Penelope Miron, Drakoulis Yannoukakos, Alexandra Stavropoulou, George Fountzilas, Helen J. Gogas, Ruth Swann, Miriam Dwek, Annie Perkins, Roger L. Milne, Javier Benítez, María Pilar Zamora, José Ignacio Arias Pérez, Stig E. Bojesen, Sune F. Nielsen, Børge G. Nordestgaard, Henrik Flyger, Pascal Guénel, Thérèse Truong, Florence Menegaux, Emilie Cordina-Duverger, Barbara Burwinkel, Frederick Marmé, Andreas Schneeweiss, Christof Sohn, Elinor Sawyer, Ian Tomlinson, Michael J. Kerin, Julian Peto, Nichola Johnson, Olivia Fletcher, Isabel dos Santos Silva, Peter A. Fasching, Matthias W. Beckmann, Arndt Hartmann, Arif B. Ekici, Artitaya Lophatananon, Kenneth Muir, Puttisak Puttawibul, Surapon Wiangnon, Marjanka K. Schmidt, Annegien Broeks, Linde M. Braaf, Efraim H. Rosenberg, John L. Hopper, Carmel Apicella, Daniel J. Park, Melissa C. Southey, Anthony J. Swerdlow, Alan Ashworth, Nicholas Orr, Minouk J. Schoemaker, Hoda Anton-Culver, Argyrios Ziogas, Leslie Bernstein, Christina Clarke Dur, Chen-Yang Shen, Jyh-Cherng Yu, Huan-Ming Hsu, Chia-Ni Hsiung, Ute Hamann, Thomas Dünnebier, Thomas Rüdiger, Hans Ulrich Ulmer, Paul P. Pharoah, Alison M. Dunning, Manjeet K. Humphreys, Qin Wang, Angela Cox, Simon S. Cross, Malcom W. Reed, Per Hall, Kamila Czene, Christine B. Ambrosone, Foluso Ademuyiwa, Helena Hwang, Diana M. Eccles, Montserrat Garcia-Closas, Jonine D. Figueroa, Mark E. Sherman, Jolanta Lissowska, Peter Devilee, Caroline Seynaeve, Rob A.E.M. Tollenaar, Maartje J. Hooning, Irene L. Andrulis, Julia A. Knight, Gord Glendon, Anna Marie Mulligan, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Mervi Grip, Esther M. John, Alexander Miron, Grethe Grenaker Alnæs, Vessela Kristensen, Anne-Lise Børresen-Dale, Graham G. Giles, Laura Baglietto, Catriona A. McLean, Gianluca Severi, Matthew L. Kosel, V.S. Pankratz, Susan Slager, Janet E. Olson, Paolo Radice, Paolo Peterlongo, Siranoush Manoukian, Monica Barile, Diether Lambrechts, Sigrid Hatse, Anne-Sophie Dieudonne, Marie-Rose Christiaens, Georgia Chenevix-Trench, Jonathan Beesley, Xiaoqing Chen, Arto Mannermaa, Veli-Matti Kosma, Jaana M. Hartikainen, Ylermi Soini, Douglas F. Easton and Fergus J. Couch
Kristen N. Stevens
Zachary Fredericksen
Celine M. Vachon
Xianshu Wang
Sara Margolin
Annika Lindblom
Heli Nevanlinna
Dario Greco
Kristiina Aittomäki
Carl Blomqvist
Jenny Chang-Claude
Alina Vrieling
Dieter Flesch-Janys
Hans-Peter Sinn
Shan Wang-Gohrke
Stefan Nickels
Hiltrud Brauch
Yon-Dschun Ko
Hans-Peter Fischer
Rita K. Schmutzler
Alfons Meindl
Claus R. Bartram
Christoph Engel
Andrew K. Godwin
JoEllen Weaver
Harsh B. Pathak
Priyanka Sharma
Hermann Brenner
Heiko Müller
Volker Arndt
Christa Stegmaier
Penelope Miron
Drakoulis Yannoukakos
Alexandra Stavropoulou
George Fountzilas
Helen J. Gogas
Ruth Swann
Miriam Dwek
Annie Perkins
Roger L. Milne
María Pilar Zamora
José Ignacio Arias Pérez
Stig E. Bojesen
Sune F. Nielsen
Børge G. Nordestgaard
Henrik Flyger
Pascal Guénel
Thérèse Truong
Florence Menegaux
Emilie Cordina-Duverger
Barbara Burwinkel
Frederick Marmé
Andreas Schneeweiss
Christof Sohn
Elinor Sawyer
Ian Tomlinson
Michael J. Kerin
Julian Peto
Nichola Johnson
Olivia Fletcher
Isabel dos Santos Silva
Peter A. Fasching
Matthias W. Beckmann
Arndt Hartmann
Arif B. Ekici
Artitaya Lophatananon
Kenneth Muir
Puttisak Puttawibul
Surapon Wiangnon
Marjanka K. Schmidt
Annegien Broeks
Linde M. Braaf
Efraim H. Rosenberg
John L. Hopper
Carmel Apicella
Daniel J. Park
Melissa C. Southey
Anthony J. Swerdlow
Alan Ashworth
Nicholas Orr
Minouk J. Schoemaker
Hoda Anton-Culver
Argyrios Ziogas
Leslie Bernstein
Christina Clarke Dur
Chen-Yang Shen
Jyh-Cherng Yu
Huan-Ming Hsu
Chia-Ni Hsiung
Ute Hamann
Thomas Dünnebier
Thomas Rüdiger
Hans Ulrich Ulmer
Paul P. Pharoah
Alison M. Dunning
Manjeet K. Humphreys
Qin Wang
Angela Cox
Simon S. Cross
Malcom W. Reed
Per Hall
Kamila Czene
Christine B. Ambrosone
Foluso Ademuyiwa
Helena Hwang
Diana M. Eccles
Montserrat Garcia-Closas
Jonine D. Figueroa
Mark E. Sherman
Jolanta Lissowska
Peter Devilee
Caroline Seynaeve
Rob A.E.M. Tollenaar
Maartje J. Hooning
Irene L. Andrulis
Julia A. Knight
Gord Glendon
Anna Marie Mulligan
Robert Winqvist
Katri Pylkäs
Arja Jukkola-Vuorinen
Mervi Grip
Esther M. John
Alexander Miron
Grethe Grenaker Alnæs
Vessela Kristensen
Anne-Lise Børresen-Dale
Graham G. Giles
Laura Baglietto
Catriona A. McLean
Gianluca Severi
Matthew L. Kosel
V.S. Pankratz
Susan Slager
Janet E. Olson
Paolo Radice
Paolo Peterlongo
Siranoush Manoukian
Monica Barile
Diether Lambrechts
Sigrid Hatse
Anne-Sophie Dieudonne
Marie-Rose Christiaens
Georgia Chenevix-Trench
Jonathan Beesley
Xiaoqing Chen
Arto Mannermaa
Veli-Matti Kosma
Jaana M. Hartikainen
Ylermi Soini
Douglas F. Easton
Fergus J. Couch
DOI: 10.1158/0008-5472.CAN-11-3364 Published April 2012
The 19p13.1 breast cancer susceptibility locus is a modifier of breast cancer risk in BRCA1 mutation carriers and is also associated with the risk of ovarian cancer. Here, we investigated 19p13.1 variation and risk of breast cancer subtypes, defined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) status, using 48,869 breast cancer cases and 49,787 controls from the Breast Cancer Association Consortium (BCAC). Variants from 19p13.1 were not associated with breast cancer overall or with ER-positive breast cancer but were significantly associated with ER-negative breast cancer risk [rs8170 OR, 1.10; 95% confidence interval (CI), 1.05–1.15; P = 3.49 × 10−5] and triple-negative (ER-, PR-, and HER2-negative) breast cancer (rs8170: OR, 1.22; 95% CI, 1.13–1.31; P = 2.22 × 10−7). However, rs8170 was no longer associated with ER-negative breast cancer risk when triple-negative cases were excluded (OR, 0.98; 95% CI, 0.89–1.07; P = 0.62). In addition, a combined analysis of triple-negative cases from BCAC and the Triple Negative Breast Cancer Consortium (TNBCC; N = 3,566) identified a genome-wide significant association between rs8170 and triple-negative breast cancer risk (OR, 1.25; 95% CI, 1.18–1.33; P = 3.31 × 10−13]. Thus, 19p13.1 is the first triple-negative–specific breast cancer risk locus and the first locus specific to a histologic subtype defined by ER, PR, and HER2 to be identified. These findings provide convincing evidence that genetic susceptibility to breast cancer varies by tumor subtype and that triple-negative tumors and other subtypes likely arise through distinct etiologic pathways. Cancer Res; 72(7); 1795–803. ©2012 AACR.
It is becoming increasingly apparent that genetic susceptibility to breast cancer varies by expression levels of estrogen receptor (ER) in breast tumors. Studies of genetic loci identified in genome-wide association studies (GWAS) have shown that variants in 5p12, 8q24, 1p11.2, 9p21.3, 10q21.2, and 11q13 are associated with ER-positive breast cancer (1–8) but not ER-negative breast cancer, whereas variants in FGFR2, 2q35, TOX3, LSP1, MAP3K1, TGFB1, RAD51L1, and ESR1 are associated with both ER-positive and ER-negative disease (8–10). In addition, only a subset of these genetic risk factors for overall breast cancer (TOX3, 2q35, 5q11, LSP1, RAD51L1, and ESR1) have been associated with triple-negative breast cancer, defined by ER, progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) expression levels (10–12). To date, no variants have been specifically associated with ER-negative or triple-negative disease.
The 19p13.1 breast cancer susceptibility locus was first identified in a GWAS of BRCA1 carriers as a modifier of breast cancer risk (9). Single-nucleotide polymorphisms (SNP), rs8170 and either rs8100241 or rs2363956 (r2 = 1), from 19p13.1 were associated with risk of breast cancer (rs8170: HR, 1.27, P = 1.5 × 10−10; rs8100241: HR, 0.84, P = 1.6 × 10−10; and rs2363956: HR, 0.84, P = 2.4 × 10−10). The same variants have also been associated with the risk of ovarian cancer in the general population (13). In addition, replication studies have suggested associations between these SNPs and ER-negative and ER-positive breast cancer (9, 12) and also with triple-negative disease (9, 12). The 19p13.1 locus contains the genes c19orf62 (MERIT40), ANKLE1, and ABHD8, but the causal variants underlying these associations with breast and ovarian cancer risk have yet to be identified.
Here, we present a study of the 19p13.1 locus and breast cancer risk in the Breast Cancer Association Consortium (BCAC), an international consortium that has identified or confirmed genome-wide significant associations between commonly inherited variants in several loci and breast cancer risk. We investigated associations between rs8170 from the 19p13.1 locus and breast cancer risk using 48,869 breast cancer cases and 49,787 controls and associations between rs8100241 and rs2363956 from 19p13.1 and breast cancer in a subset of the BCAC cohort. We also directly assessed differences in breast cancer risk by tumor subtype, defined by ER, PR, and HER2 status, and showed that 19p13.1 variants are associated specifically with risk of triple-negative breast cancer.
Study subjects were recruited on protocols approved by the Institutional Review Boards at each participating institution, and all subjects provided written informed consent.
BCAC studies
Thirty-nine studies from the BCAC contributed genotype data (rs8170, rs8100241, and/or rs2363956) to this study (Supplementary Tables S1 and S2). Women of white European ancestry were included from 37 BCAC studies based in Europe, North America, and Australia (49,897 cases and 48,306 controls). Asian women were included from 2 BCAC studies based in Thailand and Taiwan (1,198 cases and 1,481 controls). BCAC studies are described in detail in Supplementary Table S2. Study participants were recruited under protocols approved by the Institutional Review Board at each institution, and all subjects provided written informed consent.
TNBCC studies
Thirteen studies from the Triple Negative Breast Cancer Consortium (TNBCC) were included in the triple-negative–specific analysis of rs8170 (Supplementary Tables S1 and S2). These studies included 1,350 triple-negative breast cancer cases and 3,852 controls of women of white European ancestry. Samples included from the 5 TNBCC studies that are also involved in BCAC (BBCC, KARBAC, MCCS, SBCS, and POSH) are unique to the TNBCC analysis and were not included in the BCAC analyses presented in this article. TNBCC studies are described in detail in Supplementary Table S2. Study participants were recruited under protocols approved by the Institutional Review Board at each institution, and all subjects provided written informed consent.
Genotyping of rs8170, rs8100241, and rs2363956 in BCAC was conducted using a TaqMan allelic discrimination assay or the Sequenom iPLEX platform (Sequenom) via standard protocols. Robust quality control criteria, established by BCAC, were applied as detailed in previous consortium studies (4). Briefly, the genotyping concordance was verified with internal duplicates and overall data quality was ensured using independent genotyping of 96 CEU samples by each genotyping center. We excluded all samples from any study with more than 2 discordant genotypes on the CEU plate. All studies met the specified criteria for call rate (>95%).
rs8170 and rs8100241 genotyping in TNBCC samples was conducted using a single multiplex on the iPLEX Mass Array platform (Sequenom) as part of a larger 22-SNP genotyping project. Samples were plated by study as random mixtures of cases and controls with no-template and CEPH controls in every plate. Genotyping quality for SNPs and samples was evaluated using an iterative quality control process. SNPs and samples were excluded on the basis of the following criteria: SNP call rate < 95%, Hardy–Weinberg equilibrium (HWE) P value < 0.01 among controls, and sample call rate < 95%.
Pathology and tumor markers
Pathology analyses of BCAC data were conducted using studies of white European women only. All studies except CTS, GC-HBOC, and UKBGS provided data on ER and PR status of tumors and 25 studies provided data on HER2 (Supplementary Table S3). The collection of pathology and tumor marker information for BCAC has been described previously (14). Briefly, studies provided information on histopathologic subtype, grade of differentiation, tumor size, nodal involvement, and stage at diagnosis of breast tumors. ER/PR status was most commonly defined using data from medical records. ER- and PR-negative status was defined as less than 10% of the tumor cells stained. HER2-negative status was typically defined as a score of 0 or 1+ on a HER2 immunohistochemistry (IHC) scale of 0 to 3+.
TNBCC cases were defined as individuals with an ER-, PR-, and HER2-negative breast cancer. Definition of ER- and PR-negative status were <1% cells stained positive for DEMOKRITOS, DFCI, FCCC, and MCCS; <10% cells stained positive for BBCC, KARBAC; intensity score (0–3) percentage of cells stained (0%–100%) <50 for SBCS; or an Allred score <3 for RPCI and POSH. Definition of HER2-negative status was score 0 or 1+ by IHC for BBCC, DEMOKRITOS, FCCC, MCCS, POSH, RCPI, SBCS; or IHC score 0, 1+, or 2+ and FISH negative for DFCI and KARBAC. Cytokeratin 5/6 (CK5/6) and EGF receptor (EGFR) IHC data for identification of basal tumors were not available.
Departure from HWE was assessed in controls using a goodness-of-fit test. Evidence of departure was not observed in any of the participating studies (HWE, P ≥ 0.001). Single SNP analyses were conducted using unconditional logistic regression separately for white Europeans and Asians. Analyses using only BCAC case–control studies were adjusted for study, and analyses using all BCAC studies (case–control and case-only studies) were adjusted for country. SNP associations were tested in a log-additive model. To obtain additional information, we also used a 2 degree of freedom test, calculating ORs and 95% confidence intervals (CI) separately for heterozygotes and rare homozygotes. Consideration of age made no substantial difference to the results, assessed by both the exclusion of studies for which the age of controls was not known and the adjustment for age in 5-year categories and as a continuous covariate. Subtype-specific associations defined by ER, PR, and HER2 status were estimated for white Europeans with invasive breast cancer using polytomous logistic regression with control status as the reference outcome, adjusting for country or study where appropriate. SNP associations were tested in a log-additive model. Heterogeneity in the OR by subtypes was tested by applying polytomous logistic regression to cases-only, treating the number of minor alleles as the outcome. Triple-negative–specific analyses were conducted among cases with known ER, PR, and HER2 status using polytomous logistic regression with ER-negative (excluding triple negative) and triple-negative cases compared with controls as the reference outcome, adjusting for country. BCAC and TNBCC analyses were conducted in a combined data set using raw genotype data for rs8170 and rs8100241 from each consortium, and analyses were adjusted for country and consortium. Interaction and haplotype analyses were conducted using the combined BCAC and TNBCC data set adjusting for country. Haplotype analyses were conducted using the haplo.glm function from the haplo.stats package in R with default parameters.
We first evaluated 3 SNPs in the 19p13.1 locus—rs8170, rs8100241, and rs2363956—for associations with overall risk of invasive breast cancer in BCAC studies of white European women. The rs8170 was genotyped in all 37 studies (47,671 cases and 48,306 controls), whereas only a subset of studies genotyped rs8100241 (21,645 cases and 21,521 controls) or rs2363956 (17,857 cases and 20,648 controls; Supplementary Table S1). Neither rs8170 nor rs2363965 was associated with the risk of overall invasive breast cancer. However, the A allele of rs8100241 was associated with a small increased risk of breast cancer (OR, 1.04; 95% CI, 1.01–1.08; P = 2.88 × 10−3; Table 1). Results were very similar when excluding 4 case-only studies (Supplementary Table S4). No associations were observed between rs8170, rs8100241, or rs2363956 and risk of ductal carcinoma in situ (DCIS). Similarly, no association was observed between rs8170 or rs8100241 and risk of invasive breast cancer in 2 BCAC studies of Asian women including 1,198 breast cancer cases and 1,481 controls, although power to detect an association with rs8170 was limited because of a very low minor allele frequency of 0.20% in this population (Supplementary Table S5). Adjustment for age did not change the magnitude or significance of our results.
19p13.1 single SNP associations with breast cancer among white European women
Given that the 19p13.1 susceptibility locus was first identified as a modifier of breast cancer risk in BRCA1 mutation carriers (9), who predominantly develop tumors with an ER-negative or triple-negative phenotype, we next evaluated associations between these 3 SNPs and the risk of invasive breast cancer subtypes as defined by ER, PR, and HER2 status (Table 2). Because genotype data were available for rs8170 in the entire BCAC data set, we focused on this SNP in the analyses of breast cancer subtypes. When considering ER status alone, rs8170 was associated with risk of ER-negative breast cancer (OR, 1.09; 95% CI, 1.05–1.14; P = 6.69 × 10−5), but not with ER-positive breast cancer (OR, 0.99; 95% CI, 0.96–1.02; P = 0.38; PHet = 1.61 × 10−5; Table 2). A similar pattern was observed for PR status (PR-negative: OR, 1.05; 95% CI, 1.01–1.10; P = 7.39 × 10−3; PHet = 6.52 × 10−3; Table 2). When considering both ER and PR status, rs8170 was associated only with tumors negative for both markers (OR, 1.10; 95% CI, 1.05–1.16; P = 4.10 × 10−5; Table 2). Incorporation of HER2 status showed that the 19p13.1 locus was associated with risk of triple-negative breast cancer (OR, 1.21; 95% CI, 1.13–1.31; P = 2.97 × 10−7), but not any other combination of ER, PR, and HER2 status (PHet = 1.32 × 10−5). In particular, rs8170 was not associated with risk of developing HER2-negative tumors that were ER-positive or PR-positive (OR, 1.00; 95% CI, 0.97–1.04; P = 0.80), indicating that rs8170 is associated with triple-negative rather than HER2-negative disease. The estimate of effect for rs8170 was stronger among triple-negative breast cancers (OR, 1.21) than all ER-negative breast cancers (OR, 1.09). Analysis of rs8170 among cases-only was consistent with the case–control analyses (Supplementary Table S6). Similar patterns by subtype were observed for rs8100241 and rs2363956 (Supplementary Table S7). Exclusion of the 4 case-only BCAC studies did not substantially alter these findings (Supplementary Table S8).
Risk of invasive breast cancer associated with rs8170 among white Europeans defined by ER, PR, and HER2 tumor status
We next investigated whether variants in the 19p13.1 locus were associated specifically with risk of triple-negative disease by comparing triple-negative cases (ER−, PR−, HER2−) to non–triple-negative, ER-negative cases (ER−, PR+ or HER2+) in an analysis of ER-negative breast cancers with known ER, PR, and HER2 status (Table 3). The rs8170 was not associated with the risk of ER-negative breast cancer when excluding triple-negative cases (OR, 0.98; 95% CI, 0.89–1.07; P = 0.63) but remained strongly associated with risk of triple-negative breast cancer (OR, 1.21; 95% CI, 1.13–1.31; P = 2.94 × 10−7; PHet = 9.07 × 10−5). Given that basal-like tumors account for approximately 80% of triple-negative tumors (15), we also evaluated the influence of CK5/6 and EGFR basal tumor marker status on the 19p13.1 association with breast cancer risk. Because of limited data for these markers (Supplementary Table S3), we focused on rs8170 to maximize power to detect differences by basal status. The rs8170 was significantly associated with risk of basal-like triple-negative tumors (OR, 1.27; 95% CI, 1.07–1.50; P = 0.0069) but was not associated with risk of non-basal triple-negative tumors (OR, 1.03; 95% CI, 0.79–1.34; P = 0.83; PHet = 0.026; Supplementary Table S9). Furthermore, rs8170 was not associated with either ER-positive basal tumors (n = 301; OR, 0.90; 95% CI, 0.73–1.10; P = 0.30) or ER-negative, non-basal triple-negative tumors (n = 122; OR, 0.89; 95% CI, 0.64–1.23; P = 0.48; PHet = 0.80). This suggests that the 19p13.1 locus is exclusively associated with triple-negative basal-like tumors. However, because of the small sample size and potential misclassification of CK5/6 and EGFR, these results need to be confirmed in larger studies of breast cancer subtypes.
Triple-negative–specific risk associated with rs8170
We next extended our evaluation of 19p13.1 variants to nonoverlapping subjects (1,350 triple-negative cases and 3,852 controls) from the TNBCC (Supplementary Table S1; ref. 12). Among the TNBCC studies alone, rs8170 was associated with an increased risk of triple-negative breast cancer (OR, 1.26; 95% CI, 1.13–1.40; P = 3.02 × 10−5; Table 3). Importantly, the combined rs8170 genotype data from BCAC and TNBCC (n = 3,566 triple-negative cases) yielded a genome-wide significant association with the risk of triple-negative breast cancer (OR, 1.25; 95% CI, 1.18–1.33; P = 4.24 × 10−13; Table 3). There was no evidence for heterogeneity of the ORs by country for either triple-negative or non–triple-negative, ER-negative breast cancer in the combined analysis (Fig. 1). The difference in effect estimates between triple-negative and non–triple-negative, ER-negative breast cancer was highly significant (PHet = 2.51 × 10−6), indicating that rs8170 is a triple-negative–specific risk variant. A similar pattern was observed for rs8100241, which was inversely associated only with triple-negative disease (OR, 0.81; 95% CI, 0.76–0.86; P = 1.91 × 10−12) and not with non–triple-negative, ER-negative disease (OR, 0.94; 95% CI, 0.86–1.03; P = 0.19) in the combined data set (PHet = 3.30 × 10−3; Supplementary Table S10).
19p13.1 (rs8170) association with risk of non–triple-negative, ER-negative and triple-negative (TN) breast cancer. Forest plots for rs8170 and risk of (A) non–triple-negative, ER-negative breast cancer and (B) triple-negative breast cancer are shown by country. Country-specific ORs (95% CIs) are denoted by black boxes (black lines). Overall OR estimates are represented by black diamonds, where diamond width corresponds to 95% CI bounds. Box and diamond heights are inversely proportional to precision of the OR estimate. P values for heterogeneity (PHet) of ORs by country are shown.
To better understand the influence of 19p13.1 variants on risk of triple-negative breast cancer, we included both rs8170 and rs8100241 in a multivariate model in the combined BCAC and TNBCC data set. Both rs8170 (OR, 1.16; 95% CI, 1.07–1.26; P = 6.14 × 10−4) and rs8100241 (OR, 0.85; 95% CI, 0.79–0.91; P = 5.10 × 10−6) remained significantly associated with risk of triple-negative breast cancer with only slight attenuation of the ORs. However, when considering the association of one SNP stratified by the genotype of the other, we found that the effect of rs8170 was restricted to individuals with the rs8100241 "GA" genotype (OR, 1.29; 95% CI, 1.14–1.45; P = 3.13 × 10−5) and that the effect of rs8100241 was restricted to individuals with the rs8170 "CC" genotype (OR, 0.82; 95% CI, 0.76–0.89; P = 9.90 × 10−7; Supplementary Table S11a). This is reflected by a significant interaction between these SNPs (interaction OR, 1.21; 95% CI, 1.06–1.37; P = 0.0036; Supplementary Table S11b). A haplotype analysis for these 2 SNPs found that the C-G and T-G haplotypes (rs8170–rs8100241) were both associated with risk of triple-negative breast cancer compared with the C-A haplotype (C-G: OR, 1.17; 95% CI, 1.09–1.25; P = 1.00 × 10−5 and T-G: OR, 1.35; 95% CI, 1.25–1.46; P = 2.51 × 10−14), whereas the T-A haplotype was not observed at all (Supplementary Table S12), suggesting that both SNPs tag the causal variant. No interactions were observed between these SNPs among other subtypes defined by any combination of ER, PR, and HER2 status.
Because of the overlap between the BCAC samples in this analysis and a subset of those in SEARCH and the TNBCC, which were previously examined in an initial generalization of 19p13.1 SNP associations with BRCA1-related tumors (9), we conducted a sensitivity analysis removing these studies from the ER and ER/PR/HER2 subtype analyses. The effect estimates in this sensitivity analysis were very similar to those from the complete BCAC analysis, with only slight attenuation of significance (Supplementary Table S13).
Here, we report on the identification of the first triple-negative breast cancer–specific susceptibility locus at 19p13.1. We found that rs8170 was strongly associated with the risk of triple-negative breast cancer (OR, 1.25; P = 4.24 × 10−13) but was not associated with ER-positive (OR, 0.99; P = 0.38) or non–triple-negative, ER-negative (OR, 0.98; P = 0.63) breast cancer. Further analyses based on basal tumor markers suggested that the 19p13.1 variants are associated specifically with basal-like TN tumors (OR, 1.27; P = 0.0069). Ongoing histopathology studies in BCAC involving characterization of the CK5/6 and EGFR status of tumors may increase the numbers of triple-negative basal cases and allow reevaluation of this finding in the future. We were well powered to detect an association between 19p13.1 variants and these breast cancer subtypes in more than 32,000 cases and 48,000 controls. Importantly, our ability to evaluate risk of breast cancer across histologic subtypes in a single, large consortium strengthens the validity of the findings. Heterogeneity in hormone receptor and basal marker status across studies may influence our ability to detect associations with breast tumor subtypes at 19p13.1. However, in a sensitivity analysis including only cases from studies with the most stringent criteria for defining hormone receptor status (<1% of cells stained positive for ER, PR, and HER2: 0 or 1+ on IHC), the effect estimates were very similar to those from the complete analysis of the ER-negative, non–triple-negative and triple-negative subtypes. These findings have important implications for understanding genetic susceptibility to breast cancer because they suggest that additional susceptibility variants for specific subtypes of breast cancer remain to be identified.
Triple-negative breast cancer accounts for approximately 15% of all breast cancer among women of European descent and differs substantially from other subtypes of breast cancer by expression and genomic profiles and by epidemiologic characteristics (15). Women with triple-negative breast cancer are more likely to be younger, have an earlier age at menarche, higher body mass index during premenopausal years, higher parity, and a lower lifetime duration of breast feeding and in the United States are more likely to be African-American or Latina (16–18), and triple-negative tumors are associated with more aggressive disease and poorer survival (15, 19, 20). The biologic and clinical distinctions between biologic and other breast cancer subtypes are concordant with the identification of triple-negative–specific genetic risk factors and provide additional evidence for a distinct triple-negative tumor etiology. This highlights the importance of additional subtype-specific breast cancer studies and studies of breast cancer in additional populations such as African-Americans and Latinas, as it is not known whether similar associations with the SNPs described here exist in these populations.
The 3 19p13.11 variants measured in this study are located in the genes C19orf62 and ANKLE1 and are approximately 13 kb from the gene ABHD8. C19orf62, which encodes the MERIT40 protein, is currently hypothesized to be the most likely cancer susceptibility gene in this region because of the known interaction between MERIT40 and BRCA1. MERIT40 is integral to the localization of the BRCA1-A complex during DNA double-strand break repair, specifically through the recruitment and retention of the BRCA1–BARD1 ubiquitin ligase and the BRCC36 deubiquitination enzyme (21–24). However, both ANKLE1 (ankyrin repeat and LEM domain containing 1) and ABHD8 (abhydrolase domain containing 8) encode proteins of uncharacterized functions, making conjecture about the involvement of these proteins in cancer-related processes difficult.
It is unknown whether a single causal variant or multiple rare variants underlie the 19p13.1 association, affecting triple-negative risk through dysregulation of these or other nearby genes. Conversely, the causal variant at 19p13.1 may lie in a regulatory element that confers risk to triple-negative disease through long-range effects on distant genes. Although the biology underlying this association is unknown, it is likely that the functional consequences of variants at 19p13.1 are to modify genes or proteins that cooperate with other factors in signaling pathways critical to the development of the triple-negative phenotype. One can speculate that the causal 19p13.1 variants directly initiate and promote triple-negative tumor development, or alternatively that the 19p13.1 causal variants act to change the morphology of an existing malignant breast lesion to a triple-negative phenotype early in tumorigenesis. Resequencing and fine-mapping efforts in triple-negative breast cancer cases will be important for identification of the causal variants in the 19p13.1 locus and the mechanism by which these variants specifically influence risk of triple-negative breast cancer.
In conclusion, our study provides convincing evidence that the 19p13.1 locus is specifically associated with risk of triple-negative disease, confirming that some breast cancer susceptibility loci differ by histologic breast tumor subtype defined by ER, PR, and HER2 status. This report provides further evidence that triple-negative tumors and other subtypes likely arise through distinct etiologic pathways. Genetic and functional studies of triple-negative breast cancer will be necessary to identify the mechanism underlying the 19p13.1 association and to identify additional triple-negative–specific susceptibility loci.
No potential conflicts of interests were disclosed.
This work was supported by the NIH grant CA122340, a Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), the Komen Foundation for the Cure and the Breast Cancer Research Foundation (BCRF); the BCAC is funded by Cancer Research UK (C1287/A10118 and C1287/A12014), by the European Community's Seventh Framework Programme under grant agreement no. 223175 (HEALTH-F2-2009-223175; COGS), and by the European Union COST programme (BM0606). D.F. Easton is a Principal Research Fellow of Cancer Research UK; SBCS: Breast Cancer Campaign (2004 Nov 49 to A. Cox) and Yorkshire Cancer Research Core Funding (Institute for Cancer Studies); ABCS: Dutch Cancer Society grant (NKI 2009–4363 and NKI 2007–3839 to M.K. Schmidt) and the Dutch National Genomics Initiative; ACP: Breast Cancer Research Trust, UK. E. Sawyer is funded by National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre, Guy's & St. Thomas' NHS Foundation Trust in partnership with King's College London. I. Tomlinson is funded by the Oxford Biomedical Research Centre; ABCFS, NC-BCFR and OFBCR: National Cancer Institute, NIH under RFA-CA-06–503, and through cooperative agreements with members of the Breast Cancer Family Registry (BCFR) and Principal Investigators, including Cancer Care Ontario (U01 CA69467), Northern California Cancer Center (U01 CA69417), University of Melbourne (U01 CA69638); ABCFS: National Health and Medical Research Council of Australia, the New South Wales Cancer Council, the Victorian Health Promotion Foundation (Australia), and the Victorian Breast Cancer Research Consortium. J.L. Hopper is a National Health and Medical Research Council (NHMRC) Australia Fellow and a Victorian Breast Cancer Research Consortium Group Leader. M.C. Southey is an NHMRC Senior Research Fellow and a Victorian Breast Cancer Research Consortium Group Leader; CNIO-BCS: Genome Spain Foundation, the Red Temática de Investigación Cooperativa en Cáncer and grants from the Asociación Española Contra el Cáncer and the Fondo de Investigación Sanitario (PI081583 and PI081120); The California Teachers Study: California Breast Cancer Act of 1993, NIH (R01 CA77398), the Lon V Smith Foundation [LVS39420]), and the California Breast Cancer Research Fund (contract 97–10500); UCIBCS: NIH (CA58860 and CA92044) and the Lon V Smith Foundation (LVS39420); ESTHER: Baden Württemberg Ministry of Science, Research and Arts, and the VERDI study supported by a grant from the German Cancer Aid (Deutsche Krebshilfe); GENICA: Federal Ministry of Education and Research (BMBF) Germany (01KW9975/5, 01KW9976/8, 01KW9977/0 and 01KW0114), the Robert Bosch Foundation, Stuttgart, Deutsches Krebsforschungszentrum (DKFZ) Heidelberg, Institute for Prevention and Occupational Medicine of the German Social Accident Insurance (IPA), Bochum, and the Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany: KBCP: Finnish Cancer Society, the Academy of Finland (grant number 127220), the special Government Funding (EVO) of Kuopio University Hospital (grant number 5654113 and 5501) and by the strategic funding of the University of Eastern Finland; OBCS: Finnish Cancer Foundation, the Academy of Finland, the University of Oulu, the Oulu University Hospital and Biocenter Oulu; RPCI: P30 grant to RPCI (CA016056-32); The Breakthrough Generations Study: Breakthrough Breast Cancer and the Institute of Cancer Research (ICR). ICR acknowledges NHS funding to the NIHR Biomedical Research Centre; PBCS: Intramural Research Funds of the National Cancer Institute, Bethesda, MD; HEBCS: Helsinki University Central Hospital Research Fund, Academy of Finland (132473), the Finnish Cancer Society, and the Sigrid Juselius Foundation; MARIE: Deutsche Krebshilfe e.V., grant number 70-2892-BR I, the Hamburg Cancer Society, the German Cancer Research Center (DKFZ), and the Federal Ministry of Education and Research (BMBF) Germany grant 01KH0402; GESBC: Deutsche Krebshilfe e. V. (70492) and the state of Baden-Württemberg through the Medical Faculty of the University of Ulm (P.685); BSUCH: Dietmar Hopp Foundation, the German Cancer Research Center, DKFZ, and the Helmholtz association; GC-HBOC: Deutsche Krebshilfe (107054), the Center of Molecular Medicine, Cologne, the German Cancer Research Center, DKFZ, and the Helmholtz society; BBCS: Cancer Research UK, Breakthrough Breast Cancer and the National Cancer Research Network (NCRN); kConFab: National Breast Cancer Foundation, the National Health and Medical Research Council (NHMRC) and by the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia, the Cancer Foundation of Western Australia, and Cancer Australia #628333; LMBC: 'Stichting tegen Kanker' (232–2008 and 196–2010); MCCS: Australian National Health and Medical Research Council (grants #209057, 251533, 396414, and 504711), Cancer Council Victoria, and VicHealth; ORIGO: Dutch Cancer Society; SEARCH: Cancer Research UK (C8197/A10123, C8197/A10123, and C490/A10124). A.M. Dunning was supported by Cancer Research UK grant (C8197/A10865) and by the Joseph Mitchell Fund; FCCC: NIH (U01 CA69631, 5U01 CA113916 to A.K. Godwin), the Eileen Stein Jacoby Fund, The University of Kansas Cancer Center, and the Kansas Bioscience Authority Eminent Scholar Program. A.K. Godwin is the Chancellors Distinguished Chair in Biomedical Sciences endowed Professor.
See Supplementary Material for acknowledgments.
Received October 10, 2011.
Revision received December 30, 2011.
Accepted January 19, 2012.
Stacey SN,
Manolescu A,
Sulem P,
Rafnar T,
Gudmundsson J,
Gudjonsson SA,
Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer. Nat Genet 2007;39:865–9.
Thorlacius S,
Jonsson GF,
Common variants on chromosome 5p12 confer susceptibility to estrogen receptor-positive breast cancer. Nat Genet 2008;40:703–6.
Garcia-Closas M,
Chanock S
. Genetic susceptibility loci for breast cancer by estrogen receptor status. Clin Cancer Res 2008;14:8000–9.
Hall P,
Nevanlinna H,
Pooley K,
Morrison J,
Richesson DA,
Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics. PLoS Genet 2008;4:e1000054.
Thomas G,
Jacobs KB,
Kraft P,
Yeager M,
Wacholder S,
Cox DG,
A multistage genome-wide association study in breast cancer identifies two new risk alleles at 1p11.2 and 14q24.1 (RAD51L1). Nat Genet 2009;41:579–84.
Turnbull C,
Ahmed S,
Pernet D,
Renwick A,
Maranian M,
Genome-wide association study identifies five new breast cancer susceptibility loci. Nat Genet 2010;42:504–7.
Ghoussaini M,
Healey CS,
Humphreys MK,
Platte R,
Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2. Nat Genet 2009;41:585–90.
Figueroa JD,
Humphreys M,
Hopper JL,
Southey MC,
Associations of common variants at 1p11.2 and 14q24.1 (RAD51L1) with breast cancer risk and heterogeneity by tumor subtype: findings from the Breast Cancer Association Consortium. Hum Mol Genet 2011;20:4693–706.
Antoniou AC,
Wang X,
Fredericksen ZS,
McGuffog L,
Tarrell R,
Sinilnikova OM,
A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population. Nat Genet 2010;42:885–92.
Broeks A,
Schmidt MK,
Sherman ME,
Couch FJ,
Dite GS,
Low penetrance breast cancer susceptibility loci are associated with specific breast tumor subtypes: findings from the Breast Cancer Association Consortium. Hum Mol Genet 2011;20:3289–303.
Dunning AM,
Baynes C,
Maia AT,
Scollen S,
Vega A,
Association of ESR1 gene tagging SNPs with breast cancer risk. Hum Mol Genet 2009;18:1131–9.
Stevens KN,
Vachon CM,
Lee AM,
Slager S,
Lesnick T,
Olswold C,
Common breast cancer susceptibility loci are associated with triple-negative breast cancer. Cancer Res 2011;71:6240–9.
Bolton KL,
Tyrer J,
Song H,
Ramus SJ,
Notaridou M,
Jones C,
Common variants at 19p13 are associated with susceptibility to ovarian cancer. Nat Genet 2010;42:880–4.
Yang XR,
Chang-Claude J,
Goode EL,
Milne RL,
Associations of breast cancer risk factors with tumor subtypes: a pooled analysis from the Breast Cancer Association Consortium studies. J Natl Cancer Inst 2011;103:250–63.
Foulkes WD,
Smith IE,
Reis-Filho JS
. Triple-negative breast cancer. N Engl J Med 2010;363:1938–48.
Rimm DL,
Lissowska J,
Brinton LA,
Peplonska B,
Differences in risk factors for breast cancer molecular subtypes in a population-based study. Cancer Epidemiol Biomarkers Prev 2007;16:439–43.
Schneider BP,
Winer EP,
Garber J,
Perou CM,
Richardson A,
Triple-negative breast cancer: risk factors to potential targets. Clin Cancer Res 2008;14:8010–8.
Millikan RC,
Newman B,
Tse CK,
Moorman PG,
Conway K,
Dressler LG,
Epidemiology of basal-like breast cancer. Breast Cancer Res Treat 2008;109:123–39.
Bauer KR,
Brown M,
Cress RD,
Parise CA,
Caggiano V
. Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype: a population-based study from the California cancer Registry. Cancer 2007;109:1721–8.
Irvin WJ Jr.,
Carey LA
. What is triple-negative breast cancer? Eur J Cancer 2008;44:2799–805.
Feng L,
Huang J,
Chen J
. MERIT40 facilitates BRCA1 localization and DNA damage repair. Genes Dev 2009;23:719–28.
Shao G,
Patterson-Fortin J,
Messick TE,
Feng D,
Shanbhag N,
Wang Y,
MERIT40 controls BRCA1-Rap80 complex integrity and recruitment to DNA double-strand breaks. Genes Dev 2009;23:740–54.
Wang B,
Hurov K,
Hofmann K,
Elledge SJ
. NBA1, a new player in the Brca1 A complex, is required for DNA damage resistance and checkpoint control. Genes Dev 2009;23:729–39.
Dong Y,
Hakimi MA,
Chen X,
Kumaraswamy E,
Cooch NS,
Godwin AK,
Regulation of BRCC, a holoenzyme complex containing BRCA1 and BRCA2, by a signalosome-like subunit and its role in DNA repair. Mol Cell 2003;12:1087–99.
You are going to email the following 19p13.1 Is a Triple-Negative–Specific Breast Cancer Susceptibility Locus
Cancer Res April 1 2012 (72) (7) 1795-1803; DOI: 10.1158/0008-5472.CAN-11-3364
TRβ2 Bypasses Rb-Dependent Proliferation in RB1−/− Cells
DHHC3 Regulates Breast Tumor Growth In Vivo
Role of Fibroblasts in Pathogenesis of Fibroids
Show more Molecular and Cellular Pathobiology


text:
Tibet religious figures oppose Dalai Lama's latest remarks
Several Tibet religious figures have expressed opposition to the Dalai Lama's remarks concerning what he called "cultural genocide" and "terror rule" in Tibet.
"The remarks that the Dalai Lama made at a press conference are totally ungrounded and against reality," said Lhadar Ngawang Daindzin, vice-president of the Tibetan Branch of the Buddhist Association of China.
The Dalai Lama cited a "rule of terror" and "cultural genocide" in his latest remarks after Friday's Lhasa riots, according to media reports.
Over the past half-century, great changes had taken place in Tibet. People fully enjoyed freedom and democracy and their living standards had improved significantly. "Anyone who has ever been to Tibet will see the reality," said Ngawang Daindzin, who is also a living Buddha.
The Dalai Lama's remarks concerning "cultural genocide" were false and unfounded, he said.
He also called on the government to punish those who initiated the riots on Friday, which involved beating, looting and burning.
Thirteen civilians had been confirmed dead, he said. "The rioters who wore cassocks were no real monks at all. What they did is completely against the tenets of Buddhism."
Tubdian Targyai, a living Buddha at the Gandan Monastery, said "The protection and maintenance of monasteries are the best protection of Tibetan culture."
"In recent years, the government has poured huge sums into the repair of monasteries and heritage buildings, which demonstrated the Chinese government's protection of Tibetan culture," he said.
(Xinhua News Agency, March 17, 2008)
- FM: Recent Tibetan monks' rally a deliberate plot
- Dalai Lama urged to drop secessionist activities
- Dalai's description on Lhasa riot ridiculous
- Dalai coterie's secessionist attempts doomed to fail
- Tibeten officials refute Dalai's 'rule of terror' remarks
- Tibet official on Lhasa rioting
- Tibetan students stage campus sit-in in Beijing
- Xiyue Temple -- 'Forbidden City of Shaanxi'
- China will not rush to get to moon
- Lhasa revives from riot nightmare


text:
On Memorial Day
by Jeri Turner • May 31, 2010 • 0 Comments
We are the proud parents of two heroes—Army Infantrymen who have served this country with honor and valor. The Lord has spared us the grief of having to deal with the loss of either one, but each one has paid a great price in their service to this country. They both came back from the war changed men.
Proverbs 18:24 comes to mind when I think about these things: "A man of many companions may come to ruin, but there is a friend who sticks closer than a brother." One thing I have learned from my sons is the close bond that forms between comrades-in-arms. The battle is not just about their own survival, but the struggle to survive becomes for them a continual fight to protect and watch the back of the man next to them. They live and breathe this existence as they daily face enemy fire. To lose a buddy then, can be absolutely devastating.
Our oldest son still wears a bracelet, which contains the name of Sergeant Hector Leijah, who was killed in Iraq by a sniper, during what has become known as the Battle of Haifa Street. The bracelet, made of blackened aluminum, has become scratched and faded over the past two years, but our son carries Sgt. Leijah's memory as a daily reminder of that life cut short in service to our country.
Then there are those who have taken the hit and survived—some with visible and some with invisible scars. Our youngest son took a hit in Afghanistan last year. I can still recall the fear and worry we experienced in those first couple of days—not fully knowing the extent of his injuries or what the outcome would be. Thank God, he has pretty much recovered, although his injuries have left him with constant pain and cut short his military career. But it is the invisible scars that most concern me. I cannot begin to understand what my boys have gone through. I get overwhelmed and find myself having to mentally tune out during some of their discussions about their experiences; disturbed by the images of war—of what sound to me like hell on earth—that will live in their minds for the rest of their lives.
Another verse that comes to mind when I think about our country's heroes is John 15:3: "Greater Love has no one than this, that he lay down his life for his friends." I know at the very least, there are two individuals who are still alive in this world because of each of our son's willingness to risk his life for his friend. Our youngest son is the recipient of a Bronze Star with Valor for rescuing one of his comrades in the midst of enemy fire. He seems a bit embarrassed about the attention given him in this, and I have seen the same humble reaction in both our sons and in other service-members as well—who are thanked or otherwise lauded for their service by grateful citizens. He doesn't talk much about these things, and to this day, we don't know the full story of what happened on that day.
Our other son was in a convoy of strikers vehicles. The front vehicle was hit by an IED bomb. He told us the harrowing story of how his men dragged their brother-in-arms from the burning vehicle—his legs badly mangled from the blast—and how they raced through the dark streets of Baghdad with only their navigation screen to guide them. Our son attended to his friend, desperately attempting to stop the bleeding and keep him alert. The toll his friend paid in service to this country was huge; he lost both legs that night. After the incident, our son had no contact with his comrade. Recently, however, they reconnected on facebook and met up. Our son learned that his buddy had flat-lined more than once that night, and had no recollection of anything that happened, except that someone kept yelling at him to stay awake. That was my son.
I am so extremely proud of both of our sons and for all of our service-members, who daily risk life and limb for this country and for our freedoms. I have had a small taste of the worry and agony of being the parent of a son in the line of fire. My heart hurts for the loved ones of those who have paid the ultimate price. I cannot fathom the depth of their sorrow. My biggest concern is that our sons and daughters would be facing down death on a daily basis without God's love and presence as a bulwark against the enemy of their souls.
Please pray with me that those who are serving would know the truth that sets them free—and the deep love and compassion of God, who renews our hearts and gives us hope. Pray for a revival in our country and within our military. Pray also for those who struggle daily to overcome the emotional and physical challenges of their post-war lives. Finally let's remember the grieving family members and friends for whom this day is no picnic.
All Scripture references from the NIV
← True Hope
Who is the beholder of your beauty →


text:
'use strict';

(function(){

angular
  .module('bitcoincom.services')
  .factory('sideshiftService', sideshiftService);

  function sideshiftService(sideshiftApiService, gettextCatalog) {

    var service = {
      // Variables
      coinIn: '',
      coinOut: '',
      withdrawalAddress: '',
      returnAddress: '',
      amount: '',
      marketData: {},
      coins: {
        'BTC': {name: 'Bitcoin', symbol: 'BTC'},
        'BCH': {name: 'Bitcoin Cash', symbol: 'BCH'}
      },

      // Functions
      getMarketData: getMarketData,
      shiftIt: shiftIt
    };

    return service;

    function handleError(response, defaultMessage, cb) {
      if (response && typeof response.error === "string") {
        cb(new Error(response.error));
      } else if (response && response.error && response.error.message) {
        cb(new Error(response.error.message));
      } else {
        cb(new Error(defaultMessage));
      }
    }

    function getMarketData(coinIn, coinOut, cb) {
      service.coinIn = coinIn;
      service.coinOut = coinOut;
      sideshiftApiService
        .marketInfo(service.coinIn, service.coinOut)
        .then(function (response) {
          if (!response || response.error) {
            handleError(response, 'Invalid response from Sideshift', cb);
          } else {
            service.marketData = response;
            service.rateString = service.marketData.rate.toString() + ' ' + coinOut.toUpperCase() + '/' + coinIn.toUpperCase();
            cb(null, response);
          }
        });
    }

    function shiftIt(coinIn, coinOut, withdrawalAddress, returnAddress, amount, cb) {
      // Test if the amount is correct depending on the min and max
      if (!amount || typeof amount !== 'number') {
        cb(new Error(gettextCatalog.getString('Amount is not defined')));
      } else if (amount < service.marketData.minimum) {
        cb(new Error(gettextCatalog.getString('Amount is below the minimun')));
      } else if (amount > service.marketData.maxLimit) {
        cb(new Error(gettextCatalog.getString('Amount is above the limit')));
      } else {

        // Init service data
        service.withdrawalAddress = withdrawalAddress;
        service.returnAddress = returnAddress;
        service.coinIn = coinIn;
        service.coinOut = coinOut;
        service.amount = amount;

        // Check the address
        sideshiftApiService
          .ValidateAddress(returnAddress, coinOut)
          .then(function onSuccess(response) {
            if (response && response.isvalid) {
              // Prepare the transaction sideshift side
              sideshiftApiService.NormalTx(service).then(function onResponse(response) {
                // If error, return it
                if (!response || response.error) {
                  handleError(response, gettextCatalog.getString('Invalid response from Sideshift'), cb);
                } else {
                  var txData = response;

                  // If the content is not that it was expected, get back an error
                  if (!txData || !txData.orderId || !txData.deposit) {
                    cb(new Error(gettextCatalog.getString('Invalid response from Sideshift')));
                  } else {
                    // Get back the data
                    service.depositInfo = txData;
                    var sideshiftData = {
                      coinIn: coinIn,
                      coinOut: coinOut,
                      toWalletId: service.toWalletId,
                      minAmount: service.marketData.minimum,
                      maxAmount: service.marketData.maxLimit,
                      orderId: txData.orderId,
                      toAddress: txData.deposit
                    };
                    cb(null, sideshiftData);
                  }
                }
              });
            } else {
              cb(new Error(gettextCatalog.getString('Invalid address')));
            }
          });
      }
    }
  }
})();

redpajama_set_name: RedPajamaGithub


text:
IFFR Coverage Thrillers Weird Videos All News Weird Reviews
September 25 2015, 12:00 PM
Fantastic Fest 2015 Review: RUINED HEART, A Doomed Love Song Of Two Humans
J Hurtado
Editor, U.S. ; Dallas, Texas (@HatefulJosh)
Filipino director Khavn De La Cruz burst onto the radar of avant garde film lovers around the world with his 2010 feature Mondomanila. While far from a debutante with dozens of shorts and features behind him, Khavn's film made an impression, especially on our Kurt Halfyard, who remarked that the film was "gutter poetry at its finest," and "not to be missed."
Unfortunately, the film kind of disappeared, so far with only a DVD release in Germany to remind people around the world that Khavn still exists. However, with his latest feature, Ruined Heart, Khavn stands up to be counted, and as long as you can groove to his beat, it's quite a ride.
Ruined Heart (subtitled, "Another Love Story Between a Criminal and a Whore") treads familiar ground without feeling repetitive. It's a film that bursts with emotion, even though it is nearly wordless. It follows a brief episode in the lives of the titular Criminal, played by Japanese indie darling Asano Tadanobu, and the Whore, portrayed by Post Tenebras Lux star Nathalia Acevedo. as they fall in love, find themselves in trouble, and make a run for it. The film has almost no dialogue, and plot details are deliberately vague, so its construction can certainly leave less active viewers scratching their heads. For those willing to submit to the experience, however, the rewards are many.
As suggested by its long subtitle, Ruined Heart is another attempt at telling a familiar story. The Criminal is tasked with protecting The Godfather's favorite girl, and in the process The Criminal and The Whore fall in love. The Godfather doesn't like this and soon after, the star-crossed lovers are on the lam.
While many dozens of films and stories have been made from these well worn bones, Khavn manages to use his unique perspective to make Ruined Heart unlike any of those. With the help of superstar cinematographer Christopher Doyle and French-German electronic lo-fi duo Stereo Total, the film takes on an otherworldly feeling that removes the viewer from the very real surroundings and places them in a world completely of Khavn's creation.
The lack of dialogue creates both unique challenges and opportunities for reward for Khavn and the cast and crew of Ruined Heart. Asano's trademark slacker persona works extremely well in the role of The Criminal. His ability to emote from a place of almost complete silence is remarkable. Far from his bombastic and flamboyant performance in Ichi the Killer, Asano's Criminal is a heartsick ne'er do well looking to protect the only thing he really cares about. Nathalia Acevedo's Whore creates a perfect counterpoint with her emotive, effusive, and electric performance. The two portray perfect Yin and Yang in the process of creating this world in which nothing matters but them, and for which every experience brings deeper passion for themselves and the world they inhabit.
I would be crazy, though, if I didn't explicitly address the more formal aspects and technical brilliance of Ruined Heart. Khavn was fortunate to collaborate with his Mondomanila producers REM Films out of Germany on this feature, and as such connects with their previous collaborators in Doyle and Stereo Total. That pair also worked on REM's previous Pink musical, Underwater Love, a film that landed on my top ten back in 2011. However, where Underwater Love was an emotionally dense lo-fi softcore porn film, Ruined Heart requires more than a little additional finesse, and Doyle and Stereo Total definitely bring their "A" game.
The world has become familiar with Doyle's signature work with Hong Kong auteur Wong Kar Wai, Ruined Heart presents him with opportunities to create images beyond his usual scope. Fans of films like Chungking Express are accustomed to Doyle's visual flights of fancy, however, this film is on a whole other level. I don't have the technical details at hand, but the look is that of a thousand Go Pro cameras placed everywhere, and even long stretches with Asano holding a camera in his own outstretched hands. So the look of Ruined Heart is wild and free. While it's definitely sure to give some people headaches, I definitely found this experimentation exciting and quite fitting with the overall tone.
Similarly tangential to what we might expect from this kind of film is the score. While the complete score is the work of many artists in concert with the occasional diegetic interlude, it is definitely Stereo Total whose work steals the show. The duo's work on Underwater Love was exceptional, and this follow-up is possibly even better.
If the cinematography propels the film forward, the music of Ruined Heart does an amazing job of displacing the viewer from the image. I don't know if the streets of Manila typically throb with the beat of a two piece electronic band, but in its juxtaposition with the familiar streets and visual language of poverty, the music allows the viewer to contextualize the story as a universal one. That's not even to mention the remarkably apropos outbursts of onscreen music from such disparate sources as Ska legend John Holt and backwoods rockabilly pioneer Hasil Adkins. Khavn's ability to blend these pieces at all speaks to a monumental talent.
If there's a descriptor that bothers me more than any other when reading film criticism, it's "tone poem." This seems to be the default for many out there when other descriptions fail. Films that don't rely on standard linear narrative are often referred to as tone poems, simply due to the difficulty difficult in pinning down the actual meaning behind the mood.
I fear that Ruined Heart will fall subject to this description more often than it deserves. The film is fresh, explosive, and new, and at this point, more than a hundred years after the invention of the medium, the fact that anyone can come up something new deserves as much attention as possible.
Asano TadanobuChristopher DoyleFantastic FestGermanyKhavyn De La CruzPhilippines
More from Around the Web
Fantastic Fest 2015: RUINED HEART
More about Ruined Heart
Now On Blu-ray: RUINED HEART And Kitano Takeshi's HANA-BI From Third Window FIlms UK
Exclusive! Third Window Films Brings Tsukamoto, Sono, Asano Tadanobu, And UZUMASA LIMELIGHT To The UK
Doyle, Asano And Khavn Collide In The RUINED HEART Trailer


Men never get breast cancer, right?
Wrong. Men not only get breast cancer, but, when they do, they are more likely to die from it than women are. The reason for the difference in mortality rate is largely because of the stigma that men feel about being diagnosed with a disease that is seen to be only for women. Cancer, of any kind, can be life-threatening, but, no matter who it strikes, one of the key factors in survival rates is early detection. The more advanced the disease is, the greater the odds against beating it. Men rarely pay attention unless there is a noticeably large lump. Unfortunately, by this time, it is more than likely to already be growing and possibly spreading.
The embarrassment of having a "woman's disease" aside, there is far less attention paid to breast cancer in men. There is a reason that all of the awareness campaigns are in pink: roughly, the odds of breast cancer for women are 1 in 8, while for men, they are 1 in 1,000. Once diagnosed, the treatment and prognosis for men and women are basically the same. Bringing medical attention to breast cancer in men would increase early detection and save lives.
By some estimates, there is a gap of more than a year and a half between when the first symptom appears and diagnosis for men. That is simply too long.
Happy 40th birthday! The big 4-0 is a big milestone to reach, and you should be proud of yourself. But 40 is also an important time in your life in regard to medical checkups, especially for mammograms. Some of you may be wondering how mammograms came about and what improvements have been made to them over the years.
In the 1960s, radiologists performed mammography exams using general purpose X-ray tubes, without compression. They captured the imaging onto direct-exposure films, similar to chest X-rays. These were low-contrast images and the area of tissue close to the chest wall appeared "white" due to underexposure.
A decade later, mammography advanced significantly with the introduction of screen-film mammography, which made imaging faster, required lower radiation dose, and provided greater contrast, making it easier to "see through" breast tissues. Improvements in screen-film technology and the establishment of dedicated mammography units during the 1980s and 1990s improved mammography even more.
As the technology improved, mammography screenings became more common due to two factors. First, the results of multiple randomized and controlled trials demonstrated the effectiveness of mammographies in lowering breast cancer mortality rates. Second, the development of effective pre-operative image-guided wire localization techniques made it easier to make tissue diagnosis for suspicious lesions detected by mammograms.
The 90's saw an uptick in mammography use, resulting in an increase in mammography regulations as well. As the exam became widely used and breast cancer received more publicity, concerns about mammography quality grew. After uncovering various quality issues, a series of Congressional hearings were dedicated to mammography, leading to the Mammography Quality Standards Act of 1992, forcing uniform standards nationwide, affecting the quality of breast imaging as well as the standards that radiologists must comply with.
Around 2000, breast imaging experienced another significant advancement with the introduction of digital mammography. While digital mammography procedures are essentially the same as X-ray mammographies from the patient's point of view, the new digital mammography machines produce images that can be read on computers rather than X-ray film, which has improved oncologist's ability to identify symptoms, give diagnoses, and treat their patients.
As expected, most radiology practices in the U.S. now use digital mammography rather than analog film, as it provides better images with improved tissue contrast. This is important for patients with dense breast tissue, especially younger patients, who tend to have denser breasts than older patients. Digital mammography is also beneficial compared to more traditional mammographies as the patient receives less radiation exposure.
Moving forward, digital breast tomosynthesis (DBT) is an emerging technology that captures multiple low-dose mammographic images of the breasts. DBT has been shown to reduce false-positives and improve detection of invasive cancers. Hence, DBT has been called "a better mammogram" and will likely become the standard for mammographic screening.
Mammography has come a long way from its humble beginnings of direct-exposure films. Breast imaging radiologists now have more tools in their arsenal than ever before. As additional technological innovations are achieved, mammography is expected to remain a critical part of early detection efforts.
Early detection remains critical to reducing mortality. Mammography remains the most effective and cost-effective tool for detecting breast cancer and we recommend annual mammography screening beginning at age 40.


text:
Adrian Hart
Adrian Hart joined Crash as Production Manager in 2011. He is a graduate in music performance at the Purcell School of Music and the Royal Irish Academy of Music and studied music technology and composition at Trinity College Dublin. Adrian has worked throughout Europe and America as a performer, composer, sound engineer and producer.
As a musician, Adrian has recorded and performed on stage with many leading recording artists from Ireland, UK, Europe and the US. He is a member of the Irish groups I Draw Slow, Yurodny, Dulra and the Clare Memory Orchestra. In 2012 he was nominated for an IBMA award for his fiddle playing on the I Draw Slow album Redhills.
As a composer, Adrian Hart is primarily interested in the exploration of acoustic sound through electronic manipulation. Specialising in Irish, North-American and Eastern-European traditional fiddle repertoire, Adrian's compositions focus on the development of techniques found in traditional and non-classical styles of music within a contemporary context. Adrian's works have been commissioned and performed throughout Ireland, the UK and Europe and have been broadcast internationally.
As a sound engineer and producer, Adrian has worked with some of the leading names in contemporary music, including Ergodos, Contempo Quartet, Concorde, Kevin Volans, Gerrald Barry, Barry Guy, Nico Muhly, Steve Reich and Michael Gordon. Adrian produces the highly acclaimed Kaleidoscope Night concerts monthly in Dublin.


We spent Father's Day with our extended family members Strawberry Kiss, Melty Moments and D'list Donut at the Shopkins Macaron Cafe to celebrate the launch of Season 8 "World Vacation"….and it's definitely Sippy Cup Approved!
Our apartment decor is compliments of Shopkins. If you have a kid who loves them as much as Sunny does then you know exactly what I'm talking about. These little plastic characters find their way into my bathtub, makeup kit, high heels, food pantry and more. So, when we heard about the French themed Shopkins Macaron pop-up cafe in Tribeca on Father's Day weekend we knew we had to go!
Luckily Ryan hit the RSVP site the second it opened and snagged us three spots for today. Boy oh boy was Sunny surprised.
After eating Ryan gave Sunny a Shopkins manicure and we played with the new Season 8 toys!
We left with a swag bag filled with lots of Shopkins goodies. Of course Sunny asked me if we can now make some Shopkins macarons of our own. Between us, I might cheat and buy some ready made macarons like our friends at StudioDIY.com did using these nifty pens from Amazon.
Draw on your own macarons!
We also found out about the Shopkins Live Tour "Shop It Up" – they don't have any NYC dates but there are some NJ dates in September.
We'll be goin' to Jersey for this one!


I've heard recently about gps rollover week sort of like the y2k scare years ago, but this one must be different, my ifd550 master clock just reset to August 1999. How do I get it reset ?
Get the GPS rollover patch at https://lz314.infusionsoft.com/app/form/gpsrolloverupdate. Your avionics shop can also get it for you.
I just did the rollover patch on my IFD-540.
I have a ~5yo battery kept on a maintainer.
I have a cigarette lighter voltmeter.
I turned all of the avionics off except the 540.
decreased to 10.9 volts almost immediately.
Start with a good battery in the airplane.
Keep the battery maintainer plugged in and all unnecessary current draws turned off.
Have the Service Bulletin open on your laptop or phone before you start.
Follow the procedure...quite simple actually.
In my case I didn't need an external power source.
for your airplane. Follow the Avidyne procedure!!!!
I updated April 12th. I saw no difference before/after (meaning no problems). Saw an UTC mismatch message after update but I had seen it about a month ago also.


Ken Townsend is a freelance ENG/EFP, Cinematographer and Editor working out of Toronto. His shooting is centered around high impact, creative, visual story telling with a focus on factual content.
Whether electronic news gathering or electronic field production my experience in the broadcast industry ensures versatility and a creative approach to coverage in time-sensitive production environments.
2014 Ken Townsend. All right reserved.


I produce work in a variety of media including painting, drawing, collage and ceramics.
My studio is at home and visitors are welcome by appointment.
There are many strands to my work.
For as long as I can remember I have used drawing, painting, and making things as a way to express my ideas, to tell stories, to observe and to understand. The choice of medium is sometimes random or becomes clear when I start developing an idea. These ideas may be around cultural issues, historical themes, dreams or memories. Media include acrylic, watercolour, pencil, crayon, ink, collage and printmaking.
Alongside this work I also have the desire to produce items of beauty and originality, be they functional or sculptural, I enjoy learning and developing new skills and then experimenting. Hence my ceramic work includes reduction fired porcelain, stoneware, paperclay, raku and saggar fired pieces.
I also enjoy the discipline of life drawing. I have the privilege of having my own models so can use poses which reflect my interests at the time, such as the bodies found at Pompeii, or the expression of emotions such as anger or joy. These drawings then often become the basis of paintings or collage. They also inform some of my sculptural work in clay.
Galleries exhibiting my work : Catharine Miller, Hollywood Road Gallery, Chelsea, Yarmouth Gallery, Mini Big Art, Bembridge.


OKLAHOMA CITY — An amendment that would ban Oklahoma courts from considering international or Islamic law discriminates against religions and a Muslim community leader has the right to challenge its constitutionality, a federal appeals court said Tuesday.
The court in Denver upheld U.S. District Judge Vicki Miles-LaGrange's order blocking implementation of the amendment shortly after it was approved by 70 percent of Oklahoma voters in November 2010.
Muneer Awad, the executive director of the Council on American-Islamic Relations in Oklahoma, sued to block the law from taking effect, arguing that the Save Our State Amendment violated his First Amendment rights.
The amendment read, in part: "The courts shall not look to the legal precepts of other nations or cultures. Specifically, the courts shall not consider international law or Sharia law."
Backers argued that the amendment intended to ban all religious laws, that Islamic law was merely named as an example and that it wasn't meant as a specific attack on Muslims. The court disagreed.
"That argument conflicts with the amendment's plain language, which mentions Sharia law in two places," the appeals court opinion said.
The court also noted that the backers of the amendment admitted they did not know of any instance when an Oklahoma court applied Sharia law or used the legal precepts of other countries.
Awad argued that the ban on Islamic law would likely affect every aspect of his life as well as the execution of his will after his death. The appeals court pointed out that Awad made a "strong showing" of potential harm.
"When the law that voters wish to enact is likely unconstitutional, their interests do not outweigh Mr. Awad's in having his constitutional rights protected," the court said.


Location: Situated W of Y Drewen chapel, in Cwm Cou village.
Later C18 and C19 water-powered corn-mill on the Gwenffrwd stream. Datestone I.Gs. 1791 may be imported. Overshot 15 foot wheel has gone. There was also a wheel on the shaft to link to a gas-engine stood ouside. Interior remodelled in late C19.
Rubble stone with slate roofs. Two storeys and loft. Irregular facade of two 4-pane casements to centre and left over ground floor window, door window, roughly aligned with windows above. 6-pane window to left, broad doorway with cambered head on oak lintel and four-pane casement to right. I.Gs. 1791 on plaque over door. Loft lights in each gable, door and window to first floor at rear. Right end has wheelpit of former overshot wheel. Left end has attached later C19 lofted cow-house with two loft windows under eaves and ground floor brick-headed door, window, door, door, and added brick lean-to. Door in end-wall, in angle to mill, to former kiln-room.
Full later C19 machinery. Ground floor line-shaft to two spur-wheels turning shafts for two first floor mill-stones. Shaft driven bolter in panelled cupboard. Sack-hoists in loft and five hoppers. Roof has two oak pegged collar-trusses, otherwise early C20 pine. Pine floor joists.
A good example of a small rural mill retaining its machinery.
Situated on S side of B4570, some 800m NW of Cwm Cou.