>>WELCOME EVERYBODY TO THE
WALS LECTURE.
IT'S MY VERY GREAT PLEASURE TO
INTRODUCE TO YOU DR.
LUNA DIATCHENKO, AND SHE
HAS APPOINTMENTS ON THE FACULTY
OF MEDICINE AND WITHIN THE
FACULTY OF DENTISTRY AT
McGILL UNIVERSITY IN
MONTREAL. DOCTOR
DIATCHENKO AND I FIRST MET WHEN
SHE BECAME A GRANTEE OF NIDCR
DURING MY TENURE AS DIRECTOR
THERE AND I THINK THAT MIGHT
HAVE BEEN HER FIRST NIH GRANTS
BUT I'LL LET HER CORRECT ME IF I
MISSPOKE AND I WILL TELL YOU AT
THAT TIME, HER GROUND BREAKING
WORK REALLY OFFERED NOVEL
MECHANISTIC AND GENETIC INSIGHTS
INTO CHRONIC PAIN AND REALLY
REPRESENTED A MUCH WELCOME
DEPARTURE FROM THE EXISTING
PORTFOLIO THAT THE INSTITUTE HAD
AT THE TIME AND I HAVE TO SAY,
IN MANY WAYS, HER WORK CATALYZED
A REAL SHIFT INTO THE FUTURE
DIRECTIONS OF PAIN RESEARCH AT
NIDCR AND BEYOND AND SO FOR THAT
WE ARE VERY GRATEFUL TO YOU.
NOW, I COULD SAKE A LOT OF THE
REST OF THE TIME ALLOTTED FOR
THIS PRESENTATION TO OUTLINE THE
MANY HONORS THAT L UDA HAS
GAINED BUT LET ME JUST NAME A
FEW.
FOR EXAMPLE N2019 SHE RECEIVED
THE FUTURE OF PAIN SCIENCE AWARD
FROM THE AMERICAN PAIN SOCIETY,
SHE'S AN HONORARY PROFESSOR AT
[INDISCERNIBLE] UNIVERSITY--AND
FOR THOSE OF YOU NOT FAMILIAR
WITH THE CANADIAN SYSTEM, THAT'S
A BIG DEAL SO CONGRATULATIONS ON
THAT.
SO WITH THAT I, I WILL LIKE TO
WELCOME EVERYBODY AND WELCOME
DR. DIATCHENKO
AND THE FLOOR IS YOURS.
>> THANK YOU SO MUCH, I REMEMBER
VIVIDLY OUR FIRST INTERACTION,
TOO AND SO THAT WAS THE FIRST
GRANT FOR GENETIC OF PAIN NIDCR
STUDYING THE GENE WHICH WAS THE
[INDISCERNIBLE] TRANSFER ACE,
AND I THINK WILL BE INTERESTING
FOR YOU TO KNOW, LARRY THAT
TODAY IT IS THE MOST STUDIED
GENE.
SO WE DO ALL THIS WORK AND MANY,
MANY PEOPLE USE OUR RESULTS AND
IT'S A MOST SCIENTIFIC HUMAN
IMAGING.
SO THANK YOU VERY MUCH FOR THIS
OPPORTUNITY TO PRESENT MY
RESEARCH TODAY.
I WILL START TO SHARE WITH YOU
THE MOST EXCITING LINE I HAVE
RIGHT NOW IN MY PROGRAM.
OH AND I WILL START WITH THE
OPENING REMARK THAT PAIN IS THE
MOST PREVALENT DISEASE, YOU CAN
SEE IT HERE, IT'S A SOCIETAL
COST OF THE CHRONIC PAIN AND
THOSE WHO ARE NOT IN THE PAIN
FIELD OFTEN FIND THIS SURPRISING
THAT THE CAUSE OF THE PAIN IS
HIGHER THAN CANCER AND DIABETES
COMBINED AND IF YOU CAN SEE BY
THE GRAY BAR HERE, NIH FUNDING
IS STILL NOT CATCHING UP WITH
THE SOCIETAL CAUSE, ESPECIALLY
IF YOU COMPARE WITH THEM IN THE
FIELD IN THE SIZE OF THE FIELD,
THE SEARCH FIELD OF THE PAIN.
SO IT IS BEYOND OUR--ALL OF US
FEEL THIS WAY FOR SLOW
PROGRESSION IN THE PAIN FIELD
THE PROGRAM I WOULD SAY IS PAIN
IS RISING ADDICTION IN AMERICA,
SO UNDERSTANDING OF
PATHOPHYSIOLOGY OF THE CHRONIC
PAIN WILL ALSO HELP US TO FIGHT
ADDICTION.
SO SAYING THAT PATHOPHYSIOLOGY
OF CHRONIC PAIN IS NOT WELL IN
THIS BOOK.
SO WE DO KNOW THAT AFTER INJURY,
WE HAVE PERIPHERAL ACTIVITY AND
PERIPHERAL SENSITIZATION LEADING
TO CENTRAL SENSITIZATION WHICH
LEADS TO THE SYMPTOMS OF CHRONIC
PAIN.
BUT [INDISCERNIBLE]
PATHOPHYSIOLOGY OF CHRONIC PAIN
IS LARGELY UNKNOWN.
SO THOSE RIGHT NOW IN THOSE FROM
THE PAIN FIELD, THEY WILL TELL
ME, THEY KNOW A LOT ABOUT
MOLECULAR PATHOPHYSIOLOGY OF
PAIN ABOUT BUT WE WOULD ARGUE WE
KNOW A LOT ABOUT HYPER
SENSITIVITY.
BUT NOT WITH HUMAN CHRONIC PAIN.
AND WHAT I DO IN MY LAB AND I
DID FROM THE BEGINNING IS I
STUDY A HUMAN PATHOPHYSIOLOGY
THROUGH RUMAN GENETIC STUDY AND
I WILL TELL YOU THAT YOU KNOW
WHY I BELIEVE IT'S VERY
PRODUCTIVE FRUIT, THIS IS
BECAUSE [INDISCERNIBLE] THE
PATHOPHYSIOLOGY OF CHRONIC PAIN,
IT'S VERY DIFFICULT TO MAKE THE
ANIMAL MODEL OF SUCH, RIGHT?
SO, MY GROUP WAS PRODUCTIVE AND
SUCCESSFUL IS TO TAKE
INFORMATION FROM HUMAN STUDIES
AND THEN KIND OF--BIOLOGY, YOU
KNOW WE HAVE THE DNA AND RNA
PROTEIN WHICH THEN TRANSLATED TO
PHENOTYPE.
SO IN ALL THE STAGES, WE CAN
LOOK FOR BIOMARKER AND WE ALSO
CAN LOOK FOR THIS INFORMATION
ABOUT WHAT'S ACTUALLY HAPPENED
WITH THE BODY.
YEAH AND FOR EXAMPLE, ASSOCIATED
MOLECULES, WE CAN USE IT VERY
PRODUCTIVELY IN THE PERSONALIZED
MEDICINE BUT ALSO JUST FOR THE
ROLE OF BIOLOGICAL INSIGHTS.
NOW I WILL START WITH GENETIC
AND I WILL GIVE YOU A FEW
EXAMPLES, SO I WILL START WITH
GENETIC AND WHEN WE TALK ABOUT
VARIABILITY, GENETIC
VARIABILITY, WE KNOW THERE IS
FAMILIARIAL, IN THOSE IT IS
[INDISCERNIBLE] WHICH IS COMMON
IN POPULATION.
IN TERMS OF MONOGENIC DISORDERS,
THERE ARE A NUMBER OF GENE HAS
BEEN IDENTIFIED WHICH IS
RESPONSIBLE FOR SOME VERY SEVERE
CHRONIC PAIN CONDITION AND THE 1
IN WHICH PEOPLE OFTEN RECOGNIZE
IS CONGENITAL INSENSITIVITY TO
PAIN, WHEN PEOPLE ARE UNABLE TO
FEEL PAIN, AND THE HIGHEST
ATTENTION HAS BEEN DRAWN TO SO
THE SODIUM CHANNEL OF NAV1.7
BECAUSE WHAT HAS BEEN IDENTIFIED
IS THE NEW MUTATION, WHICH
PEOPLE TO HAVE THE INABILITY TO
FEEL PAIN BUT ALSO THE MUTATION
WHICH LEAD TO CONSTANT INCREASE
OF THE RECEPTOR ACTIVITY IN
WHICH TUNE [INDISCERNIBLE] PAIN.
BUT STILL WE CAN DID SOMETHING
ABOUT PATHOPHYSIOLOGY OF CHRONIC
PAIN FROM THE LIST OF THE
MANAGING DISORDERS BUT YOU KNOW
I THINK WE CAN LEARN MUCH MORE
LOOKING FOR THE COMMON
PERSISTENT PAIN CONDITION, LIKE
FIBROMYALGIA, THOSE THAT AFFECT
OFTIO ARTHRITIS, THOSE HAD WHICH
ARE HIT REALLY HIGH PERCENT OF
THE POPULATION, IN FACT 20% OF
AMERICANS REPORT CHRONIC PAIN
AND OF COURSE THEY CAN STUDY
THIS FROM GENETIC MARKERS.
AND WE SEE THIS RIGHT NOW WHEN
WE DEVELOP ALGORITHMS OF HUMAN
GENETICS, IF WE CAN INTEGRATE
THIS KNOWLEDGE ON ALL DIFFERENT
LEVEL OF [INDISCERNIBLE] EXISTS
THIS, IS WHERE WE CAN COME TO
THE MOST MULTIDIMENSIONAL
FEATURE BASED ON THIS PAIN AND
THE PROCESSES LIKE WHAT'S BEEN
HAPPENING IN ONCOLOGY WHICH IS
PROBABLY RELATED FIELD IN THIS
APPROACH.
SO [INDISCERNIBLE], SO FIRST I
HOPE I CONVINCE YOU THAT WE
DON'T KNOW MUCH ABOUT
PATHOPHYSIOLOGY OF CHRONIC PAIN
AND THE OMICS-WIDE APPROACH IS A
NEW DEVELOPMENT.
SO I WILL TELL YOU A FEW
STORIES, AND 1 IS ON THE LEVEL
OF GENOME AND THIS IS GENOME
WIDE ANALYSIS WHICH IDENTIFIED
AXO-GENESIS IN CHRONIC
OVERLAPPING PAIN CONDITIONS.
SO THIS STUDY AS JUST BEEN
PUBLISHED IN BRAIN, IN THE FIRST
AND SO THIS BOOK HAS BEEN
PUBLISHED BY [INDISCERNIBLE], BY
THE WAY, I WON'T HAVE THE FINAL
THANK YOU SLIDE WHERE I WILL
PUT--ATTEMPT TO RECOGNIZED ALL
THE PEOPLE WHO HELPED ME WITH MY
PROJECT DURING MY TALK.
SO HERE'S THE PROJECT PAPER THAT
HAS BEEN PUBLISHED
[INDISCERNIBLE] AND STUDIED IN
THIS CASE, PAIN IN UK BIOBANK.
SO THE UK BIOBANK IS THIS
UNBELIEVABLE BIOBANK--MULTIPLE,
MULTIPLE PHENOTYPES INCLUDING
PAIN PHENOTYPE AND GWASS AND
MANY OTHER CLINICAL PHENOTYPES,
AND MORE COMMON.
SO IN UK BIOBANK WE USE
QUESTIONNAIRE WHICH ASKED PEOPLE
DID HAVE YOU PAIN IN THE LAST
MONTHS THAT IMPAIRED YOUR USUAL
DAILY ACTIVITY?
AND IF PEOPLE SAID YES, THE
SECOND QUESTION WAS HAVE YOU HAD
THIS PAIN FOR MORE THAN 3
MONTHS?
SO YOU CAN SEE, PEOPLE CAN
REPORT PAIN IN DIFFERENT BODY
SITE.
THIS IS NUMBER OF CASES WE HAVE.
SO FIRST WE DID THIS GENETIC
CORRELATION BETWEEN DIFFERENT
BODY TYPE AND WE ALSO KNOW FROM
THE EPIDEMIOLOGICAL STUDY WHICH
WAS REPRODUCED HERE IN THE
[INDISCERNIBLE], THAT IT IS A
HUGE OVERLAP BETWEEN DIFFERENT
CHRONIC PAIN CONDITION.
SO IN FACT HAVING 1 PAIN
CONDITION, IS THE RISK PREDICTOR
TO HAVE OTHER PAIN CONDITION.
SO HERE IN THE ORANGE WE SEE
VERY SIGNIFICANT GENETIC
RELATION, ALSO BETWEEN DIFFERENT
CHRONIC PAIN CONDITION, SOME OF
WHICH IS A RISING QUESTION, WHY
SO?
IS IS IT THIS OVERLAPPING
CHRONIC PAIN CONDITION IS A
SEPARATE BEAST, MAYBE IT'S A
SEPARATE DISEASE WHICH WE CAN
STUDY.
IN THIS GENETIC OF PEOPLE WITH
OVERLAPPING PAIN CONDITION, CAN
LEAD US TO UNDERSTAND THIS
PATHOPHYSIOLOGY.
SO FIRST WE DID THIS
[INDISCERNIBLE], WHAT WE MIGHT
ESTABLISH RIGHT NOW IN GWAS, SO
THIS IS MANAT AN PLOT, ACTUALLY
THIS IS SO CALLED
[INDISCERNIBLE] PLOT BECAUSE YOU
CAN SEE BOTH UP AND DOWN AND
HERE IS ALL THE SINGLE VARIANTS,
EVERYTHING WHICH IS THE
[INDISCERNIBLE], THE LINE, I
DON'T KNOW IF YOU CAN JOIN THIS,
AND HERE WE HAVE SAME SCAN FOR
THE GENE, SO YOU SEE 1 SINGLE
SIDE, THIS IS NOT MUCH GENETIC,
OKAY, THERE WAS 1 LOCITE WHICH
WAS SIGNIFICANT EPIGENOME WIDE
LEVEL, BUT IF WE KNEW THAT
MULTISITE PAIN, WHEN PEOPLE
REPORT 2 OR MORE CHRONIC PAIN
SITE, VERSUS PEOPLE WHO DON'T
REPORT ANY PAIN, CAN YOU SEE NOW
THERE IS VERY SUBSTANTIAL AND
GENETIC COMPONENT ON THE LEVEL
OF SNPs, AND EVEN MORE ON THE
LEVEL OF GENES.
SO THE NEXT ASKED QUESTION, IF
WE CAN IDENTIFY THIS GENETIC
VARIANT, WHICH IS UNIQUE FOR
MULTISITE PAIN, PLEIOTROPIC,
MEANS MAYBE THERE IS MORE SIDES
BAWSES THE SAME GENE YOU KNOW MY
FAVORITE TMT IS AT LEAST FOR
[INDISCERNIBLE] PAIN AND FOR
HEADACHE AND SO IN THE SINGLE
ROW THERE'S NOT ENOUGH FOR US TO
SEE BUT WHEN IT COMES TOGETHER,
WE START TO SEE MORE
SIGNIFICANCE.
WE HAVE SUCH UNIQUE THAT WE SEE
SOME VARIANT UNIQUE ONLY FOR ALL
OF THE PAIN CONDITION BUT YOU
DON'T SEE ANY OF THIS FOR THE
SINGLE SITE PAIN.
AND IT WAS MAINLY--IT WAS MAINLY
PLEIOTROAPIC BUT IT WAS VERY
UNIQUE.
THE MOST VARIANTS WE HAD FROM
THIS GENE CALLED DCC WHICH IS
[INDISCERNIBLE] AND WILL BE
IMPORTANT A LITTLE BIT LATER IN
MY TALK.
SO BECAUSE NEXT AFTER WE DID THE
GWAS, WE DID AFTER THIS, WE HAD
THE [INDISCERNIBLE], MEANS WE
TOOK ALL OF THIS FOR THE
INFORMATION FOR GENOME WIDE
ASSOCIATION STUDIES AND WE MAP
IT TO EXPRESSION TO DIFFERENT
HUMAN TISSUES.
SO HERE YOU CAN SEE,
ACTUALLY--IT'S NOT ALL OF THEM,
MAP IT TO ALL PUBLICLY AVAILABLE
TRANSCRIPT O--METABOLIZEDDICS OF
TISSUES, AND SURPRISINGLY OR NOT
ISSUES THE ONLY DIG 95 CANC, -
-SIGNIFICANCE, SO FIRST WE
FOLLOW THE SINGLE SIDE IN
FORWARD LAPPING CONDITION, AND
THE CENTRAL NERVOUS SYSTEM IS
THE 1, BUT VERY ROBUSTLY, TO
THIS GWAS, SO, WOULD WE SEE IS
UNIQUE--BECAUSE WE DIDN'T HAVE
THE TISSUE ON THIS.
SO NEXT WHAT WE DID WAS THE TOP
SNP-BASED PATHWAYS OF MULTISITE
PAIN FROM GWAS STUDY.
SO YOU CAN SEE THE PATHWAY WAS
OVERLAYING, BIOLOGICALLY IT WAS
CELL PROJECTION WITHIN ACTIVATED
SIGNALING PATHWAY IN REGULATION
EVER NEUROGENESIS.
SO THIS WAS ALL DRIVEN BY THE
ACTIVATION OF THE SIGNALING
PATHWAY.
WHAT IS THE AXONAL GUIDANCE,
WELL, DURING NEURONAL
DEVELOPMENT, AXONS ARE GUIDED BY
AND HERE WE CAN SEE THE
MOLECULES WHICH INVOLVED IN THIS
SO YOU CAN SEE THAT THIS
POSITIVE ATTRACT ANT FOR
MUTATING.
FOR AXONAL GUIDANCE USUALLY
SOUGHT IN THE BRAIN DEVELOPMENT,
AXONAL GUIDANCE HAVE ALSO HAVE
BEEN MINERALS BEYOND AXONAL
GUIDANCE, SO, FOR EXAMPLE, FOR
SYNAPTIC PLASTICITY, AXONAL
GUIDANCE WAS ALSO IMPLEMENTED
GREATLY IN THE CONTINUATION--WAS
IMPLEMENTED IN THE LATE ONSET
BRAIN DISORDER SUCH AS
NEURODEGENERATIVE DISEASES.
SO, OKAY, BRAIN, YES, SO THIS IS
AXONAL GUIDANCE.
SO DCC, SO WE WANTED TO MOVE IN
THE BRAIN OF THE PEOPLE WITH THE
CHRONIC PAIN CONDITION, IN THIS
STUDY HASN'T BEEN DONE BY
[INDISCERNIBLE] AT Mc GILL,
AND WE USE AGAIN BIOBANK, IT'S
UNBELIEVABLE HOW MUCH RESOURCES
WE HAVE FOR BRAIN IMAGING IN UK
BIOBANK.
SO FIRST WHAT WE DID HERE IS WE
LOOK FOR EXPRESSION OF DCC IN
HUMAN BRAIN AND YOU CAN SEE THAT
IT IS ABSOLUTELY THE HIGHEST
EXPRESS IN SUBCORTICAL REGION OF
THE SUBACCOUNTS AND HIPAA
COUNTS.
IN THIS REGION, IS THAT 1 WHICH
IS USUALLY KNOWN FOR CORTICAL
INDEX SYSTEM WHICH IS INVOLVED
IN MOTIVATION BUT ALSO
INDICATION OF GROWING PAIN.
SOY THEN WE WERE THINKING ABOUT
WHAT WE CAN MOVE TO AXONAL
GEPMENT AND IF --DEVELOPMENT.
AND IF YOU LOOK AT THE WHITE
MATTER, ALSO BECAUSE WE COULD DO
THIS IN UK BIOBANK IN USING THIS
[INDISCERNIBLE] PATIENT.
SO THIS SPECIAL ORIENTATION IS A
KIND OF A MIX OF SPECIAL
ORGANIZATION OF MATRIX, OF
AXONS.
AND THEY LOOK TO SEVERAL OF THEM
WHICH IS CONNECTING THE
SUBCORTICAL LIMBIC REGION CORTEX
AND WE SAW THAT UNCINATE
FASCICULUS IS CONNECT TO THE
STRUCTURES WAS REALLY GREATLY
DIFFERENT IN THEIR O. D.,
BETWEEN PEOPLE WHO HAVE NO PAIN
AT ALL AND HAVE MULTISITE PAIN
OR HAVE ONLY SINGLE SITE PAIN
AND YOU SEE THERE'S THIS POINT
IN THE RELATIONSHIP.
SO AS A CONCLUSION 1 TO MY FIRST
STORY, THERE IS--SO THEY KNOW
ALL CONFUSION, THE RESULT OF
GWAS, STUDIES CAN BE USED FOR
UNDERSTANDING OF MOLECULAR
PATHOPHYSIOLOGY OF CHRONIC PAIN.
WE CAN USE THIS TO DECIDE THE
IMPAIRMENT.
BY THE WAY, MAYBE I SHOULD SAY
HERE THAT IT'S NOT ONLY THAT O.
D. WAS DIFFERENT BETWEEN PAIN
AND MULTISITE, BUT WHAT THIS
MEANS IS HIGHER, IT DOESN'T MEAN
IT'S HIGHER, IT MEANS THEY'RE
NOT [INDISCERNIBLE], SO THERE
HAS NOT BEEN GROWING IN THE NICE
ORGANIZED PART.
AND SO, WHAT WE SEE HERE THAT
ALTHOUGH AXONAL GUIDANCE CAN BE
OF COURSE AFFECTED DURING OUR
LIFE [INDISCERNIBLE], PEOPLE CAN
ALSO HAVE OPTIMAL AXONAL
GUIDANCE ROLES, SO PEOPLE HAVE
[INDISCERNIBLE] FOR
PREDEVELOPING PAIN CONDITION.
SO NOW THAT BRINGS US TO THE
SECOND EXAMPLE ABOUT THE OMICS
EPITHELIALIGRATION AND THIS TIME
I WILL TELL YOU STORY ABOUT THE
UNBIAS IMMUNE PROFILING THAT
REVEALS A NATURAL KILLER CELL
PERIPHERAL NERVE AXIS IN
FIBROMYALGIA PATIENTS.
SO IN THIS STUDY, WE RECORDED
FIBRO MYALGIA PATIENTS AND
STUDIED BLOOD AND FINDING
FUNCTIONAL SAVING AND GENETIC
AND TRANSCRIPT
O--METABOLIZEDDICS IN THE SYSTEM
AND THEN ALSO ANALYZED IN
ANOTHER INDEPENDENT COHORT AND
SKIN BIOPSY.
THIS HAS ALSO BEEN JUST
PUBLISHED AND I THINK IT'S JUST
ACCEPTED IN PAIN AND HAS BEEN
[INDISCERNIBLE] AND GRADUATE
STUDENT [INDISCERNIBLE].
SO FIRST JUST THE RESULT OF THE
EFFORT WE FOUND 2 CELL TYPES
THAT WERE DIFFERENT BETWEEN
CASES IN CONTROL.
IT WAS A B-CELLS AND NK CELLS.
THE MOST SIGNIFICANT--IN THE WAY
THAT B-CELLS WAS PLACED IN FIBRO
MYALGIA PATIENTS AND NK CELLS
WAS BASICALLY DEPLETED.
AND WE FOUND THIS DIFFERENCE
REALLY CAME FROM NK CELLS AND
THIS IS WHAT WE FOLLOW.
AND IN FACT MOST NK CELLS AND
B-CELLS CONTRIBUTION TO FIBRO
MYALGIA WAS PROBABLY NOT THE
PRIMARY HYPOTHESIS OF OURS OR WE
NEED PEOPLE TO STUDY PAIN AND
ESPECIALLY IN NK CELLS SO THIS
IS WHY THERE WAS GREAT INTEREST
IN THIS CELL TYPE.
SO NEXT WE CHARACTERIZE THIS NK
CELLS AND WHAT WE SAW IN IT NK
CELLS, THAT THEY HAD DECREASED,
SO FIRST EXPRESSION OVER NK
CELLS, YOU KNOW AS YOU CAN SEE
BY CD16, CD8-6 AND CD96 SURFACE
MARKER.
BUT, WE HAVE INCREASED SOME FREE
EXPRESSION OF THE EVALUATION
MARKER, CD107A AND THEN THE
[INDISCERNIBLE] MARKER.
SO BASICALLY IT'S A VERY TYPICAL
MARKER, THIS IS VERY TYPICAL
PICTURE OF CELL EXHAUSTION
PHENOTYPE.
SO WE COMPUTED THE DOWNWARD
CELLS BY EXHAUSTED IF FIBRO
MYALGIA PATIENTS.
SO REMEMBER THEY--YEAH, THEY
ACTIVATE.
SO THERE IS SOME--THEY'VE BEEN
DEGRANNULATED SO THEY HAVE HIGH
REGULATION VIA ABSORPTION.
SO DEEP NK ACTIVATION IS STUDIED
AND THEN WE USE 2 DIFFERENT
[INDISCERNIBLE], SO HLA MINUS
ASSAY WHICH ACTUALLY OR WHICH
STUDY DID FUNCTIONAL CYTOTOXIC
POTENTIAL OF THE NK CELLS AND SO
WE ALSO DID THE ADNKA ASSAY,
WHICH--BECAUSE OUR CELLS ARE
EXHAUSTED THEY WILL NOT BE
ACTIVE.
BUT IN FACT IT WAS HAPPY
RESPONSIVE, THERE WAS HAPPIER
RESPONSIVE IN HLA, ASSAY, FOR
THIS CCL4, WHICH IS ALSO
MACROPHAGE INFLAMMATORY PROTEIN
1 BETTER, HAS BEEN MUCH MORE--BY
THE WAY, THE BASE LINE FIBRO
MYALGIA IN CONTROL, THEY WERE
NOT DIFFERENT, RIGHT?
SO ONLY AFTER ACTIVATION, YOU
KNOW QUITE A BIG DIFFERENCE IN
ALPHA WHICH FIBRO MYALGIA
PATIENT HAS BROUGHT MUCH MORE
NUMEROUSLY, SECRETING BUT ALSO
CD17 WHICH IS ALSO HYPER
RESPONSIVE MARKER.
SO AS YOU SEE THE NK, DID IT
PRACTICES DUCE ANY DIFFERENCE IN
CELLS?
BUT SAYING IT WELL, IT'S
PROBABLY BECAUSE WE SAW THAT
CD16 ARE NK CELL IN FIBRO
MYALGIA CASES, HAVE MORE
EXPRESSION OF CD16, CD16 WAS
PORTION OF ANTIBODY IS CRUCIAL
IN MEDIATING ANTIBODY DEPENDENT
NK CELL ACTIVATION, SO YES,
THERE WASN'T REALLY ABLE TO
RESPOND TO ANTIBODY DEPENDENT
ASSAY.
BUT AGAIN, [INDISCERNIBLE] WAS
MUCH MORE TOXIC AND WAS HYPER
RESPONSIVE, SO THE NEXT CAME
FROM FOOD GENETICS AND FOOD
TRANSCRIPT OMICS, WHEN WE DID
FULL RNASEQ, OF FIBRO MYALGIA
PATIENTS BUT WE ALSO DID GENOME
WIDE ANALYSIS OF FIBRO MYALGIA
PATIENT, IN FACT IN BOTH BACK IN
THE UK BIOBANK AND SO IN THIS
CASE, WE DID ANALYSIS, AND WHEN
WE DID THE [INDISCERNIBLE]
IMMUNE CELLS IN CELL ACTIVATION
AND REGULATION.
YOU CAN SEE MOST TRANSCRIPT
OMICS ARE GENETIC.
THE ONLY SOLUTION YOU CAN HEAT
IF YOU HAD IN WORSE CASE WAS
ABOUT SELECT NK CELL ACTIVATION
AND REGULATION OF NK CELLS.
AGAIN, NOT SOMETHING WHICH WE
EXPECT.
SO THEN WE WERE THINKING LIKE,
WHAT NK CELLS CAN DO IN FIBRO
MYALGIA, SO THEN THE HYPOTHESIS
COME FROM 2 LINES, SO 1
IS--ACTUALLY SEMINOLE
PUBLICATION FROM CANNED WHAT WHO
OBSERVE IN AND REPORTED BI
SEVERAL OTHERS WERE FIRST IN
THIS 1, THE FIBRO MYALGIA
PATIENT HAD DISPLACED MORE FIBRO
NEUROPATHY.
YOU CAN SEE THE SMALL FIBER
NEUROPATHY, RIGHT?
IT'S THE DERMAL AND SUBDERMAL
AND THEY DISAPPEAR AND THEY'RE
SHORT AND NOT FORT RIGHT SHAPE.
IN THE SECOND PUBLICATION WHICH
MAKE YOU THINK ABOUT WHAT NK
CELLS CAN DO, CAME FROM A
PUBLICATION OF ALEX DAVIS IN
CELL 2019 WHEN SHE SHOWED THAT
MAKE SURE KILLER CELLS
REGENERATE SENSORY AFERENT AFTER
NERVE INJURY.
SO BASICALLY HE WAS SAYING IF
THE NERVE WAS DAMAGED, THE NERVE
STARTS TO EXPRESS RECEPTOR FOR
NK CELLS AND IF THEY DON'T
REMOVE IT, IT'S A PROBLEM.
SO WHAT WE DID, WE INCORPORATED
THIS AND TOOK THE SKIN AND WORK
WITH THEM ON THE SKIN BIOPSY OF
FIBRO MYALGIA OF PATIENTS WE
MENTIONED IN STUDIES, THEN WE
SEE EXPRESSION IS MUCH MORE FOR
THE RECEPTOR FOR THE NK CELL, SO
THE NORMAL NERVE NEVER EXPRESS
[INDISCERNIBLE] FOR NK CELLS OR
EXPRESS VERY LOAD.
SO EVERY TIME WHEN THERE IS A NK
CELL RECEPTOR ON, YOU KNOW MAYBE
ANY CELLS--ENRICHMENT FOR THE
NERVE WHICH EXPRESSES IN NK
CELLS BUT ALSO NOT SIGNIFICANT
BUT DEFINITELY INCREASE OR VERY
CLOSE TO THIS INCREASE NUMBER OF
NK CELLS.
AND SO WHAT ALSO WANT IMPORTANT
THAT MOST NUMBER OF NK CELLS
AROUND THE NERVE AND THERE IS
RECEPTOR NK CELLS WAS
SIGNIFICANTLY HIGHLY CORRELATED
AND MOST RECEPTOR FOR NK CELLS
AND NK CELLS THEMSELVES, AROUND
THE NERVE WAS VERY SIGNIFICANTLY
CORRELATED, RISK FIBRO MYALGIA
PAIN SCORE.
SO, OKAY, TOGETHER WOULD WE CAME
WITH THE PROPOSAL FROM THE THIS
HEURISTIC MODEL, WE COULD SEE
WHAT HAPPENED IN FIBRO MYALGIA
IS THE NERVE EXPRESS AREY
RECEPTOR FOR NK CELLS, THEY
CONSTANTLY ATTRACT NK CELLS, AND
NK CELLS OVERTIME BECOME
EXHAUSTED, BUT IT'S ALSO LEAD TO
THE DISTRIBUTION OF NK CELLS TO
[INDISCERNIBLE].
SO IN CONCLUSION 2, CONCLUSION
TO MY SECOND STORY, WHAT WE
LEARN FROM THIS UNBIASED
[INDISCERNIBLE] THERE IS A
REDISTRIBUTION OF NK CELLS FROM
PERIPHERAL BLOOD TO THE INTRA
DERMAL NERVE FIBERS IN FMS
PATIENTS, BUT THESE NK CELL
EXHIBITED ACTIVATED BUT
EXHAUSTED PHENOTYPES AND INTRA
DERMAL NERVE FIBERS IN FMS
PATIENTS EXPRESS RECEPTOR FOR NK
CELLS.
SO THE NEXT BIG QUESTION, I
WOULD SAY IS WHY THE INTRA
DERMAL NERVE FIBERS ATTRACT
PERIPHERAL NK CELLS, WHY ARE
THEY MARKING THEMSELVES TO BE
REMOVED?
AND THIS SEEMS TO BE THE CHRONIC
PROCESS.
SO THIS NOW WILL BE THE END OF
MY SECOND STORY WITH THE
FINDINGS AND I WILL TELL YOU
LAST STORY, LAST UNDERSTANDING
THAT WAS REVEALED ABOUT
PATHOPHYSIOLOGY OF CHRONIC PAIN,
FOR THE ACUTE INFLAMMATORY
RESPONSE VIA NEUTROPHIL
ACTIVATION PROTECTS AGENCY
KRONIFICATION, SO IN ACUTE
INFLAMMATORY RESPONSE, DURING
NUTRIFILL ACTIVATION PROTECTS
AGAINST PAIN CLONIFICATION, AND
I WILL SHOW YOU RESULTS AND I
HOPE YOU WILL EXCITED WITH ME
ABOUT MORE THIS NEW INSIGHTS.
SO THIS PAPER RIGHT NOW IN
SUBMISSION STAGE.
IN THIS STORY, WE STARTED WITH
HUMAN TRAN SCRIPT ORDER OF
MICRONSICS SO THE SAMPLES CAME
FROM ITALY FROM [INDISCERNIBLE]
AND WE HAD PEOPLE WHOSE LOW BACK
PAIN, IT WAS ACUTE PAIN ABOUT 6
WEEKS OF ACUTE [INDISCERNIBLE]
AND WE HAD BLOOD OF THE PATIENTS
AND WE ALSO HAD BLOOD OF THOSE
PATIENTS 3 MONTHS LATER AND SO,
HALF OF THESE PEOPLE RESOLVED
PAIN AFTER 3 MONTHS, AND HALF OF
THEM STILL WAS HAVING PAIN.
SO WE DID NOTICE THE TRAN CRYPT
ORDER OF MICRONSICS IN 4
DIFFERENT WAYS, SO FIRST WHAT WE
ALMOST, ALMOST, ALMOST,
INTERESTING, WHAT IS THE
DIFFERENCE BETWEEN THOSE WHO
HAVE PERSIST PAIN AND THOSE
AREAS OF PAIN INDICATE STAGE,
RIGHT.
SO THEY ALL WOULD LIKE TO MOVE
THE BIOMARKER FOR THIS PAIN, BUT
BY THE WAY, THE FIRST ANSWER IN
THIS STUDY IS NOT
[INDISCERNIBLE] IN MY LAB.
SO HERE'S THE PLOT, UPREGULATED
GENES, DOWN REGULATED GENES AND
EVERYTHING BELOW THE PINK LINE
IS NOT SIGNIFICANT SO WE
ACTUALLY DIDN'T SEE ANY
SIGNIFICANT GENES IN THE STAGE,
THEY WERE ALL ACUTE.
BUT IN 3 MONTHS WE COMPARED
THOSE WITH RESULT PAIN,
[INDISCERNIBLE] GENES WE SAW
ALMOST 2000 GENES UP AND DOWN
REGULATED, DIFFERENT BETWEEN
PEOPLE [INDISCERNIBLE] OF PAIN
AND [INDISCERNIBLE] OF PAIN.
UPON FOR PEOPLE IN THEM, FOR
THOSE RESULTS.
AND THIS IS WHAT EXPLOSION IS
REALLY HAPPENED IS WHEN YOU LOOK
AT THE PEOPLE WHO OBSERVE PAIN
OVER TIME, YOU SLEEP APNEA AND
OBESITYY THERE'S HALF OF THE
GENOME DIFFERENTIALLY EXPRESSED
AT GENOME WIDE [INDISCERNIBLE]
SO IT'S LIKE UNBELIEVABLE
RESPONSE, IN THOSE WHO RESOLVE
PAIN.
IN THOSE WHO DON'T RESOLVE PAIN,
WHAT HAS HAPPENED?
ABSOLUTELY NOTHING.
IT ABSOLUTELY COLLAPSE
TRANSCRIPTION RESPONSE.
SO WE ALSO RECONSTRUCT FROM
TRANSCRIPT OMICS FROM THE
DIFFERENT CELLS AND WHERE WE SAW
THE DIFFERENCE IS AGAIN WHEN WE
FOLLOW THE RESOLVERS OVERTIME,
IN THIS CASE, WE THE MOST
SOLUTION IS THE DOWN REGULATION
OF NUTRIFILLS OVER TIME AND DOWN
REGULATION OF MASS CELLS
OVERTIME BUT UPREGULATION OF
T-CELLS AND UPREGULATION OF NK
CELLS OVER TIME AND THOSE WERE
THE RESULTS.
SOY NEXT WE ASK THE QUESTION,
OKAY, WELL, STILL SOMETHING MUST
HAPPEN AT ACUTE STAGE THAT LEADS
TO ALL THIS MASSIVE
TRANSCRIPTION CHANGES IN THESE
STUDIES SO MAYBE WE CAN USE
OTHER TOOLS WHICH WILL BE MORE
STATISTICALLY POWERFUL AND WHAT
WE DID WAS THE PATHWAY ANALYSIS.
SO WHEN WE DID PATHWAY ANALYSIS,
MANY, MANY PATHWAY WAS
SIGNIFICANT AT TIME 0
[INDISCERNIBLE], BUT THE 2
[INDISCERNIBLE] WAS INFLAMMATORY
RESPONSE.
NEARER FROM THE RESPONSE FOR THE
ACUTE INFLAMMATORY RESPONSE.
THE SURPRISE THOSE WHO RESOLVED
PAIN HAVE MUCH HIGHER
INFLAMMATORY RESPONSE, WHICH IN
THIS INFLAMMATORY RESPONSE WAS
SIGNIFICANTLY DOWN REGULATED
OVER TIME SO THEY HAVE IT VERY
HIGH FOR THIS STAGE DOWN
REGULATED.
SO, IT'S--IT'S ALSO KIND OF
CONSISTENT WHICH WAS
DIFFERENTIATED FOR
[INDISCERNIBLE] AND
NON[INDISCERNIBLE], AND
LEUCOCYTE ACTIVATION, AND FROM
LEUCOCYTE ACTIVATION IT WAS
NUTRIFILL WHICH WAS
SIGNIFICANTLY MORE DIFFERENT.
SO IT WAS NUTRIFILL ACTIVATION
AND NUTRIFILL GRANULATION WHICH
WAS MUCH HIGHER AGAIN IN PEOPLE
WHO VIEWED THIS PAIN, IN THIS
RESPONSE WAS DONE REGULATED AND
THE RESULT WAS VERY SIGNIFICANT
OVER 3 MONTHS.
AND SO, ALSO WE LOOK AT OVERALL
RESPONSE ESPECIALLY BECAUSE I
COULDN'T FIRST UNDERSTAND THE
DIFFERENCE BETWEEN--SO HOW COME
WE HAVE ONLY LIKE 2000 GENE
BETWEEN [INDISCERNIBLE] AND
RESOLVERS IN 3 MONTHS BUT SUCH
EXPLOSION ON DIFFERENTIAL
EXPRESSION IN PEOPLE WHO RESOLVE
PAIN AND THE ANSWER IS, WELL,
THE MOST RESOLVED PAIN AND
UNRESOLVED PAIN, THE TRANSCRIPT
OMICS CORRELATE OVER TIME, SO
HERE'S THE GOLDEN LINE, IT'S THE
PERFECT CORRELATION.
BUT YOU SEE WE HAVE THIS MA
JEBTA LINE, VERY SIGNIFICANT,
YEAH, BUT THIS DIFFERENCE
PROVIDE US 30% DIFFERENCE, SO
THOSE WHO DON'T RESOLVE PAIN
THEY KIND OF TRIED TO MOVE THE
SAME THINGS, THEY TRIED TO
UPREGULATE THE SAME PATHWAY, BUT
THIS RESPONSE IS VERY,
VERY--VERY BLUNTED, YOU KNOW
[INDISCERNIBLE].
SO FINALLY THIS IS WHAT WAS
SUGGESTED ON THE HUMAN STUDY,
WHAT'S HAPPENING, AT ACUTE STAGE
WE HAVE HIGH INFLUENCER RESPONSE
IN HIS AREAS, BUT THIS
INFLAMMATORY RESPONSE GOES DOWN,
BUT WHAT I DIDN'T HAVE TIME TO
FOCUS, THE REPLICATE THIS
RESOLVE, IN 2 OTHER COHORT SO 1
OF THEM WAS IN [INDISCERNIBLE],
IT'S A FACIAL PAIN, ALSO WE HAD
ACUTE ASK CHRONIC AND OTHER
SYSTEM AND IT WAS THE SAME.
SO INFLAMMATORY RESPONSE IS HIGH
IN THOSE AREAS OF PAIN--ACUTE
STAGE, THERE IT IS WORSE EVEN,
YOU KNOW CONTINUE TO GO UP AND
UP AND UP AND UP AND THIS IS
WHAT WOULD EXPLAIN, THIS WOULD
EXPLAIN WHAT WE SEE THAT IN
CHRONIC PAIN PATIENT, THERE IS
MORE GREAT INFLAMMATION, IT IS
MORE GREAT INFLAMMATION IN
PERSISTENT PATIENTS BECAUSE,
YEAH, THEY DIDN'T DO THE CORRECT
UPREGULATION AND DOWN REGULATION
YOU KNOW IN THE ACUTE STAGE.
AND SO ALSO FROM OTHER CORPORATE
CONSTRUCT WHAT HAPPENED, BEFORE
EVEN IF ACUTE STAGE IN THE BASE
LINE IS PEOPLE WHO WILL HAVE THE
HIGH INHIBITORY RESPONSE, ALSO
THEY INCLUDE THE INHIBITORY
RESPONSE BEFORE THEY RESOLVE.
IN THOSE WHO HAVE NO RESPONSE,
THEY WERE ALREADY HIGH.
SO IT'S THIS [INDISCERNIBLE]
RESPONSE INTO THIS
[INDISCERNIBLE] Q-RESPONSE, SO
THEN WE STARTED ANIMAL STUDIES
AND WE STUDIED THIS IN THE LAB
OF JEFF [INDISCERNIBLE] IN HIS
POST DOC LUCAS AND SO JEFF
ORIGINALLY HE SAID, YOU KNOW IT
CANNOT BE BECAUSE WHAT YOU'RE
SAYING THAT THE INFLAMMATION IS
GOOD BUT WE ALL KNOW THAT
INFLAMMATORY DRUG INDUCE PAIN.
AND THEN WE TALK MORE AND HE
SAID, WELL, PEOPLE PROBABLY
NEVER LOOK OVER TIME, SO LET'S
SEE WHAT'S HAPPENED OVER TIME.
SO JEFF AND LUCAS CAME IN AND
THEY TOOK MICE, THEY DID SEVERAL
ANIMAL PAIN MODEL BUT HERE WE'RE
TALKING PRESENT IT'S A C-FRAME
INFLAMMATORY--CFA INFLAMMATORY
MODEL SO WE SEE THE MICE AND
THEY INJECT TO MICE DEXAMETHA
SEWN FOR A FEW DAYS, FOR 3 DAYS,
ASK THEN THEY WAY AND THEN LOOK
AT PAIN BEHAVIOR OF THE MICE.
AND YOU SEE THIS MOVE IS
HAPPENING AT ACUTE STAGE AND AT
ACUTE STAGE MICE THAT RECEIVED
DEXAMETHASONE, IT'S HIGH AND THE
WORK IS ALAN GEEZIC AND MICE WHO
RECEIVE SALIVA--SALIVAINE, THEY
WILL HAVE ANALGESIC, BUT IF YOU
FOLLOW THEM OVER TIME, IT'S A
CLOSE SWITCH BECAUSE AT DAY 15,
THE MICE WAS [INDISCERNIBLE]
ALREADY BUT MICE WHO RECEIVE THE
DEXAMETHASONE, THEY BECAME HYPER
ANALGESIC AND THESE NUMBERS ARE
VERY SIMILAR WHEN IT WAS
RESOLVED VERY QUICKLY, SO YOU
SEE THIS MAY CERTIFY MICE WHO
RECEIVED DEXAMETHASONE, IT TOOK
THEM 140 DAYS, I MEAN IT'S LIKE
A HALF--HALF LIFE JUST FOR 2
SHORT OF DEXAMETHA SEWN AT A
VERY ACUTE STAGE.
AND WE THEN CHECK OTHER DOCS,
AND WE CHECK ON GABBAPENTINE
REGIMENIN AND LIDOCAINE AND
[INDISCERNIBLE], AND DOING THE
SAME THING, SO FIRST OF ALL,
USUALLY ALL THIS ANALGESIC
DRUGS, THEY ARE ANALGESIC SO AT
ACUTE STAGE, THEY ARE ANALGESIC,
THEY HAVE MICE BUT WHAT'S
HAPPENED THIS MICE WHO RECEIVED
THE [INDISCERNIBLE], THEY
DEVELOP THEIR OWN HYPER
ANALGESIC STAYS FOR A VERY, VERY
LONG TIME.
SO FINALLY, WE DECIDED TO CHECK,
YOU KNOW NUTRIFILL, REMEMBER IN
HUMANS IT WAS PATHWAY ANALYSIS
IN THE CELL COMPOSITION, IT WAS
SUGGEST THAD ROOTS NEUTROPHIL
THAT IS CRITICAL FOR THE
CONTRIBUTORS TO PAIN
KRONIFICATION OF PAIN, SO THEN
WE REMOVE THIS ANTIBODY WHICH
REMOVE NEUTROPHIL WHICH IS
EXACTLY THE SAME PICTURE AS
USING DEXAMETHASONE, SO IT'S
CREATE THIS, MAYBE A LITTLE BIT
ANALGESIC PHENOTYPE IN THE
BEGINNING BUT LONG, LONG, LONG
HYPER [INDISCERNIBLE].
TO OUR DEXAMETHA SEWN STUDY, SO,
THE DEXAMETHA SEWN YOU SEE THE
DEXAMETHA SEWN, AND THEY DEVELOP
LONG TIME HYPER ALGEESIA, BUT IF
YOU GIVE MICE IN THE NEUTROPHILS
OR, SO PROTEIN WHICH IS ACE
HUNDRED 8 OR 9 WHICH IS THE
SIGNALING THAT MANY RECEIVE IN
MOLECULES OF NEUTROPHILS, YOU
COMPLETELY ELIMINATE THIS HYPER
ALGEESIA.
SO FINALLY FOR THIS STORY FROM
MY FAVORITE UK BIOBANK IS
REMEMBER IN UK BIOBANK, WE HAD
THIS PAIN SITE BUT WE ALSO HAVE
LIKE AMARKER OF ACUTE PAIN
BECAUSE THE FIRST QUESTION YOU
REMEMBER WAS IN THE LAST MONTHS,
HAVE YOU EXPERIENCED ANY OF THE
FOLLOWING PAIN WHICH INTERFERED
WITH YOUR USUAL ACTIVITY.
SO, PEOPLE CAN SAY, YES IN THE
LAST MONTH BUT SAY NO IT HASN'T
BEEN FOR 3 MONTHS.
SO WHAT WE DID, WE LOOK AT THE
BASE LINE FOR ACUTE PAIN FOR
BIOBANK, PEOPLE SAY YES, I HAVE
PAIN BUT NO, IT'S NOT 3 MONTHS
AND THEN WE SO MOVE THEM, WE
HAVE DRUG USAGE FOR THESE
PEOPLE, ALL OF THEM DEVELOP
CHRONIC PAIN AT THE SECOND VISIT
WHICH WAS 2-6 YEARS LECTURE.
AND AGAIN, SURPRISE, SURPRISE,
LOOK AT THE ALL DRUG AVAILABLE,
YOU LOOK AT ALL DRUGS AVAILABLE
WHEN AT LEAST 10 PEOPLE THAT
WOULD TAKE A DRUG AT THAT STAGE
AND SO HERE WE END UP HAVING
NSAID AND ANTI[INDISCERNIBLE],
AND YOU SEE ONLY SIGNIFICANT IN
A DIFFERENT MODEL IN THE WAY
THAT PEOPLE WHO TAKE NSAIDS WHEN
THEY HAD ACUTE EPISODE, THEY
WERE 1.7 TIMES MORE LIKELY TO
DEVELOP CHRONIC--TO HAVE CHRONIC
PAIN AT THE SECOND VISIT.
INCLUDING CORRECTION FOR ALL
DRUGS.
YES THERE IS AN ADAPTIVE
COMPONENT IN THE IMMUNE SYSTEM,
IN ACUTE GROWING TRANSITION IN
THE LIKE THE OTHER CHRONIC PAIN
CONDITION.
AND SO THERE'S IMMEDIATE ACTIVE
IMMUNE RESPONSE IN HUMAN, THIS
PHYSICAL INJURY MAY LEAD TO PAIN
CHRONIFICATION.
SO THE CONCLUSION OF THIS THEN,
THERE'S DESPITE HIGHER EFFICACY
AT EARLY TIME POINT THE INHIB
THORS INCREASE IN BODYITION OF
ACUTE INFLAMMATORY RESPONSE
MANAGEMENT MAY BE COUNTER
PRODUCTIVE FOR LONG-TERM OF
OUTCOME OF [INDISCERNIBLE] PAIN
SUFFERS.
SO WITH THIS, I WANT TO THANK
YOU VERY MUCH FOR YOUR
ATTENTION.
I WANT TO SAY THANK TO YOU OUR
GROWING PAIN GENETICS GROUP
WHICH IS A BIG GROUP OF
[INDISCERNIBLE] STUDENTS AND I
WANT TO SAY THANK YOU FOR ALL
FUNDING AGENCY UPON STARTING AT
NIH, AND OF COURSE Mc GILL
UNIVERSITY TO DO ALL THE
RESEARCH.
THANK YOU VERY MUCH.
>> I AM A SCIENTISTS FOR
NATIONAL CENTER FOR
BIOTECHNOLOGY AND INFORMATION,
FROM NCBI AND I AM
INVOLVED IN THE ACUTE
[INDISCERNIBLE] SESSION TODAY,
THANK YOU VERY MUCH DOCTOR FOR
YOUR WONDERFUL TALK.
YOU HAVE SEVERAL QUESTIONS FOR
YOU AND WE DON'T HAVE TIME FOR
ALL THESE QUESTIONS AND FIRST OF
ALL IT WAS TO CONTINUE MEDICAL
EDUCATION, THEY SEE
[INDISCERNIBLE] FOR IT IS 37933.
I WILL REPEAT IT.
37933.
I WILL USE MY [INDISCERNIBLE] TO
USE FOR Q&A SESSION AND I WILL
ASK FIRST, DOCTOR, DURING YOUR
TALK YOU STATED A POTENTIALLY
LONG EFFECT TO FIND INFLAMMATORY
DRUGS FOR DIFFERENT PAIN
CONDITIONS AND WHAT WOULD YOU
SUGGEST TO USE?
WE ARE HAVING THOUGHTS ABOUT
DEVELOPING A NEW THERAPY FOR
CHRONIC PAIN.
>> YES, WE SPEND A LOT OF TIME
THINKING IF WE CAN'T USE NSAID,
WHAT CAN WE USE?
AND I THINK WHAT IS IMPORTANT IF
WE THINK ABOUT OUR RESULTS IS
THAT--THE UNUSUAL OR UNEXPECTED
KIND OF ANGLES OF OUR DISCOVERY
IS THAT IT'S NOT WHAT WE USUALLY
THINK ABOUT THAT IT'S NOT 1
MOLECULE AND IT'S NOT LINEAR
RESPONSE.
SO WE OFTEN THINK ABOUT PROCESS
AND THE PAIN PROCESS THAT THERE
IS 1 GENE SHOULD CONTINUE AND
THE FURTHER IT GOES, THE MORE
YEAH IT CONTINUES TO THE
PROCESS, BUT WHAT WE SAW FROM
OUR DATA, NO, UPON IT'S
[INDISCERNIBLE] AND IT'S ALSO
HUGE ACTIVITY WHICH IS
ASSOCIATED WITH THE PROCESS OF
CAN [INDISCERNIBLE], OKAY?
SO ANOTHER THOUGHT PROCESS IS
THAT WE ONLY STUDY PEOPLE WHO
DEVELOP CHRONIC PAIN.
BUT, IF YOU REMEMBER, MY, YOU
KNOW VERY FIRST SLIDE, REALLY
THOSE WHO RESOLVE PAIN, THIS IS
WHERE THE ACTION IS.
THOSE WHO DON'T RESOLVE PAIN,
NOTHING HAPPEN.
IT IS VERY DIFFICULT TO FIND
BLACK CAT IN BLACK ROOM, RIGHT?
IT'S VERY DIFFICULT TO
UNDERSTAND WHAT DIDN'T HAPPEN TO
THESE PEOPLE.
SO FIRST OF ALL WE NEED TO STUDY
WHAT'S HAPPENED IN PEOPLE WHEN
ON RESOLVE PAIN AND SECOND, YOU
KNOW IN ACCORDANCE WITH THIS
DATA, I UPON SAW THAT THEN MAYBE
SHOULD WORK IS THE THERAPY WHICH
WOULD INHIBIT SOME PROCESSES,
BUT UPREGULATE SOME PROCESSES,
UPREGULATE OUR IMMUNE RESPONSE.
AND THEN WHAT WE KNOW, LOOKING
FOR PAIN, WELL WE KNOW PHYSICAL
THERAPY IS WORKING, EXERCISE IS
WORKING, ACCUPUNCTURE, ACTIVATED
[INDISCERNIBLE], ACTIVATED
THROMBOW SIGHTS SO I THINK IT'S
CONSISTENT, SO STEM CELLS, SO
IT'S THERAPY WHICH LEADS TO
UPREGULATION OF OUR RESPONSE,
OUR IMMUNE RESPONSE.
AND YOU KNOW I WOULD LIKE, YEAH,
I WOULD LIKE MY NEXT STEPS WILL
BE TO STUDY HOW THESE THERAPIES
ARE WORKING BUT IT REALLY WORKS
THROUGH UPREGULATION OF OUR
NATURAL ADAPTIVE RESPONSE AND
YOU KNOW SO WHICH PATHWAY THIS
HAPPEN AND WHAT IS THE
CONSEQUENCE OF THESE PATHWAYS.
>> THANK YOU.
THANK YOU VERY MUCH.
IT SOUNDS INTERESTING AND IT
SOUNDS LIKE [INDISCERNIBLE] NOT
SO ADDITIONAL, ESPECIALLY IN THE
USA MEDICINE RIGHT NOW.
OKAY, OUR NEXT QUESTION, NEXT
QUESTION I HAVE FROM DR. TABAK,
AND DO YOU THINK THAT MODULATION
OF NK CELLS IN FIBRO MYALGIA
PATIENTS REDUCE DISEASE
PROGRESSION?
AMELIORATE THE SYMPTOMS?
>> IT'S A VERY GOOD QUESTION.
SO WE WERE ALSO THINKING ABOUT
THIS AND SO ORIGINALLY WE
THOUGHT THIS IS HOW WE NEED TO
TREAT CHRONIC PAIN BECAUSE WE
NEED TO ENHANCE NK CELLS.
AND MAYBE IT IS BUT THE PROBLEM
IS, LIKE, WHY NERVES MARK
THEMSELVES WITH THE NK CELL
RECEPTOR.
WHY NERVE SIGNAL TO NK CELLS
THAT THEY NEED TO BE REMOVED?
BECAUSE NK CELLS SUPPOSEDLY DO
THEIR JOB, THEY HAVE BEEN ASKED
TO COME AND THEY COME AND THEY
KILL THE NERVES RIGHT?
SO RIGHT NOW, I AM NO THINKING
THAT WE NEED TO FIGURE OUT WHY
SERVES EXPRESS RECEPTOR FOR NK
CELLS, SO RIGHT NOW, OUR THOUGHT
IS DEVELOPING ALONG WITH THIS
OTHER WHICH WE FIRST DIDN'T, YOU
KNOW DIDN'T HAVE TIME AND DIDN'T
PAY SO MUCH ATTENTION WITH THE
B-CELLS, INCREASE IN B-CELLS AND
INCREASE OF THE OUTING AND THIS
RECENT PAPER, IN NCI WITH A BIG
RESEARCHERS WHICH SHOWED THAT
FIBRO MYALGIA PATIENT HAVE
[INDISCERNIBLE] CELLS IN DRGs
SO YOU KNOW IN WHAT WE WOULD
LIKE TO SEE IF THIS IS THE
REASON WHY THE NERVE DEVELOP
EXPRESS RECEPTOR FOR NK CELLS
BECAUSE THERE IS SOMEHOW
ACTIVATED, THEY GENERATED BY
THIS SATELLITE CELLS, SENSING
NEURONS SO I'M SORRY, IT'S A
LONG ANSWER BUT I GUESS THE
SHORT 1.
IESM NOT SURE.
I DON'T THINK SO.
I THINK WE NEED TO LOOK UPSTREAM
OF THE NK CELLS.
>> THANK YOU.
NEXT 2 QUESTIONS I HAVE FROM OUR
AUDIENCE, FIRST 1, UPON
[INDISCERNIBLE] FOR OTHER
NEUROLOGICAL DISEASES?
IT'S WELL KNOWN THAT CHRONIC
PAIN IS CO MORBIDITY DEPRESSION,
WHAT HAPPENS IN FMS THAT LEADS
TO [INDISCERNIBLE] NK CELLS?
>> SO THE NK CELLS OR
[INDISCERNIBLE]?
>> ACTIVATED NK CELLS.
>> IN THE BEGINNING OF THE
QUESTION?
>> BEGINNING OF THE QUESTION,
ARE SNPs RECEPTOR FOUND FOR
OTHER NEUROLOGICAL DISEASES?
>> OKAY, OKAY, SO LET'S STOP
HERE BECAUSE IT'S 2 DIFFERENT
QUESTION, RIGHT?
SO THERE'S NK AND--THEY ACTUALLY
NOT RELATED.
YEAH, SO BECAUSE I PROBABLY
SHOULD HAVE, YOU KNOW TELL
EVERYBODY, WELL, I'M NOT YET CAN
CONNECT ALL THE DOTS BUT YOU
KNOW I CAN FIND--
>> YEAH, OKAY.
>> SO YEAH, [INDISCERNIBLE]
RECEPTOR JUST AS WE'VE SEEN
RECENTLY HAS BEEN IN THE
[INDISCERNIBLE] THE LAST 2 YEARS
BIG TIME TO DEPRESSION,
SCHIZOPHRENIA AND MANY OTHER
NEUROLOGICAL DISEASES, SO YEAH,
IT WOULD EXPLAIN AND
OTHER--ACTUALLY NEAR THE
DEGENERATIVE DISEASES.
SO IT'S DEFINITELY--DEFINITELY
WILL BE IN LINE WITH CO
MORBIDITY BETWEEN CHRONIC PAIN
AND NEUROLOGICAL
[INDISCERNIBLE].
>> OKAY.
>> AND THE SECOND QUESTION WAS
ABOUT NK CELLS, RIGHT?
>> YES, UNLESS THERE NEEDS TO BE
ACTIVATED ARE NK CELLS?
>> YEAH, YEAH, EXCELLENT
QUESTION.
I DO NOT KNOW.
I WISH--AND SO, THAT'S WHY WE
PUBLISH IT IN PAIN BECAUSE WE
SPENT A LOT OF TIME TRYING TO
FIGURE OUT WHAT'S HAPPENED IN
FIBRO MYALGIA PATIENTS WHY THEY
ATTRACT NK CELLS.
YEAH.
WE DON'T KNOW.
, OKAY.
NEXT QUESTION IS FOR
DR. [INDISCERNIBLE], MESSAGE IS
DID YOU LOOK FOR SIGNS OF
MICROBIOTA IN [INDISCERNIBLE]
FOR EXAMPLE, DNA IN THE BLOOD,
SAMPLES OF PEOPLE WITH CHRONIC
PAIN?
>> NO, I'M WONDERING, MAYBE WE
CAN TALK LATER, I AM WOBDERRING
WHY YOU ASK [INDISCERNIBLE],
WAWE TRY TO LOOK IS FOR THE
VIRUSES.
WE TRY TO LOOK FOR THE VIRUSES
ESPECIALLY BETWEEN--BECAUSE OF
THE RESPONSE TO THE VIRUS IN OUR
RNA, FULL RNA SEQ DATA SET WAS
ALSO TOP SO WE MUST--THIS WILL
EXPLAIN OKAY, THERE IS A VIRAL
INFECTION IN SENSORY NEURONS AND
IN SENSORY NEURON EXPRESSED
RECEPTOR NEAR NK CELLS AND NK
CELLS COMES IN [INDISCERNIBLE],
BUT THE PROBLEM IS IN THE BLOT
WE DIDN'T FIND VIRUSES, LIKE NK
RESPONSE--GO CHECK.
BUT, YEAH THIS WILL BE
CONSISTENT WITH VIRAL APPROACHES
TO FIBRO MYALGIA WHICH HAS BEEN
PROPOSED FROM DIFFERENT ANGLES
IN THE LAST 20 YEARS.
>> AND 1 MORE QUESTION IS HERE
FOR YOU, IT LOOKS LIKE MORE
TECHNICAL, DURING SOME PART OF
THE TALK, MAYBE I MISS THIS BUT
WHERE ARE PATIENTS
[INDISCERNIBLE] ON THE SAME
TREATMENT?
YOU SAY [INDISCERNIBLE] WHERE'S
THE TREATMENT CORRELATES THESE
OUTCOME?
AND WHERE WILL THE TREATMENTS
INVOLVE IMMUNE REGULATION?
>> EXCELLENT QUESTION.
I WOULD REVIEWER DEFINITELY ASK
THE SAME QUESTION, THE ANSWER IS
THIS, SO IT WASN'T CLINICAL
TRIAL, SO THE PATIENT WAS UNDER
STANDARD OF CARE TREATMENT AND
MODEL CITIZEN JORRITY OF THE
PATIENT WOULD GET NSAID OR
STEROIDS BUT NOT ALL OF THEM.
MANY PATIENTS ALSO GIVE OPIOIDS
AND ALL OTHER ANALGESIC BUT
USUALLY PEOPLE WITH ACUTE BACK
PAIN GET IT.
HOWEVER, YOU GET--WE LOOK AT
DATA ON THE DRUG USE FOR EACH
PATIENT BUT IT WAS NO
SIGNIFICANT ASSOCIATION WITH THE
DRUG USE IN THIS PATIENT AND IT
WAS NO ASSOCIATION REALLY WITH
THE INFLAMMATORY RESPONSE IN
THIS PATIENT AND SO, WHICH LEADS
ME TO THINK THAT ALTHOUGH LIKE
SEQ AND STEROID, LEAD TO
IMPAIRMENT OF THE IMMUNE
RESPONSE, THERE IS ALSO
INTRINSIC INABILITY OF SOME
PEOPLE TO UPREGULATE ADAPTIVE
RESPONSE.
AND IT'S ALSO LED TO ME THINK,
OKAY, SOME PEOPLE WHO TAKE AND
SEQ THEY DON'T COMPLETELY DOWN
REGULATE IMMUNE RESPONSE, THIS
WILL BE [INDISCERNIBLE]
REPUTATION [INDISCERNIBLE].
>> I THINK WE HAVE TIME FOR THE
LAST QUESTION.
THE LAST QUESTION IS PRACTICES
PROFESSOR DAVID WHI TCOMB AND
WHAT IS THE LAB [INDISCERNIBLE]
CHRONIC PAIN AND DEPRESSION, FOR
GENERAL ANXIETY DISORDERS?
>> REALLY HARD.
I DON'T REMEMBER ON THE TOP OF
MY HEAD, BUT BASICALLY
DEPRESSION IS 1 OF THE MAJOR
FACTOR AFTER PRESENCE OF
[INDISCERNIBLE] CHRONIC PAIN
CONDITION.
>> OKAY.
THEN THE MOST LAST QUESTION FOR
YOU.
YOU SHOW QUITE ROBUST WITH
INFLAMMATION AND PAIN
[INDISCERNIBLE] WHY DO YOU SEE
SCIENTISTS DID NOT OBSERVE IT
PREVIOUSLY?
>> YEAH, SO WE WERE THINKING
ABOUT THIS, TOO, LIKE HOW COME
YOU CAN MISS IT, RIGHT?
IT'S BLACK AND WHITE HOW YOU CAN
LIKE--SPECIFICALLY PUT THIS
SLIDE, YEAH, AND I THINK IT'S
BECAUSE THE WAY HOW WE STUDY THE
WAY WE BELIEF THE PAIN PROGRESS
BECAUSE I THINK I ALREADY
MENTIONED THIS, I THINK WE FIRST
OF ALL WE CONSTANTLY STUDIED
PEOPLE WHO HAVE PAIN, SO IN THIS
SLIDE IS THIS PEOPLE.
OKAY, IF YOU DON'T HAVE ANY
SIGNIFICANT DIFFERENCE, WE
CANNOT--IT'S DIFFICULT TO LEARN
SOMETHING FROM THIS.
YEAH, BECAUSE IT'S ABSENCE OF
THE FACT.
WE CONSTANTLY ARE LOOKING FOR
WHAT WENT WRONG IN THE PEOPLE
WITH CHRONIC PAIN.
AND IT'S, YEAH, SO FAR I DON'T
THINK PEOPLE'S VERY SUCCESSFUL
UPON BUT OUR STUDIES SHOW THAT
IF WE ASK A QUESTION, WHAT WENT
RIGHT IN THE PEOPLE WHO DID
RESOLVE PAIN, THERE IS SO MUCH
INFORMATION THAT, YOU WE
DEFINITELY CAN HAVE SOMETHING TO
CHEW ON.
>> OKAY, I SEE YOUR PINT.
THANK YOU.
THANK YOU VERY MUCH.
DOCTOR I WANT TO THANK YOU AGAIN
FOR YOUR WONDERFUL TALK AND I
ALSO WANT TO SAY HOW PROUD WE
ARE TO HAVE SPONSORED THIS
PRESENTATION HERE IN THE NIH
WEDNESDAY AFTERNOON LECTURE
SERIES AND WE WERE PLEASED TO
HEAR ABOUT THE GREAT ADVANCES
AND ESPECIALLY ABOUT YOUR
ACHIEVEMENTS IN THE SUCCESS OF
YOUR COLLEAGUES IN UNDERSTANDING
OF CHRONIC PAIN.
IT WAS ALSO A PLEASURE TO LEARN
MORE ABOUT THE MECHANISM IN THE
REGULATION OF CHRONIC PAIN AND
THE FUTURE [INDISCERNIBLE] THANK
YOU FOR JOINING US.