and tech tech talks. I'm Jay Fidel here on a given Tuesday morning and we're talking about spikes and cyber attacks with two guys who can see and know what's going on. Maybe even they can deal with it. Phyllis Arestram Stylanda and we have a special guest today, Gerhardt Rickert and he's a I'll let you I'll let you define yourself. What what are you doing here and how did you get into our studio back here? Well, I'm the CEO of Pacific Global Security Group, a former CISO of Dark Matter and currently in Hawaii, supporting our war fighters and government and cybersecurity consulting and work together here with Attila. Okay, so Attila, you know what's going on here? We have a spike in cyber attacks and we are referring to Hawaii. This is a spike in cyber attacks in Hawaii. Is it beyond Hawaii? What has this come to your attention? Well, that's the main thing here, Jay. So and this is why everyone who's listening should pay attention is that if they are doing business with the government in any way shape or form, either as a prime or a subcontractor, know that you've been targeted over the past few weeks by a highly sophisticated spearfishing attempt. Now spearfishing, what that means is that's an email that looks very believable. Now, Jay, I'm sure has disseminated the information, but if you want to, you can go to our blog or on the ThinkTech blog and you'll see the what it looks like. And it's a very convincing email that we've been seeing from a number of government contractors. They've been forwarding us these emails and, you know, we were just trying to get the word out to be careful. Those emails direct you to a webpage where they are harvesting credentials. What that means is usernames and passwords to your email accounts, to your share point, to anything that could be relevant to your business. And unfortunately, if you are reusing those passwords anywhere, that means that if they get access to one, they have access to more. And the reason this is important right now is that government contractors often have proprietary information. And a highly targeted attack like this means that they're trying to probably get into government resources. And not only could that be detrimental to our economy here and to our government, but it can be detrimental to your company.  It's a nationwide just Hawaii. Mind you, Hawaii has a lot of government contract. We have the highest density in all of the country. So this is why Gerhard is so important here, because he has the other perspective, which is what does it look like from the other side? Who are these guys that are trying to get into our economy and destroy it? And how can we protect ourselves? And part of what he does on his side, which is why he's so vital to the community here, is to protect our economy. And he knows who these guys are on the other side, so I wanted to have him speak to us on that. Yeah, Gerhard, thanks for joining the show. How much of what it tell us that is true? 100%. It is nationwide. Hawaii is having a spike right now due to all the government spending within Hawaii to bolster the presence within the Pacific against China or whatnot, any type of adversaries that may be interested in starting issues here. So these APTs, these advanced persistent threats, these nation states are constantly probing primarily China, a lot of Russia, but other places as well. Why a spike now? Well, it's due to all the spending that's starting, right? Everybody knows that they're going to dump lots and lots of money. It's an obscene amount of money that's coming into the Hawaiian islands to fortify the Hawaiian islands, as we're the first line of defense. Yeah, he's correct. We asked for $4 billion. We got $7 billion here. $7 billion over the next year. That never happens to me. Never. Yeah, so Gerhard is absolutely correct. That is going to make us a target. And you're not looking at, you're not, they're not going after, say, the military directly, right? The military bylaw has to use these small companies. These small companies provide these services, Joe Begadon's shop of widgets and digits, and the government needs to use these by SBA rules and regulations. Well, guess what? They're not so secure. They reuse passwords. They probably don't have certain type of security technology in place, and they're easy targets. So whatever they have, whatever information they have on their government contract or what they're doing at work, this could be stolen and used against them. And then eventually the critical infrastructure will be the next attack. The critical infrastructure here in Hawaii is probably the most sought after attack. What does that mean? What does that mean, Gerhard? What is critical infrastructure? Electricity, water, everything. Why go after the base itself, the military itself, when you can take down the infrastructure around it first, right? Cause a lot of problems, cause a lot of havoc, cause chaos within the islands. Lots of money needs to be spent to fix it up. So yeah, this is something that we've been preaching about day in and day out. So what's the theory? If I knock off, say, the power grid or water or the internet in general in Hawaii, that is going to take everybody down, including these defense contractors and subcontractors. So if I knock off the platform, then everybody in the platform, including them are affected. Am I right? Absolutely. Absolutely. Now, you know, the base is obviously they're built for redundancy, but the rest of the islands, it's a minimum of six hour flight anywhere, if you want to go somewhere, right? So just the chaos that would be created, the havoc that would be created within the islands from a major cyber attack on any of the major facilities would. It's not just the defense facilities, defense contractors and subcontractors. It's all of us because if they go for the platform, they're affecting everyone in the state, every man, woman and child in the community. Well, and to, you know, have a little bit of evidence for current events. Remember how just, what was it about a month ago? It was all over the local news about how a fiber circuit was almost taken down. One of our primary interconnects between here and the mainland almost was taken down. And it was a coordinated effort, you know, multinational effort to stop it from happening. I mean, imagine if our communications infrastructure was interrupted, but it all comes from these small seemingly insignificant, you know, email taps or, you know, let's go to that. You know, so you describe what you call spearfishing and it's relatively unsophisticated. It's relatively clumsy.  So why are these nation states doing this kind of attack when they could do something much more sophisticated and get right to the heart of it without relying on fishing? Sophistication takes time and effort. You know, spearfishing, you're fishing the masses, right? And are these people intelligent enough to understand what type of fishing campaign is going on? For the most part, no, it doesn't mean that they're not intelligent. It's just this is a new wave of issues that are hitting the Hawaiian islands. And it's time for the Hawaiian islands to really understand that, hey, cybersecurity, cyber threats here are real. It's the real thing. It's not just in the movies. It's not just in the mainland. It's not just, you know, overseas. It's right here in our backyard. You know, it's a big problem we have is China is one of the main culprits here, but we have a very big Chinese demographic here in Hawaiian. People think, oh, well, it won't happen to us because we have a lot of Chinese here. No, that's not true. You know, it's happening as we speak and the training that has to go into, you know, getting these small businesses and these big businesses to understand that those emails look real. Those emails will get you unless you have a trained eye to identify it. And it's not hard. You know, if you kind of get the hang of it, if you kind of understand what you're looking at, you can identify a fishing attempt pretty quick. The average person can identify a fishing attack pretty quick with the proper training, 10 minutes of training and vigilance, right? Understanding it, learning it, and then all of a sudden not using it doesn't work. So, you know, once you understand what to look for, continuously do that. You know, we're in, it's a different world now. And I don't, I don't want to paint a doomsday picture, but... Well, you'll be okay if I ask you what essentially to summarize what that training is. Because if you, if you talk in public about what that training is, you're really tipping the other side off, the attackers off, who may be watching or who watch later. And they say, ah, you know, Gerhard is talking about, you know, the training and what the people are looking for. We'll bypass that. We'll bypass this training. How much can you talk about this training in public? It's public training. That's not anything, there's no secret sauce behind it, right? It's under, you know, it's looking at things like the email address, making sure that when you hover over it, it's actually the right email address. These tend to come from different countries that English is not the first language. So read, carefully read what's going on, look for the mistakes in the spelling. Sure, they may have a properly drafted email, but, you know, at the end of the day, there's some key points that, that will, will tip you off to some type of attack. And then it's the integrated technologies that companies bring into their, to help fight the battle, right? So the human aspect is one aspect, but there's other aspects, there's other technical aspects that can really help in the fight against this. And keep in mind, this is just one avenue of attack. Well, can you talk about some others? Talk about whatever you are. How much time do you have, Jay? Yeah.  Isn't there technology that would block it somehow? Yeah, there, there is technology, but for me, it's the basics and configuration management is to me one of the biggest problems we have when you have a misconfigured server or technology or security device that can do the job, but is not configured properly. You know, that's half the battle, though, what humans, you know, really need to do is not rely 100% on technology itself. I think it was in Star Trek where the Borg said that technology or computers is an imperfect machine built by imperfect beings, right? So you can't, you can't rely on computers to protect you 100% of the time. You heard it here on Think Tech Hawaii, yeah. Yeah, absolutely right.  How much, how much of the problem is that these companies don't take it seriously? And they don't do that quarterly training. And they don't, you know, motivate their employees to be careful. They sort of let it go at default, which is, it's never going to bother me. I'm smarter than that. How do they, how do you, or the government for that matter, get people and companies excited enough to actually take steps here? Well, unfortunately, as we've seen in the past, especially in Hawaii, it takes a compelling event to happen.  And at that point, you know, the people are brought in the Paxx, the Mandians and whatnot are brought in.  But what is that here? What is damage control? So you get a call.  And they say, come and help me. Well, A, you know, what, what happened to make them call you and, and B, what can you do you do to do the damage control? Because sometimes this is also quotable. Sometimes it's too late, isn't it? Usually after the fact that it is pretty tough. But what I tell most people, I've watched in my previous life, I've watched seasoned PhD cybersecurity people freeze up in the middle of an incident. So my first piece of advice, if this happens is stop, take a breath, understand what's going on and then move forward, you know, get in touch with your cybersecurity professionals, get in touch with Paxx or Cylanda or whatnot. Both of us will probably respond at the same time. And then at that point, you know, we'll figure out what the damage is. But our goal is to, you know, promote cybersecurity awareness and learning so that you can get ahead of the cue ball so that, you know, you understand and you start to see the attack happening. What could the damage be? You know, I have a little company, let's take the company we began with, it does defense contracting for the government or some prime. And, and they are, they are very concerned with aberrations that are happening on their system. They're not sure, but they're worried because they've read about this and they know about the surge, the spike, if you will. And so what kind of damage could we have?  That would, that would be nice, you know, and if it's a world work like that nowadays, but fortunately, we are too well connected. Let's see how quick, how long somebody can turn their cell phone off and see how long they can go out without that, right? So, you know, if you wanted to get into the, the statistics of it, a mentor of mine from Central Pacific Bank, he taught me a site called Pony Modern, he taught me all about statistics. And you get in there and you look at the statistics of how much a compromise costs most companies and you're looking at between three to four hundred thousand dollars an incident. So what does that mean for the small business here? If you're compromised and all of a sudden you're, you're hammered with three to four hundred thousand dollars worth of damages, well, guess what? You're out of business and slowly but surely, domino effects happen and people just go out of business. But what's the damage? In other words, am I losing data? Is that classified or, you know, proprietary data being destroyed? What is happening? You could lose data, you know, data could get compromised, they could get encrypted, it could get, you know, what malware could, could interest. Like ransomware, you talked about. Reputational damage. But there's an assurance, right? Yeah, here we go with insurance. There we go. Okay, insurance is never going to cover this kind of thing. Yeah, don't quote me, but the insurance company has come out and said, if it's a nation-state attack that they're not going to pay out, that's why you see a lot of companies dropping their cybersecurity insurance because major companies are getting hit by nation-states, they're getting hit by APT.  And then they'll take advantage of that and you're done. What's in it for them? Some kind of geopolitical gain? Some kind of government there paying them to do this? Yeah, it could be geopolitical. It could be the safety of our people. It could be the safety of our warfighters. You know, and that, that hits home for me, right? That's a very personal part of, of, as a veteran, you know, I want to make sure my warfighters are safe and, you know, so that's a very a daring point in my heart. But let me go to the other side of this whole question. We have a little time to discuss this, but I'm so curious. Okay, we know, I know China is doing this and they're probably very, very good at it, but Russia's doing it too. And we read about Russia. Matter of fact, there was a very interesting suit filed this morning in District of Columbia by some lawyer against Mark Zuckerberg, remember him? For his shenanigans with Cambridge Analytica, trying to hold him personally responsible for the damage that was suffered by the misinformation and disinformation that Cambridge Analytica spread around. Anyway, that all reminds me of the ERA in a nondescript building in downtown Moscow. You wouldn't, you wouldn't tell it from any of the buildings here, you know, why nondescript, okay? And somewhere in this building, probably not a lot of floor space, is a bunch of guys whose job it is to do attacks like this. And, you know, if you can do it in a nondescript building in Moscow, you can do one in Tehran, in Pyongyang, you know, name it. And so, I'd like you to take me there. Take me to the ERA type of nondescript building where you have a bunch of smart guys with, you know, advanced degrees from that country who know well enough what they want to do. How do they do it? They're working presumably in teams. They have trainers. They have a lot of resources available. They probably start at, like, the fallen book or something really, you know, basic like that. And then they wind up with a list of people to send fishing attacks to. I mean, tell me how it works. How do they get in on this?  Well, there's, so we've identified the buildings and stuff in certain countries of where those particular groups sit. And at any point in time, there's about 100,000 people that are actively targeting from one particular building at any time. So the, you know, it's, and let's get the degree out of the way, right? It's not, you know, highly educated degrees and stuff. There's some of that. But there are people that are natural geniuses of this. And they, you know, they do a lot of damage. But if you look at the APT and how they're doing it, there's many different ways. One of them, one of the biggest ways of doing it is just basically automating it, spamming it, having it, having it shoot across the internet and, you know, looking for any kink in the armor. And once it hits it, then they'll get eyes on last to see what that particular vulnerability was. And if they'll do some research on it, and if it's worth moving any further, they will, or they'll put it in their back pocket. If you're targeted, then obviously they have a dossier on you.  It happens. There are spies in Hawaii. There are spies all over the world. You can read multiple books on this. You can listen to multiple YouTube videos on this. Just watch Netflix. There's a million movies all about all these spies. And some of that has to be true. Well, yeah. And I mean, there's a couple of things that happened in America lately, you know, with certain demographics of spies and whatnot that we've heard. But here in Hawaii, you know, there's a dedicated amount that are here that are currently tracked. And I think that goes all over America as well. Gerhard, do you, and tell us, do you guys think that they're tracking you? Worse yet, do you think they're tracking me?  I go up on top of them all the time. So What don't you think they want to know how you operate? Don't you want to, don't you think they want to know how you train, how your clientele? I, so I primarily service the U.S. government. And I'm, you know, I bleed red, white, and blue. I love my country. You know, and as a patriot, I would hope that my government trusts me enough to, you know, not, and if they do, that's fine. I have nothing to hide, right? Everything I do is above board. So I don't know how you feel about that. I tell, I agree with him immediately. Well, here's the thing. In order for us to do what we do, we need to have certain standards in place. We need to pass certain requirements. We need to be, we need to follow the same rules that we ask our clients to follow, which is making sure we have a security awareness training program that we have a lease privilege and proper security measures in effect that we're not running around with equipment that could potentially be, you know, stolen or lost and then provide access to our customers networks.  And then, or should I say, the other, the other thing is that, you know, we got to eat, we got to eat their own dog, our own dog food. Is that how it works? Yeah.  You have to do, you have to do it yourself first.  Or are you looking for that real fit, you know, muscular guy to show you how to do the exercises correctly? So this explains why I can never get a job in a gym.  It's part of the profession, isn't it? Yeah. And another thing is, is yet you have to have, if you want to catch the bad guys, you have to think like a bad guy as well. You know, and you have to have one here in the dark, as well as the light. Well, I wanted to ask you about that, Gerhard.   And part of that is, we know who's doing this.  That's impressive. But do they also have the names of the people in the ERA building in downtown Moscow or Tehran or Pyongyang or Beijing? But, you know, can't we get, can't I look at the invisible addresses of that very email, okay, that Attila was showing at the beginning of the show and track it back to where it, from whence it came, from whom it came and can I do that? Isn't there a technology that would let me identify the individuals and organizations involved? And then I can take much more aggressive steps against them. So it's, it's interesting, that's an interesting question because, you know, I've asked the same thing, right? Why don't we just hack back and, well, the answer to that and I don't know if it's a viable answer, but it's the United States of America and we need to be, we need to be a, you know, a beacon of good of what we're doing. We need to have the right principles in place. Now, maybe, maybe there's some ruffles here and there, but for the most part, you know, the United States is not going to do the same type of terrorist activities. Well, I mean, defensive though.  But where do you go from that, right? So if you're getting attacked, you stop the attack, you mitigate the attack. You ask any cybersecurity professional, would you want to hack back? Sure. You want to see where it's going. You want to shut them down. You don't want them to do it ever again. Will they stop? No. So the best you can do is, you know, is the government here to help? They're a part of the fabric. I would say if you rely on the government to protect your infrastructure and whatnot, then you're opening up a very big Pandora's box that you don't want to get into. I think you should take the responsibility as a company owner or as a CEO or as a CISO to do every type of due diligence to protect your infrastructure against any type of threat when, you know, coming down to even just the basics, vulnerability, you know, vulnerability management, asset management, configuration management, firewall management, all these housekeeping basics, you know, you get that down and you get that proper. And then you'd be surprised how much, you know, the government now starts to fade away. If you're relying on the government to protect your assets, then it's not, the government doesn't move that quick, you know. Well, you know, suppose I go back to the beginning, what was his name, Berners-Lee, Berners-Lee Movan, to the beginning of the internet. And I say, wait, just like on my phone, you know, when I log in on my computer, we have two-step verification. Except that I apply that to the whole enchilada, to all of the internet. Attila and I have discussed this before. Go back and, you know, reform the whole thing, have an issue from the very beginning and say, if you want to get on the internet, you want to use the internet anyway, you have to have two-step verification. And, you know, it's going to stay, get a hard record. That's what it's going to say.  Okay. And then if you mess around, we know who you are and you will be shut out. And so the whole internet is kind of a reveal. It's an open book in the sense that we know who's there. Why can't we fix that? Would Berners-Lee agree to that? Do we have to have all this freedom on the internet? Why can't we have a price of admission in terms of the identification through two-step verification, whatever you like, to make sure we know who's around? Attila, you've answered this. You completely dissolved my question when I asked it last time. Let's see if you can do that again. Well, you know, one thing about the internet is we do have the federal governments to thank for that. I mean, that came out of DARPA. It was the original ARPANET. And one thing about technology, which is important, is to remember that hindsight is 20-20. At the time, we don't know what's going to happen. When Bitcoin first came out, it was a joke. Who's laughing now? All the Bitcoin billionaires. Maybe they're not laughing as of recent months. But I'll tell you this, in general, things become adopted over time and they become the norm. That's from in hundreds of years. We're talking about the history of the automobile, the history of the internet, history of modern medicine, even GPS satellites, we forget. That technology has only been available to the public for 20 years. These are all relatively new things. And internet security is the same. Internet security 20 years ago was different. And even, I would even argue, five years ago was different. Pre-COVID was different. Now we have an entire workforce that is now used to working remotely. The technology isn't new, but it's improved over the past couple of years just because of COVID. And because of that, the attack surface has increased. We now need to take these things a little bit more seriously. We have all these great new flexibilities. I got to say, even two years ago, it was Disney Plus and Apple TV Plus didn't exist. Paramount Plus didn't exist. We have all these wonderful new innovations that are occurring, not just on the consumer side, but on the business side. And everyone, especially if you're doing business with the government in any way, shape, or form, you need to really take this seriously because the internet of a couple of years ago doesn't exist anymore. This is the new normal. And if you don't get on board, someone else who does will put you out of business. He did it again. He completely dissolved my question. But let me ask you, Gerhard, isn't there something that we can do? For example, Twitter can say, Donald Trump can't come on here. We're withdrawing his privileges, whatever it is. So why can't there be a policing mechanism that says, if you're going to do a nation state hacking cyber attacks, we're going to take away all the IP addresses that you could use. And we have the technology to identify you. You're toast, man. You're toast. Why can't we do that? And is it in your interest? And is it in Attila's interest to come up with that? Because you'd be pulling the rug out from under your own delves, wouldn't you? Yeah. I mean, if you're talking about cybersecurity employment, right? And I don't think there's going to be a shortage of that even if we were to put it in place because technology was meant to be broken and people will find their way around it and they'll get through it over and over and over again. So we can start from the very beginning, but that's a hypothetical thought, right? And the fact of the matter is it's the real world right now. This is what we're dealing with at this particular time, at this particular day. And I would love to go back and redo everything. Windows 95 should go away. But there's nothing that we can do to change the past. All we can do right now is really work hard to fortify the future and keep as much security and integrity within the companies and the government as possible. What is the future in terms of the technology of dealing with this bad technology? The technology of stopping it or at least limiting it and dealing with the bad guys. I mean, you say, well, okay, we're going to train these people to look for suspicious emails. That's not at a high level of technology. That's a low level of technology. We're getting way past that, right? I mean, you're looking at AI, artificial intelligence, deep machine learning and whatnot and getting that involved into the cybersecurity realm. You talk about putting me out of work. AI will put me out of work. I'm not worried about, there'll always be humans messing up, right? I'll always be the moment you get artificial intelligence involved, then cybersecurity starts to to look really, really dim for the practitioner.  I particularly like Michio Kaku on his ideas on artificial intelligence. So I don't think we'll be seeing any type of loss of jobs in the industry for the next maybe 67 years. So does the security. So does the different types of technology advances. We move into pre-COVID. Pre-COVID was more on the industry, more on the company, more on the data center, more on the hot, hot, the hot cold type data centers and disaster recovery and everything else. And then COVID hit and now all of a sudden the, I hate this term new norm, but the norm is everybody's remote. Everybody's working remote and technology had to balance itself out to accommodate that. And that opened up a lot of different vulnerabilities, a lot of different things that people weren't looking at before. And they had to focus on it. Yeah. And worry about it. I mean, clearly, we're in another time. Maybe COVID, you know, somehow accelerated that time. But here we are. And it's just another thing to worry about when you get up in the morning. That's why I think about the Margaritas. So Gerhard, you're closing advice to people and then Attila will have his closing advice to them. Get the basics down. If you're a business owner, get the basics down. Get your housekeeping in order. If you need a security professional, get yourself a VC. So if you're a small, medium company, that's a fractional C. So we provide the service if you need. And get the basics down. You'd be surprised how much you can button up in your company with the basics squared away. And then we can talk about the cream on the coffee and all that at a later point of view. So I think that would be my biggest advice. Understand what your business is doing it, doing it and get the basics down. Okay, Attila. You started this conversation. Let's see if you can provide some closing remarks on it. Yeah, absolutely. I mean, the basics that Gerhard mentions, that's a great place to start. And be kind to yourself. Many of the organizations we all come in contact with, no one's perfect. Back in the day, I remember in Think Tech, we used to meet in person. Now we have to do this imperfect Zoom thing. I mean, we're all just kind of doing best effort here on some of this stuff. But when it comes right down to it, every organization that we work with that exists, we also solve problems. So the bigger your problem that you're solving, the more at risk you are. If that problem is federal work, that's a big problem that has a lot of responsibility behind it. You got to do the basics and more and keep up with the trends. This is not a one-time thing. You don't take a shower just once and then you're finished. You take a shower more often. You brush your teeth more often. Cyber hygiene is a very real part of that. And it's going to be up to your organization to make sure that you keep up with it. And sometimes you don't have the time. Hey, guys, I don't have the time to change the oil in my car anymore. You probably don't have the time to change your technology and keep it up to date. The thing is, what I take from this is that, and this goes for our country and our society. It's everybody's job. At the end of the day, we're talking about national security. I mean, both on the economic level and on the security level. And you can't just bob it off to someone else. We're all part of it. We also take steps. We all have to be conscious. We all have to be part of the solution. Anyway, thank you, Matt. Thank you for telling us to rest. And Gair Hart, I guess that's right, Gair Hart-Rickert. Thank you very much for joining us. It's been a great discussion. I learned a lot and I appreciate you coming on. Thanks so much. And by the way, next time, we're going to get into the cream and the coffee. That was a very oblique reference, Gair Hart. We're not going to let you go on that. We have to understand what's in the cream. Like maybe they have chips in the cream. I'm only kidding. All right, we'll talk soon. Aloha. Stay safe. Thank you so much for watching Think Tech Hawaii. If you like what we do, please like us and click the subscribe button on YouTube and the follow button on Vimeo. You can also follow us on Facebook, Instagram, Twitter, and LinkedIn, and donate to us at thinktechhawaii.com. Mahalo.


Call all hands beat the quarters and buy this tablet battery one broadside into it if you please Captain Bush pointers on target Lin stocks ready Presenting Michael Redgrave as C.S. Forester's indomitable man of the sea Horatio Hornblower The story of the fabulous Horatio Hornblower wedded since early youth to Britain ships and Britain's destiny at sea Adventuring across the seven oceans as midshipmen as lieutenant as captain of the line Hornblower has seen the threatening shadow of Napoleon Bonaparte fall on half the world has himself Even been Napoleon's prisoner of war in France But now respite has come home again in England laden with honors Relieved from duty by his king ex-captain Hornblower can relax at last the year is 1812 When you've been many years at sea it sometimes seems a little difficult I might even say arduous to live ashore Especially when your lovely wife or adored recent bride rather expects you to become a country gentleman Well life is made up of change they say but for an old seadog new tricks come harder than for other breeds I think Well, there I was not long returned from confinement in France as the unwelcome guest of Bonaparte Granted a knighthood happily married to my enchanting lady Barbara free of all financial cares at last and yet and yet so Yes, I knew it for my fault, but Somehow there in the quiet English countryside. I hadn't quite come home as yet More bathwater sir. Oh heaven forbid it's mostly on the deck the floor already, isn't it? Tins of the size of a teapot fine way for a grown man to bathe himself. Yeah, all right. I've had enough give me that towel Ridiculous contrivance is give me a washdeck pump and gallons of cold seawater remember brown. Oh, I remember sir Aracia's belay that sir Aracia old terms are good enough aren't they you idiot? Yes, sir It's a lovely morning, sir. Is it? Yes, yes, I suppose so Still and quiet it's very quiet It's queer when I wake here. I still keep listening for the sounds rattle of blocks the cordage wheezing and Oh, never mind. I've laid out your new suit, sir. But you mean that tight buff color thing. It's a beautiful suit, sir I think I'll do you tight trousers fancy coat flowered waistcoat and a stock Oh, I'll never draw an easy breath in that confounded choker Well, let's get it on mustn't keep lady Barbara waiting downstairs for her breakfast I Welcome to the new Squire of Smallbridge laughing at me, you know perfectly well Barbara how I felt about that insufferable ceremony yesterday I do know my dear and you were sweet suffering it all without complaint Only the faintest glare of defiance now and then during the speechmaking Coffee dear. Thank you. Well, what we have planned today. I thought that you and I might drive across the downs this morning Of course you said you had a lot of reading you'd been putting off Gibbon was it well. Yes, sir Yes, I do want to get at that. It's a Yes quite soon in fact a letter for you, sir ratio. Oh, thank you Wiggins. The messenger is waiting my lord He's from the Admiralty in London the Admiralty Admiralty Darling it It couldn't be listen to this the Lord's commissioners request that I present myself at once a Matter of extreme importance, which cannot even be discussed except in Hey Wiggins, where's brown tell him to get out my best uniform and sword tell him to pack my things for the night And look tell him that you're going to London right away I love the letter says at once remember we're still at war with Bonaparte now off with you Wiggins Tell Brown I'll be upstairs immediately. I want him to drive me. We'll take the chariot I wished I didn't need to look at her just then after the first surprise she would try so hard to appear calm and and pleased that I was pleased I Hadn't been quite frank with her perhaps to be exact to the letter asked whether or not I would accept a new appointment. I Didn't know what to say to Barbara, but oh my dear. It's merely for the night. I'll be back in the morning Whatever this am I still yes for a day or so perhaps? Oh Just look at your brazen child excited as a midshipman. It's breaking over you in waves Do you suppose I don't see it? Oh my dear when well when the Admiralty itself Well, I must at least find out. I know what you'll find out wild horses couldn't hold you now, of course Do you know how long we've lived here at small bridge? Why? Two months two months tomorrow. I oh dearest I've always known Retirement simply isn't in your line It's a great honor to be recalled so soon You must be pleased and I am too if they If they appointed me a Commodore well, they might you know well well if they did I I might have to go back to see again Darling, we've been married six whole months a wonderful half-year I've had that much of happiness with you and Whatever happens you'll come back to me. I know you will of course.  I never understood the peculiar beast The Brown was good at everything best captains coxswain in the Navy and now the perfect man servant still Rather thought he mightn't mind going back to sea again There was a queer look in his eye Especially when we drew up before the Admiralty in Whitehall and I was ushered into the first Lord Sit down sit down captain or a show Well, well left your newfound domestic miss behind a when you received our letter Well, may I ask what it is you have in mind for me, sir? Of course you may The Baltic Horatio the Baltic is Russia coming into the water who knows I wish I did That very questions of the heart of this whole project Our letter did say didn't it that you'd take rank as Commodore with a captain under you You have six ships the nun such 74 a ship of four nun such I know her well, sir Both the Russians are and Prince Bernadotte of Sweden have teetered back and forth for months You know from all I've heard bony's making tempting offers to them both and Bernadotte's a Frenchman after all Is there really any chance that they might join us? They might if we handle them sensibly They have as much fear as we know bony's gobbled up most of the continent The dial be cast any day we think If we can show those Baltic power some British naval strength to count on I understand that at any rate We've got to keep the Baltic open for supplies So much that we need here comes by those sea lanes Well, are you ready? Is it settled? Yes, it's settled good. Now. Tell me who would you like for captain of the nuns? I'll do you I'd like to have Bush sir if he's available. I'd hate to go to sea without old Bush I rather thought you'd ask for him That wouldn't leg of his won't be a handicap. Oh, I think not sir You two have seen some things together. Haven't you first made as young left tenants on the over and now Well, then Bush it shall be now then let's walk across and see the foreign secretary. He's sure to have some secret orders for you Time had come to say goodbye to Barbara She drove with me from small bridge to deal jet it The nuns such and the five others of my pretty new squadron lay far offshore half lost in morning mist Brown was looking much too pleased. I had to take him down a little Stop moaning at those mast heads Brown go hire a Luggerman to take us out step lively not yes captain Commodore that is Winds veering Norrid a little West by north now, I think yes dear so you remarked as we were driving I beg your pardon You were telling me about my shirts. I interrupted you. No, I'd finished with the shirts What I was saying was that all your cold weather things are in the flat sea chest The sheeps can coat and heavy socks and mittens and oh Well brown understands He also hasn't his care a certain little package a surprise surprise with you After all I wouldn't try to surprise you. It's just a woolen neck scarf I've been knitting for you. It's likely to be cold up in the Baltic even now. Yes. I don't like cold I hope I do hope so much that you'll be back before the winter. So do I Both men's alongside sir if you're ready. Yes, Brian Well Now my dear you're going out by the ordinary Lugger. I could come too. He could bring me back No, no, that would be foolish. Look at that choppy seed be quite wet and cold Well, I may even be seasick in that nutshell sometimes. I'm you know, just at the start.  It's all my fault. I see it now. What have I done to our our sweet life together? I needn't have taken this Just think of the high compliment you'll pay by this command your ships are beautiful Yes, but there is to leave you now. Oh It was much too proud much too impulsive. I I should have told them that I'm Stayed at home you darling. Don't be absurd Brands in the boat with all your gear they're waiting you must go think of me Barbara I'll need you ask that you'll write me everything Everything won't you the bad things too, of course Goodbye Come back to me come back to me It touched me that you should say that come back to me like any witless wife of any common seamen If by some power of my own I could control French cannon shot You made my heart a tool that she should say such foolish things for all her pride and elegance a Little lager pitched and rolled a long trip all alone out to my ship. I Could have let her come along. It would have done no harm They'd seen me from the nuns such as we came tossing up the wind and laid into the big two-deckers Lee My old friend bush as captain had turned the whole crew out full dress And I was piped aboard with all the honors of a Commodore Ship and every man aboard was in a state of polish right brass work six side boys in white gloves the whole Marine Guard and their band double lane of Bosen's mates with pipes Childish display perhaps some say it is but though it has its Well exhilarations among There was old bush on the quarterdecks surrounded by his officers and all saluting stiffly I had to check myself or I might actually have been that that would have been ruinous to discipline So naturally I just stalked up the line and it's a loop Morning captain bush. Good morning, sir. Welcome aboard sometimes since we've met captain bush Bush was stiff and correct, but his craggy face kept softening up at me as if he wanted me to laugh This made it very difficult of course before the men your notes, sir that your penance going up Commodore's flag to designate your ship in the flotilla. Oh Indeed well captain bush We shall get underway at once if you don't mind no time to lose be good enough to signal the others of the squadron Hi, sir, very good. We sail on secret orders. I'll appraise you of their nature captain bush if you'll kindly dine with me this afternoon I I should be there sir. Thank you. Mr. Adams pass the word to our five other ships Underway at once and keep formation What bush I see who's scouting off to starboard sir. May I find your glass? Is it the sloops? No, no, no, it's nothing bush No, I was just trying to make out the jetty my wife's there Mist hasn't quite cleared yet Michael Redgrave returns as Horatio Hornblower and now continuing our story Michael Redgrave as Horatio Hornblower awaits his old friend captain bush in his Commodore's cabin aboard the flagship none such Captain bush will be dining with me here. Be sure the things come up hot from the galley, will you? Of course, sir I finished your unpacking. I trusted satisfactory, sir. I Place the gift from Lady Barbara there on the um falcare show. Yes, I saw it brown. Oh, it's a beautiful neck scarps A such fine soft wool. Yes, I was um to remind you to wear it sir cold morning. Yes. Yes.  So flattered that you'd asked for me Horatio. I Come and sit down. My dinner will be coming any minute. I'm glad to see you my old friend. Oh, well, let's go down to things of more importance Look, I've been studying my so-called secret orders and these charts were headed for the skagger act my friend I was inclined to think so sir then through the catagat and up the narrows The Danes will resist I suppose can't help themselves Napoleon's on their backs. And what about the Swedes? That's just what no one seems to know It's touch and go apparently with both the Swedes and Russians. We have to be prepared for anything Catagat sound is only three miles wide part of the way Sweden to port Denmark to starboard real skillet and Caribbean, huh? Well bush the powers that be of left decisions up to us and we are going to have to improvise Now once we're off Götterborg I'm going to try and pick up some fresh news on Swedish doings Well, let's hope that Bernadotte is leaning our way by then so yes bush. If not, we'll simply have to blast our way in somehow Up through the North Sea into the skagger act scarcely a sail sighted off our bows the whole first week Deserted waters even in the skagger act off Denmark Now and then we'd see a tiny fishing boat far off none within hail They had no news We strained our eyes for some revealing sign Had Bernadotte made up his mind by now were he and Russia enemies Neutral or even friends if handled sensibly Before sunrise I found bush on the quarter deck. Well, still no news Are we to run the gauntlet then we're nearing the Helsingboard narrows I wonder bush how many guns are on that Swedish shore Multitudes, sir. You may be sure the charts show a good dozen forts Shouldn't we send a boat in sir find out how Sweden stands last night? I thought so bush. It has its logic. I admit On the other hand a boat would surely advertise our presence But sir if both sides of the category to hostile we could dash in the moment There is light enough to see the channel surprise them and and perhaps get through even if Sweden does resist Yes Then if Sweden has joined Bonaparte Won't we be bottled up inside the Baltic? Well the Baltic is a sizable sea bush. I suspect we could maintain ourselves a while Still almost an hour till dawn and gives us time to clear our decks Yes, I think we'll go in bush this morning Very good, sir voice the yard arm lanterns signal all vessels clear for action if you please All hands to quarters. Mr. Adams clear for action pass the word All ships to clear for action We came into the narrow channel just as the dawn broke in a dollar gray mist To starboard hostile Denmark to port the riddle Sweden Was she our enemy? Well, we'd soon know at all events are the guns run out Captain Bush Hi, sir, and the fire pumps manned on every ship here is for it then What signal for hoisting to our other ships are the signal is proceed to lured in battle order Lotus shall lead Lotus she'll lead so did you say I did We'll bring up the rear bush naturally your face I Know I know it's disappointing not to lead, but we're the shepherd of this little flock We're the best built the lead ships might get through before those shore gunners wake up Wake already. Hmm. What sure fire that the Danes they seen us sir. Yes. There's the drifter smoke to starboard Is firing to starboard captain bush Yes, mr. Adams, so I gather by the way, did you know that those low cliffs are else in or where Hamlet walked I beg your pardon We've no time now for literary small talk. Have we signal to Lotus mr. Bush return the fire to starboard We'll keep exact station the star of the Harvey if you please I say Lotus and clam are giving back as good as they're getting They are they are bush bush this channel's full of souls. I remember that from years ago I remember too, sir. I've put ledsman in the chains. They'll sing out when we're reaching shallow water The sloops and the three others don't draw as much as well. Let me compliment you bush. You thought of everything. Well, Brown You're next car. Oh nonsense in the midst of an action.  It's very cold this early in the morning begging your pardon, sir. I had my orders you'll get below brown or all right All right, give me the scarf Yes, the air is a bit chilly We've else in or about the channel widened we were out of range from shore There'd be about an hour. I reckon before we reached the further narrows a longer gauntlet to be run And if it's end to Danish islands salt home and Amagan we had to pass between these close to both Full daylight now. They'd see us coming. We could no longer profit by surprise But anyhow all hands at breakfast and relaxed and waited as I knew for the real test An infernal din of guns broke out as we approached the channel The last starboard guns can speak together after all well done. I wasn't too sure about that it else nor a little ragged So far the Swedish guns had all stayed silent and as if to make up for that though the Danes were throwing in everything They had at us salt home and wider waters seemed a very long way off If I must have walking up and down well that wouldn't do indifference Commodore so I stood still looked about me casual in Six films are quite an plant they bush with the tide making I think so sir I wouldn't care to risk less than five though her just now Put another list one on the Port chains quickly adults look bush salt home and Amiga at last See them reeling up ahead there. Those grisling are be bound. Yes smoke bursting from Amiga already This tells the story doesn't it so tall is where they keep their power stored Shaving a show. That's certain. I hope Bush the Harvey's hit Oh men must on We're nearing those shows do Harvey's quite help is a Damnable luck bush. We'll be a long cider in a moment back the main tops Speaking jumping We'll bring this demand of all here then send men down for him Captain Bush What's that we hit to a mism top mask on That's better we must be bearing off the show Near here that one reaching as much to easily from salt home. I don't like it. Yes, sir short range Now that we're delayed look here those powder stores of theirs. Let's make a try for those They might line just beyond the highest fort. It seems fairly logical. Why not? But sir, how do we know where to? Aye aye sir, certainly. Mr. Adams has starboard batteries raised sites try for a hit beyond that big red fort say by Why 15 yards by 15 yards past the water Adams instantly Wild idea, I suppose bush, but we simply can't sit here till the Harvey is in tow It's too much like duck hunting with the nuns such as the duck Oh good sir, and the Harvey's got us trapped under those guns. They'll sink her any minute and ask with her Let's try another salvo bush 20 yards beyond the board this time Pass the word Adams 20 yards Even taken the fort with it at least they're single at this island I still don't quite believe my eyes Lucky guess in place of sound ballistics, eh? That makes no sense Well, hmm. Yeah to business now. Where's my trumpet? Mr. Smith, Mr. Smith, have you our lines? Are they secure ready to get out of here? Well, the cables coming over now. We'll take you out stand first understand Well, sir not a bad afternoon. Harvey's in tow Lotus took one poor hit We have a whole or two in our own shroud, but no ships lost. I Can't forget what we did to those powder stores on salt home. Yes, that was a satisfactory moment There's been no firing for a good 10 minutes. They can't quite reach us anymore We'll sail around false to vote clear of all batteries. I think I'm a bit tired Adams, uh, mr. Adams is mr. Mound been brought up yet. Yes, sir.  Yes. Thank you, sir We're taking him below the sick bay in a moment I'm proud of all my young officers today mind Not too uncomfortable. Oh, did all of us get through sir all our ships that we did What pleases me those Danish guns raked us with all they had but not one shell from Sweden's coast They're they're not against us yet at any rate Shivering atoms as cold as afternoon. Yeah, what this scarf around his neck and shoulders. I don't need it But sorry, he's bleeding at your spot. Oh, come on take it. Oh, well, then I'll do it myself That better man Yes, wonderful. Thank you. We held a fishing boat a few minutes ago Mound found out the Blanche Fleur passed through the border yesterday big French Corvette with at least 20 guns She must be just ahead of us You have to get well quickly mind Won't want to miss the fun, will you? Thank you Wiggins Why? Why it's from I thought so Milady. I'm very pleased for you my dearest wife I Found a means of sending this brief note to you by way of Sweden And I want you to know that all is well with us here in the Baltic On the whole we've had a remarkably quiet time few slightly sticky moments getting in The Danes on the shore showed a bit of ill temper, but There's very little to report that isn't merely ships routine My dear you're such a bare-faced liar, I'm sure But I do love you very much It is my hope that somehow I shall soon receive letters from England and know thereby that you well and happy I'm sure you will like hearing that Brown takes magnificent care of me Fastes over me far too much seems to think that in doing so he's following someone's orders. I can't think The weather is surprisingly fine. We'll be glad to know that it's quite warm. I haven't even needed the handsome scarf you needed lately But rest assured that all goes well with me. I Send you my whole My heart's of love starring Michael Redgrave is based on the novels by C.S. Forester The radio script was written by Philo Higley music composed and conducted by Sydney torch produced by Harry Ellen towers


Great. Thank you very much. So first of all, thank you very much for the invitation to speak. And even before starting, I actually did want to preface just by two things. One, clearly listening to the talks over the past two days, you guys really are data users of TCGA. I think you have to look at me more of a data abuser. Yeah. So that's kind of one way to take this into account. The other thing I'd like to say also in prefacing the talk is we're trying to use the TCGA data in a very different way from most of the presentations that we've spoken about. So clearly the problem that we focused on is ovarian and breast cancer. Clearly I'm showing here the number of cases, which all of you guys know, the number of cases, the number of deaths, prevalence in the population. And at Mount Sinai, what we've been doing really, focusing primarily on gyna on cancers, we've set up a whole bioinformatic platform and biorepository to take samples in as they come from the OR, directly bring them into the lab, start blood samples, start cell lines, start animal models, collectives, with the idea that really as we talk about patients, and clearly so many of the talks are geared this way, we really do think about at the time of patients' diagnosis, their original surgery, chemotherapy, their progression, their overall survival progression. But what I wanted to talk about today was not this paradigm, but really more this paradigm, thinking about risk genes. And so clearly, being a pediatrician, being a geneticist, my clinic thinks about risk much more frequently. And so what we wanted to do was really take a different approach using the families that we'd collected, I'll show you a couple of pedigrees, and a different approach in finding cancer susceptibility genes. And so really the rationale for the approach is family-based studies to identify ovarian and breast cancer susceptibility genes. So as most people will know, family history is the strongest single predictor of a woman's chance of developing breast and ovarian cancers. While BRCA 1-2 mutations still represent the strongest known genetic predictors, they really are responsible for less than 50% of all families. And I can tell you from the clinical side, the clinicians are faced with this every day where a patient comes in, know that they have a strong familial risk for developing myriad testing or whatever testing now will come back as negative, and these women are really faced with really loneliness and just a confusion what to do next, as is the physician. So any kind of a study that can identify other susceptibility genes would be a real help in the clinic. So again, really what I'm talking about is more of a patient-centric or family-centric bias. But from a gene discovery standpoint, things become more evident on the population level, which are not evident when viewed in isolation. And I say this again where having families are always a great way to start doing genetic studies, but the problem is then you have a single family and then determining whether or not you have a rare private allele, or is this something that's more prevalent or frequent in the population becomes a little tricky. So materials and methods. So to start these studies, we actually did this in collaboration with two groups, Dr. Lilian Jara, who gave us 70 families with three or more affected. She's from the University of Chile. We also included a number of families with male affected, and Kunlea Dunce from Rosswell Park, who gave us 72 families with more than 72 affected. As a preliminary test, we started by sequencing 21 exomes. We did this level of coverage, and then we went through all the data, again, looking for potential susceptibility genes. And here's a representative ovarian cancer family. This is family 311. You see that there are three affected women, the age of onset 48, 43, and 25, and these three individuals. They all have parents or grandparents. They're affecting their clue. They're all related. Here's a breast cancer family, again, with a number of individuals. These were actually screened by myriad as being a BRCA negative. These are other individuals in the family. So here's just the average coverage per base for BRCA 112, because, again, the idea that we started with is that we should be looking for families that are BRCA 112 wild type to look for other susceptibility genes. So we tested the BRCA coverage. Indeed, one of our families, which had been screened as negative, actually turned out to be positive. These are families that had males in them. And then to start the analysis, and this is where our collaboration with the gene pool, and there's a poster outside, poster 55, that describes some of this work. So you can see we took these three individuals, and as we did the sequencing and we did the analysis, we had a couple of filters that we wanted to apply that rationally made sense for gene discovery in families. So we looked at the number of variants in genes, and then the filters that we started applying to the data. And this is actually kind of nice. The gene pool allowed us to do this kind of alluvian filtering. So if we ever wanted to go backwards, say either the filter was too tight or it's something that we wanted to change, we could go back in position. So we removed all the variants with allele frequency of greater than 1%. We kept variants that had either a higher moderate impact. We kept variants that were present in all samples. In other words, all three individuals in this particular family had to have the same variants, if we believe it to be Mendelian trait. And then we kept genes containing only one variant. So in other words, if there was a particular gene that had seven variants in it, we excluded that from the analysis. And so from starting from a large number, we came down to a more reasonable number, but still too many genes for us to do any kind of a functional validation. And again, we're coming from a different perspective in the laboratory than having, you know, hundreds of samples to look at. So what we did, we actually then manually curated for the variants that were likely to validate, the ones that were unlikely to validate either by low coverage or where they were in the gene. And doing that, we then ended up with 24 candidate genes. So these genes were shared between all three individuals. All of them were validated by Sanger sequencing. So now we had a little bit of a problem, right? Because again, each of these were equally likely to be the susceptibility gene. And this is where I'm going to ask my first apology from you, other than hopefully going over time, which I won't do. But I cannot include the names here because it's being broadcast. I can't show the names, but what I would say to everyone here, please, if you stop by poster 55, I am more than happy to share the genes here, the candidate genes, because I think that's important, but I just can't show them on the slide here. But what we did in collaboration with the TCGA and Sendeepsanga from Station X was able to get the TCGA data for ovarian cancer. And what we asked was not the mutation frequency in the tumors, but the mutation frequency in the germ lines of these individuals. We had 240 samples that we could look at, and we split those by BRCA status. Again, using another filter, we essentially said which of those sample sets we believed to have a BRCA mutation, BRCA 1 or 2, which were wild type. And then the filter, the last filter we applied was, we looked at the fraction of samples in each of the individual gene candidates and the chance that they had mutations in them in the germ line. So again, the idea was, well, if you actually have a very high fraction of samples that have lots of mutations in them, again, it's probably not a highly conserved gene, whereas if you're on this end of this trimodal distribution, you're more likely to have a functional or something that's being preserved. And so we went from 24 candidates by using then the TCGA data down to eight candidates. Again, using the wild type or the BRCA wild type in these 160 samples, we could look at the number of samples that actually had mutations, the same mutations as in our family, family 311. So five of the genes of these eight genes actually had the same specific variant in the TCGA germ line data set. And these were present in about 1% to 2% of this population. Two of these, when we then looked at the 1,000 genome database, were actually increased, so the frequency was actually increased in TCGA with a p-value relatively low, 0.02. So again, if we had more samples, again, we could probably increase the confidence in that. So another parallel line of support was we went back to that list of 24 genes that we had here, and then we applied a functional impact of mutations. We used mutation assessor Boris Riva, who was one of the developers of the program, actually helped us look at all of our 24 genes, and independently of the TCGA data went through and tried to score the functional impact. So seven of the variants were assessed as functional. One of them had a switch of function, which is this one here, so this is actually the DNA binding domain. It changed the proline to a serine. Three of the genes actually had involvement in cancer. When we looked at the overlap of our eight genes by TCGA and the seven genes here, four of them actually overlapped and stayed together in the final analysis. So we then looked at the pancancer. We took all those 15 genes between the mutation assessor and the TCGA. We looked at the pancancer to look at the distribution of mutations there. We broke it down then into the ovarian cancer data, so we could see one of these genes actually had about 6%, which we think is too high looking at the function. Again, I'm more than happy to share the gene name and its function later. And a couple of these actually had some interesting distributions, 0% here just because it's below the threshold of 1%. That one gene that we showed here that has the three mutations, this is actually the gene here. These are the mutations that are found. It's also mutated in breast. Again, interesting that Brock had mutations in both breast and ovarian cancer. And this is another paper that actually had come out earlier in the year of February looking the same kind of analysis, taking the germline TCGA data from the ovarian cancer group and essentially going through functional filters and coming up with a couple of new candidates that kind of bundled into these functional pathway of significance. What's interesting, I think, is that our final list of candidates don't overlap at all with these. I think the value of having some families, informative families, can still lead to new gene identifications. Here, just quickly running through this New York breast cancer, we selected three of the women for sequencing. We did the same kind of flow-through using the gene pool software. We ended up with 22 genes. Again, we then sequenced six of the individuals here of those 22 genes. Six of six women have shared one gene. Five of six have shared the same mutation in five of the genes. Then there was a distribution, four, three, two, one. Again, given that this is breast cancer and the population prevalence is one in eight women, one in seven women will develop breast cancer. In their lifetimes, again, we assume that some of these, they could all be familial or they could even be familial and a sporadic form. What was interesting when we looked at one of the top candidates and we looked at its potential clinical significance in overall survival in breast cancer, if you actually take BRCA1 and you plot the overall survival, this is what the distribution looks like. If you take one of those candidate genes, again, more than happy to share that, we get a very similar survival curve from there. So again, it's not functional proof, but it is interesting that that happens. So in conclusion, we think we've identified a number of high-interest aid candidate ovarian and breast cancer susceptibility mutations in genes. And this was taken either through a personalized approach within families and between families. The use of the germline TCGA data allowed refinement of the candidate list and really now the next step is validation. And if you hear a little tremor in my voice, it really is one because the functional studies now are really going to take up a lot of time. And so, you know, one of the thoughts we had again is if there's anyone that's interested again in looking through more of the breast or the ovarian families, if there's additional data to share again, we're more than willing to share because if we can trim down that list of candidates, it'll allow us to do more of the functional studies, again, generating mice, generating animal models, generating these mutations in cell lines to try understanding the actual impact on the biology. So with that being said, the acknowledgments, I just wanted again to acknowledge all the families that participated in these studies, a number of individuals, Peter Dutino is my collaborator at Mount Sinai, Slav Kendall, who's the postdoc in the lab, and I guess in the TCGA, as you say, the manuscript committee, so I guess Slav is the manuscript committee by himself, Boris Riva, who looked at these with a mutation assessor, individuals here at Roswell Park in Chile, and also Sandeep Sanger from Station X, who helped design and modify the software so we could do these studies. With that being said, thank you very much for your attention. Have you looked at the mutation? Is there any SNP associated with specific mutation? Can you use GWAS to validate your finding that we're much faster? Yeah, so there are. So a couple of genes actually are rare. They do not have SNPs, so let's say the eight that we pulled out, I believe, three have no associated SNPs, the others, again, in a European and, you know, population less than 1 percent. Again, that was part of our filter, but... Okay. Do we have the next speaker? Chai Bandlamoudi. Okay, here we go. Okay, the next talk is discovery and functional characterization of our current gene fusions from primary tumor transcriptomes across 19 human cancers.


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G'day, welcome to Boot Lossophy, my channel reviewing boots and boot related things. And if we haven't met before, my name is Tech. I acknowledge the traditional custodians of the land that I live and work on in Perth, Western Australia, the Wajik people of Nungabuja. As you know, I like and have a lot of pairs of Chelsea boots and today, I'm taking a look at this one, the Blake Chelsea Boot in Mojave, Suede, from Huckbury's House Boot brand, Rhodes. This is a Chelsea boot, the name of the type of boot that doesn't have laces and that slip on by virtue of these elastic panels at the sides called goreng panels. The Chelsea boot may look modern and its name being coined by hip people following the Beatles and others in London's swinging 60s seem to indicate that it was invented in the 1960s in the Chelsea suburb of London. In fact, they were invented way back in 1837 by Queen Victoria's shoemaker, Mr J. Sparks Hall, who made a boot to meet the Queen's demand for a comfortable, easy to pull on walking boot that she could also ride in. His first iteration was more similar to a job per boot with buckles and it wasn't until Charles Goodyear invented the method of vulcanizing rubber just a few years later that Sparks Hall inserted the goreng panels and made it a true pull on boot. At the time Sparks Hall called it his patent elastic ankle boot and by 1900 it was a fashion item but horse riders then took it up and it increased popularity. As an aside the term Chelsea boot was actually coined earlier than in Queen Victoria's reign but it referred to a completely different looking boot and that term was forgotten until it came back as the popular name for this type of boot in the 1960s. Up until then they were simply called elastic sided boots or pull on riding boots but when the Beatles had their pairs made by a theatrical customer with pointy toes and Cuban heels they kicked up again in popularity. See what I did there? And the Chelsea boot was reborn. This version is called the Blake boot and has the characteristics no lace silhouette with wide goreng panels, two cloth pull tabs on a rubber wedge sole.  The others are made of a couple of panels and there are seams under the goreng. In this case this is made up of four pieces of leather. The vamp, the instep piece and two small rear quarters at the back.  It leans toward work boot Chelsea's but this is obviously not a work boot being made of a soft suede. The design in profile is pretty low volume and with a low toe box and from the top it looks roomy with an almond toe. In this light tan suede called Mojave it looks a relaxed casual boot for kicking around at home or out on social occasions or just generally doing your shopping and relaxing. Actually the colorway is called Mojave slash peach. I'm not sure why as it looks more Mojave desert to me than peach but there is a hint of peach flush in some lights. So that's a pointer to how you would style this boot. It is casual so casual occasions only, maybe stretching to a relaxed business casual if your office allows that. The color means it goes with all kinds of neutrals from blacks and blues to whites and earth tones. I think it looks great with a pair of faded black jeans, a relaxed button down and a waxed trucker jacket, this one also from Huckbury. You can wear it with denim jeans and a simple t-shirt and maybe layer with a leather bomber jacket for a simple relaxed look. In cool weather an Australian Rover's waxed cotton coat over dark brown moleskin trousers and a tan jumper would look good. Continuing the earth tones it would really go well with tan chinos and a light colored jumper over a button up with a contrasting dark blazer. Now let's take a look at the Rhodes brand and the owner Huckbury. Note that this pair was provided to me for review by Huckbury. Now that's not going to stop me telling you things I don't like about this boot but just note that they were supplied to me. Ok so Rhodes is Huckbury's house brand or footwear. I'll leave a link to the Huckbury website below where you can check out this boot as well as the other boots and shoes that Rhodes make. Now over the years Rhodes have made quite a few pairs of boot models. Early in my channel's beginnings I reviewed a pair of Rhodes Owen boots which I bought when my boot collection was below double digits. You can check out the review up here. The channel StrideWise has also reviewed their Dean boots. I'll put a link to that video down below. Now over the Covid years whether through dropping demand or production and maybe supply chain difficulties their range has dropped by a few models and while I see them come back on and off again they now have a reduced consistent range which includes this Blake boot. The others that are more consistently available are rancher or roper boots, a couple of chucker designs, a couple of service boots, a few shoes and another Chelsea design. Most of them sell for under 250 US dollars which looks good value. They are made in Leon, Mexico not in the US if that's important to you but Leon is recognized at least in North America as the leather and boot making capital of Mexico. The tanneries there are like Lafac supply to a number of good American brands and of course you recognize that Thursday boots use them and they are made in Leon. The brand owner Hutbury is an American men's outdoorsy clothing and gear retail website. The founders started the website in 2010 deciding to combine menswear in that outdoorsy format with all kinds of EDC gear, good service and create the feeling of a journal to gather and buy men's stuff. They sell clothing, footwear, watches, bags, EDC stuff, accessories like sunnies, scarves, gloves, even home goods all geared towards that manly outdoorsy aesthetic. Apart from their own house brands they also carry lots of other brands like Bellroy, Dana, Astorflex, Filson, Patagonia, New Balance, even Viberg. There is a pretty consistent sales page with ever changing items on sale worth a look of that style attracts you. Now let's turn to the construction of the Blake Chelsea boot. As usual I'll start at the bottom. This boot is 360 degree Goodyear welter. You can check out my Goodyear welting video up there. Basically it means that a strip called a welt usually leather goes all the way around the edge of the boot. On the inside the welt is sewn to the insole and the uppers and on the outside it's sewn through the welt and onto the midsole. In this case it's a leather welt and it's a storm welt meaning that it has a raised lip on the welt that gets pushed against the side of the uppers creating a water barrier. Goodyear welting itself is meant to be water resistant because the two stitches that hold the sole to the uppers are first on the inside and the other on the outside so no holes go through from outside to in. The storm welt adds to the water resistance. Not though resistant not waterproof. In time if you stood in water it will eventually get through and the suede is not waterproof. The contrasting stitching on the welt is pretty but it's not perfectly put together. You can see that where the stitching starts and ends there's a blob of thread quite evident. On the other hand the ends of the welt where it starts and ends are well scarved to fit and you can just feel the joint. The outsole is a rubber compound wedge sole made to look like raw rubber crepe. I haven't worn this a lot in bad weather but on wet concrete paving the grip has been pretty good. On smooth tiles however like wet bathroom tiles it's not great. The advantage over a raw rubber crepe sole is that this doesn't pick up as much dirt and hair and all kinds of crap but the disadvantage is that it's a little firmer so the shock absorption isn't as good. Not bad just not that soft raw rubber bounciness. Another disadvantage maybe that because it's firmer it may wear faster than raw rubber than what happens to grip I don't know. I'll have to wait and see. I'm not sure if there's a shank which is supposed to support your arches between your heel and the ball of your feet but being a wedge sole I'm not sure it needs one. If it doesn't have one and in my wearing of it so far I haven't felt my feet getting tired like on cheap shoes. The outsole is glued to the midsole which is sewn to the welt. Now it's quite hard to tell but I think this midsole is leatherboard because of the fibres that I can see in there. Fibre boards made from scraps of leather all cut up and chipped and then mixed with glue and pressed into a sheet. It's okay as a material certainly cheaper than solid leather but it may break up faster than real solid leather. So as in most leatherboard midsole when you re-sole the outside the midsole and therefore the welt may have to be replaced. Taking what up inside the boot it has a leather comfort insole that's lightly padded. From the feel apart from the padding on the underside of the comfort insole I'm thinking that it feels like it has a foam filler. In a good new welted boot the welt itself is about 5mm thick and it goes around the boot so it obviously creates like a well or cavity inside the circumference. The gold standard is to fill this with cork or leather but nowadays a lot of modern and even established boot makers will fill that cavity with foam or poron so that it feels more like a sneaker. The advantage of foam is that it's cheaper so you can buy a boot under a certain price and it feels immediately comfortable like a sneaker. The disadvantage is that it may break down in time and actually become less comfortable in time whereas cork or leather will shape itself to the shape of your feet as your weight presses down on it making it more comfortable all the time. If you had a pair of $700 vibergs I'd want the feeling to last a long time because the boot may last you a generation. With lower priced boots you may not worry about eventual comfort because by then you may decide not to re-sole the boot but just to move on. In the words of the economist John Maynard Keynes in the long run we're all dead. The inside of the boot is fully leather lined. Now it's interesting you can't see this but the lining is in pieces matching the pieces of the leather making up the uppers. Often it's one piece that gets sewn onto the assembled uppers but in this case it looks like as they cut each piece they also cut the lining and back each piece with lining before they sew it all together. Now nothing wrong with that except it may cause you some friction because of the seams inside the boot. I don't feel them but you may if you have sensitive or high volume insteps and ankles. The uppers are suede from Mexican tannery Alphamex. They're based in Leon and it has goal-rated certification which means it is audited against strict environmental standards. This is the Bentley suede which they tan with slightly tighter fiber structures to produce a smooth velour like feel in the nap. It has a really pleasant feel to it and with a nap not as long as say Stead's more treated suede it's probably a little better at getting scuffs and dirt on it. This is not a work boot don't get me wrong but beer spillage and stubbing your toe will add to the patina. The stitching of the panels is fine. There's no crazy loose stitching and they're pretty even. It's double stitched in most places except on the single piece backstay. Underneath the toe box is very lightly structured and by feel I'm guessing it's thermoplastic as is the light internal heel counter. The goring panels are stitched securely and the elastic used feels good and stretchy. The nylon textile pull tabs look like they're securely stitched on and I like the size of them. You can easily put your fingers through them. Being suede and this particularly short nap suede I've leaned toward not being too fastidious about keeping it totally clean. Personally with this type of suede that looks and maybe even feels like rough out I'd like to see it mark with use and gain patina that way. All I do I think is just brush it with a soft brush to brush off any sand or dust and then use a stiffer suede brush to knock the net back up the right way. However if you do want to keep it looking as untouched and new as possible do all the above but also clean it with the usual suede kit of suede rubber and brush to spot clean it and if you have to there are spray on and even brush on suede shampoos out there. But honestly I would not go crazy. Now to sizing. As with most American boots I recommend going down a half size from your true size as measured on a brand new device. If by some coincidence your brand size is the same size as your sneaker size then go a half down from your sneaker size but seriously I wouldn't rely on something as unreliable and go get yourself measured at a shoe store. Using myself as an example I measure a US 8.5 in D width. I usually buy boots in an 8. I take an 8 in Thursday boots, Redwing Iron Rangers and their Mock Toes, Grant Stone boots in the Leo and the Floyd last and the same in Truman boots, Ellen Edmonds, Wolverine and Olden. This pair is the same. It's an 8. Their sizes go from 8 to 13 with half sizes in between which is pretty good. However they don't have different widths so I guess if you have wider feet you may have to size up by half a size in other words you're going through the size. Best to check with Huckbury. This size 8 is the right size for me.  The volume is fine for me which is important in a Chelsea boot since you can't cinch up the laces. If I have a complaint in fit it's that the heel to throat is a little loose. The throat itself I find to be quite open.  In these I do feel a tendency to heel slip because the throat doesn't grip me tightly. Now I haven't broken these in by a long chalk. Having only worn them for about 5 or 6 days and usually I find I need a couple of weeks wear to totally break in the sole and welt and the flex points. You can see how stiff they are. I raise that because the heel slip may be caused by the stiffness of the sole and welt so that as I walk it doesn't flex enough yet and my heel lifts inside the boot. We'll see. Another thing about the open throat. Now I know this is a first world problem but if I'm wearing slim pants the hems of both legs will always catch on both the front and rear tabs. This sort of thing happens with many Chelsea boots on and off but in this case it happens all too often in slim pants. Comfort wise apart from the initial snugness and the heel slip, really nice. Underfoot it's well cushioned and shock absorption when I walk is really good. The leather is supple and soft and doesn't cause any hot spots other than that initial knuckle on my right foot. In fact the way it stretched quite quickly there leads me to think that this will break into an even better comfort factor. As to value, this is listed at $198 US dollars on the Hubberry website. In and of itself that's pretty good value. Apart from some artificial material it's good leather and rubber. The stitching and quality control look good. In this class they compare with Thursday's three models of Chelsea's which all sell for just about the same price. I don't have a pair of Thursday's Chelsea's but I do have five other pairs of their boots and the quality of this looks the same as those. I would not compare these with the higher end Chelsea's like Red Wing. Forget about Carmina and Aaron Williams. Totally different class. Don't compare a Korean hatchback as good as they are with an European sedan. In terms of durability in the long term I can't see anything that tells me these will fall apart but let's see after I've worn them for a year or so and I'll bring them back to you. Yeah I'd buy these as a pair of casual relaxed everyday Chelsea boots. In summary then I'd class these as a lower end but not cheap everyday easy pull on boot. If you lead a casual lifestyle with no pretensions these will be suitable for your boots that you keep by the door for when you go out to meet friends or go to the shops. They're well made and with good enough materials for the price and they look stylish. So there are some small issues with finish and fit but hey again therefore relax easy days and you're not looking for top of the range. Well I hope you liked my review. Go check them out for yourself and don't forget to click on the like below and if you haven't already please click on subscribe. It will really help me to grow my channel which means I get to earn some ad revenue which means I can afford to spend some time out of my day job to keep making these videos and to buy boots to review and bring them to you. Go for it click. Until the next time take care and I'll see you soon.