>> OKAY, I HOPE YOU ALL HAD A

HAPPY THANKSGIVING.

SO, OVER THE WEEKEND, I GOT AN

E-MAIL FROM KURT HARRIS AND HE

HAS AN OBLIGATION AND FOUR BUT

HE'S GOING TO BE HERE AT FIVE TO

SPEAK TO YOU, SO, OUR FIRST

SPEAKER THEN IS GOING TO BE

DR. OLAKU FROM NCBI AND MANY OF

HAVE YOU GONE TO THE TUMOR

BOARDS AND CASE REPORTS AND FOR

THOSE WHO HAVEN'T DR. OLAKU WILL

BE SHOWING SOME PREPORTS FROM

TODAY.

>> THANK YOU EVERYBODY.

WE'RE TALKING ABOUT CASE REPORTS

TODAY AND AM GOING TO GO BRIEFLY

OVER SOME INFORMATION WHAT I

LIKE TO ACHIEVE AT THE END OF

THIS LECTURE IS TO DESCRIBE SOME

OF THE HISTORY OF CASE REPORTS

AS IT RELATES TO CANCER, RULES

OF CASE REPORTS AND THEN IN

BETWEEN DESCRIBE SOME CASE

REPORTS.

AND OUTLINE SOME PATTERN

INFORMATION FOR A GOOD CASE

REPORT THIS IS ONE DEFINITION OF

CASE REPORTS.

IT'S A BRIEF IT'S A BRIEF REPORT

DESCRIBING ISOLATED CLINICAL

CASE OR A SMALL NUMBER OF CASES.

THEY DESCRIBE ALL NEW UNCOMMON

DIAGNOSIS, UNUSUAL OUTCOMES OR

PROGNOSIS, NEW OR INFREQUENTLY

USED THERAPIES AND NOT USUALLY

DISCOVERED IN CLINICAL TRIALS.

ANY PATIENT THAT GOES THROUGH

THE DASHIS HOSPITAL IS A

POTENTIAL CASE PREPORT.

THAT'S FROM THE MONTE REAL

GENERAL HOSPITAL.

THERE'S BEEN A HISTORY ABOUT

CASE REPORTS OF CANCER AND

MILLER WILL DESCRIBE THE CASE

REPORT THAT THE FIRST LINE OF

EVIDENCE, WHERE EVERYTHING

BEGINS SOME OF THE ALIAISON AS

REPORTS FROM THE CASE REPORS

FROM CANCER TREATMENT CAN BE

TRACED BACK FROM RECORDS BACK TO

ANCIENT EGYPTIAN MEDICINE OF

APPROXIMATELY 600 B. C.

THESE RECORDS WERE ONE OF THE

FIRST REPORTED IN INCUCURABLE

TUMORS OF THE BREAST.

THE CASE REPORTS DESCRIBING

NEODIAGNOSIS.

CASES OF MELANOMA BY EPISODES

THAT ARE DESCRIBED IN THE FIRST

LINE [INDISCERNIBLE] AND CASE

REPORTS WERE LETTERED BETWEEN

PHYSICIANS AND THAT SUBSIDIARY

WENT--SUBSEQUENTLY LED TO THE

ORIGINS SWREE TODAY.

IT'S FROM HODGKINS FROM THE

MEDICAL SOCIETY OF LONDON AND

WHICH IS WHAT WE KNOW AS

HODGKINS LYMPHOMA TODAY.

THE BUCKET DESCRIBED THE TUMOR

IN THE JAW OF AN AFRICAN CHILD

AND WHAT WE KNOW AS BURKEET'S

LYMPHOMA TODAY.

AND 1990, HE AND HIS COLLEAGUE

DESCRIBE A T-CELL TO LYMPHOMA

THAT LED TO MORE RESEARCH IN

THAT AREA.

THE CASE REPORTS UNUSUAL

TREATMENT RESPONSE.

CASE REPORTS HAVE BEEN USED TO

DESCRIBE UNUSUAL TREATMENT AND

RESPONSES AND HIS COLLEAGUES ARE

DESCRIBED INTERESTING CLINICAL

RESPONSE IN GLOBA NEMIA AND SO

IN THE FIELD IT'S NAME THE I

HAVE AG RA.

--VIAGRA.

NOW THIS IS A CASE OF AN 82

YEAR-OLD LADY WHO WAS DIAGNOSED

WITH CANCER WITH A CT SCAN IN

SEPTEMBER 2006.

THEY ALSO FOUND THERE WAS SOME

SMALL GASTROHIPATTIC LYMPHNODES

AND WASN'T ANY EVIDENCE OF

METASTASIS TO ANY OTHER ORGANS.

PAST MEDICAL HISTORY, SHE HAD

HYPERTENSION, HISTORY OF HYPER

ATTENTION AND SHE HAD A FAMILY

HISTORY OF GASTRIC CANCER.

IN OCTOBER OF THE SAME YEAR, SHE

HAD THE GASTROSCOPY THAT

REVEALED THE MATH ABOUT

25-MILLIMETERS AND A FLAT SHAPED

MASS ABOUT 50-MILLIMETERS.

THE ENDOSCOPIC BIOPSY THAT WAS

WELL DIFFERENTIATED WITH P53

MUTATION, AS WITH MY NUCLEAR

ACTIVITY.

BECAUSE OF HER AGE, ABOUT

QUALITY OF LIFE CONCERNS, SHE

DID NOT HAVE SURGERY.

HOWEVER SHE WAS GIVEN THIS

EXTRACT OF [INDISCERNIBLE]

EXTRACT WHICH HE TOOK AND FIVE

MONTHS LATER THE GASTROCOPEY AND

CT SCAN AND THAT DEMONSTRATED

THAT THE [INDISCERNIBLE] HAD

DECREASED AND THE FLEET LESION

HAD SHRUNK SLIGHTLY.

BIOCHEMICAL PARAMETERS LOOKING

AT THE [INDISCERNIBLE] REALAL

AND SHE DID NOT KNOW HER LIMITS

AND SHE DID NOT EXPERIENCE

SIGNIFICANT SIDE EFFECTS FROM

THIS TREATMENT.

NOW YOU CAN SEE FROM THE CT

SCAN, THAT'S THE PROLIFERATE

MASS THIS, IS BEFORE AND THIS IS

THE AFTER HARDLY VISIBLE ON THIS

SO ON THE B-SIDE.

THIS IS THE 50-MILLIMETER ONE.

, THIS SHE TOOK THE RBS.

THERE IS HISTOLOGY, AND THAT IS

WITH IMMUNO HISTOCHEMICAL

STAINING.

SO FOR THREE WOMEN WHO WERE

ALLERGIC TO ABDOMINAL PAIN AND

LOST ABOUT FIVE KILOGRAMS IN

THREE MONTHS.

AND REVEAL THE MASS TWO BY

2-CENTIMETERS IN THE HEAD AND IN

FIELD TRIPS SURROUNDING THE

CONNECTIVE TISSUE.

AND ALSO ON THE LIVER OF THE

THESE.

C19 ILEVELS AND SHE HAD EXMORRA

TORRIVE SURGERY FOR METASTATIC.

AND AND QUADRAT RICK CARCINOMA.

SHE WENT, SHE UNDERWENT SURGERY,

THEY REMOVED THE HEAD OF THE PAN

KRIST AS AND USING THIS SHE WAS

DIAGNOSED AT STAGE FOUR DISEASE.

AFTER THIS SHE HAD THE SURGERY,

FOR NINE SICKLES SEVERAL WEEKS

BECAUSE OF THE SEVERE SIDE EASTS

THAT THE PATIENT EXPERIENCED.

FOR EXAMINATION, SHE WAS IN

REMISSION OF THE HEPATIC

METASTASIS.

10 MONTHS AFTER FINISHING HER

THERAPY THERE WAS EVIDENCE OF

TUMOR PROGRESSION AND THE 99

LEVEL HIS COMPLETELY NORMALIZED.

INTERESTED IN THIS CASE WAS AT

THE TIME SHE HAD SHE HAD THE

SURGERY, SHE WAS ALSO CONSULTING

AN ALTERNATIVE OF WHO PRACTICE

HOMEIO PATH.

SHE WAS TAKING THE INTERVENTIONS

AT THE SAME TIME, AND SHE

STARTED IT ABOUT THE SAME TIME

AND THOSE ARE ON THE LIVER AFTER

WE HAVE CASES.

AND REACTIVE AND ALL THEY'RE

SUPPOSED TO DO ANY CLINICAL

STUDY OR THEY HAVE THE CASE

SERIOUS.

AND PHYSICIANS WHO SAW PATIENTS

WOULD HAVE TO RELY ON CASE

REPORTS AND CONTINUOUS CASES,

AND SEVERAL PEOPLE HAVE REPORT

INDEED THE LITERATURE.

EVERYTHING CASE REPORT AND

CONTROL SERIES, CAN BE THE FIRST

STEP AND A GOOD CASE REPORT

USUALLY HAS AN ELEMENT OF

SURPRISE.

NOW GO TO THIS, IT'S ATTRACTION,

IN THE LEFT BREAST, YOU H. H.
I.T

THE LUMP AND THE MAMMOGRAM

SHOWED THE LUMP IN THE LEFT

BREAST.

THAT'S THE MASS AND THAT'S THE

RETRACTION.

AND FINAL ASPIRATION LESION, HE

HAD A MODIFIED RADICAL

MASTECTOMY AND THERE'S

INCITU CARCINOMA.

AND AND NUMBER TWO FROM NEUTRAL

LEVEL TWO THAT WERE FOUND TO BE

INVOLVE BIDE METASTATIC BREAST

CANCER D. MUCH.

THERE WASN'T A SECOND LEVEL OF

NODES, THEY FOUND THE HIGH GRADE

B-CELL, WITH THE ANTIGENS.

WITH THE CLASSIFICATION, THE

B-CELL LYMPHOMA THEY DIDN'T FIND

ANY OF THE [INDISCERNIBLE] USING

CT OR PET SCANS.

THEY SHOOT IT CAN SIX COURSES OF

CHEMO THERAPY AND ALSO

TAMOXIFEN.

SO THAT'S THE CASE OF THE CASE

BECAUSE THE BREAST CANCER IT'S

VERY TO THE INCIDENCE, THIS

[INDISCERNIBLE] WHO HAD SURGERY

FOR OVARIAN CANCER STAGE THREE,

TO EXTEND IT TO THE AND YOU HAVE

SURGERY TO REMOVE THE UTERROUS

AND THE OVARIES AND IN THE

FRONT, THE ORGANS SHE HAD THIS,

[INDISCERNIBLE].

TWO YEARS AFTER, SHE PRESENTED

WITH NUMBNESS WHICH IS

ABNORMALITY IN SENSATION, CAN BE

DESCRIBED BY STAIN, AND

PROGRESSING WEAKNESS IN ALL

[INDISCERNIBLE] WITH URINARY

RETENTION.

SHE IT STUDIES OF THIS IMAGE

THAT ARE THE MIDLESION THAT ARE

ABLE TO ASSIST THOSE AND THEY

ARE UNDER THE FIRST

[INDISCERNIBLE] WE CALL THAT

EXPANSION AND EDEMA EXPANDING TO

THE MEDULLA AND SPINAL CORD.

TWO MORE [INDISCERNIBLE] WAS

ALSO NORMAL AND THE CT SCANS

WERE ALL NEGATIVE.

INFECTION SCREEN WAS NEGATIVE

BECAUSE THAT WAS OF THE

NEUROLOGICAL, MIDLINE VALVE AND

DEBULKING OF THE MASS, THE MRI

SCAN HEPATIC SURGERY EXPECTED

CHANGES IN THE TUMOR.

MRI AND THIS IS POST SURGERY,

THE POST SURGERY AND AFTER

REHABILITATION.

ALL OF A SUDDEN SHE HAD SUDDEN

LOSS OF ABILITY TO USE HER LEGS

AND IT WAS SPINAL EPIDURAL

TUMOR.

AND UNFORTALATELY THE PATIENT

PASSED FIVE MONTHS AND SHOW

METASTASIS, [INDISCERNIBLE].

SHE IS SPINED [INDISCERNIBLE] SO

IT WILL GO TO THE OTHER ORGANS,

THE ABNORMALITIES DOMEN, THE

LIVER, THAT'S WHY IT'S AGAIN, AN

OPPORTUNITY TO SEE HOW THIS CASE

WAS MANAGED BUT THIS IS A 40

YEAR-OLD LADY WHO PRESENTED AT

AGE 54, MUSK LO SKELETAL PAIN.

SIX YEARS AFTER THAT TIME SHE

HAD GRAFT RICK BYPASS BECAUSE OF

SEVERE OBESITY AND FIVE YEARS

BEFORE THEN SHE HAD RADICAL

MASTECTOMY FOR BREAST CANCER WEB

SITE, SHE RECEIVED TAMOXIFEN

[INDISCERNIBLE] WAS HIGH AND

BOTH CAN REVIEW THE ACTIVITY AND

AT THE TIME THEY THOUGHT THAT

WAS MOST LIKELY DUE TO

METASTASIS, SHE HAD THE PRIMARY

BREAST CANCER.

MAMMOGRAPHY OF THE LEFT BREAST

CT SCANS, CHEST, ABNORMALITIES

DOMEN ALL WERE NEGAATIVE.

HOWEVER, THEY DID NOT DO ANY

BIOPSY OF THE SECOND THAT THEY

SAW ON SCAN.

SHE CONTINUED TO EXPERIENCE THE

PAIN, CT SCANS THAT WERE DONE

TWICE AFTER THAT ALL WERE

NEGAATIVE.

AND AT EIGHT TIME-64, SHE

CONSUMMITTED A PHYSICIAN BECAUSE

SHE HAD PAIN AROUND HER RIB

CAGE.

SHE HAD LOST A HUNDRED POUNDS,

SHE CONSULTED ABOUT A

POSSIBILITY OF VITAMIN D

DEFICIENCY.

AND 25, VITAMIN D WAS

UNDETECTABLE, THE PAIN RESOLVED,

THE LEVEL OF VITAMIN D WAS STILL

BELOW NORMAL, BUT

UNDETICKETTIBLE TO A LEVEL AND

SHE CONTINUED TO [INDISCERNIBLE]

AND FREE AND THE LEVEL OF

VITAMIN D WAS STILL BELOW

NORMAL.

AND DIFFERENT PLACES OR DISTANT

PRACTICES.

AND LOCATION THIS CAN PROVIDE AN

OPPORTUNITY FOR EDUCATION AND

DISCUSSION.

THIS IS PUBLISHED CASE REPORTS

AND BE MANAGED AND THAT CAN BE

AN OPPORTUNITY FOR PHYSICIANS IN

DIFFERENT PATHS.

AND SO THE CASES ARE MANAGED

[INDISCERNIBLE] HOW TO PREPARE

THEM AND MY OWN FIRST

PUBLICATION FROM A CASE REPORT.

THERE'S EXAMPLES WITH THE GILLS

AT HOPKINS.

AND THE HUMAN TEMPORAL BONE.

AT THE TIME [INDISCERNIBLE]

NEW YORK OPPORTUNITY ON A

PATIENT OF WHAT AX PEERED TO

BE--APPEARED AND ONE OF THEM GOT

TOGETHER AND AND NORMAL BODIES

SO, YOU CAN SEE THEM IN

TWOALATIONS-OF TWO LOCATIONS AND

WHAT IT WOULD BE FOUND, AND

CLINICAL ENTITIES.

NOW CASE REPORTS ARE VERY

IMPORTANT IN THIS ERA OF

EVIDENCE.

WE HAVE SOME CASE REPORTS

CONTINUING KDING DO MORE BAD

THAN GOOD BY EMPHASIZING THE

PRESERVE, HOWEVER OUR CLINICIANS

WOULD NOT BE TOO HAPPY, IN THE

CLASS IN THE MEDICAL CASE

REVIEW.

EVIDENCE BASED MEDICINE LOOKS

FOR THE BEST EVIDENCE FOR

CLINICAL DECISION.

TO A PARTICULAR PATIENT, ON

CLINICAL TRIALS ESPECIALLY WHEN

WE'RE NOT SURE [INDISCERNIBLE]

HOWEVER, CASE REPORTS, THE AIMS

ARE EQUALLY IMPORTANT BUT

DIFFERENT BUT THEY'RE DIFFERENT

FOR THE PROGRESS OF MEDICAL

SCIENCE AND EDUCATION.

WHAT ARE THE POTENTIAL RULES OF

CASE REPORTS ON CASE SERIES.

IT CAN BE USED FOR THE

RECOGNITION AND DESCRIPTION OF

NEW DISEASES.

AND THAT MAYBE ADVERSE AND IT

CAN BE USE INDEED MEDICAL

EDUCATION AND AUDIT AND

[INDISCERNIBLE] OF THE PATIENTS

OF DISEASE.

BY EXAMPLE IN 1999 CASE SERIES,

THE NEWS WAS PRECEPTED BY THE

EPIDEMIC OF WEST NILE INSEVERE

MITRALLA LIGHTIS IN NEW YORK

CITY.

AND IT CAN ALSO BE BENEFICIAL TO

REPORT SIDE EFFECTS OF DRUGS.

AND THE SIDE EFFECTS CAN ADUP TO

THE BE ADVERSE EARLY ON.

CASE REPORTS FROM MOST IF NOT

ALL RETRACTIONS OF DRUGS FROM

THE MARKETS, IT'S A PROCESS THAT

IT GREW OUT OF CASE REPORT FROM

DETECTION OF THE EFFECTS.

AND THAT WAS DEVELOPED FROM THE

SIDE EFFECT OF THE ANTIHYPER

TENSIVE AGENT, LIKE

[INDISCERNIBLE] IT WAS DEVELOPED

AND IT HAS BEEN SEEN AND IT'S

BENEFICIAL AND ALSO WE DRAW THE

LINK TO DEPRESSION.

BEEF THE WAY TO THE USE OF

ANTIDEPRESSANT DRUGS AND SMOKING

SECESSION AGENTS.

CLINICAL [INDISCERNIBLE] LED TO

THE DISCOVERY OF [INDISCERNIBLE]

LED TO THE DESCRIBE OF DIABETES

WITH DEAFNESS AND THIS IN TURN

FURTHER LED TO CLUES OF

UNDERSTANDING MITOCHONDRIAL

DISEASES, CASE REPORTS FOR THE

SUBSTRATES FOR RESEARCH MANY

YEARS AFTER THE ORIGINAL

PUBLICATION.

IN THIS EXAMPLE, 1886

[INDISCERNIBLE] DESCRIBE FIRST

CASE REPORT OF SIGNIFY TELOMERA

AND WITH BILATERAL ADRENAL

TUMOR.

ONE OR ANOTHER, ONE YEAR LATER.

IT'S ON SEVEN, NEWMAN AND HIS

COLLEAGUES WERE FOR RELATIVES OF

THE SAME PATIENT AND FOUND THAT

THAT PATIENT HAD A MUTATION AND

HER FAMILY HAD MULTIPLE

ENDOCRANIAL PLATEIN.

SO, THAT'S A GREAT BIG BENEFIT,

OR A BENEFIT OF CASE REPORTS OF

OF WHAT IT CAN DO BECAUSE AT THE

TIME THE PRIMARY CASE WAS

REPORTED WE DIDN'T HAVE THE

TECHNOLOGY WE HAVE FOR TODAY.

THIS HAS LOOKED AT CASE REPORT

IS SYSTEMIC REVIEWS AND

META-ANALYSIS TO TRY AND GET THE

BEST OUT OF CASE REPORTS.

MAY FIELD AND GOREIN LOOKED AT

CASES OF TAX OX FIN

[INDISCERNIBLE] CASES IN BRAOF

THE CANCER PATIENTS.

AFTER REVIEW, THIS LED TO BETTER

UNDERSTANDING OF THE NATURE AND

DISTRIBUTION OF BASE TOXICITY

AND AS WELL AS THE SEVERITY OF

THE OICALLA FINDINGS.

IT ALSO ALLOWED TO THEM TO

RECOGNIZE THE DIFFICULT

NEUROECTODERMAL ISOLATING

TOXICITY DUE TO TAMOXIFEN,

TOXICITY OR DUE TO OTHER RETINAL

LOCATION NOLL MACULAR OR

[INDISCERNIBLE] ABNORMALITIES.

NOTED IN THE LIT ARRAY REVIEW OF

THE [INDISCERNIBLE] OF THE FLAIL

OPENNIAN TUBE, THIS ALLOWED FOR

BETTER UPLINE OF PATIENT

CHARACTERISTICS.

ALLOWED TO HYPOTHESIZE OF THE

DIAGNOSIS OF THE CASES, OF THE

OFFICE OF TREATMENT FAILURE.

AND AS A RESULT OF THIS STUDY,

META-ANALYSIS, WE FOUND THAT

THERE WAS LOOK LACK OF CONTROL

TRI OUTS AND THEY ALSO FOUND THE

USEFULNESS OF THE SECOND

LAPROSCOPY FOR RESPONSE OF THE

TREATMENT GIVEN.

SO WITHOUT THIS CASE REVIEW, IT

MIGHT HAVE BEEN DIFFICULT TO

FIND OUT ALL THESE THINGS I JUST

TALKED ABOUT.

WE LOOKED AT THERAPY IN CANCER

PATIENTS FROM 1966 USING THE

MEDLINE AND SOME OTHER THINGS TO

LOOK AT CANCER--THERAPY IN

CANCER PATIENTS.

CASE REPORTS HAD ANTITUMOR

EFFECT AND 21 CASE REPORTS

REVIEWED TOXICITY EFFECTS.

WE FOUND THAT AT THE TIME THERE

WERE 34 CLINICAL TRIALS.

LOOKING AT GREEN TEA 27 FOR

PHYTOESTROGENS AND ONE FOR NO

NEED ON GAMMA DESCENDANTS AND

SOME OTHER THINGS LIKE

[INDISCERNIBLE] HAVE ALSO BEEN

STUDIED PROSPECTIVELY.

WHAT WE FOUND THAT THERE ARE

PROMISING CASE REPORT FINDING

FROM MANY LABS HOWEVER NOT MANY

OF THEM HAVE BEEN EXPLORED OR

CLINICALLY, BUT IT'S BEING DONE.

AND THE RESULT OF ALL THAT, THEY

HAVE NOT BEEN REPORT INDEED

ENGLISH JOURNALS.

THE META-ANALYSIS OF CASE

REPORTS, WE ALL AGREE THAT IT'S

NOT THE BEST EVIDENCE AVAILABLE.

HOWEVER IN CASES WHERE THE

DISEASE IS RARE, AND IS NOT

POSSIBLE TO CONDUCT CLINICAL

STUDIES, CASE REPORT MIGHT BE

THE BEST LINE OF EVIDENCE AND

THIS HAS TO BE TAKEN INTO

ACCOUNT.

JUST GOING TO GO BRIEFLY ABOUT

CASE REPORTS AND LEGAL THINGS.

THIS IS THE FEDERAL REGULATIONS

DEFINITION OF RESEARCH.

IT'S THE SYSTEMIC INVESTIGATION

INCLUDING RESET TESTING,

DEVELOPMENT, DESIGN AND DEVELOP

A TRIBUTE TO GENERALIZE NIH, THE

OFFICE OF HUMAN RESEARCH AND GO

INTO RESEARCH AND WHAT IS NOT

RESEARCH AND THE BENEFITS OF OR

USES IN EVIDENCE.

SOME BEFORE--MAYBE ONE OF THE

MEMBER SYSTEM BECAUSE THERE'S NO

TIME THAT THE REPORTING CASE

REPORTS SO THEY WENT ABOUT

TRYING TO DEVELOP A REVIEW

INSTRUMENT.

THAT JOURNALS COULD USE AND

INTERNS CAN USE TO SELECT WHICH

CASE REPORT THEY'LL PUBLISH IN

THEIR JOURNALS.

AND IN THIS CASE, THEY LOOKED

ABOUT--THEY LOOK LIKE 28 CASE

REPORTS.

13 OF THEM WERE PUBLISHED, 15 OF

THEM WERE NOT PUBLISHED AND THEY

HAD FOUR REVIEWERS WHO RATED

EACH OF THESE THINGS ON

PROPERTIES OF [INDISCERNIBLE],

AND ALL THE WAY DOWN AND THEN,

THERE WAS AN 11th ITEM, WE

SAID, SHOULD THIS CASE REPORT BE

PUBLISHED OR NOT.

AND AFTER THE REVIEW, THEY

REVIEWED LIKE I SAID, 28 CASE

REPORTS AND THE REASON WHY THEY

HAVE THAT, THEY WERE TRYING TO

GET CASE REPORTS THAT WERE NOT

PUBLISHED BUT IT WAS VERY

DIFFICULT FOR THEM TO GET

EDITORS TO RELUC UNPUBLISHED

CASE REPORTS SO THIS ONE FORMED,

SOME OF THEIR COLLEAGUES HAD

REVIEWED THE CASES SO THEY GOT

THIS NUMBER.

AND THEY TRY TO FIND THE

CORRELATION AND WHAT IN THESE 10

ITEMS WILL HELP THEM MAKE

WHETHER IT WOULD BE THE CASE

REPORT, SHOULD BE PUBLISHED OR

NOT.

AND THEY CAME UP WITH RATIONAL

FOR REPORTING THE CASE AND IT'S

UNIQUENESS, PRESENTING A PATENT

ASSPEGHTS OF PHYSICAL

EXAMINATION, IMPLICATION OF THE

CASE IMPORTANT WITH RESPECT TO

PRACTICE, RESEARCH POLICY,

REGULATORY STABBED ARDS AND

[INDISCERNIBLE] PUBLIC HEALTH.

IMPLICATIONS REVEAL ADEQUATE AND

CASE REPORT MAKES AN IMPORTANT

ADDITION TO THE MEDICAL

LITERATURE.

HOWEVER, WHEN THEY LOOK AT

THYROID CARCINOMA PHYSICIAN,

THEY REVIEW IT AND LOOK AT IF

THE CASES WERE ACTUALLY

PUBLISHED OR NOT, THEY DIDN'T

FIND ANY CORERATION.

SO THIS IS JUST LIKE I SAID, AN

ATTEMPT BY SOME PEOPLE TO MAYBE

CREATE SOME SANITYY IN THE

POSITION WHEREBY THERE'S NO

STANDARDS FOR PUBLISHING CASE

REPORTS.

EMPLOY.

[INDISCERNIBLE] ON MEDICAL

IMPACT RESEARCH, IN 2005 OUR

COLLEAGUES LOOKED AT THE LAND

[INDISCERNIBLE] FROM A DIARY OF

1995 TO JUNE OF 96 AND THEY

LOOKED AT ALL THE PUBLISHED CASE

REPORT FROM LANCET AND TO SEE IF

THEY HAD ANY IMPACT AND THIS IS

WHAT THEY FOUND.

OUT OF 64 CASE REPORTS, 16 OF

THEM HAD 21 OR MORE CITATIONS.

11 OF THEM WERE FOLLOWED BY

PUBLISHED TRIAL.

AT THAT TIME, 67 DO

[INDISCERNIBLE] SCRIBED TO THE

CLASS OF DISEASE, 27% ON EACH

SIDE IS IMPROVEMENT, AND 69% OF

FAILURE AT FIVE%.

THEY LOOK AT CASES AND LANCET

CASES AGAIN AND THEY LOOK AT 21

AND ABOVE 50%, ONLY NINE AND IF

THERE ARE PUBLISHED TRIALS, 31%,

KIND OF SIMILAR BETWEEN THE CASE

REPORTS AND THE CASE SERIES.

SO THIS IS TRYING TO SHOW THAT

THE CASE REPORTS AND SHOWING THE

CASE BETWEEN [INDISCERNIBLE] WAS

A Ph.D. SCIENTIST AND

[INDISCERNIBLE] WAS A PHYSICIAN

AND THEY COMBINED TO WRITE A

CASE REPORT.

SO MAYBE THAT MIGHT BE AN

OPPORTUNITY FOR SOME OF YOU TO

PARTICIPATE IN THE CASE REPORTS

IN THE FUTURE.

THERE MUST BE A SINGLE MESSAGE

THAT WOULD BE CLEAR WHY IS THE

INHIBITION IMPORTANT AND SOME

CHARRISHED BOX.

AND WHY WOULD THAT BE MISSED„i.

AND THE CASE REPORT SHOULD BE

DONE IN A MANNER.

AND IN THE REAR EXPAINSS, WHERE

CLINICAL TRIALS AND THE ONLY

EVIDENCE AVAILABLE TO RECOMMEND

TREATMENT AND THANK AND YOU I'M

THANKFUL TO MY COLLEAGUES

DR. WEISS AND DR. ZEAM.

>> PERHAPS CAN YOU ELABORATE ON

CASES WHERE THE DIAGNOSIS AND

NOT CLEAR.

FIGURE OUT THE BEST WAY TO

PROCEED WITH THAT PATIENT

[CHECK]

>> ALL RIGHT.

IN CASE STUDIES, THE--IT'S NOT

THE--THE WAY FOR IS NOT CLEAR.

ONE OF THE THINGS THAT HAS TO BE

DONE UPFRONT IS THAT THEY HAVE

TO BE VERY GOOD HISTORY.

TAKEN FROM THE PATIENT, THE

CLINICAL MOCK UP WAS NOT VERY

GOOD.

SO A GOOD PHYSICAL EXAMINATION,

VERY GOOD INVESTIGATION THAT ARE

DONE AND DEPENDING ON WHERE THIS

OCCURS.

IF YOU HAVE PEOPLE WHO WITHIN

THE SAME FACILITY OR THAT HAVE

THE SAME EXPERTISE, YOU CAN

COME, CAN YOU DISCUSS THE CASE

IN SOME CASES AND DON'T HAVE

SOMEBODY WITH THE FOR EXAMPLE I

DON'T KNOW THE WORD FOR IT.

AND THE EXPERT AT NIH, IT'S

SOMETHING THAT JUST¨5( NEEDS

DISCUSSION ABOUT THE PHONE AND

SAY GO FORWARD, THAT MIGHT

HAPPEN BUT IN SOME CASE, IT

MIGHT ACTUALLY BE NEEDED TO

TRANSFER THE PATIENT TO THE

EXPERT SO THAT THE PATIENT HAS

THE BEST OF WHAT IS AVAILABLE.

SO THAT IS THE KIND OF THING

THAT HAPPENS IN INSTITUTIONS

WHERE YOU DON'T KNOW THE WAY

FORWARD.

IN TODAY'S DAY AND TECHNOLOGY,

THE U.S. HAS AND CONTINUES TO

HELP A LOT OF DEVELOPING

COUNTRIES BY PROVIDING

RESOURCES.

SO THEY HAVE SOME INSTYPINGSS,

THEY HAVE INSTITUTIONS IN SOME

DEVELOPING COUNTRIES WHERE YOU

HAVE A PROBLEM OR THE NOTION OF

OF STUDYING THINGS, THEY CAN USE

E-MAIL TO COMMUNICATE WITH THEIR

COLLEAGUE IN THE U.S. WHO WILL

REVIEW THE CASE AND THEN GET

BACK TO THEM AND SOME OF THEM

USE LIVE VIDEO CAST, ALSO.

SOPHISTICATED IT'S NOT ONLY

WITHIN A COUNTRY.

NOW IT'S GONE INTERNATIONAL

WHERE YOU CAN REVIEW, CASES, I

KNOW THAT THE RADIOLOGYSTS IN

THIS PART OF THE WORLD WHO

REVIEW RADIOLOGY AND IMAGES IN

THE U.S. BECAUSE OF SEVERAL

REASONS.

I WON'T GO INTO THAT.

>> OKAY, WELL, THANK YOU.

>> THANK YOU.

>> OKAY 94 NEXT SPEAKER IS KURT

HAIR AND I GUESS HE GOT HIS M.

D. DEGREE FROM THE SCHOOL OF

MEDICINE; AND PRACTICING INTERN

ACTIVITIES AND PROJECTS MEDICINE

AND HE THEN CAME TO THE NCI SUCH

AS AWARDS FROM THE COLLEGE OF

PHYSICIANS INTERNATIONAL UNION

OF TOXICOLOGY, THE AACR, HE

RECEIVED THE DISTINGUISH SERVICE

MEDAL FROM THE U.S. PUBLIC

HEALTH SERVICE.

>> THAT'S ENOUGH.

>> OKAY, BUT HIS BUGGEST

CONTRIBUTION IS THE JOURNAL OF

CARCINOGENESIS; THERE'S

MANUCRYPTS THERE AND KURT'S DONE

A GREAT SERVICE ESTABLISHING

THIS JOURNAL FOR US.

HIS TITLE:  INNATE IMUMITY,

SINCE'VE SIN ESTIMATE THAD ENS,

MicroRNA AND P53 NETWORKS.

>> I'LL TRY TO TIE APPROXIMATE

TOGETHER FOR YOU TO MAKE SOME

SENSE OUT OF IT.

SO INFORMATION IN CANCER SOME

PEOPLE SAY, GOES BACK TO

[INDISCERNIBLE] WHO IS A GERMAN

PATHOLOGIST BUT THERE'S ACTUALLY

A DUTCH PHYSICIAN IN THE 17th

CENTURY, MADE THE CONNECTION

BETWEEN INFLAMMATION AND CANCER.

O THIS IS A VERY OLD CONCEPT AND

THEN WE GO THROUGH SOME

INTRODUCTORY AND FIRST OF ALL

BOTH CHRONIC INFLAMMATION AND

INFECT CAN INCREASE CANCER RISK

AND CAN BE LARGELY INHERITED

SUCH AS HEMOCHROMEATOSEIS, IRON

OVERLOAD OR LIVER OR KRONES

KRONES--CROHNS OR ULCRY COLITIS

FOR THYMATORY CANCER OR BOWEL

DISEASE OMOST FREE WENTLY

ACQUIRED AND THIS MEANS

INFECTIONS BY VIRUSES, BY

BACTERIA, OR BY PARASITIC

ORGANANISMS AND THEN THERE'S THE

CATEGOR THAT'S MOST PEOPLE

HAVEN'T PAID MUCH ATTENTION TO

UNTIL RECENTLY AND THAT'S

CHEMICAL, AND PHYSICAL AND

METABOLIC.

SO ACID REFLUX, BARRETT'S SERKS

SOV GUS INCREASES RISK OF THEARS

NOME AASBESTOS DOES A LOT OF

THING BUS IT IS ALSO AN

INFLAMMATORY AGENT FOR MACK

WOPHAGES.

OBESITY I'LL MAKE A POINT MORE

ABOUT THAT AS MANY PEOPLE

CONSIDER IT TO BE A CHRONIC

INFLAMMATORY DISEASE, SMOKING,

CIGARETTE SMOKE CONTAIN60 OR

MORE CHEMICAL CAR SIN
CARCINOGENS AND

WITHIN THIS WITCH'S BREW THERE

ARE ALSO A NUMBER OF

PROINFLAMMATORY AGENTS AND

INFLAMMATION PLAYS A ROLE THERE.

THAT WAS ESTIMATEDDED A FEW

YEARS AGO, BY THE INTERNATIONAL

AGENCY RESEARCH ON CANCER THAT

ABOUT 18% OF ALL HUMAN CANCERS

ARE RELATED TO INFECTION.

AND THAT'S OVER A MILLION AND A

HALF A YEAR AND THAT'S NOT

COUNTING THESE KINDS OF CANCERS

OR THESE KINDS OF CANCERS.

SO I'M SURE THAT IT'S

SUBSTANTIALLY MORE THAN THAT.

BUT I DON'T WANT TO GIVE YOU THE

IMPRESSION THAT ALL INFECTIOUS

AGENTS CAUSE AN INFLAMMATORY

RESPONSE OR THAT ALL

INFLAMMATION, INFLAMMATORY

DISEASES ARE ASSOCIATE WIDE

CANCER.

SO THERE ARE TWO EXAMPLES, ONE

RHEUMATOID ARTHRITIS, PRIMARILY

OF THE JOINTS, BUT ONE NEVER

SEES JOINT SARCOMAS.

THERE WAS A VERY SMALL INCREASE

IN LYMPHOID TUMORS AND SOME OF

THAT MIGHT BE RELATED FOR THEIR

THERAPY.

NOT ALL ONCAGENIC VIRUSES, WHICH

ARE CANCER PRONE LEAD TO

INFECTIONS AND HUMAN PAPILLOMA

VIRUS IS A VERY GOOD EXAMPLE OF

THAT.

NOW I SAID THAT THAT OBESITY IS

A CHRONIC INFLAMMATORY DISEASE,

THERE'S TWO LANDMARK PAPERS,

BOTH IN THE JOURNAL OF CLINICAL

INVESTIGATION WHICH MADE THE

LINK BETWEEN INFLAMMATION, AND

OBESITY.

AND OBESITY ASSOCIATED WITH

NEUROLOGICAL DISEASES,

CARDIOVASCULAR DISEASES AND OF

COURSE, CANCER, AND DIABETES AND

OTHER THINGS, AND THESE TWO

PAPERS CAME UP WITH THE DATA

SUPPORTING OBESITY CHRONIC

INFLAMMATORY DISEASE, BECAUSE

ONE OF THE THINGS THEY DID WAS

JUST ANALYZE FAT.

AND FAT CONTAINS A LARGE NUMBER

OF MACROPHAGES.

AND THOSE MACROPHAGES, FORM

LOOPS.

AND THOSE PRODUCE CYTOKINES AND

ONE IS THE OXYGEN BASED FREE

RADICALS RADICALS LESS THE

HYDROGEN BASED FREE RADICALS.

AND PROTEINS INCLUDING LEADING

TO DECREASED DNA REPAIR, AND

DECREASE APOPTOSIS, AND THE CAP

BASES, AND THEY ALSO DAMAGE DNA,

AND THAT DAMAGE ISN'T REPAIRED

BY BASIC INSIPGZ REPAIR AND CAN

CAN LEAD TO MUTATION.

AND NOW IT CAN DIRECTLY AND

MAYBE NITRIC OXIDE, EXPOSE TOWER

CELLS WOULD CAUSE AN INCREASE IN

DNA METHYLATION.

AND TRANSCRIPTIONAL SILENCING OF

GENES, AND ALSO, LEAD THROUGH

LIP I PEROXIDATION AND ACID

CASCADE AND LEAD TO INCREASED

CELL PROLIFERATION AND ACTIVATE

COX2 WHICH I'LL MENTION IN A

MOMENT.

LIPID PEROXIDATION CAN LEAD TO

HIGHLY REACTIVE CHEMICALS.

MAILEDDA AILEDDA HIDE AND THE

LAT PROCEDURE DUCES ATHEN O

ADDICTS WHICH ARE REMOVE BIDE

BASIC CISION REPAIR AND ALSO

HIGHLY MUTE O GENIC.

SO ONE STRATEGY TO INVESTIGATE

THE ROLE OF INFLAMMATION, IS TO

EITHER EXPOSE CELLS TO SPECIFIC

AGENTS SUCH AS FREE RADICALS

RADICALS SUCH AS NITRIC OXIDE OR

DO CULTURES OF MACROPHAGES WITH

TARGET CELLS, THIS IS A VERY

CRUDE ATTEMPT TO LOOK AT

CELL-CELL INTERACTION AND

MICROENVIRONMENT.

AND THEN COMPARE THESE KINDS OF

RESULTS WITH EACH OTHER BUT WITH

WHAT'S HAPPEN NOTHING THE CLINIC

SUCH AS INFLAMMATORY BOWEL

DISEASE, THE ULCATORY COLITIS,

CROHN'S DISEASE WHICH ARE CANCER

PRONE AND LOOKING DOWN A

COLONOSCOPE, THIS IS WHAT

HOPEFULLY ALL OF YOUR EPITHELIUM

LOOKS LIKE IN THE COLON.

IF YOU HAVE ULCRY COLITIS AND

IT'S ACTIVE, IF WILL LOOK LIKE

THIS.

IT'S ABOUT ONE IN A HUNDRED

PEOPLE HAVE ONE OR THE OTHER OF

THOSE DISEASES.

AND THERE ARE ANIMAL MODELS

AVAILABLE SO LET'S SUMMARIZE

WORK THAT OUR GROUP AND OTHERS

HAVE DONE IN REGUARDS TO CHRONIC

INFLAMMATION AND THE

NITRIC--NIGHT ROSINE REACTIVE

FREE RADICALS THAT I MENTIONED.

AND PRIMARILY, IRPT LUKEIN SIX

AND EIGHT AND ONE B WILL

INCREASE THE ENZYME CALLED

INDUCIBLE NITRIC OXIDE SYNTHASE

OR NOS-TWO.

IT'S PART OF THE INNATE IMMUNE

SYSTEM THAT ALLOWS ONE TO HAVE

ACUTE RESPONSES TO PATHOLOGICAL

ORGANISMS FOR EXAMPLE.

AND PRODUCES NITRIC OXIDE, IT

CAN CAUSE DNA DAMAGE AT LOW

CONCENTRATION AND THIS ACTIVATES

P53 TUMOR SUPPRESSOR THAT HAS

ANTICARCINOGENIC EFFECTS AND

AMONG OTHER THINGS, CAN LEAD TO

INESTIMATE THAD ENS OF CELLS.

BUT THE DNA DAMAGE CAN CAUSE

MUTATIONS IN CANCER RELATED

GENES INCLUDING P53 GENE WHICH

WE'VE SHOWN FOR ULCRY COLITIS

AND CROHN'S DISEASE AND

HEMACHROMEATOSE AND I GUESS

HEPATITIS B VIRUS INFECTION AND

THIS HAS MULTIPLE EFFECTS.

ONE PROCARCINOGENIC EFFECTS,

GENOMIC INSTABILITY AND

DECREASED CELL CYCLE CHECK POINT

AND THEY REPAIR APOPTOSIS AND

SIN ESTIMATE THAD ENS WHICH I'M

BRINGING HOME THE MESSAGE ABOUT

SIN ESTIMATE THAD ENS HERE.

--AS WE SHOWED A NUMBER OF YEARS

AGO, TRANSFER EXPRESSES

EXPRESSION OF I-NOS, AND THIS IS

P53 MUTATIONS AND OR A LOSS OF

WILD-TYPE P53, YOU END UP WITH

VERY HIGH AND CHRONIC LEVELS OF

NITRIC OXIDE.

IT'S GOING TO CAUSE MUTATIONS IN

A VARIETY OF GENES.

NOW THESE ARE EXAMPLES OF GENES

AND MECHANISMS„i REGULATING

SENESCENCE, EMPHASIZE P53 AND

I'VE ALREADY MENTIONED NITRIC

OXIDE BUT THERE ARE OTHER

PATHWAYS INCLUDING PRO

INFLAMMATORY SIGNALING THAT WILL

CAUSE SENESCENCE OF CELLS.

THOSE STROMAL CELLS CELLS AND

EPITHELIAL CELLS.

P53 YOU'RE ALL FAMILIAR WITH,

BUT IT'S BEEN RECOGNIZED AGAIN,

FAIRLY RECENTLY THAT P53 IS

CRITICAL IN AGING AND CELLULAR

SENESCENCE AND THAT CELLULAR

SENESCENS IS A TUMOR SUPPRESSOR

MECHANISM IN VIVO.

THESE COME FROM STUDIES OF

PRECANCEROUS LESIONS AND BENIGN

TUMORS IN HUGH MANS AS WELL AS

EXPERIMENTAL ANIMALS THAT

CONTAIN A LOT OF SIN ESTIMATE

THADENT CELLS AND IT'S IN A

MOMENT WHEN THESE BENIGN TUMORS

BECOME CANCEROUS TUMORS THEY

THEY--THESE ARE SOME OF THE

FIRST STUDIES BUT THE DISEASES

AND ANIMAL STUDIES HAVE SHOWN

THAT RESTORATION OF P53 CAN LEAD

TO TUMOR REGREGZ, THROUGH

SENESCENCE.

EVERYBODY'S WELL, IS IT ALL

APOPTOSIS AND THE ANSWER IS NO.

A LOT OF IT IS SENESCENS.

THE NEXT QUESTION THEY ASK, IS

WELL IF IT'S SENESCENCE, DO THE

CELLS JUST HANG AROUND AND THE

ANSWER IS NO.

SIN ESTIMATE THADENT CELLS ARE

RECOGNIZED BY THE IMMUNE SYSTEM,

BY MACROPHAGES AND THEY'RE

CLEARED AND THAT CLEARANCE IS

VERY IMPORTANT IN REGUARD TO

REMOVING THE CELLS BECAUSE THE

SIN ESTIMATE THADENT CELLS CAN

PRODUCE THE PROINFLAMMATORY

CYTOKINES.

AND OF COURSE THERE,'S A

CONNECTION WITH AGING.

SO CELLULAR SENESCENS WAS

DISCOVERED BY A GUY NAMED

HAYFLICK, QUITE A FEW YEARS AGO

AND THE CULTURE, THE TULA MERS

GET SHORTER AND SHORTER NOTHING

THEY LEAD TO A DAMAGE DNA

RESPONSE AND ONE MEASURE OF THAT

IS GAMMA HTWO AX POSITIVITY.

THIS LEADS TO DNA DAMAGE

SIGNALING CASCADE THAT ACTIVATES

P53.

YOU CAN DAMAGE DNA IN OTHER WAYS

BY CAR SIN CARCINOGENS FOR
EXAMPLE, CAN

CAN LEAD TO P53 OR ONCA GENES

SUCH AS RAS CAN ACTIVATE THE ARF

PATHWAY AND LEAD TO SENESCENCE

THROUGH RB AND P16.

SO THESE ARE THREE FOLKS IN OUR

GROUP THAT'S BEEN STUDYING

SENESCENCE IN P53 ISOFORMS AND

MICRORNAS IS PHYSIOLOGICAL

REGULATORS ARE REPLICATED

SENESCENCE INVITRO AND I'M

SHOWING YOU THESE DATA TO MAKE A

COUPLE OF POINTS.

ONE IS ABOUT 80% IT WAS OHM

ABOUT 40%, AND ENHANCING EFFECTS

OR INHIBITORY EFFECTS OR

COMPLETELY DIFFERENT EFFECTS IN

THE GENE THAT YOU'RE STUDYING.

OKAY.

THAT'S LESSON NUMBER ONE.

LESSON NUMBER TWO IS, P53 IS A

GOOD EXAMPLE OF THIS, THERE ARE

13 DIFFERENT SPLICE MESSAGES, OR

USING ALL THE PROMOTERS IN THE

10 DIFFERENT PROTEINS.

SO WHEN YOU DO

IMMUNOHISTOCHEMISTRY FOR P53, OR

WESTERN FOR PPEAR, YOU'RE

LOOKING PRIMARILY LOOKING AT ONE

UNLESS YOU'RE DOING IT IN A

SPECIAL WAY.

SO WE'VE BEEN STUDYING ONE OF

THESE, TWO OF OF THESE ISOFORMS

IN DETAIL, P53 BETA THAT IS

SPLICED CAR BOXY TERMINUS AND

N-DELTA 133 THAT USES A SECOND

PROMOTER AND USES THIS ATG SITE

AT 133 AND PRODUCES THIS

TRUNCATED PROD TEEN.

AND SENESCENCE THERE'S THIS

DELTA 133 AS YOU SEE HERE TO

WHEN THE CELLS ARE HERE, THERE'S

AN INCREASE IN BETA AND A

DECREASE IN DELTA 133 AND THESE

ARE TWO DIFFERENT HUMAN CELL

STRAINS.

DELTA 40, P53 BETA DOESN'T

CHANGE, SO WE STOPPED STUDYING

THAT.

AND THEN, ASKING THE QUESTION IS

THIS REALLY IMPORTANT IN

SENESCENS.

IF YOU KNOCK DOWN THIS DOMINANT

NEGATIVE FORM OF DELTA 133,

SHOWN HERE, AND HERE WITH A

DIFFERENT ANTIBODY, IT LEADS TO

AN INCREASE IN P21, AND MORE

IMPORTANT TO SENESCENCE.

BY A NUMBER OF DIFFERENT

MARKERS, SO KNOCK DOWN

EXPERIMENTS ARE ALWAYS MORE

INTERESTING THAN OVEREXPRESSION

EXPERIMENTS AS YOU ALL KNOW, AT

LEAST THOSE WHO DO LABORATORY

WORK, SO THAT'S THE FIRST THING

YOU WANT TO DO.

EXPRESSION EXPERIMENTS, WE

OVEREXPRESSED A DELTA 133, P53,

TO SEE IF IN FACT IT CAUSED

SENESCENCE AND THIS IS JUST CELL

NUMBER HERE, IT'S CELL NUMBER

VERSES THE VECTOR CONTROL AND

HERE IS USING ONE OF THE MARKERS

OF SENESCENCE, THERE'S ABOUT, OH

E50% INCREASE OR MORE IN

SENESCENT CELLS IN THESE TWO

STRAINS IF YOU OVEREXPRESS THE

BETA.

AND WE OVEREXPRESSED AT LEVELS

THAT WE FIND DURING REPLICATED

SENESCENCE.

WHAT HAPPEN FIST YOU OVEREXPRESS

THE DELTA 133, THE QUESTION WE

ASK IS DOES IT DELAY SENESCENCE.

SO WE TOOK CELLS AT A NEAR

SENESCENCE AND THESE ARE

COUPULATED POPULATION DOUBLINGS

OVER EXPRESSION OF DELTA 133.

SHOWN HERE.

THE CELLS CONTINUE TO GROW

ANOTHER 15 OR¨— SO POPULATION

DOUBLINGS, IT'S ABOUT THE

EQUIVALENT IF YOU KNOCK DOWN ALL

THE WILD-TYPE P53.

SO THIS IS A VERY EFFECTIVE

TOMINANT NEGAATIVE.

SO LET'S GO BACK TO THIS ISSUE I

MENTIONED ABOUT BENIGN TUMORS

VERSES MALIGNANT TUMORS.  THIS

IS A NICE CARTOON FROM ONE OF

SERANO'S REVIEWS AND THESE BLUE

CELLS ARE REPRESENTING

SENESCENCE CELLS, ASSOCIATED

BETA GELF ACTIVITY, AS YOU CAN

SEE IN THESE PREMALIGNANT TUMORS

THERE'S A LOT COMPARED TO

MALIGNANT TOMB OAR AND THIS IS A

GENERAL OBSERVATION.

AND WE FOUND IT IN THE STUDIES

WE WERE GOING TO, AND THIS IS

USING SENESCENS OF THE HIRE

ACTIVITY THIS IS A NONTUMOR AREA

AND INCREASE IN P16 AND THE

OTHER PART OF THE SIN ESTIMATE

THADENT AND THE BIFURCATED

PATHWAY, P53, AND RB, OR BSCAN

INCREASES IN THE ADENOMAS DELTA

133 GOES DOWN AND P53 BETA GOES

UP.

THERE'S TWO CARC NOME AS, THEY

HAVE WILD-TYPE P53 AND THOSE WHO

HAVE MUTANT P53 SO WE PROPOSE

THAT THE DELTA 133, P53 BETA

SWITCH WOULD OHM PLAY AN

IMPORTANT ROLE AT LEAST THE

DELTA ONE P53 TUMORS CARCINOMAS

AND IT'S SIGNIFICANT IN THESE

BETA AND THE TUMORS THAT ALREADY

HAVE A MUTATION IN P53, NO

DIFFERENT EVEN THOUGH, IT'S A

BETA DECREASE.

SO THESE ARE CONSISTENT WITH THE

DELTA FUNCTIONING IS THE

DOMINANT NEGATIVE.

SO THERE ARE A NUMBER OF

INDUCTION MECHANISMS FOR

SENESCENCE, P53 BETA.

DECREASED DELTA 133, INCREASED

P16, ILSIX, DNA DAMAGE BY

VARIOUS CAUSES.

AND YOU CAN BYPASS THESE TWO AND

ONE IS SWITCHING AND THE CO

TRANSACT VOITOR WILD-TYPE AND

BUT MORE EFFECTIVE THAN THIS IS

JUST CAUSING MUTATION IN THE

GENE.

P53.

AND THIS MAY BE ONE OF THE

REASONS THAT P53 IS ALWAYS DOWN

DOWN--FOUND TO BE HIGHLY MUTATE

INDEED ALMOST EVERY CANCER IN

ALL THE TOTAL GENOME SEQUENCING

P53 ALMOST ALWAYS COMES UP YOU

CAN HAVE DNA METHYLATION AND

SILENCING OF P16 BUT MORE

EFFECTIVE THAN THAT IS P16.

NOW LET'S MOVE FROM THAT, AS AN

EXAMPLE OF SENESCENCE AND

INFLAMMATION AND THE P53 NETWORK

TO NONCODING RNAs.

SO, THIS IS THE CURRENT CLASSES

OF NONCODING RNAs AND I PUT

THEM AS SMALL OR LARGE AND

THEY'RE ALL BEING INVESTIGATED

IN MANY DIFFERENT LABORATORIES.

IT'S VERY EXCITING AREA OF

RESEARCH THE FIRST THAT WAS

INVESTIGATED WAS THE MICRO

RNAs AND THE FIRST INDICATION

OF A MICRORNA PLAY NOTHING A

ROLE IN THIS DEVELOPMENT IN

C.ELEGANS WAS FOUND IN 1992 BY

ACTUALLY TWO DIFFERENT GROUPS OF

PUBLISHED BACK-TO-BACK PAPERS IN

CELL, BUT VICTOR AMROSE FOR

REASONS THAT ARE NOT CLEAR TO

ME, GETS MOSTS OF THE CREDIT FOR

THE FIBBING THEY WERE SUBMITTED

ON THE SAME KAY, THEY WERE

PUBLISH OFFICE OF DIVERSITY THE

SAME SAY BUT BOS THEY DID IT IN

TANDEM BUT ANYWAY, THAT WAS THE

INITIAL THOUGHT THAT THERE MAY

BE A DIFFERENT CLASS OF RNAs

THAT MIGHT HAVE A REGULATORY

ROLE, NOT BY PRODUCING A

PROTEIN, BUT BY INTERACTING WITH

OTHER MICRO--WITH OTHER RNAs

INCLUDING MESSAGES.

THESE RNAs AFFECT THE

TRANSMISSION OF LITERALLY

HUNDREDS OF TARGETS SO EACH ONE

SUCH AS LED SEVEN FOR EXAMPLE

WILL AFFECT MANY, MANY DIFFERENT

PROTEIN CODING GENES.

INITIALLY BY THOSE-OF BY

DESTABILIZING THE MESSAGE OR

LESSENING THE EXTENT BY

INHIBITING TRANSLATION, I'LL

SHOW YOU A SUMMARY SLIGHTED OF

THAT IN A MOMENT.

SO THAT WAS IN 92, MICRO RNAs

WERE DISCOVER INDEED HUMAN,

CELLS IN THE YEAR 2000.

IN IT 2002, CARLA KOSHY MADE THE

OBSERVATION THAT MICRO RNAs

ARE DIFFERENTIALLY EXPRESS

INDEED HUMAN CANCERS AND THIS

WAS THE SEMINOLE STUDY AND HIS

BODIES DID STUDYING LYMPHOCYTIC

LEUKEMIA.

SO ONE STRATEGY IS TO

MICROARRAYS, IT'S ALWAYS A GOOD

IDEA AND IN FACT, I THINK IT'S

ESSENTIAL NOT TO RELY ON THESE

RESULTTO YOU USE ANOTHER TYPE OF

ASSAY SUCH AS REALTIME PC R TO

QUANTITATE SPECIFIC MICRO

RNAs.

YOU DO INCITUHYBRIDDIZATION

BECAUSE YOU'RE INTERESTED IN

WHERE IN THE CELL AND WHICH

CELLS MIGHT BE EXPRESSING

PARTICULAR MicroRNA AND THIS

TECHNOLOGY HAS IMPROVED.

AND THEN, FUNCTIONAL STUDIES,

MOST OF US ARE INTERESTED IN

WHAT DO THEY DO, AND WHAT

HAPPENS IF YOU INHIBIT THEM.

AND HOW THEY PLAY AN IMPORTANT

ROLE IN DISEASE INCLUDING

CANCER.

AND THE LAST IS THE CAVEAT.

AND THE ALGORITHMS THAT PREDICT

TARGETS OF MICRORRNAs AND OUR

EXPERIENCE AND THE FIELD'S

EXPERIENCE IS ABOUT ONE IN FOUR

OF THOSE PREDICTED TARGETS

ACTUALLY ARE FUNCTIONAL.

SO YOU HAVE TO DO THE LABORATORY

STUDIES AND NOT RELY ON THE

BIOINFORMATIC O SINGLE THIS

CASE, SO A MENTIONED THAT

MICRORNAs PROCESSED THEIR

GENES OBVIOUSLY, THEY'RE

TRANSCRIBED PRIMARILY BY PAUL

TWO INTO A PREOR PRA-MICRORNA

WHICH HAS THESE LOOP KINDS OF

STRUCTURES.

AND THEN P53 WHICH WE MENTIONED

EARLIER FORMS A COMPLEX WITH P68

WHEN IS AN RNA HELIX CASE AND

CARRIES THE HELIX CASE TO

DORSHIRE WHICH IS AN RNA.

AND THERE'S VERY SIMPLE CARTOON

OF THAT, IT CLEAVES THE PRIOR

MICRO RNATO PREMICRORNA THAT'S

TRANSPORTED INTO THE CYTOPLASM

AND THE SECOND RNAs DICER THEN

CLEAVES IT FURTHER AND IT FORMS

A COMPLEX IN THE RISK SET OF

PROTEINS AND I PUT P63 HERE

BECAUSE P63 IS ONE OF THE

TRANSCRIPTION FACTORS AND IT'S A

MEMBER OF THE P53 FAMILY THAT IS

IMPORTANT IN TRANSCRIBING, IN

THE LEVELS OF DICER.

AND IF YOU HAVE A MUTANT IN P53,

THIS RNAHELIX CASE DOESN'T GO

HERE THIS, THERE'S LESS

ACTIVATION OF DICER BY P63

BECAUSE MUTANT P53 ACTUALLY FORM

A COMPLEX WITH P63, SO, THIS IS

ANOTHER AREA IN WHICH, THE P53,

PROTEIN AND IT'S MUTANT PROTEIN

PLAYS A ROLE IN ANOTHER

BIOLOGICAL PROCESS.

ALL RIGHT.

THERE ARE EXAMPLES EVER WAYS OF

ACTIVATING A PECULIAR MICROR NA

OF THE GENE TAKEN--THEY ENCODES

THAT MIKE ARE RNA, GENE

APPLICATION, GENE DELETION,

CELLULAR STRESS, EPIY GENETIC

MECHANISMS, DNA METHYLATION AND

OF COURSE INFLAILATION,

PARTICULARLY PROINFLAMMATORY

CYTOKINE WHICH IS IS ILSIX AND

ILEIGHT.

THERE ARE DOWN STREAM TARGETS

AND PATHWAYS AND THATEE HOW

THESE MICRORNAs FUNCTION.

THEY'RE NOT LIKE THE ANTISENSE

EXPERIMENTS THAT YOU MIGHT DO IN

A LABORATORY WHERE YOU DO

EVERYTHING POSSIBLE NOT HAVE ANY

OFFTARGET EFFECTS.

YOU ONLY WANT THE TO AFFECT THAT

PARTICULAR MESSAGE AND THAT

PARTICULAR PROTEIN AND NOTHING

ELSE.

WELL, IN BIOLOGY, MICRO RNAs

HAVE MANY OFFTARGET EFFECTS

THAT'S HOW THEY FUNCTION.

THAT'S HOW A PLAY A REGULATORY

ROLE.

A STUDY WE DID WITH CARLOW WAS

TO ASK A SIMPLE QUESTION, IF YOU

TAKE HUMAN CANCERS BREAST,

COLON, LUNG, STOMACH AND YOU

ANALYZE ALL THE MIKE ARE RNAs

THAT WERE KNOWN AT THE TIME AND

THAT WAS 280, THEY'RE CLOSE TO

2000 THAT IDENTIFY IT AT THIS

POINT, AND ASK THE QUESTION,

WHICH OF THESE MICRO RNAs ARE

THE MOST OVEREXPRESSED.

AND IN MOST OF THE TUMORS AND

MIRAKA 21 WAS HIGHLY EXPRESSED

AND ONE THE RACE AS BEING THE

MOST HIGHLY EXPRESSED MicroRNA

IN THESE COMMON TYPES OF HUMAN

CANCER AND SINCE THEN IT'S BEEN

SHOWN TO BE UB UPREGULATE INDEED

13 MAJOR CANCER TYPES.

SO THAT PEEKED OUR INTEREST IN

MIR 21 AS A POSSIBLE BIOMARKER

OF RISK CAN IS GENE

ENVIRONMENTMENT INTERACTIONS AND

HERE YOU THINK ABOUT PREVENTION

AND SCREENING OR PROGNOSIS,

TREAT OR NOT TO TREAT, AND

MACROMETASTASIS IS PRESTY EASY

FOR US IN THE CLINIC TO

IDENTIFY, DOING SCANS AND SO ON

AND SO FORTH.

HIKE ROW METASTASIS ARE NOT SO

EASY.

I'LL OF YOU AN EXAMPLE.

ONE OF MY PRIMARY SYSTEM LUNG

CANCER AND ABOUT--A STAGE ONE

LUNG CANCER, SURGEON REMOVES IT,

LOADS A NEGATIVE, AND THE

SURGEON SAYS, WELL, I THINK WE

GOT IT ALL.

IN REALITY ABOUT 40% OF THOSE

PEOPLE HAVE MICROMETASTASIS AND

WILL BE DEAD IN FIVE YEARS SO

THAT'S AND THAT'S FROM CLINICAL

PHARMACOLOGY, I WOULD NO LONGER

DO THAT.

THEY COME INTO PLAY.

SO WE'RE PARTICULARLY INTERESTED

IN EARLY STAGE CANCERS THAT HAVE

NO EVIDENCE OF METASTASIS, BUT

WE KNOW THERE'S A PERCENTAGE OF

THOSE PEOPLE WHO HAD MICRO

METASTASIS AND THEN THERE'S

ISSUES IN TERMS OF USE OF

BIOMARKERS FOR THERAPY RELATED

ISSUES.

SO THIS IS THE SWRIEWM O, AND

QUITE A NICE FELLOW, GOOD

FELLOW, BOTH GOOD AND A HIGH

QUALITY SCIENTIST.

AND HE FOUND THAT IN LUNG CANCER

THAT MicroRNA PROFILES WERE

TYPICALLY DIFFERENT BOTH BETWEEN

PRIMARY LUNG CANCERS AND

NONCANCEROUS TISSUE, SO MATCH

PAIRS AND AMONG THE LIFT HOE

LOGICAL TYPES SO HE COULD TELL

THE ADENO, AND SMALL CELL AND

NEUROENDOCRINE AND LARGE CELL

AND SO ON AND SO FORTH AND THESE

FIVE MICRO RNAs WERE ASSOCIATE

WIDE DIAGNOSIS OF PROGNOSIS

INCLUDING STAGE ONE LUNG CANCER.

SO MIR 21 MIR 155, 106, THESE

ARE ALL INCREASE AND OUR

ASSOCIATE WIDE POOR PROGNOSIS.

LCERTAINLY--CERTAINLY P-SEVEN

AND DECREASED AND ASSOCIATE WIDE

POOR PROGNOSIS.

SO IN A CRUDE WAY YOU CAN SAY

THIS IS A SUPPRESSOR MICRO

RNAs AND YOU CAN SAY THESE ARE

MICRONKA GENIC LUNG CANCERS BUT

THESE WERE INITIALLY DISCOVERED

BY TAKA HASHI, WHO WAS A

CLINICAL FELLOW ABOUT THE TIME

THAT I WAS.

IN THE--WHEREVER IT WAS.

WAS IT [INDISCERNIBLE] AT THE

TIME, I THINK IT WAS THE VA AT

THE TIME.

AND FRANK SLACK WHO WAS AT YALE.

SO WHEN YOU LOOK AT MULTIPLE

COHORTS, FROM MARYLAND FROM

NORWAY, FROM JAPAN AND THESE ARE

CANCER SPECIFIC MORTALITY.

THESE ARE CAP LANMEYER PLOTS,

HUNDRED% SURVIVAL, ZERO%

SURVIVAL.

THIS TIME IN MONTHS IT'S A FIVE

YEAR POINT, SO IF THE LEVEL OF

MIR 21 WAS BELOW THE MEDIAN,

THEY HAD BETTER SURVIVAL THAN IF

IT WAS ABOVE THE MEDIAN IN THAT

COHORT AND THIS COHORT AND IN

THAT COHORT.

ON THOSE GROUPS, IT'S SHOWN TO

BE THE CASE.

NOW IT'S TURN TO COLON CANCER

AND AARON AND JANE IDENTIFIED

MIRAKA 21 EXPRESSION.

AS A POTENTIAL BIOMARKER IN ONE

OF OUR COHORTS, AND THEN, TO

REQUIRE THE VALIDATION IN

ANOTHER COHORT AND SO, WE DID

THIS WITH OUR COLLEAGUES IN HONG

KONG.

--FOR SURVIVAL IN THE TUMOR,

DOESN'T MAKE ANY DIFFERENCE

WHETHER HIGH OR LOW IN THE

NONTUMOR MATCHED PAIR AND IN THE

SECOND INDEPENDENT COHORT,

AGAIN, HIGH LEVELS WERE

ASSOCIATED WITH POOR SURVIVAL.

IN THE NEXT QUESTION AS IT'S

RELATED TO THERAPY AND THIS WAS,

STILL BEING USED IN THE CLINIC

FOR COLON CANCER.

AT THAT POINT, THEY WERE USING

FIVE OF THE FEW AND THE MARYLAND

CO HORDE, THOSE WHO RECEIVE FIVE

FU, WE FOUND THAT HIGH LEVELS OF

MIR21 WAS SOCKED WITH THE POOR

PROGNOSIS AND IN THE HONG KONG

COHORT THIS, IS STAGE TWO AND

STAGE THREE COLON CANCER CASES,

HUNDRED% SURVIVAL, ZERO%

SURVIVAL.

THIS IS FIVE YEAR POINT.

THE RED LINE AND HIGH MIR 21

WITHOUT THERAPY.

THEY RECEIVE THERAPY, SOME

BENEFIT BUT THOSE WHO ENTERED

THE STUDY WHO HAD LOW MIR 21,

AND IF THEY HAD LOW MIR 21,

THEREFORE RESPONSE WAS EVEN

BETTER.

SO YOU COULD SEGREGATE PEOPLE ON

BASIS OF MIR 21 STATUS AND SO,

THIS IS ACTUALLY LEADING TO A

CLINICAL TRIAL THAT WERE

INVOLVED IN.

AND, IT'S VERY IMPORTANT IN

THESE KINDS OF STUDIES AND

ALMOST ANY KINDS OF CLINICAL

STUDIES OR EPIDEMIOLOGICAL

STUDIES OR BIOMARKER STUDIES TO

LOOK AT MULTIVARIANT ANALYSIS.

ARE THERE OTHER CO VARIANTS THAT

ARE EITHER AN INDEPENDENT OR

DEPENDENT ON THE ONE THAT YOU'RE

PRIMARILY INTERESTED IN.

SO MIR 21, IS INDEPENDENT OF

ADJUVANT THERAPY, AND

INDEPENDENT OF STAGE AS A

MULTIVARIANT EACH THOUGH IT WAS

AT A PROGNOSIS.

SO HAVE YOU THERAPY THERAPY AND
THIS HAS

BEEN FOUND NOT ONLY IN LUNG

CANCER AND COLON CANCER AND BY

OTHERS BUT IN PANCREATIC CANCER,

HEAD AND NECK CANCER, TONGUE

CANCER, SIGNIFY TELOMERA AND

CHRONIC LIMO SITTIC LEUKEMIA SO

HAVING HIGH LEVELS OF MIR 21 IS

NOT GOOD.

AND THAT LED TO THE QUESTION, IS

MIR21 AN ONCA GENE CAUSING

CANCER.

AND IS THERE ADDICTION TO MIR

21.

AND CAN IT BE A PREVENTIVE OR A

THERAPEUTIC TARGET.

SO I WILL SHOW YOU A COUPLE

THREE ANIMAL STUDIES RIGHTED NOW

THAT PERTAIN THIS.

THIS IS YALE, AND FRANK SHOWED

THAT INCREASED MIR 21 EXPRESSION

INDUCES PREE B LYMPHOMAS IN

MICE, AND HE HAD A TELL ALL

SYSTEM.

SO THERE WAS DOCS, MIR21 WOULD

BE TURNED OFF AND THAT'S THE

GREEN LINE UP THERE WHICH IS THE

SAME AS THE CONTROL.

IF IT'S EXPRESSED OR ESSENTIALLY

FROM THE LYMPHOMAS.

NOW THE ONCA GENE ADDICTION, OR

THE ONCA ADDICTION, YOU DO A

DIFFERENT EXPERIMENT AND YOU

WAIT TILL THE ANIMAL VS TUMORS.

YOU CAN SEE AS I RECALLLY HERE,

TUMORS GET SMALLER AND SMALLER

AND SMALLER.

MIR 21 INVOLVED IN THESE KINDS

OF EXPERIMENTS IN CAUSING CANCER

AND KEEPING CANCER DRIVING

FORWARD.

ANOTHER KIND OF EXPERIMENT, WAS

DRIVEN AT SOUTHWESTERN IN THE

BACK UP MODEL IN TYLER JACKSON

DEVELOPED AT MIT, ON LUNG CANCER

ENRICHED.

IT'S OVEREXPRESSION OF KRAS, AND

IN THIS EXPERIMENT, THEY FOUND

THAT MIR 21 EXPRESSION INCREASES

THE LUNG CANCER INCIDENCE TO„i

KRAAS S MODEL AND THIS IS

KRAS ALONE AND THIS IS THE

OVEREXPRESSION OF THE TRANSGENE

MIR 21.

AND YOU CAN SEE THE DIFFERENCE

IN THE NUMBER OF TUMORS, THE

OPPOSITE IS TO KNOCK OUT MIR 21

AND MARRY THOSE ANIMALS WITH THE

KRAS PRODUCING ANIMALS AND WHEN

TIM DID THESE EXPERIMENTS HE

FOUND THAT THIS IS THE USUAL

NUMBER OF KRAS LUNG ADENOMAS OR

CARCINOMAS, YOU CAN SEE THEM

HERE.

BUT, IF THIS IS IN A MIR 21

KNOCK OUT MOUSE, MARKEDLY

DIMINISHED.

NOW IS THERE A CONNECTION

BETWEEN MIR 21 AND INFLAMMATION?

THAT'S WHAT--ONE ASPECT OF THIS

TALK IS ALL ABOUT.

SO RAS CAN LEAD TO AN INCREASE

IN MIR 21 THROUGH THESE

TRANSCRIPTION FACTORS AND WHEN

WE ANALYZE MIR 21 IN THE RAS

INDUCED TUMORS IN WILD-TYPE

MICE, WE FOUND THIS LEVEL BUT IN

THE KNOCK OUT, IN THESE CASES,

THE KNOCK OUT MOUSE, INDUCIBLE

NITRIC OXIDE SIN TASE, MICE, WE

FOUND IT WAS DECREASED AND ONE

COULD DO INCITU HYBRIDIZATION

AND THERE'S LESS HERE THAN THIS

IS A SCRABBLE.

THIS IS A CONTROL HERE, MIRAKA

21, MIR 21.

MIR21.

AND THESE MICE THAT AND KRASE

MODEL.

AND IF THEY'RE IN THE KNOCKOUT

MICE, THEY LIVE LONGER.

THAT'S SIGNIFICANT AND THEY HAD

SMALLER TUMORS SO THESE ARE THE

LUNG TUMORS FROM THE NOS TWO

KNOCKOUT MICE, INCLUESED BY RAS,

SMALLER, SMALLER, AND IT WAS

HIGHER NUMBER OF KI 67 CELLS,

MEASURE OF PROLIFERATION THIS

THOSE THAT H. I.T THE WILD-TYPE

AND TUMORS IN CARCINOMAS, BUT

NOT IN ADENOMAS, IT WAS

DECREASED IN THOSE KNOCK OUT. 

AND THIS IS JUST THE

VISUALIZATION OF THIS, AND THIS

IS WHAT THE IMMUNOHISTOCHEMISTRY

LOOKS LIKE.

AND THEN LASTLY, INFLAMMATION.

SO, WHAT ARE THE OBSERVATIONS

THAT TYLER MADE A NUMBER OF

YEARS AGO BUT REALLY DIDN'T

FOLLOW UP ON IS THAT IN THIS

MODEL, THIS KRAS MODKNEEL

WILD-TYPE MICE THERE,'S A LOT OF

INFLAMMATION AND MACROPHAGES IN

PARTICULAR THAT YOU CAN SEE HERE

AND HERE.

IN THE KNOCKOUT MICE, THE

NOS-TWO KNOCKOUT MICE, THE

ALVEOLAR ASSESSINGS ARE FAIRLY

CLEAR.

AND THE NUMBER OF MACROPHAGES

HERE CAN BE QUANTITATED VERSES

THE KNOCK OUT.

SO LET'S SUMMARIZE ALL THIS

BEFORE GOING ON TO THE VERY LAST

POINT.

THERE ARE SEVERAL WAYS--LET ME

PUT IT THIS WAY, THERE'S A

MECHANISTIC UNDERPINNING BETWEEN

ALL OF THESE KINDS OF BIOMARKER

STUDIES OF MIRAKA 21.

ONE GENE APPLICATION IS OF THIS

SITE IS FREQUENTLY FOUND A

VARIETY OF DIFFERENT CANCERS, IT

CAN BE SILENCED BY DNA

METHYLATION, THE EGFR PATHWAY,

FOR THE MUTATIONS IN THE

EPIDERMAL GROWTH RECEPTOR

PATHWAY AS WE SHOWED IN PNAS

PAPER A COUPLE YEARS AGO WILL

LEAD TO INCREASE OF MIR 21,

ANDITE O KINE, INTERFERON

THROUGH STAT THREE, A

TRANSCRIPTION FACTOR WILL

UPREGULATE MIR 21.

FOX O THREEA INH	BITS VARIOUS

TYPES OF GENOMIC STRESS, WHETHER

IT'S FREE RADICALS OF THE OPTION

VARIETY OR NITROGEN VARIETY

PAPER WE JUST SUBMITTED OR

IONIZING A RADIATION INCREASE

FOR MIR 21 AND I'VE JUST LISTED

SOME OF THE GENES THAT ARE

TARGETING SYSTEM--THAT ARE

TARGETS AND MIR 21 AND THEY'RE

RELATED TO METASTASIS AND THESE

ARE ESSENTIALLY ANTIMETASTASIS

AND IN SOME CASES ANTITUMOR

GENES AND MIR 21 PLAYS A ROLE IN

INHIBITING ALL OF THESE BUT IN A

PARTICULAR TUMOR IT MAY NOT BE

ALL OF THEM.

IT MAY BE A SUBSET OF THEM AND A

DIFFERENT KIND OF TUMOR SUCH AS

A LUNG TUMOR VERSES COLON CANCER

THERE MAY BE SUBSETS.

SO INFLAMMATION, OKAY, THESE ARE

EXAMPLES OF STUDIES IN WHICH

PEOPLE HAVE LOOKED AT

INFLAMMATORY GENE EXPRESSION AND

ASKED THE QUESTION, ARE THERE

PROFILES FOR THOSE INFLAMMATORY

GENES THAT PREDICT PROGNOSEIS?

THIS IS A STUDY DONE BY

SHIN WONG AND THEY FOUND IN

LIVER CANCER A SET OF GENES THAT

WERE OVEREXPRESSED THAT WERE

ASSOCIATE WIDE POOR PROGNOSIS

AND ALSO WITH RECURRENCE.

AND THEN, MASA, ANOTHER JAPANESE

FELLOW IN OUR GROUP STUDIED LUNG

ADENO CARCINOMAS, AND FOUND THAT

IN ONE GROUP OF INDIVIDUALS, ALL

STAGES, HUNDRED% SURVIVAL, ZERO%

SURVIVAL FIVE YEARS THAT THIS

INFLAMMATORY RISK WAS ASSOCIATE

WIDE POOR SURVIVAL AND EVEN IN

STAGE ONE, LUNG CANCER WHICH I

SAID EARLIER IS WHAT WE'RE

PARTICULARLY INTEREST TED IN SO

LET'S GO BACK TO COLON CANCER

AND INITIATION.

TUMOR PROGRESSION AND MAY TAFT

SIS, AND AS I MENTIONED A COUPLE

TIMES CHRONIC INFLAMMATORY

DISEASES SUCH AS CROHN'S AND

ULCRY COLITIS INCREASED THE RISK

OF COLON CANCER AND NONSTEROIDAL

ANTIINFLAMMATORY GENE, DRUG K'S

REDUCE THE RISK TO COLON CANCER

AND THERE ARE POLYMORPHISMS IN

THE INFLAMMATORY GENES THAT ARE

ASSOCIATED WITH RISK AND

FINALLY, THE PRESENCE OF

INFLAMMATORY CELLS AND

EXPRESSION OF GENES ARE

ASSOCIATED WITH COLON CANCER

PROGNOSIS.

AND THIS IS ONE OF THE STUDIES

AGAIN DONE BY AARON AND SHANE IN

WHICH THE COMBINATION OF

EXPRESSION OF THESE INFLAMMATORY

GENES IN THE NONCANCEROUS COLON

AS WELL AS IN THE CANCEROUS

COLON TOGETHER ACCIDENT

COOPERATE TO INFLUENCE

INDIVIDUALS CANCER RISK AND THIS

IS JUST SHOWN HERE, BREAKING THE

HONG KONG COHORT INTO A HIGH

INFLAMMATORY RISK, VERSES LOW

AND THIS IS THE TRAINING AND

VERY IMPORTANT TO VALIDATION

CORHOOTER WHICH IS THE MARILYN

COHORT, SO, HIGH INFLAMMATORY

RISK FOR POOR PROGNOSIS COMPARED

TO LOW INFLAMMATORY SCORE.

SO WHY AM I SHOWING YOU THIS?

WELL, IT'S TO SHOW YOU THE NEXT

TWO OR THREE SLIDES.

THAT'S PUTTING TOGETHER

NONCODING RNAs AND CODING

RNAs FOR PREDICTION OF

PROGNOSIS.

SO THESE ARE THE DATA I JUST

SHOWED YOU.

SO INFLAYATORY RISK, POOR

PROGNOSIS, THEN LOW INFLAMMATORY

RISK OR SHOWING YOU THE DATA ON

MIR 21.

AND THE COLON CANCERS AGAIN,

HIGH MIR 21 ABOVE THE MEDIAN,

POOR PRO

PUT THEM TOGETHER BUT THERE ARE

LOW AND LOW, SO THIS ONE PLUS

THAT ONE EFFECTIVE PROGNOSIS IF

EITHER ONE IS HIGH, THEN

INTERMEDIATE PROGNOSIS IN BOTH

ARE HIGH, MUCH FOR PROGNOSE AND

I GUESS THOSE ARE CAP LANMEYER

CREWS AND WE DO THE ANALYSIS TO

SHOW THAT THE INFLAMMATORY RISK

SCORE IS INDEPENDENT OF MIR 21

AND THEY'RE BOTH EACH

INDEPENDENT OF TUMOR STAGE.

SO WHAT'S THE PRINCIPLE HERE?

I'VE SHOWN YOU PER COLON CANCER

BUT THE SAME PRINCIPLE HOLDS FOR

ESOPHAGEAL CANCER AND LUNG

CANCER AND YOU CAN COMBINE

CODING RNAs AND CODING RNAS

AND COME UP WITH CAP LANMEYER

KIRBS THAT LOOK LIKE THIS AND

WHAT'S THE PRINCIPLE BEHIND

THIS.

WELL, BOTH OF THESE RNA CLASSES

CONSIDER AN AAGREEMENT WILL GIVE

YOU A MORE ROBUST PROGMOSTIC

CLASSIFIER, BUT EACH MYTH

CLASSIFYS SOME OF THE PATIENTS

BUT THEY MISS CLASSIFIED

DIFFERENT PATIENTS.

SO I'LL SAY THAT ONCE MORE.

IF THEY'RE TWO INDEPENDENT

BIOMARKERS,„i STATISTICALLY

MECHANISTICALLY THEY'RE

INDEPENDENT BIOMARKERS.

AND YOU ASK THE QUESTION, IF YOU

PUT THE TWO TOGETHER WILL THEY

GIVE YOU MORE OF A CLASSIFIER,

IN THIS CASE, PROGNOSEIS, THE

ANSWER IS YES.

BUT WHY?

AND THE„i REASON IS YOU MISSED

EACH BIOMARKER DOES MISCLASSIFY

SOME OF THE CASES.

SO, NEXT TO THE VAST SLIDE,

IMPLICATIONS OF MICRO RNAs

INNATE IMMUNE MEDIATORS AND P53

ISOFORMS INSIDE AND SIGNALING

PATHWAYS INVOLVE THE

CARCINOGENESIS AND PROGRESSION,

PREVENTION, DIAGNOSIS IT'S EARLY

OR LATE STAGE, PREDICTION OF ONE

THERAPEUTIC OUTCOME, BUT SLACK

AND ONE OF HIS POST DOCS HAVE A

NATURE REVIEWS IN CANCER THAT

JUST CAME OUT THIS MONTH.

SO I WOULD DRAW YOUR ATTENTION

TO THAT, REVIEW IN WHICH, YOU

LOOKED AT DIFFERENT KINDS OF

THERAPIES IN THE VALUE OF MICRO

RNAs AND THEN, PREVENTION

THERAPEUTIC TARGETING SYSTEMLES

AND I THINK I--TARGETS AND I

THINK I MENTIONED MOST PEOPLE WE

WERE COLLABORATING WITH OR IN

OUR GROUP HERE AT THE NCI.

SO I THANK THEM AND WE'RE DONE.

IF HAVE YOU ANY QUESTIONS I'D BE

HAPPY TO ANSWER THOSE.

[ APPLAUSE ]

>> [INSIGNIFY CERNIBLE QUESTION

FROM AUDIENCE ]

>> NO.

SO OVEREXPRESSION OF MIR 21 LEDS

TO THOSE TUMORS AND ACTUAL IT

WAS AN INTERESTING

STORY--SEMIINTERESTING STORY.

HE WAS TRYING TO GET

NEUROLOGICAL TUMORS AND ENDED UP

GETTING THESE PRECELL LYMPHOMAS.

BUT IT WORKED OUT.

HE GOT HIS NATURE PAPER ON IT.

>> SO THEY WERE

OVEREXPRESSED--AND THEN ... DID

NOT, YEAH.

SO THAT GAVE YOU THE CONTROL

WHERE YOU ALLOW THE TUMORS TO

GROW AND THEN YOU KNOCK DOWN MIR

21 AND THEY REROUTE.

SO THAT'S THE ORCHGA TEAM

ADDICTION, OR ONCA-MIR ADDICTION

THAT WAS PREDICTED ABOUT 15

YEARS AGO WHEN IT WAS INITIALLY

FOUND BY BERNIE WEINSTEIN AND

OTHERS.

AND THOSE ARE--THAT--THERE'S

IMPLICATION OF THAT, THAT MEANS

IT'S A VERY INTERESTING TARGET

FOR THERAPY.

NOT ONLY IS THE BIOMARKER BUT

BUT IT'S AN INTERESTING TARGET

FOR BIOTHERAPY AND THERE'S BEEN

INTERESTING STUDIES DONE WITH

BENNOGRAPHS AND--EXTEN O GRAPHS

AND CULTURE AND IN THE NEXT YEAR

OR SO, THERE WILL BE A CLINICAL

STUDY STARTED WITH ANTIMIR 21.

ANYTHING ELSE?

SURE.

>> [INAUDIBLE QUESTION FROM

AUDIENCE ]

>> YEAH.

THAT'S--THAT THAT STUDY WAS DONE

WITH NICOLE--I'M BLOCKING ON THE

NAME RIGHT NOW WITH RADIATION

SIMON--RADIATION ON ONCOLOGY

BRANCH SO SHE JUST MOVED TO

JEFFERSON AND ENGAGE INDEED THAT

STUDY.

--ENGAGED IN THAT STUDY.

>> YES?

>> [INAUDIBLE QUESTION FROM

AUDIENCE ]

>> OH YOU SHOULD TALK TO ONE OF

MY CANCER PREVENTION FELLOWS.

YES.

THAT'S ONE OF THE THINGS THAT

SHE'S DOING RIGHT NOW.

>> IF YOU WERE GOING TO DEVELOP

[INDISCERNIBLE] I FEEL LIKE

[INDISCERNIBLE] YOU'RE SAYING

THAT PLACE, BY KNOCKING THEM

OUT, IT'S--[INDISCERNIBLE].

>> YEAH, IT'S A QUESTION OF

CAUSATION AND WHETHER OR NOT

IT'S A CONTINUATION, IT'S ASKING

THAT QUESTION.

I GAVE YOU THE LIST OF HOW MIR21

CAN BE UPREGULATED IN THE

CANCERS, IT'S AMPPLIFICATION AND

IN A WAY IT'S DOING A

MECHANISTIC STUDY OF TRYING TO

LINK CHRONIC INFLAMMATION OR

GENE APPLICATION TO CAUSING

CANCER AND WE FIND HIGH LEVELS

OF MIR 21 IN HUMAN CANCERS AND

HOPEFULLY IN THE NOT TOO DISTANT

FUTURE TELL BE KNOCKED DOWN IN

THE HUMAN CANCERS AND WE'LL SEE

IF IT REALLY--IT SHOWS ONCA GENE

ADDICTION IN HUMAN CANCERS AND

NOT JUST IN EXPERIMENTAL

ANIMALS.

>> THANKS KURT, THAT WILL DO IT.

[ APPLAUSE ]