TRACO 2018 – Pancreatic cancer and Nanotechnology

>> THIS IS OUR LAST TRACO LECTURE FOR 2018 AND I WOULD LIKE TO ACKNOWLEDGE JONATHAN WEAST FOR THE FINANCIAL SUPPORT FOR THIS COURSE AND THE VIDEOCAST COST A PRETTY PENNY AND I’D LIKE TO ACKNOWLEDGE SIKU, STRIGLE HERE IN BUILDING 50 FOR PAIKING THE VIDEOCAST VERY GOOD AND I’D ALSO LIKE TO ACKNOWLEDGE NCI FREDERICK, WE VIDEOCAST LIVE THERE. AND CHRIS GRAHAM AND OTHERS HELP SET UP THAT ROOM FOR THE FED RICK PARTIC PLAN TO ANALYZE BY AGES. SO OUR FIRST SPEAKER TODAY IS PARIS HUSSEIN AND HE GOT HIS Ph.D. IN INDIA AND HE DID A POST DOCTORAL FELLOWSHIP AT THE SWISS INSTITUTE FOR RESEARCH ON CANCER IN LUSA AN, AND SUBSEQUENTLY CAME TO THE U.S. HE WAS HERE AT NCI, HE WAS AT THE UNIVERSITY OF MARYLAND SCHOOL OF MEDICINE AND IN 2009 HE BECAME A TENURED TRACK INVESTIGATOR AND RECEIVED HIS TENURE LAST YEAR. CONGRATULATIONS. HIS TITLE PANCREATIC CANCER CURRENT UNDERSTANDING AND FUTURE CHALLENGES. >> THANK YOU. TERRY FOR THE KIND INTRODUCTION AND GIVING ME THE OPPORTUNITY TO TALK ABOUT PAN REATIC CANCER AND SO WHAT I’M GOING TO DO TODAY, IS DISCUSS SOME OF THE RECENT ADVANCEMENT, SOME BASIC KNOWLEDGE ABOUT PANCREATIC CANCER AND WHAT ARE THE CHALLENGES, SO LET’S GET STARTED. CAN YOU HEAR ME? GREAT. SO LET ME START WITH THIS SLIDE AND WE SHOW SOME OF THE DISTURBING FACTS ASSOCIATED WITH PAN KRISTATTIC CANCER. IT’S THE FOURTH LEADING CAUSE OF CANCER DEATHS IN THE UNITED STATES. MEDIAN SURVIVAL ISULOSIS THAN SIX MONTHS. ESTIMATED 55,440 NEW CASES AND 44,330 DEATHS IN 2018 AND THERE ACCORDING TO THE ESTIMATE, TELL BE THE LEADING CAUSE OF CANCER DEATH BY 2030. THIS WAS PUBLISHED A FEW YEARS AGO IN CANCER RESEARCH. SO WHAT ARE THE RISK FACTORS AND INHERITED SYNDROMES OF PANCREATIC CANCER. THERE ARE SEVERAL RISK FACTORS, SMOKING, DIABETES, CRANIC PAN KRE TINSA TIGHT ISOTOPE AND OBESITY IN NONBLOOD GROUP THERE ARE ALSO SEVERAL GENETIC SYNDROME OR INHERITED DISEASES. FOR EXAMPLE, HERITTED PAN KRE TINSA TIGHT ISOTOPE, IN INCREASING MORE AND MELANOMA SYNDROME, THAT HAS P16, ALTERATIONS, HEREDITARY BREAST AND OVARIANCE CANCER SYNDROME WHERE YOU HAVE PRCA ONE AND BRCA-TWO AND P A LB-TWO, CANCER AND SO FORTH. THE MOST COMMON TYPES OF PANCREATIC CANCER AND PANCREATIC DUBLGHTAL CARCINOMA THAT CONSITUTES 90% OR MORE THAN 90% OF ALL THE PANCREATIC CANCER AND LESS THAN FIVE% ARE NEUROENDOCRINE TUMORS AND FEWER THAN THAT ARE ADENO CARCINOMA IS THE MOST DEADLY ONE WHICH IS COMMONLY FOUND IN THE PATIENTS SO MOST PATIENTS HAVE ADVANCE DISEASE AT THE TIME OF DIAGNOSE, THERE IS NO EARLY DETECTION MARKER, SO MAJORITY OF THE PATIENTS WHO ARE DETECTED WITH PANCREATIC CANCER THEY ARE PRESENTED WITH ADVANCED DISEASE AS CAN YOU SEE HERE, 90% ARE EARLY DIAGNOSIS, ALMOST 40% ARE REGIONALLY ADVANCED AND THERE’S ADSCRANSED DISEASE, TO DIFFERENT ORGANS. SO PROGRESS IN THE TREATMENT OF ADVANTAGE DISEASE IS DISAPPOINTING. THESE ARE THE CAP LANMEYER ANALYSIS SHOWING THAT A STANDARD OF CARE DRUG FOR EXAMPLE GEMSIGHTA BIN WHICH HAS BEEN STANDARD OF CARE FOR MORE THAN 40 YEARS AND MEDIAN SURVIVAL IS ONLY LESS THAN SIX MONTHS IN ADVANCED DISEASE. THE BEST THAT WE HAVE RIGHT NOW IN ADVANCE DISEASE IS FOLFIRINOX, SO FOFOLFIRINOX IS A COMBINATION OF CHEMO THERAPY DRUGS BUT IT’S HIGHLY TOXIC BUT THE MEDIAN SURVIVAL IS LESS THAN A YEAR BUT IT IS BETTER THAN GEM CYTOBIEN ALONE. AND IF IT IS DETECTED EARLY ON, AND PATIENTS UNDERGO SURGICAL RESECTION, THE SURVIVAL IS BETTER WITH THE ADJUVANT THERAPY WHICH USED TO BE GEMCITABIEN, NOW IN THE TRIAL IN 2017, IT IS FOUND THAT A COMBINATION OF GEMCITABINE, CAN ENHANCE FIVE YEAR SURVIVAL IN RESECTED PATIENTINGS WITH THIS STAGE ONE DISEASE AND NEGATIVE SEGMENT THE MARGIN IF SIGNIFICANTLY HIGHER AND RECENTLY IN THIS YEAR THE TRIAL WAS–RESULTS FROM THE TRIAL WAS RESENTED THAT MODIFIED FOLFIRINOX IN A STAGE ONE RECEPTOR PATIENTS SIGNIFICANTLY ENHANCED THE FIVE YEAR SURVIVAL SO THAT IS GOING TO BECOME THE STANDARD OF CARE SO ONE OF THE–ONE OF THE INTERESTING OBSERVATION IN PANCREATIC CANCER PATIENT IS ALTHOUGH WE KNOW THAT THIS OUTCOME IS DUE TO LATE DIAGNOSIS AND THERAPEUTIC RESPONSE, BUT IN SOME OF THE RESECTED PATIENTS, ALTHOUGH HERE ALSO, MEDIAN SURVIVAL IS LESS THAN TWO YEARS, BUT WE SEE VARIABLE OUTCOME. SOME OF THE RESECTED PATIENTS MAY DIE WITHIN SIX MONTHS. STAGE ONE COMPLETE RESECTION, NEGATIVE MARGIN BUT SOME SURVIVE MORE THAN FIVE YEARS OR EVEN TEN YEARS. SO ONE OF THE HYPOTHESIS IS THAT THERE ARE MOLECULAR DISTINCTION IN TUMORS FROM PATIENTS WITH EXTREME PROGNOSIS AND MAY PROVIDE INSIGHT INTO THE UNDERLYING MECHANISMS OF AGGRESSIVENESS. SO ONE STUDY WAS RECENTLY PUBLISHED BY STEPHEN LEACH AND COLLEAGUES AND WHAT THEY FOUND–WHAT THEY DID, THEY COMPARED THE EXTREME SURVIVALS LIKE PATIENTS WHO SURIVE TEN YEARS AND THE PATIENT WHO IS DIED WITHIN ONE YEAR AND WHAT THEY FOUND THAT A GROUP PROGNOSIS PAICIALT, THEY HAD HIGHESTNY O ANTIGEN NUMBERS, ABUNKED ABT CD8 POSITIVE T-CELL INFILTRATE ANDNY O ANTIGEN QUALITY PROMOTES T-CELL ACTIVITY IN LONG-TERM SURVIVOR SO THIS IS ONE OF THE STUDIES AND THAT IS PROVIDING UNDERLYING MECHANISMS OF DISEASE AGGRESSIVENESS. SO HOW WE CAN IMPROVE THE OUTCOME IN PANCREATIC CANCER PATIENTS. SO OF COURSE, WE NEED EFFECTIVE THERAPY AND TO HAVE EFFECTIVE TREATMENT, WE NEED MOLECULAR TARGETS, WE DON’T HAVE ANY RIGHT NOW. WE NEED TO IDENTIFY MOLECULAR SUBGROUPS AND SO THAT WE CAN TREAT THE PATIENTS WITH SELECTIVE TARGETED THERAPY AND TREATMENT CAN BE SELECTED AND ALSO DRUG DELIVERY. IT IS OBSERVED THAT BECAUSE OF THE DISMOPLASTIC NATURE OF THE STROAMA WHICH I WILL TALK ABOUT IN MORE DETAILS, THE DRUG DOESN’T REACH TUMOR BECAUSE IT’S HIGHLY DISMORPH PLASTIC AND HIGHLY HYPOVASCULAR AS COMPARED TO OTHER TUMORS, THERE ARE LESS VASCULARIZATION IN THE PANCREATIC TUMORS. AND ALSO WE NEED EARLY DETECTION MARKERS. AND THE MARKERS THAT CAN IDENTIFY PRECANCEROUS LESIONS SO THAT CANCER CAN–CAN BE DETECTED BECAUSE BEFORE IT BECOMES CARCINOMA. SO, TO ACHIEVE THIS, WE NEED TO UNDERSTAND THE TUMOR BIOLOGY INCLUDING GENETICS, EPIGENETICS, TUMOR STROAMAL INTERACTIONS AND PROGRAMMING AND TRANSCRIPTIONAL DISREGULATIONS. SO TALKING A LITTLE BIT ABOUT THE PROGRESSION OF PANCREATIC CANCER AND THIS IS ABOUT PANCREATIC DUCTILE CARCINOMA, MAJORITY OF THE PANCREATIC DUCTILE CARCINOMA ARISE FROM PANCREATIC INTRA THEL PLASTIC LESIONS WHICH ARE CLASSIFIED AS PAN ONE, TWO, AND THREE AND THAT DEVELOPS INTO FULL BLOWN CANCER AND THERE ARE SEVERAL GENETIC ALTERATIONS THAT HAPPENS AT DIFFERENT TIME POINTS. CURIOUS MUTATION OCCURS FROM BEGENERATEDDING IN MORE THAN 90% OF THE TUMORS, P16 ALTERATIONS AND THEN FOLLOWED BY TP53 AND SMADFOUR MUTATIONS AND TP53 IS IN 50% OF THEM AND THE OTHERS CONTAIN SMAD FOUR MUTATION IS ASSOCIATED WITH THE METASTATIC NATURE OF PANCREATIC TUMORS. SO AS I MENTIONED, THESE ARE THE MAJOR GENETIC ALTERATIONS, THERE ARE ALSO MINOR GENE ALTERATIONS THAT ARE LISTED HERE. SO AS I MENTIONED THERE IS A PROMINENT STROKA ASSOCIATED WITH–STROMA ASSOCIATE WIDE CANCER. WE CALL THIS PLASTIC AND STROAMA YOU SEE HERE IN THE HNE HISTOPATHOLOGICAL SECTION AND THERE IS A STRONG STROMAL TUMOR INTERACTIONS IN THE PANCREATIC CANCER THAT ARE RESPONSIBLE FOR DEVELOPMENT OF PROGRESSION AND ALSO THERAPEUTIC RESISTANCE IN PANCREATIC CANCER. SO ONE MAJOR COMPONENT OF STROMA AND PANCREATIC CELLS IN FACT PRODUTIESS THE STROMA AND THESE CELLS ARE ACTIVATED AND PRODUCED BY TUMOR CELLS THAT ACTIVATES THAT PLAYS AN IMPORTANT ROLE IN IMMUNE SUPPRESSION AND THERAPEUTIC RESISTANCE AND PROGRESSION OF PANCREATIC CANCER. SO THIS DESCRIBES THAT ACTIVATION LEADS TO INCREASED EXTRA CELLULAR METRICS AND IN ADDITION CD T-CELLS AND IT ENHANCES AND THE ANTITUMOR IMMUNE RESPONSE SUPPRESSION BY ENHANCING THE TREG CELLS, MYELOID DERIVED SUPPRESSOR CELLS WITH THE TUMOR MACROPHAGES. AS I MENTIONED THERE THERE EARLY DETECTION OF PANCREATIC CANCER, CURRENTLY CN19-NINE IS THE ONLY MARKER WHICH IS INCREASED IN PANCREATIC PATIENTS AND SPECIFICITY IS VERY LOW FOR THIS PARKER. IN A RECEIPT STUDY, I THINK IN 2015 FROM RAGO CALORIE LAB, THEY DESCRIBE THE PROTEIN COMPLEXIO GLUE MARIOUS CAMOT TUMOR DERIVED EXOSTUDIES OF MULTIPLE ENDOCRINES CAN DISTINGUISH BETWEEN DONEARS, PANCREATIC DISEASE AND LESION AND PANCREATIC DUCTILE CARCINOMA. AND SPECIFICITY ALMOST A HUNDRED%. BUT THIS NEEDS TO BE VALIDATED IN A PROSPECTIVE COHORT WHICH HAS NOT BEEN DONE OR I THINK IN THE PROCESS OF VALIDATION. ANOTHER IMPORTANT POINT IS THAT WHEN YOU SEE THAT SOME TUMOR RESPONDS TO THE AVAILABLE CHEMO THERAPEUTIC DRUG TO SOME EXTENT, SO THERE ARE TUMOR HETEROGENEITY, ARE THERE SEVERAL MOLECULAR SUBTIPS OF THE DUCTILE CARCINOMA SO THE ANSWER IS YES THERE ARE MANY STUDIES, THE EARLIEST ARE THE FIRST STUDY THAT WAS DONE IN [INDISCERNIBLE] LAB AT HOPKINS WHERE THEY DID THE GENOMIC PROFILING OF 17, I THINK 27 TUMORS AND WHAT THEY FOUND WAS THAT EACH TUMOR HAD 63 GENETIC AFFAIRS TEAM LEADERERATIONS THAT AFFAIRS TEAM LEADERRER 12 CORE SIGNALING PATHWAYS THAT ARE MENTIONED HERE AND IN EACH TUMOR EACH OF THESE PATHWAYS THEY’RE AFFAIRS TEAM LEADERRERRED BECAUSE OF THE MUTATIONINGS IN DIFFERENT GENES. IT WAS NOT THE SAME GENE THAT WAS AFFAIRS TEAM LEADERRERRED IN THE DIFFERENT–ALTERED INTO THE DIFFERENT PATHWAY OF MUTATIONS, IT’S HIGHLY HETEROGENEOUS ROW GENIUS TUMOR MAKE UP AND THIS IS FOLLOWED BY A SERIES OF STUDIES USING AND GENOME PROFILING AND CHROMOSOMAL METRICS TAB O LICK METABOLIC FINDINGS AND THIS IS TRANSCRIPTOMIC ANALYSIS OF PANCREATIC TUMORS DESCRIBED TWO DIFFERENT SUBTYPES. –DESCRIBE THAT THE STROAMAL GENES IF THEY’RE ACTIVE OR IF THEY’RE NOT ACTIVE BASED ON THEIR ACTIVATION, THERE ARE TWO SUBTYPES AND THEY HAVE DIFFERENT PROGNOSIS AS SHOWN HERE IN TERMS OF SURVIVAL. AND THEN AGAIN THIS IS THE VERY LARGE STUDY ALMOST 500 SAMPLES, SAMPLES AND THEY ALSO DESCRIBE FOUR DIFFERENT SUBTYPES BUT RECENTLY MOST RECENT STUDY, THAT WAS DONE BY RALPH REUBEN AND COLLEAGUES AT HOPKINS AND USING THE TC GTHEY ARE ACTUALLY TWO DIFFERENT SUBTYPES THAT CAN BE DIVIDED INTO TWO DIFFERENT SUBTYPES AND THEY HAVE DIFFERENT PROGNOSIS AND THEY TOOK INTO CONSIDERATION THE NEOPLASTIC SIMILARITY AND THIS IS THE DISTINCTION BETWEEN THIS STUDY AND THE PREVIOUS STUDY BECAUSE IF YOU LOOK AT THE PANCREATIC TUMORS, THE NEW SIMILARITY IS ABOUT 20-30% RISK OF THE TUMOR IN THE OTHER THAT CHESZ TAKEN INTO CONSIDERATION, SO THAT IS THE DIFFERENT SUBTYPES OF PANCREATIC CANCER. NOW THE RECOLLECT IS THEICANCY METRICSA METABOLIC SEPARATIONS. ONE OF THE DIGS TIRCHGHT METABOLICALLY PROGRAMMING IS THE GLUTA MINE METABOLISM WHICH PANCREATIC TUMORS USE FOR A REDOCKS BALANCE AS COMPARED TO THE OTHER TUMORS AND THEN AGAIN INCREASED GLYCOL SIS AND THEN THE FLUX INTO THE NONOXIDATIVE PATHWAY OF THOSE PHOSPHATE PATHWAY AND HEXO’S BIOENTHETIC PATHWAY. SO BASED ON IT IS ALSO FOUND THERE IS METABOLIC INTERACTION BETWEEN THE STROMA AND TUMORS. AND HERE STUDIED BY SOUZA AND ALL [INDISCERNIBLE] LAB AT HARVARD MEDICAL SCHOOL, THEY FOUND THAT THE CELLS I DESCRIBED EARLIER IS AN IMPORTANT COMPONENT OF THE STROAMAL CELL, THEY PROVIDEALANINE FOR THE TUMOR CELLS, HOWEVER THEY DON’T KNOW HOW TUMOR CELLS ACTIVATE PANCREATIC CELLS, SO THERE IS A METRICSA BOLLIC COOPERATION BETWEEN, STROMAL CELLS AND THE TUMOR AND BASED ON THE METABOLIC MAKEUP THEY DIVIDED THE PANCREATIC TUMORS INTO DIFFERENT SUBTYPES, SLOW PROLIFERATING GLYCOLLIC AND LIPO GENIC PATHWAY. SO THE ONGOING COURSE RIGHT NOW IS OF COURSE TO UNDERSTAND THE BIOLOGY OF EACH SUBTYPES BECAUSE NOW WE KNOW THAT THERE ARE DIFFERENT SUBTYPES, HOW WE CAN MAKE USING OF THIS SUBTYPES TO UNDERSTAND THE UNDERLYING MECHANISMS OR DISTINCTION IN THESE SUBTYPES SO THAT THE KEY PATHWAYS CAN BE TARGETED AND IDENTIFYING KEY METABOLIC VULNERABILITIES WITH OUT THERAPEUTIC SIGNIFICANCE. SO AS I BRIEFLY MENTIONED ONE STRATEGY TO IMPROVE OUTCOME IS TO IMPROVE THE DRUG DELIVERY. SO TO TARGET THE STROMA. AND A LOT OF STUDIES THAT ARE GOING ON OR HAVE BEEN DONE IN THIS DIRECTION USED A MOUSE MODEL OF PANCREATIC CANCER, WE JUST CALL IT KPC-MOUSE MODEL. THIS MOUSE MODEL IS VERY MUCH SIMILAR TO THE DEVELOPMENT AND PROGRESSION OF HUMAN PANCREATIC CANCER AND THIS HAS PANCREAS SPECIFIC MUTATION AND P53 MUTATION AND THE DEVELOP BOTH PRECANCEROUS LESIONS AND THEN DUCTILE ADEN O CARCINOMA IN ABOUT FOUR TO FIVE MONTHS TIME. SO ONE OF THE FIRST STUDIES THAT SHOWED THAT IF YOU INHIBIT HEMMING HOG SIGNALING WAY WAY THAT DEPLETE THE STROMA, IT ENHANCES DRUG DELIVERY AND IMPROVED SURVIVAL HERE AS SHOWN HERE. SO THEY USED THE INHIBITOR, THEY DEPLETED THE STROMA, VASCULARIZATION, DRUG DELIVERY AND ENHANCED SURVIVAL AS WELL AS DECREASE THE LIVER METASTASIS. THE SAME AUTHORS HAVE ALSO FOUND THAT THEY TOOK ANOTHER APPROACH. WHAT THEY FOUND IS THAT THERE IS A HUGE INTERSTITIAL PRESSURE IN THE STROMA. AND THE VESSELS, BLOOD VESSELS ARE COMPRESSED BECAUSE OF THAT PRESSURE AND THAT WAS BECAUSE OF THE DEPOSIT OF THE HILUR ANTIC ACID AND INCREASE INTERSTITIAL PRESSURE AND THE CONSTRICTION ON THE BLOOD VESSELS, THAT WILL WILL BE IMPROVING THE DRUG DELIVERY AND THEY FOUND ENHANCED SURVIVAL IN THESE MICE AND ALSO REDUCED METASTASIS, SO THIS THIGH BROUGHT THAT TO CLINICAL TRIAL, WITH SUCCESS AND CURRENTLY THE PHASE THREE CLINICAL TRIAL IS GOING ON. SO THERE ARE TWO PHASES OF ANTISTROMAL THERAPY. AFTER THESE STUDIES WE ARE PUBLISHED, TWO PROMINENT STUDIES CAME OUT SAYING IF YOU TARGET THE STROMA, IN FACT IT ENHANCES PAN KRE TINSAT IRK CANCER PROGRESSION AND THESE TWO STUDIES ARE HERE, BRIEFLY WHAT THEY DID THAT THEY INHIBITED SONIC HEDGE HOG IN THIS MOUSE MODEL AND THAT ENHANCED THE DECREASED SURVIVAL ENHANCED PROGRESSION AS YOU CAN SEE HERE. AND THEY INCREASED METASTASIS. ANOTHER STUDY IN WHICH THEY DECREASE THE ONE BLAST IN THE STROMA WHICH IS THE ACTIVE FOAM OF THE CELLS AND DECREASING THE ONE BLAST IN THE STROMA AGAIN ENHANCED PANCREATIC TUMOR DEVELOPMENT AND PROGRESSION AND ALSO DECREASED SURVIVAL. SO WHAT WE SEE THAT THE INTERACTION BETWEEN TUMOR AND THE STROAMA IS HIGHLY COMPLEX IN PANCREATIC CANCER AND SOME STUDIES SUGGESTED THAT TARGETING THE STROAMA CAN BE BENEFICIAL, SOME STUDIES SUGGESTED THAT TARGETING STROMA CAN BE HARMFUL. SO WHY IT IS SO? SO JUST LAST MONTH A VERY INTERESTING PAPER CAME OUT IN CANTSER DISCOVERY FROM DAVID’S LAB THAT RESOLVED SOME OF THESE MYSTERY AND SINCE THIS PAPER IS NOT PUBLISHED IN ITS ORIGINAL FORM, IT WAS JUST ACCEPTED PAPER, SO THAT IS RESOLUTION OF THE FIGURE IS NOT THAT WELL. SO WHAT THEY DESCRIBED THERE ARE HETEROGENEITY IN THE CANCER ASSOCIATED ONE BLAST ARE MY O ONE BLASTS. SO THERE ARE TWO TYPES OF CANCER ASSOCIATED ONE BLASTS. ONE IS THE MY O ONE BLASTIC, ONE BLAST AND THERE IS INFLAMMATTORY CANCER ASSOCIATED ONE BLAST. AND THAT MAKES THE DIFFERENCE. SO INFLAMMATORY CANCER ASSOCIATED ONE BLAST HAVE INCREASED IL-ONE SIGNALING, ENHANCES NF CAPPA B PATHWAY AND INCREASE LIFT AND ACTIVATION OF JAGASTAT AND INCREASED CLSIX AND ONE THAT ENHANCES TUMOR PROGRESSION. OT OTHER HAND MYO ONE BLASTS TAKE THE ONE BLAST TUMOR RESTRAINING IN FACT THAT WORKS THROUGH TGF BETA SIGNALING THAT INHIBITS IL-ONE SIGNALING. SO WHAT THEY ARE PROPOSING THAT IF IT IS TARGETED, STROAMAL THERAPY THAT WOULD BE MORE BENEFICIAL THAN THE GENERAL TARGETING OF HIS STROAMA. SO, TARGETING DISTANT ONE BLASTIC INFLAMMATORY CANCER ASSOCIATED ONE BLAST. ANOTHER THING I WOULD LIKE TO MENTION IS THE PANCREATIC CANCER ORGANOID. I THINK IT’S A HIGHLY PROMISING MODEL FOR PANCREATIC CANCER AND THIS WAS AGAIN RECENTLY ESTABLISHED IN DAVID’S LAB AT THEULAR BORTLES LABORATORY AND THEY COULD MAKE IT BOTH FROM THE PRIMARY RESECTED TUMORS AND ALSO FROM THE FINE ASPERRATES AND THE SIDE. SO CURRENTLY THE RESEARCH COMMUNITY WAS USING CELL LINES OR PATIENT DERIVED TUMORS XENOGRAPHS THAT HAS CERTAIN LIMITATIONS BECAUSE MOST OF THEM CAME FROM THE PRIMARY RESECTD TUMORS AND NOT FROM THE METASTATIC TUMOR SITES ORGANOIDS WERE GENERATED FROM BOTH PRIMARY TUMORS AS WELL AS SITES AND IT RETAINS THE PATHOLOGY AND BIOLOGY OF PRIMARY TUMORS, SO IN A RECENT STUDY, THAT WAS PUBLISHED A COUPLE OF MONTHS AGO, THEY USE THIS MODEL TO PREDICT THE OUTCOME OF A CERTAIN TREATMENT, AVAILABLE AT HOW YOU CAN STRATIFY PATIENTS FOR THE TREATMENT AND WHAT THEY FOUND IS THAT ALL THESE DIFFERENT CHEMO THERAPY AND ACTIVITIES AND PROJECTSUTIC DRUGS, THEY PERFORM DIFFERENTLY AT DIFFERENT SET OF PATIENTS AND THIS ORGANOID WAS VERY HELPFUL IN PREDICTING THOSE OUTCOME. SO ORGANOID MODELS ARE MAYBE HELPFUL IN A STRATIFYING PATIENTS FOR TREATMENT. SO AS I MENTIONED THAT UNDERSTANDING TUMOR BIOLOGY IS IMPORTANT TO IMPROVE OUTCOME AND TO HAVE EFFECTIVE TREATMENT STRATEGY, AND ONE OF THE ASPECT OF PANCREATIC TUMOR BIOLOGY IS INFLAMMATION AND INFLAMMATORY MEDIATORS AMONG THE KEY REGULATES OF PANCREATIC TUMOR BIOLOGY. SO AS WE KNOW THAT CHRONIC PAIN KRE TINSA TIGHT ISOTOPE ENHANCES THE RISK OF PANCREATIS CANCER AND WE HAVE NFCAPPA B SIGNALING PATHWAY AND WE HAVE HIGHLY INFLAMMATORY PANCREATIC TUMOR SECRETES A DIFFERENT NUMBER OF INFLAMMATORY CYTOKINES AND PRODUCES FREE RADICALS RADICALS AND CAUSES LOSS THAT ENHANCES THE PRODUCTION OF FREE RADICALS. SO I WILL GIVE YOU AN EXAMPLE OF ONE OF OUR STUDIES WHICH WE ARE DOING HERE IN OUR LABORATORY. SO THE HYPOTHESIS, WE TESTED IS THAT INFLAMMATORY GENE SIGNALLURE IS ASSOCIATED WITH–SIGNATURE IS ASSOCIATED WITH CANCER PROGRESSION AND DISEASE AGGRESSIVENESS SO WE DID THAT GENE EXPRESSION FOR FILING AND WE IDENTIFIED 250 INFLAMMATORY GENE SETS THAT COULD DIVIDE PANCREATIC PATIENTS IN TWO DIFFERENT GROUPS AND THE PREDICTED PROGNOSIS AS YOU CAN SEE HERE. THEN THESE FINDINGS COULD BE VALIDATED AND THE TWO INTERCONNECTED INFLAMM ATORY MEDIATORS IS MIGRATION AND MIRROR IMAGE GRATTATORY FACTOR MYTH AND THEY’RE EXPRESSED IN TUMORS AS COMPARED TO NONTUMOR AND THE PATIENTS WHO HAD VERY HIGH EXPRESSION OF MIF [INDISCERNIBLE] EXTREMELY POOR PROGNOSIS. SO I WILL TALK A LITTLE BIT ABOUT MORE IN DETAILS ABOUT MIF DHS KHI IS A PROINFLAMMATORY CYTOKINE. IT IS EXPRESS INDEED INFLAMMATORY CELLS AND IT EFFECTS IMMUNE INFLAMMATORY RESPONSES AND INCREASES EXPRESSION IN TUMORS AND ACTIVATES ONCOGENIC SIGNALING PATHWAYS FOR EXAMPLE, NFCAPPA B AND ACT ONE AND TWO PATHWAYS AND INHIBITS ANTIINFLAMMATORY FUNCTIONS OF GRIEWT CO CORTICOIDS AND P53 AND RBE TWO F PATHWAY AND ENHANCES, NOS TWO AND COX TWO THAT CATALYZES SEVERAL REACTIONS GIVING RISE TO FREE RADICALS AND PROOF THE O GLANDINS. SOPHISTICATEDY WE STARTED SIMPLE HYPOTHESIS. THATMIF CONTRIBUTES TO CANCER PROGRESSION AND PREDICTS DISEASE OUTCOME. SO WHEN WE LOOK AT THE TUMOR BY IMMUNE OTHERWISE STOIKASTIC MODELIOMETRY, WE FOUND HIGH PRESS OF MIF IN THE EXPRESSION OF NORMAL DUCTS. THESE ARE THE NONTUMORS AND TUMORS, MIF EXPRESSION BY QRTPC R, VALIDATION AND PUBLICLY AVAILABLE DATA SETS AND A TUMORS WITH HIGH RISK EXPRESSION OF MIF, THE PATIENTS WITH HIGH MIF EXPRESSION IN TUMORS SHOWED POORER SURVIVAL AS COMPARED TO PATIENTS WITH LOW MIF EXPRESSION, THIS IS THE VALIDATION AND INDEPENDENT COHORTS. SO THIS WAS SIMPLY THE ASSOCIATION. SO WE TESTED THE HYPOTHESIS THAT MIF ENHANCES PANCREATIC TUMOR GROWTH AND PROGRESSION, SO WE FIRST USE THE XEIN, OGRAPHS AS YOU CAN SEE, MIF EXPRESSING TUMORS SHOWED ENHANCED GROWTH AND METASTASIS. WHEN WE SLICE THESE TUMORS WE FOUND THAT EVERY SINGLE TUMOR WERE POORLY DIFFERENTIATED AS COMPARED TO CONTROL TUMORS THAT WAS VERY MODERATELY DIFFERENTIATED AND THEN YOU DO THE GENE EXPRESSION PROFILING, YOU SEE THAT MIF INDUCED CHANGE IN GLOBAL GENE EXPRESSION PROFILE, AND OVEREXPRESSING TUMORS SHOWED EXPRESSION OF EMT MARKER GENES. SO WHAT HAPPENS IN THE HUMAN TUMORS? WE DICHOTOMIZED THE HUMAN TUMORS IN TWO DIFFERENT GROUPS. PATIENTS WHO HAD TUMORS WITH HIGH MIF EXPRESSION, PATIENTS WHO HAD TUMORS WITH LOW MIF EXPRESSION. WE DID AN INTEGRATIVE TRANSCRIPTOMIC ANALYSIS, BOTH MICRO RNA AND MRNA QUESTIONS, AND ASK TWO QUESTIONS ARE THOSE MOLECULAR DISTINCTIONS AND WHAT IS THE MECHANISTIC AND FUNCTIONAL ROLE OF MIF AND TUMOR PROGRESSION AND WHAT WE FOUND IS THAT MIF MAY BE THREE RCT TWOAX SESES AND ENHANCED TUMOR PROGRESSION AND I’M NOT GOING INTO THE DETAILS BECAUSE THIS IS RECENTLY PUBLISHED PAPER, BUT MIF-ENHANCED AKT PATHWAY AND THEN IT ENHANCES MICRO RNA 301 B THAT TARGETED NRTHREE C TWO GENES AND NRTHREE C T TWO, SO WHEN THE NRTHREE CTWO WAS TARGETED IT ENHANCED EMT AND ENHANCES PANCREATIC CANCER PROGRESSION. SO,–SO WHAT DOES IT MEAN, SO WE TOOK THE KPC MICE AS I DESCRIBED EARLIER, WE DELETED MIF GENES FROM THIS MICE AS YOU CAN SEE HERE. AND WHAT WE FOUND IS THAT MIF DELETED MICE, SHORT ENHANCED SURVIVAL AND ALSO LOWER METRICS TAFTIS SO ENHANCED SURVERIFIAL AND DECREASED METASTASIS, SO, HOW WE CAN TRANSLATE THESE FINDINGS IN A CLINICALLY RELEVANT WAY, SO THERE ARE SEVERAL STRATEGIES FOR MIF INHIBITION USING THE SMALL MOLECULE INHIBITORS AND ANTIMIF ANTIBODIES, AND SEVERAL OTHER STRATEGIES. CURRENTLY WE ARE USING SMALL MOLECULE ANTAGONIST AND ANTIMIF ANTIBODY TO INHIBIT TUMORS IN KPC MICE, ONCE THEY DEVELOP TUMORS. SO WHAT WE ARE DOING, WE ARE TAKING THE KPC MICE AND THEN WE ARE DOING THE IMAGING, ONES THAT DEVELOP TUMORS WE TREAT THIS MICE WITH THE ANTIMIF ANTIBODY AND INHIBITORS AND THENT POINT IS SURVIVAL, EITHER WE ARE USING IT ALONE OR IN COMBINATION WITHSTAND ARD OF CARE DRUG, [INDISCERNIBLE] WE ARE ALSO USING PATIENT DERIVED TUMOR XENOGRAPHS OR ORGANOIDS AS I MENTIONED TO INVESTIGATOR THE EFFECT OF ANTITUMOR, ANTIMIF COMPOUNDS. SO THIS STUDIES ARE IN PROGRESS RIGHT NOW AND WE DON’T HAVE THE STUDIES TO DISCUSS, BUT RIGHT NOW, WHAT I WOULD LIKE TO END WITH IS THIS SLIDE THAT IMPROVING THIS OUTCOME IN PANCREATIC CANCER PATIENTS REALLY INVOLVE THE INDEPENDENT UNDERSTANDING OF THE PANCREATIC TUMOR BIOLOGY AND THE UNDERLYING MECHANISMS, MECHANISM THAT EXPANDS FROM MOLECULAR SUBGROUPS, BIOLOGY OF THE EACH SUBGROUPS TO HAVE THE–THE PATIENT CERTIFICATION, THEN ENHANCING THE DRUG DELIVERY. IDENTIFYING THE METABOLIC VARIABILITY AND ALSO THE INFLAMMATORY SIGNALING PATHWAYS AND WE HAVE SOME OF THE DATA THAT SUGGESTS THAT INFLAMMATORY SIGNALING PATHWAY CAN ALSO REGULATE METABOLIC INFLAMMATORY PATHWAY. SO SIGNALING CAN BE ONE OF THE KEY TARGET FOR TREATMENT. SO I WILL STOP HERE AND TAKE YOUR QUESTIONS IF YOU HAVE ANY AND TRY TO DISCUSS FURTHER. THANK YOU. [ APPLAUSE ] >> [INAUDIBLE QUESTION FROM AUDIENCE ] >> SO EARLY DETECTION, THERE ARE NO SIGNS OR SYMPTOMS, SO WHAT HAPPENS IS IT IS DETECTED ACCIDENTALLY BUT WHAT THEY HAVE STARTED FOR THE FAMILIAL HISTORY THE PEOPLE WHO HAVE PANCREATIC CANCER START DOING THE ENDOSCOPEY CT SCAN IN THE FAMILY MEMBERS AND HOPKINS HAVE SEVERAL STUDIES GOING ON AND IT’S QUITE ENCOURAGING THAT MANY OF THOSE FAMILY MEMBERS HAVE BEEN DIAGNOSED EARLY ON AND THEY’RE EARLY PRECURSOR LESIONS ARE REMOVED EITHER THROUGH FULL PANCREAT ECTOMY OR DISSECTION. THEY SAY THAT DIABETES AND SMOKING, BUT THERE’S NOTHING THAT THAT STRONG. >> [INAUDIBLE QUESTION FROM AUDIENCE ] >> SO THERE, IT HASN’T WORKED SO FAR SO IT’S VERY IMPORTANT TO FIND OUT SOME PATHWAYS DOWN THE STREAM OF RATTINGS AND DOWN STREAM OF [INDISCERNIBLE]. AND THEY WOULD BE K-RASE MODEL SO THAT WOULD BE ONE PROMISING PATHWAYS TO TARGET BUT CURRENTLY NOTHING HAS WORKED. >> WORK IN PROGRESS? >> YEAH, I MUST SAY IN LAST TEN YEARS THERE HAS BEEN ENORMOUS PROGRESS, NOW WE ARE AT A POINT THAT WE WILL SEE MAJOR ADVANCEMENT AND MAJOR BREAK THROUGH BECAUSE GROUND WORK HAS BEEN PROGRESSED ENORMOUSLY AND AT LEAST WE KNOW NOW DIFFERENT MOLECULAR SUBGROUPS AND IF WE ARE ABLE TO EVEN TARGET A SMALL SUBGROUP OF PATIENTS USING THESE THAT WOULD BE MARVELOUS. [INDISCERNIBLE] >> YES, YES, AND THEY DO FIND IT. >> [INDISCERNIBLE]. >> NO, AGAIN IT IS TOO LATE AT THAT POINT, YEAH. >> OKAY, THANK YOU VERY MUCH. OUR NEXT SPEAKER IS MARINA DOBROVOLSKAIA. SHE WAS EDUCATED IN RUSSIA AND SUBSEQUENTLY SHE CAME TO THE NATIONAL CANCER INSTITUTE. SHE’S ALSO BEEN AT UNIVERSITY OF MARYLAND, AT BALTIMORE, MARYLAND. DONE RESEARCH IN COMPANIES, ALSO AS A GOP LABORATORY AND DEVELOPMENT IN RICHMOND, AND SHE JOINED THE NCI IN FREDERICK AND SHE’S CURRENTLY A SENIOR PRINCIPAL SCIENTIST IMMUNOLOGY SECTION HEADS AT THE NANO TECHNOLOGY CHARACTERIZATION LAB. HER TITLE: NANO TECHNOLOGY FOR CANCER THERAPY, BENEFITS, CONCERNS AND EFFECTSOT IMMUNE SYSTEM. MARINA? >> THANK YOU. THANK YOU FOR THE INVITATION AND INTRODUCTION, GOOD EVENING EVERYONE. SO WE’RE GOING TO TALK ABOUT NANO TECHNOLOGY AND CANCER. THIS IS OUTLINE OF MY PRESENTATION. WE WILL TALK BRIEFLY ABOUT SOME DEFINITIONS OF NANO TECHNOLOGY. I WILL GIVE YOU SOME EXAMPLES OF NANO PARTICLE USE IN DAILY LIFE. WE WILL LOOK AT SOME NANO TECHNOLOGY BASED FORMULATIONS APPROVED FOR MEDICAL USE. WE’LL TALK ABOUT NANO PARTICLE USE FOR CANCER DIAGNOSIS AND THERAPY AND IN THIS SECTION, OUR MAIN FOCUS WILL BE ON FENNISTERATION FITS, I WILL SHOW YOU EXAMPLES OF BENEFITS AND THE OTHER SIDE OF THE COIN OF SOME OF THE SAFETY CONCERNS ASSOCIATE WIDE NANO TECHNOLOGY. AND THEN THE SECOND PART OF MY PRESENTATION WILL BE FOCUSING ON NANO MATERIALS EFFECTSOT IMMUNE SYSTEM. SO WHAT IS NANO TECHNOLOGY? THERE IS NO UNIVERSAL DEFINITION, IT IS DEFINED NANO PARTICLES AS OBJECT AND SIZE WITH AT LEAST ONE DIMENSION FROM ONE TO 100 NANO METERS HOWEVER FOR THE URETTERY PURPOSES FOR THE UNITED STATES FDA CONSIDERS ANY PARTICLE WITH THE SIZE LESS THAN 1000 NANO METERS, SO LESS THAN 1 MICRON IS A NANO TECHNOLOGY [INDISCERNIBLE] ASSOCIATED WITH THE SIZE. GLOBAL NANO TECHNOLOGY MARKET ANALYSIS DEMONSTRATES THAT COUPLE OF YEARS AGO IN 2015, MAJORITY OF THE PRODUCTS WERE ENVIRONMENTAL FOLLOWED BY ELECTRONICS AND CANCER PRODUCTS. HOWEVER BUSINESS REPORTS PREDICT HIGH GROWTH RATE FOR NANO TECHNOLOGY INBIOMEDICAL FIELDS IN IT IS THE NEXT FEW YEARS UNTIL 2021. IN THE REPORT FROM THE UNITED STATES FOOD AND DRUG ADMINISTRATION, THE LANDSCAPE OF NANO TECHNOLOGY BASED PROD UBLGHTS SUBMITTED TO THE FDA FOR REGULATORY APPROVAL DOMINATED BY LIPO STUDIES OF MULTIPLE ENDOCRINES FOLLOWED BY NANO CRYSTALS AND FOLLOWED BY [INDISCERNIBLE]. YOU SEE THE OTHER TYPES OF THE PLATFORMS THAT ARE CONSIDERED FOR MEDICAL APPLICATIONS. SO IN DEVICES. BUT [INDISCERNIBLE] NANO TECHNOLOGY PRODUCTS IN DAILY LIFE. HERE YOU SEE THE EXAMPLES OF THE PRODUCTS IN CLOTHING, IN WOUND DRESSING, SPORTS EQUIPMENT, SUNSCREENS, COSMETICS. THIS IS EXAMPLE OF NANO TECHNOLOGY PRODUCTS THAT ARE USED IN MEDICINE AND THEY ARE APPROVED FOR MEDICAL USE, A SPECIAL INTEREST FOR ONCOLOGIST, THIS FORMULATION SHOWN ON THE BOTTOM, [INDISCERNIBLE], THESE ARE CANCER THERAPEUTICS. THIS IS SMALL ONCOLOGY DRUGS FORMULATED USING NANO TECHNOLOGY PLATFORM AND THERE ARE REASONS FOR THIS FORMULATION, THE MAIN REASON IS TRYING TO REDUCE TOXICITY SO ENGAGING THE [INDISCERNIBLE] FOR EXAMPLE, AND I WILL IN THE NEXT SLIDE I WILL SHOW YOU SOME OF THE EXAMPLE. IN CASE OF THE DAUNOXOME, THIS WAS CARDIAC TOXICITY BY FORMULATING INTO THE LIPO STUDIES OF MULTIPLE ENDOCRINE, THE CARDIAC TOXICITY WAS OVERCOME. HESE ARE THE REASONS WHY OF WHY NANO TECHNOLOGY PLATFORMS ARE CONSIDERED FOR CANCER NANO TECHNOLOGY AND TO THAT IN MANY OTHER AREAS OF PUBLICATION, AND PARTICLES MAY IMUVE[INDISCERNIBLE] HYDRO PHOBIC DRUGS AND THEY MAY HAVE FULTY FUNCTIONAL CAPABILITIES SUCH AS RESEARCHERS CAN DELIVER CANCER DRUG AND IMAGING AGENTUTESSING THE SAME PLATFORMS AND THOSE FORMS ARE CALLED [INDISCERNIBLE] OR DIAGNOSTICS IN THE THERAPEUTICS. SOME NANO TECHNOLOGY PLATFORMS ALLOW TUMOR TARGETING. THEY ALSO CAN PROVIDE DELIVER EXPE CONTROLLED RELEASE. SO NOW LET’S LACK AT SOME OF THE BENEFITS OF NANO TECHNOLOGY. THIS IS AN IMAGE THAT WAS SHARED WITH ME BY DR. [INDISCERNIBLE] FROM SIGHT IMMUNE SCIENCES FROM THE LUNG MANY YEARS OF COLLABORATION WITH HIM AND DR. EGGERMAN TREATED I PATIENT WITH ELANNOMA AND THIS TUMOR WAS INOPERABLE SO WHAT THEY DID, THEY PERFORMED ISOLATED LYMPHFUSION WHERE THE BLOOD VESSELS FEED IN JUST THE EFFECTED LIMB, THEY WERE ISOLATED AND THE BLOOD WAS CIRCULATING USING A PUMP AND THEY USED THERAPEUTIC PROTEIN TUMOR NEUROECTODERMALCROSEIS PRODUCT ALPHA THIS CANNOT BE USED FOR [INDISCERNIBLE] DUE TO TOXICITY. SO THE GOOD NEWS WAS THAT THE LIMO FUSION PROVIDED BENEFIT AND AS YOU SEE ON THIS IMAGES BENEFIT BY THE TUMOR REDUCTION. THIS PROCEDURE WAS APPROVED FOR CLINICAL USE IN EUROPE HOWEVER IT IS NOT APPROVED FOR THE CLINICAL USE IN THE UNITED STATES. AND UNFORTUNATELY, THE DOSE OF TNF, THAT IS REQUIRED TO PROVIDE THERAPEUTIC BENEFIT IS TOO HIGH TO BE ADMINISTERED SYSTEMICALLY SO IT WOULD BE TOO TOXIC SO THE SIGHT IMMUNE SCIENCES IMMOBILIZED TUMOR NEUROECTODERMALCROSEIS ALPHA ON THE SURFACE OF THE NANO PARTICLES THAT ARE [INDISCERNIBLE] AND THEN ALLOWED THEM TO DELIVER THIS SAME DOSE OF TNF AS WAS DELIVERED BY DOCTOR EGGERMONT BY THE PROCEDURE AND THIS IS THE SYSTEMIC ADMINISTRATION WITHOUT REACHING MAXIMUM CALIBRATED DOSE. THIS IS ANOTHER CONCEPT, I MENTIONED TO YOU [INDISCERNIBLE] WHICH IS LIPO STUDIES OF MULTIPLE ENDOCRINAL DOCKS O RUBE SIN FORMULATION THIS, IS BASIC RESEARCH STUDY REPORTED BY SCIENTIST AT MED IMMUNE, WHAT THEY SHOWED WAS YOU SEE ON THIS SLIDE, THAT THERE IS NO EFFICACY, NO EFFICACY AT 5-MILLIGRAM PER KILOGRAM DOSE WITH DOCKS O RUBE SIN, AND THEY USE IT IN THE MICE, THEY ABSORB DELAY IN THE TUMOR GROWTH IN THE DOCKSILE GROUP SO THAT SUGGESTED THEM THAT THE LIP O STUDIES OF MULTIPLE ENDOCRINAL [INDISCERNIBLE] AND FORMULATION PROVIDES ADDITIONAL BENEFIT SO THE [INDISCERNIBLE] IS STILL UNKNOWN HOWEVER DOCKSILE IS CONSIDERED AS AN IMPROVEMENT FOR IMMUNOTHERAPYS IN THIS BASIC RESEARCH STUDY, THEY COMBINED DOCKSILE WITH DIFFERENT IMMUNE O THERAPEUTIC DRUGS, ANTIPD ONE AND CTLA-FOUR, AND THE LIGANDS AND YOU SEE THAT ESPECIALLY IN THE ANTIPDONE COMBINATION, THEY OBSERVED COMPLETE RESPONSE IN 11 OUT OF 12 [INDISCERNIBLE]. SO THERE IS AN IMPROVED BENEFIT FROM USING AINANCE O TECHNOLOGY FORMULATION AND COMBINING IT WITH TRADITIONAL IMMUNE O THERAPEUTIC DRUGS. NANO PARTICLES HAVE SHOWN A LOT OF BENEFIT IN DELIVERING ANTIGENS AND IMPROVING EFFICACY OF VACCINES. NANO PARTICLES ARE CONSIDERED FOR THIS TYPE OF DELIVERIES ARE [INDISCERNIBLE] PLEXUS AND LIPO STUDIES OF MULTIPLE ENDOCRINES. ON THIS SLIDE, I SHOW YOU EXAMPLE OF THE PLATFORM CALLED [INDISCERNIBLE] DEVELOPED BY THE PDS BIOTECHNOLOGY, THIS PLATFORM IS MADE BY POSITIVELY CHARGED LIPID AND IN THE SERIES OF STUDIES THEY DEMONSTRATED WHETHER DELIVERY OF ANTIGENS TO THE DENDRITIC CELL RIDDIC CELLS, MATURATION OF DENDRITIC CELLS, AND CHANGE IN TUMOR MICROENVIRONMENT, THAT PROVIDES OPTIMAL IMMUNE RESPONSE TO THE [INDISCERNIBLE]. SO NOW WE SAW THE BRIGHT SIDE OF NANO TECHNOLOGY AND WE’LL TALK NOW ABOUT THE OPPOSITE SIDE. WE’LL TALK ABOUT SAFETY CONCERNS. ALWAYS IN LIFE, THERE IS NOTHING ABSOLUTELY SAFE, OR GOOD, SO ALWAYS THERE IS A COMBINATION OF BOTH [INDISCERNIBLE]. ONE OF THE CHARACTER IEOF THETICS OF NANO TECHNOLOGY FORMULATED DRUGS IS THAT THE DRUG TOXICITY MAY CHANGE AND DEPENDS ON THE TYPE OF THE NANO TECHNOLOGY CARRIER THAT IS USED TO DELIVER THIS DRUG. IN THIS CASE, I AM USING EXAMPLE OF MOLL MOLL KIEWM ANTICANCER DRUG DOXORUBE SIN, IT IS NORMALLY ADMINISTERED AND IN BONE MARROW AND RESULTS IN CARDIO TOXICITY AND MILD SUPPRESSION. I MENTIONED TO YOU ALREADY [INDISCERNIBLE] DOXORUBE SIN CALLED DOXORUBEILE WAS REDUCE AND IT WAS SUBSTANTIAL BENEFIT TO THE PATIENT, HOWEVER HA WHAT WAS DISCOVERED DURING CLINICAL STUDIES AND FULL AND CLINICAL EXPERIENCE WITH THIS FORMULATION AFTER APPROVAL IS THAT THE LIP O STUDIES OF MULTIPLE ENDOCRINES ARE A–LIPO STUDIES OF MULTIPLE ENDOCRINES ARE ACCUMULATED BY DENDRITIC CELLS IN THIS AND THEY CAUSE INFLAMMATION IN THE RESULTS SO CALLED HAND OR FOOT SYNDROME OR [INDISCERNIBLE]. THIS TOXICITY IS MANAGEABLE FOR CORTICO STEROIDS BUT AGAIN IT IS ONE OF THE TYPE OF TOXICITIES THAT PHYSICIANS HAVE TO DEAL WITH FOR DOXORUBICIN, AND SOME PATIENTS ARE MORE SUSCEPTIBLE TO THIS TYPE OF TOXICITY I GUESSITY. N WAS NOT INCORPORATED INTO THE NANO PARTICLES AND THIS FORMULATION DID NOT HAVE [INDISCERNIBLE] TOXICITY HOWEVER THIS FORMULATION ACCUMULATED THE KIDNEY AND RESULTED IN DRUG MEDIATED NECRO TOXICITY. SO VERY IMPORTANT TAKE HOME MESSAGE FROM CURRENT KNOWLEDGE FROM THIS STUDIES IS THAT [INDISCERNIBLE] AND DRUG CAN BE TOXIC BUT IN CASE OF THE NANO TACKNOLOGY FORMULATION, THE TOXICITY CAN BE DEPENDENT ON WHAT TYPE OF NANO TECHNOLOGY PLATFORM IS USED SO BASICALLY DRUG WILL BE TOXIC TO WHETHER THE NANO PARTICLE WILL TAKE THIS DRUG. AND NOW, LET’S TALK ABOUT THE NANO PARTICLE FOR THE SYSTEM, THESE ARE SOME TOPICS THAT I COVER DM MY PRESENTATION, I WILL TALK ABOUT NANO PARTICLE INTRACTION WITH PLASMA PROTEINS AND IT’S [INDISCERNIBLE] BIODISTRIBUTION, WE’LL TALK ABOUT EPITELOMERE BLOOD CELLS AND BLOOD COAGULATION SYSTEM AND WE’LL TALK ON CURRENT KNOWLEDGE OF [INDISCERNIBLE] AND MEDIATED TOXICITY AND DELAY HYPER SENSITIVITY REACTIONS AS WELL AS ABOUT CYTOKINE AND IMO GENERATEDISSITY. THERE ARE A COMMUNICATION IN THE NANO PARTICLES AND PROTEIN AND THIS IS SHOWNOT DIAGRAM. ON THE ONE HAND PROTEINS BIND INTO ARTICLES RESULTING IN CHANGE IN PARTICLE PROPERTIES. OT OTHER HAND, PROPERTIES OF THE PROTEINS BOUND TO THE PARTICLE SURFACE MIGHT ALSO CHANGE. THE CONFIRMATION OF THE PROTEIN MAY CHANGE, ACTIVITY OF THE PROTEIN MAY CHANGE AS A RESULT OF THIS INTERACTION. SO HERE YOU SEE EXAMPLE FROM THE STUDY CONDUCTED BY TOM [INDISCERNIBLE] GROUP AND DEMONSTRATING HOW THE BINDING OF THE COMMON PLASMA PROTEINS TO NANO PARTICLES SURFACE DEPENDS ON THE SIZE OF THE PARTICLES. HERE I SHOW YOU THE EFFECT OF THE PROTEINSOT SIZE OF NANO PARTICLES. THIS IS [INDISCERNIBLE] PARTICLES THAT HAVE THEORETICAL NANO METER SIZE OF 50 NANO METERS AND THEY’RE SCATTERED HAVING THE SIZE OF 33 NANO METERS WHICH IS CLOSE TO THE NOMINAL SIZE HOWEVER AFTER INCUBATION WITH PLASMA PROTEINS THERE IS THIS PLASMA PROTEIN LAYER FORMED ON THE SURFACE OF THE PARTICLE THAT RESULTS IN THE CHANGE OF THE PARTICLE HYDRO DYNAMIC SYSTEM TO 36 NANO METERS SO WHY IT IS IMPORTANT BECAUSE PATIENTS WILL NOT DEAL WITH THE WITH THE PARTICLE THAT HAS 76 NANO METERS HYDRODYNAMIC SIZE AND IT HAS IN THIS CASE, MADE OF THE GOLD PARTICLE AND THE SOFT LAID OF THE PROTEINS IN PLASMA AND BECAUSE THERE IS NOT [INDISCERNIBLE]. THERE IS NO BOND IN THE PARTICLE SURFACE, THE PROTEINS MAY DETACH FROM THE PARTICLE SURFACE AND OTHER PROTEINS MAY COME AND BIND. SO IT’S VERY DYNAMIC SYSTEM. RIGHT NOW, IT IS VERY WELL ESTABLISHED, KNOWLEDGE THAT IF PARTICLES BIND A LOT OF PROTEIN, THE PROTEIN, THERE IS NO PROTECTIVE COATINGOT PARTICLE SURFACE AND THEY BIND TO A LOT OF PLASMA PROTEINS LIKE YOU CAN SEE HERE, FROM TWO DIMENSIONAL ELECTROPHORESIS, THEN THESE TYPES OF PARTICLES ALSO ACCUMULATE BY IN MACROPHAGES, INVITRO AND THEN IN THE NUCLEAR FOR THE SYSTEM AND INVIVO. IF HOWEVER, THE PARTICLE HAS PROTECTIVE CODE [INDISCERNIBLE] THEY BIND LESS PROTEIN, THEY DO NOT ACCUMULATE IN MACROPAGES INVITRO AND THEY ARE NOT REGULATED ELIMINATED BY THE NUCLEAR FOR THE SYSTEM ORGANS INVIVA, SO IT IS VERY WELL ESTABLISHED THAT THE FAT OF PROTEIN BINDING CAN PREDICT THE CIRCULATION TIME OR LONGEVITY OF THE PARTICLES OF CIRCULATION IN THE PLOOD. HOWEVER, WHAT IS CURRENTLY UNKNOWN IS THAT BYPASSING OF INDIVIDUAL PROTEINS AND HOW IT CONTRIBUTES TO THE PARTICLE OF THE [INDISCERNIBLE], THE BASIC WERE SIDE IS WHAT TYPE OF THE PROTEINS BIND TO THE PLACE, THE EFFICACY MAY CHANGE OR THERE’S SOME TARGETING TO BE EFFECTED BUT THERE IS NO ACCURATE WAY OF DETECTING AND QUANTIFYING PROTEIN [INDISCERNIBLE] ESPECIALLY IN INDIVIDUAL PATIENTS BECAUSE [INDISCERNIBLE] OF THE PLASMA IS DYNAMIC SYSTEM, PROTEINS THAT ARE CONSTITTIVELY EXPRESSED BUT THOSE LEVELS MAY DEPENDING ON THE DIET OR LEVEL OF STRESS AND PHYSIOLOGY AND SO FORTH. THERE ARE DIFFERENT MODELS AVAILABLE FOR THE PARTICLE CAPTURE BY THE MPS, I SHOW YOU TWO MODELS THAT ARE SUGGESTED BY DR. WILLIAMS AND [INDISCERNIBLE] AT UNIVERSITY OF NORTH CAROLINA. HE SUGGESTED ONE MOLD CAPTURE. THIS IS WHEN THE PARTICLES DELIVERED AND ACCUMULATED BY CELLS IN TISSUES, LIKE IN TUMOR OR LIVER OR SPLEEN IN THIS CASE. IN THE SECOND MODEL, CALLED HIJACKING PARTICLE IS TAKEN UP BY MONOCYTES IN THE BLOOD STREAM AND THEN THESE MONOCYTES ACT AS A VEHICLE TO DELIVER THE PARTICLES OF THE TUMORS IN THE LIVER AND SPLEEN AND IN FACT ONE OF THE AREAS OF ACTIVE RESEARCH IS USING THIS HIJACKING MODEL TO BASICALLY UTILIZE MONONUCLEAR SYSTEMS TO DELIVER SOME PARTICLES TO SHORTEN TISSUES SUCH AS BRAIN TUMORS FOR EXAMPLE. PARTICLES CAN BE TOXIC TO IMMUNE CELLS AND THIS TOXICITY DEPENDS ON THEIR PHYSICAL CHEMICAL PROTEINS. THE HOM OLDER PEOPLE SIS IS TOXICITY THAT RESULTS FROM PARTICLE DAMAGING EFFECT ON RED BLOOD CELLS EREGHTROCYTES AND IT DEPENDS ON PARTICLE SIZE AS WELL AS IT DEPENDS ON THE PARTICLE CHARGE. AND I SHOW YOU THIS EXAMPLE, OF PARTICLES CALLED DENDRITIC CELL RAMERES, [INDISCERNIBLE] WITH THIS PARTICLES WITH THREE DIFFERENT SURFACE FUNCTIONALITIES CAN BE FOUND THAT ONLY PARTICLES WITH [INDISCERNIBLE] PARTICLES OF THE LARGE SIZE ARE DAMAGING WHILE PARTICLES WITH THE SAME TYPE OF SURFACE, BUT SMALLER SIZE DO NOT DAMAGE ERYTHROCYTES. THESE ARE [INDISCERNIBLE] NEUTRAL COUNTERPARTS OF THE SAME SIZE DAMAGE ERYTHROCYTES. SO AGAIN THE SIZE AND THE CHARGE ARE VERY IMPORTANT. SAME APPLIES FOR PARTICLE REGULATION FOR SYSTEM, PARTICLES CAN BE ENGINEERED TO SPECIFICALLY AVOID OR INTERACT WITH THE CALCULATION SYSTEM AND THE CALCULATION SYSTEM IN HEALTH IS A CONSTANT BALANCE WITH THE PRODUCTIVITY AND ANTICO AGULATE ACTIVITY. IF THE ACTIVITY IS TOO STRONG WE HAVE TO DEAL WITH THROMBOSIS, IF THE ACTIVITY IS STLONGER WE HAVE TO DEAL WITH HEMORRHAGE. SO IT IS VERY IMPORTANT TO MAINTAIN THE HEMOSTASEIS IN BALANCE AND SOME OF THE PARTICLES MAY CHANGE THIS BALANCE DEPENDING ON THEIR PROGRESS. PARTICLES MAY INTERCEPT WITH THE FACTOR AND THEY MAY BIND AND DEPLETE THE REGULATION FACTORS, THEY MAY–THEY IRPT ACT WITH THE EPITHELIAL CELLS AND THE RESULTS IN CYTOTOXICITY AND ALSO INDUCE SOME INFLAMMATION ANDOXIDATIVE STRESS IN THESE CELLS. THEY CAN INTERACT WITH PLATELETS OR THROMBOW SIGHTS INDUCING DIRECT ACTIVATION OF THE CELLS AND ALSO INFLUENCE THE CELL RESPONSE OF THE RESULT IN AN INHIBITION. HERE I’M USING THE EXAMPLE OF A DEPPED ROUGH ATOM MERE, AND YOU SEE THIS HAS ALL GERMINAL GROUPS PRESENT AS A MEANS THAT THIS PARTICLES ARE VERY THROMBOW GENIC. THEY ACTIVATE [INDISCERNIBLE] AS STRONG AS THE POSITIVE CONTROL COLLAGEN. HOWEVER, THEN, AMINSOT PARTICLE SURFACE ARE MASKED, THEN GRADUALLY, WE REDUCE THIS PROPERTY TO THE VERY LOW LEVEL. SO THE POTENTIAL IS VERY IMPORTANT AND THE LESS CHARGED GROUPS WE HAVE ON THE PARTICLE SURFACE, THE LESS ACTIVATION SUCH PARTICLES WILL HAVE ON [INDISCERNIBLE]. PARTICLE COMPOSITION MAY ALSO CONTRIBUTE TO THE ISHT ACTION WITH [INDISCERNIBLE]. HERE I USE PARTICLES, I COMPARE PARTICLES FROM THE SAME CLASS, DENDRITIC CELL ROUGH ATOM MERES BUT I USE DIFFERENT COMPOSITION, [INDISCERNIBLE] DENDRITIC CELL ROW MERES AND THEN WE SEE IN BOTH TYPES OF THE PLATFORMS THAT WE OBSERVE THE SIZE DEPENDENT, THE GREATER THE PARTICLE, THE MORE THE STRONGER THE ACTIVATE PLATNINS, BUT IN BOTH CASES WE CAN ALSO SEE THE COMMON DENDRITIC CELL ROUGH ATOM MERES ARE MORE IMPORTANT THAN THESE DENDRITIC CELL ROUGH ATOM MERES AND THAT HAS TO DO WITH THE ARCHITECT AND YOU ARE THE BUILDING LOOKS OF THIS MATERIALS. PARTICLES MAY CAUSE [INDISCERNIBLE]. HERE I SEE–I SHOW YOU THE DIFFERENT TYPES OF THE ALLERGY. THIS IS GELS AND [INDISCERNIBLE] CLASSIFICATION THAT THIS MAIN HYPER SENSITIVITY REACTIONS IN TYPE ONE IMMEDIATE TYPE ONE HYPER SENSITIVITY REACTIONS, TYPE TWO, TYPE THREE AND TYPE FOUR. AND THEN WE WILL LOOK IN THE CURRENT LITERATURE WITH NANO MATERIALS, WE SEE MATURITY OF THE REPORTS, COME ABOUT THE SO CALLED PSEUDOALLERGY, THIS IS THE IMMEDIATE HYPER SENSITIVITY REACTION, BUT IT IS INDEPENDENT ON THE UNIGLOBUE LYNN SCENE AND THE PLAIN PLAYER IS [INDISCERNIBLE]. SO A LOT OF PARTICLES MAY ACTIVATE COMPLEMENT AND THEY WILL TRIGGER THIS TYPE OF HYPER SENSITIVITY OR ALLERGIC REACTION. BUT THERE IS A LIMITED AMOUNT OF CASES IN THE LITERATURE SUCH AS SOME PARTICLES MAY CAUSE DELAY TYPE HYPER SENSITIVITY REACTIONS. AND AGAIN, THIS IS AREA OF STEEL ACTIVE RESEARCH, THERE IS NOT TOO MUCH DATA AND HOWEVER, THE REASON WHY IT IS IMPORTANT IS BECAUSE WE KNOW THAT THERE WERE DRUGS ENCLUEDING ONCOLOGY DRUGGINGS ARE APPROVED FOR CLINICAL USE AND THEN DISCONTINUED LATER ON DURING THE PROCESS DUE TO IMMUNE TOXICITY ISOTOPITY MEDIATED AND HYPER SENSITIVITY REACTIONS TO THE IMMUNE MEDIATED ADVERSE REACTIONS ARE THE 11 OF THE REASONS FOR THIS DISCONTINUATION. THIS IS AN EXAMPLE OF THE DATA FROM CLINICAL STUDY. HERE YOU SEE THE LEVELS OF THE GERMINAL COMPLEMENT COMPLEX IN THE PLASMA, OF VARIOUS PATIENTS THAT WERE TREATED WITH REGULATED DOXIL, SO TEN MINUTES AFTER ADMINISTRATION INTO THE PATIENTS WE SEE SOME PATIENTS SHOW REALLY HIGH LEVEL OF THE COMPLEMENT TERMINAL COMPLEX, SOME PATIENTS SHOW LOWER LEVELS AND SOME DO NOT RESPOND AT ALL. SO AGAIN THIS, IS ACTIVE AREA OF THE SEARCH, THE PHENOMENON IS CALLED [INDISCERNIBLE], COMPLEMENT ACTIVATION, ALLERGY IS A PIE O NEAR AND THE MAIN WORLD EXPERT IN THIS FIELD. SO THIS IS EXAMPLE OF ITS STUDY OF DENDRITIC CELL RAMERE OF THE NANO PARTICLE [INDISCERNIBLE] HYPER SENSITIVITY REACTION AND IN THIS CASE, IT WAS INDUCED BY DEBD ROUGH ATOM MERES AND FROM MY KNOWLEDGE THIS IS THE ONLY STUDY THAT RECORDS SUCH ADVERSE RESPONSE, DELAYED RESPONSE TO ENVIRONMENTAL EXPOSURE TO NANO PARTICLES. THIS WAS A STUDENT WORKING IN THE LAB SYNTHESIZING DENDROMERES, CAME WAS TREATED WITH STEROIDS AND CAME BACK TO WORK AND EXPERIENCED THE TOXICITY AGAIN, THE TOXICITY UNDERLYING THE CAUSE IS STILL UNKNOWN. NOW LET’S TALK ABOUT THE CYTOKINE STORM, IT’S A COMMON TOXICITY FOR BIOTECHNOLOGY PRODUCT. HERE I SHOW YOU EXAMPLE OF THE BIOTECHNOLOGY PRODUCT WHICH IS CD8 [INDISCERNIBLE] ANTIBODIES, AND THIS IS METASTATIC STATUS IN NON[INDISCERNIBLE] AND HOWEVER IT WAS BASIC IN PHASE ONE CLINICAL TRIALS, ALL PATIENTS WHO RECEIVED THIS MEDICATION DEVELOPED CYTOKINE STORM AND THE SICKNESS IS VERY SEVERE, WHAT YOU SEE ON THIS PICTURE IS NECKROSIS IN THE FINGERS DUE TO EXCESSIVE PRODUCTION OF TUMOR NECKROSIS TUMOR ALPHA, SO IT TOOK SEVERAL YEARS TO UNDERSTAND THAT THE EXPERIMENTS THAT WERE PERFORMEDUTESSING HEALTHY DONOR’S BLOOD,OT NUCLEAR CELLS WAS PREDICTIVE AND SHOWED HIGH LEVELS OF TNF. THE BIG QUESTION WAS WHY MONKEYS DID NOT SHOW THIS TOXICITY AND THAL CASE, IT WAS–IN MOST CASES, NONHUMAN PRIMATES WOULD BE PREDICTIVE AND IN THIS SPECIFIC CASE UNFORTUNATELY FOR PATIENTS, THE HUMAN CD28 AND MONKEY CD28, WERE IDENTICAL EXCEPT FOR FEW IMINNOW ACIDS THAT WERE DIFFERENT WITH THE MONKEYS AND HUMANS AND THESE IMMUNE O ACIDS WERE THE EPITAUPE WHICH THEY RECOGNIZE, BUT THIS CASE, TAUGHT US IMPORTANT LESSON THAT WE STILL HAVE TO USE IN THE STUDIES AND WE DO PRECLINICAL WORK, HOWEVER, IF WE HAVE ACCESS TO NORMAL HUMAN BLOOD, THE INVITRO ASSAYS USING PBMC WOULD HELP OVERCOME THIS TRAGEDIES LIKE THE ONE FOR TGN 12. THE NANO PARTICLES INDUCE CYTOKINES AND AGAIN IT DEPENDS ON THE PHYSICAL CHEMICAL PROPERTIES. CATAIONIC LIP O STUDIES OF MULTIPLE ENDOCRINES AND GENERAL ARE INFLAMMA ARE TOY AND YOU SEE THE EXAMPLE OF THE CYTOKINE AND CHEMO KINE INDUCTION BY CAT IONIC LIP O STUDIES OF MULTIPLE ENDOCRINES. THE METHOD IS UNDERLYING CHEEMEE KINE INDUCTION, RELYS ONOX DAYLIGHTIVE STRESS, WHAT YOU SEE HERE IS A ALSO STRUCTURE OF [INDISCERNIBLE] STATUS SHOWING THAT THE VARIOUS LIP O STUDIES –LIP O STUDIES OF MULTIPLE ENDOCRINES HAVE STRESS, THEY DON’T INDUCE THE STRESS, DO NOT INDUCE CHEMO KINES HOWEVER LIPO STUDIES OF MULTIPLE ENDOCRINES INDUCE HIGH LEVELS OF CHEMO KINE AND THIS CHEMO KINE PRODUCTION MAY BE INHIBIT BOOED I ADDITION OF THE ANTIOXIDANTS SUCH AS [INDISCERNIBLE] SHOWN THAT YOU SEE ON THIS SLIDE. AND THIS GOES TO THE DEBATE IN WHETHER THIS PROPERTY IS BENEFICIAL OR NOT. SO FROM PREVIOUS SPEAKERS WE KNOW THAT SOME INFLAMMATION IN THE TUMOR AND PRODUCTION OF& CERTAIN CYTOKINES IN THE TUMOR MAY PROMOTE TUMOR GROWTH SO WE USE NANO PARTICLES TO DELIVER OF CYTOTOXIC BLOOD IF THE DRUG FORMED SO IT IS INTENDED TO HEAL THE TUMOR BUT IF IT IS THE CYTOKINE IT WOULD BE COUNTY PRODUCTIVE TO THE ROLE THAT IS PLAYED BY THE ONCOLOGY DRUG. SO THIS IS VERY IMPORTANT INFORMATION AND AGAIN IT’S AN AREA OF ACTIVE RESEARCH AT THE MOMENT. THIS IS ANOTHER INTERESTING MECHANISM OF HOW SOME OF THE PARTICLES MAY INDUCE CYTOKINES AND IN THIS CASE INSTEAD OF THE CHEMO KINES, I AM USING INTERLUKEIN ONE. CAT IONIC PARTICLES ARE KNOWN TO INDUCE ILONE SECRETION FOR ACTIVATION OF THE PREINFLAMMA STUDIES OF MULTIPLE ENDOCRINE AND IT IS TRIGGERED BY THE MECHANISM CALLED [INDISCERNIBLE] SPONGE MECHANISM, THE CAT IONIC AREA, ACCUMULATES IN THE LYSOSOMES AND TRIES TO NEUTRALIZE THE AREA AND PUMPING WATER INTO THE LYSOSOME THAT LEADS TO THE LYSOSOMAL RUPTURE THAT IS TRIGGERED IN THE INFLAMMA STUDIES OF MULTIPLE ENDOCRINE ACTIVATION. THIS TYPE OF CYTOKINE ACTIVATION BY NANO PARTICLE IS BENEFICIAL FOR VACCINES LIKE CAT IONIC LIPIDS, FULLY PLEXUS, IMPROVED VACCINATED MECHANISM AND INFLAMMA STUDIES OF MULTIPLE ENDOCRINE ACTIVATION CAN BE USED TO SCREEN FOR THE NANO PARTICLES WITH SOME ADJUVANT PROPERTIES, HOWEVER, PARTICLES THAT HAVE THIS PROPERTIES INTENDED FOR SYSTEMIC ADMINISTRATION WILL BE TOO TOXIC SO THERE IS ALWAYS A BALANCE BETWEEN THE PRODUCT OF THE PARTICLE AND ALSO THE ADMINISTRATION THAT IS INTEBDED FOR THE USE. SOME DRUGS THAT ARE DELIVERED BY NANO PARTICLES MAY ALSO BE IMMUNE O TOXIC AND IN THIS CASE, I WOULD LIKE TO FOCUS ON THE CRISPR CAS, SYSTEM, I AM DOING A STUDY WE DID WITH IDT TO LOOK AT THE ABILITY OF THE SINGLE GUIDE RNA TO INDUCE INTERFERON RESPONSE. AND WHAT WE SHOW HERE IS THAT AGENT OF THE SINKLE GUIDE RRKTS NA TO INDUCE INTERFERON DEPENDS ON SEVERAL PROPERTIES. RNA CONSTRUCTS MORE IMPORTANT IN PRODUCING [INDISCERNIBLE] THAN DNA BASED ONE. SINGLE GUIDE RNA THAT IS INVITRO TRANSCRIBE SIDE INDUCING INTERFERONS HOWEVER, REMOVAL OF THE FIVE PRIME [INDISCERNIBLE] RESULTS IN REDUCTION IN THE INTERFERON LEVELS. SINGLE GUIDE RNA THAT IS PREPARED USING CHEMICAL SYNTHESIS, INDUCES INTERFERONS, HOWEVER, IF THIS SINGLE GUIDE RNAs ARE CHEMICALLY MODIFIED TO INCLUDE THE [INDISCERNIBLE], MOETY AND ALSO TO CHANGE THE BACKBONE TO PHOSPHOR DISCIPLINARY ESTHER, THEN THIS ABILITY IS COMPLETELY REDUCED. SO AGAIN, WHY THIS INFORMATION IS INTERESTING IF WE ARE USING THE CRISPR CAS SYSTEM TO EDIT THE GENES IN MORE IMMUNE APPLICATIONS THAN WE WOULD LIKE TO MODIFY LOW GUIDE RNA SO THAT WE AVOID ADVERSE IMMUNE RESPONSE DUE TO INTERFERON INDUCTION. HOWEVER IF THESE SYSTEMS ARE USED FOR VACCINES SO IMMUNE REGULATORY THEORIES THEN THE ABILITY OF THE API MAY BE BENEFICIAL. IMMUNE O GENERATEDISSITY IS VERY INTERESTING INFORMATION. YOU KNOW THAT IN THE FIELD OF BIOTECHNOLOGY THERAPEUTICS, SOME PATIENTS RESPOND WELL TO THERAPEUTIC PROTEIN OR ANTIBODY AND THEN AFTER CERTAIN TIME, THEY CANNOT BENEFIT FROM THERAPY ANYMORE BECAUSE THEIR BODY DEVELOPS THAT ARE NEUTRALIZED IN THIS THERAPEUTIC PROTEIN. IN THE FIELD OF NANO PARTICLES WE KNOW THAT PARTICLES BY THEMSELVES ARE NOT IMMUNOGENIC. HOWEVER, ANTIBODIES COULD BE ERASED AGAINST NANO PARTICLES, IF PARTICLES ARE CONJUGATED TO THE PROTEIN AND ALSO ARE INJECTED THROUGH SPECIAL IMMUNIZATION PROCEDURE USING STRONG ADJUVANTS. SO FAR, THERE IS NO REPORT IN THE LITERATURE, SHOWN THAT THERAPEUTIC–THE NANANO PARTICLES THAT DESIGN AND OPTIMIZE FOR THE OPERATING GLOBALLYLICATION CAN INDUCE THE ANTIPARTICLE RESPONSE. SOME RESEARCH EXAMPLE IS SHOWING THAT THERAPEUTIC PROTEINS CAN BE DELIVERED BY FLAN O PARTICLES AND–NANO PARTICLES AND PREVENT IMMUNE O GENERATEDISSITY OF THESE PROTEINS. HOWEVER THERE IS A CATEGORY OF THE PARTICLES WHICH ARE CALLED ACCIDENTAL PARTICLES. THEY MAY CONTAMINATE THE [INDISCERNIBLE] AND THE AXAL PARTICLES MAY CONTRIBUTE TO THE PROTEIN AGGREGATION AND CONTRIBUTE TO IMMUNE O–IMMUNE O GENERATEDISSITY THE. SO VERY TAKE HOME MESSAGE IS THAT CAN BE ENGINEERED TO BE NONIMOWN O GENIC AND THEY CAN ENGINEERED TO REDUCE THESE PROTEINS HOWEVER THEY MAULS MAY ALSO ENHANCE THESE PROTEINS AND PEPTIDES AND AGAIN THE CHOICE WITHIN THE PLATFORMS AND THE ANTIGEN IS MADE DEPENDING ON THE INTENDED APPLICATION OF THE FORMULATION. HOWEVER, ACCIDENTAL NANO PARTICLES REPRESENT [INDISCERNIBLE], THEY ARE NOT EQUAL TO NANO METERS, BUT THEY CREATE SOME PROBLEMS IN THE FIELD OF THE BIOTECHNOLOGY THERAPEUTICS. AND FINALLY, I WOULD LIKE TO TALK ABOUT A VERY NEW AREA TO THE RESISTANT ANTIBODIES. [INDISCERNIBLE] IS COMMONLY USED IN NANO TECHNOLOGY TO IMPROVE CIRCULATION TIME OF NANO TECHNOLOGY PARTICLES AND CARRIERS. SEVERAL STUDIES HOWEVER REPORTED EXISTENCE OF [INDISCERNIBLE] SO CALLED PREEXISTENT ANTIBODIES, HOWEVER FUNCTIONAL SIGNIFICANCE OF THE ANTIBODY SYSTEM NOT COMPLETELY OONTD. THIS IS AN EXCERPT FROM A RECENT STUDY PUBLISHED DURING THE JOURNAL OF [INDISCERNIBLE] CLINICAL IMMUNOLOGY, REPORTING THAT THE HIGH LEVEL OF PREEXISTING ANTIBODIES ARE ASSOCIATED WITH ALLERGIC REACTION TO REGULATED RNA [INDISCERNIBLE]. WE CONDUCTED THE STUDY INVITRO USING PLOOD FROM NORMAL HUMAN DONORS, AND WE LOOKED AT THE TIGHTER OF THEANTIBODIES. AND WE DETECT INDEED SOME DONORS RELATIVELY HIGH LEVELS OF THE ANTIBODIES. IF WE LOOK AT THE CUTCHES THAT COMPARE THE INCIDENTS OF THIS ANTIBODIES IN MALES OR FEMALES WE SEE THAT THEY’RE COMMONLY DETECTED IF FEMALES THAN IN MALES AND FROM IS CURRENT DISCUSSION IN THE LITERATURE IS JUST WOMEN USE MORE [INDISCERNIBLE] PRODUCTS AND THEREFORE CONTRIBUTES TO THEIR GREATER IMMUNIZATION OF THE [INDISCERNIBLE] WHICH IS [INDISCERNIBLE] AND CREAMS AND LOTIONS AND SOAPS AND SO FORTH. DESPITE THE FACT THAT WE DEDUCTED HIGH LEVELS OF ANTIBODIES IN SOME PATIENTS WE COULD NOT FIND FUNCTIONAL SIGNIFICANCE. AND IN THIS STUDY WE ROOKEDDA THE COMPLEMENT ACTIVATION, I TOLD YOU EARLY IN MY PRESENTATION THAT COMPLEMENT ACTIVATION CONTRIBUTES TO [INDISCERNIBLE]. COMPLEMENT ACTIVATION TO THE IRG, SO WHAT WE WANTED TO SEE IF THE DONORS THAT HAVE HIGH LEVEL OF ANTIBODIES WOULD ALSO HAVE GREATER COMPLEMENT ACTIVATION BY REGULATED NANO PARTICLES. YOU SEE, THE DARKER BLUE COLLAR MEANS THE HIGHER LEVEL OF THE ANTI[INDISCERNIBLE]. WITH IN-PATIENTS, WITH THE DONORS BLOOD. THE GREAT–THE DARKER THE RED COLOR, THE GREATER THE COMPETENT ACTIVATION OF THE DOXORUBE O RUBE SIN IN THE PLASMA DONOR AND IN THESE TWO DONORS THEY HAVE HIGH LEVEL OF ANTIBODIES BUT ONE DONOR VERY STRONGLY RESPOND WITH COMPLEMENT ACTIVATION TO THE DOXORUBEILE, WHILE ANOTHER DONOR DOES NOT HAVE THE SAME RESPONSE. SO THE CONCLUSION FROM THIS STUDY FOR US WAS THAT THE [INDISCERNIBLE] ANTIBODY LEVELS [INDISCERNIBLE] IS IMPORTANT BUT AT THIS POINT WE CAN USE IT FOR MECHANISTIC PURPOSES, HOWEVER, IF WE WANT TO DETECT TOXICITY OR WE WANT TO PRO DETECTION ANTIBODY TOXICITY, WE PREDICT NANO FORMULATIONS THEN WE USE FUNCTIONAL ASIGNIFY SUCH AS COMPLEMENT ACTIVATION AND ELIZA AND I WOULD LIKE TO FINISH THIS PRESENTATION WITH HIGHLIGHT AND FUTURE DIRECTIONS OBVIOUSLY, THERE ARE MULTIPLE FUTURE DIRECTIONS THAT ARE MANY GAPS AND NANO PARTICLES CAN BE USED TO OVERCOME SOME BIOLOGICAL BARRIERS AND THERE IS ACTIVE AREA OF RESEARCH TRYING TO FIND THE OPTIMAL PLATFORMS FOR DELIVERY OF BLOOD BRAIN BARRIER, BRAIN CANCER IMPROVED DELIVERY IN GENERAL, IMPROVE EFFICACY AND SAFETY OF NANO TECHNOLOGY FORMULATION, BUT ONE OF THE VERY IMPORTANT DIRECTION IS RECOMBIN ANT INFUSION REACTIONS AND THIS INFUSION REACTIONS THIS IS NOT UNIQUE TO NANO MEDICINE, YOU HEAR ABOUT THEM, FOR ALL DIFFERENT KINDS OF THE DRUGS OR PROTEINS AND ANTIBODIES AND SMALL MOLECULES AND THERAPEUTICS. HOWEVER, INFUSION REACTIONS CREATE A SPECIAL AREA OF [INDISCERNIBLE] NANO TECHNOLOGY BECAUSE OF THEIR COMPLEX NATURE AND VERY COMPLEX REGULATORY APRAWFAL PROCESS. SO IN SUMMARY, NANO PARTICLES COULD BE IMMUNE O TOXIC AND THIS COULD BE EITHER GOOD OR BAD, WHICH DEPENDS ON THE INTENDED APPLICATION AND UNDERSTANDING THEIR STRUCTURE ACTIVITY RELATIONSHIP WHICH IS PARTICLE PHYSICAL CHEMICAL PROPERTIES IN GREENS IN THE INTERACTION WITHIN THE SYSTEM HELPS TO CREATE EFFICIENT DRUG DELIVERY SYSTEMS AND IMPROVE THEIR SAFETY. FOR THIS I WOULD LIKE TO THANK EVERYBODY FOR YOUR ATTENTION AND THE NANO TECHNOLOGY LAB ESPECIALLY THE MEMBERS OF MY TEAM WHO CONTRIBUTED THE DATA I SHARED WITH YOU. SO, THANK YOU. [ APPLAUSE ] >> [INAUDIBLE QUESTION FROM AUDIENCE. >> THIS IS VERY GOOD QUESTION. SO THE QUESTION WAS ABOUT THE METABOLISM AND EXCRETION OF NANO PARTICLES. IT DEPENDS ON THE NANO PARLIAMENTS. SO SOME METALLIC PARTICLES TEND TO NOT METABOLIZE AND
ACCUMULATE IN THE LIVER AND SPLEEN AND THEY CAN STAY THERE FOR A VERY LONG TIME THIS IS WHY RESEARCHERS TRY TO AVOID [INDISCERNIBLE] NANO PARTICLES FOR DRUG DELIVERY AND THAT EXPLAINS WHY THE MAJORITY OF APPROVED FORMULATIONS ARE USING LIPO STUDIES OF MULTIPLE ENDOCRINES BECAUSE THEY’RE BIODEGRADABLE, THEY DELIVER THE DRUG AND THEN THEY ARE DEGRADED BUT YES IT’S VERY ACTIVE AREA OF RESEARCH AS WELL. >> THANK YOU.
01:17:22.938,00:00:00.000
>> [APPLAUSE ]

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