In college what happens is we work on our interest, if we are interested in that subject we do the project very well, if we are not interested in doing something we leave it, same thing is with studies you know if I do not like the topic I leave it, but here for next 8 weeks you do not have a choice, whatever you do you have to do with full completeness wrong word full completeness basically it should be complete. So this is one thing which will happen for example say I am taking one example very simple example that suppose you are creating a page ok let me I want to know how many students are third year and how many are second year, so second year please raise your hats basically 50-50 I can say that easily as of now, so what happens is I do not know whether you have built any page for example let us look at a page and a field x field called name, so what happens when you take a field or when you do a program say factorial yes 101 or introduction to programming all of you have done, so one of the programs that we normally do is factorial right, so what we do we know the formula n factorial is equal to n cross n minus 1 right, if you are doing recursion otherwise you write a follow is it correct, this is how you do now when you do a program for a real time when the users on the internet are going to use or when you are making the same program for a product and what all things you need to check, can you just think about it what will be the difference, so yes it should not be non negative it should not be negative if I put 4.2 will it be fine, it should not be negative it should not be floating point or it should not cross integer limits and it should not be a character also, so input validation, so when you want to write a program which is for a general user two things are very important one are that any kind of input that comes from the user it should not go into a error like the page should not be blank, there should be a graceful termination of the program, second thing is that whatever input is taken from the user you validate each kind of units inputs available and then accept only the correct input and if the input is wrong a valid error message is required so very important thing is whatever input you take from the user validations number two if graceful execution graceful end of the program gracefully it should error out, now this is from there second thing is if I put 578 as a input what will happen somebody else who want to answer, so we need to also verify in our processing that whatever is the limitation of our processor that should be taken care of, are you all with me on that and then the output I cannot just print the number I have to write the entire message correct, now you can understand how much difference it is from this program which was written in CS101 and which you may have to write over here, can you all make it out, can you see the difference, so if it takes two hours to write in CS101 it may take eight hours to write over here there is another thing very important that here we have three kinds of servers one is a development server which probably may be your machine where you actually develop the code, once you develop your piece of code it will go to a test server in the test server one thing is interesting you cannot make changes to the code, so your code will be tested, now I think everybody has come is there someone who is left alone or can we say 90 percent of the people have come, so let me introduce myself my name is Shweta Tharani and I will be today covering my SQL with you folks, about me basically I run over here the blended MOOCs software and the blended MOOCs software lead and also IIT Bombay's MIS system lead and I have a small team of five members in which we take care whatever is required to run blended MOOCs and also whatever IIT Bombay's faculty wants any kind of information we collect that information and provide it, so it is an online system available, I think yesterday if you would have attended Avinash Sirs presentation and Mahendra's presentation you know some things about blended MOOCs and how many of you have participated in blended MOOCs program by any chance are there anyone who have participated last year in blended MOOCs program? No? Okay, probably next year this was about coding so probably I will take another five minutes of yours to talk about what kind of work, so this was all about coding and testing, so once the test server everything is fine then it goes to production, you do not even have a right probably you may not even have a right to enter the values in production because production users will be different right, so what I want to say is that the quality of the code has to be so good that when it goes to production it works fine, have you ever seen Facebook just crashing down like this even if it crashes then you get a message proper message that probably try it again or something is not working, so this is the kind of code that we expect you to write, coming to the design part, now you have to design the system in such a way that it is extendable and probably you may be writing a part of the system so you have to also take care of the integration with the other person with whom you are doing, so when you design your code you have to be careful about it, for example validations now when he said non-negative number not allowed right, so he probably may write a function everybody understands function right CS101, those who have come new and are wondering what we are discussing is we were discussing a small factorial program how it works, the issue is that there is a technical glitch so I thought we will discuss few things and then we will start with the MySQL, so what we were saying is that for a factorial you cannot have non-negative number, so a validation is required, so design issue could be write a function for validation and if your partner is also using the same function then you can always refer him saying use this function, so you have that validation function should be in library are you getting it, so this becomes very interesting till now when you used to do any project in pairs what you used to do you are my friend you finish the project we both will give the Viva correct, now here since you are working in an industry kind of environment everybody will be assigned some task he has to complete that task and if you start doing other person your friends task then you are nowhere already you are working 9-10 hours a day 10-10-20 non-sustainable it is very difficult people can do that some people are fast some people are slow but still I feel that it is bit difficult so you have to take care of your friends, so it is a very interesting thing it is not only learning at the point of view of what coding you will do definitely will improve in that but this is another thing which you have to take care third is the requirements part for example I will give you one example lot of projects yesterday did you attend all the projects that we did do you know everything is coming from most of them are from government of India correct so and there is something called RTI write to information, so one of the interesting things that is there in our project is we cannot delete any information because today if I delete for example let us look at T10KT training program okay your teacher registers and then finally what happens is that your teacher says no I will not do it so he will cancel the test okay so I have a software where it gets cancelled I cannot delete that name because tomorrow if there were 10,000 teachers and at the end we teach around say 9,980 teachers and ministry asked why were 20 teachers not taught so we have a cancellation of these list and the cancellation reasons along with it that because of these reasons these teachers were not taught it could be family emergency it could be some work in the college anything is possible right now in your case also you may realize that some of your friends may have wanted to join some program or some other place and they were not able to join because of some family issue sometimes some personal issue or they got a better opportunity etc is it possible it is possible right so these are the few things in the requirements which will be interest you so now give me five minutes I will set the things meanwhile I would request few of you were third year students and you have studied database very few third year students here okay how many are electronic and communication students okay so you do you know data structures have you done data structures course not extensively but you have some idea okay I was just thinking okay so for the benefit of food doesn't know database can someone explain databases to them good morning all this is Satirani and database is collection of data database is used to store data whatever the data is like social websites etc there must be a repository to store that now that's why database are used to store data and more or that there are many database are there like relational databases etc we can give queries to databases to retrieve data usually database are used to store data at the same time they try the data you can perform many operations on that that's it thank you in a crux says that any application on website which you have used or any application in your college which you have used needs a place to store data in a computer data is stored normally how they are stored hard disk hard disk how does it store files agreed now earlier all the data was stored in files so every file will have a file format etc slowly as it progressed there was a software which hide that information how to store it in the file and what happened is that data there was a management system created in which hide this information how the data is stored in files and users found it much easier to use it and that was a kind of database management system so that was database management system in terms of file management system is bit different you know it is more to do with blocks etc database management system is that you give the data in a particular format it may store in the file in any other format you may not know about it it may store in the same file it may store in two different files two types of data in the same file but that was the whole idea of having dbms database management system now over the years one of the database which is very common is relational database what is relational database is that data is stored in a table format let us take one example okay let's look at this do you all are present on social media all of you so first thing to be present on social media say Facebook what is important that you need to register on the Facebook account right everybody has seen the register page no someone who has not seen it okay great so what information do you feel okay great name email ID age nationality okay and can you please come and write it out okay so name age email ID and nationality so everybody of us will fill this information now this data should go into a table right otherwise it is very difficult because on social media you search for a name you search for your friend's name you get the information about that person right okay name age let us say we store we give a lot of information hobbies they ask so many pages of information right let us look at these five fields as of now so we all agree to this that we should store this information into a table right everybody someone who feels that it should be stored in a different format anybody no it is possible you can store in many formats yes what format it is possible that all of them will not provide age and date of birth so we don't need to provide space for that but in a table format we'll have to provide the space to maintain their table okay this is very interesting what he's saying basically what he's saying is that when we fill any data in on the social media form there are maybe say hundreds of fields to be filled your interest your college your parents so much information but as a user I may choose I choose that whether I may enter that information or may not enter that information so what he's saying is that there's a possibility that some people may not fill that data then that table will have lots of holes right look at this particular auditorium this is more than half empty right in a way we are wasting that space now this is very interesting what you have raised the point and this resulted into a database called document database on a no SQL database but I would not like to cover that topic away right now right but thanks you touch that topic as of today space is very cheap you realize that hard disk cost 80 GB hard disk what it will cost 3000 2000 anything like that right so it doesn't matter to us if 50% of a space gets goes free right but there is definitely another kind of database which is called object-oriented database which takes care of this information that normally people will not enter 90% of the data and then how to handle that kind of data so what I can do is I can give you a small taste of it by example ok I will need your information about this can you please provide this information to me home car ok home car correct 19 ok you can skip your date of birth Indian home cars had a gmail for example this much information is available so I can create a database like this in which I say let me call it person and then say if the next person comes in who will volunteer to give you their email ID we don't want any other information from you say you are a very private person you don't want to share anything else you just say name so basically a database will be such this is a another form of database not a form of table where this kind of information is told it's called document database or something called no SQL which is very in thing right now a lot of companies are using it the reason of it being over here there is that we believe that the processors are very fast and we have a lot of space but we want a searching to be faster so this helps searching to be faster than so those who have done databases they know that we store data in relational databases 3 nm but here data is stored at 1 nm ok so this is only for third year students second year students don't need to worry about it ok let me start this so anybody has worked on no SQL database anyone of you you have worked which database what do you mean wow so how did you find it how different it is have you used my SQL so how different it is from my SQL so when you use basic things all the basic facilities are available what are the basic facilities so what are the basic facilities available in my SQL very inquiring query the database very good inserting in the database from the database sorry deleting from the database inserting into database deleting from the database updating updating the database or updating a table right ok good what about create a create table in my SQL we have to create table sure ok but in no SQL it is all mixed up in form of like JSON like thing yeah so it's kind of a documents there is no structure in no SQL but my SQL is structured ok great so very interesting although I never wanted to cover it but it got covered and thanks to you all this is just for your information probably I don't think anyone of you will be using MongoDB by any chance ok but that the MongoDB is a document database so like you write a document the data is stored in that information in that format ok and in my SQL data is stored in tables are we all agree understanding that can you all think that data is stored in a form of a table right like you get your marks in a form of a table first semester marks subject one marks obtain this or a grade whatever you get CPI whatever subject to this subject 3 m3 suppose now I want to check for the entire class what it will have your roll number name subject one marks obtained name name to subject one marks obtained correct ok so now let us look at this particular thing let us come back to this example I like the example now you have to create a table for this ok now what should be the type of name like in your programming language you have a type attached to a variable right where care ok yeah so someone please come and write it down with name you can write what it is she said where can't write ok where care do you think we should assign a size to it because we are talking about a table so we are we need to know how many by its or how many characters it will 20 ok will it fit some people have names like Ram Nara and Krishna Moorthy and all that it will fit very important how big it should be what do you think what size that's what now so what should be the we are designing an application ok so if you are a designer what value would you like to put so we are looking at students from India so what do you think 50 length of characters will do people write such big names you know so we are when we are talking about India we are also talking about something here normally when you build an application you don't build for this particular set of years we have become global so we have to think globally and say so how big so one of the things which is very interesting is over here people have started writing in different languages right so we set our database type to utf-8 you know what is utf-8 okay let's leave it let's not divert it over there but normally any language can be data can be visible using a data type using a type colleague type called utf-8 just for your information because I think everybody will work on databases at least 70 to 80% okay so let us say 200 to be on the safe side space is cheap right but I don't want any of my program to error out because the sizes so what you have to take care in your form is that name should not be greater than 200 characters and if it is greater than 200 characters then you have to ask the user to truncate your name right correct okay age is integer minus 10 is it allowed no so what should it be unsigned in okay okay or we can give a we can say there is a constraint that it should be greater 0 we should not allow greater than 0 okay so we can write greater than 0 over there date of birth date field is correct okay this is perfectly fine nationality where can then how much do you want yes United States of America will it fit in 50 characters is there any country bigger than this USSR is no more okay and email ID 150 okay now one of the things in the database which we normally do is this is very nice thank you so much and this is how you create a table also what you do is you just put a comma over here and X nobody will understand after think of a database where you have 50 tables right can you understand X create table so very important table name should be good otherwise tomorrow when you leave and go then we would be thinking what is X what is why what is that what is it be right so the name should be very meaningful thank you so much thank you we will clap for everybody at the end but he did a really good job so this is how you create a table in my SQ okay one of the very important thing in the relational database is a unique column for example name like Omkar there could be thousands of students whose name is Omkar right to identify a record uniquely I will add a ID column type number and to save myself two people updating the database on same time etc. I will use something called auto increment auto increment okay this will be our primary key so anybody wants to explain what is primary key it has to be unique it cannot be null unique non-null unique correct so primary key the fund of primary key is that using that key you can identify the entire rule of the day correct so I here I can say you can see gamma primary key so I am not worried whether you get the syntax right or not the whole idea is that if you get a requirement you should be able to choose the fields what are the fields you should be able to decide what type it should be you should be able to decide the optimal size about it and you should be able to create a key for that okay I think we should be able to write anyone has questions on this because this will be the basis to go further so once we create a table next step comes is to insert the data into table correct is it insert so anybody who wants to help us in inserting the data into table anybody okay please come so meanwhile there are few examples which are there any name you can put your name so now everybody knows Omkar because Omkar was there and Cypress are those private person okay so few things which may help you further while you were developing an application is that many times we want to save a backup of the table right so what you can do is probably can just note it down for your troubleshooting purpose or something you want to try something and you want to save a backup of the table so we use a create table command we say for example create table person backup as select star from person so what it does is that entire table gets copied sometimes we want to just copy the structure of the table because say we are running a program which is related to data migration then we can say create table person underscore migration as select star from person where 1 equal to 2 is it possible to have ever 1 equal to 2 so no data gets selected and your table gets created so these are the few small things which may help you when you are developing your applications okay so those who have not understood it it's okay just something is there you know about it you probably may need to use it sometime whenever it is required night comes to your mind okay thank you so he said insert into person Omkar 20 he make made him one year older what is this is date of birth okay but he did not give the date of birth randomly don't generate ever generate in your application any random date of birth any random data please okay one thing you should be sure is that in your application you start creating something randomly and the person who is going to troubleshoot maintain it will have a tough time to find out from where that data is come okay thank you so much so when this data is not available what we can write here is null so null is a special value which is neither 0 nor empty codes nothing is there okay it's a special value when you say null that means that space is empty okay huh Indian and your address so he is a better data privacy person gave ABC okay now I have a table which is 100 fields right but we have asked user for only five fields right like here one two three four five correct so one way of saying insert is one issue where person values look the syntax is not that important what is important right now is that you should understand that this is how you insert the data these are the ways to insert the data okay so here if I decide that I will not take input as data but okay then what I can write over here is I can say name comma age comma nationality comma right so I will say insert into person name age nationality email values omka 20 Indian ABC accurate correct sometimes what we need to do is that we would like to insert data from one table to another table for example let us look at person database we are talking about students of India so you are students for four years then you go and do your jobs so I want to remove you from the person table but government project how can I remove you so I do this create table person underscore now you all may pass out by it said 2017 2018 17 18 right as select star prop person we are one equal to two okay now this is very interesting let us look at this now I have a table this person table this is a kind of a table I have right ages 19 20 19 nationality is Indian now this is very common we may write nationality but there will be people who will write Hindi who will write Punjab they are people who will write right Indian can be written in multiple ways correct but do you want your table to be like this so what you need to do okay drop-down list that means you need to create another table called nationality which shows one is India two is USA three is China okay like this right so we have a drop-down in a table and a good idea will be to store instead of India many times I can store the index ID 1111 now nationality in case of something called students of India is a very bad choice right is it to some extent right right so a state would have been a much more informative choice although we may have say point one person students which are outside India maybe part of exchange program or a NRI or anything but it hardly matters when I want to know any information about students because less than point one person I may not be interested also so very important thing is how you create your table what is relevant okay so the state would have been a more interesting thing because one of the things which every government or every report would like to know is what is the distribution how many students are from northeast how many students are from Jammu and Kashmir or if their colleges from Maharashtra they will be interested in knowing how many are Maharashtrian students because suppose I run a university and I want to start say a Marathi medium college then this could be a good data for me to start working right you got the point so let me change this and make it to state 13 being Maharashtra for example and 14 being Rajasthan so what happens is that I have a requirement saying that I want to see the list of students who are from Maharashtra okay correct so what I can do is I will go through the entire table and I will select the records which are from Maharashtra Maharashtra is 13 sorry correct are you with me all of you I only want their names what will I do with their age or I only want their email IDs because I probably may want to send the information by email saying that we have started with a new college in Maharashtra on Marathi if you are interested you can let your your you can join in or your friends can join in or you may start a Marathi drama group or something like that then does it make sense right so you select only those students who are from state equal to 13 and you select their email IDs so what it becomes it you make from person where are you all getting it so in a particular project if you are working with database creation of a table normally a project may have fifty to hundred tables so there would be hundred to fifty creates and each table you may have a insert right selection for one table it could be hundred also so querying a database is the maximum work that is done in a project compared to insertion and updation because when you take data the interest is what is there in the data what kind of data you are receiving what we can infer is it clear to you all of you sorry I just I was creating a table right that time select email from person I will show it on the screen so here the database that we are talking about is employee and department so if you see there's a department database department ID a department name employee last name and department ID simple two tables okay so sometimes you miss a particular column like in our case we missed our state right so we can say alter table table name add that column with that type right then you insert the data like we inserted the data when you select the data this is how you update the data my one question to all of you is that asking age from a person look at this particular table do you think is it a good idea to ask the age of a person date of birth is actually not necessary it's our personal choice if you want to enter it okay but it'll be helpful in like reminding birthdays or something okay otherwise you are saying age is better okay anybody else who is who want to counter that please very good you can say loudly okay yes secondly age changes from time every year the age should increase right then who will increase it in the database if I am writing the code I would not like to do that so you can calculate it using current type minus the date of birth okay so there's another point of view saying that if I get date of birth I can calculate it now in the social media you can also somebody's entering the information right there is no way we can say whether he's ethically at bring it correctly or not I showed you an example of Indian you know people can write XYZ people can write idiot and that is also acceptable right some people if you look at Facebook you type idiot you will get a lot of Facebook profiles right smart also you get too many so one thing which is very interesting about this computer applications is that you don't have any control over users so what you consider them is one way of saying it is that you consider them dumb and then you ensure that they put the right date still data could be wrong so one way is that you make date of birth mandatory and then you keep calculating the age if it is very important second thing is that you can especially in social media you have to have that acceptance checkbox saying that yes you are above 18 years of age and you could be part of the application right so there are various ways of doing it so very important when you create a table you know why I am coming back on the creation of table is because if your table is created correctly then all your applications will work fine otherwise I store Omkar as 19 years and after 10 years if I ping him I will think he is 19 years old so you will have all the teenage girlfriends okay so very important right this is something which we will never use in our projects delete but just for completeness this is how you delete so in this case how will you delete delete from person where name is Cyprus up it is deleting from the database right but in reality you don't delete a person there is something called a status field you use status field in that even in Facebook they don't actually delete your profile they just have a status field say in your case where care one which could be either zero or one okay zero means he's inactive one means he's active so this is called symbolic delete so if somebody says delete my internally you don't delete it you just say update person set status equal to zero where ID is equal to whatever ID yes one of the very important thing when you do update or a delete is that that you use ID field or a primary key to do it think if I say they'll update person set status equal to zero your name is equal to Omkar 10,000 Omkar will become inactive then everybody will start searching there is no Omkar in our account all their friends will be deleted and it becomes very difficult think if I delete someone with last name as Kumar then 50% of the students will be out so very important what you delete okay till you have everybody's fine this is another thing drop a table we will never drop a table so whenever you do no delete no drop because we work for government of India projects ideally any application because the space is so cheap we never delete it do you realize that now since the computers have become cheaper the prokarmas have become expensive and because of this now all these frameworks have come in which we build applications because the rapid development framework has come in right we will study about one framework now Django framework which is again a rapid application development framework so that everything you develop applications past programmers are damn expensive okay one table by itself has no meaning we always need to join tables okay so this is very interesting for example if I want to show this information to anybody can I show 13 14 15 I have to show Maharashtra Rajasthan Gujarat Maharashtra right so I have to join data of in person table with states table says states table how do you all want to see the report and someone give any requirement which state do you block Gujarat Uttam wants to see all his friends from Gujarat right Uttam's friends so he selects Gujarat okay so what will I do ideally I will join this to this like this I will say Maharashtra this is Gujarat this is Maharashtra Gujarat Rajasthan and then select people and display the information right so what I would say I will say is I will do a join of these two tables I would say select whatever from person comma state where how they should match this is a state and this is ID column right this is every table has an ID column so where person dot state that means this part should match with state dot with this part right okay so all Uttam's friends should come Sheena and Sai should come here okay and what should I select do I need ID column is Uttam interested in ID column so what will he need so person dot name comma a email ID may be person dot email comma person dot age is it correct what I have written do you think something is missing over here good so what he's saying is that the requirement of state being Gujarat has not been included so what should I write over here and what should be the requirement state dot state is equal to Gujarat right so first part was joined the second part is the condition of the data and third part is the projection what data we want to show so the whole idea is whenever you get any report or a thing you should think like this first how these two tables could be joined okay first whenever you get a requirement first you say these are the tables which I have to look then you look the relation between those tables we are talking about relational databases right you decide the relation you write those joints then you write the requirements and then you write what the user wants to see so let me take another requirement this is fine right joints because this is something which we will be using a lot and I totally agree that in one hour nobody loves my skin but the whole idea is that you have some idea and when you start working on it at least you know what to Google so now there is a requirement which says this is the requirement this is the kind of requirement you will get for example which says that I have list of all the students of India okay and I want a report like this here are all the states and here are the age group states and say types of college okay so types of engineering colleges that you have is one is the government college IITs NITs government colleges private colleges autonomous colleges colleges which belong to a university government university private university I'm just throwing that probably you can put it in better format correct there could be various so I want this kind of report so I have a state stable to all of them all the 29 states I have types let me define type stable as one as government to as private third is autonomous or as affiliated for example okay now I want this kind of data so I will say Arunachal Pradesh government colleges private autonomous affiliated Bihar Chattisgarh right so how can I get this data can I do a join on these two tables although it has no relation between them this is called cross join you have done cross of two sets right everybody has done cross of two sets A cross B it's same thing over here right what output this is how the report has to come right but what I need information is this table that I need is AP government AP private AP autonomous AP affiliated okay so very simple thing what you need to do is select from states comma types there is no wear clause because there is no relation right requirement table and this are you clear with it is anyone who is not clear it's called cross join so we are done with so in this example if you see there's a department ID column which is together this is cross join Cartesian product this is something which we did now right so once we get this data then we go back to person's table and find those students right and get their numbers over there so something like this it looks but in our case they were only two columns which we were joining inner join was something which we did before that it's called inner join if you don't write inner join like this look at the second query select start from employee department where employee dot department ID is equal to department or department ID this is what we did with states and person table very interesting null we saw a null that unique value was there now we have to specially take care of null we have to say whether it the value is null or not null for example I want to see on this particular person table how many users have kept data of birth as null so I will say select start from person where DOB is null so very important when you join null with any condition results to null so neither it is true nor false so it never gets selected so you have to be very careful about it each one is the same thing as inner join but it is equality comparison this is very interesting outer joins for example if I want to list all let us take this example once again I say these are the states of India and these are the number of students from each state now in our database there is a possibility although co as a engineering college this Sikkim there is no student from Sikkim so what will happen if I do a join of person with states Sikkim will never get selected right because we are doing a equi joint saying that person dot state I state is equal to state dot id right let us write that right so if I don't have anybody from Sikkim that per Sikkim state will not get selected but when if I want to display all the states so what I will do is I will see this state left outer join person left outer join means the table on the left will lead the day lead the joining facility so each value of state dot id will be used in the person's table to fetch data so how the data will come for Sikkim like this Sikkim C21 Sikkim because there is no data in the person table null null null and if you put it on the right if you want the right table to be the driving table you say right outer join so look over here select staff of employee left outer join department so this will select all the employees who do not belong to any department also for example you too you all do not belong to any project right now have you all been assigned projects probably by end of the day you will be assigned right so if I want to know information about you along with us I will say select start from employee because as of now for eight weeks you are our employees right but you don't belong to any department left outer join department so your department id will be null but I will be able to view so now let's take another example we have started some projects or say some departments only because you have come in we don't have so many resources so since you have joined we wanted to do some part which because of which we have called you like you are here so we will so basically you all will make a group and you will start working on that project okay so if I say select start from employee right outer join department okay so for example there's a project on big data which we don't run normally because we have come so the department big data will come but there will not be any employees because right now you are not assigned to any department right and you all will never come in because I did a right outer join with the department okay so very important when to do a left outer join when to do a right outer join and there's something called full outer join full outer join will ensure that you all also come in and also the departments which don't have employees also come in okay so in this case if I do a full outer join then I get those person who do not select any states I also get those states where no person exist so I get the entire data set so let us summarize it what all we studied anybody what all we did we did not do create database but we did create tables insert update delete yes okay what are the different types of choice okay I hope you understood it well or he had a good teacher in college anything else cross-join okay update delete we also talked about how to design if we have a requirement how to create a table right and I hope that this particular one hour will be useful to you sometime in next eight weeks okay do you have any questions so thank you


Okay, so I can still hear myself in a double loop. Okay, so back to some examples of, is there no loop? I can hear it, but okay. So it's confusing to me because it's running, coming back to me. Let me try and ignore it. Okay, I am muted. You're muted. Yeah, but it says microphone on. But I don't know why. I started with microphone off. And then I don't know what it is. Okay, maybe now it will work. Well, we don't hear you, right? Maybe. Oh, because you hit that, you think? Because who knows, right? Okay, I'm sorry. So I want to talk about the, the contact structures, and here were some examples and now we're, I'm sorry, I got a little distracted. So just basic facts about contact structures is that our Buddha says that all contact structures are locally homogenous and all locally look like the standard contact structure that we had here. On the other hand, Benekin in 1980s, early 80s showed that there's contact structures on R3 that are not standard contact structures. So if a contact structure is like contains a disk, like the one we see here in the picture, then this disk is called an over twisted disk. The contact structure is called over twisted. And if a contact structure has no disk that looks like that, then it's called tight. So this dichotomy between tight and over twisted was introduced by Eli Arzbeck and he proved that there is a huge difference between over twisted and tight contact structures. Over twisted contact structures are classified up to isotope by their homotopy classes, plane fields and in every homotopy class of plane fields, there is a contact structure. On the other hand, tight contact structures do not exist in every homotopy plane, in every homotopy class of plane fields. And in some homotopy class of plane fields, there are tight contact structures that are homotopic as plane fields, but are not isotopic as contact structure and not sometimes even isomorphic as contact structures. So the early examples are due to Giroux and Eliashberg and Polterovich and they were on T3 and Paul Aliska who is giving the next talk and I back in probably 1995, but it got published in 97. Publications always took a bit of time. Young people now know it takes even longer, but we had examples of homotopic structures on homology spheres that are homotopic as plane fields, but not isomorphic. So anyway, this is just a short history to introduce basic questions which are to construct, recognize and classify tight contact structures. In the realm of constructions, Eliashberg introduced this theorem where he recognized the contact structures that we call Stein fillable, which live on boundaries of Stein domains which are certain kinds of complex symplectic manifolds, but the way to think about them by this construction of Eliashberg is to think about them as obtained as adding two handles along Legendrian knots in S3 or after adding some one handles to S3. So Eliashberg and Gromov proved that all the fillable contact structures are tight, and here I talked about Stein fillable, but there are several kinds of fillability and here's some differences that were established throughout history. So tight contact structures contain weakly-symplectically fillable, which contain strongly-symplectically fillable, and this difference is about how the contact structures and the symplectic structures interact near the boundary, and then the smallest family is the Stein fillable contact structures, and there are these differences established by Etnair-Honda between tight and weakly-symplectically fillable, Eliashberg between weakly and strongly-symplectically fillable, and here's in red, I'm talking about the contact invariant in 2005, Gigini used the contact invariant developed by Osvat and Sabo to show that there are strongly-symplectically fillable manifolds that are not Stein fillables. So I want to talk about the contact invariant. So in 1997, Kronheim and Rovka published a paper, Monopoles and Contact Structures, that introduced an invariant of contact structures in Monopole floor homology. And in probably early 2000s, but paper published in 2005, Osvat and Sabo defined an analog of this invariant in their Higart floor homology, in the paper Higart floor homology and contact structures. So the invariant I want to talk about today is the refinement of this Higart floor homology contact invariant. So in order to do a definition of it, I have to say something about the standard classical contact invariant. So first of all, Osvat and Sabo, of course, defined Higart floor homology for a three-manifold, and they defined various flavors of it, and for a contact manifold, M3xi, in the Higart floor homology with various flavors, they defined a contact element. So I'm today going to talk about the contact invariant in the HET floor homology and its refinement. So you can just think about HET everywhere where you see HF if it's not written. So the properties of this invariant are if xi is over twisted, then xi of xi is zero. And the other property really comes from one of the main theorems in that paper, except for the theorem that the definition of this invariant doesn't depend on various choices made, is that if M prime xi prime is obtained by a Legendian surgery, so adding a two-handle with a particular framing along a Legendian knot in M xi, then there is a co-boardism that's induced by this surgery between M and M prime, and this co-boardism induces a map on Higart floor homologies, and this map takes the contact structure invariant of xi prime to C of xi. So remember that Eliasberg said that all steinfillable contact structures can be obtained by a Legendian surgery on a link in a three-sphere. Then we know that if M xi is steinfillable, then there is this co-boardism from S3 to M, and the contact structure of xi is mapped onto the contact structure of S3, and from easy, you know, super easy calculation is that the contact structure of the standard contact invariant of the standard contact structure is non-zero. So here is a theorem of Osat and Sabo that C of xi is zero for an over-twisted contact structure, and C of xi is not zero for a steinfillable contact structure. So clearly there was a, you know, a natural couple of questions to ask is that if contact structure is zero, is xi then over-twisted? And the other question is, the answer is no, and there are these examples that I kind of alluded to in the beginning called contact structures with Jiru torsion, which keep the contact structure tight, but have zero contact invariant. On the other hand, if C of xi is not zero, does it conclude that xi is fillable? And the answer again is no, and there are various examples, a lot of people, many of them here, methods of proof, often accorded boardisms are built to examples that are known to be not steinfillable, and so sort of ad hoc and clever, various clever ways to prove, still usually and often using in some way the contact invariant, but proving that xi is not fillable. So here's a little bit more straightforward way to prove sometimes that a contact manifold is not steinfillable. So we define an invariant O of xi, which is either a non-negative integer or infinity that we call spectral order, such that this O of a tight contact structure is zero, O of a steinfillable contact structure is infinity, and this is a little confusing statement, but O of M can be detected from a given open-book decomposition. So we don't have to worry about open-book decompositions with different pages, but I'm gonna talk about it in a second. So why is this theorem useful? Calculating this invariant O is very difficult, unless we can show it is zero or we can show it is infinity. Calculating lower bounds is extremely difficult, but finding upper bounds is not that hard sometimes, and so what can we do with just upper bounds? Well, if we have an upper bound and it is not infinity, then we can conclude that the contact structure is not steinfillable, even when the contact invariant is actually not zero. So I'll give you some examples of that. I promised the definition and because O is a refinement of Hiegert-Fleur contact invariant, this is somewhat of a long story that has to mention the definition of the contact invariant, and so the contact invariant is defined as follows. So C of psi is an element in Hiegert-Fleur homology of the three manifold with opposite orientation, but we'll just ignore that, and there is a theorem of Giroud that says that every contact structure corresponds to certain family of open book decompositions on the manifold, and these open book decompositions that are used then to construct the Hiegert decomposition and read off this contact invariant. Quickly, what's an open book decomposition? Starting from a different direction, I'm going to say, first of all, if we're given a pair of a surface with boundary and the difhumorphism of that surface to itself, which fixes the boundary, then we can look at S cross zero one and mod out by an equivalent relation where we send point x1 and identify with point H of x0. We identify all the points with different T and T primes when x is on the boundary, and so when we collapse this boundary, we get what we call a binding, and in the neighborhood of the binding, we have this open book picture that's where the open book name comes from, and you can see from here that we can cut along two opposite planes in these open pages in this open book decomposition and get Hiegert decomposition. So if we cut our S cross zero one in half, because S has a boundary, we can get handle bodies, and in each of these handle bodies, we find compressing disc that gives us a Hiegert diagram. So when we're coming to this Hiegert decomposition from the open book decomposition, this Hiegert diagram has a particular form. So the red handle body has this nice set of arcs that come from the curved alpha along which we cut, and the beta handle body has a form where these blue arcs are H of the red arcs. So it's hard to really be precise about this in a short period of time, but if we have... So here is an example. If we have... So this example is where the surface is the genus one surface with two boundary components, and the H is the composition of dame twists around curves A, B, and C. And so if we did the picture like that, we would have to cut this surface into a disc and then look at where our red curves are mapped to and get this right-hand side to just see what the contacting variant is. Where is the contacting variant here? It's this special point. It's the intersection of alpha and beta curves. And in the picture where we just concentrate on the page and the picture on the page, those points appear in pairs at the ends of this alpha arcs. So anyway, once we have this picture of the Higard diagram, then Osat and Sabo had defined the Higard flow homology by looking at this chain complex with chain groups freely generated by tuples of intersection points of alphas and beta curves and with the boundary map counting certain pseudo-holomorphic curves that realize certain domains in the surface where the domains have some number of boundary components on the red curves and some number of boundary components on the blue curves and they might have genus, but that's sort of the picture when we do this count and we count all the domains from different y's that start at x and go to y's by this formula. So this is the definition of the boundary map on this chain complex and Osat and Sabo proved that the homology of the chain complex is independent of choices and so on. That's the Higard flow homology but when we have a contact structure and we construct the Higard diagram as up here, then there is a contact point, there is a special point which is the intersection of alpha and beta curves on the portion where the picture is standard that defines the contact invariant. So now with this out of the way, I want to talk about the definition of O of the spectral order of the contact structure. So what we do is we introduce a filtration on this boundary map and this filtration is considered by, comes from considering a certain complexity on these domains A. And the complexity of domain A involves this following definition. We're going to define the complexity j plus of A by saying that we're going to add the mass-low index mu of A minus 2E of A plus the difference of the order of x minus or the size of x minus size of y where by the size we count the number of cycles in the permutation of the element where x is a tuple x1 through xd of intersection points of alpha and beta curves and if we think of xi living on alpha i then we look at what beta curves they live on that beta curve that defines for us a certain permutation associated to x and we count the number of cycles in that permutation. So in particular if we think about the contact invariant xxi what is its order? So because the contact invariant is defined to be the homology class of this special point where I intersect the alpha curves with its associated beta curves what we see is that the permutation is just the identity and therefore this is just the number of curves in the set of arcs to cut this down. So there is a reformulation of this in terms of a Lipschitz formula and we get for mass love index one domains j plus of a in more local and combinatorial form where this nx of a and ny of b this is supposed to be a are in terms of some sort of local multiplicities of the points x and y at the corners of x and y of the domain a at the corners of x and y so for example if I have some xi that's an intersection of alpha i and beta sigma of i and the domain a comes in like this then this nx would be one quarter on the other hand if the domain came in like this then this would be three quarters and so on so it's very very combinatorial so why am I talking about this j plus because it turns out that the j plus of a is an integer and not just an integer an even integer and so what we can do is we can split the boundary map of hf by taking each one of these guys to be the sum like we had for the boundary map in standard here floor homology but sum just over the things that have j plus equals l so the boundary of any x splits into these boundaries and there what we get is more precisely the following so we are going to introduce a more complicated complex by tensoring our standard complex by f of tt inverse and then defining the boundary map so splitting the boundary map into d0, d1, d2 components shifting to the left by l and so when we have a situation like this we can do filtration we can introduce the filtration on this complex and by taking fp summing everything from p to the left and what we see is that we get a filtered complex and we can talk about the spectral sequence for this complex and we can define the order of this complex to be the smallest k such that the contact element x psi is dyes in the kth page of the spectral sequence so it would be nice if this was all we needed to do because then we could, yes sorry the filtration doesn't involve the contact structure but the filtration is like not it depends on everything and too much and it doesn't if you just do the homology it's just like not really invariant we don't really know how to make that filtration invariant under anything okay yeah right, yeah so it's even worse it's even when you just restrict to the contact element things still depend on choices so for example if you have an over twisted manifold then it is known that you can choose an open book that has an arc that's taken to the left and so that in the picture for that over twisted manifold there is going to be an arc and then there is going to be a domain simple domain with O equals 0 that kills the contact element so it's going to get killed on the first page so O is 0 okay for that choice unfortunately not every open book for an over twisted contact structure has such an arc so but you may still hope that you still get O equals 0 but no it's not true so here's an example this is an open book with the three times punctured disc and with the twists as noted here so I'm just giving an example which we ran into you can carefully study the whole picture for the Hieger's diagram for this H and you can find that there is actually a J plus equals 2 domain that's the only thing that kills the contact invariant so we know the contact invariant is killed so we know in some level it's going to get killed and it actually gets killed with J plus 2 and so from this the O is 1 so we don't have independence of the open book okay so well how do you fix you don't have independence well you just define it away so so we define O of M of Xi to be the minimum of all open books of O of S H A J and now it's an invariant so well it's not a very calculable invariant and we don't you know it might just be nothing on the so what we do prove is there is the independence of the almost complex structure like for the for the Hieger's Fleur there is also independence of S of H and A so first of all then the thing I said is that we have independence of the open book we have an independence of the open book as long as we allow ourselves to take more than just the basis of arcs so we're going to have to have A be not just cutting to a disc but maybe to a whole bunch of discs how does that solve that question that problem I had before on that on this example so if we add a parallel arc here as I did this green arc on the right-hand side you can see this immersed disc and this immersed disc is a domain plus equals zero that kills the contact invariant and so once I allow myself to have extra arcs then I don't have to change the open book SH that's nice in some sense but it's not nice because we don't know how many arcs we have to add to achieve the actual minimum so there is a problem with calculations is that we don't have an upper bound so now we have an invariant because you have to take an arbitrary number of extra arcs to take a minimum over it's hard to find the lower bound so if you're found O equals zero then that's the lower bound so that's a situation where we can do calculations we can also deal with Stein-Fillable Manifolds we can show that like for the standard contact invariant the O for Stein-Fillable Manifold is special and it is as for the standard contact invariant the Legendian surgery in some sense honors the contact situation in the class but what we have is that if M psi is obtained from psi by Legendian surgery then we have that the O does not decrease so in particular we're calculating that the O of the standard contact structure on S3 is infinity and knowing that the Stein-Fillable Manifold can be obtained by a sequence of Legendian surgeries what we get is this result that O of a Stein-Fillable Manifold is infinity so if we have an example where we find that O is finite well maybe we don't know how much it is but if we find an upper bound then we know it's finite then we know the contact manifold is not Stein-Fillable so here's a couple of examples so the example that I sort of plopped before maybe I can talk about it here a little bit more so I'm looking at a genus 2 surface a genus 1 surface with two boundary components and we're going to cut it up into a disk by putting an arc A1 here and then putting an arc maybe so I'm going to think about this here handle made by identifying those two guys think about cutting this surface along this green thing here so I have the blue arc A2 would be like that I have this green arc that goes that's long like this ok so we cut our genus 1 surface into a disk and with this identification I can draw this genus 1 surface picture like this and so now I have my twists my open book is the diffeomorphism is obtained by twisting to the right along this boundary component this is A and along this boundary component this is B and then it's twisting to the left along C which is like a curve maybe here so when you do these twists and you come to these arcs then you get this picture where the arcs original arcs are dotted and their images are the full arcs and then we're looking for domains that whose boundaries alternate between straight and curly arcs and we want those domains that hit the contact invariant the contact invariant is this pair of points we should really think about one point X1 and then there is this pair of points this pair of points is X2 and then there is this pair of points or X3 ok and so then we're looking for the domains that might hit the contact invariant and so very careful analysis of situation after very careful analysis we can conclude the following here is this point Y which is a triple X1, Y2, 1, 3 that I did in green here and from X1, Y2, Y3 there are two domains and only two domains that leave it so when we calculate the boundary of X1, Y2, Y3 we can see that this gray domain sends it to X1, X2, X3 and there is this one other domain that sends it to X1, W2, W3 so in short the the boundary head map of Y is the sum of these two domains each one has only one representative because that can also be proved and so what we see is that the boundary zero of Y is the contact invariant so we see that X1 is zero on the other hand it's a fact and it falls from some work of Conway and some work of Heden and Plamenevskaya that C of Xi here is not zero okay and it's not zero because this element Y bar doesn't get mapped by the standard boundary head to the contact class so that's one of the higher complexity terms in order for this to happen so there is some more examples here there is a whole family of examples on genus 2 surface with two boundary components and with this here monodromy map with a triple twist around one twist around here one left twist along C and any number of twists P along this D so the fact about this manifold this is negative one over P surgery on a horizontal curve in the circle bundle with $4 on the genus 2 surface so here the Xi zero is a unique virtually over twisted contact structure on Y zero which was shown to be not fillable by Liscan's tip sheets again the same theorems I mentioned before give that this contact class is non-zero and we prove that O for all of these manifolds and contact for all of these contact manifolds is zero by a careful argument that shows that this domain is the only that gives us is domain with J plus equals zero that gives us the O equals to zero so so I want to say that J plus equals zero domains are pretty simple they're immersed they're immersed polygons with what we would call naked corners so so here is one of them so here is Y1, Y2, Y3, Y4 and there's an immersed polygon going down to the contact invariant which is X1, X2, X3, X4 so that's it the thing is that when that it you can prove that if you minimize overall A for a given open book you will have achieved the minimum you don't have to do minima over open books that was the statement that I made that you can figure out the invariant from any given open book as long as you increase the number of As that's our theorem and that was what that example was that I was saying to change the open book for this over twisted manifold to get O equals 0 I just need to add this is sort of a throwback to end this sort of collapsing domains so yes I would actually I just realized I forgot to say our idea for this J plus came from a similar thing by Mike Hutchins who was doing something it's an appendix to a paper of Lachov and Wendell on the you know my brain just stopped like in contact homology right so there is torsion in contact homology and there is a paper there where he does something for ECH that's supposed to be a parallel to their thing and so we were motivated by that to actually do this and I think the thing that we have here is some sort of calculability with the hands on we thought we had them and then our proof fell apart because at some point we thought we can add do we have an upper bound we need to add and as I said it's extremely hard to prove the lower bound if you can keep adding infinitely many things so we don't know we suspect there is but we can prove it because we can't figure out how to impose lower bounds effectively so in principle it's possible that it only really takes zero and infinity values so maybe just one other thing Cass and Kang looked for O in sort of like a region that would describe Ziru torsion and they found that there is upper bound if all the definitions work out like because they are not all worked out yet then you could see that O is finite so that would be another way to see that anything that contains Ziru torsion is not fillable is not fillable


With the Cold War looming, President John F. Kennedy identified the need for more unconventional warfare capabilities in the U.S. military. On January 1, 1962, the Navy answered by creating the SEAL teams. These commandos were trained to operate in all environments, sea, air, and land, from which they get their name. They first commissioned SEAL Team 1 in San Diego, California and SEAL Team 2 in Little Creek, Virginia. These commands were tasked to conduct small-unit, high-impact, clandestine guerrilla warfare in the maritime and riverine environments. Areas where larger forces find it difficult, if not impossible to operate. The SEAL teams were formed using the legendary frogmen from the already existing UDT or underwater demolition teams. The Vietnam War was the proving ground for these naval commandos. Their unorthodox tactics and fearsome combat effectiveness led the Viet Cong to call them the Devils with green faces. Here, the SEALs gained the almost mythical reputation that they have to this day. From their creation up to now, Navy SEALs have taken the lead in virtually every U.S. military action. SEALs also operate remote or urban areas, with the climate extremes of sweltering deserts, humid jungles, or the frigid Arctic. There are currently eight SEAL teams and one SEAL delivery vehicle team. All the elements of naval special warfare are fighting the war on terrorism in the Middle East and hotspots throughout the world. From Washington, I'm Pitt Officer James Stillpeck.


Thank you very much. I'd like to thank the planning committee for the opportunity to present on behalf of the thyroid group our work today. So today we're going to talk about the view of the data from 30,000 feet.  So I was thrilled when the TCGA announced that we're going to do thyroid. Thyroid cancer can sort of get shortchanged in the big scheme of cancer. I think one of the reasons that they did is because thyroid cancer is clearly on the rise. However, the mortality of thyroid cancer is not that high. It's actually over the same period has actually trended down flat and now is rising up. But clearly it's one of the few cancer types that is actually increasing in incidence. So I am a professor of pathology, so I have to show some histology. No, just kidding. This is important because the papillary carcinoma, which is what our project's on, has three main types and it'll come through in the data. So I really wanted to spend just a minute to express this. So papillary carcinoma gets its name from the tumor on the left here, which is a tumor that has finger-like projections or papillae. But not all papillary carcinomas are actually papillary in terms of their architecture. There's a group here that we recognize that are called the follicular variant. Not to be confused with follicular carcinoma, but the follicular variant of papillary carcinoma. And then there's a third main type, the tall cell variant, in which the cells are more columnar than cuboidal. And so we recognize these three variants, and it's kind of important. We know from lots of papers that these have different genetic profiles and different gene expression profiles, and that will also come out in our data set. These are the common genetic defects in thyroid cancer. Now we're just looking at papillary carcinoma. This whole chart shows the whole spectrum of thyroid cancer, but it's worth looking at. This one on here is post-Ternobal, so radiation-induced cancers. So ret rearrangements are common in papillary carcinoma, even more common in radiation-induced areas. BRAF mutation, very high rate of V600E mutations. Some small rate of BRAF rearrangements, which we'll see. NTRK rearrangements. RAS mutations are quite interesting. So notice it goes from zero to 21%. So depending on the cohort of papillary carcinoma, you'll get different numbers. But we definitely know that the follicular variant is enriched for RAS mutations, just as follicular carcinoma. Pax-8P-pargamma rearrangements are thought to be present mostly in follicular carcinoma, but there's been a few recent studies that show that they can also occur in some papillary carcinomas, again, the follicular variant. And then beta-catenin and P53 mutations are sort of things that occur down here when tumors show histologic progression to poorly differentiated and undifferentiated carcinoma. So that's the genetic landscape.  So if you genotype thyroid cancers, differentiated thyroid cancers, you only find one of these driver mutations in about three-fourths of the cases. So we don't know what those other mutations are. So this project is all teed up to try to find those other mutations. And this is important not just for understanding the cancer biology, but there are already cancer diagnostic tests on the market based on genotype. So if we can expand the genotypic universe of papillary thyroid cancer, those tests will get better. So again, this is the first look at the data. We did a data freeze about just less than a month ago. Much of what I'll show you today was generated by the FireHose platform. We're really just getting started, and Gaddy wanted me to stress that much of this has not been validated. Here's the sample counts. We're pretty far along in the project, and the remaining cases are sort of in the pipeline. So we're thinking we might just wait until we full it out to the full 500, but we're still discussing that. Here's some of the clinical data. Thyroid cancer occurs in a younger population. The mean age is 46. You know, I'm sort of envious when I saw those survival plots. That's really not so easy in thyroid cancer. There's not a lot of deaths. To do a good outcome study in thyroid cancer, you sort of need 15 years of follow-up. And so we're not going to have too many Cap and Meyer plots anytime soon. You can see we've had one death so far. Like in all endocrine diseases, way more common in females, almost three to one. And we have a good breakdown of the different histologic types. So here's some of the data. So again, I want to stress that papillary carcinoma is a differentiated tumor. And overall, it has a low mutation rate. So here's the mutations per sample. It's generally uniform across here, but you can see there's a few samples that are jumping up and showing that they have a much higher mutation rate. The sequencing coverage is outstanding. And then down here, we can see the rate is quite low. Please, someone showed that plot earlier. I don't know if anyone looked. I looked for thyroid. It was definitely on the left end of that plot away from the head and the excrements cancer. So it's a low mutation rate. Not surprising because it is such a well differentiated tumor. So this is a great slide that integrates a lot of the data. And I'll spend a little time going through this. This shows the common mutations with BRAF here, representing 57% of our cohort. We have some RAS genes. And notice the BRAF and the RAS genes and the fusions down here are all mutually exclusive, which we've known in thyroid cancer, the thinking being that having more than one of these doesn't add any biological advantage. The histologic data is up here. And so it's hard to see, so I'll explain it. So the BRAF tumors are enriched for the classical type and the tall cell type, which is consistent with the literature. The RAS mutant tumors are almost all the follicular variants. Again, this is consistent with what we've known. The tumors with the fusions are mixed between classical type and follicular type. And then these so-called wild type tumors where we don't know the driver mutation have really a smattering of histologic types. So immediately we're seeing a very strong correlation between genotype and histologic type. And so that gives me a lot of confidence that this is a quality data set. We could see the fusions, as I mentioned briefly, are here. RET fusions are the most common, but we're also picking up some Pax-8-P Pargamma, NTRK, and a few BRAF fusions down here. And again, mutually exclusive with BRAF-RAS. I want to bring your attention to this point right here, which is this initiation factor. And it's also mutually exclusive with these other common mutations and the fusion. So that's telling me, suggesting to us that this is a biologically significant mutation, even though we've not validated that. And then the copy number changes are shown here. Notice across the BRAF cohort, there's not a lot of copy number changes. Across the follicular variant or the NRAS cohort, there's not a lot. But notice there's a band right here that represents chromosome 22. So there's an enrichment for loss of chromosome 22 in these RAS mutant tumors. The tumors with fusions are also pretty quiet. And then the remaining 20%, the so-called wild type tumors, can be divided into two groups, those with more changes and those that are pretty silent. So the first thing I want to do as a pathologist is I want to go back and look at these tumors over here that don't have a lot of changes and just review their pathology. Because truth is, endocrine pathologists, we fight over diagnoses a lot. So we need to look at that. There's also messenger RNA differences that we know, some genes here, and then microRNA, which I'll show a little bit more. So this tells a very compelling story, this one slide, that integrates much of the data and shows that this is a quality data set. Yes, we've replicated some things that we've known. But the integration of all the data in this setting, I don't think anybody has come close to doing. So this is that new potentially novel mutation, this X-linked translation initiation factor. It's very interesting, there's no known role in thyroid cancer. And in fact, we could find just one other synonymous mutation in the cosmic database. So this will take validation, but it's certainly an interesting finding. Fusions, I showed some fusion data. Truth is, we're still going through this. There's much work to be done on fusions. This was some data from an earlier analysis that showed this fusion right here, which is in the business called RET-PTC1, which is the most common version. And then we have some more novel things, this ETv6, NTRK3, which, in speaking with Jim Fagan, he's validated this in an independent cohort from the Ukraine, both in radiation and non-radiation cases. So we think this is a real finding. And then Pax-8-Pepar-gamma, as we'd expect in a few cases. Onto the methylation work, the methylation profiling identifies four classes of tumors that generally correlate again with histologic type and mutational status. So we can see there's two groups over here on the left that are mostly the classical type and the tall cell type. And they are enriched with BRAF mutations. And on this side, which is more similar to the normals, we have an abundance of the follicular variants and tumors with RAS mutations. So the methylation work is integrating nicely into the same compelling story. A few interesting molecules, Mir21, which you heard a little bit about this morning, and Mir146B, both been worked on in thyroid cancer. But not at the methylation level, and here we show inverse expression between methylation and expression. So these are interesting leads for us to work on. And then as a thyroidologist, we always like to look at thyroid-specific genes. Not because they tell us that much about the cancer biology, but more they give us thoughts about progression and possibly loss of radioactive iodine treatment. And so that's a big issue in our field when tumors become a little less differentiated and no longer respond to radioactive iodine. So here we can show one gene, thyroid peroxidase, that actually shows a differential methylation profile based on the different types, classical, follicular, and tall cell. And we're from my group and others, we know that TPL goes down in BRAF mutant tumors compared to the follicular variant. And sure enough, methylation is playing a role here. Again, inversely expressed between methylation and expression. So that's a potentially interesting story. And we need to look at other genes in the thyroid like the sodium simporters, sodium iodine simporters and others. MicroRNAs, we can use various tools to cluster these. Here's a cluster driven by Mir21. So we can get four types or seven types. And notice the four types is actually showing some, again, correlation to histologic type, which we know reflects genotype. So I think the microRNAs will fit in nicely. This needs some work, though. If you look at the British Columbia software versus fire hose, you can generate different clustering algorithms and then actually compare them head to head and start to make some sense of how much you believe them. This is kind of interesting. So this is the British Columbia software versus fire hose. Four groups versus three. And you can see some cohorts line up nicely here and other cohorts get sort of scattered into others. So we have some work to do to try to figure out what's the most meaningful way to look at the microRNA data in a global sense. But clearly there's some useful data in there. And then cancer regulome, Lisa Ipe was kind enough to prepare some slides for us in which they look at all the factors, all the measurements throughout the data set. And we just started with something simple, like histologic type. And she was able to show that there's many, many, many associations shown here. And sure enough, some of the more interesting ones is mere 21, which I just showed you, what had differential methylation expression, and here's BRAF. So these are all potential leads and we'll certainly be using some of these software tools, which are at our disposal. So in conclusion, I would argue that we're making good progress. I think we're progressing as planned. I think the cohort is outstanding and truly representative of the disease. I make this point because that's not true for every paper in the literature. People cherry pick cases and what they're publishing is not representative of the broader disease. So I really do think this cohort is accomplishing that. We have a low overall mutation rate with few copy number changes, but we have a few tumors that have increased copy number changes, which we'll spend more time working on. And we've uncovered and reproduced strong associations between the tumor morphology, its genotype, its gene expression profile, copy number changes, and methylation status. And we've uncovered many interesting novel leads, mutations, and gene expression patterns to keep us busy for quite some time. So there's much to do. We still have to decide whether we're going to fill out the whole cohort and publish where we're at now. But I do think we're on track for our first paper in the middle of next year. As with all the projects, there's many, many people to thank, and I would hate to go through these individually because I'm sure I've left some people out, but clearly I'd like to thank Gaddy Getz, who I've not met yet. So Gaddy, if you're here, come up and introduce yourself. But thank you very much. Oh, there you are. Tom, thank you very much. You think that the fact that so many of them have BRAF mutations would suggest that the BRAF inhibitors might be a therapeutic approach for them? Well, I wish maybe Jim Fagan can answer that. He's more in tune to the clinical trials. There's certainly many clinical trials ongoing. Steve Sherman at MD Anderson is working on that, but I've not heard, it's not distilled down into like this home run where people are ready to give up radioactive iodine. I know Matt. Sure, so just a couple questions and then a comment. My first question is about the relationship between thyroid carcinoma and lung adenocarcinoma, because I think there are a number of similarities. First, the major, as you very well know, the major marker in one of the leading amplified genes in lung adenocarcinoma was the thyroid transcription factor one gene, suggesting potentially some common etiology. And, you know- There's also retry arrangements, too, that are common. There's retry arrangements, BRAF and RAS mutations. And I'm wondering if you've started to look at commonalities between the diseases or have thoughts about how to do so. Certainly that would be a good comparison, but there's some things that jump out, there's very few EGFR mutations in thyroid. So I think the similarity is there, but I don't know how strongly it'll hold up. And I think my second thing is more of a comment, which is I think if the rest of the cancer community could do as well as the thyroid cancer community has done, we probably wouldn't need TCGA or a National Cancer Institute. So we were very struck by the survival data. Yes, yes, well, that's not to belittle thyroid cancer. Most of the deaths though are actually in those poorly differentiated and anti-plastics. If I showed those survival plots, the survival plot for anti-plastic is measured in six months. So thyroid cancer represents the whole spectrum and I'm hoping that we're gonna get to a more aggressive thyroid cancer project, which will then nicely integrate right into this. Because we have many cases that have both papillary carcinoma sitting right next to anti-plastic carcinoma. It'd be nice to profile both of those in parallel. Thank you, Matt. Could I ask one last question? Yeah. Thyroid cancer is one of the most interesting ones with respect to heritability and familial syndromes and sibling risk. And it's been in the past discussed that the outcome may be related to whether the early onset family driven cases versus the more sporadic later ones. When you look at the data set you've put together, are you able to in any way parse out or do you have information on the heritability in terms of family related cases or the like? So we have to separate obviously medullary thyroid carcinoma, which has a much stronger familial association than sort of follicular cell thyroid cancers. I know the group at Ohio State has worked on this. There's some germline mutations of, I believe, TTF1 that make you susceptible to papillary. So there are familial cases of familial papillary carcinoma, but it's not nearly as strong as medullary. That's something that I think we'll get around to looking at, but it's not something that's gonna jump out at us right away. Thank you.


On tier fighters, tier fighters, portraying the thrilling advance of daring pioneers whose tremendous courage and sacrifices in the face of overwhelming odds made possible the exploration and settlement of the West. One of the first white men to explore the Black Hills of South Dakota was General Koster. In the year 1874, he set out with engineers, photographers and geologists. When the report of the expedition was finally published, there was but one phrase in it that people remembered. That phrase was, I found gold. The magic words inflamed the imagination, and in late September of 1874, Thomas Gordon of Sioux City attempted to organize a party of twenty-eight, but he met with unexpected opposition. Now wait a minute, wait a minute, let me say something, don't you men realize that all that land's waiting for us? Sure, but we ain't sure of the country. You were in the 49 gold rush? Sure I was, but I knew the country there, besides the government's warned everybody out of the decoders, kind of the Indians. All right, all right, but just let me say this, just let me say this, I ain't gonna force anybody to sign up with us, but General Koster's report is good enough for me. If his expedition got across the Badlands, I can do it too, and I ain't worried about getting twenty-eight men. And you know what they say, Gordon, fools walk in where angels fear to tread.  And you're not an angel either. Well, one man got through, another can do the same thing. Maybe, but remember, Koster's force had soldiers, men used to fighting, and they weren't dragging women with him either. All right, all right, but if you... Just a minute, just a minute, I'd like to have a few words. Well, sure, Mrs. Talens, I guess there ain't any more for me to say. Then I'll say it for you, Mr. Gordon. Jim? What? You said something about dragging women along. Don't forget that women went across the prairies all the way into the California, and they weren't dragged along. They fought their way with the men. All right. Yes, and I'm willing to do the same thing, and so are the other women with us. Well, if a woman's gonna have that much fun, I guess I can't let myself down by backing out, but give me that book to sign it out. Oh, that's fine. Fired by the heroic example of any de-talent, the band set out from Sioux City on October 6th, 1874.  No one knew exactly what lay ahead. But onward moved the six-covered wagon. Then late October brought winter closer. Came icy winds biting snow. By November, they would be crossing the Badlands. A place of terror and desolation in the bleak winter. Finally, when they reached the White River, Gordon called a halt. All right, we'll stop here. Get to those wagons up ahead and fill them the hole up. What's the idea of stopping, Gordon? Gotta have water, Jim. Well, I didn't know all we gotta have, Gordon. This is getting worse every minute. Only because you're making it that way. Get everything out of your wagons you don't need and fill this space with ice. I'll get ice, but I'm not unloading anything from my wagons. And I don't think me and mine is going on any further. I look up ahead there. Snow, ice, Badlands. I knew we'd come to this, Gordon. Oh, well, it's a trouble. Honey, now we gotta chop ice to get water. Gotta throw away our belongings, because if we don't... If you don't, you'll regret it. And not me. Well, Mrs. Talons, I think this is the end. I can't hold them any longer. Wait a minute. Give me that axe. What? What for? Please, give me that axe. Here. Robert, Robert, tell your father to throw things out of the wagon and get some buckets. Hey, look at Mrs. Talons. Well, I'll be... And just because you gentlemen decide you don't want water is no reason why my family shouldn't have it. Oh, Annie, what's the idea of telling Robert? Hey, give me that axe.  Get yourself one, Dave. Everyone has to help. Well, Jim, looks like a woman. They showed you up again. Is that so? But get me an axe. Once more, the dominant courage of Annie Talons held the little band together. The weary dull November days moved slowly. The Gordon party literally crawled across the Badlands of the Dakotas. Every last one, except three of the party, cursed their leader. Those three were Annie Talons, her husband, Dave, and their little son, Robert. December came. The cold grew more bitter. The icy winds cut through even the heaviest of clothing. The food, always precious, began to run short. Even water was being rationed. Then, during one bitter night, Annie Talons called softly to her husband. Dave, wake up. Oh, Annie, what's the matter, the Indians? Not so loud. No, not Indian. What are you talking about, Anne? I... I want water. Annie, what's the matter with you? Robert. He's hilarious, Dave. The fever. Robert. I want water. Annie, Annie, throw him. Swallow him. Must be Quincy. Give me the other blanket. You can't take it away from yourself, Anne. Give her mine. Here, now, I'll start a fire. Make some hot tea and fix some compresses for the throat. Let me out. No, Dave, no, don't... No, Annie, what's the matter with you? The boy's sick. If he isn't taking care of it, we'll die. Oh, I know that, Dave, but we can't afford to rob the camp. We can't afford to have him die, Annie. I'm going to get a fly. No, Dave, don't just see what it would mean. They'd find out their sickness in camp. They'd get into a panic, and then there'd be no holding them together at all. This is a fight you've got to fight along, Dave. How could we lose Robert? Think about that, Dave. We mustn't. There are plenty of candles, light them, and heat some water in a pan. You can't still look by and let the others know how badly off we are. Annie, Annie... Dave, we've come this far, and somehow I don't think God will let us fail now. All right, Annie. Anything you say. I'll get the candles. Oh, yes, dear. My throat hurts. Oh, yes, darling, but we're going to be all right. Mother says you are. All right. I'll try to get better. Oh, dear God, help me. Just this once more. Without alarming the rest of the party, Annie Taland and her husband David struggled to the long night. The boy Robert recovered, while on and on with the band of pioneers, deeper and deeper into the badlands. The situation grew worse. The faithful oxen, weary of the long trek, grew weak. Their hooves, after days of pounding over ice, snow, and rock, were worn to the quick. Finally, in desperation, a little caravan halted. Hell, it ain't no use. These stubborn critters won't move out of their tracks. I'll show them. No, you ain't going to whip them. Robert, quit grabbing that whip. Hey, what's all the trouble here? Hey, Jim, what's the matter? I mean, nothing the matter. This brat minds his own business. He wasn't going to whip the oxen, so I grabbed the whip. What's the matter with you, Jim? Taking it out on these bull critters. Gordon, you're sticking your nose in again. These are my oxen, and I'll treat them the way I want them. Give me that whip, Robert. Hey, that's the only whip I got. And I ain't got any. Hi, Harry, Gordon, we followed you this far, but we ain't going to do it no more. Without oxen, we can't travel. Beat them won't help. Better get back to your wagon, Robert. Yes, sir.  Tear up old clothes, rags, anything. Wrap it around the feet of your oxen. Go ahead. See, when I had some burl up, we were saving Mr. Gordon. Anybody's welcome to what we have. Thank you, Mr. Talent. Seems to me you ought to be the leader of this train. That's me. Now go on, you men. Do as I said. If we're going to move, we've got to protect our oxen. Hurry up, or you'll freeze to death down there. Go on! With burl up, rags, anything they could find, members of the party wrap the feet of the oxen and press on. More hardships, bitter weather, quarrels, dissension. Then one day, some of the men approach Gordon. There is Gordon now. Hey, Gordon, wait a minute. Well, boys, Gordon, we just about made up our minds that this here's pretty foolish. We ain't aiming to get ourselves killed. Well, I think we were pulling and going by. Why, you... Easy there, Gordon. We took a vote of the men, and they're forgiven enough. Let the Dakotas stay where they are. We're going back to where there's milder weather. Ain't nothing up ahead, but more winter. Maybe injuring. That's right, Gordon. We're getting out of the forts too late. Now wait a minute, Gordon. We're giving orders now. All right, men, turn them wagons around. We're heading for home. Just a minute. Just a minute. For you, Gordon, we got our minds made up. Hey, hey, what are you doing with that gun? Just what you think, Jim. The first man that makes a move to turn back now is going to get shot. You can't do it, Gordon. Then try to turn your wagon. All right, Harry, we will. And nobody's going to stop us. All right, boys, get them wagons turned. I warn you. No, Gordon, that's not the way. Wait. Wait. Please, everyone. Mrs. Talent, we listened to you before, but we ain't going to do it no more. Now get out of the way. You've got to listen just this once more, please, for the sake of your wife. Mrs. Talent, please. You don't want to go back? Yes, I might do. But don't you see what you're doing? I see that we're going to die out here if we don't turn back.  I know it. We've got to go on. Don't you see what would happen if you turn back now? The whole wagon train would be weakened. Those of us who go on would be unable to fight. You who turn back might be set upon by Indians. Oh, my little boy is with me. One night, he almost died. We didn't know that. Nobody did, but my husband and I. Oh, Jim, he, the rest of you, it means so much to all of us to keep going. That's why I didn't tell anyone, Robert, who's sick, but to a man, man willing to go on and fight. Gee, Mrs. Talbot, by thunder, I ain't turning back now. I'm with you, Gordon. Not with me, Pete, with Mrs. Talbot. Oh, good, Pete. Now how about you, Jim?  All right, men, come on, let's go. Who's with her? Oh, come on, come on, come on, come on. The wagons move on, Mrs. Allen. I think what I said the other day holds true now more than ever. The Gordon party is led by you. And so, thanks to the magnificent example set by Annie D. Talant, the Gordon party reached its destination. Privation and hardships were still their lot, but courage and the invincible will of a woman held them together until their goal was reached. Annie Talant was the first white woman to set foot in the Dakotas. She mined something far more precious than gold. She brought education and civic pride into a once bleak country. Today, there is a statue erected to the memory of a gallant woman, Annie D. Talant, a true frontier fighter.