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0:05
>>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
1:02
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
1:47
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
2:44
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
3:49
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
4:41
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]
5:42
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
6:36
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
7:44
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
8:33
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
9:26
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
10:19
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
11:21
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
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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
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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
14:05
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
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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
15:40
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
16:33
[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, -
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-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
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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
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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
20:32
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
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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
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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
23:42
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
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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.
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
36:36
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
37:14
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
37:59
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
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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
39:49
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
40:31
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.
41:16
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,
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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
42:52
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,
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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
44:28
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
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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]
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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
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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
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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
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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
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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
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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
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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.
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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
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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
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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
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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,
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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
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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?
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>> 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
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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
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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
1:00:12
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.
1:01:04
>> 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
1:01:55
ACTIVATED ARE NK CELLS? >> YEAH, YEAH, EXCELLENT QUESTION. I DO NOT KNOW. 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
1:02:42
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.
1:03:37
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.
1:04:23
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
1:05:13
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.
1:05:56
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?
1:06:43
>> 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.
1:07:25
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
1:08:04
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 01:08:37.800,00:00:00.000 YOU FOR JOINING US.
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