[119] Exploring biological fluid for these candidates in global proteomic studies require extensive sample fractionation to isolate the low-mass portion, followed by enrichment of this portion to detect lowly abundant proteins.[119-122] A standardized global low-mass, low-abundance proteomic experiment and global metabolomics experiment is comparable (Figs 2, 3). Standard methods of analyte precipitation and mass fractionation can be used to isolate the molecules of interest (i.e. immunoaffinity chromatography columns, electrophoresis, or ultrafiltration), and samples are injected into an LC-MS (or MS/MS) Y-27632 cost system with or without enzymatic digestion.[21, 96,

120, 123] Enzymatic digestion

is often not employed in low-mass proteomics analysis with a rationale that disconnect between peptide and in vivo protein convolutes later stage identification;[124] however, without protein cleavage, free in vivo small peptides can escape selleck detection as they do not ionize well in their endogenous state. To maximize small peptide discovery, it is advisable to enzymatically digest the sample but to treat the ensuing MS data as undigested in subsequent compound identification analysis (as databases may contain entries for peptides that were able to be detected in previous nondigested experiments). A typical MS (parent ion) scan for small proteins and peptides may be set at a range of approximately 350–1800 m/z, with Selleckchem Depsipeptide molecules detected in multiple charge states depending on the sample type and MS instrument. A global metabolomics study meanwhile has a scan range commonly between 35 and 1000 m/z, with an expectation

of singularly charged molecules. A second analyzer can be used for further fragmentation and characterization, with the resulting mass spectrum (product ions) being representative of a peptide/small protein’s sequence and structure. Protein/peptide sequence and structural information is attributed to the experimentally observed MS/MS spectra by mathematical physicochemistry modeling, and identification is made by matching the experimental MS data with catalogued protein/peptide MS and sequence information. This allows for specific and accurate compound recognition in a complex biosample. Confidence score of an identification is based on the number of peptides in the sample that are attributable to the hypothetical protein. For global metabolomics, identification is made by accurate m/z measurement (Fig. 3).[21, 116] Peptides/small proteins/metabolites may exist freely or be part of a larger protein or complex in media such as the blood circulation and have specific functions as hormones, neurotransmitters, cytokines, etc. based on this circumstance (that may be transitory).

1 examined liver biopsy samples from 72 of 204 patients (i.e., 35% of the total cohort). However, the use of different liver biopsy techniques, such as transjugular liver biopsy, native liver biopsy, and postmortem biopsy, may have induced variations in the histological patterns. Centrilobular necrosis (CN), which corresponds to massive hepatic necrosis type 1 in this study, is an important but infrequent histopathological pattern of autoimmune hepatitis; centrilobular necrosis with

sparing of the portal tracts was present in 3.5% of the cases reported by Hofer et al.2 This particular pattern is of crucial RAD001 supplier importance because it may be indicative of an early stage of the disease. For the series described by Stravitz et al., it would be interesting to have a description of the phenotype and, more CHIR-99021 purchase specifically, the prognosis of the patients with isolated centrilobular necrosis. The fact that the centrilobular zone is damaged during an early stage by the immune process is intriguing and suggests that specific autoantigens in this area could be presented to the immune system early during the course of liver

disease. Clearly, the identification of these potential targets during an initial phase of the disease would be of considerable interest. In addition, it is unfortunate that the identification of a pattern typical of severe autoimmune hepatitis (AIH) is based only on this experience; in several reports, researchers have attempted to describe this entity, and experiences besides those of the US Acute Liver Failure Study Group should be cited.3-6 In particular, the characteristics of the patients may differ between the studies. In our cohort,

8 of 16 patients (50%) suffered from grade 3/4 encephalopathy,3 whereas 26 of 72 patients (39%) in Stravitz et al.’s study did. The most important and problematic issue in the management of severe autoimmune liver disease is corticosteroid therapy. Of course, if a response to corticosteroid therapy is an important argument in favor Amino acid of an autoimmune process, it is important that any decision to administer this therapy be balanced against the high potential risk of sepsis; infections occurred in 5 of 12 patients (42%) during steroid therapy in our study.3 If treatment failure seems to be predicted by changes in the Model for End-Stage Liver Disease–Sodium score and the UK Model for End-Stage Liver Disease score on day 7,7 specific scores on entry must be defined for making decisions about the administration of steroid therapy. Jean-Charles Duclos-Vallée M.D., Ph.D.* † ‡, Philippe Ichai M.D.* † ‡, Didier Samuel M.D., Ph.D.* † ‡, * Centre Hépato-Biliaire, Hôpital Paul Brousse, Assistance Publique–Hôpitaux de Paris, Villejuif, France, † Unités Mixtes de Recherche en Santé 785, Université Paris-Sud, Villejuif, France, ‡ Unité 785, Institut National de la Santé et de la Recherche Médicale, Villejuif, France.

To confirm the presence of an independent association between impaired liver VDR expression and the diagnosis of NASH, we compared clinical and metabolic

parameters of patients affected by NASH with those obtained in the comparison subjects. The two groups were comparable for sex, age, and BMI. In all these subjects, we measured fasting blood glucose Sotrastaurin datasheet (mg/dL), basal insulin (μU/mL), and adiponectin, and calculated the HOMA-IR. No significant differences were found between metabolic parameters of NASH patients and the comparison group [25(OH)D3, 54.7 ± 30.7 nmol/L versus 52.9 ± 11.02 nmol/L, P value not significant; basal insulin, 18.4 ± 11 μU/mL versus 19.8 ± 12.4 μU/mL, P value not significant; HOMA-IR, 5.5 ± 4.7 versus 3.87 ± 2.6, P value not

significant; Dasatinib cost adiponectin (p = 0.25), 16.03 ± 8.7 ng/mL versus 17.8 ± 13.3 ng/mL], excluding fasting blood glucose (106.3 ± 26.2 mg/dL versus 93.6 ± 9 mg/dL, P = 0.038). The bivariate correlation analysis showed the presence of a negative association between VDR expression in cholangiocytes and in hepatocytes and the diagnosis of NASH (Spearman’s coefficient, −0.5, P = 0.001, and Spearman’s coefficient, −0.4, P = 0.01, respectively), whereas no correlation was found between liver VDR positivity and basal insulin, HOMA-IR, adiponectin, or BMI. Stepwise multiple regression analysis considering liver VDR expression as dependent variable and sex, age, BMI, HOMA-IR, adiponectin, and the diagnosis of NASH as independent variables confirmed the presence of a strong association between low liver VDR expression and the diagnosis of NASH independently from all other metabolic parameters (unstandardized β coefficient, −18.7; standardized β coefficient, 0.51; P = 0.027). In the CHC population mean serum 25(OH)D3 levels were comparable with those observed

in patients affected by NASH (50.75 ± 26.7 versus 54.7 ± 30.7 nmol/L; P value not significant) those and correlated with CYP2R1 expression on hepatocytes (Spearman’s coefficient, 0.50; P = 0.02). VDR expression was found in both the nuclei and cytosol of cholangiocytes and hepatocytes and was strongly associated with hepatic reactivity for CYP27A1 and CYP2R1 (Table 3), but did not correlate with either serum 25(OH)D3 levels or other clinical and biochemical parameters. The degree of VDR expression on cholangiocytes and the expression of CYP27A1 were significantly reduced compared with those observed in the comparison group (Spearman’s coefficient, −0.69, P < 0.001, and Spearman’s coefficient, −0.5, P < 0.001, respectively), as shown in Table 2. Interestingly, the portal inflammation was inversely correlated with VDR positivity on inflammatory cells (Spearman’s coefficient, −0.55; P < 0.009), and on hepatocytes (Spearman’s coefficient, −0.43; P < 0.

To confirm the presence of an independent association between impaired liver VDR expression and the diagnosis of NASH, we compared clinical and metabolic

parameters of patients affected by NASH with those obtained in the comparison subjects. The two groups were comparable for sex, age, and BMI. In all these subjects, we measured fasting blood glucose selleck chemicals llc (mg/dL), basal insulin (μU/mL), and adiponectin, and calculated the HOMA-IR. No significant differences were found between metabolic parameters of NASH patients and the comparison group [25(OH)D3, 54.7 ± 30.7 nmol/L versus 52.9 ± 11.02 nmol/L, P value not significant; basal insulin, 18.4 ± 11 μU/mL versus 19.8 ± 12.4 μU/mL, P value not significant; HOMA-IR, 5.5 ± 4.7 versus 3.87 ± 2.6, P value not

significant; see more adiponectin (p = 0.25), 16.03 ± 8.7 ng/mL versus 17.8 ± 13.3 ng/mL], excluding fasting blood glucose (106.3 ± 26.2 mg/dL versus 93.6 ± 9 mg/dL, P = 0.038). The bivariate correlation analysis showed the presence of a negative association between VDR expression in cholangiocytes and in hepatocytes and the diagnosis of NASH (Spearman’s coefficient, −0.5, P = 0.001, and Spearman’s coefficient, −0.4, P = 0.01, respectively), whereas no correlation was found between liver VDR positivity and basal insulin, HOMA-IR, adiponectin, or BMI. Stepwise multiple regression analysis considering liver VDR expression as dependent variable and sex, age, BMI, HOMA-IR, adiponectin, and the diagnosis of NASH as independent variables confirmed the presence of a strong association between low liver VDR expression and the diagnosis of NASH independently from all other metabolic parameters (unstandardized β coefficient, −18.7; standardized β coefficient, 0.51; P = 0.027). In the CHC population mean serum 25(OH)D3 levels were comparable with those observed

in patients affected by NASH (50.75 ± 26.7 versus 54.7 ± 30.7 nmol/L; P value not significant) this website and correlated with CYP2R1 expression on hepatocytes (Spearman’s coefficient, 0.50; P = 0.02). VDR expression was found in both the nuclei and cytosol of cholangiocytes and hepatocytes and was strongly associated with hepatic reactivity for CYP27A1 and CYP2R1 (Table 3), but did not correlate with either serum 25(OH)D3 levels or other clinical and biochemical parameters. The degree of VDR expression on cholangiocytes and the expression of CYP27A1 were significantly reduced compared with those observed in the comparison group (Spearman’s coefficient, −0.69, P < 0.001, and Spearman’s coefficient, −0.5, P < 0.001, respectively), as shown in Table 2. Interestingly, the portal inflammation was inversely correlated with VDR positivity on inflammatory cells (Spearman’s coefficient, −0.55; P < 0.009), and on hepatocytes (Spearman’s coefficient, −0.43; P < 0.

To confirm the presence of an independent association between impaired liver VDR expression and the diagnosis of NASH, we compared clinical and metabolic

parameters of patients affected by NASH with those obtained in the comparison subjects. The two groups were comparable for sex, age, and BMI. In all these subjects, we measured fasting blood glucose Dorsomorphin datasheet (mg/dL), basal insulin (μU/mL), and adiponectin, and calculated the HOMA-IR. No significant differences were found between metabolic parameters of NASH patients and the comparison group [25(OH)D3, 54.7 ± 30.7 nmol/L versus 52.9 ± 11.02 nmol/L, P value not significant; basal insulin, 18.4 ± 11 μU/mL versus 19.8 ± 12.4 μU/mL, P value not significant; HOMA-IR, 5.5 ± 4.7 versus 3.87 ± 2.6, P value not

significant; MEK inhibitor adiponectin (p = 0.25), 16.03 ± 8.7 ng/mL versus 17.8 ± 13.3 ng/mL], excluding fasting blood glucose (106.3 ± 26.2 mg/dL versus 93.6 ± 9 mg/dL, P = 0.038). The bivariate correlation analysis showed the presence of a negative association between VDR expression in cholangiocytes and in hepatocytes and the diagnosis of NASH (Spearman’s coefficient, −0.5, P = 0.001, and Spearman’s coefficient, −0.4, P = 0.01, respectively), whereas no correlation was found between liver VDR positivity and basal insulin, HOMA-IR, adiponectin, or BMI. Stepwise multiple regression analysis considering liver VDR expression as dependent variable and sex, age, BMI, HOMA-IR, adiponectin, and the diagnosis of NASH as independent variables confirmed the presence of a strong association between low liver VDR expression and the diagnosis of NASH independently from all other metabolic parameters (unstandardized β coefficient, −18.7; standardized β coefficient, 0.51; P = 0.027). In the CHC population mean serum 25(OH)D3 levels were comparable with those observed

in patients affected by NASH (50.75 ± 26.7 versus 54.7 ± 30.7 nmol/L; P value not significant) before and correlated with CYP2R1 expression on hepatocytes (Spearman’s coefficient, 0.50; P = 0.02). VDR expression was found in both the nuclei and cytosol of cholangiocytes and hepatocytes and was strongly associated with hepatic reactivity for CYP27A1 and CYP2R1 (Table 3), but did not correlate with either serum 25(OH)D3 levels or other clinical and biochemical parameters. The degree of VDR expression on cholangiocytes and the expression of CYP27A1 were significantly reduced compared with those observed in the comparison group (Spearman’s coefficient, −0.69, P < 0.001, and Spearman’s coefficient, −0.5, P < 0.001, respectively), as shown in Table 2. Interestingly, the portal inflammation was inversely correlated with VDR positivity on inflammatory cells (Spearman’s coefficient, −0.55; P < 0.009), and on hepatocytes (Spearman’s coefficient, −0.43; P < 0.

Remarkably, we revealed a significant down-regulation of the Mat1a protein specifically in the livers of Mdr2-KO/FVB mice (Fig. 6A,B). The Mat enzyme catalyzes the synthesis of S-adenosyl methionine, a universal donor of the methyl group for all methylation reactions in the cell. It is encoded by the genes Mat1a and Mat2a/2b; patients with liver cirrhosis have reduced activity of this enzyme.34 Mat1a

is highly expressed in the adult liver and keeps hepatocytes in a quiescent state. In human liver cancer, Mat1a expression is reduced, whereas Mat2a is increased; this switch facilitates cancer cell growth.35 We demonstrated previously that most hepatocytes of the Mdr2-KO/FVB strain undergo cell cycle arrest between the ages 3 and 9 months, Small molecule library concentration and this is characterized by a high level of cyclin D1 in hepatocyte nuclei.4, 36 Our current findings demonstrate that selectively in the Mdr2-KO/FVB mice, this stage of hepatocyte cycle arrest is characterized by a decreased level of the http://www.selleckchem.com/products/i-bet-762.html Mat1a protein and up-regulation of the Mat2b transcript (Supporting Table 2). Despite the inverse differential expression of the Mbd1 transcript in the two Mdr2-KO strains (Supporting Table 2), protein expression

in both strains was increased in the mutant liver versus the control liver (Fig. 5). The Mbd1 protein binds methylated DNA and functions mainly as a transcriptional repressor;

its higher level in the Mdr2-KO/B6 strain versus the Mdr2-KO/FVB strain could be one of the factors responsible for a significantly lower number of up-regulated genes in the former mutant. Published data on the genotypic and phenotypic differences between the B6 and FVB strains are summarized in Supporting Table 4. There are several known differences between these strains that could be responsible Clomifene for the different courses of chronic hepatitis and HCC development in the two Mdr2-KO mutants. The most prominent among them are (1) a deficiency of complement C5 protein in the FVB strain, (2) mutations in mitochondrial DNA in the FVB strain, and (3) a Tnfaip3 (A20) polymorphism that is responsible for the less effective feedback suppression of Tnf-α–induced NF-κB activation in the B6 strain (see the references in Supporting Table 4). In conclusion, we have demonstrated that the B6 murine strain has a remarkable resistance to both chronic hepatitis and HCC development caused by the Mdr2-KO mutation. By a comparative analysis of liver gene expression in the two Mdr2-KO strains, we determined a set of regulatory genes that could be responsible for affecting the severity of chronic hepatitis in these strains at an early age. The most prominent was the differential expression of multiple regulators of the NF-κB pathway, which is critical for manifestations of the Mdr2-KO phenotypes.

Methods: All (n=41) patients included in analysis had Child’s B (n=35 ) or C (n= 6) cirrhosis and received sofosbuvir 400mg daily + simeprevir 150mg daily, with (n=7) or without (n= 34) ribavirin, for an anticipated course of 12 weeks. Interim safety and efficacy data are presented. SVR 4 and SVR 12 data to follow. Results: Of the 41 patients in this cohort, 32 (78%) were male, 23 (56%) had failed prior treatment and 26 (63%) were genotype 1A. Prior decompensating events included enceph-alopathy (49%), fluid overload (85%), variceal hemorrhage (22%), and hepatocellular carcinoma (15%). Median MELD score was 12 (range 6-25). Eleven patients (27%) have completed

12 weeks of therapy. The remaining 30 patients have been treated for a median of 6 weeks (range 1-11). Treatment was well-tolerated overall with more than one-half (51%) reporting no adverse events. In those reporting adverse events, Luminespib supplier Venetoclax the most common were insomnia (n=5), headache (n=5), nausea (n=4), weakness (n=3), and grade 1 rash (n=2). One patient developed chemical pancreatitis that did not require treatment discontinuation. 3/7 patients who received ribavirin developed anemia; 2 requiring blood transfusions & 1 dose reduction. Of the 30 patients that had week 4 on-treatment virologic response data; HCV RNA clearance was achieved in 19 (63%) while HCV RNA levels were <200 IU/ml in the remaining with 4 patients having

levels below the limit of quantitation. 100% of patients who completed treatment (11/11) had end of treatment response defined as negative HCV RNA at week 12. Conclusion: Sofosbuvir plus simeprevir appears to be very well tolerated in patients with advanced Child’s B/C cirrhosis. 100% of patients who completed 12 weeks of combination therapy had EOT response. Anemia may occur more frequently in those receiving ribavirin. Disclosures: Apurva A. Modi – Speaking and Teaching: Salix, Merck, Gilead Hector Nazario – Advisory Committees or Review Panels: Gilead; Speaking and Teaching: Gilead, Merck, Abbvie, Salix Stevan A. Gonzalez – Speaking and Teaching: Gilead, Salix,

AbbVie Jeffrey S. Weinstein – Speaking and MycoClean Mycoplasma Removal Kit Teaching: Merck Parvez S. Mantry – Consulting: Salix, Gilead, Janssen, Abbvie; Grant/Research Support: Salix, Merck, Gilead, Boehringer-Ingelheim, Mass Biologics, Vital Therapies, Santaris, Vertex, Bristol-Myers Squibb, Abbive, Bayer-Onyx; Speaking and Teaching: Gilead, Janssen, Salix, Bayer-Onyx The following people have nothing to disclose: Manjushree Gautam, Maisha Barnes, Adil Habib, Jean L. McAfee, Olga Teachenor, Lauren Tujague, James F. Trotter Introduction: Many individuals with recent HCV infection may be able to receive shortened duration therapy. This study evaluated the efficacy of response-guided therapy with pegylat-ed-interferon alfa-2a (PEG-IFN) and ribavirin (RBV) for people with recent HCV infection.

From Darwin’s statement (above) about the superiority of natural selection over the argument from design, we might imagine that Ray’s questions about reproduction would have been answered soon after the publication the Origin in 1859. Not so. Natural selection was, and still is, a better conceptual framework for

thinking about the natural world, and provided a compelling and straightforward explanation for the existence of parasites and parasitoids. Sex, however, continued to be a mystery, and because Darwin largely avoided questions about the Everolimus number of sperm and copulation behaviour, it was almost a century before anyone tackled these questions and offered a convincing answer. Retrospectively, biologists such

as Smith (1984, 1998) attributed Darwin’s lack of interest in promiscuity to a statement in Descent: ‘It is shown by various facts, given hereafter, and by the results fairly attributable to sexual selection, that the female, though comparatively passive, generally exerts some choice and accepts one male in preference to the others’ (Darwin, 1871). The emphasis here being on one male, a clear indication that Darwin assumed females at least to be sexually monogamous. I have suggested that Darwin made this assumption as a way of avoiding embarrassment, both with the public and within his selleck compound family, especially his wife Emma and daughter Etty (Henrietta), the latter who helped him correct the proofs of Descent (Birkhead, 1997). Darwin’s desire to avoid offending his family, undoubtedly Celecoxib reinforced by Victorian prudery, inhibited his writing on sexual matters. When he felt it necessary to discuss the sexual swellings of female primates, for example in Descent he wrote the passage in Latin knowing that Etty would be unable to read it. Darwin was well aware of female promiscuity, from the literature, from his correspondents and from personal observation (Barrett et al., 1987; Smellie, 1790). With reference to the pigeons he kept and bred, Darwin (1868) wrote: ‘even when a male does break his marriage-vow, he does not permanently desert his

mate’. Notice here that the emphasis is the male rather than the female breaking the marriage vow. Most pigeon breeders, however, including Girton (1765), whose book Darwin owned, recognized the existence of extra-pair copulations, pointing to the fact that selective breeding could easily be disrupted by a ‘false tread’ (an extra-pair copulation). Even more significantly, Darwin was aware of the extensive literature on so-called ‘thief pigeons’ in which particularly attractive males could cause paired females to abandon their partner in favour of themselves – even during the incubation period (Darwin, 1871; Birkhead, 2008). Darwin also knew that whatever it was that made these males irresistible to females was inherited, for pigeon breeders could select for it.

From Darwin’s statement (above) about the superiority of natural selection over the argument from design, we might imagine that Ray’s questions about reproduction would have been answered soon after the publication the Origin in 1859. Not so. Natural selection was, and still is, a better conceptual framework for

thinking about the natural world, and provided a compelling and straightforward explanation for the existence of parasites and parasitoids. Sex, however, continued to be a mystery, and because Darwin largely avoided questions about the Inhibitor Library cell line number of sperm and copulation behaviour, it was almost a century before anyone tackled these questions and offered a convincing answer. Retrospectively, biologists such

as Smith (1984, 1998) attributed Darwin’s lack of interest in promiscuity to a statement in Descent: ‘It is shown by various facts, given hereafter, and by the results fairly attributable to sexual selection, that the female, though comparatively passive, generally exerts some choice and accepts one male in preference to the others’ (Darwin, 1871). The emphasis here being on one male, a clear indication that Darwin assumed females at least to be sexually monogamous. I have suggested that Darwin made this assumption as a way of avoiding embarrassment, both with the public and within his Ganetespib manufacturer family, especially his wife Emma and daughter Etty (Henrietta), the latter who helped him correct the proofs of Descent (Birkhead, 1997). Darwin’s desire to avoid offending his family, undoubtedly PRKACG reinforced by Victorian prudery, inhibited his writing on sexual matters. When he felt it necessary to discuss the sexual swellings of female primates, for example in Descent he wrote the passage in Latin knowing that Etty would be unable to read it. Darwin was well aware of female promiscuity, from the literature, from his correspondents and from personal observation (Barrett et al., 1987; Smellie, 1790). With reference to the pigeons he kept and bred, Darwin (1868) wrote: ‘even when a male does break his marriage-vow, he does not permanently desert his

mate’. Notice here that the emphasis is the male rather than the female breaking the marriage vow. Most pigeon breeders, however, including Girton (1765), whose book Darwin owned, recognized the existence of extra-pair copulations, pointing to the fact that selective breeding could easily be disrupted by a ‘false tread’ (an extra-pair copulation). Even more significantly, Darwin was aware of the extensive literature on so-called ‘thief pigeons’ in which particularly attractive males could cause paired females to abandon their partner in favour of themselves – even during the incubation period (Darwin, 1871; Birkhead, 2008). Darwin also knew that whatever it was that made these males irresistible to females was inherited, for pigeon breeders could select for it.

In a previous work we showed that transduction of normal rat liver with a SV40 vector encoding IGF-I conferred protection against CCl4 toxic injury.7 In that study treated rats had a normal liver and resisted toxic injury click here with less tissue damage than controls. However, it remained to be investigated whether IGF-I-based gene therapy was able to improve or to revert a previously established cirrhotic lesion. In this work we show that rats with well-established liver cirrhosis treated with SVIGF-I experience an improvement of liver function and a marked reduction of liver fibrosis. These effects are

observed not only in CCl4-induced cirrhosis but also in the TAA model, which represents MK-8669 a more difficult condition to treat. The efficacy of the therapy in the two forms of liver cirrhosis reinforces the concept that regression of the lesion is due to the therapeutic effect of SVIGF-I and not to spontaneous resolution of

fibrosis. IGF-I gene transfer to the cirrhotic liver was accomplished using an SV40 vector. Although this vector has a wide host range, liver specificity can be improved by hepatic artery administration as performed in our study. Advantages of SV40 vector include low antigenicity, long duration of transgene expression, ability to infect liver cells, and a small virus particle size that would facilitate penetration through the collagenous extracellular matrix. In the present study, IGF-I expression was constant until half a year after SVIGF-I vector administration in rats (data not shown). The level of transgene expression using SV40 vectors is relatively low as compared with other vectors.7, 21 For our purposes this characteristic may be advantageous because low intrahepatic expression of transgenic IGF-I would restrict the hormone effects to the liver

without unduly increasing its serum values. In fact, in our study (-)-p-Bromotetramisole Oxalate we were able to increase intrahepatic IGF-I level (Fig. 1A,B) without raising serum concentration (data not shown). We addressed the molecular mechanisms that could mediate IGF-I therapeutic effects on liver cirrhosis. Liver expression of the transgenic IGF-I should be sensed by IGF-IR, predominantly expressed by nonparenchymal liver cells within fibrous septa surrounding cirrhotic nodules. This receptor is expressed poorly by rat hepatocytes (Fig. 1D-F).22, 23 Thus, it seems possible that IGF-I acts on nonparenchymal cells to activate a tissue-repair program able to improve liver architecture and function. Interestingly, we found that induction of IGF-I led to up-regulation of IGF-IR in the septa, suggesting the existence of an amplification loop that would favor the efficacy of the therapy (Fig. 1F).