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A Dual Role of Caspase-8 in Triggering and Sensing Proliferation-Associated DNA Damage, a Key Determinant of Liver Cancer Development

A Dual Role of Caspase-8 in Triggering and Sensing Proliferation-Associated DNA Damage, a Key Determinant of Liver Cancer Development

but not Mcl-1 Dhep /TNFR1 / mice, displayed substantial cas- pase-8 cleavage ( Figures S3 C and S3D). Similar to LPS/DGal- challenged wild-type mice treated with the caspase-8 inhibitor zITED ( Figure S3 E), Mcl-1 Dhep mice treated with zITED also dis- played significantly decreased ALT levels (and AST, data not shown) and significantly less hepatocyte apoptosis ( Figures S3 F and S3G). In contrast, treating Mcl-1 Dhep mice with the cas- pase-1 inhibitor, YVAD-CMK, used as an off-target control for zITED, did not affect ALT levels ( Figure S3 F). Thus, hepatocyte apoptosis in Mcl-1 Dhep mice was caspase-8 dependent. Remarkably, Mcl-1 Dhep /TNFR1 / mice demonstrated a sig- nificantly reduced tumor incidence at 1 year compared with Mcl-1 Dhep mice (28% versus 50%, p < 0.05; Figures 3 C and 3D). In line with the data presented above, those Mcl-1 Dhep / TNFR1 / mice that developed liver tumors also displayed significantly higher transaminase levels at 2 months ( Figure 3 E). Further analyses of the microenvironment of Mcl-1 Dhep livers revealed: (1) no activation of canonical nuclear factor kB (NF-kB) signaling ( Figure S3 H), (2), no or only low levels of inflam- masome activation as determined by cleaved caspase-1 and cleaved interleukin-1b (IL-1b) levels ( Figure S3 I and data not shown), and (3) a significant increase expression of several in- flammatory cytokines IL6, IL33, and IFNg (with reduced levels of IL6, IL33, and IFNg in Mcl-1 Dhep /TNFR1 / livers; Figure S3 J). Collectively, these findings show that the association between high apoptotic activity of hepatocytes (in early disease stages) with subsequent liver cancer development previously described for CLD patients also exists in Mcl-1 Dhep mice. Furthermore, they suggest that persistently increased hepatocyte apoptosis, resulting in regenerative proliferation and high DNA replica- tion rate, determines hepatocarcinogenesis. This hypothesis is underpinned by stochastic considerations ( Figure S4 ).
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Gutenberg Open Science: Patient-derived cancer cells to dissect the molecular basis of treatment response in primary liver cancer: a mechanistic and functional approach

Gutenberg Open Science: Patient-derived cancer cells to dissect the molecular basis of treatment response in primary liver cancer: a mechanistic and functional approach

Developing a new liver cancer model, which would fulfill these important criteria, could help to better understand complex processes that occur during disease initiation and progression, but most importantly, to help finding adequate treatment strategy for each patient. We successfully generated seven PDCL from a Western cohort of patients as a representative model to study hepatocellular and cholangiocarcinoma. In our study, we comprehensively analyzed the newly generated PDCL and matched primary cancers on several different levels. We perform transcriptomic and genomic analyses to confirm the utility of the newly- derived PDCL as a patient-specific in vitro model. A key goal of our study was to explore whether PDCL closely resemble the molecular and phenotypic features as well as key oncogenic alterations present in matched primary tumors. Therefore, we performed long-term cultivation of PDCL and propagated them continuously for more than 30 passages in vitro. Finally, we tried to identify potentially actionable genetic and transcriptomic targets for individual PDCL and predict a treatment response in order to determine potential utility of PDCL for individualized treatments strategies.
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Conditional gene targeting of Hif1a reveals an unexpected protective role of myeloid cells in liver cancer cachexia

Conditional gene targeting of Hif1a reveals an unexpected protective role of myeloid cells in liver cancer cachexia

Introduction case of a non-cirrhotic liver or a liver with atypical nodules, pathological analyses should be performed with biopsy samples collected from patients [18]. Treatment of HCC can be carried out with curative or palliative intent. HCC patients diagnosed with early-stage cancer according to Barcelona Clinic Liver Cancer (BCLC) strategy are treated by surgical resection, liver transplantation, or ablation. These treatments can be classified as curative due to their high rate of complete responses [17]. However, early detection is usually difficult in liver cancer, and patients are commonly diagnosed at late stages of the disease. In this case, curative approaches are no longer considered as a treatment option, since complete tumor resection is difficult and post-operative liver failure becomes a risk factor. Transarterial chemoembolization (delivery of chemotherapy agents to tumor via the hepatic artery) and sorafenib (a multikinase inhibitor having activity against c-Raf, B-Raf, VEGFR2, PDGFR, and c-Kit) treatment are palliative approaches with improved survival rates [19, 20]. Arterial embolization without chemotherapy, systemic chemotherapy, external radiotherapy, and radioembolisation failed to prove significant survival benefits for HCC patients [19, 21].
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A Dual Role of Caspase-8 in Triggering and Sensing Proliferation-Associated DNA Damage, a Key Determinant of Liver Cancer Development

A Dual Role of Caspase-8 in Triggering and Sensing Proliferation-Associated DNA Damage, a Key Determinant of Liver Cancer Development

but not Mcl-1 Dhep /TNFR1 / mice, displayed substantial cas- pase-8 cleavage ( Figures S3 C and S3D). Similar to LPS/DGal- challenged wild-type mice treated with the caspase-8 inhibitor zITED ( Figure S3 E), Mcl-1 Dhep mice treated with zITED also dis- played significantly decreased ALT levels (and AST, data not shown) and significantly less hepatocyte apoptosis ( Figures S3 F and S3G). In contrast, treating Mcl-1 Dhep mice with the cas- pase-1 inhibitor, YVAD-CMK, used as an off-target control for zITED, did not affect ALT levels ( Figure S3 F). Thus, hepatocyte apoptosis in Mcl-1 Dhep mice was caspase-8 dependent. Remarkably, Mcl-1 Dhep /TNFR1 / mice demonstrated a sig- nificantly reduced tumor incidence at 1 year compared with Mcl-1 Dhep mice (28% versus 50%, p < 0.05; Figures 3 C and 3D). In line with the data presented above, those Mcl-1 Dhep / TNFR1 / mice that developed liver tumors also displayed significantly higher transaminase levels at 2 months ( Figure 3 E). Further analyses of the microenvironment of Mcl-1 Dhep livers revealed: (1) no activation of canonical nuclear factor kB (NF-kB) signaling ( Figure S3 H), (2), no or only low levels of inflam- masome activation as determined by cleaved caspase-1 and cleaved interleukin-1b (IL-1b) levels ( Figure S3 I and data not shown), and (3) a significant increase expression of several in- flammatory cytokines IL6, IL33, and IFNg (with reduced levels of IL6, IL33, and IFNg in Mcl-1 Dhep /TNFR1 / livers; Figure S3 J). Collectively, these findings show that the association between high apoptotic activity of hepatocytes (in early disease stages) with subsequent liver cancer development previously described for CLD patients also exists in Mcl-1 Dhep mice. Furthermore, they suggest that persistently increased hepatocyte apoptosis, resulting in regenerative proliferation and high DNA replica- tion rate, determines hepatocarcinogenesis. This hypothesis is underpinned by stochastic considerations ( Figure S4 ).
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Deleted in Liver Cancer 3 (DLC3) in the regulation of junctional Rho signaling and cell polarity

Deleted in Liver Cancer 3 (DLC3) in the regulation of junctional Rho signaling and cell polarity

DLC1, the best studied family member, was first discovered in 1998 as candidate tumor suppressor which is lost in primary hepatocellular carcinoma (HCC) and HCC-derived cell lines (Yuan et al., 1998). Later it was shown that p122RhoGAP, originally identified as a phospholipase Cδ1 (PLCδ1)-interacting protein in rat brain (Homma and Emori, 1995), represents the rat orthologue of human DLC1. This is an example for the existence of DLC orthologues in other vertebrates, which is the case for each of the three DLC proteins. Apart from HCC, DLC1 expression is lost in numerous types of cancer, including breast, colorectal, lung, ovarian and prostate cancer. Deregulated DLC1 levels are caused by deletion of the DLC1 locus, mapped to chromosome 8 (8p21.3-22), or epigenetic gene inactivation by promotor hypermethylation (Durkin et al., 2007b). Reconstitution of DLC1 expression in tumor cell lines lacking endogenous DLC1 inhibited cell proliferation and tumor development in the mouse model, supporting its function as candidate tumor suppressor (Yuan et al., 2003). Moreover, stable expression of DLC1 in human liver and breast cancer cell lines reduced the migration and invasion properties of these cells (Goodison et al., 2005; Wong et al., 2005). Finally, the role of DLC1 as a tumor suppressor was clearly proven in a new mouse model of liver cancer (Xue et al., 2008). Investigations of the cellular effects of DLC1 depletion by RNA-interference revealed enhanced stress fiber and focal adhesion formation in breast cancer cells associated with increased cell migration. Conversion of cells towards this motile phenotype was induced by aberrant Rho signaling and activation of the Rho effector protein Dia1 (Holeiter et al., 2008). In general, DLC1 displays a broad tissue distribution with high expression levels in lung and ovary and moderate abundance in kidney, spleen, intestine and thyroid. Four different transcript variants have been reported for the DLC1 locus, but their relative abundance, tissue distribution and biological functions remain to be determined (Ko et al., 2010; Lukasik et al., 2011). The finding that DLC1 knockout causes a lethal phenotype in mice due to severe neural tube, brain and cardiac defects (Durkin et al., 2005; Sabbir et al., 2010), points out the relevance of DLC1 in embryonic development and tissue morphogenesis.
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The transforming growth factor-beta signaling axis in liver cancer progression and intrahepatic metastasis / submitted by Petra Koudelkova

The transforming growth factor-beta signaling axis in liver cancer progression and intrahepatic metastasis / submitted by Petra Koudelkova

HCC is the most common primary liver malignancy and accounts for 90% of all liver cancer cases worldwide (Llovet, Zucman-Rossi et al., 2016). The cellular origin of HCC has been for a long time a matter of discussion, as the HCC evince high degree of heterogeneity not only among the various cases but also within the same tumor. Several HCC tumors show stem cell features and combined HCC-iCCA may show an intermediate phenotype between cholangiocytes and hepatocytes (Sia, Villanueva et al., 2017). Thus, hepatic progenitor cells have been suggested to be a possible source of several liver tumors with stem-like properties (Lee, Heo et al., 2006, Roskams, 2006, Roskams, Libbrecht et al., 2003). However, some authors suggest that only mature hepatocytes may directly give rise to HCC (Marquardt, 2016, Mu, Espanol-Suner et al., 2015, Shin, Wangensteen et al., 2016). Plasticity of mature hepatocytes together with their origin in progenitor cells enables a switch between hepatocytes, progenitor cells and cholangiocytes. Hepatocytes may dedifferentiate into their precursors and give rise to a tumor with progenitor properties or transdifferentiate into cholangiocyte-like cells and give rise to iCCA (Chen, Wong et al., 2012, Tarlow, Pelz et al., 2014). Mature cholangiocytes lack this plasticity and they can only give rise to cholangiocarcinoma (Guest, Boulter et al., 2014, Tanimizu, Nakamura et al., 2013). Regardless to the cellular origin, HCCs which evince stem-cell features are generally more aggressive with worse clinical prognosis (Kim, Choi et al., 2011, Roskams, 2006).
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HCV-induced epigenetic changes associated with liver cancer risk persist after sustained virologic response

HCV-induced epigenetic changes associated with liver cancer risk persist after sustained virologic response

cDNA-uPA þ/þ /SCID þ/þ (uPA/SCID) mice were created and human hepatocytes were transplanted as described previously. 1 Mice were intravenously inoculated with serum samples containing 10 5 HCV particles. The viremic serum was obtained from an HCV-infected (genotype 1b) DAA- naïve patient who provided written informed consent to participate in the study, according to the process approved by the ethical committee of the hospital and in accordance with the ethical guidelines of the 1975 Declaration of Hel- sinki. Blood sampling was done weekly, and serum samples were divided into small aliquots and stored in liquid ni- trogen before measurement of HCV RNA. All animal pro- tocols were performed in accordance with the Guide for the Care and Use of Laboratory Animals (https://grants.nih. gov/grants/olaw/guide-for-the-care-anduse-of-laboratory- animals.pdf). The experimental protocol was approved by the Ethics Review Committee for Animal Experimentation of the Graduate School of Biomedical Sciences at Hiroshima University (A14-195). Sixteen mice were divided into 3 groups: 6 mice were infected with HCV and treated with DAAs, 5 mice were infected with HCV but were not treated with DAAs, and 5 uninfected and untreated mice were used as controls. After the establishment of stable viremia, HCV- infected mice were treated with a combination of MK-7009 (vaniprevir; Merck Sharp & Dohme Corp, Kenilworth, NJ) and BMS-788329 (NS5A inhibitor; Bristol-Meyers Squibb, New York, NY) as described previously. 2 Elimination of HCV in 6 treated mice was confirmed by the absence of HCV viremia 12 weeks after cessation of therapy and by unde- tectable HCV RNA by reverse transcription-nested poly- merase chain reaction from extracted liver tissue. Five viremic mice and 5 control mice were sacri ficed at week 8. All liver samples were snap frozen and stored at 80  C before analysis.
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The functional role of TRIM71 in childhood liver cancer

The functional role of TRIM71 in childhood liver cancer

Genetic alterations in several chromosomes were identified, for instance, the gains of chromosomes 1q, 2q, 2p, 6q, 8q, 17q and 20q, and losses of chromosome 4q [12]. Recently, Cairo and his group [13] found that gains on chromosomal region 8q and 2q were associated with a C2 subclass of HB. It is named C1 and C2 by using gene expression profiling this group that identified two subclasses of HB tumors. C1 and C2 exhibit similarity with distinct phases of liver development. Compared to the fetal-like C1 subclass, C2 conforms to an proliferate faster embryonal histotype. In addition, the group investigated that the C2 tumors display intensive nuclear accumulation of β-catenin and the cell cycle related genes are highly expressed. They introduced a 16-gene signature which classify the tumors into C1 and C2 subclasses based on the most differentially expressed genes [13]. Remarkably, the 16-gene signature can not only predicted prognosis with high accuracy, but also discriminates invasive and metastatic HB [14]. Recently, Gröbner et al. analyzed 24 types of adult cancer entities and all major childhood cancer entities and proved that HB has the lowest mutation rate among all kinds with about 4 mutations per tumor [15]. Notably, among all abnormal signaling pathways in HB, β-catenin mutations [16, 17] present with the highest rate (50-90%). Moreover, the Wnt/β- catenin signaling pathway plays a wildly known major role in hepatic-related tumor development. Other important signaling pathways in HB genesis are AKT-signaling and the LIN28B/let-7 pathway, which are also altered in many kinds of human cancers.
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Liver and Intrahepatic Bile Ducts Cancer (ICD-10 C22) in Germany

Liver and Intrahepatic Bile Ducts Cancer (ICD-10 C22) in Germany

Worldwide, liver cancer accounts for 5.9% of all cancer cases and 9.2% of all cancer related-death, thus ranking the third among the most leading cause of cancer mortality (1). In the year 2008, there were a total of 749,000 new cases diagnosed with this cancer around the world, of this approx. 696,000 people died (1). Generally, liver cancer is associated with a very poor prognosis. In Europe, liver cancer survival rate is among the worst survival rates observed for cancer patients, third only to cancers of the pancreas and pleura (2). The most common risk factors for liver cancer are hepatitis B and C viral infections, heavy alcohol consumption and contamination of food with aflatoxins B1. Other possible risk factors include smoking, obesity and type 2 diabetes (3,4). Liver cancer occurrence varies widely and its time trend is changing across the world which suggests variability in the distribution of the above mentioned risk factors (5,6). High incidence and mortality rates are reported in developing countries in East and Southeast Asia, and sub-Saharan Africa (1). However, declining trends were already observed mainly in Asia regions (7,8) as a result of implementation of control measures against hepatitis viruses and aflatoxins B1 which are highly prevalent among liver cancer patients in those regions (5,9,10). On the other hand, rising trends of this cancer have been observed in many developed countries where liver cancer is less frequent (11-16). Reasons for these increases are not clearly understood, however, the rising prevalence of HCV infection (5,11,17), and possibly diabetes and obesity are likely to have contributed (18).
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The role of growth hormone receptor in liver fibrosis and cancer / submitted by Patricia McMahon

The role of growth hormone receptor in liver fibrosis and cancer / submitted by Patricia McMahon

tumor suppressors and activating oncogenic pathways (Aravalli et al., 2008; Arzumanyan et al., 2013; Roberts and Gores, 2005). Each tumor acquires about 30-40 mutations, including gain of function, loss of function and point mutation, which give rise to very heterogeneous tumors (Cleary et al., 2013; Guichard et al., 2012; Kan et al., 2013; Villanueva et al., 2007). Multiple deep-sequencing studies revealed that CTNNB1 and TP53 are often mutated in HCC and are commonly mutually exclusive (Cleary et al., 2013; Guichard et al., 2012). A recently discovered mutation in the telomerase reverse-transcriptase (TERT) promoter was found to be mutated in 60% of all HCC cases, making it an important target for future HCC treatment (Nault et al., 2013). Many different signaling pathways have been implemented to play a critical role in liver cancer development. Amongst them are growth promoting, survival and proliferative pathways (e.g. PI3K/AKT/mTOR and RAS/RAF/MEK/ERK) (Ito et al., 1998; Wang et al., 2013; Zhou et al., 2011) as well as developmental pathways (e.g. HGF/c-MET and WNT/β-catenin) (Goyal et al., 2013; Takigawa and Brown, 2008). In addition, growth factors and their receptors including EGF/EGFR, VEGF/VEGFR, PDGF/PDGFR and IGF- 1/IGF1R are important key players in the establishment of HCC (Cervello et al., 2012). Of note, EGFR was found to be overexpressed in more than 60% of human HCC cases and gene copy number was altered in over 44% of cases (Buckley et al., 2008). Nevertheless, EGFR inhibitors have failed to give promising results in clinical trials. Recently, active EGFR signaling in infiltrating macrophages was reported to play a crucial role during HCC development, which led to IL-6 up-regulation and tumor growth (Lanaya et al., 2014).
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Mast Cells in Liver Fibrogenesis

Mast Cells in Liver Fibrogenesis

2.3.1. Chemical-Based Injury Models Most common are models in which a toxic chemical substance (hepatotoxin), such as carbon tetrachloride (CCl 4 ) or thioacetamide (TAA), is repeatedly administrated over a longer period [ 75 , 77 ]. At early time points, the applied toxins induce acute inflammation, while long-term intoxication results in robust and highly reproducible fibrosis, cirrhosis, or even HCC. During the acute phase, Kupffer cells induce an inflammatory response associated with secretion of chemokines, cytokines, and many other pro-inflammatory factors. This milieu attracts phagocytic active white blood cells (monocytes, neutrophils, and lymphocytes), stimulating parenchymal necrosis. While short-term injections of toxins are often used to study liver regeneration after toxic injury, the prolonged application of these compounds are the most widespread models for analyzing hepatic fibrogenesis. Toxic drugs much less frequently used in liver fibrosis research are dialkyl nitrosamines, such as dimethylnitrosamine (DMN) and diethylnitrosamine (DEN). These are hepatocarcinogens that provoke severe liver damage in mice when given parenterally or orally [ 81 ]. In the acute phase, these compounds provoke intense neutrophilic infiltration and extensive centrilobular haemorrhagic necrosis. When applied for longer periods, both DMN and DEN induce massive bile duct proliferation, ending in fibrosis, bridging necrosis, and in liver cancer [ 81 ]. Based on their mutagenic and carcinogenic properties, DMN and DEN are frequently used in translational research by investigators interested in recapitulating the multi-stage process of human liver carcinogenesis or the formation of HCC.
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Outcomes of liver transplantation for non-alcoholic steatohepatitis: A European Liver Transplant Registry study

Outcomes of liver transplantation for non-alcoholic steatohepatitis: A European Liver Transplant Registry study

Recipient factors analysed included age at transplant, sex, height, weight, BMI, blood group, primary liver diagnosis, pres- ence of HCC, serum creatinine, serum bilirubin, international normalized ratio (INR) and the model for end-stage liver disease (MELD) score. Creatinine, bilirubin and INR had high frequencies of missing data (>50%), and thus were not used as independent variables in analyses but contributed to MELD when possible. Of note, other metabolic risk factors including smoking, type 2 dia- betes, hypertension, hyperlipidaemia and a prior history of ischaemic heart disease were not included in the dataset. Donor factors included age at death/donation, sex, BMI, blood group, and type of donor (donation after circulatory death (DCD), dona- tion after brainstem death, living related donor, domino donor). Outcome domains comprised of patient and graft survival status, re-transplant rates, duration of follow-up and causes of death, as coded in the ELTR database. Primary causes of death were used for analyses. Secondary, tertiary and un-coded free- text causes of death were considered if the primary cause was coded as other or unknown.
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Applied precision cancer medicine in metastatic biliary tract cancer

Applied precision cancer medicine in metastatic biliary tract cancer

Emerging techniques, such as profiling tumor molecular alterations and mutations, identifying molecular targets ame- nable to specific treatments, and developing drug treatments specific to an individual patient, have created the potential for novel and effective therapies. This approach is known by a number of different names, including individualized, stratified, tailored, or precision cancer medicine (PCM). The main rationale of PCM is to match a therapeutic agent to its corresponding molecular target to allow a precise treatment tailored to a specific patient. It aims to achieve a better and more sustained response than do more generic treatments, without damaging healthy cells and tissues.
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Shaping the future of liver surgery: Implementation of experimental insights into liver regeneration

Shaping the future of liver surgery: Implementation of experimental insights into liver regeneration

vWF-Ag during liver regeneration in mice [ 27 ]. They showed the central importance of vWF-Ag-dependent platelet accumulation especially during the early pe- riod after induction of liver regeneration. Indeed, the significance of platelets and platelet stored factors for a well-functioning liver regeneration has previ- ously been shown by our group as well as by other researchers [ 12 , 28 , 29 ]. Thus, we took a closer look at vWF-Ag secretion during the early phase of liver re- generation (i. e., the first 2 h after portal vein ligation) in the human setting. Astonishingly, our results pre- cisely followed the experimental data by Kirschbaum et al. We were able to validate previous reports on platelet accumulation within the regenerating liver. Interestingly, we also observed an increase in vWF-Ag within no more than 2 h of induction of liver regener- ation. Most importantly, this initial increase was only seen in patients who did not develop LD in the post- operative time course, while patients with LD were not able to substantially secrete vWF-Ag in the early phase of liver regeneration. This led to the hypothesis that an initial burst in vWF-Ag might be relevant for induction of platelet-mediated liver regeneration.
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Mechanisms of liver fibrosis resolution

Mechanisms of liver fibrosis resolution

Conclusions Important mechanisms for the reversibility of liver fibrosis are the cessation of chronic damage (allowing hepatocyte recovery and modulating the microenvironment), shifting the balance from inflammation to resolution (leading to phenotypic adjustments of the immune cells, especially induction of restorative macrophages), deactivation of myofibroblasts (by senescence, apoptosis and inactivation) and, finally, matrix degradation (reflected by an altered balance between matrix stabilizing and matrix degrading factors).

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Gutenberg Open Science: Dietary wheat amylase trypsin inhibitors worsen chronic liver disease in preclinical models of non-alcoholic fatty liver disease and liver fibrosis

Gutenberg Open Science: Dietary wheat amylase trypsin inhibitors worsen chronic liver disease in preclinical models of non-alcoholic fatty liver disease and liver fibrosis

The intestinal microbiota possess approximately 100-fold more genetic information that the mammalian body and much of this information is conveyed to the host via secretion of various metabolites and hormones directly into the gut and the intestinal lamina propria. Additionally, the liver is a central organ located between the intestine and other organs representing a unique “buffer zone” that directly receives signals from the gut that stem from, e.g. nutrients, metabolites toxins, or hormones. Therefore, the interaction between the intestine and the liver including also the immune systems of these organs and the first hepatic metabolism of gut derived nutrients, toxins and metabolites in the liver has gained great attention. In this context and expanding number of studies both in vivo and in vitro have focused on this gut-liver axis demonstrating its relevance in health or disease of both organs and other organs of the body. Primary diseases that are affected by the gut-liver axis are, e.g. alcoholic (ALD) and non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), cholestatic liver diseases, hepatocellular carcinoma (HCC) and liver fibrosis/cirrhosis and their further complications in general. 54 Importantly,
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Deficiency in Thrombopoietin Induction after Liver Surgery Is Associated with Postoperative Liver Dysfunction

Deficiency in Thrombopoietin Induction after Liver Surgery Is Associated with Postoperative Liver Dysfunction

Postoperative LD was evaluated based on the previously proposed criteria by Balzan et al [ 25 ]. The so-called “50–50 criteria” identify patients with a prothrombin time (PT) < 50% and a serum bilirubin (SB) level > 50 µmol/l corresponding to an SB concentration > 2.9 mg/dl. Balzan et al. were able to demonstrate that patients with an SB value > 50 µmol/l and a PT < 50% on POD 5 had a significant increase of postoperative mortality. Furthermore, in patients with significant morbidity this “50–50 criterium” was met 3 to 8 days before clinical evidence of complications. We thus recorded the respective liver function parameters during the first postoperative week. As the focus of this study was to detect delayed hepatic regeneration and not only complete liver failure, an SB concentration > 2.9 mg/dl and a PT value < 50% on any day within the first postoperative week were defined as postopera- tive LD.
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Cancer in Germany2009/2010

Cancer in Germany2009/2010

nificantly more differentiated diagnostics and the use of multimodal therapy concepts. In the early 1980s the chances of children with cancer being still alive five years after diagnosis were 67 %; this figure has risen to 84 % since then. Looking at all patients of the registry population who were diagnosed bet- ween 2001 and 2010 and followed up, the overall chance of survival is 84 % after five years, 82 % after ten years, and 81 % after 15 years. The encouraging increase in the number of long-term survivors is increasingly focusing attention on the long-term observation of former paediatric cancer patients. The GCCR provides an ideal data basis for carrying out studies with long-term survivors. As the above figu- res show, it is already possible to provide information on long-term survival (for example after 15 years) and to estimate the risk of developing a second malig- nancy after cancer in childhood. Examples of further research possibilities include the incidence of other long-term effects, such as the possible effects of the- rapy on fertility, and studies examining the health risks of the descendants of fathers and mothers who had childhood cancer. About 22,000 of the more than 37,000 patients currently known to be alive have been under observation by the registry for at least ten years. About three quarters of these patients are at least 18 years old.
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Dual CTLA-4 and PD-L1 Blockade Inhibits Tumor Growth and Liver Metastasis in a Highly Aggressive Orthotopic Mouse Model of Colon Cancer

Dual CTLA-4 and PD-L1 Blockade Inhibits Tumor Growth and Liver Metastasis in a Highly Aggressive Orthotopic Mouse Model of Colon Cancer

inhibition. Immunohistological analyses revealed significantly lower vessel maturation, an increase in VEGFR2-positive angiogenic microvessels and significantly enhanced VEGF-A levels after dual CTLA-4 and PD-L1 blockade ( Figure 6 ). Nevertheless, no major alterations in the amplitude A, a parameter of the relative blood volume, were measured by DCE-MRI, demonstrating that these changes were restricted to the microvessels and that the functional vasculature was not influenced by either sole or dual immune checkpoint inhibition. Moreover, combination therapy induced a stromal reaction, as obvious by the significant accumulation of PDGFR-β + and FAP+ fibroblasts and strong deposition of collagen I in the colon carcinomas ( Figure 6 ). Tumor-associated fibroblasts have been shown to promote angiogenesis by secreting VEGF-A and other cytokines and chemokines as well as matrix metalloproteinases which may provide an explanation for the increase in VEGFR2-positive angiogenic microvessels [46,47] . However, contradictory observa- tions have been made with regard to their role in cancer progression. On the one hand, tumor-promoting functions of fibroblasts have been described (e.g., by facilitating cancer cell invasion, by stimulating tumor angiogenesis and by modulating tumor immuni- ty), they have been identified as mediators of drug resistance and are currently discussed to be involved in resistance towards immune checkpoint blockade [46] . On the other hand, activation of fibroblasts can be induced as a defense mechanism in order to impair cancer progression. Recently, fibroblasts have been shown to inhibit cancer progression in a mouse model of pancreatic ductal adenocarcinoma, and depletion of these cells resulted in a diminished survival of the tumor-bearing mice [48] . Whether the stromal response induced in the orthotopic colon tumors upon dual immune checkpoint inhibition reflects stable disease due to efficient immunotherapy or is rather indicative for a compensatory mechanism of the tumor to induce therapy resistance needs further investigation. In conclusion, our findings show that dual CTLA-4 and PD-L1 blockade exert synergistic inhibitory effects on growth and metastasis of the orthotopic CT26 colon tumors by increasing CD8+ and CD4+ T cells associated with a Th1 response mediated by CTLA-4 inhibition and by inducing a shift towards M1 macrophage polarization, which can mostly be ascribed to PD-L1 blockade. The pronounced stromal response observed after dual immune checkpoint blockade underlines that the effects of immune checkpoint inhibition go beyond immune cell modulation and highlights the link between immunomodulation and desmoplasia.
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Editorial: Cancer Models

Editorial: Cancer Models

We just have to mention that during the last 10 years, the biggest impact and improvement in cancer survival were without any doubt the introduction of new ways to raise the patient’s immune defense against cancer cells as a new form of therapy. This was achieved not only through the newly developed humanized antibodies that recognize cancer cells through binding to neo-antigens, but also due to more subtle interference with the natural regulators of the immune system, for instance IL2, aiming at the induction of apoptosis of tumor cells without imposing a general cytostatic load onto the patient. Spectacular examples of cancers where 5-year survival was extremely low and a complete cure is now possible include certain forms of melanoma ( 14 ). Models for tumor immunology are extremely challenging and will be addressed in a separate research topic.
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