Podcasts about mbq

En el episodio de hoy me siento con el Dr. José F. Rodríguez-Orengo, quien tiene un bachillerato en química de la Universidad de Puerto Rico, Recinto de Río Piedras, un  Ph. D. en química de Texas A&M University y un Post Doctoral Fellowship en Química de Cornell University. Actualmente, el Dr. Rodríguez-Orengo es profesor de bioquímica en la Escuela de Medicina de la Universidad de Puerto Rico, CEO y CSO de FDI Clinical Research, una organización de investigación clínica en San Juan, Puerto Rico y es miembro cofundador y CEO de MBQ Pharma. Rodríguez-Orengo me cuenta cómo fueron sus años creciendo en el pueblo de Yauco, Puerto Rico, el momento en el que se enamoró del campo de la investigación, su llegada a FDI Clinical Research gracias a la Dra. Maribel Rodríguez-Torres, los comienzos de MBQ Pharma y el estudio PROSPECT en colaboración con Harvard University. También hablamos sobre los inicios de MBQ Pharma, el compuesto MBQ-167, el impacto del alcohol en nuestra salud cardiovascular, cómo nos afecta el aislamiento social y la importancia de tener un equipo que te rete. Tres "takeaways" de este episodio: 1. El aislamiento social, o la soledad, es como si estuvieses fumándote 14 cigarrillos al día. 2. La vida te da oportunidades que uno tiene que aprovechar. Si ves una oportunidad, toma el riesgo. 3. Para tu equipo, tú tienes que buscar gente que esté a un nivel que te pueda retar en todo momento. El trabajo del Dr. Rodríguez-Orengo: Estudio PROSPECT - https://www.hsph.harvard.edu/prospect/ FDI Clinical Research - https://fdiclinicalresearch.com/ MBQ Pharma - https://mbqpharma.com/ No olvides suscribirte a nuestro canal de Youtube.

In honor of Mark Rothko’s Latvian heritage, Latvian jazz ensemble the Māris Briežkalns Quintet commissioned ten Latvian composers to each create an original jazz composition, arranged and performed by the Quintet. Each composition is created to illustrate the moods and atmosphere evoked by an iconic Rothko painting selected by the composer. This program is underwritten by Peter Ragauss. Performers include Māris Briežkalns – drums, band leader; Viktors Ritovs – piano, keys; Raimonds Macats – harmonica, cello, keys; Kristaps Lubovs – saxophone; and Andris Grunte - double bass Māris Briežkalns Quintet (MBQ) is one of the leading acoustic mainstream bands on the Latvian jazz scene, stretching special accents on pop, jazz, and Latin jazz. MBQ has performed on several international stages, including MIDEM, Pori Jazz, London Jazz Festival, Ottawa Jazz, Jazz at Castle in Prague, Venice Jazz Festival, Blue Note Jazz Club in New York, and Tokyo Jazz Fest. MBQ’s project Latvian Evergreens has two volumes, showcasing Latvian classical and pop music in versatile jazz arrangements. Māris Briežkalns Quintet released five albums: Felix Jazz, Latvian Evergreens Vol 1, Jazz At Castle, Latvian Evergreens Vol 2, and Rothko In Jazz. Māris Briežkalns, the leader of the quintet, is a drummer and producer. Among other things, he is the Head of Latvian Radio Recording Studios Department, was the Artistic Director of Latvian Radio Big Band for several years and has participated in the recording of over 70 music albums, has hosted workshops in Norway, Germany, Great Britain. He runs the Contemporary Music Centre and produces the "Rigas Ritmi Festival” and the International Jazz Artists Competition “Riga Jazz Stage”. Māris Briežkalns has been nominated for and received many awards, including the highest Latvian state honor, The Order of the Three Stars.

The RunRunLive 4.0 Podcast Episode 4-321 – Steve Chopper live from Cape Cod  (Audio: link) [audio:http://www.RunRunLive.com/PodcastEpisodes/epi4321.mp3] Link epi4321.mp3 MarathonBQ – How to Qualify for the Boston Marathon in 14 Weeks - http://www.marathonbq.com/qualify-for-the-boston-marathon-in-14-weeks/ Hey people.  How are you?  I’m tired.  I was out in San Diego this week as my ‘Abundance Tour’ continues.  Since we last talked I was in Phoenix, came back home and drove down to the Cape to see Steve and then was back on a plane out to San Diego this week.  This week I am going to be in Boston, but I have a conference in the city that I’ll need to drive in for a couple days.  And I’m speaking a this one so I have to come up with a talk for that and get ready.  Then the following week I’m back out in San Diego for another week-long conference that will require me to leave on Saturday.   So…When I came off my epic adventure out in Portland I woke up to find all this travel and I’ll be honest it stressed me out.  This time of year is when all of the conferences in my industry happen.  It’s not hard work but you’re on all the time and talking to people.  Many times I’ll be out late entertaining and up early for the events – it can wear on you if you don’t pace yourself.    I thought about it though and remembered how lucky I am to be able to do all the things that I do and decided to try to rewire my thinking process.  I decided to call it “The Abundance Tour – 2015.  Like a rock and roll tour.  I’m going to get T-shirts made with the venues and dates on them, right?  It helps but I’m still exhausted.  I managed to get out and run almost every day last week in Phoenix including my favorite run up Camelback Mountain before the sunrise.  One of the days the event had an impromptu 5K which was fun for me! I just treated it as a fun run and chatted up clients because I didn’t want to be ‘that guy’ – the guy who tries to hammer everyone else in a fun run.   This week in San Diego I was unable to get out at all.  I was unable to do any of my daily practice.  And it bothers me.  But I’ll be back on the bus soon enough.   Today we will have a recording that I made sitting at the table in my Cape Cod house with Steve Chopper.  Steve is cycling from Concord MA to Yorktown on a folding bicycle and he’s calling it the American Revolutions Tour.  I met him as he was cycling down to my place from Provincetown and we rode 50 or so miles on the Cape Cod Rail Trail.  In The first section I’m going to talk through something that came up this week which is the situation where people have bad workouts late in their training cycles and it freaks them out.   In the second section I have a piece that tries to summarize my reading and learning about how to access deeper portions of your mind and potentially the universal mastermind. The thing I discover about myself with these conferences is how much of an introvert I am.  Having authentic interactions with other humans all day and all night is exhausting.  I’ve been practicing trying to actually listen to people instead of ‘waiting to talk’.   Trying to ask questions instead of trying to demonstrate how smart I am.   When you do this, amazingly enough, it’s not as exhausting.  When you let go the need to make it some sort of competition or sell something you can connect better and people remember you and you remember them.     On with the show! Section one - Running Tips Am I ready for my goal race?  http://runrunlive.com/am-i-ready-for-my-goal-marathon Voices of reason – the conversation Steve Chopper  The American Revolutions Tour Hi guys, I'm cycling from Old North Bridge, Concord, down to Georgetown. These are pretty fitting start and end points chronologically for an adventure taking in the main places from the War of Independence. I'll be putting together a travelogue (as my one from last year cycling the Danube to Budapest is almost done). I'm doing it on my 2 speed fold up Brompton cycle (pic attached), which folds up easily into a box which meets general airline checked luggage sizes. I rescheduled the trip by a week as I found out the UCI world road racing championships are taking place in Richmond VA the week of 21st September. I gave them a bit of marketing about the trip and Brompton have kindly given me a guest pass into the Brompton World Championships USA which is part of that closed roads cycling festival. I'll be meeting up with quite a few Bromptoneers along the way, theres a host I know in NYC, and a few hundred will be flying into RIchmond. I'm also catching up with workmates in Delaware and they will be helping me reenact the famous "Washington crossing the Delaware" painting with my bike, will make a good anecdote!    I'll be carrying my camping kit, but will hopefully mainly stay with Warmshowers.com hosts. I attach my schedule. Due to the best low cost flight schedule/ prices back to Boston from Richmond, I'll be coming back to Boston on Saturday 26th and have a day in Boston on the Sunday. I will be cycling around 60 miles a day so will be quite leisurely and leave time for plenty of site seeing/ beer!!!   If you have any observations on this plan that would help me refine it, or anyone you think it would be good to catch along the way, then feel free to let me know Hope to see you soon - all then best!!  Section two – The Universal Mastermind http://runrunlive.com/uncertainty-trust-and-the-universal-mastermind Outro - Closing comments MarathonBQ – How to Qualify for the Boston Marathon in 14 Weeks - http://www.marathonbq.com/qualify-for-the-boston-marathon-in-14-weeks/ Like I think I said last time I’m cutting back on my training for September because of my crazy schedule.  I basically didn’t run this week.  I’ve got to get back on it because I’m putting on weight and feel like crap!  With any luck the time off will heal up all my bent and broken bits and I’ll be able to get a quality training cycle in during the fall and winter seasons.  Now that my heart is fixed up I’d really like to load up some speedwork and maybe get some of that pace back that I had a couple years ago.  If I look at my own pace tables from the MBQ plan the paces should be quite doable for me.  The BQ paces I need now are almost a full minute off what I needed when I first qualified in the fall of 1997. I’m also terrified when I start thinking about this because what if I can’t do it?  What if I just get injured again?  What if I just don’t have the time in my life and have to give up part of the way through? I guess I won’t know until I try.   And I’m also concerned that if I commit to a hard training cycle it will suck up all the free oxygen in my life and keep me from being successful in other areas of my life that need attention.   If I kick off a cycle in October that would line up with a race the first couple weeks of January.  Maybe I’ll do that.  Then I could schedule our 3rd annual Groton Marathon as a last long training run around Christmas.  This is how my brain works.   It would also get me into decent shape for the Thanksgiving races.   … As I was working through how to survive and thrive over this month of heavy travel I was thinking a lot about how to make the interaction I have with people more valuable.  I usually just put on a smile and work the room but that is a very emotionally thin way of engaging people.  A veneer of bonhomie does not produce any value.   If you are putting on an act, unless you are a really good actor, people sense that and it is off-putting.  I asked myself the question ‘why do you have that light, insincere avatar approach?’  And the answer I got was that because in these business relationships I don’t really trust the people I’m interacting with.  Essentially I’m interacting with my guard up – talking and smiling with one hand on my gun.   Then, I asked the next question which was ‘Why don’t you trust these people?  What are you afraid of?’  And the surprising answer that popped up was that I’m afraid of them.  I’m afraid looking stupid.  I’m afraid of getting hurt.   Think about that.  I’m having these smiling, friendly conversations with my industry peers that are full of content but also based in fear.  And I thought to myself ‘Gee, that’s not a very abundant way to approach life.” Then, stay with me, I asked the next question, which was, “What could happen if you weren’t afraid of getting hurt, if you trusted these people?”  What would this bring to you?   It’s a work in process but I have been practicing being authentic in these interactions.  It many cases it really changes the value and the outcome of the interaction.  Instead of trying to think one step ahead and figure out what you think they want to hear or what you should say in this situation – you just let go of it, step outside the conversation and say what is important.   It’s much less stressful and being calm in the moment can be sensed by people and they are attracted to that.   I’ll tell you a story.   I was sitting at a table having breakfast last week.  At the table was a CEO who was one of the keynote speakers.  I’m chatting with folks.  I chat with this guy talking about mutual friends and such, just being chill.  He starts to lock in on me.  He asks me what I do.  Instead of the usual I’m an executive at XYZ company and run the ABC group type of safe answer I said “I like to read, write and speak, I love endurance sports and new ideas and I’m currently an executive at XYZ company.”  That my friends is not an answer anyone expects and says volumes about who I am as a person and the true value that I bring to the world beyond the company and the industry.  After a few more minutes of chat he says, “Well you’ve got to talk to John Doe who runs my Americas team because we need someone to run the Eastern part of the country so we can grow this business.  Now, let’s be clear.  I haven’t heard anything else from this guy since then and I have no idea if I’d be interested working for them.  That’s not the point of the story.  The point of the story is I wasn’t pitching this guy or trying to impress him or really even paying all that much attention to him but he was attracted to me by my authentic attitude.   He felt my detached attitude of abundance and heard something different and valuable in the way I interacted.  This was a demonstration of what the mystics might consider the law of attraction.   But more importantly it was a demonstration of how we can modify our own selves by asking good introspective questions and then reflecting that self-aware attitude out into the world (or perhaps, the universe).   So ponder on this as you’re out and about this week.  The way we think influences how we manifest to others.  How are you manifesting in your world? What are you programming yourself to attract? And I’ll see you out there.  http://wapack.freeservers.com/ MarathonBQ – How to Qualify for the Boston Marathon in 14 Weeks - http://www.marathonbq.com/qualify-for-the-boston-marathon-in-14-weeks/ Http://www.marathonbq.com http://runrunlive.com/my-books  

The RunRunLive 4.0 Podcast Episode 4-321 – Steve Chopper live from Cape Cod  (Audio: link) [audio:http://www.RunRunLive.com/PodcastEpisodes/epi4321.mp3] Link epi4321.mp3 MarathonBQ – How to Qualify for the Boston Marathon in 14 Weeks - http://www.marathonbq.com/qualify-for-the-boston-marathon-in-14-weeks/ Hey people.  How are you?  I'm tired.  I was out in San Diego this week as my ‘Abundance Tour' continues.  Since we last talked I was in Phoenix, came back home and drove down to the Cape to see Steve and then was back on a plane out to San Diego this week.  This week I am going to be in Boston, but I have a conference in the city that I'll need to drive in for a couple days.  And I'm speaking a this one so I have to come up with a talk for that and get ready.  Then the following week I'm back out in San Diego for another week-long conference that will require me to leave on Saturday.   So…When I came off my epic adventure out in Portland I woke up to find all this travel and I'll be honest it stressed me out.  This time of year is when all of the conferences in my industry happen.  It's not hard work but you're on all the time and talking to people.  Many times I'll be out late entertaining and up early for the events – it can wear on you if you don't pace yourself.    I thought about it though and remembered how lucky I am to be able to do all the things that I do and decided to try to rewire my thinking process.  I decided to call it “The Abundance Tour – 2015.  Like a rock and roll tour.  I'm going to get T-shirts made with the venues and dates on them, right?  It helps but I'm still exhausted.  I managed to get out and run almost every day last week in Phoenix including my favorite run up Camelback Mountain before the sunrise.  One of the days the event had an impromptu 5K which was fun for me! I just treated it as a fun run and chatted up clients because I didn't want to be ‘that guy' – the guy who tries to hammer everyone else in a fun run.   This week in San Diego I was unable to get out at all.  I was unable to do any of my daily practice.  And it bothers me.  But I'll be back on the bus soon enough.   Today we will have a recording that I made sitting at the table in my Cape Cod house with Steve Chopper.  Steve is cycling from Concord MA to Yorktown on a folding bicycle and he's calling it the American Revolutions Tour.  I met him as he was cycling down to my place from Provincetown and we rode 50 or so miles on the Cape Cod Rail Trail.  In The first section I'm going to talk through something that came up this week which is the situation where people have bad workouts late in their training cycles and it freaks them out.   In the second section I have a piece that tries to summarize my reading and learning about how to access deeper portions of your mind and potentially the universal mastermind. The thing I discover about myself with these conferences is how much of an introvert I am.  Having authentic interactions with other humans all day and all night is exhausting.  I've been practicing trying to actually listen to people instead of ‘waiting to talk'.   Trying to ask questions instead of trying to demonstrate how smart I am.   When you do this, amazingly enough, it's not as exhausting.  When you let go the need to make it some sort of competition or sell something you can connect better and people remember you and you remember them.     On with the show! Section one - Running Tips Am I ready for my goal race?  http://runrunlive.com/am-i-ready-for-my-goal-marathon Voices of reason – the conversation Steve Chopper  The American Revolutions Tour Hi guys, I'm cycling from Old North Bridge, Concord, down to Georgetown. These are pretty fitting start and end points chronologically for an adventure taking in the main places from the War of Independence. I'll be putting together a travelogue (as my one from last year cycling the Danube to Budapest is almost done). I'm doing it on my 2 speed fold up Brompton cycle (pic attached), which folds up easily into a box which meets general airline checked luggage sizes. I rescheduled the trip by a week as I found out the UCI world road racing championships are taking place in Richmond VA the week of 21st September. I gave them a bit of marketing about the trip and Brompton have kindly given me a guest pass into the Brompton World Championships USA which is part of that closed roads cycling festival. I'll be meeting up with quite a few Bromptoneers along the way, theres a host I know in NYC, and a few hundred will be flying into RIchmond. I'm also catching up with workmates in Delaware and they will be helping me reenact the famous "Washington crossing the Delaware" painting with my bike, will make a good anecdote!    I'll be carrying my camping kit, but will hopefully mainly stay with Warmshowers.com hosts. I attach my schedule. Due to the best low cost flight schedule/ prices back to Boston from Richmond, I'll be coming back to Boston on Saturday 26th and have a day in Boston on the Sunday. I will be cycling around 60 miles a day so will be quite leisurely and leave time for plenty of site seeing/ beer!!!   If you have any observations on this plan that would help me refine it, or anyone you think it would be good to catch along the way, then feel free to let me know Hope to see you soon - all then best!!  Section two – The Universal Mastermind http://runrunlive.com/uncertainty-trust-and-the-universal-mastermind Outro - Closing comments MarathonBQ – How to Qualify for the Boston Marathon in 14 Weeks - http://www.marathonbq.com/qualify-for-the-boston-marathon-in-14-weeks/ Like I think I said last time I'm cutting back on my training for September because of my crazy schedule.  I basically didn't run this week.  I've got to get back on it because I'm putting on weight and feel like crap!  With any luck the time off will heal up all my bent and broken bits and I'll be able to get a quality training cycle in during the fall and winter seasons.  Now that my heart is fixed up I'd really like to load up some speedwork and maybe get some of that pace back that I had a couple years ago.  If I look at my own pace tables from the MBQ plan the paces should be quite doable for me.  The BQ paces I need now are almost a full minute off what I needed when I first qualified in the fall of 1997. I'm also terrified when I start thinking about this because what if I can't do it?  What if I just get injured again?  What if I just don't have the time in my life and have to give up part of the way through? I guess I won't know until I try.   And I'm also concerned that if I commit to a hard training cycle it will suck up all the free oxygen in my life and keep me from being successful in other areas of my life that need attention.   If I kick off a cycle in October that would line up with a race the first couple weeks of January.  Maybe I'll do that.  Then I could schedule our 3rd annual Groton Marathon as a last long training run around Christmas.  This is how my brain works.   It would also get me into decent shape for the Thanksgiving races.   … As I was working through how to survive and thrive over this month of heavy travel I was thinking a lot about how to make the interaction I have with people more valuable.  I usually just put on a smile and work the room but that is a very emotionally thin way of engaging people.  A veneer of bonhomie does not produce any value.   If you are putting on an act, unless you are a really good actor, people sense that and it is off-putting.  I asked myself the question ‘why do you have that light, insincere avatar approach?'  And the answer I got was that because in these business relationships I don't really trust the people I'm interacting with.  Essentially I'm interacting with my guard up – talking and smiling with one hand on my gun.   Then, I asked the next question which was ‘Why don't you trust these people?  What are you afraid of?'  And the surprising answer that popped up was that I'm afraid of them.  I'm afraid looking stupid.  I'm afraid of getting hurt.   Think about that.  I'm having these smiling, friendly conversations with my industry peers that are full of content but also based in fear.  And I thought to myself ‘Gee, that's not a very abundant way to approach life.” Then, stay with me, I asked the next question, which was, “What could happen if you weren't afraid of getting hurt, if you trusted these people?”  What would this bring to you?   It's a work in process but I have been practicing being authentic in these interactions.  It many cases it really changes the value and the outcome of the interaction.  Instead of trying to think one step ahead and figure out what you think they want to hear or what you should say in this situation – you just let go of it, step outside the conversation and say what is important.   It's much less stressful and being calm in the moment can be sensed by people and they are attracted to that.   I'll tell you a story.   I was sitting at a table having breakfast last week.  At the table was a CEO who was one of the keynote speakers.  I'm chatting with folks.  I chat with this guy talking about mutual friends and such, just being chill.  He starts to lock in on me.  He asks me what I do.  Instead of the usual I'm an executive at XYZ company and run the ABC group type of safe answer I said “I like to read, write and speak, I love endurance sports and new ideas and I'm currently an executive at XYZ company.”  That my friends is not an answer anyone expects and says volumes about who I am as a person and the true value that I bring to the world beyond the company and the industry.  After a few more minutes of chat he says, “Well you've got to talk to John Doe who runs my Americas team because we need someone to run the Eastern part of the country so we can grow this business.  Now, let's be clear.  I haven't heard anything else from this guy since then and I have no idea if I'd be interested working for them.  That's not the point of the story.  The point of the story is I wasn't pitching this guy or trying to impress him or really even paying all that much attention to him but he was attracted to me by my authentic attitude.   He felt my detached attitude of abundance and heard something different and valuable in the way I interacted.  This was a demonstration of what the mystics might consider the law of attraction.   But more importantly it was a demonstration of how we can modify our own selves by asking good introspective questions and then reflecting that self-aware attitude out into the world (or perhaps, the universe).   So ponder on this as you're out and about this week.  The way we think influences how we manifest to others.  How are you manifesting in your world? What are you programming yourself to attract? And I'll see you out there.  http://wapack.freeservers.com/ MarathonBQ – How to Qualify for the Boston Marathon in 14 Weeks - http://www.marathonbq.com/qualify-for-the-boston-marathon-in-14-weeks/ Http://www.marathonbq.com http://runrunlive.com/my-books  

Between 2007 and 2010 more than 50 patients with spontaneous dissections of cervical arteries have been examined and scanned with a modified cervical MRI and fluorodeoxyglucose (18F) PET CT protocol at the Institute of Clinical Radiology, LMU Munich. Within this prospective, mono-centric study all imaging data was obtained by using a 3.0 tesla scanner (Magnetom Verio; Siemens Healthcare) and two PET CT scanners (Philips Gemini; Philips Healthcare and Siemens Biograph 64; Siemens Healthcare). This study was based on and conducted by a strong cooperation between the Department of Neurology and the Department of Nuclear Medicine. Detailed data sets regarding patient history and clinical parameters were recorded for every patient. The MRI protocol included a time-of-flight angiography, fat-saturated T1- and T2- weighted black-blood sequences before and after the administration of contrast medium (Gadovist®, Bayer-Schering). The scans covered the supra-aortic vessels from the aortic arch to the base of the skull with a best in plane resolution of 0.5 x 0.5 mm2. Every patient received an additional diffusion-weighted brain-MRI for evaluation of ischemia. The supra-aortic vessels of the same patients were also scanned by a low dose FDG/PET-CT. Measurements of standardized uptake values for every vessel segment were obtained after the administration of the tracer (activity: 5 MBq/kg bodyweight). The calculated effective dose was 8 mSv per patient. Along with quantitative PET-CT analysis, experienced radiologists performed qualitative evaluation of vessel wall inflammation for PET-CT and the MR images. Local inflammatory changes at the site of dissection were distinguished from generalized inflammation of the vascular system.

In der Therapie des Urothelkarzinoms treten nach transurethraler Resektion (TUR) in nahezu 80% aller Fälle Rezidive durch disseminierte Tumorzellen auf. Die sofortige Instillation von Mitomycin C reduziert diese Rezidivrate zwar um 39%, dennoch kommt es zu einem Wiederauftreten des Blasentumors bei 15–40% aller Patienten innerhalb von 5 Jahren nach TUR. Ziel dieser Studie war daher die Entwicklung eines orthotop xenotransplantierten Mausmodells zur Bewertung einer neuen adjuvanten Therapiestrategie. Die zur Modelletablierung verwendete Luciferasetransfizierte humane Blasenkarzinom-Zelllinie EJ 28-luc weist mit 5,1 x 105 EGFR-Molekülen pro Zelle eine deutliche Überexpression des EGF-Rezeptors auf. Eine Überexpression des EGFR wird in bis zu 86% aller Urothelkarzinome beobachtet. Als therapeutisches Agens wurde der hoch zytotoxische α-Emitter 213Bi (HWZ 45,6 min), gekoppelt an einen monoklonalen anti-EGFR-MAk (EMD 72000), verwendet. Aufgrund einer geringen Reichweite im Gewebe von ca. 50-90 μm und einem hohen linearen Energietransfer (LET) von 60-150 keV/μm eignen sich die von 213Bi emittierten α-Partikel zur effizienten Abtötung einzelner Tumorzellen oder kleiner Tumore. Zur Bewertung der therapeutischen Effizienz sowie der Toxizität der 213Bi-anti-EGFR-Konjugate wurden Tumorentwicklung und Überleben orthotop xenotransplantierter Tiere nach intravesikaler Instillation der Radioimmunkonjugate untersucht. Zur Erfassung der Tumorentwicklung wurden nicht invasive bildgebende Verfahren wie Ultraschall, 11C-Cholin-PET und Biolumineszenz Imaging verglichen. Ausschliesslich mittels Biolumineszenz Imaging liess sich eine Tumormanifestation ab dem 7. Tag nach intravesikaler Zellinstillation sowie eine posttherapeutische Tumorregression zuverlässig nachweisen. So betrug die Tumorangehrate nach intravesikaler Instillation der EJ 28-luc Zellen nahezu 80%. Die Biodistribution von 213Bi-anti-EGFR-Konjugaten, welche hochspezifisch an EJ 28-luc Zellen binden, wurde nach intravesikaler Instillation an tumorfreien und an tumortragenden Tieren untersucht. Dabei zeigte sich eine sehr gute Retention des Radioimmunkonjugats in der Blase mit vernachlässigbarer systemischer Verteilung. Die therapeutische Effizienz der 213Bi-anti-EGFR-Konjugate wurde in Abhängigkeit von der applizierten 213Bi-Aktivität und dem Zeitpunkt der Applikation nach intravesikaler Instillation der Tumorzellen im Vergleich zu einer untherapierten Kontrollgruppe ermittelt. Der Median der Überlebenszeit der Tiere, die mit 0,37 bzw. 0,925 MBq 213Bi-anti-EGFR-MAk 1 h nach Zellinstillation therapiert wurden, lag mit >300 d hochsignifikant über dem Median des Überlebens untherapierter Kontrolltiere von nur 41 d. Bei intravesikaler Instillation von 213Bi-anti-EGFR-MAk am Tag 7 nach Zellinokulation lag der Median der Überlebenszeit bei Applikation von 0,925 MBq ebenfalls bei >300 Tagen, während sich bei 0,37 MBq kein signifikanter Unterschied zum Überleben der Kontrollgruppe ergab (medianes Überleben 49 d). Bei Einsatz von 0,925 MBq 213Bi-anti-EGFR-MAk 14 d nach Zellinstillation betrug der Median der Überlebenszeit 55 d. Demnach sind die Tumore 14 d nach Zellinstillation grösser als die Reichweite der α-Partikel, so dass nicht alle Zellen abgetötet werden konnten. Die intravesikale Therapie mit Mitomycin C 1 h bzw. 7 d nach Zellinstillation bewirkte mit 289 d bzw. 251 d ebenfalls ein signifikant verlängertes medianes Überleben im Vergleich zur Kontrollgruppe. Jedoch zeigten sich bei diesen Tieren pathologische Veränderungen der Niere in Form von Nephrozirrhosen, die nach Therapie mit 213Bi-anti- EGFR-MAk nicht beobachtet wurden. Intravesikal instilliertes 213Bi-anti-EGFR Radioimmunkonjugat erwies sich als sehr effektiv in der Abtötung disseminierter Tumorzellen und verursachte keine makroskopisch erkennbare Schädigung des murinen Urothels. Diese Studie zeigte hochsignifikant verlängerte Überlebenszeiten der mit 213Bi-anti-EGFR-MAk behandelten Tiere ohne toxische Nebenwirkungen. Daher könnte sich der Einsatz intravesikal instillierter 213Bi-anti-EGFR-Radioimmunkonjugate in Patienten mit Harnblasenkarzinom nach TUR als vielversprechend im Hinblick auf ein rezidivfreies Überleben erweisen.

Plattenepithelkarzinome des Kopf-Hals-Bereichs (HNSCC) haben, vor allem im fortgeschrittenen Stadium, wegen einer hohen Rate an lokalen Lymphknotenmetastasen und Fernmetastasen eine schlechte Prognose. Aus diesem Grunde ist man auf der Suche nach effektiven adjuvanten Therapiemöglichkeiten. Das Prinzip der Radioimmuntherapie scheint hierfür sehr viel versprechend zu sein. Plattenepithelkarzinome des Kopf-Hals-Bereichs exprimieren die tumorassoziierten Antigene EpCAM und CK8. Ziel dieser Arbeit war es, die Biodistribution und die therapeutische Wirksamkeit der an 131I bzw. 123I gekoppelten Antikörper gegen EpCAM und Cytokeratin 8 (C215 und HK-8) in vivo im SCID-Mausmodell zu untersuchen. Zunächst wurden Studien zur Biodistribution durchgeführt. Zu definierten Zeitpunkten nach i.v.-Applikation von 131I-markierten IgG2a-Antikörper C215 bzw. HK-8 wurden Mäuse euthanasiert und der prozentuale Anteil der injizierten Dosis pro Gramm Gewebe (%ID/g) in den einzelnen Organen sowie im Tumor bestimmt. Szintigraphiestudien mit 123I-C215 und 123I-HK-8 ergaben ebenfalls Aufschlüsse über die systemische Verteilung der Radioimmunkonjugate (RIK). Zudem wurde die therapeutische Wirksamkeit von 131I-C215 untersucht. Hierzu wurden den xenotransplantierten Mäusen 25, 15 oder 5 MBq des RIK systemisch verabreicht. Die Kontrollgruppen erhielten entweder den unmarkierte Antikörper oder sterile Kochsalzlösung. In den Untersuchungen zur Biodistribution und in der Szintigraphie ließ sich eine spezifische Anreicherung der markierten Antikörper im Tumor nachweisen. Die erreichten Tumor/Nicht-Tumor- (T/NT-) Verhältnisse waren bei Vergleich beider RIK ähnlich. Durch Anstieg der T/NT-Verhältnisse nahezu aller Proben, konnte in beiden Fällen eine stetige Zunahme der RIK-Anreicherung im Tumor nachgewiesen werden. Das Nicht-Blut/Blut-Verhältnis zeigte ebenfalls sowohl für 131I-CK8 als auch 131I-C215 eine spezifische Anreicherung im Tumor. Das Problem eines relativ hohen Anteils beider RIK in Milz und Leber konnte durch zusätzliche Applikation von unspezifischem CD20-IgG2a verhindert werden, da dieser Effekt unter anderem auf einen Mangel an endogenem IgG2a in SCID-Mäusen zurückzuführen ist. In der Therapiestudie zeigten die Mäuse, denen 15 MBq injiziert worden waren, 24 Tage p.i. ein im Vergleich zum Applikationszeitpunkt relatives Tumorvolumen von 0,38. Bei den Mäusen, die 25 MBq erhalten hatten war an Tag 17 p.i. ein relatives Tumorvolumen von 0,56 zu verzeichnen. Es war also zu einer deutlichen Reduktion des Tumorvolumens um 44 bzw. 62 Prozent gekommen. Dies konnte jedoch nur auf Kosten einer hohen Toxizität erreicht werden. In der Therapiegruppe, die 5 MBq erhalten hatte und in den beiden Kontrollgruppen (NaCl oder unmarkierter Antikörper) war kein antitumoraler Effekt festzustellen. Hier zeigte sich erwartungsgemäß ein exponentielles Tumorwachstum. Die vorliegenden Ergebnisse lassen darauf schließen, dass Antikörper gegen EpCAM gut geeignet sind für eine radioimmuntherapeutische Behandlung von HNSCC, da die applizierten Antikörper in ausreichender Menge ihr Target, d. h. die Tumorzellen erreichten. Allerdings erwiesen sich die gewählten Dosierungen von 15 und 25 MBq 131I-C215 bei tumortragenden Mäusen als radiotoxisch.

Bei diffusen Magenkarzinomen treten in 50% aller Fälle Mutationen im Gen für das Adhäsionsmolekül E-Cadherin auf. Bei einem Fünftel dieser Mutationen ist Exon 9 deletiert, was die Expression einer mutationsspezifischen Proteinstruktur zur Folge hat (d9-E-Cad). Gegen diese tumorspezifische Bindungsstelle wurde ein monoklonaler Antikörper entwickelt(d9MAk). Dieser Antikörper wurde mit Wismut-213 (Bi-213) gekoppelt, einem hochenergetischen alpha-Emitter mit einer Reichweite von 80 µm im Gewebe, einem hohen linearen Energietransfer von 100 keV/µm und einer Halbwertszeit von 45,6 min. Um das therapeutische Potential des lokoregional applizierten Bi-213-Immuinkonjugats bei disseminierter Tumorzellaussaat gegen die Nebenwirkungen auf den Organismus beurteilen zu können, wurde ein Modell der Peritonealkarzinose bei Nacktmäusen durch intraperitoneale Inokulation von humanen Magenkarzinomzellen mit d9-Cad-Expression entwickelt. Sonographie und Kernspintomographie zeigten für die Visualisierung abdominaler Tumormanifestation und posttherapeutischer Tumorregression eine unzureichende Auflösung, während die In-vivo-Fluoreszenzanalyse "Optical Imaging" für diese Anwendungen erste, viel versprechende Ergebnisse lieferte. Diese Darstellungsmethode könnte in weiteren Studien für die Peritonealkarzinose optimiert werden. Mittels Biodistributionsstudien wurde die spezifische Bindung des Bi-213-d9MAk an den Tumor sowie die Verteilung im Organismus im Vegleich zu einem unspezifischen Kontrollantikörper untersucht. Die Bioverteilung zeigte neben einer hochspezifischen Bindung des Bi-213-d9MAk in Tumoren mit d9-E-Cad-Expression niedrige Konzentrationen des Radioimmunkonjugates im Blut und in den Organen. Bei vorliegendem Aszites blieb ein Großteil des Bi-213-d9MAk abdominal retiniert. Die Überlebenszeiten der Tiere nach Inokulation von 1x10E7 Tumorzellen wurden in Abhängigkeit von der applizierten Aktivität des Bi-213-d9MAk in verschiedenen Peritonealkarzinosestadien erfasst. Die mittlere Überlebenszeit von Tieren, die intraperitoneal mit 7,4 MBq Bi-213MAk am Tag 1 nach Tumorzellinokulation therapiert wurden, war mit 232 Tagen etwa zehnmal länger als jene von untherapierten Kontrolltieren, die bereits 24 Tage nach Tumorzellinokulation Aszites, große Tumormassen oder Tumokachexie zeigten. Bei spezifischer Therapie am Tag 8 nach Tumorzellinokulation, also bei fortgeschrittenem Karzinosestadium, verlängerte sich das Überleben der Mäuse auf 187 Tage. Der Unterschied im mittleren Überleben der Tiere nach Applikation von spezifischem Bi-213-d9MAk bzw. von unspezifischem Radioimmunkonjugat war nur bei Therapie am Tag 8 nach Tumorzellinokulation signifikant, da auch unspezifische Radioimmunkonjugate injiziert am Tag 1 nach Tumorzellinokulation deutliche Therapieerfolge bewirkten. Eine i.p. applizierte Aktivität von 22,2 MBq (600 µCi) führte etwa 180 Tage p.i. zu chronischem Nierenversagen. Ohne Nierenprotektion durch kationische Aminosäuren stellt die Niere somit das dosislimitierende Organ bei der Therapie mit Bi-213-d9MAk dar. Die Bewertung von Veränderungen der Tiergewichte ergab keinen toxischen Einfluss von 7,4 MBq (200 µCi) Bi-213-d9MAk auf den Säugetierorganismus. Die Leukozytenzahlen zeigten eine Abnahme in Abhängigkeit von der applizierten Aktivität, erholten sich aber innerhalb von 30 Tagen. Die Häufigkeit chromosomaler Aberrationen erhöhte sich mit zunehmender Aktivität bis 24 h nach Injektion des Bi-213-d9MAk. Zu späteren Zeitpunkten waren keine chromosomalen Aberrationen mehr nachweisbar. Das Radioimmunkonjugat Bi-213-d9MAk eignet sich nach den Resultaten dieser Studie hervorragend für die lokoregionale Anwendung bei disseminierter Tumorzellaussaat im Abdominalraum als Folge primären Magenkarzinoms mit Expression der d9-Mutante des E-Cadherins. Hohe therapeutische Effizienz, insbesondere bei Vorliegen von kleinen Tumorzellaggregaten und Einzelzellen, und niedrige Toxizität zeichnen das neue Radiopharmakon aus. Der therapeutische Einsatz des Bi-213-d9MAk empfiehlt sich besonders perioperativ bei Resektion eines soliden Magenkarzinoms zur Prophylaxe der Peritonealkarzinose aufgrund traumatischer Tumorzelldissemination.

Autoradiographic studies on myosmine toxicokinetics in rats Myosmine, a minor tobacco alkaloid was recently detected in a wide variety of nutritional plants including cereals, nuts, cocoa and dairy products. Under acidic conditions myosmine is easily nitrosated leading to pyridyloxobutylation either directly or through the formation of N'-nitrosonornicotine (NNN). In NNN-treated rats DNA adducts releasing 4-hydroxy-(3-pyridyl)-1-butanone (HPB) are made responsible for tumours in oesophagus, oral and nasal cavities. Whereas the pharmacokinetics and metabolism of NNN have been studied in detail no such data have been available for myosmine. In the present study time-dependent distribution, binding and excretion of radiolabelled myosmine was investigated in pigmented and albino rats by quantitative whole-body autoradiography. One rat each was sacrificed by CO2 asphyxiation six and 15 minutes as well as 1, 4 and 24 hours after intravenous injection Zusammenfassung / Summary 91 of myosmine (5-3H: 1.4 µg/kg; 8.49 MBq/kg or 2’-14C: 0.27 mg/kg; 3.74 MBq/kg). Sagittal sections of 40 µm thickness obtained after deep freezing of the rats, were exposed to image plates either before or after serial extraction with solvents and water. Additionally, sections of eyes and oesophagus of untreated rats were incubated in vitro with 2’-14C myosmine. The rats killed four and 24 hours after myosmine injection were separately housed in metabolism cages for collection of urine and faeces. High concentrations of radioactivity were present six minutes after myosmine application in Harder's gland, lacrimal, salivary and accessory genital glands, nasal cavity, liver, kidney cortex, wall of the stomach fundus as well as the melanin rich parts of the eye and skin. An accumulation of radioactivity was also seen in the contents of the stomach and bladder. A similar distribution pattern was evident after 15 minutes and one hour with stronger accu-mulation in oesophagus, medulla of kidneys and accessory genital glands. An increasing labelling was observed throughout the contents of the gastrointestinal tract. Four hours after myosmine application the labelling intensity of most organs and tissues decreased conside-rably with exception of the accessory genital glands showing an extraordinary high concen-tration of radioactivity. Additionally, the oesophagus showed more marked labelling at this time. After 24 hours nearly all of the applied labelled myosmine has eliminated from the body. However, a significant labelling was still present in melanin rich tissues and in the preputial gland. The high accumulation of radioactivity in the accessory genital glands within the first four hours after myosmine injection is a new finding which has not been reported for similar compounds such as nicotine, cotinine and tobacco-specific nitrosamines. Direct determina-tion of radioactivity in the excised glands confirmed the result obtained by quantitative autoradiography. After extraction of the slices most of the radioactivity was removed from the tissues. An increased proportion of radioactivity remained in melanin rich tissues, nasal cavity, oesopha-gus, lung and liver. A distinct labelling of oesophageal mucosa as well as pigmented parts of the eyes could also be observed after in vitro incubation of slices from untreated rats. In most of the tissues, the drop of radioactivity followed a first order elimination kinetic with half lives between 0.4 hours for salivary glands and 1.2 hours for skin melanin. Within 24 hours 72 and 15 percent of the dose have been excreted in urine and faeces, respectively. The results demonstrate the suitability of saliva and hair for biomonitoring human myosmine uptake. The increased proportion of non-extractable radioactivity in the oesophagus supports our hypothesis of the possible implication of myosmine as an initiator of human oesophageal adenocarcinoma.

Introduction: Having in mind the promising results of lymphoscintigraphy and intraoperative gamma probe application for the detection of sentinel lymph nodes (SLN) in malignant melanoma, breast and penis cancer, we tried to identify the SLN in prostate cancer by applying a comparable technique. Materials and Method. 350 patients with prostate cancer were examined after providing informed consent. The day before pelvic lymphadenectomy technetium-99m nanocolloid was transrectally injected into the prostate under ultrasound guidance. A single central application was done per prostate lobe in most cases. Activity attained 90400 MBq, and the total injected volume was about 2-3 ml. Hereafter, lymphoscintigraphy was carried out. Those lymph nodes having been identified as SLN by means of gamma probe detection and lymphoscintigraphy were removed intraoperatively. Later, most of the cases had different types of pelvic lymphadenectomy. SLN received serial sections and immunohistochemistry, non-SLN step sections. Results: 335 patients showed at least 1 SLN in lymphoscintigraphy. 24.7% had lymph node metastases. In 2 patients, metastases in non-SLN were found without at least one SLN being affected (false-negative patient). Conclusion:Our experience suggests that the SLN identification is not only feasible in breast cancer and malignant melanoma, but also in prostate cancer with a comparable technique. Copyright (C) 2003 S. Karger AG, Basel.

The incidence of lens opacifications that impaired vision (cataract) was analyzed among 831 patients who were injected with known dosages of 224Ra in Germany shortly after World War II. The dependence of the incidence on dosage, i.e., injected activity per unit body weight, and on time after treatment was determined. The observations are equally consistent with proportionality of the incidence of cataract to the square of dosage or with a linear dependence beyond a threshold of 0.5 MBq/kg. The possibility of a linear dependence without threshold was strongly rejected (P less than 0.001). The analysis of temporal dependences yielded a component that was correlated with the injected amount of 224Ra and a component that was uncorrelated. The former was inferred by a maximum likelihood analysis to increase approximately as the square of the time after treatment. The component unrelated to the treatment was found to increase steeply with age and to become dominant within the collective of patients between age 50 and 60. The relative magnitudes of the two components were such that a fraction of 55 to 60% of the total of 58 cataracts had to be ascribed to the dose-related incidence. Impaired vision due to cataract was diagnosed before age 54 in 25 cases. In terms of injected activity per unit body weight no dependence of the sensitivity on age was found; specifically there was no indication of a faster occurrence of the treatment-related cataracts in patients treated at older ages.