Thank you, Harmeet, and I'd like to thank the organizers for doing this. I think it's a very important and special thing to do for the basic science and the basic science research, to the point I'm wearing a tie, that always means something. No disclosures. So to give you, when I was first approached about this, I was very excited about the concept of doing this. I think it's important. I think it's something wonderful that the society is doing. And then reality hit me a little bit, and I started looking at the numbers. Okay, so we had about 3,400 abstracts submitted to the liver meeting this year, 70% acceptance rate. That means about 971 of those abstracts were basic or translational science, or almost nearly half of all the submitted abstracts. So that was my pool from which to choose. There were 21 poster categories to go through that were basic or translational. There were seven parallel sessions. There were 20 early morning workshops, and on Saturday, in tandem with the basic science symposium, there were five meet the professor luncheons, and those seemed to be very well attended in all, and that's a very good sign. Just to summarize some of the things covered by our SIGs on Friday and on Sunday, these are the basic science SIGs and their topics. So in the cholestatic and autoimmune liver disease, they looked at bowel acid signaling and cholestatic liver diseases. The hepatotoxicity SIG worked on DILI, assessing risk and predicting outcome. Of course, DILI is a very important issue in hepatotoxicity, especially in epithic drug-induced liver injury, trying to identify if there is some underlying mechanisms that determine individual risk. The NAFLD session was on cross-talk with the microbiome and NAFLD progression. There were some very excellent talks in that session. Liver fibrosis SIG had novel approaches to study and treat liver fibrosis from bench to bedside and back again. This emphasizes that translational research is bidirectional, and information we get from the clinics can then be applied to the bench to better understand mechanisms and identify new therapies. The liver cell biology and hepatic diseases SIG had regenerative medicine in the bioartificial liver. Some very interesting talks there later in the session, especially about bioartificial livers and scaffolding as not only possibly transient support devices, but also facilitating repopulation of the liver. Hepatic neoplasia SIG had a very nice session on obesity and metabolic syndrome and hepatocellular carcinoma and the interaction that leads to a higher risk for individuals who have obesity-induced liver disease. We have, of course, two basic science programs that happen every year at the liver meeting. We have the BSS, the basic science symposium. This is current trends in liver regeneration and repair. Xiaomin Yin and George Michaelopoulos were the chairs of that session. They focused on liver regeneration, hepatobiliary cell transdifferentiation, hepatic progenitor cell and liver repair, and hepatic reconstitution. What I saw of that, it was very well attended and some excellent talks. The basic research workshop was a new era of genomic and biomarkers in hepatocellular carcinoma. Chairs were Tushar Patel and Emmanuel Thomas, and again, especially in the post-DAA field, this is DAA era, who is truly at risk for HCV after a stain viral response is a very important issue that we still don't have a handle on. So, these are the kind of general groups, and don't blame me for the groups. This is the, when you submit your abstracts to AASLD, these are the groups under which you can submit. So I use these as my leitmotif to go through some of the abstracts that I found. Now as you saw, there were 927 abstracts, so it would be like putting my mouth up to a fire hose if I tried to cover everything and do everything. So what I did is I picked two or three abstracts from each of these categories to try to highlight why I think these might be critical and impactful projects. So we'll focus first on liver fibrogenesis and non-parenchymal cell biology. So the first abstract I'd like to talk about is Castorelli, Abstract 19, inhibition of autophagy promotes small EV release to drive hepatic stellar cell activation in liver disease. The thing about this study that was very interesting was they were looking at the release of exosomes and microvesicles in response to PDGF in hepatic stellate cells. Now we know that EVs will have different packages depending on the disease state. So the EVs released by hepatic stellate cells are differential from EVs released from inactivated stellate cells. So these can serve as potentially biomarkers for liver disease. But what they showed in this study also is that these are potentially mechanistic biomarkers because they actually do mediate phenotypic responses in neighboring cells, especially with moving cells back and forth. It was a very elegant study and what they identified under these conditions is that mTOR signaling seems to play a critical role in the canonical pathway of inhibiting autophagy, but also in a non-canonical pathway mediated via ROCK1. So both microvesicles and exosomes were responsive to mTOR inhibition. This talk was very interesting and presented this morning, Hepatic Stellate Cells Promote Regeneration Following Partial Hepatectomy and Toxic Liver Injury by Yenetal, it's abstract 24. Now what I found very fascinating about this abstract, if you had asked me what would happen if you take out the hepatic stellate cells and do a partial hepatectomy, I would have predicted a phenotype, but I would have predicted that phenotype would have been about 72 hours after partial hepatectomy when the liver is trying to rebuild the vasculature. But what they found is very early after partial hep, they saw an impairment in liver regeneration. They also saw an impairment in liver regeneration in TcPoBop-induced hepatomegaly and also in carbon tetrachloride-induced liver damage. They did, they looked at several different mechanisms that were involved and it didn't seem to be the classic HSC activation pathways by PDGF, in fact they showed that the phenotype they were seeing preceded HSC activation in their model. Also it did not respond to activation of production of collagen or other pathways along those same lines. They do have some data that suggests that this may be mediated via Wnts that are released by the hepatic stellate cells and we'll get back to the implications of that in a minute. This talk was also presented, this is Epigenomic Regulation of Hepatic Stellate Cells Responses to Liver Injury, Abstract 73 by Wang et al. This is building on the idea that we know that hepatic stellate cells, once they have transdifferentiated, if they go quiescent and they get stimulated again, they respond more robustly, suggesting that there is an epigenetic change in their phenotype. And the authors of this presentation were chasing this down to try to attempt to identify that. So what they did is they knocked out UHRF1 in their hepatic stellate cells, which is a master regulator of DNA methylation, and they saw a very large decrease in methylation patterns in their hepatic stellate cells. Quite interestingly, in response to chronic carbon tetrachloride under these conditions, they actually saw an exacerbation of fibrosis, suggesting that not only do these methylation patterns potentially mediate the enhanced response, but altering these methylation patterns also probably unmasked or inhibited some of the senescent responses. So gut-liver access in microbiome is next. And of course, the gut-liver access has been long proposed. We in the liver field were actually the first to really propose a gut access with another organ. That was Nolan and the Bodas in the mid-70s. So this concept has co-evolved with what we understand in chronic liver disease since. We of course have evolved quite a lot since then, and what we're looking at now is specific targeting of specific cell types in dysbiosis. And we know that dysbiosis is involved in several different liver diseases. This talk here used a bacteriophage cocktail for eradication of eclipsal pneumonia in PSC. Now in this study, what they showed is they had already observed that KP dysbiosis correlates with PSC under some conditions. So they did a very large study to look at more in depth at what that risk factor was. And what they saw is indeed versus IBD and versus healthy controls, there was an enrichment of KP dysbiosis in patients with PSC. But what they did next was very elegant and I think something that we're going to see more and more in the field of dysbiosis. So if it is indeed KP, the hypothesis would be that eradicating KP would maybe be protective under these conditions. Now keep in mind, PSC disease modifying agents are going to be much more beneficial than antifibrotics for these individuals. So what they did is they took the feces from these patients and plated them out and pulled out the KP and then they exposed them to cocktails of various bacteriophages and identified several cocktails that would eradicate the KP infection selectively. This of course is going to be much more effective and have fewer side effects than an antibiotic based technique to eradicate the dysbiosis. So if indeed it is one particular bacterium that is driving the phenotype in some individuals with PSC, this may be an emergent therapy that could be done. This is a talk, Fecal Microbial Transplant Can Improve Brain Inflammation, Lessons from Human Studies in Animals. This is building on some clinical trials in which fecal microbiota transplant and decompensated cirrhosis is protective against hepatic encephalopathy. What I found beautiful about this study is they took it a little further. So what they did is they took the FMT from human patients and inoculated them to germ-free mice and then looked at the phenotype in the brain. But what's really elegant is they actually had each patient serve as their own temporal control. So they took the supernatant and the entire stool and inoculated the germ-free mice and looked at the outcome. And then they took the same samples from the same patient post-FMP therapy and did it again. So basically the mice are serving as before and after controls. As you can see, indices of innate immune response activation and inflammation are pretty largely induced in the mice that were inoculated with these feces. And that post-FMT, you can see a nice diminution of that response. So a nice proof of concept of what they have been observing in the clinic actually has biological outcomes in experimental models. Now this talk I actually saw about 45 minutes ago. And so I think this is an excellent piece of work. This is post-prandial signals in the hepatic portal system regulate glycemia through immune responses, abstract 234. And what the authors of this study were proposing was that lipopolysaccharide release into the portal blood, which happens under basal conditions, especially with food, may be actually a physiologic stimulus. And what they showed is that IL-10 production in response to insulin is enhanced by LPS exposure at low concentrations. And in doing so, this may be a mechanism by which we get a normal postprandial response and glycemic control that is lost oftentimes in patients with obesity and fatty liver disease. What I mean by that is if you have insulin resistance, you have loss of tolerance to low-dose LPS. Perhaps it's because you don't have this co-signaling pathway involved where insulin and LPS are working together to turn on IL-10, which is one of the main mediators of the tolerance response. Next is biliary physiology and experimental cholestasis. So this is a very interesting study. It's actually being presented tomorrow, so I had to talk to the authors ahead of time. This is novel evidence for the role of mast cells in histamine signaling in late-stage primary biliary cirrhosis, new kids on the block. And what the authors are showing here is that there is an enrichment of activated mast cells in the portal area in PBC patients and that in experimental models, blocking histamine release or blocking histamine 2 receptor is protective against the induction of senescence in cholangiocytes, which of course is a key mechanism by which PBC goes forward. And I recommend you attend this talk tomorrow. I believe in the translational plenary session in the morning. This is abstract by Yuto et al., transposon mutagenesis screen in mice identified TRAF6 as a novel tumor suppressor of cholangiocellular carcinoma. So what they did here is they took a Sleeping Beauty transposon mutation library mouse model and co-expressed this with P10 knockouts. Now the P10 knockouts generally get some cholangiocarcinoma and they were looking for the most common mutation that led to a cholangiocarcinoma phenotype in the outcomes. It's a very elegant work and they identified the most common one was a TRAF3 mutation. So loss of TRAF3 in the hepatocyte seemed to be immunosuppressive. And then they did follow-up studies in knockouts of whole liver specific knockouts of TRAF3. They did hepatocyte specific knockouts of TRAF3 and cholangiocyte specific knockouts of TRAF3 and compared them. Now the whole liver knockouts were again protected against cholangiocarcinoma as you can see over here. And if they did the hepatocyte specific knockouts, they got a very similar phenotype. Whereas the cholangiocyte specific knockouts did not have that phenotype. They suggest from this that maybe the source of the cells that have this tumor suppressor loss that are cholangiocytes and the cholangiocarcinoma may actually be originally transdifferentiated hepatocytes. Next group was cell and molecular biology. So this is an abstract. Do you remember at the end of that presentation with hepatic stellate cells involved in liver regeneration one of the last things they identified was Wnt signaling seemed to be critical in the response. In this study these authors actually have supported that hypothesis. Now the nice thing too is there was some concerns about the stellate cell knockout study because they used diphtheria toxin to kill the stellate cells. Here they're actually specifically knocking out a mediator from the stellate cells that impairs liver regeneration. And also it seems to be involved in modulating a little bit of the metabolic zonation found in the liver caused by the Wnt beta-catenin system. And you can see there is a decrease in cyclin D1 expression and there is impaired regeneration after partial hepatectomy. So again, these data suggest that hepatic stellate cells may be releasing something possibly Wnt that is directly involved in the early response to liver regeneration. This next is by Splinter et al., Abstract 105, the transcription factor ETS1 interacts with histone acetyltransferase P300 promoting the apoptosis resistance phenotype of senescent cholangiocytes by the transcription of anti-apoptosis gene BCL2L1 and wins the award for the longest title that I have in this presentation. So what the authors are doing here is they're building on the finding that ETS1 seems to be associated with cholangiocyte senescence and they want to get into the underlying mechanisms. And what they identified is that ETS1 via its interaction with P300 seems to induce the expression of BCLXL and thereby selectively makes these cells apoptosis resistant. And they also showed that by targeting BCLXL or by targeting ETS1 they could remove that phenotype and make these cells again more sensitive to apoptosis. And again, what I want to emphasize about this particular field is disease modifying agents are going to be much more beneficial therapeutically than anti-fibrotics. Next area is hepatotoxicity, one of my favorite. So this study is decreased hepatic autophagy promotes synergistic IL-1 beta and tumor necrosis factor hepatotoxicity in mice. Now for many years we have known that there's a phenotypic switch in fatty livers in response to cytokines. One, the macrophages are primed to produce more pro-inflammatory cytokines, but at the same time the hepatocytes are sensitized to dive more robustly from those cytotoxic stimuli. So this study is focusing predominantly on that latter phenomenon and they were looking at to determine whether autophagy, which is known to be protective in NAFLD, may be an underlying mechanism of this sensitization. So what they did is they knocked out ATG5 and thereby pretty much eradicated the autophagic response and exposed the cells to IL-1 beta and or TNF and looked at apoptosis and inflammation. They also did a follow-up study using hepatocyte specific ATG5 knockouts where they gave IL-1 beta and TNF alpha and looked at cell death. And what they found is indeed it seems as if autophagy is a protective mechanism against cell death mediated via IL-1 beta and or TNF alpha under these conditions. So the sensitization mechanism may be immensely tied with the autophagic response. Nerve activation mediates the protection against acetaminophen-induced injury in hepatocyte specific SHIP-deficient mice. This is abstract 216. We know well that acetaminophen causes toxic liver injury and the mechanism by which this occurs is of very good interest because if we can prevent this, most patients, once the injury time is over, will recover from that damage. And this is the classic pathway where acetaminophen is metabolized to NAPQI and this leads to glutathione depletion and mitochondrial damage and thereby necrosis and altered apoptosis. Now what the authors are proposing is that SHIP induction under these conditions is inhibiting the NIRF2 response and the NIRF2 response then is inducing antioxidant response and one of them is to make glutathione which directly protects against the NAPQI adducts and also protects against the cell death. Now this is elegant in that it's building more and more into our understanding of the molecular mechanisms downstream in toxic liver injury that it's not simply hepatocyte sees a toxin and then the hepatocyte dies. That there are places in between that we can potentially target and maybe extend out the therapeutic window for intervention in our patients. Lastly is category inflammation in immunobiology. And this is platelets promote distant metastasis by facilitating NETs capturing of circulating tumors after liver surgery. Now in hepatic resection surgery one of the major risk factors is metastatic disease usually in the lungs. And it has been hypothesized that the surgery itself may release some of these metastatic cells called circulating tumor cells, CTCs, into other sites. And so the authors have built this model where they do a schema of perfusion to mimic the surgery and then they inject metastatic cholangiocarcinoma cells that then inoculate the lung. And they have shown previously that this is affiliated with the formation of NETs in the lung and that the NETs seem to actually work as NETs and capture the cancer cells and bring them in and allow them a chance to inoculate the lung. Now what they showed here is that also the innate immune response activation, namely the platelet activation caused by the surgery, is also involved in this process and directly targeting platelet activation. And I think they did pharmacologic also but they focused here these are platelet specific TLR4 knockouts. And you can see the formation of the NETs in the lungs was much less robust under these conditions. And again this is something that can be readily translatable as a therapy that can improve outcomes in hepatic resection surgery which has about, I think they said, a 36% chance of developing metastatic disease in distal sites. And this presentation gets the award for cramming the largest number of slides into a 15-minute talk that I've ever seen. This is some elegant work by Subramanian and this is abstract 233 entitled Spatial Temporal Control of NRRP3 Inflammasome Assembly and Activation by GSK3 Beta PI4 K2 Alpha Axis. And what this is building on is there was some conflict in the literature about where the NRRP inflammasome is localized during its activation and where does it put together the disk. One group said it was in the mitochondria, another group said it was in the Golgi. But what they showed very elegantly here, it depends when you take the snapshot, and that it's actually a much more dynamic situation in that GSK3 Beta is binding to the NRRP inflammasome and acting as kind of a facilitator of moving through the mitochondria, from the mitochondria to the Golgi and then it appears as if the disk is formed adjacent to the Golgi and that leads to the full-blown inflammasome activation. Also what's very interesting about this, and it's something I think is going to be on the radar more and more in science these days, is they are looking at MAMs and the formation of crosstalk between the mitochondria and adjacent organelles and how regulation of those organelles and dysregulation of those organelles can interrupt that crosstalk and alter signaling just by spatial separation of those points. So that, in a nutshell, is my summary. And I apologize if you guys expected me to summarize all 937 abstracts. I don't think I could do that even if I was a professional auctioneer, but I hope you enjoyed it. Now this is my personal opinion of what I thought was interesting, there was a lot of fantastic things going on, keep in mind lots of impactful research, there's a lot of conceptually innovative hypotheses, a lot of technically innovative approaches, and what we're doing in the basic sciences can translate into new understanding and new therapies for the future. Thank you.

basic science research

liver meeting

liver fibrogenesis

microbiome influences

regenerative medicine

immune responses in liver diseases