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GOOD AFTERNOON, I'M ALLAN

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WEISSMAN,

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AND BEFORE INTRODUCING OUR

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SPEAKER I WOULD REMIND EVERYBODY

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TO SIGNIFY LEPS THEIR PHONES AND

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SO THAT ANYONE WATCHING REMOTELY

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CAN HEAR. 

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IT'S A PLEASURE TO INTRODUCE

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00:00:26,307 --> 00:00:29,210
DR. ZEEV ROIN AI, HE EARNED HIS

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Ph.D. IN 1980 AND AFTER

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JOINING THE FACULTY AT MOUNT

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SINAI WHERE HE IS NOW THE

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DIRECTOR OF THE DESIGNATED

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CANCER CENTER--I'M SORRY ABOUT

15
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THAT, BEFORE THAT HE WAS AT

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MOUNT SINAI AND MOVED TO

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LA JUDGE, CORRELATED YA TO JOIN

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THE MEDICAL DISCOVERY INSTITUTE

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WHERE HE'S NOW THE DIRECT

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OVERLAPPING THE NCI DESIGNATE

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THE CANCER CENTER.

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HE IS THE PROFESSOR OF CANCER

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METABOLISM AND MICROBIOME

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00:01:01,175 --> 00:01:02,309
PROGRAM, OVER A NUMBER OF YOAN

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MONCADAERS HE HELD A NUMBER OF

26
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OTHER POSITIONS AND PLAYED A

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MAJOR ROLE IN THE LEADERSHIP

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COMMUNITY INCLUDING ESTABLISHING

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LARGE GRANT INITIATIVES AND

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CHIEF AND MELANOMA RESEARCH, FOR

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SEVERAL YEARS HE ALSO DIVIDED

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HIS TIME BETWEEN LA JOYA AND

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THEY APPLIED HIS VISION OF

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INTEGRATED ADVANCED PRINCIPLES

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AND COMPUTATIONAL BIOLOGICAL

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SCIENCE CAN APPLIED THIS TO HIS

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PASSION FOR UNMET NEEDS IN

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CANCER RESEARCH.

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HIS OVER 300 PUBLICATIONS HAVE

40
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INBEEN CITED OVER 3000 TIMES, HE

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IS THE NUMEROUS RECIPIENT OF

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AWARDS, HE'S BEEN INVITED TO

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SEVERAL FORUMS AND SEVERAL

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CONFERENCES AND BEING AWARDED

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THE MELANOMA'S LIFETIME

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ACHIEVEMENT AWARD IN 2016.

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THE OVERALL EMPHASIS OF HIS

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RESEARCH IS ON EPIGENETIC

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MODIFICATIONS, UNDERLYING ISSUES

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OF TUMOR DEVELOPMENT, PROGRESS

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AND RESISTANCE AS WELL AS OTHER

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POST TRANSLATIONAL

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MODIFICATIONS, I COULD GO ON ADD

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INFINITE UM ABOUT HIS ACHIEVE

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AMS SO I WILL MENTION A FEW

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THINGS, ZEEV HAS MADE

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CONTRIBUTIONS IN IMMEDIATE

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STRESS RESPONSES PARTICULARLY

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HIS EARLY WORK ON GENE KINASE

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AND ALTERATIONS IN SIGNALING

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THROUGH KINASES AND CANCER IN

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GENERAL EMPLOY HE'S MADE MANY

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PARADAME SHIFTING IN THE ROLES

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OF LIGASES AND FUNDAMENTAL

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CELLULAR PROCESSES INCLUDING

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PROCESSES AND CANCER RESISTANCE

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AND THERAPY AS WELL AS

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AUTOIMMUNITY.

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HIS RECENT WORK DEMONSTRATING

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THAT LOW LEVELS MAP KINASE

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INHIBITORS IN MELANOMA HAS LED

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TO CLINICAL TRIALS THAT ARE

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ONGOING ON THE UNIVERSITY OF

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OREGON USING COMPARITTORS OF

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GENE UP TAKE INTO THE CELL.

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HIS WORK ON METHYLTRANSFERASE 5,

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HAVE ALREADY PROVED TO BE

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EFFECTIVE WITH TUMOR IRMUNITY.

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WITHOUT FURTHER ADO I WILL TURN

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IT OVER TO ZEEV FOR HIS TALK.

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[ APPLAUSE ]

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>> THANK YOU FOR THE

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INTRODUCTION AND JUST KNOW IT BE

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DOWN HILL FROM HERE.

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[LAUGHTER]

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[ APPLAUSE ]

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ONE OF THE SLIDES I WILL SHARE

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DURING MY PRESENTATION WAS

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COVERED IN LENGTH MAYBE 10 YEARS

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AGO AND YOU WILL FIGURE OUT

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00:03:42,570 --> 00:03:44,405
WHERE IT COMES FROM.

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YOU ARE GOING TO HEAR ABOUT WHAT

93
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I THINK ABOUT CERTAIN ASPECTS,

94
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BELIEFS AND THEY'RE ONLY MINE.

95
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SO TAKE IT WITH A GRAIN OF SALT

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OF COURSE.

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TO TOPICS I WOULD LIKE TO

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DISCUSS WITH YOU TODAY OTHERS

99
00:04:06,193 --> 00:04:08,495
BOTH ARE BASICALLY REFLECTING

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WITH RESEARCH AND I WILL START

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00:04:10,764 --> 00:04:12,666
WITH PUBLISHED AND END UP WITH

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UNPUBLISHED IN BOTH CASES.

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00:04:13,734 --> 00:04:15,603
THE FIRST WILL BE THE MICROBI

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00:04:15,603 --> 00:04:18,772
OTA PATH IN THE UNEXPECTED WAY

105
00:04:18,772 --> 00:04:20,875
AND THE SECOND UBIQUITIN LIGASE,

106
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BOTH OF THEM STEM FROM THE

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00:04:22,877 --> 00:04:27,114
STORY, SECOND IS MORE UBIQUITIN

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LIKE BASED STORY.

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ASK I'M GOING TO DWELL A LITTLE

110
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BIT ABOUT THE FIELD OF UBIQUITIN

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LIGASE,RY MIND ME A LITTLE BIT

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OF THE FIELD OF PROTEIN

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PHOSPHATASES CHA IS HOW TO

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MAINTAIN BECAUSE I DON'T SEE

115
00:04:41,195 --> 00:04:42,730
CTGAs AND THE LIKE BUT I WILL

116
00:04:42,730 --> 00:04:46,467
SPEAK ABOUT THIS A LITTLE LATER.

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SO THE CROSS TALK BETWEEN THE

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00:04:48,569 --> 00:04:50,004
TUMOR AND THE MICROENVIRONMENT

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AND THIS IS A SIMPLE

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PRESENTATION OF THE DIFFERENT

121
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COMPLEMENTS THAT ARE PRESENT IN

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THE MICROENVIRONMENT THAT THEY

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00:04:57,378 --> 00:04:59,313
PLAY A ROLE IN TUMOR EVOLUTION,

124
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SO IT'S NOT ONLY THE TUMOR

125
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BEHAVIOR BUT IT'S INTERACTION OF

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THE MICROENVIRONMENT THAT

127
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DETERMINE WHAT AND HOW IT WILL

128
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EVOLVE, AND WE USED TO THINK

129
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ABOUT--LET'S SEE HOW THAT WORKS,

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WE USED TO THINK ABOUT THE CAPS

131
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AND THEIR INTERACTION WITH THE

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TUMOR CELLS, WE PAY A LOT OF

133
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ATTENTION TO IMMUNE CELLS,

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IMMUNE CELL COMPETENT AND THEN I

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BELIEVE TO INFILTRATE THE TUMOR

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CELLS AND FIGHT THE TUMOR CELLS,

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I THINK THE STORY IS WAY MORE

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COMPLICATED, I THINK THE STORY

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HAS TO DO WITH IMMUNE CELLS

140
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INTERACTION WITH THIS TRAUMA

141
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BEFORE IT IS EDUCATED TO DO

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SOMETHING WITHIN OR INTO THE

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TUMOR, AND THAT'S A PART OF A

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PROJECT WE ARE CURRENTLY PAYING

145
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ATTENTION AT THE LAB TO.

146
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WHEN WE ARE SPEAKING ABOUT

147
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EPIIMENETTIC AND THE WHOLE TALK

148
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WILL DISCUSS EPIGENETIC

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REGULATION RATHER THAN GENETICS,

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WE USED TO THINK ABOUT

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METHYLATION, HISTONES

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ACETYLATION AND LESS WE THINK

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ABOUT PROTEIN METHYLATION,

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PROTEIN MODIFICATION, THIS IS A

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MASS SPEC WE HAVE BEEN DWELLING

156
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ON AND PAYING A LOT OF ATTENTION

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IN RECENT YEARS.

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I WILL SPEAK ABOUT UBIQUITIN

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LIGASE AS A MEDIATOR OF OTHER

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SIGNALING PATHWAY AND HOW THOSE

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ARE ABLE TO EFFECT BOTH THE

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TUMOR AND THE MICROENVIRONMENT

163
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AND NOT NECESSARILY IN THE SAME

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WAY.

165
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AND SO THAT'S 1 THING THAT 1 OF

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THE TAKE HOME MESSAGES--I'M

167
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GOING TO TRY TO MAKE THE STORY

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TELLERS A LITTLE BIT MORE SIMPLE

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AND THE STORY BEGAN FROM A

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UBIQUITIN LIGASE THAT WE WORKED

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ON FOR QUITE A FAW YEARS IN THE

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LABORATORY PROTEIN NUMBER 5, RNA

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5, GENERATED THE MICE MAYBE 20

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YEARS AGO THAT LIKE THE GENE AND

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THEY DIDN'T HAVE PHENOTYPE AND

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THEY DESIGNATED THE MICE AS THE

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BORING MICE, NOTHING

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INTERESTING, AND THAT IS UNTIL

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[INDISCERNIBLE] DECIDED TO PUT

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MELANOMA CELLS INTO THESE MICE

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AND GUESS WHAT, MELANOMA DIDN'T

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GROW.

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SO THAT WAS THE BEGINNING OF A

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VERY EXCITING PROJECT, WHERE

185
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USING DIFFERENT MELANOMA TYPES

186
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WE WERE ABLE TO DEMONSTRATE THAT

187
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THE MICE ARE COMPLETELY

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RESISTANT TO TUMOR DEVELOPMENT

189
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AND WAS NOT ONLY MELANOMA, WE

190
00:08:05,299 --> 00:08:09,336
WERE ABLE TO SHOW IT FOR COLON

191
00:08:09,336 --> 00:08:10,804
CANCER AS WELL.

192
00:08:10,804 --> 00:08:14,475
SOON AFTER, WE DEMONSTRATED THAT

193
00:08:14,475 --> 00:08:15,776
THE REASON MELANOMA DIDN'T GROW

194
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IN THESE ANIMALS IS BECAUSE

195
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THERE IS EXTENSIVE INFILTRATION

196
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OF IMMUNE CELLS INTO THE TUMOR,

197
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WHICH FOUGHT THE TUMOR.

198
00:08:22,116 --> 00:08:26,720
SO IN THIS CASE, YOU CAN SEE THE

199
00:08:26,720 --> 00:08:37,030
CD4, CD8 POSITIVE

200
00:08:40,234 --> 00:08:40,868
T-CELLS--ESTABLISH THIS

201
00:08:40,868 --> 00:08:42,069
INFILTRATION OF THESE T-CELLS

202
00:08:42,069 --> 00:08:43,604
THAT CAUSE THE REJECTION

203
00:08:43,604 --> 00:08:46,707
PHENOTYPE THAT WE HAVE SEEN.

204
00:08:46,707 --> 00:08:47,641
AND NEUTRALIZING ANTIBODY

205
00:08:47,641 --> 00:08:49,910
AGAINST CD8 IS SHOWN THIS SLIDE

206
00:08:49,910 --> 00:08:52,346
WAS SUFFICIENT TO BLOCK THE

207
00:08:52,346 --> 00:08:53,747
INHIBITION OF TUMOR GROWTH, WE

208
00:08:53,747 --> 00:08:59,620
LOST IT WHEN WE NEUTRALIZE CD8

209
00:08:59,620 --> 00:09:00,587
ANTIBODIES.

210
00:09:00,587 --> 00:09:02,956
SO, UBIQUITIN LIGASE CAUSE

211
00:09:02,956 --> 00:09:06,226
ANTITUMOR MOBILITY, LIMITED

212
00:09:06,226 --> 00:09:07,494
GROWTH, HOW DOES IT WORK?

213
00:09:07,494 --> 00:09:11,865
SO YOU WANT TO DEMONSTRATE THIS

214
00:09:11,865 --> 00:09:12,933
IS IMMUNE INHERIT MECHANISM IS

215
00:09:12,933 --> 00:09:15,302
TO DO BONE MARROW TRANSFER, TAKE

216
00:09:15,302 --> 00:09:18,172
THE BONE MARROW FOR 1 MICE, FOR

217
00:09:18,172 --> 00:09:19,473
ANOTHER MICE, IF THE IT HAS TO

218
00:09:19,473 --> 00:09:21,108
DO WITH THE IMMUNE SYSTEM, IT

219
00:09:21,108 --> 00:09:22,876
WILL TRANSFER TO THE RECIPIENT

220
00:09:22,876 --> 00:09:24,845
MICE AND HERE WE GO, IT'S IMMUNE

221
00:09:24,845 --> 00:09:26,013
RELATED BUT IN THIS PARTICULAR

222
00:09:26,013 --> 00:09:27,781
CASE, IT DID NOT.

223
00:09:27,781 --> 00:09:29,616
SO THAT FOR US WAS THE FIRST

224
00:09:29,616 --> 00:09:31,218
INDICATION THAT SOMETHING ELSE

225
00:09:31,218 --> 00:09:33,287
IS GOING ON HERE WHICH IS

226
00:09:33,287 --> 00:09:34,955
INDEPENDENT OF THE INHERIT

227
00:09:34,955 --> 00:09:35,822
IMMUNE SYSTEM.

228
00:09:35,822 --> 00:09:37,691
SO WHAT CAN THIS BE.

229
00:09:37,691 --> 00:09:41,795
ASK THIS WAS THE TIME NOW, WE'RE

230
00:09:41,795 --> 00:09:44,331
TALKING 2017, 18, WHERE THE

231
00:09:44,331 --> 00:09:49,169
MICROBIOME WAS A VERY ATTRACTIVE

232
00:09:49,169 --> 00:09:50,370
AREA, STUDIES FROM LEFT AND

233
00:09:50,370 --> 00:09:52,439
RIGHT CAME ABOUT AND YOU SEE

234
00:09:52,439 --> 00:09:57,177
JUST A SMALL COLLECTION HERE

235
00:09:57,177 --> 00:09:59,012
DEMONSTRATING THAT A SPECIFIC

236
00:09:59,012 --> 00:10:03,083
BACTERIA STRAINS ARE SUFFICIENT

237
00:10:03,083 --> 00:10:09,489
TO CAUSE ENHANCED AUTOIMMUNITY

238
00:10:09,489 --> 00:10:10,057
BY INCREASING CTLA-4.

239
00:10:10,057 --> 00:10:13,727
IT WENT TO THE GREE THAT EVEN

240
00:10:13,727 --> 00:10:14,428
THE SINGLE BACTERIAL STRAIN WAS

241
00:10:14,428 --> 00:10:16,597
TO MAKE THIS WORK, UNFORT MATILY

242
00:10:16,597 --> 00:10:17,864
THINGS DIDN'T WORK OUT LATER IN

243
00:10:17,864 --> 00:10:19,733
CLINICAL TRIALS BUT THE MESSAGE

244
00:10:19,733 --> 00:10:21,835
WAS LOUD AND CLEAR, BACTERIA IT

245
00:10:21,835 --> 00:10:27,708
HAVE AN EFFECT ON THE DEGREE OF

246
00:10:27,708 --> 00:10:28,742
ANTITUMOR FIGHT BY

247
00:10:28,742 --> 00:10:29,109
[INDISCERNIBLE].

248
00:10:29,109 --> 00:10:33,347
SO WE CHECKED WHETHER IT COULD

249
00:10:33,347 --> 00:10:35,983
BE IF IT'S NOT IMMUNE RELATED

250
00:10:35,983 --> 00:10:38,919
WHICH WAS THE BONE MICROBIOME

251
00:10:38,919 --> 00:10:41,121
HERE, IT COULD BE THE MICROBIOME

252
00:10:41,121 --> 00:10:42,456
AT PLAY HERE SO WHEN WE TARTED

253
00:10:42,456 --> 00:10:43,890
TO MAP THE COMPOSITION OF THE

254
00:10:43,890 --> 00:10:45,892
MICROBI OTA IN THE KNOCKOUT MICE

255
00:10:45,892 --> 00:10:48,395
VERSUS THE WILD-TYPE, WE

256
00:10:48,395 --> 00:10:50,664
IMMEDIATELY SAW THE 2 DIFFERENT

257
00:10:50,664 --> 00:10:51,765
DISTRIBUTION 2 DIFFERENT

258
00:10:51,765 --> 00:10:52,799
CONCENTRATION OF BUGS

259
00:10:52,799 --> 00:10:55,168
SUGGIESTING THAT THERE IS

260
00:10:55,168 --> 00:10:57,337
SOMETHING DIFFERENT IN THE

261
00:10:57,337 --> 00:10:59,072
COMPOSITION OF MICROBI OTA IN

262
00:10:59,072 --> 00:11:02,309
THE KNOCKOUT MICE COMPARED TO

263
00:11:02,309 --> 00:11:02,809
THE WILD-TYPE.

264
00:11:02,809 --> 00:11:06,647
THAT LED US TO DO 2 VERY SIMPLE

265
00:11:06,647 --> 00:11:08,915
EXPERIMENTS AND SIMPLE,

266
00:11:08,915 --> 00:11:10,817
SOMETIMES IS GOOD, SOMETIMES IS

267
00:11:10,817 --> 00:11:11,852
BETTER AND THE FIRST SIMPLE

268
00:11:11,852 --> 00:11:13,487
EXPERIMENT IS TO TAKE THE MICE,

269
00:11:13,487 --> 00:11:15,822
TREAT THEM WITH A COCKTAIL OF

270
00:11:15,822 --> 00:11:17,858
ANTIBIOTICS THAT IS KNOWN TO

271
00:11:17,858 --> 00:11:18,992
ELIMINATE MOST OF THE STRAINS,

272
00:11:18,992 --> 00:11:22,863
SO IF I TAKE MICE ELIMINATE THE

273
00:11:22,863 --> 00:11:23,930
BACTERIA POPULATION BY A

274
00:11:23,930 --> 00:11:30,437
COCKTAIL OF ASPECT BIOTICS, I

275
00:11:30,437 --> 00:11:32,673
CAN WHETHER THESE THE MICROBI

276
00:11:32,673 --> 00:11:34,074
OTA WAS RESPONSIBLE FOR THE

277
00:11:34,074 --> 00:11:35,242
PHENOTYPE AND THIS THE

278
00:11:35,242 --> 00:11:36,910
EXPERIMENT SHOWN HERE, WE SEE

279
00:11:36,910 --> 00:11:38,278
THE EJECTION PHENOTYPE IN THE

280
00:11:38,278 --> 00:11:41,114
KNOCKOUT MICE AND WE LOST IT

281
00:11:41,114 --> 00:11:43,317
LARGELY UPON TREATING WITH

282
00:11:43,317 --> 00:11:45,886
ANTIBIOTIC MIX TOUR.

283
00:11:45,886 --> 00:11:48,055
SO THAT FIRST, NOT DIRECT BUT

284
00:11:48,055 --> 00:11:49,923
THE FIRST INDICATION THAT INDEED

285
00:11:49,923 --> 00:11:54,961
BUGS OR MICROBI OTA CAN BE

286
00:11:54,961 --> 00:11:56,196
INVOLVED THE SECOND EXPERIMENT

287
00:11:56,196 --> 00:12:00,667
WAS EVEN BETTER THAN THE FIRST

288
00:12:00,667 --> 00:12:01,535
EXPERIMENT THE SECOND WAS MIXING

289
00:12:01,535 --> 00:12:03,804
THE MICE FROM THE KNOCK OUT WITH

290
00:12:03,804 --> 00:12:04,771
THE WILD-TYPE MICE ASKING

291
00:12:04,771 --> 00:12:11,278
WHETHER THE CO HOUSING WHEN

292
00:12:11,278 --> 00:12:12,713
SHARING IT FOR A COUPLE WEEKS

293
00:12:12,713 --> 00:12:14,948
WILL BE SUFFICIENT TO ELIMINATE

294
00:12:14,948 --> 00:12:16,383
THE TUMOR TYPE OF INHIBITION.

295
00:12:16,383 --> 00:12:18,652
AND AS CAN YOU SEE THE TUMOR

296
00:12:18,652 --> 00:12:20,487
INHIBIT THAT WAS ALONE WAS LOST

297
00:12:20,487 --> 00:12:24,091
UPON THE CO HOUSING EXPERIMENT.

298
00:12:24,091 --> 00:12:26,727
THAT SUGGEST THAD BUGS ARE

299
00:12:26,727 --> 00:12:28,528
INDEED INVOLVED.

300
00:12:28,528 --> 00:12:30,497
AGAIN INDIRECTLY.

301
00:12:30,497 --> 00:12:37,204
SO WE MOVE ON ALONG THE SAME

302
00:12:37,204 --> 00:12:38,372
LINE THE PHENOTYPE I'VE SHOWN

303
00:12:38,372 --> 00:12:40,807
YOU BEFORE WAS ALSO LOST UPON

304
00:12:40,807 --> 00:12:41,975
THIS CO HOUSING.

305
00:12:41,975 --> 00:12:44,277
IN OTHER WORDS INFILTRATION OF

306
00:12:44,277 --> 00:12:46,847
CD4 OR CD8 T-CELLS ARE NO LONGER

307
00:12:46,847 --> 00:12:48,348
SEEN UPON THIS CO HOUSING

308
00:12:48,348 --> 00:12:50,550
EXPERIMENT WHICH IS SHOWN HERE.

309
00:12:50,550 --> 00:12:52,986
AND THAT'S OKAY, WELL, YOU HAVE

310
00:12:52,986 --> 00:12:55,055
THE MICROBI OTA THAT DICTATES

311
00:12:55,055 --> 00:12:56,423
ANTITUMOR IMMUNITY AND IF YOU

312
00:12:56,423 --> 00:12:57,924
ARE MESSING UP WITH THAT

313
00:12:57,924 --> 00:13:00,360
COMPOSITION, YOU ARE GOING TO

314
00:13:00,360 --> 00:13:05,465
ELIMINATE OR ABOLISH THE SECOND

315
00:13:05,465 --> 00:13:05,932
PHENOTYPE.

316
00:13:05,932 --> 00:13:07,367
SO WE WENT 1 STEP FORWARD AND WE

317
00:13:07,367 --> 00:13:10,504
SAID LET'S SEE IF WE CAN TAKE

318
00:13:10,504 --> 00:13:11,805
THE FECAL SAMPLES FROM THE

319
00:13:11,805 --> 00:13:13,874
KNOCKOUT MICE, GIVE THEM TO THE

320
00:13:13,874 --> 00:13:15,509
WILD-TYPE MICE, WOULD WE BE ABLE

321
00:13:15,509 --> 00:13:24,718
TO KEEP THE PHENOTYPE OF TUMOR

322
00:13:24,718 --> 00:13:25,018
INHIBITION.

323
00:13:25,018 --> 00:13:26,253
AND THIS SAMPLE YOU ARE LOOKING

324
00:13:26,253 --> 00:13:30,157
AT HERE WAS SUFFICIENT TO GROW

325
00:13:30,157 --> 00:13:30,957
TUMOR INHIBITION WHILE

326
00:13:30,957 --> 00:13:32,325
INFILTRATING INHIBITION OF THE

327
00:13:32,325 --> 00:13:33,126
IMMUNE CELLS.

328
00:13:33,126 --> 00:13:34,694
SO TRANSFERRING THE FECAL FROM

329
00:13:34,694 --> 00:13:35,996
THE WILD-TYPE TO THE KNOCK OUT

330
00:13:35,996 --> 00:13:38,298
WAS SUFFICIENT TO MAINTAIN THE

331
00:13:38,298 --> 00:13:40,300
MELANOMA IN THE RECIPIENT MICE.

332
00:13:40,300 --> 00:13:41,368
OKAY, SO THAT'S 1 STEP FORWARD

333
00:13:41,368 --> 00:13:45,672
BUT TILL NOT GOOD ENOUGH BECAUSE

334
00:13:45,672 --> 00:13:49,643
WHO WOULD ASK WHAT ARE THE

335
00:13:49,643 --> 00:13:51,011
BACTERIAL RESPONSE FOR THIS

336
00:13:51,011 --> 00:13:51,244
CHANGE?

337
00:13:51,244 --> 00:13:51,978
AND THAT EXPERIMENT TOOK US

338
00:13:51,978 --> 00:13:54,414
ABOUT A YEAR TO SORT OUT WHAT IS

339
00:13:54,414 --> 00:13:59,753
INDEED INVOLVES AND WE USED

340
00:13:59,753 --> 00:14:01,421
MAYBE 4 OR 5 EXTREMELY COMPUTER

341
00:14:01,421 --> 00:14:04,624
SCIENCE FOLKS TO HELP US OUT,

342
00:14:04,624 --> 00:14:05,459
[INDISCERNIBLE] WAS 1 OF THEM.

343
00:14:05,459 --> 00:14:08,395
AND THE RESULT OF THAT WAS

344
00:14:08,395 --> 00:14:11,198
MAPPING THE DIFFERENT SEQUENCES

345
00:14:11,198 --> 00:14:13,533
WE HAVE MET 16A SEQUENCING AT

346
00:14:13,533 --> 00:14:14,935
THE TIME AND THIS PICTURE YOU'RE

347
00:14:14,935 --> 00:14:16,570
LOOKING AT HERE TOOK US ABOUT A

348
00:14:16,570 --> 00:14:17,871
YEAR TO GENERATE AND I'M SERIOUS

349
00:14:17,871 --> 00:14:19,206
ISSUES I CAN GIVE A WHOLE

350
00:14:19,206 --> 00:14:20,907
LECTURE ON HOW WE GENERATE AND

351
00:14:20,907 --> 00:14:25,579
CAME TO THIS COP CLIEWGZ.

352
00:14:25,579 --> 00:14:27,614
AND WHAT HAS ALLOWED US TO

353
00:14:27,614 --> 00:14:29,282
SIMPLY MAP THE STRAINS OF THE

354
00:14:29,282 --> 00:14:30,684
DIFFERENT IN THE KNOCK OUT

355
00:14:30,684 --> 00:14:32,319
VERSUS THE WILD-TYPE MICE.

356
00:14:32,319 --> 00:14:35,121
AND WITH THAT, WE WERE NOW

357
00:14:35,121 --> 00:14:37,724
EQUIPPED WITH THE KNOWLEDGE OF

358
00:14:37,724 --> 00:14:39,526
THE SPECIFIC BUT STRAINS WE CAN

359
00:14:39,526 --> 00:14:41,027
ADMINISTER TO THE MICE, YOU KNOW

360
00:14:41,027 --> 00:14:42,329
TO SEE WHETHER THEY BY

361
00:14:42,329 --> 00:14:44,531
THEMSELVES WOULD BE SUFFICIENT

362
00:14:44,531 --> 00:14:45,232
TO INHIBIT TUMOR.

363
00:14:45,232 --> 00:14:46,533
THAT'S EXACTLY WHAT WE HAVE

364
00:14:46,533 --> 00:14:47,667
DONE.

365
00:14:47,667 --> 00:14:50,437
WE HAVE SELECTED 11 BACTERIAL

366
00:14:50,437 --> 00:14:51,271
STRAINS, NOW FROM THE CANNED

367
00:14:51,271 --> 00:14:53,874
WHAT WE HAVE IN OUR BODY, LISTEN

368
00:14:53,874 --> 00:14:57,310
IS A ERROR REDUCTIONIST

369
00:14:57,310 --> 00:14:58,245
APPROACH.

370
00:14:58,245 --> 00:14:59,279
ELEVEN BACTERIAL STRAINS

371
00:14:59,279 --> 00:15:01,848
ADMINISTERED TO MICE AND

372
00:15:01,848 --> 00:15:02,782
MELANOMA INOCULATED IN THESE

373
00:15:02,782 --> 00:15:06,119
MICE AND THE MELANOMA WAS NICELY

374
00:15:06,119 --> 00:15:06,953
INHIBITED, TOGETHER WITH

375
00:15:06,953 --> 00:15:08,355
INFILTRATION OF THE IMMUNE

376
00:15:08,355 --> 00:15:10,857
SYSTEM AND ANTITUMOR IMMUNITY.

377
00:15:10,857 --> 00:15:12,392
SO, FROM EVERYTHING THAT WE HAVE

378
00:15:12,392 --> 00:15:15,395
DONE, WE ARE NOW AT A STAGE

379
00:15:15,395 --> 00:15:17,297
WHERE WE FORGOT ABOUT UBIQUITIN

380
00:15:17,297 --> 00:15:18,598
LIGASE, WE ARE DOWN TO THE

381
00:15:18,598 --> 00:15:21,868
BACTERIAL STRAINS THAT ARE

382
00:15:21,868 --> 00:15:23,937
UNIQUE, VERY UNIQUE UPON THE

383
00:15:23,937 --> 00:15:27,007
LOSS OF LIGASE AND THOSE 11

384
00:15:27,007 --> 00:15:28,108
STRAINS WERE BY THEMSELVES

385
00:15:28,108 --> 00:15:31,044
ENOUGH TO INHIBIT TUMOR GROWTH

386
00:15:31,044 --> 00:15:34,514
AND EMPHASIZE IN MICE, IN MICE

387
00:15:34,514 --> 00:15:35,181
THAT IS GERM-FREE.

388
00:15:35,181 --> 00:15:39,953
AND SO, THIS IS A VERY IMPORTANT

389
00:15:39,953 --> 00:15:43,857
POINT TO MAKE BECAUSE IN THIS

390
00:15:43,857 --> 00:15:45,926
ANIMAL, THE ONLY 11 BACTERIAL

391
00:15:45,926 --> 00:15:47,494
STRAIN TOGETHER WITH THE BASAL

392
00:15:47,494 --> 00:15:49,329
MIX OF 8 FOR THESE MICE TO,A LOW

393
00:15:49,329 --> 00:15:59,706
THEM TO EVEN SURVIVE.

394
00:16:00,707 --> 00:16:02,909
SO SUPRISING HERE, AND I WILL

395
00:16:02,909 --> 00:16:04,978
NOT EMPHASIZE IT BUT WE HAVE

396
00:16:04,978 --> 00:16:06,947
REACHED THE TAIJ WHERE A SELECT

397
00:16:06,947 --> 00:16:09,349
SET OF BACTERIAL STRAINS

398
00:16:09,349 --> 00:16:10,417
TAKEN--THEY BY THEMSELVES

399
00:16:10,417 --> 00:16:10,984
INHIBIT TUMOR GROWTH.

400
00:16:10,984 --> 00:16:12,218
WHAT DO WE DO WITH THAT?

401
00:16:12,218 --> 00:16:14,521
THAT TAKES ME TO THE UNPUBLISHED

402
00:16:14,521 --> 00:16:16,256
PORTION OF THE WORK WE'VE BEEN

403
00:16:16,256 --> 00:16:17,924
CONDUCTING SO WE ASK A SIMPLE

404
00:16:17,924 --> 00:16:19,659
EXPERIMENT AND WE ASK A SIMPLE

405
00:16:19,659 --> 00:16:22,963
QUESTION AND THE QUESTION WAS,

406
00:16:22,963 --> 00:16:24,464
INDEED WE INOCULATED 11 BUGS

407
00:16:24,464 --> 00:16:26,800
INTO THE MICE, AND INDEED WE

408
00:16:26,800 --> 00:16:28,335
HAVE SEEN INHIBITION OF TUMOR

409
00:16:28,335 --> 00:16:31,871
GROWTH 20 DAYS LATER, BUT WE DID

410
00:16:31,871 --> 00:16:35,609
NOT ASSESS HOW MANY OF THOSE 11

411
00:16:35,609 --> 00:16:37,510
BUGS WERE PROMINENT AFTER 20

412
00:16:37,510 --> 00:16:38,211
DAYS.

413
00:16:38,211 --> 00:16:41,848
IN OTHER WORDS, IS IT POSSIBLE

414
00:16:41,848 --> 00:16:44,918
THAT NOT ONLY 11 PROPAGATED THE

415
00:16:44,918 --> 00:16:45,986
SAME EFFICIENCY, AND THE END OF

416
00:16:45,986 --> 00:16:47,721
THE EXPERIMENT WE DIDN'T HAVE 11

417
00:16:47,721 --> 00:16:49,456
BUT WE HAD FEWER STRAINS THAT WE

418
00:16:49,456 --> 00:16:52,459
MAY WANT TO PAY ATTENTION TO.

419
00:16:52,459 --> 00:16:55,395
AND THAT'S WHAT WE ARE DONE,

420
00:16:55,395 --> 00:16:58,965
PAID ATTENTION TO THE

421
00:16:58,965 --> 00:17:00,000
CONCENTRATION OF BACTERIAL

422
00:17:00,000 --> 00:17:01,167
STRAINS AND PREVALENCE OF THEM

423
00:17:01,167 --> 00:17:02,268
AT THE END OF THE EXPERIMENT AND

424
00:17:02,268 --> 00:17:03,937
NOT THE BEGINNING AND THAT LED

425
00:17:03,937 --> 00:17:05,872
US TO 3 BACTERIAL STRAINS, SO

426
00:17:05,872 --> 00:17:09,109
ONLY 3 OUT OF 11 WERE FROMINENT

427
00:17:09,109 --> 00:17:10,944
AT THE END OF THE EXPERIMENT, SO

428
00:17:10,944 --> 00:17:12,345
THE NEXT OBVIOUS QUESTION IS,

429
00:17:12,345 --> 00:17:15,148
CAN YOU DO THE SAME EXPERIMENT

430
00:17:15,148 --> 00:17:17,317
RETREAT AND WOULD YOU BE ABLE TO

431
00:17:17,317 --> 00:17:20,687
GET INHIBITION OF MELANOMA WITH

432
00:17:20,687 --> 00:17:23,256
3, 2, OR 1 STRAINS?

433
00:17:23,256 --> 00:17:24,991
AND AS CAN YOU SEE HERE, TO MACK

434
00:17:24,991 --> 00:17:26,526
A LONG STORY SHORT BECAUSE THIS

435
00:17:26,526 --> 00:17:28,261
PROJECT HAS BEEN GOING ON FOR

436
00:17:28,261 --> 00:17:30,063
THE LAST COUPLE OF YEARS, 1

437
00:17:30,063 --> 00:17:36,369
BACTERIA WILL STRAIN, NOT 3 IS

438
00:17:36,369 --> 00:17:38,304
ENOUGH TO GET INHIBITION OF THE

439
00:17:38,304 --> 00:17:44,110
MICE, AND THE DEGREE IS PRETTY

440
00:17:44,110 --> 00:17:44,477
NOTABLE.

441
00:17:44,477 --> 00:17:46,646
NOW I HAVE TO SAY THESE

442
00:17:46,646 --> 00:17:47,681
EXPERIMENTS ARE BEING DONE IN

443
00:17:47,681 --> 00:17:49,215
NEBRASKA BECAUSE IN OUR FACILITY

444
00:17:49,215 --> 00:17:52,786
AND OUR PLACE, WE DON'T HAVE A

445
00:17:52,786 --> 00:17:53,420
[INDISCERNIBLE] MOUSE FACILITY,

446
00:17:53,420 --> 00:17:56,022
YOU NEED A SPECIAL FACILITY TO

447
00:17:56,022 --> 00:17:57,190
ACCOMMODATE THESE ANIMALS AND

448
00:17:57,190 --> 00:17:58,358
THESE EXPERIMENTS ARE DONE

449
00:17:58,358 --> 00:17:59,392
MULTIPLE TIMES AND NOW WE'RE

450
00:17:59,392 --> 00:18:00,894
ASKING HOW IT'S POSSIBLE THAT

451
00:18:00,894 --> 00:18:04,898
THE 1 BUG CAN HAVE AN EFFECT ON

452
00:18:04,898 --> 00:18:08,568
TUMOR GROWTH INHIBITION, AGAIN

453
00:18:08,568 --> 00:18:09,369
IN AUTOBIOTIC ENVIRONMENT.

454
00:18:09,369 --> 00:18:10,837
SO WE'VE DONE 2 TYPE OF ANALYSIS

455
00:18:10,837 --> 00:18:12,906
WHICH I WILL SHOW IN THE NEXT

456
00:18:12,906 --> 00:18:14,007
COUPLE OF MINUTES, THE FIRST ASK

457
00:18:14,007 --> 00:18:15,675
WHAT HAPPENS TO THE TUMORS, SO

458
00:18:15,675 --> 00:18:18,812
IF WE TAKE THE TUMORS THAT WERE

459
00:18:18,812 --> 00:18:20,080
AFFECTED, GREW LOWER, SOME OF

460
00:18:20,080 --> 00:18:23,650
THEM DIDN'T APPEAR AT ALL, CAN

461
00:18:23,650 --> 00:18:24,751
WE IDENTIFY ANY SIGNALING

462
00:18:24,751 --> 00:18:26,686
PATHWAY THAT STAND OUT IN THESE

463
00:18:26,686 --> 00:18:28,521
TUMORS AND THE SECOND

464
00:18:28,521 --> 00:18:30,356
EXPERIMENT, TAKE THE FECAL

465
00:18:30,356 --> 00:18:32,158
SAMPLES OF THESE ANIMAL ANDS DO

466
00:18:32,158 --> 00:18:34,294
A WHOLE METRICS TAB O LOAMIC

467
00:18:34,294 --> 00:18:37,630
ANALYSIS AND SEE IF WE CAN FIND

468
00:18:37,630 --> 00:18:39,299
ENRICHMENT OR DECREASE OF

469
00:18:39,299 --> 00:18:40,967
METABOLITES THAT MAY HAVE BEEN

470
00:18:40,967 --> 00:18:43,136
AFFECTED BY THIS BACTERIA WHICH

471
00:18:43,136 --> 00:18:45,638
COULD ALSO EXPLAIN HOW IT'S

472
00:18:45,638 --> 00:18:45,905
POSSIBLE.

473
00:18:45,905 --> 00:18:47,440
SO WHEN WE HAVE DONE THE

474
00:18:47,440 --> 00:18:50,677
ANALYSIS GEAP, THIS IS A PCA AND

475
00:18:50,677 --> 00:18:54,881
THIS IS AN INITIAL--OH WOW THIS

476
00:18:54,881 --> 00:18:56,750
IS MOVING WITHOUT ME EVEN

477
00:18:56,750 --> 00:18:59,185
TOUCHING SO THIS IS COOL.

478
00:18:59,185 --> 00:19:01,688
SO LOOKING AT THE RNASEQ

479
00:19:01,688 --> 00:19:02,722
ANALYSIS, THE PRIMARY CHANGES

480
00:19:02,722 --> 00:19:04,491
THAT YOU CAN ADENTIFY HERE ARE

481
00:19:04,491 --> 00:19:06,893
CHANGES IN THE IMMUNE SYSTEM.

482
00:19:06,893 --> 00:19:09,195
WELL, NOT SO SURPRISING BECAUSE

483
00:19:09,195 --> 00:19:10,697
WE ALREADY KNEW FROM THE

484
00:19:10,697 --> 00:19:12,766
PREVIOUS EXPERIMENTS THAT WHEN

485
00:19:12,766 --> 00:19:13,833
YOU HAVE ACTIVATION OF THE

486
00:19:13,833 --> 00:19:16,469
IMMUNE SYSTEM, YOU WILL BE ABLE

487
00:19:16,469 --> 00:19:17,771
TO DO SIEWMOR GROWTH AND SIZE,

488
00:19:17,771 --> 00:19:20,106
AND THIS IS WHAT WE SEE IN THESE

489
00:19:20,106 --> 00:19:23,176
TUMORS THAT RESPOND TO 1 BUG, SO

490
00:19:23,176 --> 00:19:32,418
SORT OF VALIDATION I WOULD SAY

491
00:19:32,418 --> 00:19:32,986
SO.

492
00:19:32,986 --> 00:19:35,221
THIS WAS A METABOLIC ANALYSIS,

493
00:19:35,221 --> 00:19:38,992
AND THE METABOLISM WAS DONE IN

494
00:19:38,992 --> 00:19:40,460
COLLABORATION WITH DAN KELLIE

495
00:19:40,460 --> 00:19:45,031
AND CHRIS [INDISCERNIBLE] AT

496
00:19:45,031 --> 00:19:46,466
UPEN, ANALYSIS OF EXTENSIVE LINE

497
00:19:46,466 --> 00:19:48,434
OF METABOLITES AND THE 1S THAT

498
00:19:48,434 --> 00:19:50,570
STAND OUT HERE IS DECREASE IN

499
00:19:50,570 --> 00:19:52,705
TRYPTOPHAN AND DECREASE IN

500
00:19:52,705 --> 00:19:55,475
TYROSEEN IN THE ANIMALS THAT

501
00:19:55,475 --> 00:19:57,677
RECEIVED THOSE SINGLE BUGS, SO

502
00:19:57,677 --> 00:19:59,579
WHEN YOU LOOK AT THAT TO SAY,

503
00:19:59,579 --> 00:20:03,550
WELL, OKAY, WHAT DOES IT MEAN?

504
00:20:03,550 --> 00:20:05,385
RIGHT?

505
00:20:05,385 --> 00:20:08,087
BUT APPARENTLY BOTH TRYPTOPHAN

506
00:20:08,087 --> 00:20:10,523
AND TYROSEEN HAVE BEEN TODAYED

507
00:20:10,523 --> 00:20:12,859
IN THE CONTEXT OF THE IMMUNE

508
00:20:12,859 --> 00:20:13,893
ACTIVATING SYSTEM AND THIS IS 1

509
00:20:13,893 --> 00:20:15,094
EXAMPLE OF PAPER THAT WAS

510
00:20:15,094 --> 00:20:16,830
PUBLISHED JUST A YEAR AGO OR

511
00:20:16,830 --> 00:20:20,500
LESS THAN THAT THAT DEMON TRAITS

512
00:20:20,500 --> 00:20:22,135
HOW TRYPTOPHAN NEGATIVELY

513
00:20:22,135 --> 00:20:23,570
REGULATE THE'MUNE SYSTEM,

514
00:20:23,570 --> 00:20:24,604
ANTITUMOR IMMUNITY.

515
00:20:24,604 --> 00:20:26,840
SO IF TRYPTOPHAN, AND THERE ARE

516
00:20:26,840 --> 00:20:28,474
MORE THAN THIS SINGLE PAPER.

517
00:20:28,474 --> 00:20:31,110
IF TRYPTOPHAN SERVED TO BLOCK

518
00:20:31,110 --> 00:20:34,714
THE IMMUNE SYSTEM, REDUCE LEVEL

519
00:20:34,714 --> 00:20:35,682
OF TRYPTOPHAN AND ENABLE THE

520
00:20:35,682 --> 00:20:37,417
IMMUNE SYSTEM AND THIS IS THE

521
00:20:37,417 --> 00:20:38,751
PHENOTYPE WE OBSERVE.

522
00:20:38,751 --> 00:20:41,554
NOW YOU CAN ASK, WHY THERE IS A

523
00:20:41,554 --> 00:20:43,723
DECREASE IN TRYPTOPHAN IN THE

524
00:20:43,723 --> 00:20:48,027
FIRST PLACE, AND I WILL--AND

525
00:20:48,027 --> 00:20:51,998
ANSWER AND SAY THAT

526
00:20:51,998 --> 00:20:52,665
[INDISCERNIBLE], WAS IDENTIFIED

527
00:20:52,665 --> 00:20:54,767
AND SUFFICIENT TO CAUSE THE

528
00:20:54,767 --> 00:20:57,203
CHANGE IS KNOWN TO CONSUME

529
00:20:57,203 --> 00:21:01,641
TRYPTOPHAN, TO RELY ON

530
00:21:01,641 --> 00:21:02,508
[INDISCERNIBLE] TRYPTOPHAN, SO

531
00:21:02,508 --> 00:21:06,346
IT CONSUMES IT BECAUSE OF THAT,

532
00:21:06,346 --> 00:21:09,782
THERE IS LESS INHIBITION OF THE

533
00:21:09,782 --> 00:21:11,651
UMPIRESUNE SYSTEM, AND THE

534
00:21:11,651 --> 00:21:14,954
RESULT IS THE ANTITUMOR

535
00:21:14,954 --> 00:21:18,725
IMMUNITY.

536
00:21:18,725 --> 00:21:19,192
YES?

537
00:21:19,192 --> 00:21:20,727
>> [INAUDIBLE QUESTION
FROM

538
00:21:20,727 --> 00:21:30,904
AUDIENCE ]

539
00:21:41,881 --> 00:21:44,584
>> IT REMINDS ME OF A
PAPER BY

540
00:21:44,584 --> 00:21:45,718
[INDISCERNIBLE] IN NATURE, LAST

541
00:21:45,718 --> 00:21:47,153
YEAR ARE I THINK IT WAS THAT

542
00:21:47,153 --> 00:21:50,223
DEMON TRAITED THE LACK OF

543
00:21:50,223 --> 00:21:51,724
[INDISCERNIBLE] IMMUNE SYSTEM

544
00:21:51,724 --> 00:21:53,960
AND IN PART BY AFFECTING

545
00:21:53,960 --> 00:21:55,561
RIBOSOME BIOSYNTH TIS PATHWAYS

546
00:21:55,561 --> 00:21:56,963
AND I'M FAMILIAR WITH THAT AND

547
00:21:56,963 --> 00:22:07,273
AS I SAID, THIS IS ONLY 1.

548
00:22:07,273 --> 00:22:09,976
SO WE HAVE TO PROVE THAT IN OUR

549
00:22:09,976 --> 00:22:11,945
SYSTEM, THE HYPOTHESIS I JUST

550
00:22:11,945 --> 00:22:14,080
LAID OUT IS CORRECT, THE

551
00:22:14,080 --> 00:22:19,719
EVIDENCE SUPPORT THAT EXISTS.

552
00:22:19,719 --> 00:22:21,888
BUT WE NEED TO DEMONSTRATE THAT

553
00:22:21,888 --> 00:22:24,424
IN OUR CASE WE INCREASE

554
00:22:24,424 --> 00:22:26,859
TRYPTOPHAN AND EFFECTIVE ILY

555
00:22:26,859 --> 00:22:27,794
ELIMINATE THE [INDISCERNIBLE]

556
00:22:27,794 --> 00:22:30,196
WILL BE 1 SIMPLE EXPERIMENT YOU

557
00:22:30,196 --> 00:22:32,732
CAN STOP IT.

558
00:22:32,732 --> 00:22:33,199
YES?

559
00:22:33,199 --> 00:22:34,067
>> [INAUDIBLE QUESTION
FROM

560
00:22:34,067 --> 00:22:44,243
AUDIENCE ]

561
00:23:07,133 --> 00:23:10,436
>> SO WHAT GLEN REFERS TO
IN

562
00:23:10,436 --> 00:23:11,237
RUEING TRYPTOPHAN, 1 MAY USE IT

563
00:23:11,237 --> 00:23:13,339
TO GET THE EFFECT HERE, I AM

564
00:23:13,339 --> 00:23:14,374
TOTALLY WITH YOU, THE ONLY

565
00:23:14,374 --> 00:23:17,377
COMMENT I WOULD MAKE IS THAT

566
00:23:17,377 --> 00:23:20,213
EVIDENCE OF TRYPTOPHAN IS

567
00:23:20,213 --> 00:23:21,948
CONFIRMATION OF THE ABILITY OF

568
00:23:21,948 --> 00:23:23,383
DIVERSE SYSTEMS USING DIFFERENT

569
00:23:23,383 --> 00:23:26,085
MOUSE MODELS, SO, I WOULD ASSUME

570
00:23:26,085 --> 00:23:27,153
THAT THE RELATIVE AMOUNT SHOULD

571
00:23:27,153 --> 00:23:29,088
NOT BE TOO HIGH, TO OBSERVE THE

572
00:23:29,088 --> 00:23:30,923
DIFFERENCE ISSUES THE LEVEL WE

573
00:23:30,923 --> 00:23:34,060
LOOK AT HERE IS PICO MOLAR SO I

574
00:23:34,060 --> 00:23:39,832
THINK THAT IT IS FEASIBLE DO I

575
00:23:39,832 --> 00:23:40,433
RECOMMEND TO ELIMINATE

576
00:23:40,433 --> 00:23:43,970
TRYPTOPHAN FROM THE FOOD, NOT

577
00:23:43,970 --> 00:23:44,137
YET.

578
00:23:44,137 --> 00:23:45,838
I WILL GET TO THAT IN ANOTHER

579
00:23:45,838 --> 00:23:47,473
STUDY FOR THE NEXT FEW MINUES

580
00:23:47,473 --> 00:23:49,108
BUT IT DOES GIVE US AN

581
00:23:49,108 --> 00:23:50,276
INTERESTING HYPOTHESIS TO FOLLOW

582
00:23:50,276 --> 00:23:52,378
UP, AS PER HOW TO EXPLAIN THE

583
00:23:52,378 --> 00:23:57,116
OBSERVATION WE JUST MADE HERE. 

584
00:23:57,116 --> 00:24:00,286
A ALL RIGHT, SO I JUST RELATED

585
00:24:00,286 --> 00:24:02,388
TO THAT AND I DISCUSSED IT AND

586
00:24:02,388 --> 00:24:04,757
THE KEY QUESTION WE'RE ASKING

587
00:24:04,757 --> 00:24:08,094
OURSELVES CAN USE A

588
00:24:08,094 --> 00:24:09,729
PHARMAICOLOGICAL APPROACH TO

589
00:24:09,729 --> 00:24:11,130
MIMIC OR PHENOCOPY THE

590
00:24:11,130 --> 00:24:12,298
OBSERVATION MADE BECAUSE 1

591
00:24:12,298 --> 00:24:15,034
BACTERIAL STRAIN TO ADMINISTER

592
00:24:15,034 --> 00:24:17,503
TO A MICE, EVEN THAT HAS A

593
00:24:17,503 --> 00:24:18,438
COMPLETE MICROBI OTA AND MOST

594
00:24:18,438 --> 00:24:20,306
LIKELY TO HAVE THE IMPACT, SO WE

595
00:24:20,306 --> 00:24:22,442
NEED TO COME AT THIS FROM A

596
00:24:22,442 --> 00:24:24,410
DIFFERENT DIRECTION.

597
00:24:24,410 --> 00:24:29,415
THAT TAKES ME TO THE BIGGER

598
00:24:29,415 --> 00:24:29,882
QUESTION.

599
00:24:29,882 --> 00:24:31,717
CAN THE SINGLE BACTERIAL STRAIN

600
00:24:31,717 --> 00:24:32,852
MAKE A DIFFERENCE?

601
00:24:32,852 --> 00:24:34,087
I PERSONALLY DON'T THINK SO, BUT

602
00:24:34,087 --> 00:24:36,055
IT CAN TEACH US A LOT ABOUT AN

603
00:24:36,055 --> 00:24:38,491
UNDERLYING MECHANISM THAT WE CAN

604
00:24:38,491 --> 00:24:42,328
LEARN FROM AND ENHANCE AND

605
00:24:42,328 --> 00:24:44,297
AMPLIFY, I. E. THE TRYPTOPHAN I

606
00:24:44,297 --> 00:24:46,766
JUST SHARED WITH YOU.

607
00:24:46,766 --> 00:24:50,203
ARE THERE ALTERNATIVES,

608
00:24:50,203 --> 00:24:51,270
PREBIOTICS, PRO BIOTICS NO DOUBT

609
00:24:51,270 --> 00:24:53,906
HAVE SHOWN IF YOU ADMINISTER

610
00:24:53,906 --> 00:24:56,476
PROBIOTIC, YOU ARE CHANGING THE

611
00:24:56,476 --> 00:25:06,752
EQUILL LIBRARY 

612
00:25:08,387 --> 00:25:09,355
EQUILL LIBRARY FOUNDATIONIUM.

613
00:25:09,355 --> 00:25:10,690
WE'RE TALKING ABOUT FIBERS AND

614
00:25:10,690 --> 00:25:14,293
FIBROLIKE AND I WILL SHOW YOU 1

615
00:25:14,293 --> 00:25:17,763
EXAMPLE THAT YOU CAN IMAGINE

616
00:25:17,763 --> 00:25:19,632
ADDING TO A SERIAL IN THE

617
00:25:19,632 --> 00:25:22,435
MORNING TO HAVE A CHANGE IN YOUR

618
00:25:22,435 --> 00:25:25,938
MICROWIMBERLY OTA POSITION TO

619
00:25:25,938 --> 00:25:26,806
IMPART ANTITUMOR IMMUNITY.

620
00:25:26,806 --> 00:25:28,141
AND FASCINATING BY A GROWING

621
00:25:28,141 --> 00:25:29,308
NUMBER OF TODAYS THAT SHOWS THE

622
00:25:29,308 --> 00:25:31,210
COP NEKS BETWEEN OUR BRAIN AND

623
00:25:31,210 --> 00:25:32,478
THE GUT MICROBIOME AND THE

624
00:25:32,478 --> 00:25:34,714
IMMUNE SYSTEM BY WAY OF

625
00:25:34,714 --> 00:25:37,850
INNOVATION AND HOW THOSE AFFECT

626
00:25:37,850 --> 00:25:38,384
MICROBI OTA COMPOSITION,

627
00:25:38,384 --> 00:25:39,619
SOMETHING WE NEED TO TAKE INTO

628
00:25:39,619 --> 00:25:43,022
CONSIDERATION WHEN LOOKINGA THE

629
00:25:43,022 --> 00:25:43,723
THIS GOING FORWARD.

630
00:25:43,723 --> 00:25:46,459
SO BASED ON THE STUDIES I'VE

631
00:25:46,459 --> 00:25:48,928
JUST SHOWED WITH YOU, KNOCKOUT

632
00:25:48,928 --> 00:25:50,796
MICE AND MET ALL THE MICROBI OTA

633
00:25:50,796 --> 00:25:52,398
FOR THESE MICE, WE ASK WHETHER

634
00:25:52,398 --> 00:25:54,901
THERE COULD BE A PREBIOTIC THAT

635
00:25:54,901 --> 00:25:57,103
COULD PHENOCOPY EACH IN PART,

636
00:25:57,103 --> 00:25:58,771
PARTLY, CHANGES WE HAVE SEEN IN

637
00:25:58,771 --> 00:26:00,606
THE KNOCKOUT MICE, AND WHETHER

638
00:26:00,606 --> 00:26:01,474
THIS PREBIOTIC WOULD HAVE THE

639
00:26:01,474 --> 00:26:03,643
EFFECT THAT WE'VE SEEN IN THE

640
00:26:03,643 --> 00:26:04,610
KNOCKOUT MICE AND I'M JUST

641
00:26:04,610 --> 00:26:06,179
SHOWING YOU A COUPLE OF SLIDES,

642
00:26:06,179 --> 00:26:08,514
NOT MORE THAN THAT DEMONSTRATING

643
00:26:08,514 --> 00:26:13,819
THAT INDEED, 2 PREBIOTIC

644
00:26:13,819 --> 00:26:15,321
[INDISCERNIBLE] WERE FOUND TO

645
00:26:15,321 --> 00:26:17,890
HAVE EFFECT IN TUMOR GROWTH

646
00:26:17,890 --> 00:26:21,194
INHIBITION, IN THE MELANOMA MICE

647
00:26:21,194 --> 00:26:23,896
MODEL AND WHILE INHIBITING THEY

648
00:26:23,896 --> 00:26:26,532
WERE ACTIVATING THE ANTITUMOR

649
00:26:26,532 --> 00:26:26,799
IMMUNITY.

650
00:26:26,799 --> 00:26:29,202
IT WAS TO THE DEGREE THAT BEING

651
00:26:29,202 --> 00:26:31,304
NOT BE SUBSTANTIATED BY PDL431,

652
00:26:31,304 --> 00:26:32,438
SO THAT LED US TO CONCLUDE

653
00:26:32,438 --> 00:26:33,806
TAKEN--THEY WE ARE MORE OR LESS

654
00:26:33,806 --> 00:26:36,475
ON THE SAME PATHWAY AS PDL1

655
00:26:36,475 --> 00:26:37,310
WOULD HAVE OTHERWISE DONE.

656
00:26:37,310 --> 00:26:39,545
NOT ONLY THAT WE'RE ABLE TO

657
00:26:39,545 --> 00:26:40,713
INHIBIT MELANOMA GROWING BUT

658
00:26:40,713 --> 00:26:42,048
ALSO ABLE TO OVERCOME RESISTANCE

659
00:26:42,048 --> 00:26:43,216
TO THERAPY AND IN THIS

660
00:26:43,216 --> 00:26:46,118
PARTICULAR CASE, WE LOOKED AT

661
00:26:46,118 --> 00:26:46,919
[INDISCERNIBLE] RESISTANCE

662
00:26:46,919 --> 00:26:48,688
MANAGE WE HAVE AS AN UNMET NEED

663
00:26:48,688 --> 00:26:50,823
TODAY IN THE CLIPPIC SO THIS

664
00:26:50,823 --> 00:26:53,693
PREBIOTIC CAN PLAY A ROLE IN

665
00:26:53,693 --> 00:26:56,662
MEDIATING THOSE CHANGES EMPLOY

666
00:26:56,662 --> 00:26:58,531
SO THIS IS 3 YEARS OLD, SO WE

667
00:26:58,531 --> 00:26:59,332
CONSIDER IT OLD.

668
00:26:59,332 --> 00:27:00,766
WHAT HAVE WE DONE SINCE THEN IN

669
00:27:00,766 --> 00:27:02,435
1 THING, SO THIS IS THE

670
00:27:02,435 --> 00:27:03,669
COMBINATION OF PD1 THAT I JUST

671
00:27:03,669 --> 00:27:04,203
MEPGZED TO YOU.

672
00:27:04,203 --> 00:27:08,674
IT DOES NOT DO BETTER

673
00:27:08,674 --> 00:27:10,876
SUGGIESTING THAT WHATEVER THE

674
00:27:10,876 --> 00:27:13,279
IMUT MICROBIOME CHANGES, THEY

675
00:27:13,279 --> 00:27:15,781
HAVE MADE, AFFECTED MORE OR LESS

676
00:27:15,781 --> 00:27:16,649
SIMILAR TO PD1 BECAUSE OTHERWISE

677
00:27:16,649 --> 00:27:19,619
I WOULD HAVE EXPECTED TO SEE

678
00:27:19,619 --> 00:27:19,852
CHANGES.

679
00:27:19,852 --> 00:27:21,254
SO 1 APPROACH THAT WE UNDERTAKE

680
00:27:21,254 --> 00:27:22,688
AND I STILL DON'T KNOW THE

681
00:27:22,688 --> 00:27:23,656
RESULT OF THIS ONGOING STUDY IN

682
00:27:23,656 --> 00:27:27,960
THE LAB IS TO TRY TO TAKE

683
00:27:27,960 --> 00:27:29,028
INIULYN WHICH WAS THE BETTER

684
00:27:29,028 --> 00:27:30,429
BETWEEN THE 2 I JUST SHARE WIDE

685
00:27:30,429 --> 00:27:34,400
YOU AND SEE IF WE CAN USE THE

686
00:27:34,400 --> 00:27:37,770
SIMPLER VERSION OF INULIN FOR

687
00:27:37,770 --> 00:27:41,340
THE SAME EFFECT? 

688
00:27:41,340 --> 00:27:42,508
IT'S COMING FROM A

689
00:27:42,508 --> 00:27:46,045
[INDISCERNIBLE] PLANT AND HAS A

690
00:27:46,045 --> 00:27:48,147
COMPLEX COMCISION OF ABOUT 60

691
00:27:48,147 --> 00:27:49,315
POLARIZED UNITS THAT ARE ON EACH

692
00:27:49,315 --> 00:27:51,684
OTHER. 

693
00:27:51,684 --> 00:27:56,255
AND THE VARIETY OF INULIN

694
00:27:56,255 --> 00:27:57,189
DEPENDS, VARIESOT SOLUTIONS YOU

695
00:27:57,189 --> 00:27:57,356
GET.

696
00:27:57,356 --> 00:28:01,427
MOST OF THEM ARE ABOUT 50, 60

697
00:28:01,427 --> 00:28:02,962
ISSUES UNITS THAT ARE COUPLED TO

698
00:28:02,962 --> 00:28:04,697
EACH OTHER, SO WE ASK IS IT

699
00:28:04,697 --> 00:28:06,766
POSSIBLE TO DO THIS WITH A

700
00:28:06,766 --> 00:28:08,734
VERSION OF ONLY 10, 10 IS THE

701
00:28:08,734 --> 00:28:09,535
MEANING AND THIS EXPERIMENT

702
00:28:09,535 --> 00:28:11,270
GOING NOW AND I CAN TELL YOU

703
00:28:11,270 --> 00:28:12,204
THAT THE FIRST GLANCE IT TOOKS

704
00:28:12,204 --> 00:28:15,474
LIKE YOU CAN GET THE SAME EFFECT

705
00:28:15,474 --> 00:28:18,811
WITH SMALLER OR SIMPLER VERSION

706
00:28:18,811 --> 00:28:20,313
OF INULIN BUT THIS IS JUST THE

707
00:28:20,313 --> 00:28:22,848
BEGINNING OF AN EXPERIMENT.

708
00:28:22,848 --> 00:28:25,451
AND THE BIGGER QUESTION IS CAN

709
00:28:25,451 --> 00:28:30,222
YOU DO IT EVEN SIMPLER AND I

710
00:28:30,222 --> 00:28:32,858
DON'T KNOW HOW MANY OF YOU ARE

711
00:28:32,858 --> 00:28:34,593
FAMILIAR WITH [INDISCERNIBLE], A

712
00:28:34,593 --> 00:28:36,162
FRENCH SCIENTIST IN THE

713
00:28:36,162 --> 00:28:37,730
[INDISCERNIBLE] IN PARIS WHO

714
00:28:37,730 --> 00:28:39,532
HAVE DONE A VERY SIMPLE

715
00:28:39,532 --> 00:28:40,800
EXPERIMENT WHERE HE DEMON

716
00:28:40,800 --> 00:28:44,437
TRAITED THAT YOU CAN EFFECT THE

717
00:28:44,437 --> 00:28:47,506
MEMORY OF MICE BY TRANSPLANTING

718
00:28:47,506 --> 00:28:48,908
FECAL SAMPLES FROM OLD MICE TO

719
00:28:48,908 --> 00:28:52,144
YOUNG MICE AND YOUNG MICE WILL

720
00:28:52,144 --> 00:28:52,578
LOSE THE MEMORY.

721
00:28:52,578 --> 00:28:53,913
SO IF YOU CAN DO SOMETHING LIKE

722
00:28:53,913 --> 00:28:56,315
THAT AND THIS IS PUBLISHED, IT'S

723
00:28:56,315 --> 00:28:57,016
GOOD STUFF.

724
00:28:57,016 --> 00:29:00,353
IF THIS IS PUBLISHED, CAN WE

725
00:29:00,353 --> 00:29:03,923
THINK ABOUT SYSTEMS IN CANCER

726
00:29:03,923 --> 00:29:04,957
WHERE WE CAN COMPARE THE YOUNG

727
00:29:04,957 --> 00:29:07,426
AND THE OLD AND SEE WHETHER WE

728
00:29:07,426 --> 00:29:08,994
CAN AFFECT 1 OR ANOTHER VICE

729
00:29:08,994 --> 00:29:10,329
VERSA AND IN THIS LINE OF

730
00:29:10,329 --> 00:29:11,630
EXPERIMENT THAT'S GOING ON IN

731
00:29:11,630 --> 00:29:14,133
THE LAB AT THE MOMENT.

732
00:29:14,133 --> 00:29:18,471
SO JUST THE KEY PLAYERS,

733
00:29:18,471 --> 00:29:20,206
[INDISCERNIBLE] DID MOST OF THE

734
00:29:20,206 --> 00:29:20,873
WORK.

735
00:29:20,873 --> 00:29:22,241
[INDISCERNIBLE] DID THE

736
00:29:22,241 --> 00:29:23,075
PREBIOTIC EXPERIMENTS.

737
00:29:23,075 --> 00:29:24,510
AND AT THE MOMENT THE PERSON WHO

738
00:29:24,510 --> 00:29:26,979
RUNS THIS LINE OF EXPERIMENT IS

739
00:29:26,979 --> 00:29:27,346
[INDISCERNIBLE].

740
00:29:27,346 --> 00:29:29,415
WE'VE BEEN ASH CYSTED BY A LONG

741
00:29:29,415 --> 00:29:33,152
LIST OF COLLABORATORS, I WILL

742
00:29:33,152 --> 00:29:36,555
JUST OUTLINE THE CANNED WHAT

743
00:29:36,555 --> 00:29:38,591
FROM THE UNIVERSITY OF NEBRASKA

744
00:29:38,591 --> 00:29:44,397
AND CANNED  CANNED--[INDISCERNI]

745
00:29:44,397 --> 00:29:45,164
BIOINFORMATIC ANALYSIS THAT

746
00:29:45,164 --> 00:29:47,500
HELPS US LOOK AT THINGS LEFT TO

747
00:29:47,500 --> 00:29:47,867
RIGHT.

748
00:29:47,867 --> 00:29:49,368
MOVING TO THE SECOND PART OF MY

749
00:29:49,368 --> 00:29:51,237
TALK, I STILL HAVE TIME SO

750
00:29:51,237 --> 00:29:52,438
THAT'S GOOD.

751
00:29:52,438 --> 00:29:54,707
UBIQUITIN LIGASES BECAME A

752
00:29:54,707 --> 00:29:56,142
PAINFUL TOPIC ISSUES YES A NOBEL

753
00:29:56,142 --> 00:29:59,578
PRIZE WAS GIVEN TO 2 SCIENTISTS,

754
00:29:59,578 --> 00:30:02,648
A FEW YEARS AGO BECAUSE THEY

755
00:30:02,648 --> 00:30:03,149
DISCOVERED UBIQUITIN.

756
00:30:03,149 --> 00:30:04,650
IT IS BELIEVED TO PLAY AN

757
00:30:04,650 --> 00:30:07,253
IMPORTANT ROLE IN BIOLOGY NOT

758
00:30:07,253 --> 00:30:09,221
ONLY BECAUSE IT MARKED PROTEIN

759
00:30:09,221 --> 00:30:09,522
DEGRADATION

760
00:30:09,522 --> 00:30:11,857
GRATES--GRATUEIGATION BUT ALSO

761
00:30:11,857 --> 00:30:13,259
BECAUSE IT SIGNALED COMPLEX

762
00:30:13,259 --> 00:30:14,460
ACTIVITY AND COLONIZEITION AND I

763
00:30:14,460 --> 00:30:18,264
CAN KEEP ON GOING BUT THERE IS A

764
00:30:18,264 --> 00:30:18,998
PROBLEM, YOU DON'T DETECT IT.

765
00:30:18,998 --> 00:30:24,136
SO IF YOU ARE TRYING TO SEE WHAT

766
00:30:24,136 --> 00:30:26,138
HAPPENS TO UBIQUITIN LINES OF

767
00:30:26,138 --> 00:30:27,740
YOUR CHOOSING, YOU WILL NOT FIND

768
00:30:27,740 --> 00:30:28,808
ANYTHING BECAUSE IT'S BORE,

769
00:30:28,808 --> 00:30:34,013
THEY'RE ALL THE SAME.

770
00:30:34,013 --> 00:30:35,748
AND THE PROTEIN ITSELF IS HARD

771
00:30:35,748 --> 00:30:36,816
TO DETECT, BECAUSE THEY ARE

772
00:30:36,816 --> 00:30:39,251
BUILT IN A WAY THAT IS DESIGNED

773
00:30:39,251 --> 00:30:40,085
TO SELF-DESTRUCK, THEY'RE SO

774
00:30:40,085 --> 00:30:41,120
IMPORTANT THAT ANY RELATIVE

775
00:30:41,120 --> 00:30:43,222
AMOUNT OF THE PROTEIN IS

776
00:30:43,222 --> 00:30:44,056
CRITICALLY IMPORTANT FOR THEIR

777
00:30:44,056 --> 00:30:48,694
ACTIVITY AND THEREFORE IF YOU

778
00:30:48,694 --> 00:30:50,896
LIMIT THAT, THAT'S THE WAY

779
00:30:50,896 --> 00:30:51,597
BIOLOGY WORKS.

780
00:30:51,597 --> 00:30:54,333
SO YOU DON'T DETECT THE RNA, YOU

781
00:30:54,333 --> 00:30:55,334
DON'T--YOU BARELY PROTECT THE

782
00:30:55,334 --> 00:30:57,036
PROTEIN, YOU HAVE TO REALLY DO

783
00:30:57,036 --> 00:31:00,372
TRICKS TO SEE THE PROTEIN, AND

784
00:31:00,372 --> 00:31:03,976
BECAUSE OF THAT, IT'S VERY HARD

785
00:31:03,976 --> 00:31:06,879
TO HAVING THEM APPRECIATE IT, SO

786
00:31:06,879 --> 00:31:10,382
THE COMMON--COMMON THAT YOU GET

787
00:31:10,382 --> 00:31:12,151
ON PAPERS OR ON GRANTS, IF YOU

788
00:31:12,151 --> 00:31:14,553
DON'T SEE THEM, THEY'RE NOT

789
00:31:14,553 --> 00:31:15,588
IMPORTANT.

790
00:31:15,588 --> 00:31:16,455
BUT WHEN I'M GOING TO SHOW YOU

791
00:31:16,455 --> 00:31:21,260
IN THE NEXT FEW MINUES UE--MINUS

792
00:31:21,260 --> 00:31:24,230
IS 1 CASE OF UBIQUITIN LIGASE

793
00:31:24,230 --> 00:31:25,197
WHICH IS CRITICAL IMPORTANT FOR

794
00:31:25,197 --> 00:31:26,398
CANCER AND WHY WE BELIEVE IN

795
00:31:26,398 --> 00:31:26,599
THAT.

796
00:31:26,599 --> 00:31:29,835
I WILL SPEAK ABOUT 1 BUT THIS IS

797
00:31:29,835 --> 00:31:31,670
PART OF A REVIEW WE PUBLISHED A

798
00:31:31,670 --> 00:31:33,706
FEW YEARS AGO AND IF YOU CAN

799
00:31:33,706 --> 00:31:37,176
SEE, CAN YOU SEE A NUMBER OF

800
00:31:37,176 --> 00:31:39,478
UBIQUITIN LIGASES UNDER

801
00:31:39,478 --> 00:31:41,981
DIFFERENT SECTIONS, AREAS IN

802
00:31:41,981 --> 00:31:43,015
TERMS OF FUNCTIONAL SIGNIFICANCE

803
00:31:43,015 --> 00:31:45,117
AND ALL OF THOSE THAT ARE LISTED

804
00:31:45,117 --> 00:31:48,787
THERE, ARE SOMEHOW SCREWED UP,

805
00:31:48,787 --> 00:31:49,488
DEREGULATED IN CANCER.

806
00:31:49,488 --> 00:31:53,893
SO THE EVIDENCE FOR THE

807
00:31:53,893 --> 00:31:55,528
IMPORTANCE OF THIS UBIQUITIN

808
00:31:55,528 --> 00:31:56,962
LIGASE COMES FROM A VARIETY OF

809
00:31:56,962 --> 00:31:58,130
STUDIES CONDUCKED OVER THE LAST

810
00:31:58,130 --> 00:31:59,532
2 DECADES.

811
00:31:59,532 --> 00:32:02,034
WE KNOW THEY ARE CRITICALLY

812
00:32:02,034 --> 00:32:03,536
IMPORTANT BUT TODAY WHEN

813
00:32:03,536 --> 00:32:07,473
EVERYBODY LOOKS AT THOSE TCGA

814
00:32:07,473 --> 00:32:08,774
ONCO9, WHAT NOT, IT'S HOW TO

815
00:32:08,774 --> 00:32:09,275
MAKE A CASE.

816
00:32:09,275 --> 00:32:15,381
SO I'M GOING TO SPEAK ABOUT

817
00:32:15,381 --> 00:32:16,215
UBIQUITIN LIGASE, 2 MEMBERS OF

818
00:32:16,215 --> 00:32:19,618
THE FAMILY, THE COMPOSITION OF

819
00:32:19,618 --> 00:32:24,156
THIS AS SHOWN HERE IS VERY

820
00:32:24,156 --> 00:32:26,458
SIMPLE CLASSIC COMBINATION OF

821
00:32:26,458 --> 00:32:28,227
600 QUING FINGER PROTEINS IN THE

822
00:32:28,227 --> 00:32:29,728
CELL, THE RING REALLY

823
00:32:29,728 --> 00:32:33,465
INTERESTING GENE, THAT'S WHAT

824
00:32:33,465 --> 00:32:35,601
RING STAND FOR.

825
00:32:35,601 --> 00:32:37,102
THEY CONTAIN ACTIVE PORTION OF

826
00:32:37,102 --> 00:32:42,041
PROTEIN THAT IS ENABLING THE

827
00:32:42,041 --> 00:32:43,509
UBIQUITIN CONJUGATION

828
00:32:43,509 --> 00:32:44,443
CAPABILITIES, THE STRUCTURAL

829
00:32:44,443 --> 00:32:47,980
LIGASE WAS MET OVER 10 YEARS AGO

830
00:32:47,980 --> 00:32:50,049
BY DAVID PATTLE AND COLLEAGUES

831
00:32:50,049 --> 00:32:52,751
SHOWING TO BE A DIMER, SO THAT

832
00:32:52,751 --> 00:32:54,653
IS INTERESTING FOR THE NOTION

833
00:32:54,653 --> 00:32:56,555
THAT IF YOU DON'T ALLOW TO FORM

834
00:32:56,555 --> 00:32:57,756
A DIMER, MOST LIKELY YOU'RE NOT

835
00:32:57,756 --> 00:33:00,159
ABLE TO GET ACTIVITY.

836
00:33:00,159 --> 00:33:01,827
AND OVER THE YEARS WE HAVE DEMON

837
00:33:01,827 --> 00:33:03,829
TRAITED THAT THE LIGASE CAN

838
00:33:03,829 --> 00:33:05,197
RECOGNIZE A NUMBER OF DIFFERENT

839
00:33:05,197 --> 00:33:06,899
SUBSTRATES AND I WILL SPEND OUR

840
00:33:06,899 --> 00:33:08,667
FOCUS ON 2 BECAUSE OF THEIR

841
00:33:08,667 --> 00:33:09,101
IMPORTANCE.

842
00:33:09,101 --> 00:33:10,736
THE FIRST IS A WORK OF

843
00:33:10,736 --> 00:33:12,137
[INDISCERNIBLE] AND NOW WE'RE

844
00:33:12,137 --> 00:33:14,640
TALKING ABOUT 20 YEARS AGO WHO

845
00:33:14,640 --> 00:33:16,709
SHOWED THAT THE LIGASE IS

846
00:33:16,709 --> 00:33:20,346
IMPORTANT IN THE CONTROL OF

847
00:33:20,346 --> 00:33:22,815
HYPOXIA, AND THERE THE REASON

848
00:33:22,815 --> 00:33:25,384
FOR THE HYPOXIA IS BECAUSE IT'S

849
00:33:25,384 --> 00:33:27,219
HYDROX LACE 1 AND 3 AND IN DOING

850
00:33:27,219 --> 00:33:29,054
THAT IT'S DETERMINES HOW MUCH

851
00:33:29,054 --> 00:33:32,157
WHICH NEED TO BE MODIFIED BY

852
00:33:32,157 --> 00:33:34,226
POLYHYDROXALATION BEFORE IT CAN

853
00:33:34,226 --> 00:33:36,462
BE TARGETED FOR DEGRADATION BY

854
00:33:36,462 --> 00:33:38,497
VHL, THAT WILL DETERMINE HOW

855
00:33:38,497 --> 00:33:40,899
MUCH WILL BE AVAILABLE IN THE

856
00:33:40,899 --> 00:33:41,533
CELL.

857
00:33:41,533 --> 00:33:43,869
SO, THIS IS--WAS THE BEGINNING

858
00:33:43,869 --> 00:33:45,804
OF OUR JOURNEY AND WE WERE VERY

859
00:33:45,804 --> 00:33:47,840
EXCITED ABOUT THIS PLAYING A

860
00:33:47,840 --> 00:33:50,109
ROLE IN HYPOXIA CONTROL, UNTIL

861
00:33:50,109 --> 00:33:52,544
WE REALIZE THAT HYPOXIA IS ONLY

862
00:33:52,544 --> 00:33:53,479
SMALL PORTION OF A BIGGER

863
00:33:53,479 --> 00:33:56,682
PICTURE AND THE BIGGER PICTURE

864
00:33:56,682 --> 00:34:05,691
WAS THE UPL, SO SIAH, NOT ONLY

865
00:34:05,691 --> 00:34:15,134
CONTROL LEAF BUT ATF IS ALSO

866
00:34:15,134 --> 00:34:17,002
REGULATABILITY.

867
00:34:17,002 --> 00:34:19,571
THIS CONTROLS STRESS AND HYPOXIA

868
00:34:19,571 --> 00:34:22,741
AND THESE ARE 2 KEY FUNDAMENTAL

869
00:34:22,741 --> 00:34:23,842
PROCESSES THAT ARE ESSENTIAL FOR

870
00:34:23,842 --> 00:34:25,310
MUCH OF WHAT HAPPENED IN THE

871
00:34:25,310 --> 00:34:27,279
CELL, ESPECIALLY IN THE CANCER

872
00:34:27,279 --> 00:34:28,414
CELL.

873
00:34:28,414 --> 00:34:30,249
AND OVER THE YEARS AND I'M GOING

874
00:34:30,249 --> 00:34:32,484
TO JUST BROWSE THROUGH THIS VERY

875
00:34:32,484 --> 00:34:33,552
QUICKLY, WE HAVE DEMON TRAITED

876
00:34:33,552 --> 00:34:37,256
HOW THE LIGASE IS CRITICAL FOR

877
00:34:37,256 --> 00:34:38,257
MELANOMA, FOR PROSTATE CANCER,

878
00:34:38,257 --> 00:34:40,159
NEXT COUPLE OF SLIDES AND OTHER

879
00:34:40,159 --> 00:34:41,660
SCIENTIST VS SHOWN HOW IMPORTANT

880
00:34:41,660 --> 00:34:43,495
THIS CONTEXT OF DIFFERENT CANCER

881
00:34:43,495 --> 00:34:43,762
TYPES.

882
00:34:43,762 --> 00:34:46,899
AND IN THE CASE OF MELANOMA, WE

883
00:34:46,899 --> 00:34:51,203
WERE ABLE TO DISTINGUISH BETWEEN

884
00:34:51,203 --> 00:34:53,405
HYPOXIA DEPENDENT CONTROL WHICH

885
00:34:53,405 --> 00:34:55,674
AFFECT METASTASIS TO PRIMARY

886
00:34:55,674 --> 00:34:58,410
TUMOR CONTROL WHICH EFFECT THE

887
00:34:58,410 --> 00:34:59,478
PRIMARY TUMOR FORMATION, THERE

888
00:34:59,478 --> 00:35:00,746
WERE SOME SECURITIZATION. NIICAL

889
00:35:00,746 --> 00:35:03,082
TRICK WE HAVE USED AT THE TIME

890
00:35:03,082 --> 00:35:05,117
THAT ENABLED US TO DISTINGUISH

891
00:35:05,117 --> 00:35:09,621
BETWEEN THE 2 PATHWAY AND THE 2

892
00:35:09,621 --> 00:35:10,622
KEY SIGNALING EVENTS.

893
00:35:10,622 --> 00:35:15,294
LATER ON A MORE COMPLEX STUDY

894
00:35:15,294 --> 00:35:17,129
SHOWNING IN PROSTATE CANCER IF

895
00:35:17,129 --> 00:35:20,866
YOU HAVE A CR, YOU GET LIVER

896
00:35:20,866 --> 00:35:21,667
METASTASIS, VERY ABUNDANTLY BUT

897
00:35:21,667 --> 00:35:24,470
IF YOU DON'T HAVE THIS UBIQUITIN

898
00:35:24,470 --> 00:35:26,071
LIGASE, YOU DON'T SEE THE

899
00:35:26,071 --> 00:35:27,272
METASTASIS AND WE

900
00:35:27,272 --> 00:35:29,074
MECHANISTICALLY EXPLAINED HOW

901
00:35:29,074 --> 00:35:29,908
THAT WORK ANDS HOW IT IS

902
00:35:29,908 --> 00:35:31,677
IMPORTANT IN THE CONTROL OF

903
00:35:31,677 --> 00:35:32,945
THESE PROCESSES AND THIS IS WHAT

904
00:35:32,945 --> 00:35:34,613
I BELIEVE I SPOKE ABOUT 10 YEARS

905
00:35:34,613 --> 00:35:40,452
AGO IN WHEN I WAS HERE.

906
00:35:40,452 --> 00:35:43,322
AND SEBS QUENT FROM THAT WE WENT

907
00:35:43,322 --> 00:35:44,690
THROUGH THE CAPSER RESISTANT

908
00:35:44,690 --> 00:35:46,125
WHICH ARE THE MORE AGGRESSIVE

909
00:35:46,125 --> 00:35:48,227
FORMS OF CANCER AND DEMONSTRATED

910
00:35:48,227 --> 00:35:51,396
HOW THE LIGASE IS IMPORTANT IN

911
00:35:51,396 --> 00:35:53,632
THOSE FORMS OF CANCER THROUGH A

912
00:35:53,632 --> 00:35:54,433
TOTALLY DIFFERENT MECHANISM THAT

913
00:35:54,433 --> 00:35:59,271
HAS TO DO WITH CONTROL OF

914
00:35:59,271 --> 00:36:00,038
ANDROGEN RECEPTOR SIGNALING.

915
00:36:00,038 --> 00:36:02,775
SO THROUGH A NUMBER OF SYSTEMS,

916
00:36:02,775 --> 00:36:05,511
A NUMBER OF PATHWAYS WE'VE SHOWN

917
00:36:05,511 --> 00:36:07,713
OW THIS UBIQUITIN PATHWAY IS

918
00:36:07,713 --> 00:36:09,748
TUMOR FORMATION BUT COMMON TO

919
00:36:09,748 --> 00:36:12,317
ALL OF THEM IS THE INTRINSIC

920
00:36:12,317 --> 00:36:15,788
TUMOR EFFECT, SO IN ALL CASES,

921
00:36:15,788 --> 00:36:17,523
THIS UBIQUITIN LIGASE CONTROLLED

922
00:36:17,523 --> 00:36:18,123
TUMOR FORMATION BECAUSE OF

923
00:36:18,123 --> 00:36:20,759
CHANGES IN THE TUMOR ITSELF, WE

924
00:36:20,759 --> 00:36:22,528
HAVE NOT TOUCHED UNTIL NOW THE

925
00:36:22,528 --> 00:36:22,928
MICROENVIRONMENT.

926
00:36:22,928 --> 00:36:24,630
SO NOW WE STARTED TO ASK WHAT

927
00:36:24,630 --> 00:36:27,065
HAPPENED IN THE

928
00:36:27,065 --> 00:36:29,835
MICROENVIRONMENT, WHAT--IS THIS

929
00:36:29,835 --> 00:36:31,036
UBIQUITIN LIGASE, AS IMPORTANT

930
00:36:31,036 --> 00:36:31,537
IN THE MICROENVIRONMENT.

931
00:36:31,537 --> 00:36:34,006
AND THIS IS WORK THAT IN THE LAB

932
00:36:34,006 --> 00:36:37,276
OVER THE LAST FEW YEARS, AND AS

933
00:36:37,276 --> 00:36:41,380
YOU CAN SEE, TUMORS THAT ARE

934
00:36:41,380 --> 00:36:51,890
GROWN IN ANIMALS THAT LACK THE

935
00:36:52,090 --> 00:36:53,325
UBIQUITIN LIGASE, SIAH, 2, AND

936
00:36:53,325 --> 00:36:57,029
YOU HAVE ON DO A KNOCK OUT OF

937
00:36:57,029 --> 00:36:58,497
SI,A H 2 TO GET AS FAR AS CAN

938
00:36:58,497 --> 00:37:01,233
YOU GET FOCUSED ON GET THE TOTAL

939
00:37:01,233 --> 00:37:02,134
KNOCK OUT APPROACH.

940
00:37:02,134 --> 00:37:04,303
AND THAT WAS SUFFICIENT TO SEE

941
00:37:04,303 --> 00:37:05,370
INHIBITION OF TUMOR GROWTH.

942
00:37:05,370 --> 00:37:08,740
THAT WAS SUFFICIENT TO IDENTIFY

943
00:37:08,740 --> 00:37:11,743
UPREGULATION OF ANTITUMOR

944
00:37:11,743 --> 00:37:12,978
IMMUNITY.

945
00:37:12,978 --> 00:37:15,047
THAT WAS THE PHENOTYPE.

946
00:37:15,047 --> 00:37:18,650
WELL THE TUMOR ITSELF IS

947
00:37:18,650 --> 00:37:20,018
SIAH UNTOACHED BUT THE

948
00:37:20,018 --> 00:37:23,889
MICROENVIRONMENT DOESN'T HAVE

949
00:37:23,889 --> 00:37:24,323
SIAH[INDISCERNIBLE].

950
00:37:24,323 --> 00:37:25,090
I EMPHASIZE THIS BECAUSE I WILL

951
00:37:25,090 --> 00:37:27,059
PLAY THE OPPOSITE ROLE IN ABOUT

952
00:37:27,059 --> 00:37:29,494
5 MINUTES SO I EMPHASIZE WE NEED

953
00:37:29,494 --> 00:37:32,030
TO ELIMINATE FROM THE OLD

954
00:37:32,030 --> 00:37:33,665
MICROENVIRONMENT, FROM THE

955
00:37:33,665 --> 00:37:36,802
SYSTEMIC ELIMINATION OF SIAH,

956
00:37:36,802 --> 00:37:37,970
TUMORS ARE STILL INHIBITED AND

957
00:37:37,970 --> 00:37:40,639
THEY ARE IPT GREATER HIB

958
00:37:40,639 --> 00:37:42,407
THORSITTED BECAUSE THERE IS AN

959
00:37:42,407 --> 00:37:44,543
INCREASE IN THE

960
00:37:44,543 --> 00:37:45,911
INFILTRATION--I'M SORRY,

961
00:37:45,911 --> 00:37:48,080
DECREASED IN THE INFILTRATION OF

962
00:37:48,080 --> 00:37:49,615
TREGS, REGULATORY CELLS WHICH

963
00:37:49,615 --> 00:37:51,516
ARE NEGATIVELY REGULATE THE

964
00:37:51,516 --> 00:37:52,017
IMMUNE SYSTEM.

965
00:37:52,017 --> 00:37:58,557
THIS IS A SIMPLE MAP FROM SINGLE

966
00:37:58,557 --> 00:38:02,728
CELL RNASEQ ANALYSIS, AND

967
00:38:02,728 --> 00:38:04,763
FURTHER DEMONSTRATED HERE BY WAY

968
00:38:04,763 --> 00:38:07,299
OF FAX ANALYSIS WHERE WE

969
00:38:07,299 --> 00:38:08,834
DEMONSTRATE THERE IS REDUCTION

970
00:38:08,834 --> 00:38:12,437
IN T-CELL AND ESPECIALLY TREGS.

971
00:38:12,437 --> 00:38:14,673
THERE IS ENHANCED CYTOTOXIC

972
00:38:14,673 --> 00:38:17,476
INFILTRATION WHILE THERE IS

973
00:38:17,476 --> 00:38:20,212
REDUCTION OF TREGULATORY CELL

974
00:38:20,212 --> 00:38:23,115
INFILTRATION AND THAT ALLOW TO

975
00:38:23,115 --> 00:38:24,516
ENHANCE ANTITUMOR IMMUNITY, THE

976
00:38:24,516 --> 00:38:25,918
MECHANISM UNDERLYING THE CHANGES

977
00:38:25,918 --> 00:38:27,419
I'VE JUST DESCRIBED HAS TO DO

978
00:38:27,419 --> 00:38:30,822
WITH A KNOWN SUBSTRATE FOR THE

979
00:38:30,822 --> 00:38:33,592
UBIQUITIN LIGASE, LEVEL OF P27,

980
00:38:33,592 --> 00:38:35,460
UPREGULATED IN THE ABSENCE OF

981
00:38:35,460 --> 00:38:39,498
THE SIA AND WHEN WE PUT BACK

982
00:38:39,498 --> 00:38:42,567
SIA, P27, WHEN WE INHIBIT P27 IN

983
00:38:42,567 --> 00:38:44,803
THIS 1 TEXT WE'RE ABLE TO

984
00:38:44,803 --> 00:38:47,906
RESCUE, GET TUMOR NO LONGER

985
00:38:47,906 --> 00:38:49,775
INHIBITED, THEY GROW BETTER IN

986
00:38:49,775 --> 00:38:53,211
THE ABSENCE OF P27, SUBSTANTIATE

987
00:38:53,211 --> 00:38:56,782
THE ROLE OF THE SUBSTRATE

988
00:38:56,782 --> 00:38:58,650
MEDIATING THE PHENOTYPE THAT WE

989
00:38:58,650 --> 00:38:59,251
HAVE DISCUSSED HERE.

990
00:38:59,251 --> 00:39:01,086
ONE COOL THING ABOUT THIS

991
00:39:01,086 --> 00:39:04,489
FINDING WITH THE SIAH KNOCKOUT

992
00:39:04,489 --> 00:39:05,791
MICE IS THE PHENOTYPE WOE HAVE

993
00:39:05,791 --> 00:39:08,760
NOTED IN THESE MICE RESEMBLE

994
00:39:08,760 --> 00:39:13,031
VERY MUCH PHENOTYPES THAT ARE

995
00:39:13,031 --> 00:39:16,501
SEEN IN ANIMALS THAT WERE

996
00:39:16,501 --> 00:39:17,703
TREATED IN CDK46 INHIBITION AND

997
00:39:17,703 --> 00:39:22,574
USED IN THE CLINIC AND THE CA2

998
00:39:22,574 --> 00:39:24,076
KNOCKOUT MICE BY EXPRESSION OF

999
00:39:24,076 --> 00:39:25,978
PROFILE AND BEHAVIOR HAD VERY

1000
00:39:25,978 --> 00:39:29,381
SIMILAR CHARACTERISTIC TO THE

1001
00:39:29,381 --> 00:39:33,552
CDK46 INHIBITION AND INDEED,

1002
00:39:33,552 --> 00:39:36,488
WITH THE PD1, ALSO KNOCK OUT 2

1003
00:39:36,488 --> 00:39:39,157
MICE, CR2 KNOCKOUT MICE IN THIS

1004
00:39:39,157 --> 00:39:42,728
PARTICULAR CASE WAS VERY NICELY

1005
00:39:42,728 --> 00:39:44,463
RESPONSIVE ENHANCE AUTOIMMUNITY

1006
00:39:44,463 --> 00:39:52,637
WHEN SUBJECTED TO COMBINATION

1007
00:39:52,637 --> 00:39:52,804
PD1.

1008
00:39:52,804 --> 00:39:57,242
SO TO SUMMARIZE THIS PORTION OF

1009
00:39:57,242 --> 00:39:59,778
MY SIAH PRESENTATION, I

1010
00:39:59,778 --> 00:40:00,912
EMPHASIZED IMPORTANCE IN

1011
00:40:00,912 --> 00:40:02,647
HYPOXIA, I SPOKE A LITTLE BIT

1012
00:40:02,647 --> 00:40:05,550
ABOUT ITS ROLE IN AT4 AND UPL, I

1013
00:40:05,550 --> 00:40:07,285
DID MENTION THE FINDING THAT

1014
00:40:07,285 --> 00:40:09,421
IT'S IMPORTANT IN THE

1015
00:40:09,421 --> 00:40:11,623
MITOCHONDRIA FISSION, LACK OF

1016
00:40:11,623 --> 00:40:13,158
TIME, IMPORTANT PROSTATE CANCER,

1017
00:40:13,158 --> 00:40:15,694
MELANOMA AND THE ROLE OF TUMOR

1018
00:40:15,694 --> 00:40:16,328
INTRINSIC AND EXTRINSIC SO

1019
00:40:16,328 --> 00:40:20,866
EVERYTHING I TOLD YOU SO FAR IS

1020
00:40:20,866 --> 00:40:22,768
THAT SIAH IS SERVING AS AN ORCHG

1021
00:40:22,768 --> 00:40:25,170
O GENE IN THE TUMOR AND IN THE

1022
00:40:25,170 --> 00:40:26,671
MICRO ENVIRONMENT AND THE

1023
00:40:26,671 --> 00:40:31,076
INHIBITION OF SI,A H WOULD

1024
00:40:31,076 --> 00:40:32,110
INHIBIT TUMORS REGARDLESS OF

1025
00:40:32,110 --> 00:40:34,146
INHIBITION IN THE TUMOR ITSELF

1026
00:40:34,146 --> 00:40:34,913
OR THE MICROENVIRONMENT, SO NOW

1027
00:40:34,913 --> 00:40:39,785
I WILL TELL YOU THIS IS NOT SO

1028
00:40:39,785 --> 00:40:40,052
SIMPLE.

1029
00:40:40,052 --> 00:40:41,153
AND TECHNOLOGY ALLOWED US TO GO

1030
00:40:41,153 --> 00:40:43,688
FROM TOTAL KNOCK OUT TO

1031
00:40:43,688 --> 00:40:44,489
CONDITIONAL KNOCK OUT.

1032
00:40:44,489 --> 00:40:46,525
ASK WHEN HAVE YOU CONDITIONAL

1033
00:40:46,525 --> 00:40:48,894
KNOCKOUT MICE, WE CAN ASK WHAT

1034
00:40:48,894 --> 00:40:52,564
CAN HAPPEN TO ELIM NATION OF

1035
00:40:52,564 --> 00:40:53,965
THIS UBIQUITIN LIGASE ONLY IN

1036
00:40:53,965 --> 00:40:57,235
SPECIFIC TISSUE TYPE AND WE

1037
00:40:57,235 --> 00:40:57,936
START WITH MACROPHAGES.

1038
00:40:57,936 --> 00:40:59,638
GIVEN THE EFFECT WE HAVE SEEN SO

1039
00:40:59,638 --> 00:41:00,906
FAR, WE FOCUSED ON THE

1040
00:41:00,906 --> 00:41:03,708
MACROPHAGES AND WE KNOCKED OUT

1041
00:41:03,708 --> 00:41:06,311
SIAH 1 AND 2 IN MACROPHAGES OR

1042
00:41:06,311 --> 00:41:08,380
SIAH 1 INDEED TUMOR MACROPHAGES

1043
00:41:08,380 --> 00:41:10,715
WITH THIS CONDITION AND ASK WHAT

1044
00:41:10,715 --> 00:41:12,884
HAPPENED TO TUMOR GROWTH.

1045
00:41:12,884 --> 00:41:14,519
AND TO OUR SURPRISE, WE FOUND

1046
00:41:14,519 --> 00:41:18,323
THAT IN BOTH CASES, LUNG CANCER

1047
00:41:18,323 --> 00:41:24,062
AND MELANOMA GREW BETTER IF SIAH

1048
00:41:24,062 --> 00:41:26,264
1, 2, IN THE CASE OF LUNG OR

1049
00:41:26,264 --> 00:41:28,400
WOOR 1 BY ITSELF IN THE CASE OF

1050
00:41:28,400 --> 00:41:29,234
MELANOMA WERE

1051
00:41:29,234 --> 00:41:29,701
CERTAINLY--CERTAINLY

1052
00:41:29,701 --> 00:41:30,769
EMILYINATEED ONLY IN

1053
00:41:30,769 --> 00:41:31,069
MACROPHAGES.

1054
00:41:31,069 --> 00:41:32,671
SO OPPOSITE TO WHAT I'VE JUST

1055
00:41:32,671 --> 00:41:37,876
SHOWED YOU, A FEW MINUTES AGO,

1056
00:41:37,876 --> 00:41:38,677
ELIMINATION ONLY IN MACROPHAGES

1057
00:41:38,677 --> 00:41:42,180
WILL HAVE AN OPPOSITE EFFECT.

1058
00:41:42,180 --> 00:41:43,815
AND THIS IS A VERY IMPORTANT

1059
00:41:43,815 --> 00:41:47,319
LESSON FOR ALL OF US TO KNOW

1060
00:41:47,319 --> 00:41:49,154
BECAUSE THE MORE YOU DIG, THE

1061
00:41:49,154 --> 00:41:50,522
BETTER YOU FIND THE RELATIVE

1062
00:41:50,522 --> 00:41:51,423
PORTION AND ACTIVITY OF A

1063
00:41:51,423 --> 00:41:52,858
PROTEIN THAT YOU STUDY.

1064
00:41:52,858 --> 00:41:57,729
AND THAT'S A LESSON THAT WE

1065
00:41:57,729 --> 00:42:01,233
LEARNED IN OUR APPLICATIONS.

1066
00:42:01,233 --> 00:42:02,534
IN THE LUNG CANCER FORMATION WE

1067
00:42:02,534 --> 00:42:04,402
PENTINE REGIMEN TO LUNG CANCER

1068
00:42:04,402 --> 00:42:05,804
IMMUNITY BECAUSE A MAJ OR

1069
00:42:05,804 --> 00:42:08,440
PHENOTYPE WE'VE SEEN IS INCREASE

1070
00:42:08,440 --> 00:42:12,010
IN OR DECREASE IN AVERMEN

1071
00:42:12,010 --> 00:42:12,777
INFECTED OULAR MACROPHAGE

1072
00:42:12,777 --> 00:42:13,378
PRODUCTION ASK WHEN YOU SLEEP

1073
00:42:13,378 --> 00:42:15,947
APNEA AND OBESITYY DECREASE IN

1074
00:42:15,947 --> 00:42:17,816
THE LEVEL OF ALVEOLAR

1075
00:42:17,816 --> 00:42:20,418
MACROPHAGES SHOWN HERE, WE LOOK

1076
00:42:20,418 --> 00:42:22,521
INTO LUNG AND LUNG CARCINOGEN

1077
00:42:22,521 --> 00:42:25,490
WAS SUFFICIENT TO HAVE A

1078
00:42:25,490 --> 00:42:26,992
PHENOTYPE AND THERE WERE MORE

1079
00:42:26,992 --> 00:42:28,093
TUMORS, MORE LUNG TUMORS THAT

1080
00:42:28,093 --> 00:42:33,231
WERE FORMED IN THE ABSENCE OF

1081
00:42:33,231 --> 00:42:36,234
SIAH 1, 2, IN THE MACROPHAGES

1082
00:42:36,234 --> 00:42:36,601
ONLY.

1083
00:42:36,601 --> 00:42:38,136
AND FOLLOW DEMONSTRATING THROUGH

1084
00:42:38,136 --> 00:42:43,074
SINGLE CELL RNA SEQ AND WHAT

1085
00:42:43,074 --> 00:42:44,576
NOT, THEY--THE EXHAUSTIAN OF

1086
00:42:44,576 --> 00:42:46,344
T-CELL POPULATION THAT WAS

1087
00:42:46,344 --> 00:42:51,349
IDENTIFIED IN THOSE ANIMALS THAT

1088
00:42:51,349 --> 00:42:52,317
[INDISCERNIBLE] ONLY

1089
00:42:52,317 --> 00:42:52,651
MACROPHAGES.

1090
00:42:52,651 --> 00:42:57,622
AND THE MORE RECENT STUDY, WE

1091
00:42:57,622 --> 00:43:00,325
FOCUSED ON 1 LIGASE, AND

1092
00:43:00,325 --> 00:43:01,726
ELIMINATION OF ONLY 1 IN

1093
00:43:01,726 --> 00:43:04,462
MACROPHAGES WAS ENOUGH TO

1094
00:43:04,462 --> 00:43:05,096
INCREASE MELANOMA CAN THAT YOU

1095
00:43:05,096 --> 00:43:09,601
SLEEP APNEA AND OBESITYY  THE

1096
00:43:09,601 --> 00:43:11,503
INCREASE PRETTY STRONGLY.

1097
00:43:11,503 --> 00:43:15,407
SO, OVER THE LAST 20 YEARS

1098
00:43:15,407 --> 00:43:18,076
PERHAPS, THERE ARE DOZENS OF

1099
00:43:18,076 --> 00:43:20,478
STUDIES ON THIS UBIQUITIN

1100
00:43:20,478 --> 00:43:21,079
LIGASES.

1101
00:43:21,079 --> 00:43:23,081
IN MOST CASES PEOPLE LOOKED AT

1102
00:43:23,081 --> 00:43:25,050
THE BIOCHEMISTRY IN TERMS OF HOW

1103
00:43:25,050 --> 00:43:26,785
THIS DO WHATEVER THEY DO IN

1104
00:43:26,785 --> 00:43:29,020
CULTURE, OR IN VITRO, AND THERE

1105
00:43:29,020 --> 00:43:31,256
WERE NO DIFFERENCES THAT PEOPLE

1106
00:43:31,256 --> 00:43:33,925
COULD POINT OUT BETWEEN 1 ANY 2,

1107
00:43:33,925 --> 00:43:36,461
WE AND OTHERS CONSIDER THEM MORE

1108
00:43:36,461 --> 00:43:38,997
OR DOING THE SAME.

1109
00:43:38,997 --> 00:43:42,367
COUPLE OF STUDIES AND I MEAN

1110
00:43:42,367 --> 00:43:44,469
COUPLE, 1-2-MAYBE 3, OVER THE

1111
00:43:44,469 --> 00:43:53,678
LAST 10 YEARS SUGGIESTED THAT S

1112
00:43:53,678 --> 00:43:55,680
IH1 MAY SERVE BUT NO BEDDING AS

1113
00:43:55,680 --> 00:43:57,549
TO WHY IT WOULD HAPPEN.

1114
00:43:57,549 --> 00:43:59,284
THIS STUDY HERE MAY PROVIDE THE

1115
00:43:59,284 --> 00:44:01,486
FIRST BLUEPRINT TO UNDERSTAND

1116
00:44:01,486 --> 00:44:03,655
HOW UBIQUITIN LIGASE UNDER IN A

1117
00:44:03,655 --> 00:44:05,056
SPECIFIC TISSUE ENVIRONMENT CAN

1118
00:44:05,056 --> 00:44:09,394
BEHAVE AS A TUMOR SUPPRESSOR.

1119
00:44:09,394 --> 00:44:11,596
SO WHAT WE NOTICED IN THIS

1120
00:44:11,596 --> 00:44:13,698
PARTICULAR CASE, THEY'RE

1121
00:44:13,698 --> 00:44:15,233
INCREASING THE NTSCs, DECREASE

1122
00:44:15,233 --> 00:44:18,303
IN THE IMPORTANT CELLS THAT WILL

1123
00:44:18,303 --> 00:44:20,105
OTHERWISE MEDIATE ANTITUMOR

1124
00:44:20,105 --> 00:44:21,506
IMMUNITY, CD4, CD8 AND NK AND

1125
00:44:21,506 --> 00:44:23,608
THE PATHWAY AND I DON'T SHOW

1126
00:44:23,608 --> 00:44:31,216
YOU, THE RESULT BECAUSE OF TIME,

1127
00:44:31,216 --> 00:44:34,653
SUGGIESTS THAT CO1 A CONTROL THE

1128
00:44:34,653 --> 00:44:38,823
P300 COMPLEX PROTEINS, CONTROL

1129
00:44:38,823 --> 00:44:40,592
HISTONE ACETYLATION AND

1130
00:44:40,592 --> 00:44:41,426
CONSEQUENTLY THE CHANGES WERE

1131
00:44:41,426 --> 00:44:44,562
NOTED IN THE PPLGAMMA AND

1132
00:44:44,562 --> 00:44:46,531
INFLAMMATORY GENES IS AN

1133
00:44:46,531 --> 00:44:48,600
MECHANISM THAT UNDERLIE TUMOR

1134
00:44:48,600 --> 00:44:49,768
SUPPRESSOR ACTIVITY.

1135
00:44:49,768 --> 00:44:51,569
AGAIN, TUMOR SUPPRESSOR IN

1136
00:44:51,569 --> 00:44:51,970
MACROPHAGES.

1137
00:44:51,970 --> 00:44:54,539
SO THE QUESTION IS:  WHICH 1

1138
00:44:54,539 --> 00:44:55,006
WINS?

1139
00:44:55,006 --> 00:44:59,911
IF YOU GO AND DEVELOP A DRUG

1140
00:44:59,911 --> 00:45:01,313
AGAINST UBIQUITIN LIGASE WITH AN

1141
00:45:01,313 --> 00:45:03,181
APPROACH FOR A TOTAL KNOCK OUT

1142
00:45:03,181 --> 00:45:05,450
THAT WOULD BE INSUFFICIENT FOR

1143
00:45:05,450 --> 00:45:07,052
TUMORS OR RABLGHTER GO AFTER 1

1144
00:45:07,052 --> 00:45:09,821
OF THESE LIGASE ONLY SIAH 2 IS

1145
00:45:09,821 --> 00:45:12,691
AN ONCA GENE AND AVOID TOUCHING

1146
00:45:12,691 --> 00:45:13,825
SIAH1A AND THEY'RE VERY, VERY

1147
00:45:13,825 --> 00:45:16,227
SIMILAR TO EACH OTHER AND IF YOU

1148
00:45:16,227 --> 00:45:20,131
DO SO, MAYBE YOU WILL HAVE A

1149
00:45:20,131 --> 00:45:22,233
MOLD, DRUG OF INTEREST THAT CAN

1150
00:45:22,233 --> 00:45:25,804
BE FURTHER ARK ASSESSESSED AND

1151
00:45:25,804 --> 00:45:26,771
DEVELOPED.

1152
00:45:26,771 --> 00:45:27,505
--ASSESSED AND DEVELOPED.

1153
00:45:27,505 --> 00:45:31,543
SO, I JUST COVERED THAT AND I'LL

1154
00:45:31,543 --> 00:45:34,512
FINISH BY GOING BACK TO A SLIDE

1155
00:45:34,512 --> 00:45:38,616
THAT I STARTED WITH, WHERE I'VE

1156
00:45:38,616 --> 00:45:41,319
OUTLINES THE DIFFERENT STROMA

1157
00:45:41,319 --> 00:45:46,491
COMPETENT THAT ARE SURROUNDING

1158
00:45:46,491 --> 00:45:49,260
THE TUMOR AND ARE REQUIRED FOR

1159
00:45:49,260 --> 00:45:50,228
TUMOR REVOLUTION AND IT'S NO

1160
00:45:50,228 --> 00:45:52,664
LONGER GOING TO BE A ONE-ON-ONE

1161
00:45:52,664 --> 00:45:55,166
INTERACTION BUT RATHER A CROSS

1162
00:45:55,166 --> 00:45:56,434
TALK BETWEEN STROMAL CONFIDENCE

1163
00:45:56,434 --> 00:45:57,602
THEMSELVES BEFORE THEY CAN DO

1164
00:45:57,602 --> 00:46:02,140
ANYTHING ON THE TUMOR ITSELF, SO

1165
00:46:02,140 --> 00:46:04,809
FOR 1, THE POSSIBILITY OF THE

1166
00:46:04,809 --> 00:46:06,978
TIER CELLS NEED TO BE EDUCATED

1167
00:46:06,978 --> 00:46:09,681
OR GET PERMISSION QUOTE-UNQUOTE

1168
00:46:09,681 --> 00:46:11,049
FROM STROMA BEFORE THEY INFILL

1169
00:46:11,049 --> 00:46:12,617
STRAIGHT IS AN APPEALING

1170
00:46:12,617 --> 00:46:13,451
HYPOTHESIS THAT WE HAVE SOME

1171
00:46:13,451 --> 00:46:15,754
REASON TO BELIEVE IS WORKING AND

1172
00:46:15,754 --> 00:46:19,290
WE ARE TESTING IT OUT.

1173
00:46:19,290 --> 00:46:22,394
THE CR-GROUP STARTED WITH

1174
00:46:22,394 --> 00:46:23,328
[INDISCERNIBLE] DISCOVERED

1175
00:46:23,328 --> 00:46:23,962
POLYHYDROX LACE, [INDISCERNIBLE]

1176
00:46:23,962 --> 00:46:26,364
DID ALL THE WORK IN PROSTATE

1177
00:46:26,364 --> 00:46:29,300
CANCER AND [INDISCERNIBLE]

1178
00:46:29,300 --> 00:46:33,638
DIFFUSION AND ALL THE TUMOR

1179
00:46:33,638 --> 00:46:34,906
EXTRENSIC MECHANISMS, TUMOR

1180
00:46:34,906 --> 00:46:38,143
MICROENVIRONMENT WORK BY MARZIA.

1181
00:46:38,143 --> 00:46:40,945
SO TO SUMMARIZE, I TOLD YOU 2

1182
00:46:40,945 --> 00:46:42,847
STORIES TODAY, 1 HAD TO DO WITH

1183
00:46:42,847 --> 00:46:46,551
THE MICROBI OTA, AND THE SECOND

1184
00:46:46,551 --> 00:46:48,620
WITH THE TUMOR EXTRINSIC

1185
00:46:48,620 --> 00:46:49,087
FUNCTION.

1186
00:46:49,087 --> 00:46:54,192
NOT SO SIMPLE AS 1 CAN THINK,

1187
00:46:54,192 --> 00:46:57,862
ARE WE ABLE TO LEARN FROM THE

1188
00:46:57,862 --> 00:47:00,632
ABILITY OF SINGLE BACTERIA TO

1189
00:47:00,632 --> 00:47:01,800
ELIMINATE OR INHIBIT TUMOR

1190
00:47:01,800 --> 00:47:02,967
GROWTH, CAN WE TAKE IT FARTHER

1191
00:47:02,967 --> 00:47:05,637
AND WHAT DOES IT MEAN, 1 OF THE

1192
00:47:05,637 --> 00:47:10,241
TAKE HOME MESSAGES AND THE

1193
00:47:10,241 --> 00:47:16,981
SECOND IS, IS IT POSSIBLE TO

1194
00:47:16,981 --> 00:47:17,949
TARGET UBIQUITIN LIGATION TO

1195
00:47:17,949 --> 00:47:18,716
INTERFERE WITH CANCER, SOMETHING

1196
00:47:18,716 --> 00:47:19,851
I WILL LEAVE WITH YOU TO THINK

1197
00:47:19,851 --> 00:47:25,089
OF AS WE ARE DWELLING IN THIS

1198
00:47:25,089 --> 00:47:25,457
OURSELVES.

1199
00:47:25,457 --> 00:47:26,891
CURRENT LAB MEMBERS INCLUDE

1200
00:47:26,891 --> 00:47:27,959
FOLKS THAT ARE INVOLVED IN EACH

1201
00:47:27,959 --> 00:47:31,229
OF THE STUDIES I DISCUSSED WITH

1202
00:47:31,229 --> 00:47:32,530
YOU AND SOME OF THOSE THAT I

1203
00:47:32,530 --> 00:47:36,134
HAVE NOT, AND WE HAVE BEEN

1204
00:47:36,134 --> 00:47:36,835
COLLABORATIVE, COLLABORATING

1205
00:47:36,835 --> 00:47:40,271
EXTENSIVELY WITH MEMBERS OF OUR

1206
00:47:40,271 --> 00:47:41,573
DRUG DISCOVERY, CENTER AND

1207
00:47:41,573 --> 00:47:42,974
MELANOMA THAT WE'RE GETTING FROM

1208
00:47:42,974 --> 00:47:45,610
ALL OVER THE WORLD,

1209
00:47:45,610 --> 00:47:46,444
BIO-INFORMATICS FROM ALL OVER

1210
00:47:46,444 --> 00:47:48,713
THE WORLD AND LOCAL AND

1211
00:47:48,713 --> 00:47:50,148
MICROBIOME STUFF THAT WE ARE

1212
00:47:50,148 --> 00:47:52,550
BEING HELPED BY EXPERT AS WELL.

1213
00:47:52,550 --> 00:47:56,788
I WILL BE GLAD TO ANSWER ANY

1214
00:47:56,788 --> 00:48:05,063
QUESTIONS; THANK YOU.

1215
00:48:05,063 --> 00:48:05,964
COMPREHEND.

1216
00:48:05,964 --> 00:48:06,698
>> ANOTHER TOUR DEFORCE.

1217
00:48:06,698 --> 00:48:11,002
THAIRNGS --THANKS, THAT WAS GRE.

1218
00:48:11,002 --> 00:48:12,971
I HAVE A QUESTION FOR EACH PART,

1219
00:48:12,971 --> 00:48:15,373
WHEN YOU KNOCK OUT SIAH, AND THE

1220
00:48:15,373 --> 00:48:16,708
TARGET IT TO MACROPHAGES, MAYBE

1221
00:48:16,708 --> 00:48:19,878
I MISSED THIS DID YOU TARGET IT

1222
00:48:19,878 --> 00:48:20,879
TO A SPECIFIC MACROPHAGE AND

1223
00:48:20,879 --> 00:48:22,747
EITHER WAY DID YOU KNOW IF IT

1224
00:48:22,747 --> 00:48:23,781
CHANGED THE MACROPHAGE IN THE

1225
00:48:23,781 --> 00:48:25,850
KNOCK OUT SO IT CHANGED THE

1226
00:48:25,850 --> 00:48:29,554
FUNCTION OF THE MACROFAJ?

1227
00:48:29,554 --> 00:48:30,989
>> SO IN THE CASE OF THE
LUNG

1228
00:48:30,989 --> 00:48:33,024
CANCER STUDY WE'VE DONE 2 KNOCK

1229
00:48:33,024 --> 00:48:38,496
OUT BY 2 DIFFERENT CREES, CD11 C

1230
00:48:38,496 --> 00:48:40,265
AND LYS2 AND WHICH STARTED A

1231
00:48:40,265 --> 00:48:40,999
DIFFERENT POPULATION OF

1232
00:48:40,999 --> 00:48:48,439
MACROPHAGES AND IN DOING SO WE

1233
00:48:48,439 --> 00:48:49,374
COVERED DIFFERENT ASPECTS.

1234
00:48:49,374 --> 00:48:52,577
THE MAJOR CHANGE WE'VE SEEN WAS

1235
00:48:52,577 --> 00:48:53,244
DIFFERENTIATION, DEVELOPMENTAL

1236
00:48:53,244 --> 00:48:54,312
IN THE [INDISCERNIBLE] 1S,

1237
00:48:54,312 --> 00:48:57,415
SOMETHING THAT DOES NOT HAVE

1238
00:48:57,415 --> 00:49:02,153
[INDISCERNIBLE] IN THE MELANOMA

1239
00:49:02,153 --> 00:49:02,520
STORY.

1240
00:49:02,520 --> 00:49:04,822
WE DID CHANGE, WE DID SEE BY

1241
00:49:04,822 --> 00:49:06,324
PERFORMING YEEN EXPRESSION

1242
00:49:06,324 --> 00:49:07,959
PROFILES WITHIN THE MACROPHAGE

1243
00:49:07,959 --> 00:49:11,529
THEMSELVES, SO JUST THE LACK OF

1244
00:49:11,529 --> 00:49:13,932
CI IS SUFFICIENT TO CAUSE THOSE

1245
00:49:13,932 --> 00:49:14,632
CHANGES.

1246
00:49:14,632 --> 00:49:16,601
WE BELIEVE THAT PART OF THEM HAS

1247
00:49:16,601 --> 00:49:18,169
TO DO WITH THE ASPECT OF

1248
00:49:18,169 --> 00:49:18,870
CIRCULATION AND WE'RE

1249
00:49:18,870 --> 00:49:20,371
CO-WORKERSING ON THAT NDO YOU

1250
00:49:20,371 --> 00:49:21,573
THINK THOSE CHANGES, START A

1251
00:49:21,573 --> 00:49:23,541
CASCADE THAT STARTS WITH THE

1252
00:49:23,541 --> 00:49:24,375
MACROPHAGE AND TRIGGERS THESE

1253
00:49:24,375 --> 00:49:28,112
OTHER THINGS THAT YOU SEE?

1254
00:49:28,112 --> 00:49:29,013
>> YES, CORRECT.

1255
00:49:29,013 --> 00:49:29,414
>> OKAY.

1256
00:49:29,414 --> 00:49:31,749
>> AND THEN THE
MACROPHAGES WILL

1257
00:49:31,749 --> 00:49:33,217
DETERMINE ACTIVITY AND

1258
00:49:33,217 --> 00:49:35,119
MACROPHAGE FUNCTION SHIFT TO

1259
00:49:35,119 --> 00:49:35,787
COMPACT [INDISCERNIBLE] VICE

1260
00:49:35,787 --> 00:49:38,423
VERSA AND SO ON AND SO FORTH.

1261
00:49:38,423 --> 00:49:40,291
NAND DO YOU THINK THAT CAN

1262
00:49:40,291 --> 00:49:43,561
HAPPEN WITHOUT GENETIC

1263
00:49:43,561 --> 00:49:46,097
ENGINEERING IN THE PATIENT BY

1264
00:49:46,097 --> 00:49:47,565
SOME OTHER MECHANISM?

1265
00:49:47,565 --> 00:49:53,471
>> I DO THINK SO, AND
AGAIN,

1266
00:49:53,471 --> 00:49:54,639
THIS--THIS ANSWER DOES NOT RELY

1267
00:49:54,639 --> 00:49:58,276
ON WHAT WE'VE DONE IN

1268
00:49:58,276 --> 00:50:00,612
MACROPHAGES PER SE, BUT WHAT

1269
00:50:00,612 --> 00:50:02,347
WE'VE LEARNED IS CI BEHAVIOR,

1270
00:50:02,347 --> 00:50:07,552
AND CI IS A CLASSIC STRESS

1271
00:50:07,552 --> 00:50:09,020
RESPONSIVE UBIQUITIN LIGASE.

1272
00:50:09,020 --> 00:50:11,089
SO TO ACTIVATE CI IN CELLS YOU

1273
00:50:11,089 --> 00:50:12,624
NEED STRESS, BY SAYING STRESS, I

1274
00:50:12,624 --> 00:50:15,093
MEAN YOU NEED TO ACCOUNTAIVATE

1275
00:50:15,093 --> 00:50:19,230
UPR, THIS IS CONTROLLED BY

1276
00:50:19,230 --> 00:50:19,964
[INDISCERNIBLE] SPLICE X-BP1.

1277
00:50:19,964 --> 00:50:21,966
SO UNLESS YOU HAVE ACTIVATION OF

1278
00:50:21,966 --> 00:50:23,034
UPL SIGNALING STRESSED TO A

1279
00:50:23,034 --> 00:50:24,802
CERTAIN DEGREE, YOU DON'T SEE CR

1280
00:50:24,802 --> 00:50:26,104
GETTING INTO THE ACTION AND I

1281
00:50:26,104 --> 00:50:27,639
THINK IN THE MACROPHAGE, IT

1282
00:50:27,639 --> 00:50:31,476
WOULD BE SOMEWHAT SIMILAR AND WE

1283
00:50:31,476 --> 00:50:33,678
KNOW THAT THAT THE HARSH

1284
00:50:33,678 --> 00:50:34,946
ENVIRONMENT WILL CAUSE

1285
00:50:34,946 --> 00:50:36,014
EPIGENETIC CHANGES THAT COME IN

1286
00:50:36,014 --> 00:50:38,149
THE FORM OF UPL SIGNALING THAT

1287
00:50:38,149 --> 00:50:39,017
ARE UPREGULATED SO I THINK THIS

1288
00:50:39,017 --> 00:50:41,586
WILL BE THE MECHANISM FOR CR

1289
00:50:41,586 --> 00:50:43,454
RESPONSE, YOU DON'T NEED TO DO

1290
00:50:43,454 --> 00:50:44,989
GENETIC, IT WOULD BE EPIGENETIC

1291
00:50:44,989 --> 00:50:45,857
NETWORK MAKES SENSE, AND THEN

1292
00:50:45,857 --> 00:50:47,925
THE OTHER QUESTION ON THE FIRST

1293
00:50:47,925 --> 00:50:51,262
PART OF THE TALK IS A BIT MORE

1294
00:50:51,262 --> 00:50:51,629
PHILOSOPHICAL.

1295
00:50:51,629 --> 00:50:53,598
YOU KNOW YOU HAVE A BEAUTIFUL

1296
00:50:53,598 --> 00:50:55,500
TRYPTOPHAN MODEL WHICH I THINK

1297
00:50:55,500 --> 00:50:56,801
THERE'S ALSO EVIDENT FOR BUT I

1298
00:50:56,801 --> 00:50:58,836
WOULD BET THAT IF, YOU KNOW 12

1299
00:50:58,836 --> 00:51:01,072
PEOPLE OR 24 PEOPLE DID STUDIES,

1300
00:51:01,072 --> 00:51:04,842
THEY WILL FIND ANOTHER BACTERIUM

1301
00:51:04,842 --> 00:51:06,678
THAT DID SOMETHING ELSE AND I

1302
00:51:06,678 --> 00:51:07,545
WAS WONDERING IF YOU THINK WE

1303
00:51:07,545 --> 00:51:08,980
WILL GET TO THE POINT WHERE

1304
00:51:08,980 --> 00:51:11,416
MAYBE WE WILL IDENTIFY A HANDFUL

1305
00:51:11,416 --> 00:51:12,350
OF BACTERIA THAT HAVE GREATER

1306
00:51:12,350 --> 00:51:13,651
THAN THE SUM OF THE PARTS WHICH

1307
00:51:13,651 --> 00:51:16,220
IS WHY I ASK YOU ABOUT THE

1308
00:51:16,220 --> 00:51:17,255
TRYPTOPHAN LOGISTICS AND I

1309
00:51:17,255 --> 00:51:19,257
WONDER IF AT THAT POINT, YOU BE

1310
00:51:19,257 --> 00:51:22,160
USE SORT OF BROAD SPECTRUM

1311
00:51:22,160 --> 00:51:23,528
ANTIBIOTICS IN PATIENTS, AND

1312
00:51:23,528 --> 00:51:25,496
THEN RECONSITUTE THEIR SYSTEM

1313
00:51:25,496 --> 00:51:27,365
WITH A COCKTAIL OF BACTERIA THAT

1314
00:51:27,365 --> 00:51:31,803
MIGHT BE ANTITUMOR GENIC?

1315
00:51:31,803 --> 00:51:33,638
>> IT'S A GOOD QUESTION
AND IT

1316
00:51:33,638 --> 00:51:35,073
REFLECTS ON THE AGONY THAT WE

1317
00:51:35,073 --> 00:51:36,274
THE COMMUNITY HAVE WHEN WE LOOK

1318
00:51:36,274 --> 00:51:37,675
AT WHAT HAPPENED TO THE

1319
00:51:37,675 --> 00:51:40,878
MICROBIOME FIELD OVER THE LAST

1320
00:51:40,878 --> 00:51:41,312
5, 6 YEARS.

1321
00:51:41,312 --> 00:51:42,313
BECAUSE THERE WERE A NUMBER OF

1322
00:51:42,313 --> 00:51:43,981
STUDIES THAT CLAIM FOR ACTIVITY

1323
00:51:43,981 --> 00:51:45,683
OF THIS BUG OR THAT BUG DEPENDS

1324
00:51:45,683 --> 00:51:49,353
ON WHERE IT CAME FROM AND NONE

1325
00:51:49,353 --> 00:51:51,589
OF THEM CAME TO FRUITION,

1326
00:51:51,589 --> 00:51:52,857
CLINICAL TRIALS WERE HELD,

1327
00:51:52,857 --> 00:51:53,925
COMPANIES WERE ESTABLISHED, NONE

1328
00:51:53,925 --> 00:51:55,226
OF THEM WENT ANY FARTHER FELT

1329
00:51:55,226 --> 00:51:57,628
THIS IS THE BOTTOM LINE, IN ALL

1330
00:51:57,628 --> 00:52:00,064
OUR STUDIES THAT TRAY TO EXPLAIN

1331
00:52:00,064 --> 00:52:00,364
WHY NOT?

1332
00:52:00,364 --> 00:52:02,066
IN 1 OF THE EXPLANATION IS THAT

1333
00:52:02,066 --> 00:52:03,801
THE BUGS IN PARIS ARE DIFFERENT

1334
00:52:03,801 --> 00:52:05,503
THAN THE BUGS IN CHICAGO AND THE

1335
00:52:05,503 --> 00:52:10,241
BUGS IN WASHINGTON OR IN TEXAS.

1336
00:52:10,241 --> 00:52:11,642
I DON'T THINK THIS IS THE CASE,

1337
00:52:11,642 --> 00:52:13,511
BUT I DON'T THINK THIS WILL BE

1338
00:52:13,511 --> 00:52:14,812
THE SOLUTION, SO I THINK THE

1339
00:52:14,812 --> 00:52:18,783
SOLUTION TO THE PROBLEM WILL NOT

1340
00:52:18,783 --> 00:52:21,719
BE BUG A, BUG B, BUG C TO BE

1341
00:52:21,719 --> 00:52:23,321
COMBINED BUT RATHER WHAT IS IT

1342
00:52:23,321 --> 00:52:25,456
THAT THEY PRODUCE THAT WE CAN

1343
00:52:25,456 --> 00:52:25,957
PUT TOGETHER.

1344
00:52:25,957 --> 00:52:28,893
SO IF WE CAN IDENTIFY WHAT ARE

1345
00:52:28,893 --> 00:52:31,796
THE METABOLITES THAT ARE

1346
00:52:31,796 --> 00:52:33,297
ELICITING THE PHENOTYPE, WE WILL

1347
00:52:33,297 --> 00:52:37,502
BE MUCH STRONGER POSITION TO

1348
00:52:37,502 --> 00:52:40,004
REPRODUCE DATA REGARDLESS WHERE

1349
00:52:40,004 --> 00:52:40,605
IT CAME FROM.

1350
00:52:40,605 --> 00:52:45,276
NOW WE ALL KNOW THAT DIFFERENT

1351
00:52:45,276 --> 00:52:46,878
BACTERIAL STRAINS CAN PREVIOUSLY

1352
00:52:46,878 --> 00:52:47,845
PRACTICES METABOLITE BUT QUITE

1353
00:52:47,845 --> 00:52:50,081
FEW THAT PRODUCE THE SAME

1354
00:52:50,081 --> 00:52:52,383
METABOLITES, AND IT'S NOT ONLY

1355
00:52:52,383 --> 00:52:53,684
PRODUCK, IT'S ALSO DEPENDENCE ON

1356
00:52:53,684 --> 00:52:55,219
SO IT'S A LITTLE MORE COMPLEX

1357
00:52:55,219 --> 00:52:56,721
RELATIONSHIP THAT HAPPENS HERE.

1358
00:52:56,721 --> 00:52:59,924
THE BOTTOM LINE IS, I THINK WE

1359
00:52:59,924 --> 00:53:00,992
NEED TO MAKE METABOLITES AND

1360
00:53:00,992 --> 00:53:03,261
ONCE WE HAVE MET THEM,

1361
00:53:03,261 --> 00:53:05,396
ADMINISTER THEM AND DEMON TRAIT

1362
00:53:05,396 --> 00:53:07,498
THAT THEY'RE ABLE TO TO ELICIT A

1363
00:53:07,498 --> 00:53:09,767
PHENOTYPE. 

1364
00:53:09,767 --> 00:53:11,536
WHEN WE ARE ON THOSE GROUNDS IT

1365
00:53:11,536 --> 00:53:13,604
WILL BE MUCH SAFER EXTERIOR US

1366
00:53:13,604 --> 00:53:14,872
TO PROCEED, WE ARE NOT THERE, WE

1367
00:53:14,872 --> 00:53:16,941
ARE HEADING THERE YOU ABOUTY WE

1368
00:53:16,941 --> 00:53:21,646
ARE NOT THERE?

1369
00:53:21,646 --> 00:53:22,079
>> [INDISCERNIBLE]

1370
00:53:22,079 --> 00:53:23,381
>> I WISH.

1371
00:53:23,381 --> 00:53:24,448
GLEN INDICATED COMBINATION IS A

1372
00:53:24,448 --> 00:53:30,354
POSSIBILITY, I HOPE SO.

1373
00:53:30,354 --> 00:53:30,555
ALAN?

1374
00:53:30,555 --> 00:53:33,391
>> SO GETTING BACK TO THE
RNF5

1375
00:53:33,391 --> 00:53:36,828
AND THE CD8S, ANY CLUES ABOUT

1376
00:53:36,828 --> 00:53:41,833
DIRECT SUBSTRATES OR WHAT'S

1377
00:53:41,833 --> 00:53:42,633
BEING AFFECTED?

1378
00:53:42,633 --> 00:53:43,267
>> [INDISCERNIBLE]

1379
00:53:43,267 --> 00:53:43,734
>> YEAH, YEAH, YEAH.

1380
00:53:43,734 --> 00:53:47,672
>> SO THE QUESTION IS HOW
IT

1381
00:53:47,672 --> 00:53:49,240
AFFECT THE MICROBI OTA?

1382
00:53:49,240 --> 00:53:50,541
HOW THIS HAPPENED IN THE FIRST

1383
00:53:50,541 --> 00:53:50,741
PLACE?

1384
00:53:50,741 --> 00:53:52,977
SO WHAT I HAVE NOT AND I

1385
00:53:52,977 --> 00:53:54,378
APOGGIZE FOR THIS, IS JUMPING

1386
00:53:54,378 --> 00:53:55,580
OVER A LARGE BODY OF EVIDENCE

1387
00:53:55,580 --> 00:53:58,549
THAT WE GENERATED AT THE TIME

1388
00:53:58,549 --> 00:54:05,857
DEMON 

1389
00:54:05,857 --> 00:54:06,490
DEMONSTRATING THAT L-STRESS

1390
00:54:06,490 --> 00:54:09,360
HAPPENS AND IT HAPPENS IN THE

1391
00:54:09,360 --> 00:54:10,328
INTESTINAL EPITHELIAL CELLS AND

1392
00:54:10,328 --> 00:54:11,729
THAT IS BY ITSELF SUFFICIENT TO

1393
00:54:11,729 --> 00:54:16,234
CAUSE CHANGE IN THE MICROBI OTA

1394
00:54:16,234 --> 00:54:17,068
COMPOSITION.

1395
00:54:17,068 --> 00:54:18,936
AND WE DEMONSTRATED THE SIMILAR

1396
00:54:18,936 --> 00:54:20,671
CHANGES IN THE SIGNALING PATIENT

1397
00:54:20,671 --> 00:54:23,074
THAT ARE BETTER AND NOT

1398
00:54:23,074 --> 00:54:25,977
RESPONSIVE TO IMMUNE CHECK POINT

1399
00:54:25,977 --> 00:54:29,614
THERAPIES, SO IT HAS TO DO WITH

1400
00:54:29,614 --> 00:54:35,219
UPLSHAIZ CHANGE IN THE

1401
00:54:35,219 --> 00:54:36,287
INTESTINAL EPITHELIAL CELLS.

1402
00:54:36,287 --> 00:54:39,290
>> SO IN REGARDS, YOU KNOW

1403
00:54:39,290 --> 00:54:42,660
IDENTIFIED METABOLITES THAT FROM

1404
00:54:42,660 --> 00:54:45,096
THE BACTERIA IN THE GUT, SO THE

1405
00:54:45,096 --> 00:54:48,299
STUDY REFER TO TRYPTOPHAN AND

1406
00:54:48,299 --> 00:54:51,135
TRYPTOPHAN THAT IS THE PRECURSOR

1407
00:54:51,135 --> 00:54:51,602
OF SEROTONIN.

1408
00:54:51,602 --> 00:54:54,705
SO IT'S PROBABLY THAT ALL OF US

1409
00:54:54,705 --> 00:54:55,640
[INDISCERNIBLE] STUDY BUT COULD

1410
00:54:55,640 --> 00:54:57,742
IT BE POSSIBLE AS ACTUALLY THE

1411
00:54:57,742 --> 00:55:03,414
REAR TARGET IS A METABOLITE THEN

1412
00:55:03,414 --> 00:55:05,850
TO AFFECT THE NEUROSYSTEM, TO

1413
00:55:05,850 --> 00:55:09,353
THEN COME BACK TO AFFECT TO

1414
00:55:09,353 --> 00:55:10,988
REGULATE THE IMMUNE RESPONSE.

1415
00:55:10,988 --> 00:55:15,493
>> I CANNOT EXCLUDE THAT

1416
00:55:15,493 --> 00:55:16,294
POSSIBILITY.

1417
00:55:16,294 --> 00:55:17,228
ABSOLUTELY POSSIBLE.

1418
00:55:17,228 --> 00:55:19,030
IT'S POSSIBLE A METABOLITE

1419
00:55:19,030 --> 00:55:20,698
AFFECT INDIRECT IMMUNE

1420
00:55:20,698 --> 00:55:21,866
DYSFUNCTIONUNE CELLS, AND

1421
00:55:21,866 --> 00:55:23,634
THEY--THE WAY BY WHICH I CAN

1422
00:55:23,634 --> 00:55:29,307
POINT TO ARROWS THAT CAUSE THIS

1423
00:55:29,307 --> 00:55:30,241
INDIRECT IS ENDLESS ALMOST BUT

1424
00:55:30,241 --> 00:55:31,876
WE DO NEED TO REMEMBER THAT

1425
00:55:31,876 --> 00:55:34,645
THESE BUGS EAT TO SURVIVE,

1426
00:55:34,645 --> 00:55:36,747
CONSUME TO SURVIVE, AND WHAT

1427
00:55:36,747 --> 00:55:40,618
THEY CONSUME IS ACTUALLY

1428
00:55:40,618 --> 00:55:40,885
DEPLETED.

1429
00:55:40,885 --> 00:55:44,021
SO THE CHANGE IN THIS

1430
00:55:44,021 --> 00:55:46,791
EQUILIBRIUM WHERE WE HAVE

1431
00:55:46,791 --> 00:55:48,292
CERTAIN DECREASE IN METABOLITE

1432
00:55:48,292 --> 00:55:50,094
ANDS OTHERS IS THE BALANCE THAT

1433
00:55:50,094 --> 00:55:51,262
KEEPS IN MIND PHENOTYPE AND THAT

1434
00:55:51,262 --> 00:55:54,865
COULD BE THE TRYPTOPHAN LOSS

1435
00:55:54,865 --> 00:55:57,969
BECAUSE THIS SPECIFIC BUG LIKE

1436
00:55:57,969 --> 00:55:59,570
INDEPENDENT ON THIS, MAY BE THE

1437
00:55:59,570 --> 00:56:00,871
MECHANISM TO EXPLORE FURTHER BUT

1438
00:56:00,871 --> 00:56:03,307
I CANNOT ROLL OUT THAT THERE IS

1439
00:56:03,307 --> 00:56:06,844
INDIRECT EFFECT THAT IS MEDIATED

1440
00:56:06,844 --> 00:56:08,846
BY MORE ENTICING MECHANISM,

1441
00:56:08,846 --> 00:56:09,180
ABSOLUTELY.

1442
00:56:09,180 --> 00:56:09,914
>> JUST HAD A THOUGHT

1443
00:56:09,914 --> 00:56:12,283
EXPERIMENT, I DON'T KNOW IF

1444
00:56:12,283 --> 00:56:16,387
YOU'VE EVER DONE YOUR RNF5 CROSS

1445
00:56:16,387 --> 00:56:18,322
WITH A PML MODEL OR WHETHER YOU

1446
00:56:18,322 --> 00:56:19,957
THINK THAT WOULD ELIMINATE ITS

1447
00:56:19,957 --> 00:56:22,960
ABILITY TO CONTROL A B16 TUMOR

1448
00:56:22,960 --> 00:56:25,863
MODEL GIVEN ITS EFFECTS ON CD8.

1449
00:56:25,863 --> 00:56:27,732
>> NO, WE HAVE NOT DONE
THAT

1450
00:56:27,732 --> 00:56:28,065
EXPERIMENT.

1451
00:56:28,065 --> 00:56:29,467
WE HAVE DONE AN EXPERIMENT WHICH

1452
00:56:29,467 --> 00:56:31,669
AGAIN I DID NOT MENTION WHERE WE

1453
00:56:31,669 --> 00:56:34,872
HAVE CROSSED IT WITH TLR 4 KNOCK

1454
00:56:34,872 --> 00:56:35,706
OUT OR SOMETHING ALONG THOSE

1455
00:56:35,706 --> 00:56:37,975
LINES AND WE LOST THE PHENOTYPE

1456
00:56:37,975 --> 00:56:39,076
AS WELL.

1457
00:56:39,076 --> 00:56:43,447
SO, VERY, VERY CLEVERLY, A LOSS

1458
00:56:43,447 --> 00:56:45,883
OF 5 TRIGGER ANTITUMOR IMMUNITY

1459
00:56:45,883 --> 00:56:48,419
AND PLAYING WITH THE KEY

1460
00:56:48,419 --> 00:56:50,121
COMPETENCE WHETHER IT'S A MYD88

1461
00:56:50,121 --> 00:56:53,124
WAS THE KNOCK OUT WE USE THE AT

1462
00:56:53,124 --> 00:56:54,792
TIME WAS SUFFICIENT TO ELIMINATE

1463
00:56:54,792 --> 00:56:57,094
THE PHENOTYPE BUT IT BASICALLY

1464
00:56:57,094 --> 00:56:59,797
COMES FROM INTESTINAL EPITHELIAL

1465
00:56:59,797 --> 00:57:01,032
CELLS TO START WITH CAN WHEN YOU

1466
00:57:01,032 --> 00:57:03,501
TRY TO MESS UP WITH ICs IT'S

1467
00:57:03,501 --> 00:57:04,335
WAY MORE COMPLICATED.

1468
00:57:04,335 --> 00:57:08,339
I CAN TELL YOU THAT.

1469
00:57:08,339 --> 00:57:10,408
ALL RIGHT, THANK YOU VERY MUCH.

1470
00:57:10,408 --> 00:57:20,618
[ APPLAUSE ]