24 HGF might be a key element in the process leading to improvement of liver cirrhosis because this molecule is a powerful hepatoprotective factor and an inducer of hepatocellular differentiation endowed with antifibrogenic activities.17, 25 HGF strongly inhibits the expression of profibrogenic factors such as TGFβ and CTGF, whereas it activates MMP2, MMP9, and MMP14 and reduces TIMP-1 and TIM-2 expression in different cells (reviewed25). These changes were found in SVIGF-I-treated livers making possible a participation of HGF/c-met induction in the antifibrogenic effect Selleckchem Poziotinib of IGF-I (Figs. 5, 6, Supporting Fig. 3). MMP1, MMP2, and MMP14

act as efficient collagen proteases, which could account for the fibrolysis observed with IGF-I therapy. Reduced activation

of HSCs could also result from decreased expression of PDGF, VEGF, and TGFβ (Fig. 6), which have been involved in activation, proliferation, migration, and increased extracellular matrix deposition from HSCs.14, 15 Therefore, IGF-I may favor resolution of the cirrhotic lesion by activation of fibrolysis and reduction of fibrogenesis. This is similar to what has been described for spontaneous reversion of cirrhosis in rats26 and opposite to the mechanisms involved in cirrhosis progression in humans,27 opening the possibility that IGF-I treatment could also decrease fibrosis progression in patients. Although the presence of cross-linking of collagen can make long-standing liver cirrhosis selleck inhibitor in humans more difficult to revert than in experimental animals, still IGF-I-based therapy may have a role in these cases as it may exert

hepatoprotective activities, halt fibrogenesis, and partially revert liver fibrosis. Activated HSCs decrease in SVIGF-I-treated livers (Fig. 4). We could not determine with certainty whether activated HSCs undergo apoptosis and/or deactivation. Although we could not clearly detect HSC apoptosis at the time of the sacrifice, this process might have occurred at an earlier timepoint taking into account the marked reduction in fibrous septa observed in SVIGF-I-treated rats. However, as mentioned above, up-regulation of neurotrimin and the presence of vimentin-positive, αSMA-negative cells in the find more remaining septa of cirrhotic rats given SVIGF-I argue in favor of HSC deactivation (Supporting Fig. 2). Importantly, IGF-I-based therapy also leads to improvement of liver function probably due to the induction of hepatoprotective factors, such as HGF, together with up-regulation of HNF4α, which stimulates differentiated hepatocellular functions (Fig. 7).20 Up-regulation of HNF4α is paralleled by down-regulation of WT-1 (Fig. 7), a nuclear factor that mediates the loss of differentiated hepatocellular functions.19 WT-1 is up-regulated by TGFβ and it seems possible that the reduction in the expression of this cytokine may contribute to diminish WT-1 and to increase HNF4α abundance.

24 HGF might be a key element in the process leading to improvement of liver cirrhosis because this molecule is a powerful hepatoprotective factor and an inducer of hepatocellular differentiation endowed with antifibrogenic activities.17, 25 HGF strongly inhibits the expression of profibrogenic factors such as TGFβ and CTGF, whereas it activates MMP2, MMP9, and MMP14 and reduces TIMP-1 and TIM-2 expression in different cells (reviewed25). These changes were found in SVIGF-I-treated livers making possible a participation of HGF/c-met induction in the antifibrogenic effect selleck chemicals llc of IGF-I (Figs. 5, 6, Supporting Fig. 3). MMP1, MMP2, and MMP14

act as efficient collagen proteases, which could account for the fibrolysis observed with IGF-I therapy. Reduced activation

of HSCs could also result from decreased expression of PDGF, VEGF, and TGFβ (Fig. 6), which have been involved in activation, proliferation, migration, and increased extracellular matrix deposition from HSCs.14, 15 Therefore, IGF-I may favor resolution of the cirrhotic lesion by activation of fibrolysis and reduction of fibrogenesis. This is similar to what has been described for spontaneous reversion of cirrhosis in rats26 and opposite to the mechanisms involved in cirrhosis progression in humans,27 opening the possibility that IGF-I treatment could also decrease fibrosis progression in patients. Although the presence of cross-linking of collagen can make long-standing liver cirrhosis selleck compound in humans more difficult to revert than in experimental animals, still IGF-I-based therapy may have a role in these cases as it may exert

hepatoprotective activities, halt fibrogenesis, and partially revert liver fibrosis. Activated HSCs decrease in SVIGF-I-treated livers (Fig. 4). We could not determine with certainty whether activated HSCs undergo apoptosis and/or deactivation. Although we could not clearly detect HSC apoptosis at the time of the sacrifice, this process might have occurred at an earlier timepoint taking into account the marked reduction in fibrous septa observed in SVIGF-I-treated rats. However, as mentioned above, up-regulation of neurotrimin and the presence of vimentin-positive, αSMA-negative cells in the selleck remaining septa of cirrhotic rats given SVIGF-I argue in favor of HSC deactivation (Supporting Fig. 2). Importantly, IGF-I-based therapy also leads to improvement of liver function probably due to the induction of hepatoprotective factors, such as HGF, together with up-regulation of HNF4α, which stimulates differentiated hepatocellular functions (Fig. 7).20 Up-regulation of HNF4α is paralleled by down-regulation of WT-1 (Fig. 7), a nuclear factor that mediates the loss of differentiated hepatocellular functions.19 WT-1 is up-regulated by TGFβ and it seems possible that the reduction in the expression of this cytokine may contribute to diminish WT-1 and to increase HNF4α abundance.

4, 5 The role of β-catenin in hepatic progenitors has been recently identified. Significant colocalization of the oval cell and ductular marker A6 and β-catenin is observed after DDC feeding in mice.6 In β-catenin null liver, atypical ductular proliferation is significantly blunted, indicating a role of β-catenin in induction and proliferation of ductular cells after DDC injury. Likewise, another study reported expression of β-catenin and multiple

Wnt ligands in oval cells after DDC injury.7 Here we investigate the role of β-catenin in chronic hepatobiliary injury in mice in response to long-term DDC exposure, which resembles the primary sclerosing cholangitis (PSC) phenotype and leads to chronic atypical ductular proliferation and oval cell response.2, 8 Wildtype (WT) and β-catenin conditional liver knockout (KO) mice were exposed to the DDC diet for 80-150 days and examined histologically and biochemically Tipifarnib research buy for the ductular response and liver injury. Interestingly, we found that, in the absence of β-catenin, a sustained atypical ductular proliferation occurs in the long term, along with the development of significant hepatic fibrosis, which results in significant intrahepatic cholestasis. Further evaluation identified a small subset of hepatocytes LDK378 ic50 in baseline KO livers that escape albumin-cre-mediated β-catenin deletion that have a growth advantage after the DDC injury and eventually repopulate the KO livers

by β-catenin-positive hepatocytes, which results in modest but significant alleviation of hepatocyte injury. Although both WT and KO livers after chronic DDC exposure displayed enlargement of the livers, KO livers also showed nodular overgrowth due to increased hepatocyte proliferation, although there was no evidence of tumorigenesis. ALP, alkaline phosphatase; ALT, alanine amino transferase; AST, aspartate amino transferase; CEBPα, CCAAT enhancer binding protein-alpha; DAPI, 4,6-diamidino-2-phenylindole;

DDC, 3,5-diethoxycarbonyl-1,4-dihydrocollidine; GS, glutamine synthetase; HNF, hepatocyte nuclear factor; KO, IHC, immunohistochemistry; β-catenin conditional liver knockout mice; PCNA, proliferating cell nuclear antigen; RIPA buffer, radioimmunoprecipitation assay buffer; WT, wildtype littermate control mice. β-Catenin conditional knockout in liver was created as see more described.9 The genotype for these animals is Ctnnb1loxp/loxp; Alb-Cre+/− and are referred to as knockout (KO) mice throughout. As reported previously, all other genotypes were unequivocally devoid of any phenotype and referred henceforth as wildtype (WT) controls. Only male mice were used for all experiments. At the time of sacrifice, retro-orbital bleed was performed for serum biochemistry. Portions of lobes from excised liver were fixed in 10% neutral buffered formalin and processed for paraffin embedding. Part of liver was frozen in Tissue-Tek OTC compound for cryosections.

4, 5 The role of β-catenin in hepatic progenitors has been recently identified. Significant colocalization of the oval cell and ductular marker A6 and β-catenin is observed after DDC feeding in mice.6 In β-catenin null liver, atypical ductular proliferation is significantly blunted, indicating a role of β-catenin in induction and proliferation of ductular cells after DDC injury. Likewise, another study reported expression of β-catenin and multiple

Wnt ligands in oval cells after DDC injury.7 Here we investigate the role of β-catenin in chronic hepatobiliary injury in mice in response to long-term DDC exposure, which resembles the primary sclerosing cholangitis (PSC) phenotype and leads to chronic atypical ductular proliferation and oval cell response.2, 8 Wildtype (WT) and β-catenin conditional liver knockout (KO) mice were exposed to the DDC diet for 80-150 days and examined histologically and biochemically find more for the ductular response and liver injury. Interestingly, we found that, in the absence of β-catenin, a sustained atypical ductular proliferation occurs in the long term, along with the development of significant hepatic fibrosis, which results in significant intrahepatic cholestasis. Further evaluation identified a small subset of hepatocytes X-396 in baseline KO livers that escape albumin-cre-mediated β-catenin deletion that have a growth advantage after the DDC injury and eventually repopulate the KO livers

by β-catenin-positive hepatocytes, which results in modest but significant alleviation of hepatocyte injury. Although both WT and KO livers after chronic DDC exposure displayed enlargement of the livers, KO livers also showed nodular overgrowth due to increased hepatocyte proliferation, although there was no evidence of tumorigenesis. ALP, alkaline phosphatase; ALT, alanine amino transferase; AST, aspartate amino transferase; CEBPα, CCAAT enhancer binding protein-alpha; DAPI, 4,6-diamidino-2-phenylindole;

DDC, 3,5-diethoxycarbonyl-1,4-dihydrocollidine; GS, glutamine synthetase; HNF, hepatocyte nuclear factor; KO, IHC, immunohistochemistry; β-catenin conditional liver knockout mice; PCNA, proliferating cell nuclear antigen; RIPA buffer, radioimmunoprecipitation assay buffer; WT, wildtype littermate control mice. β-Catenin conditional knockout in liver was created as selleck products described.9 The genotype for these animals is Ctnnb1loxp/loxp; Alb-Cre+/− and are referred to as knockout (KO) mice throughout. As reported previously, all other genotypes were unequivocally devoid of any phenotype and referred henceforth as wildtype (WT) controls. Only male mice were used for all experiments. At the time of sacrifice, retro-orbital bleed was performed for serum biochemistry. Portions of lobes from excised liver were fixed in 10% neutral buffered formalin and processed for paraffin embedding. Part of liver was frozen in Tissue-Tek OTC compound for cryosections.

4, 5 The role of β-catenin in hepatic progenitors has been recently identified. Significant colocalization of the oval cell and ductular marker A6 and β-catenin is observed after DDC feeding in mice.6 In β-catenin null liver, atypical ductular proliferation is significantly blunted, indicating a role of β-catenin in induction and proliferation of ductular cells after DDC injury. Likewise, another study reported expression of β-catenin and multiple

Wnt ligands in oval cells after DDC injury.7 Here we investigate the role of β-catenin in chronic hepatobiliary injury in mice in response to long-term DDC exposure, which resembles the primary sclerosing cholangitis (PSC) phenotype and leads to chronic atypical ductular proliferation and oval cell response.2, 8 Wildtype (WT) and β-catenin conditional liver knockout (KO) mice were exposed to the DDC diet for 80-150 days and examined histologically and biochemically BYL719 manufacturer for the ductular response and liver injury. Interestingly, we found that, in the absence of β-catenin, a sustained atypical ductular proliferation occurs in the long term, along with the development of significant hepatic fibrosis, which results in significant intrahepatic cholestasis. Further evaluation identified a small subset of hepatocytes www.selleckchem.com/products/Everolimus(RAD001).html in baseline KO livers that escape albumin-cre-mediated β-catenin deletion that have a growth advantage after the DDC injury and eventually repopulate the KO livers

by β-catenin-positive hepatocytes, which results in modest but significant alleviation of hepatocyte injury. Although both WT and KO livers after chronic DDC exposure displayed enlargement of the livers, KO livers also showed nodular overgrowth due to increased hepatocyte proliferation, although there was no evidence of tumorigenesis. ALP, alkaline phosphatase; ALT, alanine amino transferase; AST, aspartate amino transferase; CEBPα, CCAAT enhancer binding protein-alpha; DAPI, 4,6-diamidino-2-phenylindole;

DDC, 3,5-diethoxycarbonyl-1,4-dihydrocollidine; GS, glutamine synthetase; HNF, hepatocyte nuclear factor; KO, IHC, immunohistochemistry; β-catenin conditional liver knockout mice; PCNA, proliferating cell nuclear antigen; RIPA buffer, radioimmunoprecipitation assay buffer; WT, wildtype littermate control mice. β-Catenin conditional knockout in liver was created as selleck described.9 The genotype for these animals is Ctnnb1loxp/loxp; Alb-Cre+/− and are referred to as knockout (KO) mice throughout. As reported previously, all other genotypes were unequivocally devoid of any phenotype and referred henceforth as wildtype (WT) controls. Only male mice were used for all experiments. At the time of sacrifice, retro-orbital bleed was performed for serum biochemistry. Portions of lobes from excised liver were fixed in 10% neutral buffered formalin and processed for paraffin embedding. Part of liver was frozen in Tissue-Tek OTC compound for cryosections.

The inflammation and CYC202 solubility dmso fibrosis score of each group: The score of blank group is lower than other experimental groups and has statistical significance (P < 0.05); TNBS group and MSODN I, II, III group have no statistical significance (P > 0.05); The scores of Decoy ODN I, II, III group are lower than TNBS group, MSODN I, II, III group and have statistical significance (P < 0.05); Decoy ODN I, II, III group have statistical significance among three groups (P < 0.05). 3. The expression level of IL-1β, TNF-α, Col-IIIα mRNA: Three mRNA expression level of blank group are lower than other experimental groups and

have statistical significance (P < 0.05); TNBS group and MSODN I, II, III group have no statistical significance (P > 0.05); Three mRNA expression level of Decoy ODN

I, II, III group are lower than TNBS group, MSODN I, II, III group and have statistical significance (P < 0.05); Decoy ODN I, II, III group have statistical significance among three groups (P < 0.05). 4. The protein expression change of NF-κB, TGF-β1: The NF-κB, DAPT TGF-β1 protein expression of blank group are lower than other experimental groups and have statistical significance (P < 0.05); TNBS group and MSODN I, II, III group have no statistical significance (P > 0.05);: The NF-κB, TGF-β1 protein expression of Decoy ODN I, II, III group are lower than TNBS group, MSODN I, II, III group and have statistical significance (P < 0.05); Decoy ODN I, II, III group have statistical significance among three groups (P < 0.05). Conclusion: 1. It confirms that selleck chemicals TNBS/EtOH enema can induce the chronic intestinal fibrosis of mice by observing the disease activity index, colonic general observation, pathology and fibrosis of each group. 2. NF-κB Decoy ODN treat for 6 weeks is most significantly which can reduce intestinal inflammation and fibrosis in mice, NF-κB MSODN has no effective treatment. 3. The mechanism of NF-κB Decoy ODN for reducing intestinal inflammation and

fibrosis is to decrease the mRNA expression level of IL-1β, TNF-α, Col-IIIα and the protein expression of NF-κB, TGF-β1. NF-κB Decoy ODN can be a new effective drug for IBD therapy. Key Word(s): 1. IBD; 2. TNBS; 3. intestinal fibrosis; 4. NF-κB Decoy ODN; Presenting Author: JIANMEI YANG Additional Authors: XIAOJING LIU, YU FU, KAIFANG ZOU Corresponding Author: KAIFANG ZOU Affiliations: Huazhong University of Science and Technology; Union Hospital, Tongji Medical Collage, Huazhong University of Science and Technology Objective: Tfh cell plays an important role in humoral immunity. This study aimd at investigating the changes of Tfh cell numbers, plasma cell numbers and the titers of autoantibody in immune-complex induced colitis. Methods: Twelve male BALB/C mice were randomly divided into two groups: control group and model group.

The inflammation and selleck compound fibrosis score of each group: The score of blank group is lower than other experimental groups and has statistical significance (P < 0.05); TNBS group and MSODN I, II, III group have no statistical significance (P > 0.05); The scores of Decoy ODN I, II, III group are lower than TNBS group, MSODN I, II, III group and have statistical significance (P < 0.05); Decoy ODN I, II, III group have statistical significance among three groups (P < 0.05). 3. The expression level of IL-1β, TNF-α, Col-IIIα mRNA: Three mRNA expression level of blank group are lower than other experimental groups and

have statistical significance (P < 0.05); TNBS group and MSODN I, II, III group have no statistical significance (P > 0.05); Three mRNA expression level of Decoy ODN

I, II, III group are lower than TNBS group, MSODN I, II, III group and have statistical significance (P < 0.05); Decoy ODN I, II, III group have statistical significance among three groups (P < 0.05). 4. The protein expression change of NF-κB, TGF-β1: The NF-κB, Cytoskeletal Signaling inhibitor TGF-β1 protein expression of blank group are lower than other experimental groups and have statistical significance (P < 0.05); TNBS group and MSODN I, II, III group have no statistical significance (P > 0.05);: The NF-κB, TGF-β1 protein expression of Decoy ODN I, II, III group are lower than TNBS group, MSODN I, II, III group and have statistical significance (P < 0.05); Decoy ODN I, II, III group have statistical significance among three groups (P < 0.05). Conclusion: 1. It confirms that selleckchem TNBS/EtOH enema can induce the chronic intestinal fibrosis of mice by observing the disease activity index, colonic general observation, pathology and fibrosis of each group. 2. NF-κB Decoy ODN treat for 6 weeks is most significantly which can reduce intestinal inflammation and fibrosis in mice, NF-κB MSODN has no effective treatment. 3. The mechanism of NF-κB Decoy ODN for reducing intestinal inflammation and

fibrosis is to decrease the mRNA expression level of IL-1β, TNF-α, Col-IIIα and the protein expression of NF-κB, TGF-β1. NF-κB Decoy ODN can be a new effective drug for IBD therapy. Key Word(s): 1. IBD; 2. TNBS; 3. intestinal fibrosis; 4. NF-κB Decoy ODN; Presenting Author: JIANMEI YANG Additional Authors: XIAOJING LIU, YU FU, KAIFANG ZOU Corresponding Author: KAIFANG ZOU Affiliations: Huazhong University of Science and Technology; Union Hospital, Tongji Medical Collage, Huazhong University of Science and Technology Objective: Tfh cell plays an important role in humoral immunity. This study aimd at investigating the changes of Tfh cell numbers, plasma cell numbers and the titers of autoantibody in immune-complex induced colitis. Methods: Twelve male BALB/C mice were randomly divided into two groups: control group and model group.

It is important to clinically

validate these models by testing patients diagnosed with schizophrenia on tasks with competing emotional and contextual response determinants. Control NVP-AUY922 in vivo and schizophrenia groups completed a novel task that elicited motor responses consistent with, or in opposition to, pre-potent emotional actions (i.e., approach vs. avoidance). An analogous non-emotional task was also used to examine cue-conflict impairment more generally. The groups demonstrated statistically equivalent performance decrements on incongruent versus congruent trials on both tasks. However, within the schizophrenia group, the incongruency effect was significantly greater in the emotional versus non-emotional task. These data suggest that,

while patients with schizophrenia were able to employ contextual response cues to override competing emotional responses, they were slower to resolve emotional versus non-emotional response conflict. When patients were subdivided according to the presence or absence of disorganized symptoms, this effect was confined to patients with disorganized symptoms. “
“Objective. This study explores the possibility that a post-traumatic amnesia (PTA) like phenomenon is caused by the administration of drugs in hospital following injury and that this may be observed in patients who have not suffered a traumatic brain injury (TBI). This work also explored the possibility for an additional contribution to this phenomenon of demographic and psychological variables. Method. Sixty-three orthopaedic PD-0332991 clinical trial patients with no evidence of brain injury were recruited to a two-phase study. Medication records, demographic, and psychological data were obtained at the phase 1. At follow-up interviews (phase 2), psychological data (mood and post-traumatic stress

disorder, PTSD) were again obtained and retrospective assessment of PTA using the Rivermead PTA protocol was carried out in 47 patients. Results. Thirty-eight per cent (N=18) of the click here total sample (N=47) reported a PTA-like phenomenon despite not having suffered TBI. A logistic regression model including the receipt of opioids, surgery, and anxiety-related variables, was significant in predicting this phenomenon (χ2=22.054, df=4, p≤.01) and accounted for up to 57.5% of variation in the data. Age, either alone or in interaction with opioid use, depression, and PTSD symptoms were not significant predictors. PTA-like phenomenon did not occur without at least one predictive factor. Conclusion. Receiving opioids, undergoing surgery, and suffering clinical levels of anxiety at an early stage following injury, can lead patients who have not suffered a TBI to report a PTA-like phenomenon at follow-up.

It is important to clinically

validate these models by testing patients diagnosed with schizophrenia on tasks with competing emotional and contextual response determinants. Control buy LY294002 and schizophrenia groups completed a novel task that elicited motor responses consistent with, or in opposition to, pre-potent emotional actions (i.e., approach vs. avoidance). An analogous non-emotional task was also used to examine cue-conflict impairment more generally. The groups demonstrated statistically equivalent performance decrements on incongruent versus congruent trials on both tasks. However, within the schizophrenia group, the incongruency effect was significantly greater in the emotional versus non-emotional task. These data suggest that,

while patients with schizophrenia were able to employ contextual response cues to override competing emotional responses, they were slower to resolve emotional versus non-emotional response conflict. When patients were subdivided according to the presence or absence of disorganized symptoms, this effect was confined to patients with disorganized symptoms. “
“Objective. This study explores the possibility that a post-traumatic amnesia (PTA) like phenomenon is caused by the administration of drugs in hospital following injury and that this may be observed in patients who have not suffered a traumatic brain injury (TBI). This work also explored the possibility for an additional contribution to this phenomenon of demographic and psychological variables. Method. Sixty-three orthopaedic www.selleckchem.com/products/wnt-c59-c59.html patients with no evidence of brain injury were recruited to a two-phase study. Medication records, demographic, and psychological data were obtained at the phase 1. At follow-up interviews (phase 2), psychological data (mood and post-traumatic stress

disorder, PTSD) were again obtained and retrospective assessment of PTA using the Rivermead PTA protocol was carried out in 47 patients. Results. Thirty-eight per cent (N=18) of the selleck products total sample (N=47) reported a PTA-like phenomenon despite not having suffered TBI. A logistic regression model including the receipt of opioids, surgery, and anxiety-related variables, was significant in predicting this phenomenon (χ2=22.054, df=4, p≤.01) and accounted for up to 57.5% of variation in the data. Age, either alone or in interaction with opioid use, depression, and PTSD symptoms were not significant predictors. PTA-like phenomenon did not occur without at least one predictive factor. Conclusion. Receiving opioids, undergoing surgery, and suffering clinical levels of anxiety at an early stage following injury, can lead patients who have not suffered a TBI to report a PTA-like phenomenon at follow-up.

g., H77 and Con1), whereas they are refractory to infection by other HCV isolates (e.g., J6 and JFH1; Fig. 1). Second, knockdown of endogenous CLDN6 expression in HuH6 cells confirmed that those isolates that infect these cells do so through CLDN6 (Fig. 3). Of note, we previously showed that naïve HuH6 cells are rendered permissive for viruses with J6-derived envelope proteins upon restoration of CLDN1 expression,[8] thus excluding a general refractoriness of these cells to infection by this HCV type. Third, ectopic expression of CLDN6 and CLDN1 in 293T cells with very low endogenous expression of CLDNs revealed that those strains that infect HuH6

cells (e.g., H77 and Con1) use both CLDN1 and CLDN6, whereas those isolates that are

unable to infect HuH6 cells only efficiently use CLDN1 (e.g., J6 and JFH1; Fig. 2). Finally, transfer of the first portion of the CLDN1 extracellular loop into the backbone of CLDN6 Akt inhibitor rendered cells expressing the chimeric protein partially permissive for isolates with narrow CLDN tropism (Fig. 4). Collectively, these observations strongly support the conclusion of isolate-dependent usage of CLDN1 and CLDN6 by HCV. We did not investigate CLDN9 usage in this work. However, because the respective subdomain is almost fully conserved between CLDN6 and CLDN9 (only residue 28 is polymorphic), it is likely that also CLDN9 usage will be strain specific. In the future, it will be interesting to map viral determinants responsible

for differential CLDN usage, because such signatures may be useful to predict CLDN receptor usage. Such information learn more could be particularly relevant for future therapeutic strategies aiming to block the interaction between HCV and CLDN1 to prevent HCV infection. Recently, Fofana et al. reported potent neutralization of HCV infection by means of CLDN1-specific Abs.[13] Such Abs could be particularly valuable to prevent infection of the donor liver by HCV in the course of liver transplantation. In such a context, it would click here be reasonable to assess the CLDN tropism of the circulating virus and/or to confirm that the Abs used prevent both CLDN1- and CLDN6/CLDN9-dependent HCV cell entry. Notably, we report here that HCV strains with broad CLDN tropism (e.g., Con1 and, particularly, the GT3a-derived S52 strain) are capable of escaping CLDN1-specific Abs by using endogenous levels of CLDN6 coexpressed in Huh-7.5 cells (Fig. 5). Therefore, future work should address whether this route of escape is possible also in humanized mice repopulated with primary human hepatocytes. If that is true, Abs that bind both CLDN1 and CLDN6/CLDN9 or a mixture of Abs blocking these CLDN family members could be used to prevent viral escape. Finally, this model could also be used to test whether the endogenous level of CLDN6 (possibly also CLDN9) is critical to permit viral escape from CLDN1-specific Abs.