Hi, this is Simon from Lincolnshire in the UK, and you're watching Trucker Josh, so sit back, enjoy, and don't forget to subscribe. Good morning people of planet Earth. Wherever else you might be watching this, leave a comment if you're somewhere else. We're here in Calgary, Alberta. We're about to deliver this freight I got behind me. I got those, I don't know what they're called, they're like Mobile Generator Lights, Mobile, Mobile Generator Lights. Let's go take a look. I'll show you in just a sec. We're going to deliver them just down the road here, and then we're headed up to Edmonton, and we've got to wait until tomorrow at 1pm to load a big fuel tank that's going down to Bryan, Georgia. It's got to be there next Thursday, so I've got some time to stop at home on the way down. It's a four and a half day trip down from here. We're going to be leaving all of this wonderful snow and white stuff behind, and I have a feeling that around Bryan, Georgia, there may be some palm trees. Just saying. One can only hope, because in Bryan, Georgia is like a county, and I'm delivering it to a new Love's truck stop that's being built there. I thought I heard a phone ringing. Oh, that was weird. Is someone calling you, Diesel? It's going down to Bryan, Georgia, which is right by Savannah, Georgia anyways. Distractions. I'm like, scary. And I know Savannah, Georgia has palm trees. I've been there. It's not fallout of the truck. What's wrong with me this morning? Jeez. Yeah, we're here at the Flying J. This is all I got left on my trailer. These 10 Generac mobile lights, tower lights. That's all. Yeah. I'm going to deliver those just around the corner here and make our way up to Edmonton. We got lots of time, so. Down the street here. I went to that deer foot in casino yesterday when I got here in the evening for some supper. They have a nice, like a pub grill or whatever in there. I went in there and had some nice fish and chips. And while I was in there, I figured, well, whatever, I'll put a $20 bill in the slots there and like one of those really cheap machines works. You know, we'll lose a lot of money.  I won 100 bucks. Ha! Cashed out and walked out. Had my meal paid for. Everything. I walked out of there richer than I walked in. That's the way you do it. I'm not a big gambler at all.  I might, like I said, throw a 20 in there. See what happened? It's fun. But, uh, yeah, that worked out. Somewhere around here is my delivery point. Somewhere around here. What do I do here? Turn left? Okay, so I'll go around this corner here. This is an interesting way to build a road. Still makes more sense than anything in Winnipeg. The beaver trails down by my creek on the property, they make more sense than the roads in Winnipeg. I think it's this building on the left here. Yeah, that'll be it. There's some generators down the street there. He just said turn right into the yard. So on Google it looked like a kind of a tight space in there. Oh, and it's the gate is closed. You have arrived. Well, I can't block the whole road here. Why is the gate closed? Well, that literally took 10 minutes. So I'm back here at the Flying J. Came back here to grab a coffee and figure out what we're going to do for the rest of the day. Figure out my route where I'm going to stop. And we're going to go to the Flying J on Pembina Road in Sherwood Park, which is Edmonton. I don't know what's going on here, but this guy doesn't want to really move. He's right in the way. I have to give him a honk sometime soon. What are you doing, bud? What are you doing? What are you doing? Oh, he just about got the honk. He started moving just in time. Just in time. Park's right in the middle of the main thoroughfare of the parking lot. Right there. Who needs a parking spot? No one's parked here. Let's just park here. Pull the brakes. I don't know why people are honking at me. So I just put in winter and a freeze, or winter washer fluid, pardon me, into my truck here. Because yesterday I was driving through minus 23 at some points there in Celsius. And my windshield washer fluid was freezing. I used up the rest of that and put in winter stuff now. It's actually a really nice temperature here in Calgary right now. It's about, say, plus five Celsius, so probably around, I don't know, 40 Fahrenheit? Somewhere around there? Not too bad at all. Let's get out there. Let's get on the road. We have just over a three-hour drive up to Edmonton. We're going to do our walk once we get there. I want to make sure I get a parking spot at the Flying J. We're going to be arriving there around 3.30 or 4 o'clock whenever it depends on how many times we stop on the way up. So we should get a parking spot, but usually by 6 o'clock that whole parking lot's just packed. Just like this one was yesterday. Remember we got here at what? Quarter after 7? It was just packed at the park alongside the driveway. Alberta really needs some more truck stops. The ones they have are very nice. Don't get me wrong. Need a few more around Calgary and Edmonton. So we're just arriving in Edmonton now. Traffic is moving abnormally slow, in my opinion. All lanes. There's a couple of people way at the front. I can see them that are just driving 20 under the speed limit for no reason. All side by side. As they do. You know. It's a thing people do. For those of you who don't know, I guess I can let you know that if you're going slow, move to the right. If people want to pass you, move to the right. If you are passing other people, use the left lane and then return to the right lane after passing. How about that? In a situation like this, leave that left lane open for people who actually want to go faster than you. I know, right? It's a revolutionary thought for some people. I understand. I understand. It might be a lot to take in. Just got to take it in slow. Take a deep breath. Get out of the left lane. Drive side by side. One of my pet peeves. I'm trying to get back into that right lane there. There's someone beside me. One of my pet peeves of driving is when people drive the exact same speed limit as me and just sit right beside me.  I slow down to go behind them and they slow down. I know that they're not even realizing that they're doing it because they're just trying to keep up with traffic, but nothing more frustrating than that. Then you turn your signal on and then they just sit there. You know they can see your signal, but they just sit there. One of my pet peeves. So there you go. There you go. Some Trucker Josh knowledge and wisdom. Soak it up children. There's the sign. Welcome to Edmonton, Alberta's capital city. Is that their slogan? It's kind of a lame slogan. Southern city in Alberta. Their slogan is the New West or the heart of the New West. Calgary, the heart of the New West. It's a little different in Edmonton. It's Edmonton. This is our capital city, eh? Alberta's capital. So this is where government sits in Alberta. What am I supposed to go here? I've got to turn right? Can I keep left? What? Okay, so I've got to keep left? But then I've got to turn right. Okay Karen, don't lead me wrong here. I'm serious. It's just going to be three lanes. I want to get over to the right. Signal on. Nobody beside me checking on my mirrors. You never know. People are sneaky.  So I can't always see. If you don't have your headlights on, I can't even see if you're beside me. So here's another tip for you. This one's free. Karen, this is important. Don't interrupt me. This is important. This is important. Turn your lights on. There you go. That one's free. Turn your lights on. It doesn't matter if it's daytime. Always, always have your lights on because my mirrors are dirty now because of all the road dirt. If people are beside me and don't have their lights on, I have no idea that they're there. No idea. Keep to the left and then keep to the right. Okay. Gotcha, Karen. Better know what you're talking about because I didn't double check your work. I just trusted you. Well, it's a bad idea. I know, but I'm taking our relationship to the next level here. Next level of trust, Karen. Don't wreck it. In 300 meters, keep to the right on Highway 216 East Avenue, Hyundai Drive. Why am I stuck behind this guy? Speed limit's 80. Come on, buddy. What are you doing? Can't nobody beside me? I don't get paid by the hour. Okay, so we're going around to the east side of Edmonton where we're going to stop at the Flying J. We can hook into the internet, watch some Netflix. One kilometer, keep to the left on Highway 216 East. And have a shower. We're going to go for a walk as soon as we get there. Get that out of the way for the day. Make it good choices. It's my lane end. My lane ends, doesn't it? My lane ends. Am I getting this lane? Leaders, keep to the left on Highway 216 East. All the pumps are busy. And you know what? Every single one of these trucks that I see parked in here, none of them are even fueling except for this guy. So I came in behind this guy because he's obviously going to move first. The rest of these guys all just parked in the pumps and went inside. All of them. All of them diesel. You can already hear the comments today. You're doing a lot of whining today, Trucker Josh. A lot of whining. Yes, I'm whining. Today was a day that merited some whining. Ah, people. My show here on YouTube is partly about the whining. That's sort of part of the vlog. I like pointing out when people are maybe doing something that they don't even realize is not very courteous, is not very nice and is very selfish and very... Maybe they don't even realize it, you know?  Oh, I do that all the time. Maybe I should stop doing that. Yes, you should. Yes, you definitely should. But other than this, it's still been a good day. It's still been a good day. I'd just like to point out these things and complain about them because then, you know, a few people hear me every time. A few new people hear me every time that they didn't realize, oh, that's not the proper etiquette or that's not the proper way to do it. Okay, I'll do it different next time. There's always somebody, so that's who I'm talking to. That's who I do this for. So I just got away. This guy's just hanging up the pumps. That's a good sign. He's got a flat bed, so he's not going to need to fuel up his reefer. Oh, now he's going to wash his mirrors and windows after he was done fuel. Why didn't you do that while you were fueling? Yes, you are absolutely right, person in the comments typing away. Why does he complain so much? It's always complaining. His vlogs used to be so much better. Laning, Josh. Hi, Diesel. No, that's not what they sound like. I know, but... All right, buddy. Come on. Let's go. We're moving. Hallelujah.  There's no way you need to park there yet. Don't do it. Don't do it. You're going to do it. You're totally going to do it. Okay. All right, buddy, just don't take too long. I trust you. I'm trusting you. Don't block me in. I'm going to go fuel and then find a parking spot. Nice Kenworth off to the left there. Lowered everything? Oh, that's nice. I want that with a studio sleeper. So there's something positive. I don't complain about everything. That is a beautiful truck. I handle compliments too every now and then. Nice trailer too. You just need to wash it. Okay, let's see if we can find a parking spot here. Is this one right up front here? Is this a handicap spot? I think it is. I'm not going to take it just in case. It's handicap parking only. Yeah. Okay. That's why nobody's parked there. It's got a blue square on it. Okay. All right, let's go see what's available for the Trucker Josh and the Weasel. I see one over there. It's a nice spot. Okay. I like to be in a spot where I can just drive straight out the driveway in the morning. And that way, you know that the people who back in beside you will have quite an easy time. So they're not going to hit you. There we go. Wait in the back. How about that? How about that? Is she like straight ahead there? That's a perfect spot. You just, you never know who your neighbors are going to be though. Don't want to park beside that guy. That guy's got to reefer this. Man, that Volvo's been there a while.  Oh, is that corner spot open? No way. Is it open? It's open? No way. Oh, sweet. I'm taking it. I'm taking it. It's mine. Dibs. Dibs backing in. Sweet. I know, right? I'm excited too.  Look at this. No neighbors over here. No neighbors over there. A bobtail in that spot there, which shouldn't be there. You can see it in the mirror, right? Dilo, can you move your head? Can you move your head? There you go. There's a bobtail in beside me there, which has been parked there for weeks by the looks of it. Not very nice, but at least we won't have any neighbors there, right, Diesel? And those of you asking me about my poppy. There it is, right there. It's there all year round. 365 days a year. Remember and stay.  So, yes, this is where we're going to spend the night. Sometimes I don't always like being in the back corner like this because I'm worried someone's going to come and steal my fuel. But I noticed that there's a big light right above my truck. You're shining down on my truck. So as long as that light works, we'll be nicely lit. Hopefully no one steals our fuel. I need to get locking fuel caps. Keep forgetting, but those are important. There are douchebags out there who will come and steal your fuel at night because they're cheap, they're mean, they're evil, and they're bad. But hey, bad people exist in this world, right? That's why we have to try to be good people because if the good people don't do anything, then the bad people automatically win. Isn't that how the saying goes? All that it takes for evil to triumph is for good men to do nothing. So you just got to try to be that good person. I'm not tired at all. So it's 3.30 p.m. here. Still got a lot of caffeine in my system. My blood pressure was really good this morning, by the way, speaking of caffeine, and really good last night as well. It was something like 119 over 74 this morning and 118 over 78 last night. So it was actually really good. So I don't know what was causing my high blood pressure, but we got to keep monitoring it. I have an appointment next month, early next month, to get my family doctor, my doctor, to give me a full lookover. I got to get a full physical, full checkup. Fun stuff. Oh no, somebody's idling with an engine fan. Is that you? Oh no, no, no, no. It's that international down over there, I think. This guy, this guy here's not idling. That international down there. Just so you guys know, here's a little tip from a guy who's been trucking for more than 10 years. When you park at a truck stop, if you want a quiet night, don't park beside an idling international or an idling Peterbilt. Because their engine fan kicks on every three minutes. And for some reason, internationals and Peterbilt's have very, very obnoxiously loud engine fans. So you have this like, whoo, kick on for one minute or so every three minutes. Drives a person insane who's just trying to sleep. I'm a little picky when I want to sleep. You guys know this, you know me. I want a quiet night. That's why we park back here where we have no neighbors. Perfect. And I can walk the weasel right here. And hey, if this was summertime, I could even go for a dip and swim in there. I wouldn't recommend that. I've never actually done that and I wouldn't, but hey, there's a pond right next to me. So thanks for watching today. Thanks for listening to me complain. Thanks for all the comments talking about me complaining. I appreciate it. Thanks for all you complainers out there who are going to start complaining about me complaining. Hey, we can all complain together. We'll have a little complaining circle back and forth. So go down below, leave me a comment. Let me know what you think. Give me a thumbs up if you liked the vlog. If you hated the vlog, give it a thumbs down. If you liked it, share it with your friends so they can enjoy it too. If you hated it, share it with your friends so that they can see how terrible it was as well. Spread the word either way. I'll see you guys tomorrow. Tomorrow we pick up that tank that's headed to Georgia.


Beautiful day for some baseball as Brainerd hosted Fergus Falls. McHale Peterson with the single they would pile it on early and get up 5 to nothing later. Peterson on the mound, trying to keep the shutout rolling. Runner on 3rd gets the grounder. He needed to get out of the inning alive. Brainer bats cooking all game long. Max Boren swings for a single into right and in the third of pair of runs come home for the Warriors. They would go up and win 7 to excuse me. They would go up 7 to nothing. Eventually take it 9 to nothing. However, a different story in game too. As they would fall 7 to 6 to Fergus Falls. If you enjoyed this segment of Lakeland news, please consider making a tax deductible contribution to Lakeland PBS.


Good morning and welcome. There's still a few seats left in the back, so please help yourself. My name is Mark Pigram. I'm the newest kid on the block, arguably, on the faculty. I joined Stanford about three months ago now in the oncology division, and I'm the new director of the breast oncology program, so it's really a treat to be able to meet with you this morning and give you a little bit of an update. I have kind of a hard act to follow after Ron Johnson, and I'm not quite in the same vein as him in terms of speaking style. I asked my wife this morning, I said, I'm not sure what I should wear. Maybe I should wear a black turtleneck and blue jeans, and she said, you don't have a black turtleneck. Then I said, well, I should probably wear a hoodie. And she said, well, you have a hoodie, but it says UCLA on it. Maybe you better not wear that, because I was on the faculty at UCLA for many years back in the day. So we're here to talk about breast cancer, and I know not all of you have an oncology background, so I'm going to keep this fairly basic, and then we'll have time for Q&A and discussion at the end. But we have a small group here, so if you have anything that's on your mind during the presentation, I have no problem at all for you to chime in. This is being taped, and so we will pass around a mic for you, so just wait for the mic if you want to raise a point anywhere along the way. Please feel free. This is entirely informal. So I'm going to talk about some genomic applications that have been applied recently to breast cancer in terms of new molecular diagnostics and how those have led to new therapeutic opportunities and what the future might hold for new diagnostics and therapies in breast cancer based on a fundamental understanding of the molecular biology of breast cancer. So as I hope most of you know, cancer is a disease of the genes. It's a disease of acquired genetic mutations. Now some of these mutations can be inherited in a familial fashion, so there are some family cancer syndromes. You all are probably aware of familial breast cancers and ovarian cancers, etc. So sometimes you can be unlucky to inherit a genetic predisposition, but most of the time the mutations that occur that give rise to the most common types of breast cancer are acquired mutations that happen during your lifetime, probably as a result of exposure to environmental carcinogens, to ionizing radiation in the background, whatever. But these are acquired events that happen during normal cell division. And so this is a so-called chromosome painting experiment. The technical term is a spectral karyotype. These are all the normal human chromosomes that all of us have in every single cell in our body. And the chromosomes are where the DNA reside, and that is the instructions given out to all cells, programming those cells into some physiologic function or another that they must execute for us all to stay healthy. So you can see that there are pairs of chromosomes, they're highly organized, very tidy indeed, very efficient packaging for all of the genomic information. But what happens in cancer? In cancer the genome is highly disorganized as a result of all these mutations. You can see that in some cases some chromosomes are missing altogether. In other instances there are too many copies of the chromosomes due to duplication of whole chromosomes. In many cases there are rearrangements of the chromosomes where the chromosomes simply are scrambled one with another, and this puts genes into new environments, into contexts that they are not normally supposed to reside, and that can cause the expression of those genes to go crazy. And this can lead to abnormal cell growth and give rise to a tumor. So highly disorganized, highly mutated genomes are the rule in breast cancers as well as other tumor types indeed. So it's this accumulation of genetic alterations that give rise to cancers. At first maybe there are only a few mutations that occur and that can give rise to areas of abnormal tissue called hyperplasia or dysplasia. These are just abnormal growths, abnormal collections of cells, but they're not full cancers yet. These are just pre-malignant conditions. And then you can actually get to a situation where the cells in these collections can sometimes resemble a cancer and they're actually called a carcinoma because they look so much like tumor cells under the microscope, but they don't have the ability to invade. So this is a pre-cancerous condition. In breast cancer this is called ductal carcinoma in situ. And these are actually readily cured, usually with surgery and or surgery plus radiation alone. Just a simple lumpectomy often is all that's needed to cure this condition because it's incapable of spreading. It doesn't invade into the normal surrounding tissues yet. And with the advent of imaging tools, this is the ideal. If we could catch lesions early, then we could prevent them from evolving into a full-blown cancer. And with new technologies of detection, more and more we're finding smaller and smaller lesions, many of which are now in the pre-malignant stages. One of the pluses of mammography, for example, is a stage migration to these earlier stages, which are much more amenable to successful treatments and far superior outcomes long term. So this is one of the advantages of early detection. Now with enough genetic alterations, you can reach a stage where these tumor cells acquire a capacity to invade into normal adjacent tissues and they can gain access to vascular channels. They can actually break into the bloodstream where they can move around to other parts of the body and set up shop and other vital organs. And that's what at the end of the day really causes the damage in cancers is its ability to spread. It's called metastasis. And that's the deadly form of the disease, actually. These cancer cells can also gain access to the lymph channels as well as the bloodstream. So both types of channels can be invaded by the growing and invading tumor.  So there are hallmarks of a cancer phenotype that occur along the way as a result of this accumulation of more and more genetic mutations. And one of the things that happens early on is an ability to proliferate more rapidly than normal. That's a hallmark of cancer.  That's how it's supposed to happen. But cancers can pick up a phenotype where they forget to senesce and die. The term is called programmed cell death. That's a normal physiologic function that all cells are supposed to go through. But cancers can evade programmed cell death. The Greek term for that is apoptosis. I think it's great, I didn't study Greeks, I don't know. But there's also a phenotype of insensitivity to normal anti-growth signals that keep cells in check and keep them from accumulating aberrantly. So cancers can pick up this phenotype. Cancers can actually recruit new blood vessels because for a tumor to grow beyond about two millimeters, it has to acquire a brand new blood supply to deliver oxygen and nutrients. So really, you must think of cancer really as a true organ. It has lots of normal cells mixed in with it. Blood vessel cells, blood cells, immune cells, support cells like fibroblasts. It's a collection of a variety of cell types. It's not just the cancer. A tumor is very complex, very heterogeneous. It's an intermingling of many normal cell types mixed in with the abnormal cells altogether, acting truly as an organ with its own blood supply. Then there's this limitless potential for cell division where these cells live beyond their normal lifespan and they have limitless potential for replication. Stem cells are like this. Then tissue invasion and metastasis is the hallmark of cancer. So these hallmarks have been cataloged in the literature and in textbooks. These half dozen or so phenotypes are the clinical hallmarks of all human cancers. If you think about it, each of these processes is an opportunity for development of new diagnostics, also an opportunity for development of new therapeutics. For example, if we can block the ability of tumors to recruit a new blood supply, then we can have successful anti-angiogenic therapies, and that in fact is the case. We do have drugs that are used for other cancers that do just that. There are drugs that block growth factor signaling. I'll show you an example of that in just a minute. There are drugs that can block invasion and metastasis, for example. Each of these is really a paradigm for diagnosis as well as treatment in the future. Next, I'd like to talk about some technology that was pioneered here at Stanford and is now in all the textbooks in breast cancer. You can take a tumor in the laboratory that's been frozen in liquid nitrogen usually, and you can grind up that tumor and you can extract the DNA and the RNA out of that tumor and then analyze it. And in this fashion, you can measure which genes are turned on and which genes are turned off in the whole genome in a single experiment using a gene chip that has a representation for each gene on the chip. And by assigning different colors for relative abundance of the expression of genes, you can actually get a molecular portrait of all the genes that are turned on and all the genes that are turned off in a particular patient's tumor. Now, for an analysis of a particular spot on this array, remember I told you that tumors are highly heterogeneous. They're admixtures of normal cells mixed with tumor cells, and so there can be dilutional artifacts because of all the normal cells in there that will have normal expression of genes. And so a particular spot on this array may not be incredibly accurate because of this dilutional artifact, but it's really not the specific gene that is important for this technology. It's the overall pattern that's important. So as long as we capture the pattern faithfully, we can do so whether we have precision on any one gene or not, and that's still okay. Let me show you an example for that. Here's an example where the pixels are not truly faithful. So each one of these pixels is not particularly accurate. Nevertheless, we can still get a glimpse of what the overall picture is, and this is me enjoying the Grand Canyon on my summer vacation. So this gene chip microwave technology can do the same thing by looking at expression of gene patterns throughout the whole genome in a single experiment, and you can do this on each individual patient's tumor, readily, in the laboratory. And so in published data from laboratories here at Stanford, we had for the first time the molecular portrait of human breast cancer. And this was incredibly revealing because it revealed that there are approximately five intrinsic subtypes of breast cancer. This is not just one disease. Until this time, we had just sort of treated all breast cancers the same, because under the microscope and in the clinic and on the mammograms, they resemble each other and they start in the breast, so we call them breast cancer. But we knew, based on history, that certain tumors behave differently from one individual to the next. Some patients relapse, some patients are cured. Why is that? Well, it turns out that there are intrinsic molecular subtypes that were identified here at Stanford that can distinguish one type of breast cancer from another. For example, these types, called Lumil-A, are almost always estrogen receptor positive. In fact, this first branch point in this analysis is basically taking all the ER estrogen receptor positive genes and putting them next to each other because they resemble each other, and then all the estrogen receptor negative tumors actually cluster together when you analyze these expression patterns. And so these Lumil-A tumors typically will respond to anti-estrogen treatments like tamoxifen, for example. This group of tumors here in pink have amplification of an oncogene called HER2, human epidermal growth factor receptor number two. And there is a treatment for that called Herceptin that can vastly improve the outcome of patients with this subtype. And now we're working in the laboratory to identify new therapeutic targets in these other intrinsic subtypes. And as I mentioned, these subtypes did correlate with long-term clinical outcome, with some subtypes having a particularly poor prognosis. This is the relapse over time, and lower is worse. Here are the Lumil-A's. They tend to fare better in terms of molecular subtypes. So these phenotypes are biologically and clinically relevant because they can track prognosis and they can suggest and inform therapeutic decisions because of the targets that are known to be expressed in some of these subtypes. And it provides an opportunity to discover new targets in these unmet needs for other tumor types for which we do not yet have targeted therapeutics. And so that's a very intense focus for our research now at Stanford. Now I told you that these chips, these spots on the chips are not particularly faithful or accurate in terms of their gene expression on an individual experimental run. But there are other technologies that can actually make it incredibly precise and actually quantitative. And it turns out that you probably don't need to measure all 20,000 human genes in order to get these patterns into a useful format that can be applied clinically. In fact, our colleagues at Genomic Health Institute nearby here in the Bay Area, they have developed a panel of 21 genes and they use a technology called PCR, which is more precise than these chip approaches. And they can precisely measure the expression of several genes that are involved in uncontrolled proliferation, several genes that are known to be influenced by estrogen receptor expression, genes that are responsible for invasion. Here's that oncogene that I mentioned called the HER2 gene and associated genes. There's a suite of reference genes that are provided as internal controls. And then a few other genes that are associated with prognosis and breast cancer from the literature. And you can quantitate these and give them a score and give them weighting factors and an algorithm and you can come up with a quantitative measure of risk of recurrence. It's called the recurrence score. And if the recurrence score is low, then they have a low probability of having a relapse event in the next 10 years. There's an intermediate zone and then a high risk that we think especially are needy in terms of treatment. So this has been applied not only for prognosis, but also for prediction of response to therapy. In particular, response to chemotherapy. Back in the day when we didn't have this understanding of intrinsic subtypes and how diverse and unique each breast tumor is, we used to treat them all the same. If tumors grew beyond a certain size, we recommended chemo to all those patients in the 90s and the early 2000s. It didn't matter because we weren't sophisticated enough to understand who really needs chemo and who didn't. We didn't want to miss the opportunity for somebody to get an advantage. We didn't want to miss the opportunity for somebody to treat with chemo back in those days. And what the NCI in collaboration with Genomic Health found looking at large historical data sets is that if you have a low risk recurrence score and you randomize patients to receive chemo or not, it didn't really matter. These are statistical p-values and for a p-value to be significant in a biological or medical field, this is much greater than .05. So these differences are not significant. You can see that these survival curves are overlapping one another. So this suggests that chemo does not work in patients with a low risk recurrence score. What about high risk? And high risk recurrence scores, if the patients don't receive chemo, they have a poor outcome. Only about a 60% chance of this is a distant relapse-free survival. So that's the absence of metastasis. Only about 60% of patients in this study had the absence of spread of their cancer after a decade later. Whereas if they got chemotherapy, they had nearly a 90% chance of being free of distant metastatic relapse 10 years later. So this is very powerful technology. It can discriminate who needs chemotherapy from those who don't need chemotherapy. That's a huge advance. So this has been applied now routinely since about 2004. And here's data from University of Pennsylvania. And this has been mimicked in clinics all over the country, mine included. In the pre-oncotype era, that's the recurrence score trademark, oncotype DX. Before that, back in the early 2000s, chemo was given to about 40% of newly diagnosed breast cancers presenting with early stage, usually stage one or stage two. So it hasn't spread to other parts of the body, for example, those early cases. But chemo was still given to about 40% of those patients back in the early 2000s and 80s and 90s. Within a year or so, after the advent of this technology and its commercialization and availability nationally and even globally, the use of chemotherapy was cut virtually in half at this institution. And it's similar data across the globe at this point. So this is a huge advance, eliminating unnecessary toxic chemotherapy. And it's based on a molecular understanding of the molecular portraits of different subtypes of breast cancer. Extremely important advance practice changing indeed. So this is just the likelihood of recommending by the oncologist. It fell from 56% to 26%. Obviously, even though the oncologist recommended it, 56% of the time, only about 40% of the subjects had something right there. They knew that there was a propensity for overtreatment even back in those days. So an important advance. Now, this whole cell growth and senescence and cell death paradigm is highly regulated in normal physiological circumstances. In order for something to be that fine-tuned, it has to function as a network. And here's just an example of a schematic that was created by cell biologists. Showing the normal physiological circumstance of signaling receptors. There are ligands. An example of a receptor would be insulin receptor. And an example of a ligand would be insulin itself, for example. So there are a number of receptor families. This is the human epidermal growth factor receptor family, which is important in a variety of cancers. EGF receptor, the parent of this family, is very important in lung cancer. For example, HER2 is very important in a subset of breast cancers, as I mentioned. HER4 may be mutated in melanomas, for example. So this is just one example of one signaling receptor family. And you can see all of these downstream signaling intermediates in the circuit in a highly regulated and coordinated network. So this is how cells are supposed to function. This is the normal physiological circumstance in normal breast cells. This is what happens every day. Now, what do you suppose would happen to this network if all of a sudden there were an accumulation of genetic mutations for the genes that control all of these network signaling intermediates? The network would likely become deranged and look something more like this, I would argue. This I snapped on another vacation in Ho Chi Minh City a couple summers ago. So this is a deranged network, but it is highly functional. It gets the job done, however disorganized. And cancers are just like this. They're highly disorganized, but they still are dangerous because they're still highly functional. But I will argue that even though this is a highly functional network, it points out a vulnerability that we could potentially exploit. For example, what do you suppose would happen if you chopped down this telephone pole? The power would go out in probably half of South Vietnam. I mean, you've seen those things even in North America, the blackouts on the East Coast because somebody hit a telephone pole in Ohio or something. So this is a vulnerability. And if we could identify the telephone poles in cancer cells, we might really have something. And we've done that. And one example would be the estrogen receptor. That is something that works.  We treat them with anti-estrogen drugs and their tumors can melt away. It really works. HER2 is another example. You can treat a HER2-positive patient with herceptin and other treatments in some of those cases. That will bring down the network. So HER2 would be another example of another telephone pole. So now the mission in research is to find more of these common nodes in an otherwise disorganized network so that we can bring the house down in breast cancer. That's the goal. So I've talked a lot about HER2. This is what a lot of my research has been focused on since the early 90s. Here's a mutation where you can actually see the HER2 genes using a colorometric probe. This is a fluorescent probe that binds directly to the HER2 gene. And this type of a mutation in these HER2-altered breast cancers are an example of what's called gene amplification. Normally you have two copies of every gene in your gene, one from your father, one from your mother. That's the normal situation. You should have just two. But in these tumor cells, during cell division, instead of making just two copies of the HER2 gene, it's like a Xerox machine getting stuck in the on position. It made bunches of HER2 genes by mistake. This is a mutation, a gene amplification mutation. And so there can be 20 or 30 or even 50 copies of the HER2 gene. And if there's too much of the HER2 gene, it'll make too much of the signaling receptor. And the receptor will become aberrantly activated. It's always turned on. And this is a growth factor that signals the cells to grow in an uncontrolled fashion. Here's an experiment we did in the laboratory when I was at UCLA. These are normal cells that lack over expression of the HER2 oncogene. And you can see a few little colonies here in this colony count assay growing in some soft auger. But if you introduce this gene and over express it to the same degree as you see in clinical tumor samples with HER2 gene amplification, you can see a marked increase in tumor growth. And you can even see depletion of nutrients in this Petri dish, because this pink color here is a reflection of the pH in the soft auger. And you can see that it's being bleached here because these cells are growing so fast they're depleting the nutrients and altering the pH in these dishes. So this is a striking change as a result of an accumulated alteration due to a mutational event. And this happens in about 20% of all breast cancers globally. And so we identified this as a target. This would be a target for both diagnostics and also a target for therapeutics because if we could interrupt this process perhaps we could have a successful therapeutic intervention. And that in fact has been the case. Here's an experiment in a large study involving thousands of patients that were randomized to conventional chemotherapy. These are the initials of the various chemotherapy drugs. I'm not going to bore you with the details of the names. If you treated patients with newly diagnosed early-stage breast cancer that had not yet spread to any other organs you can see that over time these patients still had relapses and had a relatively poor prognosis in the absence of HER2 targeted therapy. But if you added a drug that blocks this aberrant HER2 signaling in this case Herceptin, the generic name is Trastuzumab for those of you who are aficionados and generic nomenclature. This made a vast impact on the probability of a recurrence of the cancer. These patients had far fewer relapse events. In fact the event rate was cut about in half. This is called a hazard ratio and it's the fraction of patients who have not yet had a relapse event. So it was cut nearly in half by simply adding Herceptin to the standard treatment recipe. And if you looked at their overall survival over time the hazard ratio for the overall survival is 0.67.  And here I told you earlier about P-values here's a P-value that's significantly less than 0.05. So these are highly statistically significant results. And this was practice changing. This was published in the New England Journal of Medicine and is now the standard of care for treatment of HER2 positive breast cancer globally everywhere. So one of the next projects that I took on in the lab is a project that was to build on this concept of mixing Herceptin with chemo. The problem with Herceptin mixed with chemo is that the patients that are treated with chemo still all have the side effects of chemo. Upset stomach, hair loss, low blood counts, infections. Many of you are aware of the common side effects of chemo. And those are very troublesome. Some in fact can even be dangerous. So this is not ideal still. And we wondered is there some way that we could exploit the ability to target this receptor with Herceptin and get rid of the chemo side effects. And so one idea that we had was instead of just giving the chemo separately and giving the Herceptin separately, we thought what if we actually chemically bound the chemo directly to the Herceptin drug itself. This Y-shaped glob here is actually Herceptin. It's an antibody protein. It's a protein that normally is part of the immune system that fights infections. And we simply redirected it so that it could bind to her, too. So in this case, we're using Herceptin not as necessarily a way to block signaling, but we're using it as a vehicle to merely deliver a toxic payload by chemically linking the chemo directly onto the Herceptin molecule. So when this reaches the tumor, in theory, hopefully the chemotherapy would become freed up through some chemistry that happens in the hostile environment within tumors. And as the Herceptin binds to the target, hopefully the chemotherapy will be liberated and that will specifically attack the tumor. And then the chemo isn't spread around the rest of the body. That was the idea. And so we tested this in experimental systems. And here are some of the results. Here's a control human, her too positive breast tumor that's untreated, essentially. They got some control vehicle solutions. Here is chemo and Herceptin given separately, the old-fashioned way, in the maximum tolerated dose of these drugs. And you can see it's effective. It reduces the tumor burden by at least half. So quite effective. Well, here's this so-called antibody drug conjugate where we directly coupled the chemo onto the Herceptin. But this had similar activity to the free chemo and the free Herceptin, but it only one-tenth the dose. So at one-tenth the dose, we got all of the effectiveness. And at one-tenth the dose, you have only one-tenth the toxicity. Now, the problem with this project was that it was in collaboration with a small biotech company at Atlanta. And this particular molecule, the first one that we published, this was the first publication of this concept in literature back in the early 2000s, this molecule did not survive the so-called valley of death due to lack of funding. We couldn't get this into human trials because to do that, you have to satisfy all the federal regulatory authorities to do all the manufacturing products, stability testing, purity, non-clinical toxicology and pharmacology testing. All that stuff is expensive and it's not covered typically in NIH grants. They don't fund that kind of work. They expect industry to do it. So this little biotech company didn't survive. But there's another larger biotech company here in South San Francisco that had deeper pockets than we had. And so they did the same thing, borrowing on the same idea. They coupled a different chemo than the one that we published. And they picked one that's even more toxic than the one we were working with. They picked one called metansin, which is a very potent toxic species. It's so toxic you can't even give it as a free agent. It was tried and it's not tolerable. And here's Herceptin again. They coupled it directly to Herceptin. It binds to the HER2 receptor on the cell surface. This is the surface of a cancer cell. This is the HER2 receptor. And it's actually drawn to be anatomically correct based on the X-ray crystal structure in this particular cartoon. So this cartoon is actually fairly accurate. What happens when Herceptin binds to this receptor is that the receptor is internalized in a process called receptor mediated endocytosis. I'll give you a quiz after this. So it goes into this compartment in the cell called the endosome. And the endosome is a very hostile compartment. It's got low pH, has tons of enzymes.  The beauty of this is that this particular Herceptin-based antibody drug conjugate has no nausea, no vomiting, no hair loss, no drop in the white blood cell counts. So far safer than chemo plus Herceptin. So we put this to the test. This drug is called TDM1. It doesn't even have a name yet, it's so new. We put this to the test in a large, randomized trial of HER2 positive breast cancers with metastasis. With a thousand patients, we randomly assign them to the standard FDA approved treatment for this condition, which is another HER2 targeted agent called Lepatinib. We don't have time to get into that today. Lepatinib plus a chemo called capesidobene. That's the standard. And we tested this new antibody drug conjugate head to head versus the FDA approved standard treatment. And I can tell you that this study is positive. That's in the public domain because there's already been a press release. And this study will be presented for the first time at the American Society for Clinical Oncology meeting in about a week and a half in Chicago. And I'm pleased to be a co-author on that paper. It'll be presented in the plenary session. So anything that's plenary at ASCO, you know that it's going to be significant and practice changing. And there's already a paper in progress to be submitted for publication. In the interest of time, I'm going to fast forward here and wrap up quickly. You all know that we now have sequencing technology so that we can sequence the entire genome of an individual. And this has now been applied to sequencing individual cancers. And when this is done, you can actually catalog all the mutations on all the chromosomes. This is called a circus plot. And it has each of the chromosomes numbered in this circus around the outside of the cell. These are all the chromosomes. And then wherever there's a mutation in the chromosomes, these little black lines indicate point mutations. Wherever there are amplifications, those are shown in green. And areas where genes are deleted, those are shown in red on this part of the circus. And then wherever there are rearrangements where the chromosomes are scrambled and fused together, those are in these arcs in the middle showing connection of one chromosome to another across, you know, large areas of the genome. So you can catalog all these changes in a breast cancer. And you can see that it's extremely complex. In this one particular breast cancer case, there were 157 different gene rearrangements alone and many more point mutations. So extremely complex. When you do this in a large cohort of breast cancers, this is the first 500 cases that have been analyzed in this way, just presented, not yet published, just presented in December for the first time at a national meeting. You can see that there are many, many different genes that are mutated in human breast cancer and no two are alike. Every single tumor is unique. In fact, within one patient, in different parts of the tumor or in different metastases, there can be different mutations as well. So highly complex. This is both an opportunity, but also a challenge. The opportunity is, many of these might be potential therapeutic targets. That's fantastic. And we're really excited in the lab to take a critical look at these, to see which ones are drug-able and come up with new therapeutic strategies that can be personalized and individualized to a particular and tailored to a particular patient's alterations. But it is a daunting challenge because that means a whole lot more work. This will take an army of post-docs and grad students and lots of thesis projects to get this work done. So that's where you come in because this is going to take a lot of support. So any of you with college-age kids can send them over to our labs, please. We'll put them to work. Here's an example of a cancer cell line from my laboratory, her two-positive cell line. And we selected clones that were resistant to her two-targeted therapy, in this case Lepatinib. And so we asked the question, well, what happens to the genomes of these cells as a result of drug resistance? Well, they just go crazy. There were 37 new point mutations around the circuit. There are dozens of copy gains and losses that are new and new rearrangements that occur. So this is just underscoring the complexity of just a simple experiment giving rise to drug resistance. This is happening in patients all the time and we need to understand this and embrace it and exploit it. So in conclusion, we have now this challenge of this relevant genomic information. What we know today is pretty simplistic. The only things that are routinely measured in human breast cancer in the clinics right now are estrogen receptor, progesterone receptor, HER2, and then that 21 gene assay that I showed you add a few more to the list. But what we need to know is much more dynamic and complex than that and will require informatics, bioinformatics, new research tools, tons of computing power. It's staggering how much computing power you need to be able to dissect these complex networks, especially when they're drained and especially when they're unique to each individual patient. So we've talked about conventional cancer therapy and the limitations there are particularly toxicity and the one size fits all model that we used to have for breast cancer employing surgery, radiation, chemotherapy. These are still tried and true and they're going to be around with us for a time. But these are old school. Molecularly targeted personalized therapy is highly sophisticated. It's complex. It exploits new technology. It's sexy but it's expensive. And so I don't know that this is necessarily going to be the only solution. It may be that in the future we have integration and synergy of this new translational personalized medicine into the traditional methodologies and we have to be smart to come up with the right balance of integration of new treatment methods in the clinic and hopefully do a little bit better than this fiat. So with your help, it's my hope that we will accelerate the pace of discovery here at Stanford. Sorry this came out a little bit blurry. I was drinking a Starbucks and talking on my cell phone and I drive with a manual so it was a little bit blurry. Thank you very much for your attendance this morning. I really appreciate it. I can't thank you enough for taking time out of it. All of you have very busy schedules like the rest of us and it's really exciting and thrilling to see a packed house upstairs today and all of you coming to the sessions were really grateful. Thanks for your participation. Questions or comments? Yes, please. We have a mic for you. Good. I'm interested in what company is producing TDM-1. That would be Roche Genentech. When I said a large biotech company in South San Francisco that was the code for Genentech. They're the 900 pound gorilla in the room usually. Thanks for a great talk Dr. P. Grapp. The translational aspect, we know there's been tremendous strides and you've sort of shown that on your last slide. So what do we need to get to that next step where we bring what's in the bench or in the computer I guess to the clinic? What do we need next? There are a number of barriers. As you know, one of the barriers is patient participation. We need patients to understand what the research needs are, what the needs are in the pathology laboratories for sophisticated diagnostic approaches including genetic approaches which has a whole layer of ethical and social issues with regards to insurance and the legal system etc. We need patients who are willing to volunteer for new therapeutic strategies some of which we know aren't going to be successful. Not all of the experiments we do work. For everyone that works like TDM-1, there are nine others that don't make it. So it's frustrating both from our point of view and also from a patient's point of view knowing that when they are volunteering to participate in an early phase of testing that it may not work for them. They have to be altruistic. So patient participation is critical and nationally in adults, adult patient cancer participation in clinical trials is single digit as a percentage. It's very low. Whereas in pediatrics it's about 95% plus and you'll notice that the advances in pediatric oncology have far outpaced those in adults and that's one of the reasons. The next limitation is this whole translation issue that you bring up. There has to be collaboration between so many different types of experts because there are physicists and biochemists and cell biologists and imaging people and physicians and statisticians and all these people have to work together and use a common language and be focused on the same problem. The problem is the same but you're looking at it from many different points of view and that's extremely difficult to pull off and it requires enormous resources space, expertise, recruitment, just all of the things that are so rich here and we're so fortunate to be here at Stanford to have access to these kinds of tools and the expertise but it's difficult to maintain and that's one of the other limitations. The next thing is just the complexity of human cancer. I think nobody imagined that there would be so few genes that are frequently mutated in breast cancer. What we were hoping to find from those first 500 patients is maybe 20 other genes that are mutated half the time or 70% of the time or even 20% of the time that would be the next estrogen receptor and the next HER2. That's what we were hoping to find. What we found instead is dozens and dozens of genes that are only affecting 1% or 2% of patients and that's going to challenge the current therapeutic development paradigm from the regulatory point of view from the FDA's point of view and from industry's point of view because to get a new oncology product to market now costs more than a billion dollars. If you go to the boardroom at Roche and say, well I want to invest a billion dollars for a market that's 1% of breast cancer they'll laugh and then kick you right out. So this is going to have to be a revolution in new paradigms to bring these discoveries to practical application and the regulators are going to have to be satisfied with something less than these thousand patient randomized placebo controlled trials. You can't do that with 1% of breast cancer. So there aren't enough patients on the planet to do a thousand patient study necessarily. So the regulators are going to have to... Please join me in giving Dr. Pegram a big hand. Thank you very much. Please stay and ask a few questions. Please do. We need to make room for the next session that's coming in. Thank you Dr. Pegram. The preceding program is copyrighted by the Board of Trustees of the Leland-Stanford Junior University. Please visit us at med.stanford.edu.


నరర్పంఠ్ కిర్నిస్చి పారినిలూన్ పఇతిశి కొతి నివరారారిస్పానిన్ నుదనండి సింటికికిసింది స్త్హేపి పరాసికి స్లికికొట్ ంపిస� మని tämäట౉వతార靈 మిసి నీజాన్వి సిసి � preliminary libraries సిసి. మనిసి స౿లి 對ోటిలై Kerry jlift shami. PU00 and నీట్ Titanbuilt Game for a time బిళ్రఀనా player Schmya మిఝరోల్ approved నిహోలైалలైలి. ఇంతిరారర్త్రం ఆరికింతాలూత్ ఆరిమ్త్మానో ఆండికిక్తెచెందివందియాద్ సాసితారిరడిందారికి స౗ిషానిటరిం౦ిందిందేత౏ందిన౉మానిక� నితకిసింమా బెంది నిసాభింద్దంపి మ౻తాది రిస్ని పిలెయాస్ప్త్లైముసి రెఎల్ని కారికి పి వాబిలోవాసిమి ఇదిలో కిందికి మానరిల్చ బార్ర్ర్గార్లు కార్టిమెన్ట్గాదారియియాన్చ్నింపాణ మిందార్ట్పిందియటార్ అథరిరోయికార్ప్టందిన్టిసిటార్లపనా ప్రర్వని పార� and next one is power management so that is mainly used for the mobile devices because our mobile devices have limited battery lifetime so we need to manage the power we try to use as much less power as possible next one is low memory killer so low memory killer basically what we do is sometime we start the many application in the mobile device so at one point will be reached when the memory your memory RAM will be full at that time you want to start some another process so what android will do it will check okay RAM is full now you you want to start the new process so for the new process android will automatically kill some other processes which are not used by user so that is our low memory killer so next one is a runtime walkthrough so the booting process of the android is the same as a linux bootloader will load the linux kernel and this linux kernel will initialize the environment for executing the c code once this is done android will kernel will mount the root file system and it will start the first user space process which is init process now once init process is started it will in a start the basic demons so few demons are like usb demons that is our connect connected with usb port then adb demon that is our android debug bridge demon so basically this android debug bridge demon will allow to communicate with your computer and debugger demon that is used for debugging purpose and last one is RILD demon that is a radio interface layer demon so this radio interface layer demon is connected with your mobile communication like you get SMS at that time this RILD we use if you are calling someone at that time this RILD demons will be used once this demon is started android will start the zygote process so this zygote what the zygote is zygote is the main part of the android so what it will do it will start the first delvik instant of the VM then it will links all core library and it will share between all the processes which is created by the zygote and it will use copion write mechanism so what is basically is thing when you are creating starting some new application like you pressed home button or maybe you press your contact button so at that time the request will be go to the zygote to open that contact that zygote once zygote will get the request it will start the contact process and it will share the library between zygote and the contact process so that's why he use the copion write so whenever contact will try to write anything which is the said between the zygote and the contact process at that time this copion write use will be used and separate copy will be created for that contact process so once this is the done zygote is done in it will start the runtime process of the android this runtime process will start the service manager so basically this service manager is a kind of a context manager for the binder so what what is the use of this service manager is to use that all our application which is providing some services which are service provider they all will register their services to service manager and now whenever you your application need to use some service like you want to use a location manager so you will contact the GPS location service provider at that time your application need to contact the service manager that I want I want to use the service of the GPS location so this service manager will return the binder object to the your application and then at that time your application will be able to communicate with the GPS location manager next one is one this is done then runtime will inform the zygote that now you can start the system server so for that zygote will start the new delvik vm instant and the system server code will be loaded and system server will be started so main purpose of the system server is to start the other application other application android application of the system so what we will do it will do it will first start the two native services which one is the audio flinger and the surface flinger that surface flinger is your screen that is screen of your device so like yeah whenever you are seeing the battery status your tower status or maybe your something else whichever is so on in your screen that is coming through the application which will contact the surface flinger the surface flinger will handle your screen now next one is audio flinger that audio flinger will connected with your speaker and your headphone part so whenever you boot your tablet you will listen sound that is the because of the audio flinger so if you are not starting audio flinger in at the boot time you will not able to listen it well this is done so surface flinger and audio flinger providing this type of the services like as I mentioned that surface flinger is providing a control of the screen and audio flinger is providing the control of the speaker so suppose you are writing an application for the media player okay so at that time your application will use the service provided by the audio flinger so as we can see here that both they have to register their services to the service manager so whenever you will write your application well like you are creating some new media player or yeah so at that time your application first will first will contact those service manager that I want to use the audio flinger service provided by audio flinger and that service manager will return the minor object and then at that time your application can only use the services was this is done so starting of native services is done it will start the other package men other manager which are used in the android like content manager window manager which is here related with your application window then activity manager which is used for a life cycle life cycle of the process then telephony service that is the telephony services as I mentioned that when you are calling someone or you are receiving call from someone at that time this telephony service will be used then bluetooth service that is bluetooth of the your devising package manager so basically package manager will know which are packages are installed for the particular application then connectivity service that is related with wi-fi and etc connection with the power manager that is used for managing power of your android device and then location manager that is providing location of your cell phone one this is that now your system is ready to run so what will happen when you are starting the home page so whenever you click a home button of your device so that new application request will be go to the zygote zygote what zygote will do it will create a copy its own memory layout so basically to make it faster zygote will instead of creating new memory layout for the application zygote will copy its own memory layout and it will see the common classes said between the home application and the zygote itself those common classes are linked with zygote and remaining classes are loaded in a home memory area so what this is done home application code will be loaded in the new delvik the new delvik instant and the new home process will be started so what this is done now suppose you are after opening home page you are opening a contact so same thing will happen new delvik instant VM will be created by the zygote and the process will be loaded so main point is that each and every application has their own address space their own delvik VM all those application will the share library through the zygote and those library are marked as a used copy on write now we will see the binder part so what are the inter process communication so two process trying to exchange the data like suppose maybe we can write in C language that code for the two process that both two process will use same file descriptor they are accessing the same file at the time with same file descriptor so they are mainly exchange the data with each other why we need IPC so as we have mentioned both to two different processes so if both processes are on different different address space if although both processes will run in same address space at that time we don't need to do the IPC mechanism the main reason is the behind the IPC mechanism is the because of its own address space then provide data isolation we are keeping some data isolated from other application we don't want to show the some data we want to only show the few data to the application another one is avoid direct interaction so obviously this is the main reason about the avoiding direct interaction like if you are putting two running two processes in same address space then there will be no data isolation will be there right that second process can access the any data of the process one so let's talk about the IPC mechanism in the Linux so first one is the signal so that is the just signal which is just some type of the interrupt to the given to the process so in that we cannot distribute differently means you need to create the as many signal as for each and everything like a wake-up signal you stop signal keep this iodix signal so all those are signal we need to create it and pipe that is our unidirectional community mechanism that is we can one process one go on to communicate with process two and process two with go on to communicate with process one so at that time they are co if you are there community communicating with pipe then we need to create two pipe first one is to write process one to process two data and the second one is the process two to process one then socket that socket is a bidirectional communication so in that process can listen from that particular socket and he can process can also write that data to that socket that same of four that is our said said variable between two different processes and message you that is one process will write two pointers are defined first one is a write pointer and second one is read pointer so writing process will write the data in the message you and it will update the write pointer and reading process will the read data from the message you and it will the read the data from the message you the third one is a said memory so said memory in the Linux how need two different processes are sharing the memory is the by their page table entry so two different process have their page table each every in that page table some physical frame are mapped so on the same physical frame is there their page table entry is pointing to the same physical frame and that's why they are sharing the memory now we are those old this these are old old mechanism and Android has introduced a new mechanism that is the binder that is the lightweight remote procedure code so what was the problem with the old mechanism where first one is the processes are separate and security hold so security hold in the same like as I mentioned if you are sharing the memory area so how sharing will be done sharing will be done at the process level it is not done at the kernel level because the sharing part there will be done through the page table entry so if it is possible that third process can have same page table will get the same page table entry and he is able to process can able to the access that said a said physical memory area so those are the problem with the old IPC mechanism now next one we have provided the solution so what can be possible the solution is let's move the shared IPC mechanism to the driver level it means we will provide the driver in the kernel part for the IPC mechanism we will use the shared memory here is the shared memory is different than the Linux shared memory because the in the Linux shared memory will done at the process level and in this thing shared memory will be done at the kernel level so kernel will be will handle this shared memory so we will see example one of example for the shared memory then per process thread pool so what different is application provider which is the providing some services those provider has some pool of the thread so each and every thread will be will be handled by the particular the client so each and every client has a one thread so whenever the client request will come client one request will come thread one will be handle and the client two request will become thread two will handle it that that request so each and every client has a particular thread then synchronization so synchronization in the sense like as I mentioned first client will communicate then service provider will communicate it so synchronization problem it may be happen in the old mechanism which is in the socket mechanism because socket is the bidirectional inter-process communication so it may be possible that when server client is writing something and the server can send the data at that time also so that avoid that we have provided synchronization here next one is like let see the binder with the service manager so how the binder how the client will able to access the service by provided the service provider so what will happen when service provided so service provider will start it will first register its services to the service manager for registering service registering service to the service manager add service function will be then in the service manager package so that function will be used and the service will be registered to service manager now service user want to use that service so each and every binder has its own address and its token number so service user don't know that binder address and that token number so what it will do it will contact to the service manager this service manager will contact okay that particular client want to the particular service so it will contact the binder driver so basic work of the binder driver is to create a memory shared memory for the state service provider and the service user so binder will binder driver will create that shared memory and it will return the information to the service manager and those old information like a binder address binder token number all those thing and shared memory area will return to the service user and now service user has binder of the service provider so he can communicate with the service provider next one is like as I mentioned now my process service user has its binder address and everything so now they will communicate through the binder so what you how to how it's working like process a will write something in a common common shared area so binder will not even notify it and when writing is done binder will send notification to the process B and the process B will read it from the that shared memory area so this is the how binder transaction will work so let's see the limitation of the binder so what when communication communication will happen between two processes what is exactly happening like process one one will send the data to the process two okay so what will happen process one will send the data to the binder binder will do the parceling of the data it will create the parcel of the data and that that parcel will go to the process B process two and that process two will unparsal it and read it the data so if your data is very large so that time will be consumed for the creating the parcel and then again time will be spent to unparsal that data so main limitation of the binder is to it is not ideal for transferring the large data between the two two processes so because the because of that the communication time will be increased while creating the parcel and while creating the parcel now next one is the layer interaction so we will see that we will we all of you know that Android has a four different layer those are application layer second one is application framework layer and library layer and the last one is the Linux kernel so how the those layer will interact with each and every layer we and how they will get the services from the kernel layer so first one is your application will contact the runtime service application and that service will directly contact to the library and that library will contact to the Linux kernel another way is to do is your application will contact to the runtime service this runtime service will contact to the native service and a that native service will contact through the library third one is application it will contact with the runtime service and it will contact with with the dating view and then it will contact with the library so, which type of the layer interaction will happen, it is a depend on the type of the application and the type of the negative library, so, let us see how the layer interaction will happen, so for the layer interaction we need, so, what we are doing is basically we are using నును నినిిండికండి.పునుచిండి.icial . so for that our application are written in the java which will try to communicate with the code written in the c or c++ for that we need the interface that is our java native interface which will the gateway for bridge between application layer and the library because our libraries are written in c or c++ so your java code will contact through a library through a j and i so first one is the try to contact you through the runtime service so what will happen so first one is your application which is running in your application layer so it will use the binder IPC and it will get the services provided by runtime service so basically this runtime service is your manager started by the system server it can be a window manager or maybe activity manager or package manager anything so that as runtime service which is running in the application framework layer it will use the j and i and it will contact through a native service binding so that is our library and this library dynamically load the hla library so this hla library is hardware abstraction layer library which is provided specially to communicate with the linux driver so hla will provide some sort of the library like audio library your radio interface library so those library are presented in hla layer and that hla this library will contact to the kernel driver so let us see an example suppose your application want to find the location of your cell phone so what will happen your application will contact to the service manager and it will ask for the service provided by the location manager so here is your runtime service which is your location manager so your application will get the binder from the service manager and it will use that binder to the contact to the location manager now that location manager will use the GPS location provider that is our java written code so what we will do is we will contact the already written code in the c or c++ that is our GPS location provided that is our library through j and i so it will contact to the libraries through j and i this library will load the gprs library which is provided in hardware abstraction layer so dynamically load it it will contact to the kernel driver and the process response will be written to the application so this way layer interaction will happen when you are getting the using the location manager so next one is the doing the native service so what will happen it may be possible sometime you use the native services so like native services are those services specially made for the android like as we see during the boot process that audio flinger and surface flinger two are native services so what will happen application will contact to the runtime services and this runtime service will contact to the native service binding through j and i and it will use the binder IPC so different between the previous layer interaction this one is that binder will take place here instead of here because in previous when you are using runtime services only at that time binder is taking interaction between application and application framework in this case binder will taking here between the native service binding code and the native services this service again will load the hla library and the hla library will contact the kernel driver so let's see the example so here is the example of the media player suppose your application is somehow using media player so what will happen so your application will contact to the media player and that media player will contact to the already built in library written in c or c++ code through j and i so this media player will contact to the audio flinger because audio flinger only will have only will able to handle the speaker part so that it will contact through a binder audio flinger will dynamically load leave audio and hardware library and it will contact to the kernel driver so this way layer interaction will happen during the native servicing now if you are using a native depot how layer interaction will happen so basically what is the different between native service and native depot is that native services are introduced by introduced by android itself and the native depot so those are depots which are taken from the linux itself so those are depots are taken from the linux which are using the socket to get any request so this is the majorly difference that native service will we can communicate to the native service only through a binder and we can communicate to the native depot through a socket so what will happen your application will contact to the runtime service that runtime service will contact to the native service binding through j and i this j and i will send a request to the particular socket which is related to particular depot that depot will load the hli library and that hli library will contact to the kernel yeah this is also so let us see the example of the native depot like if your application is using a telephony manager like your application sending some sms to some other mobile so what can happen application will contact the telephony manager it will contact the telephony manager library telephony manager library will send the request to particular socket for rild that is our radio interface layer depot and this depot will dynamically load the rl library and it will contact the kernel driver so that is why native depots will be used and when we are using the native depots socket will be used instead of the binder so let me zoom it so this is the all over architecture so here we can see is the first layer is your application layer so it is containing a stoke android application which are your application like bluetooth service browser which is coming by default in your mobile or in your android device and here is can be your application or market app so those app will the application api they will communicate to the system server or may be application provided at the application framework so at that time binder will come and that this application application framework layer will interact with the library layer this one is our library layer through a jni part application framework will always contact to the library through jni only and that jni will contact to the Linux kernel so that is it this is our normal layer interaction between among the layer


Hello there, everyone, and welcome. This is Melissa Armo with the stocks, whoosh, and I'm reviewing the spy. Market took a tumbley to today, and very interesting, because we were green.  It's heavy, it's lower. And when I said that, it was into the open. And I'm just gonna go back and show you here. I'm gonna take all this off. There are a lot of people that were on the market today. Here's where we open, and we open down, and then we rally, and we were full on green. Full on green, high, and here was 387. We were full on green, rally, rally, rally. And I didn't believe the rally. So we didn't do it. I said, the play is not along today. Not along today, boom. Anyways, long story short, rally, rally, rally. And here we go, and here is this, and there it is. And look at that. I mean, incredible. So what an amazing drop-off. So as soon as I saw it, I said, something's happening, guess what? Trump tweeted tariffs on China as of September 1st, another 10%. And I knew it. I called it, I called it, I called it, I called it, I called it, I called it. So I've been calling it on Fox News, I've been saying it on TV, I've been saying it since May, May, June, July, last three months, and nobody probably believed me. So this is what the sell-off is, and we'll see where we go tomorrow. But today is August 1st, so September 1st is a month away. So really, really nice reversal here. A complete and total, 100% reversal in the market. And we will see where we go from here. So I did not think the play was long today, it was right. In fact, I never went back and looked at what GM did. What did GM do? Oh my linty, ah. Good luck everyone, we'll see where this leads. We'll see where we get tomorrow morning. Email me and Melissa at thestockswish.com if you wanna sign up for the Golden Gap course. If you do that, you're eligible to join the live trading room and get the calls called the market spot on this week. Spot on from yesterday and then spot on today. I am on fire. Have a good day everyone.