父なし日比混血児（ジャピーノ）が今日なんと１０万以上！ 残されたフィリッ
ピン母子家庭が生活や病気に苦しんでいます。いいかえれば、１０万以上の（自
分の実質的な「妻子」を顧みぬ）「無責任な」日本人男性が日本に（死んだ振り
をしたり、姿をくらまして）潜んでいるということです。（日本男子として）と
ても恥ずべきことであるばかりではなく、ジャピーノ孤児（あるいは母子家庭）
に大変同情します。彼らは英語が話せるので、日本ばかりではなく、豪州にも就
職のため移民して、現在の貧しい (窮乏) 生活から脱出して、「人生を立て直す」
ことができるはずです。
戦後、アメリカ駐留軍の将校や兵士たちが、（日本、韓国、台湾、フィリピンな
どのアジア諸国で）原住民の女性と性関係を結び、同様に無数の「父なし混血孤
児（アメラジアン）」を無責任にも、現地に残したまま、ゆうゆうと母国アメリ
カに帰国していった恥ずべき歴史があります。その混血児たちを救おうとして、
孤軍奮闘した少なくとも２人の偉大な女性がいます。その一人は、不朽の名作
「大地」を書いたノーベル作家、パール・バック女史（１８９２ー１９７３）で
す。彼女は自分の私財を投じて、これら孤児の養子養女斡旋をするために「ウエ
ルカム・ハウス」や「パール・バック財団」を設立し、死ぬまでその活動を続け
ました （詳しくは、「パール・バック伝：この大地から差別をなくすために」
の下巻を参照されたし）。
もう一人は、神奈川県大磯にある別荘の敷地内に「エリザベス・サンダース・ホー
ム」を設立して、２千人近くの混血孤児の養育をした澤田美喜女史（１９０１ー１９８０）
です。澤田女史（旧三菱財閥、岩崎家の娘、初代国連大使「澤田廉三」の妻）の社会
福祉事業に感銘したセントルイス生まれの（「レジオン・ドヌール勲章」に輝く）
有名な黒人（混血）女性ジャズ歌手／ダンサー、ジョセフィン・ベーカー（１９
０６ー１９７５）は、合計１２人ほどの色とりどりのアメラジアンを（「虹鱒の
子供たち」と称して）自分の家庭に養子として引き取ると共に、わざわざフラン
スから来日して、日本各地で連日ジャズ／ダンスショーを開催し、その興行収益
を全部「エリザベ・スサンダース・ホーム」に寄付したそうです。
以後半世紀ほどの歳月が経過し、日本人男性（特に弁護士）の有志の間に、「ジャピー
ノ」の救済をめざすＮＰＯ「新日系人ネットワーク」が２００６年に設立されました。
現地で日本語学校を直接経営し、新日系人母子に当面「無料で受講」させて、
日本での就学・就労に備えて１５０時間を修了させています。日本語能力検定四
級のレベルを目指して、毎週３回の授業を行い「ひらがな」「カタカナ」の読み書
きと日常会話をこなします。詳しくは、ウエッブサイト http://www.shinnikkei.net
を訪問されたし。
2008年12月28日日曜日
2008年12月21日日曜日
2016 US Presidential Election: Caroline Kennedy as the Democrats Candidate
Promising the "Change", Barack Obama won a landslide victory at the 2008
US presidential election against the old Republican candidate John McCain.
Obama will restore the lost world popularity caused by Iraq War and the
current financial crisis through the withdrawal of US forces from Iraq
and a series of reforms in US financial sector and Auto/Car industry,
hopefully during the coming two terms (2009-2017). There is no doubt that
he will run for the 2012 US presidential election and be re-elected for
his second term. There is a huge vacuum in the Republican side, and no
Republican candidate can beat the full speed Obama.
Thus, naturally our focus on the US politics would be shifted to the 2016
US election, in which Obama will not allowed to run for a third term, even
if he would be extremely successful during the first two terms, as FDR
who served US presidency for four terms. Who would run the presidential
election as the Democrats side in 2016? It is rather unlikely that Hillary
Clinton would run again, because she would be around 68 then, and would be too
old to become the first woman US President. That is why she took a cabinet
job as the Secretary of State which appears to be her last political ambition
to be fulfilled. So the case seems to be against her.
There is a strong rumor that Caroline Kennedy (51), an attorney and the
only surviving child of John Kennedy (JFK), seeks the US Senator seat in
New York State which Hillary Clinton occupied since 2001. Caroline strongly
supported Obama's presidential campaign, representing her Kennedy Clan led
by Ted Kennedy. This Senator seat was occupied by her uncle, Bobby Kennedy,
from 1965 till he was assassinated toward the end of 1968 US presidential
election. After her father JFK was killed in 1963, two younger brothers of
JFK ran for the US President. Bobby Kennedy (RFK) in 1968, and his younger
brother Ted Kennedy in 1980, but unsuccessfully. Caroline could be the last
chance for the Kennedy family to have a second US President.
Although Caroline was not involved in US politics until the 2008 Obama's
presidential campaign, she seems to be quite popular among the US voters,
mainly because of her (Kennedy) family legacy. She has obviously a strong
liberal view as the whole Kennedy family, although she has never expressed
her own political view in public until recently.
There is a significant change in US political tide favoring the idea for
the first female US President, which was enforced by Hillary Clinton, although
the "dark horse" (black American) Obama, snatched her chance, at the last
moment of Democrats nomination in Denver. Hillary was exhausted of both
her money and energy.
Thus, the younger Caroline would have a good chance to represent the "woman"
political power in 2016 election. Her popularity and Kennedy's wealth would
sustain her long election campaign, and there is no more opposing "dark
horse" in the scene and no strong Republican candidate, perhaps except for
the rather silly local governor in Alaska, Sarah Palin (now 44), who served
as the running mate of John MaCain, the VP (vice-president) candidate in
Republican side. Sarah is an "ultra-conservative" and ignorant politician
who thought, can you imagine? that "Africa" were the name of a country,
instead of the black continent. She might be good for governing the remote
northern state of Eskimos, moose and polar bears, but not for the whole United
States or the rest of world.
Caroline graduated from Harvard University and Columbia Law School, while
Obama graduated from Columbia University and Harvard Law School. Her major
expertise has been in NY school education, rebuilding the US education system
to regain their "intellectual" competitiveness. I am sure that the energetic
former "dark horse", Obama family, will give a strong support to the campaign
for both her first NY Senator election in 2010, and US presidential election
in 2016, directly from the White House, using his powerful internet network.
So I wish Caroline all the best with her bold political adventure for the coming
years, to realize the dream of all American women's, as someone said, YES WE CAN!
US presidential election against the old Republican candidate John McCain.
Obama will restore the lost world popularity caused by Iraq War and the
current financial crisis through the withdrawal of US forces from Iraq
and a series of reforms in US financial sector and Auto/Car industry,
hopefully during the coming two terms (2009-2017). There is no doubt that
he will run for the 2012 US presidential election and be re-elected for
his second term. There is a huge vacuum in the Republican side, and no
Republican candidate can beat the full speed Obama.
Thus, naturally our focus on the US politics would be shifted to the 2016
US election, in which Obama will not allowed to run for a third term, even
if he would be extremely successful during the first two terms, as FDR
who served US presidency for four terms. Who would run the presidential
election as the Democrats side in 2016? It is rather unlikely that Hillary
Clinton would run again, because she would be around 68 then, and would be too
old to become the first woman US President. That is why she took a cabinet
job as the Secretary of State which appears to be her last political ambition
to be fulfilled. So the case seems to be against her.
There is a strong rumor that Caroline Kennedy (51), an attorney and the
only surviving child of John Kennedy (JFK), seeks the US Senator seat in
New York State which Hillary Clinton occupied since 2001. Caroline strongly
supported Obama's presidential campaign, representing her Kennedy Clan led
by Ted Kennedy. This Senator seat was occupied by her uncle, Bobby Kennedy,
from 1965 till he was assassinated toward the end of 1968 US presidential
election. After her father JFK was killed in 1963, two younger brothers of
JFK ran for the US President. Bobby Kennedy (RFK) in 1968, and his younger
brother Ted Kennedy in 1980, but unsuccessfully. Caroline could be the last
chance for the Kennedy family to have a second US President.
Although Caroline was not involved in US politics until the 2008 Obama's
presidential campaign, she seems to be quite popular among the US voters,
mainly because of her (Kennedy) family legacy. She has obviously a strong
liberal view as the whole Kennedy family, although she has never expressed
her own political view in public until recently.
There is a significant change in US political tide favoring the idea for
the first female US President, which was enforced by Hillary Clinton, although
the "dark horse" (black American) Obama, snatched her chance, at the last
moment of Democrats nomination in Denver. Hillary was exhausted of both
her money and energy.
Thus, the younger Caroline would have a good chance to represent the "woman"
political power in 2016 election. Her popularity and Kennedy's wealth would
sustain her long election campaign, and there is no more opposing "dark
horse" in the scene and no strong Republican candidate, perhaps except for
the rather silly local governor in Alaska, Sarah Palin (now 44), who served
as the running mate of John MaCain, the VP (vice-president) candidate in
Republican side. Sarah is an "ultra-conservative" and ignorant politician
who thought, can you imagine? that "Africa" were the name of a country,
instead of the black continent. She might be good for governing the remote
northern state of Eskimos, moose and polar bears, but not for the whole United
States or the rest of world.
Caroline graduated from Harvard University and Columbia Law School, while
Obama graduated from Columbia University and Harvard Law School. Her major
expertise has been in NY school education, rebuilding the US education system
to regain their "intellectual" competitiveness. I am sure that the energetic
former "dark horse", Obama family, will give a strong support to the campaign
for both her first NY Senator election in 2010, and US presidential election
in 2016, directly from the White House, using his powerful internet network.
So I wish Caroline all the best with her bold political adventure for the coming
years, to realize the dream of all American women's, as someone said, YES WE CAN!
2008年12月15日月曜日
抗生物質「プロポリス」の抗腫瘍作用および抗炎症作用
ミツバチが、巣箱の幼虫を外敵から保護するために、木の芽や樹液などから作り
出す最古の抗生物質「プロポリス」の抗腫瘍メカニズムの一部が、(我々による)
最近の研究によって、明らかになってきた。
勿論、産地によって、プロポリスの成分が非常に違うので、一般化することはで
きないが、少なくともカフェイン酸フェネチルエステル (CAPE) を主成分とする
ニュージーランド産のプロポリス (例えば、Ｂｉｏ ３０）とアルテピリンＣ (ARC) を
主成分とするブラジル産グリーンプロポリスに限っていえば、両方とも、CAPE あ
るいはARCにより、発ガン性酵素の一種 (キナーゼ) である「ＰＡＫ」の機能を遮
断することが証明された。この「ＰＡＫ」は、ヒトの癌の７割以上の増殖に必要
であり、かつ癌転移および (固形癌の増殖に必須な) 血管新生にも必要である。
従って、上記のプロポリスは、乳癌、前立腺癌、すいぞう癌、大腸癌、脳腫瘍や
ＮＦ(神経線維腫症)、メラノーマ、卵巣癌、子宮癌、MM (多発性骨髄腫) などの
(「ＰＡＫ」依存性の) 腫瘍に良く効くことが予想され、実際これらの癌に優れ
た治療効果をあげつつある。さらに、プロポリスの抗炎症作用も、CAPE あるいは
ARCによることがわかっている。従って、この物質が多く含れているプロポリス製
品は、抗癌作用や抗炎症作用が強いことが予想される。
もう１つ付け加えれば、プロポリスには、従来使用されて来た一連の制癌剤 (主
にDNA毒) と違って、脱毛を起こしたり免疫機能を抑制するという「副作用」がな
いばかりではなく、逆に発毛作用や免疫機能を高める作用があることも一般的に
知られている。従って、極めて安全かつ有効な天然「代替医療」と言えるだろう。
出す最古の抗生物質「プロポリス」の抗腫瘍メカニズムの一部が、(我々による)
最近の研究によって、明らかになってきた。
勿論、産地によって、プロポリスの成分が非常に違うので、一般化することはで
きないが、少なくともカフェイン酸フェネチルエステル (CAPE) を主成分とする
ニュージーランド産のプロポリス (例えば、Ｂｉｏ ３０）とアルテピリンＣ (ARC) を
主成分とするブラジル産グリーンプロポリスに限っていえば、両方とも、CAPE あ
るいはARCにより、発ガン性酵素の一種 (キナーゼ) である「ＰＡＫ」の機能を遮
断することが証明された。この「ＰＡＫ」は、ヒトの癌の７割以上の増殖に必要
であり、かつ癌転移および (固形癌の増殖に必須な) 血管新生にも必要である。
従って、上記のプロポリスは、乳癌、前立腺癌、すいぞう癌、大腸癌、脳腫瘍や
ＮＦ(神経線維腫症)、メラノーマ、卵巣癌、子宮癌、MM (多発性骨髄腫) などの
(「ＰＡＫ」依存性の) 腫瘍に良く効くことが予想され、実際これらの癌に優れ
た治療効果をあげつつある。さらに、プロポリスの抗炎症作用も、CAPE あるいは
ARCによることがわかっている。従って、この物質が多く含れているプロポリス製
品は、抗癌作用や抗炎症作用が強いことが予想される。
もう１つ付け加えれば、プロポリスには、従来使用されて来た一連の制癌剤 (主
にDNA毒) と違って、脱毛を起こしたり免疫機能を抑制するという「副作用」がな
いばかりではなく、逆に発毛作用や免疫機能を高める作用があることも一般的に
知られている。従って、極めて安全かつ有効な天然「代替医療」と言えるだろう。
2008年12月10日水曜日
Oncogenic PAK/ERK-Synapsin-GABA Signaling:
A Common Link in LD of Down Syndrome and NF1
Old drug Pentylenetetrazole (PTZ) and Bio 30 may improve learning and memory
in Down Syndrome (DS) and other LD victims such as NF1 children
Recently Alcino Silva's group at UCLA found that NF1 model of mice which
is associated with memory deficit or LD (Learning Deficit/Disability) is
in part due to the abnormal release of GABA, which is caused by ERK-mediated
phosphorylation of synapsin 1, and a GABA antagonist called picrotoxin can
reverse the LD symptom of NF1 mice.
Interestingly, in 2002 Yasuharu Sasaki's group at Kitasato University in Japan demonstrated that PAK1 phosphorylates synapsin 1 at Ser 603. It is also known that PAK1 activates the kinase ERK through the kinases Raf and MEK.
In other words, abnormal activation of PAK1 in NF1 patients also could cause an excess release of GABA through the phosphorylation of synapsin 1 by either stimulating the kinase Erk or its direct action on Ser 603, and anti-PAK1 drugs such as Bio 30 could improve the impaired learning ability of NF1 children, in addition to suppression of the growth of NF1 tumors such as MPNST.
Similarly, in 2007 a group led by Craig Garner, a director of the Down Syndrome
Research Center at Stanford University, found that an old drug called PTZ
(Pentylentetrazole) improves the impaired learning ability of DS model of
mice. PTZ was once used as an epilepsy drug, and antagonizes GABA as does
picrotoxin.
These findings altogether suggest a common cause, PAK/ERK-synapsin-GABA link,
in LD of DS and NF1.
Thus, US researchers are now considering a clinical trial to test whether PTZ
has a similar effect in humans with Down syndrome or NF1.
Oncogenicity of GABA!
More interestingly, in 2007 Hidewaki Nakagawa's group at Tokyo University
(IMS) found that GABA (gamma-Aminobytyric acid) A receptor is over-expressed
in pancreatic cancers, and GABA promotes the growth of pancreatic cancer
cells by stimulating ERK. Thus, there is an oncogenic vicious cycle of ERK
and GABA which activate each other. Anti-PAK1 drugs that block the PAK1-mediated
ERK activation could suppress this vicious cycle.
Thus, it wouldn't be a great surprise that more than two decades ago, a Japanese
couple of scientists (called Furusawa) at University of Hawaii reported
that PTZ, a GABA antagonist, indeed suppresses the growth of a few cancers
such as LLC (Lewis Lung Carcinoma) xenografts in mice, presumably by blocking
the GABA signaling. By the way, PTZ is an alkaloid from Narcissus flower (水仙)。
in Down Syndrome (DS) and other LD victims such as NF1 children
Recently Alcino Silva's group at UCLA found that NF1 model of mice which
is associated with memory deficit or LD (Learning Deficit/Disability) is
in part due to the abnormal release of GABA, which is caused by ERK-mediated
phosphorylation of synapsin 1, and a GABA antagonist called picrotoxin can
reverse the LD symptom of NF1 mice.
Interestingly, in 2002 Yasuharu Sasaki's group at Kitasato University in Japan demonstrated that PAK1 phosphorylates synapsin 1 at Ser 603. It is also known that PAK1 activates the kinase ERK through the kinases Raf and MEK.
In other words, abnormal activation of PAK1 in NF1 patients also could cause an excess release of GABA through the phosphorylation of synapsin 1 by either stimulating the kinase Erk or its direct action on Ser 603, and anti-PAK1 drugs such as Bio 30 could improve the impaired learning ability of NF1 children, in addition to suppression of the growth of NF1 tumors such as MPNST.
Similarly, in 2007 a group led by Craig Garner, a director of the Down Syndrome
Research Center at Stanford University, found that an old drug called PTZ
(Pentylentetrazole) improves the impaired learning ability of DS model of
mice. PTZ was once used as an epilepsy drug, and antagonizes GABA as does
picrotoxin.
These findings altogether suggest a common cause, PAK/ERK-synapsin-GABA link,
in LD of DS and NF1.
Thus, US researchers are now considering a clinical trial to test whether PTZ
has a similar effect in humans with Down syndrome or NF1.
Oncogenicity of GABA!
More interestingly, in 2007 Hidewaki Nakagawa's group at Tokyo University
(IMS) found that GABA (gamma-Aminobytyric acid) A receptor is over-expressed
in pancreatic cancers, and GABA promotes the growth of pancreatic cancer
cells by stimulating ERK. Thus, there is an oncogenic vicious cycle of ERK
and GABA which activate each other. Anti-PAK1 drugs that block the PAK1-mediated
ERK activation could suppress this vicious cycle.
Thus, it wouldn't be a great surprise that more than two decades ago, a Japanese
couple of scientists (called Furusawa) at University of Hawaii reported
that PTZ, a GABA antagonist, indeed suppresses the growth of a few cancers
such as LLC (Lewis Lung Carcinoma) xenografts in mice, presumably by blocking
the GABA signaling. By the way, PTZ is an alkaloid from Narcissus flower (水仙)。
2008年12月7日日曜日
日本には市民を代表する「勝手連」による「維新」が必要！
腐敗（あるいは無能化）した政党による「衆愚政治」をつぶせ！
戦後６０年余りの日本政治史を省みるにつけて、日本の政治家の大部分には、社
会を良くする情熱も才覚もない。他方、一般国民の大部分には、民主主義とは何
かがちっともわかっていない。選挙の度に惰性的に投票すれば、それで民主主義
だと思っている。それは、単なる「衆愚政治」に過ぎない！ だから、保守的な
自民党が相変わらず、日本の議会の過半数をほとんど常に占め、腐敗政治を半世
紀以上続けている。そして、その自民党に代わって、政権を狙っている民主党も
本質的には、自民党とほとんど変わらないし、大部分は小沢代表を筆頭に元「自
民党」の議員連中である。与党の名前が変わっても、その中身は従来と本質的に
同じである。かといって、革新政党である共産党や社民党は、衰退の一途をたど
り、比例区で辛うじて数名が当選できるが、小選挙区では、もはや当選者を出せ
なくなっている。もし、政府が比例区を廃止したら、これら革新政党は全て国会
から消滅することになる。笑い事ではない！
いいかえれば、現在の保守衆愚政治は、江戸時代末期の幕府の状況に酷似してい
る。日本国民の「眠り」を覚ますために、「黒船」か新しい「維新」が必要だ！ そ
ういう風な危機感を毎日ひしひしと感じているのは、恐らく私独りではなかろう。
今の膠着した政治体制をつぶすために、外国からの侵略をできれば歓迎したくな
い。「イラク戦争」の二の舞をするからだ。自国の問題は、自国民の手で解決し
なければ、長続きしない。さて、「維新」をするには、どうしたら良いだろうか！
まず、国民投票で、今の政党政治に満足している国民が一体何％いるかを問うべ
きだろう。もし、過半数が不満足であれば、今後、政党政治を廃止すべきだ。ま
ず、全ての政党を非合法化して解散させる。次に、日本のヘッド（首相や大統領）
を、今後国民による直接投票で選ぶか、従来通り国会で（無所属）議員の投票に
よって、間接的に選ぶかについて、国民投票で問う。もし、国民の過半数が直接
投票で大統領を選ぶことを望んだ場合には、無所属の全ての有権者あるいは、い
わゆる「勝手連」の代表が、大統領に立候補できるチャンスを得ることができる。
つまり、誰でも、その才覚さえあれば、皮膚の色や性別にかかわらず（バラク・
オバマのように）将来若くして大統領になれるという「夢」や「希望」が、日本
国民全体に沸き上がるのだ（我々には、老いぼれの大統領など要らない！）。
これが、私の期待する「維新」（無血革命）の内容である。例えば、今の皇太子
にも（本人が）望めば、選挙権が与えられ、大統領に立候補できる。勿論、憲法
は大幅に改正され、弟１条から８条まで全面削除、（世襲制の非人間的な）天皇
制は廃止される。弟９条の行方も内容も、国民による直接投票の結果で決定され
る。従って、「護憲」のごとき曖昧な熟語に全く意味がなくなる。問題はどう
「改憲」するかだ。どうだろうか？
戦後６０年余りの日本政治史を省みるにつけて、日本の政治家の大部分には、社
会を良くする情熱も才覚もない。他方、一般国民の大部分には、民主主義とは何
かがちっともわかっていない。選挙の度に惰性的に投票すれば、それで民主主義
だと思っている。それは、単なる「衆愚政治」に過ぎない！ だから、保守的な
自民党が相変わらず、日本の議会の過半数をほとんど常に占め、腐敗政治を半世
紀以上続けている。そして、その自民党に代わって、政権を狙っている民主党も
本質的には、自民党とほとんど変わらないし、大部分は小沢代表を筆頭に元「自
民党」の議員連中である。与党の名前が変わっても、その中身は従来と本質的に
同じである。かといって、革新政党である共産党や社民党は、衰退の一途をたど
り、比例区で辛うじて数名が当選できるが、小選挙区では、もはや当選者を出せ
なくなっている。もし、政府が比例区を廃止したら、これら革新政党は全て国会
から消滅することになる。笑い事ではない！
いいかえれば、現在の保守衆愚政治は、江戸時代末期の幕府の状況に酷似してい
る。日本国民の「眠り」を覚ますために、「黒船」か新しい「維新」が必要だ！ そ
ういう風な危機感を毎日ひしひしと感じているのは、恐らく私独りではなかろう。
今の膠着した政治体制をつぶすために、外国からの侵略をできれば歓迎したくな
い。「イラク戦争」の二の舞をするからだ。自国の問題は、自国民の手で解決し
なければ、長続きしない。さて、「維新」をするには、どうしたら良いだろうか！
まず、国民投票で、今の政党政治に満足している国民が一体何％いるかを問うべ
きだろう。もし、過半数が不満足であれば、今後、政党政治を廃止すべきだ。ま
ず、全ての政党を非合法化して解散させる。次に、日本のヘッド（首相や大統領）
を、今後国民による直接投票で選ぶか、従来通り国会で（無所属）議員の投票に
よって、間接的に選ぶかについて、国民投票で問う。もし、国民の過半数が直接
投票で大統領を選ぶことを望んだ場合には、無所属の全ての有権者あるいは、い
わゆる「勝手連」の代表が、大統領に立候補できるチャンスを得ることができる。
つまり、誰でも、その才覚さえあれば、皮膚の色や性別にかかわらず（バラク・
オバマのように）将来若くして大統領になれるという「夢」や「希望」が、日本
国民全体に沸き上がるのだ（我々には、老いぼれの大統領など要らない！）。
これが、私の期待する「維新」（無血革命）の内容である。例えば、今の皇太子
にも（本人が）望めば、選挙権が与えられ、大統領に立候補できる。勿論、憲法
は大幅に改正され、弟１条から８条まで全面削除、（世襲制の非人間的な）天皇
制は廃止される。弟９条の行方も内容も、国民による直接投票の結果で決定され
る。従って、「護憲」のごとき曖昧な熟語に全く意味がなくなる。問題はどう
「改憲」するかだ。どうだろうか？
2008年12月5日金曜日
日本に（国政を担当する）政治家など要るのだろうか？
私は「要らない」と思う。私だけではない！ 国民の過半数（６割）はそう思っ
ている。なぜなら、戦後６０年以上、国民大衆のために、政治家たちは何にも益
になることをしてくれていないからだ！ それなら、都道府県の地方自治を任せ
られている政治家たちは、一体要るのだろうか？ これももう要らないと思う。
要るのは区役所や市役所、あるいは町役場の実直な職員たちで十分だ。最低、水
道、し尿、ゴミの管理および教育施設の経営、旅券の発行をしてくれる役場があれば、
それで十分だ。あとは（必要ならば）我々市民たち自身（勝手連）で自主的に組織、
管理、処理すれば良い。そう結論したら、総選挙や都知事選など全くバカバカしく
なってきた。歌舞伎などを観るに等しい。我々庶民の生活とは全く無関係の「茶番劇」だ！
だから、もう政党など全部解散しなさい！ 政治家（屋）さん、もっと地道な職を
見つけて、生活費を稼ぎなさい！
追伸：
もっとも、米国の「オバマ」大統領のような若い立派な（英知と情熱に溢れた）
政治家が日本にも出現すれば、今の考えを変えてもよいが、これから百年以内に
そのような政治家が我が国に誕生する素地は全くない！ やっぱり「勝手連」に
頼るほかない。
ている。なぜなら、戦後６０年以上、国民大衆のために、政治家たちは何にも益
になることをしてくれていないからだ！ それなら、都道府県の地方自治を任せ
られている政治家たちは、一体要るのだろうか？ これももう要らないと思う。
要るのは区役所や市役所、あるいは町役場の実直な職員たちで十分だ。最低、水
道、し尿、ゴミの管理および教育施設の経営、旅券の発行をしてくれる役場があれば、
それで十分だ。あとは（必要ならば）我々市民たち自身（勝手連）で自主的に組織、
管理、処理すれば良い。そう結論したら、総選挙や都知事選など全くバカバカしく
なってきた。歌舞伎などを観るに等しい。我々庶民の生活とは全く無関係の「茶番劇」だ！
だから、もう政党など全部解散しなさい！ 政治家（屋）さん、もっと地道な職を
見つけて、生活費を稼ぎなさい！
追伸：
もっとも、米国の「オバマ」大統領のような若い立派な（英知と情熱に溢れた）
政治家が日本にも出現すれば、今の考えを変えてもよいが、これから百年以内に
そのような政治家が我が国に誕生する素地は全くない！ やっぱり「勝手連」に
頼るほかない。
2008年12月4日木曜日
YES, WE CAN Monitor the Growth of Gliomas by NIRS
In near future, it might become possible to monitor by NIRS the therapeutic effect of anti-PAK1 drugs such as Bio 30 in glioma and NF patients.
Intra-operative characterization of gliomas by near-infrared spectroscopy
(NIRS): possible association with prognosis.
Asgari S, R・rborn HJ, Engelhorn T, Stolke D. (2003)
Department of Neurosurgery, University Hospital, Essen, Germany. siamek.asgari@uni-
essen.de
BACKGROUND: Growth and expansion of gliomas are highly dependent on vascular
neogenesis. An association of microvascular density and tumour energy metabolism
is assumed in most human gliomas. The purpose of this investigation was
to characterize a series of gliomas by intra-operative NIRS, and to elucidate
the relationship between microvascular blood volume (BV), oxygen saturation
(SaO(2)), histology and patient survival.
METHOD: The study included 13 patients with gliomas, in whom complete tumour
resection according to postoperative MRI criteria was achieved. Intra-operatively,
one low grade astrocytoma, five anaplastic astrocytomas and seven glioblastomas
with the ipsilateral cortex were investigated by NIRS revealing capillary
BV (total haemoglobin) and SaO(2). Intratumoural BV (tBV) and SaO(2) (tSaO(2)
) were additionally used in relation to histology and survival.
FINDINGS: The mean tBV of the astrocytomas was 4.96 mg/ml compared to 18.40
mg/ml in the glioblastoma group. Mean tSaO(2) was 36% in the astrocytoma
group and 52% in the glioblastomas, respectively. Both tBV and tSaO(2) were
significantly higher (p<0.01) in the glioblastoma group.
Median survival time was shortest for patients with glioblastoma (12.5 months)
, with tBV >10/mg/ml (10 months), and tSaO(2) >50% (10 months). Longest
median survival times were observed in the astrocytoma group (32.5 months),
in patients with Tbv <10/mg/ml (30 months), and tSaO(2) <50% (27.5 months).
The differences were highly significant (p<0.01).
INTERPRETATION: Intra-operative characterization of gliomas by NIRS is feasible.
High tBV represents extensive angiogenetic activity of the tumour, whereas
high tSaO(2) may be result of non-oxidative glucose metabolism with less
oxygen extraction from the capillary bed of the tumour. However, the extent
of tBV and tSaO(2) are both of possible prognostic value thus resulting
in additional information about the tumour.
Intra-operative characterization of gliomas by near-infrared spectroscopy
(NIRS): possible association with prognosis.
Asgari S, R・rborn HJ, Engelhorn T, Stolke D. (2003)
Department of Neurosurgery, University Hospital, Essen, Germany. siamek.asgari@uni-
essen.de
BACKGROUND: Growth and expansion of gliomas are highly dependent on vascular
neogenesis. An association of microvascular density and tumour energy metabolism
is assumed in most human gliomas. The purpose of this investigation was
to characterize a series of gliomas by intra-operative NIRS, and to elucidate
the relationship between microvascular blood volume (BV), oxygen saturation
(SaO(2)), histology and patient survival.
METHOD: The study included 13 patients with gliomas, in whom complete tumour
resection according to postoperative MRI criteria was achieved. Intra-operatively,
one low grade astrocytoma, five anaplastic astrocytomas and seven glioblastomas
with the ipsilateral cortex were investigated by NIRS revealing capillary
BV (total haemoglobin) and SaO(2). Intratumoural BV (tBV) and SaO(2) (tSaO(2)
) were additionally used in relation to histology and survival.
FINDINGS: The mean tBV of the astrocytomas was 4.96 mg/ml compared to 18.40
mg/ml in the glioblastoma group. Mean tSaO(2) was 36% in the astrocytoma
group and 52% in the glioblastomas, respectively. Both tBV and tSaO(2) were
significantly higher (p<0.01) in the glioblastoma group.
Median survival time was shortest for patients with glioblastoma (12.5 months)
, with tBV >10/mg/ml (10 months), and tSaO(2) >50% (10 months). Longest
median survival times were observed in the astrocytoma group (32.5 months),
in patients with Tbv <10/mg/ml (30 months), and tSaO(2) <50% (27.5 months).
The differences were highly significant (p<0.01).
INTERPRETATION: Intra-operative characterization of gliomas by NIRS is feasible.
High tBV represents extensive angiogenetic activity of the tumour, whereas
high tSaO(2) may be result of non-oxidative glucose metabolism with less
oxygen extraction from the capillary bed of the tumour. However, the extent
of tBV and tSaO(2) are both of possible prognostic value thus resulting
in additional information about the tumour.
2008年12月1日月曜日
抗生物質「アスコフラノン」でアフリカ「睡眠病」患者を救おう！
Humanism in Drug Development: A New Cure for Sleeping Sickness in Africa
我が後輩（北潔君）によるヒューマニズムに溢れた国際的な医学貢献を以下に紹介したい！
詳しくは、最近 「眠リ病は眠らない： 日本発！ アフリカを救う新薬」という本が岩波書店
から出版されたので、それを参照してもらいたい。
まず、アフリカ「睡眠病」（眠り病）とは、トリパノソーマという原虫が原因で
発症する感染症だが、この原虫自身が人間や動物のからだに直接入り込むのでは
なく、ツェツェバエというアフリカ大陸中央部に生息する吸血性のハエにより媒
介される。このハエに刺されると、皮膚の傷口から原虫が血液に侵入して、病気
を発症させる。
初期のころは噛まれた場所が赤く腫れて寒気を感じたり、発熱したりするだけで
そのまま治る場合もある。２ー８年ぐらいはそんな軽い症状が続き、感染に気が
つかない人もいる。ところが治療を受けないままに慢性感染が続くと危険だ。昼
間からうとうと眠るようになり、やがて脳で原虫が増殖し始め、最終的には昏睡
状態に陥り、死に至る恐ろしい病気だ。
さて、１９７２年に東大農学部の田村学造教授により発見された抗生物質「アス
コフラノン」は、抗癌作用および免疫増強作用をもつことが知られていた。 ＲＡＳ
ーＲＡＦシグナル伝達系を抑制するので、ＰＡＫが遮断されている可能性が強い。
２５年後の１９９７年になって初めて、東大医学部の北潔教授らにより、アフリカ
「睡眠病」の病原体であるトリパノソーマ原虫の増殖を、この抗生物質が低濃度
で特異的に阻害することが発見された。２００３年には、マウスを使った実験で、
アスコフラノンは投与後３０分でトリパノソーマ原虫をほとんど血中から消失さ
せるなど、少量で劇的な作用を示すことが確認された。また、アスコフラノンは
哺乳類にはないミトコンドリアの呼吸酵素を標的とするため、ヒトへの安全性が
高いと予想されている。
ただ、この抗生物質は再発見された「既知」化合物なので、アフリカ「睡眠病」
治療薬の開発に製薬企業の協力が得られる可能性は低い。そこで北教授らは、非
営利団体ＤＮＤｉ（顧みられない病気のための新薬開発イニシアチブ）が案件募
集をしていたアフリカ睡眠病の開発プロジェクトに応募し、採択された。
さて、この企画のパートナーである「アリジェン製薬」は、日本発のアフリカ睡
眠病治療薬「アスコフラノン」の開発を目指す非営利プロジェクト「ｊＨＡＴ
（日本主導によるアフリカ睡眠病治療薬の開発計画）」の設立に向けて、資金
（約１０億円）調達に乗り出す。ｊＨＡＴは、この抗生物質の「日本アイデンティ
ティー」を確立するため、原薬生産から製剤化、第I相試験までを、日本国内主導
で実施することに意義を置いている。その後、大手製薬企業に無料で導出する計
画で、最終的にはＷＨＯ等の協力を得て、途上国のアフリカ睡眠病患者に「無償」
提供する。ただし、導出先の製造・販売者には、ロイヤリティーを支払う代わり
に、「アフリカの人々のために日本人によって開発された」ことを、製品ラベル
や添付文書等に明記することを義務づけている。
アスコフラノンは、アフリカ睡眠病の症状が出現したステージII向けの治療薬と
して開発が目下進められている。現在ステージIIには、メラルソプソル、エフロ
ルニチンの２種類しか治療薬が存在しない。しかも、メラルソプソルはヒ素剤で、
投与患者の約10％が死亡するなど、安全性に大きな問題がある。また、エフロル
ニチンは高価で、14日間の点滴が必要となるため、多くの患者に対応できないの
が現状だ。
これに対し、アスコフラノンは１回の注射で治療が可能だ。ｊＨＡＴでは、先ず
注射剤として上市し、最終的には１回投与の経口剤の開発を目指している。既に
アスコフラノンの全合成にも成功し、ケニアでヤギを用いた動物実験を重ねた結
果、極めて少量で高い有効性が確認されている。
最後にちょっと触れておきたいもう１つの（日本発の）古い抗生物質がある。１９
８０年代初頭に北里研究所の大村智らと米国の製薬会社「メリク」との共同研究で
「駆虫剤」として開発された「イベルメクチン」という抗生物質である。アフリカ
で、主に腸内線虫の駆除に長らく活躍してきた安価かつ安全な特効薬である。
１回の経口投与 (0.2 mg/kg)でほとんど完全に駆虫される。線虫のＧＡＢＡ
レセプターを非常に低濃度で特異的に阻害することが知られている。
ところが面白いことには、その後２５年近く経ってから、この抗生物質に強い制
癌作用もあるらしいことが分かってきた。最初にその「再発見」をしたのは、ロ
シアのモスクワにある科学アカデミーの研究グループである。２００４年のこと
だった。我々はこの古い（メラノーマに関する）文献に基づいて、ごく最近、そ
れが脳腫瘍にも効くことを確認し、その制癌作用のメカニズムを目下、解明しつ
つある。
我が後輩（北潔君）によるヒューマニズムに溢れた国際的な医学貢献を以下に紹介したい！
詳しくは、最近 「眠リ病は眠らない： 日本発！ アフリカを救う新薬」という本が岩波書店
から出版されたので、それを参照してもらいたい。
まず、アフリカ「睡眠病」（眠り病）とは、トリパノソーマという原虫が原因で
発症する感染症だが、この原虫自身が人間や動物のからだに直接入り込むのでは
なく、ツェツェバエというアフリカ大陸中央部に生息する吸血性のハエにより媒
介される。このハエに刺されると、皮膚の傷口から原虫が血液に侵入して、病気
を発症させる。
初期のころは噛まれた場所が赤く腫れて寒気を感じたり、発熱したりするだけで
そのまま治る場合もある。２ー８年ぐらいはそんな軽い症状が続き、感染に気が
つかない人もいる。ところが治療を受けないままに慢性感染が続くと危険だ。昼
間からうとうと眠るようになり、やがて脳で原虫が増殖し始め、最終的には昏睡
状態に陥り、死に至る恐ろしい病気だ。
さて、１９７２年に東大農学部の田村学造教授により発見された抗生物質「アス
コフラノン」は、抗癌作用および免疫増強作用をもつことが知られていた。 ＲＡＳ
ーＲＡＦシグナル伝達系を抑制するので、ＰＡＫが遮断されている可能性が強い。
２５年後の１９９７年になって初めて、東大医学部の北潔教授らにより、アフリカ
「睡眠病」の病原体であるトリパノソーマ原虫の増殖を、この抗生物質が低濃度
で特異的に阻害することが発見された。２００３年には、マウスを使った実験で、
アスコフラノンは投与後３０分でトリパノソーマ原虫をほとんど血中から消失さ
せるなど、少量で劇的な作用を示すことが確認された。また、アスコフラノンは
哺乳類にはないミトコンドリアの呼吸酵素を標的とするため、ヒトへの安全性が
高いと予想されている。
ただ、この抗生物質は再発見された「既知」化合物なので、アフリカ「睡眠病」
治療薬の開発に製薬企業の協力が得られる可能性は低い。そこで北教授らは、非
営利団体ＤＮＤｉ（顧みられない病気のための新薬開発イニシアチブ）が案件募
集をしていたアフリカ睡眠病の開発プロジェクトに応募し、採択された。
さて、この企画のパートナーである「アリジェン製薬」は、日本発のアフリカ睡
眠病治療薬「アスコフラノン」の開発を目指す非営利プロジェクト「ｊＨＡＴ
（日本主導によるアフリカ睡眠病治療薬の開発計画）」の設立に向けて、資金
（約１０億円）調達に乗り出す。ｊＨＡＴは、この抗生物質の「日本アイデンティ
ティー」を確立するため、原薬生産から製剤化、第I相試験までを、日本国内主導
で実施することに意義を置いている。その後、大手製薬企業に無料で導出する計
画で、最終的にはＷＨＯ等の協力を得て、途上国のアフリカ睡眠病患者に「無償」
提供する。ただし、導出先の製造・販売者には、ロイヤリティーを支払う代わり
に、「アフリカの人々のために日本人によって開発された」ことを、製品ラベル
や添付文書等に明記することを義務づけている。
アスコフラノンは、アフリカ睡眠病の症状が出現したステージII向けの治療薬と
して開発が目下進められている。現在ステージIIには、メラルソプソル、エフロ
ルニチンの２種類しか治療薬が存在しない。しかも、メラルソプソルはヒ素剤で、
投与患者の約10％が死亡するなど、安全性に大きな問題がある。また、エフロル
ニチンは高価で、14日間の点滴が必要となるため、多くの患者に対応できないの
が現状だ。
これに対し、アスコフラノンは１回の注射で治療が可能だ。ｊＨＡＴでは、先ず
注射剤として上市し、最終的には１回投与の経口剤の開発を目指している。既に
アスコフラノンの全合成にも成功し、ケニアでヤギを用いた動物実験を重ねた結
果、極めて少量で高い有効性が確認されている。
最後にちょっと触れておきたいもう１つの（日本発の）古い抗生物質がある。１９
８０年代初頭に北里研究所の大村智らと米国の製薬会社「メリク」との共同研究で
「駆虫剤」として開発された「イベルメクチン」という抗生物質である。アフリカ
で、主に腸内線虫の駆除に長らく活躍してきた安価かつ安全な特効薬である。
１回の経口投与 (0.2 mg/kg)でほとんど完全に駆虫される。線虫のＧＡＢＡ
レセプターを非常に低濃度で特異的に阻害することが知られている。
ところが面白いことには、その後２５年近く経ってから、この抗生物質に強い制
癌作用もあるらしいことが分かってきた。最初にその「再発見」をしたのは、ロ
シアのモスクワにある科学アカデミーの研究グループである。２００４年のこと
だった。我々はこの古い（メラノーマに関する）文献に基づいて、ごく最近、そ
れが脳腫瘍にも効くことを確認し、その制癌作用のメカニズムを目下、解明しつ
つある。
2008年11月30日日曜日
Glycine N-methyltransferase (GNMT) is a tumor suppressor that blocks the oncogenic PAK1-Cyclin D1 signaling pathways.
Recently a group led by Arthur Chen in Taiwan found that knocking out of
GNMT gene in mice causes HCC (hepatocellular carcinoma), a liver cancer,
and activates both PAK1 and Cyclin D1 genes. This clearly suggests that
GNMT is a tumor suppressor which normally down-regulates both PAK1 and Cyclin
D1 genes, and an interesting possibility arises that anti-PAK1 drugs such
as FK228 and Bio 30 could be potentially useful for the treatment of such
a liver cancer, too. GNMT is normally involved in DNA methylation among
others.
I. J. Cancer (2008)
Characterization of a glycine N-methyltransferase gene knockout mouse model
for hepatocellular carcinoma: Implications of the gender disparity in liver
cancer susceptibility
Yi-Jen Liao, Shih-Ping Liu, Cheng-Ming Lee, Chia-Hung Yen, Pei-Chun Chuang,
Chia-Yen Chen, Ting-Fen Tsai, Shiu-Feng Huang, Yan-Hwa Wu Lee,
Yi-Ming Arthur Chen*
http://www.ibms.sinica.edu.tw/mmp/chen_yi_ming-revised.pdf
Molecular Medicine Program, Institute of Public Health, School of Medicine,
National Yang-Ming University, Taipei, Taiwan
Abstract
Hepatocellular carcinoma (HCC) is the fifth common cancer in the world and
it mainly occurs in men. Glycine N-methyltransferase (GNMT) participates
in one-carbon metabolism and affects DNA methylation by regulating the ratio
of S-adenosylmethionine to S-adenosylhomocystine. Previously, we described
that the expression of GNMT was diminished in human HCC.
Here, we showed that 50% (3/6) male and 100% (7/7) female Gnmt-/- mice developed
HCC, and their mean ages of HCC development were around 17 months. In addition,
43% (3/7) of female Gnmt-/- mice had hemangioma. Wnt reporter assay demonstrated
that Gnmt is a negative regulator for canonical Wnt signaling pathway.
Beta-catenin, Cyclin D1 and c-Myc, genes related to Wnt pathway, were up-regulated
in the liver tissues from both 11 weeks and HCC stage of Gnmt-/- mice. Furthermore,
global DNA hypomethylation and aberrant expression of DNA methyltransferases
1 and 3b were found in the early and late stages of HCC development. Hierarchical
cluster analysis of 6,023 transcripts from microarray data found that gene
expression patterns of HCC tumors from male and female Gnmt-/- mice were
distinctively different.
Real-time PCR confirmed that Gadd45a, PAK1, MAPK3 and Dsup3 genes of MAP
kinase pathway were activated in Gnmt-/- mice, especially in the female
mice. Therefore, GNMT is a tumor suppressor gene for liver cancer, and it
is associated with gender disparity in liver cancer susceptibility.
GNMT gene in mice causes HCC (hepatocellular carcinoma), a liver cancer,
and activates both PAK1 and Cyclin D1 genes. This clearly suggests that
GNMT is a tumor suppressor which normally down-regulates both PAK1 and Cyclin
D1 genes, and an interesting possibility arises that anti-PAK1 drugs such
as FK228 and Bio 30 could be potentially useful for the treatment of such
a liver cancer, too. GNMT is normally involved in DNA methylation among
others.
I. J. Cancer (2008)
Characterization of a glycine N-methyltransferase gene knockout mouse model
for hepatocellular carcinoma: Implications of the gender disparity in liver
cancer susceptibility
Yi-Jen Liao, Shih-Ping Liu, Cheng-Ming Lee, Chia-Hung Yen, Pei-Chun Chuang,
Chia-Yen Chen, Ting-Fen Tsai, Shiu-Feng Huang, Yan-Hwa Wu Lee,
Yi-Ming Arthur Chen*
http://www.ibms.sinica.edu.tw/mmp/chen_yi_ming-revised.pdf
Molecular Medicine Program, Institute of Public Health, School of Medicine,
National Yang-Ming University, Taipei, Taiwan
Abstract
Hepatocellular carcinoma (HCC) is the fifth common cancer in the world and
it mainly occurs in men. Glycine N-methyltransferase (GNMT) participates
in one-carbon metabolism and affects DNA methylation by regulating the ratio
of S-adenosylmethionine to S-adenosylhomocystine. Previously, we described
that the expression of GNMT was diminished in human HCC.
Here, we showed that 50% (3/6) male and 100% (7/7) female Gnmt-/- mice developed
HCC, and their mean ages of HCC development were around 17 months. In addition,
43% (3/7) of female Gnmt-/- mice had hemangioma. Wnt reporter assay demonstrated
that Gnmt is a negative regulator for canonical Wnt signaling pathway.
Beta-catenin, Cyclin D1 and c-Myc, genes related to Wnt pathway, were up-regulated
in the liver tissues from both 11 weeks and HCC stage of Gnmt-/- mice. Furthermore,
global DNA hypomethylation and aberrant expression of DNA methyltransferases
1 and 3b were found in the early and late stages of HCC development. Hierarchical
cluster analysis of 6,023 transcripts from microarray data found that gene
expression patterns of HCC tumors from male and female Gnmt-/- mice were
distinctively different.
Real-time PCR confirmed that Gadd45a, PAK1, MAPK3 and Dsup3 genes of MAP
kinase pathway were activated in Gnmt-/- mice, especially in the female
mice. Therefore, GNMT is a tumor suppressor gene for liver cancer, and it
is associated with gender disparity in liver cancer susceptibility.
Westermarck Effect: A Wider Implication?
"Reverse" sexual imprinting: when two people live in close domestic proximity
during the first few years in the life of either one, both are desensitized
(immune) to later close sexual attraction. This phenomenon, known as the
"Westermarck effect", was first formally described by a Finnish anthropologist
(philosopher and sociologist), Edvard Westermarck (1862-1939). The Westermarck
effect has since been observed in many places and cultures, including in
the Israeli kibbutz system, and the Chinese Shim-pua marriage customs, as
well as in biological-related families.
In the case of the Israeli kibbutzim (collective farms), children were reared
somewhat communally in peer groups, groups based on age, not biological
relation. A study of the marriage patterns of these children later in life
revealed that out of the nearly 3,000 marriages that occurred across the
kibbutz system, only fourteen were between children from the same peer group.
Of those fourteen, none had been reared together during the first six years
of life. This result provides evidence not only that the Westermarck effect
is demonstrable, but that it operates during the critical period from birth
to the age of six (Shepher, 1983).
When close proximity during this critical period does not occur, for example,
where a brother and sister are brought up separately, never meeting one
another, they may find one another highly sexually attractive when they
meet as adults. This phenomenon is known as "genetic sexual attraction".
This observation is consistent with the theory that the Westermarck effect
evolved because it suppressed inbreeding. This attraction may also be seen
with cousin couples such as FDR and his wife Eleanor Roosevelt.
A Cause of Extra-marital Affair?
So-called "extra-marital affair" might be in part due to the Westermarck
effect of the married couples in adult age, a desensitization to mutual
sexual attraction in the family.
It is basically same as immunological tolerance to our own body's components,
and a therapy called desentization of allergic reaction by an excess allergen.
When people get used to each other, they would lose each other's attraction
(or interest), as they get tired of each other. In other words we have
to keep "refreshing" ourselves as much as possible.
A very long time ago (more than a half century ago), when I was still a
small boy, my late father told me once or a few times that it would be ideal
for a couple to meet each other (or live together) only during weekends.
During weekdays, both are very busy in doing their own jobs whatever it
might be. So only during weekends they could take a rest, and enjoy each
other's company. I thought it a brilliant wisdom, although he have never
taken his own wisdom, probably because he had to take care of three young
children of his own closely every day at home, while my mother kept working
outside to earn our living. My father was a very rare (exceptionally inspiring)
house-husband among the post-war Japanese society.
In Europe and US, I know many academic couples, husband and wife of whom
work in different cities, such as Boston and Denver, and only during weekends
they live together. Their marriage appear to last for good, as my father's
wisdom hinted a long time ago.
Change your field often to keep your creativity or uniqueness
Likewise, we must change working place or field reasonably often (every
several years) so that we could get a fresh stimulus from our new colleagues
and give a fresh idea of our own back to them for a creative work. In a
new field we can see things in a quite different angle (view point), leading
to a new insight for a great leap of the field, hopefully. The "permanent"
employment system in Japan has blocked the "creativity" in science and any
other academic fields. Likewise, the abolition of the retirement age (around
65) in US and Australia recently causes a similar problem.
I know many senior (or senile) scientists in US over 70s or even 80s still
sitting on the same chair in the same lab for over a half century, doing
basically nothing productive or creative, mainly because they don't know
what they would do after their retirement. People tend to call it their
"dedication" to science, but honestly I don't think so. Instead of occupying
a high-paid salary position, give your "overtime" position to a younger talented
person, and do a volunteer work in whatever field you like for the rest of
your life, as long as your brain works.
For instance, my own mother (nearly 91) in Tokyo still keeps working as a
volunteer at a local hospital, a few days a week, to help disabled or "old"
people (actually much younger than herself). This new life style during her
last three decades (since her retirement) actually keeps her in a very good
health without any stress on herself and any other people.
during the first few years in the life of either one, both are desensitized
(immune) to later close sexual attraction. This phenomenon, known as the
"Westermarck effect", was first formally described by a Finnish anthropologist
(philosopher and sociologist), Edvard Westermarck (1862-1939). The Westermarck
effect has since been observed in many places and cultures, including in
the Israeli kibbutz system, and the Chinese Shim-pua marriage customs, as
well as in biological-related families.
In the case of the Israeli kibbutzim (collective farms), children were reared
somewhat communally in peer groups, groups based on age, not biological
relation. A study of the marriage patterns of these children later in life
revealed that out of the nearly 3,000 marriages that occurred across the
kibbutz system, only fourteen were between children from the same peer group.
Of those fourteen, none had been reared together during the first six years
of life. This result provides evidence not only that the Westermarck effect
is demonstrable, but that it operates during the critical period from birth
to the age of six (Shepher, 1983).
When close proximity during this critical period does not occur, for example,
where a brother and sister are brought up separately, never meeting one
another, they may find one another highly sexually attractive when they
meet as adults. This phenomenon is known as "genetic sexual attraction".
This observation is consistent with the theory that the Westermarck effect
evolved because it suppressed inbreeding. This attraction may also be seen
with cousin couples such as FDR and his wife Eleanor Roosevelt.
A Cause of Extra-marital Affair?
So-called "extra-marital affair" might be in part due to the Westermarck
effect of the married couples in adult age, a desensitization to mutual
sexual attraction in the family.
It is basically same as immunological tolerance to our own body's components,
and a therapy called desentization of allergic reaction by an excess allergen.
When people get used to each other, they would lose each other's attraction
(or interest), as they get tired of each other. In other words we have
to keep "refreshing" ourselves as much as possible.
A very long time ago (more than a half century ago), when I was still a
small boy, my late father told me once or a few times that it would be ideal
for a couple to meet each other (or live together) only during weekends.
During weekdays, both are very busy in doing their own jobs whatever it
might be. So only during weekends they could take a rest, and enjoy each
other's company. I thought it a brilliant wisdom, although he have never
taken his own wisdom, probably because he had to take care of three young
children of his own closely every day at home, while my mother kept working
outside to earn our living. My father was a very rare (exceptionally inspiring)
house-husband among the post-war Japanese society.
In Europe and US, I know many academic couples, husband and wife of whom
work in different cities, such as Boston and Denver, and only during weekends
they live together. Their marriage appear to last for good, as my father's
wisdom hinted a long time ago.
Change your field often to keep your creativity or uniqueness
Likewise, we must change working place or field reasonably often (every
several years) so that we could get a fresh stimulus from our new colleagues
and give a fresh idea of our own back to them for a creative work. In a
new field we can see things in a quite different angle (view point), leading
to a new insight for a great leap of the field, hopefully. The "permanent"
employment system in Japan has blocked the "creativity" in science and any
other academic fields. Likewise, the abolition of the retirement age (around
65) in US and Australia recently causes a similar problem.
I know many senior (or senile) scientists in US over 70s or even 80s still
sitting on the same chair in the same lab for over a half century, doing
basically nothing productive or creative, mainly because they don't know
what they would do after their retirement. People tend to call it their
"dedication" to science, but honestly I don't think so. Instead of occupying
a high-paid salary position, give your "overtime" position to a younger talented
person, and do a volunteer work in whatever field you like for the rest of
your life, as long as your brain works.
For instance, my own mother (nearly 91) in Tokyo still keeps working as a
volunteer at a local hospital, a few days a week, to help disabled or "old"
people (actually much younger than herself). This new life style during her
last three decades (since her retirement) actually keeps her in a very good
health without any stress on herself and any other people.
2008年11月26日水曜日
Annexin A1: FK228-induced Suppressor
of both Cancer and Inflammation.
Annexin is a family of proteins which bind negatively charged lipids such
as phospholipids in the plasma membranes in a Ca-dependent manner. The first
member of this family (called "synexin") was discovered in 1977 by Harvey
Pollard's group at NIH. Annexin family of over 160 different proteins is
involved in a wide variety of cell physiology in general, depending on each
member. Some of them appear to form a Ca ion channel.
Annexin A1 antagonizes PAK1
Annexin A1 (also called " Lipocortin-1") is involved mainly in both promoting
apoptosis (programmed cell death)/growth arrest and blocking inflammation.
According to the 2003 report from Egle Solito's group of Imperial College
London, the annexin causes the apoptosis of PMN (polymorphonuclear) neutrophils
by Ca-dependent dephosphorylation (activation) of pro-apoptotic BAD. Also
the annexin down-regulates cyclin D1, leading to the growth arrest. In other
words the annexin blocks both up-regulation of cyclin D1 and phosphorylation
(inactivation ) of BAD which are mediated by the oncogenic kinase PAK1.
Thus, clearly the annexin shuts down the PAK1 signaling.
Interestingly, annexin A1 gene was recently found by Marina Konopleva's
group at MD Anderson Cancer Center to be activated by a ring peptide called
FK228. FK228 is so far the most potent anti-cancer drug which blocks PAK1
by inhibiting HDAC (histone deacetylase), though this drug is not available
on the market as yet (currently at phase 2 of sluggish clinical trials mainly
for CTCL, cutaneous T-cell lymphoma).
FK228 is both anti-cancerous and anti-inflammatory
This drug is known to activate a specific set of several tumor suppressor
genes such as p21 (a CDK inhibitor) and Rap1 (a RAS antagonist). p21 causes
the growth arrest of cancer cells by inhibiting CDK (cyclin dependent kinase)
. The GTPase Rap1 could block the activation of PAK1 by blocking the interaction
of oncogenic RAS and PI-3 kinase, eventually causing both growth arrest
and apoptosis of cancer cells, and also blocking their metastasis and angiogenesis.
Interestingly FK228 is known to suppress the inflammatory diseases such
as arthritis and asthma in mouse/rat models, in addition to blocking the
malignant growth of tumor cells. How does this drug block the inflammation?
I believe that FK228-induced activation of Annexin A1 gene could explain
the reason why. For Annexin A1 is known to block the inflammation. Also Annexin
A1 appears to be responsible in part for FK228-induced apoptosis and growth
arrest.
MIR-196a inactivates Annexin A1 gene
More recently, an oncogenic micro RNA called MIR-196a was shown, by another
group led by Dr. R. Luthra at MD Anderson Cancer Center, to down-regulate
Annexin A1 gene. Thus, it is likely that MIR-196a could cause the inflammation,
in addition to the development of cancers. This close relationship between
cancer and inflammation appears to be strengthened by the fact that CAPE
(caffeic acid phenethyl ester) and ARC (artepillin C), the major anti-cancer
ingredients in propolis extracts such as Bio 30 and GPE (Brazilian green
propolis extract), respectively, could suppress the inflammation as well.
These propolis extracts, now available on the market, have been widely
used for the treatment of both cancer and inflammation.
So I wonder if CAPE and ARC also activate Annexin A1 gene or suppress MIR-196a
gene. Both CAPE and ARC selectively block the oncogenic PAK1 signaling pathways
as does FK228. These findings further suggest a possibility that PAK1 might
be involved in the inflammatory reactions such as the activation of PMN
neutrophils, in addition to the oncogenicity.
Continued
as phospholipids in the plasma membranes in a Ca-dependent manner. The first
member of this family (called "synexin") was discovered in 1977 by Harvey
Pollard's group at NIH. Annexin family of over 160 different proteins is
involved in a wide variety of cell physiology in general, depending on each
member. Some of them appear to form a Ca ion channel.
Annexin A1 antagonizes PAK1
Annexin A1 (also called " Lipocortin-1") is involved mainly in both promoting
apoptosis (programmed cell death)/growth arrest and blocking inflammation.
According to the 2003 report from Egle Solito's group of Imperial College
London, the annexin causes the apoptosis of PMN (polymorphonuclear) neutrophils
by Ca-dependent dephosphorylation (activation) of pro-apoptotic BAD. Also
the annexin down-regulates cyclin D1, leading to the growth arrest. In other
words the annexin blocks both up-regulation of cyclin D1 and phosphorylation
(inactivation ) of BAD which are mediated by the oncogenic kinase PAK1.
Thus, clearly the annexin shuts down the PAK1 signaling.
Interestingly, annexin A1 gene was recently found by Marina Konopleva's
group at MD Anderson Cancer Center to be activated by a ring peptide called
FK228. FK228 is so far the most potent anti-cancer drug which blocks PAK1
by inhibiting HDAC (histone deacetylase), though this drug is not available
on the market as yet (currently at phase 2 of sluggish clinical trials mainly
for CTCL, cutaneous T-cell lymphoma).
FK228 is both anti-cancerous and anti-inflammatory
This drug is known to activate a specific set of several tumor suppressor
genes such as p21 (a CDK inhibitor) and Rap1 (a RAS antagonist). p21 causes
the growth arrest of cancer cells by inhibiting CDK (cyclin dependent kinase)
. The GTPase Rap1 could block the activation of PAK1 by blocking the interaction
of oncogenic RAS and PI-3 kinase, eventually causing both growth arrest
and apoptosis of cancer cells, and also blocking their metastasis and angiogenesis.
Interestingly FK228 is known to suppress the inflammatory diseases such
as arthritis and asthma in mouse/rat models, in addition to blocking the
malignant growth of tumor cells. How does this drug block the inflammation?
I believe that FK228-induced activation of Annexin A1 gene could explain
the reason why. For Annexin A1 is known to block the inflammation. Also Annexin
A1 appears to be responsible in part for FK228-induced apoptosis and growth
arrest.
MIR-196a inactivates Annexin A1 gene
More recently, an oncogenic micro RNA called MIR-196a was shown, by another
group led by Dr. R. Luthra at MD Anderson Cancer Center, to down-regulate
Annexin A1 gene. Thus, it is likely that MIR-196a could cause the inflammation,
in addition to the development of cancers. This close relationship between
cancer and inflammation appears to be strengthened by the fact that CAPE
(caffeic acid phenethyl ester) and ARC (artepillin C), the major anti-cancer
ingredients in propolis extracts such as Bio 30 and GPE (Brazilian green
propolis extract), respectively, could suppress the inflammation as well.
These propolis extracts, now available on the market, have been widely
used for the treatment of both cancer and inflammation.
So I wonder if CAPE and ARC also activate Annexin A1 gene or suppress MIR-196a
gene. Both CAPE and ARC selectively block the oncogenic PAK1 signaling pathways
as does FK228. These findings further suggest a possibility that PAK1 might
be involved in the inflammatory reactions such as the activation of PMN
neutrophils, in addition to the oncogenicity.
Continued
2008年11月21日金曜日
Laron Syndrome (Dwarfism) caused by IGF-1 Deficiency
Protects People from Cancer and Diabetes, and Prolongs Life Span.
Dr. Jamie Guevara of the Ecuador Institute of Endocrinology measures the
height of patients with Laron Syndrome (Dwarfism). They all share the same
genetic mutation that blocks the growth hormone (GH) receptors in their
bodies. This mutation eventually causes IGF-1 (insulin-like growth factor)
deficiency.
Guevara first began working with the patients from Southern Ecuador
in the 1980s. After 10 years of research he began to notice a pattern:
None of the Laron dwarfs seemed to get cancer or diabetes.
(Jeffrey Kofman/ABC News)
Hormones (Athens). 2008 ;7 :24-7.
The GH-IGF1 axis and longevity. The paradigm of IGF1 deficiency.
Zvi Laron
Endocrinology and Diabetes Research Unit, Schneider Children's Medical Center
of Israel, Petah Tikva, Sackler Faculty of Medicine, Tel Aviv University,
Israel. laronz@clalit.org.il
Inactivation of the IGF1 gene or of the GH receptor in both invertebrates
(nematodes-C. elegans, flies-Drosphila) and rodents (mice and rats), leading to IGF1
deficiency, prolong life, particularly in females.
In man, evaluation of the 2 largest cohorts of patients with Laron syndrome
(inactive GH receptor resulting in IGF1 deficiency) in Israel and Ecuador
revealed that despite their dwarfism (and marked obesity), patients are
alive at the ages of 75-78 years, with some having reached even more advanced
ages. It is assumed that a major contributing factor is their protection
from cancer, a major cause of death in the general population.
IGF1-PAK1-Foxo Signaling Pathways Controlling both Cancer and Life Span
According to recent study in the nematode C. elegans, IGF-1 activates the
oncogenic kinase PAK1 that normally inactivates Foxo, a tumor suppressing
transcription factor, which normally blocks malignant growth of cells and
prolongs life span. Thus, IGF-1 deficiency in Laron Syndrome would inactivate
PAK1, leading to the reactivation of Foxo, thereby suppressing cancer growth and prolong life span.
So if we treat cancer patients (adults) with anti-IGF-1 drugs or anti-PAK1
drugs, we could cure cancers and prolong their life span, without causing
such a dwarfism. Thus, several anti-PAK1 drugs have been developed or identified
among antibiotics. Among them, a unique ring peptide called FK228 is so
far the most potent, that blocks the oncogenic PAK1 by inhibiting HDAC (histone
deacetylase). However, FK228 is still in clinical trials (phase 2) mainly
for CTCL (cutaneous T-cell lymphoma), and not available on the market.
We have recently found that two propolis extracts, Bio 30 from New Zealand
(NZ) and GPE (green propolis extract) from Brazil, block selectively PAK1
signaling pathways, and almost completely suppress the growth of PAK1-dependent
tumors such as NF, pancreatic and breast cancer, and glioma xenografts in
mice. Both Bio 30 and GPE are now available on the market (internet sale)
from Manuka Health in NZ and Yamada Bee Farm in Japan, respectively.
It is now clear that more than 70% of all human cancers require PAK1 for
their growth. These PAK1-dependent cancers include breast and prostate cancers,
colon, pancreatic and ovarian cancers, glioma, melanoma, and MM (multiple-myeloma)
.
Common in Beekeepers and Laron Dwarfs
Very interestingly, like Laron Dwarfs, honeybee keepers never catch cancer,
or only one in 3,000 keepers, far less than general population (one in
3-4 people). It is most likely that propolis protects beekeepers from cancers.
For none of other bee products such as honey, royal jelly, and bee venom has
any anti-cancer activity. Bio 30 is CAPE (caffeic acid phenethyl ester)-rich
propolis, whereas GPE is ARC (artepillin C)-rich propolis. Both CAPE and
ARC are anti-cancer polyphenols that block PAK1.
The highest in the world
Late Sir Edmund Hillary (1919- 2008), who scaled Mt. Everest (8850 m) for
the first time with his Sherpa, Tenzing Norgay in 1953, never got cancer,
though he was very "tall" (and slender). He used to keep honey bees near
Auckland in NZ.
CAPE comes mainly from young buds of poplar trees. The CAPE content of NZ
propolis such as Bio 30 is the highest among propolis samples around the world.
Continued
height of patients with Laron Syndrome (Dwarfism). They all share the same
genetic mutation that blocks the growth hormone (GH) receptors in their
bodies. This mutation eventually causes IGF-1 (insulin-like growth factor)
deficiency.
Guevara first began working with the patients from Southern Ecuador
in the 1980s. After 10 years of research he began to notice a pattern:
None of the Laron dwarfs seemed to get cancer or diabetes.
(Jeffrey Kofman/ABC News)
Hormones (Athens). 2008 ;7 :24-7.
The GH-IGF1 axis and longevity. The paradigm of IGF1 deficiency.
Zvi Laron
Endocrinology and Diabetes Research Unit, Schneider Children's Medical Center
of Israel, Petah Tikva, Sackler Faculty of Medicine, Tel Aviv University,
Israel. laronz@clalit.org.il
Inactivation of the IGF1 gene or of the GH receptor in both invertebrates
(nematodes-C. elegans, flies-Drosphila) and rodents (mice and rats), leading to IGF1
deficiency, prolong life, particularly in females.
In man, evaluation of the 2 largest cohorts of patients with Laron syndrome
(inactive GH receptor resulting in IGF1 deficiency) in Israel and Ecuador
revealed that despite their dwarfism (and marked obesity), patients are
alive at the ages of 75-78 years, with some having reached even more advanced
ages. It is assumed that a major contributing factor is their protection
from cancer, a major cause of death in the general population.
IGF1-PAK1-Foxo Signaling Pathways Controlling both Cancer and Life Span
According to recent study in the nematode C. elegans, IGF-1 activates the
oncogenic kinase PAK1 that normally inactivates Foxo, a tumor suppressing
transcription factor, which normally blocks malignant growth of cells and
prolongs life span. Thus, IGF-1 deficiency in Laron Syndrome would inactivate
PAK1, leading to the reactivation of Foxo, thereby suppressing cancer growth and prolong life span.
So if we treat cancer patients (adults) with anti-IGF-1 drugs or anti-PAK1
drugs, we could cure cancers and prolong their life span, without causing
such a dwarfism. Thus, several anti-PAK1 drugs have been developed or identified
among antibiotics. Among them, a unique ring peptide called FK228 is so
far the most potent, that blocks the oncogenic PAK1 by inhibiting HDAC (histone
deacetylase). However, FK228 is still in clinical trials (phase 2) mainly
for CTCL (cutaneous T-cell lymphoma), and not available on the market.
We have recently found that two propolis extracts, Bio 30 from New Zealand
(NZ) and GPE (green propolis extract) from Brazil, block selectively PAK1
signaling pathways, and almost completely suppress the growth of PAK1-dependent
tumors such as NF, pancreatic and breast cancer, and glioma xenografts in
mice. Both Bio 30 and GPE are now available on the market (internet sale)
from Manuka Health in NZ and Yamada Bee Farm in Japan, respectively.
It is now clear that more than 70% of all human cancers require PAK1 for
their growth. These PAK1-dependent cancers include breast and prostate cancers,
colon, pancreatic and ovarian cancers, glioma, melanoma, and MM (multiple-myeloma)
.
Common in Beekeepers and Laron Dwarfs
Very interestingly, like Laron Dwarfs, honeybee keepers never catch cancer,
or only one in 3,000 keepers, far less than general population (one in
3-4 people). It is most likely that propolis protects beekeepers from cancers.
For none of other bee products such as honey, royal jelly, and bee venom has
any anti-cancer activity. Bio 30 is CAPE (caffeic acid phenethyl ester)-rich
propolis, whereas GPE is ARC (artepillin C)-rich propolis. Both CAPE and
ARC are anti-cancer polyphenols that block PAK1.
The highest in the world
Late Sir Edmund Hillary (1919- 2008), who scaled Mt. Everest (8850 m) for
the first time with his Sherpa, Tenzing Norgay in 1953, never got cancer,
though he was very "tall" (and slender). He used to keep honey bees near
Auckland in NZ.
CAPE comes mainly from young buds of poplar trees. The CAPE content of NZ
propolis such as Bio 30 is the highest among propolis samples around the world.
Continued
2008年11月20日木曜日
The "Wild Australia" Revitalized in Film!
"AUSTRALIA" is an epic and romantic action adventure, set in that country on the explosive brink of World War II.
In it, an English aristocrat (Nicole Kidman) travels to the faraway continent, where she meets a rough-hewn local (Hugh Jackman) and reluctantly agrees to join forces with him to save the land she inherited. Together, they embark upon a transforming journey across hundreds of miles of the world's most beautiful yet unforgiving terrain, only to still face the bombing of the city of Darwin by the Japanese forces that attacked Pearl Harbor.
With his new film, Luhrmann is painting on a vast canvas, creating a cinematic experience that brings together romance, drama, adventure and spectacle (from Cinema "Nova").
映画評：
一口で言えば、この映画は豪州を舞台にした西部劇である。しかし、登場人物は
アパッチなどの「アメリカインデアン」の代わりに、「アボリジナル」（豪州
の原住民）の孤児、ジョン・ウエインなどの代わりに、豪州独特のカウボーイ
（ロバート）や英国からやって来た若い貴婦人（サラ）がロマンスを交じえて、
活躍する。時代は欧州で第二次世界大戦が始まった１９３９年から真珠湾攻撃の
直後、日本軍が豪州の北端ダーウインを奇襲（空爆）する１９４２年の３年間に
わたる。最後に、ヒーローである豪州のカウボーイがアボリジナルの孤児（少年）を、
日本軍による空爆から救った後まもなく、空爆から辛うじて助かった恋人のサラと再開し、
ハッピー・エンドとなる。実はこの小さな少年が映画の語り手で、子供でも大人でも楽しめる
映画。さらに、アボリジナルの老人が魔術を使って、彼らの危機を何回か救うと
いうファンタジー的な場面も出てくる。丸で「ハリー・ポッター」と西部劇を組み合わせ
たような映画で、ユーモアたっぷりの冒険物語。 豪州の雄大な自然をたっぷ
り紹介しながら、観客を楽しませるいわば「豪州観光への招待」も兼ねた傑作であ
る。
In it, an English aristocrat (Nicole Kidman) travels to the faraway continent, where she meets a rough-hewn local (Hugh Jackman) and reluctantly agrees to join forces with him to save the land she inherited. Together, they embark upon a transforming journey across hundreds of miles of the world's most beautiful yet unforgiving terrain, only to still face the bombing of the city of Darwin by the Japanese forces that attacked Pearl Harbor.
With his new film, Luhrmann is painting on a vast canvas, creating a cinematic experience that brings together romance, drama, adventure and spectacle (from Cinema "Nova").
映画評：
一口で言えば、この映画は豪州を舞台にした西部劇である。しかし、登場人物は
アパッチなどの「アメリカインデアン」の代わりに、「アボリジナル」（豪州
の原住民）の孤児、ジョン・ウエインなどの代わりに、豪州独特のカウボーイ
（ロバート）や英国からやって来た若い貴婦人（サラ）がロマンスを交じえて、
活躍する。時代は欧州で第二次世界大戦が始まった１９３９年から真珠湾攻撃の
直後、日本軍が豪州の北端ダーウインを奇襲（空爆）する１９４２年の３年間に
わたる。最後に、ヒーローである豪州のカウボーイがアボリジナルの孤児（少年）を、
日本軍による空爆から救った後まもなく、空爆から辛うじて助かった恋人のサラと再開し、
ハッピー・エンドとなる。実はこの小さな少年が映画の語り手で、子供でも大人でも楽しめる
映画。さらに、アボリジナルの老人が魔術を使って、彼らの危機を何回か救うと
いうファンタジー的な場面も出てくる。丸で「ハリー・ポッター」と西部劇を組み合わせ
たような映画で、ユーモアたっぷりの冒険物語。 豪州の雄大な自然をたっぷ
り紹介しながら、観客を楽しませるいわば「豪州観光への招待」も兼ねた傑作であ
る。
2008年11月18日火曜日
The "Wild West" Is Gone: No More Riding "Your Own Horse or Car".
Take "Public Transportation" (Buses and Trains)!
In the summer of 1973, in the midst of "Oil Shock", I left Japan by a huge
American cargo liner, crossing the Pacific Ocean, and landing on Seattle
after non-stop 9 days voyage. Then crossing a half way of the big continent
to Denver, the center of mid west (or "Wild West") by a Greyhound Bus. Then
a year later, I crossed the remaining half by an Amtrak train to Washington,
DC.
Just before I left my hometown Tokyo that hot summer, I determined not to
drive any car of my own. In Tokyo we don't need a car to work or for shopping,
and I never got any driver license. Since then I worked overseas for more than 35 years, for 10 years in US, 5 years in Germany and 20 years in Australia, but have never driven a car of my own, keeping my own pledge...
Well, after 35 years, US car industries (GM, Chrysler and Ford) are facing
their bankruptcy or serious financial crisis. They look like getting unable
to make or sell any more "owner" cars, but trucks or buses. The Wild West
is finally gone! The time is come for all the people in US and the rest
of world to take public transportation (buses and trains), just like I have
been doing for last 35 years wherever I lived in western world.
We should urge the US automobile sector to reform or perish! It would not
be wise for the forthcoming Obama government to give them a rescue package
from American tax money, without any effort of their own, to reform seriously
their own shortsighted "owner car" production program.
Continued
トヨタ・ショック「さらば、自家用車！」
Farewell to Own Cars!
これを次代の自動車業界の「立て直し」キャッチフレーズにすべきです。
どういうことかと言いますと、一人一人が通勤、通学、レジャーにオートバイや
「自家用車」を乗り回すと、道路がやたら混雑し、大気が汚染し、世界中の石油
の埋蔵量が激減します。これらの自家用車の代わりに、バスや市電、その他の電
車（地下鉄、市内電車、長距離電車）などの陸路を走る「公共」の交通機関、あ
るいは自転車を大部分の人々が使うようになると、道路の混雑、大気の汚染、石
油の消費が激減し、地球の温暖化が止り、この世界はより住みやすくなります。
このような考え方が、人口密度の高い日本ばかりではなく、比較的人口密度の低い
欧米の社会にも段々、浸透し始めています、だから、自家用車が年々売れなくなっ
ているのです。それに気づかず、あるいはそれを敢えて無視して、今まで通り、
オートバイや自家用車ばかり作っていると、景気が悪くなるととたんに、自動車
（特に、自家用車）メーカーに赤字が出てきます（トヨタ・ショック！）。業界は
「先見の明」をもって、バスや電車などの「大型」交通機関や運搬用のトラックの
生産ヘギア・チェンジ（頭の切り換え）をすれば、景気の良し悪しにかかわらず、
安定な売れ行き（収入）が保証されます。つまり、カーメーカーの生産プラン（姿勢）
の抜本的改革が必須です。
これを、特に（今回の世界的不況の「原点」である）米国に「チェンジ」（変革）
をめざす「オバマ新政権」へ強く進言したいと思っています。馬や自家用車を
一人で乗り回すいわゆる「ワイルド・ウエスト」（西部劇）時代は、もう「過去の
歴史」になったのだということを、米国のカーメーカー３社（GM、クライスラー、
フォード）にわからせる、そして、都市／州政府や連邦政府が率先して、市電、
地下鉄、長距離鉄道路線の建設に大量の資金を出すことが、車体
メーカー業界の立直り（改革）を促する有効な「グリーン・ニューディール」政
策となるでしょう。そういう「自己改革」が実行できなければ、（地球を破壊し
つつある）「自家用車」生産にだけ頼る「石頭の」カー業界は、遅かれ早かれ潰
れるべきです！ 地球を愛する人々は誰も、そんな古臭い業界にもう同情しない
でしょう！
American cargo liner, crossing the Pacific Ocean, and landing on Seattle
after non-stop 9 days voyage. Then crossing a half way of the big continent
to Denver, the center of mid west (or "Wild West") by a Greyhound Bus. Then
a year later, I crossed the remaining half by an Amtrak train to Washington,
DC.
Just before I left my hometown Tokyo that hot summer, I determined not to
drive any car of my own. In Tokyo we don't need a car to work or for shopping,
and I never got any driver license. Since then I worked overseas for more than 35 years, for 10 years in US, 5 years in Germany and 20 years in Australia, but have never driven a car of my own, keeping my own pledge...
Well, after 35 years, US car industries (GM, Chrysler and Ford) are facing
their bankruptcy or serious financial crisis. They look like getting unable
to make or sell any more "owner" cars, but trucks or buses. The Wild West
is finally gone! The time is come for all the people in US and the rest
of world to take public transportation (buses and trains), just like I have
been doing for last 35 years wherever I lived in western world.
We should urge the US automobile sector to reform or perish! It would not
be wise for the forthcoming Obama government to give them a rescue package
from American tax money, without any effort of their own, to reform seriously
their own shortsighted "owner car" production program.
Continued
トヨタ・ショック「さらば、自家用車！」
Farewell to Own Cars!
これを次代の自動車業界の「立て直し」キャッチフレーズにすべきです。
どういうことかと言いますと、一人一人が通勤、通学、レジャーにオートバイや
「自家用車」を乗り回すと、道路がやたら混雑し、大気が汚染し、世界中の石油
の埋蔵量が激減します。これらの自家用車の代わりに、バスや市電、その他の電
車（地下鉄、市内電車、長距離電車）などの陸路を走る「公共」の交通機関、あ
るいは自転車を大部分の人々が使うようになると、道路の混雑、大気の汚染、石
油の消費が激減し、地球の温暖化が止り、この世界はより住みやすくなります。
このような考え方が、人口密度の高い日本ばかりではなく、比較的人口密度の低い
欧米の社会にも段々、浸透し始めています、だから、自家用車が年々売れなくなっ
ているのです。それに気づかず、あるいはそれを敢えて無視して、今まで通り、
オートバイや自家用車ばかり作っていると、景気が悪くなるととたんに、自動車
（特に、自家用車）メーカーに赤字が出てきます（トヨタ・ショック！）。業界は
「先見の明」をもって、バスや電車などの「大型」交通機関や運搬用のトラックの
生産ヘギア・チェンジ（頭の切り換え）をすれば、景気の良し悪しにかかわらず、
安定な売れ行き（収入）が保証されます。つまり、カーメーカーの生産プラン（姿勢）
の抜本的改革が必須です。
これを、特に（今回の世界的不況の「原点」である）米国に「チェンジ」（変革）
をめざす「オバマ新政権」へ強く進言したいと思っています。馬や自家用車を
一人で乗り回すいわゆる「ワイルド・ウエスト」（西部劇）時代は、もう「過去の
歴史」になったのだということを、米国のカーメーカー３社（GM、クライスラー、
フォード）にわからせる、そして、都市／州政府や連邦政府が率先して、市電、
地下鉄、長距離鉄道路線の建設に大量の資金を出すことが、車体
メーカー業界の立直り（改革）を促する有効な「グリーン・ニューディール」政
策となるでしょう。そういう「自己改革」が実行できなければ、（地球を破壊し
つつある）「自家用車」生産にだけ頼る「石頭の」カー業界は、遅かれ早かれ潰
れるべきです！ 地球を愛する人々は誰も、そんな古臭い業界にもう同情しない
でしょう！
2008年11月12日水曜日
"Disabled" Financial Sector:
To be Bailed out, Nationalized or Slashed?
経営能力のない大企業（金融企業）を政府が（国民からの税金で）破産から救う
理由は全くない！ 自然淘汰によって、そのような金融企業（銀行や保険／証券
会社）はつぶれ、健全な経営をする堅実な企業だけが生き残れば、世界経済はもっ
と健全になるはずだ！ それ（自由競争）が嫌なら、大企業は全て民営ではなく
「国（公）営」にすべきである。(一般大衆を騙して) ボロ儲けをしている時期だけ
「資本主義」を主張し続け、赤字（借金）が貯まって首が回らなくなったとたんに、
政府による救済（社会主義）を求めて泣きつくのは、ひどく虫が良過ぎる！
そう思いませんか？
(本音を言わせてもらえば) だいたい、金を左から右へ移すだけで利鞘を儲け、
実質的に何も生産しない金融企業 や株屋 (社会にはびこる「寄生虫」) など
に同情の余地などない。 皆んな潰れてしまえ！ と言いたい。実直に生産活動
をしている者(理系) の素直な感想だ！
さて、小泉内閣による郵政の「民営化」も結局は、「公営化」に戻すことになり
そうである。民営化を支持する「チルドレン」がすっかり姿を消してしまったか
ら(民営化に真っ向から反対して、小泉に苦杯をなめさせられた野田議員らが
返り咲いて、現麻生内閣で涼しい顔をしている！)。
理由は全くない！ 自然淘汰によって、そのような金融企業（銀行や保険／証券
会社）はつぶれ、健全な経営をする堅実な企業だけが生き残れば、世界経済はもっ
と健全になるはずだ！ それ（自由競争）が嫌なら、大企業は全て民営ではなく
「国（公）営」にすべきである。(一般大衆を騙して) ボロ儲けをしている時期だけ
「資本主義」を主張し続け、赤字（借金）が貯まって首が回らなくなったとたんに、
政府による救済（社会主義）を求めて泣きつくのは、ひどく虫が良過ぎる！
そう思いませんか？
(本音を言わせてもらえば) だいたい、金を左から右へ移すだけで利鞘を儲け、
実質的に何も生産しない金融企業 や株屋 (社会にはびこる「寄生虫」) など
に同情の余地などない。 皆んな潰れてしまえ！ と言いたい。実直に生産活動
をしている者(理系) の素直な感想だ！
さて、小泉内閣による郵政の「民営化」も結局は、「公営化」に戻すことになり
そうである。民営化を支持する「チルドレン」がすっかり姿を消してしまったか
ら(民営化に真っ向から反対して、小泉に苦杯をなめさせられた野田議員らが
返り咲いて、現麻生内閣で涼しい顔をしている！)。
2008年11月6日木曜日
米国史上初の黒人系大統領 (オバマ) の誕生！
１１月４日の選挙の結果、民主党のバラク・オバマ候補（４７）が共和党のジョ
ン・マケイン候補（７２）を大幅に破って、４４代目の米国大統領に当選した
（オバマ ３６４票、マケイン１７４票）。黒人系（黒人と白人とのハーフ）の
候補が大統領に当選するのは、米国史上初めての快挙である。米国の人口の
８０％は白人系、黒人系はわずか１３％に過ぎない。
少数派が大統領に選ばれたのは、１９６０年にカトリック教徒として初めて当選
したジョン・ケネディー（１９１７ー１９６３）についで４８年振りのことである。
キリスト教徒が人口の８割近くを占める米国では、新教徒（プロテスタント）が人
口の５０％に対して、旧教徒（カトリック）は２５％に過ぎない。
人口の半分を占める女性は、厳密にいえば（数の上では）いわゆる「少数派」で
はないが、歴史的な理由で、いまだに米国や日本では、国家の長（大統領あるい
は首相）に選れたことがない。今回の米国大統領選挙で、民主党大統領候補の指
名をめぐって、オバマ候補と接戦を演じたヒラリー・クリントン（６０）が４年後、
あるいは８年後に再出馬すれば、米国史上初の女性大統領の誕生も夢ではな
いだろう。
さて、オバマ夫妻（バラクとミシェル）は共に、ハーバード大学法学部出身のエ
リートである。クリントン夫妻（ビルとヒラリー）は共に、エール大学法学部出
身のエリートだった。今後ホワイトハウスや議会でそれぞれ、両夫妻の協力によっ
て、英知を絞って、今後良い政治を行ない、米国ばかりではなく、地球全体をよ
り平和な、経済的に安定（健全）な、しかも「グリーンな」（環境にやさしい）
世界に作り替える努力をしてもらいたいものだと、我々は切に望む。
オバマ政権の重要閣僚ポスト（国務長官、財務長官、国防長官を始め、保健長官、
労務長官、環境長官など）に一体誰を起用するか、大変楽しみである。また、駐
日米国大使として誰を抜擢するか、注目される。日米関係の将来を占う材料とな
るだろう。
さて、日本の最大野党である民主党は、今回の米国大統領選挙から一体何を学ん
だろうか？ 来年１月から米国では、大統領 （ホワイトハウス） のみならず、下院
および上院でも民主党が過半数を占めることになる。
来たる総選挙で、民主党を軸とする（日本の）革新陣営は、衆議院でも過半数を
獲得し、念願の「政権交代」を実現できるだろうか？
第３政党の在り方
さて、豪州で起こなわれた最近の地方（首都キャンベラ) 選挙で、革新野党「グリー
ン党」が飛躍的な躍進を果たしたことが政界で注目されている。これまで議会
（全部で１７議席）の過半数を占めて与党だった労働党が７議席に後退 (過半数
を割り)、保守的な野党「自由党＝自民党」も６議席に後退する中、グリーン党が
４議席（３議席も倍増）も獲得し、次期キャンベラ地区（ＡＣＴ）の知事を労働
党党首、あるいは自民党党首にするかを決定するという重要な鍵を握ることになっ
た。
結局、「グリーン党」は (いくつかの「政治改革」を最終的に受け入れた) 労働
党を支持することを決定し、連立政権をつくらずに、与党 (労働党) の政策をコ
ントロールするというユニークな方針を打ち出した。もし、与党が公約を守らな
ければ、グリーン党はただちに野党側に回り、与党の知事に解散 (辞職) を迫る
ことになる。
このように、第３政党は（日本の公明党のように）第一党と連立政権を組むより
も（豪州のグリーン党のように）「閣外協力」で、与党をより効率良く (自由自在に)
コントロールできる可能性が生まれてきた。もし近い将来、民主党が第一党になり、
過半数を得るために他党の支持を必要とした場合、（少数）革新野党である社民党
や共産党などは、グリーン党の路線（「条件つき」閣外協力）を採用する方がずっと
賢明であると、私は思う。
ン・マケイン候補（７２）を大幅に破って、４４代目の米国大統領に当選した
（オバマ ３６４票、マケイン１７４票）。黒人系（黒人と白人とのハーフ）の
候補が大統領に当選するのは、米国史上初めての快挙である。米国の人口の
８０％は白人系、黒人系はわずか１３％に過ぎない。
少数派が大統領に選ばれたのは、１９６０年にカトリック教徒として初めて当選
したジョン・ケネディー（１９１７ー１９６３）についで４８年振りのことである。
キリスト教徒が人口の８割近くを占める米国では、新教徒（プロテスタント）が人
口の５０％に対して、旧教徒（カトリック）は２５％に過ぎない。
人口の半分を占める女性は、厳密にいえば（数の上では）いわゆる「少数派」で
はないが、歴史的な理由で、いまだに米国や日本では、国家の長（大統領あるい
は首相）に選れたことがない。今回の米国大統領選挙で、民主党大統領候補の指
名をめぐって、オバマ候補と接戦を演じたヒラリー・クリントン（６０）が４年後、
あるいは８年後に再出馬すれば、米国史上初の女性大統領の誕生も夢ではな
いだろう。
さて、オバマ夫妻（バラクとミシェル）は共に、ハーバード大学法学部出身のエ
リートである。クリントン夫妻（ビルとヒラリー）は共に、エール大学法学部出
身のエリートだった。今後ホワイトハウスや議会でそれぞれ、両夫妻の協力によっ
て、英知を絞って、今後良い政治を行ない、米国ばかりではなく、地球全体をよ
り平和な、経済的に安定（健全）な、しかも「グリーンな」（環境にやさしい）
世界に作り替える努力をしてもらいたいものだと、我々は切に望む。
オバマ政権の重要閣僚ポスト（国務長官、財務長官、国防長官を始め、保健長官、
労務長官、環境長官など）に一体誰を起用するか、大変楽しみである。また、駐
日米国大使として誰を抜擢するか、注目される。日米関係の将来を占う材料とな
るだろう。
さて、日本の最大野党である民主党は、今回の米国大統領選挙から一体何を学ん
だろうか？ 来年１月から米国では、大統領 （ホワイトハウス） のみならず、下院
および上院でも民主党が過半数を占めることになる。
来たる総選挙で、民主党を軸とする（日本の）革新陣営は、衆議院でも過半数を
獲得し、念願の「政権交代」を実現できるだろうか？
第３政党の在り方
さて、豪州で起こなわれた最近の地方（首都キャンベラ) 選挙で、革新野党「グリー
ン党」が飛躍的な躍進を果たしたことが政界で注目されている。これまで議会
（全部で１７議席）の過半数を占めて与党だった労働党が７議席に後退 (過半数
を割り)、保守的な野党「自由党＝自民党」も６議席に後退する中、グリーン党が
４議席（３議席も倍増）も獲得し、次期キャンベラ地区（ＡＣＴ）の知事を労働
党党首、あるいは自民党党首にするかを決定するという重要な鍵を握ることになっ
た。
結局、「グリーン党」は (いくつかの「政治改革」を最終的に受け入れた) 労働
党を支持することを決定し、連立政権をつくらずに、与党 (労働党) の政策をコ
ントロールするというユニークな方針を打ち出した。もし、与党が公約を守らな
ければ、グリーン党はただちに野党側に回り、与党の知事に解散 (辞職) を迫る
ことになる。
このように、第３政党は（日本の公明党のように）第一党と連立政権を組むより
も（豪州のグリーン党のように）「閣外協力」で、与党をより効率良く (自由自在に)
コントロールできる可能性が生まれてきた。もし近い将来、民主党が第一党になり、
過半数を得るために他党の支持を必要とした場合、（少数）革新野党である社民党
や共産党などは、グリーン党の路線（「条件つき」閣外協力）を採用する方がずっと
賢明であると、私は思う。
2008年10月22日水曜日
A Big Victory for "Greens" in ACT, Canberra in Australia!.
The outcome of recent election in Canberra, ACT (Australian Capital Territory)
showed a big swing from the ruling ALP (Australian Labor Party) to Greens.
Out of 17 seats, ALP won 7 seats, Liberal Party (LP, a conservative opposition)
won 6 seats, and Greens won 4 seats. Without Greens, either ALP or LP cannot
assemble the ACT government.
Currently Greens are negotiating with both ALP and LP to decide which party they would support to form the government. Thus, Greens are in the position of so-called "King Maker" by choosing the leader of ALP (Jon Stanhope) or LP (Zed Seselja) as the ACT premier (Chief Minister).
Since the "Tampa incident" in 2001 during the federal election when the
opposition ALP failed to speak out for human rights of "boat people" (refugee
over boats), many ALP supporters (in particular left-wing fraction) began
to switching their support to Greens led by Dr. Bob Brown of Tasmania Island,
the only opposition party that spoke out for these poor people. During last
several years about 30% of ALP supporters in total shifted their support
to Greens which focus mainly on environmental conservation and fundamental
human rights, and are firmly against Iraq War.
Unlike Japan and Europe, there is no socialists' or communists' party here
in Australia. The Australian political view is rather moderate, and Greens
represent the voice of the most progressive people in this country.
ACT Greens storm into balance of power (26/10/2008)
The ACT Greens have managed to produce a significant swing of 7 % polling just under 16%. The Greens won eventually 4 seats, holding the balance of power in the Legislative Assembly.
In the electorate of Molonglo The Greens have won two seats, polling
19 % up 7 %, ensuring Shane Rattenbury and Caroline Le Couteur.
In the electorate of Brindabella The Greens have polled 14 % up 7 % giving Amanda Bresnan a seat, and in Ginninderra The Greens polled 15 % up 6% which gives Meredith Hunter a seat.
Australia must embrace UN's "Green New Deal" (23/10/2008)
Top global economists from the United Nations Environment Program and Deutsche
Bank overnight launched a plan for a "Green New Deal", echoing FDR's "New
Deal" to work US out of the Great Depression, to tackle the current economic
and climate crisis together.
"Greens" Senator Christine Milne called on the Aussie Government led by
Kevin Rudd to embrace the plan which would see a massive investment in energy
efficiency, renewable energy, alternative transport and forest protection,
creating high quality, permanent jobs in a thriving, prosperous, green economy.
showed a big swing from the ruling ALP (Australian Labor Party) to Greens.
Out of 17 seats, ALP won 7 seats, Liberal Party (LP, a conservative opposition)
won 6 seats, and Greens won 4 seats. Without Greens, either ALP or LP cannot
assemble the ACT government.
Currently Greens are negotiating with both ALP and LP to decide which party they would support to form the government. Thus, Greens are in the position of so-called "King Maker" by choosing the leader of ALP (Jon Stanhope) or LP (Zed Seselja) as the ACT premier (Chief Minister).
Since the "Tampa incident" in 2001 during the federal election when the
opposition ALP failed to speak out for human rights of "boat people" (refugee
over boats), many ALP supporters (in particular left-wing fraction) began
to switching their support to Greens led by Dr. Bob Brown of Tasmania Island,
the only opposition party that spoke out for these poor people. During last
several years about 30% of ALP supporters in total shifted their support
to Greens which focus mainly on environmental conservation and fundamental
human rights, and are firmly against Iraq War.
Unlike Japan and Europe, there is no socialists' or communists' party here
in Australia. The Australian political view is rather moderate, and Greens
represent the voice of the most progressive people in this country.
ACT Greens storm into balance of power (26/10/2008)
The ACT Greens have managed to produce a significant swing of 7 % polling just under 16%. The Greens won eventually 4 seats, holding the balance of power in the Legislative Assembly.
In the electorate of Molonglo The Greens have won two seats, polling
19 % up 7 %, ensuring Shane Rattenbury and Caroline Le Couteur.
In the electorate of Brindabella The Greens have polled 14 % up 7 % giving Amanda Bresnan a seat, and in Ginninderra The Greens polled 15 % up 6% which gives Meredith Hunter a seat.
Australia must embrace UN's "Green New Deal" (23/10/2008)
Top global economists from the United Nations Environment Program and Deutsche
Bank overnight launched a plan for a "Green New Deal", echoing FDR's "New
Deal" to work US out of the Great Depression, to tackle the current economic
and climate crisis together.
"Greens" Senator Christine Milne called on the Aussie Government led by
Kevin Rudd to embrace the plan which would see a massive investment in energy
efficiency, renewable energy, alternative transport and forest protection,
creating high quality, permanent jobs in a thriving, prosperous, green economy.
2008年10月21日火曜日
A Huge Change ("Blue" Shift) in Ohio and Florida
for Recovery from Deep Financial Crisis
Al Gore and John Kerry lost to George Bush in the 2000 and 2004 US election,
mainly due to their narrow loss in both Ohio and Florida. Because of this
fatal loss, during last 8 years all of us have suffered from a series of
ill-managements by his cabinet such as the 9/11 Attack, Iraq War, Hurricane
"Katrina", Global Warming and current Deep Depression. To recover from these
huge damages, we need a new FDR to combat these problems with his new vision
and decisive action.
For such a drastic change in US politics for the coming years, the majority
of eligible minds in the two "marginal" (closely contesting) states, both
Ohio and Florida, have to be changed from "Red" (for McCain ) to "Blue"
(for Obama). Without this landslide "Blue" shift, our situation in both
US and the rest of our world would get progressively worsen towards the "Great
Depression".
Who is the "right" commander-in-chief?
Also I would like to remind you of one more thing. John McCain fought for
the "wrong" war (Vietnam War). Bobbie Kennedy fought 1968 election to stop
this "wrong" war. Barack Obama stood firmly against another "wrong" war
(Iraq War) from the very beginning.
So if you ask who would be the "right" commander-in-chief, I would say,
Obama, and not McCain. McCain was not the "right" decision maker.
FDR was the last US president who supported the "right" war (WWII) against
Nazi Germany and Japan which attacked China and eventually "Pearl Harbor".
WWII was the only war that boosted US economy for last seven decades. His
"New Deal" and WWII rescued US from the Great Depression.
mainly due to their narrow loss in both Ohio and Florida. Because of this
fatal loss, during last 8 years all of us have suffered from a series of
ill-managements by his cabinet such as the 9/11 Attack, Iraq War, Hurricane
"Katrina", Global Warming and current Deep Depression. To recover from these
huge damages, we need a new FDR to combat these problems with his new vision
and decisive action.
For such a drastic change in US politics for the coming years, the majority
of eligible minds in the two "marginal" (closely contesting) states, both
Ohio and Florida, have to be changed from "Red" (for McCain ) to "Blue"
(for Obama). Without this landslide "Blue" shift, our situation in both
US and the rest of our world would get progressively worsen towards the "Great
Depression".
Who is the "right" commander-in-chief?
Also I would like to remind you of one more thing. John McCain fought for
the "wrong" war (Vietnam War). Bobbie Kennedy fought 1968 election to stop
this "wrong" war. Barack Obama stood firmly against another "wrong" war
(Iraq War) from the very beginning.
So if you ask who would be the "right" commander-in-chief, I would say,
Obama, and not McCain. McCain was not the "right" decision maker.
FDR was the last US president who supported the "right" war (WWII) against
Nazi Germany and Japan which attacked China and eventually "Pearl Harbor".
WWII was the only war that boosted US economy for last seven decades. His
"New Deal" and WWII rescued US from the Great Depression.
2008年10月19日日曜日
Mini RNA-7 is a Major Tumor Supressor
that Blocks the Oncogenic EGFR-PAK1 Signaling
Mini RNA of 21-22 nucleotides (also called SiRNAs) are known to regulate
gene expression, which were first discovered in the nematode C. elegans,
just a decade ago by Craig Mello of University of Massachusetts and Andrew
Fire of Stanford University (2006 Nobel laureates).
In 2005 one of the nematode mini RNAs called Let-7 was found by Frank Slack's group at Yale University to be a suppressor of Let-60/RAS gene, suggesting that this mini RNA (or a related human counterpart) could work as a tumor suppressor in human RAS cancers such as pancreatic and colon cancers.
Cell. 2005 ;120: 635-47.
RAS is regulated by the let-7 microRNA family.
Johnson SM, Grosshans H, Shingara J, Byrom M, Jarvis R, Cheng A, Labourier
E, Reinert KL, Brown D, Slack FJ.
Department of Molecular, Cellular and Developmental Biology, Yale University,
P.O. Box 208103, New Haven, CT 06520, USA.
Interestingly, this year two groups in US, Ben Purow's group at University
of Virginia and Rakesh Kumar's group at MD Anderson Cancer Center, found
that one of mini RNAs called MIR-7 (or Micro RNA-7) suppresses the malignant
growth of cancer cells such as glioma by inhibiting the expression of at
least two oncogenes encoding EGF receptor (EGFR or ErbB1) and the kinase
PAK1. According to the latter's group, the expression of MIR-7 is under
the control of a homeobox transcription factor called HoxD10.
Thus, in principle,any drugs that can activate this homeobox protein might serve as anti-cancer therapeutics that block the oncogenic EGFR-RAS-AKT-PAK1 signaling pathways which are essential for the growth of more than 70% of all human cancers and NF (neurofibromatosis) tumors.
All-trans retinoic acid (RA) was reported to induce HoxD10 gene (Merril et
al, 2004). Is RA alone sufficient to activate MIR-7 gene, inactivating PAK1 gene?
MIR-7 GFP Fusion Gene for Anti-cancer Drug Screening
If the promoter region of MIR-7 gene is identified, we could express GFP
under the control of this promoter, and using the GFP as a reporter, we
could screen for anti-cancer drugs that activate this promoter in nematode
in vivo, or human glioma cells in vitro.
It is of great interest to note that human MIR-7 is expressed mainly in brain,
pancreas and thyroid (Lee et al, 2008), where abnormal activation of PAK1
causes lethal cancers.
Cancer Res. 2008 May 15; 68: 3566-72.
microRNA-7 inhibits the epidermal growth factor receptor and the Akt
pathway and is down-regulated in glioblastoma.
Kefas B, Godlewski J, Comeau L, Li Y, Abounader R, Hawkinson M, Lee
J, Fine H, Chiocca EA, Lawler S, Purow B.
Division of Neuro-Oncology, Neurology Department, University of Virginia
Health System, Charlottesville, Virginia, USA.
Cancer Res. 2008 Oct 15; 68: 8195-200.
MicroRNA-7, a homeobox D10 target, inhibits p21-activated kinase 1 and
regulates its functions.
Reddy SD, Ohshiro K, Rayala SK, Kumar R.
Department of Molecular and Cellular Oncology, The University of Texas
MD Anderson Cancer Center, Baylor College of Medicine, Houston, Texas 77030,
USA.
gene expression, which were first discovered in the nematode C. elegans,
just a decade ago by Craig Mello of University of Massachusetts and Andrew
Fire of Stanford University (2006 Nobel laureates).
In 2005 one of the nematode mini RNAs called Let-7 was found by Frank Slack's group at Yale University to be a suppressor of Let-60/RAS gene, suggesting that this mini RNA (or a related human counterpart) could work as a tumor suppressor in human RAS cancers such as pancreatic and colon cancers.
Cell. 2005 ;120: 635-47.
RAS is regulated by the let-7 microRNA family.
Johnson SM, Grosshans H, Shingara J, Byrom M, Jarvis R, Cheng A, Labourier
E, Reinert KL, Brown D, Slack FJ.
Department of Molecular, Cellular and Developmental Biology, Yale University,
P.O. Box 208103, New Haven, CT 06520, USA.
Interestingly, this year two groups in US, Ben Purow's group at University
of Virginia and Rakesh Kumar's group at MD Anderson Cancer Center, found
that one of mini RNAs called MIR-7 (or Micro RNA-7) suppresses the malignant
growth of cancer cells such as glioma by inhibiting the expression of at
least two oncogenes encoding EGF receptor (EGFR or ErbB1) and the kinase
PAK1. According to the latter's group, the expression of MIR-7 is under
the control of a homeobox transcription factor called HoxD10.
Thus, in principle,any drugs that can activate this homeobox protein might serve as anti-cancer therapeutics that block the oncogenic EGFR-RAS-AKT-PAK1 signaling pathways which are essential for the growth of more than 70% of all human cancers and NF (neurofibromatosis) tumors.
All-trans retinoic acid (RA) was reported to induce HoxD10 gene (Merril et
al, 2004). Is RA alone sufficient to activate MIR-7 gene, inactivating PAK1 gene?
MIR-7 GFP Fusion Gene for Anti-cancer Drug Screening
If the promoter region of MIR-7 gene is identified, we could express GFP
under the control of this promoter, and using the GFP as a reporter, we
could screen for anti-cancer drugs that activate this promoter in nematode
in vivo, or human glioma cells in vitro.
It is of great interest to note that human MIR-7 is expressed mainly in brain,
pancreas and thyroid (Lee et al, 2008), where abnormal activation of PAK1
causes lethal cancers.
Cancer Res. 2008 May 15; 68: 3566-72.
microRNA-7 inhibits the epidermal growth factor receptor and the Akt
pathway and is down-regulated in glioblastoma.
Kefas B, Godlewski J, Comeau L, Li Y, Abounader R, Hawkinson M, Lee
J, Fine H, Chiocca EA, Lawler S, Purow B.
Division of Neuro-Oncology, Neurology Department, University of Virginia
Health System, Charlottesville, Virginia, USA.
Cancer Res. 2008 Oct 15; 68: 8195-200.
MicroRNA-7, a homeobox D10 target, inhibits p21-activated kinase 1 and
regulates its functions.
Reddy SD, Ohshiro K, Rayala SK, Kumar R.
Department of Molecular and Cellular Oncology, The University of Texas
MD Anderson Cancer Center, Baylor College of Medicine, Houston, Texas 77030,
USA.
2008年10月13日月曜日
物理学に強いが、医学に弱い日本人の頭脳？
今秋のノーベル物理学賞の受賞者が３人共いずれも日本人学者、南部、小林、益
川の諸氏となり、第一号の湯川氏を含めて合計７人の日本物理学者（七人の侍）
の独創的な業績が今日まで世界的な評価を受けたことが明白になった。ノーベル
化学賞をもらった日本学者も今秋で合計５名になった。ところが医学の分野では、
日本人でノーベル賞をもらった学者は一人もいない。１９８７年に米国ＭＩＴの
利根川進氏（京大の理学部化学科出身）が医学生理学賞を受賞したが、彼の研究
内容は抗体遺伝子の進化／発生分化に関するもので、医学というよりは、「分子
生物学」と呼ばれる部類に属するもので、病気の治療には直接役立たない。しか
も、彼の研究は日本国内で行われたものではなく、スイスのバーゼル研究所で始
められ、かつ完成したもので、日本における医学や生物学の研究水準とは全く無
関係である。
さて、今秋ノーベル化学賞をもらった米国の学者３名の中に、日本人であるが米
国で長い間ＧＦＰ研究をやってきた生化学者の下村氏（長崎大学薬学部出身）が
含まれている。彼がプリンストン大学で留学 (ポスドク) 中、１９６０年頃から
始めた、緑色の蛍光を発するクラゲから発見したＧＦＰという蛍光蛋白に関する
開拓的な研究に対して、与えられたものである。これも純粋な生化学であり医学
には直接関係ないし、日本国内での研究成果でもない。日本では一体なぜ、世界
的な評価に価する独創的な医学研究が育ちにくいのだろうか？ 今秋（「ノーベ
ル賞への近道」といわれる）「ラスカー医学賞」をもらった遠藤氏は製薬会社
「三共」勤務時代に、世界に先駆けて、コレステロール低下薬「スタチン」を開
発した研究者であるが、東北大の農学部出身である。
ちなみに（私が制癌剤開発研究のため２０年以上永住している）豪州の人口は日
本の人口のわずか６分の１（約２千万人）に過ぎないが、ノーベル医学生理学賞
学者を戦後、なんと６名も産んでいる。戦後すぐ、抗生物質「ペニシリン」の開
発でノーベル賞第一号をもらったハワード・フローリーを始め、（胃潰瘍や胃癌
の発生主因である）ピロリ菌の発見で、最近ノーベル賞をもらったバリー・マー
シャル とロビン・ワレンなど全員、医学部出身である。もっとも数学を始め基
礎科学がかなり遅れている豪州では、物理学や化学でノーベル賞をもらったとい
う学者の例はまだ聞いていない。
医学部に進学するいわゆるエリート学生は、理系（自然科学志望）の学生の中で
最も頭脳明晰である（少なくとも、入学試験の合格点数が最も高い）といわれて
いる。従って、物理学や化学を専攻する学生よりも、学力的に劣っているとは考
えられない。とすると、日本において医学研究が不作な（独創性に欠けている）
のは、日本の大学の（法学部と同様、伝統的に最も封建的な）医学部における教
育のあり方、研究に対する基本姿勢に根本的な問題があるのだろうか？
巷では、日本人の研究が世界的な評価を受けにくいのは、日本人が英語の表現力
や会話力に弱いからだといわれている。しかし、果してそうだろうか？ 素粒子
の研究で今秋ノーベル賞をもらった益川氏は、「英語嫌い」で海外の学会に出か
けない変人で有名だそうだが、海外でもちゃんと評価されている。医学部出身、
あるいは医学関係の研究者は、特に英語に弱いのだろうか？ 多くの実例をみる
と、そんなことはとても考えにくい。（海外生活３５年の私自身の体験によれば）
海外の学会でも、極めて流暢な英語を話している医学関係者が多い。
川の諸氏となり、第一号の湯川氏を含めて合計７人の日本物理学者（七人の侍）
の独創的な業績が今日まで世界的な評価を受けたことが明白になった。ノーベル
化学賞をもらった日本学者も今秋で合計５名になった。ところが医学の分野では、
日本人でノーベル賞をもらった学者は一人もいない。１９８７年に米国ＭＩＴの
利根川進氏（京大の理学部化学科出身）が医学生理学賞を受賞したが、彼の研究
内容は抗体遺伝子の進化／発生分化に関するもので、医学というよりは、「分子
生物学」と呼ばれる部類に属するもので、病気の治療には直接役立たない。しか
も、彼の研究は日本国内で行われたものではなく、スイスのバーゼル研究所で始
められ、かつ完成したもので、日本における医学や生物学の研究水準とは全く無
関係である。
さて、今秋ノーベル化学賞をもらった米国の学者３名の中に、日本人であるが米
国で長い間ＧＦＰ研究をやってきた生化学者の下村氏（長崎大学薬学部出身）が
含まれている。彼がプリンストン大学で留学 (ポスドク) 中、１９６０年頃から
始めた、緑色の蛍光を発するクラゲから発見したＧＦＰという蛍光蛋白に関する
開拓的な研究に対して、与えられたものである。これも純粋な生化学であり医学
には直接関係ないし、日本国内での研究成果でもない。日本では一体なぜ、世界
的な評価に価する独創的な医学研究が育ちにくいのだろうか？ 今秋（「ノーベ
ル賞への近道」といわれる）「ラスカー医学賞」をもらった遠藤氏は製薬会社
「三共」勤務時代に、世界に先駆けて、コレステロール低下薬「スタチン」を開
発した研究者であるが、東北大の農学部出身である。
ちなみに（私が制癌剤開発研究のため２０年以上永住している）豪州の人口は日
本の人口のわずか６分の１（約２千万人）に過ぎないが、ノーベル医学生理学賞
学者を戦後、なんと６名も産んでいる。戦後すぐ、抗生物質「ペニシリン」の開
発でノーベル賞第一号をもらったハワード・フローリーを始め、（胃潰瘍や胃癌
の発生主因である）ピロリ菌の発見で、最近ノーベル賞をもらったバリー・マー
シャル とロビン・ワレンなど全員、医学部出身である。もっとも数学を始め基
礎科学がかなり遅れている豪州では、物理学や化学でノーベル賞をもらったとい
う学者の例はまだ聞いていない。
医学部に進学するいわゆるエリート学生は、理系（自然科学志望）の学生の中で
最も頭脳明晰である（少なくとも、入学試験の合格点数が最も高い）といわれて
いる。従って、物理学や化学を専攻する学生よりも、学力的に劣っているとは考
えられない。とすると、日本において医学研究が不作な（独創性に欠けている）
のは、日本の大学の（法学部と同様、伝統的に最も封建的な）医学部における教
育のあり方、研究に対する基本姿勢に根本的な問題があるのだろうか？
巷では、日本人の研究が世界的な評価を受けにくいのは、日本人が英語の表現力
や会話力に弱いからだといわれている。しかし、果してそうだろうか？ 素粒子
の研究で今秋ノーベル賞をもらった益川氏は、「英語嫌い」で海外の学会に出か
けない変人で有名だそうだが、海外でもちゃんと評価されている。医学部出身、
あるいは医学関係の研究者は、特に英語に弱いのだろうか？ 多くの実例をみる
と、そんなことはとても考えにくい。（海外生活３５年の私自身の体験によれば）
海外の学会でも、極めて流暢な英語を話している医学関係者が多い。
2008年10月10日金曜日
61 plus Nobel laureates support Obama for his US presidency!
Martin Chalfie, the Professor at Columbia University born in Chicago, said the first thing he did after finding out he was a 2008 Nobel Prize winner in Chemistry was to pledge his glowing support for Democrat Barack Obama for US president.
Sixty-one Nobel prize winners last month signed an open letter stating their support for the Illinois senator in Chicago, and Martin said he wanted to join that list.
In their letter, the Nobel winners said America "urgently needs a visionary leader who can ensure the future of our traditional strengths in science and technology and who can harness those strengths to address many of our greatest problems: energy, disease, climate change, security, and economic competitiveness."
"We are convinced that Senator Barack Obama is such a leader," they said.
http://www.news.com.au/story/0,23599,24469500-23109,00.html
Sixty-one Nobel prize winners last month signed an open letter stating their support for the Illinois senator in Chicago, and Martin said he wanted to join that list.
In their letter, the Nobel winners said America "urgently needs a visionary leader who can ensure the future of our traditional strengths in science and technology and who can harness those strengths to address many of our greatest problems: energy, disease, climate change, security, and economic competitiveness."
"We are convinced that Senator Barack Obama is such a leader," they said.
http://www.news.com.au/story/0,23599,24469500-23109,00.html
2008年10月9日木曜日
“GFP” Pioneers Won the 2008 Nobel Prize in Chemistry
Green Fluorescent Protein (GFP) was first isolated from a jellyfish called Aequorea victoria by a group at Princeton University in 1962. The major players in this team were a young Japanese scientist, Osamu Shimomura, and his boss, Prof. Frank Johnson. They also isolated from the same jellyfish another protein called Aequorin which emits blue light when it binds Ca2+ ion.
How is the blue light from Aequorin transformed to green fluorescence through GFP? To study the detailed mechanism was the major task of Dr. Shimomura for almost 2 decades since then. In 1979 he found that GFP contains a specific chromophore, an indole ring formed by oxidation of amino acid residues 65-67 (Ser-Gly-Tyr), which absorbs blue light and emits green fluorescence.
For this pioneering work, he was eventually awarded the Nobel prize in chemistry this year, together with two American scientists, Martin Chalfie of Columbia University and Roger Tsien of UCSD. What is the major contribution of these American scientists in GFP research field?
In 1992, GFP gene (cDNA) was cloned from the jellyfish by Douglas Prasher of Woods Hole Oceanographic Institute. However, due to a lack of research fund, he could not express this gene in E. coli or other organisms to prove that this gene alone is sufficient to produce the fully functional fluorescent protein.
Many doubted the GFP gene would produce the glowing protein on its own, mainly because its activation involves the oxidation of residues 65-67. Luckily, however, when Martin Chalfie put it in bacteria or transparent nematode and shined a blue light on them, they glowed. His 1994 paper on the GFP gene popularized it as a genetic marker. Scientists could link the GFP gene with another gene; were this piece of DNA present in a cell, it would shine.
Roger Tsien then mutated the GFP gene around its chromophore region to produce various colors. He also managed to make it brighter. The GFP found in the jellyfish produces some of its light when hit by ultraviolet light, some when hit by various shades of blue. His version of the protein produces all of its light when hit by a single color.
So the revolution of GFP technology continues. During 2007-2008, even my own team started to use a set of gene-promoter GFP constructs to quantify the expression level of a group of genes including Hsp16 in the nematode C. elegans to screen in vivo a series of anti-cancer synthetic compounds or natural products such as CAPE (caffeic acid phenethyl ester) from propolis which block the oncogenic PAK1 signal pathways. For PAK1 appears to inactivate a transcription factor called FOXO which is essential for the activation of Hsp16 and CKI1/p21 genes. If the nematode carrying the Hsp16 gene promoter-GFP construct is treated with one of anti-PAK1 drugs just overnight, this tiny transparent nematode of 1 mm long in a dish starts glowing under blue light. Such a GFP nematode system would eventually lead to the automation of in vivo anti-cancer drugs screening on (96-well) micro titer plates.
Continued.
How is the blue light from Aequorin transformed to green fluorescence through GFP? To study the detailed mechanism was the major task of Dr. Shimomura for almost 2 decades since then. In 1979 he found that GFP contains a specific chromophore, an indole ring formed by oxidation of amino acid residues 65-67 (Ser-Gly-Tyr), which absorbs blue light and emits green fluorescence.
For this pioneering work, he was eventually awarded the Nobel prize in chemistry this year, together with two American scientists, Martin Chalfie of Columbia University and Roger Tsien of UCSD. What is the major contribution of these American scientists in GFP research field?
In 1992, GFP gene (cDNA) was cloned from the jellyfish by Douglas Prasher of Woods Hole Oceanographic Institute. However, due to a lack of research fund, he could not express this gene in E. coli or other organisms to prove that this gene alone is sufficient to produce the fully functional fluorescent protein.
Many doubted the GFP gene would produce the glowing protein on its own, mainly because its activation involves the oxidation of residues 65-67. Luckily, however, when Martin Chalfie put it in bacteria or transparent nematode and shined a blue light on them, they glowed. His 1994 paper on the GFP gene popularized it as a genetic marker. Scientists could link the GFP gene with another gene; were this piece of DNA present in a cell, it would shine.
Roger Tsien then mutated the GFP gene around its chromophore region to produce various colors. He also managed to make it brighter. The GFP found in the jellyfish produces some of its light when hit by ultraviolet light, some when hit by various shades of blue. His version of the protein produces all of its light when hit by a single color.
So the revolution of GFP technology continues. During 2007-2008, even my own team started to use a set of gene-promoter GFP constructs to quantify the expression level of a group of genes including Hsp16 in the nematode C. elegans to screen in vivo a series of anti-cancer synthetic compounds or natural products such as CAPE (caffeic acid phenethyl ester) from propolis which block the oncogenic PAK1 signal pathways. For PAK1 appears to inactivate a transcription factor called FOXO which is essential for the activation of Hsp16 and CKI1/p21 genes. If the nematode carrying the Hsp16 gene promoter-GFP construct is treated with one of anti-PAK1 drugs just overnight, this tiny transparent nematode of 1 mm long in a dish starts glowing under blue light. Such a GFP nematode system would eventually lead to the automation of in vivo anti-cancer drugs screening on (96-well) micro titer plates.
Continued.
2008年10月8日水曜日
Discovery of Human Papilloma Virus in 1976:
Leading to the Recent Development of an Anti-cancer Vaccine.
The first oncogenic virus (oncovirus) was discovered in chicken sarcoma by Peyton Rous (1879-1970) of Rockefeller Institute in 1911. This virus was later called Rous Sarcoma Virus (RSV). In an attempt to find its possible link to mammalian or human cancers, he tried to fish an oncovirus in mammalian tumors, but in vain. So he eventually left this oncovirus research field.
However, during 1950s-1960s, a few oncoviruses were found in mouse or rat tumors. Some of them carry oncogenic mutants of RAS genes called Ha-RAS and Ki-RAS. Because of these mammalian oncoviruses, Rous at age of 87 was awarded the 1966 Nobel prize, more than a half-century after his discovery of RSV. Yet human oncovirus still remained to be identified…
Since then many onco-virologists including Robert Gallo of NIH, who is an expert in HIV virus as well, raced to find the very first “human” oncovirus, in an attempt to prove that some of human cancers are caused by viruses.
Harald zur Hausen in Germany also joined this highly-heated human oncovirus hunting. In 1976, he published the hypothesis that human papilloma virus (HPV) plays an important role in the cause of cervical cancer. Interestingly, the first established human cell line known “HeLa” cells carries HPV, which was derived from cervical cancer of a black woman called “Henrietta Lacks”.
This pioneering research of zur Hausen’s eventually contributed to the development of a HPV vaccine which was introduced in 2006.
Rev Med Virol. 2006 May-Jun;16:139-49.
Human papilloma virus vaccines.
Stanley MA.
Department of Pathology, Cambridge, UK. mas@mole.bio.cam.ac.uk
A wealth of epidemiological and molecular evidence has led to the conclusion that virtually all cases of cervical cancer and its precursor intra-epithelial lesions are a result of infection with one or other of a subset of genital human papilloma viruses (HPVs) suggesting that prevention of infection by prophylactic vaccination would be an effective anti-cancer strategy.
The papilloma viruses cannot be grown in large amounts in culture in vitro, but the ability to generate HPV virus like particles (VLPs) by the synthesis and self-assembly in vitro of the major virus capsid protein L1 provides for a potentially effective sub unit vaccine. HPV L1 VLP vaccines are immunogenic and have a good safety profile.
Published data from proof of principle trials and preliminary reports from large Phase III efficacy trials suggest strongly that they will protect against persistent HPV infection and cervical intra epithelial neoplasia. However, the duration of protection provided by these vaccines is not known, the antibody responses induced are probably HPV type specific and immunisation should occur pre-exposure to the virus. Second generation vaccines could include an early antigen for protection post-exposure and alternative delivery systems may be needed for the developing world. Copyright (c) 2006 John Wiley & Sons, Ltd.
However, during 1950s-1960s, a few oncoviruses were found in mouse or rat tumors. Some of them carry oncogenic mutants of RAS genes called Ha-RAS and Ki-RAS. Because of these mammalian oncoviruses, Rous at age of 87 was awarded the 1966 Nobel prize, more than a half-century after his discovery of RSV. Yet human oncovirus still remained to be identified…
Since then many onco-virologists including Robert Gallo of NIH, who is an expert in HIV virus as well, raced to find the very first “human” oncovirus, in an attempt to prove that some of human cancers are caused by viruses.
Harald zur Hausen in Germany also joined this highly-heated human oncovirus hunting. In 1976, he published the hypothesis that human papilloma virus (HPV) plays an important role in the cause of cervical cancer. Interestingly, the first established human cell line known “HeLa” cells carries HPV, which was derived from cervical cancer of a black woman called “Henrietta Lacks”.
This pioneering research of zur Hausen’s eventually contributed to the development of a HPV vaccine which was introduced in 2006.
Rev Med Virol. 2006 May-Jun;16:139-49.
Human papilloma virus vaccines.
Stanley MA.
Department of Pathology, Cambridge, UK. mas@mole.bio.cam.ac.uk
A wealth of epidemiological and molecular evidence has led to the conclusion that virtually all cases of cervical cancer and its precursor intra-epithelial lesions are a result of infection with one or other of a subset of genital human papilloma viruses (HPVs) suggesting that prevention of infection by prophylactic vaccination would be an effective anti-cancer strategy.
The papilloma viruses cannot be grown in large amounts in culture in vitro, but the ability to generate HPV virus like particles (VLPs) by the synthesis and self-assembly in vitro of the major virus capsid protein L1 provides for a potentially effective sub unit vaccine. HPV L1 VLP vaccines are immunogenic and have a good safety profile.
Published data from proof of principle trials and preliminary reports from large Phase III efficacy trials suggest strongly that they will protect against persistent HPV infection and cervical intra epithelial neoplasia. However, the duration of protection provided by these vaccines is not known, the antibody responses induced are probably HPV type specific and immunisation should occur pre-exposure to the virus. Second generation vaccines could include an early antigen for protection post-exposure and alternative delivery systems may be needed for the developing world. Copyright (c) 2006 John Wiley & Sons, Ltd.
2008年10月7日火曜日
My “New” Home in MELBOURNE
In an early October, I have decided to move in a small (studio-type) flat for rent in North Melbourne to stay there alone for a few years until I shall get enough money to buy a flat for myself. This flat, which reminds me of Abe Lincoln’s birth place (one-room log cabin) in Kentucky, is an extra home behind an old lady’s main house, near the top of a hill, only a half block from Royal Park with a lot of gum trees (eucalyptus) where I walk around for a hour every afternoon. I am now a retired scientist (65) living on pension, and have a plenty of time between writing books and blogs.
The main reason why I suddenly decided to leave our own house in North Melbourne where I used to share with one of my twin step-daughters and her husband is as follows:
Around 16 years ago, another twin step-daughter of mine in US decided to marry a Russian concert pianist in San Francisco around her 30th birthday. So her twin sister living in Melbourne was also quickly engaged to marry a nice Aussie gentleman. Fortunately, at that time, house boom here reached the very bottom, and it was the best time for us to buy a house. So two of us (I and her fiancé in Melbourne) decided to buy our own house so that three of us can live together. We eventually found an old two-story brick house in North Melbourne, located in 15-min walk from my own laboratory at Royal Melbourne Hospital (RMH). As I am a “Greens” supporter, I never drive a car, and have to walk to RMH or for grocery shopping.
Well, although this Victorian house built in 1882 is very comfortable for me, my step daughter nicknamed “Sunflower” has a complaint: it has no “sunny” bedroom (facing to north). She was born in Ghana, Africa, and loves a “hot” weather. So since then, almost every Saturday, she kept looking for her “dream” two-story house around Melbourne area where she could have a “sunny” bedroom. Eventually during my “hot summer” holiday in Tokyo when she had a “cold, windy and rainy (miserable) winter” in Melbourne, she managed to find that “dream” house, built in 1880 in West Melbourne. So When I returned to Melbourne in the end of August, she told me that we should sell our present house in North Melbourne in order to buy her dream house in West Melbourne which would cost around 1 million dollars. Her dream house has indeed a very large “sunny” bedroom and also a quite large backyard where her husband could enjoy his favorite gardening. It would be ideal for this young couple. So I agreed to sell our own house to make their dream come true.
However, I don’t like the location (surrounding) of their dream house. It is located right next to North Melbourne train station which is now under construction. Furthermore, this house is surrounded by a lot of factories, and along nearby streets, there is no green tree. It is also far away (not in a walking distance) from a nearby oriental grocery shopping center. So it is not my taste at all. So I decided not to move in their dream house, but stay alone in North Melbourne where both Royal Park and shopping center are nearby. However, since our own house is now on sale, I have to find a small flat for rent there to live alone. For we don’t have any money left in our own pocket enough to buy even a small flat or house.
Surely I feel very sad to realize that three of us no longer live together at least for a while until the construction of that train station will be completed in a few years and also most of factories will move away from that area of West Melbourne hopefully for several years so that the surrounding of their dream house would become far more agreeable to me… Until then I shall try to keep visiting their dream house to see them at least during weekends.
Although I lost a comfortable house of our own in North Melbourne, I might take an advantage in living alone. First of all, certainly I can have a very quiet (undisturbed) life suitable for writing several books to be published. Perhaps I might be given another bonus. I could have no steady (close) lady-friend for last two decades since I moved to Melbourne from US, mainly because I have dedicated most of my life time to the development of new anti-cancer drugs called “signal therapeutics” that block the oncogenic PAK1 signal pathways. However, after my recent retirement from cancer research, the time might be finally ripe for me to start looking for my “soul mate” seriously who could share the rest of our “twilight” life with me. Together we might be able to find a new “sweet” home of our own… It would be certainly nice to cherish such a pleasant dream of our own, whether it is eventually realized or not.
The main reason why I suddenly decided to leave our own house in North Melbourne where I used to share with one of my twin step-daughters and her husband is as follows:
Around 16 years ago, another twin step-daughter of mine in US decided to marry a Russian concert pianist in San Francisco around her 30th birthday. So her twin sister living in Melbourne was also quickly engaged to marry a nice Aussie gentleman. Fortunately, at that time, house boom here reached the very bottom, and it was the best time for us to buy a house. So two of us (I and her fiancé in Melbourne) decided to buy our own house so that three of us can live together. We eventually found an old two-story brick house in North Melbourne, located in 15-min walk from my own laboratory at Royal Melbourne Hospital (RMH). As I am a “Greens” supporter, I never drive a car, and have to walk to RMH or for grocery shopping.
Well, although this Victorian house built in 1882 is very comfortable for me, my step daughter nicknamed “Sunflower” has a complaint: it has no “sunny” bedroom (facing to north). She was born in Ghana, Africa, and loves a “hot” weather. So since then, almost every Saturday, she kept looking for her “dream” two-story house around Melbourne area where she could have a “sunny” bedroom. Eventually during my “hot summer” holiday in Tokyo when she had a “cold, windy and rainy (miserable) winter” in Melbourne, she managed to find that “dream” house, built in 1880 in West Melbourne. So When I returned to Melbourne in the end of August, she told me that we should sell our present house in North Melbourne in order to buy her dream house in West Melbourne which would cost around 1 million dollars. Her dream house has indeed a very large “sunny” bedroom and also a quite large backyard where her husband could enjoy his favorite gardening. It would be ideal for this young couple. So I agreed to sell our own house to make their dream come true.
However, I don’t like the location (surrounding) of their dream house. It is located right next to North Melbourne train station which is now under construction. Furthermore, this house is surrounded by a lot of factories, and along nearby streets, there is no green tree. It is also far away (not in a walking distance) from a nearby oriental grocery shopping center. So it is not my taste at all. So I decided not to move in their dream house, but stay alone in North Melbourne where both Royal Park and shopping center are nearby. However, since our own house is now on sale, I have to find a small flat for rent there to live alone. For we don’t have any money left in our own pocket enough to buy even a small flat or house.
Surely I feel very sad to realize that three of us no longer live together at least for a while until the construction of that train station will be completed in a few years and also most of factories will move away from that area of West Melbourne hopefully for several years so that the surrounding of their dream house would become far more agreeable to me… Until then I shall try to keep visiting their dream house to see them at least during weekends.
Although I lost a comfortable house of our own in North Melbourne, I might take an advantage in living alone. First of all, certainly I can have a very quiet (undisturbed) life suitable for writing several books to be published. Perhaps I might be given another bonus. I could have no steady (close) lady-friend for last two decades since I moved to Melbourne from US, mainly because I have dedicated most of my life time to the development of new anti-cancer drugs called “signal therapeutics” that block the oncogenic PAK1 signal pathways. However, after my recent retirement from cancer research, the time might be finally ripe for me to start looking for my “soul mate” seriously who could share the rest of our “twilight” life with me. Together we might be able to find a new “sweet” home of our own… It would be certainly nice to cherish such a pleasant dream of our own, whether it is eventually realized or not.
CAPE-rich Propolis Extract Reduces AD-related Amnesia in Mice
Propolis from NZ (New Zealand) and China are rich in an anti-cancer polyphenol called CAPE (caffeic acid phenethyl ester), and we have recently shown that Bio 30, CAPE-rich extract of NZ propolis (100 mg/kg), indeed suppresses almost completely the growth of brain tumors such as glioma and NF tumor xenografts in mice.
In this fall, Rui Wang’s group at Lanzhou University in China found that water-soluble (CAPE-rich) extract of Chinese propolis (100 mg/kg) effectively reduces the scopolamine-induced learning/memory impairment (amnesia) in mice, suggesting that such a propolis extract would be potentially useful for the treatment of AD (Alzheimer’s Disease) and other neurodegenerative diseases such as HD (Huntington’s Disease).
Although they tend to believe that its anti-AChE activity is responsible for the anti-amnesia action, the anti-AD/HD action is more likely due to its anti-PAK1 activity leading to the activation of Foxo and heat shock genes such as Hsp16 which would eventually block the beta-amyloid (BA) or polyQ (polyGln) –induced neurotoxicity, according to our recent study using the nematode C. elegans.
Pharmacol Biochem Behav. 2008 Sep;90: 441-6.
Water-soluble derivative of propolis mitigates scopolamine-induced learning and memory impairment in mice.
Chen J, Long Y, Han M, Wang T, Chen Q, Wang R.
Institute of Biochemistry and Molecular Biology, Lanzhou University, 222 Tian Shui South Road, Lanzhou, 730000, PR China.
The water-soluble derivative of propolis (WSDP) was prepared from fresh Chinese propolis. It has been reported that propolis possessed a broad spectrum of biological activities but including few studies on learning and memory by now. Thus, this study was aimed to investigate the effect of WSDP on scopolamine-induced learning and memory impairment in mice. WSDP (100 mg/kg) was given by intragastric administration (i.g.) 40 min prior to the intraperitoneal (i.p.) injection of scopolamine (1 mg/kg).The effect on amnesia was investigated with both hidden-platform acquisition training and probe trial testing in Morris water maze test. The results from 100 mg/kg WSDP group showed significant mitigation scopolamine-induced amnesia in mice.
Furthermore, WSDP (100 mg/kg) significantly inhibited acetylcholinesterase (AChE) activity in the hippocampus of scopolamine-treated mice. These results indicated that WSDP may mitigate amnesia in vivo through inhibition of AChE activity in the hippocampus, which suggested propolis may have potential as a pharmaceutical of brain protection with elderly population for preventing Alzheimer's disease (AD) and other neurodegenerative diseases.
In this fall, Rui Wang’s group at Lanzhou University in China found that water-soluble (CAPE-rich) extract of Chinese propolis (100 mg/kg) effectively reduces the scopolamine-induced learning/memory impairment (amnesia) in mice, suggesting that such a propolis extract would be potentially useful for the treatment of AD (Alzheimer’s Disease) and other neurodegenerative diseases such as HD (Huntington’s Disease).
Although they tend to believe that its anti-AChE activity is responsible for the anti-amnesia action, the anti-AD/HD action is more likely due to its anti-PAK1 activity leading to the activation of Foxo and heat shock genes such as Hsp16 which would eventually block the beta-amyloid (BA) or polyQ (polyGln) –induced neurotoxicity, according to our recent study using the nematode C. elegans.
Pharmacol Biochem Behav. 2008 Sep;90: 441-6.
Water-soluble derivative of propolis mitigates scopolamine-induced learning and memory impairment in mice.
Chen J, Long Y, Han M, Wang T, Chen Q, Wang R.
Institute of Biochemistry and Molecular Biology, Lanzhou University, 222 Tian Shui South Road, Lanzhou, 730000, PR China.
The water-soluble derivative of propolis (WSDP) was prepared from fresh Chinese propolis. It has been reported that propolis possessed a broad spectrum of biological activities but including few studies on learning and memory by now. Thus, this study was aimed to investigate the effect of WSDP on scopolamine-induced learning and memory impairment in mice. WSDP (100 mg/kg) was given by intragastric administration (i.g.) 40 min prior to the intraperitoneal (i.p.) injection of scopolamine (1 mg/kg).The effect on amnesia was investigated with both hidden-platform acquisition training and probe trial testing in Morris water maze test. The results from 100 mg/kg WSDP group showed significant mitigation scopolamine-induced amnesia in mice.
Furthermore, WSDP (100 mg/kg) significantly inhibited acetylcholinesterase (AChE) activity in the hippocampus of scopolamine-treated mice. These results indicated that WSDP may mitigate amnesia in vivo through inhibition of AChE activity in the hippocampus, which suggested propolis may have potential as a pharmaceutical of brain protection with elderly population for preventing Alzheimer's disease (AD) and other neurodegenerative diseases.
2008年9月23日火曜日
CEP-1347 for HD (Huntington’s Disease) Therapy
In 2002 we found that CEP-1347 is an inhibitor specific for Rac/CDC42-dependent kinases (PAKs/MLKs), and suppresses the growth of both RAS cancer and NF (neurofibromatosis) tumor cells where PAK1 is abnormally activated.
Interesting, like SAHA, CEP-1347 can pass through BBB (blood brain barrier) effectively so that it can reach brain tissues when this drug is administered systemically.
In 2003 Gillian Bates' group in London found that SAHA dramatically improves the motor impairment in HD mouse model (R6/2 mice). Like FK228, SAHA inhibits HDAC (histone deacetylase) directly, and eventually blocks the PAK1 signal pathways. However, neither FK228 nor SAHA was then available on the market. Besides, FK228 cannot cross the BBB.
In this fall Leslie Thomson’s group of UCI (University of California at Irvine) found that, like SAHA, CEP-1347 significantly reduces or delays the HD (Huntington’s Disease) symptom, both in vitro (cell culture) and in vivo (HD mouse model), suggesting that CEP-1347 and a few other anti-PAK1 drugs such as SAHA and Bio 30 could be potentially useful for the therapy of HD.
Since CEP-1347 is not available on the market as yet, it is likely that only two remedies so far available on the market, SAHA (expensive anti-CTCL drug) or Bio 30 (inexpensive healthcare product), would be used for the systemic (oral) treatment of HD patients at present. Like SAHA, Bio 30 can cross the BBB.
Mol Cell Neurosci. 2008 Sep;39: 8-20.
CEP-1347 reduces mutant huntingtin-associated neurotoxicity and restores BDNF levels in R6/2 mice.
Apostol BL, Simmons DA, Zuccato C, Illes K, Pallos J, Casale M, Conforti P, Ramos C, Roarke M, Kathuria S, Cattaneo E, Marsh JL, Thompson LM.
Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92697, USA.
Huntington's disease (HD) is a devastating neurodegenerative disorder caused by an expanded polyglutamine repeat within the protein Huntingtin (Htt). We previously reported that mutant Htt expression activates the ERK1/2 and JNK pathways [Apostol, B.L.et al, 2006]. Chemical and genetic modulation of these pathways promotes cell survival and death, respectively.
Here we test the ability of two closely related compounds, CEP-11004 and CEP-1347, which inhibit Mixed Lineage Kinases (MLKs) and are neuroprotective, to suppress mutant Htt-mediated pathogenesis in multiple model systems. CEP-11004/CEP-1347 treatment significantly decreased toxicity in mutant Htt-expressing cells that evoke a strong JNK response. However, suppression of cellular dysfunction in cell lines that exhibit only mild Htt-associated toxicity and little JNK activation was associated with activation of ERK1/2. These compounds also reduced neurotoxicity in immortalized striatal neurons from mutant knock-in mice and Drosophila expressing a mutant Htt fragment.
Finally, CEP-1347 improved motor performance in R6/2 mice and restored expression of BDNF, a critical neurotrophic factor that is reduced in HD. These studies suggest a novel therapeutic approach for a currently untreatable neurodegenerative disease, HD, via CEP-1347 up-regulation of BDNF.
Interesting, like SAHA, CEP-1347 can pass through BBB (blood brain barrier) effectively so that it can reach brain tissues when this drug is administered systemically.
In 2003 Gillian Bates' group in London found that SAHA dramatically improves the motor impairment in HD mouse model (R6/2 mice). Like FK228, SAHA inhibits HDAC (histone deacetylase) directly, and eventually blocks the PAK1 signal pathways. However, neither FK228 nor SAHA was then available on the market. Besides, FK228 cannot cross the BBB.
In this fall Leslie Thomson’s group of UCI (University of California at Irvine) found that, like SAHA, CEP-1347 significantly reduces or delays the HD (Huntington’s Disease) symptom, both in vitro (cell culture) and in vivo (HD mouse model), suggesting that CEP-1347 and a few other anti-PAK1 drugs such as SAHA and Bio 30 could be potentially useful for the therapy of HD.
Since CEP-1347 is not available on the market as yet, it is likely that only two remedies so far available on the market, SAHA (expensive anti-CTCL drug) or Bio 30 (inexpensive healthcare product), would be used for the systemic (oral) treatment of HD patients at present. Like SAHA, Bio 30 can cross the BBB.
Mol Cell Neurosci. 2008 Sep;39: 8-20.
CEP-1347 reduces mutant huntingtin-associated neurotoxicity and restores BDNF levels in R6/2 mice.
Apostol BL, Simmons DA, Zuccato C, Illes K, Pallos J, Casale M, Conforti P, Ramos C, Roarke M, Kathuria S, Cattaneo E, Marsh JL, Thompson LM.
Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92697, USA.
Huntington's disease (HD) is a devastating neurodegenerative disorder caused by an expanded polyglutamine repeat within the protein Huntingtin (Htt). We previously reported that mutant Htt expression activates the ERK1/2 and JNK pathways [Apostol, B.L.et al, 2006]. Chemical and genetic modulation of these pathways promotes cell survival and death, respectively.
Here we test the ability of two closely related compounds, CEP-11004 and CEP-1347, which inhibit Mixed Lineage Kinases (MLKs) and are neuroprotective, to suppress mutant Htt-mediated pathogenesis in multiple model systems. CEP-11004/CEP-1347 treatment significantly decreased toxicity in mutant Htt-expressing cells that evoke a strong JNK response. However, suppression of cellular dysfunction in cell lines that exhibit only mild Htt-associated toxicity and little JNK activation was associated with activation of ERK1/2. These compounds also reduced neurotoxicity in immortalized striatal neurons from mutant knock-in mice and Drosophila expressing a mutant Htt fragment.
Finally, CEP-1347 improved motor performance in R6/2 mice and restored expression of BDNF, a critical neurotrophic factor that is reduced in HD. These studies suggest a novel therapeutic approach for a currently untreatable neurodegenerative disease, HD, via CEP-1347 up-regulation of BDNF.
2008年9月22日月曜日
Mesothelioma: A new oncogenic target (YAP1)
of the tumor suppressor “Merlin”
In 2004 we found that Merlin, an NF2 gene product, directly inhibits the oncogenic kinase PAK1, and anti-PAK1 drugs such as CEP-1347 and FK228 suppress the growth of NF2-deficient mesothelioma and Schwannoma cell lines.
In summer of 2008, Yoshitaka Sekido’s group at Aichi Cancer Center, Japan, found another target of tumor suppressor “Merlin”, which is also an oncogene product of 65 kDa called YAP1 (YES-associated protein 1). YAP1 is active as a transcription-coactivator (activating a p53-related transcription factor called p73) only when it is localized in nucleus. However, “Merlin” causes the phosphorylation of YAP1 at Ser 127 by the kinase LATS1, and blocks the nuclear localization of YAP1. Thus, “Merlin” is the negative regulator of two oncoproteins, YAP1 and PAK1.
It should be worth noting that unlike PAK1, YAP1 does not bind "Merlin" directly, and nobody knows how "Merlin" activates LATS1. It is possible that PAK1 normally inactivate LATS1, and "Merlin" simply reverses the action of PAK1...
Interestingly, in malignant pleural mesotheliomas (MPMs), YAP1 gene is often over-expressed, and NF2 gene is often deleted (or dysfunctions). This could be explained by the fact that "Merlin" inactivates YAP1 gene somehow.
Since we discovered that “Bio 30”, a CAPE-rich water-miscible extract of propolis from NZ (New Zealand) , suppresses the growth of NF2-deficient Schwannoma cells both in vitro (cell culture) and in vivo (xenograft in mice) by blocking the oncogenic PAK1 pathways, it would be of great interest to examine whether like “Merlin”, Bio 30 causes the phosphorylation of YAP1 at Ser 127, inactivating YAP1. If so, since YAP1 is essential for the growth of these MPMs, Bio 30 could be useful for the treatment of the formidable MPMs, in addition to brain tumors such as NF (neurofibromatosis) and gliomas as well as pancreatic and breast cancers.
Carcinogenesis (PubMed, 2008 Aug 25):
YAP1 is involved in mesothelioma development and negatively regulated by Merlin through phosphorylation.
Yokoyama T, Osada H, Murakami H, Tatematsu Y, Taniguchi T, Kondo Y, Yatabe Y, Hasegawa Y, Shimokata K, Horio Y, Hida T, Sekido Y.
Division of Molecular Oncology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan.
We previously reported the results of BAC-array-CGH of malignant pleural mesotheliomas (MPMs), including two cases with high-level amplification in the 11q22 locus. In this study, we found that the YAP1 gene encoding a transcriptional co-activator, was localized in this amplified region and overexpressed in both cases, suggesting it as a candidate oncogene in this region. We analyzed the involvement of YAP1 in MPM proliferation, as well as its functional and physical interaction with Merlin encoded by the neurofibromatosis type 2 (NF2) tumor-suppressor gene, which is frequently mutated in MPMs. YAP1-RNAi suppressed growth of a mesothelioma cell line NCI-H290 with NF2 homozygous deletion, probably through cell-cycle arrest and apoptosis induction, while YAP1 transfection promoted the growth of MeT-5A, an immortalized mesothelial cell line. We also found that the introduction of NF2 into NCI-H290 induced phosphorylation at Ser127 of YAP1, which was accompanied by reduction of nuclear localization of YAP1, whereas nuclear localization of a YAP1 S127A-mutant was not affected. Furthermore, results of immunoprecipitation and in vitro pull-down assays indicated a physical interaction between Merlin and YAP1. These results suggest that YAP1 is involved in mesothelial cell growth, and that the transcriptional co-activator activity of YAP1 is functionally inhibited by Merlin through the induction of phosphorylation and cytoplasmic retention of YAP1. This is the first report of negative-regulatory signaling from Merlin to YAP1 in mammalian cells. Future studies of transcriptional targets of YAP1 in MPMs may shed light on the molecular mechanisms of MPM development and lead to new therapeutic strategies.
In summer of 2008, Yoshitaka Sekido’s group at Aichi Cancer Center, Japan, found another target of tumor suppressor “Merlin”, which is also an oncogene product of 65 kDa called YAP1 (YES-associated protein 1). YAP1 is active as a transcription-coactivator (activating a p53-related transcription factor called p73) only when it is localized in nucleus. However, “Merlin” causes the phosphorylation of YAP1 at Ser 127 by the kinase LATS1, and blocks the nuclear localization of YAP1. Thus, “Merlin” is the negative regulator of two oncoproteins, YAP1 and PAK1.
It should be worth noting that unlike PAK1, YAP1 does not bind "Merlin" directly, and nobody knows how "Merlin" activates LATS1. It is possible that PAK1 normally inactivate LATS1, and "Merlin" simply reverses the action of PAK1...
Interestingly, in malignant pleural mesotheliomas (MPMs), YAP1 gene is often over-expressed, and NF2 gene is often deleted (or dysfunctions). This could be explained by the fact that "Merlin" inactivates YAP1 gene somehow.
Since we discovered that “Bio 30”, a CAPE-rich water-miscible extract of propolis from NZ (New Zealand) , suppresses the growth of NF2-deficient Schwannoma cells both in vitro (cell culture) and in vivo (xenograft in mice) by blocking the oncogenic PAK1 pathways, it would be of great interest to examine whether like “Merlin”, Bio 30 causes the phosphorylation of YAP1 at Ser 127, inactivating YAP1. If so, since YAP1 is essential for the growth of these MPMs, Bio 30 could be useful for the treatment of the formidable MPMs, in addition to brain tumors such as NF (neurofibromatosis) and gliomas as well as pancreatic and breast cancers.
Carcinogenesis (PubMed, 2008 Aug 25):
YAP1 is involved in mesothelioma development and negatively regulated by Merlin through phosphorylation.
Yokoyama T, Osada H, Murakami H, Tatematsu Y, Taniguchi T, Kondo Y, Yatabe Y, Hasegawa Y, Shimokata K, Horio Y, Hida T, Sekido Y.
Division of Molecular Oncology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan.
We previously reported the results of BAC-array-CGH of malignant pleural mesotheliomas (MPMs), including two cases with high-level amplification in the 11q22 locus. In this study, we found that the YAP1 gene encoding a transcriptional co-activator, was localized in this amplified region and overexpressed in both cases, suggesting it as a candidate oncogene in this region. We analyzed the involvement of YAP1 in MPM proliferation, as well as its functional and physical interaction with Merlin encoded by the neurofibromatosis type 2 (NF2) tumor-suppressor gene, which is frequently mutated in MPMs. YAP1-RNAi suppressed growth of a mesothelioma cell line NCI-H290 with NF2 homozygous deletion, probably through cell-cycle arrest and apoptosis induction, while YAP1 transfection promoted the growth of MeT-5A, an immortalized mesothelial cell line. We also found that the introduction of NF2 into NCI-H290 induced phosphorylation at Ser127 of YAP1, which was accompanied by reduction of nuclear localization of YAP1, whereas nuclear localization of a YAP1 S127A-mutant was not affected. Furthermore, results of immunoprecipitation and in vitro pull-down assays indicated a physical interaction between Merlin and YAP1. These results suggest that YAP1 is involved in mesothelial cell growth, and that the transcriptional co-activator activity of YAP1 is functionally inhibited by Merlin through the induction of phosphorylation and cytoplasmic retention of YAP1. This is the first report of negative-regulatory signaling from Merlin to YAP1 in mammalian cells. Future studies of transcriptional targets of YAP1 in MPMs may shed light on the molecular mechanisms of MPM development and lead to new therapeutic strategies.
2008年9月18日木曜日
Bio 30 Blocks the Growth of Deadly Gliomas
Bio 30, a CAPE-rich water-miscible extract of propolis from NZ (New Zealand),
has been shown by us (Demestre, M. et al, 2008) to suppress the growth of several tumors in vivo (xenografts in mice): deadly pancreatic cancer, breast cancer, and NF (neurofibromatosis) tumors (both deadly NF1 MPNST and NF2 Schwannoma).
Several years ago David Kaplan's group in Canada found that the GTPase Rac is essential for the growth of glioma cells (Senger, D. et al, 2002). Interestingly, CAPE down-regulates Rac, eventually inactivating the oncogenic kinase PAK1.
Thus, we recently tested the therapeutic effect of Bio 30 (100-300 mg/kg,
i.p., twice a week) on human grade 4 glioma (U87MG) xenograft in mice over
a few weeks. Both doses of Bio 30 turned out to be sufficient for the
complete suppression of glioma growth (Messerli, S. et al, 2008). We continue testing if Bio 30 also causes any regression of this deadly tumor.
Anti-cancer ingredients such as CAPE (caffeic acid phenethyl ester) in Bio
30 can easily pass the BBB (blood brain barrier), and CAPE alone has been shown by a Taiwanese group to suppress the growth of glioma (C6) xenograft in mice a few years ago (Kuo, HG et al, 2006).
However, CAPE has never been used clinically (and is not available on the market), because of its poor bioavailability. Unlike CAPE alone, Bio 30 has a very good bioavailabity, because it contains a plenty of lipids which solubilize CAPE and several other water-insoluble anti-cancer ingredients. Besides, like many other propolis, Bio 30 can boost the immune system to suppress the growth of cancers in general. Thus, Bio 30 would be potentially good for the systemic treatment of brain tumors such as NF and gliomas.
So far no effective therapeutic for glioma is available on the market. Thus,
it is likely that Bio 30 (alcohol-free liquid) from Manuka Health, NZ would serve as the first effective therapeutic for gliomas. It is both very safe and inexpensive
(costing only a dollar for the daily treatment). The recommended daily dose
would be 1 ml per 10 kg (bodyweight), meaning 6 ml per day for patients weighing
60 kg (130-135 pounds) who suffer from glioma or other PAK1-dependent tumors
such as NF and pancreatic cancers.
Continued
has been shown by us (Demestre, M. et al, 2008) to suppress the growth of several tumors in vivo (xenografts in mice): deadly pancreatic cancer, breast cancer, and NF (neurofibromatosis) tumors (both deadly NF1 MPNST and NF2 Schwannoma).
Several years ago David Kaplan's group in Canada found that the GTPase Rac is essential for the growth of glioma cells (Senger, D. et al, 2002). Interestingly, CAPE down-regulates Rac, eventually inactivating the oncogenic kinase PAK1.
Thus, we recently tested the therapeutic effect of Bio 30 (100-300 mg/kg,
i.p., twice a week) on human grade 4 glioma (U87MG) xenograft in mice over
a few weeks. Both doses of Bio 30 turned out to be sufficient for the
complete suppression of glioma growth (Messerli, S. et al, 2008). We continue testing if Bio 30 also causes any regression of this deadly tumor.
Anti-cancer ingredients such as CAPE (caffeic acid phenethyl ester) in Bio
30 can easily pass the BBB (blood brain barrier), and CAPE alone has been shown by a Taiwanese group to suppress the growth of glioma (C6) xenograft in mice a few years ago (Kuo, HG et al, 2006).
However, CAPE has never been used clinically (and is not available on the market), because of its poor bioavailability. Unlike CAPE alone, Bio 30 has a very good bioavailabity, because it contains a plenty of lipids which solubilize CAPE and several other water-insoluble anti-cancer ingredients. Besides, like many other propolis, Bio 30 can boost the immune system to suppress the growth of cancers in general. Thus, Bio 30 would be potentially good for the systemic treatment of brain tumors such as NF and gliomas.
So far no effective therapeutic for glioma is available on the market. Thus,
it is likely that Bio 30 (alcohol-free liquid) from Manuka Health, NZ would serve as the first effective therapeutic for gliomas. It is both very safe and inexpensive
(costing only a dollar for the daily treatment). The recommended daily dose
would be 1 ml per 10 kg (bodyweight), meaning 6 ml per day for patients weighing
60 kg (130-135 pounds) who suffer from glioma or other PAK1-dependent tumors
such as NF and pancreatic cancers.
Continued
2008年9月15日月曜日
2008 "Lasker" Award for Clinical Research
http://www.laskerfoundation.org/awards/2008_c_description.htm
Winner: Akira Endo (74)
For the discovery of the statins — drugs with remarkable LDL-cholesterol-lowering properties that have revolutionized the prevention and treatment of coronary heart disease.
The 2008 Lasker~DeBakey Award for Clinical Medical Research honors a scientist who discovered statins—drugs with remarkable LDL-cholesterol-lowering properties that have revolutionized the prevention and treatment of coronary heart disease (CHD). Akira Endo (Biopharm Research Laboratories, Inc., Tokyo) sifted through thousands of organisms, hunting for natural substances that block a key enzyme in the biochemical pathway that produces cholesterol, a major contributor to CHD. Remarkably, the compound that Endo found lowers concentrations of LDL (the bad cholesterol) but not HDL (the good cholesterol) in the bloodstream of animals and humans. His work stimulated Merck, Sharp & Dohme Research Laboratories (Merck) to launch a drug-development program that led, 20 years ago, to the first statin approved for medical use. This advance paved a path for other pharmaceutical companies to follow.
LDL in the bloodstream can form fatty deposits that narrow blood vessels. When this process occurs in arteries that deliver blood to the heart, it can lead to CHD, the major cause of chest pain and heart attack and the top killer in the industrialized world. In the US, more than 450,000 people died from CHD in 2004. In 2005, the American Heart Association estimated that 16 million Americans had CHD and 1.2 million would have a new or recurrent heart attack that year. Statin use is increasing—30 million people worldwide are taking them—and has begun to make a dent in those numbers. The drugs dramatically reduce the risk of CHD and its associated life-threatening events. Furthermore, studies with statins have erased long-standing doubt about the possibility of safely reducing cholesterol quantities with pharmaceutical agents.
Promising Early Results
In the 1950s and 1960s, epidemiological studies suggested a link between LDL cholesterol in the blood and CHD. Reducing LDL would shrink the incidence of this illness, some experts reasoned. However, many scientists and clinicians questioned whether doing so would stir trouble. Cholesterol is a crucial component of the membranes that encase our cells, and it serves as a raw material for other essential molecules, including some hormones and the sheath that insulates nerves. Further exacerbating uncertainty, most early agents that reduced cholesterol quantities in the blood cut concentrations only modestly and triggered unwelcome side effects. Therefore, skepticism simmered about the wisdom of lowering cholesterol concentrations.
Despite the concerns, efforts pushed forward. Humans acquire cholesterol from food and we also make it in our bodies, mostly in the liver. Dietary interventions to limit cholesterol intake had met with poor success and the idea of short-circuiting our ability to produce the compound seemed attractive. An enzyme called HMG-CoA reductase plays a central role in the manufacture of cholesterol. In the biochemical pathway that generates cholesterol, it converts a precursor molecule, HMG-CoA, into the next compound, mevalonate.
By 1971, when Endo began his work (at Sankyo Company in Tokyo), thwarting the reductase seemed like a possible way to keep the body's cholesterol production in check. Endo had a novel idea about how to find substances that block the reductase. Aware that organisms can secrete compounds with powerful biological activities—presumably to kill their competitors—Endo proposed that some creatures might spit out chemicals that foil the reductase and thus impede a vital activity of their neighbors.
Over the next two years, Endo and colleagues grew more than 6000 fungi, harvested the broth in which each had grown, and tested whether the material could interfere with an early step of cholesterol synthesis in a test tube. They then separated its components from one another, keeping track of the active material. By this and additional methods, he purified a substance from the fungus Penicillium citrinum, called mevastatin or "compactin", that blocks the reductase.
Additional analysis revealed that compactin resembles HMG-CoA and competes strongly with it for the site on the enzyme that catalyzes HMG-CoA's conversion to mevalonate. This capacity to bind specifically to the spot normally reserved for the enzyme's substrate suggested that the potential drug would not randomly clasp molecules in cells and disrupt other important activities.
Endo wondered whether compactin would reduce enzyme activity in animals, as it does in test tubes. In 1979, he showed that the compound dramatically lowers blood cholesterol in dogs and monkeys with no obvious toxic effects.
While these results were coming in, Endo and physician Akira Yamamoto (National Cardiovascular Center in Osaka) gave compactin to patients with extremely high LDL-cholesterol levels. In 1980, they reported that it cut LDL in the blood by an average of 27%. The next year, Hiroshi Mabuchi of Kanazawa School of Medicine published similarly promising findings. Furthermore, he established that the compound did not perturb quantities of a molecule that is involved in the cell's energy-production system whose concentrations experts thought might drop when HMG-CoA activity was stymied. These observations fed hope that compactin could reduce cholesterol without causing harm.
At the same time, different researchers were demonstrating the mechanism by which the drug acted, which provided a rationale for how it could operate safely. In 1974, Michael Brown and Joseph Goldstein (Lasker Basic Medical Research Award and Nobel Prize, 1985) at the University of Texas Southwestern Medical School discovered that cell-surface molecules known as LDL receptors on liver cells grab LDL in the blood. In 1981, they showed that, when statins lower reductase activity and cholesterol production wanes, cells place additional LDL receptors on their surfaces. Statins thus harness a normal mechanism by which cells drain cholesterol from the blood, yet ensure a steady supply of the molecule internally for vital activities.
Statins reducing cholesterol:
Compactin (C), the first statin, discovered by Akira Endo;
Lovastatin (L), the first statin approved for clinical use, developed by Merck.
the compound "L" is a methylated form of the compound "C".
Statins in the Clinic
In 1978, Endo left Sankyo and joined the faculty of Tokyo Noko University. There, he isolated additional HMG-CoA reductase inhibitors, including one called monacolin K, from another fungus. Merck scientists, led by Alfred W. Alberts, independently identified—from a different organism—the same compound, which they called mevinolin (and subsequently renamed "lovastatin"). The company had been pursuing statin-related research since soon after Endo published his first papers in 1976. At that time, P. Roy Vagelos, then President of Merck Research Laboratories, had signed an agreement with Sankyo and obtained samples of compactin from Endo, with which Merck confirmed Endo's results and launched its own program.
In April 1980, Merck began clinical studies of lovastatin. Several months later, rumors emerged from Sankyo that the drug caused tumors in dogs. Merck halted its studies. However, experts in the field urged the company forward. The dogs were receiving exceptionally high doses and Sankyo provided no data for others to assess. Investigators were witnessing dramatic benefits with compactin, particularly to individuals who have a genetic alteration in one of their two copies of the gene for the LDL receptor and thus carry colossal quantities of circulating cholesterol; these patients are extremely difficult to treat.
Several years later, Merck picked up its clinical trials on lovastatin. In 1987, the FDA approved the drug (Mevacor®).
The success of compactin and lovastatin inspired efforts to improve the statins by chemically modifying the natural compounds or crafting synthetic ones. Because the statins curb LDL so much more than any of the existing treatments, it became possible to demonstrate unequivocally that the drugs decrease CHD events without serious side effects. For example, in 1994, the Scandinavian Simvastatin Survival Study (4S study) showed that treatment with simvastatin (the second Merck statin) —for as short a period as five years—lowered LDL levels by 35%; this reduction was associated with a drop of 40% in CHD deaths. A 2005 analysis of more than 90,000 people in multiple 5-year randomized studies obtained similar results. Furthermore, this work established that people reap these benefits without an increase in cancer, other diseases, or deaths from any cause.
Statins are now routinely used to prevent and treat CHD throughout the world. Although CHD is aggravated by multiple risk factors in addition to high LDL—cigarette smoking, high blood pressure, obesity, and diabetes —reducing LDL levels alone makes a significant impact.
By discovering statins, Endo ushered in a new era in preventing and treating CHD, the leading cause of death in the US and a major source of human suffering. His work has touched millions of people and promises to prolong and improve the lives of many millions more.
by Evelyn Strauss, Ph.D.
Winner: Akira Endo (74)
For the discovery of the statins — drugs with remarkable LDL-cholesterol-lowering properties that have revolutionized the prevention and treatment of coronary heart disease.
The 2008 Lasker~DeBakey Award for Clinical Medical Research honors a scientist who discovered statins—drugs with remarkable LDL-cholesterol-lowering properties that have revolutionized the prevention and treatment of coronary heart disease (CHD). Akira Endo (Biopharm Research Laboratories, Inc., Tokyo) sifted through thousands of organisms, hunting for natural substances that block a key enzyme in the biochemical pathway that produces cholesterol, a major contributor to CHD. Remarkably, the compound that Endo found lowers concentrations of LDL (the bad cholesterol) but not HDL (the good cholesterol) in the bloodstream of animals and humans. His work stimulated Merck, Sharp & Dohme Research Laboratories (Merck) to launch a drug-development program that led, 20 years ago, to the first statin approved for medical use. This advance paved a path for other pharmaceutical companies to follow.
LDL in the bloodstream can form fatty deposits that narrow blood vessels. When this process occurs in arteries that deliver blood to the heart, it can lead to CHD, the major cause of chest pain and heart attack and the top killer in the industrialized world. In the US, more than 450,000 people died from CHD in 2004. In 2005, the American Heart Association estimated that 16 million Americans had CHD and 1.2 million would have a new or recurrent heart attack that year. Statin use is increasing—30 million people worldwide are taking them—and has begun to make a dent in those numbers. The drugs dramatically reduce the risk of CHD and its associated life-threatening events. Furthermore, studies with statins have erased long-standing doubt about the possibility of safely reducing cholesterol quantities with pharmaceutical agents.
Promising Early Results
In the 1950s and 1960s, epidemiological studies suggested a link between LDL cholesterol in the blood and CHD. Reducing LDL would shrink the incidence of this illness, some experts reasoned. However, many scientists and clinicians questioned whether doing so would stir trouble. Cholesterol is a crucial component of the membranes that encase our cells, and it serves as a raw material for other essential molecules, including some hormones and the sheath that insulates nerves. Further exacerbating uncertainty, most early agents that reduced cholesterol quantities in the blood cut concentrations only modestly and triggered unwelcome side effects. Therefore, skepticism simmered about the wisdom of lowering cholesterol concentrations.
Despite the concerns, efforts pushed forward. Humans acquire cholesterol from food and we also make it in our bodies, mostly in the liver. Dietary interventions to limit cholesterol intake had met with poor success and the idea of short-circuiting our ability to produce the compound seemed attractive. An enzyme called HMG-CoA reductase plays a central role in the manufacture of cholesterol. In the biochemical pathway that generates cholesterol, it converts a precursor molecule, HMG-CoA, into the next compound, mevalonate.
By 1971, when Endo began his work (at Sankyo Company in Tokyo), thwarting the reductase seemed like a possible way to keep the body's cholesterol production in check. Endo had a novel idea about how to find substances that block the reductase. Aware that organisms can secrete compounds with powerful biological activities—presumably to kill their competitors—Endo proposed that some creatures might spit out chemicals that foil the reductase and thus impede a vital activity of their neighbors.
Over the next two years, Endo and colleagues grew more than 6000 fungi, harvested the broth in which each had grown, and tested whether the material could interfere with an early step of cholesterol synthesis in a test tube. They then separated its components from one another, keeping track of the active material. By this and additional methods, he purified a substance from the fungus Penicillium citrinum, called mevastatin or "compactin", that blocks the reductase.
Additional analysis revealed that compactin resembles HMG-CoA and competes strongly with it for the site on the enzyme that catalyzes HMG-CoA's conversion to mevalonate. This capacity to bind specifically to the spot normally reserved for the enzyme's substrate suggested that the potential drug would not randomly clasp molecules in cells and disrupt other important activities.
Endo wondered whether compactin would reduce enzyme activity in animals, as it does in test tubes. In 1979, he showed that the compound dramatically lowers blood cholesterol in dogs and monkeys with no obvious toxic effects.
While these results were coming in, Endo and physician Akira Yamamoto (National Cardiovascular Center in Osaka) gave compactin to patients with extremely high LDL-cholesterol levels. In 1980, they reported that it cut LDL in the blood by an average of 27%. The next year, Hiroshi Mabuchi of Kanazawa School of Medicine published similarly promising findings. Furthermore, he established that the compound did not perturb quantities of a molecule that is involved in the cell's energy-production system whose concentrations experts thought might drop when HMG-CoA activity was stymied. These observations fed hope that compactin could reduce cholesterol without causing harm.
At the same time, different researchers were demonstrating the mechanism by which the drug acted, which provided a rationale for how it could operate safely. In 1974, Michael Brown and Joseph Goldstein (Lasker Basic Medical Research Award and Nobel Prize, 1985) at the University of Texas Southwestern Medical School discovered that cell-surface molecules known as LDL receptors on liver cells grab LDL in the blood. In 1981, they showed that, when statins lower reductase activity and cholesterol production wanes, cells place additional LDL receptors on their surfaces. Statins thus harness a normal mechanism by which cells drain cholesterol from the blood, yet ensure a steady supply of the molecule internally for vital activities.
Statins reducing cholesterol:
Compactin (C), the first statin, discovered by Akira Endo;
Lovastatin (L), the first statin approved for clinical use, developed by Merck.
the compound "L" is a methylated form of the compound "C".
Statins in the Clinic
In 1978, Endo left Sankyo and joined the faculty of Tokyo Noko University. There, he isolated additional HMG-CoA reductase inhibitors, including one called monacolin K, from another fungus. Merck scientists, led by Alfred W. Alberts, independently identified—from a different organism—the same compound, which they called mevinolin (and subsequently renamed "lovastatin"). The company had been pursuing statin-related research since soon after Endo published his first papers in 1976. At that time, P. Roy Vagelos, then President of Merck Research Laboratories, had signed an agreement with Sankyo and obtained samples of compactin from Endo, with which Merck confirmed Endo's results and launched its own program.
In April 1980, Merck began clinical studies of lovastatin. Several months later, rumors emerged from Sankyo that the drug caused tumors in dogs. Merck halted its studies. However, experts in the field urged the company forward. The dogs were receiving exceptionally high doses and Sankyo provided no data for others to assess. Investigators were witnessing dramatic benefits with compactin, particularly to individuals who have a genetic alteration in one of their two copies of the gene for the LDL receptor and thus carry colossal quantities of circulating cholesterol; these patients are extremely difficult to treat.
Several years later, Merck picked up its clinical trials on lovastatin. In 1987, the FDA approved the drug (Mevacor®).
The success of compactin and lovastatin inspired efforts to improve the statins by chemically modifying the natural compounds or crafting synthetic ones. Because the statins curb LDL so much more than any of the existing treatments, it became possible to demonstrate unequivocally that the drugs decrease CHD events without serious side effects. For example, in 1994, the Scandinavian Simvastatin Survival Study (4S study) showed that treatment with simvastatin (the second Merck statin) —for as short a period as five years—lowered LDL levels by 35%; this reduction was associated with a drop of 40% in CHD deaths. A 2005 analysis of more than 90,000 people in multiple 5-year randomized studies obtained similar results. Furthermore, this work established that people reap these benefits without an increase in cancer, other diseases, or deaths from any cause.
Statins are now routinely used to prevent and treat CHD throughout the world. Although CHD is aggravated by multiple risk factors in addition to high LDL—cigarette smoking, high blood pressure, obesity, and diabetes —reducing LDL levels alone makes a significant impact.
By discovering statins, Endo ushered in a new era in preventing and treating CHD, the leading cause of death in the US and a major source of human suffering. His work has touched millions of people and promises to prolong and improve the lives of many millions more.
by Evelyn Strauss, Ph.D.
2008年8月31日日曜日
The "PAK" Story
Leading to a New Therapy of Cancers and NF
The origin of PAK
The new word "PAK" was created by a Brit scientist called Edward Manser
around 1994. Ed and his colleagues at IMCB of Singapore National University then cloned
a new gene from mammalian brain, which encodes a new enzyme, Ser/Thr kinase,
that is uniquely activated by two GTPases (or G proteins) called Rac and
CDC42 of 21K daltons. Then these small GTPases were collectively called
p21. So he proudly coined this new enzyme "PAK" (standing for p21-activated
kinase). Unfortunately, however, just a year before, another protein of
21K daltons was cloned, and named p21, WAF1 or CIP1, depending on its discoverers.
This new protein (p21/WAF1/CIP1) has nothing to do with these small GTPases,
but an inhibitor of another kinase called CDK (cyclin-dependent kinase).
To avoid the potential confusion, many "wise" experts in this kinase field
decided not to use the terminology p21 for a very large family of small
GTPases any more, and began to use only the simple word "PAK" for this Rac/CDC42
(p21)-dependent Ser/Thr kinase. On the other hands, this CDK inhibitor of
21K daltons continued to be called "p21" world wide till now.
Since then so many members of PAK family kinase have been cloned from mammalian
tissues, and called PAK1, PAK2, PAK3, PAK4, PAK5, PAK6 and so forth. Also
another family of Rac/CDC42-dependent Ser/Thr kinases was discovered in
mammals, and called "MLK" (standing for mixed linage kinase). Well, back
to 1977, when I used to work at Ed Korn's lab of NIH, we discovered a new
Ser/Thr kinase in a soil amoeba, which phosphorylates the heavy chain of
a unique single-headed myosin called Myosin I. So we called this kinase "Myosin
I heavy chain kinase" (MIHCK). This kinase is essential for the activation
of this myosin ATPase by F-actin (actin filaments) . Shortly after PAK1
was cloned from mammals, we compared the amino acid sequence of PAK1 and
MIHCK, and found that these two kinases are very closely related. Both enzymes
contain the Rac/CDC42-binding site at N-terminal half, and the kinase (catalytic)
domain at C-terminal half. Furthermore, like PAK1, MIHCK is indeed activated
by Rac/CDC42. In other words, our MIHCK was the first identified member
of PAK kinase family, perhaps called "PAK0" (O for "zero" or "origin"). Yes,
both MIHCK (PAK0) and PAK1-3 (class I PAK) are involved in the regulation
of non-muscle cell movements such as membrane ruffling and cell migration
in primitive amoeba and mammalian cells.
PAK-dependent diseases
During last decade, PAK (in particular PAK1) research entered medical field,
in particular molecular oncology. The major reason was that the GTPases
Rac and CDC42 were found by Frank McCormick's group of Onyx Pharm during
1995-1996 to be essential for RAS-induced malignant transformation of normal
fibroblasts such as NIH/3T3 cells. RAS, the small GTPase of 21K daltons,
is mutated oncogenically in more than 30% of all human cancers. Most notably,
RAS is mutated in more than 90% of pancreatic cancers, and more than 50%
of colon cancers. Oncogenic RAS somehow activates both Rac and CDC42 to
cause these cancers. In 1997, Jeff Field's group at University of Pennsylvania
found that PAK1 is essential for RAS-induced malignant transformation of
a fibroblast. This discovery triggered many scientists including us to investigate
further the potential role of PAK1 in many other cancers and even several
other diseases.
In 1998, Jeff's group reported that PAK1 is essential for the growth of
NF1 tumor in mice. NF stands for neurofibromatosis, a group of genetic diseases often associated
with tumors in brain, along spine and on skin. There are two types of NF.
Type 1 (NF1) is caused by dysfunction of NF1 gene product, a RAS GAP of
2818 amino acids. (Loss-of-function) mutation of this tumor suppressor gene
causes the abnormal activation of RAS, which is very similar to oncogenic
mutation of RAS, and eventually leads to the abnormal activation of PAK1.
Type 2 (NF2) is caused by dysfunction of NF2 gene product called "Merlin"
which we recently found is an inhibitor of PAK1, another tumor suppressor.
Thus, dysfunction of "Merlin" also causes the abnormal activation of PAK1.
NF2 is associated with brain/spine tumors called Meningioma and Schwannoma.
In other words, RAS cancers such as pancreatic and colon cancers are closely
related to both NF1 and NF2 tumors at molecular levels, being caused by
the oncogenic PAK1. However, until recently no effective therapeutics was
available on the market for these cancer or NF patients.
Anti-PAK drugs
Thus, during last several years, we have identified or developed a series
of anti-PAK1 drugs from synthetic chemicals and natural products for the
therapy of these PAK1-dependent cancers/tumors. Among them, so far the antibiotic
(a ring peptide) called FK228 is the most potent. It was originally developed
by Fujisawa Pharm around 1994 for suppressing the growth of RAS cancer cells,
and then later found to be a specific inhibitor of HDAC (histone deacetylase)
which we found eventually blocks the oncogenic PAK1 pathways. FK228 is now
in clinical trials (phase 2) mainly for CTCL (cutaneous T-cell lymphoma).
However, in animal models, FK228 was found to suppress the growth of so
many other cancers such as breast, prostate, pancreatic cancers, NF tumors,
and glioma, which altogether represent more than 70% of all human cancers.
Furthermore, FK228 suppresses several other diseases such as asthma and
arthritis in mouse models. These findings strongly suggest that PAK1 is involved
in the majority of cancers, and even several non-tumor diseases. Using other
anti-PAK1 drugs, we and others confirmed that formidable blood cancers such
as MM (multiple myeloma), and Alzheimer diseases (AD), Parkinson's diseases
(PD), AIDS (HIV-infection), epilepsy, malaria and autism such as Fragile
X syndrome also require PAK1. These additional findings hint the potentially
huge market value of these anti-PAK1 drugs. However, among these synthetic
anti-PAK1 chemicals, so far only one drug is available on the market with
FDA approval. It was originally called "SAHA", but Merck brand-named "Zolinga"
in October of 2006 only for the treatment of CTCL. Like FK228, SAHA is
an HDAC inhibitor, but less potent than FK228.
Anti-PAK drugs in Nature
Since clinical trials of these anti-cancer/anti-PAK1 drugs usually would
take a decade or more to be completed for each drug to get ready for marketing,
none of these cancer or NF patients would get any immediate benefit from
these potent anti-PAK1 drugs such as FK228, CEP-1347, TAT-PAK18, OSU-03012,
and GL-2003/GL-2005 for the coming decade. Thus, a few years ago, responding
to the urgent cry from many cancer/NF patients or their families, we decided
to identify an effective anti-PAK1 product in the nature, that is among all
sorts of vegetables, fruits or healthcare food supplements available on the
market.
After try and error (and educated guess), we eventually found the first effective
natural anti-PAK1 product. It has been sold as a healthcare food supplement under
the brand name of "Bio 30" mainly in New Zealand (NZ). Interestingly, the million-
years wisdom of NZ honey bees has contributed to this recent finding of ours.
Bio 30 is produced by bee keepers outskirts of Auckland where Sir Edmond
Hillary (1919-2008) used to live. He was best known to reach first the summit
of Mt. Everest (8850 m high) with his SherpaTenzing Norgay in 1953, but
also known as a life-long bee keeper. It has been said for many decades
that no bee keeper suffers from any cancer. Sir Edmond indeed was never
caught by cancer. However, nobody knew why.
Two decades ago, however, a Jewish scientist at Columbia University found
the first clue to this mystery. Dr. Grunberger identified the major anti-cancer
ingredient in propolis extract. It was CAPE (caffeic acid phenethyl ester).
Honey bees collect CAPE mainly from young buds of poplar trees, making "honey
wax" (also called "propolis" first by Hippocrates) to seal the honeycombs,
protecting their larva from all sorts of pathogenic bacteria or viruses.
Because of its anti-infectious action, ancient Egyptian people used propolis
for healing wounds and preparing mummies. Interestingly, the CAPE content
of NZ propolis turns out to be the highest among propolis samples around
the world. Indeed around Auckland there are so many poplar trees.
CAPE down-regulates the GTPase Rac, and eventually inactivates PAK1. During
2006-2007 we found that Bio 30, CAPE-rich water-miscible extract of NZ propolis,
can suppress the growth of RAS cancers such as pancreatic cancers, NF tumors,
and breast cancers in mice most effectively. Thus, many patients, in particular
NF and pancreatic cancer patients, began to take Bio 30. Bio 30 costs only
a dollar for daily treatment, being among the least expensive anti-cancer
drugs, and is very safe. The only minor problem with Bio 30 is that 1-2
% of people turns out to be allergic to CAPE in this propolis extract, developing
an itchy rash on their skin.
http://www.ncbi.nlm.nih.gov/pubmed/18726924?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
For those who are allergic to CAPE, Brazilian green propolis extract (GPE)
would do the same job, suppressing the growth of NF tumors and RAS cancers,
and does not cause any allergy, although GPE is much more expensive than
Bio 30 on the market. The major anti-cancer ingredient in GPE is ARC (Artepillin
C), and we recently confirmed that ARC also selectively blocks the oncogenic
PAK1 pathway. This year a report said that red propolis extract (RPE) from
Brazil also suppresses the growth of PAK1-dependent pancreatic cancer cells,
suggesting that RPE also blocks PAK1 pathway, although RPE contains neither
CAPE nor ARC. In other words, honey bees wherever they live must have developed
a unique instinct (or biological mechanism) to detect that CAPE or ARC or
a third anti-cancer ingredient in RPE are anti-PAK1, through their million-years
experience.
An addiction for healthier and longer life
In a tiny nematode of just 1 mm long called C. elegans, we recently discovered
that PAK1 increases their heat-sensitivity and shortens their life span
by inactivating a tumor suppressor called Foxo. When this worm is treated
with anti-PAK1 drugs such as CAPE and ARC (or PAK1 gene is knocked out),
they become very heat-resistant (acquire thermo-resistance), lay far fewer
eggs and have a prolonged life span. Thus, it is likely that honey bees
also feel quite comfortable or even happy somehow when they take-in sugars
(glucose or fructose) or anti-PAK1 ingredients such as CAPE and ARC from
their favorite flowers or trees, and they have developed a sugar/anti-PAK1
addiction over centuries. Such an addiction would help honey bees collect
sugar for making "honey", and anti-PAK1 ingredients for making "propolis"
to feed and protect their larva in honeycombs.
Interestingly, we, human beings, also carry a similar Foxo gene(s) that
is responsible for suppressing tumors and prolonging life span. So if people
also develop such an anti-PAK1 drug addiction, they could survive the escalating
global warming and enjoy a cancer /disease-free long life. The optimum temperature
for normal (wild-type) nematodes is around 20oC, and they would die at 35oC
in a few hours. However, if PAK1 gene is deleted, they would live happily
even at 35oC. Recently the major anti-cancer ingredient in red grape called
resveratrol (or trans R3) can activate Foxo, leading to a longer life span,
by both inactivating PAK1 and activating another kinase called AMPK which
is responsible for the regulation of glucose up-take. Thus, the R3-rich
red wine/grape juice would be good not only for treating diabetes and obesity,
but also for leading a cancer-free healthier life.
In short, the historic discovery of mammalian PAK by Ed Manser's group opened
a new "natural" avenue/approach leading us to the much more improved quality
of life, over a decade detailed basic research by my own group and many
others.
The origin of PAK
The new word "PAK" was created by a Brit scientist called Edward Manser
around 1994. Ed and his colleagues at IMCB of Singapore National University then cloned
a new gene from mammalian brain, which encodes a new enzyme, Ser/Thr kinase,
that is uniquely activated by two GTPases (or G proteins) called Rac and
CDC42 of 21K daltons. Then these small GTPases were collectively called
p21. So he proudly coined this new enzyme "PAK" (standing for p21-activated
kinase). Unfortunately, however, just a year before, another protein of
21K daltons was cloned, and named p21, WAF1 or CIP1, depending on its discoverers.
This new protein (p21/WAF1/CIP1) has nothing to do with these small GTPases,
but an inhibitor of another kinase called CDK (cyclin-dependent kinase).
To avoid the potential confusion, many "wise" experts in this kinase field
decided not to use the terminology p21 for a very large family of small
GTPases any more, and began to use only the simple word "PAK" for this Rac/CDC42
(p21)-dependent Ser/Thr kinase. On the other hands, this CDK inhibitor of
21K daltons continued to be called "p21" world wide till now.
Since then so many members of PAK family kinase have been cloned from mammalian
tissues, and called PAK1, PAK2, PAK3, PAK4, PAK5, PAK6 and so forth. Also
another family of Rac/CDC42-dependent Ser/Thr kinases was discovered in
mammals, and called "MLK" (standing for mixed linage kinase). Well, back
to 1977, when I used to work at Ed Korn's lab of NIH, we discovered a new
Ser/Thr kinase in a soil amoeba, which phosphorylates the heavy chain of
a unique single-headed myosin called Myosin I. So we called this kinase "Myosin
I heavy chain kinase" (MIHCK). This kinase is essential for the activation
of this myosin ATPase by F-actin (actin filaments) . Shortly after PAK1
was cloned from mammals, we compared the amino acid sequence of PAK1 and
MIHCK, and found that these two kinases are very closely related. Both enzymes
contain the Rac/CDC42-binding site at N-terminal half, and the kinase (catalytic)
domain at C-terminal half. Furthermore, like PAK1, MIHCK is indeed activated
by Rac/CDC42. In other words, our MIHCK was the first identified member
of PAK kinase family, perhaps called "PAK0" (O for "zero" or "origin"). Yes,
both MIHCK (PAK0) and PAK1-3 (class I PAK) are involved in the regulation
of non-muscle cell movements such as membrane ruffling and cell migration
in primitive amoeba and mammalian cells.
PAK-dependent diseases
During last decade, PAK (in particular PAK1) research entered medical field,
in particular molecular oncology. The major reason was that the GTPases
Rac and CDC42 were found by Frank McCormick's group of Onyx Pharm during
1995-1996 to be essential for RAS-induced malignant transformation of normal
fibroblasts such as NIH/3T3 cells. RAS, the small GTPase of 21K daltons,
is mutated oncogenically in more than 30% of all human cancers. Most notably,
RAS is mutated in more than 90% of pancreatic cancers, and more than 50%
of colon cancers. Oncogenic RAS somehow activates both Rac and CDC42 to
cause these cancers. In 1997, Jeff Field's group at University of Pennsylvania
found that PAK1 is essential for RAS-induced malignant transformation of
a fibroblast. This discovery triggered many scientists including us to investigate
further the potential role of PAK1 in many other cancers and even several
other diseases.
In 1998, Jeff's group reported that PAK1 is essential for the growth of
NF1 tumor in mice. NF stands for neurofibromatosis, a group of genetic diseases often associated
with tumors in brain, along spine and on skin. There are two types of NF.
Type 1 (NF1) is caused by dysfunction of NF1 gene product, a RAS GAP of
2818 amino acids. (Loss-of-function) mutation of this tumor suppressor gene
causes the abnormal activation of RAS, which is very similar to oncogenic
mutation of RAS, and eventually leads to the abnormal activation of PAK1.
Type 2 (NF2) is caused by dysfunction of NF2 gene product called "Merlin"
which we recently found is an inhibitor of PAK1, another tumor suppressor.
Thus, dysfunction of "Merlin" also causes the abnormal activation of PAK1.
NF2 is associated with brain/spine tumors called Meningioma and Schwannoma.
In other words, RAS cancers such as pancreatic and colon cancers are closely
related to both NF1 and NF2 tumors at molecular levels, being caused by
the oncogenic PAK1. However, until recently no effective therapeutics was
available on the market for these cancer or NF patients.
Anti-PAK drugs
Thus, during last several years, we have identified or developed a series
of anti-PAK1 drugs from synthetic chemicals and natural products for the
therapy of these PAK1-dependent cancers/tumors. Among them, so far the antibiotic
(a ring peptide) called FK228 is the most potent. It was originally developed
by Fujisawa Pharm around 1994 for suppressing the growth of RAS cancer cells,
and then later found to be a specific inhibitor of HDAC (histone deacetylase)
which we found eventually blocks the oncogenic PAK1 pathways. FK228 is now
in clinical trials (phase 2) mainly for CTCL (cutaneous T-cell lymphoma).
However, in animal models, FK228 was found to suppress the growth of so
many other cancers such as breast, prostate, pancreatic cancers, NF tumors,
and glioma, which altogether represent more than 70% of all human cancers.
Furthermore, FK228 suppresses several other diseases such as asthma and
arthritis in mouse models. These findings strongly suggest that PAK1 is involved
in the majority of cancers, and even several non-tumor diseases. Using other
anti-PAK1 drugs, we and others confirmed that formidable blood cancers such
as MM (multiple myeloma), and Alzheimer diseases (AD), Parkinson's diseases
(PD), AIDS (HIV-infection), epilepsy, malaria and autism such as Fragile
X syndrome also require PAK1. These additional findings hint the potentially
huge market value of these anti-PAK1 drugs. However, among these synthetic
anti-PAK1 chemicals, so far only one drug is available on the market with
FDA approval. It was originally called "SAHA", but Merck brand-named "Zolinga"
in October of 2006 only for the treatment of CTCL. Like FK228, SAHA is
an HDAC inhibitor, but less potent than FK228.
Anti-PAK drugs in Nature
Since clinical trials of these anti-cancer/anti-PAK1 drugs usually would
take a decade or more to be completed for each drug to get ready for marketing,
none of these cancer or NF patients would get any immediate benefit from
these potent anti-PAK1 drugs such as FK228, CEP-1347, TAT-PAK18, OSU-03012,
and GL-2003/GL-2005 for the coming decade. Thus, a few years ago, responding
to the urgent cry from many cancer/NF patients or their families, we decided
to identify an effective anti-PAK1 product in the nature, that is among all
sorts of vegetables, fruits or healthcare food supplements available on the
market.
After try and error (and educated guess), we eventually found the first effective
natural anti-PAK1 product. It has been sold as a healthcare food supplement under
the brand name of "Bio 30" mainly in New Zealand (NZ). Interestingly, the million-
years wisdom of NZ honey bees has contributed to this recent finding of ours.
Bio 30 is produced by bee keepers outskirts of Auckland where Sir Edmond
Hillary (1919-2008) used to live. He was best known to reach first the summit
of Mt. Everest (8850 m high) with his SherpaTenzing Norgay in 1953, but
also known as a life-long bee keeper. It has been said for many decades
that no bee keeper suffers from any cancer. Sir Edmond indeed was never
caught by cancer. However, nobody knew why.
Two decades ago, however, a Jewish scientist at Columbia University found
the first clue to this mystery. Dr. Grunberger identified the major anti-cancer
ingredient in propolis extract. It was CAPE (caffeic acid phenethyl ester).
Honey bees collect CAPE mainly from young buds of poplar trees, making "honey
wax" (also called "propolis" first by Hippocrates) to seal the honeycombs,
protecting their larva from all sorts of pathogenic bacteria or viruses.
Because of its anti-infectious action, ancient Egyptian people used propolis
for healing wounds and preparing mummies. Interestingly, the CAPE content
of NZ propolis turns out to be the highest among propolis samples around
the world. Indeed around Auckland there are so many poplar trees.
CAPE down-regulates the GTPase Rac, and eventually inactivates PAK1. During
2006-2007 we found that Bio 30, CAPE-rich water-miscible extract of NZ propolis,
can suppress the growth of RAS cancers such as pancreatic cancers, NF tumors,
and breast cancers in mice most effectively. Thus, many patients, in particular
NF and pancreatic cancer patients, began to take Bio 30. Bio 30 costs only
a dollar for daily treatment, being among the least expensive anti-cancer
drugs, and is very safe. The only minor problem with Bio 30 is that 1-2
% of people turns out to be allergic to CAPE in this propolis extract, developing
an itchy rash on their skin.
http://www.ncbi.nlm.nih.gov/pubmed/18726924?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
For those who are allergic to CAPE, Brazilian green propolis extract (GPE)
would do the same job, suppressing the growth of NF tumors and RAS cancers,
and does not cause any allergy, although GPE is much more expensive than
Bio 30 on the market. The major anti-cancer ingredient in GPE is ARC (Artepillin
C), and we recently confirmed that ARC also selectively blocks the oncogenic
PAK1 pathway. This year a report said that red propolis extract (RPE) from
Brazil also suppresses the growth of PAK1-dependent pancreatic cancer cells,
suggesting that RPE also blocks PAK1 pathway, although RPE contains neither
CAPE nor ARC. In other words, honey bees wherever they live must have developed
a unique instinct (or biological mechanism) to detect that CAPE or ARC or
a third anti-cancer ingredient in RPE are anti-PAK1, through their million-years
experience.
An addiction for healthier and longer life
In a tiny nematode of just 1 mm long called C. elegans, we recently discovered
that PAK1 increases their heat-sensitivity and shortens their life span
by inactivating a tumor suppressor called Foxo. When this worm is treated
with anti-PAK1 drugs such as CAPE and ARC (or PAK1 gene is knocked out),
they become very heat-resistant (acquire thermo-resistance), lay far fewer
eggs and have a prolonged life span. Thus, it is likely that honey bees
also feel quite comfortable or even happy somehow when they take-in sugars
(glucose or fructose) or anti-PAK1 ingredients such as CAPE and ARC from
their favorite flowers or trees, and they have developed a sugar/anti-PAK1
addiction over centuries. Such an addiction would help honey bees collect
sugar for making "honey", and anti-PAK1 ingredients for making "propolis"
to feed and protect their larva in honeycombs.
Interestingly, we, human beings, also carry a similar Foxo gene(s) that
is responsible for suppressing tumors and prolonging life span. So if people
also develop such an anti-PAK1 drug addiction, they could survive the escalating
global warming and enjoy a cancer /disease-free long life. The optimum temperature
for normal (wild-type) nematodes is around 20oC, and they would die at 35oC
in a few hours. However, if PAK1 gene is deleted, they would live happily
even at 35oC. Recently the major anti-cancer ingredient in red grape called
resveratrol (or trans R3) can activate Foxo, leading to a longer life span,
by both inactivating PAK1 and activating another kinase called AMPK which
is responsible for the regulation of glucose up-take. Thus, the R3-rich
red wine/grape juice would be good not only for treating diabetes and obesity,
but also for leading a cancer-free healthier life.
In short, the historic discovery of mammalian PAK by Ed Manser's group opened
a new "natural" avenue/approach leading us to the much more improved quality
of life, over a decade detailed basic research by my own group and many
others.
2008年8月27日水曜日
制癌剤としての「サリドマイド」
http://www.asahi.com/health/news/TKY200808260329.html
厚生労働省は、主に妊婦向け「つわり薬」として、１９５８年から日本国内で販売された「サリドマイド」を、「多発性骨髄腫」（ＭＭ）などの血液がんの治療薬として承認するかどうかの本格的な検討に入った。深刻な薬害（特に「奇形児」の発生）のため、１９６２年にとうとう販売が中止されたが、癌患者らは早期承認を求めて議論が活発化しそうだ。
８月２６日に始まる同省検討会に、承認申請している藤本製薬（大阪府松原市）や患者団体などが、処方できる医師や扱える病院、卸売業者を限定するとした「安全管理基準書案」を提出。同省は２７日に薬事・食品衛生審議会の部会を開き、さらに検討を進める。
サリドマイドは近年、欧米で「多発性骨髄腫」など固形癌への効果が高いと認められ、日本でも医師の個人輸入が急増。未承認のまま使用されており、「日本骨髄腫患者の会」などは早期承認を求めている。
多発性骨髄腫（ＭＭ）とは
多発性骨髄腫（Multiple Myeloma、ＭＭ）は、血液癌の一種であり、骨髄で腫瘍性形質細胞が増殖し、その産物として異常グロブリンである Ｍ蛋白が血液中に出現する。治療法としては、ＭＰ療法（メルファランとプレドニゾロン）やＣＰ療法（シクロホスファミドとプレドニゾロン）などの化学療法や、自家造血幹細胞移植などがあるが、治癒は一般的に困難であり予後は望ましくない。このため近年、欧米を中心に新規治療の開発がめざましく、サリドマイドやプロテアソーム阻害剤ボルテゾミブ（ベルケイド）が新しい治療法として注目されている。しかしながら、これらの治療法は飽く迄も対処療法に過ぎず、必ずしもＭＭの根治には至っていない。
ＭＭ細胞の癌化の根本的な (遺伝子レベルの) 原因についてはまだ不明な点が多々残っているが、少なくとも欧米では、ＭＭ患者の４ー５割にＲＡＳ遺伝子の変異が発見されている。今世紀初頭に入って、ＭＭ細胞の癌化のメカニズムが解明され始めるに伴い、ＭＭのシグナル遮断療法への道が開けつつある。そのきっかけの１つは、２００５年にオランダのユトレヒト大学医学センターのアンディー・ブロム研究室によって発見された興味深い現象である。(ＲＡＳ癌の場合と同様) ＭＭ細胞の増殖がゲラニル化酵素（ＧＴａｓｅ）の阻害剤によって、抑制されることがまず判明した。この酵素によって、活性化されるＧ蛋白がいくつか知られているが、そのうちでＧ蛋白「ＲＡＣ」がＭＭ細胞の増殖に必須であることを、彼らは突き止めた。
さらに２００７年になって、ＰＡＫを直接阻害する合成化学物質「ＯＳＵー０３０１２」がＭＭ細胞の増殖を抑制することが、少なくとも培養系で、インディアナ大学医学部の骨髄移植センター所長、シェリフ・ファラク (豪州メルボルン大学医学部出身) のグループによって明らかにされた。言い換えれば、ＭＭ細胞の増殖には、ＲＡＣとそのすぐ下流にあるＰＡＫが必須であることになる。そういう観点から、今までに発表された研究論文を調べ直してみると、それを間接的に裏付けるいくつかの興味深い実験結果が浮かび上がってくる。まず、ＰＡＫ遮断剤であるいくつかのＨＤＡＣ阻害剤、例えばＦＫ２２８、ＳＡＨＡ、クルクミンがＭＭ細胞の増殖を培養系で抑制することが、２００４年にハーバード大学医学部のダナ・ファーバー癌センターのケン・アンダーソンら によって、報告されている。もし、これらのＰＡＫ遮断剤や (後述する) ミツバチの英知「Ｂｉｏ ３０」あるいは「赤ブドウ療法」（レスベラトロール）により、実際に動物実験でＭＭ腫瘍の増殖が抑えられることが確認されれば、難病ＭＭが根治される日も、そう遠くはないだろう。
サリドマイド： 半世紀前の悲劇を越えて
サリドマイドという合成化学物質が、１９５０年代に一万人近い奇形児をもたらした理由は、「薬効（薬理作用）もわからぬ」新しい物質を、まるで食品のごとく「毒性がない」という理由だけで、あるドイツの製薬会社が市販したからである。この毒性実験には、予期せぬ２つの大きな落し穴（墓穴）があった。その１つは、マウスやラットでは、代謝されにくいので、毒性が検出しにくい。もう１つは、（妊婦が服用して初めてわかったことだが）最大の毒性は「奇形を起こす」作用にあるが、当時の動物実験では、「妊娠した動物」を試験材料に使わなかったので、この毒性がみつからなかった。偶々「つわり」にどうやら効くらしいということがわかり、この症状に悩む妊婦たちが、この得体の知れぬ「薬」を飲む「人体実験」を自ら始めるや、世界的な悲劇が起こり始めた。こうして、１９６０年代初頭に、サリドマイドは「悪魔の薬」と呼ばれ、とうとう発売禁止になった。
さて、このサリドマイドといういわくつきの鎮静剤（いわゆる「つわり」の特効薬）が、なぜＭＭの治療薬として２００６年以来、使われ始めたかを簡単に触れてみたい。妊娠婦がサリドマイドを服用すると奇形が発生する主因の１つは、胎児の血管新生を抑制するからであることがようやく判明したのは、１９９４年ごろだった。それでは、一体どんなメカニズムで、血管新生を抑制するのだろうか？ この長年の疑問に対する解答を最近になって見つけたのは、ドイツのケルン大学病院のユルゲン・クノブロッホのグループ だった。その研究結果が２００８年初頭に発表されて、あっと驚いたのは恐らく私のみではなかろう。実はこの薬剤は、胎児の発生に重要な役割を果たす「ＢＭＰ」（骨形成因子）という蛋白を介して、ＰＴＥＮを安定化することによって、その分解を阻止するのである。その結果、すぐ下流にある (血管新生に必須な) ＰＡＫやＡＫＴの機能が遮断される。
言いかえれば、使いようによっては（妊婦以外の患者を対象にして、適切に服用すれば）、サリドマイドはＰＡＫ遮断剤という「善玉」（あるいは「奇跡の薬」）にもなりうるのだ。それゆえに、ＭＭなどの癌ばかりではなく、１９６０年代から難病「ハンセン病」や結核、さらにエイズなどの感染症の特効薬として、活躍してきたのである（詳しくは「神と悪魔の薬サリドマイド」を参照されたし）。
なお、サリドマイドは水に難溶性であるが、２００４年ごろになって、米国の「セルジーン」社（１９９５年ごろ、サリドマイドを「エイズ」治療薬として初めて開発した製薬会社）が、水溶性で副作用の少ない（芳香環にアミノ基を導入した）サリドマイド誘導体「ＣＣー４０４７」や「ＣＣー５０１３」などを開発、ＭＭ患者などを対象に目下治験を進めているという明るいニュースが入って来つつある。さらに副作用に関して、重要な点を１つ付け加えれば、サリドマイドは妊娠したウサギから奇形児をもたらすが、「ＣＣー５０１３」は奇形を全くもたらさない。従って、奇形の原因は、どうやら「血管新生抑制作用」のみではなさそうだ。言い換えれば、血管新生を抑制するＰＡＫ遮断剤は、（万が一、妊婦が服用しても）必ずしも奇形をもたらすわけではないことになる。
「つわり」とサリドマイド
さて、長年の「謎」がもう１つまだ解決されずに残っている。なぜ、サリドマイドは「つわり」（妊娠初期に起こる吐き気）に効いたのだろうか？ 「つわり」の根本原因が何か、分子レベルでまだよくわかっていないようだが、はっきりしていることは、妊娠に伴うホルモンの変化、特に女性ホルモンの一種「エストロゲン」が急激に（妊娠前の１００倍近く）上昇することが一因のようだ。このホルモンが上昇すると、ＰＡＫを活性化して、胎児の成長に必須な血管新生や細胞分裂を促進する。前述したが、サリドマイドは、間接的にＰＡＫの活性化を抑制することによって、血管新生を抑える。従って、もし、妊娠後の「つわり」がエストロゲンによるＰＡＫの異常活性化に起因するとすれば、サリドマイドは当然、「つわり」に効くはずである。もし、この仮説が正ければ、ＰＡＫ遮断剤である「Ｂｉｏ ３０」などのプロポリスや赤ブドウ・ジュース、あるいは「キムチ」や「ゴーヤ」なども「つわり」に効くはずである。。。
「つわり」症状を軽減する天然物として伝統的に良く知られているものに、生姜（ショウガ）とビタミンＢ６がある。ほとんど同程度に効果があるらしい。 なお食品の中で、ビタミンＢ６の含量が一番高いのは、何と「ニンニク」であることがわかった。従って、ニンニクと（詳しくは後述するが、ＰＡＫ遮断剤「カプサイシン」を含む）チリ胡椒がたっぷり入っているキムチが、「つわり」を乗り越えるのに役立ったのいう話には、詳しいメカニズムはともかくとして、科学的にかなり説得力（裏付け）がありそうだ。
それでは、なぜビタミンＢ６は「つわり」を抑えることができるのだろうか？
「つわり」は欧米で「朝の病」と呼ばれるごとく、しばしば朝起きてまもなく起こる。その主因の1つは、空腹のため、糖（グルコース）レベルが低いためだといわれている。ビタミンＢ６はアミノ酸の合成にも必須であるが、グリコーゲンを分解して、グルコースを生産する反応を促進する。従って、ビタミンＢ６によって糖レベルが高まることによって、「つわり」が軽減されるとも解釈できる。さらに２００３年になって、広島大学の加藤範久教授の研究室により、ビタミンＢ６（ＰＬＰ）が血管新生の抑制により、癌の増殖を抑えることも明らかにされた。
さて、生姜はどうして「つわり」に有効なのだろうか？ 手ががりがやっと最近出てきた。２００７年に米国ミシガン大学医学部婦人科のレベッカ・劉 のグループによって、生姜、特にその成分である「６ージンジャロール」が血管新生を抑え、例えば子宮癌の増殖を抑えることが見つけられた。従って、恐らくＰＡＫ遮断作用をもっているのだろう。生姜湯やキムチを毎朝（あるいは毎晩）食べれば、「つわり」のみならず癌を予防、あるいは癌を治すことも可能だろう。
以上の傍証から、サリドマイドの薬理作用(ＰＡＫ遮断、血管新生抑制) と抗「つわり」作用、抗癌作用が分子レベルで、どうやら密接な関係をもっていることが強く示唆されている。もう一度強調するが、血管新生の抑制は必ずしも奇形をもたらしすわけではない。なぜなら、キムチや生姜を常食している母親たちが「奇形児」を産んだという話など一度も聞いたことがないからだ。もし、そんな馬鹿化たことが起こるならば、朝鮮半島は奇形児ばかりになっているだろう。
韓国在住のあるネット欄に、こんな質問応答があった：
質問： 韓国の女性は、妊娠中でもキムチを食べますか？
答え： 妻は韓国人ですが、妊娠中でもキムチを普通に食べていました。
というわけで、４００年以上の伝統があるキムチで奇形児が誕生する恐れはなさそうだ。恐らく、生姜でも同様だろう（少なくとも、治験では副作用はなかった！）。
フィッシャー・ラスムッセンらの妊娠悪阻に対する生姜処理（1990年）
デンマークのコペンハーゲン大学病院で、生姜のつわりの吐き気に対する調査を二重盲検 (被験者を二つのグループに分け、一方には本物をもう一方には偽薬を与えて検査するもの）によって行った。約１ｇの乾燥ショウガを２～４回に分けたものを妊娠悪阻（つわり）で入院している人に飲ませた。4日間与えた結果、27人のうちの19人が吐き気の軽減を感じた。
タイ国チェンマイ大学のTeraporn Vutyavanich博士ら
吐き気を報告する67人のうち32人に、１日4回250mgの生姜のカプセルを4日間与えた。残りは偽薬を与えた。大部分はその前の日嘔吐している。4日後に、生姜をとったグループは30％だけが嘔吐した。偽薬グループは66％だった。ショウガを与えられた女性の88パーセントは、自分達の徴候が改善するとコメントした。その一方で偽薬を与えられた人達の29パーセントだけが改良を報告した。比較して、ショウガをとる女性に吐き気の軽減が見られることがわかった。副作用は（女性にもその胎児のにも）観察されなかった。
上の論文で使われている１日乾燥ショウガ１ｇというのは、新鮮な生姜小さじ一杯分にあたり、日常で家庭で使われている量と余り変わらない。この量ならおおよそ安全であろう。ショウガは、ＦＤＡ（アメリカ食品・医薬品局）の一般に安全と認められているリストに載っており、副作用もめったに引き起こさない。
続く
厚生労働省は、主に妊婦向け「つわり薬」として、１９５８年から日本国内で販売された「サリドマイド」を、「多発性骨髄腫」（ＭＭ）などの血液がんの治療薬として承認するかどうかの本格的な検討に入った。深刻な薬害（特に「奇形児」の発生）のため、１９６２年にとうとう販売が中止されたが、癌患者らは早期承認を求めて議論が活発化しそうだ。
８月２６日に始まる同省検討会に、承認申請している藤本製薬（大阪府松原市）や患者団体などが、処方できる医師や扱える病院、卸売業者を限定するとした「安全管理基準書案」を提出。同省は２７日に薬事・食品衛生審議会の部会を開き、さらに検討を進める。
サリドマイドは近年、欧米で「多発性骨髄腫」など固形癌への効果が高いと認められ、日本でも医師の個人輸入が急増。未承認のまま使用されており、「日本骨髄腫患者の会」などは早期承認を求めている。
多発性骨髄腫（ＭＭ）とは
多発性骨髄腫（Multiple Myeloma、ＭＭ）は、血液癌の一種であり、骨髄で腫瘍性形質細胞が増殖し、その産物として異常グロブリンである Ｍ蛋白が血液中に出現する。治療法としては、ＭＰ療法（メルファランとプレドニゾロン）やＣＰ療法（シクロホスファミドとプレドニゾロン）などの化学療法や、自家造血幹細胞移植などがあるが、治癒は一般的に困難であり予後は望ましくない。このため近年、欧米を中心に新規治療の開発がめざましく、サリドマイドやプロテアソーム阻害剤ボルテゾミブ（ベルケイド）が新しい治療法として注目されている。しかしながら、これらの治療法は飽く迄も対処療法に過ぎず、必ずしもＭＭの根治には至っていない。
ＭＭ細胞の癌化の根本的な (遺伝子レベルの) 原因についてはまだ不明な点が多々残っているが、少なくとも欧米では、ＭＭ患者の４ー５割にＲＡＳ遺伝子の変異が発見されている。今世紀初頭に入って、ＭＭ細胞の癌化のメカニズムが解明され始めるに伴い、ＭＭのシグナル遮断療法への道が開けつつある。そのきっかけの１つは、２００５年にオランダのユトレヒト大学医学センターのアンディー・ブロム研究室によって発見された興味深い現象である。(ＲＡＳ癌の場合と同様) ＭＭ細胞の増殖がゲラニル化酵素（ＧＴａｓｅ）の阻害剤によって、抑制されることがまず判明した。この酵素によって、活性化されるＧ蛋白がいくつか知られているが、そのうちでＧ蛋白「ＲＡＣ」がＭＭ細胞の増殖に必須であることを、彼らは突き止めた。
さらに２００７年になって、ＰＡＫを直接阻害する合成化学物質「ＯＳＵー０３０１２」がＭＭ細胞の増殖を抑制することが、少なくとも培養系で、インディアナ大学医学部の骨髄移植センター所長、シェリフ・ファラク (豪州メルボルン大学医学部出身) のグループによって明らかにされた。言い換えれば、ＭＭ細胞の増殖には、ＲＡＣとそのすぐ下流にあるＰＡＫが必須であることになる。そういう観点から、今までに発表された研究論文を調べ直してみると、それを間接的に裏付けるいくつかの興味深い実験結果が浮かび上がってくる。まず、ＰＡＫ遮断剤であるいくつかのＨＤＡＣ阻害剤、例えばＦＫ２２８、ＳＡＨＡ、クルクミンがＭＭ細胞の増殖を培養系で抑制することが、２００４年にハーバード大学医学部のダナ・ファーバー癌センターのケン・アンダーソンら によって、報告されている。もし、これらのＰＡＫ遮断剤や (後述する) ミツバチの英知「Ｂｉｏ ３０」あるいは「赤ブドウ療法」（レスベラトロール）により、実際に動物実験でＭＭ腫瘍の増殖が抑えられることが確認されれば、難病ＭＭが根治される日も、そう遠くはないだろう。
サリドマイド： 半世紀前の悲劇を越えて
サリドマイドという合成化学物質が、１９５０年代に一万人近い奇形児をもたらした理由は、「薬効（薬理作用）もわからぬ」新しい物質を、まるで食品のごとく「毒性がない」という理由だけで、あるドイツの製薬会社が市販したからである。この毒性実験には、予期せぬ２つの大きな落し穴（墓穴）があった。その１つは、マウスやラットでは、代謝されにくいので、毒性が検出しにくい。もう１つは、（妊婦が服用して初めてわかったことだが）最大の毒性は「奇形を起こす」作用にあるが、当時の動物実験では、「妊娠した動物」を試験材料に使わなかったので、この毒性がみつからなかった。偶々「つわり」にどうやら効くらしいということがわかり、この症状に悩む妊婦たちが、この得体の知れぬ「薬」を飲む「人体実験」を自ら始めるや、世界的な悲劇が起こり始めた。こうして、１９６０年代初頭に、サリドマイドは「悪魔の薬」と呼ばれ、とうとう発売禁止になった。
さて、このサリドマイドといういわくつきの鎮静剤（いわゆる「つわり」の特効薬）が、なぜＭＭの治療薬として２００６年以来、使われ始めたかを簡単に触れてみたい。妊娠婦がサリドマイドを服用すると奇形が発生する主因の１つは、胎児の血管新生を抑制するからであることがようやく判明したのは、１９９４年ごろだった。それでは、一体どんなメカニズムで、血管新生を抑制するのだろうか？ この長年の疑問に対する解答を最近になって見つけたのは、ドイツのケルン大学病院のユルゲン・クノブロッホのグループ だった。その研究結果が２００８年初頭に発表されて、あっと驚いたのは恐らく私のみではなかろう。実はこの薬剤は、胎児の発生に重要な役割を果たす「ＢＭＰ」（骨形成因子）という蛋白を介して、ＰＴＥＮを安定化することによって、その分解を阻止するのである。その結果、すぐ下流にある (血管新生に必須な) ＰＡＫやＡＫＴの機能が遮断される。
言いかえれば、使いようによっては（妊婦以外の患者を対象にして、適切に服用すれば）、サリドマイドはＰＡＫ遮断剤という「善玉」（あるいは「奇跡の薬」）にもなりうるのだ。それゆえに、ＭＭなどの癌ばかりではなく、１９６０年代から難病「ハンセン病」や結核、さらにエイズなどの感染症の特効薬として、活躍してきたのである（詳しくは「神と悪魔の薬サリドマイド」を参照されたし）。
なお、サリドマイドは水に難溶性であるが、２００４年ごろになって、米国の「セルジーン」社（１９９５年ごろ、サリドマイドを「エイズ」治療薬として初めて開発した製薬会社）が、水溶性で副作用の少ない（芳香環にアミノ基を導入した）サリドマイド誘導体「ＣＣー４０４７」や「ＣＣー５０１３」などを開発、ＭＭ患者などを対象に目下治験を進めているという明るいニュースが入って来つつある。さらに副作用に関して、重要な点を１つ付け加えれば、サリドマイドは妊娠したウサギから奇形児をもたらすが、「ＣＣー５０１３」は奇形を全くもたらさない。従って、奇形の原因は、どうやら「血管新生抑制作用」のみではなさそうだ。言い換えれば、血管新生を抑制するＰＡＫ遮断剤は、（万が一、妊婦が服用しても）必ずしも奇形をもたらすわけではないことになる。
「つわり」とサリドマイド
さて、長年の「謎」がもう１つまだ解決されずに残っている。なぜ、サリドマイドは「つわり」（妊娠初期に起こる吐き気）に効いたのだろうか？ 「つわり」の根本原因が何か、分子レベルでまだよくわかっていないようだが、はっきりしていることは、妊娠に伴うホルモンの変化、特に女性ホルモンの一種「エストロゲン」が急激に（妊娠前の１００倍近く）上昇することが一因のようだ。このホルモンが上昇すると、ＰＡＫを活性化して、胎児の成長に必須な血管新生や細胞分裂を促進する。前述したが、サリドマイドは、間接的にＰＡＫの活性化を抑制することによって、血管新生を抑える。従って、もし、妊娠後の「つわり」がエストロゲンによるＰＡＫの異常活性化に起因するとすれば、サリドマイドは当然、「つわり」に効くはずである。もし、この仮説が正ければ、ＰＡＫ遮断剤である「Ｂｉｏ ３０」などのプロポリスや赤ブドウ・ジュース、あるいは「キムチ」や「ゴーヤ」なども「つわり」に効くはずである。。。
「つわり」症状を軽減する天然物として伝統的に良く知られているものに、生姜（ショウガ）とビタミンＢ６がある。ほとんど同程度に効果があるらしい。 なお食品の中で、ビタミンＢ６の含量が一番高いのは、何と「ニンニク」であることがわかった。従って、ニンニクと（詳しくは後述するが、ＰＡＫ遮断剤「カプサイシン」を含む）チリ胡椒がたっぷり入っているキムチが、「つわり」を乗り越えるのに役立ったのいう話には、詳しいメカニズムはともかくとして、科学的にかなり説得力（裏付け）がありそうだ。
それでは、なぜビタミンＢ６は「つわり」を抑えることができるのだろうか？
「つわり」は欧米で「朝の病」と呼ばれるごとく、しばしば朝起きてまもなく起こる。その主因の1つは、空腹のため、糖（グルコース）レベルが低いためだといわれている。ビタミンＢ６はアミノ酸の合成にも必須であるが、グリコーゲンを分解して、グルコースを生産する反応を促進する。従って、ビタミンＢ６によって糖レベルが高まることによって、「つわり」が軽減されるとも解釈できる。さらに２００３年になって、広島大学の加藤範久教授の研究室により、ビタミンＢ６（ＰＬＰ）が血管新生の抑制により、癌の増殖を抑えることも明らかにされた。
さて、生姜はどうして「つわり」に有効なのだろうか？ 手ががりがやっと最近出てきた。２００７年に米国ミシガン大学医学部婦人科のレベッカ・劉 のグループによって、生姜、特にその成分である「６ージンジャロール」が血管新生を抑え、例えば子宮癌の増殖を抑えることが見つけられた。従って、恐らくＰＡＫ遮断作用をもっているのだろう。生姜湯やキムチを毎朝（あるいは毎晩）食べれば、「つわり」のみならず癌を予防、あるいは癌を治すことも可能だろう。
以上の傍証から、サリドマイドの薬理作用(ＰＡＫ遮断、血管新生抑制) と抗「つわり」作用、抗癌作用が分子レベルで、どうやら密接な関係をもっていることが強く示唆されている。もう一度強調するが、血管新生の抑制は必ずしも奇形をもたらしすわけではない。なぜなら、キムチや生姜を常食している母親たちが「奇形児」を産んだという話など一度も聞いたことがないからだ。もし、そんな馬鹿化たことが起こるならば、朝鮮半島は奇形児ばかりになっているだろう。
韓国在住のあるネット欄に、こんな質問応答があった：
質問： 韓国の女性は、妊娠中でもキムチを食べますか？
答え： 妻は韓国人ですが、妊娠中でもキムチを普通に食べていました。
というわけで、４００年以上の伝統があるキムチで奇形児が誕生する恐れはなさそうだ。恐らく、生姜でも同様だろう（少なくとも、治験では副作用はなかった！）。
フィッシャー・ラスムッセンらの妊娠悪阻に対する生姜処理（1990年）
デンマークのコペンハーゲン大学病院で、生姜のつわりの吐き気に対する調査を二重盲検 (被験者を二つのグループに分け、一方には本物をもう一方には偽薬を与えて検査するもの）によって行った。約１ｇの乾燥ショウガを２～４回に分けたものを妊娠悪阻（つわり）で入院している人に飲ませた。4日間与えた結果、27人のうちの19人が吐き気の軽減を感じた。
タイ国チェンマイ大学のTeraporn Vutyavanich博士ら
吐き気を報告する67人のうち32人に、１日4回250mgの生姜のカプセルを4日間与えた。残りは偽薬を与えた。大部分はその前の日嘔吐している。4日後に、生姜をとったグループは30％だけが嘔吐した。偽薬グループは66％だった。ショウガを与えられた女性の88パーセントは、自分達の徴候が改善するとコメントした。その一方で偽薬を与えられた人達の29パーセントだけが改良を報告した。比較して、ショウガをとる女性に吐き気の軽減が見られることがわかった。副作用は（女性にもその胎児のにも）観察されなかった。
上の論文で使われている１日乾燥ショウガ１ｇというのは、新鮮な生姜小さじ一杯分にあたり、日常で家庭で使われている量と余り変わらない。この量ならおおよそ安全であろう。ショウガは、ＦＤＡ（アメリカ食品・医薬品局）の一般に安全と認められているリストに載っており、副作用もめったに引き起こさない。
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