>> WELCOME TO THE STARS IN NUTRITION AND CANCER LECTURE SERIES. THE DIVISION OF CANCER PREVENTION AT THE NATIONAL CANCER INSTITUTE SPONSORS THESE LECTURES TWICE A YEAR. WE HIGHLIGHT THE RNT ROLE THAT NUTRITION PLAYS IN CANCER AND CANCER PREVENTION IN PARTICULAR AND WE HIGHLIGHT THOSE SCIENTISTS THAT HAVE BOTH BASIC TRANSLATIONAL AND CLINICAL THAT HAVE A LARGE BODY OF WORK IN THIS AREA. TODAY, WE ARE DELIGHTED TO HAVE DR. STEVE HURSTING, STEVE WAS A CANCER PREVENTION FELLOW HERE, HE OBTAINED HIS Ph.D. IN BIOCHEMISTRY AND MASTERS OF PUB LIBRARY FOUNDATION HEALTH AND NUTRITIONAL EPIDEMIOLOGY FROM UNC CHAPEL HILL. HE CAME HERE FOR HIS CANCER PREVENTION FELLOWSHIP, WENT ON TO THE UNIVERSITY OF TEXAS IN AUSTIN TO HAVE AN ENDOWED CHAIR THERE IN NUTRITION AND MOLECULAR AND SCIENCES AND THEN HE RETURNED TO THE UNIVERSITY OF NORTH CAROLINA CHAPEL HILL TO RUN THE NUTRITION INSTITUTE AND BE PART OF THE LINEBERGER COMPREHENSIVE CANCER CENTER. PLEASE JOIN ME IN WELCOMING STEVE, WE'RE GLAD TO HAVE HIM BACK AND LOOK FORWARD TO YOUR TALKS. >> GREAT. THANK YOU. [ APPLAUSE ] THANK YOU TO THE NUTRITION SCIENCE RESEARCH GROUP. HAD A WONDERFUL MORNING WITH YOU GUYS, HAROLD AND THE WHOLE TEAM AND I WILL SAY, YOU GUYS DID SUCH A GREAT JOB OF PROMOTING THE FIELD AND MUCH APPRECIATED AND ALSO ARE SO PATIENT AND ENCOURAGING WHEN I CALL AND OUR GRANT HASN'T BEEN REVIEWED OR DIDN'T GET A SCORE SO I APPRECIATE ALL YOUR KINDNESS IN THAT REGARD. >> [INDISCERNIBLE]. >> THAT'S HALF PSYCHOLOGISTS IT SEEMS LIKE, THAT'S IMPORTANT. I AM AN ALUM OF NCI AND IT'S A REAL PLEASURE TO BE BACK AND JUST HAD A WONDERFUL 10 YEARS HERE AND IT'S AN HONOR TO BE ABLE TO TALK TO YOU ABOUT OBESITY AND CANCER, PARTICULARLY WHAT ARE WE GOING TO DO ABOUT THIS CANCER LINK. SO I THOUGHT I WOULD START WITH EVIDENCE FROM BOTH HUMANS AND ANIMALS REGARDING THIS LINK, PARTICULARLY MY AREAS IN THE PRECLINICAL WORLD SO LESSONS FROM PRECLINICAL STUDIES ON THE MOLECULAR AND METABOLIC CONNECTIONS, UNDERLYING OBESITY AND I WILL PARTICULARLY GIVE EXAMPLES FROM OUR WORKING MODELS OF BREAST, COLON AND PANCREATIC CANCER AND KIND OF THE PUNCH LINE HERE IS THE RURAL GROWTH FACTORS AND THEIR SIGNALS, INSULIN AND RELATED FACTORS THROUGH THE MECHANISTIC TARGET OF RAPPA MICEIN, TARGET AND THEIR SIGNALS AS WELL AS OTHER INFLAMMATORY SIGNALS CERTAINLY ARE PLAYING A ROLE AND WE ARE FINDING THAT THERE'S--MANY OF THESE ARE UNDER EPIGENETIC CONTROL AND OBESITY, IT DOES SEEM TO REPROGRAM SOME OF THESE SO WE'LL GET INTO THAT, BUT I PARTICULARLY WANT TO TALK ABOUT WHAT ARE WE GOING TO DO ABOUT THIS ISSUE? WHAT ARE TARGETS AND STRATEGIES FOR REVERSING THE OBESITY CANCER LINK AND IN PARTICULAR, YOU KNOW THE EVIDENCE IS PRETTY LIGHT ON THIS. I THINK IT'S STILL AN OPEN QUESTION, JUST HOW REVERSIBLE SOME OF THESE ARE AND I'LL SHOW YOU SOME EVIDENCE THAT INDEED WE CAN REVERSE, BUT IT'S--IT MAY BE NOT QUITE SO SIMPLE. SO WE'LL TALK ABOUT THAT AT THE END. ONE OF THE GREAT PRIVILEGES AND REALLY MOST FULFILLING INITIATIVES I'VE BEEN INVOLVED WITH HAS BEEN THE AMERICAN INSTITUTE FOR CANCER WORLD, CANCER RESEARCH FUND, EXPERT REPORT SERIES. SO I ACTUALLY GOT INVOLVED IN THIS IN 1999 AND JOHN MILLENER PLAYED A BIG ROLE IN MANY OF OUR PARTICIPANTS HERE ARE JOHN MILLENER FELLOWS IN THE PRACTIUM, AND I'LL TELL YOU MORE STORIES ABOUT JOHN, SHORT 1S BUT ANYWAY, WHAT A CONTRIBUTION I THINK THIS HAS BEEN TO THE FIELD OF NUTRITION AND CANCER STARTING IN 97 AND 07 REPORT, JOHN GOT ME INVOLVED IN THE MECHANISTIC PART OF THE 07 REPORT AND I'VE BEEN ON THE EXPERT PANEL FOR THE 2018 REPORT THAT GAME OUT, ABOUT A YEAR AGO LAST MAY IT'S STRIKING HOW STRONG THE DATA HAS GOTTEN OVER THE YEARS, IT STARTED OFF MOSTLY CASE CONTROL DATA, 97, A MIX IN 07 AND LARGELY A PERSPECTIVE DATA AND CLINICAL TRIAL IN THE 2018 REPORT. ONE OF THE MAIN FINDINGS, SOME OF THE FACTORS THAT WE MIGHT HAVE THOUGHT WERE LINKED TO CANCER IN TERMS OF DIETARY FACTORS DROPPED OUT, SOME OF THE MICRONUTRIENTS, BUT OBESITY REALLY EMERGED AS A VERY STRONG COMPONENT HERE AND A DOZEN OBESITY ASSOCIATED CANCER TYPES EMERGE WHERE THE DATA'S CONVINCING THAT OBESITY IS A RISK FACTOR FOR THOSE CANCERS AND WE'LL GET INTO MORE OF THE DETAILS ON THAT LATER AND WHEN YOU LOOK AT THE TOP LINE RECOMMENDATIONS FROM THIS WORK, REALLY, THE FIRST 6 I SEE IN THERE IS REALLY WEIGHT CONTROL IS THE MAJOR RECOMMENDATION. SO BE A HEALTHY WEIGHT, BE PHYSICALLY ACTIVE, EAT A DIET RICH IN GREEN VEGGIES, WHOLE BEANS, LIMIT FAST FOOD AND SUGAR, LIMIT RED AND PROCESSED MEET AND SUGAR AND SUGAR BEVERAGES SO THOSE ARE THE BLUEPRINT FOR FOLLOWINGA I DIETARYET APPROACH TO REDUCE RISK OF CANCER THAT'S COME FROM THIS. THERE'S ALSO A CHAPTER AT THE END THAT TALKS ABOUT THE KIND OF FUTURE DIRECTIONS THAT--SO WE THINK, YOU KNOW SHOULD BE EMERGING FROM THIS EFFORT AND THE NUMBER 1 WAS REALLY A BETTER UNDERSTANDING OF MECHANISMS, UNDERLYING MANY OF THESE ASSOCIATIONS THAT ARE COMING, I WILL SAY THE HALLMARK OF THE EXPERT REPORT, REALLY THIS IS THE WORLD'S COLLECTION OF SYSTEMATIC REVIEWS AND META-ANALYSIS, VIRTUALLY EVERY DIETARY FACTOR AND VIRTUALLY EVERY CANCER AND SO REALLY COMPREHENSIVE AND A BEAUTIFUL JOB OF META-ANALYSIS AND SYSTEMATIC REVIEW FROM THE IMPERIAL COLLEGE TEAM THAT DOES THIS. BUT AT THE END, WE TALK ABOUT FUTURE AND MECHANISMS OF THESE ASSOCIATIONS ARE LACKING FOR THE MOST PART AND IN FACT, I THINK THERE ARE A NUMBER OF IMPLICATIONS FROM THIS WORK REGARDING MECHANISTIC RESEARCH AND I THINK THIS CAN BE A REAL ENGINE FOR PRIORITIZING THE MECHANISM BASED WORK THAT SHOULD GO FORWARD IN NUTRITION, PHYSICAL ACTIVITY, THAT WILL FILL IMPORTANT GAPS IDENTIFIED BY THE REPORT AND I THINK THAT THIS--THIS IS PROBABLY THE PLACE I WOULD START IF I WAS SAYING, WELL, WHERE SHOULD I PUT MY MONEY TOWARDS SOMETHING THAT'S GOING TO BE LINKED TO HUMAN CANCER. THIS IS 1. WE WILL TALK MORE ABOUT THE OBESITY CANCER STORY AND TODAY THAT'S BEEN THE FOCUS OF OUR EFFORTS. COFFEE, HOW MANY COFFEE DRINKERS, PROBABLY MOST EVERYBODY, LOTS OF INTEREST IN THIS, COFFEE EMERGED AS I POTENTIALLY ANTICANCER EXPOSURE, PARTICULARLY FOR LIVER AND ENDOMEETRIOL, MAYBE A LITTLE BREAST AS WELL SO THAT MIGHT BE GOOD NEWS FOR MANY OF YOU AND WE DON'T KNOW MET MECHANISMS BEHIND THIS. MEAN AND CANCER RISK, THAT'S 1 THAT IS A LITTLE CONTROVERSIAL, I MEAN I THINK WE SUSPECT IT'S NITROS MINES, MAYBE HEME, BUT DON'T REALLY HAVE A GREAT UNDERSTANDING. SO FOR THOSE GOING INTO THIS EFFORT, I THINK, THESE ARE PRETTY GOOD CLUES FOR WHAT TO DO. I THINK IT'S ALSO A CALL TO ACTION, FOR THOSE OF US IN THE FIELD TO MAKE SURE OUR REPORTS CAN BE SYSTEMATICALLY REVIEWED AND ANALYZED IN THE FUTURE. WE HAD A LOT OF EFFORT IN APPLYING SOME OF THE PRINCIPLES OF THE EPIDEMIOLOGIC ANALYSIS THAT'S GONE ON IN TERMS OF REALLY LOOKING AT IN A SYSTEMATIC WAY. WE HAVE A PROTOCOL ACTUALLY IN PLACE TO DO THAT FOR THE ANIMAL LITERATURE AND THE MECHANISTIC HUMAN LITERATURE, BUT YOU KNOW, WITH THE FEW EXCEPTIONS, MOST OF THE DATA IS SORT OF TOO INCONSISTENTLY REPORTED TO BE ABLE TO DO THAT TYPE OF WORK AND THIS IS A CALL TO MOST OF US IN MY FIELD AND THERE ARE GUIDELINES EMERGED, THE ARRIVED GUIDELINES ARE BEING INCORPORATED BY MANY JOURNALS NOW THAT ARE LIKE THE EPIDEMIOLOGIC GUIDELINES FOR REPORTING ON WHETHER YOU RANDOMIZE AND HOW YOU DID IT AND YOU KNOW CLEAR STATEMENTS OF DOSE AND STAT ANALYSIS AND SO ON THAT ARE SOMETIMES MISSING IN THE ANIMAL DATA SO THAT'S SORT OF A CALL TO ARMS TO THIS, SO THAT IN 10 YEARS WE CAN ACTUALLY INCORPORATE SYSTEMATIC REVIEWS AND META-ANALYSIS OF THE ANIMAL DATA PERHAPS AS WELL. A RELATED EFFORT THAT ALSO JUST CAME OUT LAST YEAR IS IT'S HAND BOOK 16 FROM THE INTERNATIONAL AGENCY FOR RESEARCH ON CANCER AND THEY ARE CANCER PREVENTION SERIES, BODY FATNESS AND CANCER AND A NICE SUMMARY IN THE NEW ENGLAND JOURNAL A COUPLE YEARS AGO RIGHT AFTER WE DID THIS WAS OUT AND THERE WAS A 400 PAGE REPORT FOR THE IARC REGARDING THIS AND THIS WAS A SLIGHTLY DIFFERENT APPROACH RATHER THAN SORT OF THIS KIND OF REALLY THOROUGH SYSTEMATIC REVIEW, THIS WAS AN EFFORT, MORE OF AN EXPERT PANEL AND THERE WERE 3 TEAMS THAT WERE PUT TOGETHER BY THE IARC TO DO THIS, 1 WAS AN EPIDEMIOLOGIC TEAM LED BY GRAHAM AND RUDOLPH, GOOD CONCORDANCE BETWEEN THE WARC AND IARC REGARDING OBESITY IN CANCER TYPES. SO HERE ARE THE 13 DISTINCT CANCER TYPES THAT WERE FOUND BY THE AIRC REPORT TO BE SIGNIFICANTLY ASSOCIATED WITH CANCER, WHAT'S DIFFERENT MENCH I DON'T MEANA AND MULTIPLE MYELOMA, WE SAW SIGNALING FOR DIDN'T THINK THE DATA WAS QUITE STRONG ENOUGH TO INCLUDE SOME RECENT--MORE RECENT DATA TO COME OUT WHEN THE IARC EFFORT WAS DONE SO THOSE MADE THE LIST, SO 13 DIFFERENT CANCER TYPES WERE FOUND TO BE ASSOCIATED AND GOOD CONCORDANCE WITH THE IARWCRF. THE IARC TEAM WAS LOOKING FOR ASSOCIATIONS BUT WHAT ARE THOSE REVERSIBILITY, THOSE INTENTIONAL--DOES INTENTIONAL WEIGHT LOSS REVERSE ANY OR MANY OF THESE CANCER TYPES AND UNFORTUNATELY, THE EVIDENCE WAS KIND OF LIGHT HERE SO INTENTIONAL WEIGHT LOSS IN OBESE WAS OUR CONCLUSION, MAY REDUCE RISK OF SOME CANCERS AND THAT'S BASED ON PRIMARILY ON BARIATRIC SURGERY DATA SO HERE'S A BIG GAP IN THIS FIELD IS THIS IS THE REVERSIBILITY SIDE. I WAS PART OF AN ANIMAL MODELS TEAM AND WE FOUND THAT OBESITY CONSISTENTLY PROMOTES CANCER IN RODENT MODELS OF THE SAME CANCER TYPES THAT WE WERE SEEING FROM THE HUMAN SIDE, SO SOME CONSISTENCY THERE FROM ANIMAL TO HUMAN BUT AGAIN, THE NUMBER OF STUDIES FROM MANY SITES WAS LIMITED AND THIS MAY SURPRISE YOU BUT THERE'S A LOT MORE DATA ON CALORIE RESTRICTION, THE OTHER SIDE OF THE COIN AND INDEED THERE'S--WE DEEM SUFFICIENT EVIDENCE IN EXPERIMENTAL MODELS FOR EFFECTIVE CALORIE RESTRICTION, A LARGE AMOUNT OF LITERATURE AND SOME CONTRIBUTED TO THAT FOR MORE CANCER SITES, MORE LIMITED IS THE OBESITY BUT THE CONSISTENCY FROM THE MOUSE IN RAT AND HUMAN CONNECTION, BUT AGAIN WE WERE TASKED WITH LOOKING AT THE REVERSIBILITY QUESTION AND WE FOUND THE SAME THING, REALLY LIMITED PRECLINICAL EVIDENCE THAT INTENTIONAL WEIGHT LOSS IS SEVERE ENOUGH, CAN REVERSE THE PROCANCKER EFFECTS OF OBESITY, SO THERE'S SOME, BUT THIS HAS BEEN AN UNDERSTUDIED AREA FOR SURE, THAT WILL BE 1 TAKE HOME MESSAGE THAT HOPEFULLY, YOU WILL BRING BACK TO YOUR LABS AND SO ON. WE ALSO HAD A MECHANISMS TEAM, AND I WAS PART OF THAT AS WELL. THIS HAS BEEN A FOCUS OF MY LAB FOR PROBABLY THE LAST 10 YEARS IS KIND OF UNDERSTANDING WHAT'S UNDERLYING THIS LINK BETWEEN OBESITY AND CANCER SO CHRONIC POSITIVE ENERGY, BALANCE, DRIVING TO OBESITY AND A NUMBER OF SYSTEMIC METABOLIC CHANGES ARE ASSOCIATE WIDE THIS SO INCREASED INSULIN, IGF 1, NUMBER OF CYTOKINES AND LEPTIN AND CHEMO KINES ARE ELEVATED IN A SMOLDERING INFLAMMATORY STATE IT'S REFERRED TO, THINGS LIKE PLASMA AND ACTIVATOR INHIBITOR, THAT IS RELATED TO VASCULAR BIOLOGY IS ALSO AFFAIRS TEAM LEADERRERRED AND ESTRADIOL IS INCREASED IN THE OBESE SITUATION AND THESE FACTORS SIGNAL THROUGH THE RECEPTORS SO INSULIN IGF 1 THROUGH THE RECEPTOR TYROSINE KINASE PATHWAY, VIA THEIR RECEPTORS, LEPTIN CAN INTERACT WITH THAT BUT LEPTIN'S SIGNALING THROUGH AT CYTOKINE RECEPTOR AND SO, CAN KIND OF CROSS BOTH THE GROWTH FACTOR AND THE CYTOKINE SIGNALING SIDE OF THINGS. OF COURSE ESTRADIOL RECEPTOR, SO INSULIN AND PARTICULAR THROUGH RTKs DRIVES GROWTH FACTOR SIGNALING AND I'LL SHOW YOU DATA BUT OF MOST INTEREST IS THIS PII 3 KINASE AKT MTOR, RECKANIST INCREASE IN BODY TARGET RAP O MICEIN PATHWAY WHICH IS A CLEAR DRIVER OF CANCER RISK AND PROGRESSION. OF COURSE THERE'S AN INFLAMMATORY STORY WITH THE CYTOKINES AS WELL AS SOME OF THE EDIPO KINE SIGNALS INVOLVING PATHWAYS SUCH AS NF CAPPA B AND COX 2 AND ENHANCING INFLAMMATORY SIGNALS AND THERE'S ALSO VASCULAR EFFECTS THAT WE ARE SEEING PARTICULARLY THROUGH VEG F AS WELL AS SOME OF THE TISSUE PLASMA ANTIGEN ACTIVATED PATHWAYS. SO A LOT'S GOING ON HERE, BUT A CLEAR OBESITY, THESE ARE--WERE DEEMED ESTABLISHED MECHANISMS, EVIDENCE WAS SUFFICIENT TO DEEM THESE ESTABLISHED FOR THE CONNECTION BETWEEN OBESITY AND CANCER RISK AND PROGRESSION. A NUMBER OF EMERGING MECHANISMS DID,A PEER WHERE THE--MAYBE IT WASN'T QUITE THERE YET, BUT A LOT OF INTEREST AND CERTAINLY SUPPORTING EVIDENCE, AND THE MICROBIOMES IN THIS CATEGORY CLEARLY OBESITY IS CHANGING, REPROGRAMMING MICROBI OTA, AND THAT SEEMS TO BE PLAYING A ROLE, ADA POSE REMODELING, I KNOW THE MILLENER PRACTICUM FOLKS JUST HEARD A TALK ON ADIPOSE TISSUE AND WE SEE MAJOR ADIPOSE REMODELING THAT GOES ON WITH OBESITY, AND THEN A PROCESS OF FIBROSIS THAT CERTAINLY RELATED TO THE INFLAMMATORY EFFECTS BUT A DISTINCT PRO FIEB ROTTIC, PLASTIC SORT OF RESPONSE TO OBESITY, SEEMS TO BE EMERGING AS WELL. AS I MENTIONED, WE'RE SEEING EVIDENCE FOR EPIGENETIC CHANGES, THERE'S A REPROGRAMMING, PROBABLY ASSOCIATIONED WITH THESE SYSTEMIC MARKERS BUT CLEARLY HISTONE MODIFICATION AND MIKE ARE RNAs IN RESPONSE TO OBESITY ARE EMERGING, IMMUNE FUNCTION, THAT'S THE HOTTEST TOPIC IF YOU'RE GOING TO THE AMERICAN ASSOCIATION FOR CANCER RESEARCH MEETING NEXT MONTH, YOU WILL GET A LOT OF IMMUNE. THIS IS THE HOTTEST TOPIC IN CANCER RESEARCH AND A LOT BEING LEARNED ABOUT THE CANCER IMMUNE RELATIONSHIP. OBESITY DOES SEEM TO IMPACT IMMUNE SIGNALING AS WELL, AND IMMUNE FUNCTION AND SO THAT WAS KIND OF AN EMERGING BUT I THINK A VERY INTERESTING TOPIC TO DIG INTO. WE AND OTHERS HAVE FOUND THIS SORT OF AN OBESITY STORY IN TERMS OF PROMOTING THE STEMNESS OF MANY TUMORS, SO SORT OF A CANCER STEM CELL ENRICHMENT AND PROMOTION OF THOSE, OF THE SURVIVAL OF THOSE CELLS SEEMS TO BE ASSOCIATED WITH OBESITY AND THE EMT, THE EPITHELIUM TRANSITION IS PART OF THAT PROCESS AND PROBABLY RELATES, AS I'LL SHOW YOU IN A FEW MINUTES TO THE PROTEIN COMPLEX METASTATIC EFFECT OF OBESITY AS WELL. THERE'S A CONCEPT THAT'S EMERGING THAT KIND OF RELATES SYSTEMIC METABOLIC CHANGES, SO THESE ALTERATIONS AND INSULIN AND IGF 1 AND DIPICONS AND WITH CANCER CELL IN METABOLISM AND THAT'S BEEN AN EMERGING FIELD, BEEN IN THE FIELD FOR A LONG TIME BUT WE KNOW A LOT MORE ABOUT SORT OF THE METABOLIC CHANGES OF CANCER CELLS SPECIFICALLY UNDERGO IN TERMS OF UTILIZING GLUCOSE FOR DAUGHTER CELL PRODUCTION, PROCESS CALLED THE AUTOWARBURG EFFECT, AUTOWARBURG DISCOVERED THAT MORE THAN A HUNDRED YEARS AGO. BUT THIS INTERACTION BETWEEN SYSTEMIC CHANGES WITH METABOLIC OBESITY AND THESE CANCER SPECIFIC INTRINSIC METABOLIC CHANGES AS NOT REALLY BEEN WELL ADDRESSED. THE 2 FIELDS HAVE NOT GOTTEN TOGETHER UNTIL RECENTLY BUT WE SEE THERE ARE INTERACTIONS, A CANCER CELL DOES CARE IF IT'S IN A HOST, IT'S OBESE, IT'S THE BOTTOM LINE HERE IN TERMS OF METABOLISM AND IN FACT WHAT WE'RE FINDING PRIMARILY IS OBESITY IS DRIVING SORT OF A WARBERG LIKE CHANGE IN MOVING CELLS AWAY FROMOXIDATIVE PHOSPHORYLATION TO MORE OF A GLYCO LYTIC METABOLISM AND SO THAT IS ANOTHER PIECE THAT'S EMERGING BUT THIS INTERACTION BETWEEN SYSTEMIC AND SO INTRINSIC IS GOING TO BE A REAL HOT TOPIC AND SO THESE ARE KIND OF THE ESTABLISHED AND EMERGING MECH NESMS THAT ARE DRIVING CANCER RISK. AND I'LL UNPACK THIS A BIT FOR YOU. WE'VE BEEN WORKING ON SOME OF THESE AREAS FOR YEARS AND FOR EXAMPLE, WE CAN MAKE MICE LEAN WITH A CALORIE RESTRICTED DIET, THIS IS THE TYPICAL CONTROL IS REALLY AN OVERWEIGHT ANIMAL THAT SORT OF A PURIFIED DIET THAT IS FIT OVER A LONG PERIOD WILL BECOME AN OVERWEIGHT ANIMAL AND WE CAN REDUCE OBESITY BY A D. I. O. REGIMEN AND YOU CAN SEE THE RANGE OF BODY FATS FROM 30ISH TO 50ISH ACROSS THIS DIETARY SPEC RUM AND WE WERE--SPECTRUM, AND WE WERE GUESSING WHAT MARKERS MIGHT BE ASSOCIATED WITH THIS. WHAT SYSTEMIC MARKERS SO WE WERE LOOKING AT INSULIN AND LEPTIN AND I'LL INCLUDE IL6 AS THE REPRESENTATIVE FOR THAT, WHAT WE FIND IS THAT IN THE CALORIE RESTRICTED STATE, THE LEAN STATE, IGF IS A LOW INSULIN'S UNDER NICE CONTROL, THE LEPTIN ADIPONECTOMYOSININ IS LOW, WITH THESE CIRCULATING CYTOKINES SORT OF QUITE LOW. AND UNDER THESE CONDITIONS, TUMORS DEVELOP LATE, IF THEY DEVELOP AT ALL AND ARE TYPICALLY NOT VERY AGGRESSIVE IN THOSE CONDITIONS IN THE CONTRAST IN AN OBESE ANIMAL WE SEE HIGH IGF 1, INSULIN, CERTAINLY HYPER INSULIN ANEMIA, MOVING TOWARDS A REALLY A HIGHLY INSULIN RESISTANT SORT OF SITUATION, LEPTIN ADIPONECTIN RATIO REALLY SHIFTS WHERE IT'S MUCH HIGHER HERE, MANY FOLD HIGHER AND IL6 AND OTHER INFLAMMATORY CYTOKINES ARE ELEVATED AND UNDER THESE CONDITIONS TUMORS DEVELOP EARLY, EITHER AGGRESSIVE OFTEN KILL THE ANIMALS QUITE EARLY AND SO, QUITE A CONTRAST THERE AND IN THE OVERWEIGHT SITUATION, IT'S REALLY INTERMEDIATE IN TERMS OF ALL THESE MARKERS AND TUMOR PROGRESSION. SO CONVOLUTED COMPLEX STORY HERE, LOTS OF FACTORS CHANGING AND 1 NICE THING, HERE'S THE PLUS OF THE PRECLINICAL WORK AS WE'RE ABLE TO COME IN WITH GENETIC MODELS AND PHARMACOLOGIC APPROACHES AND REALLY BEGIN TO DECONVOCABULARY LIEWT SOME OF THIS SO WE WORKED ON THIS FOR A NUMBER OF YEARS AND BOTH NORMAL AND TUMOR TISSUE AND SKIN LIVER PROSTATE COLON PANCREAS AND MAMMARY, WE FOUND I THINK AT LEAST EVIDENCE FOR THIS MTOR PATHWAY AS BEING QUITE IMPORTANT AND SO, WHAT WE FIND IS UNDER THE OBESE SITUATION, THIS ENTIRE PATHWAY, AGAIN WE THINK IT'S REALLY DRIVEN BY INSULIN AND IGF 1 RECEPTOR SIGNALING, THESE RECEPTOR TYROSINE KINASE SIGNALS DRIVING THE MTOR, THIS IS A NUCLEOTIDES T-REGENT SENSING PATHWAY THAT IS LINKED TO CELL PROLIFERATION, PROTEIN TRANSLATION, NUCLEOTIDE PRODUCTION AS WELL. SO YOU CAN THINK THIS IS SORT OF A MASTER REGULATOR, AND NOT ONLY--CERTAINLY A CANCER RELATED TARGET BUT IT'S ALSO A MASTER METABOLIC REGULATOR THAT SORT OF CONDUCTING THIS WHOLE THING AND WHAT WE FIND IS THAT OBESITY ACTIVATES THIS PATHWAY ALL THE WAY THROUGH, SO WE'RE ABLE TO MEASURE THESE--THESE ARE ALL KINASES, WE'RE ABLE TO MEASURE THEIR PHOSPHORYLATION AND WE SEE ACTIVATION INCREASE PHOSPHORYLATION, EVERY STEP OF THE WAY, ASSOCIATE WIDE INCREASED PROTEIN TRANSLATION, AND CELL GROWTH. AND THAT'S CERTAINLY A PART OF THIS OBESITY STORY IN CONTRAFORT CALORIE RESTRICTION DECREASED EVERY STEP OF THE WAY, IT DECREASED THE SIGNALING THROUGH THIS MTOR PATHWAY, AND SORT OF GAVE MORE CONTROL, LIMITED TRANSLATIONAL CAPACITY, LIMITED PROLIFERATION, UNDER THESE STEPS, SO THIS IS A PART OF IT, NOW HOW MUCH--HOW MUCH OF A ROLE IS IGF 1 AND INSULIN PLAYING IS SOMETHING WE WERE QUITE CURIOUS ABOUT AND WHAT WE FIND IS THAT IN OBESE MICE, IF WE KNOCK DOWN THE IGF 1 RECEPTOR OR INSULIN RECEPTOR OR MTOR ITSELF, EITHER GENETICALLY OR FORMICOLOGICALLY, WE MIMIC THE CALORIE RESTRICTION CENTER FOR EXCELLENCE ON AGING EXACTLY, EVEN THOUGH THE MICE ARE OBESE, SO THIS IS 1 OTHER TAKE HOME MESSAGE IS I THINK OBESITY, THE ATAPOSSITY IS A TRIGGER FOR MUCH OF THIS, BUT IT'S NOT NECESSARILY THE SOLUTION, IT'S THESE METABOLIC CHANGES, I THINK ARE THE TARGETS WE NEED TO GO AFTER, AND CONVERSELY AND LEAN MICE, IF WE ACTIVATE THE IGF 1 RECEPTOR, INSULIN RECEPTOR OR MTOR, AGAIN WE SEE IT MIMICKING THE OBESE SITUATION EVEN THOUGH THOSE MICE ARE LEAN, SO THIS IS--I THINK AN ARGUMENT MA MAYBE THESE ARE THE TARGETS ISSUES AT LEAST PART OF THE STORY TO GO AFTER. THE OTHER PART OF STORY, I THINK THAT'S PARTICULARLY IMPORTANT IS THE INFLAMMATORY SIDE, AGAIN I THINK THE TRIGGERS REALLY ARE THESE ENGORGED DIP LO SIGHTS WITH OBESITY ACCUMULATE TRI GLYCERIDE, THEY GET PATHOLOGIC REALLY, THE SECRET OWN CHANGES, THEY BECOME INFLAMMATORY, THAT ATTRACTS MACROPHAGES AND OTHER IMMUNE CELLS TO KIND OF CLEAN UP THE MESS AND YOU GET THIS REALLY, YOU KNOW CONCERT OF PRO INFLAMMATORY IMMUNE ACTIVATED TISSUE THAT SEEMS TO BE, AS I SAID, THINK OF AS THE TRIGGER MAYBE OF THIS PROCANCKER EFFECTS ASSOCIATED WITH OBESITY. AND YOU SEE A NUMBER OF THESE FACTORS ISHT LUKEINS, FREE FATTY ACIDS, DIP LO KINES THAT ARE BEING SPILLED FROM THE SITUATION AND THEY HAVE A NUMBER OF EFFECTS BOTH LOCALLY AND SYSTEMICALLY, 1 PIECE WE PICKED UP ON IS LEPTIN IN THE ROLE IN THE STEMNESS STORY AND IT IS--IT SEEMS TO BE SOME CANCERS AND PARTICULARLY TRIPLE NEGATIVE BREAST CANCER WHERE WE'VE BEEN STUDYING DO IS HAVE A TENDENCY TO BE ENRICHED IN THESE STEM LIKE CANCER CELLS, CANCER STEM CELLS OR TUMOR INITIATING CELLS, SOME WILL REFER TO AND WHAT WE FOUND IS IN THIS MODEL THAT WENT 1 DRIVEN AND THIS IS A PATHWAY KNOWN TO BE RELATED TO STEM CELL BIOLOGY AND IS NOTES AN UNCOMMON DRIVER OF THE BREAST CANCER, COLON IS AS WELL, APC MUTATION IS EFFECTING THIS WENT SIGNALING PATHWAY SO WE NIEND OBESITY IN THIS SPONTAIN USIOUS MODEL DRIVEN BY WENT 1, OBESITY REALLY ACCELERATES THE TUMOR DEVELOPMENT AND THESE TUMORS ARE QUITE AGGRESSIVE AS WELL AND WHAT LAURA BOWERS WHO WAS A POST DOC IN THE LAB AND IS NOW IN HER OWN LAB AT PURDUE FOUND THAT AGAIN THESE CHANGES IN ADIPOSE TISSUE AND MAMMARY GLAND DRIVING UP LEPTIN PRODUCTION AND LEPTIN THROUGH ITS RECEPTOR, THE OBR RECEPTOR IS DRIVING DOWN BOTH A CLASSIC CYTOKINE SIGNALING PATHWAY, THROUGH ITS RECEPTOR, THE JACK STAT PATHWAY BUT ALSO TICKLING THIS PI-3 KINASE AKT MTOR PATHWAY AND THAT COMBINATION SEEMS TO PARTICULARLY DRIVE AN ENRICHMENT OF THE EMT AND STEM CELL MARKERS THAT WE ASSOCIATE WITH A REALLY KIND OF A DANGEROUS KIND OF CANCER SETTING. SO WE SEE CANCER STEM CELL ENRICHMENT BOTH IN TERMS OF VIABILITY, THEY MIGRATE MORE, THEY INVADE MORE AND SO WE THINK THAT LEPTIN IS CONTRIBUTING TO THE STORY BOTH THROUGH ITS KIND OF PROINFLAMMATORY CONTRIBUTIONS AND PROBABLY CYTOKINE INDEPENDENT EFFECTS AS WELL. SO WE'RE STILL LEARNING ABOUT WHAT'S UNDERLYING THIS OBESITY CANCER CONNECTION BUT I THINK A MESSAGE THAT'S COMING FROM BOTH THE IARC AND THE IACR INIT CAN I HAVES I WANT TO SHARE IS IT'S TIME O PIVOT A BIT IN TERMS OF FOCUS AND WE'VE BEEN REALLY KIND OF IN THE MODE OF PROVING WHAT'S THERE FOR A NUMBER OF YEARS NOW? AND WHETHER THIS IS A RISK FACTOR FOR MANY CANCERS IS CHRONIC OBESITY ON CANCER, HOW DO WE REDUCE THAT BURDEN AND AGAIN, AS WE MENTIONED, THE LITERATURE IS LACKING TO A LARGE PART ON THIS. WE'VE TRIED TO--ABOUT HALF MY LAB IS REALLY FOCUSED ON THIS QUESTION NOW AND OUR FIRST STUDY AND KEY WORD HERE IS PERSIST BUT WE SAW THAT MICE CHRONICALLY OBESE REVERSE THAT OBESITY IN BOTH THESE CASES WITH A LOW FAT DIET AND REVERSE THEIR WEIGHT BACK TO A CONTROL LEVEL, CHALLENGE THEM WITH OUR TUMOR MODEL AND WHAT WE SAW WAS A PERSISTENCE OF TUMOR PROGRESSION DESPITE THE NORMALIZATION OF WEIGHT. AND SO WE SAW THAT IN BOTH CASES, 1 WE WERE ABLE TO REVERSE PARTIALLY WITH RAT O WITH AN MTOR INHIBITOR SO AGAIN THAT MTOR STORY IS THERE AND WE HAVE MAYBE A 25-30% REDUCTION WITH THAT. THE OTHER AND ACTUALLY EMILY ROSSI IS IN THE AUDIENCE, SHE'S A CANCER PREVENTION FELLOW BUT WAS A GRAD STUDENT AT UNC. --LARGELY DRIVEN BY THE PROGRAM I'LL UNPACK THAT FOR YOU ABOUT THIS KEY PERSISTENCE EFFECT AND YOU MIGHT SAY HEY, WITH DIABETES IT ONLY TAKES WEIGHT LOSS AND WE NORMALIZE INSULIN RESISTANCE PRETTY EFFECTIVELY, OFTEN IN THAT SETTING HOW COME NOT CANCER BUT I THINK, YOU KNOW WE HAVE TO THINK ABOUT CANCER JUST ACCUMULATION OF GENETIC AND EPIGENETIC ALTERATIONS AT THE STARTING POINT'S DIFFERENT THAN THE END POINT AND SO, SINCE WE'RE SEEING THIS TRIGGER OF OBESITY DRIVING THINGS FORWARD, MAY NOT BE AT THE SAME PLACE AT THE END AND IT MAY BE A BIT HARDER TO REVERSE. THAT DOESN'T MEAN WE CAN'T REVERSE IT AND I'LL SHOW YOU AT THE END, SOME APPROACHES TO THAT, BUT HERE WE ARE, QUESTION IS OBESITY REVERSAL BY A LO FAT DIET, DOES THAT REVERSE THE EFFECTS OF OBESITY HERE, AND WHAT WE FIND AND I'LL WALK YOU THROUGH THE EXPERIMENT HERE, AND SO WE HAVE A COHORT OF MICE ON OBESITY REDUCING REGIMEN AND WE RANDOMIZED PART OF THAT COHORT TO A LOW FAT DIET AFTER 17 WEEKS OF OBESITY, SO WE HAVE A GROUP OBESE ALL THE WAY THROUGH, A GROUP THAT WAS OBESE FOR 17 WEEKS AND THEN FORMALIZE THEIR WEIGHT WITH THE LOW FAT DIET THEREAFTER AND THEN WE HAVE A GROUP THAT WAS NEVER OBESE AT THE CONTROL HERE WAS ALWAYS ON A CONTROL AI93 G DIET ALL THE WAY THROUGH AND WE INJECTED THEM WITH TUMORS AFTER ABOUT 10 WEEKS AFTER THE DIET SWITCH. AND WHAT WE FIND HERE AFTER WEEK 17 WHEN THEY WERE EITHER OBESE OR CONTROL, WE SEE A DIFFERENCE IN BODY FAT WHERE WE GET 50% BODY FAT IN THE OBESE GROUP, THAT WAS NORMALIZED AFTER THE SWITCH, AND THIS IS WHAT WE CALL FORMALLY OBESE MICE. ALSO NORMALIZED WE SEE LEPTIN BACK TO NORMAL IN THAT FORMAL OBESE GROUP, AND THE LEPTIN RATIO NORMALIZED, WE SEE INSULIN FORMALIZED AS WELL, BUT 2 THINGS DID NOT, THE INSULIN GROWTH FACTOR 1 LEVELS REMAIN AT LEAST INTERMEDIATE AFTER THE DIET SWITCH, AND WE DIDN'T SEE MUCH CORRECTION OF THE INFLAMMATORY STATE AFTER THE DIET SWITCH AT ALL, A NUMBER OF CYTOKINES REMAINED UP AND WHAT ABOUT TUMOR? WELL AGAIN WE CHALLENGED AFTER ABOUT 10 WEEKS AFTER THE DIET SWITCH AND SO WEIGHT AT TIME OF CANCER CHALLENGE WAS IMPORTANT, WELL, THEN, WE SHOULD SEE THE FORMER OBESE DOWN, BUT IF THERE WAS A PERSISTENT METABOLIC CHANGE EVEN AFTER THE WEIGHT, WE MIGHT NOT SLEEP APNEA AND OBESITYY THAT CHANGE AND--AND INDEED WE DID NOT SO THERE'S THE CHANGE WITH THE OBESE DESPITE BEING AT NORMAL WEIGHT WHEN THEY WERE CHALLENGED. NOW LOTS OF CAVEATS HERE, THIS IS A TRANSPLANT MODEL, WE'RE LIMITED TO TALKING ABOUT PROGRESSION HERE AND THIS IS--IN EMERGING ITS OF OUR TIMING THEY'RE OBESE FOR YOU KNOW FOR 17 WEEKS, BUT THEN NORMALIZED FOR 10, SO MAYBE IF WE WAITED 30 WEEKS OUT, AFTER NORMALIZATION, MAYBE THINGS WOULD HAVE CORRECTED AND WE'RE TESTING THAT CURRENTLY BUT AT LEAST UNDER THESE CONDITIONS, YOU CAN'T SAY, IT'S A WEIGHT--IT'S SIMPLY A WEIGHT CANCER LINK. THERE'S SOMETHING ELSE GOING ON AND IT WASN'T ACTUALLY INSULIN OR SOME OF THE USUAL SUSPECTS, BECAUSE THAT NORMALIZED SO WE GOT TO WONDERING WHAT? AND I HAVE TO GIVE EMILY ROSSI CREDIT HERE AND SHE BROUGHT AN INTEREST OF EPIGENETICS TO THE LAB AND SAW THIS RIGHT AWAY AND SAID, AH, I BET METHYLATION IS NOT CHANGING AND INDEED, THAT'S WHAT WE SAW. SO WE DID A REDUCED REPRESENTATION, SHE DID, A REDUCED REPRESENTATION BY SULFIDE SEQUENCING APPROACH HERE TO LOOK AT DNA METHYLATION AND WHAT WE FOUND IS WHEN YOU COMPARE THE OBESE AND THE CONTROL, THERE WERE 39 GENES THAT WERE SIGNIFICANTLY HYPER METHALATED AND MOST OF THESE WERE REGULATORS OF INFLAMMATION OR FIBROSIS, WE WERE FORTUNATE ENOUGH WITH THE CAROLINA BREAST CANCER STUDY TO COMPARE WHAT WE WERE FINDING IN TERMS OF OBESITY ASSOCIATED MOABLGHTALATION TO THAT POPULATION, AND WE SAW HIGH CONCORDANCE WITH DNA METHYLATION PROFILES IN THOSE WOMEN BUT HERE IS THE KICKER AND I REMEMBER THE DAY EMILY BROUGHT THIS OUT THAT ONLY 2 GENES SIGNIFICANTLY REVERSED IN THE FORMERLY OBESE MICE IN EMERGING ITS OF METHYLATION, SO THE REST STUCK AFTER THIS CHRONIC OBESITY UNDER OUR CONDITIONS AND SO IT LOOKS LIKE THERE MIGHT BE A EPIGENETIC PROGRAM THAT NEEDS TO BE LOST, BUT WE SCRATCHED OUR HEADS AND WHAT DO WE KNOW ABOUT REVERSIBILITY AND WE LEARNED THAT BARIATRIC SURGERY DOES SEEM TO BE EFFECTIVE AT REVERSING. THERE ARE 6 META-ANALYSIS, THIS WAS THE FIRST 1 BY KRIOF THEA AND COLLEAGUES THAT LOOKED AT ALL CANCERS AND BREAST CANCERS AND HERE'S THE INCIDENCE OR THE RISK OF 5 YEAR INCIDENCE OF BREAST CANCER OR ALL CANCERS IN BARIATRIC PATIENTS COMPARED TO, I THINK IT WAS ALL WOMEN AS I RECALL FROM THIS STUDY THAT WERE--THAT WERE NOT UNDERGOING THE BARIATRIC SURGERY OR OBESE WOMEN AND YOU SEE BOTH ALL CANCERS AND BREAST CANCER, YOU SEE A STRIKING REDUCTION IN CANCER RISK IN THESE MORBIDLY OBESE PATIENTS. MOST OF THESE STUDIES DO NOT KIND OF LOOK ACROSS A NUMBER OF CANCER TYPES BUT WE--WE WERE PARTICULARLY INTERESTED IN THIS MULTISITE COHORT PAPER THAT CAME OUT A YEAR AND HALF AGO LOOKING AT ALL CANCER AS WELL AS OBESITY SPECIFIC CANCER SPECIFICALLY PANCREATIC AND ENDOMEETRIOLE AND BREAST, AGAIN A STRIKING CONSISTENT STORY HERE WHERE THE POST BARIATRIC SURGERY WOMEN ARE ACTUALLY BOTH GENDERS HERE WERE PROTECTED IN TERMS OF RELATIVE TO NONSURGERY TREATED SUBJECTS AFTER THIS BARIATRIC SURGERY. SO YOU SEE PARTICULARLY PANCREATIC AND ENDOMETRIUM BREAST AND SHOWING STRONG IN THE SURVEY SO COULD WE BRING THAT INTO MOUSE MODELS BECAUSE I WILL SAY WHAT'S LACKING IS MECHANISM, LOTS OF SPECULATION ABOUT HOW THE BARIATRIC SURGERY MIGHT BE WORKING BUT IT'S DIFFICULT TO DECONVOLUTE SO WE BROUGHT THAT INTO OUR ANIMAL STUDIES, EMILY LEARNED HOW TO DO AND ACTUALLY SUBREEM IS HERE AS WELL, GETTING HER Ph.D. THROUGH THE GEORGE TOWN NIH GRADUATE PROGRAM THAT'S HERE. BUT EMILY SET THIS UP WITH AGAIN A LARGE COHORT OF OBESE MICE THAT WERE FED THE DIET INDUCED OBESE REGIMEN FOR 17 WEEKS AND THEN RANDOMIZED TO 1 OF 3 GROUPS EITHER SWITCHED TO A LOW FAT CONTROL DIET WITH A SHAM SURGERY, TO CONTROL FOR ANY ABDOMINAL SURGERY EFFECTS SO THAT'S SIMILAR TO THAT FORMER OBESE GROUP THAT WE JUST SAW. ANOTHER SUBSET WAS SWITCHED TO THE CONTROL DIET AND SLEEVE GHAST RECTIFIED ME AND I WILL TELL YOU ABOUT WHAT THAT IS IN A MOMENT. SO THAT'S THE FORMER OBESE SURGERY GROUP OR A GROUP THAT WAS MAINTAINED OBESE DIET ALL THE WAY THROUGH AND ALSO SHAM SURGERIED AND THESE WERE COMPARED TO A CONTROL GROUP HERE THAT WOULD NEVER ALLOW TO GET OBESE AND THEY ALSO UNDERWENT THE ABDOMINAL SURGERY WITH NO STOMACH MANIPULATION. AND HERE'S EMILY AND SABREEM AND OH YEAH, HERE'S THE SLEEVE GHAST RECTIFIED ME, SO ABOUT A 60% REMOVAL OF STOMACH AND SO YOU ARE TURNING THE STOMACH TO A POUCH INTO A SLEEVE, HENS THE NAME AND WE FIND THAT THAT--CERTAINLY THAT NICELY REVERSES BODY WEIGHT AS IT DOES IN MOST HUMANS, PROBABLY--UNFORTUNATELY NOT ALL RESPOND BUT MOST OF THE INTERVENTION, THIS IS THE MOST COMMON FORM OF BARIATRIC SURGERY IN THE UNITED STATES, MOST ARE SEEING THIS KIND OF EFFECT INITIALLY OF A REVERSAL OF THE OBESITY, BUT STRIKINGLY ON THIS LOW FAT DIET WE DO PRETTY WELL, WE GET PRETTY CLOSE TO THE WEIGHT LOSS OF A BARIATRIC SURGERY, IT TAKES A LITTLE LONGER BUT WE IMET THERE AND SO, IT'S PROBABLY NOT WEIGHT, ANY EFFECT THAT WE'RE SEEING MAY NOT BE--MAY NOT BE WEIGHT SPECIFIC AND WHAT EMILY AND SUBREEN FOUND IN THIS IS THAT THIS FORMER SURGERY HAD SIGNIFICANTLY LOWER TUMOR GROWTH IN THIS CASE WE USE THE EO771 TRIPLE NEGATIVE BRAOF THE CANCER MODEL THAT METASTASIZED SO WE COULD LOOK AT THAT PART OF THE QUESTION, BUT THE SURGERY HAD LOWER TUMOR GROWTH THAN THE OBESE AND WERE NOT DIFFERENT THAN THE CONTROL. SO WE NORMALIZE THEIR TUMOR GROWTH BACK TO THE CONTROL LEVEL, EVEN THOUGH THESE WERE QUITE OBESE. AND IN CONTRAST THE FORMER OBESE DIET MICE THAT LOW FAT DIET GROUP VERSUS OBESE MICE NO DIFFERENT, AGAIN IN THOSE SIGNIFICANT DIFFERENCE IN THEIR TUMOR GROWTH, SO SURGERY REVERSED AT THE LOW FAT DIET DID NOT. WE'RE IN THE MIDST OF TRYING TO GET THIS--IN FACT I'M MEETING WITH EMILY AND SUBREEN RIGHT AFTER THIS TO GET OUR FINAL PIECES TOGETHER FOR THIS PAPER AND WE'VE THROWN EVERY OMICS QUESTION WE COULD. IT'S AN EBS PENSIVE STUDY SO WE WANT TO GET EVERYTHING WE CAN OUT OF IT SO WE'RE LOOKING AT A NUMBER OF TRANSSCREPT OMIC, AND THE EPIGENOME, WE'VE KIND OF FINISHED THAT AND I WILL TELL YOU A BIT ABOUT THAT, BIG MICROBIOME CHANGES ARE EVIDENT, LOTS OF CHANGES IN THE SECRETE OHM WITH THE SURGERY, MANY OF THEM MIMIC THE DIET BUT THERE ARE SOME UNIQUE ASPECTS OF THIS AND 1 OF THE PROCESS OF GETTING OUR METABOLOMIC ANALYSIS COMPLETED SO WE'RE HOPEFUL TO GET SOME CLUES ABOUT THIS, BUT WE ALSO HAVE A TRANSLATIONAL ARM TO THE STUDY WHERE WE--WE'RE DOING AT LEAST THE SECRET O--METABOLIZEDDICS PART FROM OBESE WOMEN PREAND POST BARIATIC SURGERY SO AGAIN THE BAR--WE WILL NOT DIG TOO DEEPLY INTO THIS BUT WE AT LEAST CAN SEE IF SOME OF THE FINDINGS THAT WE'RE SEEING WITH THE MICE ARE CONSISTENT WITH THE HUMAN STORY. SO THAT'S WHERE WE ARE. I WILL QUICKLY SUMMARIZE, SOME WE HAVE ALREADY SEEN. SO THE SLEEVE GHAST RECTIFIED ME BUT NOT THE DIET REVERSED THE EPIGENETIC PROGRAM. I THINK THAT'S A BIG PART OF WHY IT'S SO EFFECTIVE AND SO THOSE FIEB ROTTIC AND IMMUNE RELATED GENES THE METHYLATION OF THOSE DID REVERSE AND SO THAT'S GOOD. THE SLEEVE GASTRIC BUT NOT THE LOW FAT DIET REVERSED OBESITY ASSOCIATED MAMMARY INFLAMMATION SO CROWN LIKE STRUCTURES SORT OF A TISSUE MEASURE OF INFLAMMATORY STATE REMAINED EVEN AFTER THE FORMER OBESE MICE WITH THE DIET THAT WAS REVERSED BY THE SLEEVE IN A NUMBER OF CYTOKINES ALSO REVERSED. BOTH THE SLEEVE AND THE LO FAT DIET NORMALIZE MOST OF THE GUT PEPTIDES, THAT WAS MY HYPOTHESIS GOING IN, NOT EMILYS, SHE LIKES TO REMIND ME THAT I MISSED THAT 1. BECAUSE BOTH OF THEM CHANGED CCK AND MANY OF THE GUT PEPTIDES THAT I THOUGHT MIGHT BE INVOLVED, ALTHOUGH I WILL SAY, THERE'S STILL AN OPEN DEPARTICIPATE IN A TRIAL BECAUSE WE'RE MOVING SO MUCH OF THE STOMACH DRAMATICALLY DECREASES WITH THE SLEEVE AND THAT COULD STILL BE A COMPONENT SO WE'RE THINKING ABOUT HOW TO ADDRESS THAT, AND AGAIN, SO FAR GOOD MOUSE HUMAN CONCORDANCE ON THE INFLAMMATORY SIGNALS THAT WE'RE--WE THUS FAR MEASURED AND THAT WOMEN STUDY AS WELL, IS IN THE MICE, SO THAT'S WHERE WE ARE WITH THIS. SO A FEW TAKE HOME MESSAGES, SO WE KNOW OBESITY INCREASES CANCER RISK AND PROGRESSION, IT WORSENS PROGNOSIS FOR MANY CANCER TYPES, WEIGHT LOSS TO REVERSE PROCANCKER EFFECTS OF OBESITY STILL QUESTION MARK, IN THE EPIs KIND OF UNCLEAR EXCEPT FOR BARIATRIC SURGERY, HERE'S A GAP AREA, OUR FINDINGS SUGGIEST THAT THE SLEEVE GHAST RECTIFIED ME, REVERSED OR LOWERED EFFECTS OF CHRONIC OBESITY, MECHANISMS TO BE DETERMINED AGAIN IT'S A COMPLICATED PIECE, IT DOES LOOK LIKE EPIGENETICS IS PART OF THIS, WE DO SEEM TO BE REVERSING THE IPT GREATER FLAMMATORY, PERSISTENT INFLAMMATORY STATE. WE'RE GETTING A MICROBIOME, BIG CHANGES WITH THAT, SO THAT MAY BE CONTRIBUTING PROBABLY TO THE INFLAMMATORY STATE THROUGH METABOLITES COMING FROM THE GUT, THERE IS A--THERE IS AGAIN A FAT REMODELING STORY HERE, WE DID SEE A BIG INCREASE IN BROWN ADIPOSE TISSUE, AFTER THE SLEEVE GHAST RECTIFIED ME, SO THAT'S--THAT MAY BE ALSO CONTRIBUTING. HERE'S WHERE WE'RE GOING WITH THIS, WE'VE BEEN TRYING A NUMBER OF COMBINATION REGIMENS OF VARIOUS SORT OF DIETARY ISHT VENTIONS, WITH ANTIINFLMATORYS WITH METABOLIC REPROGRAMMER, SORT OF AGENTS AND OUR GOAL IS REALLY TO TRY TO MIMIC THIS ANTICANCER EFFECTIVE BARIATRIC SURGERY WITHOUT DOING THE SURGERY. I GOT QUOTED AFTER A TALK 1 TIME AND SAID, I THOUGHT BARIATRIC SURGERY WAS THE SOLUTION TO THE OBESITY CANCER PROBLEM. NO. WE WILL NOT SOLVE IT THROUGH SURGERY BUT PERHAPS THROUGH THE MECHANISTIC APPROACHES WE CAN IDENTIFY THE RIGHT TARGETS TO MIMIC AND REDUCE THE BURDEN OF OBESITY INDUCED BREAST CANCER AND OTHER CANCERS WITH, YOU KNOW WITH TD SORT OF COMBINATION APPROACH AND SO FAR WE'RE GETTING AN INTERMITTENT ENERGY RESTRICTION APPROACH, A 5-2 DIET AS MANY OF YOU MIGHT HAVE HEARD OF, IT'S 5 DAYS OF A PRETTY HEALTHY DIET, 2 DAYS OF A LOW CARBOHYDRATE LOW ENERGY DIET, AVOID THE KEETOSEIS YOU WOULD GET IN A CHRONIC KIND OF LOW CARB SETTING BUT IT SEEMS TO BE MORE ANTIINFLAMMATORY THAN EVEN A CHRONIC CALORIE RESTRICTION OR A CHRONIC KETOGENIC DIET AND THAT LOOKS GOOD AND IS PARTICULARLY WHEN IT'S COMBINED WITH ANTIINFLAMMATORY AND WE'VE TESTED A NUMBER--THE NONSTEROIDAL INFLAMMATORY DRUG IS THE BEST IN OUR HANDS IN THAT. AND SO, AGAIN WE'RE GETTING PRETTY CLOSE TO MIMICKING THOSE ANTICANCER EFFECT OF HIS SURGERY. I'LL LEAVE YOU--I HAVE A COUPLE MINUTES, GOOD. I WANTED TO LEAVE YOU WITH SOME IS KIND OF WHERE I THINK THE FIELD IS GOING. WHAT ARE THE EMERGING TOPICS, PARTICULARLY IN RELATION TO THE MECHANISTIC RESEARCH AND OBESITY AND ENERGETICS IN CANCER SO THE FIRST I'LL TOUCH BASE ON, IS THE LINK BETWEEN OBESITY AND CANCER METASTASIS AND I'LL INCLUDE IN THIS, AS WELL RESPONSE TO CHEMO THERAPY OR IMMUNOTHERAPY, ALMOST NOTHING IS KNOWN ABOUT THESE CONNECTIONS AND THIS IS THE MAJOR KILLER, YOU KNOW? AS METASTATIC DISEASE, SO, WE KNOW A LOT ABOUT LINKS WITH RISK, DON'T KNOW A LOT ABOUT REVERSING IT AND WE KNOW ALMOST NOTHING ABOUT METASTATIC PROCESS AND HOW OBESITY DRAWS THAT AND I'LL SHOW YOU A LITTLE DATA WE'VE GOT ON THAT. THERE'S ALSO--I WILL SAY I FELT SOME FRUSTRATION GOING THROUGH THESE EXERCISES, OR THESE INITIATIVES THAT ARE WONDERFUL AND REALLY IMPORTANT WITH THE AICR, AND THE IARC BECAUSE THESE ARE ALL SORT OF ONE-SIZE-FITS-ALL RECOMMENDATIONS THAT WE'RE ENDING UP WITH AND LOOKING AT BIG PICTURE AND YOU HAVE TO DO THAT BUT WE ALSO REALLY NEED TO MOVE TOWARDS A PRECISE DIRECTION HERE, PRECISION NUTRITION AND HOW DO WE DO THAT AND INCORPORATE GENETIC QUESTIONS? WE ALL DIFFER IN OUR GENETIC AND OUR MICROBIOME, HOW DO WE BEGIN TO INCORPORATE THESE SORTS OF DIFFERENCES IN, BECAUSE WHAT MIGHT WORK FOR ME, WON'T WORK FOR YOU AND VICE VERSA AND THAT'S PARTICULARLY CHALLENGING IN THE ANIMAL WORLD WHERE WE'VE REDUCED DOWN TO SINGLE BACKGROUND TRAINS AND YOU KNOW INBRED LINES, AND SO, I'LL TELL YOU A BIT ABOUT EFFORTS TO INTEGRATE MODELS GENETIC HETEROGENEITY INTO BOTH THE OBESITY AND CANCER MODELS THAT WERE WORKING WITH. SO I'LL TOUCH BASE ON THAT. AS I SAID A LOT OF PROGRESS GGZ ON IN CANCER IMMUNOLOGY, THE MICROBIOME, PREMALIGNANT BIOLOGY, I DON'T THINK WE CAPITALIZED ON THAT IN THE PREVENTION WORLD AND THIS IS SOMETHING THAT IS EMERGING,A BUT IT'S SOMETHING WE NEED TO ACCELERATE. AND ULTIMATELY, LINDA IS IN THE AUDIENCE SO I HAVE TO GIVE A SHOUT OUT TO THE TRACK PROGRAM AND THE IMPACT IT HAD ON THE FIELD BUT PARTICULARLY I THINK WE'RE JUST STARTING TO GET BETTER AT TRANSDITION PLINARY INTEGRATION OF PRECLINICAL AND EPIDEMIOLOGIC AND CLINICAL AND BEHAVIORIAL SORTS OFESTS ON THIS, IT WILL TAKE THE WHOLE WHOLE VILLAGE IF YOU WILL OF APPROACHING THIS AND WE HAVE TO ACCELERATE THIS EFFORT AND INTEGRATE BETTER SO AISLE LEAVE YOU WITH JUST THOUGHTS ON THAT. BUT I'LL SHOW YOU AN EXAMPLE OF THE OBESITY METASTASIS STORY. SO 1 OF THE CHALLENGES, MOST OF THE MOUSE MODELS OF CANCER DON'T METASTASIS AND WE HAD TO WORK PRETTY HARD, WE'VE GOT THIS WENT-DRIVEN BREAST CANCER, WE'VE ISOLATED A NUMBER OF CELL LINES FROM INCLUDING THIS MWENT LINE, SHOULD BE METASTATIC AS ALL GET OUT, IT INVADES LIKE CRAZY BUT WHEN WE TRANSPLANT, ORTHOTOPICALLY TRANSPLANT THOSE TUMORS THEY DEVELOP THEM QUICKLY THAT DON'T METASTASIS AND THAT WAS FRUSTRATING TO US SO WE DID A SERIAL TRANSPLANT AND EMILY WAS THE DRIVE OF THIS ALSO, MAN, YOU WERE GOOD? AFTER THE FIFTH SERIAL TRANSPLABT OF THE MWENT TUMOR, WE BEGAN TO GET METASTATIC LESIONS AND WE ISOLATED A LESION FROM THE LUNG AND FROM THE LIVER AND MADE CANCER CELL LINES FROM THOSE LINES. AND WE WERE CURIOUS, WELL WHAT'S DIFFERENT FROM THE PARENT LINE, THE PARENT AND THESE METASTATIC LINES BECAUSE WE COULD NOW REPEAT, THEY ARE METASTATIC, WE GET A HIGH RATE OF METS AFTER NOW TRANSPLANTING THOSE, WHAT CHANGED, WAS THE QUESTION? WHAT MADE THEM METASTATIC, WE DID A GENE ARRAY ANALYSIS AND WE FIND THAT PARTICULARLY, THERE'S DIFFERENCES IN KRASE MODEL SIGNALING, EMT RELATED GENES WERE DIFFERENT BUT PARTICULARLY STRIKING WAS THIS INFLAMMATORY DIFFERENCE. THAT SHOWS UP WHEN WE COMPARE EITHER OF THE METASTATIC LINES TO THE PARENT MWENT LINE HERE AND THAT LED US TO WONDER WELL, WE HAD GOOD LUCK WITH SULMAC, WITH A PRIMARY STANDPOINT OF REVERSING THE PROCANCKER EFFECTS OF OBESITY, MAYBE THAT WOULD WORK IN A METASTATIC SETTING TOO. SO WE SET AN EXPERIMENT WITH A LARGE NUMBER OF FEMALE BLACK 6 MICE, THEY WERE PUT EITHER ON THE OBESITY OR CONTROL DIET FOR 15 WEEKS AND THAL CASE AND THEN SWITCHED TO EITHER MAINTAIN THE CONTROL WITHOUT ANYTHING OR WITH SONENMAC, WITHOUT ADDITIONAL MUTATION WITH SOULMAC, AND WE DID THAT AT 4 WEEKS LATER IS THAT RIGHT? AFTER THAT TREATMENT? WE INJECTED THEM WITH 3 DIFFERENT METASTATIC TRIPLE NEGATIVE BREAST CANCER CELL LINES, THIS EO771 LINE I MENTIONED PREVIOUSLY ARE WELL ESTABLISHED THIS IS LUNG VERSION OF THE MWENT LINE AND THIS LIVER SPECIFIC METASTATIC LINE FROM THE LINE, AND FOLLOW THAT OUT FOR 13 WEEKS OR SO, AND HARVEST IT, AND WHAT WE FOUND WAS THAT IN ALL 3 GROUPS WE SEE THE STRONG PROTEIN COMPLEX METASTATIC EFFECT OF OBESITY SO YOU SEE SOME LONG METS IN THE EO771 AND THAT'S KNOWN TO BE A METY METASTATIC CELL LINE AND ORTHOTOPICALLY TRANSPLANTED INTO A MOUSE UNDER CONTROL CONDITIONS, NOT MANY METS, THE EFFECT HERE, THE OBESITY TRIPLING THE METASTATIC POTENTIAL OF THIS LINE BUT IT DOES A NICE JOB OF NORMALIZING IT BACK TO THE CONTROL LEVEL. SIMILARLY IN THE MET MWENT LUNG LINE, A LOW LEVEL OF METASTATIC DEVELOPMENT IN THE CONTROLS, OBESITY AGAIN ABOUT TRIPLED THE METASTATIC POTENTIAL AND IN THIS CASE, THE SULINDAC COMPLETELY ABLATED THE FORM. THIS WAS 1 STRIKING BECAUSE THERE'S A CONCEPT IN THE METASTATIC CANCER WORLD CALLED TROAPISM SO TYPICALLY A LESION FROM 1 ORGAN HONES TO TO THAT ORGAN BUT APPROXIMATE WON'T GO ANYWHERE ELSE, SO THERE'S SPECIFICITY, AND IT'S FASCINATED ME ANYWAY, SO WE LOOKED IN OUR LUNGS, AT THE LIVER, METASTATIC LIVER LINE AND AS YOU CAN SEE UNDER MOST CONDITIONS WE DON'T GET ANY METS FORMING AND THAT WOULD BE CONSISTENT WITH THAT TROPISM, THEY DON'T HONE BUT THERE'S SOMETHING ABOUT OBESIT THAT BROKE THAT TROAPIC KIND OF LINE. AND WE'RE GETTING LUNG METS FROM THIS LIVER LINE IN RESPONSE TO OBESITY SO THAT IS CAUGHT OUR ATTENTION AS WELL. I JUST GOT AN RO1 WITH A PURDUE TEAM THAT I'VE KNOWN FOR A NUMBER OF YEARS WHERE WE'RE LOOKING AT METABOLIC REGULATION OF THE MET TAKEN--THEY STATIC PROCESS INCLUDING WITH OBESITY, IS A BIG PART OF THAT, AND TROAPISM IS 1 OF OUR AIMS TO LOOK AT, SO WE'RE--WE'RE HOPEFULLY GOING TO BE ABLE TO UNCOUPLE THIS, BUT BOTTOM LINE, OBESITY AT LEAST IN OUR MODEL IS STRONGLY PRO METASTATIC AND IT LOOKS LIKE ANTIINFLAMMATORY INTERVENTIONS LIKE SULINDAC MAY BE MORE EFFECTIVE THAN IN THE PRIMARY SETTINGS, SO THAT'S 2 PIECES WE'RE PRETTY EXCITED ABOUT, SHANE MCDONALD IS A MD-Ph.D. STUDENT LEADING THIS WORK AND HE'S TAKING US IN A SINGLE CELL SEQUENCING DIRECTIONS SO WE'RE GETTING IT SORT OF HETEROGENEITY WITHIN THE TUMOR OF METASTATIC POPULATIONS IN EMERGING ITS OF THEIR GENE EXPRESSION AND WHAT THIS REALLY IS ALLOWING US TO DO IS SORT OUT WHAT CELLS ARE COMING INTO THESE PRIMARY METASTATIC LESIONS TO INTERACT WITH THE CANCER CELLS, REALLY FASCINATING DATA WE'RE GETTING ALREADY. SO HE'S PULLING US IN THAT DIRECTION. I WANTED TO MENTION A BIT ABOUT THIS HETEROGENEOUS ROW GENERATED AIC ISSUE AND AGAIN WE'RE SO FOCUSED IN THE REDUCTION OF SYSTEMS DOES THAT REALLY REFLECT THE HUMAN POPULATION, LOOK AT US HERE, WE WILL HAVE TO LOOK AT IT GENETIC SINCE IT'S A CONTRIBUTOR AND HOW DO WE SOLVE THAT, THE MOUSE GENETICS COMMUNITY REALLY GOT TOGETHER ABOUT 12, 14 YEARS AGO AND CREATED WHAT THEY CALL A COLLABORATIVE CROSS SO THEY'VE TAKEN 8 STRAINS OF MICE AND THEY'VE CROSSED THEM IN A FUNNEL SORT OF WAY THISSA IS ATTRACTABLE AND ANALYZE GENETIC CONTRIBUTIONS THAT UNDERLIE A PHENOTYPE THAT YOU'RE WANTING TO CHASE AND WHAT YOU END UP WITH IS FROM THESE 8 INBRED FOUNDERS SORT OF A MOSAIC OF A GENETIC BACKGROUND, SO THEY'RE CURRENTLY ABOUT 70 OF THESE COLLABORATIVE CROSS LINES AVAILABLE, OUR UNC SYSTEMS GENETIC PROGRAM HAS LED THE WAY ON THIS SO YOU CAN GET MICE, ANYBODY CAN GET MICE FROM OUR SYSTEMS GENETICS FOLKS, BUT THESE--THESE COLLABORATIVE CROSS GENOMES HAVE BEEN SEQUENCED AND HOMOSWRAIGOUS MOSAIC OF 8 FOUNDERS SO THE INBRED LINES, EVERY MOUSE IS THE SAME WITHIN A LINE BUT THEY'RE REALLY INTERESTING PHENOTYPES THAT YOU GET OUT OF THESE AND THE ABILITY TO LOOK AT QUANTITATE UF TRAIT LOCI THAT MAY BE UNDERLYING THESE INTERESTING THINGS, SO THAT'S A USEFUL TOOL, PARTICULARLY FOR THE REPEATED MEASURES OF TRAITS I THINK OF THESE AS VALIDATING ONCE WE FIND A GENETIC VARIANT, THIS IS A WAY TO TEST THAT, HOW DO WE FIND THE UNDERLYING GENETIC VARIANT IS A TOUGHER QUESTION, AND A HUMAN YOU MIGHT SAY, WELL WE COULD DO A GWAS, AND DO HALF A MILLION PEOPLE AND IDENTIFY PEOPLE WE'VE NEVER IDENTIFIED BEFORE AND THAT'S REAL LE EXPENSIVE BUT WHAT IF I COULD DO GWAS IN MICE FOR $20,000 AND THAT MIGHT HAVE RELEVANCE WITH A HUMAN. THAT'S WHERE WE ARE TRYING TO GO WITH THIS. THIS USES AN OUTCROPPING OF THE COLLABORATIVE CROSS MICE CALLED DIVERSITY OUTBRED AND THIS IS SOMETHING THE JACKSON LABS HAS INSTITUTED THEY'VE CREATED THIS SORT OF MOUSE LINE THESE MICE CONTAIN 45 MILLION SNPs, SO DEPENDING ON WHO YOU TALK TO WE HAVE 50-A HUNDRED MILLION SNPs, IN GENETIC VARIANCE SO WE'RE GETTING CLOSE. A SINGLE CFEIVE BLACK 6 HAS 1 FEIVE SNPs, SO WE'RE NOT EVEN CLOSE WITH A BACKGROUND LIKE THAT, SO THIS IS A--I THINK A REALLY GOOD TOOL, THEY'RE MAINTAINED BY RANDOM MATING, EACH MOUSE IS GENETICALLY UNIQUE JUST LIKE US, SO YOU GET A POPULATION OF A COUPLE HUNDRED MICE, AND 1 DIFFERENCE WEAN MICE AND THESE MICE AND HUMAN, THEY HAVE A HIGH GENETIC DIVERSITY THAT REFLECTS THE HUMAN BUT THEY HAVE A HIGH MINOR ALLELE FREQUENCY AND THATIA THE HUMAN STRIPPER IN THE GWAS AND THE MINOR FREQUENCY QUITE LOW. THE WAY THEY'VE DONE THE CROSSING YOU CAN PICK THESE UP, AND THERE'S ALSO A COMBINATION STRUCTURE THAT YOU CAN SEE. THESE ARE KIND OF IDEA FOR GENOME WIDE ASSOCIATION STUDIES AND WE'RE PICKING UP SCORES WITH A LOT OF MICE. I'LL GIVE YOU 1 EXAMPLE, WE'RE LOOKING AT INDIVIDUAL BODY WEIGHT CHANGE AFTER DIET INDUCED OBESITY FOLLOWED BY CALORIE RESTRICTION REGIMEN SO WEIGHT GAIN, WEIGHT LOSS AND CAN WE USE THESE MICE TO IDENTIFY NEW QTLs THAT ARE IN THE LINE SO WE DID A 12 WEEK HIGH FAT DIET INDUCED OBESITY PERIOD, AND WHAT YOU SEE HERE, THESE ARE MALES AND THESE ARE FEMALES BODY WEIGHT. WHAT YOU SEE IS REMETABOLISMENDOUS HETEROGENEITY, SOME MICE GAIN INCREDIBLE, SOME ARE TRIPLE QUADRUPLE THEIR WEIGHT IN THE 12 WEEK PERIOD IN RESPONSE TO THE OBESITY AND SOME HAVEN'T GAINED VERY MUCH AT ALL AND JUST LIKE PEOPLE AND UNFORTUNATELY JUST LIKE PEOPLE AS WELL, SOME MICE LOST A LOT OF WEIGHTOT CALORIE RESTRICTIVE DIET AND HAD 2 MICE GAIN WEIGHTOT CALORIE RESTRICTIVE DIET AND MOST WERE ALL OVER THE MAP ON THIS, AND SAME, MALES, FEMALES REFLECTED EACH OTHER QUITE WELL SO THIS REALLY IS, WE'RE WORKING WITH LEE CAP LANFROM THE HUMAN SIDE OF THINGS, SOME OF THE FOLKS AT UIN, C AND OUR DISTRIBUTIONS REALLY DO REFLECT WHAT WE SEE IN A HUMAN WHERE, HE BASICALLY DID A CALORIE RESTRICTIVE STUDY AND SAME THING, YOU KNOW SOME PEOPLE GAIN VERY FEW, BUT SOME PEOPLE GAIN ON THAT, AND SOME PEOPLE LOSE A LITTLE BIT, SOME, VERY KIND OF SMALL FRACTION, LOSE A LOT AND IT'S KIND OF A SAME AFTER THE HIGH FAT DIET AND GAIN WE SEE THE SAME KIND OF DISTRIBUTION AND EVERY POSSIBLE PERMIAITATION IS THERE, SO WE'RE--WE'RE THINKING WE'RE AT LEAST IN THE BALL PARK OF REFLECTING HUMAN HETEROGENEITY AND HAVE A CHANCE AT FINDING WHAT WE THINK WILL BE NEW GENETIC VARIANCE THAT MIGHT UNDERLIE THESE RESPONSES ARE PRELIMINARY QTL ANALYSIS LOOKS GOOD. WE HAVE ABOUT A DOZEN SCORES THAT ARE REALLY QUITE HIGH AND FORTUNATELY THE MOUSE GENETICS FOLK VS REALLY A NICE PIPELINE FOR MAPPING YOU KNOW THE LINKAGE ANALYSIS AND SOMETHING I'M FASCINATED BY IS PARTICULARLY THE EPISTATIC NETWORK AND THAT MEANS, YOU MIGHT FIND 1 SNP ASSOCIATED WITH THE WEIGHT LOSS AND ANOTHER SNP MAY BE QUITE DISTANT FROM THAT SO SPATIALLY YOU MAY NOT BE ABLE TO MAKE SENSE THROUGH THAT BUT THROUGH THE EPISTATIC NETWORK APPROACH, THERE ARE CLEARLY INTERACTIONS BETWEEN THESE GENETIC VARIANTS AND SO THEY'RE ABLE TO PICK THAT UP, SO WE'RE QUITE EXCITED ABOUT THAT, SO JUST A--JUST A PEEK, THIS ISN'T THE ONLY WAY TO GO ABOUT THIS, BUT IT'S CAUGHT OUR ATTENTION AS A WAY TO GET TO THE PRECISION NUTRITION APPROACH AND THAT WAS A PICTURE OF JEFF FRENCH WHO'S LEADING THE WAY, AND WE CAN CROSS THESE MICE, THE COLLABORATIVE CROSS WITH GENETIC MODELS OF CANCER AND SO BRING OUR CANCER QUESTIONS INTO THIS GENETIC HETEROGENERATED AITY ISSUE TOO. I THINK I BETTER SHUT IT DOWN SO I'LL LEAVE YOU WITH 1 FINAL SLIDE HERE. THIS IS LINDA [INDISCERNIBLE] FROM TREK, THIS IS SUPPOSED TO BE IN PIRSPIRRATIONAL, AND IT INSPIRES ME AS A BASIC SCIENTIST BUT VERY MUCH INTERESTED IN CANCER PREVENTION AND LINKING WITH POPULATION FOLKS AND I THINK THIS IS REALLY THE ANSWER IS BETTER TEAMING IN LINKING OUR PRECLINICAL WORK WITH CLINICAL WORK AS WELL AS POPULATION BASED TO BETTER UNDERSTAND. SO I'LL LEAVE YOU WITH THAT IMAGE AND LET ME JUST POP ON, THE FINAL POINT WAS ALSO 1 WAY TO DO THIS IS TO BETTER INTEGRATE OUR MOUSE MODELS, WITH HUMAN STUDIES AND WE'RE TRYING TO DO THAT WITH A NUMBER OF FOLKS WE'VE BEEN DOING THESE CO TRIALS WITH CAROL FABIAN OF KANSAS WHO DOES CANCER PREVENTION TRIALS AND HIGH RISK WOMEN. SO I'LL JUST BUZZ THROUGH THAT. THAT'S SORT OF--WE HAVE HAD SOME SUCCESS WITH THAT PARTICULARLY IN THE WEIGHT LOSS AND OMEGA 3 AREAS FOR CONNECTING UP. SO I'LL STOP THERE. HERE'S THE GROUP THAT DOES THE HARD WORK. I HAVE KIND OF 2 GROUPS, 1 IN OUR SCHOOL PUBLIC HEALTH IN CHAPEL HILL, THE SCHOOL OF PUBLIC HEALTH WITH EMILY AND SUBREEN, SO INDICATED AND THEN A GROUP [INDISCERNIBLE] THAT ARE DOING THE GENETIC WORK IN OUR NUTRITION RESEARCH EN--STRATEGIESITUTE OUT THERE. SO THANK YOU VERY MUCH FOR YOUR ATTENTION AND FOR JOINING. GREAT TO BE BACK HERE AND I'LL LEAVE YOU--I'LL PUT THIS UP, WE CAN MAYBE DO QUESTIONS BUT AICR WILL BE IN CHAPEL HILL, THE AMERICAN INSTITUTE FOR CANCER RESEARCH MEETING BE IN CHAPEL HILL. SO COME DOWN AND SEE US, WE SHOULD HAVE A GOOD TIME. THIS WILL BE FAYE 15th AND I WILL LET YOU READ THROUGH WHAT WE'RE DOING WITH THAT. THANK YOU. THANK YOU VERY MUCH. [ APPLAUSE ] YES? >> CAN YOU COMMENT ON VISCERAL FAT AND CANCER AND ALSO THE EFFECTS OF [INDISCERNIBLE]. , I'LL REPEAT THE QUESTION. SO, THE QUESTION WAS KIND OF A COMMENT ON THE VISCERAL FAT. QUITE FRANKLY WE THINK VISCERAL IS THE TRIGGER AND WE'RE IN THE PROCESS OF DOING FAT TRANSPLANTS WHERE WE'RE MOVING THESE THINGS AROUND TO KIND OF ESTABLISH THAT. SO BUT I DO THINK METABOLICALLY MORE ACTIVE, PARTICULARLY MORE INFLAMMATORY AND SO WE THINK THAT THAT'S PROBABLY THE CULPRIT TO REALLY GO AFTER. NOW THE FASTING, A LOT OF INTEREST IN FASTING, FASTING MIMICKING DIETS, TIME RESTRICTED FEETING AND WE TESTED A NUMBER OF THESE ALREADY, 5-2 THAT SEEMS TO BE ABOVE AND BEYOND THE ENERGY THAT WE LIKE AND SO, THAT'S BEEN THE BEST IN OUR HANDS, WE'VE HAVEN'T REALLY GIVEN THE TIME RESTRICTED FEEDING A GREAT SHOT YET SO WE'RE IN THE PROCESS OF DESIGNING THOSE EXPERIMENTS BECAUSE I DO THINK THAT THAT'S--I'M ACTUALLY TRYING TO DO THAT MYSELF, BUT WHEN YOU TRAVEL IT'S SO HARD. I'M STRUGGLING TO KEEP TO MY TIMING ON THAT. >> FIVE-2 [INDISCERNIBLE]. , HUMANS AND MICE. >> AND AGAIN WE HAVE PARALLEL, I HAVE A FREEZER FULL OF TISSUE FROM THE MANCHESTER GROUP THAT'S DONE A LOT WITH BREAST CANCER WITH HIGH RISK WOMEN AS WELL AS PATIENTS AND COMPARE THEM ACROSS LAURA BOWERS, WE'RE ABOUT TO WRITE THAT AND GET THAT PAPER OUT OF THE 5-2 KIND OF--IT'S AS GOOD AS CANNED WHAT, IT MAY BE BETTER AS AN ANTIINFLAMMATORY CHRONIC CALORIE RESTRICTED SO I THINK A PUBLIC HEALTH MESSAGE WILL BE GOOD THERE BECAUSE THAT'S RELATIVELY EASY TO FOLLOW AND ADHERIN TO A THIRD% CALORIE RESTRICTION, YES? >> [INDISCERNIBLE] >> THAT'S CORRECT THE REAL WHY IS WHERE YOU GET INTO TROUBLE WITH THE MICRONUCLEOTIDES T-REGENT ABNORMALITIES SORNGZ BUT YOU HAVE TO WORRY ABOUT IRON WITH THE SLEEVE A BIT EMPLOY WE POP THE IRON UP A BIT. >> YEAH,IVE WAS WONDERING IF THE CONTROLS IF ARE THAT AND THE MODEL [INDISCERNIBLE] OF OTHER NUTRIENTS THAT COULD BE [INDISCERNIBLE]. , COULD BE CERTAINLY TRUE LIKE I SAY FOR THE MORE SEVERE, THE HUMAN PART, I SHOULD HAVE NOTED, OF THAT STUDY WHERE WE HAVE THE ASPIRATE FLUID THAT INCLUDED SLEEVE AND [INDISCERNIBLE]. I WORRY ABOUT SOME CONFOUNDING FROM THAT. THERE MAY BE DIFFERENTIAL ABSORPTION EFFECTS BUT YOU KNOW& I WILL SAY THE SHORT-TERM OF OUR EXPERIMENT, I'M NOT SO WORRIED, WE DO HAVE A SORT OF A VITAMIN MINERAL MIX ENRICHMENT WITH THE DIET BUT IT WAS ONLY--WHAT WAS IT 10 WEEKS AFTER THE SLEEVE, YOU DID THE TRANSPLANT, PROBABLY NOT GOING TO GET TOO FAR OUT OF WHACK WITH ANYTHING OTHER THAN IRON WAS WHAT WAS OUR THINKING. >> [INDISCERNIBLE] >> AH! COULD THAT BE A COMPONENT OF IT? >> YEAH. >> WELL THAT'S--YEAH. WHAT'S THAT? >> [INDISCERNIBLE] >> YEAH, WE DID SEE--THE WE WERE AT FIRST DISAPPOINTED THAT THE WEIGHTS WEREN'T THE SAME AND THEN WE THOUGHT THIS IS GREAT BECAUSE NOW IN A WAY WE KIND OF RULE OUT A LOT OF THOSE ISSUES. WE THINK THAT POINTS TO METABOLIC DIFFERENCES INDEPENDENT OF WEIGHT OR MALNUTRITON OR ANY OF THAT SORT. YEAH. THAT'S AN INTERESTING THOUGHT. WE KIND OF WANT--WE KIND OF GOT THE [INDISCERNIBLE] AND WHY DOWN THAT WE HAD A SURGEON FROM MICHIGAN WHO HAD DONE A LOT OF THE PIONEERING WORK IN MICE AND RATS, TEACH US AND [INDISCERNIBLE] WASN'T SO BAD, IT WAS I LITTLE MESSY WAS THE PROBLEM BUT I AM INTRIGUED BECAUSE WE WOULD PROBABLY SEE MORE EFFECT WITH THAT VERSION, BUT ANYWAY, THAT'S A GOOD THOUGHT. >> STEVE, HERE AT THE MIC? >> HEY, LINDA, QUESTION, FIRST GREAT TALK, THANK YOU FOR THE SUMMARY. IN THE KIND OF WORK THAT BACKGROUND WORK YOU WERE DOING WITH THE AICR, EXPOSURE OF OBESITY FROM EARLY STAGES OF LIFE TO INFLUENCE AND INCREASE CANCER RISK, DO YOU HAVE SOME THOUGHTS OR DIRECTION IN TERMS OF HOW THAT STATUS IS ALSO CREATING AN INCREASED DIRECTION FOR, YOU KNOW CANCER DEVELOPMENT AT EARLIER STAGES IN LIFE, BECAUSE WE'RE SEEING SOME OF THAT IN OUR EPIDEMIOLOGIC EVIDENCE. >> YEAH, WE ACTUALLY TRIED TO LOOK AT THAT, WE--THERE JUST WASN'T ENOUGH TO BE ABLE TO METAANALYZE THAT QUESTION, BUT WE CERTAINLY SAW SOME LARGE COHORTS DID HAVE DATA, SOME OF THE HARVARD DATA WAS SUGGESTING AS I RECALL KIND OF THE STRONGEST SIGNAL WAS MAYBE THE 25-30 AGE RANGE. >> EXACTLY. >> WE SAW THAT. WE DIDN'T ADDRESS IT IN THE ULTIMATE ANALYSIS JUST BECAUSE IT WAS KIND OF AN EMERGING TOPIC, HOPEFULLY THAT'S SOMETHING--IT'S A LITTLE UNCLEAR, 1 OF THE DISCUSSION POINTS AT AICR WILL BE WHAT WILL WCRF BE DOING IN THE FUTURE SOPHISTICATEDY THAT WILL BE--I'M KIND OF CURIOUS MYSELF, IF THEY'RE GOING TO TRY TO TACKLE SOME OF THOSE ISSUES ABOUT, CERTAINLY FOOD PATTERNS IS 1, I KNOW THAT'S A CLEAR 1. BUT SORT OF THE LIFE COURSE QUESTION I THINK IS REALLY IMPORTANT. THANKS LINDA. >> OKAY, THANK YOU VERY MUCH. GREAT TO BE BACK. THANK YOU.