1 00:00:05,323 --> 00:00:06,991 WELCOME EVERYONE AND THANK 2 00:00:06,991 --> 00:00:08,693 YOU FOR JOINING. 3 00:00:08,693 --> 00:00:14,632 THIS IS THE OADR SCIENCE TALKS 4 00:00:14,632 --> 00:00:16,234 AND I'M DR. VICKIE SHNG. 5 00:00:16,234 --> 00:00:19,537 I'M THE DIRECTOR OF AUTOIMMUNE 6 00:00:19,537 --> 00:00:20,571 RESEARCH AT THE NIH. 7 00:00:20,571 --> 00:00:22,106 IT'S A PLEASURE TO HAVE YOU WITH 8 00:00:22,106 --> 00:00:24,041 US TODAY. 9 00:00:24,041 --> 00:00:27,578 WE'RE DELIGHTED TO BE JOINED BY 10 00:00:27,578 --> 00:00:29,313 SOME OF THE SMARTEST SCIENTISTS 11 00:00:29,313 --> 00:00:30,548 IN THE FIELD TODAY TO TALK ABOUT 12 00:00:30,548 --> 00:00:34,318 THE INTERSECTION OF AUTOIMMUNITY 13 00:00:34,318 --> 00:00:35,720 AND CANCER. 14 00:00:35,720 --> 00:00:39,857 THIS EVENT WILL BE RECORDED AND 15 00:00:39,857 --> 00:00:42,760 THE RECORDING WILL BE AVAILABLE 16 00:00:42,760 --> 00:00:44,228 IN THE VideoCast ARCHIVE. 17 00:00:44,228 --> 00:00:47,431 IF YOU NEED CAPTIONS, THE 18 00:00:47,431 --> 00:00:49,500 CAPTIONS WILL BE BEST VIEWED 19 00:00:49,500 --> 00:00:53,104 THROUGH VideoCast SO FEEL 20 00:00:53,104 --> 00:00:57,375 FREE TO LOG ON AND LON -- LOG 21 00:00:57,375 --> 00:00:59,610 OFF AND LOG ON TO THE 22 00:00:59,610 --> 00:01:00,611 VideoCast. 23 00:01:00,611 --> 00:01:01,946 YOU CAN GET IT THROUGH ZOOM AS 24 00:01:01,946 --> 00:01:02,146 WELL. 25 00:01:02,146 --> 00:01:04,215 THIS IS AN OPEN SESSION SO 26 00:01:04,215 --> 00:01:06,484 PLEASE BE CONSIDERATE AND 27 00:01:06,484 --> 00:01:09,053 RESPECTFUL WHEN YOU'RE USING THE 28 00:01:09,053 --> 00:01:09,654 Q&A FUNCTION. 29 00:01:09,654 --> 00:01:11,155 IF YOU HAVE ANY TECHNICAL 30 00:01:11,155 --> 00:01:14,725 CHALLENGES, FIRST TRY LEAVING 31 00:01:14,725 --> 00:01:17,495 THE WEBINAR AND REJOIN AND THAT 32 00:01:17,495 --> 00:01:19,130 USUALLY DOES FIX THE PROBLEM. 33 00:01:19,130 --> 00:01:20,031 HERE IS AN OUTLINE FOR TODAY'S 34 00:01:20,031 --> 00:01:20,798 EVENTS. 35 00:01:20,798 --> 00:01:23,601 WE'RE EXCITED TO BE JOIN THE BY 36 00:01:23,601 --> 00:01:25,636 THREE INCREDIBLE SCIENTISTS WHO 37 00:01:25,636 --> 00:01:28,639 WILL EACH PRESENT FOR 30 MINUTES 38 00:01:28,639 --> 00:01:31,576 ON THEIR TOPIC AND THEN WE'LL 39 00:01:31,576 --> 00:01:35,146 HAVE A PANEL QUESTION AND ANSWER 40 00:01:35,146 --> 00:01:37,682 SESSION THAT WILL BE AN OPEN 41 00:01:37,682 --> 00:01:37,882 FORUM. 42 00:01:37,882 --> 00:01:40,785 WE HAVE TWO MODERATORS FOR 43 00:01:40,785 --> 00:01:43,087 TODAY'S EVENT AND I WANT TO 44 00:01:43,087 --> 00:01:45,122 INTRODUCE THEM TO YOU NOW. 45 00:01:45,122 --> 00:01:48,459 WE'LL BE USING THE Q&A FUNCTION 46 00:01:48,459 --> 00:01:49,226 THROUGH ZOOM, SO REMEMBER, IF 47 00:01:49,226 --> 00:01:52,630 YOU FIND YOUR ZOOM TOOLBAR, YOU 48 00:01:52,630 --> 00:01:56,367 CAN GO TO Q&A AND WE WILL HE 49 00:01:56,367 --> 00:01:57,835 ALLOW THE UP-VOTE OPTION FOR 50 00:01:57,835 --> 00:01:58,102 QUESTIONS. 51 00:01:58,102 --> 00:02:01,105 IF THERE IS A BURNING QUESTION, 52 00:02:01,105 --> 00:02:02,974 YOU CAN UP VOTE IT HERE. 53 00:02:02,974 --> 00:02:07,411 THE TWO MODERATORS WILL BE DR. 54 00:02:07,411 --> 00:02:10,281 LILLIAN QUOA WHO IS A PROGRAM 55 00:02:10,281 --> 00:02:14,018 DETECTOR IN THE HEMATOLOGY AND 56 00:02:14,018 --> 00:02:16,220 ETIOLOGY BRANCH IF HE NATIONAL 57 00:02:16,220 --> 00:02:18,923 CANCER INSTITUTE AND DR. HEY 58 00:02:18,923 --> 00:02:24,662 PARK WHO IS A PROGRAM DIRECTOR 59 00:02:24,662 --> 00:02:26,397 FOR AUTO INFLAM DISEASE PROGRAM 60 00:02:26,397 --> 00:02:33,070 AT THE NATIONAL INSTITUTE OF 61 00:02:33,070 --> 00:02:34,605 ARTHRITIS, MUSCULAR SKELETAL AND 62 00:02:34,605 --> 00:02:35,239 SKIN DISEASES. 63 00:02:35,239 --> 00:02:39,343 WITH THAT, I'LL PASS THE MIKE RE 64 00:02:39,343 --> 00:02:41,979 PHONE OVER TO DR. PARK TO 65 00:02:41,979 --> 00:02:45,483 INTRODUCE THE FIRST SPEAKER. 66 00:02:45,483 --> 00:02:46,817 >> THANK YOU DR. SHANMUGAM. 67 00:02:46,817 --> 00:02:54,325 I WILL TURN IT OVER TO DR. SHAH 68 00:02:54,325 --> 00:02:57,094 FROM THE JOHN HOPKINS SCHOOL OF 69 00:02:57,094 --> 00:03:02,700 MEDICINE AND A CODIRECTOR OF THE 70 00:03:02,700 --> 00:03:06,804 MEUN CENTER. 71 00:03:06,804 --> 00:03:10,374 AUTOIMMUNE CENTER. 72 00:03:10,374 --> 00:03:13,310 SHE INVESTIGATES THE CONNECTION 73 00:03:13,310 --> 00:03:14,045 BETWEEN [INDISCERNIBLE] AND 74 00:03:14,045 --> 00:03:16,547 CANCER. 75 00:03:16,547 --> 00:03:18,449 THE FLOOR IS NOW YOURS. 76 00:03:18,449 --> 00:03:24,055 >> THANK YOU, DR. PARK FOR THAT 77 00:03:24,055 --> 00:03:28,025 KIND DESTRUCTION AND FOR THE 78 00:03:28,025 --> 00:03:28,592 OPPORTUNITY TO SPEAK IN THIS 79 00:03:28,592 --> 00:03:28,993 EXCITING SESSION. 80 00:03:28,993 --> 00:03:29,627 SO I WILL BE SPEAKING TODAY 81 00:03:29,627 --> 00:03:32,530 ABOUT THE LINK BETWEEN 82 00:03:32,530 --> 00:03:34,098 SCLERODERMA AND CANCER. 83 00:03:34,098 --> 00:03:36,167 THESE ARE MY DISLOISHERS. 84 00:03:36,167 --> 00:03:39,236 MY GOALS TODAY ARE TO BRIEFLY 85 00:03:39,236 --> 00:03:44,275 REVIEW THE COMPLEX AND BODY 86 00:03:44,275 --> 00:03:44,909 DIRECTIONAL RELATIONSHIP BETWEEN 87 00:03:44,909 --> 00:03:49,013 CANCER AND AUTOIMMUNITY IN 88 00:03:49,013 --> 00:03:50,448 SCHERM DETERMINA. 89 00:03:50,448 --> 00:03:54,752 I'LL REVIEW CLINICAL 90 00:03:54,752 --> 00:04:00,091 IMPLICATIONS FOR SCHERMA AND 91 00:04:00,091 --> 00:04:01,192 CANCER-INDUCED DISEASE. 92 00:04:01,192 --> 00:04:01,892 WHILE MY FOCUS WILL BE ON 93 00:04:01,892 --> 00:04:08,933 SCHERMA DETERMINA, DESCRSH 94 00:04:08,933 --> 00:04:17,108 SCLERODERMA, IT MAY RELATE 95 00:04:17,108 --> 00:04:17,641 TOMORROW OTHER CONDITIONS. 96 00:04:17,641 --> 00:04:23,914 TO PROVIDE A BRIEF PRIMER ON 97 00:04:23,914 --> 00:04:27,551 SCLERODERMA, THIS IS AN 98 00:04:27,551 --> 00:04:32,923 AUTOIMMUNITY SYSTEM EXAGGERATED. 99 00:04:32,923 --> 00:04:35,659 IT'S THE INTERSECTION BETWEEN 100 00:04:35,659 --> 00:04:37,128 THE DIFFERENT MECHANISMS THAT 101 00:04:37,128 --> 00:04:40,798 LEADS TO THE CLINICAL 102 00:04:40,798 --> 00:04:42,733 MANIFESTATIONS FOR OTHER THINGS 103 00:04:42,733 --> 00:04:46,170 LIKE HYPERTENSION, SKIN 104 00:04:46,170 --> 00:04:49,974 THICKENING AND INTERSTCIAL LUNG 105 00:04:49,974 --> 00:04:55,913 LUNG -- INTERSTECIAL DISEASES. 106 00:04:55,913 --> 00:04:58,649 THIS IS CHALLENGING TO PREDICT 107 00:04:58,649 --> 00:05:00,584 FOR AN INDIVIDUAL PATIENT THEIR 108 00:05:00,584 --> 00:05:02,253 LIKELY RISK OF DIFFERENT 109 00:05:02,253 --> 00:05:03,420 COMPLICATIONS OVER TIME. 110 00:05:03,420 --> 00:05:08,125 ONE OF THE THINGS THAT WOULD HE 111 00:05:08,125 --> 00:05:09,093 AS RHEUMATOLOGISTS DO IS PERFORM 112 00:05:09,093 --> 00:05:13,531 A SUBSETTING TO CLASSIFY OUR 113 00:05:13,531 --> 00:05:16,200 PATIENTS AS TOE WHETHER THEY 114 00:05:16,200 --> 00:05:21,205 HAVE THE LIMITED OR DIFFUSE 115 00:05:21,205 --> 00:05:22,706 MANIFESTATIONS OF THE DISEASE. 116 00:05:22,706 --> 00:05:28,112 SHOWN IN THE TOP ARE THE DIFFUSE 117 00:05:28,112 --> 00:05:30,848 SCHERMA DETERMINA. 118 00:05:30,848 --> 00:05:33,150 THE LIMITED IS SHOWN IN THE 119 00:05:33,150 --> 00:05:39,657 BOTTOM PANEL OF IMAGES INCLUDING 120 00:05:39,657 --> 00:05:42,059 DIGITAL LOSS AND HYPERTENSION. 121 00:05:42,059 --> 00:05:45,496 WE KNOW THIS CONSTRUCT DOES NOT 122 00:05:45,496 --> 00:05:52,436 TELL THE WHOLE STORY BECAUSE 123 00:05:52,436 --> 00:05:53,537 PATIENTS WITH DIFFUSE MAY HAVE 124 00:05:53,537 --> 00:05:55,573 OTHER MANIFESTATIONS AND THOSE 125 00:05:55,573 --> 00:06:00,177 WITH LIMITED MAY HAVE SCHERM 126 00:06:00,177 --> 00:06:01,846 DETERMINA LUNG DISEASE. 127 00:06:01,846 --> 00:06:12,523 THE THREE MOST COMMON YA -- THE 128 00:06:25,135 --> 00:06:29,540 AUTOIMMUNITY ANTIBODIES PREDICT 129 00:06:29,540 --> 00:06:30,875 OTHER DISEASE. 130 00:06:30,875 --> 00:06:33,677 THERE ARE OBSERVATIONAL COHORT 131 00:06:33,677 --> 00:06:37,181 STUDIES AND SYSTEMIC REVIEWS IN 132 00:06:37,181 --> 00:06:38,916 GENERAL SUGGEST THERE IS AN 133 00:06:38,916 --> 00:06:42,453 INCREASED RISK OF CANCER IN 134 00:06:42,453 --> 00:06:46,090 PATIENTS WITH SCLERODERMA. 135 00:06:46,090 --> 00:06:48,893 THESE RISK ESTIMATES HAVE RANGED 136 00:06:48,893 --> 00:06:53,564 FROM 1.4 TO 1.8 FOLD RISK OF 137 00:06:53,564 --> 00:06:55,466 CANCER IN PATIENTS WITH SCHERRA 138 00:06:55,466 --> 00:06:56,200 DRMA. 139 00:06:56,200 --> 00:06:59,703 THERE IS A HIGH RISK OF CANCER 140 00:06:59,703 --> 00:07:03,641 BUT A WIDE ARRAY OF TUMOR TYPES 141 00:07:03,641 --> 00:07:05,609 HAVE BEEN REPORTED AS, HIGH RISK 142 00:07:05,609 --> 00:07:06,911 IN THE PATIENT POPULATION. 143 00:07:06,911 --> 00:07:08,679 WHAT IS THE POTENTIAL LINK 144 00:07:08,679 --> 00:07:13,517 BETWEEN CANCER AND SCLERODERMA? 145 00:07:13,517 --> 00:07:17,388 IT IS CONCEIVABLE THAT SOME OF 146 00:07:17,388 --> 00:07:24,228 THE AUTOIMMUNE TREATMENTS MAY 147 00:07:24,228 --> 00:07:25,562 INTERFERE WITH THIS. 148 00:07:25,562 --> 00:07:29,166 IT'S POSSIBLE THERE IS A 149 00:07:29,166 --> 00:07:32,870 DECREASED ABILITY TO CLEAR VIRAL 150 00:07:32,870 --> 00:07:35,272 INFECTIONS IN OUR PATIENTS 151 00:07:35,272 --> 00:07:37,041 RELATED TO THE THERAPIES WE 152 00:07:37,041 --> 00:07:37,675 EMPLOY. 153 00:07:37,675 --> 00:07:39,343 IT IS ALSO POSSIBLE AT THAT 154 00:07:39,343 --> 00:07:42,479 DAMAGE FROM THE DISEASE COULD 155 00:07:42,479 --> 00:07:47,985 PREDISPOSE A PATIENT FROM HAVING 156 00:07:47,985 --> 00:07:50,187 MALIGNANT PROBLEMS IN THE 157 00:07:50,187 --> 00:07:50,587 TISSUES. 158 00:07:50,587 --> 00:07:53,891 WE THINK OF LUNG SCANSER VEL 159 00:07:53,891 --> 00:07:57,528 DEVELOPING INTO INTERSTITIAL 160 00:07:57,528 --> 00:07:58,796 LUNG DISEASE. 161 00:07:58,796 --> 00:08:01,899 IT'S POSSIBLE THAT RAID YEATION 162 00:08:01,899 --> 00:08:04,335 TREATMENTS AND OTHER TREATMENTS 163 00:08:04,335 --> 00:08:10,007 COULD PREDISPOSE PATIENTS TO 164 00:08:10,007 --> 00:08:13,510 DEVELOPING SCLERODERMA AND LIKE 165 00:08:13,510 --> 00:08:14,511 DISEASES. 166 00:08:14,511 --> 00:08:22,386 A PATIENT DEVELOPED CYTO TOXIC 167 00:08:22,386 --> 00:08:33,163 AND ANOTHER THAT DEPOS TESTIMONT 168 00:08:33,897 --> 00:08:35,232 OR DISEASE. 169 00:08:35,232 --> 00:08:41,972 THE DISEASE COULD BE PARA 170 00:08:41,972 --> 00:08:43,640 NEOPLASTIC. 171 00:08:43,640 --> 00:08:44,908 ACKNOWLEDGING THAT THERE ARE 172 00:08:44,908 --> 00:08:47,011 MANY POTENTIAL LINKS BETWEEN 173 00:08:47,011 --> 00:08:52,282 CANCER AND SCLERODERMA. 174 00:08:52,282 --> 00:08:53,917 I'LL FOCUS ON WHETHER A SUBSET 175 00:08:53,917 --> 00:08:57,988 OF OUR PATIENTS WOULD HAVE 176 00:08:57,988 --> 00:08:58,622 PARANEOPLASTIC DISEASE. 177 00:08:58,622 --> 00:09:00,758 OUR INTEREST IN THIS AREA WHEN 178 00:09:00,758 --> 00:09:03,694 WE SAW THIS PATIENT AND OTHERS 179 00:09:03,694 --> 00:09:04,461 LIKE HER. 180 00:09:04,461 --> 00:09:06,697 THIS IS A 43-YEAR-OLD WOMAN WHO 181 00:09:06,697 --> 00:09:09,433 CAME TO OUR CENTER AND DESCRIBED 182 00:09:09,433 --> 00:09:12,936 THAT IN SHE GOT SWELLING OF 183 00:09:12,936 --> 00:09:14,772 OTHER HANDS AND FACE. 184 00:09:14,772 --> 00:09:18,308 WHEN SHE WAS UNDERGOING 185 00:09:18,308 --> 00:09:24,615 TREATMENT FOR THIS, SHE HAD A 186 00:09:24,615 --> 00:09:35,192 LUNG BLAST AND TREATED WITH PRO- 187 00:09:38,896 --> 00:09:42,066 SHE GOT SKIN THICKENING WORSE IN 188 00:09:42,066 --> 00:09:43,867 THE FIELD OF RADIATION BUT 189 00:09:43,867 --> 00:09:45,202 EXTENDING BEYOND THAT AREA. 190 00:09:45,202 --> 00:09:48,238 THIS PATIENT WAS FOUND TO BE 191 00:09:48,238 --> 00:09:51,742 POSITIVE FOR POSITIVE RA 3 192 00:09:51,742 --> 00:09:53,811 ANTIBODIES. 193 00:09:53,811 --> 00:09:56,780 WE WERE IMPRESSED BY THIS 194 00:09:56,780 --> 00:10:01,185 PATIENT AND HAD SEVERAL 195 00:10:01,185 --> 00:10:02,820 HYPOTHESES ON WHY THESE WERE 196 00:10:02,820 --> 00:10:03,587 HAPPENING TOGETHER. 197 00:10:03,587 --> 00:10:06,190 THE QUESTION WAS WHETHER 198 00:10:06,190 --> 00:10:11,695 SCLERODERMA WAS A BI-PRODUCT OF 199 00:10:11,695 --> 00:10:13,297 THIS. 200 00:10:13,297 --> 00:10:16,166 WE WANT TODZ KNOW IF COULD WE 201 00:10:16,166 --> 00:10:19,002 USE THIS AS A TOOL TO INTERIMAIT 202 00:10:19,002 --> 00:10:23,273 IF RELATIONSHIP BETWEEN CANCER 203 00:10:23,273 --> 00:10:24,808 AND SCLERODERMA. 204 00:10:24,808 --> 00:10:26,877 THAT LED TO THIS PILOT STUD CAN 205 00:10:26,877 --> 00:10:31,648 I WHERE WEIGH RECRUITED CANCER 206 00:10:31,648 --> 00:10:36,553 PATIENTS AND WE COULD GET THEIR 207 00:10:36,553 --> 00:10:39,590 TISSUE FROM WHETHER THE 208 00:10:39,590 --> 00:10:41,125 PROCEDURES WERE PERFORMED. 209 00:10:41,125 --> 00:10:42,659 WE WERE INTERESTED IN TIMING AND 210 00:10:42,659 --> 00:10:45,896 THAT'S WHAT I'M SHOWING YOU IS 211 00:10:45,896 --> 00:10:48,565 HOW LONG PATIENTS HAD 212 00:10:48,565 --> 00:10:49,533 SCLERODERMA WHEN THEY WERE 213 00:10:49,533 --> 00:10:50,968 DIAGNOSED WITH CONDITIONSER AND 214 00:10:50,968 --> 00:10:56,106 THE Y AXIS REFLECTS THE 215 00:10:56,106 --> 00:10:56,874 SCLERODERMA ONSET. 216 00:10:56,874 --> 00:10:59,743 WHEN WE LOOKED AT THE SUB 217 00:10:59,743 --> 00:11:04,414 GROUPS, WE IDENTIFIED THAT THE 218 00:11:04,414 --> 00:11:06,817 TYPE 3 ANTIBODIES HAD THE FIRST 219 00:11:06,817 --> 00:11:10,888 SIGNS OF SCLERODERMA OFTEN WITH 220 00:11:10,888 --> 00:11:15,792 CANCER AS THE ONSET AND THIS WAS 221 00:11:15,792 --> 00:11:20,197 DIFFERENT THAN THE ANTIBODY 222 00:11:20,197 --> 00:11:20,797 SUBGROUPS. 223 00:11:20,797 --> 00:11:22,866 WITH WE LOOKED AT THE COHORT, WE 224 00:11:22,866 --> 00:11:27,971 WERE ABLE TO CONFIRM THAT THE 225 00:11:27,971 --> 00:11:33,777 PATIENTS WITH PULL PULMONARY 3A 226 00:11:33,777 --> 00:11:37,614 HIGHER RISK FOR CANCER. 227 00:11:37,614 --> 00:11:42,019 SIMILAR FINDINGS WERE FOUND IN 228 00:11:42,019 --> 00:11:44,188 OTHER SCLERODERMA COHORTS 229 00:11:44,188 --> 00:11:45,055 INTERNATIONALLY. 230 00:11:45,055 --> 00:11:47,691 WE WERE IMPRESSED THAT THIS 231 00:11:47,691 --> 00:11:50,394 SEEMED TO SEGREGATE IN THIS 232 00:11:50,394 --> 00:11:53,030 IMMUNE RESPONSE SUBGROUP AND WE 233 00:11:53,030 --> 00:11:55,465 WERE INTERESTED IN INVESTIGATING 234 00:11:55,465 --> 00:11:58,502 WHETHER OR NOT SCLERODERMA 235 00:11:58,502 --> 00:12:01,838 ANTIGENS WERE, PRESSED IN THESE 236 00:12:01,838 --> 00:12:02,239 PATIENTS. 237 00:12:02,239 --> 00:12:06,210 I SHOW YOU SOME MANIES FROM TWO 238 00:12:06,210 --> 00:12:06,877 SCLERODERMA PATIENTS. 239 00:12:06,877 --> 00:12:10,214 ONE OF WHOM HAD OVARIAN CANCER 240 00:12:10,214 --> 00:12:11,715 AND ONE HAD BREAST CANCER. 241 00:12:11,715 --> 00:12:13,784 YOU CAN SEE WITH THIS BROWN 242 00:12:13,784 --> 00:12:23,393 STAINING THAT THESE PATIENTS HAD 243 00:12:23,393 --> 00:12:29,032 EVEN IN THEIR CANCERS TISSUES. 244 00:12:29,032 --> 00:12:35,572 THESE DATA SUGGESTED TO US THAT 245 00:12:35,572 --> 00:12:42,512 CANCEROUS SPECIFIC AUTOIMMUNE 246 00:12:42,512 --> 00:12:45,782 AND WHETHER THE SCR SCLERODERMA 247 00:12:45,782 --> 00:12:46,917 WAS RELATED. 248 00:12:46,917 --> 00:12:54,558 WE WONDERED IF THIS HIGH IMMUNE 249 00:12:54,558 --> 00:12:56,126 RESPONSE COULD HELP US 250 00:12:56,126 --> 00:12:56,860 UNDERSTAND THE CONNECTION 251 00:12:56,860 --> 00:13:00,163 BETWEEN CANCER AND SCLERODERMA. 252 00:13:00,163 --> 00:13:01,698 WE INCLUDED 16 PATIENTS WITH 253 00:13:01,698 --> 00:13:06,603 CANCER WHO HAD ADEQUATE QUALITY 254 00:13:06,603 --> 00:13:09,873 CANCEROUS TISSUE TO ENABLE 255 00:13:09,873 --> 00:13:11,108 GENETIC SEQUENCING. 256 00:13:11,108 --> 00:13:15,245 THERE WERE EIGHT PATIENTS 257 00:13:15,245 --> 00:13:22,185 POSITIVE FOR ANTITAUPEO 258 00:13:22,185 --> 00:13:23,220 ANTIBODIES. 259 00:13:23,220 --> 00:13:25,756 THE SECOND COLUMN REFLECTS THE 260 00:13:25,756 --> 00:13:31,328 TIME WINDOW FOR RNA 3, THEY 261 00:13:31,328 --> 00:13:32,996 TENDED TO HAVE A SHORT INTERVAL 262 00:13:32,996 --> 00:13:35,966 BETWEEN THE TWO DIAGNOSIS OFTEN 263 00:13:35,966 --> 00:13:40,003 WITH CANCER PRECEDING 264 00:13:40,003 --> 00:13:43,307 SCLERODERMA AND THIS LOOKS 265 00:13:43,307 --> 00:13:48,745 DIFFERENT FROM THE OTHER 266 00:13:48,745 --> 00:13:49,313 ANTIBODIES. 267 00:13:49,313 --> 00:13:51,048 BREAST CANCER WHICH IS THE MOST 268 00:13:51,048 --> 00:13:53,784 COMMON CANCER WAS THE MOST 269 00:13:53,784 --> 00:13:55,452 COMMON CANCER UNDER STUDY AS 270 00:13:55,452 --> 00:13:56,753 WELL. 271 00:13:56,753 --> 00:13:59,589 WHEN THESE PATIENTS CANCEROUS 272 00:13:59,589 --> 00:14:01,792 TISSUTISSUES WERE SCWERNSED, ITS 273 00:14:01,792 --> 00:14:04,094 IDENTIFIED THAT THREE OF THE 274 00:14:04,094 --> 00:14:11,001 PATIENTS WITH THE RNA 3 HAD A 275 00:14:11,001 --> 00:14:14,404 PRESENTATION OF THE CANCER AND 276 00:14:14,404 --> 00:14:20,510 FIVE HAD EVIDENCE OF LOSS OF HET 277 00:14:20,510 --> 00:14:28,652 OORO DIGSITY. 278 00:14:28,652 --> 00:14:32,055 THESE WERE FLOT SEEN IN THE 279 00:14:32,055 --> 00:14:34,624 SCLERODERMA PATIENTS AND NOT 280 00:14:34,624 --> 00:14:37,127 EVEN WITH CANCER PATIENTS IN 281 00:14:37,127 --> 00:14:38,762 GENERAL. 282 00:14:38,762 --> 00:14:46,770 THOSE THAT HAD -- ALL THEY 283 00:14:46,770 --> 00:14:50,674 PATIENTS HAD EVIDENCE OF AUTO 284 00:14:50,674 --> 00:14:53,543 ANTIBODIES THAT DID NOT 285 00:14:53,543 --> 00:15:00,650 DISCRIMINATE BETWEEN THE TYPES. 286 00:15:00,650 --> 00:15:02,519 A PATIENT MAY HAVE A DEVELOPING 287 00:15:02,519 --> 00:15:05,155 CANCER AND ACQUIRE A MUTATION IN 288 00:15:05,155 --> 00:15:09,292 A GENE ENCODING FOR AN AUTO 289 00:15:09,292 --> 00:15:12,162 ANTIGEN IN THEIR TISSUE. 290 00:15:12,162 --> 00:15:14,164 THIS COULD TRIGGER A RESPONSE 291 00:15:14,164 --> 00:15:17,934 SPECIFIC FOR THE AUTOIMMUNE 292 00:15:17,934 --> 00:15:18,769 RESPONSE. 293 00:15:18,769 --> 00:15:23,707 IF THIS SPREADS TO THE AUTO 294 00:15:23,707 --> 00:15:25,308 ANTIGEN THIS COULD TRIGGER 295 00:15:25,308 --> 00:15:29,146 CANCER BUT THIS COULD LAY THE 296 00:15:29,146 --> 00:15:32,649 GROUNDWORK FOR THE DEVELOPMENT 297 00:15:32,649 --> 00:15:36,052 OF AUTOIMMUNITY. 298 00:15:36,052 --> 00:15:39,322 THERE MAY BE SHARED ANTIGEN 299 00:15:39,322 --> 00:15:42,159 EXPRESSION BETWEEN CANCELERS AND 300 00:15:42,159 --> 00:15:44,161 TISSUES TARGETED BY THE IMMUNE 301 00:15:44,161 --> 00:15:46,663 RESPONSE. 302 00:15:46,663 --> 00:15:53,170 THERE IS EVIDENCE IN THE 303 00:15:53,170 --> 00:15:54,671 PARAKNEEO PLASTIC AND WE THINK 304 00:15:54,671 --> 00:16:00,777 ABOUT THIS IN THE CONTEXT OF 305 00:16:00,777 --> 00:16:01,645 MELANOMAA. 306 00:16:01,645 --> 00:16:06,349 THIS WAS A STUDY CONDUCTED BY MY 307 00:16:06,349 --> 00:16:09,953 COLLEAGUE AT JOHNS HOPKINS WHERE 308 00:16:09,953 --> 00:16:13,156 SHE WAS LOOKING AT MI 22 YOU CAN 309 00:16:13,156 --> 00:16:16,660 SEE ON THE RIGHT MI 2 WAS HIGHLY 310 00:16:16,660 --> 00:16:18,495 EXPRESSIONED FROM BREAST AND 311 00:16:18,495 --> 00:16:21,231 LUNG CANCERS BUT ALSO EXPRESSED 312 00:16:21,231 --> 00:16:26,036 IN DETERMINAITE MUSCLE 313 00:16:26,036 --> 00:16:29,539 ESPECIALLY UNDERGOING REPAIR. 314 00:16:29,539 --> 00:16:35,679 SO AS A CLINICIAN AS SEVERAL KEY 315 00:16:35,679 --> 00:16:37,647 QUESTIONS ARISE IN THIS BODY OF 316 00:16:37,647 --> 00:16:40,917 WORK, IF CANCER COULD BE A 317 00:16:40,917 --> 00:16:44,521 TREATMENT FOR THE TREATMENT EVER 318 00:16:44,521 --> 00:16:46,623 SCLERODERMA, HOW SHOULD WE 319 00:16:46,623 --> 00:16:48,792 SCREEN FOR CANCER FOR PATIENTS 320 00:16:48,792 --> 00:16:52,896 WITH NUANCED SCLERODERMA CAN WE 321 00:16:52,896 --> 00:16:58,435 USE THESE AS TOOLS FOR AT-RISK. 322 00:16:58,435 --> 00:17:04,875 AND COULD CANCER THRI THERAPY BE 323 00:17:04,875 --> 00:17:07,611 EFFECTIVE FOR SCLERODERMA 324 00:17:07,611 --> 00:17:08,178 PATIENTS. 325 00:17:08,178 --> 00:17:12,382 WE OFTEN HAVE CASE REPORTS WITH 326 00:17:12,382 --> 00:17:13,884 PATIENTS DIAGNOSED WITH 327 00:17:13,884 --> 00:17:16,786 SCLERODERMA AND CANCER. 328 00:17:16,786 --> 00:17:22,025 IT'S CHALLENGING TO KNOW WHETHER 329 00:17:22,025 --> 00:17:26,963 THE SUPPRESSIVE THERAPIES ARE 330 00:17:26,963 --> 00:17:28,999 INDEPENDENTLY TREATING THE 331 00:17:28,999 --> 00:17:30,267 CONDITIONS OR IS THE TREATING 332 00:17:30,267 --> 00:17:35,472 THE CANCER RESULTING IN A 333 00:17:35,472 --> 00:17:37,440 TREATMENT FOR SCLERODERMA. 334 00:17:37,440 --> 00:17:41,177 THIS IS A 43-YEAR-OLD WOMAN WITH 335 00:17:41,177 --> 00:17:44,781 DIFFUSE SCLERODERMA AND POLY MY 336 00:17:44,781 --> 00:17:45,348 SITEIS. 337 00:17:45,348 --> 00:17:50,387 AROUND THE TIME OF HER DISEASE 338 00:17:50,387 --> 00:17:57,694 ONSET, SHE HAD A DISEUD OWE 339 00:17:57,694 --> 00:18:00,997 PAPILLARY PAN CRITIC NEOPLASM. 340 00:18:00,997 --> 00:18:05,502 WE FOUND THERE WAS INCREASED 341 00:18:05,502 --> 00:18:08,572 EXPRESSION IN THE TUMOR TISSUE. 342 00:18:08,572 --> 00:18:11,408 THE TUMOR WAS SERGE CLI 343 00:18:11,408 --> 00:18:12,075 RECEPTIVE. 344 00:18:12,075 --> 00:18:13,843 THE PATIENT DID NOT RECEIVE 345 00:18:13,843 --> 00:18:14,911 ADDITIONAL CAPSER THERAPY BUT 346 00:18:14,911 --> 00:18:18,548 THERE WAS A DRAMATIC RESOLUTION 347 00:18:18,548 --> 00:18:22,152 OF SKIN THICKENING AND THE 348 00:18:22,152 --> 00:18:25,322 PATIENT WAS TAKEN OFF THE 349 00:18:25,322 --> 00:18:27,324 TREATMENT. 350 00:18:27,324 --> 00:18:30,360 THERE WAS IMPROVEMENT IN THE 351 00:18:30,360 --> 00:18:31,895 RHEUMATIC DISEASE PHENOTYPE. 352 00:18:31,895 --> 00:18:34,764 AS A RHEUMATOLOGIST, I'M LEFT 353 00:18:34,764 --> 00:18:35,999 WITH THIS IMPORTANT QUESTION OF 354 00:18:35,999 --> 00:18:38,168 WHO IS AT RISK FOR CANCER, WHEN 355 00:18:38,168 --> 00:18:41,237 ARE THEY AT RISK AND FOR WHAT 356 00:18:41,237 --> 00:18:43,106 TUMOR TYPES. 357 00:18:43,106 --> 00:18:45,408 WE PERFORMED A STUDY TO LOOK AT 358 00:18:45,408 --> 00:18:47,711 CANCEL CONSIDER INCIDENTS IN OUR 359 00:18:47,711 --> 00:18:48,778 SCLERODERMA POPULATION AND TO 360 00:18:48,778 --> 00:18:50,747 COMPARE THIS TO THE GENERAL 361 00:18:50,747 --> 00:18:53,049 POPULATION USING THE UNITED 362 00:18:53,049 --> 00:18:55,018 STATES REGISTRY AND WOARP 363 00:18:55,018 --> 00:18:57,420 SPECIFICALLY INTERESTED IN 364 00:18:57,420 --> 00:18:59,623 EXAMINING WHETHER CANCER RISK 365 00:18:59,623 --> 00:19:01,691 OVERALL DIFFERS BY THE FILTERS 366 00:19:01,691 --> 00:19:07,697 THAT WE THINK ARE CLINICALLY AND 367 00:19:07,697 --> 00:19:09,432 BIOLOGICAL SIGNIFICANT. 368 00:19:09,432 --> 00:19:14,504 WE NEED TO KNOW THE OUGHT OFER 369 00:19:14,504 --> 00:19:18,008 ANTIBODY SUBSET AND CUTANEOUS 370 00:19:18,008 --> 00:19:19,309 SUBSETS AND TIMING. 371 00:19:19,309 --> 00:19:24,547 WE REVIEWED 2383 PATIENTS WITH 372 00:19:24,547 --> 00:19:25,782 205 CANCERS. 373 00:19:25,782 --> 00:19:26,950 I WANT TO WALK YOU THROUGH SOME 374 00:19:26,950 --> 00:19:28,718 OF THE KEY FINDINGS IN THIS 375 00:19:28,718 --> 00:19:29,085 STUDY. 376 00:19:29,085 --> 00:19:31,688 IN THE TOP GRAPH I'M SHOWING YOU 377 00:19:31,688 --> 00:19:33,456 THE NUMBER OF CANCER CASES WE 378 00:19:33,456 --> 00:19:38,361 OBSERVE OTH OVER TIME IN OUR COT 379 00:19:38,361 --> 00:19:39,796 IN BLUE. 380 00:19:39,796 --> 00:19:43,400 THIS IS THE NUMBER OF CANCER 381 00:19:43,400 --> 00:19:47,270 CASES YOU EXPECT TO SEE WHEN YOU 382 00:19:47,270 --> 00:19:48,872 ADJUST FOR THE DATA SHOWN HERE 383 00:19:48,872 --> 00:19:50,306 IN RED. 384 00:19:50,306 --> 00:19:52,909 IN EACH ONE OF THESE GRAPHS, THE 385 00:19:52,909 --> 00:19:57,180 X AXE ILINGS IS TIMED FROM 386 00:19:57,180 --> 00:19:59,482 SCLERODERMA WHERE TIME ZERO IS 387 00:19:59,482 --> 00:20:00,350 THE ONSET. 388 00:20:00,350 --> 00:20:03,987 I WANT TO SHOW YOU THE RATIO AS 389 00:20:03,987 --> 00:20:08,992 A STANDARDIZED INCIDENT RATIO. 390 00:20:08,992 --> 00:20:11,695 SIR OF 1 IS RISK EQUIVALENT TO 391 00:20:11,695 --> 00:20:13,029 THE BACKGROUND GENERAL 392 00:20:13,029 --> 00:20:13,396 POPULATION. 393 00:20:13,396 --> 00:20:19,202 IN THE BOTTOM GRAPH, I SHOW YOU 394 00:20:19,202 --> 00:20:23,139 CUMULATIVE CANCER IN BLUE WITH A 395 00:20:23,139 --> 00:20:27,844 95% CONFIDENCE AND THE EXPECTED 396 00:20:27,844 --> 00:20:29,446 CUMULATIVE INCIDENTS BASED ON 397 00:20:29,446 --> 00:20:30,747 DATA IN RED. 398 00:20:30,747 --> 00:20:32,615 WHETHER YOU LOOK AT THE JEFER 399 00:20:32,615 --> 00:20:35,719 ALL POPULATION, WE DID NOT SEE 400 00:20:35,719 --> 00:20:37,253 AN INCREASE OF CANCER BUT WHEN 401 00:20:37,253 --> 00:20:42,926 YOU LAYER ON AUTO ANTIBODY AS A 402 00:20:42,926 --> 00:20:45,328 FILTER, YOU CAN SEE DIFFERENT 403 00:20:45,328 --> 00:20:46,963 PATTERNS EMERGE. 404 00:20:46,963 --> 00:20:48,665 WE IELDED THAT THERE WERE MANY 405 00:20:48,665 --> 00:20:50,800 MORE CANCER CASES OBSERVED THAN 406 00:20:50,800 --> 00:20:53,336 EXPECTED AROUND THE TIME OF 407 00:20:53,336 --> 00:20:54,504 SCLERODERMA ONSET. 408 00:20:54,504 --> 00:20:57,607 TRANSLATING TO AN INCREASED 409 00:20:57,607 --> 00:20:58,942 STANDARDIZED RATIO FOR CANCER AT 410 00:20:58,942 --> 00:21:02,512 THE TIME OF DISEASE ONSET AND A 411 00:21:02,512 --> 00:21:07,450 HIGHER CUMULATIVE INCIDENTS OF 412 00:21:07,450 --> 00:21:09,219 CANCER OVER TIME. 413 00:21:09,219 --> 00:21:13,523 IN PRIOR STUDIES WE WERE COMPARE 414 00:21:13,523 --> 00:21:14,958 BEING DETERMINA PATIENTS WITH 415 00:21:14,958 --> 00:21:17,327 THE RESPONSE AND WITHOUT THE 416 00:21:17,327 --> 00:21:17,894 IMMUNE RESPONSE. 417 00:21:17,894 --> 00:21:20,330 WE DID NOT KNOW THE CANCER RISK 418 00:21:20,330 --> 00:21:23,399 IN THE GENERAL POPULATION THAT 419 00:21:23,399 --> 00:21:25,435 WOULD INFORM WHETHER THEY WOULD 420 00:21:25,435 --> 00:21:27,837 BENEFIT FROM CANCER DETECTION 421 00:21:27,837 --> 00:21:29,139 STRATEGIES. 422 00:21:29,139 --> 00:21:31,508 WHEN WE LOOK WITHIN THREE YEARS 423 00:21:31,508 --> 00:21:36,279 WE SEE THAT THE RNA 3 ANTIBODIES 424 00:21:36,279 --> 00:21:40,216 AND A TWOFOLD RISK AND THEY 425 00:21:40,216 --> 00:21:43,386 SEEMED TO DIFFER BASED ON THE 426 00:21:43,386 --> 00:21:44,154 CLINICAL EXPRESSION. 427 00:21:44,154 --> 00:21:46,689 SO THAT'S WITH DIE FUSE HAD 428 00:21:46,689 --> 00:21:49,826 HIGHER RISKS OF BREAST, PROSTATE 429 00:21:49,826 --> 00:21:53,797 AND TONGUE CANCER WHERE AS THOSE 430 00:21:53,797 --> 00:21:56,566 WITH LIMITED SCLERODERMA HAD A 431 00:21:56,566 --> 00:21:57,634 LOWER RISK OF CANCER. 432 00:21:57,634 --> 00:22:00,270 THIS IS FROM A SINGLE CENTER 433 00:22:00,270 --> 00:22:01,137 COSHORT. 434 00:22:01,137 --> 00:22:04,307 THIS REQUIRES REPLICATION IN 435 00:22:04,307 --> 00:22:06,376 EXTERNAL COHORTS, BUT THE DATA 436 00:22:06,376 --> 00:22:10,446 SUGGESTS THAT AUTO ANTIBODY TYPE 437 00:22:10,446 --> 00:22:13,449 AND PHENOTYPE COULD BE USEFUL 438 00:22:13,449 --> 00:22:15,418 TOOLS TO BEMENTER TARGET OUR 439 00:22:15,418 --> 00:22:17,253 CANCER DETECTION STRATEGIES. 440 00:22:17,253 --> 00:22:20,323 I WANTED TO SHOW YOU SOME OF THE 441 00:22:20,323 --> 00:22:23,927 FINDINGS FROM THE OTHER MAJOR 442 00:22:23,927 --> 00:22:28,064 AUTO ANTIBODY SUB GROUPS. 443 00:22:28,064 --> 00:22:35,839 THE THIRD COLUMN HAS ANTIPOLR 3 444 00:22:35,839 --> 00:22:36,272 ANTIBODIES. 445 00:22:36,272 --> 00:22:38,174 WHAT WAS A SURPRISE FOR US WAS 446 00:22:38,174 --> 00:22:39,576 THE SECOND COLUMN HERE OF 447 00:22:39,576 --> 00:22:48,117 PATIENTS WITH ANTICENTER MUIR 448 00:22:48,117 --> 00:22:51,754 ANTIBODIES WHERE THELD A LOWER 449 00:22:51,754 --> 00:22:53,256 CUMULATIVE RISK OF CANCER 450 00:22:53,256 --> 00:22:53,523 OVERTIME. 451 00:22:53,523 --> 00:22:55,592 THIS WAS AN UNEXPECTED FINDING 452 00:22:55,592 --> 00:22:56,326 FOR US. 453 00:22:56,326 --> 00:22:59,195 WHEN WE THINK OF THIS SUBGROUP, 454 00:22:59,195 --> 00:23:02,131 THEY OFTEN HAVE A PROFOUND TEEN 455 00:23:02,131 --> 00:23:04,100 TYPE TO THEIR DISEASE. 456 00:23:04,100 --> 00:23:08,371 WE WONDER IF IN EFFECT THERE IS 457 00:23:08,371 --> 00:23:16,779 AN ANTIANTIJENS EFFECT HERE. 458 00:23:16,779 --> 00:23:19,749 COULD THIS DETERMINE AN EFFECT 459 00:23:19,749 --> 00:23:25,555 IN THEMSELVES? 460 00:23:25,555 --> 00:23:28,291 THEMSELVES COMING BACK TO THE 461 00:23:28,291 --> 00:23:29,726 RNA 3 STORY, IT'S IMPORTANT IT 462 00:23:29,726 --> 00:23:33,329 NOTE IN OUR COHORT ABOUT 20% OF 463 00:23:33,329 --> 00:23:37,033 THESE PATIENTS HAVE A CANCER 464 00:23:37,033 --> 00:23:39,335 DIAGNOSE AND 80% DO NOT. 465 00:23:39,335 --> 00:23:41,604 A KEY QUESTION IS WHO NEEDS 466 00:23:41,604 --> 00:23:44,274 ENHANCED CANCER DETECTION 467 00:23:44,274 --> 00:23:48,645 STRATEGIES AND ARE THERE OTHER 468 00:23:48,645 --> 00:23:51,648 FEATURES THAT CAN BETTER HELPS 469 00:23:51,648 --> 00:23:52,782 SEGREGATE THOSE PATIENTS THAT 470 00:23:52,782 --> 00:23:55,118 THAT WILL HAVE A DETECTABLE 471 00:23:55,118 --> 00:23:55,752 CANCER OR NOT. 472 00:23:55,752 --> 00:23:57,387 IT RAISES AN INTERESTING 473 00:23:57,387 --> 00:23:59,455 QUESTION OF COULD CANCER BE A 474 00:23:59,455 --> 00:24:02,091 DRIVER IN 1-PERCENT OF THE 475 00:24:02,091 --> 00:24:06,162 PATIENTS WITH RNA 3 ANTIBODIES 476 00:24:06,162 --> 00:24:09,632 OR IS IT NOT REACHING A CLINICAL 477 00:24:09,632 --> 00:24:10,833 DETECTION EXCEPT FOR THE 20% 478 00:24:10,833 --> 00:24:13,169 THAT WE OBSERVED? 479 00:24:13,169 --> 00:24:16,973 THIS RAISES THE QUESTION OF 480 00:24:16,973 --> 00:24:18,074 CANCER EDITING. 481 00:24:18,074 --> 00:24:19,609 IF YOU THINK ABOUT IN THE 482 00:24:19,609 --> 00:24:22,245 CONTEXT OF A DEVELOPMENT 483 00:24:22,245 --> 00:24:24,747 MALIGNANCY, THERE MAY BE AN 484 00:24:24,747 --> 00:24:25,615 ANTITUMOR RESPONSE MOUNTED 485 00:24:25,615 --> 00:24:26,382 AGAINST THE CANCER. 486 00:24:26,382 --> 00:24:28,918 YOU CAN ENVISION THREE DIFFERENT 487 00:24:28,918 --> 00:24:30,853 SCENARIOS RILTING FROM THE 488 00:24:30,853 --> 00:24:33,156 INTERSECTION BETWEEN THE 489 00:24:33,156 --> 00:24:35,358 MALIGNANCY AND IMMUNE SYSTEM. 490 00:24:35,358 --> 00:24:40,730 THE FIRST IS THE THAT THE IMMUNE 491 00:24:40,730 --> 00:24:42,265 SYSTEM WOULD BE POALTANT 492 00:24:42,265 --> 00:24:44,867 RESULTING IN ERADICATION OF THE 493 00:24:44,867 --> 00:24:46,903 UNDERLYING CANCER SHOWN HERE IN 494 00:24:46,903 --> 00:24:49,739 THE ELIMINATION PHASE DESCRIBED. 495 00:24:49,739 --> 00:24:51,975 ALTERNATIVELY THE IMMUNE SYSTEM 496 00:24:51,975 --> 00:24:54,844 MAY EXPERT PRESSURE ON A 497 00:24:54,844 --> 00:24:57,046 DEVELOPING MALIGNANCY AND THE 498 00:24:57,046 --> 00:25:00,316 TUMOR MAY UNDERGO EDITING 499 00:25:00,316 --> 00:25:03,486 RESULTING IN A DELICATE DANCE 500 00:25:03,486 --> 00:25:06,422 BETWEEN A DEVELOPING CANCER AND 501 00:25:06,422 --> 00:25:08,091 I IMMUNE SYSTEM THAT KEEPS A 502 00:25:08,091 --> 00:25:10,593 CANCER FROM EMERGING BUT 503 00:25:10,593 --> 00:25:13,463 PREVENTS IT FROM BEING 504 00:25:13,463 --> 00:25:14,097 ERADICATED. 505 00:25:14,097 --> 00:25:15,631 THAT'S REPRESENTED HERE. 506 00:25:15,631 --> 00:25:17,934 THE LAST SCENARIO IS WHERE THE 507 00:25:17,934 --> 00:25:20,570 CANCER IS ABLE TO ESCAPE THE 508 00:25:20,570 --> 00:25:23,773 IMMUNE RESPONSE AND CLINICALLY 509 00:25:23,773 --> 00:25:24,007 EMERGES. 510 00:25:24,007 --> 00:25:25,808 COULD IT BE WE'RE SEEING THE 20% 511 00:25:25,808 --> 00:25:28,444 OF CASES HERE BUT COULD CANCER 512 00:25:28,444 --> 00:25:35,885 BE A DRIVER AMONG THE OTHER RNA 513 00:25:35,885 --> 00:25:37,620 PULLEN RI 3 RESPONSES. 514 00:25:37,620 --> 00:25:45,828 ARE THERE OTHER THINGS THAT CAN 515 00:25:45,828 --> 00:25:48,097 HELP US IDENTIFY THE STUDY. 516 00:25:48,097 --> 00:25:52,402 WE CONDUCTED A STUDY OF 300 517 00:25:52,402 --> 00:25:55,538 PATIENTS HALF OF WHOM HAD CANCER 518 00:25:55,538 --> 00:25:57,340 AND HAVE DID NOT AFTER FIVE 519 00:25:57,340 --> 00:25:58,875 YEARS OF FOLLOW-UP. 520 00:25:58,875 --> 00:26:00,843 IN THE NO-CANCER GROUP, THERE 521 00:26:00,843 --> 00:26:03,713 WERE ADDITIONAL IMMUNE RESPONSES 522 00:26:03,713 --> 00:26:05,314 BRENT AND IN THIS PARTICULAR 523 00:26:05,314 --> 00:26:08,951 STUDY IDENTIFIED, ONE SUCH 524 00:26:08,951 --> 00:26:19,495 IMMUNE RESPONSE IS A RESPONSE TO 525 00:26:20,430 --> 00:26:23,466 IT. 526 00:26:23,466 --> 00:26:27,537 COULD IT BE A CANCER PROTECTIVE 527 00:26:27,537 --> 00:26:27,837 COMBINATION? 528 00:26:27,837 --> 00:26:29,038 IT WAS AROUND THE TIME THAT WE 529 00:26:29,038 --> 00:26:31,040 WERE BEGINNING THESE STUDIES 530 00:26:31,040 --> 00:26:34,343 THAT WE WERE TABLE TO ATTEND A 531 00:26:34,343 --> 00:26:41,250 LECTURE IN A GROUP STUDYING BM H 532 00:26:41,250 --> 00:26:44,954 21, A SMALL MOLECULE HAD 533 00:26:44,954 --> 00:26:48,357 DEMONSTRATED IT HAD ANTITUMOR 534 00:26:48,357 --> 00:26:49,859 ACTIVITY. 535 00:26:49,859 --> 00:26:52,061 THIS WAS INTERESTING TO US. 536 00:26:52,061 --> 00:26:53,896 WHEN WEIGH LOOKED BACK IN THIS 537 00:26:53,896 --> 00:26:58,267 GROUP OF 168 SCER DETERMINA 538 00:26:58,267 --> 00:27:00,336 PATIENTS CAN, WE FOUND THAT 18% 539 00:27:00,336 --> 00:27:04,740 OF THE GROUP WITHOUT CANCER HAD 540 00:27:04,740 --> 00:27:11,314 ANTIBODIES TO THE RNA PLUMBER 541 00:27:11,314 --> 00:27:12,115 ACE ONE. 542 00:27:12,115 --> 00:27:15,718 WE FOUND THERE WERE OTHER 543 00:27:15,718 --> 00:27:18,221 ANTIBODIES PRESENT IN THE 544 00:27:18,221 --> 00:27:20,423 NO-CANCER GROUP INCLUDING THOSE 545 00:27:20,423 --> 00:27:23,059 TARGETING OTHER COMPONENTS OF 546 00:27:23,059 --> 00:27:25,661 THE COMPLEX. 547 00:27:25,661 --> 00:27:27,230 THIS DATA RAISES THE IMPORTANT 548 00:27:27,230 --> 00:27:31,901 QUESTION ON WHETHER A BROADER 549 00:27:31,901 --> 00:27:35,605 IMMUNE RESPONSE, COULD IT HAD A 550 00:27:35,605 --> 00:27:39,342 MORE POTENT CANCER EFFECT. 551 00:27:39,342 --> 00:27:41,310 TO LOOK IF I IN A MORE 552 00:27:41,310 --> 00:27:43,713 COMPREHENSIVE WAY, WE PARTNERED 553 00:27:43,713 --> 00:27:48,851 WITH THE PITTSBURGH BERG 554 00:27:48,851 --> 00:27:51,787 SCLERODERMA CENTER WHERE WE HAD 555 00:27:51,787 --> 00:27:54,123 OVER 600 CASES AND 600 CONTROLS 556 00:27:54,123 --> 00:27:57,026 THAT WHO DID NOT HAVE CANCER FOR 557 00:27:57,026 --> 00:27:58,694 AT LEAST FIVE YEARS AFTER 558 00:27:58,694 --> 00:27:59,762 FOLLOW-UP. 559 00:27:59,762 --> 00:28:05,368 WE STUDIED 11 DIFFERENT 560 00:28:05,368 --> 00:28:06,469 SPECIFICITSES SHOWN HERE. 561 00:28:06,469 --> 00:28:08,437 IN THIS STUDY, WE WERE ABLE TO 562 00:28:08,437 --> 00:28:18,881 IDENTIFY THAT INDEED RNAPL 563 00:28:19,315 --> 00:28:24,120 PLUMMERACE AND ANTI52 AND THIS 564 00:28:24,120 --> 00:28:26,722 ASSOCIATED WITH A HIGH RISK OF 565 00:28:26,722 --> 00:28:28,691 CANCER AT THE TIME OF 566 00:28:28,691 --> 00:28:30,126 SCLERODERMA ONSET. 567 00:28:30,126 --> 00:28:40,536 IN THIS DA STUDY WE WERE NOT 568 00:28:40,536 --> 00:28:44,574 INTERESTED IN JUST WHETHER AN 569 00:28:44,574 --> 00:28:47,176 INDIVIDUAL SPECIFICITY 570 00:28:47,176 --> 00:28:49,712 ASSOCIATED WITH A HIGHER OR OVER 571 00:28:49,712 --> 00:28:53,249 RISK OF CANCER BUT WHETHER THE 572 00:28:53,249 --> 00:28:56,786 LOWER RISK COULD HELP US 573 00:28:56,786 --> 00:29:00,289 IDENTIFY THOSE THE CANCER RISKS. 574 00:29:00,289 --> 00:29:02,124 WE PERFORMED A WAY TO LOOK AT 575 00:29:02,124 --> 00:29:05,828 THIS BETTER AND BY IDENTIFYING 576 00:29:05,828 --> 00:29:08,130 FIVE SCLERODERMA RESPONSES WE 577 00:29:08,130 --> 00:29:11,100 CAN BETTER RISK STRATIFY OUR 578 00:29:11,100 --> 00:29:14,170 PATIENTS INTO HIGH RISK AND LOW 579 00:29:14,170 --> 00:29:17,740 RISK AS SHOWN HERE. 580 00:29:17,740 --> 00:29:19,976 SO, THUS FAR, WE'VE SHOWN THERE 581 00:29:19,976 --> 00:29:23,446 IS A CLOSE TEMPORAL RELATIONSHIP 582 00:29:23,446 --> 00:29:25,948 BETWEEN CANCER AND SCLERODERMA 583 00:29:25,948 --> 00:29:31,454 ONSET WITH THE SCLERODERMA 584 00:29:31,454 --> 00:29:41,564 PATIENTS WITH RNA PLUMMER'S 585 00:29:41,564 --> 00:29:45,801 THREE. 586 00:29:45,801 --> 00:29:46,102 PLUMMERACE 587 00:29:46,102 --> 00:29:47,003 THREE. 588 00:29:47,003 --> 00:29:50,039 THIS RAISED SOME INTERESTING 589 00:29:50,039 --> 00:29:51,173 QUESTIONS ON WHETHER OR NOT 590 00:29:51,173 --> 00:29:53,643 THESE ARE ANTICANCER IMMUNE 591 00:29:53,643 --> 00:29:56,512 RESPONSES THAT COULD BE AERNASED 592 00:29:56,512 --> 00:29:57,480 THERAPY CLI. 593 00:29:57,480 --> 00:30:01,117 WE THINK ANTITYPE AND PHENOTYPE 594 00:30:01,117 --> 00:30:03,185 COULD BE USEFUL TOOLS TO 595 00:30:03,185 --> 00:30:05,588 IDENTIFY CANCER LAYING THE 596 00:30:05,588 --> 00:30:09,191 FOUNDATION FOR STUDYING TARGETED 597 00:30:09,191 --> 00:30:11,827 CANCER SCREENING STUDIES. 598 00:30:11,827 --> 00:30:14,530 WHILE I'VE BEEN FOCUSED ON 599 00:30:14,530 --> 00:30:16,499 SCLERODERMA, WE THINK A LOT OF 600 00:30:16,499 --> 00:30:19,802 THE KEY PRINCIPLES MAY BE MORE 601 00:30:19,802 --> 00:30:22,838 BROADLY APPLICABLE FOR 602 00:30:22,838 --> 00:30:24,907 AUTOIMMUNE DISEASES. 603 00:30:24,907 --> 00:30:33,683 WE THINK OF DERMATTA. 604 00:30:33,683 --> 00:30:36,319 THIS RISK IS HIGHEST IN 605 00:30:36,319 --> 00:30:38,220 DESCRIRCHGHT AUTO ANTIBODY 606 00:30:38,220 --> 00:30:39,855 SUBSETS. 607 00:30:39,855 --> 00:30:47,963 IN DAMONG PATIENTS WITH HIGH RIK 608 00:30:47,963 --> 00:30:50,299 AUTO ANTIBODIES, IT'S BEEN SHOWN 609 00:30:50,299 --> 00:30:53,035 IN BOTH DISEASES THAT BROADENING 610 00:30:53,035 --> 00:30:55,338 THE IMMUNE RESPONSE ASSOCIATES 611 00:30:55,338 --> 00:31:00,076 WITH AN ATTENUATION OF RISK AND 612 00:31:00,076 --> 00:31:09,318 ITHERE IS ANECDOTAL EVIDENCE THT 613 00:31:09,318 --> 00:31:12,621 THERE MAY BE COLAITION AND DATA 614 00:31:12,621 --> 00:31:14,724 SUGGESTING THAT CANCER SCREENING 615 00:31:14,724 --> 00:31:17,126 COULD BE TARGETED BY AUTO 616 00:31:17,126 --> 00:31:19,195 ANTIBODY TYPE AND CLINICAL 617 00:31:19,195 --> 00:31:20,296 FEATURES OF THE DISEASE. 618 00:31:20,296 --> 00:31:22,264 WE DON'T HAVE MUCH TIME TOLD TO 619 00:31:22,264 --> 00:31:24,533 TALK ABOUT CANCER SCREENING AND 620 00:31:24,533 --> 00:31:25,768 OTHER IMPLICATIONS FOR OUR 621 00:31:25,768 --> 00:31:26,202 PATIENTS. 622 00:31:26,202 --> 00:31:27,737 BUT I DID WANT TO HIGHLIGHT THAT 623 00:31:27,737 --> 00:31:30,706 IT'S IMPORTANT THAT WE REMEMBER 624 00:31:30,706 --> 00:31:33,442 AGE, SEX AND RISK FACTORS IN 625 00:31:33,442 --> 00:31:36,078 THESE PATIENTS AND THERE ARE 626 00:31:36,078 --> 00:31:38,280 SEVERAL STUDIES UNDERWAY LOOKING 627 00:31:38,280 --> 00:31:41,784 AT THE UTILITY OF MEASURES IN 628 00:31:41,784 --> 00:31:44,954 THE HIGH-RISK PATIENTS. 629 00:31:44,954 --> 00:31:47,556 MORE WORK NEEDS TO BE DONE TO 630 00:31:47,556 --> 00:31:50,626 INVESTIGATE CANCER THERAPY AS 631 00:31:50,626 --> 00:31:51,727 SCLERODERMA THERAPY. 632 00:31:51,727 --> 00:31:55,231 OFTEN PATIENTS WITH SCLERODERMA 633 00:31:55,231 --> 00:31:59,034 ARE DENIED ACCESS TO CANCER 634 00:31:59,034 --> 00:32:02,405 IMMUNEO AND RADIATION THERAPY 635 00:32:02,405 --> 00:32:04,206 TREATMENT BECAUSE THERE COULD BE 636 00:32:04,206 --> 00:32:10,546 CAUSES OF FLAIR UPS TO THE 637 00:32:10,546 --> 00:32:12,448 DISEASE BUT THERE IS EVIDENCE 638 00:32:12,448 --> 00:32:16,051 THEY ARE NOT CONTRA INDICATIVE. 639 00:32:16,051 --> 00:32:18,654 WE THINK THAT MULTI-DISCIPLINARY 640 00:32:18,654 --> 00:32:20,623 DECISION MAKING IS CRITICAL TO 641 00:32:20,623 --> 00:32:23,025 HELP OUR PATIENTS MAKE THE BEST 642 00:32:23,025 --> 00:32:25,094 DECISIONS WHEN THEY ARE 643 00:32:25,094 --> 00:32:26,762 CONFRONTING HAVING BOTH 644 00:32:26,762 --> 00:32:28,697 SCLERODERMA AND CANCEL. 645 00:32:28,697 --> 00:32:31,300 AND SO WITH THAT, I WITH WANT TO 646 00:32:31,300 --> 00:32:33,002 THANK YOU AGAIN FOR THIS 647 00:32:33,002 --> 00:32:34,837 OPPORTUNITY TO SPEAK TODAY. 648 00:32:34,837 --> 00:32:36,939 I WANTED TO ACKNOWLEDGE THE WORK 649 00:32:36,939 --> 00:32:39,074 I PRESENTED WAS THE WORK OF 650 00:32:39,074 --> 00:32:40,109 MANY, MANY PEOPLE. 651 00:32:40,109 --> 00:32:42,511 WE'RE GRATEFUL TO OUR FUNDING 652 00:32:42,511 --> 00:32:43,846 SOURCES INCLUDING SUPPORT FROM 653 00:32:43,846 --> 00:32:47,183 THE NIH. 654 00:32:47,183 --> 00:32:50,519 TO THANK YOU VERY MUCH. 655 00:32:50,519 --> 00:32:53,022 >> DR. FOR THAT WONDERFUL TALK. 656 00:32:53,022 --> 00:32:55,658 YOUR QUESTIONS WERE PERTAINING 657 00:32:55,658 --> 00:33:02,465 TO OTHER AUTOIMMUNE DISEASES AND 658 00:33:02,465 --> 00:33:04,300 THAT WILL BE A FRUITFUL 659 00:33:04,300 --> 00:33:04,934 DISCUSSION. 660 00:33:04,934 --> 00:33:08,070 I'M DELIGHTED TO INTRODUCE OUR 661 00:33:08,070 --> 00:33:09,972 SECOND SPEAKER DR. MAUER SEEN 662 00:33:09,972 --> 00:33:11,273 SU. 663 00:33:11,273 --> 00:33:15,044 SHE'S THE MORRISON FAMILY 664 00:33:15,044 --> 00:33:21,150 PROFESSOR IN MIKE 665 00:33:21,150 --> 00:33:23,619 AUTOIMMUNOLOGY. 666 00:33:23,619 --> 00:33:25,788 SHE GRADUATED FROM HARVARD 667 00:33:25,788 --> 00:33:31,560 MEDICAL SCHOOL AND COMPLETED HER 668 00:33:31,560 --> 00:33:33,762 TRAINING AT THE UNIVERSITY OF 669 00:33:33,762 --> 00:33:35,297 CALIFORNIA SAN FRANCISCO. 670 00:33:35,297 --> 00:33:38,367 AS A FELLOW IN THE DEVELOPMENT 671 00:33:38,367 --> 00:33:43,506 PROGRAM FOR PEDIATRICS, SHE 672 00:33:43,506 --> 00:33:49,545 DELINEATED MECHANISMS FOR THE 673 00:33:49,545 --> 00:33:50,646 AUTOIMMUNE DISEASE. 674 00:33:50,646 --> 00:33:55,050 SHE LEADS AN IMMUNOLOGY RESEARCH 675 00:33:55,050 --> 00:34:01,056 PROGRAM FOCUSING ON ANTICANCER 676 00:34:01,056 --> 00:34:03,592 IMMUNITY AND SEX DIFFERENCES IN 677 00:34:03,592 --> 00:34:04,493 IMMUNITY. 678 00:34:04,493 --> 00:34:08,397 SHE SERVES FOR THE UCLA TRAINING 679 00:34:08,397 --> 00:34:10,399 PROGRAM SO SHE'S A TRIPLE 680 00:34:10,399 --> 00:34:11,734 THREAT. 681 00:34:11,734 --> 00:34:14,336 DR. SU, WITH THAT, I'LL PASS THE 682 00:34:14,336 --> 00:34:15,671 MIC OVER TO YOU. 683 00:34:15,671 --> 00:34:17,206 >> THANK YOU SO MUCH. 684 00:34:17,206 --> 00:34:19,008 IT'S A PLEASURE TO BE HERE 685 00:34:19,008 --> 00:34:19,275 TODAY. 686 00:34:19,275 --> 00:34:24,847 THANK YOU FOR THE INVITATION. 687 00:34:24,847 --> 00:34:32,187 SO -- SORRY. 688 00:34:32,187 --> 00:34:37,760 I'M HAVING A LITTLE TROUBLE. 689 00:34:37,760 --> 00:34:44,433 I'M A PEDIATRIC ENDOCRINOLOGIST. 690 00:34:44,433 --> 00:34:50,539 I HELP CHILDREN WITH MEUNITY AND 691 00:34:50,539 --> 00:34:56,045 THAUTOIMMUNITY AND THYROID 692 00:34:56,045 --> 00:34:56,712 DISEASE. 693 00:34:56,712 --> 00:35:04,687 I HAD A PATIENT WITH SYMPTOMS 694 00:35:04,687 --> 00:35:07,356 TYPICAL FOR DIABETES. 695 00:35:07,356 --> 00:35:13,596 SHE HAD HIGH BLOOD SUGARS. 696 00:35:13,596 --> 00:35:18,033 AND POSITIVE FOR KETONES IN HER 697 00:35:18,033 --> 00:35:23,205 BLOOD. 698 00:35:23,205 --> 00:35:33,716 TOGETHER -- THIS IS A PICTURE 699 00:35:39,054 --> 00:35:42,925 CONSISTENT WITH DIABETIC KE 700 00:35:42,925 --> 00:35:44,026 KETOACIDOSIS. 701 00:35:44,026 --> 00:35:48,097 IT'S A STATE THAT WEIGH SEE WITH 702 00:35:48,097 --> 00:35:49,865 TYPE I DIABETES. 703 00:35:49,865 --> 00:35:52,401 IMPORTANTLY FOR THIS PATIENT, 704 00:35:52,401 --> 00:35:57,039 NINE MONTHS PRIOR SHE HAD BEEN 705 00:35:57,039 --> 00:36:00,576 DIAGNOSED WITH CARCINOMAA AND 706 00:36:00,576 --> 00:36:04,980 TREATED WITH THERAPIES. 707 00:36:04,980 --> 00:36:06,315 ADDITIONAL LAB TESTING SHOWED 708 00:36:06,315 --> 00:36:10,452 SHE HAD A LOW C PEPTIDE THAT 709 00:36:10,452 --> 00:36:13,389 INDICATED THAT HER BODY'S 710 00:36:13,389 --> 00:36:18,093 INSULIN PRODUCTION WAS IMPAIRED. 711 00:36:18,093 --> 00:36:20,729 AND SO THIS IF PICTURE WAS 712 00:36:20,729 --> 00:36:23,499 CONSISTENT WITH AUTOIMMUNE OR 713 00:36:23,499 --> 00:36:27,670 TYPE I DIABETES INDUCED BY 714 00:36:27,670 --> 00:36:32,574 ANTICANCER IMMUNOTHERAPY. 715 00:36:32,574 --> 00:36:35,411 WE PUBLISHED THIS CASE AS A CASE 716 00:36:35,411 --> 00:36:42,885 REPORT IN PRECE PEDIATRICS TO AT 717 00:36:42,885 --> 00:36:44,486 DOCTORS THAT PATIENTS RECEIVING 718 00:36:44,486 --> 00:36:46,488 CANCER THERAPIES WERE AT 719 00:36:46,488 --> 00:36:49,792 INCREASED RISKS FOR AUTOIMMUNE 720 00:36:49,792 --> 00:36:55,330 CONDITIONS LIKE DIABETES. 721 00:36:55,330 --> 00:37:00,169 >> TO HSU, WO SU, WOULD YOU REIO 722 00:37:00,169 --> 00:37:01,804 TAKE OVER CONTROL? 723 00:37:01,804 --> 00:37:03,439 >> THAT WOULD BE LOVELY. 724 00:37:03,439 --> 00:37:06,075 >> AND DR. SU, JUST SAY NEXT 725 00:37:06,075 --> 00:37:07,176 WHEN YOU'RE READY. 726 00:37:07,176 --> 00:37:10,245 >> THANK YOU. 727 00:37:10,245 --> 00:37:13,615 ANTIPD-1 AND OTHER INHIBITORS 728 00:37:13,615 --> 00:37:15,050 HAVE REVOLUTIONIZED CANCER 729 00:37:15,050 --> 00:37:15,818 THERAPY. 730 00:37:15,818 --> 00:37:18,854 50% EVER CANCER PATIENTS ARE NOW 731 00:37:18,854 --> 00:37:24,093 ELIGIBLE FOR IMMUNEO CHECKPOINT 732 00:37:24,093 --> 00:37:25,994 INHIBITORS AND THIS WORKS 733 00:37:25,994 --> 00:37:29,031 BECAUSE INCREASED ACTIVATION 734 00:37:29,031 --> 00:37:30,666 INCREASES. 735 00:37:30,666 --> 00:37:36,271 PD-1 IS USUALLY EXPRESSED ON T 736 00:37:36,271 --> 00:37:36,839 CELLS. 737 00:37:36,839 --> 00:37:39,408 WHEN THIS INTERSECTION HAPPENS, 738 00:37:39,408 --> 00:37:46,348 IT SENDS AN INHIBITORY SIGNAL TO 739 00:37:46,348 --> 00:37:53,555 THE T CEL CELLS. 740 00:37:53,555 --> 00:37:56,825 WHEN PD 1 IS GIVEN THE T CELL 741 00:37:56,825 --> 00:38:00,028 CAN BE ACTIVATED, THE BRAKES ARE 742 00:38:00,028 --> 00:38:04,733 REMOVED AND THE T CELL CAN KILL 743 00:38:04,733 --> 00:38:06,268 OFF THE CANCER. 744 00:38:06,268 --> 00:38:09,138 THIS OFFERS A CURE BUT COMES AT 745 00:38:09,138 --> 00:38:11,874 A PRICE. 746 00:38:11,874 --> 00:38:17,112 60% OF PATIENTS DEVELOP 747 00:38:17,112 --> 00:38:18,447 IMMUNE-RELATED ADVERSE EVENTS 748 00:38:18,447 --> 00:38:23,485 THAT ARE AL AUTOIMMUNE CONDITIOS 749 00:38:23,485 --> 00:38:26,321 THAT AFFECT THE CELLS. 750 00:38:26,321 --> 00:38:28,991 ABOUT 50% ARE HOSPITALIZED FOR 751 00:38:28,991 --> 00:38:30,492 THESE SO THEY CAN BE SERIOUS. 752 00:38:30,492 --> 00:38:33,095 ON THE RIGHT HERE IS A SCHEMATIC 753 00:38:33,095 --> 00:38:36,198 OF SOME OF THE DIFFERENT TISH TS 754 00:38:36,198 --> 00:38:43,739 THAT ARE AFFECTED BY IRAEs 755 00:38:43,739 --> 00:38:48,210 RESULTING IN DIABETES. 756 00:38:48,210 --> 00:38:52,815 THHERE WE HAVE A PARADOX IN THE 757 00:38:52,815 --> 00:39:03,358 COURSE EVER ENHANCING IMMUNITY, 758 00:39:07,429 --> 00:39:11,433 AUTOIMMUNEITY CAN BE UNLEASHED. 759 00:39:11,433 --> 00:39:14,803 ONE THING THAT HAS BEEN 760 00:39:14,803 --> 00:39:16,905 DESCRIBED AS AN ANTICANCER 761 00:39:16,905 --> 00:39:19,875 IMMUNITY IS THE PRESENCE OF THE 762 00:39:19,875 --> 00:39:24,112 T CELLS. 763 00:39:24,112 --> 00:39:28,684 THEY'RE CD POSITIVE AND REFLECT 764 00:39:28,684 --> 00:39:29,985 MARKERS. 765 00:39:29,985 --> 00:39:32,788 THESE CELLS ARE STEM-LIKE IN 766 00:39:32,788 --> 00:39:36,892 THAT THEY CAN SELF-RENEW AND ARE 767 00:39:36,892 --> 00:39:41,096 LONG-LIVED AND CAN DIFFER SHAITT 768 00:39:41,096 --> 00:39:43,966 SHAILT INTO OTHER CELL TYPES. 769 00:39:43,966 --> 00:39:47,469 BECAUSE THESE PROGENITORS ARE 770 00:39:47,469 --> 00:39:49,538 LONG-LIVED, WE THINK THEY'RE 771 00:39:49,538 --> 00:39:57,212 MEEMEDIATING THE AUTOIMMUNE 772 00:39:57,212 --> 00:39:59,314 RESPONSE. 773 00:39:59,314 --> 00:40:01,950 THEY SEEM TO BE THE CELLS 774 00:40:01,950 --> 00:40:05,420 TARGETED BY ANTIPD-1 THERAPY. 775 00:40:05,420 --> 00:40:09,391 IN THIS PAPER PUBLISHED IN 776 00:40:09,391 --> 00:40:13,862 IMMUNITY AND OTHER PAUPERS, THE 777 00:40:13,862 --> 00:40:16,265 POSITIVE STEM-LIKE PROGENITORS 778 00:40:16,265 --> 00:40:18,667 SEEM TO BE THE CELLS RESPONDING 779 00:40:18,667 --> 00:40:26,642 TO CHECKPOINT BLOCK 5EUAIDING TE 780 00:40:26,642 --> 00:40:27,776 THERAPY. 781 00:40:27,776 --> 00:40:29,845 THEY SEEM TO PUSH THEIR 782 00:40:29,845 --> 00:40:36,952 CONVERSION INTO THE DETEACTERS S 783 00:40:36,952 --> 00:40:41,089 AND KILL THE CANCER CELLS SO 784 00:40:41,089 --> 00:40:45,827 ANTICANCER IMMUNITY IS ENHANCED. 785 00:40:45,827 --> 00:40:48,664 RECENTLY MULTIPLE GROUPS HAVE 786 00:40:48,664 --> 00:40:51,300 REPORTED THE STEM-LINE 787 00:40:51,300 --> 00:40:55,203 PROGENITORS ARE AN IMPORTANT 788 00:40:55,203 --> 00:41:00,275 PLAYER IN AUTOIMMUNE DIABETES. 789 00:41:00,275 --> 00:41:04,546 THESE POSITIVE CELLS HAVE BEEN 790 00:41:04,546 --> 00:41:09,785 FOUND IN TYPE 1 DIABETES RENEW 791 00:41:09,785 --> 00:41:15,590 AND GIVE RISE TO THE DEFERKTS 792 00:41:15,590 --> 00:41:18,627 FOR BETA -- DEFECTORS RESULTING 793 00:41:18,627 --> 00:41:20,395 IN TYPE 1 DIABETES. 794 00:41:20,395 --> 00:41:22,764 BECAUSE THESE STEM-LIKE 795 00:41:22,764 --> 00:41:25,300 PROGENITORS ARE LONG LIVED, IT'S 796 00:41:25,300 --> 00:41:31,506 FELT THAT THE KR KRONISITY IS DE 797 00:41:31,506 --> 00:41:34,176 TO THE PRESENCE OF THE STEM-LIKE 798 00:41:34,176 --> 00:41:34,977 PROGENITORS. 799 00:41:34,977 --> 00:41:38,880 SIMILAR TO CANCER, ANTIPD-1 800 00:41:38,880 --> 00:41:41,783 SEEMS TO WORK IN THE PROGENITOR 801 00:41:41,783 --> 00:41:42,351 CELLS. 802 00:41:42,351 --> 00:41:46,555 IT WORKS BY DECREASING INTO THE 803 00:41:46,555 --> 00:41:49,458 DEFECTORS AND WE SEE THIS 804 00:41:49,458 --> 00:41:51,493 ACCELERATED FORM OF TYPE 18 805 00:41:51,493 --> 00:41:53,762 DIABETES WITH 806 00:41:53,762 --> 00:42:01,003 CANCER-IMMUNOTHERAPY. 807 00:42:01,003 --> 00:42:02,938 SO, AS I SHOWED YOU PREVIOUSLY, 808 00:42:02,938 --> 00:42:05,507 THERE ARE A NUMBER OF DIFFERENT 809 00:42:05,507 --> 00:42:12,147 TISSUES THAT CAN BE EFFECTED BY 810 00:42:12,147 --> 00:42:13,682 IRAEs. 811 00:42:13,682 --> 00:42:16,018 THESE INCLUDE AUTOIMMUNE 812 00:42:16,018 --> 00:42:17,285 DIABETES AS WELL AS THYROID 813 00:42:17,285 --> 00:42:17,753 DISEASE. 814 00:42:17,753 --> 00:42:26,361 THESE ARE TWO AUTOIMMUNE ENDO 815 00:42:26,361 --> 00:42:36,972 KRIEN-O KRIENOPATH ISTHYS. 816 00:42:50,352 --> 00:42:53,155 A SCIENTIST DID JUST THAT. 817 00:42:53,155 --> 00:42:57,726 SHE PERFORMED THYROID BIOPSIES 818 00:42:57,726 --> 00:43:03,532 ON PISHTS WITH MASH MOATOS 819 00:43:03,532 --> 00:43:07,602 THYROIDIS WITH A THYROID IRAE 820 00:43:07,602 --> 00:43:14,810 AND SUBB SUBJECTED THESE TO THE. 821 00:43:14,810 --> 00:43:25,487 SHE SSHE SAW POSITIVE FERKTS. 822 00:43:28,790 --> 00:43:33,962 WHEN SHE DID PSUEDO TIME 823 00:43:33,962 --> 00:43:35,597 TRAJECTORY OF THE DATA, YOU 824 00:43:35,597 --> 00:43:46,274 COULD SEE A DIFF DIFFERENTIAL. 825 00:43:56,351 --> 00:43:59,221 WHEN WE SEPARATED OUT THE CELLS 826 00:43:59,221 --> 00:44:01,623 BY GROUP, WE COULD SEE THAT 827 00:44:01,623 --> 00:44:04,126 WHETHER OR NOT PATIENTS RECEIVE 828 00:44:04,126 --> 00:44:08,630 THE INPRIPTER CHANGED THEIR 829 00:44:08,630 --> 00:44:11,633 DIFFERENTIATION TRAJECTORY. 830 00:44:11,633 --> 00:44:15,871 THIS IS SELF-FREQUENCY ON THE Y 831 00:44:15,871 --> 00:44:18,073 AXIS AND IN THE READ ARE THOAS 832 00:44:18,073 --> 00:44:22,210 THAT RECEIVED PREFECTURE AND IN 833 00:44:22,210 --> 00:44:33,421 DEFECTORS.THERE ARE MORE CELLS E 834 00:44:35,891 --> 00:44:44,466 PATIENTS THAN THOSE ARE MASH 835 00:44:44,466 --> 00:44:48,103 HASHIMOTO'S DISEASE. 836 00:44:48,103 --> 00:44:50,038 THIS WAS CORROBORATED WHEN WE 837 00:44:50,038 --> 00:44:55,644 LOOKED AT THE PROPORTION OF 838 00:44:55,644 --> 00:44:56,945 CELLS. 839 00:44:56,945 --> 00:44:59,481 THERE WAS AN INCREASE IN A KOWM 840 00:44:59,481 --> 00:45:01,383 LAITION OF THE THE CELLS IN 841 00:45:01,383 --> 00:45:05,253 PATIENTS WITH THYROIDITIST 842 00:45:05,253 --> 00:45:10,425 IRAEs COMPARED TO THOSE WITH 843 00:45:10,425 --> 00:45:13,395 HASHIMOTOS. 844 00:45:13,395 --> 00:45:16,731 TOGETHER THESE DATA PAINT A 845 00:45:16,731 --> 00:45:19,534 PICTURE DEMONSTRATING THE 846 00:45:19,534 --> 00:45:23,038 IMPORTANCE OF PROGENITOR T 847 00:45:23,038 --> 00:45:28,743 CELLS. 848 00:45:28,743 --> 00:45:33,315 UNLIKE MOST AUTOIMMUNE DISEASES, 849 00:45:33,315 --> 00:45:35,517 ENDOCRINE DISEASES ARE NOT 850 00:45:35,517 --> 00:45:41,489 TREATED WITH IMMUNOTHERAPIES. 851 00:45:41,489 --> 00:45:49,064 TYPE 1 TYPE BEAT 1 DIABETES WASD 852 00:45:49,064 --> 00:45:53,034 AND WE GIVE THERAPY REPLACING 853 00:45:53,034 --> 00:45:55,270 THE MISSING HORMONE. 854 00:45:55,270 --> 00:45:57,706 THERE WAS A NEED TO IDENTIFY THE 855 00:45:57,706 --> 00:46:01,176 TARGETS FOR ENDOCRINE DISEASE SO 856 00:46:01,176 --> 00:46:04,312 WE CAN DEVELOP THERAPEUTIC 857 00:46:04,312 --> 00:46:06,047 MEDICINES FOR THESE CONDITIONS. 858 00:46:06,047 --> 00:46:10,285 WE ASKED WHICH MECHANISMS ARE 859 00:46:10,285 --> 00:46:12,053 CONVERTING THEM TO AUTO 860 00:46:12,053 --> 00:46:14,923 EFFECTERS. 861 00:46:14,923 --> 00:46:19,728 IT CAN POTENTIALLY INTERRUPT THE 862 00:46:19,728 --> 00:46:21,896 DEIF HE CANNERS AND PROTECT FROM 863 00:46:21,896 --> 00:46:22,464 DISEASE. 864 00:46:22,464 --> 00:46:28,803 WE WERE PARTICULARLY INTERESTED 865 00:46:28,803 --> 00:46:33,575 IN ANTIGENETIC MECHANISMS 866 00:46:33,575 --> 00:46:38,747 BECAUSE THE EPIGENETIC 867 00:46:38,747 --> 00:46:41,783 MECHANISMS PLAY A KEY ROLE. 868 00:46:41,783 --> 00:46:45,954 ON THE TOP OF IS A TRAJECTORY ON 869 00:46:45,954 --> 00:46:50,025 THE T CELL AND ENDING WITH 870 00:46:50,025 --> 00:46:52,961 TERMINALLY DIFFERENTIATED 871 00:46:52,961 --> 00:46:53,895 EFFECTERS. 872 00:46:53,895 --> 00:46:57,432 THEY WERE INCREASING THEIR 873 00:46:57,432 --> 00:47:00,835 TRANSCRIPTION OF EFFECTER GENES 874 00:47:00,835 --> 00:47:03,271 WHILE DECREASING THEIR STEM-LIKE 875 00:47:03,271 --> 00:47:03,805 GENES. 876 00:47:03,805 --> 00:47:07,876 THIS CHANGE IN PROFILES IS 877 00:47:07,876 --> 00:47:09,911 ACCOMPANIED BY THE DISTINCT 878 00:47:09,911 --> 00:47:10,679 EPIGENETIC CHANGES. 879 00:47:10,679 --> 00:47:12,981 THE CIRCLES THAT HAVE CHECKERS 880 00:47:12,981 --> 00:47:23,525 IN THEM ARE HI HYSTONES AS 881 00:47:26,661 --> 00:47:31,299 PREFECTURE GENES ARE INCREASING 882 00:47:31,299 --> 00:47:42,010 THEY GAIN THE GREEN HEX HEXAGON. 883 00:47:44,813 --> 00:47:46,848 OPPOSITE OCCURS -- IF YOU GO 884 00:47:46,848 --> 00:47:49,017 BACK FOR A SECOND. 885 00:47:49,017 --> 00:47:54,989 THE STEM-LINE GENES ARE ALTERING 886 00:47:54,989 --> 00:48:04,599 THEIR HYTONE ABILITY AND 887 00:48:04,599 --> 00:48:06,134 SHUTTING DOWN GENE 888 00:48:06,134 --> 00:48:07,035 TRANSCRIPTION. 889 00:48:07,035 --> 00:48:16,010 THIS CHANGE IN HYSTO MARKS IS 890 00:48:16,010 --> 00:48:25,987 NOT RANDOM BUT REGULATED BY UTX. 891 00:48:25,987 --> 00:48:29,691 IT ALTERS CHROMOSOME 892 00:48:29,691 --> 00:48:30,125 ACCESSIBILITY. 893 00:48:30,125 --> 00:48:31,893 WE WERE PARTICULARLY INTERESTED 894 00:48:31,893 --> 00:48:35,630 IN UTX GIVEN A RECENT PAPER 895 00:48:35,630 --> 00:48:39,100 SUGGESTING THAT IT PLAYS A ROLE 896 00:48:39,100 --> 00:48:44,939 IN CONTROLLING CT-8 RESPONSES IN 897 00:48:44,939 --> 00:48:46,341 TUMOR IMMUNITY. 898 00:48:46,341 --> 00:48:48,743 GIVEN THE PARALLELS BETWEEN 899 00:48:48,743 --> 00:48:53,648 ANTICANCER IMMUNITY AND 900 00:48:53,648 --> 00:48:56,985 AUTOIMMUNE, WE FOUND IT WAS 901 00:48:56,985 --> 00:49:01,923 PROMOTING TYPE I DIABETES BY 902 00:49:01,923 --> 00:49:06,361 CHANGING THEM FROM ANTITUMOR TO 903 00:49:06,361 --> 00:49:07,896 STEM-LIKE EFFECTERS. 904 00:49:07,896 --> 00:49:15,637 WE UTILIZED THE UTX MOUSE MODEL. 905 00:49:15,637 --> 00:49:19,674 IT MIMICS DIABETES IN MANY WAYS. 906 00:49:19,674 --> 00:49:20,809 THERE ARE MULTIPLE DIFFERENT 907 00:49:20,809 --> 00:49:25,747 GENES THAT CONTRIBUTE TO 908 00:49:25,747 --> 00:49:27,282 AUTOIMMUNE PREDISPOSITION. 909 00:49:27,282 --> 00:49:33,755 IT'S KNOWN THAT AUTO REACTIVE T 910 00:49:33,755 --> 00:49:35,790 CELLS ARE KILLING THE BETA 911 00:49:35,790 --> 00:49:36,891 CELLS. 912 00:49:36,891 --> 00:49:40,061 ABOUT 8 O% OF FEMALES DEVELOPED 913 00:49:40,061 --> 00:49:42,096 DIABETES SO IT'S A PRO BUST 914 00:49:42,096 --> 00:49:44,566 MODEL. 915 00:49:44,566 --> 00:49:48,736 LIKE THE PAPER THAT ORIGINALLY 916 00:49:48,736 --> 00:49:54,175 DESCRIBED THIS MOUSE WE SAW 80% 917 00:49:54,175 --> 00:49:56,945 INCIDENTS IN OUR COLONY. 918 00:49:56,945 --> 00:50:02,417 AND WHEN WE KNOCKED OUT UTX 919 00:50:02,417 --> 00:50:06,454 SPECIFICALLY IN T CELLS, WE SAW 920 00:50:06,454 --> 00:50:09,224 THAT THE NOD MICE WERE NOW 921 00:50:09,224 --> 00:50:10,625 COMPLETELY PROTECTED. 922 00:50:10,625 --> 00:50:14,229 BY 30 WEEKS, NONE OF THE MICE 923 00:50:14,229 --> 00:50:14,896 HAD DIABETES. 924 00:50:14,896 --> 00:50:25,840 WHEN WE LOOKED IN THE PANCREATIE 925 00:50:25,840 --> 00:50:35,450 MICE THEY HAD THE NO EYELETS AND 926 00:50:35,450 --> 00:50:40,288 THE OTHERS HAD INTACT EYELETS. 927 00:50:40,288 --> 00:50:42,991 THERE WERE A LOT OF EYELETS THAT 928 00:50:42,991 --> 00:50:48,596 HAD MAJORITY OF INFILTRATION 929 00:50:48,596 --> 00:50:57,272 WHERE THE UTXTCD HAD MINIMAL. 930 00:50:57,272 --> 00:51:00,642 WE PERFORMED TESTS ON THE LYMPH 931 00:51:00,642 --> 00:51:06,981 NODES FROM THE WILD TYPE AND THE 932 00:51:06,981 --> 00:51:11,920 UTXTCD MICE. 933 00:51:11,920 --> 00:51:13,988 13 WEEKS WAS THE DISEASE PROCESS 934 00:51:13,988 --> 00:51:17,392 WHICH WAS RIGHT BEFORE THE MICE 935 00:51:17,392 --> 00:51:19,160 DEVELOPED TYPE I DIABETES. 936 00:51:19,160 --> 00:51:25,166 WHEN WE FOCUSED ON THE TCD 937 00:51:25,166 --> 00:51:27,936 CELLS, WE WERE ABLE TO IDENTIFY 938 00:51:27,936 --> 00:51:34,275 A PROGENITOR CLUSTER. 939 00:51:34,275 --> 00:51:36,611 WHEN WE PERFORMED ANOTHER 940 00:51:36,611 --> 00:51:39,080 ANALYSIS THERE WAS A PROJECTION 941 00:51:39,080 --> 00:51:41,149 THAT PROGRESSED THROUGH THE 942 00:51:41,149 --> 00:51:43,251 FACTOR MEDIATORS. 943 00:51:43,251 --> 00:51:48,289 AND WE COULD SEE THAT 944 00:51:48,289 --> 00:51:50,391 TRANSCRIPTION OF STEM-LIKE GENES 945 00:51:50,391 --> 00:51:53,127 WERE HIGHEST IN THE PROGENITOR 946 00:51:53,127 --> 00:52:00,568 POPULATIONS, TCX 1 AND 108 WERE 947 00:52:00,568 --> 00:52:03,538 HIGHEST AT THE BEGINNING OF THE 948 00:52:03,538 --> 00:52:04,739 TRAJECTORY. 949 00:52:04,739 --> 00:52:06,941 AND THE PREFECTURE GENES WERE 950 00:52:06,941 --> 00:52:10,745 HIGHEST IN THE PREFECTURE 951 00:52:10,745 --> 00:52:13,615 POPULATIONS, T. 952 00:52:13,615 --> 00:52:16,017 IT WAS LOW IN PROGENITORS AND 953 00:52:16,017 --> 00:52:18,753 HIGHEST IN THE PREFECTURES. 954 00:52:18,753 --> 00:52:21,456 WE NEXT SEPARATED OUT THE CELLS 955 00:52:21,456 --> 00:52:27,061 THAT WERE DERIVED FROM THE WILD 956 00:52:27,061 --> 00:52:30,898 MICE FROM THOSE MICE MISSING THE 957 00:52:30,898 --> 00:52:33,201 UTX IN THEIR CELLS. 958 00:52:33,201 --> 00:52:36,270 UTX SEEMS TO HAVE AN EFFECT ON 959 00:52:36,270 --> 00:52:41,175 THE DIFFERENTIATION. 960 00:52:41,175 --> 00:52:45,446 WE HAVE UTX AND YT. 961 00:52:45,446 --> 00:52:47,615 THE LEFT PART OF THIS GRAPH, YOU 962 00:52:47,615 --> 00:52:50,084 CAN SEE IS THAT THERE IS 963 00:52:50,084 --> 00:52:51,853 ACCUMULATION OF PROGENITORS IN 964 00:52:51,853 --> 00:52:56,324 THE UTXTCD MICE AND FEWER 965 00:52:56,324 --> 00:52:58,126 EFFECTERS IN THESE MICE COMPARED 966 00:52:58,126 --> 00:52:59,594 TO THE WILD TYPE. 967 00:52:59,594 --> 00:53:01,963 WHEN WE LOOKED AT THE CELL 968 00:53:01,963 --> 00:53:03,464 FREQUENCIES, WE SAW AN INCREASE 969 00:53:03,464 --> 00:53:05,633 IN THE PROGENITOR POPULATION IN 970 00:53:05,633 --> 00:53:15,610 THE UTXTCD MICE AND DECREASE IN 971 00:53:15,610 --> 00:53:16,811 THE PREFECTURE. 972 00:53:16,811 --> 00:53:24,385 WE WANTED TO CONFIRM OUR DALT BY 973 00:53:24,385 --> 00:53:34,762 USING FLOW-CYTOOMETRY. 974 00:53:37,665 --> 00:53:38,633 STEM-LIKE PROGENITORS WERE 975 00:53:38,633 --> 00:53:40,068 IDENTIFIED AS POSITIVE AND 976 00:53:40,068 --> 00:53:40,702 NEGATIVE. 977 00:53:40,702 --> 00:53:44,539 THE PREFECTURE MEELD-ATORS WERE 978 00:53:44,539 --> 00:53:54,982 IDENTIFIED AS DY 108 CD 39 979 00:53:58,419 --> 00:53:59,020 POSITIVES. 980 00:53:59,020 --> 00:54:04,692 WHEN WE LOOKED AT THE MODE, 981 00:54:04,692 --> 00:54:06,227 ACCUMULATION OFORTS PROGENITOR 982 00:54:06,227 --> 00:54:12,667 IN THE UTXCD NICE AND A 983 00:54:12,667 --> 00:54:15,970 DEFICIENCY IN THE MEDIATOR 984 00:54:15,970 --> 00:54:16,504 POPULATIONS. 985 00:54:16,504 --> 00:54:20,641 WE THINK THAT UTX IS WORKING IN 986 00:54:20,641 --> 00:54:23,010 THE SEMI PROGENITORS TO INCREASE 987 00:54:23,010 --> 00:54:25,379 THE CONVERSION OF THE 988 00:54:25,379 --> 00:54:26,914 PROGENITORS TO THE DESTRUCTIVE 989 00:54:26,914 --> 00:54:27,448 MEDIATORS. 990 00:54:27,448 --> 00:54:32,253 AND WHEN WE KNOCK OUT UTX IN THE 991 00:54:32,253 --> 00:54:36,624 T CELLS WE HAVE AN ACCUMULATION 992 00:54:36,624 --> 00:54:44,832 IN THE CELLS AND A DETISHT DEFIN 993 00:54:44,832 --> 00:54:45,733 THE POPULATION. 994 00:54:45,733 --> 00:54:52,740 AS I TOLD YOU BEFORE, UTX 995 00:54:52,740 --> 00:54:58,613 INCREASES CHROMEO GENETIC 996 00:54:58,613 --> 00:54:59,614 TRANSCRIPTION. 997 00:54:59,614 --> 00:55:05,753 HOW DOES UTX POTENTIALLY ALTER 998 00:55:05,753 --> 00:55:07,822 THE ACCESSIBILITY AND GENE 999 00:55:07,822 --> 00:55:12,426 TRANSCRIPTION IN THE 1000 00:55:12,426 --> 00:55:15,496 PROGENITORS? 1001 00:55:15,496 --> 00:55:26,207 WE HWHEN WE LOOKED AT THE DATA,F 1002 00:55:26,841 --> 00:55:31,045 NICE EITHER WILD OR UTXCD, THERE 1003 00:55:31,045 --> 00:55:36,884 WAS AN INCREASE IN CHROMEO 1004 00:55:36,884 --> 00:55:40,822 ACCESSIBILITY AND A 1005 00:55:40,822 --> 00:55:43,357 TRANSCRIPTION OF STEM-LIKE GENES 1006 00:55:43,357 --> 00:55:48,830 IN TSPROG CELLS. 1007 00:55:48,830 --> 00:55:56,137 IT SEEMED TO BE UPGRADE IN TERMS 1008 00:55:56,137 --> 00:56:01,976 OF THERAPY CHROMOSOME 1009 00:56:01,976 --> 00:56:02,844 ACCESSIBILITIES. 1010 00:56:02,844 --> 00:56:06,848 YOU CAN SEE THAT IN THE DATA WE 1011 00:56:06,848 --> 00:56:08,749 SEE INCREASED TRANSCRIPTION AT 1012 00:56:08,749 --> 00:56:10,151 THE SAME GENES. 1013 00:56:10,151 --> 00:56:11,052 NEXT SLIDE. 1014 00:56:11,052 --> 00:56:13,821 AT THE SAME TIME, WE SAW CHANGES 1015 00:56:13,821 --> 00:56:16,958 ALSO IN PREFECTURE GENES. 1016 00:56:16,958 --> 00:56:17,859 PREFECTURE GENES. 1017 00:56:17,859 --> 00:56:23,297 ON THE RIGHT IN THE ATAC-SEQ, WE 1018 00:56:23,297 --> 00:56:25,933 CAN SEE DECREASED EXPRESSION IN 1019 00:56:25,933 --> 00:56:30,171 THE PREFECTURE GENES IN THE 1020 00:56:30,171 --> 00:56:36,844 PREFECTURE MICE. 1021 00:56:36,844 --> 00:56:42,316 THEY WERE ALL DECREASED IN THE 1022 00:56:42,316 --> 00:56:45,720 UTXCD IN TERMS EVER WILD TYPE IN 1023 00:56:45,720 --> 00:56:47,889 TERMS OF CHROMOSOME 1024 00:56:47,889 --> 00:56:48,356 ACCESSIBILITY. 1025 00:56:48,356 --> 00:56:53,027 ON THE LEFT PANEL WE SAW LESS 1026 00:56:53,027 --> 00:56:57,098 TRANSCRIPTION OF THESE GENES. 1027 00:56:57,098 --> 00:56:58,432 NEXT SLIDE. 1028 00:56:58,432 --> 00:57:00,368 WHAT WE THINK IS GOING ON IS 1029 00:57:00,368 --> 00:57:04,939 THAT UTX IS POISING PREFECTURE 1030 00:57:04,939 --> 00:57:12,213 GENES IN THESE SEMI PROGENITORS. 1031 00:57:12,213 --> 00:57:17,652 PREFECTURE GENES ARE USUALLY 1032 00:57:17,652 --> 00:57:20,054 CLOSED IN THE SEMI PROGENITORS 1033 00:57:20,054 --> 00:57:22,690 AND UTX IS OPENING THEM UP TO 1034 00:57:22,690 --> 00:57:30,564 ALLOW THEM TO BE TRAN SCRIEPED. 1035 00:57:30,564 --> 00:57:36,270 IN THE OTHERS IT IS SHUT OFF SO 1036 00:57:36,270 --> 00:57:40,541 IT'S NOT IN THE STEM-LIKE STATE. 1037 00:57:40,541 --> 00:57:42,410 ALL THE DATA HAS BEEN IN THE 1038 00:57:42,410 --> 00:57:46,781 SETTING OF GENETIC DEFICIENCY OF 1039 00:57:46,781 --> 00:57:50,584 UTX SO WE ELIMINATED UTX IN THE 1040 00:57:50,584 --> 00:57:51,585 T CELLS. 1041 00:57:51,585 --> 00:57:53,988 IS IT POSSIBLE TO TRANSLATE THIS 1042 00:57:53,988 --> 00:57:56,958 FOR THERAPEUTIC GAIN? 1043 00:57:56,958 --> 00:57:59,827 IN 2015, A SMALL MOLECULE 1044 00:57:59,827 --> 00:58:02,396 INHIBITOR WAS DESCRIBED THAT 1045 00:58:02,396 --> 00:58:06,500 INHIBITS UTX FUNCTION. 1046 00:58:06,500 --> 00:58:09,470 AND THIS INHIBITOR HAS BEEN USED 1047 00:58:09,470 --> 00:58:16,577 IN VIFO. 1048 00:58:16,577 --> 00:58:18,112 VIVO. 1049 00:58:18,112 --> 00:58:24,151 WE TREATED THE NLD MICE AND YOU 1050 00:58:24,151 --> 00:58:31,058 SEE THAT GSK-J 4 PROJECTED THE 1051 00:58:31,058 --> 00:58:32,593 MICE FROM THE DEVELOPMENT. 1052 00:58:32,593 --> 00:58:36,630 WHEN WE LOOKED AT THE PANCREATIC 1053 00:58:36,630 --> 00:58:42,203 LIMP MODE OF THE MICE WE COULD 1054 00:58:42,203 --> 00:58:50,745 SEE TH THE INCREASE OR MEDIATORN 1055 00:58:50,745 --> 00:58:56,650 THE MICE SUGGESTING THAT THE 1056 00:58:56,650 --> 00:58:59,954 GSKJ4 WAS MIMICKING THE 1057 00:58:59,954 --> 00:59:01,055 DEFICIENCY. 1058 00:59:01,055 --> 00:59:04,892 WE THINK UTX IS PLAYING AN 1059 00:59:04,892 --> 00:59:12,767 IMPORTANT ROLE IN DRIVING THE 1060 00:59:12,767 --> 00:59:16,070 SYSTEMIC EFFECTERS. 1061 00:59:16,070 --> 00:59:19,206 WHAT ABOUT PD1? 1062 00:59:19,206 --> 00:59:22,243 WE UTILIZED THE MICE AGAIN AND 1063 00:59:22,243 --> 00:59:27,748 WHEN THEY ARE TREATED WITH 1064 00:59:27,748 --> 00:59:29,984 ANTIPD 1 THEY DEVELOP DIABETES 1065 00:59:29,984 --> 00:59:30,518 RAPIDLY. 1066 00:59:30,518 --> 00:59:33,154 BY TWO WEEKS ALL THE MICE VOLE 1067 00:59:33,154 --> 00:59:35,156 DIABETES. 1068 00:59:35,156 --> 00:59:38,826 ALL THE MICE DEVELOP DIABETES. 1069 00:59:38,826 --> 00:59:42,363 IF THE MICE ARE DEFICIENT FOR 1070 00:59:42,363 --> 00:59:45,533 UTX IN THE T CELLS, WE DID NOT 1071 00:59:45,533 --> 00:59:47,268 SEE DIABETES AT ALL. 1072 00:59:47,268 --> 00:59:50,337 AFTER 30 DAYS, THE MICE WERE 1073 00:59:50,337 --> 00:59:51,472 DIABETES FREE. 1074 00:59:51,472 --> 00:59:54,275 IT SUGGESTED THAT UTX WAS 1075 00:59:54,275 --> 00:59:58,979 REQUIRED FOR ANTIPD 1 INCREWSED 1076 00:59:58,979 --> 01:00:00,614 DIABETES. 1077 01:00:00,614 --> 01:00:05,019 THE WILD MICE SHOWED 1078 01:00:05,019 --> 01:00:08,289 INFILTRATION WAR YAZ THE UTXCD 1079 01:00:08,289 --> 01:00:12,326 AFTER THREE DAYS HAD RELATIVELY 1080 01:00:12,326 --> 01:00:14,195 PROTECTED EYELET INIF I 1081 01:00:14,195 --> 01:00:15,729 TRAITION. 1082 01:00:15,729 --> 01:00:19,333 WE ALSO LOOKED IN THE PANCREATIC 1083 01:00:19,333 --> 01:00:22,169 IMP NODE OF THE NICE AND SAW A 1084 01:00:22,169 --> 01:00:26,707 PATTERN IN THE ANTIPD1 TREATED 1085 01:00:26,707 --> 01:00:29,176 MICE IN A CASE OF PROGENITORS IN 1086 01:00:29,176 --> 01:00:35,116 THE UTX, AND DECREASE IN THE 1087 01:00:35,116 --> 01:00:37,551 MEDIATOR CELL POPULATIONS. 1088 01:00:37,551 --> 01:00:41,288 SO WE THINK THAT UT EXPRKS NOT 1089 01:00:41,288 --> 01:00:45,860 ONLY IMPORTANT IN DETECTING 1090 01:00:45,860 --> 01:00:50,664 DIABETES AND THE PERFORM INDUCED 1091 01:00:50,664 --> 01:00:54,301 BY ANTIPD 1 AND WE'RE LOOKING TO 1092 01:00:54,301 --> 01:00:55,035 INCREASE CONVERSION. 1093 01:00:55,035 --> 01:01:03,277 IF YOU'RE EFFICIENCY IN UTX 1094 01:01:03,277 --> 01:01:06,313 DON'T CONVERT. 1095 01:01:06,313 --> 01:01:08,282 SO TO SUMMARIZE WHAT I TOLD YOU, 1096 01:01:08,282 --> 01:01:11,886 WE THINK THAT UTX IS A 1097 01:01:11,886 --> 01:01:16,490 POTENTIALLY DRUGABLE TARGET FOR 1098 01:01:16,490 --> 01:01:17,825 INTERRUPTING PROGENITORS TO 1099 01:01:17,825 --> 01:01:20,594 EFFECTERS IN BOTH SPONTANEOUS AS 1100 01:01:20,594 --> 01:01:24,198 WELL AS ANTIPD 1 DIABETES. 1101 01:01:24,198 --> 01:01:26,600 UTX PLAYS AN IMPORTANT ROLE TO 1102 01:01:26,600 --> 01:01:33,140 PROMOTE THEIR CONVERSION TO 1103 01:01:33,140 --> 01:01:33,908 CYTO-TOXIC EFFECTERS. 1104 01:01:33,908 --> 01:01:38,479 WE CAN PROTECT AGAINST DIABETES 1105 01:01:38,479 --> 01:01:43,651 AS WELL AS THE POTENTIAL DRUG 1106 01:01:43,651 --> 01:01:48,589 SMALL MOLECULE INHIBITOR GSKJ 4 1107 01:01:48,589 --> 01:01:51,759 AND PROTECTS FROM TYPE 1 1108 01:01:51,759 --> 01:01:52,526 DIABETES. 1109 01:01:52,526 --> 01:01:54,595 WITH THAT, I WOULD LIKE TO 1110 01:01:54,595 --> 01:01:56,063 ACKNOWLEDGE THE PEOPLE WHO DID 1111 01:01:56,063 --> 01:01:58,332 THE WORK. 1112 01:01:58,332 --> 01:02:02,069 HOWARD CHEN IS A GRAT WAD 1113 01:02:02,069 --> 01:02:04,371 STUDENT AND CLOSE TO GRADUATING. 1114 01:02:04,371 --> 01:02:06,340 WE WOULD LIKE TO ACKNOWLEDGE AND 1115 01:02:06,340 --> 01:02:15,649 GRATEFUL FOR THE SUPPORT OF THE 1116 01:02:15,649 --> 01:02:21,021 OADR AND UCLA ALLOWED US TO DO 1117 01:02:21,021 --> 01:02:23,224 MANY OF THE STUDIES THAT YOU SAW 1118 01:02:23,224 --> 01:02:24,858 TODAY. 1119 01:02:24,858 --> 01:02:29,463 AND MANNISH BEUT AND WILLY HUGO 1120 01:02:29,463 --> 01:02:32,399 ARE PART OF THIS TEAM. 1121 01:02:32,399 --> 01:02:39,840 >> THANK YOU DR. SU FOR THAT 1122 01:02:39,840 --> 01:02:40,741 UNSITEFUL PRESENTATION. 1123 01:02:40,741 --> 01:02:44,278 I WILL NOW INTRODUCE DR. 1124 01:02:44,278 --> 01:02:47,281 ANDERSON, SENIOR SCIENTIST AT 1125 01:02:47,281 --> 01:02:55,522 THE BRIGHAM HOSPITAL AND CORPS 1126 01:02:55,522 --> 01:02:57,925 FACULTY MEMBER. 1127 01:02:57,925 --> 01:02:59,560 HER LABORATORY FOCUSES ON 1128 01:02:59,560 --> 01:03:01,762 UNDERSTANDING THE PATHWAYS AND 1129 01:03:01,762 --> 01:03:04,298 MECHANISMS THAT REGULATE THE 1130 01:03:04,298 --> 01:03:06,033 T-CELL WE SPHONS IF CHRONIC 1131 01:03:06,033 --> 01:03:07,468 DISEASES PARTICULARLY IN CANCER. 1132 01:03:07,468 --> 01:03:08,869 IT'S A PLEASURE TO HAVE YOU WITH 1133 01:03:08,869 --> 01:03:09,536 US TODAY. 1134 01:03:09,536 --> 01:03:15,409 THE SCREEN IS YOURS DR. 1135 01:03:15,409 --> 01:03:15,676 ANDERSON. 1136 01:03:15,676 --> 01:03:18,545 >> THANK YOU. 1137 01:03:18,545 --> 01:03:19,280 WONDERFUL. 1138 01:03:19,280 --> 01:03:22,349 THANK YOU DR. KUO FOR THAT NICE 1139 01:03:22,349 --> 01:03:24,918 DESTRUCTION AND THANK YOU TO THE 1140 01:03:24,918 --> 01:03:28,522 OADR AND DR. SHANMUGAM FOR THE 1141 01:03:28,522 --> 01:03:29,923 INVITATION TO PRESENT AT THIS 1142 01:03:29,923 --> 01:03:40,234 INTERESTING FORUM. 1143 01:03:47,207 --> 01:03:49,810 I'M NOT HAVING LUCK AT ADVANCING 1144 01:03:49,810 --> 01:03:56,417 MY SLIDES EITHER. 1145 01:03:56,417 --> 01:03:58,152 >> DRL SHANMUGAM: IF YOU HAND IT 1146 01:03:58,152 --> 01:04:01,388 OVER TO ME, I'LL WE TAKE CARE OF 1147 01:04:01,388 --> 01:04:02,323 IT. 1148 01:04:02,323 --> 01:04:03,857 >> THANK YOU VERY MUCH. 1149 01:04:03,857 --> 01:04:05,626 GO TO THE NEXT SLIDE, PLEASE. 1150 01:04:05,626 --> 01:04:07,461 WE'VE BEEN TALKING TODAY ABOUT 1151 01:04:07,461 --> 01:04:15,135 THE LINKS BETWEEN AUTOIMMUNITY 1152 01:04:15,135 --> 01:04:16,570 AND CANCER. 1153 01:04:16,570 --> 01:04:19,673 INDEED, CANCER CAN BE THOUGHT OF 1154 01:04:19,673 --> 01:04:24,178 A DEEZ WHERE THE IMMUNE REACTION 1155 01:04:24,178 --> 01:04:28,082 IS SLOW WHERE AS IN AUTOIMMUNITY 1156 01:04:28,082 --> 01:04:31,251 YOU HAVE AN ACTIVE RESPONSE 1157 01:04:31,251 --> 01:04:33,821 AGAINST ANTIGENS. 1158 01:04:33,821 --> 01:04:35,789 AS YOU HEARD FROM THE PREVIOUS 1159 01:04:35,789 --> 01:04:37,991 TALKS, THIS RELATIONSHIP BETWEEN 1160 01:04:37,991 --> 01:04:41,829 THESE TWO DISEASES IS NOT 1161 01:04:41,829 --> 01:04:42,196 UNI-DIRECTIONAL. 1162 01:04:42,196 --> 01:04:47,601 WE CAN SEE HOW SCLERODERMA CAN 1163 01:04:47,601 --> 01:04:51,438 PREVENT BREAST CANCER AND IBD IS 1164 01:04:51,438 --> 01:04:53,741 WELL-KNOWN IT TO BE A RISK 1165 01:04:53,741 --> 01:04:57,911 FACTOR FOR THE DEVELOPMENT OF 1166 01:04:57,911 --> 01:05:00,748 COLORECTAL CANCER. 1167 01:05:00,748 --> 01:05:07,020 ICIs CAN PROMOTE THE 1168 01:05:07,020 --> 01:05:09,690 DEVELOPMENT OF IMMUNE-RELATED 1169 01:05:09,690 --> 01:05:12,493 ADVERSE EVENTS OR IRAEs IN 1170 01:05:12,493 --> 01:05:14,595 PATIENTS THAT HAVE TUMOURS AND 1171 01:05:14,595 --> 01:05:18,665 ARE BEING TREATED WITH THESE 1172 01:05:18,665 --> 01:05:19,433 IMMUNOTHERAPY AGENTS. 1173 01:05:19,433 --> 01:05:21,168 THESE LINKS AT THE LEVEL OF SORT 1174 01:05:21,168 --> 01:05:27,841 OF THE O ORGANISM AND PROPERTIES 1175 01:05:27,841 --> 01:05:29,309 DO EXIST IN ORDER TO UNDERSTAND 1176 01:05:29,309 --> 01:05:31,612 THE LINKS BETWEEN THESE TWO 1177 01:05:31,612 --> 01:05:33,781 DISEASES IT'S IMPORTANT TO GO TO 1178 01:05:33,781 --> 01:05:36,750 THE CELLS AND MOLECULAR 1179 01:05:36,750 --> 01:05:38,385 MECHANISMS. 1180 01:05:38,385 --> 01:05:42,189 SO MY TYPE OF FOCUS ON STEM-LIKE 1181 01:05:42,189 --> 01:05:43,757 T CELLS. 1182 01:05:43,757 --> 01:05:45,359 YOU HEARD ABOUT THESE FROM THE 1183 01:05:45,359 --> 01:05:46,393 PREVIOUS TALK. 1184 01:05:46,393 --> 01:05:48,929 I'LL GET MORE IN-DEPTH INTO WHAT 1185 01:05:48,929 --> 01:05:50,664 THEY ARE AND ABOUT THEIR BIOLOGY 1186 01:05:50,664 --> 01:05:54,401 IN BOTH THE CONTEXT OF 1187 01:05:54,401 --> 01:05:55,402 AUTOIMMUNE INFLAMMATION AND 1188 01:05:55,402 --> 01:05:55,936 CANCER. 1189 01:05:55,936 --> 01:06:00,207 THE STEM-LIKE T CELLS HAVE THE 1190 01:06:00,207 --> 01:06:02,810 CAPACITY TO SELF-RENEW. 1191 01:06:02,810 --> 01:06:06,046 THEY ARE THE CELLS THAT FEED THE 1192 01:06:06,046 --> 01:06:06,747 PREFECTURE RESPONSE. 1193 01:06:06,747 --> 01:06:11,685 YOU HEARD ABOUT CD 8 IN THE LAST 1194 01:06:11,685 --> 01:06:14,855 TALK AND I'LL TALK ABOUT CD-4. 1195 01:06:14,855 --> 01:06:16,557 THESE ARE CENTRAL PLAYERS IN 1196 01:06:16,557 --> 01:06:18,125 CANCER AND AUTO IMMUNITY. 1197 01:06:18,125 --> 01:06:21,428 ONE OF THE MAJOR TRAN 1198 01:06:21,428 --> 01:06:32,439 DESCRITRANSCRIPTIONFACTOR IS TC. 1199 01:06:34,975 --> 01:06:38,278 ON THE RIGHT SIDE IS A CARTOON 1200 01:06:38,278 --> 01:06:40,581 WE WROTE. 1201 01:06:40,581 --> 01:06:43,784 TCF-1 IS HAVE A RAN DESCRIPTION 1202 01:06:43,784 --> 01:06:45,452 FACTOR AND MEMBER OF THE 1203 01:06:45,452 --> 01:06:46,186 SIGNALING PATHWAY. 1204 01:06:46,186 --> 01:06:48,188 IT HAS FOUR DIFFERENT MODES OF 1205 01:06:48,188 --> 01:06:49,056 ACTIVITY. 1206 01:06:49,056 --> 01:06:52,526 IT CAN EITHER ACT AS A 1207 01:06:52,526 --> 01:06:55,496 TRANSCRIPTIONAL ACTIVATOR OR 1208 01:06:55,496 --> 01:06:58,499 SUPPRESSER DEPENDING ON WHETHER 1209 01:06:58,499 --> 01:07:08,976 IT'S ASSOCIATED WITH TCT OR 1210 01:07:10,077 --> 01:07:11,411 SIGNALING FACTOR. 1211 01:07:11,411 --> 01:07:13,046 IT COULD HAVE PIONEERING 1212 01:07:13,046 --> 01:07:13,580 FUNCTIONS. 1213 01:07:13,580 --> 01:07:22,456 IT'S KNOWN TO MODIFY HI HYT TON. 1214 01:07:22,456 --> 01:07:25,859 IT'S BEEN DESCRIBED TO ACT AS A 1215 01:07:25,859 --> 01:07:28,929 TRANS REPRESSER AND IT CAN 1216 01:07:28,929 --> 01:07:33,534 COMBINE WITH OTHERS AND 1217 01:07:33,534 --> 01:07:35,802 INTERFERE WITH THE ACTIVITY OF 1218 01:07:35,802 --> 01:07:38,805 THOSE TRANSCRIPTION FACTORS. 1219 01:07:38,805 --> 01:07:42,209 I'LL GET BACK TO THAT PARTICULAR 1220 01:07:42,209 --> 01:07:46,613 MECHANISM LATER IN MY TALK. 1221 01:07:46,613 --> 01:07:52,519 WE'RE FOCUSED ON TH-17 CELLS. 1222 01:07:52,519 --> 01:07:58,158 THESE ARE MAJOR DRIVERS OF 1223 01:07:58,158 --> 01:08:01,328 AUTOIMMUNE IN MAJOR DISEASES. 1224 01:08:01,328 --> 01:08:05,832 THEY'RE TWO TYPES OF TH-17 CELLS 1225 01:08:05,832 --> 01:08:12,272 HEN IN THE MIDDLE OF BLUE, TH-17 1226 01:08:12,272 --> 01:08:15,909 CELLS THAT ARE STEM-LIKE. 1227 01:08:15,909 --> 01:08:19,613 THEY PRODUCE ISLE 17, ISLE 22 1228 01:08:19,613 --> 01:08:20,280 AND ISLE 10. 1229 01:08:20,280 --> 01:08:24,851 THEY CAN BE IDENTIFIED BY SLAMF 1230 01:08:24,851 --> 01:08:28,488 6 ON THEIR CELL SURFACE AND HAVE 1231 01:08:28,488 --> 01:08:30,524 IMPORTANT TISSUE FUNCTIONING 1232 01:08:30,524 --> 01:08:32,292 PARTICULARLY IN THE GUT WHERE 1233 01:08:32,292 --> 01:08:34,494 THEY MAINTAIN BARRIER FUNCTION. 1234 01:08:34,494 --> 01:08:36,163 THESE CAN BE DIFFERENT SHAIPTED 1235 01:08:36,163 --> 01:08:39,967 BY ISLE 23 WHICH I'VE HE 1236 01:08:39,967 --> 01:08:42,603 DEPICTED IN RED TO BECOME THE 1237 01:08:42,603 --> 01:08:43,203 INFLAMMATORY CELLS. 1238 01:08:43,203 --> 01:08:45,806 THEY CAN BE INDUCED IN A CULTURE 1239 01:08:45,806 --> 01:08:51,445 WITH ISLE 21, 6 AND 23. 1240 01:08:51,445 --> 01:08:56,116 THESE CELLS CAN BE FOUND IN 1241 01:08:56,116 --> 01:09:02,956 VITRO BY EXPRESSION. 1242 01:09:02,956 --> 01:09:09,463 WHEN THEY'RE DIRECTED TO 1243 01:09:09,463 --> 01:09:13,400 SELF-TISSUES THEY ARE A MAIN 1244 01:09:13,400 --> 01:09:14,368 DRIVER. 1245 01:09:14,368 --> 01:09:18,238 I'M SHOWING YOU THE GENETIC MAP 1246 01:09:18,238 --> 01:09:28,315 OF MULTI MULTIPLE SCLEROSIS. 1247 01:09:28,315 --> 01:09:32,219 I DEPICTED HERE STEP THREE AND 1248 01:09:32,219 --> 01:09:33,086 STEP FOUR. 1249 01:09:33,086 --> 01:09:35,622 THESE ARE SIGNAL TRANSDUCERS 1250 01:09:35,622 --> 01:09:38,892 DOWNSTREAM OF ISLE 23 THAT 1251 01:09:38,892 --> 01:09:43,263 CONFLICTS HOMEOSTATIC TO THE 1252 01:09:43,263 --> 01:09:45,799 INFLAMMATORY TH-17 CELLS. 1253 01:09:45,799 --> 01:09:49,169 WHAT WE GOT INTO IN IS WHEN WE 1254 01:09:49,169 --> 01:09:54,307 SAW THE TCF 7 WHICH IS THE GENE, 1255 01:09:54,307 --> 01:09:59,179 IT WAS ALSO FOUND TO BE HAVE 1256 01:09:59,179 --> 01:10:01,982 SNIPS ASSOCIATED WITH MS RISK. 1257 01:10:01,982 --> 01:10:03,817 SO WE DECIDED WE NEEDED TO LOOK 1258 01:10:03,817 --> 01:10:06,353 AT THIS IN MORE DEPTH. 1259 01:10:06,353 --> 01:10:11,725 WE LOOKS AT TCF 1 EXPRESSION AND 1260 01:10:11,725 --> 01:10:20,267 MOHOMIO STATIC CELLS OR THOSE 1261 01:10:20,267 --> 01:10:22,769 SHOWN IN RED. 1262 01:10:22,769 --> 01:10:27,374 THE TCF-1 HAS A HIGHER 1263 01:10:27,374 --> 01:10:29,910 EXPRESSION RATHER THAN THE TH-17 1264 01:10:29,910 --> 01:10:31,178 CELLS. 1265 01:10:31,178 --> 01:10:35,582 IN PANEL B, WE FOUND IF WE 1266 01:10:35,582 --> 01:10:39,820 CULTURED THE CELLS AND WENT TO 1267 01:10:39,820 --> 01:10:42,656 ISLE 3, WE SAW DECREASED 1268 01:10:42,656 --> 01:10:49,896 EXPRESSION OF TCF-1 INDICATING 1269 01:10:49,896 --> 01:10:51,431 THAT ISLE 23 ONE OF THE THINGS 1270 01:10:51,431 --> 01:10:57,537 THAT IT DID TO CONVERT THE CELLS 1271 01:10:57,537 --> 01:11:00,307 THAT DRIVE AUTOIMMUNE YIPT WAS 1272 01:11:00,307 --> 01:11:02,809 TO DECREASE THE AUTO EXPRESSION. 1273 01:11:02,809 --> 01:11:08,715 WE LOOKED AT MICE WITH THE MODEL 1274 01:11:08,715 --> 01:11:10,150 FOR MS. 1275 01:11:10,150 --> 01:11:12,552 WE COULD SEE THERE WERE LOWER 1276 01:11:12,552 --> 01:11:16,723 LEVELS OF TCF-1 SHOWN IN GRAY. 1277 01:11:16,723 --> 01:11:20,560 WHEN WE DID THIS WITH THE MICE 1278 01:11:20,560 --> 01:11:27,033 WITH THE INABILITY TO SENSE ISLE 1279 01:11:27,033 --> 01:11:30,070 23, THEY RETAINED HIGHER LEVELS 1280 01:11:30,070 --> 01:11:33,807 OF TCF 1 EXPRESSION INDICATING 1281 01:11:33,807 --> 01:11:36,209 THAT I'LL 23 PROMOTES THE 1282 01:11:36,209 --> 01:11:39,913 DEVELOPMENT OF INFLAMMATORY 1283 01:11:39,913 --> 01:11:44,584 TH-17 CELL BUSINESS TURNING DOWN 1284 01:11:44,584 --> 01:11:45,552 TCF 1. 1285 01:11:45,552 --> 01:11:47,988 WE GAIN AND LOSS OF FUNCTION 1286 01:11:47,988 --> 01:11:48,722 APPROACHES. 1287 01:11:48,722 --> 01:11:55,529 WE USED A T-CELL RECEPTOR MICE 1288 01:11:55,529 --> 01:11:56,930 RECOGNIZING AN ANTIGEN AND WE 1289 01:11:56,930 --> 01:11:58,932 WERE ABLE TO CROSS THESE MICE TO 1290 01:11:58,932 --> 01:12:00,901 MICE THAT HAVE CONDITIONAL 1291 01:12:00,901 --> 01:12:07,274 DISLEETIODELETION. 1292 01:12:07,274 --> 01:12:08,809 TCF-1 IS CRITICAL DURING 1293 01:12:08,809 --> 01:12:10,443 DEVELOPMENT SO WE NEEDED TO 1294 01:12:10,443 --> 01:12:13,280 BYPASS ISSUES STEMMING FROM 1295 01:12:13,280 --> 01:12:14,281 ABNORMAL T CELL DEVELOPMENT. 1296 01:12:14,281 --> 01:12:17,450 WE WERE ABLE TO USE THESE DISTAL 1297 01:12:17,450 --> 01:12:23,723 MICE TO STUDY TCF 1. 1298 01:12:23,723 --> 01:12:26,860 WE STUDIED A MOUSE THAT 1299 01:12:26,860 --> 01:12:30,297 OVEREXPRESSES TCF 1 UNDER THE CD 1300 01:12:30,297 --> 01:12:31,164 2 PROMOTER. 1301 01:12:31,164 --> 01:12:35,302 WE WERE ABLE TO USE THE MICE TO 1302 01:12:35,302 --> 01:12:36,503 ADOPT TRANSFER EXPERIMENTS. 1303 01:12:36,503 --> 01:12:40,106 WE COULD GENERATE OUR STEM-LIKE 1304 01:12:40,106 --> 01:12:43,343 OR HOMEOSTATIC CELLS OR 1305 01:12:43,343 --> 01:12:44,878 INFLAMMATORY CELLS SHOWN IN RED. 1306 01:12:44,878 --> 01:12:46,813 ON THE RIGHT IS THE FACT THAT 1307 01:12:46,813 --> 01:12:49,583 THE DIFFERENTIATION INTO THE 1308 01:12:49,583 --> 01:12:54,521 DIFFERENT TYPES OF CH-17 1309 01:12:54,521 --> 01:12:59,125 CELLS -- TH 17 CELLS WERE 1310 01:12:59,125 --> 01:13:00,427 DIFFERENT IN THE MICE. 1311 01:13:00,427 --> 01:13:07,334 WHEN WE HL TURNING THE CELLS 1312 01:13:07,334 --> 01:13:17,777 INTO WILD TYPE MICE, THEY 1313 01:13:21,848 --> 01:13:22,782 INCREASED THE CELLS. 1314 01:13:22,782 --> 01:13:26,753 WHEN WE LOOKED AT PANEL C AT THE 1315 01:13:26,753 --> 01:13:29,890 CYTOKINE PRODUCTION OF TS T 1316 01:13:29,890 --> 01:13:34,794 CELLS ISOLATED FROM THE CENTRAL 1317 01:13:34,794 --> 01:13:39,065 SYSTEM THEY HAD INCREASED 1318 01:13:39,065 --> 01:13:45,405 AMOUNTS OF TCF 1 CKO. 1319 01:13:45,405 --> 01:13:48,575 SHOWN IN PANEL A IS THE 1320 01:13:48,575 --> 01:13:51,144 OVER-EXPRESSION OF TCF 1 AND 1321 01:13:51,144 --> 01:13:53,980 WE'RE NOT GETTING SUPER 1322 01:13:53,980 --> 01:13:57,017 PHYSIOLOGICAL, IT'S WITHIN THE 1323 01:13:57,017 --> 01:13:59,319 RANGE OF NORMAL CELLS BUT 1324 01:13:59,319 --> 01:14:02,923 THEY'RE UNABLE TO TURN DOWN 1325 01:14:02,923 --> 01:14:05,959 THEIR EXPRESSION OF TCF 1. 1326 01:14:05,959 --> 01:14:08,862 WHEN WE TRANSFERRED NIECE INTO 1327 01:14:08,862 --> 01:14:14,701 WILD TYPE RECIPIENTS, THE TCF 1 1328 01:14:14,701 --> 01:14:19,239 MICE HAD MARKEDLY LOWER DISEASE 1329 01:14:19,239 --> 01:14:19,706 DEVELOPMENT. 1330 01:14:19,706 --> 01:14:24,377 THIS WAS COMMENSURATE WITH FEWER 1331 01:14:24,377 --> 01:14:28,114 2 D 2 CELLS. 1332 01:14:28,114 --> 01:14:35,822 THESE CELLS HAD LOWER EXPRESSION 1333 01:14:35,822 --> 01:14:37,023 EXPRESSION. 1334 01:14:37,023 --> 01:14:39,392 THESE CELLS HAD LOWER EXPRESSION 1335 01:14:39,392 --> 01:14:45,298 0OF ISLE 17-A. 1336 01:14:45,298 --> 01:14:48,635 TOGETHER IT INDICATED THAT 1337 01:14:48,635 --> 01:14:52,572 MODULATION OF TCF 1 COULD 1338 01:14:52,572 --> 01:14:55,875 ENHANCE DISEASE OR ABROGATE 1339 01:14:55,875 --> 01:14:58,912 DISEASE. 1340 01:14:58,912 --> 01:15:05,785 IN ISLE C, IT DECREASES TCF 1. 1341 01:15:05,785 --> 01:15:08,888 WE REASONED THAT TRUE, IS IT 1342 01:15:08,888 --> 01:15:12,192 POSSIBLE THAT TCF 1 DEFICIENT 1343 01:15:12,192 --> 01:15:15,628 CELLS NO LONGER REQUIRE ISLE 23 1344 01:15:15,628 --> 01:15:18,531 TO BE THE DISEASE DRIVING CELLS. 1345 01:15:18,531 --> 01:15:27,107 WE LOOKED AT CELLS AND 1346 01:15:27,107 --> 01:15:31,378 TRANSFERRED THEM INTO PD-1 MACE 1347 01:15:31,378 --> 01:15:35,281 THAT COULD NOT PRODUCE THE 1348 01:15:35,281 --> 01:15:36,182 DISEASE. 1349 01:15:36,182 --> 01:15:39,686 WE FOUND THEY HAD HIGHER NUMBERS 1350 01:15:39,686 --> 01:15:43,857 OAF POSITIVE CELLS INFILTRATING 1351 01:15:43,857 --> 01:15:45,925 THE CLS. 1352 01:15:45,925 --> 01:15:49,729 THE WILD CELLS WERE MORE LIKE 1353 01:15:49,729 --> 01:15:54,567 TH-1 CELLS AND WHEN WE LOOKED AT 1354 01:15:54,567 --> 01:15:57,971 THE CYTOKINES WE FOUND THEY WERE 1355 01:15:57,971 --> 01:16:02,242 PRODUCING MORE IL 17 A. 1356 01:16:02,242 --> 01:16:03,877 THE TRULY DIFFERENTIVE 1357 01:16:03,877 --> 01:16:05,512 EXPERIMENT IS WHAT WE DID IN 1358 01:16:05,512 --> 01:16:06,646 PANEL D. 1359 01:16:06,646 --> 01:16:11,551 WE CROSSED OUR TCF KNOCKOUT MICE 1360 01:16:11,551 --> 01:16:18,958 TO ID 23 RECENTER MICE AND WE 1361 01:16:18,958 --> 01:16:22,095 CAN SEE THAT THE WILD-TYPE CELLS 1362 01:16:22,095 --> 01:16:26,933 IN IMLAK NICELY INDUCED DISEASE. 1363 01:16:26,933 --> 01:16:30,770 THE DEFICIENT CELLS WERE UNABLE 1364 01:16:30,770 --> 01:16:32,439 TO PRODUCE THE DISEASE. 1365 01:16:32,439 --> 01:16:36,943 THE LOSS OF CDF-1 WAS ABLE TO 1366 01:16:36,943 --> 01:16:38,344 ESSENTIALLY RESCUE THE INABILITY 1367 01:16:38,344 --> 01:16:43,416 OF THESE IL RESERPT KNOCK OUT 1368 01:16:43,416 --> 01:16:45,952 CELLS TO PRODUCE THE DISEASE. 1369 01:16:45,952 --> 01:16:50,824 THE MAJOR MECHANISM IN WHICH IL 1370 01:16:50,824 --> 01:16:58,031 23 WAS THE AUTO IMMUNE CELLS WAS 1371 01:16:58,031 --> 01:17:03,169 THROUGH THE LOSS OF TCF-1. 1372 01:17:03,169 --> 01:17:13,146 WE DECIDED T -- I'M SHOWING YOU 1373 01:17:13,146 --> 01:17:18,218 HERE THE RNASQ DATA. 1374 01:17:18,218 --> 01:17:22,255 WE INTRODUCED TH 17 FROM WILD 1375 01:17:22,255 --> 01:17:26,759 TYPE AND TRANSFERRED THEM INTO 1376 01:17:26,759 --> 01:17:28,962 MICE AND SAW THAT THEY 1377 01:17:28,962 --> 01:17:33,032 ACCUMULATED THE DISEASE. 1378 01:17:33,032 --> 01:17:40,039 WE DID THE RNASK FOR THESE 1379 01:17:40,039 --> 01:17:40,240 CELLS. 1380 01:17:40,240 --> 01:17:42,308 THERE WERE A LOT OF GENES 1381 01:17:42,308 --> 01:17:50,316 ASSOCIATED WITH INFLAMMATORY 1382 01:17:50,316 --> 01:17:52,018 PHENOTYPES. 1383 01:17:52,018 --> 01:17:54,087 SHOWN IN B IS WHERE WE DID A 1384 01:17:54,087 --> 01:17:55,922 TEST TO CONFIRM WHAT OUR 1385 01:17:55,922 --> 01:17:57,123 OBSERVATIONS WERE TELLING US WAS 1386 01:17:57,123 --> 01:17:57,790 TRUE. 1387 01:17:57,790 --> 01:17:59,659 WE LOOKED AT THE GENES ON THE 1388 01:17:59,659 --> 01:18:02,395 RIGHT WHICH ARE THE GENES 1389 01:18:02,395 --> 01:18:04,831 EXPRESSIONED IN THE TCF KNOCKOUT 1390 01:18:04,831 --> 01:18:07,467 JERS US THE GENES ON THE LEFT 1391 01:18:07,467 --> 01:18:09,502 EXPRESSED IN THE WILD TYPE CELLS 1392 01:18:09,502 --> 01:18:16,643 AND SCORED SIGNATURES. 1393 01:18:16,643 --> 01:18:21,481 INFLAMMATORY AND THOSE THAT 1394 01:18:21,481 --> 01:18:25,718 OVERLAPPED WITH THE TCF SLACKOUT 1395 01:18:25,718 --> 01:18:26,519 CELLS. 1396 01:18:26,519 --> 01:18:32,091 WHEN YOU SLOOK LOOK AT THE SLAMS 1397 01:18:32,091 --> 01:18:33,960 THEY OVERLAPPED WITH THE GENES 1398 01:18:33,960 --> 01:18:38,565 IN THE WILD TYPE CELLS. 1399 01:18:38,565 --> 01:18:40,900 PLEASE GO BACK TWO SLIDES. 1400 01:18:40,900 --> 01:18:43,636 SHOWN IN PANEL C IS THE DATA 1401 01:18:43,636 --> 01:18:46,706 LOOKING AT THE OPEN CHROMOSOME 1402 01:18:46,706 --> 01:18:50,343 GENES AND KNOCKOUT T CELLS. 1403 01:18:50,343 --> 01:18:58,885 WHAT WE FOUND IS THAT THE OPEN 1404 01:18:58,885 --> 01:19:05,358 CHROMATIN OVERLAPPED WITH THE 1405 01:19:05,358 --> 01:19:06,993 CHROMATIN CELLS WITH AUTO 1406 01:19:06,993 --> 01:19:08,261 IMMUNITY. 1407 01:19:08,261 --> 01:19:11,898 THEY SHARED 88% 6 THEIR 1408 01:19:11,898 --> 01:19:13,166 CHROMATIN IDENTITY. 1409 01:19:13,166 --> 01:19:19,772 JUST THE LOSS OF TCF THEMSELVES 1410 01:19:19,772 --> 01:19:24,277 IT WAS LIKE THE CELLS THAT WERE 1411 01:19:24,277 --> 01:19:27,113 INFLAMMATORY. 1412 01:19:27,113 --> 01:19:28,982 ONE OF THE THINGS I POINTED OUT 1413 01:19:28,982 --> 01:19:38,825 EARLIER IS THAT MAR GA WHEN WE D 1414 01:19:38,825 --> 01:19:42,328 AT BINDER SITES ENRICHED NEITHER 1415 01:19:42,328 --> 01:19:46,733 THE WILD TYPE CELLS OR KNOCKOUT 1416 01:19:46,733 --> 01:19:50,637 CELLS, THE KNOCKOUT CELLS HAD 1417 01:19:50,637 --> 01:19:52,338 THE TCF 1. 1418 01:19:52,338 --> 01:20:00,480 WHEN YOU SEE THAT RORGAM WA WAS 1419 01:20:00,480 --> 01:20:04,984 THE MOST BINDING SITE OF THE TCF 1420 01:20:04,984 --> 01:20:05,885 1 DEFICIENT CELLS. 1421 01:20:05,885 --> 01:20:09,355 I HAD SHOWN YOU EARLIER THAT TCF 1422 01:20:09,355 --> 01:20:12,792 1 THAT COULD ACT AS A TRANCE 1423 01:20:12,792 --> 01:20:14,994 REPRESSER. 1424 01:20:14,994 --> 01:20:17,630 WE THOUGHT MAYBE IT WAS ACTING 1425 01:20:17,630 --> 01:20:20,933 AS A REPRESSER. 1426 01:20:20,933 --> 01:20:23,770 WE TESTED WHETHER THEY COULD 1427 01:20:23,770 --> 01:20:26,806 BIND TO EACH OTHER. 1428 01:20:26,806 --> 01:20:29,142 IT'S -- THE LEFT PANEL IS NOT 1429 01:20:29,142 --> 01:20:30,777 SHOWING CLEARLY BUT THE RIGHT 1430 01:20:30,777 --> 01:20:32,745 PANEL HAS ALL THE THE DATA YOU 1431 01:20:32,745 --> 01:20:41,387 CAN SEE THAT WE COULD -- IF YOU 1432 01:20:41,387 --> 01:20:48,094 TREAT THE CELL WITH DNA, YOU SEE 1433 01:20:48,094 --> 01:20:49,629 THAT THE PRECIPITATION IS NOW 1434 01:20:49,629 --> 01:20:51,698 LOST. 1435 01:20:51,698 --> 01:20:52,799 NEXT SLIDE. 1436 01:20:52,799 --> 01:20:55,668 IN THE END, WE AGAIN, THIS IS 1437 01:20:55,668 --> 01:20:58,171 NOT DISPLAYING ENTIRELY 1438 01:20:58,171 --> 01:21:01,574 PROPERLY, WHAT WE DID IS 1439 01:21:01,574 --> 01:21:05,144 INDICATED OUR EPIGENETIC DATA 1440 01:21:05,144 --> 01:21:10,717 AND BUILT A REGULATORY NETWORK 1441 01:21:10,717 --> 01:21:13,820 BASICALLY TO VISUALIZE HOW TCF 1 1442 01:21:13,820 --> 01:21:16,222 WAS DETERMINING AND MAINTAINING 1443 01:21:16,222 --> 01:21:18,758 HOMEOSTATIC OR STEM-LIKE STATE 1444 01:21:18,758 --> 01:21:20,960 OF TH 17 CELLS. 1445 01:21:20,960 --> 01:21:23,196 SHOWN IN THE MIDDLE ARE TRANCE 1446 01:21:23,196 --> 01:21:24,163 DESCRIPTION FACTORS. 1447 01:21:24,163 --> 01:21:27,700 BLUE ARE THE TRANSCRIPTION 1448 01:21:27,700 --> 01:21:35,575 FACTORS EXPRESSED IN THE 1449 01:21:35,575 --> 01:21:38,878 HOMEOSTATIC STATE AND THE RED IS 1450 01:21:38,878 --> 01:21:41,614 INFLAMMATORY STATE. 1451 01:21:41,614 --> 01:21:44,016 WE TARGETED GENES EXPRESSED IN 1452 01:21:44,016 --> 01:21:46,352 THE RNC STAT AND LOOKED AT THE 1453 01:21:46,352 --> 01:21:49,055 WHAT THE GENES ARE AND FACILITY 1454 01:21:49,055 --> 01:21:51,657 BAMLIES AROUND THE TARGET GENES 1455 01:21:51,657 --> 01:21:53,926 AND PROCESSES THAT THEY 1456 01:21:53,926 --> 01:21:54,994 REGULATE. 1457 01:21:54,994 --> 01:21:58,297 ASPECTED YOU'D SEE THAT THE BLUE 1458 01:21:58,297 --> 01:22:02,135 TRANSCRIPTION FACTORS CONNECT 1459 01:22:02,135 --> 01:22:05,071 WITH THE HOMEOSTATIC CELLS AND 1460 01:22:05,071 --> 01:22:09,375 THE RED TRANSCRIPTION FACTORS 1461 01:22:09,375 --> 01:22:14,414 YOU SEE THINGS INVOLVED IN 1462 01:22:14,414 --> 01:22:19,152 MIGRATION, ADHESION THINGS 1463 01:22:19,152 --> 01:22:21,020 ASSOCIATESSED WITH MORE DAMAGING 1464 01:22:21,020 --> 01:22:23,689 FEENO TYPES. 1465 01:22:23,689 --> 01:22:28,027 TCF 1 MAINTAINS TH 17 CELLS BY 1466 01:22:28,027 --> 01:22:32,565 BINDING TO RORGT AND BY ORGANIZE 1467 01:22:32,565 --> 01:22:34,467 IT STRAIGHTING A REGULAR NETWORK 1468 01:22:34,467 --> 01:22:37,437 WITH A HOST OF TRAN DESCRIPTION 1469 01:22:37,437 --> 01:22:39,071 FACTORS. 1470 01:22:39,071 --> 01:22:43,643 HOMEOSTATIC TH 17 CELLS BECOME 1471 01:22:43,643 --> 01:22:47,814 INFLAMMATORY TH 17 CELLS UPON IL 1472 01:22:47,814 --> 01:22:51,250 23 DOWN REGULATION OF TCF 1. 1473 01:22:51,250 --> 01:22:54,120 NOW I'M GOING TO GIFT GEARS AND 1474 01:22:54,120 --> 01:22:55,621 TALK TO YOU ABOUT SOME OF OUR 1475 01:22:55,621 --> 01:23:01,227 WORK ON STEM-LIKE CD 8 CELLS. 1476 01:23:01,227 --> 01:23:06,165 AS DR. SU PREVIOUSLY MENTIONED, 1477 01:23:06,165 --> 01:23:07,934 THESE CELLS WERE DISCOVERED BY 1478 01:23:07,934 --> 01:23:10,770 OUR LAB AND OTHER LABS IN HUMANS 1479 01:23:10,770 --> 01:23:12,171 AND MOUSE MODELS. 1480 01:23:12,171 --> 01:23:15,775 THE STEM-LIKE T CELLS ARE 1481 01:23:15,775 --> 01:23:17,610 IMPORTANT IN MAINTAINING 1482 01:23:17,610 --> 01:23:20,179 RESPONSE TO THE BLOCKADE AND 1483 01:23:20,179 --> 01:23:22,782 THEY EXPRESS TCF 1. 1484 01:23:22,782 --> 01:23:25,551 OUR DATA SHOWN HERE A FEW YEARS 1485 01:23:25,551 --> 01:23:29,288 AGO WE WERE ALREADY INTERESTED 1486 01:23:29,288 --> 01:23:30,957 IN TCF 1. 1487 01:23:30,957 --> 01:23:34,160 IF YOU IMPLANTS CLONE TUMOURS 1488 01:23:34,160 --> 01:23:39,031 THAT EXPRESS LOW LEVELS, IF YOU 1489 01:23:39,031 --> 01:23:44,170 DO THIS IN WILD TYPE WITH 1490 01:23:44,170 --> 01:23:45,805 KNOCKOUT MICE, WE SAW THAT IF 1491 01:23:45,805 --> 01:23:48,541 YOU COMPARE THE BLUE TO THE RED, 1492 01:23:48,541 --> 01:23:51,310 THE WILD TYPE MICE RESPOND CELL 1493 01:23:51,310 --> 01:23:52,845 AND CONTROL TUMOR GROWTH. 1494 01:23:52,845 --> 01:23:54,780 IF YOU COMPARE THE LIGHT BLUE TO 1495 01:23:54,780 --> 01:23:59,352 THE PINK YOU SEE THE TCF 1 MICE 1496 01:23:59,352 --> 01:24:00,887 HAVE A MUCH MORE LIMITED 1497 01:24:00,887 --> 01:24:01,721 RESPONSE. 1498 01:24:01,721 --> 01:24:03,723 ON THE RIGHTS PANEL I SHOW YOU 1499 01:24:03,723 --> 01:24:07,760 WHERE WE INJECTED TUMOURS 1500 01:24:07,760 --> 01:24:18,070 INTERTUMOR ALLEY WITH A TR-9 1501 01:24:18,070 --> 01:24:20,740 WHICH HAS REGRESSION BUT IN THE 1502 01:24:20,740 --> 01:24:22,475 KNOCKOUT MICE MANY OF THEM 1503 01:24:22,475 --> 01:24:24,777 FAILED TO RESPOND. 1504 01:24:24,777 --> 01:24:26,846 AS SHOWN WITH THE RED ARROW, YOU 1505 01:24:26,846 --> 01:24:29,248 SAW THAT SOME OF THE KNOCKOUT 1506 01:24:29,248 --> 01:24:32,018 MICE WERE STILL ABLE TO RESPOND 1507 01:24:32,018 --> 01:24:33,286 AS WILD TYPES. 1508 01:24:33,286 --> 01:24:37,790 WE WANTED TO UNDERSTAND WHAT IS 1509 01:24:37,790 --> 01:24:40,893 TCF 1 IN CD 8 CELLS AND IS THE 1510 01:24:40,893 --> 01:24:48,000 REQUIREMENT FOR TCF ABSOLUTE? 1511 01:24:48,000 --> 01:24:49,535 WE DECIDED TO MODEL THIS. 1512 01:24:49,535 --> 01:24:53,105 WE TOOK ADVANTAGE OF TUMOR 1513 01:24:53,105 --> 01:24:56,375 MODELS THAT ARE EITHER POORLY OR 1514 01:24:56,375 --> 01:24:58,744 HIGHLY IMMUNEO JEN RICK DEPICTED 1515 01:24:58,744 --> 01:25:02,748 IN THE BLUE AND GREEN WE USED 1516 01:25:02,748 --> 01:25:04,417 THE SAME -- MODELS THAT 1517 01:25:04,417 --> 01:25:09,889 EXPRESSED THE SAME MODEL TUMOR 1518 01:25:09,889 --> 01:25:11,190 ANTIGEN. 1519 01:25:11,190 --> 01:25:14,594 WE IMPLANTED THESE TUMOURS INTO 1520 01:25:14,594 --> 01:25:17,997 WILD AND KNOCKOUT MICE AND DID 1521 01:25:17,997 --> 01:25:21,934 OUR IMMUNOTHERAPY. 1522 01:25:21,934 --> 01:25:26,038 AS YOU CAN SEE HERE WE SAW THAT 1523 01:25:26,038 --> 01:25:30,509 THESE MICE IN THE ABSENCE OF TCF 1524 01:25:30,509 --> 01:25:32,878 1 DID NOT RESPOND. 1525 01:25:32,878 --> 01:25:34,680 YOU CAN SEE THAT THE KNOCKOUT 1526 01:25:34,680 --> 01:25:37,116 MICE DIDN'T RESPOND TO THE 1527 01:25:37,116 --> 01:25:38,985 IMMUNOTHERAPY WHEREAS THE WILD 1528 01:25:38,985 --> 01:25:40,152 MICE DID. 1529 01:25:40,152 --> 01:25:45,992 HOWEVER, WHEN WE DID THIS WITH 1530 01:25:45,992 --> 01:25:51,597 MC 28 OVA, HERE WE SAW THAT TCF 1531 01:25:51,597 --> 01:25:55,201 1 WAS NOT NEED THE AT ALL. 1532 01:25:55,201 --> 01:25:57,269 BOTH KNOCKOUT AND WILD MICE 1533 01:25:57,269 --> 01:26:00,673 RESPONDED EQUALLY AS WELL. 1534 01:26:00,673 --> 01:26:02,842 WE LOOKED -- DECIDED TO START 1535 01:26:02,842 --> 01:26:06,178 WITH THE TUMOR DRAINING LIMP 1536 01:26:06,178 --> 01:26:09,148 NODE QUR THE TUMOR ANTIGENS ARE 1537 01:26:09,148 --> 01:26:09,815 PRIMED. 1538 01:26:09,815 --> 01:26:13,853 WE TRANSFERRED WILD TYPE OR THE 1539 01:26:13,853 --> 01:26:17,056 T CELLS AND GAVE A SINGLE DOSE 1540 01:26:17,056 --> 01:26:19,659 OF IMMUNE OR THERAPY TO THE 1541 01:26:19,659 --> 01:26:20,893 MICE. 1542 01:26:20,893 --> 01:26:24,497 WE CONFIRMED THAT THEY HAD 1543 01:26:24,497 --> 01:26:26,599 ESTABLISHED TIMERS AND GAVE THEM 1544 01:26:26,599 --> 01:26:27,566 IMMUNOTHERAPY. 1545 01:26:27,566 --> 01:26:29,635 WE LOOKED AT CELL DIVISION AND 1546 01:26:29,635 --> 01:26:32,772 WE SAW THAT AT IMAIS LINE, THE 1547 01:26:32,772 --> 01:26:41,313 ICE TICEO TYPE, THE T CELLS HAD 1548 01:26:41,313 --> 01:26:43,983 DIFFICULTY IN RELIVER RATING AND 1549 01:26:43,983 --> 01:26:44,784 DIVIDING. 1550 01:26:44,784 --> 01:26:47,486 WHEN WE GAVE THEM THE SINGLE 1551 01:26:47,486 --> 01:26:50,056 CHECKPOINT THERAPY, THE SMALL 1552 01:26:50,056 --> 01:26:51,590 DEFECT WAS COMPLETELY RESCUED 1553 01:26:51,590 --> 01:26:54,326 AND WERE ABLE TO DIVIDE EQUALLY 1554 01:26:54,326 --> 01:26:56,729 AS WELL AS WILD TYPE CELLS. 1555 01:26:56,729 --> 01:26:59,365 WHEN WE DID THE SAME EXPERIMENT 1556 01:26:59,365 --> 01:27:02,601 IN THE CONTEXT OF B-16 OVA TUMOR 1557 01:27:02,601 --> 01:27:04,970 WHERE WE KNOW THAT THE KNOCKOUT 1558 01:27:04,970 --> 01:27:09,075 MICE COULD NOT RESPOND WELL TO 1559 01:27:09,075 --> 01:27:10,176 IMMUNOTHERAPY, THERE WAS A 1560 01:27:10,176 --> 01:27:19,952 DEFECT IN THE MC 38-OVA, WE 1561 01:27:19,952 --> 01:27:21,620 COULD NOT REACH SAME LEVEL AS 1562 01:27:21,620 --> 01:27:24,490 WHAT WE SAW IN THE WILD TYPE 1563 01:27:24,490 --> 01:27:24,924 ANIMALS. 1564 01:27:24,924 --> 01:27:28,661 WE ARE ESSENTIALLY UNABLE TO 1565 01:27:28,661 --> 01:27:34,800 RESCUE THE PR PRO LIVE RAIVE EFT 1566 01:27:34,800 --> 01:27:39,538 OF THE CELLS. 1567 01:27:39,538 --> 01:27:46,445 TC F 1 WAS IMPORTANT TO THE 1568 01:27:46,445 --> 01:27:49,248 PRIME OR ANTIGENIC ABILITY. 1569 01:27:49,248 --> 01:27:51,584 WE NEXT WANTED TO ADDRESS HOW 1570 01:27:51,584 --> 01:27:53,452 THIS TRANSLATES TO THE TUMOR 1571 01:27:53,452 --> 01:27:54,553 ENVIRONMENT. 1572 01:27:54,553 --> 01:27:56,622 HOW DO THESE DIFFERENCES 1573 01:27:56,622 --> 01:27:58,591 TRANSLATE TO TUMOR TISSUE? 1574 01:27:58,591 --> 01:28:01,127 WE DID BASICALLY OUR SAME 1575 01:28:01,127 --> 01:28:01,894 EXPERIMENT. 1576 01:28:01,894 --> 01:28:04,296 WE TREATED WILD TYPE KNOCKOUT 1577 01:28:04,296 --> 01:28:09,802 MICE WITH EITHER B-16 OR MC-OVA 1578 01:28:09,802 --> 01:28:13,539 THERAPY AND PERFORMED RNA 1579 01:28:13,539 --> 01:28:14,140 SEQUENCING. 1580 01:28:14,140 --> 01:28:16,709 WE IDENTIFIED 8 DIFFERENT 1581 01:28:16,709 --> 01:28:17,777 CULTURES OF CELLS. 1582 01:28:17,777 --> 01:28:23,015 THE U-MAP SHOWS CLUSTERS ARE 1583 01:28:23,015 --> 01:28:24,517 STHOAN AT THE BOTTOM. 1584 01:28:24,517 --> 01:28:25,851 ON THE RIGHT-HAND SIDE I SHOW 1585 01:28:25,851 --> 01:28:32,758 YOU HERE THE PSUEDO TIME 1586 01:28:32,758 --> 01:28:34,426 TRAJECTORY. 1587 01:28:34,426 --> 01:28:36,695 NOTABLY THE LARGE BLACK SCHTICK 1588 01:28:36,695 --> 01:28:38,597 ARROWS I DREW THERE FOR YOU 1589 01:28:38,597 --> 01:28:43,169 INDICATE THAT THE TUMOR -- T-C 1590 01:28:43,169 --> 01:28:45,171 DIFFERENTIATION IS DIFFERENT. 1591 01:28:45,171 --> 01:28:55,714 IN THE MC-28 OR VA WHERE THEY 1592 01:29:01,453 --> 01:29:05,357 DIFFERENTIATE TOWARDS THE T 1593 01:29:05,357 --> 01:29:07,126 CELLS IN CLUSTER 8. 1594 01:29:07,126 --> 01:29:09,695 WE NEXT LOOKED AT HOW THE 1595 01:29:09,695 --> 01:29:12,865 CLUSTERS AND WILD TYPE CHANGE 1596 01:29:12,865 --> 01:29:14,133 UPON IMMUNOTHERAPY AND WHAT WE 1597 01:29:14,133 --> 01:29:17,469 FOUND IS THAT THIS TRANSITORY 1598 01:29:17,469 --> 01:29:23,809 PREFECTURE CLUSTER IN THE MC 38 1599 01:29:23,809 --> 01:29:26,545 TUMORS TRANSLATES INTO WILD TYPE 1600 01:29:26,545 --> 01:29:29,148 AND THE KNOCK YOWPT MICE. 1601 01:29:29,148 --> 01:29:31,617 WE KNOW THEY BOTH RESPOND WELL. 1602 01:29:31,617 --> 01:29:34,253 THAT INDICATED TO US THAT IT WAS 1603 01:29:34,253 --> 01:29:37,790 THE ABILITY OF THE TRANCE 1604 01:29:37,790 --> 01:29:38,958 EFFECTERS DRIVING THE RESPONSE 1605 01:29:38,958 --> 01:29:40,192 IN THE ANIMALS. 1606 01:29:40,192 --> 01:29:45,598 HOIFER, WHEN WE LOOKED AT B 16 1607 01:29:45,598 --> 01:29:49,235 OVA TUMORS, THEY COULDN'T MAKE 1608 01:29:49,235 --> 01:29:52,605 THE CELLS WELL, BUT THE WILD 1609 01:29:52,605 --> 01:29:54,440 MICE RESPONSIBLE AND THE 1610 01:29:54,440 --> 01:29:56,709 KNOCKOUT NICE DO NOT RESPOND 1611 01:29:56,709 --> 01:29:57,443 WELL. 1612 01:29:57,443 --> 01:29:58,777 ONE OF THE MAJOR POPULATIONS 1613 01:29:58,777 --> 01:30:02,047 THAT THE MICE RETAIN IS THE 1614 01:30:02,047 --> 01:30:06,352 DYSFUNCTIONAL T CELL POPULATION. 1615 01:30:06,352 --> 01:30:08,954 WE ZEROED IN ON THAT POPULATION 1616 01:30:08,954 --> 01:30:11,891 TO FIND OUT THE DIFFERENCE. 1617 01:30:11,891 --> 01:30:13,759 WE DID DIFFERENTIAL SCREEN 1618 01:30:13,759 --> 01:30:15,661 EXPRESS AND FOUND THAT IN THE -- 1619 01:30:15,661 --> 01:30:16,929 GENE EXPRESS AND FOUND THAT IN 1620 01:30:16,929 --> 01:30:26,438 THE ABSENCE OF TCF-1 THE CELLS 1621 01:30:26,438 --> 01:30:28,507 FAILED. 1622 01:30:28,507 --> 01:30:31,577 AND WHEN WE LOOKED AT THE 1623 01:30:31,577 --> 01:30:35,781 EXPRESSION, WE FOUND UPON 1624 01:30:35,781 --> 01:30:41,553 IMMUNOTHERAPY, THE TCF WERE LESS 1625 01:30:41,553 --> 01:30:44,223 ABLE TO SURVIVE. 1626 01:30:44,223 --> 01:30:47,426 WHEN LEE LOOKED CLOSELY A AT THO 1627 01:30:47,426 --> 01:30:49,595 AT THE GENES, A LOT OF GENES 1628 01:30:49,595 --> 01:30:53,866 WERE GENES REPORTED IN A PAPER 1629 01:30:53,866 --> 01:30:56,869 AS BEING REPRESENTATIVE OR 1630 01:30:56,869 --> 01:31:01,006 INDICATIVE OF DESTABILIZED OREN 1631 01:31:01,006 --> 01:31:04,977 STABLE DYSFUNCTIONAL T-CELLS. 1632 01:31:04,977 --> 01:31:13,652 WJUST TO SHOW WHAT THE CLINICAL 1633 01:31:13,652 --> 01:31:21,894 DEVELOP RANS ORELEVANCE OF OUR , 1634 01:31:21,894 --> 01:31:24,596 WE LOOKED AT THE GENES EFFICIENT 1635 01:31:24,596 --> 01:31:28,734 IN OUR TCF 1 KNOCKOUT T CELLS 1636 01:31:28,734 --> 01:31:31,937 AND SCORED THOSE IN THE 1637 01:31:31,937 --> 01:31:34,773 PRETREATMENT LESIONS EVER 1638 01:31:34,773 --> 01:31:36,575 MELANOMA PATIENTS. 1639 01:31:36,575 --> 01:31:38,277 THIS IS PUBLISHED DATA FROM THE 1640 01:31:38,277 --> 01:31:39,511 LAB. 1641 01:31:39,511 --> 01:31:43,449 WE SAW THAT THE PATIENTS OR 1642 01:31:43,449 --> 01:31:47,820 BIOPSY SAMPLES FAIL RESPONSE HAD 1643 01:31:47,820 --> 01:31:50,923 HIGHER EXPRESSION OF THE 1644 01:31:50,923 --> 01:31:54,326 STABILIZED DYSFUNCTIONAL T-CELL 1645 01:31:54,326 --> 01:31:56,628 DESCRIPTION. 1646 01:31:56,628 --> 01:31:59,565 IN SUMMARY, WHAT I'VE SHOWN YOU 1647 01:31:59,565 --> 01:32:02,768 IS THAT TCF 1 IS FOREIGN FOR 1648 01:32:02,768 --> 01:32:08,340 MAINTAINING FITNESS IN THE CD 8 1649 01:32:08,340 --> 01:32:09,541 CELLS. 1650 01:32:09,541 --> 01:32:15,047 WHAT WE DEMONSTRATE LOOKING AT 1651 01:32:15,047 --> 01:32:20,419 THE BC-OVA SETTING. 1652 01:32:20,419 --> 01:32:22,287 IT ENSURES 89 MAINTENANCE OR 1653 01:32:22,287 --> 01:32:24,823 GENERATION OF DYSFUNCTIONAL 1654 01:32:24,823 --> 01:32:29,962 T-CELLS THAT CAN TURN AND BETTER 1655 01:32:29,962 --> 01:32:37,770 ABLE TO SURVIVE AND PROVIDE 1656 01:32:37,770 --> 01:32:41,206 STABILITY TO THE DISFUNKAL 1657 01:32:41,206 --> 01:32:43,842 CELLS. 1658 01:32:43,842 --> 01:32:46,345 IT ENSURES THE GENERATION OF 1659 01:32:46,345 --> 01:32:48,514 DYSFUNCTIONAL CELLS FIT TO 1660 01:32:48,514 --> 01:32:55,554 SURVIVE TOX. 1661 01:32:55,554 --> 01:32:57,956 I WOULD LIKE IS TO BRING THE TWO 1662 01:32:57,956 --> 01:32:58,957 STORIES I GAVE YOU TOGETHER. 1663 01:32:58,957 --> 01:33:03,996 I TALKED TO YOU ABOUT TCF 1, 1664 01:33:03,996 --> 01:33:05,998 THERE ARE IMPLICATIONS WHAT I 1665 01:33:05,998 --> 01:33:10,803 SHOWED YOU FOR BOTH AUTOIMMUNE 1666 01:33:10,803 --> 01:33:12,304 AND CANCER. 1667 01:33:12,304 --> 01:33:17,443 THE SINGLE POLYMORPHISMS HAVE 1668 01:33:17,443 --> 01:33:19,078 BEEN ASSOCIATED WITH NOT JUST 1669 01:33:19,078 --> 01:33:24,083 WITH MS BUT WITH MULTIPLE 1670 01:33:24,083 --> 01:33:24,917 AUTOIMMUNE DISEASES. 1671 01:33:24,917 --> 01:33:27,086 NOW THE FUNCTION OF MOST OF 1672 01:33:27,086 --> 01:33:37,596 THESE SINGLE NU NUKE. 1673 01:33:42,301 --> 01:33:43,936 -- THEY MAY AFFECT 1674 01:33:43,936 --> 01:33:44,770 THE FUNCTION. 1675 01:33:44,770 --> 01:33:46,738 MAYBE THEY EFFECT THE COMBINED 1676 01:33:46,738 --> 01:33:49,508 AND PARTNER WITH OTHER 1677 01:33:49,508 --> 01:33:59,251 TRANSCRIPTION FACTORS SO 1678 01:33:59,251 --> 01:34:00,652 AFFECTING THE ABILITY TO 1679 01:34:00,652 --> 01:34:01,954 RESPOND. 1680 01:34:01,954 --> 01:34:08,594 THESE MAY PREDISPOSE TO 1681 01:34:08,594 --> 01:34:12,764 AUTOIMMUNITY BY PROMOTING OUT OF 1682 01:34:12,764 --> 01:34:15,434 THE STEM-LIKE STATE TO THE 1683 01:34:15,434 --> 01:34:17,369 INFLAMMATORY STATE. 1684 01:34:17,369 --> 01:34:19,671 THEY COULD ALSO AFFECT THE 1685 01:34:19,671 --> 01:34:21,173 STABILITY OF THE STEM-LIKE 1686 01:34:21,173 --> 01:34:22,908 POPULATION AND AFFECT THEIR 1687 01:34:22,908 --> 01:34:25,210 ABILITY TO SUSTAIN IMMUNEO THIMP 1688 01:34:25,210 --> 01:34:25,911 RESPONSE. 1689 01:34:25,911 --> 01:34:28,080 IN THE CONTEXT OF IMMUNE ORE 1690 01:34:28,080 --> 01:34:31,583 THERAPY, THEY MAY ALSO -- 1691 01:34:31,583 --> 01:34:34,520 IMMUNOTHERAPY, THEY MAY ACT TO 1692 01:34:34,520 --> 01:34:37,089 PREDISOAZ OR NOT TOE 1693 01:34:37,089 --> 01:34:40,092 IMMUNE-RELATED ADVERSE EVENTS. 1694 01:34:40,092 --> 01:34:42,394 IF WE DEVISE STRATEGIES TO BOOST 1695 01:34:42,394 --> 01:34:47,099 THE EXPRESS OF TCF 1, WE IN A BE 1696 01:34:47,099 --> 01:34:50,002 ABLE TO CONVERT THE CELLS FOR 1697 01:34:50,002 --> 01:34:53,972 THE BENEFIT OF PATIENTS WITH 1698 01:34:53,972 --> 01:34:57,543 AUTOIMMUNE DISEASE AND CANCER. 1699 01:34:57,543 --> 01:34:59,311 WITH THAT, I WILL END AND THANK 1700 01:34:59,311 --> 01:35:01,613 ALL THE PEOPLE IN THE LAB WHO 1701 01:35:01,613 --> 01:35:02,281 DID THE WORK. 1702 01:35:02,281 --> 01:35:05,217 I WOULD LIKE TO HIGHLIGHT THE 1703 01:35:05,217 --> 01:35:14,226 FEW PEOPLE WHO SPEARHEADED THE 1704 01:35:14,226 --> 01:35:19,464 INVESTIGATION STORY. 1705 01:35:19,464 --> 01:35:22,601 THERE WERE MANY WHO CONTRIBUTED 1706 01:35:22,601 --> 01:35:28,173 TO THIS STUDY OF UNDERSTANDING 1707 01:35:28,173 --> 01:35:31,643 THE POISING OF CELLS FOR OPTIMAL 1708 01:35:31,643 --> 01:35:33,812 RESPONSES TO LOW T-CELL 1709 01:35:33,812 --> 01:35:34,112 STIMULATION. 1710 01:35:34,112 --> 01:35:37,316 I WOULD LIKE TO ACKNOWLEDGE MY 1711 01:35:37,316 --> 01:35:41,386 SUPPORT FROM NCI, MS SOCIETY AND 1712 01:35:41,386 --> 01:35:43,088 ALL OF YOU FOR YOUR ATTENTION. 1713 01:35:43,088 --> 01:35:45,791 THANK YOU. 1714 01:35:45,791 --> 01:35:48,093 >> I WANT TO STHARCHG, DR. 1715 01:35:48,093 --> 01:35:52,130 ANDERSON FOR THAT WONDERFUL TALK 1716 01:35:52,130 --> 01:35:56,568 AND THANK ALL OF OUR SPEAKERS. 1717 01:35:56,568 --> 01:35:58,203 AS PEOPLE ARE GETTING THEIR 1718 01:35:58,203 --> 01:36:01,506 VIDEOS BACK ON, AND MICS READY, 1719 01:36:01,506 --> 01:36:03,976 I JUST WANTED TO REMINE PEOPLE, 1720 01:36:03,976 --> 01:36:05,877 YOU CAN PUMENT YOUR QUESTIONS IN 1721 01:36:05,877 --> 01:36:07,112 THE Q&A. 1722 01:36:07,112 --> 01:36:11,883 YOU CAN UP LOAD THE PEOPLE'S 1723 01:36:11,883 --> 01:36:14,319 QUESTIONS USING THE THUMBS UP 1724 01:36:14,319 --> 01:36:16,255 BUTTON AND I THIS IS A MIKE IS 1725 01:36:16,255 --> 01:36:18,657 GOING TO CHANGE US OVER SO 1726 01:36:18,657 --> 01:36:20,525 PEOPLE CAN SEE THE SPEAKERS ANDO 1727 01:36:20,525 --> 01:36:22,628 AND WITH THAT, I'M GOING IT PASS 1728 01:36:22,628 --> 01:36:28,267 THE NI MICROPHONE OVER TO DR. PK 1729 01:36:28,267 --> 01:36:30,235 TO GET US STARTED WITH THE FIRST 1730 01:36:30,235 --> 01:36:30,669 QUESTION. 1731 01:36:30,669 --> 01:36:30,969 >> SURE. 1732 01:36:30,969 --> 01:36:35,507 THANK YOU. 1733 01:36:35,507 --> 01:36:37,476 SO I WOULD THRIEK ASK THE 1734 01:36:37,476 --> 01:36:40,012 PRESENTER THE FOLLOWING 1735 01:36:40,012 --> 01:36:43,615 QUESTION: HOW DO YOU SEE THE 1736 01:36:43,615 --> 01:36:47,252 RESEARCH EVOLVING OVER THE NEXT 1737 01:36:47,252 --> 01:36:51,723 THREE TO FIVE YEARS. 1738 01:36:51,723 --> 01:36:55,127 >> I THINK THERE ARE SEVERAL 1739 01:36:55,127 --> 01:36:59,698 INTERESTING QUESTIONS AND AFTERD 1740 01:36:59,698 --> 01:37:01,533 AVENUES TO PER SIGH. 1741 01:37:01,533 --> 01:37:04,936 FIRST CAN WE IDENTIFY THE 1742 01:37:04,936 --> 01:37:06,838 PATIENTS AND STUDIES STRATEGIES 1743 01:37:06,838 --> 01:37:07,639 IN THESE PATIENTS. 1744 01:37:07,639 --> 01:37:09,941 I THINK ONE REALLY QUESTION IS 1745 01:37:09,941 --> 01:37:12,210 WHETHER CANCER COULD BE A DRIVER 1746 01:37:12,210 --> 01:37:16,948 FOR THE DEVELOPMENT OF 1747 01:37:16,948 --> 01:37:18,483 AUTOIMMUNITY IN ALL OF OUR 1748 01:37:18,483 --> 01:37:21,453 PATIENTS AND ARE THERE MORE 1749 01:37:21,453 --> 01:37:24,956 SENSITIVE CANCER DETECTION 1750 01:37:24,956 --> 01:37:27,326 STRATEGIES WHETHER THEY'RE 1751 01:37:27,326 --> 01:37:30,362 LIQUID BIOPSIES IS THAT WE CAN 1752 01:37:30,362 --> 01:37:38,070 DETEDETECT INS THEY PATIENTS IF 1753 01:37:38,070 --> 01:37:40,472 THERE ARE THINGS THAT DRIVE THE 1754 01:37:40,472 --> 01:37:41,440 AUTOIMMUNE DISEASE. 1755 01:37:41,440 --> 01:37:43,308 THERE ARE IMPLICATIONS AS TO 1756 01:37:43,308 --> 01:37:45,977 WHETHER OR NOT WE SHOULD THINK 1757 01:37:45,977 --> 01:37:51,316 OFFER CANCER IMMUNE PRO TIKS AS 1758 01:37:51,316 --> 01:37:56,188 FAR AS AUTOIMMUNITY. 1759 01:37:56,188 --> 01:37:58,190 THOSE ARE EXCITING DEVELOPMENTS 1760 01:37:58,190 --> 01:38:00,258 FOR THE NEXT THREE TO FIVE 1761 01:38:00,258 --> 01:38:00,692 YEARS. 1762 01:38:00,692 --> 01:38:06,264 CAN YOU MAKE ANY COMMENTS DR. 1763 01:38:06,264 --> 01:38:06,598 SU? 1764 01:38:06,598 --> 01:38:09,568 I AGREE WITH DR. SHAH. 1765 01:38:09,568 --> 01:38:14,940 I WANT TO FIND OUT WHO WILL 1766 01:38:14,940 --> 01:38:19,077 DEVELOP THE IRAEs. 1767 01:38:19,077 --> 01:38:20,946 THE PATIENT I PRESENTED IN THE 1768 01:38:20,946 --> 01:38:22,647 BEGINNING OF THE TALK, SHE DID 1769 01:38:22,647 --> 01:38:28,520 NOTE HAVE THE ANTIBODIES. 1770 01:38:28,520 --> 01:38:31,256 HER FORM OF TYPE 1 DIABETES WAS 1771 01:38:31,256 --> 01:38:34,926 DIFFERENT IN A LOT OF WAYS FROM 1772 01:38:34,926 --> 01:38:40,766 SUSTAIN YUS DIABETES FOR EXAMPLE 1773 01:38:40,766 --> 01:38:43,502 THE AUTOIMMUNE PROFILE IS NOT 1774 01:38:43,502 --> 01:38:44,903 THE SAME. 1775 01:38:44,903 --> 01:38:46,405 THIS IS THE SAME WITH OTHER 1776 01:38:46,405 --> 01:38:49,875 STHAS DO NOT HAVE THE AUTO 1777 01:38:49,875 --> 01:38:50,776 ANTIBODY PROFILE. 1778 01:38:50,776 --> 01:38:52,477 THE DISEASE COURSES FASTER AS 1779 01:38:52,477 --> 01:38:53,278 WELL. 1780 01:38:53,278 --> 01:38:55,847 IT SEEMS TO BE ACCELERATED AND 1781 01:38:55,847 --> 01:39:00,118 THE PATIENTS PRESENT WITH A 1782 01:39:00,118 --> 01:39:03,355 PRETTY SEVERE ADVANCED FORM OF 1783 01:39:03,355 --> 01:39:05,424 TYPE I DIABETES. 1784 01:39:05,424 --> 01:39:16,334 MORE SO THAN WITH SPEAN YUS TYPI 1785 01:39:16,868 --> 01:39:17,335 DIABETES. 1786 01:39:17,335 --> 01:39:19,538 HOW DO WE KNOW? 1787 01:39:19,538 --> 01:39:24,042 DO WE KNEE TO LOOK AT THE 1788 01:39:24,042 --> 01:39:24,943 TC-REPERTOIRE. 1789 01:39:24,943 --> 01:39:27,979 ARE THERE HLA LINKS WE DON'T 1790 01:39:27,979 --> 01:39:29,781 DMOA ABOUT? 1791 01:39:29,781 --> 01:39:37,122 THOSE ARE QUESTIONS THAT ARE 1792 01:39:37,122 --> 01:39:38,757 EXPLORED. 1793 01:39:38,757 --> 01:39:41,626 DOES GENDER PLAY A ROLE? 1794 01:39:41,626 --> 01:39:43,328 THAT'S A CONTROVERSIAL AREA AS 1795 01:39:43,328 --> 01:39:43,662 WITH. 1796 01:39:43,662 --> 01:39:44,329 >> THANK YOU. 1797 01:39:44,329 --> 01:39:46,865 DR. ANDERSON, DO YOU WANT TO ADD 1798 01:39:46,865 --> 01:39:48,500 MORE COMMENT? 1799 01:39:48,500 --> 01:39:48,934 >> YES. 1800 01:39:48,934 --> 01:39:49,401 ABSOLUTELY. 1801 01:39:49,401 --> 01:39:51,770 I HAVE A COUPLE OF THINGS I 1802 01:39:51,770 --> 01:39:55,040 WOULD LIKE TO NOTE. 1803 01:39:55,040 --> 01:39:57,909 THERE IS A LOT OF DEBATE IN THE 1804 01:39:57,909 --> 01:39:59,177 FIELD ESPECIALLY ON THE CANCER 1805 01:39:59,177 --> 01:40:02,047 SIDE WHETHER THE IMMUNE-RELATED 1806 01:40:02,047 --> 01:40:03,849 ADVERSE EVENTS ARE AUTO 1807 01:40:03,849 --> 01:40:04,649 IMMUNITY. 1808 01:40:04,649 --> 01:40:07,953 BECAUSE THEY ARE REVERSIBLE. 1809 01:40:07,953 --> 01:40:11,823 SO YOU KNOW, WHETHER THAT WILL 1810 01:40:11,823 --> 01:40:19,297 CHANGE WITH CONTINUOUS -- WE 1811 01:40:19,297 --> 01:40:26,905 LOOK AT DEESCALATION OF 1812 01:40:26,905 --> 01:40:27,172 PATIENTS. 1813 01:40:27,172 --> 01:40:28,473 THAT'S AN OPEN QUESTION AND 1814 01:40:28,473 --> 01:40:32,043 WOULD HE NEED MORE CLINICALLY 1815 01:40:32,043 --> 01:40:34,946 TRANSLATABLE RESEARCH. 1816 01:40:34,946 --> 01:40:36,481 PATIENT-BASED RESEARCH TO UNDER 1817 01:40:36,481 --> 01:40:37,349 THAT BETTER. 1818 01:40:37,349 --> 01:40:40,218 WE NEED MORE MODELS TO STLDY 1819 01:40:40,218 --> 01:40:42,654 SOME OF THESE KKSES BETWEEN -- 1820 01:40:42,654 --> 01:40:46,458 SO WE CAN UNDER THE AT A 1821 01:40:46,458 --> 01:40:46,925 MECHANISTIC LEVEL. 1822 01:40:46,925 --> 01:40:51,463 WE CAN DO A LOT WITH PATIENT 1823 01:40:51,463 --> 01:40:59,204 SAMPLES BUT IT'S BELTER BETTER T 1824 01:40:59,204 --> 01:41:00,505 IN MODELS. 1825 01:41:00,505 --> 01:41:02,007 WE NEED TO STUDY SOME OF THE 1826 01:41:02,007 --> 01:41:03,141 CONNECTIONS AT THE LEVEL OF 1827 01:41:03,141 --> 01:41:06,845 STISH EU FLS CELLS AND MOLECULAR 1828 01:41:06,845 --> 01:41:07,746 ISSUES. 1829 01:41:07,746 --> 01:41:09,814 I THINK HAVING TRAINED IN THE 1830 01:41:09,814 --> 01:41:11,383 AUTO IMMUNITY FIELD AND NOW 1831 01:41:11,383 --> 01:41:14,452 DOING A LOT OF CANCER WORK IN MY 1832 01:41:14,452 --> 01:41:18,089 LAB, I HAVE THE PERSPECTIVE OF 1833 01:41:18,089 --> 01:41:20,392 WHAT EACH FIELD HAS BEEN DOING 1834 01:41:20,392 --> 01:41:23,595 AND UNFORTUNATELY, WE'RE STILL 1835 01:41:23,595 --> 01:41:25,196 VERY SILOED. 1836 01:41:25,196 --> 01:41:27,599 THERE ARE A LOT OF INFORMATION 1837 01:41:27,599 --> 01:41:31,202 THAT IS NOT BEING SHARED AND 1838 01:41:31,202 --> 01:41:32,070 LEVERAGED. 1839 01:41:32,070 --> 01:41:38,276 ONE EXAMPLE IS THE -- ALLUDED TO 1840 01:41:38,276 --> 01:41:42,414 IN MY TALK IS THE GWA STUDIES 1841 01:41:42,414 --> 01:41:43,615 DONE EXTENSIVELY. 1842 01:41:43,615 --> 01:41:47,452 WE KNOW WHAT THOSE SNIPS ARE AND 1843 01:41:47,452 --> 01:41:52,223 WE CAN THINK ABOUT CREATING SNIP 1844 01:41:52,223 --> 01:41:55,493 PANELS THAT WILL SCREEN THOSE 1845 01:41:55,493 --> 01:41:58,129 PATIENTS GOING INTO THERAPY AND 1846 01:41:58,129 --> 01:42:02,767 SEE WHICH ONES ARE MORE 1847 01:42:02,767 --> 01:42:04,636 SUSCEPTIBLE TO DEVELOPING 1848 01:42:04,636 --> 01:42:07,772 AUTOIMMUNE TOKSITIES ET CETERA. 1849 01:42:07,772 --> 01:42:09,007 WE'RE NOT LEVERAGING ANY OF THAT 1850 01:42:09,007 --> 01:42:09,975 INFORMATION RIGHT NOW. 1851 01:42:09,975 --> 01:42:14,412 I THINK MORE CROSS OVER 1852 01:42:14,412 --> 01:42:15,814 INVESTIGATION AND THERE IS MAYBE 1853 01:42:15,814 --> 01:42:18,883 AN OPPORTUNITY HERE I KNOW NIH 1854 01:42:18,883 --> 01:42:20,385 HAD DONE SOMETHING A FEW 1855 01:42:20,385 --> 01:42:22,320 YEARSING ATO TRY IS TO BRING 1856 01:42:22,320 --> 01:42:23,321 INVESTIGATORS TOGETHER. 1857 01:42:23,321 --> 01:42:26,391 BUT THIS WAS SOMETHING I THINK 1858 01:42:26,391 --> 01:42:30,228 NID AND NCI COULD PERHAPS 1859 01:42:30,228 --> 01:42:31,896 PARTNER ON TO PUSH THIS FIELD 1860 01:42:31,896 --> 01:42:32,430 FORWARD. 1861 01:42:32,430 --> 01:42:37,736 THAT'S WHAT I HAVE TO SAY. 1862 01:42:37,736 --> 01:42:39,404 >> THANK YOU ALL FOR THOSE 1863 01:42:39,404 --> 01:42:39,904 THOUGHTS. 1864 01:42:39,904 --> 01:42:44,342 YOU TALKED ABOUT CROSSOVER AND 1865 01:42:44,342 --> 01:42:52,584 CROSS DISCIPLINE AIRY TRAINING. 1866 01:42:52,584 --> 01:42:54,586 WHAT RESEARCH NEEDS TO ADVANCE 1867 01:42:54,586 --> 01:42:57,422 FOR THIS COLLECTIVE RESEARCH? 1868 01:42:57,422 --> 01:42:58,189 >> I'LL START. 1869 01:42:58,189 --> 01:43:01,893 YOU KNOW, I DO THINK THAT ONE OF 1870 01:43:01,893 --> 01:43:04,663 THE CHALLENGES FOR A LOT OF 1871 01:43:04,663 --> 01:43:06,097 THESE AUTOIMMUNE DISEASES IS IS 1872 01:43:06,097 --> 01:43:09,167 THAT THESE ARE RARE MANFICATIONS 1873 01:43:09,167 --> 01:43:14,139 OR MAYOR EVENTS. 1874 01:43:14,139 --> 01:43:15,974 PARTNERING ACROSS CENTERS TO 1875 01:43:15,974 --> 01:43:17,842 AGGREGATE LARGE NUMBERS OF 1876 01:43:17,842 --> 01:43:19,110 PATIENTS EXPERIENCING THESE 1877 01:43:19,110 --> 01:43:20,578 EVENTS IS CRITICAL TO HAVE 1878 01:43:20,578 --> 01:43:22,313 FURTHER THIS TYPE OF STANDARDY 1879 01:43:22,313 --> 01:43:23,415 LOOKING AT THE CONNECTION 1880 01:43:23,415 --> 01:43:26,251 BETWEEN CANCER AND AUTO AUTO 1881 01:43:26,251 --> 01:43:26,818 IMMUNITY. 1882 01:43:26,818 --> 01:43:30,055 WHETHER WE TAKE PATIENTS WITH 1883 01:43:30,055 --> 01:43:31,456 TRADITIONAL AUTO IMMUNITY 1884 01:43:31,456 --> 01:43:34,659 DISEASES OR PATIENTS WITH 1885 01:43:34,659 --> 01:43:38,430 ADVERSE EVENTS ACROSS MULTIPLE 1886 01:43:38,430 --> 01:43:40,832 SITES, AND THE MULTIPLE 1887 01:43:40,832 --> 01:43:41,833 DISCIPLINARY COOPERATION, I 1888 01:43:41,833 --> 01:43:44,602 THINK ALL OF THAT IS REQUIRED 1889 01:43:44,602 --> 01:43:46,171 TO-US ELUCIDATE THIS AND 1890 01:43:46,171 --> 01:43:54,813 UNDERSTAND MORE. 1891 01:43:54,813 --> 01:43:57,215 >> I THINK AGGRAVATED EVENTS ARE 1892 01:43:57,215 --> 01:43:57,882 RARE. 1893 01:43:57,882 --> 01:44:02,454 AT UCLA WE SEE QUITE THE TAME 1894 01:44:02,454 --> 01:44:03,121 CASES. 1895 01:44:03,121 --> 01:44:06,958 I THINK BEING ABLE TO PARTNER 1896 01:44:06,958 --> 01:44:10,562 WITH MULTIPLE SITES TO STANDARDY 1897 01:44:10,562 --> 01:44:12,163 THIS CONDITION IS VERY IMPORTANT 1898 01:44:12,163 --> 01:44:17,402 AND SO BEING PART OF THIS ACE 1899 01:44:17,402 --> 01:44:19,604 NETWORK HAS BEEN EYE-OPENING FOR 1900 01:44:19,604 --> 01:44:22,741 ME TO SEE HOW WE CAN WORK 1901 01:44:22,741 --> 01:44:25,009 TOGETHER WITH OTHER ACEs 1902 01:44:25,009 --> 01:44:26,010 ACROSS THE COUNTRY. 1903 01:44:26,010 --> 01:44:27,712 I THINK COLLABORATION IS GOING 1904 01:44:27,712 --> 01:44:30,315 TO BE THE KEY TO THAT AND 1905 01:44:30,315 --> 01:44:32,717 GETTING INTO THE MECHANISMS 1906 01:44:32,717 --> 01:44:36,654 UNDERLYING THESE DISEASES. 1907 01:44:36,654 --> 01:44:39,691 >> WHAT I'M HEARING IS WE NEED 1908 01:44:39,691 --> 01:44:45,463 MORE CO CONSORTIA TO COME TOGETR 1909 01:44:45,463 --> 01:44:49,200 BOTH ON THE CASE SAMPLE SIDE AND 1910 01:44:49,200 --> 01:44:55,940 WE NEED SOME BIG DATA GENOMICS 1911 01:44:55,940 --> 01:44:58,443 INVESTIGATIONS AS WELL TO KNOW 1912 01:44:58,443 --> 01:45:00,278 WHAT IS GOING DOWN. 1913 01:45:00,278 --> 01:45:02,580 >> GREAT TIPS FOR US AS WE THINK 1914 01:45:02,580 --> 01:45:03,882 OF ADVANCING THE FIELDS. 1915 01:45:03,882 --> 01:45:05,984 I WANTED TO TACKLE SOME OF THE 1916 01:45:05,984 --> 01:45:07,051 QUESTIONS THROUGH THE CHAT. 1917 01:45:07,051 --> 01:45:08,686 I'M GOING TO MERGE A FEW 1918 01:45:08,686 --> 01:45:10,955 QUESTIONS TO ALLOW US TO COVER 1919 01:45:10,955 --> 01:45:13,224 MORE GROUND. 1920 01:45:13,224 --> 01:45:14,826 FIRSTLY, AND THIS IS OBVIOUSLY 1921 01:45:14,826 --> 01:45:17,061 IMPORTANT TO OUR OFFICE, WE SIT 1922 01:45:17,061 --> 01:45:18,263 WITHIN THE OFFICE EVER RESEARCH 1923 01:45:18,263 --> 01:45:20,098 ON WOMEN'S HEALTH. 1924 01:45:20,098 --> 01:45:23,601 WE KNOW MOST AUTOIMMUNE DISEASES 1925 01:45:23,601 --> 01:45:25,937 ARE MORE COMMON IN WOMEN AND 1926 01:45:25,937 --> 01:45:27,839 THERE ARE PEOPLE IN CLAT 1927 01:45:27,839 --> 01:45:30,074 WONDERING AND I WONDER, WHAT DO 1928 01:45:30,074 --> 01:45:31,776 YOU SEE WHEN YOU LOOK AT THE 1929 01:45:31,776 --> 01:45:32,944 PATIENTS THAT DEVELOP EITHER 1930 01:45:32,944 --> 01:45:36,514 CANCER ASSOCIATED WITH 1931 01:45:36,514 --> 01:45:37,849 AUTOIMMUNE OR THE FLIP THAT 1932 01:45:37,849 --> 01:45:44,222 HAVE, CANCER ALONG WITH 1933 01:45:44,222 --> 01:45:49,460 TEMPERING TEMPERING WITH AUTOIMH 1934 01:45:49,460 --> 01:45:51,629 WOMEN AND CAN YOU THINK OF WHAT 1935 01:45:51,629 --> 01:45:54,365 IS GOING ON? 1936 01:45:54,365 --> 01:45:58,703 >> I THINK ABOUT CANCER INDUCED 1937 01:45:58,703 --> 01:46:00,872 AUTOIMMUNITY IN TERMS OF 1938 01:46:00,872 --> 01:46:02,540 TRADITIONAL RHEUMATIC DISEASES, 1939 01:46:02,540 --> 01:46:05,343 WE DEFINITELY IN OUR REUM TOE 1940 01:46:05,343 --> 01:46:15,920 LSTUDIES WESEE A SEX BIAS BUT WK 1941 01:46:15,920 --> 01:46:19,257 BETWEEN CANCER AND AUTOIMMUNITY 1942 01:46:19,257 --> 01:46:21,092 IN BOTH MEN AND WOMEN. 1943 01:46:21,092 --> 01:46:25,296 WE SEE THOSE ACROSS THE TYPES 1944 01:46:25,296 --> 01:46:29,801 INCLUDING THOSE ENRICHED IN 1945 01:46:29,801 --> 01:46:32,837 MACHINE LIKE PROSTATE CANCER AND 1946 01:46:32,837 --> 01:46:39,611 WOMEN WHICH IS BREAST CASTER. C. 1947 01:46:39,611 --> 01:46:42,580 I DON'T THINK WE TEND TO SEE 1948 01:46:42,580 --> 01:46:45,283 THAT SAME SEX BIAS IN TERMS OF 1949 01:46:45,283 --> 01:46:48,786 THE PEOPLE PRESENTED WITH 1950 01:46:48,786 --> 01:46:52,123 RHEUMATIC PHENOTYPES INCLUDING 1951 01:46:52,123 --> 01:46:52,824 INFLAMMATORY ARTHRITIS. 1952 01:46:52,824 --> 01:46:57,495 I THINK WHEN DR. ANDERSON SAID 1953 01:46:57,495 --> 01:47:03,434 ARE THESE TRUE AUTOIMMUNE 1954 01:47:03,434 --> 01:47:03,701 DISEASES? 1955 01:47:03,701 --> 01:47:05,370 THERE ARE DIFFERENCES BETWEEN 1956 01:47:05,370 --> 01:47:09,307 THE TRADITIONAL AND DISEASES. 1957 01:47:09,307 --> 01:47:17,115 I'LL PASS TO DR. SU. 1958 01:47:17,115 --> 01:47:22,921 >> THE RATIO OF MALES TO FEMALED 1959 01:47:22,921 --> 01:47:27,191 AFFECTED IS 5 TO 1 SO VERY 1960 01:47:27,191 --> 01:47:28,159 BIASED. 1961 01:47:28,159 --> 01:47:33,264 IT'S FEMALE BIASED BUT MUCH LESS 1962 01:47:33,264 --> 01:47:33,698 SO. 1963 01:47:33,698 --> 01:47:36,334 IT SEEMS TO NOT BE AS DRAMATIC 1964 01:47:36,334 --> 01:47:39,037 AS WITH SPONTANEOUS THYROID 1965 01:47:39,037 --> 01:47:39,704 DISEASE. 1966 01:47:39,704 --> 01:47:41,406 WHAT IS UNDERLYING THAT IS THE 1967 01:47:41,406 --> 01:47:42,473 QUESTION THAT WE'RE INTERESTED 1968 01:47:42,473 --> 01:47:43,041 IN. 1969 01:47:43,041 --> 01:47:44,575 I THINK IT'S A WINDOW INTO 1970 01:47:44,575 --> 01:47:47,845 UNDERSTANDING WHAT IS CAUSING 1971 01:47:47,845 --> 01:47:50,114 THIS SPONTANEOUS DISEASE. 1972 01:47:50,114 --> 01:47:53,251 UTX IS ACTUALLY ON THE X 1973 01:47:53,251 --> 01:47:56,020 CHROMOSOME AND THAT IS WHAT IS 1974 01:47:56,020 --> 01:47:57,121 INTERESTING. 1975 01:47:57,121 --> 01:47:59,490 IT'S OVEREXPRESSIONED IN FEMALES 1976 01:47:59,490 --> 01:48:01,225 RATHER THAN MALES SO WE THINK 1977 01:48:01,225 --> 01:48:04,729 THAT MAY BE UNDERLYING THE SEX 1978 01:48:04,729 --> 01:48:06,464 DIFFERENCES WE SEE IN OTHER 1979 01:48:06,464 --> 01:48:15,740 IMMUNE CONDITIONS LIKE AN TROA X 1980 01:48:15,740 --> 01:48:16,307 DEPENDENTS. 1981 01:48:16,307 --> 01:48:21,813 THIS IS IMPORTANT TO ADDRESS. 1982 01:48:21,813 --> 01:48:23,815 DIABETES AND THYROID DISEASE 1983 01:48:23,815 --> 01:48:26,250 RELATED TO EXEC POINT INHIBITOR 1984 01:48:26,250 --> 01:48:29,654 IS THOUGHT TO BE A CHRONIC 1985 01:48:29,654 --> 01:48:30,621 CONDITION. 1986 01:48:30,621 --> 01:48:33,358 WINDOW DON'T THINK IT'S 1987 01:48:33,358 --> 01:48:37,428 REVERSIBLE EVEN WITH THE 1988 01:48:37,428 --> 01:48:40,164 DISCONTINUATION OF THE 1989 01:48:40,164 --> 01:48:43,501 CHECKPOINT INTRIBUTERS. 1990 01:48:43,501 --> 01:48:44,702 ONE -- INHIBITORS. 1991 01:48:44,702 --> 01:48:46,771 ONE OF THE THINGS WE'RE 1992 01:48:46,771 --> 01:48:49,307 INTERESTED IN IS WHETHER THE 1993 01:48:49,307 --> 01:48:58,983 LONG LIFE CELLS ARE INTERPRETING 1994 01:48:58,983 --> 01:49:00,084 THIS. 1995 01:49:00,084 --> 01:49:02,053 I'LL STOP THERE. 1996 01:49:02,053 --> 01:49:03,821 >> I MOON I THINK YOUR POINT 1997 01:49:03,821 --> 01:49:07,058 ABOUT THE STEM-LIKE T CELLS IS 1998 01:49:07,058 --> 01:49:09,761 WELL-TAKEN BUT I ONE DR IF IT'S 1999 01:49:09,761 --> 01:49:11,429 ABOUT THE TRIGGERS THAT MAKE 2000 01:49:11,429 --> 01:49:14,032 THOSE CELLS DIFFERENTIATE AND 2001 01:49:14,032 --> 01:49:15,900 HOW THEY DIFFERENTIATE. 2002 01:49:15,900 --> 01:49:17,935 THEY'RE NOT DESTINED TO BE BAD 2003 01:49:17,935 --> 01:49:19,037 CELLS. 2004 01:49:19,037 --> 01:49:20,204 WE NEED TO KNOW MORE ABOUT 2005 01:49:20,204 --> 01:49:21,839 CONTEXT AND WHAT MAKES THEM 2006 01:49:21,839 --> 01:49:23,608 BECOME ONE OR THE OTHER. 2007 01:49:23,608 --> 01:49:28,780 REGARDING THE SEX BIAS, IT'S 2008 01:49:28,780 --> 01:49:30,815 CURIOUS THAT FROM THE CANCER 2009 01:49:30,815 --> 01:49:32,316 PERSPECTIVE, CANCER IS MORE 2010 01:49:32,316 --> 01:49:36,054 ADDRESSIVE IN MEN. 2011 01:49:36,054 --> 01:49:38,656 BUT MEN OR MALES TEND TO RESPOND 2012 01:49:38,656 --> 01:49:40,291 BETTER TO IMMUNOTHERAPY. 2013 01:49:40,291 --> 01:49:43,795 THERE IS ACTUALLY SOME DATA TO 2014 01:49:43,795 --> 01:49:48,633 PLAIN EXPLAIN WHY AND IT HAS TOO 2015 01:49:48,633 --> 01:49:52,070 WITH THE AN TROA JEN RECEPTOR. 2016 01:49:52,070 --> 01:49:56,974 WHEN IT FUNCTIONS, IT FUNCTION 2017 01:49:56,974 --> 01:50:01,212 AS A TRANSCRIPTION FACTOR AND. 2018 01:50:01,212 --> 01:50:02,647 THERE WERE QUIEPT A FEW PAIPS 2019 01:50:02,647 --> 01:50:06,184 THAT ARE CAME IN THE LITERATURE 2020 01:50:06,184 --> 01:50:08,853 FROM MULTIPLE LABS THAT WERE ALL 2021 01:50:08,853 --> 01:50:11,589 HITTING AT THIS QUESTION OF -- 2022 01:50:11,589 --> 01:50:14,425 HINTING AT THE QUESTION OF 2023 01:50:14,425 --> 01:50:17,795 MALE/FEMALE BIAS IN RESPONSE TO 2024 01:50:17,795 --> 01:50:19,964 IMMUIMMUNOTHERAPY. 2025 01:50:19,964 --> 01:50:22,366 I THINK IT'S A LOT MORE 2026 01:50:22,366 --> 01:50:24,001 COMPLICATED THAN WE APPRECIATE. 2027 01:50:24,001 --> 01:50:26,604 I THINK WE NEED TO DO A LOT MORE 2028 01:50:26,604 --> 01:50:27,171 RESEARCH. 2029 01:50:27,171 --> 01:50:29,574 IT MAY NOT ALWAYS -- DEPENDING 2030 01:50:29,574 --> 01:50:33,845 ON THE TISH EWE AND CANCER TYPE 2031 01:50:33,845 --> 01:50:37,648 AND, THERE MAY BE OTHER 2032 01:50:37,648 --> 01:50:39,050 VARIABLES WE NEED TO THINK 2033 01:50:39,050 --> 01:50:39,650 ABOUT. 2034 01:50:39,650 --> 01:50:41,018 >> THAT'S GREAT BECAUSE IT LEADS 2035 01:50:41,018 --> 01:50:43,020 ME INTO MY NEXT QUESTION FOR THE 2036 01:50:43,020 --> 01:50:45,690 THREE OF YOU WHICH IS A FAIRLY 2037 01:50:45,690 --> 01:50:46,224 BROAD QUESTION. 2038 01:50:46,224 --> 01:50:48,526 I'M GOING TO ASK YOU TO 2039 01:50:48,526 --> 01:50:50,261 SPECULATE A LITTLE BIT AND 2040 01:50:50,261 --> 01:50:53,164 TELLING YOU WHAT YOU THINK THE 2041 01:50:53,164 --> 01:50:55,066 FIELD NEEDS IN ORDER TO AERNAS 2042 01:50:55,066 --> 01:50:58,336 SOME OF -- HARNESS SOMENT OF 2043 01:50:58,336 --> 01:50:59,203 THIS TECHNOLOGY. 2044 01:50:59,203 --> 01:51:01,139 THAT PERTAINS TO THE ISSUE OF IF 2045 01:51:01,139 --> 01:51:03,908 WE WANT TO BE ABLE TO USE THESE 2046 01:51:03,908 --> 01:51:08,913 ME ELECTRIC LAR DIAGNOSTIC 2047 01:51:08,913 --> 01:51:11,182 TECHNIQUES, THEY IDENTIFY BEST 2048 01:51:11,182 --> 01:51:12,450 TREATMENT FOR SPECIFIC 2049 01:51:12,450 --> 01:51:16,621 INDIVIDUALS BOTH IN CANCER IN 2050 01:51:16,621 --> 01:51:17,555 AUTOIMMUNITY. 2051 01:51:17,555 --> 01:51:20,358 WHAT DO WE NEED TO DO TO ADVANCE 2052 01:51:20,358 --> 01:51:22,460 THAT SCIENCE BOTH FROM A 2053 01:51:22,460 --> 01:51:23,961 STRUCTURAL POINT OF VIEW, 2054 01:51:23,961 --> 01:51:25,596 INFRASTRUCTURE POINT OF VIEW AND 2055 01:51:25,596 --> 01:51:28,466 WHAT IS NEEDED TO ADVANCE THIS 2056 01:51:28,466 --> 01:51:28,799 FIELD. 2057 01:51:28,799 --> 01:51:31,569 DR. SHAH. 2058 01:51:31,569 --> 01:51:34,438 >> I THINK A LOT OF THIS DOES 2059 01:51:34,438 --> 01:51:39,443 TIE INTO HAVING MULTI-CENTER 2060 01:51:39,443 --> 01:51:41,846 CONSORTIA THAT CAN AGGRAVATE 2061 01:51:41,846 --> 01:51:43,714 LARGE VOLUMES OF PATIENTS 2062 01:51:43,714 --> 01:51:44,849 EXPERIENCING THESE CRITICAL 2063 01:51:44,849 --> 01:51:47,885 EVENTS IN TISSUES TARGETED BY 2064 01:51:47,885 --> 01:51:55,293 THE IMMUNE RESPONSE AND BU 2065 01:51:55,293 --> 01:51:57,395 BIOSPECIMENS AND IT'S CRITICAL 2066 01:51:57,395 --> 01:51:59,397 TO ENABLE THE REST OF THIS WORK 2067 01:51:59,397 --> 01:51:59,964 TO HAPPEN. 2068 01:51:59,964 --> 01:52:03,568 I THINK ONE FEATURE OF ALL OF 2069 01:52:03,568 --> 01:52:11,242 THIS IS THE HETEROGENEITY. 2070 01:52:11,242 --> 01:52:13,110 THE DEMOGRAPHICS OF YOUR 2071 01:52:13,110 --> 01:52:15,313 PATIENTS, THE CLINICAL 2072 01:52:15,313 --> 01:52:18,049 MANIFESTATIONS AND SUBSETS OF 2073 01:52:18,049 --> 01:52:27,425 PATIENTS, THERE IS MET MET HET E 2074 01:52:27,425 --> 01:52:34,832 JHETEROGENEITY. 2075 01:52:34,832 --> 01:52:36,701 YOU NEED TO LOOK AT THE 2076 01:52:36,701 --> 01:52:39,870 SUBGROUPS THAT BEE HAICH 2077 01:52:39,870 --> 01:52:42,206 DIFFERENTLY TO TEASE SOME OF THE 2078 01:52:42,206 --> 01:52:42,773 THINGS APART. 2079 01:52:42,773 --> 01:52:45,643 I THINK THE COLLABORATION ACROSS 2080 01:52:45,643 --> 01:52:46,944 GROUPS AND BUILDING THE 2081 01:52:46,944 --> 01:52:48,379 INFRASTRUCTURE IS CRITICAL. 2082 01:52:48,379 --> 01:52:50,982 I WILL SEE IN RHEUMATOLOGY, WE 2083 01:52:50,982 --> 01:52:54,685 HAVE A NATIONWIDE SCORE SHOM 2084 01:52:54,685 --> 01:52:58,155 WITH PATIENTS WITH AUTOIMMUNE 2085 01:52:58,155 --> 01:52:59,924 ADVERSE EVENTS BECAUSE IT WILL 2086 01:52:59,924 --> 01:53:01,192 TAKE MULTIPLE PEOPLE 2087 01:53:01,192 --> 01:53:02,159 COLLABORATING TOGETHER TO CRACK 2088 01:53:02,159 --> 01:53:02,827 THIS OPEN. 2089 01:53:02,827 --> 01:53:04,262 I THINK IT'S AN IMPORTANT 2090 01:53:04,262 --> 01:53:11,369 OPPORTUNITY. 2091 01:53:11,369 --> 01:53:13,504 >> I THINK WE WERE HAVING DINNER 2092 01:53:13,504 --> 01:53:16,340 THE OTHER DAY AND THINKING ABOUT 2093 01:53:16,340 --> 01:53:19,977 WHAT WE WISH FOR IF WE COULD TO 2094 01:53:19,977 --> 01:53:22,046 CRACK OPEN THESE QUESTIONS 2095 01:53:22,046 --> 01:53:23,214 TECHNOLOGICALLY. 2096 01:53:23,214 --> 01:53:26,250 AND I THINK WHAT'S BEEN REALLY 2097 01:53:26,250 --> 01:53:30,154 EYE-OPENING FOR ME ARE THE 2098 01:53:30,154 --> 01:53:32,623 SINGLE-CELL TECHNOLOGIES THAT 2099 01:53:32,623 --> 01:53:37,962 HAVE BECOME AVAILABLE. 2100 01:53:37,962 --> 01:53:40,898 IT'S BEEN REALLY POWERFUL TO BE 2101 01:53:40,898 --> 01:53:46,937 ABLE TO LOOK AT T-CELL RESPECTER 2102 01:53:46,937 --> 01:53:47,672 CHROMEALITY. 2103 01:53:47,672 --> 01:53:51,108 AS THE COSTS COME DOWN, HOW CAN 2104 01:53:51,108 --> 01:53:54,478 WE USE TS SINGLE-CELL 2105 01:53:54,478 --> 01:53:56,247 TECHNOLOGIES TO CHARACTERIZE 2106 01:53:56,247 --> 01:53:58,883 THESE ADVERSE POPULATIONS AND TO 2107 01:53:58,883 --> 01:54:01,052 PERHAPS FIND MARKERS FOR 2108 01:54:01,052 --> 01:54:05,589 PREDICTING THE ONSET OF IRAEs 2109 01:54:05,589 --> 01:54:07,725 WITH CHECKPOINT INHIBITOR 2110 01:54:07,725 --> 01:54:08,426 THERAPIES. 2111 01:54:08,426 --> 01:54:11,495 IT'S BEEN AMAZING HOW QUICKLY 2112 01:54:11,495 --> 01:54:14,799 SINGLE CELL TECHNOLOGIES HAVE 2113 01:54:14,799 --> 01:54:20,638 CHANGED AND IECH I'VE ENJOYED G 2114 01:54:20,638 --> 01:54:22,640 THEM TO UNDERSTAND WHAT HAS BEEN 2115 01:54:22,640 --> 01:54:26,210 GOING ON IN TISSUES OF INTEREST. 2116 01:54:26,210 --> 01:54:27,745 LOOKING FORWARD TO WHERE THAT IS 2117 01:54:27,745 --> 01:54:30,514 GOING. 2118 01:54:30,514 --> 01:54:33,250 >> SO I WOULD LIKE TO BUILD ON 2119 01:54:33,250 --> 01:54:37,154 WHAT DR. SU JUST SAID. 2120 01:54:37,154 --> 01:54:40,558 AND WHAT I THINK WE NEED TO DO 2121 01:54:40,558 --> 01:54:43,294 IS BUILD ON EFFORTS SUCH AS LIKE 2122 01:54:43,294 --> 01:54:45,996 THE HUMAN CELL ATLAS WHICH WAS A 2123 01:54:45,996 --> 01:54:49,166 LARGE EFFORT TO JUST PROFILE 2124 01:54:49,166 --> 01:54:51,235 NORMAL CELLS AND TISSUES. 2125 01:54:51,235 --> 01:54:53,637 NOW THAT WE HAVE THAT 2126 01:54:53,637 --> 01:54:57,441 INFORMATION, WE CAN BUILD BUILDN 2127 01:54:57,441 --> 01:55:01,379 THAT AND PROFILE CELLS IN 2128 01:55:01,379 --> 01:55:04,682 ABNORMAL TISSUES WERE THEY'RE 2129 01:55:04,682 --> 01:55:08,185 CONVENTIONAL RA OR CHECKPOINT 2130 01:55:08,185 --> 01:55:09,553 INDUCED RUE MADDIC INVESTIGATION 2131 01:55:09,553 --> 01:55:13,257 OR WHETHER IT'S CLASSICAL SORE 2132 01:55:13,257 --> 01:55:17,228 PSORIASIS OR CHECKPOINT 2133 01:55:17,228 --> 01:55:23,234 DETERMDERMATITIS. 2134 01:55:23,234 --> 01:55:25,603 WE NEED TO ALSO THINK ABOUT THE 2135 01:55:25,603 --> 01:55:26,604 GENETICS OF THE INDIVIDUAL. 2136 01:55:26,604 --> 01:55:29,640 WOVE A LOT OF INFORMATION 2137 01:55:29,640 --> 01:55:32,309 AVAILABLE TO US THAT WE COULD 2138 01:55:32,309 --> 01:55:35,045 REALLY LEVERAGE TO SEE IS THERE 2139 01:55:35,045 --> 01:55:37,314 A PATTERN WHERE INDIVIDUALS THAT 2140 01:55:37,314 --> 01:55:48,592 HAVE CERTAIN SINGLE NUKE LA TYPO 2141 01:56:04,508 --> 01:56:06,644 TYPES. 2142 01:56:06,644 --> 01:56:07,845 >> I APPRECIATE EVERYBODY'S TIME 2143 01:56:07,845 --> 01:56:08,879 JOINING US TOAD. 2144 01:56:08,879 --> 01:56:11,115 I'M GOING TO START TO WRAP UP 2145 01:56:11,115 --> 01:56:13,184 BECAUSE WE ONLY HAVE A COUPLE 2146 01:56:13,184 --> 01:56:14,685 MINUTES LEFT. 2147 01:56:14,685 --> 01:56:18,422 AS MIKE PULLS UP THE SLIDES, I 2148 01:56:18,422 --> 01:56:20,558 WANTED TO GIVE A FEW PLUGS FOR 2149 01:56:20,558 --> 01:56:25,262 THINGS GOING ON IN THE LIFE OF 2150 01:56:25,262 --> 01:56:26,230 THE AUTOIMMUNE RESEARCH. 2151 01:56:26,230 --> 01:56:28,466 ONE IS OUR REGULAR QUARTERLY 2152 01:56:28,466 --> 01:56:30,901 UPDATES ON THE OFFICE ACTIVITIES 2153 01:56:30,901 --> 01:56:34,171 CALLED UPDATES ON OADR. 2154 01:56:34,171 --> 01:56:36,240 IT'S OPEN TO ANYONE. 2155 01:56:36,240 --> 01:56:38,776 EVENT PAGE FOR THE UP COMING 2156 01:56:38,776 --> 01:56:42,913 EVENT ON JANUARY 31ST CAN BE 2157 01:56:42,913 --> 01:56:45,115 ACTIVATED THROUGH THE QR CODES. 2158 01:56:45,115 --> 01:56:48,118 THIS WILL BEING HELD FROM NOON 2159 01:56:48,118 --> 01:56:51,822 TO 12:45 ON THE 31ST OF JANUARY. 2160 01:56:51,822 --> 01:56:53,657 TYPICALLY I WILL GIVE I BRIEF 2161 01:56:53,657 --> 01:56:55,893 UPDATE ON OFFICE AND WHAT WE'VE 2162 01:56:55,893 --> 01:56:57,595 BEEN DOING SINCE THE LAST UPDATE 2163 01:56:57,595 --> 01:56:59,296 TO THE COMMUNITY AND THEN THERE 2164 01:56:59,296 --> 01:57:02,032 IS A FORUM THAT ALLOWS US TO LET 2165 01:57:02,032 --> 01:57:03,868 COMMUNITY MEMBERS UNMUTE AND 2166 01:57:03,868 --> 01:57:05,336 TELL US WHAT IS GOING ON IN THE 2167 01:57:05,336 --> 01:57:10,541 LIFE OF THEIR ADVOCACY GROUP OR 2168 01:57:10,541 --> 01:57:11,876 AREA OF INTEREST THEY WANT TO 2169 01:57:11,876 --> 01:57:13,277 SHARE WITH THE COMMUNITY. 2170 01:57:13,277 --> 01:57:16,647 WE ALWAYS HAVE A NICE DIALOGUE 2171 01:57:16,647 --> 01:57:18,048 AT THAT EVENT AND I WANT TO MAKE 2172 01:57:18,048 --> 01:57:22,753 SURE THAT THE UP COMING DATES ON 2173 01:57:22,753 --> 01:57:25,723 YOUR RADAR -- UP COME TOKING 2174 01:57:25,723 --> 01:57:27,992 DATES ARE ON YOUR RADAR. 2175 01:57:27,992 --> 01:57:30,294 THE NEXT EVENT PUT INTO YOUR 2176 01:57:30,294 --> 01:57:33,130 CALENDARS FOR 2025 IS THE NEXT 2177 01:57:33,130 --> 01:57:34,798 SCIENCE TALKS EVENT WHICH WILL 2178 01:57:34,798 --> 01:57:37,535 BE ON MARCH 4TH FROM NOON TO 2179 01:57:37,535 --> 01:57:39,036 2:00 P.M. 2180 01:57:39,036 --> 01:57:42,172 AND WE'LL BE LOOKING AT CELL 2181 01:57:42,172 --> 01:57:44,675 THERAPIES AND KIND OF DIE 2182 01:57:44,675 --> 01:57:46,744 SEGGING THE POTENTIAL OF THESE 2183 01:57:46,744 --> 01:57:49,513 THERAPIES FOR BOTH TREATING 2184 01:57:49,513 --> 01:57:51,649 AUTOIMMUNE DISEASES AND WHAT IS 2185 01:57:51,649 --> 01:57:54,752 NEEDED TO ADVANCE THE SCIENCE OF 2186 01:57:54,752 --> 01:57:57,121 THESE TREATMENTS FOR AUTOIMMUNE 2187 01:57:57,121 --> 01:57:57,688 DISEASE. 2188 01:57:57,688 --> 01:57:59,323 I HOPE YOU CAN JOIN US AND WE 2189 01:57:59,323 --> 01:58:01,659 LOOK FORWARD TO A GRIT SESSION. 2190 01:58:01,659 --> 01:58:03,360 FINALLY, THE SCIENCE TALK 2191 01:58:03,360 --> 01:58:05,629 SESSION WILL BE PART OF A LARGER 2192 01:58:05,629 --> 01:58:11,468 CADRE EVER ACTIVI OF ACTIVITY FS 2193 01:58:11,468 --> 01:58:12,202 THIS MONTH. 2194 01:58:12,202 --> 01:58:14,371 IF YOU CAN WATCH YOUR CALENDARS 2195 01:58:14,371 --> 01:58:16,807 FOR POTENTIAL EVENTS COMING UP 2196 01:58:16,807 --> 01:58:19,910 IN MARCH 2025, WE HAVE A FULL 2197 01:58:19,910 --> 01:58:23,080 DOCKET OF ACTIVITIES PLANNED. 2198 01:58:23,080 --> 01:58:24,648 PLEASE SIGN UP FOR THE 2199 01:58:24,648 --> 01:58:26,150 E-MAILS. 2200 01:58:26,150 --> 01:58:29,186 THE QR CODE FOR THIS SLIDE IS TO 2201 01:58:29,186 --> 01:58:32,790 LET YOU SIGN UP THROUGH OUR LIST 2202 01:58:32,790 --> 01:58:33,223 SERVE. 2203 01:58:33,223 --> 01:58:36,860 YOU DO HAVE TO SCROLL DOWN ON 2204 01:58:36,860 --> 01:58:40,531 THE SIGN-UP SCREEN TO CLICK THE 2205 01:58:40,531 --> 01:58:42,533 BUTTON FOR RESEARCH IF YOU WOULD 2206 01:58:42,533 --> 01:58:43,867 LIKE TO RECEIVE THE UPDATE 2207 01:58:43,867 --> 01:58:45,169 PACIFIC TO OUR OFFICE. 2208 01:58:45,169 --> 01:58:47,838 THAT WAY, YOU'LL GET THE SIGN 2209 01:58:47,838 --> 01:58:49,807 UPS AS SOON AS THEY OCCUR. 2210 01:58:49,807 --> 01:58:51,575 WE'RE ALWAYS HAPPY TO SEE AS 2211 01:58:51,575 --> 01:58:54,011 MANY MEMBERS AS CAN JOIN THOSE 2212 01:58:54,011 --> 01:58:54,812 SESSIONS. 2213 01:58:54,812 --> 01:58:57,514 SO WITH THAT, I REALLY WANT TO 2214 01:58:57,514 --> 01:58:59,650 GIVE A HUGE ROUND OF APPLAUSE TO 2215 01:58:59,650 --> 01:59:00,784 OUR SPEAKERS TODAY. 2216 01:59:00,784 --> 01:59:03,454 THANK YOU SO MUCH TO ALL OF YOU 2217 01:59:03,454 --> 01:59:06,390 FOR SHARING YOUR SCIENCE, 2218 01:59:06,390 --> 01:59:09,793 SHARING YOUR VISION FOR THIS 2219 01:59:09,793 --> 01:59:10,427 FIELD. 2220 01:59:10,427 --> 01:59:12,730 I WANT TO THANK YOU TO THE 2221 01:59:12,730 --> 01:59:14,131 MODERATORS AND HELPING US PUT 2222 01:59:14,131 --> 01:59:15,466 THIS EVENT TOGETHER AND 2223 01:59:15,466 --> 01:59:16,767 MODERATING THE QUESTIONS. 2224 01:59:16,767 --> 01:59:18,902 AND THEN WE'RE ALWAYS HAPPY TO 2225 01:59:18,902 --> 01:59:20,771 HEAR FROM THE COMMUNITY, SO YOU 2226 01:59:20,771 --> 01:59:22,406 WOULD LIKE TO CONNECT WITH US, 2227 01:59:22,406 --> 01:59:26,010 OUR WEBSITE IS ON THIS SLIDE AND 2228 01:59:26,010 --> 01:59:27,811 WE'RE HAPPY TO FIELD QUESTIONS 2229 01:59:27,811 --> 01:59:28,412 FROM THE GROUP. 2230 01:59:28,412 --> 01:59:30,381 THANK YOU SO MUCH FOR LISTENING. 2231 01:59:30,381 --> 01:59:40,791 HAVE A GREAT AFTERNOON.