#d:201104

[hpspeedsite]

Il 2 sturmovik battle of stalingrad all planes listed

It was originally developed by the Russian software house 1C:Maddox Games but since 2012 it is under development by Team Fusion Simulations. Nvidia control panel has some settings that you can tweak for VR in general.

Depuis hier le jeu IL-2 Sturmovik: Battle of stalingrad est de sortie sur steam et sur le site officiel. Campaign General Discussions Digital Combat Simulator. If team fusion sorts it out then it could a super sweet alternative to IL2:Stalingrad and DCS (with inferior physics of course, but CLoD has some advantages too). IL-2 Sturmovik: Cliffs of Dover is a World War II combat flight simulator released in 2011. 1946 is getting long in the tooth now, and Cliffs of Dover was a mess when released, and had to be heavily modded to bring it up to scratch. IL-2 Sturmovik: Battle of Stalingrad 60fps Yak-1 gameplay. IL 2 Sturmovik Battle of Stalingrad 04 09 2016 Shot Down IL 2 Perspective. The RAF took on the Luftwaffe over British cities, countryside and coastline to thwart the enemy’s advance. First of the many, the Ju88V1 of 1936 carrying the civil registration D-QEN. There is also discussion there regarding IL-2 1946 and Cliffs of Dover, in case that's helpful. When Ubisoft and 1C Game Studios dropped support for the game, a merry band of volunteers decided to create a free mod in order to fix the many issues Cliffs of Dover had back in the years 2011 to 2013. While the two are very similar, the under the hood code is all unique and different. Mutta tiedättekös, horisontissa näkyy muutakin kuin liekehtivä Stalingrad. IL-2 Sturmovik: Battle of Stalingrad 201309: IL-2 Sturmovik: Cliffs of Dover 201104: IL-2 Sturmovik: Forgotten Battles (and Ace Expansion) 200301: Infinity: Battlescape 201909: Insurgency 200707: iDRIVING 200806 Vuelo de prueba entre Dover y el aeropuerto de Hawkinge realizado con el IL2 Sturmovik 1946 y el Mod UltraPack 3A subreddit for 1C and 777's IL-2 series of combat sims. Il2 flight simulator (Il2 original, Forgotten battles, 1946, Cliffs of Dover) Are all the same from UBI soft. Open the recording of your choice from Tacview, or simply double click the *.acmi file you want to open directly from Windows Explorer.

87 Anybody who's been feeling the recent drought of serious flight sims, anybody who's been eagerly anticipating the next project from Russian aviation engineer / game designer / genius Oleg Maddox, anybody who's been thinking fondly of the days when flight sims came with thick manuals, take a deep breath.

Also the plane selection is very limited and very few mods to play with. Uživatel Příspěvek: 936 Založený: 31.08.10 1) Postřeh ohledně lítání nad vodou - pamatuju, že v Il-2 1946 byly vidět vlny za letadlem, zčeřená hladina, když jsem letěl nízko. Child Boards: Ultra Pack Discussion & Support, Dark Blue World Discussion & Support, 4.09 Rebel Base, Community Universal Patch (C.U.P. La linea de productos Cliffs of Dover estará separado de la linea IL-2 Sturmovik: Battle of Stalingrad producida por 1C Game Studios. See what Ross Hollingsworth (rossah88) has discovered on Pinterest, the world's biggest collection of ideas. This machine soon crashed and was replaced in the test programme by … ↳ Vidéos et screenshots. Note: On Steam, customers must first purchase Battle of Stalingrad if they wish to purchase Battle of Normandy. This is a must read before using the forum board! Ehkä simugenren pelastaminen jää siis minun harteilleni, sillä Il-2 Sturmovik: Battle of Stalingrad on sen arvoinen. En gros c'est un simulateur de vieux coucou de la 2egm. Ignorance of our codes will not be excuse for removal from the squad or banning from the forum or squad site. The release date was originally planned for the first quarter of 2014. This is an addon for the game IL-2 Sturmovik 1946, which adds a fictional version of the F-86 Sabre Jet fighter to this game, the F-86J. Worth the effort, even if you ‘dumb it down’ by using auto engine management, ect. Hi, firstly thanks for all your hard work I've been using ftnoir with my sim(il2 cliffs of dover) for over a year with great success! I got it working with this flying il2 cliffs of dover.

[zhenning]

李振宁工作室OFFICIAL: (trans)

To: 25 year old Li Zhenning

letter trans.

[happykjd]

[dohyoniee]

[⚡]

[BAE173] CONCEPT PHOTO #01

#한결 #HANGYUL

1st Mini Album

[INTERSECTION : SPARK]

2020.11.19 6PM

Coming Soon

#BAE173 #비에이이173

#INTERSECTION_SPARK #Debut

[bandlucy]

[201104] bandlucy_mystic twitter update:

(D-9) “Snooze” group photos

[campusassaultpolicyforum-blog]

When Rape Isn’t a 4-Letter Word: How New York is Fighting Back Against Campus Assault

By Jacklynn Blanchard, Lauren Szczesny and Paige Allen

 As the summer wanes and the leaves begin to change color, new flocks of teenagers will descend upon campuses across America. There they will take up residency in dorms, explore their identities, and begin to etch out their lives as college students. These young adults will be expected to fend for themselves – sometimes for the first time in their lives – and certainly, mistakes will be made. Every year splashy headlines tell stories of wild frat parties, cheating scandals, and student activism gone awry, but these are just a cursory glance of the college experience. While for some college will be remembered fondly, for others the indelible marks of trauma may overshadow an otherwise carefree and happy time.

Campus sexual assault has always been and remains an epidemic. It is estimated that 20% of women will experience a sexual assault in college (Donde, Ragsdale, Koss, & Zucker, 2018). In 2019, that amounts to roughly 33.6 million women annually in the United States (Statista, 2017). To put that into context, that is more than double the number of cancer survivors currently living in the US (NCI, 2018). While the sexual assault victims’ movement has gained traction culturally, acknowledging the problem exists only goes so far in protecting women and helping them to get the justice they deserve.

While the current Me Too movement has brought sexual assault to the forefront of the women’s movement and in turn the women’s movement to the forefront of American consciousness, campus sexual assault justice has been a slow moving train. In the 1980s, Title IX was updated to include sexual assault (Lieberwitz et al., 2016). In 1990, the Cleary Act was passed after a young woman was raped and murdered in her residence hall (Lieberwitz et al., 2016). In 2011, the Obama administration specifically outlined how universities should handle campus sexual assault (Ali, 2011, p.1-19). In 2017, the Trump administration rolled these guidelines back (DeVos, 2017). This slow action by both the government and American culture has contributed to an uncertain environment in which to discuss sexual assault. We are simply not comfortable talking about it, and as a result little has changed for women on campus. Women are encouraged to share their stories but are met with mixed messages from both government and culture when they do so. A study by the National Center for Educational Statistics found the number of reported campus sex crimes increased by 205% between 2001 and 2014 (2017, pp.11). Despite this alarming increase, 89% of 11,000 colleges reported zero rapes in 2014 (Becker, 2017). More women are reporting, but it’s not leading to institutional action. If in our society we can’t have frank conversations about the problem, how can we expect colleges take corrective action when reporting anything above 0% could mean a damaged reputation or a loss of funding? What does that say about our national values?

While both government and contemporary culture promote valuing women, there is a hesitance to admit that women who are victims of sexual assault have been failed by the laws in place and by a society that has not made dismantling oppressive gender dynamics a priority. The evidence in reporting increases should be enough of a catalyst to pass protective legislation, but the unfortunate reality is evidence is not enough on its own. The hardest work is in a meaningful shift of our national values. The Me Too movement has put the spotlight to sexual assault, but the federal government has failed to tighten the laws that protect women – in Secretary DeVos’s case, these laws have even been loosened (Jackson, 2017).  

Thankfully, New York State (NYS) has stepped up as a leader in the charge to protect women on its college campuses. New York’s Enough is Enough law echoes the sentiments of women everywhere. Can New York function as a model for the rest of the country? We think so. While its system is imperfect, it is a huge step forward in not just shining a light on the issue, but actually attempting to rectify one of the greatest threats to women in our time.

 What is New York doing? Enough is Enough

In 2015, Governor Andrew Cuomo signed Enough is Enough into law. This legislation asserts that students attending college have the right to an educational environment that is safe, healthy and free from discrimination and violence (Governor’s Press Office, 2015). The law was created to address sexual assault, dating violence, domestic violence, and stalking on college campuses (Governor’s Press Office, 2015).

What is it?

Enough is Enough creates:

·       A statewide definition of affirmative consent as a knowing, voluntary and mutual decision among all participants to engage in sexual activity;

·       A statewide amnesty policy encouraging students to report incidents of sexual assault or sexual violence by granting immunity for certain campus policy violations such as drug and alcohol use when reporting sexual assault;

·       The students’ bill of rights which informs sexual assault victims of their legal rights and available resources, and requires campuses to distribute that information;

·       Training requirements for administrators, staff and students on sexual assault and related remedies (during orientations);

·       A campus requirement to annually submit to the State Education Department reports of sexual violence, which is made publicly available;

·       The sexual assault victims’ unit within the NYS police which specializes in responding to sex assaults and related crimes as well as trains local law enforcement appropriately; and,

·       Requirements for first responders to notify survivors of their rights to contact outside law enforcement (Governor’s Press Office, 2015).

Remember the victims

Victims of sexual violence have historically been subjected to blame, suspicion, and outright disdain. Campuses have swept reports under the rug, and retaliation has driven some victims to drop out or attempt suicide (Dick, 2015). Under Enough is Enough, victims have the right to:

·       Decide whether to report to university police/campus security, local law enforcement, and/or state police;

·       Report the incident to their institution and be protected by the institution from retaliation for reporting an incident; and,

·       Receive assistance and resources from their institution (Governor’s Press Office, 2015).

 Why is Enough is Enough different?

Enough is Enough differs from previous campus sexual assault initiatives because it not only applies to publicly-funded colleges, it also includes private institutions. Therefore, no students are left behind. This legislation also creates a uniform definition of consent. The affirmative consent policy does not discriminate, even if the victim was under the influence, and consent can be revoked at any time during the encounter. Silence does not equal consent. This law underpins the value of women and acknowledges historic gender dynamic imbalances that need to be addressed to move forward as a more just society. Institutionalizing a new definition of consent helps to rectify the historic power imbalance that exists in sexual situations. New York responded to the plethora of evidence that young women were not safe, recognized the failure of the laws in place, and forced an uncomfortable conversation about this epidemic.

University at Albany’s Advocacy Center

The State University of New York at Albany (UAlbany) even went so far as to create the Advocacy Center for Sexual Violence. We talked to its director, Carol Stenger, to gain insight into her work and how Enough is Enough works in practice. Carol, in conjunction with the Title IX Office, developed trainings aimed at freshman orientation. The idea behind these trainings is to underscore the importance of consent and make it clear that sexual assault is taken seriously at this school. The advocacy center offers students a safe, discreet, and comfortable space to discuss an extremely traumatic event, and to receive compassionate guidance through whatever justice process they pursue. It’s a place to learn and it’s a place to be heard. The underlying message to young women is: you are valued.  

    References:

Ali, R. (2011, April 4). Dear Colleague [Letter]. The United States Department of Education Office of Civil Rights. Retrieved from

https://www2.ed.gov/about/offices/list/ocr/letters/colleague-201104.pdf

Governor’s Press Office. (2015). Governor Cuomo launches “Enough Is Enough” public awareness campaign to educate students on new law combating sexual violence on college campuses. Retrieved 26 April 2019 from https://www.governor.ny.gov/news/governor-cuomo-launches-enough-enough-public-awareness-campaign-educate-students-new-law

Jackson, C. (2017, September 22). Dear Colleague [Letter]. The United States

Department of Education Office of Civil Rights. Retrieved from

https://www2.ed.gov/about/offices/list/ocr/letters/colleague-title-ix-201709.pdf

Lieberwitz, R.L., Jaleel, R., Kelleher, T., Scott, J.W., Young, D., Reichman, H., . . . (2016). The History, Uses, and Abuses of Title IX. AAUP. Retrieved from https://www.aaup.org/file/TitleIXreport.pdf

National Cancer Institute. (2018, April 27). Cancer statistics. Retrieved from

https://www.cancer.gov/about-cancer/understanding/statistics

Statista. (2019). Total population of the United States 2010-2024, by gender. Retrieved from https://www.statista.com/statistics/737923/us-population-by-gender/

Stenger, C. (2019, April 15) Interview with Carol Stenger.

Students' Bill of Rights. University at Albany. Retrieved from

https://system.suny.edu/sexual-violence-prevention-workgroup/policies/bill-of-rights/

[drippindiary]

‪[📢]‬ 201104

‪Upcoming Schedule | DRIPPIN On Mcountdown‬✨ ‪📌On 5 November 2020‬

‪MCOUNTDOWN Ep.689 Line up‬ ‪다크비/DRIPPIN/D-CRUNCH/마마무(MAMAMOO)/MONSTA X/박지훈/베리굿/VERIVERY/bcalm&마독스/SECRET NUMBER/CIX/AB6IX/위클리(Weeekly)/이달의 소녀/장우혁/TOMORROW X TOGETHER/TWICE(트와이스)/펜타곤/P1Harmony/홍진영‬

[onlinefriednoodles]

Pursuit in Mobility - Reviews and Comparisons of selected Architectural Exhibition

*This is a course assignment (´・ω・`)

*This is a course assignment (´・ω・`)

*This is a course assignment (´・ω・`)

1. Introduction

1.1 Overview

When people talk about Modern Architecture, the International Style and the related Weissenhof Estate (German: Weißenhofsiedlung) are among the inevitable topics. The housing showcase exhibition held in the suburb of Stuttgart with 21 buildings has caused endless discussions about the housing for the new era with new space concepts and technologies. Nevertheless, a large group of designers are trying to stimulate similar studies in today’s oriental society. The House Vision, held continuously in 2013, 2016 and 2018, is a series of architectural exhibitions curated by Japanese well-known industrial designer Kenya Hara, where in each exhibition famous architects and manufactures from Japan and China will collaborate to design and construct 10 to 12 small structures on given sites. As its name indicates, the exhibitions aim to envision the possible forms of housing in the future, especially taking the urging social problems of the two regions into consideration.

Noting the impact of these exhibitions, no one would simply regard them as building technology expos. Reading this essay of reviewing 3 selected cases, readers could have a general understanding of the topics of Housing in the field of architecture, and explore the changes of focus on housing along the history of Modernization and Urbanization.

1.2 Backgrounds

To understand the significance and influence of an exhibition, one must understand the social and cultural causes behind it. First let us look at the cities that held these exhibitions, and the politics that shape the exhibitions into their specific forms.

The city of Stuttgart is the capital and at the same time the largest city of the state of Baden-Württemberg in Germany. Unlike many would think, Stuttgart was described “had little preparation for taking on a large-scale housing program after the war.”[1] Before World War I the city has a population of almost 300,000, with a relatively low demand on housing. It had not bought enough land for massive development, which means at that time houses in Stuttgart were mainly scattered and small. But at the end of the war, the situation changed rapidly: “…the drop in the production of housing during the war, the return of veterans, and the increase in the number of marriages had produced a housing shortage…” [2] Driven by the then mayor Karl Lautenschlager and other suitable social conditions, the city council aimed to make Stuttgart as the “the rival of Frankfurt… the superior of Karlsruhe… the political and economic focal point of southwest Germany… a cultural center. ” [3] Because of that conceived the city the idea of a large housing program. However the municipal administration, the city council, the academics and other related organizations were nearly all holding objections to the Werkbund at first, under dubiousness “about the cost, style, and cosmopolitan character of the enterprise.”[4] It is said after a series of long, tiring and tedious negotiations finally did the council approve the housing program as a specimen exhibition with Mies’ planning.

When it comes to Tokyo and Beijing, the story is totally different. Opposite from Stuttgart, these two capital cities are world-famous metropolitans from the very beginning of 21st century. Needless to state that China has now the world’s largest population, and Beijing in the end of 2017 has a population of permanent residents of over 21.7 million [5]. Unlike the declining of population over the whole Japan, Tokyo is actually gaining a huge amount of population every year and finally get over the point of 13.8 million in 2018. [6] Both cities are like the black hole sucking all the capital, labor resources and cultural creativity from all over the countries. But the rapid growth is not equal to a young population; the two countries are suffering from serious aging problem, especially Japan. With no doubt, figuring out a way to satisfy the horrifying housing demand has always been one of the top issues in both cities, and apparently it is one of the fundamental reasons that the two cities become partnership in holding the new international housing exhibition.

The needs to industrial transformation and to perform as leading participants in industry is as well the important intrinsic driving force for the exhibitioners. Kenya the main curator, has mentioned so many times in different occasions that he wonders the future of Japanese manufacturing industry. In the closing remarks of House Vision 1, he wrote:

“Benefit from these experiences, I started to think, at the interchange of mature technologies and aesthetical senses, what is the possibility of Japanese industry?” [7]

As one of the leading industrial designers that gave birth to the unique style of Muji, he and his partner, a famous interdisciplinary architect called Tsuchiya Sadao, began to use housing as a starting point to inspire industry of all categories, and they were not satisfied by restricting the exploration within Japan.

“In 2011 we started to expand to the other countries in Asia. Not to export the housing industry of Japan, but to think about futures of every country as friends. ” [8]

Of course the potential enormous profit has never been excluded from the activities, but they did succeed in evolving Asia and play as leaders. The not-yet-formed exhibition soon turned to a series of Asian-wide seminars; architects and the architecture academy in China almost immediately showed great interest in becoming main participants. Shortly in 2012 the committee came to the consensus that 1-to-1-scale housing exhibitions were the best way to integrate the designers and the industry, the same conclusion as the Werkbund. Finally in 2013 the joint efforts flourished and the first House Vision in Tokyo was held successfully.

1.3 Mobility

Intriguing and contrary from public perceptions, that house or home is a stable haven full of inclusiveness that always wait you back, architects working at the front line often have the tendency to build houses with Mobility. As well acknowledged, Le Corbusier, one of the most famous exhibitioners in the Weissenhofsiedlung, had avid interest in cars, one of the most high-tech and public-affordable transportation in his time, and exactly from which he came up with the inspiration of making his entries “a sort of sleeping and dining car combined.” [9] He described the scene of eating in a “little cabdrivers’ diner” with his partner, Jeanneret:

“…a bar (of zinc), kitchen in the back, a gallery which divided the height of the room; the front opened out toward the street. One fine day they discovered this place and noticed that here all the elements were present that were necessary for the organization of a dwelling house. Simplification of light sources; only one window at each end; two transverse bearing walls, a flat root above— a box which could really be used as a house.” [10]

Thus the project had come with the famous photo of a fashionable lady standing in front of the house with a glorious Mercedes-Benz. Although the building itself is not movable at all, mobility is no doubt a core concept of the entry. Seemed destined to inherit the natural pursuit for mobility, one of the entries in the 2013 House Vision in Tokyo, a collaboration project by Sou Fujimoto and Honda tried to use cars as the key solution for housing, with a pretty straightforward name: House of Mobility and Energy.

In 2018 House Vision in Beijing, Mobility again changed its adaption; LI Hu and Xiaomi even extended the territory to Mars. They created a Mars Case, as an experiment to discover the future life in extreme environment with spiritual comfort. This time, house itself becomes the subject of moving around.

Taking Mobility as one of the key terms throughout the stories of the exhibitions, in the further discussions, a closer review of the housing qualities of the three selected projects will be made, to examine how successfully these projects responded to the very notion of Mobility.

Pommer, R., & Otto, C. F., Weissenhof 1927 and the modern movement in architecture. (Chicago: University of Chicago Press, 1991), 16.

Pommer, R., & Otto, C. F., Weissenhof 1927 and the modern movement in architecture. (Chicago: University of Chicago Press, 1991), 16.

Pommer, R., & Otto, C. F., Weissenhof 1927 and the modern movement in architecture. (Chicago: University of Chicago Press, 1991), 17.

Pommer, R., & Otto, C. F., Weissenhof 1927 and the modern movement in architecture. (Chicago: University of Chicago Press, 1991), 19.

Communiqué of the National Bureau of Statistics of People’s Republic of China on Major Figures of the 2010 Population Census (No. 1), retrieved from: http://www.stats.gov.cn/english/NewsEvents/201104/t20110428_26449.html

Capital’s Population Growth Rata has achieved 6 years flail first [Japanese], retrieved from: https://www.nikkei.com/article/DGXMZO43680170S9A410C1L83000/

Kenya HARA, Executive committee of HOUSE VISION, HOUSE VISION 2013 TOKYO EXHIBITION (China: CITIC Press Corporation, 2018), 188.

Kenya HARA, Executive committee of HOUSE VISION, HOUSE VISION 2013 TOKYO EXHIBITION (China: CITIC Press Corporation, 2018), 174.

Pommer, R., & Otto, C. F., Weissenhof 1927 and the modern movement in architecture. (Chicago: University of Chicago Press, 1991), 84.

Kirsch, K., Kirsch, G., & Britt, D., The Weissenhofsiedlung: Experimental housing built for the Deutscher Werkbund, Stuttgart (New York: Rizzoli, 1927), 100.

[take-judge]

セルメチニブにより小児神経腫瘍が縮小／NCI（米国国立がん研究所）プレスリリース（「ブログ～がん研究の動向～」は誤り）（筆者が翻訳）

免責事項

本記事には一般的な知識についての記載はありますが、利用者の方の個々の問題に対して医学的またはその他のアドバイスを提供するものではありません。筆者は本記事の内容の正確性の確保に努めておりますが、本記事の利用によって、利用者の方に何らかの損害が生じた場合でも、一切の責任を負うものではありません。

 筆者は日本癌医療翻訳アソシエイツの下で、NCIプレスリリース「Early-phase trial demonstrates shrinkage in pediatric neural tumors」（[1]）を翻訳した。そして、「セルメチニブにより小児神経腫瘍が縮小／NCI（米国国立がん研究所）プレスリリース（「ブログ～がん研究の動向～」は誤り）」（[2]）が公開された。

 上記の記事の元になる文献は、New England Journal of Medicine誌2016年12月29日号に発表された記事「Activity of Selumetinib in Neurofibromatosis Type 1–Related Plexiform Neurofibromas」（[3]）とその日本語アブストラクトである「神経線維腫症 1 型に関連する叢状神経線維腫におけるセルメチニブの活性」（[4]）である。

 神経線維腫症 1 型（neurofibromatosis type 1：NF1）（[5]，[6]，[7]，[8]）は神経線維腫症（[9]）の病型の1つで、1882年にドイツの病理学者Friedrich      Daniel von Recklinghausen（以下敬称略）が最初に報告したため、レックリングハウゼン病とも呼ばれている。最も有病率が高い神経線維腫症で、2500～3000人に1人の頻度で発生する。罹患率に性差や人種差はない。日本では指定難病の1つになっている。NF1は遺伝性疾患で、NF1の半数以上は散発的に発生する。その確率は約1/10,000である。

1990年、米国国立衛生研究所（NIH）現所長であるFrancis S. Collins氏（医学博士、当時はミシガン大学遺伝医学長）主導のチームとRay White氏（ユタ大学）主導のチームがNF1に関する疾患遺伝子を最初に同定した。なお、その遺伝子はNF1遺伝子で、17番染色体長腕（17q11.2）に位置し、ゲノムDNAは350kbに及ぶ巨大な遺伝子である。そのタンパク産物がニューロフィブロミンである。なお、ニューロフィブロミンはRAS蛋白の機能を負に制御し、細胞増殖を抑制する。

主な症状は6個以上のカフェ・オ・レ斑や神経線維腫である。

カフェ・オ・レ斑の形は長円形のものが多く、丸みを帯びたなめらかな輪郭を呈している。大きさは小児で5mm以上、成人で15mm以上である。

皮膚の神経線維腫は思春期頃より全身に多発する。この他に末梢神経内の結節性叢状（蔓状）神経線維腫（20%に合併）やびまん性叢状（蔓状）神経線維腫（10%）がみられることもある。前者は後者内に生じることが多いが、それとは無関係に皮下や腹腔内に数珠状に多発する場合もある。

NF1小児患者は最大50％の確率で叢状神経線維腫を発症する。その大部分は激痛や身体障害をもたらしたり、外観を損なったりする可能性がある。幼児期に診断されてから後、思春期を迎えるにつれて急速に増大する。

その他の症状には、皮膚病変（例．雀卵斑様色素斑、大型の褐色斑）、骨病変（例．頭蓋骨・顔面骨の骨欠損、四肢骨の変形・病的骨折、脊柱・胸郭の変形）、眼病変（例．虹彩小結節、視神経膠腫）、脳脊髄腫瘍（例．神経膠腫）などが認められる。

カフェ・オ・レ斑や雀卵斑様色素斑等の色素斑に対する治療法では、レーザー機器による治療が有効な場合もあるが、効果は一定ではない。

神経線維腫に対する治療は外科的切除が第1選択になる。しかし、外科的に腫瘍を完全切除することはほぼ不可能であり、切除不十分な腫瘍は再び増大する傾向にある。

神経線維腫症 2型（neurofibromatosis type 2：NF2）はNF1と名称は似ているが、原因や症状が異なる（9，[10]，[11]）。

 セルメチニブはアストラゼネカ社が製造している経口カプセル剤で、RASシグナル伝達経路の一部であるMEK1/2（[12]，[13]）を選択的に阻害するプロテインキナーゼ阻害剤である（[14]）。

セルメチニブは進行胆道がん（14）、再発低グレード漿液性卵巣がん・腹膜がん（[15]）、並びに、小児の再発または難治性の低グレードグリオーマの一部（[16]）に対して有効である。

セルメチニブは米国では2016年12月28日の時点で米国食品医薬品局（FDA）の承認を受けていない。一方、日本では第1相試験の段階である（[17]）。

 Collins氏らとRay White氏らの研究から、RASシグナル伝達経路の脱制御がNF1発生の原因になる可能性が最も高いことが示された。

RAS関連シグナル伝達経路を標的とする多くの薬剤がNF1患児に対する第1、2相臨床試験で調べられてきたが、いずれも不本意な結果に終わった。また、現時点ではNF1に関連する大型叢状神経線維腫の有効な治療法は存在しない。そこで、セルメチニブへの関心が生じた。

 こうした背景から、Brigitte C. Widemann医師［米国国立がん研究所（NCI）小児腫瘍学分野長代理］は、セルメチニブの多施設第1相臨床試験を主導した。

本臨床試験は、NCIがん研究センターおよびがん治療評価プログラム、小児腫瘍財団、アストラゼネカ社、並びに、小児腫瘍財団及び神経線維腫症治療迅速化プログラムからの助成金からの支援を受けた。

 本臨床試験の主要目的は、NF1および手術不能な叢状神経線維腫を有する患児におけるセルメチニブの毒性および安全性を評価することである。

本臨床試験登録は2011年9月に開始され、患児24人（男児13人、女児11人）が本臨床試験に参加した。

セルメチニブは1日2回継続投与され、治療期間中央値は 30カ月に及んだ。

患児の大多数は現在もなおセルメチニブの継続投与を受けており、中には5年間も受け続けている者もいる。

セルメチニブによる毒性の大部分は軽度で、長期にわたる継続投与による患児の発育や健康全般に関する副作用は認められなかった。

部分奏効（腫瘍容積の20％以上減少）が70％超の患児に認められた。

奏効は、かつて毎年20％超の割合で増大していた腫瘍でも、非進行性病変でも認められた。腫瘍縮小は約2年間維持された。2016年初頭時点で、どの患児にも病勢進行は認められなかった。

腫瘍に関連する疼痛の減少、運動機能の改善、および外観の回復などの臨床症状改善に関する事例が認められた。

その一方で、一部の患者でセルメチニブに対する反応の低下（緩徐に腫瘍が再増大する）が、特に減量後に認められた。

 また、Widemann氏はNF1に関連する神経線維腫マウスを使用する実験も主導した。

この実験から、神経線維腫におけるMEKの機能が阻害されること、及び、MEK阻害はセルメチニブ投与の2時間後に減弱することが確認された。

なお、神経線維腫マウスには定期的にセルメチニブが投与され、現在もなお腫瘍反応が示されている。このことから、限定的だがMEK阻害により、神経線維腫において腫瘍が縮小する可能性がある。

 また、セルメチニブに反応しなくなる腫瘍の特定を目的とする臨床試験がさらに必要となる。

NCIは現在、成人NF1患者に対するセルメチニブに関する現行の第2相試験に出資しているが、この試験で考えられるセルメチニブに対する耐性の機序に関する情報が示される可能性がある。

一方、小児を対象とする大規模第2相試験は患者を登録中で、小児に対するセルメチニブ投与の有効性の確立を促す可能性がある。この大規模試験で、腫瘍容積の測定、叢状神経線維腫に関連する外観、疼痛、生活の質、及び、機能に関するセルメチニブの効果の評価も実施されている。

一方、日本ではNF1に関する臨床試験が2件実施されている。なお、いずれも外用薬の効果等を評価するものである（[18]，[19]）。

 執筆後記

本記事の執筆時は、NF1やセルメチニブの解説の執筆に苦労した。理由は、NF1を含む神経線維腫症やセルメチニブをよく知っている人は少ないので、これらを詳しく解説する必要があるためである。

また、日本におけるNF1に関する臨床試験の情報検索にも苦労した。理由は、臨床試験に関する情報を知っている人も少ないためである。

参考文献1を翻訳している間に（その結果が参考文献2）、セルメチニブがNF1患者にとっての希望になるという確信を筆者は抱いた。

セルメチニブが一日も早く米国だけでなく、日本でも承認されることを筆者は切望する。

余談だが、拙翻訳である参考文献2がオンコロ　がんと・ひとを・つなぐ（[20]）やDoctor’s Gate（[21]）でも紹介されたことを、筆者は嬉しく、且つ、有難く思う。

参考文献

[1]　National Cancer Institute（NCI）．“Early-phase trial demonstrates shrinkage in pediatric neural tumors”．NCI　ホームページ．News & Events．Press Releases．2016年12月28日．https://www.cancer.gov/news-events/press-releases/2016/selumetinib-shrinks-pediatric-tumors,（参照2017年02月03日）

[2]　一般社団法人　日本癌医療翻訳アソシエイツ（JAMT）．“セルメチニブにより小児神経腫瘍が縮小　NCI（米国国立がん研究所）ブログ～がん研究の動向～”．海外がん医療情報リファレンス　トップページ．記事　トップページ． 2017年01月30日．https://www.cancerit.jp/53933.html,（参照2017年02月03日）

[3]　Widemann BC, et al.  Activity of Selumetinib in Neurofibromatosis Type 1 Plexiform Neurofibromas. December 8, 2016.  NEJM. DOI: 10.1056/NEJMoa1605943．http://www.nejm.org/doi/full/10.1056/NEJMoa1605943,（参照2017年02月03日）　

[4]　株式会社　南江堂．“神経線維腫症 1 型に関連する叢状神経線維腫におけるセルメチニブの活性”．南江堂　ホームページ．NEJM日本国内版オンライン　トップページ．目次．目次一覧．2016年．December 29, 2016 Vol. 375 No. 26．http://www.nejm.jp/abstract/vol375.p2550,（参照2017年02月03日）

[5]　公益社団法人　日本皮膚科学会．“神経線維腫症1型（レックリングハウゼン病）の診断基および治療ガイドライン”．会員・医療関係の皆様　ホームページ．ガイドライン・指針．ガイドライン．さ行．https://www.dermatol.or.jp/uploads/uploads/files/guideline/1372913643_3.pdf，（参照2017年02月04日）　

参考文献

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[7]　公益財団法人　難病医学研究財団／難病情報センター．“神経線維腫症Ⅰ型（指定難病34）”．難病情報センター　ホームページ．診断・治療指針（医療従事者向け）．2015年02月13日．http://www.nanbyou.or.jp/entry/3992, （参照2017年02月03日）

[8]　 GeneReviews Japan運営事務局．“神経線維腫症1型(Neurofibromatosis 1)”．GeneReviews 日本語版　トップページ．GRJ疾患リストについて．2014年03月18日．http://grj.umin.jp/grj/nf1.htm, （参照2017年02月07日）

[9]　MSD株式会社．“神経線維腫症”．MSD マニュアル　プロフェッショナル版　ホームページ．19. 小児科．神経皮膚症候群．http://merckmanual.jp/mmpej/sec19/ch283/ch283e.html,（参照2017年02月03日）

[10]　公益財団法人　難病医学研究財団／難病情報センター．“神経線維腫症Ⅱ型（指定難病34）”．難病情報センター　ホームページ．病気の解説（一般利用者向け）．2014年12月29日．http://www.nanbyou.or.jp/entry/123, （参照2017年02月08日）

[11]　公益財団法人　難病医学研究財団／難病情報センター．“神経線維腫症Ⅱ型（指定難病34）”．難病情報センター　ホームページ．診断・治療指針（医療従事者向け）．2016年10月20日．http://www.nanbyou.or.jp/entry/275, （参照2017年02月08日）

[12]　バスティアンD.ゴンパーツ・イスブラントM.クラーマー・ピーターE.R.テイサム　著．上代淑人・佐藤孝哉　監訳“12.3.2　Rasシグナル伝達経路”，“12.3.3　RasからMAPキナーゼへ，そして転写因子の活性化へ”．シグナル伝達　第2版：生命システムの情報ネットワーク．第2版第1刷，株式会社　メディカル・サイエンス・インターナショナル，2011年12月10日発行，p. 280-288

[13]　関西医科大学　附属生命医学研究所　生体情報部門．“MAPK経路とは”．関西医科大学　附属生命医学研究所　生体情報部門　トップページ．Reseach．http://www3.kmu.ac.jp/bioinfo/mapk0.html,（参照2017年02月08日）

[14]　株式会社　日経BP．“進行胆道癌の治療薬としてMEK1/2阻害剤selumetinibが有望”．日経メディカル　トップページ．癌．日経メディカルONCOLOGY．日経メディカルOncologyニュース．月別アーカイブ．2011年04月の記事一覧．2011年04月27日．http://medical.nikkeibp.co.jp/leaf/all/search/cancer/news/201104/519551.html，（参照2017年02月09日）

[15]　株式会社　日経BP．“再発低グレード漿液性卵巣癌、腹膜癌に低分子MEK阻害剤selumetinibが有効な可能性【AACR2012】”．日経メディカル　トップページ．癌．日経メディカルONCOLOGY．日経メディカルOncologyニュース．月別アーカイブ．2012年04月の 記事一覧．2012年04月03日．http://medical.nikkeibp.co.jp/leaf/all/search/cancer/news/201204/524284.html，（参照2017年02月09日）

[16]　株式会社　日経BP．“小児の再発または難治性低グレード星状細胞腫にAZD6244が有望である可能性【WFNO-SNO2013】”．日経メディカル　トップページ．癌．日経メディカルONCOLOGY．日経メディカルOncologyニュース．月別アーカイブ．2013年11月の 記事一覧．2013年11月25日．http://medical.nikkeibp.co.jp/leaf/all/search/cancer/news/201311/533771.html，（参照2017年02月10日）

[17]　日本製薬工業協会．“アストラゼネカ株式会社”．製薬協　ホームページ．くすりについて．新薬・治験情報．開発中の新薬．会社一覧．2016年11月24日．http://www.jpma.or.jp/medicine/shinyaku/development/com0030.html,（参照2017年02月10日）

[18]　国立保健医療科学院．“神経線維腫症1型の治療法のない巨大なびまん性神経線維腫に対するラパマイシン外用薬の安全性と有効性探索のためのパイロット試験”．国立保健医療科学院　トップページ．臨床研究情報ポータルサイト　トップページ．関連する治験情報　「神経線維腫症」での検索結果．2016年04月07日．http://rctportal.niph.go.jp/detail/um?trial_id=UMIN000015081,（参照2017年02月11日）

[19]　国立保健医療科学院．“神経線維腫症Ⅰ型を対象としたOSD-001の安全性と有効用量を推定するプラセボ対照二重盲検無作為化群間比較試験”．国立保健医療科学院　トップページ．臨床研究情報ポータルサイト　トップページ．関連する治験情報　「神経線維腫症」での検索結果．2016年04月05日．http://rctportal.niph.go.jp/detail/um?trial_id=UMIN000021030,（参照2017年02月11日）

[20]　株式会社　クリニカル・トライアル．“セルメチニブにより小児神経腫瘍が縮小”．オンコロ　がんと・ひとを・つなぐ　トップページ．ニュース．ピックアップ．2017年02月01日．https://oncolo.jp/pick-up/news614,（参照2017年02月11日）

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