1 00:00:05,280 --> 00:00:10,000 >>MY NAME IS 2 00:00:10,000 --> 00:00:14,720 TAKEO FUJIII, WOMEN'S MALIGNANCY 3 00:00:14,720 --> 00:00:18,360 BRANCH NCI. IT IS 1 P.M. SO WE 4 00:00:18,360 --> 00:00:23,600 WILL START OUR SECOND LECTURE 5 00:00:23,600 --> 00:00:24,080 SESSION FROM CLINICAL 6 00:00:24,080 --> 00:00:27,440 (INAUDIBLE). I'M HONORED TO 7 00:00:27,440 --> 00:00:29,080 MODERATE THIS SESSION AND WE 8 00:00:29,080 --> 00:00:31,000 WILL START FROM DR. WARNER'S 9 00:00:31,000 --> 00:00:33,280 PRESENTATION. SO LET'S INTRODUCE 10 00:00:33,280 --> 00:00:35,000 DR. BLAKE WARNER. HE RECEIVED 11 00:00:35,000 --> 00:00:39,720 HIS DDS Ph.D. AT THE OHIO 12 00:00:39,720 --> 00:00:42,440 STATE UNIVERSITY IN SUBSEQUENTLY 13 00:00:42,440 --> 00:00:44,560 COMPLETED A CLINICAL RESIDENCY 14 00:00:44,560 --> 00:00:46,800 IN ORAL MAXILLO FACIAL PATHOLOGY 15 00:00:46,800 --> 00:00:50,320 AT THE UNIVERSITY OF PITTSBURG 16 00:00:50,320 --> 00:00:51,520 AND BOARD CERTIFIED. HE 17 00:00:51,520 --> 00:00:52,960 COMPLETED THE POST-DOCTORAL 18 00:00:52,960 --> 00:00:56,840 CLINICAL RESEARCH FELLOWSHIP IN 19 00:00:56,840 --> 00:01:00,760 (INAUDIBLE) LAB NIDCR FOCUSED ON 20 00:01:00,760 --> 00:01:02,520 TRANSLATIONAL INVESTIGATION IN 21 00:01:02,520 --> 00:01:04,480 SJOGREN'S DISEASE AND RADIATION 22 00:01:04,480 --> 00:01:06,840 INDUCED DYSTONIA. IN 2018 DR. 23 00:01:06,840 --> 00:01:10,400 WARNER WAS APPOINTED ACTING 24 00:01:10,400 --> 00:01:14,200 CHIEF OF THE SJOGREN'S DISEASE 25 00:01:14,200 --> 00:01:16,960 CLINIC AND 2019 ASSOCIATE 26 00:01:16,960 --> 00:01:19,920 CLINICAL INVESTIGATOR AND WAS 27 00:01:19,920 --> 00:01:20,640 APPOINTED CHIEF OF THE 28 00:01:20,640 --> 00:01:22,200 (INAUDIBLE) DISORDERS IN 29 00:01:22,200 --> 00:01:26,640 SJOGREN'S DISEASE CLINIC. DR. 30 00:01:26,640 --> 00:01:28,320 WARNER IS A MULTI-SPECIALTY 31 00:01:28,320 --> 00:01:31,280 CLINIC AND ALLOWED FOCUSED ON 32 00:01:31,280 --> 00:01:33,200 DEEP CHARACTERIZATION OF 33 00:01:33,200 --> 00:01:36,640 SJOGREN'S DISEASE AND OTHER 34 00:01:36,640 --> 00:01:38,200 PATHOLOGY, OBJECTIVE OF HIS 35 00:01:38,200 --> 00:01:41,600 RESEARCH PROGRAM IS AIMED AT 36 00:01:41,600 --> 00:01:43,280 DEFINE SJOGREN'S SPECIFIC SOLAR 37 00:01:43,280 --> 00:01:45,440 AND MOLECULAR INTERACTIONS 38 00:01:45,440 --> 00:01:47,400 BETWEEN SALIVARY EPITHELIAL AND 39 00:01:47,400 --> 00:01:48,320 INFLAMMATORY CELLS POPULATION. 40 00:01:48,320 --> 00:01:50,360 IN THE TRANSLATIONAL NOVEL 41 00:01:50,360 --> 00:01:51,120 THERAPEUTICS STRATEGIES TO 42 00:01:51,120 --> 00:01:55,440 HUMANS. SO TODAY'S DR. WARN 43 00:01:55,440 --> 00:01:56,520 NEAR'S PRESENTATION TITLE IS 44 00:01:56,520 --> 00:01:58,160 APPLIED OMIC IDENTIFIERS 45 00:01:58,160 --> 00:02:03,160 TARGETED THERAPIES FO FOR SJOGRS 46 00:02:03,160 --> 00:02:07,760 DISEASE. 47 00:02:07,760 --> 00:02:10,440 >>DR. FUJIII, THANK YOU FOR 48 00:02:10,440 --> 00:02:11,800 THAT WARM INTRODUCTION. AGAIN, 49 00:02:11,800 --> 00:02:14,880 MY NAME IS BLAKE WARNER, 50 00:02:14,880 --> 00:02:15,680 ASSISTANT CLINICAL INVESTIGATOR. 51 00:02:15,680 --> 00:02:16,800 HOPEFULLY I WILL CHANGE THAT 52 00:02:16,800 --> 00:02:19,360 VERY SOON TO TENURE TRACK 53 00:02:19,360 --> 00:02:22,120 CLINICAL INVESTIGATOR. SO WHAT 54 00:02:22,120 --> 00:02:24,320 IS AN ORAL MAX OWE FACIAL 55 00:02:24,320 --> 00:02:26,760 PATHOLOGIST? LIKE MOLECULAR 56 00:02:26,760 --> 00:02:28,560 PATHOLOGIST I USE PATHOLOGY OR 57 00:02:28,560 --> 00:02:31,560 THE MICROSCOPE AS MY TOOL OF 58 00:02:31,560 --> 00:02:32,800 CLINICAL INVESTIGATION. BUT 59 00:02:32,800 --> 00:02:35,760 UNLIKE ANATOMIC PATHOLOGY I USE 60 00:02:35,760 --> 00:02:36,680 CLINICAL INVESTIGATION DIRECTLY 61 00:02:36,680 --> 00:02:38,720 IN THE ORAL CAVITY AND HEAD AND 62 00:02:38,720 --> 00:02:40,480 NECK REGION TO UNDERSTAND 63 00:02:40,480 --> 00:02:42,480 DISEASES AND DISEASE PROCESSES 64 00:02:42,480 --> 00:02:45,280 THAT AFFECT THE MOUTH. I BECAME 65 00:02:45,280 --> 00:02:46,520 FASCINATE WITH THE SALIVARY 66 00:02:46,520 --> 00:02:48,120 GLANDS BECAUSE I SAW THE 67 00:02:48,120 --> 00:02:49,360 CONNECTION BETWEEN THE FUNCTION 68 00:02:49,360 --> 00:02:52,040 OF AN ORGAN, THAT IS THE 69 00:02:52,040 --> 00:02:53,160 SALIVARY GLANDS AND 70 00:02:53,160 --> 00:02:56,680 IMMUNOPATHOLOGY UNDERLYING THAT 71 00:02:56,680 --> 00:03:02,080 DYSFUNCTION. THE SALIVARY 72 00:03:02,080 --> 00:03:03,760 DISORDERS UNITS STUDIES INSULTS 73 00:03:03,760 --> 00:03:05,080 AND INJURIES TO THE SALIVARY 74 00:03:05,080 --> 00:03:07,720 COMPLEX. DESPITE MODERN TYPES 75 00:03:07,720 --> 00:03:10,280 OF INSULTS THAT OCCUR THEY SEEM 76 00:03:10,280 --> 00:03:12,600 TO MANIFEST WITH THE SAME 77 00:03:12,600 --> 00:03:15,400 CLINICAL STIGMATA INCLUDING 78 00:03:15,400 --> 00:03:17,400 INCREASE PROPENSITY FOR ORAL 79 00:03:17,400 --> 00:03:21,240 INFECTION INCLUDING TALL CARRIES 80 00:03:21,240 --> 00:03:24,240 OF ORAL CANDIDIASIS BUT ALL HAVE 81 00:03:24,240 --> 00:03:26,520 UNDERLYING PATHOPHYSIOLOGIC 82 00:03:26,520 --> 00:03:27,520 MECHANISMS AND TO UNDERSTAND THE 83 00:03:27,520 --> 00:03:28,680 DIFFERENT MECHANISMS WE DON'T 84 00:03:28,680 --> 00:03:30,000 YET HAVE ANY EFFECTIVE 85 00:03:30,000 --> 00:03:32,840 MODALITIES TO PREVENT TREAT OR 86 00:03:32,840 --> 00:03:37,360 REVERSAL VARY GLAND DYSFUNCT DY. 87 00:03:37,360 --> 00:03:38,920 DESPITE A MULTIPLE OF DIFFERENT 88 00:03:38,920 --> 00:03:40,760 CLINICAL STATES WE STUDY WE DO 89 00:03:40,760 --> 00:03:42,800 FOCUS EFFORTS ON SJOGREN'S 90 00:03:42,800 --> 00:03:44,360 DISEASE SPECIFICALLY IN TRYING 91 00:03:44,360 --> 00:03:46,080 TO UNDERSTAND PATHOPHYSIOLOGY OF 92 00:03:46,080 --> 00:03:51,920 THAT DISEASE. SJOGREN'S DISEASE 93 00:03:51,920 --> 00:03:55,040 IS A SUCCINCT CHRONIC AUTOIMMUNE 94 00:03:55,040 --> 00:03:56,520 DISEASE THAT AFFECTED 3 MILLION 95 00:03:56,520 --> 00:03:57,840 PERSONS IN THE UNITED STATES 96 00:03:57,840 --> 00:04:01,200 WHICH ARE OVERWOMENNINGLY WOMEN 97 00:04:01,200 --> 00:04:03,640 WITH PREDILECTION OF 901. 98 00:04:03,640 --> 00:04:05,400 INDIVIDUALS ARE DIAGNOSED OVER 99 00:04:05,400 --> 00:04:07,440 AGE 40 YEARS BUT DOESN'T MEAN 100 00:04:07,440 --> 00:04:09,960 DISEASE PROCESSES HAPPEN ONLY 101 00:04:09,960 --> 00:04:13,200 AFTER AGE 40. THERE IS OVERLAP 102 00:04:13,200 --> 00:04:15,520 WITH OTHER DISEASES SUCH AS 103 00:04:15,520 --> 00:04:17,880 LUPUS AND RHEUMATOID ARTHRITIS 104 00:04:17,880 --> 00:04:21,000 AND IT VARIES FROM AIN'T LENT 105 00:04:21,000 --> 00:04:22,480 YET INSIDIOUS TO PATIENTS THAT 106 00:04:22,480 --> 00:04:25,440 EXHIBIT RAPID PROGRESSIVE -- 107 00:04:25,440 --> 00:04:27,120 PROGRESSION. THIS DISEASE IS 108 00:04:27,120 --> 00:04:30,640 DEFINED BY A TREMENDOUSLY 109 00:04:30,640 --> 00:04:32,160 INCREASED 20 TO 44 FOLD INCREASE 110 00:04:32,160 --> 00:04:37,160 RISK OF DEVELOPMENT OF LYMPHOMA 111 00:04:37,160 --> 00:04:39,480 THERE ARE NO FDA APPROVED 112 00:04:39,480 --> 00:04:42,440 EFFECTIVE THERAPY FOR SJOGRENS 113 00:04:42,440 --> 00:04:44,120 NOT BECAUSE WE HAVEN'T TRIED BUT 114 00:04:44,120 --> 00:04:46,880 MULTIPLE OF REASONS SUCH AS GAPS 115 00:04:46,880 --> 00:04:48,240 UNDERSTANDING THE UNDERLYING 116 00:04:48,240 --> 00:04:51,840 PATHOLOGY AND THE INTRINSIC 117 00:04:51,840 --> 00:04:53,560 DISEASE HETEROGENEITY, POOR 118 00:04:53,560 --> 00:04:54,920 OUTCOME MEASURES AND LACK OF 119 00:04:54,920 --> 00:04:56,160 CORRELATION OF TARGET ORGAN 120 00:04:56,160 --> 00:04:58,800 RESPONSE IN THOSE TRIALS MEANING 121 00:04:58,800 --> 00:05:01,600 GOING AFTER THE TARGET TISSUES 122 00:05:01,600 --> 00:05:06,040 IN PATIENTS ON MEDICATION. WHAT 123 00:05:06,040 --> 00:05:08,640 DO I MEAN BY CLINICAL AND 124 00:05:08,640 --> 00:05:10,000 BIOLOGICAL HETEROGENEITY. IN THE 125 00:05:10,000 --> 00:05:11,600 SJOGREN'S LITERATURE IF YOU LOOK 126 00:05:11,600 --> 00:05:13,360 AT PAPERS WITH TRANSCRIPTOMICS 127 00:05:13,360 --> 00:05:16,920 OF THE SALIVARY GLANDS OR OF THE 128 00:05:16,920 --> 00:05:18,880 PERIPHERAL BLOOD AND LOOK AT THE 129 00:05:18,880 --> 00:05:19,800 INDIVIDUAL CLINICAL METADATA 130 00:05:19,800 --> 00:05:22,120 WITH THOSE, IT IS PRETTY CLEAR 131 00:05:22,120 --> 00:05:24,080 THERE IS PROBABLY FOUR GROUPS OF 132 00:05:24,080 --> 00:05:26,800 PATIENTS THAT WE DEFINE AS 133 00:05:26,800 --> 00:05:27,480 SJOGREN'S DISEASE. THOSE 134 00:05:27,480 --> 00:05:29,320 PATIENTS WHO ARE RELATIVELY 135 00:05:29,320 --> 00:05:31,640 YOUNG AT DISEASE ONSET THAT HAVE 136 00:05:31,640 --> 00:05:33,480 HIGH INTERFERON SCORES AND HIGH 137 00:05:33,480 --> 00:05:37,000 TITER SSA AUTOANTIBODIES 138 00:05:37,000 --> 00:05:38,680 DIAGNOSTIC AUTOANTIBODY FOUND IN 139 00:05:38,680 --> 00:05:40,840 SJOGRENS. THEN YOU HAVE GROUPS 140 00:05:40,840 --> 00:05:42,320 RELATIVELY DIFFICULT TO 141 00:05:42,320 --> 00:05:44,480 DISENTANGLE WITH LOW INTERFERON 142 00:05:44,480 --> 00:05:45,800 SCORES AND MODERATE INTERFERON 143 00:05:45,800 --> 00:05:47,280 SCORES. THISs PATIENTS ARE A 144 00:05:47,280 --> 00:05:51,480 LITTLE BIT OLDER BUT HAVE 145 00:05:51,480 --> 00:05:52,280 DISTINCT CLINICAL 146 00:05:52,280 --> 00:05:53,360 MANIFESTATIONS. THEN OF COURSE 147 00:05:53,360 --> 00:05:56,960 THERE IS ANOTHER GROUP THAT IS 148 00:05:56,960 --> 00:05:58,160 MORE DIFFERENT THAN THOSE THREE, 149 00:05:58,160 --> 00:06:00,160 PATIENTS THAT ARE SSA 150 00:06:00,160 --> 00:06:03,240 AUTOANTIBODY NEGATIVE THAT HAVE 151 00:06:03,240 --> 00:06:05,440 PAIN DOMINANT WITH FATIGUE AND 152 00:06:05,440 --> 00:06:08,000 CLIENTS OF ORAL DRYNESS. WHAT 153 00:06:08,000 --> 00:06:10,000 YOU MIGHT THINK IS THESE 154 00:06:10,000 --> 00:06:11,160 INDIVIDUAL GROUPS MIGHT 155 00:06:11,160 --> 00:06:12,040 REPRESENT DISTINCT CLINICAL 156 00:06:12,040 --> 00:06:13,640 ENTITIES. I DON'T THINK YOU 157 00:06:13,640 --> 00:06:18,080 WOULD BE WRONG. IT TELLS US 158 00:06:18,080 --> 00:06:20,680 SYMPTOMS PREDICT PRECISE 159 00:06:20,680 --> 00:06:22,400 THERAPIES THESE CLUSTERS MAYBE 160 00:06:22,400 --> 00:06:24,040 DYNAMIC, THEY CHANGE FROM 161 00:06:24,040 --> 00:06:25,040 YOUNGER TO OLDER INDIVIDUALS. 162 00:06:25,040 --> 00:06:26,160 WE CAN'T THINK OF THIS AS 163 00:06:26,160 --> 00:06:29,000 TREATING THE SYMPTOMS BUT CAN WE 164 00:06:29,000 --> 00:06:30,560 REVERSE OR PREVENT DISEASE 165 00:06:30,560 --> 00:06:33,120 PROGRESSION AND AUGMENT 166 00:06:33,120 --> 00:06:34,640 FUNCTION. WHAT HAVE IS THE 167 00:06:34,640 --> 00:06:36,440 PATHOLOGY OF SJOGREN'S DISEASE? 168 00:06:36,440 --> 00:06:38,480 THERE ISN'T A CLEAR DEFINITION. 169 00:06:38,480 --> 00:06:41,160 IT USUALLY OCCURS IN THE CONTEXT 170 00:06:41,160 --> 00:06:43,720 OF ENVIRONMENTAL INSULT LIKE AS 171 00:06:43,720 --> 00:06:46,280 SUCH AS VIRAL INFECTION, IN A 172 00:06:46,280 --> 00:06:47,640 SUSCEPTIBILITY INDIVIDUAL WITH 173 00:06:47,640 --> 00:06:48,600 BACKGROUND APPROPRIATE GENETICS 174 00:06:48,600 --> 00:06:51,600 WITH HORMONAL AND IMMUNE SYSTEM 175 00:06:51,600 --> 00:06:54,280 ALTERATIONS LEADING TO 176 00:06:54,280 --> 00:06:56,320 INFILTRATION AND EXOCRINE ORGANS 177 00:06:56,320 --> 00:07:00,000 DEATH AND DESTRUCTION OF 178 00:07:00,000 --> 00:07:01,600 FUNCTIONAL PARENCHYMA AND 179 00:07:01,600 --> 00:07:03,960 EXPANSION OF AN IMMUNE 180 00:07:03,960 --> 00:07:07,760 INFILTRATE IN A GLAND. SO I ASK 181 00:07:07,760 --> 00:07:09,280 MYSELF FOR MANY YEARS WHAT ARE 182 00:07:09,280 --> 00:07:11,800 THE EFFECTOR AND TARGET CELLS IN 183 00:07:11,800 --> 00:07:13,520 SJOGREN'S DISEASE SALIVARY 184 00:07:13,520 --> 00:07:15,400 GLANDS? I NARROWED TO ONE ORGAN 185 00:07:15,400 --> 00:07:17,040 CLINICAL ACCESSIBLE, THERE IS 186 00:07:17,040 --> 00:07:19,480 ENOUGH CELLS FOR US TO ATTEMPT 187 00:07:19,480 --> 00:07:21,200 TO UNDERSTAND DIRECTLY IN HUMAN 188 00:07:21,200 --> 00:07:22,400 TISSUES BACK IN THE LAB WHAT IS 189 00:07:22,400 --> 00:07:24,360 GOING ON IN THOSE INDIVIDUAL 190 00:07:24,360 --> 00:07:26,680 GLANDS. TO DO THIS WE HAVE 191 00:07:26,680 --> 00:07:27,400 CLINICAL INVESTIGATIONS 192 00:07:27,400 --> 00:07:29,880 INCLUDING OBSERVATIONAL AND 193 00:07:29,880 --> 00:07:31,800 INTERVENTIONAL STUDIES. 194 00:07:31,800 --> 00:07:33,160 INCLUDING CROSS SECTIONAL 195 00:07:33,160 --> 00:07:36,280 STUDIES WE CALL CHARACTERIZATION 196 00:07:36,280 --> 00:07:37,400 OF DISEASE WITHSON GLAND 197 00:07:37,400 --> 00:07:38,560 DYSFUNCTION AND PATHOGENESIS AND 198 00:07:38,560 --> 00:07:40,360 NATURAL HISTORY STUDIES WHERE WE 199 00:07:40,360 --> 00:07:41,240 FOLLOW PATIENTS FIVE TO TEN 200 00:07:41,240 --> 00:07:45,200 YEARS. WE ALSO HAVE A SYSTEM 201 00:07:45,200 --> 00:07:49,720 THAT IS CREATED TO ENTERTAIN OR 202 00:07:49,720 --> 00:07:52,120 AT LEAST TEST NOVEL THERAPEUTIC 203 00:07:52,120 --> 00:07:54,120 APPROACHES. WHAT WE TAKE TISSUES 204 00:07:54,120 --> 00:07:55,360 AND DATA THAT WE GLEAN FROM 205 00:07:55,360 --> 00:07:58,160 THESE STUDIES BACK TO LAB FOR 206 00:07:58,160 --> 00:07:59,640 DIRECT INTERROGATION OF THESE 207 00:07:59,640 --> 00:08:01,960 TISSUES. SO THE MODELS THAT WE 208 00:08:01,960 --> 00:08:04,480 WORK WITH ARE PATIENT TISSUES. 209 00:08:04,480 --> 00:08:05,600 WE INVESTIGATE THE 210 00:08:05,600 --> 00:08:06,720 IMMUNOPATHOLOGY OF SJOGREN'S 211 00:08:06,720 --> 00:08:08,160 DISEASE TO IDENTIFY EFFECTIVE 212 00:08:08,160 --> 00:08:09,720 THERAPIES IN HUMANS AND 213 00:08:09,720 --> 00:08:12,320 HOPEFULLY TRANSLATE THIS BACK TO 214 00:08:12,320 --> 00:08:12,920 NOVEL CLINICAL TRIALS AN 215 00:08:12,920 --> 00:08:17,200 EFFECTIVE THERAPIES. I STUDY 216 00:08:17,200 --> 00:08:19,120 SALIVARY TYPE EXOCRINE ORGAN, 217 00:08:19,120 --> 00:08:21,120 THE TARGET ORGANS FOR SJOGREN 218 00:08:21,120 --> 00:08:22,800 DISEASE AND I HAVE A CARTOON I 219 00:08:22,800 --> 00:08:23,920 CREATED TO ILLUSTRATE WHAT 220 00:08:23,920 --> 00:08:25,640 HAPPENS IN THE CONTEXT OF 221 00:08:25,640 --> 00:08:27,520 SJOGREN'S YOU HAVE A HEALTHY 222 00:08:27,520 --> 00:08:29,600 SALIVARY GLAND, A FULLY 223 00:08:29,600 --> 00:08:31,240 FUNCTIONAL SAL RARE GLAND 224 00:08:31,240 --> 00:08:33,280 COMPOSED OF DIFFERENT CELL TYPES 225 00:08:33,280 --> 00:08:35,840 AND SERA MUCOUS AND OVER TIME IN 226 00:08:35,840 --> 00:08:37,760 THE CONTEXT OF DISEASE YOU LOSE 227 00:08:37,760 --> 00:08:39,560 FUNCTIONAL PARENCHYMA AND IT IS 228 00:08:39,560 --> 00:08:41,920 REPLACED BY IMMUNE INFILTRATE AS 229 00:08:41,920 --> 00:08:45,080 WELL AS ELABORATION OF FIBROSIS 230 00:08:45,080 --> 00:08:47,120 WHICH LEADS TO DYSFUNCTION IN 231 00:08:47,120 --> 00:08:48,760 THE SALIVARY GLANDS, THIS DOES 232 00:08:48,760 --> 00:08:51,920 NOT HAPPEN TO EVERY GLAND AT THE 233 00:08:51,920 --> 00:08:53,800 SAME RATE. PROPERTY DID GLANDS 234 00:08:53,800 --> 00:08:56,400 AND SUB MANDIBULAR GLANDS MAYBE 235 00:08:56,400 --> 00:08:58,000 DIFFERENTIALLY AFFECTED. SO EASY 236 00:08:58,000 --> 00:09:00,440 WAY TO LOOK AT THIS FIRST IS TO 237 00:09:00,440 --> 00:09:02,160 UNDERSTAND WHAT PATHWAYS ARE 238 00:09:02,160 --> 00:09:03,520 DISREGULATED. WHEN I FIRST 239 00:09:03,520 --> 00:09:05,240 STARTED WE USE BULK RNA 240 00:09:05,240 --> 00:09:07,760 SEQUENCING BECAUSE WE LOOKED TO 241 00:09:07,760 --> 00:09:09,160 LITERATURE AND I WASN'T HAPPY 242 00:09:09,160 --> 00:09:11,400 WITH THE AVAILABLE CLINICAL 243 00:09:11,400 --> 00:09:13,600 METADATA ASSOCIATED WITH THESE 244 00:09:13,600 --> 00:09:15,920 STUDIES THAT ALREADY BEEN 245 00:09:15,920 --> 00:09:16,960 PUBLISHED. THE CONTROL GROUPS 246 00:09:16,960 --> 00:09:20,560 THEY WERE USING WERE NOT ALWAYS 247 00:09:20,560 --> 00:09:22,760 USING VERY PRISTINELY DEFINED 248 00:09:22,760 --> 00:09:24,240 VOLUNTEERS SO THAT IS WHAT WE 249 00:09:24,240 --> 00:09:29,160 DIDID. WE USE BULK RNA SEQUENCI, 250 00:09:29,160 --> 00:09:31,080 PATHWAYS ENRICHED IN SJOGREN'S 251 00:09:31,080 --> 00:09:33,560 VERSUS HEALTHY VOLUNTEERS. 252 00:09:33,560 --> 00:09:35,720 DESPITE REDUNDANCY IN THE TOP 25 253 00:09:35,720 --> 00:09:37,520 ENRICHED PATHWAYS, ONE THING 254 00:09:37,520 --> 00:09:39,200 THAT JUMPS OUT ALWAYS EITHER 255 00:09:39,200 --> 00:09:42,320 AMONG OUR STUDIES OR IN OTHERS 256 00:09:42,320 --> 00:09:43,520 IS THAT THERE WAS THE 257 00:09:43,520 --> 00:09:46,440 INVOLVEMENT OF THE JAK STAT 258 00:09:46,440 --> 00:09:48,960 PATHWAY AND THE EXPRESS OF TYPE 259 00:09:48,960 --> 00:09:51,720 1 AND TYPE 2 INTERFERON 260 00:09:51,720 --> 00:09:53,400 STIMULATED GENES WE CAN COMPARE 261 00:09:53,400 --> 00:09:55,520 THESE INDIVIDUALS PATIENTS MINOR 262 00:09:55,520 --> 00:09:56,520 SALIVARY GLANDS AND THEIR 263 00:09:56,520 --> 00:09:58,320 CLINICAL PATHOLOGY TO SHOW THAT 264 00:09:58,320 --> 00:10:02,200 THEY ARE HIGHLY CORRELATED WITH 265 00:10:02,200 --> 00:10:03,760 THE AMOUNT OF INFLAMMATION 266 00:10:03,760 --> 00:10:06,680 GLANDS WE CALL THE FOCUS FORUM. 267 00:10:06,680 --> 00:10:08,680 SO WE THOUGHT THIS WAS GREAT TO 268 00:10:08,680 --> 00:10:11,280 LOOK AT THIS IN THE SALIVARY 269 00:10:11,280 --> 00:10:13,920 GLANDS BUT WHAT IS GOING ON IN 270 00:10:13,920 --> 00:10:16,680 PERIPHERAL BLOOD LOOKING AT 4 271 00:10:16,680 --> 00:10:18,120 PROTEIN INTERFERON SCORE AND 272 00:10:18,120 --> 00:10:19,520 PROTEOMIC DATA WITH SEE THE SAME 273 00:10:19,520 --> 00:10:21,040 THING, ABOUT TWO-THIRDS OF THE 274 00:10:21,040 --> 00:10:22,800 PATIENTS WITH SJOGREN'S COMPARED 275 00:10:22,800 --> 00:10:25,560 TO EITHER HEALTHY VOLUNTEERS OR 276 00:10:25,560 --> 00:10:27,640 NON-SJOGREN'S PATIENTS YOU HAVE 277 00:10:27,640 --> 00:10:29,320 ENRICHED TYPE 1 INTERFERON 278 00:10:29,320 --> 00:10:31,000 PROTEIN SCORE. WHAT IS THE JAK 279 00:10:31,000 --> 00:10:34,560 STAT PATHWAY? CANONICAL JAK STAT 280 00:10:34,560 --> 00:10:39,080 PATHWAY ACTIVATION IS ANY 281 00:10:39,080 --> 00:10:40,800 MOLECULE SUCH AS CYTOKINES OR 282 00:10:40,800 --> 00:10:43,800 GROWTH FACTORS, BINDING TO ITS 283 00:10:43,800 --> 00:10:46,080 COGNATE RECEPTOR, BEING ABLE TO 284 00:10:46,080 --> 00:10:48,240 TRANSMIT SIGNAL FROM AN EXTRA 285 00:10:48,240 --> 00:10:50,560 CELLULAR SPACE TO INTRACELLULAR 286 00:10:50,560 --> 00:10:53,880 SPACE. TO DRIVE VARIABLE 287 00:10:53,880 --> 00:10:55,480 TRANSCRIPTION. IN SJOGREN'S WE 288 00:10:55,480 --> 00:10:57,280 ARE THINKING ABOUT THIS FROM THE 289 00:10:57,280 --> 00:10:59,600 CONTEXT OF DRIVING PATHOGENIC 290 00:10:59,600 --> 00:11:00,720 CYTOKINES. LOOK AT MULTIPLE 291 00:11:00,720 --> 00:11:02,680 LAYERS OF THIS PATHWAY, AS READ 292 00:11:02,680 --> 00:11:05,120 OUTS OF PATHWAY ACTIVATION. 293 00:11:05,120 --> 00:11:06,680 EITHER BY LOOKING DIRECTLY AT 294 00:11:06,680 --> 00:11:09,680 THE EXPRESSION OF JACKS AND 295 00:11:09,680 --> 00:11:11,840 STATS TO UNDERSTAND WHAT ARE THE 296 00:11:11,840 --> 00:11:14,280 CELLULAR TARGETS OF CYTOKINES IN 297 00:11:14,280 --> 00:11:17,080 AN EFFECTIVE TISSUE. WE CAN LOOK 298 00:11:17,080 --> 00:11:19,680 AT THE ACTIVATION STATUS OF 299 00:11:19,680 --> 00:11:21,000 VARIOUS STATS AND THEIR 300 00:11:21,000 --> 00:11:22,960 TRANSLOCATION TO THE NUCLEUS, TO 301 00:11:22,960 --> 00:11:25,720 SAY A GIVEN CELL TYPE IS 302 00:11:25,720 --> 00:11:28,880 ACTIVATED OR WE CAN USE THINGS 303 00:11:28,880 --> 00:11:30,760 LIKE INTERFERONS AND CYTOKINES 304 00:11:30,760 --> 00:11:33,280 AS mRNA READ OUTS OR PROTEIN 305 00:11:33,280 --> 00:11:35,760 READ OUTS. OF DOWNSTREAM PATHWAY 306 00:11:35,760 --> 00:11:38,520 ACTIVATION. IN FACT THAT'S WHAT 307 00:11:38,520 --> 00:11:40,840 WE SEE. WHEN WE LOOK AT MINOR 308 00:11:40,840 --> 00:11:42,520 SALIVARY GLANDS WE SHOW 309 00:11:42,520 --> 00:11:44,680 INCREASED RATES OF JAK 3 AND 310 00:11:44,680 --> 00:11:47,120 STAT mRNA AND AT ALSO AT THE 311 00:11:47,120 --> 00:11:48,680 PROTEIN LEVEL WE CAN SEE 312 00:11:48,680 --> 00:11:51,120 INCREASE PHOSPHORYLATION OF STAT 313 00:11:51,120 --> 00:11:53,840 1 AND STAT 3 SIGNIFYING DIRECTLY 314 00:11:53,840 --> 00:11:55,960 ACTIVATION OF THIS PATHWAY IN 315 00:11:55,960 --> 00:11:57,520 MINOR SALIVARY GLANDS FROM 316 00:11:57,520 --> 00:11:59,760 SJOGREN'S PATIENTS AND AS I HAVE 317 00:11:59,760 --> 00:12:01,720 SHOWED YOU WE CAN SHOW 318 00:12:01,720 --> 00:12:03,520 EXPRESENCE OF INTERFERON STILL 319 00:12:03,520 --> 00:12:06,560 LATED GENES. WE LENDS TO 320 00:12:06,560 --> 00:12:08,440 HYPOTHESIZE WE CAN USE EXISTING 321 00:12:08,440 --> 00:12:09,920 FDA APPROVED DRUGS TO MITIGATE 322 00:12:09,920 --> 00:12:11,400 THE EFFECT AND HOPEFULLY USE 323 00:12:11,400 --> 00:12:14,720 THESE READ OUTS IN PA HUMAN 324 00:12:14,720 --> 00:12:17,320 CLINICAL TRIAL TO SHOW EFFICACY 325 00:12:17,320 --> 00:12:20,840 DIRECTLY ON TARGET ORGAN. SO THE 326 00:12:20,840 --> 00:12:22,640 SUMMARY OF PART 1 IS WE SHOW 327 00:12:22,640 --> 00:12:25,680 IMMUNE CELLS AND EPITHELIAL 328 00:12:25,680 --> 00:12:28,080 CELLS SHOW PATHOGENIC JAK STAT 329 00:12:28,080 --> 00:12:30,520 ACTIVATION WHILE FINDING IS NOT 330 00:12:30,520 --> 00:12:32,600 PARTICULARLY NOVEL, IT DOES 331 00:12:32,600 --> 00:12:33,920 ILLUSTRATE VERY CLEARLY WE CAN 332 00:12:33,920 --> 00:12:36,320 USE EXISTING DRUGS TO TREAT 333 00:12:36,320 --> 00:12:38,760 SJOGREN'S POTENTIALLY. WE ALSO 334 00:12:38,760 --> 00:12:40,440 SHOW THE NOVEL FINDING THAT 335 00:12:40,440 --> 00:12:43,520 SJOGREN'S DISEASE ESPECIALLY IN 336 00:12:43,520 --> 00:12:46,680 INFLAMED SNI INDUCTS SHOW 337 00:12:46,680 --> 00:12:49,720 DEPENDENCE ON JAK 2 AND 1 338 00:12:49,720 --> 00:12:52,760 SIGNALING TO TOPHI SIT ANYBODY 339 00:12:52,760 --> 00:12:54,840 JACK 1 INHIBITOR. THOUGH I CAN'T 340 00:12:54,840 --> 00:13:00,880 SHOW IT HERE IN FACT IN EXVIVO 341 00:13:00,880 --> 00:13:01,800 MODELS TOFF RECEIVE ANYBODY 342 00:13:01,800 --> 00:13:03,640 CORRECTS AND ACTIVATED JAK STAT 343 00:13:03,640 --> 00:13:06,920 SIGNALING IN PBMC AND PATIENT 344 00:13:06,920 --> 00:13:08,320 DERIVED SALIVARY GLAND 345 00:13:08,320 --> 00:13:12,040 EPITHELIAL CELLS SO WE DESIGNED 346 00:13:12,040 --> 00:13:15,160 NIDCR NEI MULTI-INSTITUTIONAL 347 00:13:15,160 --> 00:13:18,160 COLLABORATIVE PHASE 1 A 2B 348 00:13:18,160 --> 00:13:20,920 RANDOMIZED CONTROL TRIAL TOM 349 00:13:20,920 --> 00:13:23,360 TEST KINASE INHIBITORS IN 350 00:13:23,360 --> 00:13:25,720 SJOGREN'S PATIENTS. THE GOAL WAS 351 00:13:25,720 --> 00:13:27,560 TO LOOK LONGITUDINALLY AT 352 00:13:27,560 --> 00:13:29,560 PATIENTS TARGET ORGANS FOR 353 00:13:29,560 --> 00:13:31,520 CHANGES IN THESE OUTCOMES 354 00:13:31,520 --> 00:13:33,440 INCLUDING PHOSPHOSTATS IN THE 355 00:13:33,440 --> 00:13:37,160 PERIPHERAL BLOOD, PHOSPHOSTATES 356 00:13:37,160 --> 00:13:39,320 IN THE ORGAN AND TRANSCRIPTOMIC 357 00:13:39,320 --> 00:13:42,520 CHANGES IN THAT GLAND. WE HOPE 358 00:13:42,520 --> 00:13:45,640 TO SHOW THROUGH TREATMENT WITH 359 00:13:45,640 --> 00:13:47,160 TOFSITNIB AND SIX MONTHS OF TIME 360 00:13:47,160 --> 00:13:50,440 THAT WE CAN HOPEFULLY SHOW 361 00:13:50,440 --> 00:13:52,280 REDUCTION IN INFLAMMATION DRIVEN 362 00:13:52,280 --> 00:13:53,560 BY THIS PATHWAY AND A 363 00:13:53,560 --> 00:13:54,800 RESTORATION OF SALIVARY GLAND 364 00:13:54,800 --> 00:14:00,400 FUNCTION AS MEASURED BY SALIVA 365 00:14:00,400 --> 00:14:01,840 OUTPUT FROM AT THE GLANDULAR 366 00:14:01,840 --> 00:14:03,720 LEVEL AND THE WHOLE STIMULATED 367 00:14:03,720 --> 00:14:07,880 FLOW LEVEL. SO SO FAR WE HAVE 368 00:14:07,880 --> 00:14:10,720 ENROLLED A THIRD OF THIS TRIAL 369 00:14:10,720 --> 00:14:12,240 OUT OF 30, THERE HAVE BEEN NO 370 00:14:12,240 --> 00:14:14,520 LIFE THREATENING AEs AND SOME 371 00:14:14,520 --> 00:14:15,920 SUBJECTS ARE REPORTING LESS 372 00:14:15,920 --> 00:14:19,360 FATIGUE AND OBJECTIVELY MORE 373 00:14:19,360 --> 00:14:23,360 SALIVA. THIS LED TO ANOTHER 374 00:14:23,360 --> 00:14:25,520 QUESTION, YOU HAVE AN ONGOING 375 00:14:25,520 --> 00:14:26,360 CLINICAL TRIAL HOW ARE YOU GOING 376 00:14:26,360 --> 00:14:27,440 TO ANALYZE THE DATA YOU ARE 377 00:14:27,440 --> 00:14:31,040 COLLECT SOMETHING WHILE DOING 378 00:14:31,040 --> 00:14:32,240 THIS STUDY WE WERE WORKING 379 00:14:32,240 --> 00:14:33,200 TRYING TO UNDERSTAND WHAT THE 380 00:14:33,200 --> 00:14:35,760 POOR COMPOSITION OF THE GLANDS 381 00:14:35,760 --> 00:14:36,840 ARE IN HEALTH AND ALSO IN 382 00:14:36,840 --> 00:14:39,320 DISEASE. HOPEFULLY BEING ABLE 383 00:14:39,320 --> 00:14:41,760 TO IDENTIFY WHAT THE CORE 384 00:14:41,760 --> 00:14:42,880 EFFECTORS WERE AND WHAT THE CELL 385 00:14:42,880 --> 00:14:45,000 TYPES ARE BEING TARGETED. SO WE 386 00:14:45,000 --> 00:14:47,000 CREATED A SINGLE CELL RNA 387 00:14:47,000 --> 00:14:49,080 SEQUENCING ATLAS OF THE SALIVARY 388 00:14:49,080 --> 00:14:52,560 GLANDS WORK WITH THOMAS 389 00:14:52,560 --> 00:14:53,320 (INDISCERNIBLE) WHERE WE WERE 390 00:14:53,320 --> 00:14:55,320 ABLE TO ILLUSTRATE 31 DIFFERENT 391 00:14:55,320 --> 00:14:56,800 CELL TYPES IN THE SALIVARY 392 00:14:56,800 --> 00:15:00,120 GLANDS BUT MORE IMPORTANTLY WE 393 00:15:00,120 --> 00:15:02,200 WERE ABLE TO SHOW CHANGES IN 394 00:15:02,200 --> 00:15:05,000 CELLULARITY BOTH INCREASE RATES 395 00:15:05,000 --> 00:15:07,080 OF GRANZYME K POSITIVE CD8 396 00:15:07,080 --> 00:15:12,040 CELLS, CYTOTOXIC T-CELLS AND CD4 397 00:15:12,040 --> 00:15:14,280 T-CELLS, INGREASE IN PALACENA 398 00:15:14,280 --> 00:15:16,760 WELLS AND NK CELLS. NOT 399 00:15:16,760 --> 00:15:17,880 SURPRISING. BUT ON THE OTHER 400 00:15:17,880 --> 00:15:20,520 HAND WE SAW STATISTICALLY 401 00:15:20,520 --> 00:15:22,360 SIGNIFICANT REDUCTION IN CAM 402 00:15:22,360 --> 00:15:24,720 LAYERS AND SEROUS MUCOUS ACINAR 403 00:15:24,720 --> 00:15:26,480 CELLS. BECAUSE SEQUENCING 404 00:15:26,480 --> 00:15:28,720 CREATES A RELATIVELY SPARSE 405 00:15:28,720 --> 00:15:30,680 MATRIX, YOU NEED LOTS OF 406 00:15:30,680 --> 00:15:32,160 REPRESENTATION IN NUMBER O CELLS 407 00:15:32,160 --> 00:15:34,080 AND INDIVIDUALS, TO REALLY 408 00:15:34,080 --> 00:15:35,760 UNDERSTAND DIFFERENTIAL GENE 409 00:15:35,760 --> 00:15:37,600 EXPRESSION AN INDIVIDUAL CELL 410 00:15:37,600 --> 00:15:41,520 TYPE WE CHOSE TO LOOK NOT JUST 411 00:15:41,520 --> 00:15:43,680 AT THE DIMENSIONALITY REDUCTION 412 00:15:43,680 --> 00:15:45,480 BASED ON GENE EXPRESSION BUT WE 413 00:15:45,480 --> 00:15:48,360 LOOKED AT THIS BASED ON PATHWAY 414 00:15:48,360 --> 00:15:49,480 UTILIZATION. THIS IS WHERE 415 00:15:49,480 --> 00:15:51,720 THINGS GOT REALLY INTERESTING. 416 00:15:51,720 --> 00:15:56,080 SO WHAT WE SAW WHEN WE REFORMED 417 00:15:56,080 --> 00:15:57,160 DIMENSIONALITY REDUCTION WE 418 00:15:57,160 --> 00:15:58,960 STARTED INDIVIDUAL CLUSTERS OF 419 00:15:58,960 --> 00:16:00,560 CELL TYPES PULLING APART FROM 420 00:16:00,560 --> 00:16:04,600 THIS MAIN BODY OF MIXED CELL 421 00:16:04,600 --> 00:16:05,760 TYPES. WE DIDN'T REALLY 422 00:16:05,760 --> 00:16:06,600 UNDERSTAND WHAT THAT MEANT UNTIL 423 00:16:06,600 --> 00:16:09,960 WE STARTED TO LOOK AT INDIVIDUAL 424 00:16:09,960 --> 00:16:12,720 FEATURE ANNOTATI ANNOTATION. SOG 425 00:16:12,720 --> 00:16:14,200 JUST AT DISEASE ANNOTATION YOU 426 00:16:14,200 --> 00:16:16,560 CAN SEE THAT THESE INDIVIDUAL 427 00:16:16,560 --> 00:16:19,120 SJOGREN'S DISEASE ASSOCIATED 428 00:16:19,120 --> 00:16:22,160 CELL TYPES SEEM TO BE UTILIZING 429 00:16:22,160 --> 00:16:24,080 PATHWAYS IN A DISEASE AND CELL 430 00:16:24,080 --> 00:16:26,320 TYPE SPECIFIC MANNER. THAT'S 431 00:16:26,320 --> 00:16:27,800 REALLY IMPORTANT. THAT EACH ONE 432 00:16:27,800 --> 00:16:29,840 OF THESE CELL TYPES IN THE 433 00:16:29,840 --> 00:16:31,560 IMMUNE COMPARTMENT AND EACH 434 00:16:31,560 --> 00:16:33,520 THESE CELL TYPES IN THE 435 00:16:33,520 --> 00:16:35,560 EPITHELIAL COMPARTMENT ARE DOING 436 00:16:35,560 --> 00:16:37,040 SLIGHTLY DIFFERENT THINGS BUT 437 00:16:37,040 --> 00:16:38,560 DOING THINGS THAT ARE ALSO VERY 438 00:16:38,560 --> 00:16:39,680 DIFFERENT FROM WHAT THEIR 439 00:16:39,680 --> 00:16:43,800 HEALTHY COUNTERPARTS ARE. IN ONE 440 00:16:43,800 --> 00:16:45,160 PARTICULAR CELL TYPE WE CAN LOOK 441 00:16:45,160 --> 00:16:47,320 AT SJOGREN'S T-CELLS WHICH SEEMS 442 00:16:47,320 --> 00:16:51,480 TO BE DRIVING THE MOST 443 00:16:51,480 --> 00:16:53,240 DIFFERENCE BETWEEN HEALTH AND 444 00:16:53,240 --> 00:16:56,240 SJOGREN'S DISEASE. WE CAN FIND A 445 00:16:56,240 --> 00:16:59,440 MULTITUDE OF DIFFERENT T-CELLS. 446 00:16:59,440 --> 00:17:01,120 INCLUDING CD4 AND CD8 BUT THE 447 00:17:01,120 --> 00:17:04,240 MOST ENRICHED TYPE OF T-CELL 448 00:17:04,240 --> 00:17:07,360 WERE THESE THAT EXPRESS GRANZYME 449 00:17:07,360 --> 00:17:10,360 A AND PERFORIN AND CYTOTOXIC 450 00:17:10,360 --> 00:17:13,280 T-CELLS THAT EXPRESS GRANZYME B 451 00:17:13,280 --> 00:17:14,960 AND PERFORIN. WHEN WE LOOK AT 452 00:17:14,960 --> 00:17:16,400 PATHWAY UTILIZATION THEY SEEM 453 00:17:16,400 --> 00:17:18,600 SIMILAR. THEY BOTH SEEM TO BE 454 00:17:18,600 --> 00:17:19,640 ACTIVATED BUT THERE ARE ABOUT 455 00:17:19,640 --> 00:17:23,080 SIX TIMES AS MANY GRANZYME A AND 456 00:17:23,080 --> 00:17:25,880 K POSITIVE T-CELLS. WHEN WE 457 00:17:25,880 --> 00:17:29,720 TAKE THOSE OUTS OF THE MINOR 458 00:17:29,720 --> 00:17:31,440 SALIVARY GLAND AND STIMULATE 459 00:17:31,440 --> 00:17:35,280 WITH ANAMICIN, WORK DONE WITH 460 00:17:35,280 --> 00:17:36,400 (INDISCERNIBLE) IN THE DAN 461 00:17:36,400 --> 00:17:38,960 BARBARA LAB AT NIAID, WE CAN SEE 462 00:17:38,960 --> 00:17:42,520 IN FACT IT IS THE CD8 CD 107A 463 00:17:42,520 --> 00:17:44,400 POSITIVE T-CELLS IN SJOGREN'S 464 00:17:44,400 --> 00:17:45,760 AND NOT IN HEALTHY VOLUNTEERS 465 00:17:45,760 --> 00:17:47,760 THAT SEEMED TO BE ACTIVATING. 466 00:17:47,760 --> 00:17:49,560 WHEN WE LOOK DIRECTLY IN THE 467 00:17:49,560 --> 00:17:52,440 GLAND FOR PATHOGENIC CELL TYPES, 468 00:17:52,440 --> 00:17:53,960 IN THIS CASE AT THIS POINT WE 469 00:17:53,960 --> 00:17:55,680 DID THIS WORK WE DIDN'T HAVE 470 00:17:55,680 --> 00:17:57,320 REALLY GOOD GRANZYME K MARKER SO 471 00:17:57,320 --> 00:18:01,640 WE ARE USING GRANZYME B AS A 472 00:18:01,640 --> 00:18:03,080 NEGATIVE MARKER FOR THIS. YOU 473 00:18:03,080 --> 00:18:05,920 CAN SEE THAT MOST OF THESE CD8 474 00:18:05,920 --> 00:18:07,560 POSITIVE T-CELLS AT THE 475 00:18:07,560 --> 00:18:08,920 INTERFACE WITH INFLAMED 476 00:18:08,920 --> 00:18:11,760 EPITHELIUM THAT IS MARKED BY THE 477 00:18:11,760 --> 00:18:14,440 EXPRESSION OF MHC CLASS 1 YOU 478 00:18:14,440 --> 00:18:16,040 CAN SEE VERY FEW OF THEM IN 479 00:18:16,040 --> 00:18:19,840 ALMOST A FOUR TO ONE RATIO ARE 480 00:18:19,840 --> 00:18:22,200 CLASSIC CYTOTOXIC T-CELLS. THAT 481 00:18:22,200 --> 00:18:24,720 LED US TO HYPOTHESIZE IN FACT 482 00:18:24,720 --> 00:18:27,800 THE GRANZYME K THAT ARE EXERTING 483 00:18:27,800 --> 00:18:28,840 FUNCTIONAL EFFECT UPON THE 484 00:18:28,840 --> 00:18:31,680 SALIVARY EPITHELIUM. SO IN THIS 485 00:18:31,680 --> 00:18:33,280 TIME WE WORKED WITH ANOTHER 486 00:18:33,280 --> 00:18:35,000 GROUP AND WE PERFORMED A LARGER 487 00:18:35,000 --> 00:18:37,320 BULK RNA SEQUENCING STUDY ON 488 00:18:37,320 --> 00:18:39,320 HEALTHY VOLUNTEERS, PATIENTS 489 00:18:39,320 --> 00:18:40,560 THAT DON'T MEET CLINICAL 490 00:18:40,560 --> 00:18:42,240 CLASSIFICATION CRITERIA FOR 491 00:18:42,240 --> 00:18:44,680 SJOGREN'S AND VERY ROBUSTLY 492 00:18:44,680 --> 00:18:46,560 CHARACTERIZE SJOGREN'S PATIENTS 493 00:18:46,560 --> 00:18:49,880 AND WE COMPARED EXPRESSION OF 494 00:18:49,880 --> 00:18:53,400 GRANZYME K WITH BOTH CLINICAL 495 00:18:53,400 --> 00:18:54,760 OUTCOMES SUCH AS WHOLE 496 00:18:54,760 --> 00:18:58,400 STIMULATED SALIVA FLOW AND FOCUS 497 00:18:58,400 --> 00:19:00,880 FLORA. THERE IS A SIGNIFICANT 498 00:19:00,880 --> 00:19:02,880 SIGNIFICANT INVERSE CORRELATION 499 00:19:02,880 --> 00:19:04,720 BETWEEN SALIVARY FLOW AND THE 500 00:19:04,720 --> 00:19:06,560 AMOUNT OF GRANZYME K IN THE 501 00:19:06,560 --> 00:19:08,280 SALIVARY GLANDS BUT DIRECT 502 00:19:08,280 --> 00:19:10,320 CORRELATION BETWEEN FOCUS AND 503 00:19:10,320 --> 00:19:11,800 GRANZYME K EXPRESSION. THIS 504 00:19:11,800 --> 00:19:13,520 INDICATES THAT IN FACT WHAT IS 505 00:19:13,520 --> 00:19:15,480 DRIVING A REDUCTION IN SALIVARY 506 00:19:15,480 --> 00:19:18,520 FLOW IS THE INFILTRATION WITH 507 00:19:18,520 --> 00:19:23,680 GRANZYME K CD8 T-CELLS. SO WE 508 00:19:23,680 --> 00:19:25,720 DESIGNED A SERIES OF EXPERIMENTS 509 00:19:25,720 --> 00:19:26,760 TO UNDERSTAND WHAT GRANZYME K 510 00:19:26,760 --> 00:19:29,080 MIGHT BE DOING TO THE EFFECTED 511 00:19:29,080 --> 00:19:31,640 EPITHELIUM SO USING A THP 1 512 00:19:31,640 --> 00:19:34,240 INTERFERON STIMULATED CELLS HECK 513 00:19:34,240 --> 00:19:37,400 INTERFERON ALPHA BETA RESPONSIVE 514 00:19:37,400 --> 00:19:39,680 CELLS, A CELL LINE THAT IS 515 00:19:39,680 --> 00:19:42,240 IMMORTALIZED THAT RECAPITULATES 516 00:19:42,240 --> 00:19:43,720 ACINAR CELL DIFFERENTIATION AND 517 00:19:43,720 --> 00:19:45,840 PRIMARY SALIVARY GLAND 518 00:19:45,840 --> 00:19:47,080 EPITHELIAL CELLS FROM PATIENTS 519 00:19:47,080 --> 00:19:48,640 AND TRANSFECTED DIRECTLY 520 00:19:48,640 --> 00:19:50,800 GRANZYME K, AND B AND CONTROL 521 00:19:50,800 --> 00:19:53,160 PROTEINS AND THEN LOOKED AT 522 00:19:53,160 --> 00:19:55,920 MULTITUDE OF OUTCOMES. SO THE 523 00:19:55,920 --> 00:19:58,520 MOST BASIC READ OUT WAS DIRECTLY 524 00:19:58,520 --> 00:20:00,600 LOOKING AT WHAT HAPPENS TO THE 525 00:20:00,600 --> 00:20:02,480 CELLS AND SO HERE WE ARE SHOWING 526 00:20:02,480 --> 00:20:05,400 WITH MITOTRACKER MARKING 527 00:20:05,400 --> 00:20:06,640 MITOCHONDRIA AND GREEN MARKING 528 00:20:06,640 --> 00:20:09,320 DNA AND DAPE MARKING NUCLEUS YOU 529 00:20:09,320 --> 00:20:10,720 CAN SEE CLEARLY THERE ISN'T A 530 00:20:10,720 --> 00:20:12,880 WHOLE LOT OF DNA IN THE CYTOSOL 531 00:20:12,880 --> 00:20:16,080 BUT WHEN YOU TRANSFECT GRANZYME 532 00:20:16,080 --> 00:20:18,320 K YOU LOSE MITOCHONDRIA AND 533 00:20:18,320 --> 00:20:22,520 INCREASE THE CYTOSOLIC PRESENCE 534 00:20:22,520 --> 00:20:25,400 OF DNA. AND WHEN WE LOOK AT CELL 535 00:20:25,400 --> 00:20:28,400 TYPES THAT ARE RESPONSE TO 536 00:20:28,400 --> 00:20:29,680 STINGING A NICHE, WE SHOW DOSE 537 00:20:29,680 --> 00:20:31,520 DEPENDENT INCREASE IN STING 538 00:20:31,520 --> 00:20:33,320 ACTIVITY AND ALSO A DOSE 539 00:20:33,320 --> 00:20:35,320 DEPENDENT INCREASE IN TYPE 1 540 00:20:35,320 --> 00:20:36,400 INTERFERON ACTIVITY BUT MORE 541 00:20:36,400 --> 00:20:37,440 IMPORTANTLY WHEN WE LOOK 542 00:20:37,440 --> 00:20:39,680 DIRECTLY AT PHOSPHOIRF 3 WHICH 543 00:20:39,680 --> 00:20:42,640 IS THE CONVERGENCE OF BOTH STING 544 00:20:42,640 --> 00:20:46,560 AND RIGI PATHWAYS SHOWING 545 00:20:46,560 --> 00:20:47,680 COMMITMENT TO THAT TYPE 1 546 00:20:47,680 --> 00:20:49,880 INTERFERON SIGNALING WE CAN SHOW 547 00:20:49,880 --> 00:20:52,520 INCREASE RATES OF PHOSPHOERK 3 548 00:20:52,520 --> 00:20:56,400 IN THESE MODELS. SO SUMMARY, 549 00:20:56,400 --> 00:20:58,720 HOW DOES SJOGREN'S AFFECT THE 550 00:20:58,720 --> 00:21:01,920 CELLULARITY OF THE CELL 551 00:21:01,920 --> 00:21:04,720 INSTITUTES OF POSITIVE GLANDS? 552 00:21:04,720 --> 00:21:06,600 SJOGREN'S CELLS ARE NUMEROUS 553 00:21:06,600 --> 00:21:09,600 THAN CLASSIC CYTOTOXIC T-CELLS 554 00:21:09,600 --> 00:21:11,920 IN THE SALIVARY GLAND. AND THEY 555 00:21:11,920 --> 00:21:15,400 HAVE AN EFFECTOR PHENOTYPE AND 556 00:21:15,400 --> 00:21:16,760 EFFECTOR FUNCTION? SHOW GRAIN 557 00:21:16,760 --> 00:21:18,040 SALIVARY GLANDS. SO THE FUTURE 558 00:21:18,040 --> 00:21:20,560 WORK IS THINKING ABOUT CAN WE 559 00:21:20,560 --> 00:21:23,800 USE STYNG ANTAGONIST TO MANAGE 560 00:21:23,800 --> 00:21:25,040 SJOGREN'S DISEASE IF THIS 561 00:21:25,040 --> 00:21:26,920 PHENOMENA IS IN FACT TRUE. AND 562 00:21:26,920 --> 00:21:29,640 HERE WE DID PRELIMINARY WORK 563 00:21:29,640 --> 00:21:31,520 LOOKING AT PHOSPHOERF 3 564 00:21:31,520 --> 00:21:33,320 EXPRESSION IN SALIVARY GLANDS OF 565 00:21:33,320 --> 00:21:34,560 SJOGREN OF HEALTHY VOLUNTEERS 566 00:21:34,560 --> 00:21:39,840 AND YOU CAN SEE ACTIVATION OF 567 00:21:39,840 --> 00:21:42,040 PHOSPHOERK 3 AND STYNG 568 00:21:42,040 --> 00:21:43,680 INDICATING PATHWAY ACTIVATED. SO 569 00:21:43,680 --> 00:21:45,040 THE LAST BIT TO TALK ABOUT IS WE 570 00:21:45,040 --> 00:21:46,640 HAVE BEEN TALKING ABOUT THE 571 00:21:46,640 --> 00:21:47,560 IMMUNOINFILTRATE AND WHAT IT 572 00:21:47,560 --> 00:21:49,800 COULD DO TO THE SALIVARY GLANDS 573 00:21:49,800 --> 00:21:52,000 BUT NOW I WILL SHOW YOU WHAT 574 00:21:52,000 --> 00:21:53,480 HAPPENS TOESHOES FUNCTIONAL 575 00:21:53,480 --> 00:21:54,880 EPITHELIAL CELLS, WHAT ARE THE 576 00:21:54,880 --> 00:21:57,280 CELL TYPES AND/OR CELL STATES 577 00:21:57,280 --> 00:21:59,840 TARGETED IN SALIVARY GLANDS. I 578 00:21:59,840 --> 00:22:02,080 SAID YOU LOSE SERUM MUCOUS 579 00:22:02,080 --> 00:22:03,320 ACINAR CELLS, TWO DIFFERENT 580 00:22:03,320 --> 00:22:06,600 TYPES OF ACINAR CELLS IN THE 581 00:22:06,600 --> 00:22:09,200 GLANDS. SERA MUCOUS AND MUCOUS. 582 00:22:09,200 --> 00:22:10,920 WE SHOW SPECIFIC TARGETING OR 583 00:22:10,920 --> 00:22:12,720 LOSS OF THOSE ACINAR CELLS. BUT 584 00:22:12,720 --> 00:22:15,280 IN A MORE GRANULAR LEVEL YOU 585 00:22:15,280 --> 00:22:18,280 LOSE ONE TYPE OF SORE HAVE 586 00:22:18,280 --> 00:22:20,640 MUCOUS ACINAR CELL AND IT IS 587 00:22:20,640 --> 00:22:23,040 THESE PR 4 POSITIVE ACINAR 588 00:22:23,040 --> 00:22:25,640 CELLS. WE USE RNA VELOCITY TO 589 00:22:25,640 --> 00:22:27,360 LOOK AT HOW DIFFERENTIATED THESE 590 00:22:27,360 --> 00:22:29,280 CELLS ARE, WE IN FACT SHOW WHAT 591 00:22:29,280 --> 00:22:32,520 IS LOST ARE THESE CST 3 PR 4 592 00:22:32,520 --> 00:22:35,320 HIGH ARM OF THE TWO TYPES OF 593 00:22:35,320 --> 00:22:37,680 SERUM MUCOUS ACINAR CELL. WE CAN 594 00:22:37,680 --> 00:22:43,360 USE NC HYBRIDIZATION TO 595 00:22:43,360 --> 00:22:45,280 DEMONSTRATE LOSS OF 596 00:22:45,280 --> 00:22:46,560 HETEROGENEITY OF THE ACINAR 597 00:22:46,560 --> 00:22:49,000 COMPARTMENT. THIS IS THE PLR 4 598 00:22:49,000 --> 00:22:49,680 EXPRESSION IN IDEAL LOW, A 599 00:22:49,680 --> 00:22:51,680 MARKER OF TERMINAL 600 00:22:51,680 --> 00:22:53,040 DIFFERENTIATION OF THESE CELL 601 00:22:53,040 --> 00:22:56,560 TYPES. WFDC 2 IS A MARKER OF 602 00:22:56,560 --> 00:22:57,600 DUCK TILE LIKE DIFFERENTIATION, 603 00:22:57,600 --> 00:23:00,160 YOU CAN SEE THAT PHENOTYPICALLY 604 00:23:00,160 --> 00:23:01,440 THESE ARE ACINAR CELLS THAT 605 00:23:01,440 --> 00:23:03,320 SHOULD BE THIS GOLDEN COLOR BUT 606 00:23:03,320 --> 00:23:06,120 IN FACT WHAT WE HAVE IS A DUCT 607 00:23:06,120 --> 00:23:08,320 LIKE ACINAR CELL AND WE SUSPECT 608 00:23:08,320 --> 00:23:10,120 IS THESE ARE LESS FUNCTIONAL. SO 609 00:23:10,120 --> 00:23:12,600 NOT ONLY ARE YOU LOSING CELLS AS 610 00:23:12,600 --> 00:23:16,160 A DIRECT RESULT OF THAT GRANZYME 611 00:23:16,160 --> 00:23:21,360 K CD8T CELL INFILTRATE BUT IT IS 612 00:23:21,360 --> 00:23:22,760 SOMETHING ABILITY THE EFFECTOR 613 00:23:22,760 --> 00:23:24,360 FUNCTION OF THOSE CELLS PREVENTS 614 00:23:24,360 --> 00:23:27,160 OR RESTRAINS DIFFERENTIATION OF 615 00:23:27,160 --> 00:23:30,440 THOSE SERUM MUCOUS ACINAR CELLS 616 00:23:30,440 --> 00:23:32,920 AND HALTS THE GREATER 617 00:23:32,920 --> 00:23:34,280 HETEROGENEITY OF THE ACINAR 618 00:23:34,280 --> 00:23:37,080 CELLS. FUTURE WORK WILL BE 619 00:23:37,080 --> 00:23:39,520 LOOKING AT THESE TYPES OF 620 00:23:39,520 --> 00:23:41,520 PATHWAYS IN MAJOR SALIVARY 621 00:23:41,520 --> 00:23:45,160 GLANDS. WE CAN QUANTIFY THIS, 622 00:23:45,160 --> 00:23:47,760 THIS IS WORK WE DID 623 00:23:47,760 --> 00:23:51,320 COLLABORATIVELY WITH THE NCI 624 00:23:51,320 --> 00:23:54,320 WITH (INDISCERNIBLE) AND AFTER 625 00:23:54,320 --> 00:23:56,400 SEGMENTATION OF THE SLIDES, WE 626 00:23:56,400 --> 00:23:58,480 CAN ASSIGN PHENOTYPES TO EACH OF 627 00:23:58,480 --> 00:24:00,200 THESE TYPES OF SERUM MUCOUS 628 00:24:00,200 --> 00:24:01,640 ACINAR CELLS AND SHOW THE FULL 629 00:24:01,640 --> 00:24:02,800 CHANGE IN THE SALIVARY GLANDS. 630 00:24:02,800 --> 00:24:06,120 WHAT THIS ILLUSTRATES IS THAT 631 00:24:06,120 --> 00:24:08,600 YOU LOSE MUCOUS ACINAR CELLS AND 632 00:24:08,600 --> 00:24:09,840 PROPORTIONATELY GAIN MUCOUS 633 00:24:09,840 --> 00:24:11,360 ACINAR CELLS RELATIVELY LESS 634 00:24:11,360 --> 00:24:15,400 FUNCTIONAL. IN SUMMARY SHOW 635 00:24:15,400 --> 00:24:16,720 DIFFERENTIATING DUCT LIKE SERUM 636 00:24:16,720 --> 00:24:18,640 MUCOUS ACINAR CELLS ARE LIKELY 637 00:24:18,640 --> 00:24:19,600 ONE OF THE SPECIFIC CELLULAR 638 00:24:19,600 --> 00:24:23,080 TARGETS IN SJOGREN'S, A LESS OF 639 00:24:23,080 --> 00:24:25,440 HETEROGENEITY NOT ONLY DIRECT 640 00:24:25,440 --> 00:24:28,360 CYTOTOXICITY IS IMPLICATED IN 641 00:24:28,360 --> 00:24:29,080 PANDEMIC MA LOSS AND SIGNALING 642 00:24:29,080 --> 00:24:30,640 MAYBE DRIVING EPITHELIAL 643 00:24:30,640 --> 00:24:32,360 DYSFUNCTION. SO IN CONCLUSION 644 00:24:32,360 --> 00:24:34,680 INTEGRATED OMICS DISENTANGLE 645 00:24:34,680 --> 00:24:35,840 COMPLEX TISSUE AND DISEASE 646 00:24:35,840 --> 00:24:37,880 DEPENDENT ALTERATIONS TO 647 00:24:37,880 --> 00:24:39,120 ILLUSTRATE DRUG L PATHWAYS THE 648 00:24:39,120 --> 00:24:40,680 LOSS OF SERUM MUCOUS ACINAR 649 00:24:40,680 --> 00:24:42,960 CELLS ARE LINKED TO EXPANSION OF 650 00:24:42,960 --> 00:24:44,520 T-CELLS MOST SPECIFICALLY THE 651 00:24:44,520 --> 00:24:47,960 CD8 GRANZYME K PHENOTYPE CELLS, 652 00:24:47,960 --> 00:24:49,560 AND THESE CELLS EXERT EFFECTIVE 653 00:24:49,560 --> 00:24:51,240 PHENOTYPE. LOTS OF PEOPLE TO 654 00:24:51,240 --> 00:24:54,120 THANK. I WILL LEAVE HERE WHILE I 655 00:24:54,120 --> 00:24:55,280 TAKE IN I QUESTIONS. THANK YOU 656 00:24:55,280 --> 00:24:56,720 FOR THE OPPORTUNITY TO TALK. 657 00:24:56,720 --> 00:24:59,560 [APPLAUSE] 658 00:24:59,560 --> 00:25:03,840 >>OUR SECOND SPEAKER IS DR. 659 00:25:03,840 --> 00:25:06,440 SARA INATI. SHE IS ADULT 660 00:25:06,440 --> 00:25:07,880 NEUROLOGIST, SPECIALIZING IN 661 00:25:07,880 --> 00:25:11,520 CLINICAL NEUROPHYSIOLOGY AND 662 00:25:11,520 --> 00:25:13,600 EPILEPTIC PATHOLOGY. SHE CAME TO 663 00:25:13,600 --> 00:25:16,440 NIH IN 2010 AND SERVED AS A 664 00:25:16,440 --> 00:25:21,640 CHIEF OF THE NINDS EEG SECTION 665 00:25:21,640 --> 00:25:25,040 FROM 2012 TO 2021 WHEN SHE 666 00:25:25,040 --> 00:25:26,040 TRANSITIONED TO BE ASSISTANT 667 00:25:26,040 --> 00:25:27,200 CLINICAL INVESTIGATOR. HER 668 00:25:27,200 --> 00:25:30,040 RESEARCH IS FOCUSED ON BETTER 669 00:25:30,040 --> 00:25:31,360 UNDERSTANDING THE 670 00:25:31,360 --> 00:25:32,520 PATHOPHYSIOLOGY OF EPILEPSY WITH 671 00:25:32,520 --> 00:25:35,040 GOAL OF IMPROVED THE TREATMENT 672 00:25:35,040 --> 00:25:37,560 AND QUALITY OF LIFE OF EPILEPSY 673 00:25:37,560 --> 00:25:39,520 PATIENTS. SHE SERVED AS A 674 00:25:39,520 --> 00:25:41,960 PROGRAM DIRECTOR OF THE NINDS 675 00:25:41,960 --> 00:25:45,680 EPILEPSY FELLOWSHIP SINCE 2016. 676 00:25:45,680 --> 00:25:48,120 AND ENJOYING HELPING TO EDUCATE 677 00:25:48,120 --> 00:25:51,040 THE COMMUNITY ABOUT SEIZURES AND 678 00:25:51,040 --> 00:25:53,040 EPILEPSY. HER PRESENTATION TODAY 679 00:25:53,040 --> 00:25:56,400 IS TRACKING SEIZURE SPREAD IN 680 00:25:56,400 --> 00:26:00,640 THE BRAIN. DR. INATI. 681 00:26:00,640 --> 00:26:04,280 [APPLAUSE] 682 00:26:04,280 --> 00:26:05,800 >>THANK YOU SO MUCH FOR THAT 683 00:26:05,800 --> 00:26:07,200 NICE INTRODUCTION AND FOR THE 684 00:26:07,200 --> 00:26:10,320 INVITATION TO TALK TO Y'ALL 685 00:26:10,320 --> 00:26:12,240 TODAY. THIS IS ANOTHER 686 00:26:12,240 --> 00:26:13,240 OPPORTUNITY TO TELL YOU FIRST 687 00:26:13,240 --> 00:26:14,480 WHAT WE ARE DOING HERE AN 688 00:26:14,480 --> 00:26:17,000 EDUCATE YOU A BIT ABOUT 689 00:26:17,000 --> 00:26:19,280 EPILEPSY. SO EPILEPSY IS REALLY 690 00:26:19,280 --> 00:26:21,280 A COMBINATION OF DISEASE. SO 691 00:26:21,280 --> 00:26:24,400 SOMETIMES REFERRED TO IT AS THE 692 00:26:24,400 --> 00:26:26,280 EPILEPSIES, RANGING FROM 693 00:26:26,280 --> 00:26:28,160 NEONATAL ONSET TO ONSET IN OLDER 694 00:26:28,160 --> 00:26:29,400 ADULTS WHICH ARE THE TWO 695 00:26:29,400 --> 00:26:30,960 POPULATIONS WHERE SEIZURES 696 00:26:30,960 --> 00:26:33,000 HAPPEN THE MOST. AND SOMETIMES 697 00:26:33,000 --> 00:26:34,960 IT IS A BENIGN DISORDER WITH 698 00:26:34,960 --> 00:26:36,840 SELF-LIMITED SEIZURES NORMAL 699 00:26:36,840 --> 00:26:37,560 DEVELOPMENT AND COKE IN ADDITION 700 00:26:37,560 --> 00:26:39,800 WHICH WE PUT ON THE IDIOPATHIC 701 00:26:39,800 --> 00:26:41,440 SIDE OF THIS PATHWAY. THEN THERE 702 00:26:41,440 --> 00:26:44,440 IS NON-IDIOPATHIC THIS IS PARTS 703 00:26:44,440 --> 00:26:46,400 OF REALLY DEVASTATING SYNDROMES 704 00:26:46,400 --> 00:26:48,760 IN MY WORK I FOCUS ON ONE LITTLE 705 00:26:48,760 --> 00:26:51,040 SQUARE RIGHT HERE WHICH IS THE 706 00:26:51,040 --> 00:26:52,360 SYMPTOMATIC OR TRIP TOE GENIC 707 00:26:52,360 --> 00:26:54,880 FOCAL EPILEPSIES. SO THIS IS A 708 00:26:54,880 --> 00:26:58,240 SMALL AREA WITHIN EPILEPSY BUT 709 00:26:58,240 --> 00:27:00,800 OVERALL EPILEPSY IS THREE MILL 710 00:27:00,800 --> 00:27:02,520 AMERICANS AN 65 MILLION PEOPLE 711 00:27:02,520 --> 00:27:03,720 WORLD WILD HAVE EPILEPSY. THAT 712 00:27:03,720 --> 00:27:05,720 COMES OUT TO ONE IN 26 PEOPLE 713 00:27:05,720 --> 00:27:07,520 WHO WILL DEVELOP EPILEPSY DURING 714 00:27:07,520 --> 00:27:08,560 LIFETIME SO CHANCES ARE THERE'S 715 00:27:08,560 --> 00:27:10,160 AT LEAST ONE OR TWO PEOPLE IN 716 00:27:10,160 --> 00:27:12,200 THIS ROOM WHO HAVE HAD OR WILL 717 00:27:12,200 --> 00:27:15,200 HAVE A SEIZURE AT SOME POINT IN 718 00:27:15,200 --> 00:27:16,640 THEIR LIFE. AT TIMES 719 00:27:16,640 --> 00:27:18,040 PARTICULARLY WHEN THEY ARE 720 00:27:18,040 --> 00:27:19,840 ONGOING THEY ARE SIGNIFICANT 721 00:27:19,840 --> 00:27:20,960 NEURAL PSYCHOLOGICAL 722 00:27:20,960 --> 00:27:21,840 CO-MORBIDITIES AND INCREASED 723 00:27:21,840 --> 00:27:28,280 MORTALITY. SO AS A CLINICAL 724 00:27:28,280 --> 00:27:29,480 EPILEPSIOLOGIST, ONE MAIN 725 00:27:29,480 --> 00:27:30,520 FUNCTION WITH PATIENTS IS TO 726 00:27:30,520 --> 00:27:32,320 TREAT THEM MEDICALLY. SO OVER 727 00:27:32,320 --> 00:27:34,880 THE LAST DECADES WE HAVE SEEN 728 00:27:34,880 --> 00:27:37,560 ACTUALLY HUGE ADVANTAGES IN THE 729 00:27:37,560 --> 00:27:38,960 MEDICAL TREATMENT OF EPILEPSY AS 730 00:27:38,960 --> 00:27:41,960 YOU CAN SEE THERE HAS BEEN A TON 731 00:27:41,960 --> 00:27:43,200 OF NEW MEDICATIONS THAT COME 732 00:27:43,200 --> 00:27:44,720 OUT. THIS HAS BEEN AMAZING FOR 733 00:27:44,720 --> 00:27:48,040 OUR PATIENTS. HOWEVER, THE 734 00:27:48,040 --> 00:27:49,400 EFFICACY OF THESE MEDICATIONS 735 00:27:49,400 --> 00:27:50,840 HAS NOT CHANGED OVER TIME. SO 736 00:27:50,840 --> 00:27:52,080 WHAT IS REALLY HAPPENED IS WE 737 00:27:52,080 --> 00:27:54,040 HAVE HAD ADVANCES IN 738 00:27:54,040 --> 00:27:56,040 TOLERABILITY AND SAFETY OF THE 739 00:27:56,040 --> 00:27:57,360 MEDICINES HOWEVER THIS STILL 740 00:27:57,360 --> 00:27:59,080 HOLDS TRUE ONE DOES NOT WORK 741 00:27:59,080 --> 00:28:01,160 BETTER IN THE POPULATION LEVEL 742 00:28:01,160 --> 00:28:03,040 AT LEAST COMPARED TO OTHER 743 00:28:03,040 --> 00:28:04,400 MEDICINES, IF YOU TAKE THE FIRST 744 00:28:04,400 --> 00:28:06,760 MEDICINE HALF THE PEOPLE WILL 745 00:28:06,760 --> 00:28:08,360 BECOME SEIZURE FREE, THE SECOND 746 00:28:08,360 --> 00:28:09,920 MEDICINE CHANCES OF BECOMING 747 00:28:09,920 --> 00:28:11,480 SEIZURE FREE GO DOWN MORE TO 748 00:28:11,480 --> 00:28:14,360 ONLY ADDITIONAL 14% OF PEOPLE. 749 00:28:14,360 --> 00:28:15,640 THEN WHEN AT YOUR THIRD OR 750 00:28:15,640 --> 00:28:16,960 MULTIPLE MEDICATIONS THERE'S 751 00:28:16,960 --> 00:28:18,680 ONLY A 4% CHANCE BECOMING 752 00:28:18,680 --> 00:28:20,320 SEIZURE FREE EVEN AS YOU CYCLE 753 00:28:20,320 --> 00:28:21,120 THROUGH ALL THESE NEW 754 00:28:21,120 --> 00:28:24,960 MEDICATIONS. THIS IS WHY ONE OF 755 00:28:24,960 --> 00:28:26,640 THE MAIN FOCUSES OF MY WORK HERE 756 00:28:26,640 --> 00:28:29,600 HAS BEEN ON EPILEPSY SURGERY. SO 757 00:28:29,600 --> 00:28:31,680 CLEARLY I AM NOT A SURGEON, I 758 00:28:31,680 --> 00:28:33,600 WORK CLOSE WHETHER I WITH OUR 759 00:28:33,600 --> 00:28:35,240 NEUROSURGEONS. WHY? ONE OF THE 760 00:28:35,240 --> 00:28:36,800 MEDICAL THINGS WE TRY TO DO IS 761 00:28:36,800 --> 00:28:39,800 PREVENT OUR PATIENT GETTING TO 762 00:28:39,800 --> 00:28:41,280 SURGEONS BUT IN OUR CASE WHAT WE 763 00:28:41,280 --> 00:28:42,840 FOUND IS A RANDOMIZE CLINICAL 764 00:28:42,840 --> 00:28:44,400 TRIAL THAT SHOWED THIS IS IN 765 00:28:44,400 --> 00:28:45,480 PATIENTS THAT HAVEN'T RESPONDED 766 00:28:45,480 --> 00:28:47,360 TO THOSE FIRST TWO OR THREE OR 767 00:28:47,360 --> 00:28:50,960 FOUR MEDICINES, THE CHANCES OF 768 00:28:50,960 --> 00:28:52,400 SURGERY AND APPROPRIATELY 769 00:28:52,400 --> 00:28:54,400 SELECTED PEOPLE WILL ACTUALLY 770 00:28:54,400 --> 00:28:55,800 INCREASE THEIR CHANCES BECOMING 771 00:28:55,800 --> 00:28:57,440 SEIZURE FREE. IN THIS LAND MARK 772 00:28:57,440 --> 00:28:58,440 TRIAL THE PERCENT DAMAGE OF 773 00:28:58,440 --> 00:29:03,480 PATIENTS WITHOUT SEIZURES IMPAIR 774 00:29:03,480 --> 00:29:04,880 AIR WANS USNESS WAS 58% ONE YEAR 775 00:29:04,880 --> 00:29:06,840 IN SURGICAL GROUP AND ONLY 8% 776 00:29:06,840 --> 00:29:08,000 MEDICAL GROUP. SO THIS MEANS IF 777 00:29:08,000 --> 00:29:09,560 YOU HAVE A PATIENT WHO IS A 778 00:29:09,560 --> 00:29:11,720 SURGICAL CANDIDATE THIS MAY BE 779 00:29:11,720 --> 00:29:12,720 THEIR BEST CHANCE FOR SEIZURE 780 00:29:12,720 --> 00:29:14,680 FREEDOM. WE DIDN'T KNOW THIS FOR 781 00:29:14,680 --> 00:29:16,320 SURE UNTIL RECENTLY IN 2016 782 00:29:16,320 --> 00:29:17,360 THERE WAS ANOTHER STUDY THAT 783 00:29:17,360 --> 00:29:18,760 SHOWED THAT THE PATIENTS THAT 784 00:29:18,760 --> 00:29:20,600 DID GO ON TO HAVE BRAIN SURGERY 785 00:29:20,600 --> 00:29:22,640 HAD SIGNIFICANTLY IMPROVED 786 00:29:22,640 --> 00:29:24,200 MORTALITY AS WELL. THIS IS A BIG 787 00:29:24,200 --> 00:29:26,000 DEAL BECAUSE MANY PATIENTS ARE 788 00:29:26,000 --> 00:29:28,800 OTHERWISE RELATIVELY YOUNG AND 789 00:29:28,800 --> 00:29:30,800 HEALTHY. SO THIS IS A 790 00:29:30,800 --> 00:29:32,320 SIGNIFICANT UM PACT AND ACTUALLY 791 00:29:32,320 --> 00:29:35,320 CHANGES HOW WE COUNCIL OUR 792 00:29:35,320 --> 00:29:37,280 PATIENTS. HOWEVER, THERE HAVE 793 00:29:37,280 --> 00:29:39,400 BEEN NUMEROUS ADVANCES ALONG THE 794 00:29:39,400 --> 00:29:41,080 MEDICINES IN SURGICAL TREATMENT 795 00:29:41,080 --> 00:29:45,320 OF EPILEPSY BUT OUTCOMES ARE 796 00:29:45,320 --> 00:29:46,640 STUBBORN, ONLY ACHIEVING 797 00:29:46,640 --> 00:29:48,360 SUSTAINED SEIZURE FREEDOM IN 798 00:29:48,360 --> 00:29:50,120 ABOUT 67% OF OUR PATIENTS. THIS 799 00:29:50,120 --> 00:29:54,880 IS FOR TEMPORAL LOBE EPILEPSY, A 800 00:29:54,880 --> 00:29:56,040 GROWN WE DO THE BEST IN. THERE 801 00:29:56,040 --> 00:29:57,800 IS A SUBGROUP EVERYTHING LINES 802 00:29:57,800 --> 00:29:59,840 UP PERFECTLY AND HAVE GOOD -- 803 00:29:59,840 --> 00:30:01,360 EVEN BETTER OUTCOMES SO ABOUT 804 00:30:01,360 --> 00:30:02,720 HALF -- THREE QUARTERS OF THESE 805 00:30:02,720 --> 00:30:04,040 PATIENTS WILL BECOME SEIZURE 806 00:30:04,040 --> 00:30:05,640 FREE AFTER SURGERY. HOWEVER 807 00:30:05,640 --> 00:30:08,040 THERE IS THIS OTHER GROUP WITHIN 808 00:30:08,040 --> 00:30:10,840 THIS WHERE THINGS DON'T EXACTLY 809 00:30:10,840 --> 00:30:13,840 MATCH UP AND WE CALL THESE 810 00:30:13,840 --> 00:30:17,920 TEMPORAL LOBE PLUS EPILEPSY, 16% 811 00:30:17,920 --> 00:30:19,000 BECOME SEIZURE FREE AFTER THE 812 00:30:19,000 --> 00:30:20,680 SURGERY WE DO SO THIS IS THE 813 00:30:20,680 --> 00:30:22,360 THING THAT MOTIVATED MY RESEARCH 814 00:30:22,360 --> 00:30:24,080 QUESTIONS. SO THE QUESTION IS, 815 00:30:24,080 --> 00:30:26,440 WHY DOES THIS HAPPEN? ONE IS THE 816 00:30:26,440 --> 00:30:27,560 INCOMPLETE RESECTION. SO IN A 817 00:30:27,560 --> 00:30:29,480 LOT OF THESE PATIENTS, WE GOT 818 00:30:29,480 --> 00:30:30,720 MOST OF THE PROBLEM BUT NOT ALL 819 00:30:30,720 --> 00:30:33,720 THE PROBLEM. SO IN ABOUT HALF 820 00:30:33,720 --> 00:30:35,040 MORE OR LESS OF THESE PATIENTS 821 00:30:35,040 --> 00:30:36,800 IF YOU ACTUALLY REDO A SURGERY 822 00:30:36,800 --> 00:30:38,520 IN THE SAME AREA, THEY WILL 823 00:30:38,520 --> 00:30:41,840 ACTUALLY BECOME SEIZURE FREE. 824 00:30:41,840 --> 00:30:43,240 TOTALLY DIFFERENT PROBLEM IS 825 00:30:43,240 --> 00:30:44,600 INACCURATE LOCALIZATION, THIS IS 826 00:30:44,600 --> 00:30:46,160 THE ONE THAT IS THE FOCUS OF 827 00:30:46,160 --> 00:30:47,520 MOST OF THE REST OF MY TALK. SO 828 00:30:47,520 --> 00:30:49,200 THIS IS WHEN YOU THINK FOR 829 00:30:49,200 --> 00:30:50,400 EXAMPLE THAT THEY HAVE SEIZURES 830 00:30:50,400 --> 00:30:52,040 COMING FROM THEIR TEMPORAL LOBE 831 00:30:52,040 --> 00:30:53,120 AND TURNS OUT TO NOT BE THE 832 00:30:53,120 --> 00:30:54,800 CASE. WE THINK THIS ACCOUNTS 833 00:30:54,800 --> 00:30:56,920 FOR UP TO ONE FIFTH OF THE 834 00:30:56,920 --> 00:30:58,760 FAILURES ONGOING SEIZURES AFTER 835 00:30:58,760 --> 00:31:00,000 SURGERY AND THIS IS REALLY THE 836 00:31:00,000 --> 00:31:04,520 CASE IN A LOT OF TEMPORAL PLUS 837 00:31:04,520 --> 00:31:07,120 EPILEPSIES WHERE SEIZURES COME 838 00:31:07,120 --> 00:31:09,160 FROM SURROUNDING YARRS, INSULA, 839 00:31:09,160 --> 00:31:10,880 ORBITAL FRONTAL LOBE OR OTHER 840 00:31:10,880 --> 00:31:11,960 REGIONS SO IDENTIFYING THIS IS 841 00:31:11,960 --> 00:31:13,080 AN OPPORTUNITY FOR ADVANCEMENT 842 00:31:13,080 --> 00:31:14,960 IN THE CAR OF PATIENTS. THEN 843 00:31:14,960 --> 00:31:16,640 THE LAST IS PATIENTS DO ACTUALLY 844 00:31:16,640 --> 00:31:18,760 HAVE DIFFUSE OR MULTI-FOCAL 845 00:31:18,760 --> 00:31:20,120 DISEASE YOU CAN IMAGINE AFTER 846 00:31:20,120 --> 00:31:25,080 TRAUMATIC BRAIN INJURIES OR 847 00:31:25,080 --> 00:31:26,360 ENCEPHALITIS OR MORE DIFFUSE 848 00:31:26,360 --> 00:31:27,680 GENETIC PROBLEMS IF YOU ADDRESS 849 00:31:27,680 --> 00:31:30,880 ONE AREA THE SEIZURES MAYBE 850 00:31:30,880 --> 00:31:32,360 COMING FROM THEY MAY GO ON IN 851 00:31:32,360 --> 00:31:33,600 THE FUTURE SO IDENTIFYING WHICH 852 00:31:33,600 --> 00:31:34,760 OF THESE PATIENTS IS IMPORTANT 853 00:31:34,760 --> 00:31:37,320 TO IMPROVE SURGICAL OUTCOMES. 854 00:31:37,320 --> 00:31:40,480 SO AS I SAID I GOT HERE IN ABOUT 855 00:31:40,480 --> 00:31:42,040 2010 AND AFTER BEING HERE FOR 856 00:31:42,040 --> 00:31:43,560 SEVERAL YEARS I REALIZE WE HAD 857 00:31:43,560 --> 00:31:45,120 THESE AMAZING OPPORTUNITIES TO 858 00:31:45,120 --> 00:31:46,840 TRY TO PURSUE SOME OF THESE 859 00:31:46,840 --> 00:31:48,320 QUESTIONS HERE. SO THIS IS WHAT 860 00:31:48,320 --> 00:31:50,600 OUR TYPICAL SURGICAL EVALUATION 861 00:31:50,600 --> 00:31:52,760 LOOKS LIKE AND THIS WILL BE THE 862 00:31:52,760 --> 00:31:54,320 TRUE IN ANY EPILEPSY CENTER 863 00:31:54,320 --> 00:31:56,200 ACROSS THE COUNTRY, VERY 864 00:31:56,200 --> 00:31:57,400 STANDARD YOU CLINICALLY 865 00:31:57,400 --> 00:32:00,040 CHARACTERIZE THE PATIENT, DO 866 00:32:00,040 --> 00:32:00,720 NEUROPSYCHOLOGICAL TESTING AND 867 00:32:00,720 --> 00:32:02,440 DO EEG BETWEEN THE SEIZURES AND 868 00:32:02,440 --> 00:32:04,720 DURING THE SEIZURES SO YOU CAN 869 00:32:04,720 --> 00:32:08,680 SEE THESE AREAS OF IRRITABILITY 870 00:32:08,680 --> 00:32:09,680 THROUGH ELECTRICAL ACTIVITY OF 871 00:32:09,680 --> 00:32:11,760 THE BRAIN. THEN WE ALSO RELY 872 00:32:11,760 --> 00:32:13,000 HEAVILY ON STRUCTURAL IMAGING 873 00:32:13,000 --> 00:32:15,120 WHICH CAN IDENTIFY FOCAL 874 00:32:15,120 --> 00:32:16,240 LESIONS, FUNCTIONAL IMAGING 875 00:32:16,240 --> 00:32:18,560 THERE IS A LONG HISTORY NIH OF 876 00:32:18,560 --> 00:32:21,360 DOING PET IMAGING TO IDENTIFY 877 00:32:21,360 --> 00:32:22,760 ABNORMALITIES IN PATIENTS WITH 878 00:32:22,760 --> 00:32:24,200 EPILEPSY. THEN FUNCTIONAL 879 00:32:24,200 --> 00:32:26,080 MAPPING YOU CAN LATERALIZE AND 880 00:32:26,080 --> 00:32:27,480 SOMETIMES EVEN LOCALIZE LANGUAGE 881 00:32:27,480 --> 00:32:30,160 AREAS. THESE ARE ALL THE THINGS 882 00:32:30,160 --> 00:32:31,600 STANDARD WE WERE DOING ALL 883 00:32:31,600 --> 00:32:34,520 ALONG. THEN WE ADDED IN AS IT 884 00:32:34,520 --> 00:32:37,640 BECAME AVAILABLE HIGHER FIELD 885 00:32:37,640 --> 00:32:39,160 IMAGING AT 7T, WE HAVE THE 886 00:32:39,160 --> 00:32:40,600 OPPORTUNITY TO ACCESS HERE, WE 887 00:32:40,600 --> 00:32:42,400 ADDED ON DIFFUSION TENSOR 888 00:32:42,400 --> 00:32:43,960 IMAGING TO LOOK AT STRUCTURAL 889 00:32:43,960 --> 00:32:47,720 COKETIVETY AND WE ADD -- 890 00:32:47,720 --> 00:32:48,800 CONNECTIVITY, THEN WE ADD 891 00:32:48,800 --> 00:32:51,720 PROFUSION IMAGING THAT SHOUGHS 892 00:32:51,720 --> 00:32:52,280 CHANGES DURING THE COURSE OF 893 00:32:52,280 --> 00:32:55,640 EPILEPSY. FINALLY WE HAVE A 894 00:32:55,640 --> 00:32:56,520 REALLY INTERESTING OPPORTUNITY 895 00:32:56,520 --> 00:32:58,160 IN THESE PATIENTS BECAUSE IN THE 896 00:32:58,160 --> 00:32:59,520 CLINICAL CARE OF THESE PATIENTS 897 00:32:59,520 --> 00:33:01,880 WE OFTENTIMES GO ON TO TRY AND 898 00:33:01,880 --> 00:33:02,880 IDENTIFY WHERE SEIZURES ARE 899 00:33:02,880 --> 00:33:06,080 COMING FROM USING INVASIVE EEEG 900 00:33:06,080 --> 00:33:06,920 RECORDINGS, IN COLLABORATION 901 00:33:06,920 --> 00:33:10,840 WITH SURGEONS HERE. SO INVASIVE 902 00:33:10,840 --> 00:33:12,280 EEG RECORDINGS PUT ELECTRODES ON 903 00:33:12,280 --> 00:33:14,800 THE SURFACE OF THE BRAIN OR INTO 904 00:33:14,800 --> 00:33:15,960 TESTIMONY BRAIN AND RECORDS 905 00:33:15,960 --> 00:33:17,800 SEIZURES FROM THERE TO HELP 906 00:33:17,800 --> 00:33:19,800 GUIDE OUR SURGICAL RESECTIONS. 907 00:33:19,800 --> 00:33:22,400 AND WE DO MAPPING SO WE DO DRUG 908 00:33:22,400 --> 00:33:23,560 CORTICAL STIMULATION MAPPING AND 909 00:33:23,560 --> 00:33:24,920 YOU CAN FIND AREAS THAT ARE 910 00:33:24,920 --> 00:33:26,960 IMPORTANT FOR MOTOR OR LANGUAGE 911 00:33:26,960 --> 00:33:28,640 FUNCTION. SO THIS WHOLE 912 00:33:28,640 --> 00:33:31,160 SITUATION ALLOWS US TO TEST OUR 913 00:33:31,160 --> 00:33:33,560 HYPOTHESES FROM THE NON-INVASIVE 914 00:33:33,560 --> 00:33:35,120 IMAGING WITH INVASIVE RECORDINGS 915 00:33:35,120 --> 00:33:36,880 AND OUR RESECTIONS SO IF A 916 00:33:36,880 --> 00:33:38,160 PATIENT BECOMES SEIZURE FREE 917 00:33:38,160 --> 00:33:40,680 AFTER A SURGERY WE CAN ASSUME WE 918 00:33:40,680 --> 00:33:42,520 DID FIND THE CORRECT LOCATION 919 00:33:42,520 --> 00:33:44,680 AND THEREFORE IT CAN ASSESS 920 00:33:44,680 --> 00:33:46,160 WHETHER WE WERE CORRECT FOR 921 00:33:46,160 --> 00:33:48,040 NON-INVASIVE IMAGING. SO I WILL 922 00:33:48,040 --> 00:33:49,320 JUST TELL YOU BRIEFLY ABOUT TWO 923 00:33:49,320 --> 00:33:50,640 OF THE THINGS WE HAVE DONE OVER 924 00:33:50,640 --> 00:33:53,240 THE LAST FEW YEARS HERE. TO TRY 925 00:33:53,240 --> 00:33:56,560 TO GET A BETTER SENSE OF WHERE 926 00:33:56,560 --> 00:33:57,520 THESE SEIZURES ARE COMING FROM 927 00:33:57,520 --> 00:34:00,000 IN THE BRAIN. HERE IS AN EXAMPLE 928 00:34:00,000 --> 00:34:02,040 OF EPILEPTOGENIC LESION. EVEN 929 00:34:02,040 --> 00:34:03,600 THOUGH WHO DON'T OFTEN LOOK AT 930 00:34:03,600 --> 00:34:04,000 MRI. 931 00:34:04,000 --> 00:34:05,680 IMAGINES CAN PROBABLY SEE THIS 932 00:34:05,680 --> 00:34:06,840 DOESN'T LOOK LIKE THE REST OF 933 00:34:06,840 --> 00:34:11,600 THE BRAIN. THIS IS A CAVRANOMA 934 00:34:11,600 --> 00:34:12,880 COMMON CAUSE OF EPILEPSY IN 935 00:34:12,880 --> 00:34:15,560 PATIENTS. THIS IS THE QUINT 936 00:34:15,560 --> 00:34:16,520 ESSENTIAL LESION WE TALK ABOUT 937 00:34:16,520 --> 00:34:20,360 ALL THE TIME IN TEMPORAL LOBE 938 00:34:20,360 --> 00:34:23,240 EPILEPSY AND THIS IS ME SEW 939 00:34:23,240 --> 00:34:25,360 TEMPORAL LOBE SCLEROSIS, YOU CAN 940 00:34:25,360 --> 00:34:27,000 SEE THIS IS THE EPICAMPUS THE 941 00:34:27,000 --> 00:34:28,280 ARROW IS POINTING TO AND WHAT 942 00:34:28,280 --> 00:34:31,960 YOU CAN SEE IS THAT THE ONE 943 00:34:31,960 --> 00:34:33,440 ARROW IS POINTING TO IS SMALL 944 00:34:33,440 --> 00:34:35,240 AND BRIGHT ON THIS IMAGE SO THIS 945 00:34:35,240 --> 00:34:38,000 IS A VERY COMMON CAUSE OF DRUG 946 00:34:38,000 --> 00:34:39,400 RESISTANT EPILEPSY. IN MY 947 00:34:39,400 --> 00:34:41,280 RESEARCH THE THING I'M MORE 948 00:34:41,280 --> 00:34:43,440 FOCUSED ON HERE IS THE TYPE OF 949 00:34:43,440 --> 00:34:45,520 LESION CALLED A FOCAL CORTICAL 950 00:34:45,520 --> 00:34:47,600 DYSPLASIA. SO THESE DYSPLASIAS 951 00:34:47,600 --> 00:34:49,720 AGAIN THE RED ARROW POINTING TO 952 00:34:49,720 --> 00:34:50,960 THEM ARE SOMETIMES OBVIOUS ON 953 00:34:50,960 --> 00:34:52,760 IMAGING BUT SOMETIMES ARE VERY 954 00:34:52,760 --> 00:34:53,840 DIFFICULT TO APPRECIATE WHEN 955 00:34:53,840 --> 00:34:56,480 JUST LOOKING BY EYE. THESE 956 00:34:56,480 --> 00:34:57,760 AREN'T DEVELOPMENTAL 957 00:34:57,760 --> 00:34:59,280 ABNORMALITIES THAT HAPPEN AT 958 00:34:59,280 --> 00:35:01,520 TIME OF BIRT BIRTH. THEY DON'T D 959 00:35:01,520 --> 00:35:03,320 TO SEIZURES RIGHT AWAY. A LOT OF 960 00:35:03,320 --> 00:35:05,240 TIME SEIZURE ALSO COME UP IN 961 00:35:05,240 --> 00:35:06,560 THEIR TEENS TO EARLY 20s WHICH 962 00:35:06,560 --> 00:35:09,040 IS WHEN I SEE THEM. AND I THINK 963 00:35:09,040 --> 00:35:10,200 WHAT YOU CAN SEE WITH THE ARROW 964 00:35:10,200 --> 00:35:12,280 IS THAT THERE IS ON THE IMAGE ON 965 00:35:12,280 --> 00:35:14,080 THE RIGHT, A FLAIR IMAGE YOU CAN 966 00:35:14,080 --> 00:35:17,160 SEE THAT THERE IS A BRIGHT AREA 967 00:35:17,160 --> 00:35:18,840 AND THEN ON THE IMAGE ON THE 968 00:35:18,840 --> 00:35:20,640 LEFT, A T 1 IMAGE YOU CAN SEE 969 00:35:20,640 --> 00:35:22,920 THAT AREA OF CORTEX IS THICKENED 970 00:35:22,920 --> 00:35:24,880 AND BLURRED. THIS IS A VERY 971 00:35:24,880 --> 00:35:26,120 TYPICAL CHARACTERIZATION OF 972 00:35:26,120 --> 00:35:27,800 THESE. ONE THAT IS OBVIOUS LIKE 973 00:35:27,800 --> 00:35:29,800 THIS I THINK WOULD USUALLY BE 974 00:35:29,800 --> 00:35:31,360 SEEN BY EYE. HOWEVER, THERE ARE 975 00:35:31,360 --> 00:35:32,800 OTHER PATIENTS WHERE THIS IS 976 00:35:32,800 --> 00:35:35,080 HARD TO APPRECIATE. AND IN 977 00:35:35,080 --> 00:35:36,720 SKIMMING THROUGH THE IMAGE MOST 978 00:35:36,720 --> 00:35:38,320 PEOPLE WILL NOT IDENTIFY THIS 979 00:35:38,320 --> 00:35:40,040 AND MANY RADIOLOGISTS DO NOT 980 00:35:40,040 --> 00:35:42,240 IDENTIFY LESION IN THIS PATIENT. 981 00:35:42,240 --> 00:35:44,760 AGAIN WITH MY RED ARROW SIGN 982 00:35:44,760 --> 00:35:46,280 MAYBE YOU CAN SEE A SLIGHT BIT 983 00:35:46,280 --> 00:35:47,680 OF HYPERINTENSITY IN THE IMAGE 984 00:35:47,680 --> 00:35:49,240 ON THE RIGHT, A SLIGHT BIT OF 985 00:35:49,240 --> 00:35:50,880 BLURRING ON THE LEFT. IMAGINE AS 986 00:35:50,880 --> 00:35:52,920 YOU ARE SCROLLING THROUGH IMAGES 987 00:35:52,920 --> 00:35:53,680 THESE CAN BE VERY DIFFICULT TO 988 00:35:53,680 --> 00:35:57,840 FIND. THIS IS ONE OF THE MOST 989 00:35:57,840 --> 00:35:58,560 COMMON PATHOLOGIES IN OUR 990 00:35:58,560 --> 00:36:00,120 PATIENTS THAT ARE THOUGHT TO BE 991 00:36:00,120 --> 00:36:02,000 MRI NEGATIVE. SO INTERESTINGLY 992 00:36:02,000 --> 00:36:05,680 OUR SURGICAL OUTCOMES ARE BETTER 993 00:36:05,680 --> 00:36:07,160 IN PATIENT WHERE IS WE CAN FIND 994 00:36:07,160 --> 00:36:08,720 LESIONS AND THAT IS FOR NUMBER 995 00:36:08,720 --> 00:36:10,720 OF CAUSES BUT THERE WERE SEVERAL 996 00:36:10,720 --> 00:36:12,840 PROCEDURES OUT THERE DESCRIBED 997 00:36:12,840 --> 00:36:14,640 TO HELP USING MACHINE LEARNING 998 00:36:14,640 --> 00:36:17,800 AND IMAGE PROCESSING TO IDENTIFY 999 00:36:17,800 --> 00:36:19,480 LESIONS, BUT NONE WERE PUBLICLY 1000 00:36:19,480 --> 00:36:22,160 AVAILABLE SO WE PROCEED OUR OWN 1001 00:36:22,160 --> 00:36:23,320 EFFORTS, THIS IS ONE OF THE WAYS 1002 00:36:23,320 --> 00:36:25,920 WE CAN MAKE THE MOST QUICKLY 1003 00:36:25,920 --> 00:36:27,880 BETTER FOR OUR PATIENTS. SO WHAT 1004 00:36:27,880 --> 00:36:30,480 YOU CAN SEE HERE IS THAT USING 1005 00:36:30,480 --> 00:36:32,720 OUR OWN POST PROCESSING IMAGES 1006 00:36:32,720 --> 00:36:34,360 WE WERE ABLE TO DEVELOP THIS 1007 00:36:34,360 --> 00:36:36,080 FOCAL CORTICAL DYSPLASIA OF 1008 00:36:36,080 --> 00:36:42,200 SIMILAR PLSIMILARITY MAP. THIS R 1009 00:36:42,200 --> 00:36:43,600 INTUITIVE. THESE ARE IMAGES ON 1010 00:36:43,600 --> 00:36:47,480 THE T 1 AND FLAIR IMAGES SEEING 1011 00:36:47,480 --> 00:36:49,200 RADIO LOGICALLY, THE IMAGE ON 1012 00:36:49,200 --> 00:36:50,640 THE RIGHT IS A BRAIN IF YOU WENT 1013 00:36:50,640 --> 00:36:52,000 AND FLEETED TO ALL THE CURVES 1014 00:36:52,000 --> 00:36:54,320 ARE GONE. SO WHAT YOU CAN SEE IS 1015 00:36:54,320 --> 00:36:56,280 THERE ARE PARTS OF THE BRAIN IN 1016 00:36:56,280 --> 00:36:58,280 THIS SIMILARITY MAP THAT 1017 00:36:58,280 --> 00:36:59,720 ACTUALLY TYPICALLY LOOK VERY 1018 00:36:59,720 --> 00:37:02,360 SIMILAR TO FOCAL CORTICAL 1019 00:37:02,360 --> 00:37:03,520 DYSPLASIAS AND LEAD TO SOME OF 1020 00:37:03,520 --> 00:37:04,760 THE PROBLEMS WITH IDENTIFYING 1021 00:37:04,760 --> 00:37:06,120 THEM BECAUSE SOMETIMES THEY LOOK 1022 00:37:06,120 --> 00:37:08,080 VERY SIMILAR TO NORMAL BRAINS. 1023 00:37:08,080 --> 00:37:09,960 BUT THOSE WERE IN TYPICAL 1024 00:37:09,960 --> 00:37:12,360 LOCATIONS MOSTLY NEAR MOTOR AND 1025 00:37:12,360 --> 00:37:13,760 SENSORY CORTEX AND THE INSULA. 1026 00:37:13,760 --> 00:37:15,560 WHEN WE USED HEALTHY VOLUNTEERS 1027 00:37:15,560 --> 00:37:17,400 AN CORRECTED, YOU CAN SEE THAT 1028 00:37:17,400 --> 00:37:19,480 OUR FOCAL CORTICAL DYSPLASIA 1029 00:37:19,480 --> 00:37:21,200 STANDS OUT CLEARLY. SO THIS IS 1030 00:37:21,200 --> 00:37:23,160 THE MASK WE DREW BY HAND AND 1031 00:37:23,160 --> 00:37:24,040 DETECTION WE WERE ABLE TO 1032 00:37:24,040 --> 00:37:25,600 ACHIEVE. SO WE STILL USE THIS 1033 00:37:25,600 --> 00:37:27,400 NOW GOING FORWARD IN ALL OF OUR 1034 00:37:27,400 --> 00:37:28,880 PATIENTS AND IN A NUMBER OF 1035 00:37:28,880 --> 00:37:30,400 PATIENTS IT IS HELPED TO 1036 00:37:30,400 --> 00:37:32,280 IDENTIFY THE ABNORMALITY AND WE 1037 00:37:32,280 --> 00:37:33,680 DIRECTLY BEEN ABLE TO TRANSLATE 1038 00:37:33,680 --> 00:37:35,160 TO IMPROVED OUTCOMES IN OUR 1039 00:37:35,160 --> 00:37:39,280 PATIENTS. WE HAVE THE 1040 00:37:39,280 --> 00:37:41,360 OPPORTUNITY TO USE 7T IMAGES AND 1041 00:37:41,360 --> 00:37:42,760 WE WORKED WITH (INAUDIBLE) TO 1042 00:37:42,760 --> 00:37:43,960 ATTEMPT TO MAKE THE IMAGES 1043 00:37:43,960 --> 00:37:47,680 BETTER FOR US. YOU CAN SEE 1044 00:37:47,680 --> 00:37:48,560 ANOTHER DYSPLASIA THAT IS 1045 00:37:48,560 --> 00:37:49,920 SUBTLE, THIS IS WHAT IT LOOKS ON 1046 00:37:49,920 --> 00:37:52,640 THE RIGHT ON 3T IMEMERGENCIENING 1047 00:37:52,640 --> 00:37:55,200 IMAGINING THAN THE MP -- 1048 00:37:55,200 --> 00:37:57,040 IMAGING. WE ARE STILL WORKING 1049 00:37:57,040 --> 00:37:58,880 HOW TO OPTIMIZE THIS BUT SHOWS 1050 00:37:58,880 --> 00:38:00,760 PROMISE TO FIND THE SUBTLE 1051 00:38:00,760 --> 00:38:02,960 LESIONS. ALL RIGHT. SO WITH THE 1052 00:38:02,960 --> 00:38:05,640 TIME THAT'S LEFT, I WILL TELL 1053 00:38:05,640 --> 00:38:06,880 YOU MORE ABOUT 1054 00:38:06,880 --> 00:38:09,120 ELECTROPHYSIOLOGY. I'M AN 1055 00:38:09,120 --> 00:38:09,880 ELECTROPHYSIOLOGIST BY TRAINING 1056 00:38:09,880 --> 00:38:13,680 SO EEG IS WHAT I CAME TO ALL OF 1057 00:38:13,680 --> 00:38:15,800 THIS DOING. WE CAN LOOK AT IT 1058 00:38:15,800 --> 00:38:18,400 USING SCALP EEG STICKERS WE PUT 1059 00:38:18,400 --> 00:38:19,840 ON THE OUTSIDE OF THE HEAD. WE 1060 00:38:19,840 --> 00:38:21,880 CAN USE THIS USING MEG INSTEAD 1061 00:38:21,880 --> 00:38:23,440 OF ELECTRICAL ACTIVITY WE LOOK 1062 00:38:23,440 --> 00:38:24,680 AT MAGNETIC ACTIVITY OF THE 1063 00:38:24,680 --> 00:38:28,400 BRAIN AND WE CAN ALSO USE THE 1064 00:38:28,400 --> 00:38:31,480 INTRACRANIAL ELECTRODES WHEN WE 1065 00:38:31,480 --> 00:38:32,920 WORKED WITH DR. (INDISCERNIBLE) 1066 00:38:32,920 --> 00:38:34,440 OUR NEUROSURGEON. THERE'S TWO 1067 00:38:34,440 --> 00:38:37,040 WAYS TO PUT ELECTRODES IN OR ON 1068 00:38:37,040 --> 00:38:39,760 THE BRAIN, ONE IS SUB DO YOU 1069 00:38:39,760 --> 00:38:42,120 RECALL ELECTRODES UNDER THE DURA 1070 00:38:42,120 --> 00:38:43,360 AS YOU SUSPECT AND LIE ON THE 1071 00:38:43,360 --> 00:38:45,760 SURFACE OF THE BRAI BRAIN. A AND 1072 00:38:45,760 --> 00:38:47,640 STEREO EEG ALLOWS ELECTRODES 1073 00:38:47,640 --> 00:38:49,480 INTO THE BRAIN LIKE A NEEDLE 1074 00:38:49,480 --> 00:38:50,720 BIOPSY SO WE CAN RECORD FROM 1075 00:38:50,720 --> 00:38:52,120 THOSE. NO MATTER WHICH WAY WE DO 1076 00:38:52,120 --> 00:38:55,880 IT ON MY END, THE SQUIGGLY LINES 1077 00:38:55,880 --> 00:38:57,040 THEY LOOK SIMILAR SO WHAT YOU 1078 00:38:57,040 --> 00:38:58,960 CAN SEE HERE IS AN EXAMPLE OF 1079 00:38:58,960 --> 00:39:00,400 SOMEBODY WITH RIGHT AND LEFT 1080 00:39:00,400 --> 00:39:03,440 SIDED ELECTRODES AND YOU CAN SEE 1081 00:39:03,440 --> 00:39:06,680 THAT THEY GET WEAVEY HERE ON THE 1082 00:39:06,680 --> 00:39:07,880 RIGHT FIRST LATER SPREADS TO THE 1083 00:39:07,880 --> 00:39:09,840 LEFT. SO THE GOLD STANDARD RIGHT 1084 00:39:09,840 --> 00:39:11,400 NOW IS WHEREVER YOU SEE THE 1085 00:39:11,400 --> 00:39:12,640 SEIZURES START FIRST, THAT'S 1086 00:39:12,640 --> 00:39:15,520 WHERE WE THINK THE SEIZURES ARE 1087 00:39:15,520 --> 00:39:17,360 COMING FROM. THIS LED US TO THE 1088 00:39:17,360 --> 00:39:19,640 OUTCOMES THAT WE CURRENTLY HAVE 1089 00:39:19,640 --> 00:39:21,560 NOW, THE THICK THAT IS 1090 00:39:21,560 --> 00:39:22,640 FRUSTRATING BECAUSE YOUR 1091 00:39:22,640 --> 00:39:24,600 PATIENTS GO THROUGH THESE 1092 00:39:24,600 --> 00:39:26,880 PROCEDURES IS ON THE -- AS SOON 1093 00:39:26,880 --> 00:39:29,800 AS YOU REQUIRE INTRACRANIAL EEG 1094 00:39:29,800 --> 00:39:31,240 MONITORING YOUR OUTCOMES ARE 1095 00:39:31,240 --> 00:39:33,280 WORSE. WHY? BECAUSE YOU HAVE 1096 00:39:33,280 --> 00:39:34,160 DIFFUSE PROBLEMS MAYBE BECAUSE 1097 00:39:34,160 --> 00:39:36,040 YOU HAVE A HUGE OR MULTIPLE 1098 00:39:36,040 --> 00:39:36,960 LESIONS, MAYBE BECAUSE IT IS 1099 00:39:36,960 --> 00:39:40,400 HARD FOR US TO FIND. JUST 1100 00:39:40,400 --> 00:39:41,880 NEEDING THESE ELECTRODES MEANS 1101 00:39:41,880 --> 00:39:43,840 OUR OUTCOMES ARE GOING TO GO 1102 00:39:43,840 --> 00:39:46,320 FROM ABOUT ALMOST 80% TO ALMOST 1103 00:39:46,320 --> 00:39:48,560 40% SEIZURE FREEDOM. THE SECOND 1104 00:39:48,560 --> 00:39:49,520 PART THAT WAS POINTED OUT IN 1105 00:39:49,520 --> 00:39:52,560 THIS PAPER THAT CAME OUT IN 2019 1106 00:39:52,560 --> 00:39:55,080 I ACTUALLY RESONATED DEEPLY WITH 1107 00:39:55,080 --> 00:39:57,840 ME. WHEN THERE'S SLOW SPREAD OF 1108 00:39:57,840 --> 00:39:59,560 SEIZURES ON INTRACRANIAL EEG WE 1109 00:39:59,560 --> 00:40:01,600 DO REALLY WELL SO THE PATIENTS 1110 00:40:01,600 --> 00:40:03,680 HAVE OVER 80% SEIZURE FREEDOM. 1111 00:40:03,680 --> 00:40:05,080 THESE ARE REALLY DIFFERENT THAN 1112 00:40:05,080 --> 00:40:07,200 THE PATIENTS WHERE WE SEE THIS 1113 00:40:07,200 --> 00:40:09,840 REALLY RAPID SPREAD ON OUR 1114 00:40:09,840 --> 00:40:12,240 INTRACRANIAL EEG. WHY THAT IS IS 1115 00:40:12,240 --> 00:40:13,280 ONE OF THE QUESTIONS THAT 1116 00:40:13,280 --> 00:40:15,280 CONTINUES TO BOTHER ME AND IS 1117 00:40:15,280 --> 00:40:16,120 CONTINUED TO DRIVE RESEARCH WE 1118 00:40:16,120 --> 00:40:17,960 HAVE BEEN DOING SO HERE YOU CAN 1119 00:40:17,960 --> 00:40:19,960 SEE IF A SEIZURE REMAINS 1120 00:40:19,960 --> 00:40:21,560 CONTAINED TO THIS REGION THIS IS 1121 00:40:21,560 --> 00:40:23,400 SOMETHING THAT IF IT WAS SAFE WE 1122 00:40:23,400 --> 00:40:25,360 COULD TARGET RELATIVELY EASILY. 1123 00:40:25,360 --> 00:40:27,360 LACK DOWN HERE, THIS IS WITHIN 1124 00:40:27,360 --> 00:40:29,040 TEN SECONDS OF SEIZURES 1125 00:40:29,040 --> 00:40:30,080 STARTING, IF SPREAD THROUGH THE 1126 00:40:30,080 --> 00:40:32,120 BRAIN REGION THEN THIS IS MORE 1127 00:40:32,120 --> 00:40:34,120 DIFFICULT. AND LEADS YOU TO 1128 00:40:34,120 --> 00:40:35,280 WONDER WHAT WE ARE GETTING 1129 00:40:35,280 --> 00:40:38,080 WRONG. SO THERE ARE TWO REASONS 1130 00:40:38,080 --> 00:40:39,800 I THINK WE SOMETIMES GET IT 1131 00:40:39,800 --> 00:40:42,040 WRONG. ON MY SIDE OF THINGS. 1132 00:40:42,040 --> 00:40:44,000 ONE IS EVEN WHEN YOU PUT THESE 1133 00:40:44,000 --> 00:40:45,400 ELECTRODES ON THE SURFACE OF THE 1134 00:40:45,400 --> 00:40:47,280 BRAIN, IF YOU LOOK HERE WHEN THE 1135 00:40:47,280 --> 00:40:48,480 BRAIN IS ACTUALLY EXPOSED AND 1136 00:40:48,480 --> 00:40:50,360 YOU CAN SEE IT, IT LOOKS LIKE WE 1137 00:40:50,360 --> 00:40:52,680 HAVE REALLY COVERED EVERYTHING. 1138 00:40:52,680 --> 00:40:54,160 SO YOU SAY HOW CAN WE POSSIBLY 1139 00:40:54,160 --> 00:40:55,520 GET IT WRONG? THIS IS WHAT IT 1140 00:40:55,520 --> 00:40:56,760 LOOKS LIKE WHEN YOU PUT ON THE 1141 00:40:56,760 --> 00:40:58,200 SURFACE OF THE BRAIN IN OUR 1142 00:40:58,200 --> 00:41:00,760 IMAGES. HOWEVER, WHEN I DO THAT 1143 00:41:00,760 --> 00:41:02,000 INFLATED BRAIN I SHOWED YOU 1144 00:41:02,000 --> 00:41:05,200 BEFORE WHAT YOU SEE IS STILL 1145 00:41:05,200 --> 00:41:06,960 VERY SPARSE FACIAL SAMPLING SO 1146 00:41:06,960 --> 00:41:09,800 IN OUR BEST EFFORTS WE ONLY 1147 00:41:09,800 --> 00:41:10,600 COVER SMALL PER TAJES OF THE 1148 00:41:10,600 --> 00:41:12,640 BRAIN. IN A RECENT PAPER NO 1149 00:41:12,640 --> 00:41:15,200 MATTER THE METHOD WE USED OF 1150 00:41:15,200 --> 00:41:16,960 RECORDING IN THE REGION IN THE 1151 00:41:16,960 --> 00:41:18,960 FRONTAL LOBE WE ALMOST NEVER 1152 00:41:18,960 --> 00:41:20,800 COVER MORE THAN 3% OF THE BRAIN. 1153 00:41:20,800 --> 00:41:22,480 IN THE TEMPORAL LOBE, ALMOST 1154 00:41:22,480 --> 00:41:25,000 NEVER MORE THAN 4% OF THE BRAIN 1155 00:41:25,000 --> 00:41:26,560 SO NO MATTER WHAT HE DO WE ARE 1156 00:41:26,560 --> 00:41:27,800 UNLIKELY AT THE PLACE THE 1157 00:41:27,800 --> 00:41:30,560 SEIZURE STARTED. A SECOND REASON 1158 00:41:30,560 --> 00:41:31,960 THIS IS ACTUALLY A DIFFICULT 1159 00:41:31,960 --> 00:41:33,640 PROBLEM FOR US IS THAT THE 1160 00:41:33,640 --> 00:41:36,640 SIGNAL ON THE EEG MANY WILL SEE 1161 00:41:36,640 --> 00:41:38,360 THIS AND MEDICAL SCHOOL CLASSES 1162 00:41:38,360 --> 00:41:40,480 OR BASIC SCIENCE CLASS. YOU 1163 00:41:40,480 --> 00:41:42,400 NEVER APPRECIATE WHAT THIS MEANS 1164 00:41:42,400 --> 00:41:43,800 PRACTICALLY. WHAT THIS MEANS 1165 00:41:43,800 --> 00:41:45,040 PRACTICALLY, THIS IS THE 1166 00:41:45,040 --> 00:41:47,520 GENERATOR OF EEG, IF THESE ARE 1167 00:41:47,520 --> 00:41:49,440 NEURONS, THESE ARE THE DENDRITES 1168 00:41:49,440 --> 00:41:50,840 AND THESE ARE PLACES YOU ARE 1169 00:41:50,840 --> 00:41:51,880 RECEIVING ACTIVITY. WHAT HAPPENS 1170 00:41:51,880 --> 00:41:54,680 IN THE EEG IS WE SEE WHAT AREAS 1171 00:41:54,680 --> 00:41:57,760 ARE RECEIVING ACTIVITY BUT NOT 1172 00:41:57,760 --> 00:41:59,440 NECESSARILY WHAT REGIONS OF THE 1173 00:41:59,440 --> 00:42:00,720 BRAIN ARE SENDING THAT ACTIVITY. 1174 00:42:00,720 --> 00:42:02,280 SO WHEN LOCAL WE STILL GET IT 1175 00:42:02,280 --> 00:42:04,960 RIGHT BUT WHEN NOT LOCAL WE MAY 1176 00:42:04,960 --> 00:42:07,040 ACTUALLY BE MISLED. SO THIS IS 1177 00:42:07,040 --> 00:42:10,800 AN IMPORTANT CAVEAT. AS I WAS 1178 00:42:10,800 --> 00:42:12,040 SAYING LOCAL ACTIVITY ACTUALLY 1179 00:42:12,040 --> 00:42:14,360 IS A HUGE PART OF WHAT HAPPENS. 1180 00:42:14,360 --> 00:42:16,600 THIS IS AN ANIMAL MODEL WHERE 1181 00:42:16,600 --> 00:42:17,800 SOMEBODY I THINK THIS IS STILL 1182 00:42:17,800 --> 00:42:19,760 THE MOST ELEGANT WAY I HAVE SEEN 1183 00:42:19,760 --> 00:42:21,640 THIS SHOWN WHERE AS MANY OF YOU 1184 00:42:21,640 --> 00:42:23,440 KNOW WE MAPPED OUT VISUAL CORTEX 1185 00:42:23,440 --> 00:42:25,640 VERY CLEARLY, IF YOU FLASHLIGHTS 1186 00:42:25,640 --> 00:42:27,440 AND THIS QUADRANT WITH THIS 1187 00:42:27,440 --> 00:42:28,880 COLOR, IT WILL ACTIVATE THIS 1188 00:42:28,880 --> 00:42:30,000 PART OF THE BRAIN AND SPREAD TO 1189 00:42:30,000 --> 00:42:31,120 THESE OTHER PARTS OF THE BRAIN. 1190 00:42:31,120 --> 00:42:32,920 WHAT THEY SHOWED IN A RODENT 1191 00:42:32,920 --> 00:42:34,720 MODEL IF THEY SET OFF A SEIZURE 1192 00:42:34,720 --> 00:42:36,160 THERE IT WOULD SPREAD LOCALLY. I 1193 00:42:36,160 --> 00:42:37,720 TALK ABOUT THIS BEING A PEBBLE 1194 00:42:37,720 --> 00:42:40,320 IN A POND BUT ALSO CAN SPREAD 1195 00:42:40,320 --> 00:42:41,720 DISTANTLY. SO WE KNOW IF WE MAKE 1196 00:42:41,720 --> 00:42:46,400 USE OF ALL OF THAT, WHAT WE CAN 1197 00:42:46,400 --> 00:42:48,600 HAVE IF WE MODEL IN A POND 1198 00:42:48,600 --> 00:42:50,280 RADIAL SPREAD YOU CAN SEE IF 1199 00:42:50,280 --> 00:42:51,800 SEIZURE STARTED HERE IT WILL 1200 00:42:51,800 --> 00:42:54,040 SPREAD TO CLOSE ELECTRODES FIRST 1201 00:42:54,040 --> 00:42:56,040 MORE DISTANT ELECTRODES SECOND 1202 00:42:56,040 --> 00:42:57,520 AND YOU CAN ACTUALLY IF YOU 1203 00:42:57,520 --> 00:42:59,720 ASSUME IT IS SPREADING AT THE 1204 00:42:59,720 --> 00:43:00,960 SAME SPEED YOU CAN MODEL THIS 1205 00:43:00,960 --> 00:43:02,520 AND COME UP WITH THE MOST LIKELY 1206 00:43:02,520 --> 00:43:04,080 PLACE WHERE IT IS COMING FROM. 1207 00:43:04,080 --> 00:43:06,120 THIS ACTUALLY WORKS WELL AND IF 1208 00:43:06,120 --> 00:43:08,600 YOU HAVE MULTIPLE ELECTRODES YOU 1209 00:43:08,600 --> 00:43:09,200 CAN FIND INTERSECTION AND SEE 1210 00:43:09,200 --> 00:43:10,800 WHERE IT IS COMING FROM. THIS IS 1211 00:43:10,800 --> 00:43:12,560 ACTUALLY HOW THEY FIND WHERE 1212 00:43:12,560 --> 00:43:14,720 EARTHQUAKES ARE STARTED. SO THAT 1213 00:43:14,720 --> 00:43:16,920 IS -- THIS CAME OUT OF 1214 00:43:16,920 --> 00:43:19,600 (INAUDIBLE) LAB AND THIS IS 1215 00:43:19,600 --> 00:43:22,960 GREAT WORK BY JOSH DIAMOND. 1216 00:43:22,960 --> 00:43:24,640 THESE FOR SEIZURES THE BIGGER 1217 00:43:24,640 --> 00:43:29,040 RARER EVENTS. WE CAN ALSO DO IT 1218 00:43:29,040 --> 00:43:32,160 FOR INTERLIPI THEICAL AND HAPPEN 1219 00:43:32,160 --> 00:43:33,080 INTERMITTENTLY IN THE BRAIN. 1220 00:43:33,080 --> 00:43:35,000 THIS IS OVER SEVERAL HOURS, OVER 1221 00:43:35,000 --> 00:43:37,560 FOUR HOURS, THIS IS WHAT IT 1222 00:43:37,560 --> 00:43:39,520 LOOKS LIKE WHAT E WE CALL IT A 1223 00:43:39,520 --> 00:43:41,360 SPIKE ON THE SQUIGGLY LINES WE 1224 00:43:41,360 --> 00:43:43,800 READ. THESE ARE RECORDINGS FROM 1225 00:43:43,800 --> 00:43:45,360 THE ELECTRODES. YOU CAN SEE 1226 00:43:45,360 --> 00:43:47,240 THEY HAPPEN REALLY FREQUENTLY. 1227 00:43:47,240 --> 00:43:49,080 SO THEY GIVE LOTS OF 1228 00:43:49,080 --> 00:43:50,160 OPPORTUNITIES TO SEE THEM BUT 1229 00:43:50,160 --> 00:43:53,680 TEND TO HAPPEN MORE BROADLY THAN 1230 00:43:53,680 --> 00:43:56,880 SEIZURES. SO THEY HAPPEN IN A 1231 00:43:56,880 --> 00:43:58,120 STEREO TYPICAL PATTERN. 1232 00:43:58,120 --> 00:43:59,880 CONSISTENT WITH THE PEBBLE IN 1233 00:43:59,880 --> 00:44:01,440 THE POND TAKE OUT REGION IT IS 1234 00:44:01,440 --> 00:44:03,040 FIRST SPIKING ELECTRODE WAS, 1235 00:44:03,040 --> 00:44:05,120 THAT CORRELATES WITH GOOD 1236 00:44:05,120 --> 00:44:07,000 OUTCOMES. SO JOSH ACTUALLY 1237 00:44:07,000 --> 00:44:08,840 SHOWED THIS IN ANOTHER PAPER AND 1238 00:44:08,840 --> 00:44:10,720 HE SHOWED THAT THE LEADING 1239 00:44:10,720 --> 00:44:12,120 ELECTRODE AND IF YOU DO THE 1240 00:44:12,120 --> 00:44:13,760 DISTANCE AGAIN AND TIME OF 1241 00:44:13,760 --> 00:44:15,440 ARRIVAL YOU CAN ARRIVE WHERE 1242 00:44:15,440 --> 00:44:18,000 THEY ARE COMING FROM. AND WE -- 1243 00:44:18,000 --> 00:44:19,920 HE ALSO SHOWED NICELY THE AREA 1244 00:44:19,920 --> 00:44:21,720 THAT TURNS UP IN DISCHARGES IN 1245 00:44:21,720 --> 00:44:23,600 BETWEEN SEIZURES CORRELATES 1246 00:44:23,600 --> 00:44:25,400 CLOSELY WITH WHERE THE ACTUAL 1247 00:44:25,400 --> 00:44:27,320 SEIZURES ARE COMING FROM. AND 1248 00:44:27,320 --> 00:44:28,640 BOTH OF THEM GIVE YOU A GOOD 1249 00:44:28,640 --> 00:44:30,280 PREDICTION OF SEIZURE OUTCOMES. 1250 00:44:30,280 --> 00:44:31,880 SO IF THEY ARE OUTSIDE OF THE 1251 00:44:31,880 --> 00:44:33,360 RESECTION, THEY TEND TO HAVE 1252 00:44:33,360 --> 00:44:35,280 POORER OUTCOMES. IF INSIDE THE 1253 00:44:35,280 --> 00:44:36,400 RESECTION THEY TEND TO HAVE 1254 00:44:36,400 --> 00:44:39,680 BETTER OUTCOMES. FINALLY IN THE 1255 00:44:39,680 --> 00:44:41,480 RECENT WORK WE JUST PUT OUT WE 1256 00:44:41,480 --> 00:44:42,680 SAID WHAT ABOUT THIS OTHER 1257 00:44:42,680 --> 00:44:44,840 MECHANISM? WHAT ABOUT THIS 1258 00:44:44,840 --> 00:44:46,360 SPREAD THROUGH WHITE MATTER 1259 00:44:46,360 --> 00:44:47,800 PATHWAYS? BEFORE ALL THE WORK WE 1260 00:44:47,800 --> 00:44:50,400 DID WAS IN THIS PEBBLE IN A POND 1261 00:44:50,400 --> 00:44:51,720 SPREADING METHOD. WE ACTUALLY 1262 00:44:51,720 --> 00:44:53,120 SHOWED THAT YOU GET DIFFERENT 1263 00:44:53,120 --> 00:44:55,160 ANSWERS. SO THIS IS THE FIRST 1264 00:44:55,160 --> 00:44:56,680 ELECTRODE TO SPIKE IN RED HERE 1265 00:44:56,680 --> 00:44:59,200 WHICH YOU CAN SEE IS THE MEDIAL 1266 00:44:59,200 --> 00:45:00,600 TEMPORAL LOBE. YOU CAN SEE THE 1267 00:45:00,600 --> 00:45:02,720 WHITE MATTER SOURCES WERE SPREAD 1268 00:45:02,720 --> 00:45:04,360 REALLY THROUGHOUT MUCH OF THE 1269 00:45:04,360 --> 00:45:06,440 TEMPORAL LOBE AND WE LOOK AT 1270 00:45:06,440 --> 00:45:08,040 GRAY PLUS WHITE MATTER AND PUT 1271 00:45:08,040 --> 00:45:09,920 THOSE TOGETHER WE ARRIVED AT A 1272 00:45:09,920 --> 00:45:10,560 TOTALLY DIFFERENT SOURCE WHICH 1273 00:45:10,560 --> 00:45:12,200 WAS IN THIS AREA WHICH IS 1274 00:45:12,200 --> 00:45:13,920 OUTSIDE OF THE RESECTION AND 1275 00:45:13,920 --> 00:45:15,520 PATIENT DIDN'T BECOME SEIZURE 1276 00:45:15,520 --> 00:45:16,880 FREE. YOU CAN SEE THIS IS HOW 1277 00:45:16,880 --> 00:45:19,520 I'M USED TO READING EEGs, WHEN 1278 00:45:19,520 --> 00:45:22,480 I LOOK FOR THE LEADING SPIKE. 1279 00:45:22,480 --> 00:45:24,320 THIS WAS VERY EYE OPENING TO ME, 1280 00:45:24,320 --> 00:45:26,400 IF YOU GO BACK TO MECHANISMS OF 1281 00:45:26,400 --> 00:45:27,720 FAILURE THIS MIGHT BE SOMETIMES 1282 00:45:27,720 --> 00:45:29,760 WHY WE MISLOCALLIZE SEIZURE 1283 00:45:29,760 --> 00:45:32,600 SOURCES. TO WRAP UP IN MY FUTURE 1284 00:45:32,600 --> 00:45:35,320 DIRECTIONS WE HOPE TO USE THE 1285 00:45:35,320 --> 00:45:37,840 MAGNETIC WAVES OF THE BRAIN, 1286 00:45:37,840 --> 00:45:40,360 NON-INVASIVE IMAGING TO SEE THE 1287 00:45:40,360 --> 00:45:41,640 SAME SPREAD PATTERN. THIS IS A 1288 00:45:41,640 --> 00:45:43,800 MAP IN EARLY SEIZURE SPREAD 1289 00:45:43,800 --> 00:45:46,800 THESE DISCRETE AREAS ARE TURNING 1290 00:45:46,800 --> 00:45:48,400 UP DURING OUR SPIKES AND NOT 1291 00:45:48,400 --> 00:45:50,520 NEAR EACH OTHER SO H IS THAT 1292 00:45:50,520 --> 00:45:51,960 WHITE MATTER PROPAGATION THEN 1293 00:45:51,960 --> 00:45:52,760 SPREADING THROUGHOUT THE BRAIN 1294 00:45:52,760 --> 00:45:54,680 AND SPREADING FAR AND QUICKLY 1295 00:45:54,680 --> 00:45:56,440 THROUGHOUT THE BRAIN. SO WE ARE 1296 00:45:56,440 --> 00:45:58,760 HOPING WE CAN USE THIS TO HAVE 1297 00:45:58,760 --> 00:45:59,760 BETTER INITIAL GUESSES AND PUT 1298 00:45:59,760 --> 00:46:02,640 OUR ELECTRODES IN PLACES WE CAN 1299 00:46:02,640 --> 00:46:05,160 GET BACK AT THESE ANSWERS. SO 1300 00:46:05,160 --> 00:46:07,560 ANYWAY, THIS IS MY LITTLE 1301 00:46:07,560 --> 00:46:09,920 JOURNEY WHERE I HAVE BEEN. GOING 1302 00:46:09,920 --> 00:46:11,680 THROUGH WHERE SEIZURES ARE 1303 00:46:11,680 --> 00:46:13,080 COMING FROM AND DIFFERENT WAYS 1304 00:46:13,080 --> 00:46:14,040 TO LOOK FOR STRUCTURAL LESIONS. 1305 00:46:14,040 --> 00:46:15,960 WE HAVE ALSO USED PROFUSION 1306 00:46:15,960 --> 00:46:18,360 IMAGING TO LOOK AT LOCAL EFFECTS 1307 00:46:18,360 --> 00:46:22,880 AND THEN ACTUALLY USING 1308 00:46:22,880 --> 00:46:23,600 KNOWLEDGE OF CONNECTIVITY. 1309 00:46:23,600 --> 00:46:26,840 THANKS TO EVERYBODY IN MY LAB, 1310 00:46:26,840 --> 00:46:27,960 (INAUDIBLE) BEEN HERE FOR 1311 00:46:27,960 --> 00:46:29,120 DECADES AND THE NEUROSURGEON AND 1312 00:46:29,120 --> 00:46:31,320 PEOPLE IN OUR LAB AND PATIENTS 1313 00:46:31,320 --> 00:46:32,360 AND FAMILY WHOSE HAVE GONE 1314 00:46:32,360 --> 00:46:33,480 THROUGH ALL THESE STUDIES WITH 1315 00:46:33,480 --> 00:46:34,160 US. THANK YOU. 1316 00:46:34,160 --> 00:46:37,680 [APPLAUSE] 1317 00:46:37,680 --> 00:46:40,840 >>QUESTION FOR YOU. CONCERNING 1318 00:46:40,840 --> 00:46:43,680 YOUR MRI SLIDE YOU SHOWED 1319 00:46:43,680 --> 00:46:45,840 EARLIER, WAS HARD TO READ. ANY 1320 00:46:45,840 --> 00:46:47,280 POTENTIAL FOR AI, HAVE YOU 1321 00:46:47,280 --> 00:46:48,440 THOUGHT ABOUT AI IN THAT? 1322 00:46:48,440 --> 00:46:51,240 >>ACTUALLY THE METHOD WE 1323 00:46:51,240 --> 00:46:54,320 INCORPORATED IS A VERY BASIC AI 1324 00:46:54,320 --> 00:46:57,200 APPROACH TO DOING THIS AND OTHER 1325 00:46:57,200 --> 00:46:59,080 CENTERS HAVE ALSO DONE HUGE 1326 00:46:59,080 --> 00:47:00,320 MULTI-CENTER STUDIES THEY CAN 1327 00:47:00,320 --> 00:47:01,920 USE MORE ADVANCE NEURAL NETWORKS 1328 00:47:01,920 --> 00:47:03,960 AND THINGS LIKE THAT. THIS IS 1329 00:47:03,960 --> 00:47:05,200 DEFINITELY THE AREA AI IS 1330 00:47:05,200 --> 00:47:06,640 STARTING TO MAKE AN IMPACT. 1331 00:47:06,640 --> 00:47:08,960 >>AS ASIDE YOU PROBABLY KNOW OF 1332 00:47:08,960 --> 00:47:12,280 RON SUMMERS' WORK HERE IN THE 1333 00:47:12,280 --> 00:47:15,000 CLINICAL CENTER ON CHEST X-RAYS, 1334 00:47:15,000 --> 00:47:16,520 IF X-RAYS NOT SURE BUT HE USES 1335 00:47:16,520 --> 00:47:19,360 AI IN IDENTIFYING TUMORS. 1336 00:47:19,360 --> 00:47:21,520 >>THIS IS AN INTERESTING POINT. 1337 00:47:21,520 --> 00:47:23,800 I THINK IF YOU HAVE HUGE NUMBERS 1338 00:47:23,800 --> 00:47:25,360 OF DATA POINTS AI APPROACH 1339 00:47:25,360 --> 00:47:27,920 BECOMES EASIER WITH THE VERY 1340 00:47:27,920 --> 00:47:29,400 COMPLICATED MODELS. WE TRIED TO 1341 00:47:29,400 --> 00:47:30,680 SAY IF YOU JUST TAKE THE 1342 00:47:30,680 --> 00:47:32,040 CLINICAL IMAGES THAT YOU HAVE 1343 00:47:32,040 --> 00:47:33,600 CAN YOU TRAIN UP THE MODEL WITH 1344 00:47:33,600 --> 00:47:35,320 SMALL NUMBERS OF PATIENTS? 1345 00:47:35,320 --> 00:47:36,960 BECAUSE A LOT OF CENTERS DON'T 1346 00:47:36,960 --> 00:47:38,720 HAVE HUNDREDS OF IMAGES AND THEY 1347 00:47:38,720 --> 00:47:40,280 HAVE DIFFERENT MRIs AND ALL 1348 00:47:40,280 --> 00:47:42,080 THESE OTHER THINGS SO I THINK 1349 00:47:42,080 --> 00:47:44,880 THE ADVANTAGE OF OUR APPROACH IS 1350 00:47:44,880 --> 00:47:48,120 ABOUT 15, 20 EXAMPLES TO TRAIN 1351 00:47:48,120 --> 00:47:53,200 IT. DEFINITELY AN AREA FOR AI. 1352 00:47:53,200 --> 00:47:55,040 >>ANY OTHER -- QUESTION, USE 1353 00:47:55,040 --> 00:47:56,840 THE MIC BECAUSE PEOPLE ARE 1354 00:47:56,840 --> 00:48:01,480 WATCHING ONLINE IF YOU DON'T 1355 00:48:01,480 --> 00:48:01,680 MIND. 1356 00:48:01,680 --> 00:48:04,880 >>THANK YOU SO MUCH. SO THE 1357 00:48:04,880 --> 00:48:07,320 MIGRATIONS THAT HOW SMALL THE 1358 00:48:07,320 --> 00:48:08,640 EEG CAN DETECT THE SMALL OF THE 1359 00:48:08,640 --> 00:48:09,840 LEAGUES EEG DETECT? 1360 00:48:09,840 --> 00:48:11,440 >>SORRY HOW MANY ARE WHAT? 1361 00:48:11,440 --> 00:48:12,160 >>THE LESION. 1362 00:48:12,160 --> 00:48:14,440 >>THE LESION LIKE THE FOCAL 1363 00:48:14,440 --> 00:48:17,080 CORTICAL DYSPLASIAS? 1364 00:48:17,080 --> 00:48:19,400 INTERESTINGLY WE DON'T KNOW. A 1365 00:48:19,400 --> 00:48:22,320 LOT OF TIME IT IS ONES WE SEE 1366 00:48:22,320 --> 00:48:25,560 CLEARLY ARE CENTIMETER CAN BE 1367 00:48:25,560 --> 00:48:27,440 LESS. A LOT OF TIME IT IS 1368 00:48:27,440 --> 00:48:28,600 SMALLER THEY ARE THE LESS WE 1369 00:48:28,600 --> 00:48:30,280 FIND THEM SO IF ON PATHOLOGY A 1370 00:48:30,280 --> 00:48:32,280 LOT OF TIMES JUST IN THAT SAMPLE 1371 00:48:32,280 --> 00:48:34,000 SO WE DON'T KNOW HOW WIDESPREAD 1372 00:48:34,000 --> 00:48:35,160 OR DIFFUSE UNLESS YOU CAN SEE IT 1373 00:48:35,160 --> 00:48:37,440 ON THE MRI SO IT IS HARD TO KNOW 1374 00:48:37,440 --> 00:48:39,080 HOW SMALL THEY CAN BE BUT THEY 1375 00:48:39,080 --> 00:48:45,640 CAN BE VERY LARGE. 1376 00:48:45,640 --> 00:48:48,560 >>YOU MENTIONED EEG DOESN'T DO 1377 00:48:48,560 --> 00:48:51,440 A GOOD JOB OF SPATIALLY 1378 00:48:51,440 --> 00:48:54,000 TARGETING SEIZURES BUT IT SEEMS 1379 00:48:54,000 --> 00:48:56,040 TO BE SOMEWHAT CLINICAL 1380 00:48:56,040 --> 00:48:58,080 STANDARD. DO YOU ENVISION THAT 1381 00:48:58,080 --> 00:49:00,840 MEG COULD REPLACE EEG IN THE 1382 00:49:00,840 --> 00:49:03,840 FUTURE, IS THAT SOMETHING THAT 1383 00:49:03,840 --> 00:49:04,280 MOTIVATES YOU? 1384 00:49:04,280 --> 00:49:08,320 >>I THINK THE WAY I WOULD -- 1385 00:49:08,320 --> 00:49:10,560 EEG SCALP EEG IS REGIONAL SO BY 1386 00:49:10,560 --> 00:49:12,640 THE TIME WELCOME SEE IT ON THE 1387 00:49:12,640 --> 00:49:15,520 SCALP SURFACE, WE THINK IT 1388 00:49:15,520 --> 00:49:16,680 INCORPORATES SOMEWHERE ON THE 1389 00:49:16,680 --> 00:49:18,360 ORDER OF TEN SQUARE CENTIMETERS 1390 00:49:18,360 --> 00:49:19,960 OF BRAIN. DOES THAT WELL 1391 00:49:19,960 --> 00:49:21,400 ACTUALLY BUT CAN MISLEAD YOU 1392 00:49:21,400 --> 00:49:23,880 WHEN THERE'S RAPID PROPAGATION. 1393 00:49:23,880 --> 00:49:25,800 SO WITH ADVANCES IN IMAGING WE 1394 00:49:25,800 --> 00:49:28,160 HAVE GOTTEN BETTER USING EEG FOR 1395 00:49:28,160 --> 00:49:29,960 SOURCE LOCALIZATION. I DON'T 1396 00:49:29,960 --> 00:49:33,000 THINK MEG WILL EVER COMPLETELY 1397 00:49:33,000 --> 00:49:34,120 REPLACE IT. TESTIFY BIG 1398 00:49:34,120 --> 00:49:36,000 ADVANTAGE OF MEG AS FAR AS I 1399 00:49:36,000 --> 00:49:38,560 KNOW THERE'S 273 SENSORS THAT 1400 00:49:38,560 --> 00:49:42,040 YOU GET AUTOMATICALLY SO AND THE 1401 00:49:42,040 --> 00:49:43,640 SCALP AND PREVIOUS SURGERYINGS 1402 00:49:43,640 --> 00:49:46,000 AND ALL THESE OTHER THINGS DON'T 1403 00:49:46,000 --> 00:49:48,440 IMPACT SOURCE IMAGING AS MUCH SO 1404 00:49:48,440 --> 00:49:50,240 MEG HAS BIG ADVANTAGES TERMS OF 1405 00:49:50,240 --> 00:49:52,200 HOW TO DO THE SOURCE IMAGING BUT 1406 00:49:52,200 --> 00:49:54,560 WE WILL NEVER DO IT LONG ENOUGH 1407 00:49:54,560 --> 00:49:56,240 TO RECORD SEIZURES. SO THAT IS 1408 00:49:56,240 --> 00:49:58,280 STILL THE GOLD STANDARD. BUT 1409 00:49:58,280 --> 00:50:01,000 AGAIN, I'M VERSED IN THIS INSULA 1410 00:50:01,000 --> 00:50:03,600 ACTIVITY BECAUSE IT CAN BE LESS 1411 00:50:03,600 --> 00:50:04,200 USEFUL INFORMATION AND 1412 00:50:04,200 --> 00:50:06,200 (INDISCERNIBLE) ARE WORKING ON 1413 00:50:06,200 --> 00:50:08,080 OPMs WHICH ARE THEORETICALLY 1414 00:50:08,080 --> 00:50:09,320 PORTABLE SO EXCITED TO WORK WITH 1415 00:50:09,320 --> 00:50:10,600 THEM BECAUSE IF WE CAN HAVE A 1416 00:50:10,600 --> 00:50:13,400 PERSON SITTING AROUND WITH THAT 1417 00:50:13,400 --> 00:50:16,480 ON THEIR HEAD THAT MAY BE AN 1418 00:50:16,480 --> 00:50:17,080 INTERESTING DIRECTION IN THE 1419 00:50:17,080 --> 00:50:19,440 FUTURE. I THINK THEY BOTH HAVE 1420 00:50:19,440 --> 00:50:25,040 USES. 1421 00:50:25,040 --> 00:50:26,800 >>A LITTLE MORE GENERAL 1422 00:50:26,800 --> 00:50:29,480 QUESTION BUT HOW HAS INTRAMURAL 1423 00:50:29,480 --> 00:50:31,200 COLLABORATION IMPROVED YOUR 1424 00:50:31,200 --> 00:50:33,280 RESEARCH OR WHAT INSIGHTS HAVE 1425 00:50:33,280 --> 00:50:37,400 YOU GAINED FROM WORKING WITH 1426 00:50:37,400 --> 00:50:38,480 INDIVIDUALS INSIDE THE NIH 1427 00:50:38,480 --> 00:50:39,440 SPACE? 1428 00:50:39,440 --> 00:50:41,000 >>I CAN SAFELY SAY I HAVEN'T 1429 00:50:41,000 --> 00:50:44,240 DONE A SINGLE THING HERE WITHOUT 1430 00:50:44,240 --> 00:50:49,520 COLLABORATING. THE WHOLE THING 1431 00:50:49,520 --> 00:50:52,040 IS COLLABORATIVE. SO I CAN HAPPY 1432 00:50:52,040 --> 00:50:53,400 TO WORK WITH (INDISCERNIBLE) IN 1433 00:50:53,400 --> 00:50:54,520 THE NEUROSURGERY GROUP, I HAVE 1434 00:50:54,520 --> 00:50:56,240 BEEN HERE AND AMAZING 1435 00:50:56,240 --> 00:50:57,800 COLLABORATION. MY COLLABORATION 1436 00:50:57,800 --> 00:50:59,560 WITH THEODORE HELPED WITH PET 1437 00:50:59,560 --> 00:51:02,320 STUDIES AN FMRI AND LANGUAGE, 1438 00:51:02,320 --> 00:51:05,640 USING CHILDREN'S HOME AND FMRI 1439 00:51:05,640 --> 00:51:07,880 AND MEMORY. THE MEMORY CORES ARE 1440 00:51:07,880 --> 00:51:12,600 INSTRUMENTAL AND ANY IMAGING. 1441 00:51:12,600 --> 00:51:13,840 THE PRESENCE OF CORE FACILITIES 1442 00:51:13,840 --> 00:51:24,280 IS AMAZING. COLLABORATION IS 1443 00:51:29,600 --> 00:51:31,440 THIS IS ALL COLLABORATIVE WORK. 1444 00:51:31,440 --> 00:51:32,760 NOT THE TO MENTION COLLABORATION 1445 00:51:32,760 --> 00:51:34,880 WITH NURSING STAFF, OTHER 1446 00:51:34,880 --> 00:51:39,600 INSTITUTIONS SO ANYWAY, I THINK 1447 00:51:39,600 --> 00:51:41,760 -- THIS IS THE ONLY HOSPITAL I 1448 00:51:41,760 --> 00:51:42,800 HEARD FROM OF WHERE PEOPLE 1449 00:51:42,800 --> 00:51:45,960 AREN'T DRIVEN BY THEIR RVs SO 1450 00:51:45,960 --> 00:51:47,800 I THINK THAT GIVINGS AMAZING 1451 00:51:47,800 --> 00:51:48,920 OPPORTUNITIES TO PURSUE THINGS 1452 00:51:48,920 --> 00:51:50,320 WE MIGHT NOT HAVE THE FREEDOM TO 1453 00:51:50,320 --> 00:51:58,080 PURSUE ELSEWHERE. s SPECIALRY 1454 00:51:58,080 --> 00:52:00,200 PATIENTS WITH EPILEPSY WHO ARE 1455 00:52:00,200 --> 00:52:01,520 UNDERINSURED OR UNSURED AND 1456 00:52:01,520 --> 00:52:03,920 THERE'S STIGMA SO EXCITED TO 1457 00:52:03,920 --> 00:52:04,800 HAVE EPIPOO L THINKING ABOUT 1458 00:52:04,800 --> 00:52:06,280 THEIR PROBLEM AND WORKING TO 1459 00:52:06,280 --> 00:52:16,600 MAKE THAT BETTER. 1460 00:52:24,040 --> 00:52:29,120 >>OUR NEXT SPEAKER IS DR. LISA 1461 00:52:29,120 --> 00:52:30,040 MCREYNOLDS, GENETICS BRANCH 1462 00:52:30,040 --> 00:52:32,360 DIVISION OF TRANSLATIONAL 1463 00:52:32,360 --> 00:52:35,080 IMMUNOLOGY AND DIVISION OF NCI. 1464 00:52:35,080 --> 00:52:39,680 DR. MCRAY NOLS IS PEDIATRIC -- 1465 00:52:39,680 --> 00:52:42,320 MCREYNOLDS ONCOLOGIST AND 1466 00:52:42,320 --> 00:52:43,280 Ph.D. IN DEVELOPMENTAL 1467 00:52:43,280 --> 00:52:44,560 BIOLOGY. HER WORK IS ON GENOMICS 1468 00:52:44,560 --> 00:52:47,920 OF INHERITED BONE MARROW FAILURE 1469 00:52:47,920 --> 00:52:51,520 AND MYELOID MALIGNANCY DYSPLASIA 1470 00:52:51,520 --> 00:52:54,520 SYNDROMES. SHE WILL BE SPEAKING 1471 00:52:54,520 --> 00:52:56,920 ON HETEROZYGOTE CARRIERS AND THE 1472 00:52:56,920 --> 00:53:00,040 TITLE OF HER PRESENTATION IS 1473 00:53:00,040 --> 00:53:01,800 MOVING FROM FAMILY STUDIES TO 1474 00:53:01,800 --> 00:53:03,480 POPULATIONS CANCER RISK IN 1475 00:53:03,480 --> 00:53:13,760 FANCONI ANEMIA. 1476 00:53:14,120 --> 00:53:16,000 >>THANK YOU SO MUCH FOR THAT 1477 00:53:16,000 --> 00:53:26,480 KIND INTRODUCTION. I WILL BE 1478 00:53:28,200 --> 00:53:29,080 SPEAKING TO INHERITED BONE HAIR 1479 00:53:29,080 --> 00:53:30,640 ROW SYNDROMES. SEVERAL 1480 00:53:30,640 --> 00:53:32,480 PATHOLOGICAL PATHWAYS UNLIED 1481 00:53:32,480 --> 00:53:34,280 DISORDERS SUCH AD INHERITED BONE 1482 00:53:34,280 --> 00:53:37,800 HAIR ROW SYNDROMES TELOMERE 1483 00:53:37,800 --> 00:53:40,360 BIOLOGY DISORDERS, RIBOSOME 1484 00:53:40,360 --> 00:53:43,920 DISORDERS E, DISORDERS BY 1485 00:53:43,920 --> 00:53:46,080 HEMATOID TOE POIETIC HECTOR 1486 00:53:46,080 --> 00:53:47,280 BIOLOGY AND CELL SIGNALING 1487 00:53:47,280 --> 00:53:48,960 PATHWAYS. TODAY I WILL FOCUS ON 1488 00:53:48,960 --> 00:53:52,400 DNA REPAIR PATHWAY DISORDERS 1489 00:53:52,400 --> 00:53:53,800 INCLUDING FANCONI ANEMIA. 1490 00:53:53,800 --> 00:53:57,160 THERE'S INHERITED BONE MARROW 1491 00:53:57,160 --> 00:54:01,560 FAILURE SYNDROMES, FANCONI, 1492 00:54:01,560 --> 00:54:02,480 INCLUDING (INDISCERNIBLE) 1493 00:54:02,480 --> 00:54:05,320 DIAMOND SYNDROME AND MORE RARE 1494 00:54:05,320 --> 00:54:07,760 INCLUDING SEVERE CONGENITAL 1495 00:54:07,760 --> 00:54:11,080 NEUTROPENIA, ABSENT RADII AND 1496 00:54:11,080 --> 00:54:14,400 CONGENITAL MEGA KARYOSITIC 1497 00:54:14,400 --> 00:54:16,240 CYTOPENIA. THEY ARE LINKED TO 1498 00:54:16,240 --> 00:54:18,320 DECREASE IN BONE MARROW OUTPUT 1499 00:54:18,320 --> 00:54:19,760 AND LEADING TO BONE MARROW FILE 1500 00:54:19,760 --> 00:54:24,760 YOUR. THE TOP TWO LEADS TO 1501 00:54:24,760 --> 00:54:26,200 APLASTIC ANEMIA, PATIENTS WITH 1502 00:54:26,200 --> 00:54:27,560 THESE DISORDERS HAVE LOSSES OF 1503 00:54:27,560 --> 00:54:31,840 ALL THE MAJOR BLOOD CELL 1504 00:54:31,840 --> 00:54:33,440 LINEAGES, WHITE, RED, AND 1505 00:54:33,440 --> 00:54:35,240 PLATELET LETS. IT ONLY AFFECTS 1506 00:54:35,240 --> 00:54:41,840 THE RED CELLS AND THE SEVERE 1507 00:54:41,840 --> 00:54:43,480 NEUTROPENIA ARE RELATED TO THE 1508 00:54:43,480 --> 00:54:45,160 NEUTROPHIL LINEAGE AND THE LAST 1509 00:54:45,160 --> 00:54:46,920 TWO AFFECT PLATELETS. US A THESE 1510 00:54:46,920 --> 00:54:49,400 INCREASE THE RISK OF PATIENTS 1511 00:54:49,400 --> 00:54:51,400 GETTING MYELODYSPLASTIC SYNDROME 1512 00:54:51,400 --> 00:54:54,120 AND ACUTE MYELOID LEUKEMIA. 1513 00:54:54,120 --> 00:54:56,920 INTERESTINGLY FANCONI ANEMIA AND 1514 00:54:56,920 --> 00:54:57,480 DYSKERATOSIS CON GENERAL TA, 1515 00:54:57,480 --> 00:54:58,960 THEY HAVE HIGH RISK OF 1516 00:54:58,960 --> 00:55:01,160 DEVELOPING HEAD AND NECK 1517 00:55:01,160 --> 00:55:06,760 SQUAMOUS CE CELL CARCINOMA AT YG 1518 00:55:06,760 --> 00:55:10,040 AGE. IT HAS A EWE PEEK 1519 00:55:10,040 --> 00:55:12,400 PROPENSITY TO OSTEO SARCOMA. 1520 00:55:12,400 --> 00:55:14,480 WITHIN THE W DIVISION OF CANCER 1521 00:55:14,480 --> 00:55:15,880 EPIDEMIOLOGY AND GENETICS THE 1522 00:55:15,880 --> 00:55:20,480 NCI INHERITED BONE MARROW 1523 00:55:20,480 --> 00:55:21,720 FAILURE WAS ESTABLISHED IN 2002, 1524 00:55:21,720 --> 00:55:23,520 THIS IS A LARGE ONGOING FAMILY 1525 00:55:23,520 --> 00:55:25,440 STUDY COLLECTED THE NATURAL 1526 00:55:25,440 --> 00:55:28,840 HISTORY OF 5,000 -- 500 FAMILIES 1527 00:55:28,840 --> 00:55:31,360 AND OVER 2000 INDIVIDUALS WITH 1528 00:55:31,360 --> 00:55:34,120 INHERITABLE MARROW FAILURE 1529 00:55:34,120 --> 00:55:35,160 SYNDROMES LED BY 1530 00:55:35,160 --> 00:55:37,120 (INDISCERNIBLE), SINCE I JOINED 1531 00:55:37,120 --> 00:55:39,240 CGB IN 2016 LEADING THE GENOMIC 1532 00:55:39,240 --> 00:55:41,560 STUDIES WITHIN THE INHERITED 1533 00:55:41,560 --> 00:55:44,800 BONE MARROW FAILURE STUDY. THE 1534 00:55:44,800 --> 00:55:47,560 FAMILY STUDY PROCESS IS COMBINED 1535 00:55:47,560 --> 00:55:49,440 FIELD AND CLINICAL COHORT SO 1536 00:55:49,440 --> 00:55:51,160 SOME COME HERE TO THE NIH TO BE 1537 00:55:51,160 --> 00:55:54,240 EVALUATED AT THE CLINICAL CENTER 1538 00:55:54,240 --> 00:55:56,120 AND SOME ARE INVOLVED REMOTELY. 1539 00:55:56,120 --> 00:55:58,120 FILLING OUT QUESTIONNAIRES PADS 1540 00:55:58,120 --> 00:56:00,240 WELL AS SUBMITTING SAMPLES AND 1541 00:56:00,240 --> 00:56:02,160 COLLECTING MEDICAL RECORDS SO 1542 00:56:02,160 --> 00:56:03,760 PATIENTS ACCRUE BY 1543 00:56:03,760 --> 00:56:06,200 SELF-REFERRAL, PHYSICIAN 1544 00:56:06,200 --> 00:56:07,680 REFERRAL, OR FINDING OUT THROUGH 1545 00:56:07,680 --> 00:56:09,720 THE WEB OR OTHER PATIENT 1546 00:56:09,720 --> 00:56:11,040 ADVOCACY ORGANIZATIONS, THEY 1547 00:56:11,040 --> 00:56:14,640 CALL THE STUDY WE REVIEW THERE 1548 00:56:14,640 --> 00:56:16,040 ELIGIBILITY CRITERIA AND THEY 1549 00:56:16,040 --> 00:56:18,240 ARE SENT A LARGE SEVERAL LARGE 1550 00:56:18,240 --> 00:56:19,560 BOOKLETS OF QUESTIONNAIRES WHICH 1551 00:56:19,560 --> 00:56:22,000 FAMILIES ARE AMAZINGLY WILLING 1552 00:56:22,000 --> 00:56:23,720 TO FILL OUT AND SEND BACK. THIS 1553 00:56:23,720 --> 00:56:25,240 INCLUDES FAMILY HISTORY, 1554 00:56:25,240 --> 00:56:26,480 INDIVIDUAL HISTORY WHICH A 1555 00:56:26,480 --> 00:56:28,280 PEDIGREE IS CREATED. WE COLLECT 1556 00:56:28,280 --> 00:56:30,040 MEDICAL RECORDS FROM ALL OVER 1557 00:56:30,040 --> 00:56:32,760 THE COUNTRY THAT THESE PATIENTS 1558 00:56:32,760 --> 00:56:34,360 HAVE AND COLLECT RESEARCH CHART. 1559 00:56:34,360 --> 00:56:36,040 AT THE SAME TIME THEY CAN 1560 00:56:36,040 --> 00:56:37,160 UNDERGO GENETIC COUNSELING AND 1561 00:56:37,160 --> 00:56:40,160 TESTING IF THEY HAVEN'T HAD 1562 00:56:40,160 --> 00:56:41,920 OUTSTANDING AND SUBMIT 1563 00:56:41,920 --> 00:56:43,520 BIOSPECIMENS. THE CLINICAL 1564 00:56:43,520 --> 00:56:44,680 COHORT WE BRING PATIENTS AND 1565 00:56:44,680 --> 00:56:46,560 THEIR FAMILIES HERE A WEEK LONG 1566 00:56:46,560 --> 00:56:48,440 EVALUATION AT THE CLINICAL 1567 00:56:48,440 --> 00:56:50,200 CENTER THAT INCLUDES DEEP 1568 00:56:50,200 --> 00:56:52,960 PHENOTYPING AND ADDITIONAL 1569 00:56:52,960 --> 00:56:54,480 BIOSPECIMEN COLLECTION AND 1570 00:56:54,480 --> 00:56:58,080 REFERRALS TO NUMBER OF SUB 1571 00:56:58,080 --> 00:56:58,960 SPECIALISTS HERE WITH WITHIN THE 1572 00:56:58,960 --> 00:57:00,760 CLINICAL CENTER INCLUDING DENTAL 1573 00:57:00,760 --> 00:57:05,880 GYN ENT SUBSPECIALTIES. OVER THE 1574 00:57:05,880 --> 00:57:07,960 LAST OVER 21 YEARS NOW THE STUDY 1575 00:57:07,960 --> 00:57:11,200 HAS LED TO MAJOR ADVANCES IN THE 1576 00:57:11,200 --> 00:57:12,840 UNDERSTANDING OF THE INHERITABLE 1577 00:57:12,840 --> 00:57:15,120 MARROW FAILURE, THIS INCLUDES 1578 00:57:15,120 --> 00:57:16,480 THE MOST IMPORTANTLY QUANTIFYING 1579 00:57:16,480 --> 00:57:19,040 THE RISK OF CANCER IN EACH OF 1580 00:57:19,040 --> 00:57:21,920 MAJOR MARROW FAILURE SYNDROMES, 1581 00:57:21,920 --> 00:57:23,360 IDENTIFICATION OF MORE THAN TEN 1582 00:57:23,360 --> 00:57:25,640 GENETIC LOW SIZE AND DESCRIBED 1583 00:57:25,640 --> 00:57:27,680 QUANTIFY PHENOTYPES FOR MANY OF 1584 00:57:27,680 --> 00:57:29,240 THE OTHER AFFECTED ORGAN SYSTEMS 1585 00:57:29,240 --> 00:57:31,840 AND HERE ARE A FEW PAPERS. THE 1586 00:57:31,840 --> 00:57:32,560 MOST IMPORTANT BEING THE 1587 00:57:32,560 --> 00:57:34,200 UNDERSTANDING OF THE RATE OF 1588 00:57:34,200 --> 00:57:36,000 CANCER WITH INHERITED BONE 1589 00:57:36,000 --> 00:57:37,560 MARROW FAILURE SYNDROME, PRIOR 1590 00:57:37,560 --> 00:57:39,160 TO STUDY WE RECOGNIZE THESE 1591 00:57:39,160 --> 00:57:40,600 PATIENTS HAD INCREASE RISK OF 1592 00:57:40,600 --> 00:57:42,760 CANCER BUT REALLY DIDN'T HAVE A 1593 00:57:42,760 --> 00:57:44,960 GOOD SENSE OR QUANTIFICATION HOW 1594 00:57:44,960 --> 00:57:46,000 MUCH CANCER THESE PATIENTS 1595 00:57:46,000 --> 00:57:48,800 REALLY HAD. SO IF YOU LOOK 1596 00:57:48,800 --> 00:57:50,440 SPECIFICALLY AT FANCONI ANEMIA, 1597 00:57:50,440 --> 00:57:52,000 I AM TALKING ABOUT TODAY THESE 1598 00:57:52,000 --> 00:57:54,440 PATIENTS GET REALLY EARLY ONSET 1599 00:57:54,440 --> 00:57:56,400 CANCER, UNDER THE AGE OF 40. 1600 00:57:56,400 --> 00:57:58,640 THIS RISK IS ACTUALLY INCREASED 1601 00:57:58,640 --> 00:58:01,920 AFTER HEMATOPOIETIC STEM CELL 1602 00:58:01,920 --> 00:58:03,080 TRANSPLANT. MORE SPECIFICALLY 1603 00:58:03,080 --> 00:58:07,920 RISK OF MYELODYSPLASTIC PATIENTS 1604 00:58:07,920 --> 00:58:11,400 IN FANCONI ANEMIA IS 5,000 FOLD 1605 00:58:11,400 --> 00:58:12,760 GENERAL POPULATION AND ACUTE 1606 00:58:12,760 --> 00:58:14,760 LEUKEMIA IS 20 FOLD. WHAT IS 1607 00:58:14,760 --> 00:58:17,960 FANCONI ANEMIA, A DNA REPAIR 1608 00:58:17,960 --> 00:58:19,760 DISORDERS, THIS IS THE PATHWAY 1609 00:58:19,760 --> 00:58:21,440 THAT IS INVOLVED IN THE 1610 00:58:21,440 --> 00:58:23,000 CORRECTION OF ENTERSTEERING 1611 00:58:23,000 --> 00:58:24,720 CROSS LINKS. THREE MAYOR 1612 00:58:24,720 --> 00:58:26,400 COMPLEXES LABELED CALLED 1613 00:58:26,400 --> 00:58:27,640 UPSTREAM COLLECTION, THE ID 1614 00:58:27,640 --> 00:58:29,440 COMPLEX AND THE DOWNSTREAM 1615 00:58:29,440 --> 00:58:32,040 COMPLEX, ALL ARE IMPORTANT TO 1616 00:58:32,040 --> 00:58:33,480 RESOLVE THIS CROSS LINK THAT CAN 1617 00:58:33,480 --> 00:58:36,040 BE FORMED. THESE PATIENTS HAD 1618 00:58:36,040 --> 00:58:38,280 UNIQUE PHYSICAL FINDINGS, SORT 1619 00:58:38,280 --> 00:58:41,320 OF CLASSIC ONE UNDER HEMATOLOGY 1620 00:58:41,320 --> 00:58:43,120 BOARD IS ABNORMAL THUMB, OFTEN 1621 00:58:43,120 --> 00:58:49,360 SHORT AND CLASSIC FACE, RENAL 1622 00:58:49,360 --> 00:58:51,640 CONGENITAL CARDIAC PROBLEMS. 1623 00:58:51,640 --> 00:58:54,240 THESE PATIENTS ARE IDENTIFIED BY 1624 00:58:54,240 --> 00:58:56,800 WHAT IS CALLED THE CHROMOSOME 1625 00:58:56,800 --> 00:58:58,200 BRAY DAMAGE TESTS THESE RADIALS 1626 00:58:58,200 --> 00:59:03,760 WHICH FORM WHEN YOU APPLY DEVICE 1627 00:59:03,760 --> 00:59:07,400 C OR DB, IF THESE FORM THIS IS 1628 00:59:07,400 --> 00:59:09,840 INDICATIVE OF FANCONI ANEMIA. 1629 00:59:09,840 --> 00:59:12,120 THUS FAR 22 GENES IDENTIFIED, 1630 00:59:12,120 --> 00:59:13,920 THEY PROBABLY ARE MORE OUT 1631 00:59:13,920 --> 00:59:16,400 THERE, ALL LABELED HERE, A, B, 1632 00:59:16,400 --> 00:59:19,480 C, SO ON, SO FORTH. THE VAST 1633 00:59:19,480 --> 00:59:21,440 MAJORITY ARE AUTOSOMAL RECESSIVE 1634 00:59:21,440 --> 00:59:25,160 BUT THERE IS A X LINK AS WELL AS 1635 00:59:25,160 --> 00:59:27,760 DOMINANT FORM. SO WE KNOW 1636 00:59:27,760 --> 00:59:29,280 INCREASE RISK OF CANCER IN 1637 00:59:29,280 --> 00:59:32,160 INDIVIDUALS WITH FANCONI ANEMIA. 1638 00:59:32,160 --> 00:59:36,040 THAT HAVE TWO ABNORMAL COPIES OF 1639 00:59:36,040 --> 00:59:38,280 ONE OF THE FANCONI GENES BUT 1640 00:59:38,280 --> 00:59:39,760 WHAT ABOUT INDIVIDUALS WITH THE 1641 00:59:39,760 --> 00:59:42,040 SINGLE PATHOGENIC VARIANT THAT 1642 00:59:42,040 --> 00:59:44,360 WE CALL CARRIERS OR 1643 00:59:44,360 --> 00:59:45,040 HETEROZYGOTE? 1644 00:59:45,040 --> 00:59:47,760 OF THE 22 FANCONI ANEMIA GENES 1645 00:59:47,760 --> 00:59:49,720 FIVE ARE ALREADY CANCER 1646 00:59:49,720 --> 00:59:51,600 PREDISPOSITION GENES ON THEIR 1647 00:59:51,600 --> 00:59:53,960 OWN AND AUTOSOMAL DOMINANT 1648 00:59:53,960 --> 00:59:57,480 FASHION IN HETEROZYGOTES 1649 00:59:57,480 --> 00:59:59,320 INCLUDING THE MORE COMMONLY 1650 00:59:59,320 --> 01:00:01,760 KNOWN ONES BRACA 1 AND 2 AS WELL 1651 01:00:01,760 --> 01:00:06,200 AS GROUP 1, PARB 2 AND RAD 51C, 1652 01:00:06,200 --> 01:00:07,840 THESE ARE THE GENE NAMES AND 1653 01:00:07,840 --> 01:00:09,400 FANCONI NAMES HERE. WE KNOW THAT 1654 01:00:09,400 --> 01:00:11,200 THESE PATIENTS HAVE INCREASE 1655 01:00:11,200 --> 01:00:13,840 RISK OF CANCER, IN THE 1656 01:00:13,840 --> 01:00:15,080 HETEROZYGOTE FORM PRIMARILY 1657 01:00:15,080 --> 01:00:18,080 BREAST AND OVARIAN AS WELL AS 1658 01:00:18,080 --> 01:00:18,960 PANCREATIC CANCER. WHAT ABOUT 1659 01:00:18,960 --> 01:00:20,320 INDIVIDUALS WITH SINGLE 1660 01:00:20,320 --> 01:00:22,200 PATHOGENIC FA VARIANT, I CAN'T 1661 01:00:22,200 --> 01:00:25,280 WANT, RELATIVES OF FANCONI 1662 01:00:25,280 --> 01:00:26,960 ANEMIA PATIENTS OR OTHER 1663 01:00:26,960 --> 01:00:28,440 CARRIERS SO INCREASE RISK OF 1664 01:00:28,440 --> 01:00:29,560 CANCER? THE FANCONI COMMUNITY 1665 01:00:29,560 --> 01:00:30,960 HAS ALWAYS BEEN WORRIED ABOUT 1666 01:00:30,960 --> 01:00:32,520 THIS AND FAMILY MEMBERS HAVE 1667 01:00:32,520 --> 01:00:35,200 BEEN. BUT WE SHOULD BE WORRYND 1668 01:00:35,200 --> 01:00:36,800 BECAUSE 3% OF THE POPULATION IS 1669 01:00:36,800 --> 01:00:38,680 WALKING AROUND WITH A SINGLE 1670 01:00:38,680 --> 01:00:40,040 PATHOGENIC VARIANT WITHIN ONE OF 1671 01:00:40,040 --> 01:00:44,160 THE FA GENES. SO DID THIS 1672 01:00:44,160 --> 01:00:46,040 QUESTION, THE NCI WE DEEM THE FA 1673 01:00:46,040 --> 01:00:48,600 RELATIVE STUDY WAS FORMED. WE 1674 01:00:48,600 --> 01:00:51,600 TOOK THE NCI COHORT OF 150 FA 1675 01:00:51,600 --> 01:00:55,720 FAMILIES AND COLLECTED CANCER 1676 01:00:55,720 --> 01:00:57,040 INFORMATION, THEIR AGE OF 1677 01:00:57,040 --> 01:00:58,440 DIAGNOSIS OF CANCER, CURRENT AGE 1678 01:00:58,440 --> 01:01:00,960 OR AGE AT DEATH, AND LOOKED AT 1679 01:01:00,960 --> 01:01:02,440 PARENTS AND OFFSPRING OF 1680 01:01:02,440 --> 01:01:06,240 PATIENTS WITH FANCONI ANEMIA WHO 1681 01:01:06,240 --> 01:01:08,200 ARE OBLIGATE HETEROZYGOTES AND 1682 01:01:08,200 --> 01:01:10,240 THEN SIBLINGS AND GRAND PARENTS 1683 01:01:10,240 --> 01:01:11,760 WHICH ARE GENOTYPED. WE 1684 01:01:11,760 --> 01:01:15,000 CALCULATED THE OBSERVED EXPECTED 1685 01:01:15,000 --> 01:01:16,480 CASES USING SERE AS COMPARISON 1686 01:01:16,480 --> 01:01:19,200 AND ADJUSTED FOR AGE SECTION AND 1687 01:01:19,200 --> 01:01:21,880 BIRTH COHORT. SO WE HAD 1,038 1688 01:01:21,880 --> 01:01:23,080 RELATIVES WHICH MAY SEEM 1689 01:01:23,080 --> 01:01:24,640 RELATIVELY SMALL NUMBER BUT FOR 1690 01:01:24,640 --> 01:01:27,000 RARE DISORDER LIKE FANCONI 1691 01:01:27,000 --> 01:01:29,440 ANEMIA THIS IS HIGH OF WHICH 396 1692 01:01:29,440 --> 01:01:31,520 INDIVIDUALS WERE HETEROZYGOTES. 1693 01:01:31,520 --> 01:01:33,640 SO AS I MENTION EVERYBODY WAS 1694 01:01:33,640 --> 01:01:36,840 GENOTYPED AND WE DETERMINED THE 1695 01:01:36,840 --> 01:01:40,240 OBSERVED OVEREXPECTED SHARE. 1696 01:01:40,240 --> 01:01:42,160 THIS IS ALL THE PEOPLE THAT WE 1697 01:01:42,160 --> 01:01:48,400 CHECKED HERE. 396 HETEROZYGOTES 1698 01:01:48,400 --> 01:01:50,200 85 KNOWN WILD TYPE AND PATIENTS 1699 01:01:50,200 --> 01:01:54,680 WHO WERE NOT ABLE TO GET 1700 01:01:54,680 --> 01:01:58,280 MATERIAL FOR BUT RELATIVES OF FA 1701 01:01:58,280 --> 01:01:59,520 PATIENTS. IF WE LOOK ACROSS 1702 01:01:59,520 --> 01:02:01,760 LOOKING AT OBSERVED OVEREXPECTED 1703 01:02:01,760 --> 01:02:03,720 RATIO FOR ALL RELATIVES, KNOWN 1704 01:02:03,720 --> 01:02:06,040 WILD TYPE RELATIVES HETEROZYGOTE 1705 01:02:06,040 --> 01:02:07,760 RELATIVES THERE IS NOT AN 1706 01:02:07,760 --> 01:02:09,800 INCREASE RISK OF CANCER. I'M 1707 01:02:09,800 --> 01:02:11,560 MOST INTERESTED, WE DIDN'T 1708 01:02:11,560 --> 01:02:12,840 OBSERVE CANCER COMMON IN FA 1709 01:02:12,840 --> 01:02:15,080 PATIENTS INCLUDING AML AND HEAD 1710 01:02:15,080 --> 01:02:16,880 AND NECK SQUAMOUS CELL CARCINOMA 1711 01:02:16,880 --> 01:02:20,000 AND THE CANCER WE DID OBSERVE IN 1712 01:02:20,000 --> 01:02:21,200 HETEROZYGOTES TYPICAL AGE OF 1713 01:02:21,200 --> 01:02:24,320 ONSET OF THOSE SPECIFIC CANCER 1714 01:02:24,320 --> 01:02:26,480 SO WE DIDN'T SEE INCREASE RISK 1715 01:02:26,480 --> 01:02:29,240 IN THESE HETEROZYGOTES. 1716 01:02:29,240 --> 01:02:30,480 PARTICULARLY THE MOST COMMON 1717 01:02:30,480 --> 01:02:33,760 FORMS OF FANCONI ANEMIA ARE FANC 1718 01:02:33,760 --> 01:02:37,520 AND FANA AND WE DIDN'T SEE 1719 01:02:37,520 --> 01:02:39,320 INCHRIS RISK. HOWEVER WILL 1720 01:02:39,320 --> 01:02:41,160 THERE'S LIMITATIONS SO DESPITE 1721 01:02:41,160 --> 01:02:43,240 LARGE SAMPLE SIZE WE HAD LIMITED 1722 01:02:43,240 --> 01:02:45,600 POWER PARTICULARLY FOR THE RARE 1723 01:02:45,600 --> 01:02:48,880 FA GENOTYPES. SO WE NEEDED A 1724 01:02:48,880 --> 01:02:50,600 SECOND VALIDATION COHORT. 1725 01:02:50,600 --> 01:02:51,960 HOWEVER THIS IS THE LARGEST 1726 01:02:51,960 --> 01:02:53,440 COLLECTION OF FA RELATIVES SO 1727 01:02:53,440 --> 01:02:55,480 WHERE DID WE -- WHAT DO WE DO 1728 01:02:55,480 --> 01:02:58,720 NEXT? TURN TO LARGE BIOBANKS AND 1729 01:02:58,720 --> 01:03:01,160 GENOME FIRST APPROACH. SO THERE 1730 01:03:01,160 --> 01:03:11,840 ARE SEVERAL ADVANTAGES TO IDENTL 1731 01:03:23,600 --> 01:03:25,160 PHENOTYPES PREVIOUSLY OBSERVED 1732 01:03:25,160 --> 01:03:28,560 IN SMALLER COHORT. SO THE 1733 01:03:28,560 --> 01:03:29,640 TRADITIONAL GENETIC MODEL HAS 1734 01:03:29,640 --> 01:03:31,560 BEEN WHAT WE CALL THE PHENOTYPE 1735 01:03:31,560 --> 01:03:34,680 FIRST APPROACH. SO YOU FIND 1736 01:03:34,680 --> 01:03:36,000 INDIVIDUALS WHO HAVE SPECIFIC 1737 01:03:36,000 --> 01:03:37,200 PHENOTYPE THAT YOU ARE 1738 01:03:37,200 --> 01:03:38,520 INTERESTED IN AND BRING THEM TO 1739 01:03:38,520 --> 01:03:41,640 CLINIC AND YOU DO ASSOCIATION 1740 01:03:41,640 --> 01:03:42,840 STUDIES AND FIND THE GENOTYPE 1741 01:03:42,840 --> 01:03:46,480 AND UNDERLYING CAUSATIVE GENE. 1742 01:03:46,480 --> 01:03:50,120 THIS IS VERY EFFECTIVE BUT THE 1743 01:03:50,120 --> 01:03:51,640 PROBLEM IS IT HAS BIAS TOWARDS 1744 01:03:51,640 --> 01:03:53,320 PEOPLE WITH SEVERE PHENOTYPE, IT 1745 01:03:53,320 --> 01:03:56,240 IS RELATIVELY LOW THROUGH PUT. 1746 01:03:56,240 --> 01:03:58,960 SO IF WE FLIP THAT MODEL ON ITS 1747 01:03:58,960 --> 01:04:00,200 HEAD WE CAN DO A GENOTYPE FIRST 1748 01:04:00,200 --> 01:04:03,280 APPROACH. SO INSTEAD OF GOING 1749 01:04:03,280 --> 01:04:04,920 FROM PHENOTYPE TO GENOTYPE YOU 1750 01:04:04,920 --> 01:04:06,560 GO GENOTYPE TO PHENOTYPE. SO 1751 01:04:06,560 --> 01:04:08,280 LARGE COLLECTIONS OF PEOPLE FROM 1752 01:04:08,280 --> 01:04:12,560 BIOBANKS USUALLY IN A -- 1753 01:04:12,560 --> 01:04:14,920 HEALTHCARE COMBINED HEALTHCARE 1754 01:04:14,920 --> 01:04:16,840 SYSTEM WHICH HAS ACCESS TO 1755 01:04:16,840 --> 01:04:19,280 ELECTRONIC MEDICAL RECORDS AND 1756 01:04:19,280 --> 01:04:20,320 DO GENOTYPING AND THEN LOOK AT 1757 01:04:20,320 --> 01:04:22,560 THEIR PHENOTYPES. SO THIS IS 1758 01:04:22,560 --> 01:04:24,960 RELATIVELY HIGHER THROUGH PUT 1759 01:04:24,960 --> 01:04:26,000 THAN THE PHENOTYPE FIRST 1760 01:04:26,000 --> 01:04:28,440 APPROACH. SO FOR LOOKING AGENT 1761 01:04:28,440 --> 01:04:32,120 THE RISK OF CANCER IN FA 1762 01:04:32,120 --> 01:04:34,520 HETEROZYGOTES WE USE TWO LARGE 1763 01:04:34,520 --> 01:04:39,040 BIOBANKS FIRST IS GUY SINGER 1764 01:04:39,040 --> 01:04:42,480 COHORT OF APPROXIMATELY 175,000 1765 01:04:42,480 --> 01:04:44,400 INDIVIDUALS ALL CONSENTED TO 1766 01:04:44,400 --> 01:04:46,280 HAVE EXOME SEQUENCING, 1767 01:04:46,280 --> 01:04:48,520 PARTICIPANTS IN THE GUY SINGER 1768 01:04:48,520 --> 01:04:50,720 HEALTH SYSTEM IN NORTH EASTERN 1769 01:04:50,720 --> 01:04:52,560 PENNSYLVANIA AND LINKED TO THEIR 1770 01:04:52,560 --> 01:04:54,280 ELECTRONIC MEDICAL RECORD. AS 1771 01:04:54,280 --> 01:04:57,160 WELL AS THEIR TUMOR AND DEATH 1772 01:04:57,160 --> 01:04:59,800 REGISTRY. THIS SUB COHORT OF 1773 01:04:59,800 --> 01:05:01,120 INDIVIDUALS WHO HAVE BEEN EXOMED 1774 01:05:01,120 --> 01:05:03,200 ARE CALLED THE DISCOVER COHORT. 1775 01:05:03,200 --> 01:05:07,120 WE HAVE ACCESS TO THE UK BIOBANK 1776 01:05:07,120 --> 01:05:09,800 COHORT WHICH IS APPROXIMATELY 1777 01:05:09,800 --> 01:05:11,760 469,000 PEOPLE WHO HAD EXOME. 1778 01:05:11,760 --> 01:05:14,320 AGAIN LINKED TO THE ELECTRONIC 1779 01:05:14,320 --> 01:05:16,080 HEALTH REGISTRY, DEATH CANCER 1780 01:05:16,080 --> 01:05:17,120 REGISTRY AND NUMEROUS 1781 01:05:17,120 --> 01:05:20,040 QUESTIONNAIRES THESE INDIVIDUALS 1782 01:05:20,040 --> 01:05:24,280 UNDERGO. IF WE LOOK WE TOOK THE 1783 01:05:24,280 --> 01:05:28,360 DISCOVER COHORT FROM GEISINGER 1784 01:05:28,360 --> 01:05:31,680 AT TIME OF ANALYSIS WAS 175,300 1785 01:05:31,680 --> 01:05:32,920 INDIVIDUAL WHOSE HAD EXOME 1786 01:05:32,920 --> 01:05:34,400 SEQUENCING IDENTIFY EVERYONE WHO 1787 01:05:34,400 --> 01:05:36,200 HAD SINGLE PATHOGENIC VARIANT IN 1788 01:05:36,200 --> 01:05:38,520 ONE OF THE 22 FA GENES, WE 1789 01:05:38,520 --> 01:05:41,720 REMOVED ANYBODY WHO WAS 1790 01:05:41,720 --> 01:05:44,760 IDENTIFIED COMPOUND HETERO IS A 1791 01:05:44,760 --> 01:05:48,800 ZYGOTE, HOMOCYTE GOAT OR FA 1792 01:05:48,800 --> 01:05:50,960 VARIANT IN TWO DIFFERENT 1793 01:05:50,960 --> 01:05:55,440 VACCINES. SO THIS LEFT WITH 589 1794 01:05:55,440 --> 01:05:56,800 INDIVIDUALS, FIVE TIME MORRIS 1795 01:05:56,800 --> 01:05:58,480 PEOPLE THAN IN FA RELATIVE 1796 01:05:58,480 --> 01:06:01,760 STUDY, AND 3.4% COHORT WERE 1797 01:06:01,760 --> 01:06:02,880 HETEROZYGOTES. THIS IS SIMILAR 1798 01:06:02,880 --> 01:06:05,400 TO WHAT WE HAD PREVIOUSLY 1799 01:06:05,400 --> 01:06:07,160 DESCRIBED IN GENOME AD PROJECT 1800 01:06:07,160 --> 01:06:08,840 BUT PARTICULARLY HIGHER THAN 1801 01:06:08,840 --> 01:06:11,320 WHAT HAD PREVIOUSLY BEEN 1802 01:06:11,320 --> 01:06:14,000 DESCRIBED FOR THE RATE OF 1803 01:06:14,000 --> 01:06:16,040 FANCONI CARRIERS IN A POPULATION 1804 01:06:16,040 --> 01:06:18,440 LOOKING AT PATIENTS WHO ARE 1805 01:06:18,440 --> 01:06:20,400 IDENTIFIED. THIS WAS LINKED TO 1806 01:06:20,400 --> 01:06:22,560 THE ELECTRONIC HEALTH REGISTRY 1807 01:06:22,560 --> 01:06:25,280 AND MALIGNANCY ICD 10 CODES AND 1808 01:06:25,280 --> 01:06:26,840 COMPARE CANCER TO SERE AS WELL 1809 01:06:26,840 --> 01:06:30,560 AS INTERNAL COHORT AS A CONTROL 1810 01:06:30,560 --> 01:06:34,280 SET. THE FIRST SURPRISING THING 1811 01:06:34,280 --> 01:06:37,160 WAS THAT THE THERE'S SIGNIFICANT 1812 01:06:37,160 --> 01:06:38,560 DIFFERENCE IN THE DISTRIBUTION 1813 01:06:38,560 --> 01:06:40,560 OF FANCONI HETEROZYGOTES. IF YOU 1814 01:06:40,560 --> 01:06:42,560 TAKE ALL FANCONI ANEMIA PATIENTS 1815 01:06:42,560 --> 01:06:47,400 THE VAST MAJORITY OF FANC A G OR 1816 01:06:47,400 --> 01:06:49,200 C. LOOK AT HETEROZYGOTES WE 1817 01:06:49,200 --> 01:06:50,760 IDENTIFIED AND DISCOVERED THE 1818 01:06:50,760 --> 01:06:52,680 DISTRIBUTION ACROSS THE 22 GENES 1819 01:06:52,680 --> 01:06:54,280 IS QUITE DIFFERENT. YOU CAN SEE 1820 01:06:54,280 --> 01:07:02,080 HERE FANCA IS ONLY 13%, FANC THE 1821 01:07:02,080 --> 01:07:05,480 2%, FANCN IS MUCH MORE COMMON. 1822 01:07:05,480 --> 01:07:06,920 SECOND IS WHAT THE CANCER RATES 1823 01:07:06,920 --> 01:07:09,760 WERE. FIRST WE GROUPED THE GENES 1824 01:07:09,760 --> 01:07:12,240 WE ALREADY KNEW WERE CANCER 1825 01:07:12,240 --> 01:07:15,760 PRE-DISPOSITION GENES BRACA 1, 1826 01:07:15,760 --> 01:07:17,080 2, AND LOOKED AT THE RATE HERE. 1827 01:07:17,080 --> 01:07:18,560 YOU CAN SEE THAT THIS IS 1828 01:07:18,560 --> 01:07:20,160 SIGNIFICANTLY INCREASED RISK OF 1829 01:07:20,160 --> 01:07:21,640 CANCER IN THESE INDIVIDUALS, 1830 01:07:21,640 --> 01:07:23,840 BOTH LOOKING BY COMPARISON TO 1831 01:07:23,840 --> 01:07:28,160 SEER AS WELL AS COMPARED TO 1832 01:07:28,160 --> 01:07:30,040 INTERNAL CONTROL COHORT. 1833 01:07:30,040 --> 01:07:33,520 HOWEVER, IF WE LOOK AGAIN AT 1834 01:07:33,520 --> 01:07:36,320 JUST THE AUTOSOMAL RECESSIVE 1835 01:07:36,320 --> 01:07:38,400 INHERITED FANCONI GENES SUCH AS 1836 01:07:38,400 --> 01:07:40,960 FANC A C AND G DO NOT SEE A 1837 01:07:40,960 --> 01:07:42,200 SIGNIFICANTLY INCREASE RISK OF 1838 01:07:42,200 --> 01:07:46,280 CANCER AMONG THESE INDIVIDUALS. 1839 01:07:46,280 --> 01:07:51,200 SURPRISINGLY IN 3 GENES WE FOUND 1840 01:07:51,200 --> 01:07:52,600 SOME SIGNAL FOR INCREASE RISK OF 1841 01:07:52,600 --> 01:07:54,560 CANCER IN THESE THREE GENES. 1842 01:07:54,560 --> 01:07:56,680 HOWEVER, WHEN WE WENT TO 1843 01:07:56,680 --> 01:07:58,640 VALIDATE THIS FINDING WE CAN SEE 1844 01:07:58,640 --> 01:08:03,480 WE DID NOT SEE INCREASE RISK. 1845 01:08:03,480 --> 01:08:05,240 IN UK BIOBANK AMONG THESE THREE 1846 01:08:05,240 --> 01:08:07,480 FA GENES. SO OVERALL, WE FOUND 1847 01:08:07,480 --> 01:08:10,240 NO INCREASE RISK OF CANCER WAS 1848 01:08:10,240 --> 01:08:11,920 IDENTIFIED IN THE HETEROZYGOTE 1849 01:08:11,920 --> 01:08:15,520 RELATIVES OF FA ONLY MEMBERS THE 1850 01:08:15,520 --> 01:08:17,400 GENOME FIRST ANALYSIS IDENTIFIED 1851 01:08:17,400 --> 01:08:19,440 HIGHER RATES OF FA HETEROZYGOTE 1852 01:08:19,440 --> 01:08:21,000 MS. THE POPULATION PREVIOUSLY 1853 01:08:21,000 --> 01:08:22,360 DESCRIBED AND NOTABLY DIFFERENT 1854 01:08:22,360 --> 01:08:23,280 DISTRIBUTION OF GENES COMPARED 1855 01:08:23,280 --> 01:08:26,680 TO PATIENTS WITH FA. USING THE 1856 01:08:26,680 --> 01:08:29,080 GENOME FIRST APPROACH WE 1857 01:08:29,080 --> 01:08:31,280 VALIDATED STUDY FROM FA RELATIVE 1858 01:08:31,280 --> 01:08:33,240 AND CONFIRMED THE KNOWN CANCER 1859 01:08:33,240 --> 01:08:34,880 PRE-DISPOSITION GENES THE 1860 01:08:34,880 --> 01:08:36,600 HETEROZYGOTES HAVE INCREASE 1861 01:08:36,600 --> 01:08:38,960 CANCER RISK. IN CONTRAST OTHER 1862 01:08:38,960 --> 01:08:41,120 AUTOSOMAL INHERITED FA GENES 1863 01:08:41,120 --> 01:08:41,920 HETEROZYGOTES DON'T HAVE 1864 01:08:41,920 --> 01:08:43,320 INCREASE RISK OF CANCER AND THE 1865 01:08:43,320 --> 01:08:45,000 GENOME FIRST APPROACH ALLOWED 1866 01:08:45,000 --> 01:08:46,440 FOR STATISTICAL POWER WHEN 1867 01:08:46,440 --> 01:08:47,600 FAMILY STUDIES DID NOT 1868 01:08:47,600 --> 01:08:49,520 PARTICULARLY FOR THE FA -- THE 1869 01:08:49,520 --> 01:08:55,040 RARER FA GENOTYPES. SO THIS IS 1870 01:08:55,040 --> 01:08:56,200 COLLABORATIVE SCIENCE, LIKE TO 1871 01:08:56,200 --> 01:08:58,640 FIRST THANK MY MENTEES INVOLVED 1872 01:08:58,640 --> 01:09:02,520 IN THIS WORK, (INDISCERNIBLE) 1873 01:09:02,520 --> 01:09:04,400 THE ENTIRE TEAM HERE MY ACI 1874 01:09:04,400 --> 01:09:06,000 MENTORING COMMITTEE, 1875 01:09:06,000 --> 01:09:08,880 COLLABORATORS AT GEISINGER 1876 01:09:08,880 --> 01:09:10,000 HEALTH SYSTEM (INDISCERNIBLE) 1877 01:09:10,000 --> 01:09:11,800 AND SUPPORT STAFF THROUGHOUT DCG 1878 01:09:11,800 --> 01:09:13,840 WHO ARE AMAZING AND WONDERFUL TO 1879 01:09:13,840 --> 01:09:15,280 WORK WITH. THANK YOU. 1880 01:09:15,280 --> 01:09:21,800 [APPLAUSE] 1881 01:09:21,800 --> 01:09:29,320 >>ANY QUESTIONS? 1882 01:09:29,320 --> 01:09:30,480 SPEAKER5: GREAT. ONE OF THE 1883 01:09:30,480 --> 01:09:31,640 INTERESTING THINGS ABOUT DOING 1884 01:09:31,640 --> 01:09:34,920 GENOTYPE FIRST APPROACHES YOU 1885 01:09:34,920 --> 01:09:35,800 PROBABLY SHOULD COME UP WITH UP 1886 01:09:35,800 --> 01:09:39,960 TO A COUPLE OF HUNDRED 1887 01:09:39,960 --> 01:09:41,840 HOMOZYGOTES. SO THE QUESTION ARE 1888 01:09:41,840 --> 01:09:43,880 THERE ANY ASYMPTOMATIC OR IS 1889 01:09:43,880 --> 01:09:45,160 THERE EVIDENCE OF SUPPRESSER 1890 01:09:45,160 --> 01:09:46,560 GENES IN THE POPULATION? 1891 01:09:46,560 --> 01:09:49,240 >>IT IS A GREAT QUESTION SO WE 1892 01:09:49,240 --> 01:09:50,600 DID FIND SURPRISES IN THAT AND 1893 01:09:50,600 --> 01:09:52,320 WE ARE FOLLOWING UP NOW BUT WE 1894 01:09:52,320 --> 01:09:53,720 FIND A COUPLE OF HUNDRED PEOPLE 1895 01:09:53,720 --> 01:09:55,440 WHO LOOK LIKE THEY SHOULD HAVE 1896 01:09:55,440 --> 01:09:56,600 FANCONI ANEMIA BUT DON'T HAVE 1897 01:09:56,600 --> 01:09:58,520 ANY EVIDENCE OF IT IN THEIR 1898 01:09:58,520 --> 01:09:59,960 MEDICAL RECORDS. SO WE ARE 1899 01:09:59,960 --> 01:10:01,080 FOLLOWING THOSE UP NOW. 1900 01:10:01,080 --> 01:10:02,560 PARTICULARLY SOME SURPRISING 1901 01:10:02,560 --> 01:10:04,160 FINDINGS LIKE PEOPLE WHO SHOULD 1902 01:10:04,160 --> 01:10:06,680 HAVE VERY SEVERE FANCONI 1903 01:10:06,680 --> 01:10:09,400 PHENOTYPES, BUT WE DON'T SEE IT 1904 01:10:09,400 --> 01:10:11,240 MORE FOLLOW-UP AND WE ARE ALSO 1905 01:10:11,240 --> 01:10:14,040 DOING A STUDY CAN WE DETERMINE 1906 01:10:14,040 --> 01:10:18,960 HAVING ONE FANCA AND ONE FANCC 1907 01:10:18,960 --> 01:10:21,720 GIVE YOU FANCONI ANEMIA. SO FAR 1908 01:10:21,720 --> 01:10:23,000 NEGATIVE BUT THEY WERE HARD TO 1909 01:10:23,000 --> 01:10:24,360 GET AT, WE COULDN'T FIND THOSE 1910 01:10:24,360 --> 01:10:26,280 PEOPLE AND NOW WE HAVE WAY TO 1911 01:10:26,280 --> 01:10:27,160 ACCESS PEOPLE WITH THOSE 1912 01:10:27,160 --> 01:10:33,120 GENOTYPES. 1913 01:10:33,120 --> 01:10:34,240 >>WHAT FOLLOW-UP DURATION OF 1914 01:10:34,240 --> 01:10:36,680 THE DATA SET YOU SHOWED? 1915 01:10:36,680 --> 01:10:39,480 >>SO THE -- SO FOR THE 1916 01:10:39,480 --> 01:10:40,960 GEISINGER HEALTH SYSTEM THEY 1917 01:10:40,960 --> 01:10:42,840 MOVE THEIR ELECTRONIC HEALTH 1918 01:10:42,840 --> 01:10:44,280 RECORDS IN THE MID 90s SO WE 1919 01:10:44,280 --> 01:10:47,520 HAVE IT MORE THAN 20 YEARS 1920 01:10:47,520 --> 01:10:48,840 FOLLOW-UP. SOME OF THE PATIENTS 1921 01:10:48,840 --> 01:10:50,240 WHO JUST JOINED THE HEALTHCARE 1922 01:10:50,240 --> 01:10:51,440 SYSTEM IT IS LESS BUT THE RANGE 1923 01:10:51,440 --> 01:10:52,560 IS PRETTY DECENT. 1924 01:10:52,560 --> 01:10:59,080 >>THANK YOU. 1925 01:10:59,080 --> 01:11:00,480 >>THANK YOU ALL. 1926 01:11:00,480 --> 01:11:10,640 [APPLAUSE] 1927 01:11:16,000 --> 01:11:19,240 >>THE NEXT SPEAKER IS DR. 1928 01:11:19,240 --> 01:11:21,160 DESMOND BROWN. DR. BROWN 1929 01:11:21,160 --> 01:11:23,640 RECEIVED M.D. Ph.D. IN 2014 1930 01:11:23,640 --> 01:11:25,960 FROM RUTGERS PRINCETON 1931 01:11:25,960 --> 01:11:27,680 UNIVERSITY COMBINED M.D. Ph.D. 1932 01:11:27,680 --> 01:11:29,520 PROGRAM AND COMPLETED RESIDENCY 1933 01:11:29,520 --> 01:11:31,000 IN NEUROLOGICAL SURGERY 1934 01:11:31,000 --> 01:11:33,080 FOLLOWING FELLOWSHIP IN 1935 01:11:33,080 --> 01:11:34,640 NEUROSURGICAL ONCOLOGY MAYO 1936 01:11:34,640 --> 01:11:40,080 CLINIC IN 2021. CLINICALLY DR. 1937 01:11:40,080 --> 01:11:42,560 BROWN INTEREST IS COMPLEX 1938 01:11:42,560 --> 01:11:46,480 RESECTION OF THE INTRAAX LOW 1939 01:11:46,480 --> 01:11:50,480 GLAND LESIONS AWAKE RESECTIONS, 1940 01:11:50,480 --> 01:11:52,240 OPERATOR SPEECH AND MAPPING. DR. 1941 01:11:52,240 --> 01:11:53,800 BROWN'S RESEARCH PROGRAM IS 1942 01:11:53,800 --> 01:11:56,200 INVESTIGATING THE ROLE OF 1943 01:11:56,200 --> 01:11:57,640 PRIMARILY SERUM IN CANCER 1944 01:11:57,640 --> 01:12:00,240 MOLECULAR BIOLOGY AS SITE OF 1945 01:12:00,240 --> 01:12:02,680 INTEGRATION OF POPULACE. 1946 01:12:02,680 --> 01:12:05,760 [APPLAUSE] 1947 01:12:05,760 --> 01:12:08,000 I'M GOING TO TALK TO YOU TODAY ABOUT 1948 01:12:08,000 --> 01:12:10,040 WHAT MANY PEOPLE MIGHT THINK IS 1949 01:12:10,040 --> 01:12:13,600 A RATHER ESOTERIC TOPIC PRIMARY 1950 01:12:13,600 --> 01:12:18,000 CILIA AND TALK IN THE CONTEXT OF 1951 01:12:18,000 --> 01:12:20,480 GLIOBLASTGLIOBLASTOMA. NO DISCL. 1952 01:12:20,480 --> 01:12:22,920 PRIMARY CILIA ARE THESE 1953 01:12:22,920 --> 01:12:25,800 ORGANELLES THAT PROTRUDE FROM 1954 01:12:25,800 --> 01:12:27,480 THE CELL MEMBRANE, THEY ARE 1955 01:12:27,480 --> 01:12:29,280 SPECIALIZED SO MANY PEOPLE HAVE 1956 01:12:29,280 --> 01:12:33,320 HEARD OF THESE TUBULES THAT HAVE 1957 01:12:33,320 --> 01:12:37,040 THIS NINE PLUS ZERO ARRANGEMENT 1958 01:12:37,040 --> 01:12:39,560 AND SO THESE GROW OUT FROM THE 1959 01:12:39,560 --> 01:12:41,640 MOTHER CENTRIOLE AND THEY ARE 1960 01:12:41,640 --> 01:12:43,520 ORGANIZED IN A VERY SPECIFIC WAY 1961 01:12:43,520 --> 01:12:45,840 THAT WE WILL TALK ABOUT THAT GET 1962 01:12:45,840 --> 01:12:48,720 THEM THESE FUNCTIONS. AND THE 1963 01:12:48,720 --> 01:12:51,240 FUNCTION SPECIFICALLY ARE TO 1964 01:12:51,240 --> 01:12:54,800 REGULATE CANONICAL SIGNAL 1965 01:12:54,800 --> 01:12:57,640 TRANSDUCTION CASCADES, JUST 1966 01:12:57,640 --> 01:13:01,120 HEARD FROM LISA SHE IS A FELLOW 1967 01:13:01,120 --> 01:13:02,400 DEVELOPMENTAL BIOLOGIST, I ALSO 1968 01:13:02,400 --> 01:13:03,840 DID Ph.D. IN 1969 01:13:03,840 --> 01:13:05,080 NEURODEVELOPMENTAL AND MOLECULAR 1970 01:13:05,080 --> 01:13:07,640 BIOLOGY SO ONE OF THE HALLMARK 1971 01:13:07,640 --> 01:13:09,120 SIGNALING CAUSE FADES IS SONIC 1972 01:13:09,120 --> 01:13:11,640 HEDGEHOG SIGNALING BUT PRIMARY 1973 01:13:11,640 --> 01:13:14,040 CILIA ALSO REGULATE A NUMBER OF 1974 01:13:14,040 --> 01:13:16,160 THESE CANONICAL SIGNALING 1975 01:13:16,160 --> 01:13:20,080 CASCADES THAT ARE IMPORTANT IN 1976 01:13:20,080 --> 01:13:24,840 DEVELOPMENT AND LATER USED IN 1977 01:13:24,840 --> 01:13:27,240 PATHOLOGICAL PROCESSES. THEY ARE 1978 01:13:27,240 --> 01:13:29,680 REGULATED IN A VERY COMPLEX WAY 1979 01:13:29,680 --> 01:13:34,800 BECAUSE THEY GROW FROM THE 1980 01:13:34,800 --> 01:13:35,640 CENTRIOLE SO BASICALLY THIS 1981 01:13:35,640 --> 01:13:37,520 MEANS THAT THE ORGANELLES 1982 01:13:37,520 --> 01:13:40,640 THEMSELVES ACT AS KIND OF A G2M 1983 01:13:40,640 --> 01:13:42,120 CHECK POINT INHIBITOR WHICH IS 1984 01:13:42,120 --> 01:13:45,560 INTERESTING. SO THIS IS IMAGES 1985 01:13:45,560 --> 01:13:50,520 FROM OUR LAB TAKEN BY PRIOR MRA 1986 01:13:50,520 --> 01:13:52,000 STUDENT IN THE LAB SHOWING THAT 1987 01:13:52,000 --> 01:13:53,880 THE CILIA ACTUALLY AS SHOWN IN 1988 01:13:53,880 --> 01:13:56,760 THE CARTOON HERE FROM THIS PRIOR 1989 01:13:56,760 --> 01:14:00,040 REVIEW HAVE TO GET DISSOCIATED 1990 01:14:00,040 --> 01:14:02,520 OR DISASSEMBLED IN ORDER FOR THE 1991 01:14:02,520 --> 01:14:05,280 CELL TO PROGRESS THROUGH THE G2M 1992 01:14:05,280 --> 01:14:07,120 CHECK POINT. SO OBVIOUS THIS HAS 1993 01:14:07,120 --> 01:14:09,000 SOME IMPLICATIONS FOR CANCER 1994 01:14:09,000 --> 01:14:12,400 BROADLY BUT ALSO FOR 1995 01:14:12,400 --> 01:14:14,400 PROLIFERATION AND SIGNALING MORE 1996 01:14:14,400 --> 01:14:18,520 GENERALLY. AS A RESULT OF THE 1997 01:14:18,520 --> 01:14:24,520 IMPORTANCE OF THIS ORGANELLE IN 1998 01:14:24,520 --> 01:14:26,400 DEVELOPMENTAL CASCADES WE HAVE A 1999 01:14:26,400 --> 01:14:31,800 CLASS OF DISEASES REFERRED TO 2000 01:14:31,800 --> 01:14:34,240 BROADLY AS SILL OWEPATHYS. 2001 01:14:34,240 --> 01:14:36,240 THESE INCLUDE THINGS YOU HEARD 2002 01:14:36,240 --> 01:14:37,600 ABOUT FROM MEDICAL STUDENTS OR 2003 01:14:37,600 --> 01:14:40,480 OTHER PHYSICIANS, THINGS LIKE 2004 01:14:40,480 --> 01:14:43,000 POLYCYSTICKED KIDNEY DISEASE AND 2005 01:14:43,000 --> 01:14:44,480 RETINITIS PIGMENTOSA. THESE ARE 2006 01:14:44,480 --> 01:14:47,080 ALL DISEASES OF CELLULAR 2007 01:14:47,080 --> 01:14:48,440 DISREGULATION IN ONE WAY OR THE 2008 01:14:48,440 --> 01:14:53,200 OTHER. CILIA THEREFORE BECAUSE 2009 01:14:53,200 --> 01:14:55,080 OF THEIR UBIQUITOUSNESS AND 2010 01:14:55,080 --> 01:14:56,160 BECAUSE OF THE FACT THEY 2011 01:14:56,160 --> 01:14:59,160 REGULATE ALL THESE PATHWAYS, 2012 01:14:59,160 --> 01:15:00,600 SEVERAL PAPERS OVER THE LAST 2013 01:15:00,600 --> 01:15:04,680 DECADE OR SO HAVE SHOWN THESE 2014 01:15:04,680 --> 01:15:07,880 ARE JUST REALLY IMPORTANT FOR 2015 01:15:07,880 --> 01:15:09,480 NUMBER OF DIFFERENT BOTH 2016 01:15:09,480 --> 01:15:10,840 PHYSIOLOGIC AND PATHOLOGICAL 2017 01:15:10,840 --> 01:15:13,040 PROCESSES. THIS IS A PAPER THAT 2018 01:15:13,040 --> 01:15:15,080 IS LOOKING AT ALZHEIMER'S 2019 01:15:15,080 --> 01:15:16,640 DISEASE AND AGING AND SOME OF 2020 01:15:16,640 --> 01:15:19,320 THE NEUROPSYCHIATRIC DISORDERS 2021 01:15:19,320 --> 01:15:22,560 OBVIOUSLY, IT IS NOT FOR YOU TO 2022 01:15:22,560 --> 01:15:23,560 RECOGNIZE ANY PARTICULAR GENE, 2023 01:15:23,560 --> 01:15:25,760 JUST SHOWING YOU HERE THAT ALL 2024 01:15:25,760 --> 01:15:29,480 THESE BLUE GENES HERE ARE GENES 2025 01:15:29,480 --> 01:15:32,400 THAT ARE STRUCTURALLY IMPORTANT 2026 01:15:32,400 --> 01:15:34,400 FOR PRIMARY CILIA DEVELOPMENMEN. 2027 01:15:34,400 --> 01:15:37,440 ASIT IN THESE CORES OF GENES 2028 01:15:37,440 --> 01:15:40,320 THAT REGULATE DISEASE PROCESS 2029 01:15:40,320 --> 01:15:44,760 AND THINGS LIKE IN ALZHEIMER'S 2030 01:15:44,760 --> 01:15:45,640 DISEASE. YOU CAN SEE WHEN THEY 2031 01:15:45,640 --> 01:15:47,880 LOOK AT THE CILIA GENES SHOWING 2032 01:15:47,880 --> 01:15:49,800 RED, HOW THEY INTERACT WITH 2033 01:15:49,800 --> 01:15:51,000 GENES FOR EXAMPLE THAT ARE 2034 01:15:51,000 --> 01:15:53,080 IMPORTANT FOR THINGS LIKE AGING 2035 01:15:53,080 --> 01:15:54,400 AND ALZHEIMER'S DISEASE SHOWN 2036 01:15:54,400 --> 01:15:58,400 BETTER HERE. TRYING TO CONVINCE 2037 01:15:58,400 --> 01:16:02,760 YOU THIS IS A IMPORTANT THING. 2038 01:16:02,760 --> 01:16:04,200 BASICALLY I TOLD YOU WE TALK 2039 01:16:04,200 --> 01:16:08,200 ABOUT THIS IN A CONTEXT OF 2040 01:16:08,200 --> 01:16:12,760 GLIOBLASTOMA. THIS IS A HORRIBLE 2041 01:16:12,760 --> 01:16:16,680 DISEASE. I LIKE TAKING TIME AS 2042 01:16:16,680 --> 01:16:18,560 SARA SAID EARLIER IN HER TALK TO 2043 01:16:18,560 --> 01:16:21,920 TRY TO EDUCATE ESPECIALLY A ROOM 2044 01:16:21,920 --> 01:16:24,520 FULL OF ANYBODY I CAN GET REALLY 2045 01:16:24,520 --> 01:16:26,520 OF SMART PEOPLE TO UNDERSTAND 2046 01:16:26,520 --> 01:16:29,400 HOW DEVASTATING THIS DISEASE IS. 2047 01:16:29,400 --> 01:16:30,840 AND HOW LITTLE WE HAVE BEEN ABLE 2048 01:16:30,840 --> 01:16:35,120 TO DO COMPARATIVELY SPEAKING. TO 2049 01:16:35,120 --> 01:16:38,280 HELP THIS DISEASE. SO BASICALLY 2050 01:16:38,280 --> 01:16:40,880 WHEN SOMEONE PRESENTS WITH 2051 01:16:40,880 --> 01:16:44,280 GLIOBLASTOMA TO US IN CLINIC, IF 2052 01:16:44,280 --> 01:16:48,120 WE DIAGNOSE THEM, BUT DIDN'T DO 2053 01:16:48,120 --> 01:16:49,240 ANY SORT OF TREATMENT FROM THE 2054 01:16:49,240 --> 01:16:52,520 TIME OF SYMPTOMATIC DIAGNOSIS 2055 01:16:52,520 --> 01:16:54,080 WITHOUT TREATMENT LIFE 2056 01:16:54,080 --> 01:16:55,200 EXPECTANCY IS SOMEWHERE ON THE 2057 01:16:55,200 --> 01:17:01,440 ORDER OF SIX WEEKS. WITH SOME 2058 01:17:01,440 --> 01:17:02,800 TREATMENT MEDIAN SURVIVAL IS 2059 01:17:02,800 --> 01:17:05,480 NINE MONTHS OR SO. IF WE TRY TO 2060 01:17:05,480 --> 01:17:11,840 MAXIMIZE TREATMENT MEANING THE 2061 01:17:11,840 --> 01:17:14,240 MAXIMAL SAFE RESECTION FOLLOWED 2062 01:17:14,240 --> 01:17:15,760 BY CHEMOTHERAPY AND RADIATION 2063 01:17:15,760 --> 01:17:17,040 TOGETHER FOR A MONTH FOLLOWED BY 2064 01:17:17,040 --> 01:17:20,120 SIX MONTHS OF RADIATION, THEN WE 2065 01:17:20,120 --> 01:17:21,520 CAN GET TO 15 MONTHS OF LIFE 2066 01:17:21,520 --> 01:17:23,120 EXPECT FANCY. THAT IS WHERE WE 2067 01:17:23,120 --> 01:17:26,560 HAVE BEEN FOR DECADES QUITE 2068 01:17:26,560 --> 01:17:29,720 HONESTLY. THERE ARE NUMBER OF 2069 01:17:29,720 --> 01:17:31,000 REASONS WHY THIS IS SO DIFFICULT 2070 01:17:31,000 --> 01:17:32,800 THE TREAT. ONE IS GENETIC 2071 01:17:32,800 --> 01:17:34,600 HETEROGENEITY AS WE HEARD ABOUT 2072 01:17:34,600 --> 01:17:36,720 EARLIER CONTRIBUTES TO THAT. BUT 2073 01:17:36,720 --> 01:17:39,760 IN THIS CASE THE DISEASES ALSO 2074 01:17:39,760 --> 01:17:41,280 BEHIND THIS KIND OF FIREWALL 2075 01:17:41,280 --> 01:17:42,720 CALLED CENTRAL NERVOUS SYSTEM 2076 01:17:42,720 --> 01:17:43,840 AND BEHIND THE BLOOD BRAIN 2077 01:17:43,840 --> 01:17:45,760 BARRIER. SO IT IS REALLY 2078 01:17:45,760 --> 01:17:47,200 DIFFICULT TO GET DRUGS THAT 2079 01:17:47,200 --> 01:17:51,440 MIGHT OTHERWISE BE EFFECTIVE TO 2080 01:17:51,440 --> 01:17:53,560 GET TO TREAT THIS DISEASE. IN 2081 01:17:53,560 --> 01:17:55,880 ADDITION WHAT I HAVE HIGHLIGHTED 2082 01:17:55,880 --> 01:17:58,560 HERE WILL BE THE MEAT OF MY TALK 2083 01:17:58,560 --> 01:18:00,680 TODAY IS THAT THE DISEASE ALSO 2084 01:18:00,680 --> 01:18:06,120 IS VERY ADEPT AT MITIGATING 2085 01:18:06,120 --> 01:18:09,680 IMMUNE RESPONSES TUMORS 2086 01:18:09,680 --> 01:18:11,840 TYPICALLY GIVE TO THE IMMUNE 2087 01:18:11,840 --> 01:18:15,360 SYSTEM WHICH THEN TARGETS THE 2088 01:18:15,360 --> 01:18:17,800 CANCER. IN OTHER WORDS THE 2089 01:18:17,800 --> 01:18:18,840 CANCER, THIS PARTICULAR CANCER 2090 01:18:18,840 --> 01:18:21,160 AND SEVERAL OTHERS AS I WILL 2091 01:18:21,160 --> 01:18:24,600 SHOW YOU MITIGATE THE NATURAL 2092 01:18:24,600 --> 01:18:25,680 IMMUNITY ONE MIGHT DEVELOP 2093 01:18:25,680 --> 01:18:28,120 T-CELL ADAPTIVE IMMUNITY ONE 2094 01:18:28,120 --> 01:18:30,400 DEVELOPS TO FIGHT THE CANCER. SO 2095 01:18:30,400 --> 01:18:31,920 THAT IS WHAT WE ARE GOING TO BE 2096 01:18:31,920 --> 01:18:33,680 TALKING ABOUT A LOT TODAY. OF 2097 01:18:33,680 --> 01:18:36,480 COURSE THESE PRIMARY CELLULAR 2098 01:18:36,480 --> 01:18:38,080 CILIA ARE PRESENT IN 2099 01:18:38,080 --> 01:18:38,960 GLIOBLASTOMA, THIS IS ANOTHER 2100 01:18:38,960 --> 01:18:43,800 PICTURE FROM OUR LAB. FROM A 2101 01:18:43,800 --> 01:18:45,600 HUMAN SAMPLE OF GLIOBLASTOMA 2102 01:18:45,600 --> 01:18:49,160 SAMPLE SHOWING CLEARLY DAPI IN 2103 01:18:49,160 --> 01:18:51,440 BLUE ACETYLATED ALPHA TUBULIN 2104 01:18:51,440 --> 01:18:53,720 LOOKING AT THE MICROTUBULES AND 2105 01:18:53,720 --> 01:18:56,480 YOU CAN SEE THE CENTROSOME HERE 2106 01:18:56,480 --> 01:18:59,000 STAINED IN RED. YOU CAN SEE THIS 2107 01:18:59,000 --> 01:19:00,160 LOVELY MICROTUBULE STRUCTURE 2108 01:19:00,160 --> 01:19:02,240 GROWING OUT OF THE PRIMARY 2109 01:19:02,240 --> 01:19:03,960 CILIA. YOU CAN SEE THIS IS A 2110 01:19:03,960 --> 01:19:10,840 HUMAN SAMPLE. SO AGAIN WE HAVE 2111 01:19:10,840 --> 01:19:15,320 LOTS OF BIOINFORMATIC EVIDENCE 2112 01:19:15,320 --> 01:19:17,640 THAT THESE ORGANELLES ARE 2113 01:19:17,640 --> 01:19:21,200 IMPORTANT FROM THE WAY THAT THE 2114 01:19:21,200 --> 01:19:23,000 MOLECULAR SIGNALING OF THE 2115 01:19:23,000 --> 01:19:26,640 TUMORS WORK. I WILL FOCUS YOU 2116 01:19:26,640 --> 01:19:28,840 HERE ON THIS UPPER RIGHT PANEL 2117 01:19:28,840 --> 01:19:29,600 HERE BECAUSE I DON'T WANT TO 2118 01:19:29,600 --> 01:19:32,120 NECESSARILY TALK ABOUT THE ALL 2119 01:19:32,120 --> 01:19:33,560 THE GRAPH BUT SUFFICE IT TO SAY 2120 01:19:33,560 --> 01:19:37,280 IN THIS PAPER THEY FOUND WHICH 2121 01:19:37,280 --> 01:19:39,160 WERE UP OR COULDN'T REGULATED 2122 01:19:39,160 --> 01:19:40,400 AND DEVELOP -- DOWN REGULATED 2123 01:19:40,400 --> 01:19:42,080 AND DEVELOPED FROM A 2124 01:19:42,080 --> 01:19:43,960 MATHEMATICAL MODEL OF PREDICTING 2125 01:19:43,960 --> 01:19:46,000 A CILIARE SCORE. ON THE UPPER 2126 01:19:46,000 --> 01:19:48,280 LEFT PANEL HERE, THE GENES THAT 2127 01:19:48,280 --> 01:19:50,440 WERE OVEREXPRESSED OR HIGHLY 2128 01:19:50,440 --> 01:19:51,760 EXPRESSED THESE FUNCTIONS THAT 2129 01:19:51,760 --> 01:19:56,920 BECAME PART OF THIS CELLULAR 2130 01:19:56,920 --> 01:19:59,200 SCORE WHEN THE CILIA SCORE WAS 2131 01:19:59,200 --> 01:20:01,600 HIGH THE PROGNOSIS WAS EXTREMELY 2132 01:20:01,600 --> 01:20:02,280 POOR FOR THESE PATIENTS. THIS 2133 01:20:02,280 --> 01:20:07,600 IS THE TCG, CANCER GENOME ATLAS 2134 01:20:07,600 --> 01:20:09,560 AND IF YOU LOOK AT THE 2135 01:20:09,560 --> 01:20:10,240 GLIOBLASTOMA YOU CAN SEE 2136 01:20:10,240 --> 01:20:16,200 DIFFERENCE IN SURVIVAL WHEN YOU 2137 01:20:16,200 --> 01:20:17,600 LOOK AT THE CILIA SCORE. THIS IS 2138 01:20:17,600 --> 01:20:19,840 A BIGGER SURVIVAL DIFFERENCE 2139 01:20:19,840 --> 01:20:20,880 WITH CURRENT STANDARD OF CARE 2140 01:20:20,880 --> 01:20:24,720 THERAPY. SO REALLY IMPORTANT THE 2141 01:20:24,720 --> 01:20:30,240 CONSIDER. PRIMARY CILIA, THE 2142 01:20:30,240 --> 01:20:32,560 SIGNALING THEY OVERSEE IF YOU 2143 01:20:32,560 --> 01:20:34,040 WILL ARE CO-OPTED IN MANY 2144 01:20:34,040 --> 01:20:37,200 CANCERS SO HERE WE WILL FOCUS ON 2145 01:20:37,200 --> 01:20:38,480 GLIOBLASTOMA BUT PRIMARY CILIA 2146 01:20:38,480 --> 01:20:40,840 REPORTED TO BE INVOLVED IN 2147 01:20:40,840 --> 01:20:42,040 SEVERAL OTHER CANCERS SO IN OUR 2148 01:20:42,040 --> 01:20:44,120 LAB WE FOCUS ON A LOT OF THINGS 2149 01:20:44,120 --> 01:20:46,400 RELATED TO GLIOBLASTOMA PRIMARY 2150 01:20:46,400 --> 01:20:48,560 CILIA. IN THIS TALK WE FOCUS ON 2151 01:20:48,560 --> 01:20:51,480 THE IMMUNOSUPPRESSIVE PHENOTYPE 2152 01:20:51,480 --> 01:20:54,160 THE WAY THIS IMMUNOSUPPRESSED 2153 01:20:54,160 --> 01:20:55,800 PHENOTYPE IS THOUGHT TO WORK IS 2154 01:20:55,800 --> 01:20:57,840 ONE QUESTION SHOULD BE HOW IS IT 2155 01:20:57,840 --> 01:21:02,240 A TUMOR THAT I TOLD YOU IS LEFT 2156 01:21:02,240 --> 01:21:03,720 BEHIND THE CENTRAL NERVOUS 2157 01:21:03,720 --> 01:21:04,960 SYSTEM IN THE BLOOD BRAIN 2158 01:21:04,960 --> 01:21:08,600 BARRIER AND THE BLOOD BRAIN 2159 01:21:08,600 --> 01:21:10,840 BARRIER HOW TUMOR LEAD TO 2160 01:21:10,840 --> 01:21:13,720 SYSTEMIC IMMUNE SUPPRESSION. SO 2161 01:21:13,720 --> 01:21:17,800 ONE OF THE WAYS IN WHICH THIS IS 2162 01:21:17,800 --> 01:21:19,280 TAUGHT -- THOUGHT TO OCCUR 2163 01:21:19,280 --> 01:21:20,560 PRIMARILY THOUGHT TO OCCUR IS BY 2164 01:21:20,560 --> 01:21:24,920 THE TUMOR RELEASING THESE EXTRA 2165 01:21:24,920 --> 01:21:26,560 CELLULAR VESICLES WHICH THEN ARE 2166 01:21:26,560 --> 01:21:28,840 ABLE TO EXIT THE CENTRAL NERVOUS 2167 01:21:28,840 --> 01:21:31,760 SYSTEM BE PART OF THE SYSTEMIC 2168 01:21:31,760 --> 01:21:34,200 IMMUNE SYSTEM AT CIRCULATION AND 2169 01:21:34,200 --> 01:21:37,040 INTERACT WITH IMMUNE CELL 2170 01:21:37,040 --> 01:21:40,240 SYSTEMATICALLY CAUSING IMMUNE 2171 01:21:40,240 --> 01:21:42,040 SUPPRESSION. (INDISCERNIBLE) THE 2172 01:21:42,040 --> 01:21:44,240 SCIENTIST IN MY LAB CURRENTLY, 2173 01:21:44,240 --> 01:21:48,640 PUBLISHED THIS PAPER LAST YEAR 2174 01:21:48,640 --> 01:21:49,720 SHOWING MECHANISTICALLY MORE 2175 01:21:49,720 --> 01:21:52,200 DETAILS HOW THIS HAPPENS. SO WE 2176 01:21:52,200 --> 01:21:53,800 KNOW THINGS LIKE INTERFERON 2177 01:21:53,800 --> 01:21:55,200 GAMMA WILL BE UPREGULATED WHICH 2178 01:21:55,200 --> 01:22:00,520 LEAD TO INCREASE IN PDL 1. 2179 01:22:00,520 --> 01:22:03,560 ESSENTIALLY INCREASE IN PDL 1 2180 01:22:03,560 --> 01:22:07,240 DRIVE EXPRESSION OR INDUCTION OF 2181 01:22:07,240 --> 01:22:09,240 THESE VERY SPECIFIC TUMOR TYPES, 2182 01:22:09,240 --> 01:22:11,000 MYELOID DERIVED SUPPRESSER CELLS 2183 01:22:11,000 --> 01:22:14,000 WE SEE IN CANCER. IN TURN THESE 2184 01:22:14,000 --> 01:22:18,600 MYELOID DERIVED SUPPRESSER CELLS 2185 01:22:18,600 --> 01:22:22,240 ARE ABLE TO THEN REDUCE T-CELL 2186 01:22:22,240 --> 01:22:23,680 PROLIFERATION AND ACTIVATION 2187 01:22:23,680 --> 01:22:26,080 LEADING TO THE T-CELL 2188 01:22:26,080 --> 01:22:28,960 LYMPHOPENIA AND T-CELL 2189 01:22:28,960 --> 01:22:31,000 INACTIVATION THAT IS SEEN IN 2190 01:22:31,000 --> 01:22:32,760 PATIENTS WITH GLIOBLASTOMA IN 2191 01:22:32,760 --> 01:22:43,280 SOME OTHER KINDS OF CANCER. NO 2192 01:22:45,360 --> 01:22:46,240 LONGER ADVANCING. 2193 01:22:46,240 --> 01:22:47,360 >>ARROW IS MOVING. 2194 01:22:47,360 --> 01:22:49,840 >>CAN'T GO ANY FURTHER. HERE WE 2195 01:22:49,840 --> 01:22:52,960 GO. THINK IT IS STILL 2196 01:22:52,960 --> 01:23:00,040 DOWNLOADING. SO BASED ON THIS 2197 01:23:00,040 --> 01:23:02,040 WE THINK THIS PROVIDES AN 2198 01:23:02,040 --> 01:23:04,680 EXPLANATION FOR WHY WE HAVE SEEN 2199 01:23:04,680 --> 01:23:06,560 THAT INTERFERON GAMMA 2200 01:23:06,560 --> 01:23:08,520 UPREGULATION CORRELATE WITH 2201 01:23:08,520 --> 01:23:11,960 REALLY POOR SURVIVAL IN 2202 01:23:11,960 --> 01:23:13,280 GLIOBLASTOMA. SO WHAT IS 2203 01:23:13,280 --> 01:23:14,920 INTERESTING HERE ABOUT THIS 2204 01:23:14,920 --> 01:23:16,360 OTHER SIDE IS CHEMO RADIATION IS 2205 01:23:16,360 --> 01:23:18,600 HOW I TOLD YOU WE TREAT THESE 2206 01:23:18,600 --> 01:23:21,920 PATIENTS BUT THERE IS EVIDENCE 2207 01:23:21,920 --> 01:23:23,480 THAT THE VERY ACTIVE CHEMO 2208 01:23:23,480 --> 01:23:26,720 RADIATION INCREASES INTERFERON 2209 01:23:26,720 --> 01:23:28,400 GAMMA WHICH WORSENS THE 2210 01:23:28,400 --> 01:23:29,040 IMMUNOSUPPRESSIVE ACTIVITY OF 2211 01:23:29,040 --> 01:23:31,680 THE TUMORS. SO IT WILL BE THIS 2212 01:23:31,680 --> 01:23:33,680 KIND OF RACE BETWEEN KILLING 2213 01:23:33,680 --> 01:23:35,880 TUMOR CELLS WHICH WE CAN WITH 2214 01:23:35,880 --> 01:23:38,320 CHEMOTHERAPY AND RADIATION, AND 2215 01:23:38,320 --> 01:23:40,120 ALSO UPREGULATING THE INTERFERON 2216 01:23:40,120 --> 01:23:42,920 GAMMA WHICH MOW MIGHT HAVE A 2217 01:23:42,920 --> 01:23:44,560 DELETERIOUS AFFECT. SO THERE HAS 2218 01:23:44,560 --> 01:23:46,360 TO BE A WAY OF DOING THIS 2219 01:23:46,360 --> 01:23:48,640 BETTER. SO THIS IS WHAT WE ARE 2220 01:23:48,640 --> 01:23:49,840 SHOWING HERE THAT JUST WHEN YOU 2221 01:23:49,840 --> 01:23:54,240 TAKE HUMAN TUMOR GLIOBLASTOMA 2222 01:23:54,240 --> 01:23:57,720 CELLS. IF YOU SUBJECT THEM TOP 2223 01:23:57,720 --> 01:24:00,240 TMZ OR RADIATION 15 GRAY YOU CAN 2224 01:24:00,240 --> 01:24:02,560 SEE THAT ALONE IS ENOUGH TO 2225 01:24:02,560 --> 01:24:05,680 UPREGULATE PDL 1, WHICH AGAIN WE 2226 01:24:05,680 --> 01:24:07,280 HAVE ALREADY SHOWN HAS BEEN 2227 01:24:07,280 --> 01:24:08,720 IMPORTANT FOR THE INDUCTION OF 2228 01:24:08,720 --> 01:24:10,640 THESE MYELOID DERIVED SUPPRESSER 2229 01:24:10,640 --> 01:24:11,800 CELLS AND IMMUNOSUPPRESSIVE 2230 01:24:11,800 --> 01:24:17,360 EFFECTS. I'M GOING TO MOVE 2231 01:24:17,360 --> 01:24:19,880 FORWARD HERE. I'M SORRY I'M 2232 01:24:19,880 --> 01:24:25,760 GOING BACKWARDS. SO WE TALKED 2233 01:24:25,760 --> 01:24:29,720 ABOUT THESE EZVs, EXTRA 2234 01:24:29,720 --> 01:24:31,440 CELLULAR VESICLES A CATCH ALL 2235 01:24:31,440 --> 01:24:33,600 TERM FOR VESICLES RELEASED FROM 2236 01:24:33,600 --> 01:24:37,080 MOST CELL TYPES OF YOUR BODY. 2237 01:24:37,080 --> 01:24:39,280 BUT OUR REALLY PARTICULARLY 2238 01:24:39,280 --> 01:24:41,800 RELEASED IN REALLY LARGE VOLUMES 2239 01:24:41,800 --> 01:24:45,240 BY TUMOR CELLS. NOT JUST 2240 01:24:45,240 --> 01:24:47,520 GLIOBLASTOMAS BUT TUMOR CELLS 2241 01:24:47,520 --> 01:24:49,680 MORE BROADLY. WHAT THOSE ARE 2242 01:24:49,680 --> 01:24:51,560 ABLE TO DO BECAUSE THEY ARE 2243 01:24:51,560 --> 01:24:54,000 RELEASED AND THEN GO OFF INTO 2244 01:24:54,000 --> 01:24:56,120 THE CELLULAR MILIEU AND 2245 01:24:56,120 --> 01:24:58,640 SYSTEMICALLY THEY ARE ABLE TO 2246 01:24:58,640 --> 01:25:00,040 ESSENTIALLY COORDINATE THE 2247 01:25:00,040 --> 01:25:05,400 AFFECT OF THIS LOCAL EFFECT 2248 01:25:05,400 --> 01:25:06,920 PARACRINE EFFECT ON ADJACENT 2249 01:25:06,920 --> 01:25:09,240 TUMOR CELLS BUT ALSO CARRY OUT 2250 01:25:09,240 --> 01:25:12,680 THIS SYSTEMIC EFFECT AS WELL. WE 2251 01:25:12,680 --> 01:25:13,760 TALKED ABOUT THESE MYELOID 2252 01:25:13,760 --> 01:25:16,600 DERIVED SUPPRESSER CELLS WHICH 2253 01:25:16,600 --> 01:25:17,920 THEN THROUGH NUMBER OF SIGNALING 2254 01:25:17,920 --> 01:25:20,480 PATHWAYS THAT I WON'T GO INTO 2255 01:25:20,480 --> 01:25:23,040 TODAY, CAN LEAD TO BOTH 2256 01:25:23,040 --> 01:25:24,440 REDUCTION IN THE ACTIVITY AND 2257 01:25:24,440 --> 01:25:26,360 THE ACTUAL NUMBER OF THE T-CELLS 2258 01:25:26,360 --> 01:25:28,480 LEADING TO BOTH T-CELL 2259 01:25:28,480 --> 01:25:31,040 INACTIVATION AS WELL AS T-CELL 2260 01:25:31,040 --> 01:25:34,600 LYMPHOPENIA. AGAIN WHAT I WANT 2261 01:25:34,600 --> 01:25:36,400 TO HIGHLIGHT FOR YOU HERE IS 2262 01:25:36,400 --> 01:25:42,280 THAT THIS IS NOT A GLIOBLASTOMA 2263 01:25:42,280 --> 01:25:44,280 SPECIFIC PHENOMENON, THIS IS 2264 01:25:44,280 --> 01:25:46,280 PHENOMENON THAT INVOLVES CANCERS 2265 01:25:46,280 --> 01:25:49,960 MORE BROADLY. SO IN FACT, THE 2266 01:25:49,960 --> 01:25:52,120 IDEA TO LOOK FOR WHETHER EVs 2267 01:25:52,120 --> 01:25:54,320 WERE PART OF THE GLIOBLASTOMA 2268 01:25:54,320 --> 01:25:55,760 STORY CAME BECAUSE THIS WAS 2269 01:25:55,760 --> 01:25:57,240 ALREADY WORKED OUT IN SO MANY 2270 01:25:57,240 --> 01:25:59,520 OTHER SYSTEMIC CANCERS AND IDEA 2271 01:25:59,520 --> 01:26:01,640 WAS THAT WELL MAYBE EVs 2272 01:26:01,640 --> 01:26:03,440 PARTICIPATE IN GLIOBLASTOMAS 2273 01:26:03,440 --> 01:26:06,680 TOO. SO THIS IS AGAIN A REALLY 2274 01:26:06,680 --> 01:26:11,840 BROAD STORY HERE WITH DATA FROM 2275 01:26:11,840 --> 01:26:13,600 HEPATOCELLULAR CARCINOMA, 2276 01:26:13,600 --> 01:26:14,680 BREAST, LUNG, ET CETERA. THIS 2277 01:26:14,680 --> 01:26:17,520 IDEA THAT TUMORS LEAD TO BECAUSE 2278 01:26:17,520 --> 01:26:21,040 THEY EXPRESS THESE EPITOPES CAN 2279 01:26:21,040 --> 01:26:23,680 LEAD TO T-CELL ACTIVATION AND 2280 01:26:23,680 --> 01:26:27,480 YOUR IMMUNE SYSTEM THUS THEN 2281 01:26:27,480 --> 01:26:29,280 HELPS TO GIVE BENEFIT BY 2282 01:26:29,280 --> 01:26:30,960 TARGETING THE CANCER CELLS. IT 2283 01:26:30,960 --> 01:26:34,560 IS THE WHOLE POINT BEHIND CHECK 2284 01:26:34,560 --> 01:26:37,960 POINT THERAPY. IMMUNOTHERAPY, 2285 01:26:37,960 --> 01:26:40,600 WHICH THEN CAN HELP ACTIVATE 2286 01:26:40,600 --> 01:26:42,760 PROCESSES AND INCREASE THE 2287 01:26:42,760 --> 01:26:46,320 TARGETING OF THESE CANCER CELLS 2288 01:26:46,320 --> 01:26:50,200 HERE IS AN EXAMPLE OF THIS ONE 2289 01:26:50,200 --> 01:26:52,000 GROUP THAT WORKS WITH 2290 01:26:52,000 --> 01:26:54,240 HEPATOCELLULAR CARCINOMA, TALKED 2291 01:26:54,240 --> 01:26:57,440 ABOUT CCRK, CELL CYCLE RELATED 2292 01:26:57,440 --> 01:26:59,760 KINASE, SEEMS TO SIT AT TOP THIS 2293 01:26:59,760 --> 01:27:02,760 NETWORK THAT ULTIMATELY LEADS 2294 01:27:02,760 --> 01:27:04,880 TOICSL 6 UPREGULATION WHICH THEN 2295 01:27:04,880 --> 01:27:07,400 LEADS TO MYELOID DERIVED 2296 01:27:07,400 --> 01:27:09,800 SUPPRESSER CELL INDUCTION AND 2297 01:27:09,800 --> 01:27:12,920 THEN EXHAUSTION OF YOUR T-CELL. 2298 01:27:12,920 --> 01:27:14,760 CCRK IS ONE OF MY FAVORITE 2299 01:27:14,760 --> 01:27:17,000 PROTEINS, IT IS OVEREXPRESSED IN 2300 01:27:17,000 --> 01:27:21,520 MANY CANCER. AND ALSO I THINK 2301 01:27:21,520 --> 01:27:25,560 I'M PAUSED AGAIN. JUST GOT TO 2302 01:27:25,560 --> 01:27:29,560 WAIT ON THE SLIDE. BUT ALSO CCRK 2303 01:27:29,560 --> 01:27:31,280 WAS SOMETHING I SPENT A 2304 01:27:31,280 --> 01:27:32,320 CONSIDERABLE TIME IN GRADUATE 2305 01:27:32,320 --> 01:27:35,880 SCHOOL WORKING ON, WHEN I CLONED 2306 01:27:35,880 --> 01:27:37,760 THE FIRST CCRK KNOCK OUT MOUSE 2307 01:27:37,760 --> 01:27:40,960 AN CHARACTERIZED THAT. THIS IS 2308 01:27:40,960 --> 01:27:43,560 WHAT IS SHOWN HERE THAT WHEN WE 2309 01:27:43,560 --> 01:27:45,880 THEN LOOK AT THIS PHENOTYPE OF 2310 01:27:45,880 --> 01:27:47,760 THIS KNOCK OUT MOUSE THAT YOU 2311 01:27:47,760 --> 01:27:50,000 CAN SEE FOR THE DEVELOPMENTAL 2312 01:27:50,000 --> 01:27:51,320 BIOLOGIST IN THE ROOM YOU SHOULD 2313 01:27:51,320 --> 01:27:53,680 SEE A VERY FAMILIAR 2314 01:27:53,680 --> 01:27:56,720 CONSTELLATION OF PHENOTYPES 2315 01:27:56,720 --> 01:28:03,160 WHICH IS LOSS OF MID BRAIN -- 2316 01:28:03,160 --> 01:28:05,040 POLYSYNDACTYLY, SKELETAL DEFECTS 2317 01:28:05,040 --> 01:28:07,720 AND TOGETHER THOSE ARE VERY MUCH 2318 01:28:07,720 --> 01:28:09,720 IN SYNC WITH SONIC HEDGEHOG 2319 01:28:09,720 --> 01:28:12,640 SIGNALING DEFEC DEFECT. SO OF CE 2320 01:28:12,640 --> 01:28:14,440 SONIC HEDGEHOG I TOLD YOU IS THE 2321 01:28:14,440 --> 01:28:17,640 SORT OF PROTOTYPE PATHWAY OF 2322 01:28:17,640 --> 01:28:19,200 CANONICAL SIGNALING THAT 2323 01:28:19,200 --> 01:28:21,400 REQUIRES PRIMARY CILIA. SO WE 2324 01:28:21,400 --> 01:28:25,040 LOOK AND ASKED WHETHER PRIMARY 2325 01:28:25,040 --> 01:28:27,960 CILIA ARE CHANGED OR AFFECTED 2326 01:28:27,960 --> 01:28:29,360 MORPHOLOGICALLY OR FUNCTIONALLY 2327 01:28:29,360 --> 01:28:31,880 IN THE CCRK KNOCKOUT MICE. I 2328 01:28:31,880 --> 01:28:33,840 THINK YOU CAN CLEARLY SEE FROM 2329 01:28:33,840 --> 01:28:36,120 THE SCANNING ELECTRON MICROSCOPY 2330 01:28:36,120 --> 01:28:38,240 IMAGE FROM THE NEUROEPITHELIA OF 2331 01:28:38,240 --> 01:28:41,320 THE DEVELOPING EMBRYOS THAT THE 2332 01:28:41,320 --> 01:28:44,240 PRIMARY CILIA HERE ARE CERTAINLY 2333 01:28:44,240 --> 01:28:47,960 MORPHOLOGICALLY ABNORMAL. ONE 2334 01:28:47,960 --> 01:28:51,080 THING WE THEN DECIDED TO ASK WAS 2335 01:28:51,080 --> 01:28:54,040 WELL, THE CCRK CONNECTION TO 2336 01:28:54,040 --> 01:28:55,520 IMMUNOSUPPRESSION IN CANCER, IS 2337 01:28:55,520 --> 01:28:59,040 THAT RELATED TO THIS AFFECT OF 2338 01:28:59,040 --> 01:29:01,000 CCRK IN PRIMARY CELLULAR 2339 01:29:01,000 --> 01:29:03,720 MORPHOLOGY OR IS THIS A 2340 01:29:03,720 --> 01:29:05,960 NON-CILIARE EFFECT OF CCRK THAT 2341 01:29:05,960 --> 01:29:07,800 DOES SOMETHING ELSE IN THE ADULT 2342 01:29:07,800 --> 01:29:08,880 CONTEXT? SO THAT IS WHAT WE 2343 01:29:08,880 --> 01:29:12,680 WANTED TO ASK. THERE ARE ALSO 2344 01:29:12,680 --> 01:29:13,800 OTHER REASONS TO ASK THIS 2345 01:29:13,800 --> 01:29:16,120 BECAUSE THERE'S SOME OTHER 2346 01:29:16,120 --> 01:29:20,160 PAPERS THAT HAVE SAID THAT 2347 01:29:20,160 --> 01:29:22,680 PRIMARY CILIA ARE PROBABLY BOTH 2348 01:29:22,680 --> 01:29:23,920 IMPORTANT FOR RECEIVING EV 2349 01:29:23,920 --> 01:29:25,160 SIGNAL AND INTERPRETING THOSE 2350 01:29:25,160 --> 01:29:27,080 AND ALSO MAY BE IMPORTANT FOR 2351 01:29:27,080 --> 01:29:30,080 RELEASING EV SIGNAL IN TO THE 2352 01:29:30,080 --> 01:29:32,000 TUMOR MICROENVIRONMENT AS WELL. 2353 01:29:32,000 --> 01:29:34,080 SO WITH ALL THESE WE THOUGHT 2354 01:29:34,080 --> 01:29:36,120 WELL, THIS MIGHT MAKE SENSE THE 2355 01:29:36,120 --> 01:29:39,600 EVs ARE DOING SOMETHING. SO 2356 01:29:39,600 --> 01:29:41,840 AGAIN THE MYELOID DERIVED 2357 01:29:41,840 --> 01:29:43,240 SUPPRESSER CELLS ARE MONOSTATTIC 2358 01:29:43,240 --> 01:29:46,040 RELATED CELLS THAT YOU REALLY 2359 01:29:46,040 --> 01:29:50,480 ONLY SEE IN CANCER THAT LEAD TO 2360 01:29:50,480 --> 01:29:51,840 THIS IMMUNOSUPPRESSION THROUGH 2361 01:29:51,840 --> 01:29:55,400 VARIETY OF PATHWAYS AND 2362 01:29:55,400 --> 01:29:56,480 IMMUNOSUPPRESSION OF VARIETY OF 2363 01:29:56,480 --> 01:29:58,560 CELL TYPES, WHAT WILL BE 2364 01:29:58,560 --> 01:30:00,720 FOCUSING ON HERE IS THE EFFECT 2365 01:30:00,720 --> 01:30:04,600 ON T-CELLS. SO WE DEVELOPED AN 2366 01:30:04,600 --> 01:30:06,800 ASSAY THAT ALLOWS US TO LOOK AT 2367 01:30:06,800 --> 01:30:09,240 THIS MYELOID DERIVED SUPPRESSER 2368 01:30:09,240 --> 01:30:12,880 CELL POPULATION THAT WE DEFINE 2369 01:30:12,880 --> 01:30:16,840 AS POPULATION OF CD 14 POSITIVE 2370 01:30:16,840 --> 01:30:20,040 CD 11B POSITIVE AND HLADR 2371 01:30:20,040 --> 01:30:21,280 NEGATIVE. WE CAN ASK QUESTIONS 2372 01:30:21,280 --> 01:30:23,080 LIKE SO GOING BACK TO THIS IDEA 2373 01:30:23,080 --> 01:30:26,240 OF WHAT DOES IRRADIATION DO, 2374 01:30:26,240 --> 01:30:30,520 THIS HAS NEVER BEEN SHOWN. SO WE 2375 01:30:30,520 --> 01:30:32,320 SHOW WHEN WE IRRADIATE THESE 2376 01:30:32,320 --> 01:30:35,560 HUMAN DERIVED GLIOBLASTOMA CELLS 2377 01:30:35,560 --> 01:30:38,440 WE CAN GET CERTAINLY INDUCTION 2378 01:30:38,440 --> 01:30:39,760 OF INCREASE IN INDUCTION OF 2379 01:30:39,760 --> 01:30:42,000 THESE MYELOID DERIVED 2380 01:30:42,000 --> 01:30:44,080 SUPPRESSIONER CELLS. 2381 01:30:44,080 --> 01:30:45,880 IMPORTANTLY, THAT INCREASE IN 2382 01:30:45,880 --> 01:30:48,240 THE MYELOID DERIVED SUPPRESSER 2383 01:30:48,240 --> 01:30:52,360 CELLS FURTHER DECREASES THE 2384 01:30:52,360 --> 01:30:55,400 ACTIVITY AND PROLIFERATION OF 2385 01:30:55,400 --> 01:30:57,920 THE T-CELLS CONSISTENT WITH WHAT 2386 01:30:57,920 --> 01:31:04,080 WE HAVE HYPOTHESIZE. WAITING ON 2387 01:31:04,080 --> 01:31:07,040 THE SLIDES AGAIN. SO THE 2388 01:31:07,040 --> 01:31:08,480 QUESTION NOW AGAIN BECOMES DOES 2389 01:31:08,480 --> 01:31:10,960 LOSS OF PRIMARY CILIA THEN 2390 01:31:10,960 --> 01:31:13,400 REDUCE THIS INDUCTION OF MYLID 2391 01:31:13,400 --> 01:31:14,840 DERIVED SUPPRESSER CELLS AND 2392 01:31:14,840 --> 01:31:18,200 DOES THAT IN TURN LEAD TO 2393 01:31:18,200 --> 01:31:22,360 RESTORATION OF THAT T-CELL 2394 01:31:22,360 --> 01:31:24,840 INACTIVATION? SO WE ESSENTIALLY 2395 01:31:24,840 --> 01:31:28,680 GOT NUMBER OF GENES THAT ARE 2396 01:31:28,680 --> 01:31:30,520 ESSENTIAL FOR CILIA DEVELOPMENT 2397 01:31:30,520 --> 01:31:32,240 BECAUSE IF I JUST SHOWED YOU 2398 01:31:32,240 --> 01:31:35,000 THAT WE KNOCK DOWN CCRK AND THAT 2399 01:31:35,000 --> 01:31:37,000 MYELOID DERIVED SUPPRESSER CELL 2400 01:31:37,000 --> 01:31:38,160 WENT DOWN, THE QUESTION YOU 2401 01:31:38,160 --> 01:31:40,200 WOULD ASK ME IS HOW DO I KNOW 2402 01:31:40,200 --> 01:31:41,720 THAT THAT'S CILIA RELATED OR 2403 01:31:41,720 --> 01:31:44,400 NOT. SO WHAT WE DID IS TOOK A 2404 01:31:44,400 --> 01:31:47,080 NUMBER OF OTHER GENES IN 2405 01:31:47,080 --> 01:31:49,960 ADDITION TO CCRK THAT ARE 2406 01:31:49,960 --> 01:31:51,560 ESSENTIAL FOR CILIA GENESIS AND 2407 01:31:51,560 --> 01:31:54,840 SAID WELL, THEN, IF THIS IS A 2408 01:31:54,840 --> 01:31:57,080 CILIA GENESIS ISSUE, THEN WE 2409 01:31:57,080 --> 01:31:59,280 SHOULD BE GETTING THE SAME 2410 01:31:59,280 --> 01:32:01,280 PHENOTYPE. SO WHAT YOU CAN SEE 2411 01:32:01,280 --> 01:32:04,160 HERE IS THAT WHEN WE KNOCK DOWN 2412 01:32:04,160 --> 01:32:06,080 THESE CILIA RELATED GENES IN THE 2413 01:32:06,080 --> 01:32:08,960 HUMAN TUMOR CELLS, HARVEST THEIR 2414 01:32:08,960 --> 01:32:13,400 EVs, ADD THESE EVs TO THE 2415 01:32:13,400 --> 01:32:17,600 MONOCYTES OF NORMAL PATIENTS 2416 01:32:17,600 --> 01:32:19,840 THAT WE DON'T GET THE SAME VIGOR 2417 01:32:19,840 --> 01:32:21,040 OF INDUCTION THAT THAT SEEMS TO 2418 01:32:21,040 --> 01:32:23,400 BE DEPENDENT ON FUNCTION AND 2419 01:32:23,400 --> 01:32:25,280 PRIMARY CILIA IN THE 2420 01:32:25,280 --> 01:32:28,960 GLIOBLASTOMA PATIENTS. 2421 01:32:28,960 --> 01:32:30,440 CONSISTENT WITH THAT, WHAT WE 2422 01:32:30,440 --> 01:32:34,160 SAW WAS THAT WHEN WE DO THAT, 2423 01:32:34,160 --> 01:32:36,920 THAT T-CELL FUNCTION IS 2424 01:32:36,920 --> 01:32:40,720 RESTORED. SO THIS IS CONTROL 2425 01:32:40,720 --> 01:32:43,920 SETTING WHERE THIS INCREASE IN 2426 01:32:43,920 --> 01:32:46,800 MYELOID DERIVED SUPPRESSER CELLS 2427 01:32:46,800 --> 01:32:48,800 LEAD TO LOSS OF DYSFUNCTION AND 2428 01:32:48,800 --> 01:32:50,400 RESTORED WITH CILIA BLOCKED 2429 01:32:50,400 --> 01:32:56,640 PRIOR TO HARVESTING THE EVs. 2430 01:32:56,640 --> 01:32:58,160 ALMOST DONE, JUST WAITING ON THE 2431 01:32:58,160 --> 01:33:08,600 SLIDES TO CHANGE. SO ONE 2432 01:33:14,480 --> 01:33:18,280 QUESTION WE WANTED TO ASK WAS WE 2433 01:33:18,280 --> 01:33:21,400 SEE THIS EFFECT. SO NOW THERE IS 2434 01:33:21,400 --> 01:33:23,240 A BUY LOGICAL EFFECT. THE 2435 01:33:23,240 --> 01:33:26,080 QUESTION, IS THIS BECAUSE WE DID 2436 01:33:26,080 --> 01:33:29,720 NOT MAKE EVs TO THE SAME 2437 01:33:29,720 --> 01:33:33,960 DEGREE OR IS THIS FOR SOME OTHER 2438 01:33:33,960 --> 01:33:37,080 REASON? AS I WAIT ON THE SLIDE 2439 01:33:37,080 --> 01:33:38,320 TO TURN BECAUSE I WILL SKIP 2440 01:33:38,320 --> 01:33:39,240 THROUGH ONCE IT CHANGES, THE 2441 01:33:39,240 --> 01:33:44,920 ANSWER IS NO, WE DID NOT SEE ANY 2442 01:33:44,920 --> 01:33:47,680 CHANGES IN THE QUANTITY OF THE 2443 01:33:47,680 --> 01:33:51,040 EV WE WERE ABLE TO GENERATE OR 2444 01:33:51,040 --> 01:33:53,520 IN THE SIZE OR DISTRIBUTION OF 2445 01:33:53,520 --> 01:33:55,240 THE EVs WE WERE ABLE TO 2446 01:33:55,240 --> 01:33:56,960 GENERATE. WHAT I'M SHOWING YOU 2447 01:33:56,960 --> 01:33:58,960 HERE IS THAT WHEN WE LOOK AT 2448 01:33:58,960 --> 01:34:01,160 THESE MARKERS THAT WE KNOW ARE 2449 01:34:01,160 --> 01:34:03,240 SPECIFIC FOR THESE EVs, THESE 2450 01:34:03,240 --> 01:34:06,760 TETRA SPANS WE CAN SEE THEM 2451 01:34:06,760 --> 01:34:09,680 PRESENT AND NEGATIVE CONTROL 2452 01:34:09,680 --> 01:34:10,480 RETICK LYNN WHICH SHOULD BE IN 2453 01:34:10,480 --> 01:34:13,400 THE CELL WE DON'T SEE THAT AND 2454 01:34:13,400 --> 01:34:17,080 YOU DIDN'T GET TO SEE THE VIDEO 2455 01:34:17,080 --> 01:34:18,520 FROM THE NANOCYTE BUT WE CAN 2456 01:34:18,520 --> 01:34:19,760 GENERATE PARTICLES, WE CAN 2457 01:34:19,760 --> 01:34:21,120 QUANTIFY THEM HERE AND WHAT WE 2458 01:34:21,120 --> 01:34:24,800 SEE IS THAT THE DISTRIBUTION AND 2459 01:34:24,800 --> 01:34:25,600 SIZE AND CONCENTRATION ARE THE 2460 01:34:25,600 --> 01:34:29,200 SAME. SO THAT IS NOT WHY WE SEE 2461 01:34:29,200 --> 01:34:30,600 THIS IN RESPONSE TO THE LOSS OF 2462 01:34:30,600 --> 01:34:34,040 EVs. SO WHAT WE THEN THOUGHT 2463 01:34:34,040 --> 01:34:36,400 IS MAYBE THE PACKAGING OF THE 2464 01:34:36,400 --> 01:34:38,600 EVs ARE ALTERED IN THE SETTING 2465 01:34:38,600 --> 01:34:45,240 OF LOSS OF CILIA. THE SHORT 2466 01:34:45,240 --> 01:34:47,840 ANSWER HERE IS THAT THAT'S 2467 01:34:47,840 --> 01:34:50,840 PRECISELY WHAT WE SAW. WHEN WE 2468 01:34:50,840 --> 01:34:53,560 ALTER THE PRIMARY CILIA BEFORE, 2469 01:34:53,560 --> 01:34:56,760 THE WAY WHICH CELLS ARE PACKA 2470 01:34:56,760 --> 01:34:58,440 PACKAGED, ARE COMPLETELY 2471 01:34:58,440 --> 01:35:00,320 DIFFERENT. WHAT YOU CAN SEE HERE 2472 01:35:00,320 --> 01:35:02,800 IS THIS VOLCANO PLOT SHOWING 2473 01:35:02,800 --> 01:35:04,320 PROFOUND DIFFERENCE IN THE 2474 01:35:04,320 --> 01:35:07,120 CONTENT AT THE PROTEOME LEVEL OF 2475 01:35:07,120 --> 01:35:09,440 EVE DERIVED FROM GLIOBLASTOMA 2476 01:35:09,440 --> 01:35:11,240 THE SAME PATIENT GLIOBLASTOMA IN 2477 01:35:11,240 --> 01:35:13,240 THE CONTEXT OF A NORMAL 2478 01:35:13,240 --> 01:35:14,360 FUNCTIONING CILIA OR ABSENCE OF 2479 01:35:14,360 --> 01:35:17,960 THE CILIA. AND INTERESTINGLY 2480 01:35:17,960 --> 01:35:20,640 WHAT YOU CAN SEE IS WHEN WE DO 2481 01:35:20,640 --> 01:35:22,400 AN IP ANALYSIS OF THIS AND WE 2482 01:35:22,400 --> 01:35:24,560 ARE LOOKING AT DIFFERENTIALLY 2483 01:35:24,560 --> 01:35:27,880 EXPRESSED PATHWAYS AND 2484 01:35:27,880 --> 01:35:28,800 FUNCTIONS, YOU CAN SEE WITH LOSS 2485 01:35:28,800 --> 01:35:34,440 OF CILIA HERE, MANY OF THESE 2486 01:35:34,440 --> 01:35:35,600 IMMUNE RELATED FUNCTIONS ARE 2487 01:35:35,600 --> 01:35:38,560 LOST AND WE SEE SO MUCH INCREASE 2488 01:35:38,560 --> 01:35:43,880 OF CANCER DEATH SIGNALING. BY 2489 01:35:43,880 --> 01:35:45,800 THE WAY I WANT TO SAY THIS 2490 01:35:45,800 --> 01:35:48,120 AGREES WITH THAT PAPER, I SHOW 2491 01:35:48,120 --> 01:35:49,440 BEFORE WITH THE CILIA SCORE 2492 01:35:49,440 --> 01:35:52,200 SHOWING INCREASE CILIA SCORE 2493 01:35:52,200 --> 01:35:54,880 WILL LEAD TO WORSENED OUTCOMES. 2494 01:35:54,880 --> 01:35:57,520 HOW IS THIS HAPPENING? WHAT IS 2495 01:35:57,520 --> 01:36:02,320 GOING ON? FIRSTLY WE SHALL DO 2496 01:36:02,320 --> 01:36:03,600 WHEN WE U IRRADIATE THESE CELLS 2497 01:36:03,600 --> 01:36:05,960 WE CAN GET INCREASE MYELOID 2498 01:36:05,960 --> 01:36:08,840 DERIVED SUPPRESSER CELLS, WHAT 2499 01:36:08,840 --> 01:36:13,600 THIS I'M SHOWING YOU HERE IS 2500 01:36:13,600 --> 01:36:15,240 THAT WHEN YOU RADIATE CELLS YOU 2501 01:36:15,240 --> 01:36:17,680 GET INCREASE IN INTERFERON GAMMA 2502 01:36:17,680 --> 01:36:20,880 BUT LOSS OF ANY OF THE CILIA 2503 01:36:20,880 --> 01:36:22,600 COMPONENTS BLOCKS THIS, IT IS 2504 01:36:22,600 --> 01:36:25,080 AGNOSTIC TO WHICH ONE IT IS 2505 01:36:25,080 --> 01:36:29,480 BLOCKING, CCRK OR FD 88, ALL 2506 01:36:29,480 --> 01:36:31,200 SHARE A COMMON THING THAT THEY 2507 01:36:31,200 --> 01:36:34,160 ARE ALL ESSENTIAL FOR CILIA 2508 01:36:34,160 --> 01:36:36,840 GENESIS. IN EACH CASE WHAT YOU 2509 01:36:36,840 --> 01:36:39,240 SEE IS THAT THE UPREGULATION OF 2510 01:36:39,240 --> 01:36:42,320 INTERFERON GAMMA RESPONDS TO 2511 01:36:42,320 --> 01:36:52,880 RADIATION IS BLOCKED. I'M ALMOST 2512 01:36:58,680 --> 01:37:02,400 DONE. SO WHAT YOU CAN SEE HERE 2513 01:37:02,400 --> 01:37:04,960 IS THAT WHEN WE LOSE THE CILIA 2514 01:37:04,960 --> 01:37:07,480 ULTIMATELY AS I SHOWED YOU 2515 01:37:07,480 --> 01:37:10,920 SHOWED EARLIER HEPATOCARCINOMA 2516 01:37:10,920 --> 01:37:12,960 PAPER CCRK WAS THOUGHT THE SIT 2517 01:37:12,960 --> 01:37:14,520 ATOP THE PATHWAY THAT LED TO 2518 01:37:14,520 --> 01:37:16,560 INCREASE IN IL 6. WHAT I'M 2519 01:37:16,560 --> 01:37:19,120 SHOWING YOU HERE IS THAT WITH 2520 01:37:19,120 --> 01:37:23,640 LOSS OF PRIMARY CILIA, BY ANY OF 2521 01:37:23,640 --> 01:37:25,880 THESE THREE GENES YOU ARE SEEING 2522 01:37:25,880 --> 01:37:32,160 THAT THERE IS IL 6 LOST IN EXTRA 2523 01:37:32,160 --> 01:37:33,520 CELLULAR VESICALES. HOWEVER, 2524 01:37:33,520 --> 01:37:36,920 THERE IS NO LOSS IN LEVELS OF -- 2525 01:37:36,920 --> 01:37:39,280 SO THE IDEA IS THAT THE THOUGHT 2526 01:37:39,280 --> 01:37:45,080 WAS PDL 1 SOMEHOW ACTING IN THE 2527 01:37:45,080 --> 01:37:48,160 GLIOBLASTOMA CELLS ARE CAUSE 2528 01:37:48,160 --> 01:37:50,960 UPREGULATION IL 6 AND ULTIMATELY 2529 01:37:50,960 --> 01:37:52,640 MBSC AND WHAT THE DATA SUGGESTS 2530 01:37:52,640 --> 01:37:55,240 IS WHAT PDL 1 DOES IN THE 2531 01:37:55,240 --> 01:37:57,080 CONTEXT OF THE CANCER CELL 2532 01:37:57,080 --> 01:37:59,920 REQUIRES PRIMARY CILIA TO BE 2533 01:37:59,920 --> 01:38:01,800 PRESENT. IN FACT WHEN THE 2534 01:38:01,800 --> 01:38:04,360 PRIMARY CILIA ARE LOST PDL 1 2535 01:38:04,360 --> 01:38:06,920 LEVELS ARE INCREASED. EVEN 2536 01:38:06,920 --> 01:38:08,600 THOUGH YOU ARE NOT ABLE TO 2537 01:38:08,600 --> 01:38:11,440 SUPPRESS MYELOID DERIVED 2538 01:38:11,440 --> 01:38:13,640 SUPPRESSER CELLS SO IL 6 BASED 2539 01:38:13,640 --> 01:38:15,040 ON THIS DATA DOWNSTREAM OF THE 2540 01:38:15,040 --> 01:38:18,280 PRIMARY CILIA, WHEREAS PDL 1 IS 2541 01:38:18,280 --> 01:38:21,400 UPSTREAM AND REQUIRES PRIMARY 2542 01:38:21,400 --> 01:38:23,160 CILIA TO CONDUCT WHATEVER IT IS 2543 01:38:23,160 --> 01:38:25,720 THAT IT IS DOING. TO PROVE THIS 2544 01:38:25,720 --> 01:38:28,040 FURTHER WHAT WE CAN DO IS ASK IF 2545 01:38:28,040 --> 01:38:30,600 WE KNOCK OUT THE PRIMARY CILIA 2546 01:38:30,600 --> 01:38:35,200 THROUGH LOSS OF TIF 3A T KINESIN 2547 01:38:35,200 --> 01:38:37,200 MOTOR REQUIRED FOR CILIA 2548 01:38:37,200 --> 01:38:39,320 GENESIS, WHAT HAPPENS IF WE 2549 01:38:39,320 --> 01:38:41,720 REPLACE IL 6 IN THIS KNOCK OUT 2550 01:38:41,720 --> 01:38:43,760 WE SHOULD RESTORE MBSC INDUCTION 2551 01:38:43,760 --> 01:38:45,320 AND THAT IS PRECISELY WHAT YOU 2552 01:38:45,320 --> 01:38:50,120 CAN SEE HERE. SO BASED ON THIS 2553 01:38:50,120 --> 01:38:51,240 WHAT WE HAVE ARE COUPLE OF 2554 01:38:51,240 --> 01:38:52,600 THINGS THAT WE HAVE DONE IN THIS 2555 01:38:52,600 --> 01:38:54,680 PAPER FOR THE FIRST TIME. ONE, 2556 01:38:54,680 --> 01:38:57,000 THERE IS NO REPORT IN THE 2557 01:38:57,000 --> 01:38:59,960 LITERATURE THAT WE ARE ABLE TO 2558 01:38:59,960 --> 01:39:03,560 FIND ANY WAY CONNECTS PRIMARY 2559 01:39:03,560 --> 01:39:05,040 SIGNATURE CILIA SIGNALING TO 2560 01:39:05,040 --> 01:39:06,880 CANCER IMMUNE SUPPRESSION IN ANY 2561 01:39:06,880 --> 01:39:08,920 WAY, ONCE THE PAPER IS HOPEFULLY 2562 01:39:08,920 --> 01:39:10,080 ACCEPTED IT WILL BE THE FIRST TO 2563 01:39:10,080 --> 01:39:16,000 DO THAT. SECONDLY, THIS DATA 2564 01:39:16,000 --> 01:39:18,040 ALSO SUGGESTS AN UPDATED MODEL 2565 01:39:18,040 --> 01:39:21,240 HOW WE MIGHT THINK ABOUT THIS 2566 01:39:21,240 --> 01:39:22,840 CANCER MEDIATED 2567 01:39:22,840 --> 01:39:23,440 IMMUNOSUPPRESSION SO WHAT WE 2568 01:39:23,440 --> 01:39:25,320 HAVE HERE IS A GLEAM BLASTOMA 2569 01:39:25,320 --> 01:39:27,040 CELL WE THINK YOU CAN REPLACE 2570 01:39:27,040 --> 01:39:28,760 THIS WITH CANCER CELL MORE 2571 01:39:28,760 --> 01:39:30,360 GENERICALLY BUT IN THIS VERY 2572 01:39:30,360 --> 01:39:32,040 SPECIFIC CASE WE HAVE A 2573 01:39:32,040 --> 01:39:33,440 GLIOBLASTOMA CELL THAT HAS A 2574 01:39:33,440 --> 01:39:37,040 PRIMARY CILIA, AND THAT HAS A 2575 01:39:37,040 --> 01:39:39,640 PRIMARY CILIA SO HERE WE SHOWED 2576 01:39:39,640 --> 01:39:41,240 THAT THEN INTERFERON GAMMA LEADS 2577 01:39:41,240 --> 01:39:46,000 TO UPREGULATION OF PDL 1 WHICH 2578 01:39:46,000 --> 01:39:48,080 REQUIRES THE CILIA TO BE THERE. 2579 01:39:48,080 --> 01:39:50,960 SOMEHOW THE PRIMARY SILL YUM 2580 01:39:50,960 --> 01:39:53,080 INTERACTS WITH PDL 1 LEVELS 2581 01:39:53,080 --> 01:39:54,520 BECAUSE LOSS OF PRIMARY CILIA 2582 01:39:54,520 --> 01:39:56,600 LEADS TO FURTHER UPREGULATION OF 2583 01:39:56,600 --> 01:39:59,160 PDL 1. SO THAT MEANS THERE'S 2584 01:39:59,160 --> 01:40:00,560 PROBABLY SOME FEEDBACK CYCLE 2585 01:40:00,560 --> 01:40:04,920 BETWEEN PDL 1 AND PRIMARY CILIA 2586 01:40:04,920 --> 01:40:07,120 ONCE THE PDL 1 INTERACTS WITH 2587 01:40:07,120 --> 01:40:10,040 PRIMARY CILIA, IT LEADS TO THIS 2588 01:40:10,040 --> 01:40:13,520 DIFFERENTIAL PACKAGING OF EVs 2589 01:40:13,520 --> 01:40:15,560 AND SOME OF THE EVs MAYBE ALL 2590 01:40:15,560 --> 01:40:19,680 IN THAT CONTEXT WILL THEN HAVE 2591 01:40:19,680 --> 01:40:21,920 INTERLEUKIN 6, AND ONCE 2592 01:40:21,920 --> 01:40:23,040 INTERLEUKIN 6 IS PRESENT IT WILL 2593 01:40:23,040 --> 01:40:25,480 LEAD TO THIS UPREGULATION OR 2594 01:40:25,480 --> 01:40:27,040 THIS CONVERSION OF YOUR 2595 01:40:27,040 --> 01:40:28,600 CIRCULATING MONOCYTES IN THESE 2596 01:40:28,600 --> 01:40:32,400 CANCER PATIENTS, MYELOID DERIVED 2597 01:40:32,400 --> 01:40:33,640 SUPPRESSER CELL WHICH LEADS TO 2598 01:40:33,640 --> 01:40:37,200 THE INACTIVATION AND LOSS OF 2599 01:40:37,200 --> 01:40:39,920 PROLIFERATION OF YOUR T-CELLS. I 2600 01:40:39,920 --> 01:40:42,360 PUT THE STAT 3 THERE BECAUSE 2601 01:40:42,360 --> 01:40:45,280 MOST OF THE DATA SUGGESTS IL 6 2602 01:40:45,280 --> 01:40:48,640 LIKELY WORKS IN THIS INDUCTION 2603 01:40:48,640 --> 01:40:52,080 THROUGH STAT 3 PATHWAY. LOTS OF 2604 01:40:52,080 --> 01:40:54,320 QUESTIONS FOR US TO THINK ABOUT 2605 01:40:54,320 --> 01:40:57,680 AND FIRST TO VALIDATE, THE DATA 2606 01:40:57,680 --> 01:41:00,480 IS STRONG AN CONSISTENT ABOUT 2607 01:41:00,480 --> 01:41:03,040 THIS RELATIONSHIP BETWEEN THE 2608 01:41:03,040 --> 01:41:04,280 PRIMARY CILIA AND 2609 01:41:04,280 --> 01:41:07,560 IMMUNOSUPPRESSIVE SIGNALING. TO 2610 01:41:07,560 --> 01:41:09,880 SUMMARIZE PRIMARY CILIA PRESENT 2611 01:41:09,880 --> 01:41:12,840 IN HUMAN GLEE BLASTOMAS, THE 2612 01:41:12,840 --> 01:41:14,360 GLIOBLASTOMA DERIVED EVs 2613 01:41:14,360 --> 01:41:17,200 INDUCE MYELOID DERIVED 2614 01:41:17,200 --> 01:41:19,440 SUPPRESSER CELLS. THE LOSS OF 2615 01:41:19,440 --> 01:41:23,200 PRIMARY CILIA LEADS BLOCKS MDSC 2616 01:41:23,200 --> 01:41:26,320 INDUCTION AND RESTORESES T-CELL 2617 01:41:26,320 --> 01:41:27,520 FUNCTION AS FAR AS WE ARE ABLE 2618 01:41:27,520 --> 01:41:31,840 TO TELL. THE PROTEOME OF THE EV 2619 01:41:31,840 --> 01:41:33,840 DERIVED FROM THESE CANCER CELLS 2620 01:41:33,840 --> 01:41:38,960 ARE DEPENDENT ON THE PRESENCE OF 2621 01:41:38,960 --> 01:41:41,400 PRIMARY CILIA. PRIMARY CILIA 2622 01:41:41,400 --> 01:41:43,240 SEEMS TO WORK IN THE PACKAGING 2623 01:41:43,240 --> 01:41:46,400 OF THESE EVs IN A PROCESS THAT 2624 01:41:46,400 --> 01:41:47,800 I DON'T UNDERSTAND AND AGAIN 2625 01:41:47,800 --> 01:41:50,240 BECAUSE NO ONE ELSE HAS DONE 2626 01:41:50,240 --> 01:41:52,120 THIS YET I DON'T THINK ANYONE 2627 01:41:52,120 --> 01:41:55,320 ELSE UNDERSTANDS YET EITHER. THE 2628 01:41:55,320 --> 01:41:58,240 BIG POINT HERE IS THAT WE CAN 2629 01:41:58,240 --> 01:42:00,880 THEN THINK ABOUT HARNESSING THIS 2630 01:42:00,880 --> 01:42:03,400 NEW INFORMATION TO THINK ABOUT 2631 01:42:03,400 --> 01:42:04,200 THINGS THE CLINICAL TRIALS WE 2632 01:42:04,200 --> 01:42:08,160 ARE INTERESTED IN DOING. MANY 2633 01:42:08,160 --> 01:42:10,160 PEOPLE HAVE TRIED IMMUNE CHECK 2634 01:42:10,160 --> 01:42:13,960 POINT INHIBITORS FOR 2635 01:42:13,960 --> 01:42:15,320 GLIOBLASTOMAS, THEY FAILED ALL 2636 01:42:15,320 --> 01:42:18,320 THE TRIALS FAILED MISERABLY. 2637 01:42:18,320 --> 01:42:21,240 UNLIKE MELANOMA. IN LUNG CANCER 2638 01:42:21,240 --> 01:42:22,440 WHERE NOW THAT BECOMES STANDARD 2639 01:42:22,440 --> 01:42:24,720 OF CARE. SO IN TERMS OF CLINICAL 2640 01:42:24,720 --> 01:42:27,200 TRIAL DEVELOPMENT THE QUESTION 2641 01:42:27,200 --> 01:42:31,200 IS CAN WE COMBINE SOME OF OUR 2642 01:42:31,200 --> 01:42:32,560 CILIARE BLOCKADE WITH IMMUNE 2643 01:42:32,560 --> 01:42:34,160 CHECK POINT SIGNALING TO SEE IF 2644 01:42:34,160 --> 01:42:35,880 WE ARE ABLE TO GET SOME OF THOSE 2645 01:42:35,880 --> 01:42:38,560 EFFECTS THAT WE SEE IN OTHER 2646 01:42:38,560 --> 01:42:40,080 CANCERS. SO THOSE ARE SOME OF 2647 01:42:40,080 --> 01:42:41,200 THE THINGS WE ARE THINKING ABOUT 2648 01:42:41,200 --> 01:42:44,960 IN TERMS OF FUTURE DIRECTIONS. 2649 01:42:44,960 --> 01:42:46,920 IMMEDIATELY WE ARE WORKING ON 2650 01:42:46,920 --> 01:42:49,600 DEVELOPING AN ANIMAL MODEL IN AN 2651 01:42:49,600 --> 01:42:52,480 IMMUNE COMPETENT MODEL OF 2652 01:42:52,480 --> 01:42:55,880 GLIOBLASTOMA IN ORDER TO BE ABLE 2653 01:42:55,880 --> 01:42:57,720 TO PLAN, ASK SOME OF THOSE 2654 01:42:57,720 --> 01:43:02,320 CLINICAL QUEST TO FURTHER HELP 2655 01:43:02,320 --> 01:43:04,720 WITH CLINICAL TRIAL DEVELOPMENT. 2656 01:43:04,720 --> 01:43:07,040 WITH THAT TWO THINGS. MANY WERE 2657 01:43:07,040 --> 01:43:09,520 HELPFUL HERE AND I AM CERTAIN 2658 01:43:09,520 --> 01:43:11,240 MANY THAT SHOULD HAVE BEEN ON 2659 01:43:11,240 --> 01:43:12,680 THIS ACKNOWLEDGMENT SLIDE ARE 2660 01:43:12,680 --> 01:43:16,880 NOT HERE. SO I JUST WANT TO SAY 2661 01:43:16,880 --> 01:43:17,960 REALLY THANKS TO EVERYBODY WHO 2662 01:43:17,960 --> 01:43:20,000 HAS PARTNERED WITH US TO MAKE 2663 01:43:20,000 --> 01:43:24,640 THIS WORK HAPPEN. I STARTED HERE 2664 01:43:24,640 --> 01:43:28,840 IN 2021, DIDN'T HAVE A LAB FOR 2665 01:43:28,840 --> 01:43:30,720 SOME TIME AND GOT SLOW START. WE 2666 01:43:30,720 --> 01:43:31,680 REMEMBER ABLE TO ESTABLISH A LOT 2667 01:43:31,680 --> 01:43:32,920 IN A SHORT TIME AND I THINK THAT 2668 01:43:32,920 --> 01:43:37,640 IS A TESTAMENT TO THE REAL 2669 01:43:37,640 --> 01:43:38,920 COLLABORATIVE NATURE AND ALL THE 2670 01:43:38,920 --> 01:43:44,960 HELP WE HAVE GOTTEN THANKS FOR 2671 01:43:44,960 --> 01:43:46,760 HANGING OUT WITH ME DESPITE 2672 01:43:46,760 --> 01:43:49,160 TECHNICAL TROUBLES AND LAST TALK 2673 01:43:49,160 --> 01:43:50,160 FOR THIS SESSION. THANKS. 2674 01:43:50,160 --> 01:43:54,880 [APPLAUSE] 2675 01:43:54,880 --> 01:43:56,440 >>ANY QUESTIONS FROM OUR 2676 01:43:56,440 --> 01:43:58,200 AUDIENCE? NOTHING ONLINE. THANK 2677 01:43:58,200 --> 01:44:02,240 YOU. WAIT. QUESTION FOR YOU. 2678 01:44:02,240 --> 01:44:05,680 >>SORRY. I JUST FIGURED IT WAS 2679 01:44:05,680 --> 01:44:06,800 LATE SO PEOPLE ARE TRYING TO GET 2680 01:44:06,800 --> 01:44:08,200 OUT OF HERE. 2681 01:44:08,200 --> 01:44:10,520 >>THANK YOU FOR THE TALK. I WAS 2682 01:44:10,520 --> 01:44:14,720 GOING TO ASK MAYBE LIKE SO IN 2683 01:44:14,720 --> 01:44:19,120 TERMS OF LIKE TARGETING CILIA, 2684 01:44:19,120 --> 01:44:21,040 YOU MENTIONED THAT CLINICAL 2685 01:44:21,040 --> 01:44:24,440 TRIALS ARE GOING TO BE INTENDED 2686 01:44:24,440 --> 01:44:26,760 TO I GUESS TARGET CILIA AND 2687 01:44:26,760 --> 01:44:33,200 REDUCE CILIA. BUT I GUESS WHAT 2688 01:44:33,200 --> 01:44:36,680 ARE CERTAIN OBSTACLES THAT COME 2689 01:44:36,680 --> 01:44:40,120 WITH TREATMENTS LIKE ASSUMING 2690 01:44:40,120 --> 01:44:41,520 BECAUSE SO FAR DIFFERENT TYPES 2691 01:44:41,520 --> 01:44:43,680 OF TREATMENT SUCH AS 2692 01:44:43,680 --> 01:44:46,440 CHEMORADIATION OR IMMUNOTHERAPY 2693 01:44:46,440 --> 01:44:49,080 HAVEN'T WORKED SO WHAT CAN COME 2694 01:44:49,080 --> 01:44:51,560 OR HOW CAN THAT POTENTIALLY 2695 01:44:51,560 --> 01:44:53,080 ENHANCE AS WELL IMMUNOTHERAPIES 2696 01:44:53,080 --> 01:44:56,120 >>SO GREAT QUESTION. SO I HAD 2697 01:44:56,120 --> 01:44:57,360 THE LITTLE WHEEL, NOT GOING TO 2698 01:44:57,360 --> 01:44:58,760 BACK THROUGH MY SLIDES NOW 2699 01:44:58,760 --> 01:45:00,800 BECAUSE THEY ARE TRICKY. BUT I 2700 01:45:00,800 --> 01:45:02,280 HAD THAT WHEEL WHERE WE ARE 2701 01:45:02,280 --> 01:45:07,800 LOOKING AT GLIOBLASTOMA IN 2702 01:45:07,800 --> 01:45:09,200 GLIOBLASTOMA PRIMARY CILIA. WHAT 2703 01:45:09,200 --> 01:45:10,800 YOU CAN GARNER FROM THAT IS 2704 01:45:10,800 --> 01:45:13,360 PRIMARY CILIA TOUCHES ON A LOT 2705 01:45:13,360 --> 01:45:17,280 OF PHENOTYPES THAT ARE VERY 2706 01:45:17,280 --> 01:45:20,200 ADVANTAGEOUS TO CANCER BROADLY 2707 01:45:20,200 --> 01:45:21,760 AND GLIOBLASTOMA SPECIFICALLY. 2708 01:45:21,760 --> 01:45:24,000 US AND OTHERS HAVE FOUND THAT 2709 01:45:24,000 --> 01:45:26,000 TARGETING PRIMARY CILIA 2710 01:45:26,000 --> 01:45:27,760 INCREASES THE SENSITIVITY TO 2711 01:45:27,760 --> 01:45:30,880 THINGS LIKE CHEMORADIATION. I 2712 01:45:30,880 --> 01:45:33,040 HAVE SHOWN YOU THE DATA TODAY 2713 01:45:33,040 --> 01:45:35,800 ABOUT THE IMMUNOSUPPRESSION. 2714 01:45:35,800 --> 01:45:37,640 THERE IS ALSO DATA THAT SUGGEST 2715 01:45:37,640 --> 01:45:40,080 THAT PRIMARY CILIA BY USING SOME 2716 01:45:40,080 --> 01:45:42,120 OF THOSE DEVELOPMENTAL PATHWAYS 2717 01:45:42,120 --> 01:45:45,560 USED EARLY ON IN AXONAL GUIDANCE 2718 01:45:45,560 --> 01:45:47,520 IS HELPFUL TO THE TUMOR TO 2719 01:45:47,520 --> 01:45:49,520 SPREAD ALONG THE WHITE MATTER 2720 01:45:49,520 --> 01:45:52,960 TRACKS, ET CETERA. SO THE SHORT 2721 01:45:52,960 --> 01:45:55,400 ANSWER IS WHEN WE THINK ABOUT 2722 01:45:55,400 --> 01:45:57,520 TRYING TO APPLY THIS, IT IS 2723 01:45:57,520 --> 01:45:59,960 GOING TO BE APPLIES TO MORE THAN 2724 01:45:59,960 --> 01:46:03,560 JUST THE IMMUNOSUPPRESSION BUT 2725 01:46:03,560 --> 01:46:04,960 TRYING TO THINK THROUGH OTHER 2726 01:46:04,960 --> 01:46:06,200 THINGS PRIMARY CILIA MIGHT BE 2727 01:46:06,200 --> 01:46:07,360 INVOLVED WITH, AND SEEING HOW WE 2728 01:46:07,360 --> 01:46:09,640 CAN DO THA THAT. SO THAT'S ONE 2729 01:46:09,640 --> 01:46:12,480 THING. THE OTHER QUESTION THAT I 2730 01:46:12,480 --> 01:46:14,040 TYPICALLY GET WHICH I CAN GET 2731 01:46:14,040 --> 01:46:16,240 THE FEEL FROM YOUR QUESTION AS 2732 01:46:16,240 --> 01:46:17,760 WELL, IF THIS THING, PRIMARY 2733 01:46:17,760 --> 01:46:20,680 CILIA DO SO MANY THINGS BOTH NOT 2734 01:46:20,680 --> 01:46:23,360 JUST IN DEVELOPMENT BUT LATER ON 2735 01:46:23,360 --> 01:46:24,920 ARE YOU GOING TO HAVE A TON OF 2736 01:46:24,920 --> 01:46:27,000 SIDE EFFECTS IF YOU TARGET THEM? 2737 01:46:27,000 --> 01:46:31,880 SO FAR AT LEAST IN MICE NOT 2738 01:46:31,880 --> 01:46:35,560 REALLY MICE IT WILL RATE THESE 2739 01:46:35,560 --> 01:46:38,400 ANTI-CILIA DRUGS WELL ONCE PAST 2740 01:46:38,400 --> 01:46:41,400 DEVELOPMENTAL STAGES. AS A 2741 01:46:41,400 --> 01:46:42,640 NEUROSURGEON WE CAN THINK ABOUT 2742 01:46:42,640 --> 01:46:44,320 OTHER METHODS OF DELIVERY SUCH 2743 01:46:44,320 --> 01:46:45,880 AS LOCAL DELIVERY, WE HAVE A 2744 01:46:45,880 --> 01:46:47,800 TRIAL HERE DOING FOR EXAMPLE 2745 01:46:47,800 --> 01:46:49,320 MICROPROFUSION, THAT'S SOMETHING 2746 01:46:49,320 --> 01:46:50,360 WE CAN DO, MAYBE SOMETHING THAT 2747 01:46:50,360 --> 01:46:52,240 GOES DIRECTLY IN THE CAVITY SO 2748 01:46:52,240 --> 01:46:54,480 THAT YOU HAVE A LOCAL EFFECT SO 2749 01:46:54,480 --> 01:46:55,720 WE ARE THINKING ABOUT THOSE. 2750 01:46:55,720 --> 01:46:57,120 THAT IS KIND OF AN INDIRECT WAY 2751 01:46:57,120 --> 01:46:59,720 TO ANSWER YOUR QUESTION THAT I 2752 01:46:59,720 --> 01:47:01,920 KNOW MARK'S DEVELOPING A KIF 3A 2753 01:47:01,920 --> 01:47:05,880 INHIBITOR. WHAT IF THIS DOESN'T 2754 01:47:05,880 --> 01:47:07,120 CROSS BLOOD BRAIN BARRIER THIS 2755 01:47:07,120 --> 01:47:08,440 IS NOT HELPFUL FOR US. THESE 2756 01:47:08,440 --> 01:47:10,240 ARE THINGS WE CAN THINK ABOUT 2757 01:47:10,240 --> 01:47:11,240 LOCAL DELIVERY STRATEGIES 2758 01:47:11,240 --> 01:47:14,040 PUTTING IN THE CAVITY PEOPLE 2759 01:47:14,040 --> 01:47:15,960 HAVE DONE FOR CAVITY THAT DIDN'T 2760 01:47:15,960 --> 01:47:17,640 WORK WELL BUT THAT WAS A DRUG 2761 01:47:17,640 --> 01:47:20,200 SELECTION ISSUE. SO ON. SO 2762 01:47:20,200 --> 01:47:24,720 THAT'S HOW I THINK ABOUT THAT. 2763 01:47:24,720 --> 01:47:25,680 >>DO YOU HAVE A QUESTION 2764 01:47:25,680 --> 01:47:27,480 ONLINE. 2765 01:47:27,480 --> 01:47:31,600 >>IS IFNG ONLY COMING FROM 2766 01:47:31,600 --> 01:47:32,080 T-CELLS? 2767 01:47:32,080 --> 01:47:34,280 >>ACTUALLY THE INTERFERON GAMMA 2768 01:47:34,280 --> 01:47:35,200 THAT I SHOWED YOU HERE IS NOT 2769 01:47:35,200 --> 01:47:37,640 COMING FROM THE T-CELLS AT ALL, 2770 01:47:37,640 --> 01:47:40,720 THAT'S ON THE TUMOR CELLS. THIS 2771 01:47:40,720 --> 01:47:44,240 IS INTERFERON GAMMA THAT IS 2772 01:47:44,240 --> 01:47:45,880 UPREGULATED IN RESPONSE TO 2773 01:47:45,880 --> 01:47:46,840 CHEMORADIATION THAT IS APPLIED 2774 01:47:46,840 --> 01:47:50,880 TO THE TUMOR CELLS. YES THERE 2775 01:47:50,880 --> 01:47:54,960 MAYBE FOR EXAMPLE P -- SORRY MY 2776 01:47:54,960 --> 01:47:57,840 HANDS ARE LONG BUT PDL 1 MIGHT 2777 01:47:57,840 --> 01:48:00,640 BE IMPORTANT IN THE MONOCYTES 2778 01:48:00,640 --> 01:48:01,920 THEMSELVES, EVERYTHING I'M 2779 01:48:01,920 --> 01:48:03,680 TALKING ABOUT HERE IS UPSTREAM 2780 01:48:03,680 --> 01:48:06,080 SO THE WAY THESE ASSAYS ARE DONE 2781 01:48:06,080 --> 01:48:09,360 IS WE TAKE THE HUMAN 2782 01:48:09,360 --> 01:48:11,320 GLIOBLASTOMA CELLS AND TREAT 2783 01:48:11,320 --> 01:48:13,480 THEM CHEMOTHERAPY RADIATION, ET 2784 01:48:13,480 --> 01:48:14,720 CETERA, WE HAVE A CONTROL OR 2785 01:48:14,720 --> 01:48:16,960 BLOCK THEIR CILIA. AND THEN 2786 01:48:16,960 --> 01:48:18,960 THAT'S WHERE WE ARE SEEING THE 2787 01:48:18,960 --> 01:48:20,800 UPREGULATION OF INTERFERON GAMMA 2788 01:48:20,800 --> 01:48:23,040 LEADING TO UPREGULATION OF PDL 1 2789 01:48:23,040 --> 01:48:27,440 IN TUMOR CELLS. IN THIS PROCESS 2790 01:48:27,440 --> 01:48:29,360 THAT REQUIRES CILIA. AFTER WE 2791 01:48:29,360 --> 01:48:31,560 HARVEST THESE EVs IN THAT 2792 01:48:31,560 --> 01:48:34,640 CONTEXT WE MOVE THEM OVER FROM 2793 01:48:34,640 --> 01:48:36,200 NON-TUMOR PATIENTS TO THE 2794 01:48:36,200 --> 01:48:39,400 MONOCYTES OF NORMAL DONORS, WE 2795 01:48:39,400 --> 01:48:41,000 GO TO THE BLOOD BANK HERE 2796 01:48:41,000 --> 01:48:46,760 COLLECT NORMAL PATIENT APHERESIS 2797 01:48:46,760 --> 01:48:49,400 CONES, WE PURIFY THE MONOCYTES 2798 01:48:49,400 --> 01:48:52,040 AND ADD EVs FROM THE TUMOR 2799 01:48:52,040 --> 01:48:55,160 PATIENTS AND ASK CAN THESE TUMOR 2800 01:48:55,160 --> 01:48:58,000 EVs CAUSE THIS INDUCTION OF 2801 01:48:58,000 --> 01:49:00,400 THIS TUMOR MYELOID DERIVED 2802 01:49:00,400 --> 01:49:02,680 SUPPRESSER CELLS IN THESE NORMAL 2803 01:49:02,680 --> 01:49:04,480 PATIENTS THAT IS WHAT WE ARE 2804 01:49:04,480 --> 01:49:07,040 MEASURING. WE NEVER MEASURED 2805 01:49:07,040 --> 01:49:08,600 INTERFERON GAMMA DOWNSTREAM IN 2806 01:49:08,600 --> 01:49:11,360 T-CELL OR SO ON, THIS IS 2807 01:49:11,360 --> 01:49:11,960 UPSTREAM, GREAT QUESTION. 2808 01:49:11,960 --> 01:49:13,920 >>LOOK LIKE HE HAD A FOLLOW-UP 2809 01:49:13,920 --> 01:49:16,600 >>NK CELLS INVOLVED? 2810 01:49:16,600 --> 01:49:20,760 >>YES. SO MAYBE I SHOULD GO TRY 2811 01:49:20,760 --> 01:49:31,240 TO GO BACK. SO THIS IS WHAT IN 2812 01:49:35,800 --> 01:49:38,480 -- THIS IS BROADLY SPEAKING, 2813 01:49:38,480 --> 01:49:40,080 THIS IS JUST WHAT MYELOID 2814 01:49:40,080 --> 01:49:42,880 DERIVED SUPPRESSER CELLS IN 2815 01:49:42,880 --> 01:49:45,000 CANCER ARE THOUGHT TO DO AT 2816 01:49:45,000 --> 01:49:48,160 LEAST AS WE UNDERSTOOD IT IN 2817 01:49:48,160 --> 01:49:50,320 2012. IT IS STILL THE SAME IDEA 2818 01:49:50,320 --> 01:49:52,640 RIGHT NOW IN 2023 PEP FOR EACH 2819 01:49:52,640 --> 01:49:53,880 OF THESE THERE IS A LITTLE BIT 2820 01:49:53,880 --> 01:49:59,160 MORE DETAILS WORKED OUT. MYELOID 2821 01:49:59,160 --> 01:50:00,640 DERIVED SUPPRESSER CELLS AFFECT 2822 01:50:00,640 --> 01:50:02,800 DENDRITIC CELLS, INCREASE THE 2823 01:50:02,800 --> 01:50:05,760 IMMUNOSUPPRESSIVE T REGULATORY 2824 01:50:05,760 --> 01:50:08,840 CELLS, THEY BLOCK YOUR M 1 2825 01:50:08,840 --> 01:50:10,840 MACROPHAGE ACTIVATION. I TALKED 2826 01:50:10,840 --> 01:50:13,280 TODAY ABOUT BLOCKADE OF THE 2827 01:50:13,280 --> 01:50:15,080 T-CELL ACTIVATION AND 2828 01:50:15,080 --> 01:50:17,480 PROLIFERATION. AND WE KNOW 2829 01:50:17,480 --> 01:50:19,400 AGAIN, THE NATURAL KILLER CELLS 2830 01:50:19,400 --> 01:50:20,520 ARE ALSO BLOCKED BY THESE 2831 01:50:20,520 --> 01:50:22,800 MYELOID DERIVED SUPPRESSER 2832 01:50:22,800 --> 01:50:23,240 CELLS. 2833 01:50:23,240 --> 01:50:26,880 >>THANK YOU FOR THAT EXTRA 2834 01:50:26,880 --> 01:50:30,520 EFFORT. THAT IS ALL WITH THE 2835 01:50:30,520 --> 01:50:32,320 QUESTIONS. WE'LL CONCLUDE. ANY 2836 01:50:32,320 --> 01:50:36,200 CLOSING REMARKS, DR. FUJIII? 2837 01:50:36,200 --> 01:50:37,240 EVERYONE THERE IS A POSTER 2838 01:50:37,240 --> 01:50:39,600 SESSION GOING ON RIGHT NOW WITH 2839 01:50:39,600 --> 01:50:41,800 VARIOUS TOPICS UNTIL 4 O'CLOCK 2840 01:50:41,800 --> 01:50:44,160 AND THERE'S FOOD AND COFFEE IN 2841 01:50:44,160 --> 01:50:45,400 THERE OR THERE SHOULD BE. SO I'M 2842 01:50:45,400 --> 01:50:46,240 TOLD, MANY THE FAR END AS YOU 2843 01:50:46,240 --> 01:50:48,240 WALK IN. PLEASE ENJOY THAT. 2844 01:50:48,240 --> 00:00:00,000 THANK YOU EVERYONE FOR COMING.