Therefore,

the width of the surgical margin is unlikely t

Therefore,

the width of the surgical margin is unlikely to contribute to prognosis. Of 1481 English original articles (1980–2007) identified using “hepatocellular carcinoma” and “surgery” as key words, 29 were about studies investigating prognosis based on the width of the surgical margin. Usually, surgical margin width of 5 mm to 1 cm have been considered not to contribute to prognosis; however, Shi et al. in Hong Kong reported an RCT recommending a surgical Selleck 5-Fluoracil margin width of 2 cm or more (LF117666 level 1b). Nonetheless, the surgical margin is restricted by liver function, tumor location and size, often making it difficult to secure 2 cm or more in reality. Therefore, it is acceptable to resect a tumor with a minimum width so as to avoid exposing the tumor during hepatectomy for hepatocellular carcinoma. CQ22 Does

anatomical resection contribute to prognosis? It is recommended that hepatectomy be performed anatomically. (grade B) A retrospective study in patients with hepatocellular carcinoma of 5 cm or less in diameter demonstrated the superiority of anatomical resection over segmental resection in terms of the survival rate. Particularly, it showed a significant difference in patients with extranodal metastasis (LF001021 level 2b). An evaluation of the recurrence-free survival rate also revealed the superiority of anatomical resection over segmental resection (LF002532 level 2b). Furthermore, the systemic anatomical BGJ398 mouse segmental and sub-segmental resections were superior to non-anatomical wedge resection in terms of the survival rate and recurrence-free survival rate in patients

with solitary hepatocellular carcinoma (LF111483 level 2b). Nonetheless, it has also been reported that a difference in the recurrence-free survival rate is noted only in patients with tumors associated with neither cirrhosis nor infiltration (LF007284 level 2b). Based on the above, anatomical resection is quite likely to improve prognosis. Portal vein invasion Arachidonate 15-lipoxygenase is the most important prognostic factor. Therefore, anatomical hepatectomy should be performed in consideration of the distributions of portal veins in a localized tumor area. CQ23 How should blood products (e.g. red blood cell transfusion, frozen plasma) be used during the perioperative period? Homologous red blood cell transfusion should be avoided whenever possible. (grade B) The use of frozen plasma is recommended. (grade C1) Many reports have documented that allogeneic blood transfusion in the perioperative period of hepatectomy should be avoided whenever possible (LF006901 level 2b, LF004532 level 3, LF111453 level 2b). The reasons include that it may promote cancer recurrence, it is likely to induce hyperbilirubinemia and hepatic failure, and a lower hematocrit is desirable for microcirculation in the liver. Nonetheless, it has also been reported that the presence or absence of blood transfusion does not alter the recurrence rate (LF000314 level 3).

Therefore,

the width of the surgical margin is unlikely t

Therefore,

the width of the surgical margin is unlikely to contribute to prognosis. Of 1481 English original articles (1980–2007) identified using “hepatocellular carcinoma” and “surgery” as key words, 29 were about studies investigating prognosis based on the width of the surgical margin. Usually, surgical margin width of 5 mm to 1 cm have been considered not to contribute to prognosis; however, Shi et al. in Hong Kong reported an RCT recommending a surgical Seliciclib research buy margin width of 2 cm or more (LF117666 level 1b). Nonetheless, the surgical margin is restricted by liver function, tumor location and size, often making it difficult to secure 2 cm or more in reality. Therefore, it is acceptable to resect a tumor with a minimum width so as to avoid exposing the tumor during hepatectomy for hepatocellular carcinoma. CQ22 Does

anatomical resection contribute to prognosis? It is recommended that hepatectomy be performed anatomically. (grade B) A retrospective study in patients with hepatocellular carcinoma of 5 cm or less in diameter demonstrated the superiority of anatomical resection over segmental resection in terms of the survival rate. Particularly, it showed a significant difference in patients with extranodal metastasis (LF001021 level 2b). An evaluation of the recurrence-free survival rate also revealed the superiority of anatomical resection over segmental resection (LF002532 level 2b). Furthermore, the systemic anatomical KU-60019 segmental and sub-segmental resections were superior to non-anatomical wedge resection in terms of the survival rate and recurrence-free survival rate in patients

with solitary hepatocellular carcinoma (LF111483 level 2b). Nonetheless, it has also been reported that a difference in the recurrence-free survival rate is noted only in patients with tumors associated with neither cirrhosis nor infiltration (LF007284 level 2b). Based on the above, anatomical resection is quite likely to improve prognosis. Portal vein invasion AMP deaminase is the most important prognostic factor. Therefore, anatomical hepatectomy should be performed in consideration of the distributions of portal veins in a localized tumor area. CQ23 How should blood products (e.g. red blood cell transfusion, frozen plasma) be used during the perioperative period? Homologous red blood cell transfusion should be avoided whenever possible. (grade B) The use of frozen plasma is recommended. (grade C1) Many reports have documented that allogeneic blood transfusion in the perioperative period of hepatectomy should be avoided whenever possible (LF006901 level 2b, LF004532 level 3, LF111453 level 2b). The reasons include that it may promote cancer recurrence, it is likely to induce hyperbilirubinemia and hepatic failure, and a lower hematocrit is desirable for microcirculation in the liver. Nonetheless, it has also been reported that the presence or absence of blood transfusion does not alter the recurrence rate (LF000314 level 3).

Therefore,

the width of the surgical margin is unlikely t

Therefore,

the width of the surgical margin is unlikely to contribute to prognosis. Of 1481 English original articles (1980–2007) identified using “hepatocellular carcinoma” and “surgery” as key words, 29 were about studies investigating prognosis based on the width of the surgical margin. Usually, surgical margin width of 5 mm to 1 cm have been considered not to contribute to prognosis; however, Shi et al. in Hong Kong reported an RCT recommending a surgical this website margin width of 2 cm or more (LF117666 level 1b). Nonetheless, the surgical margin is restricted by liver function, tumor location and size, often making it difficult to secure 2 cm or more in reality. Therefore, it is acceptable to resect a tumor with a minimum width so as to avoid exposing the tumor during hepatectomy for hepatocellular carcinoma. CQ22 Does

anatomical resection contribute to prognosis? It is recommended that hepatectomy be performed anatomically. (grade B) A retrospective study in patients with hepatocellular carcinoma of 5 cm or less in diameter demonstrated the superiority of anatomical resection over segmental resection in terms of the survival rate. Particularly, it showed a significant difference in patients with extranodal metastasis (LF001021 level 2b). An evaluation of the recurrence-free survival rate also revealed the superiority of anatomical resection over segmental resection (LF002532 level 2b). Furthermore, the systemic anatomical FK228 mouse segmental and sub-segmental resections were superior to non-anatomical wedge resection in terms of the survival rate and recurrence-free survival rate in patients

with solitary hepatocellular carcinoma (LF111483 level 2b). Nonetheless, it has also been reported that a difference in the recurrence-free survival rate is noted only in patients with tumors associated with neither cirrhosis nor infiltration (LF007284 level 2b). Based on the above, anatomical resection is quite likely to improve prognosis. Portal vein invasion Reverse Transcriptase inhibitor is the most important prognostic factor. Therefore, anatomical hepatectomy should be performed in consideration of the distributions of portal veins in a localized tumor area. CQ23 How should blood products (e.g. red blood cell transfusion, frozen plasma) be used during the perioperative period? Homologous red blood cell transfusion should be avoided whenever possible. (grade B) The use of frozen plasma is recommended. (grade C1) Many reports have documented that allogeneic blood transfusion in the perioperative period of hepatectomy should be avoided whenever possible (LF006901 level 2b, LF004532 level 3, LF111453 level 2b). The reasons include that it may promote cancer recurrence, it is likely to induce hyperbilirubinemia and hepatic failure, and a lower hematocrit is desirable for microcirculation in the liver. Nonetheless, it has also been reported that the presence or absence of blood transfusion does not alter the recurrence rate (LF000314 level 3).

15-22, 26-30 The direct relationship between LDLc and SVR may par

15-22, 26-30 The direct relationship between LDLc and SVR may partially be explained by competition

for LDL receptor sites preventing viral entry into hepatocytes, increasing exposure of HCV to the host immune response in the serum. These findings suggest that serum lipids may yield some prognostic value in determining Selleckchem Galunisertib the probability of treatment success and possibly highlight new therapeutic targets. Further prospective investigation of the impacts of dietary modification and lipid-lowering agents on virological response may be warranted. Treatment trials investigating statins and fibrates to improve virological response have yielded mixed results.40-42 As documented in the Virahep-C cohort,43 insulin resistance

may also contribute to the relationship between serum lipids and SVR. In conclusion, this study suggests that serum lipid measures are predictors of SVR, but that their predictive ability is ameliorated by race such that these measures do not explain the racial disparity in treatment efficacy between CAs and AAs. However, this study underscores the potential relevance of serum lipids to virological MG-132 solubility dmso response. Future investigations may seek to assess relationships between SVR, other characterizations relevant to serum lipids, and genetic determinants of lipid metabolism. Additional Supporting Information may be found in the online version of this article. “
“1600 Clifton Road NE, Demeclocycline E-47, Atlanta, GA 30333 Chronic hepatitis

B virus (HBV) infection is a major health issue, especially in Asia. A recent genome-wide association study (GWAS) implicated genetic variants in the human leukocyte antigen (HLA)-DP locus associated with chronic hepatitis B in Japanese and Thai populations. To confirm whether the polymorphisms at the HLA-DP genes are associated with persistent chronic HBV infection in Han Chinese, we conducted an independent case-control study using 521 persistent chronic HBV carriers and 819 controls that included 571 persons with HBV natural clearance and 248 never HBV-infected (healthy) individuals. Eleven single nucleotide polymorphisms (SNPs) in a region including HLA-DPA and HLA-DPB and an adjacent SNP in strong linkage disequilibrium (LD) with a neighboring HLA-DR13 locus were genotyped using the TaqMan SNP genotyping assay. Eleven variants at HLA-DP showed a strong association with persistent chronic HBV carrier status (P = 1.82 × 10−12 to 0.01). We also stratified the analysis by HBV clearance status to test the association between these polymorphisms and HBV natural clearance; similar results were obtained (P = 2.70 × 10−11 to 0.003). Included SNPs define highly structured haplotypes that were also strongly associated with HBV chronic infection (block 1: odds ratio [OR] = 0.54, P = 8.73 × 10−7; block 2: OR = 1.98, P = 1.37 × 10−10).

CRP activates the complement pathway It is a pattern recognition

CRP activates the complement pathway. It is a pattern recognition receptor with a pentameric polypeptide structure, which binds to a variety of intrinsic and extrinsic ligands. CRP’s highest affinity is towards phosphocholine residues. CRP is produced only in hepatocytes under the transcriptional control of interleukin-6 (IL-6).1 Circulating levels of CRP increase hundred-fold in response to infections and inflammation. Determination of CRP levels is one of the most solicited laboratory tests. The literature documents an increase

in CRP levels in cancer patients. High CRP levels AZD0530 nmr may be of prognostic value since they are associated with poor survival. Among gastrointestinal tumors, esophageal,2 gastric,3 colorectal,4 and pancreatic cancers5 have reported this association. Mechanistically, high CRP levels are either a marker of reactive inflammation to a tumor or a marker of an ongoing inflammatory process that favored tumor development.

Tumors frequently show histological evidence of intratumoral and/or peritumoral inflammation. Necrotic cells release proinflammatory signals, which attract inflammatory cells from the surrounding tissue. This inflammatory response may foster the tumoral process rather than contain it. Inflammatory cells help to stimulate and to sustain angiogenesis and promote invasiveness by degrading the extracellular matrix. Inflammation is learn more now recognized as an enabling characteristic of tumors.6 CRP has gained prognostic value in hepatocellular carcinoma (HCC). In a cohort of 90 HCC patients, Nagaoka et al.7 found that CRP levels above 3 mg/dL were predictive of poor prognosis and a decreased survival rate. In patients undergoing resection for HCC, Methisazone preoperative CRP levels correlated with tumor size and vascular invasion and were predictive of early recurrence.8 In the transplantation

setting, high preoperative CRP levels were related to tumor recurrence and poor overall survival; in those specific patients with HCC beyond Milan criteria, high CRP levels were an independent predictor of poor outcome.9 Finally, in a prospective evaluation of a cohort of 133 patients with newly diagnosed HCC, Kinoshita et al.10 reported that CRP levels above 1 mg/dL predicted a shorter survival and were characteristic of high Child-Pugh, CLIP, and JIS scores. In this issue of Hepatology, Peck-Radosavljevic and co-workers11 investigated the value of serum CRP levels in a large cohort of 615 HCC patients who were not amenable to surgery. The hazard ratio of death increased with CRP values up to 2.5 mg/dL, but not beyond. CRP levels above 1 mg/dL were significantly and independently associated with poor survival upon multivariate analysis in the discovery and in the validation cohorts. Patients with a CRP above 1 mg/dL at diagnosis had a survival of 4 months compared to 20 months for patients with a CRP below 1 mg/dL.

This result effectively

ruled out the possibility that LD

This result effectively

ruled out the possibility that LDPCs could have originated from the initial nonhepatocyte cell population in culture. Next, we wanted to substantiate our PKH staining results by documenting the phenotypic changes taking place during the transformation of hepatocytes into LDPCs. To that end, we performed RT-PCR and IF analyses of hepatocyte- and LDPC-specific markers at predetermined time points during the culture period. On days 0, 4, 8, and 12, cultures were examined for expression of albumin, HNF-1α (hepatocyte specific), selleck chemicals CD45, and LMO2 (LDPC specific). RT-PCR studies showed that in the beginning, cells expressed albumin and HNF-1α and no identifiable CD45 and LMO2. By day 4, there was a rapid decline

in hepatocyte-specific markers, and LDPC-specific markers became detectable at low levels. Subsequently, on days 8 and 12, hepatocyte markers became undetectable, and LDPC markers were expressed Fludarabine cost at increasingly higher levels (Fig. 3A). IF studies revealed a similar pattern of marker expression, further confirming our RT-PCR data (Fig. 3B). In addition to these four markers, we examined the expression pattern of several other highly relevant hepatic genes during the culture period to better characterize the transformation process. We looked at the expression of mature hepatocyte markers HepPar1 and HNF-4α, immature hepatocyte marker Liv2,24 biliary ductal/oval cell

marker CK19, and liver progenitor/embryonic liver marker Sall425 in a time-dependent manner. IF staining and quantitative analysis of the images revealed a pattern (Supporting Fig. 2A,B), which was consistent with rapid transformation of mature hepatocytes into cells with liver progenitor phenotype, thus supporting our findings shown in Fig. 3. Both the RT-PCR and IF studies correlated well with the morphological changes that took place in the cultures, including temporal appearance of LDPCs. Taken together, the rat studies Montelukast Sodium strongly suggested that LDPCs originated from mature hepatocytes by direct dedifferentiation. To gain further insight into the process of dedifferentiation of hepatocytes to LDPCs and to establish a stem/progenitor cell hierarchy, we examined the expression of several oval cell markers during the culture period. We considered the possibility that hepatocytes could be transitioning through an oval cell-like stage en route to becoming LDPCs. This was based on the phenotypic similarities between oval cells and LDPCs, suggesting a potential lineage relationship. Therefore, we studied the expression of OV-6, CK7, and GGT during the dedifferentiation of hepatocytes into LDPCs.

This result effectively

ruled out the possibility that LD

This result effectively

ruled out the possibility that LDPCs could have originated from the initial nonhepatocyte cell population in culture. Next, we wanted to substantiate our PKH staining results by documenting the phenotypic changes taking place during the transformation of hepatocytes into LDPCs. To that end, we performed RT-PCR and IF analyses of hepatocyte- and LDPC-specific markers at predetermined time points during the culture period. On days 0, 4, 8, and 12, cultures were examined for expression of albumin, HNF-1α (hepatocyte specific), beta-catenin inhibitor CD45, and LMO2 (LDPC specific). RT-PCR studies showed that in the beginning, cells expressed albumin and HNF-1α and no identifiable CD45 and LMO2. By day 4, there was a rapid decline

in hepatocyte-specific markers, and LDPC-specific markers became detectable at low levels. Subsequently, on days 8 and 12, hepatocyte markers became undetectable, and LDPC markers were expressed Rucaparib at increasingly higher levels (Fig. 3A). IF studies revealed a similar pattern of marker expression, further confirming our RT-PCR data (Fig. 3B). In addition to these four markers, we examined the expression pattern of several other highly relevant hepatic genes during the culture period to better characterize the transformation process. We looked at the expression of mature hepatocyte markers HepPar1 and HNF-4α, immature hepatocyte marker Liv2,24 biliary ductal/oval cell

marker CK19, and liver progenitor/embryonic liver marker Sall425 in a time-dependent manner. IF staining and quantitative analysis of the images revealed a pattern (Supporting Fig. 2A,B), which was consistent with rapid transformation of mature hepatocytes into cells with liver progenitor phenotype, thus supporting our findings shown in Fig. 3. Both the RT-PCR and IF studies correlated well with the morphological changes that took place in the cultures, including temporal appearance of LDPCs. Taken together, the rat studies Methocarbamol strongly suggested that LDPCs originated from mature hepatocytes by direct dedifferentiation. To gain further insight into the process of dedifferentiation of hepatocytes to LDPCs and to establish a stem/progenitor cell hierarchy, we examined the expression of several oval cell markers during the culture period. We considered the possibility that hepatocytes could be transitioning through an oval cell-like stage en route to becoming LDPCs. This was based on the phenotypic similarities between oval cells and LDPCs, suggesting a potential lineage relationship. Therefore, we studied the expression of OV-6, CK7, and GGT during the dedifferentiation of hepatocytes into LDPCs.

This result effectively

ruled out the possibility that LD

This result effectively

ruled out the possibility that LDPCs could have originated from the initial nonhepatocyte cell population in culture. Next, we wanted to substantiate our PKH staining results by documenting the phenotypic changes taking place during the transformation of hepatocytes into LDPCs. To that end, we performed RT-PCR and IF analyses of hepatocyte- and LDPC-specific markers at predetermined time points during the culture period. On days 0, 4, 8, and 12, cultures were examined for expression of albumin, HNF-1α (hepatocyte specific), selleckchem CD45, and LMO2 (LDPC specific). RT-PCR studies showed that in the beginning, cells expressed albumin and HNF-1α and no identifiable CD45 and LMO2. By day 4, there was a rapid decline

in hepatocyte-specific markers, and LDPC-specific markers became detectable at low levels. Subsequently, on days 8 and 12, hepatocyte markers became undetectable, and LDPC markers were expressed ZD1839 manufacturer at increasingly higher levels (Fig. 3A). IF studies revealed a similar pattern of marker expression, further confirming our RT-PCR data (Fig. 3B). In addition to these four markers, we examined the expression pattern of several other highly relevant hepatic genes during the culture period to better characterize the transformation process. We looked at the expression of mature hepatocyte markers HepPar1 and HNF-4α, immature hepatocyte marker Liv2,24 biliary ductal/oval cell

marker CK19, and liver progenitor/embryonic liver marker Sall425 in a time-dependent manner. IF staining and quantitative analysis of the images revealed a pattern (Supporting Fig. 2A,B), which was consistent with rapid transformation of mature hepatocytes into cells with liver progenitor phenotype, thus supporting our findings shown in Fig. 3. Both the RT-PCR and IF studies correlated well with the morphological changes that took place in the cultures, including temporal appearance of LDPCs. Taken together, the rat studies Carnitine palmitoyltransferase II strongly suggested that LDPCs originated from mature hepatocytes by direct dedifferentiation. To gain further insight into the process of dedifferentiation of hepatocytes to LDPCs and to establish a stem/progenitor cell hierarchy, we examined the expression of several oval cell markers during the culture period. We considered the possibility that hepatocytes could be transitioning through an oval cell-like stage en route to becoming LDPCs. This was based on the phenotypic similarities between oval cells and LDPCs, suggesting a potential lineage relationship. Therefore, we studied the expression of OV-6, CK7, and GGT during the dedifferentiation of hepatocytes into LDPCs.

pylori)-induced gastritis through its anti-oxidative and antibact

pylori)-induced gastritis through its anti-oxidative and antibacterial actions. In this study, we investigated the in vivo activity of EGCG against H. pylori-infected gastritis in Mongolian gerbil animal models, and evaluated the role of inflammatory

cytokines pathway. Methods: Six-week-old gerbils were randomly divided into three groups: H. pylori infected group (n = 10), H. pylori infected + drinking water containg EGCG group (n = 10), and control group (n = 10). The animals were inoculated with H. pylori, drinking water containing 0.05% EGCG, and then sacrificed after 20 weeks. The stomachs were excised, processed routinely, and analyzed histologically. The mRNA levels for mucosal interleukin-1β Androgen Receptor antagonist (IL-1β), tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) in gastric mucosa were investigated with quantitative RT-PCR. Results: The pathological examination showed significant inflammatory mucosal changes in infection rate was 100% in the H. pylori infection model group. EGCG significantly decreased the severity of gastritis in the antrum and the corpus. At the same time, Relative mRNA expression levels of IL-1β, TNF-α, COX-2 and iNOS selleck chemicals llc were significantly increased in H. pylori -infected gastric mucosa[IL-1β (138 vs.1.0), TNF-α (13.7 vs.1.0), COX-2(61.9 vs.1.0)

and iNOS (36.3 vs.1.0), P < 0.001], and obviously inhibited in the EGCG group than those in the control Calpain group[IL-1β (37.7 vs.138), TNF-α (4.9 vs.13.7), COX-2(33.1 vs.61.9) and iNOS (15.2 vs.36.3), P < 0.01]. Conclusion: These results suggest that activation of IL-1β, TNF-α, COX-2 and iNOS were essential for H. pylori-induced gastritis in Mongolian gerbils. EGCG exhibits anti-inflammatory effects might through inhibition of IL-1β, TNF-α, COX-2 and iNOS in gerbil model of H. pylori -induced inflammatory. This work was part supported by

National Natural Science Foundation of China, No. 81273065 and No.81072369. Key Word(s): 1. H.pylori; 2. EGCG; 3. inflammation; 4. gerbil; Presenting Author: MICHAEL MOLLOY-BLAND Additional Authors: PETER NAGY, STEPHEN SWEET, SAGA JOHANSSON, TORE LIND Corresponding Author: MICHAEL MOLLOY-BLAND Affiliations: AstraZeneca; Research Evaluation Unit, Oxford PharmaGenesis Ltd. Objective: It has been suggested that the prevalence of Helicobacter pylori infection, a major cause of peptic ulcer disease (PUD), has stabilized in the USA but is decreasing in China. We conducted a systematic literature analysis to test this hypothesis. Methods: PubMed searches were conducted up to July 2012. Trends in the reported prevalence of H. pylori infection over time were assessed by regression analysis using Microsoft Excel. In addition, Chinese and US studies were grouped according to whether their study midpoint was before or after the mean of all study midpoints, and weighted mean prevalence estimates for H.

g, after pinealectomy and exposure to dark to stimulate melatoni

g., after pinealectomy and exposure to dark to stimulate melatonin release from the pineal gland) in the regulation of biliary functions are ongoing. Having demonstrated that AANAT is expressed by cholangiocytes and that AANAT expression is up-regulated by BDL and melatonin administration, we proposed to demonstrate that reduction of biliary AANAT expression (by Vivo-Morpholino) increases cholangiocyte proliferation and IBDM as well as the expression of SR, CFTR, and Cl−/HCO AE2 in cholangiocytes. After BDL, the increase of biliary proliferation and IBDM is followed

by the extension of the peribiliary plexus and the increase of surrounding connective tissue, which is organized Ruxolitinib around bile ducts and vessels.10 In our model, we only observed a slight CH5424802 chemical structure difference in collagen tissue content in BDL rats treated with mismatch Morpholino versus BDL rats treated with AANAT Vivo-Morpholino. This low increase of connective tissue cannot determine a clear hepatic fibrosis in our model of short time of BDL. Further studies are needed to evaluate the long-term effects of BDL on the modulation of melatonin synthesis on liver fibrosis. Also, the novel concept that AANAT regulates SRCFTRCl−/HCO AE2 expression is supported by our previous study16 showing that in vivo administration of melatonin to BDL rats decreases secretin-induced choleresis. To determine that the effects of down-regulation of AANAT

on biliary growth depend on direct effects on bile ducts, cholangiocytes Thalidomide were treated in vitro with melatonin that decreased the biliary proliferation and expression of SR, CFTR, and Cl−/HCO AE2. We overexpressed AANAT in cholangiocytes and demonstrated a decrease

in biliary proliferation and secretin-stimulated cAMP levels and Cl− efflux. In vitro, overexpression of AANAT in cholangiocytes leading to decreased biliary proliferation and secretin receptor-dependent ductal secretion (in the absence of intestinal secretin supply) was likely the result of the fact that cholangiocytes express SR and express the message for secretin and secrete secretin,7, 39, 40 which (similar to what is observed in vivo) is an important autocrine factor sustaining biliary proliferation. We propose that the modulation of biliary melatonin secretion (by chronic administration of melatonin or changes in AANAT expression; Fig. 6) may be a valuable therapeutic approach for regulating the balance between biliary growth/apoptosis. In support of this view, we have shown that in the first stage of primary biliary cirrhosis, there is an increase of cholangiocyte proliferation that resulted in a positive balance between growth and apoptosis.41 By contrast, the end stage is characterized by the collapse of the proliferative capacity of cholangiocytes, resulting in the reduction (high apoptosis rate) of the number of bile ducts (vanishing bile duct syndrome).