FINALLY, I WOULD LIKE TO ACKNOWLEDGE ALL OF THE GREAT STUDENT POST DOC TECHNICIANS I'VE HAD IN MY LEADERS PARTICULARLY IN THE LAST TEN YEAR IS EXTREMELY PRODUCTIVE [INDISCERNIBLE] WHO DID FANTASTIC WORK, WHO DID THE XPA WORK AND IDENTIFIED THE DPEAN [INDISCERNIBLE] THIS IS PATRICIA -- SHE DEVELOPED [INDISCERNIBLE] AND THIS IS [INDISCERNIBLE] AND ARE DOING THE WORK. THANKS FOR YOUR ATTENTION. [APPLAUSE] >> OKAY, VERY GOOD. THANK YOU. NOW IS THE TIME FOR ASKING QUESTIONS FROM DIFFERENT SITES. SO THE GROUND RULES ARE THAT YOU ASK ONE QUESTION AT A SITE. WE'LL GO AROUND AND THEN IF THERE ARE ADDITIONAL QUESTIONS WE'LL HAVE A SECOND ROUND. WHY DON'T WE GO TO THE BALTIMORE FIRST. EVERYONE ELSE BE SURE TO MUTE AND UNMUTE IN BALTIMORE. ARE YOU THERE, DAVID? OKAY. WELL THEN LET'S GO TO CHAPEL HILL, UNIVERSITY OF NORTH CAROLINA. >> HELLO. [INDISCERNIBLE] THANK YOU ALL FOR A VERY VERY NICE TALK BUT WE DON'T HAVE ANY QUESTIONS TODAY. >> OKAY. VERY GOOD. LET'S GO TO UNIVERSITY OF KENTUCKY. >> [INDISCERNIBLE] I WANT TO THANK YOU FOR A NICE TALK. I WAS JUST WONDERING WHETHER YOU COULD COMMENT A LITTLE BIT MORE ON THE XPA SLICE IDS WHERE YOU HAVE A IT'S BIT OF REPAIR [INDISCERNIBLE] I WONDER IF YOU WOULD ELABORATED ON WHAT YOU THINK THAT IS AT THE MOLECULAR LEVEL. >> OKAY, THANKS FOR THE QUESTION. I SHOULD ALSO SAY A COUPLE OTHER, THERE HAVE BEEN A COUPLE OTHER REPORTS IN THE LITERATURE OF PATIENTS WITH RESIDUAL XPA PROTEIN ALSO HAVING NO NEUROLOGICAL PROBLEMS. SO ONE POSSIBLE EXPLANATION TO THAT IS WHEN YOU LOOK AT, WHEN YOU ARE EXPOSED TO UV LIGHT AS A PERSON, YOU TEND TO GET A HIGH DOSE OF DNA DAMAGE WHICH YOU THEN HAVE TO DEAL WITH. AND SO IT CAN BE, YOU MAY NOT HAVE TIME TO GET RID OF ALL THAT DAMAGE BEFORE THE NEXT BLAST OF UV LIGHT COMES AND GIVES YOU MORE DAMAGE. SO CUMULATIVELY YOU GET LOTS OF DAMAGE WHICH YOU ARE NOT ABLE TO DEAL WITH ALL OF IT. HOWEVER IF ONE ASSUMES THAT THE NEUROLOGICAL PROBLEMS ARE CAUSED BY DNA ENDOGENOUS AGENT IN THE BRAIN IS GENERATED AT A VERY LOW LEVEL BUT CONTINUOUSLY. SO YOU ONLY GOT A LOW LEVEL OF NER YOU MAY BE ABLE TO DEAL WITH THAT AND CONTINUES TO GET RID OF THIS CONTINUOUS LOW LEVEL OF DAMAGE MORE EFFICIENTLY THAN YOU CAN DO WHERE YOU'RE GETTING LARGE AMOUNTS OF DNA DAMAGE LIKE YOU DO WITH EXPOSURE TO SUNLIGHT. THAT'S MY CURRENT THINKING ABOUT IT [INDISCERNIBLE] >> THAT MAKES A LOT OF SENSE. THANKS FOR THE SEMINAR AGAIN. >> IN ADDITION TO THAT THE NERVOUS SYSTEM DOESN'T DIVIDE SO YOU HAVE A LONG TIME BETWEEN THE DIVISIONS SO THE REPAIR CAN GO ON FOR A LONG TIME. WE FOUND A [INDISCERNIBLE] PATIENT [INDISCERNIBLE] GIVING VERY LOW LEVELS, JUST A FEW PERCENT OF XPC AND HAVING A VERY LOW LEVEL OF SKIN CANCER. WE HAVE ANOTHER FAMILY THAT HAD ACTUALLY MUTATION A LITTLE FARTHER DOWN AT THE END THAT HAD NO [INDISCERNIBLE] AT ALL AND THEY HAVE MANY SKIN CANCERS. IT DOESN'T TAKE MUCH IN THE XP. OKAY. LET'S MOVE ON TO STONY BROOK. >> YES, ALAN. I HAVE A QUESTION WHICHS SOMEWHAT NAIVE AND IT'S GOOD THAT KEN IS THERE TOO. DO YOU THINK THAT XP IS NOW GENETICALLY SEPARATED AND NO NEW GENE DISCOVERED TO BE INVOLVED IN IT? [LAUGHTER] >> THAT'S A TOUGHER QUESTION THAN IT SOUNDS. SO FOR ALL THE PATIENTS THAT WE HAVE SEEN WITH DNA REPAIR DEFECTS WE HAVE FOUND A MUTATION [INDISCERNIBLE] MAYBE THERE'S ONE EXCEPTION TO THAT. IF YOU WERE TO RULE IN THE CLINICAL DEFINITION -- IT DEPENDS HOW YOU DEFINE XP. AS A CLINICIAN I GUESS YOU WOULD SAY THIS PATIENT'S GOT XP THEY THEN TURN OUT NOT TO HAVE A DEFECT IN DNA REPAIR AND SO MAYBE A DIFFERENT GENE. SO MOLECULAR LEVEL CAME FROM MY PERSPECTIVE IF IT'S GOT DNA REPAIR DEFECT IN ALL THOSE 70 CASES THAT WE'VE SEEN WE KNOW THE MUTATION IS ONE OF THE KNOWN GENES. I DON'T KNOW, KEN MAY WANT TO DIFFER ON THIS. >> WE CAN GO BOTH WAYS. WE'RE FINDING PATIENTS WHO ARE UNSUSPECTED OF HAVING XP WHO ARE ADULTS WITH MULTIPLE SKIN CANCERS AND THEN WHEN WE DID THE STANDARD TESTS, IN FACT THEY HAD XP. SO THE CLINICIANS WEREN'T THINKING ABOUT IT. AND MAYBE WE ARE PARTLY RESPONSIBLE BECAUSE THE PICTURES WALT WE PUBLISH ARE THE ONES LIKE YOU SHOW OF THE VARIOUS REALLY AFFECTED PATIENTS AT AN EARLY AGE. AND MAYBE THERE ARE MILDER NORMS THAT WERE UNSUSPECTED. CERTAINLY THE [INDISCERNIBLE] IN FACT WE'VE SEEN PATIENTS WHO WERE IN THE US NAVY IN THE SOUTH PACIFIC WHO WERE IN THE WAR AND WERE NORMAL AND DEVELOPING MANY CANCERS LATER AND HAD XPC MUTATIONS. SO THAT'S ON THE ONE SIDE. THE OTHER WE WERE ALSO STUDYING PATIENTS WITH [INDISCERNIBLE] DISTROPHY AND MOST OF THEM HAVE XPD MUTATIONS. SOME OF THEM TPDA OR OTHERS BUT THIS IS A GROUP WITH NO KNOWN MUTATIONS. WE'RE LOOKING AT THEM RIGHT NOW. THEY CLEARLY HAVE TPD. >> OKAY, THANK YOU. >> YOU'RE WELCOME. PLEASE MUTE THERE. LET'S GO TO UNIVERSITY OF PITTSBURGH. >> FANTASTIC PRESENTATION, VERY INFORMATIVE, THANKS VERY MUCH ALAN. NO QUESTIONS FROM OUR GROUP HERE TODAY. THANK YOU. >> OKAY. THANK YOU. PLEASE MUTE THERE. LET'S GO TO PORTLAND, OREGON. >> HI MY NAME'S [INDISCERNIBLE] I'M A POTION DOCK IN STEVE LLOYD'S LAB. I WAS JUST CURIOUS ABOUT THE NEUROLOGICAL DEFICITS AND WHETHER ANYBODY'S ACTUALLY LOOKED AT THE ACCUMULATED DNA DAMAGE AND WHAT TYPES MIGHT BE RESPONSIBLE IN THAT PATHOLOGY. >> SOME GROUPS HAVE DONE SOME WORK ON THAT AND HAS I THINK FOUND EVIDENCE, CERTAINLY HAS PROPOSED THAT IT'S CYTOPURINES ATOMS THAT MAY BE THE CAUSE OF NEUROLOGICAL PROBLEMS BUT IT'S REALLY AS YOU CAN IMAGINE IT'S REALLY DIFFICULT TO WORK ON [INDISCERNIBLE] WHERE THEY WERE ABLE TO IDENTIFY THAT LESION. BUT I THINK IT'S AN OPEN QUESTION BUT THAT'S AN IDEA. IF YOU WANT TO ADD ANYTHING TO THAT. >> WELL THAT'S A POPULAR ONE THEN. ANYTHING ELSE FROM PORTLAND? OKAY. LET'S GO TO THE RESEARCH TRIANGLE >> DR. LEHMANN THANK YOU FOR THE EXCELLENT LECTURE. THEY JUST ASKED OUR QUESTIONS SO THANKS VERY MUCH. >> OKAY THANKS. PLEASE MUTE. LET'S GO TO ANN ARBOR MICHIGAN. ARE YOU THERE? ANYONE THERE AT ANN ARBOR. >> YES. IT'S HARD WITH THIS MUTE BUTTON WE'RE HAVING TROUBLE HERE. THANK YOU ALAN. GREAT TALK. I HAVE A QUESTION RELATED TO ANOTHER QUESTION ABOUT YOUR XP PATIENT THE OLDER GENTLEMAN THAT HAD A LITTLE BIT OF XPA. IS THAT LEVEL XPA SUFFICIENT FOR TRANSCRIPTION CULTURE REPAYERS BUT MAYBE NOT FOR GLOBAL GENOMICS REPAIR. >> THAT'S A REASONABLE SUGGESTION, YES. IF YOU CAN TRUE TRANSCRIPTION THEN NEUROLOGY IS IN BETTER SHAPE. >> RIGHT, RIGHT. OKAY. THANK YOU. GREAT TALK. >> WE'VE ACTUALLY SEEN XP8 PATIENT WITH A MUTATION NEAR THE END OF THIS PROTEIN NEUROLOGIC ABNORMALITY [INDISCERNIBLE] OKAY. WHO ELSE. ANYONE THERE AT BROOK HAIRCH? BROOK HAIRCH? HAVEN. HOW ABOUT BALTIMORE, GAVE YOU ANOTHER SHOT. DO YOU HAVE QUESTIONS? >> [INDISCERNIBLE] XPD >> I HAVEN'T ACTUALLY SEEN THE [INDISCERNIBLE] >> IN YOUR PATIENTS [INDISCERNIBLE] [LAUGHTER] WE HAVEN'T SEEN THEM EITHER. WHAT IS THE QUESTION? >> [INDISCERNIBLE] WELL THEY HAVE NEUROLOGIC PROBLEMS, THEY HAVE SKIN CANCERS. >> [INDISCERNIBLE] [LAUGHTER] >> SCIENTIFIC RESEARCH XPD PATIENTS WAS FROM HERE AND HAPPENED BOTH [INDISCERNIBLE] AND SEVERE NEUROLOGIC PROBLEMS [INDISCERNIBLE] >> I'VE SEEN WHEN THEY SAID SHE'S GOT QUITE SEVERE PROBLEMS AND SHE'S MARRIED AND THEY THINK SHE'S CONCERNED AND HER HUSBAND'S CONCERNED [INDISCERNIBLE] >> THE ONE WE HAD HAVE IS VERY SHORT STATURE. [INDISCERNIBLE] >> XPD IS VERY RARE. ANY MORE QUESTIONS? >> THIS IS STEVEN LLOYD IN PORTLAND. [INDISCERNIBLE] THANKS. ALAN THAT'S REALLY A FRAN TAS PARTICULAR PERSPECTIVE, GENUINELY APPRECIATE IT. I HAD A QUESTION CONCERNING WHETHER YOU HAVE IDENTIFIED MUTATIONS IN [INDISCERNIBLE] THAT AFFECTS THE FIDELITY OF THE POLYMERIZATION REACTION [INDISCERNIBLE] AND OTHER LESIONS BUT DOESN'T NECESSARILY AFFECT THE INTERCELLULAR TRAFFICKING OF IT BUT JUST MERELY CHANGES THE FIDELITY. >> OKAY. SO THE MAJORITY OF MUTATIONS AT TRUNKATIONS WHICH KNOCK OUT THE PROTABS WE HAVE HALF A DOZEN UNIT MUTATIONS [INDISCERNIBLE] DID YOU DO ANYTHING. [INDISCERNIBLE] >> DID YOU GET THAT. >> NO, WE DIDN'T HEAR THE ANSWER. >> SHE SAYS THE MUTATIONS ALL AFFECT THE STABILITY BUT YOU DON'T AFFECT THE YOUR THEY ALL AFFECT THE STABILITY BUT THEY'RE UNLIKELY TO AFFECT THE SEVERITY. >> SO WOULD YOU THINK IT'S AT LEAST POSSIBLE TO HAVE A MUTATION IN [INDISCERNIBLE] SOME OF THE OTHER TRANSLATION POLYMERASES -- YOU CAN PICK UP A MUTATION THAT WOULD CHANGE THAT FIDELITY. >> THAT WAS OF COURSE IN PRINCIPAL, YES. IF YOU FOUND SOMETHING WHICH DECREASED THE FIDELITY. >> ANY OTHER QUESTIONS? IF NOT, THANK YOU VERY MUCH.