In the current issue, Chen et al2 provide evidence that the chem

In the current issue, Chen et al.2 provide evidence that the chemical entity itself, particularly with respect to dose AZD1208 datasheet and its physiochemical nature (lipophilicity), is a key factor. They assessed the predictive value of dose (≥100 mg per day) and calculated octanol-water partition coefficient (logP > 3) in two independent databases of Food and Drug Administration

(FDA)-approved drugs labeled for the presence or absence of liver injury. The present study confirms previous studies that suggested both factors separately could predict hepatotoxicity3-7 and suggests that a “rule-of-two” which combines both dose and lipophilicity performs better than dose alone, increasing the positive predictive value of dose alone from 85% to 96% (“rule-of-two”) while decreasing the negative predictive value from 55% to 39%.

Whereas only 8 of 114 drugs in the two databases with no DILI concern exhibited positive “rule-of-two,” only half of the hepatotoxic drugs were positive. Thus, AUY-922 manufacturer false-positives were low but false-negatives were substantial. Clearly, the “rule-of-two” is far from perfect and cannot replace preclinical testing but could be useful as an additional guide in compound selection during drug development. One interesting clinical application of the “rule-of-two” was illustrated by performance in six cases of DILI from LiverTox who received multiple medications; in five cases the implicated drug was the only

one exhibiting a positive “rule-of-two.” This suggests that application of “rule-of-two” or a facsimile may improve causality assessment in the setting of multiple medications. Why should Tacrolimus (FK506) dose and lipophilicity be of predictive value? Likely this is because of the need for the liver to be exposed to a threshold level of the parent drug and/or reactive metabolite. Lipophilic drugs are cleared by the liver and generally require biotransformation to be eliminated. As noted by the authors, a significant relationship was observed between the extent of hepatic metabolism and logP (calculated-water partition coefficient). Therefore, logP may simply be a surrogate for extensive biotransformation and hepatic exposure to a reactive metabolite. Indeed, others have shown the increased predictive value of combining dose with information on hepatic metabolism.

In the current issue, Chen et al2 provide evidence that the chem

In the current issue, Chen et al.2 provide evidence that the chemical entity itself, particularly with respect to dose SB431542 research buy and its physiochemical nature (lipophilicity), is a key factor. They assessed the predictive value of dose (≥100 mg per day) and calculated octanol-water partition coefficient (logP > 3) in two independent databases of Food and Drug Administration

(FDA)-approved drugs labeled for the presence or absence of liver injury. The present study confirms previous studies that suggested both factors separately could predict hepatotoxicity3-7 and suggests that a “rule-of-two” which combines both dose and lipophilicity performs better than dose alone, increasing the positive predictive value of dose alone from 85% to 96% (“rule-of-two”) while decreasing the negative predictive value from 55% to 39%.

Whereas only 8 of 114 drugs in the two databases with no DILI concern exhibited positive “rule-of-two,” only half of the hepatotoxic drugs were positive. Thus, HM781-36B nmr false-positives were low but false-negatives were substantial. Clearly, the “rule-of-two” is far from perfect and cannot replace preclinical testing but could be useful as an additional guide in compound selection during drug development. One interesting clinical application of the “rule-of-two” was illustrated by performance in six cases of DILI from LiverTox who received multiple medications; in five cases the implicated drug was the only

one exhibiting a positive “rule-of-two.” This suggests that application of “rule-of-two” or a facsimile may improve causality assessment in the setting of multiple medications. Why should Benzatropine dose and lipophilicity be of predictive value? Likely this is because of the need for the liver to be exposed to a threshold level of the parent drug and/or reactive metabolite. Lipophilic drugs are cleared by the liver and generally require biotransformation to be eliminated. As noted by the authors, a significant relationship was observed between the extent of hepatic metabolism and logP (calculated-water partition coefficient). Therefore, logP may simply be a surrogate for extensive biotransformation and hepatic exposure to a reactive metabolite. Indeed, others have shown the increased predictive value of combining dose with information on hepatic metabolism.

15 Some aspects of cirrhotic cardiomyopathy, such as diastolic dy

15 Some aspects of cirrhotic cardiomyopathy, such as diastolic dysfunction, reduced cardiac index, and Q-T interval prolongation, have been shown to be significantly associated with complications of cirrhosis, such as HRS, and death (Fig. 1).16, 17 Therefore, if NSBBs further impair cardiac function in a patient with cirrhotic cardiomyopathy, Pexidartinib this could be another mechanism whereby propranolol administration would lead to an unfavorable outcome. From the opposite standpoint, propranolol reduces the risk of bleeding, and

therefore, bleeding-related death. By the same mechanism, NSBBs can also reduce bacterial translocation from the gut.18 Because bacterial translocation is the initial step in the pathogenesis of SBP, the use of propranolol has been shown to prevent the development of SBP18, 19 and postsurgical infections in cirrhosis (Fig.

1).20 It appears that the controversy regarding NSBB use in advanced cirrhosis might continue, the report from Lebrec et al. notwithstanding. NSBBs should continue to be used to prevent variceal bleeding. However, the risk/benefit ratio of such treatment may vary according to the stage of the cirrhosis, perhaps becoming unfavorable in patients with the most advanced stage. New studies GS-1101 research buy are necessary to establish if NSBBs exert different effects in different subsets of patients with cirrhosis, although it is unlikely that such studies are currently under way. Pending

the results of such studies, patients with ascites who are on NSBBs should be monitored closely, and consideration should be given to discontinuing NSBBs when either sepsis or HRS develop. “
“Peroxiredoxins (Prxs) are peroxidases that catalyze the reduction of reactive oxygen species (ROS). The active site cysteine residue of members of the 2-Cys Prx subgroup (Prx I to IV) of Prxs is hyperoxidized to cysteine sulfinic acid (Cys-SO2) during catalysis with concomitant loss of peroxidase activity. Reactivation of the Enzalutamide chemical structure hyperoxidized Prx is catalyzed by sulfiredoxin (Srx). Ethanol consumption induces the accumulation of cytochrome P450 2E1 (CYP2E1), a major contributor to ethanol-induced ROS production in the liver. We now show that chronic ethanol feeding markedly increased the expression of Srx in the liver of mice in a largely Nrf2-dependent manner. Among Prx I to IV, only Prx I was found to be hyperoxidized in the liver of ethanol-fed wildtype mice, and the level of Prx I-SO2 increased to ≈30% to 50% of total Prx I in the liver of ethanol-fed Srx−/− mice. This result suggests that Prx I is the most active 2-Cys Prx in elimination of ROS from the liver of ethanol-fed mice and that, despite the up-regulation of Srx expression by ethanol, the capacity of Srx is not sufficient to counteract the hyperoxidation of Prx I that occurs during ROS reduction.

For multicenter studies, the diagnosis of MHE or CHE by consensus

For multicenter studies, the diagnosis of MHE or CHE by consensus should utilize at least two of the current validated testing strategies: paper-pencil

(PHES) and one of the following: computerized (CRT, ICT, SCAN, or Stroop) or neurophysiological (CFF or EEG).[66] In the clinical routine or single-center studies, investigators may use tests for assessing the severity of HE with which they are familiar, provided that normative reference data are available and the tests have been validated for use in this patient population.[66] High blood-ammonia levels alone do not add any diagnostic, staging, or prognostic value in HE patients Trametinib with CLD.[87] However, in case an ammonia level is checked in a patient with OHE and it is normal, the diagnosis of HE is in question. For ammonia-lowering drugs, repeated measurements of ammonia may be helpful to test the efficacy. There may be logistic challenges to accurately measure blood ammonia, which should

be taken into consideration. Ammonia is reported either in venous, arterial blood, or plasma ammonia, so the relevant normal should be used. Multiple methods are available, but measurements should only be employed when laboratory standards allow for reliable analyses. Computed tomography (CT) or magnetic resonance (MR) or other image modality scans do not contribute diagnostic or grading information. However, the risk of intracerebral selleck chemicals hemorrhage is at least 5-fold increased in this

patient group,[88] and the symptoms may be indistinguishable, so a brain scan is usually part of the diagnostic workup of first-time HE and on clinical suspicion of other pathology. 3. Hepatic encephalopathy should be treated as a continuum ranging from unimpaired cognitive function with intact consciousness through coma (GRADE III, A, 1). 4. The diagnosis of HE is through Y27632 exclusion of other causes of brain dysfunction (GRADE II-2, A, 1). 5. Hepatic encephalopathy should be divided into various stages of severity, reflecting the degree of self-sufficiency and the need for care (GRADE III, B, 1). 6. Overt hepatic encephalopathy is diagnosed by clinical criteria and can be graded according the WHC and the GCS (GRADE II-2, B, 1). 7. The diagnosis and grading of MHE and CHE can be made using several neurophysiological and psychometric tests that should be performed by experienced examiners (GRADE II-2, B, 1). 8. Testing for MHE and CHE could be used in patients who would most benefit from testing, such as those with impaired quality of life or implication on employment or public safety (GRADE III, B, 2). 9. Increased blood ammonia alone does not add any diagnostic, staging, or prognostic value for HE in patients with CLD. A normal value calls for diagnostic reevaluation (GRADE II-3, A, 1). At this time, only OHE is routinely treated.

nicotianae in regions that are at risk of contracting tobacco bla

nicotianae in regions that are at risk of contracting tobacco black shank disease and that the Ypt1 gene is a novel and effective target of P. nicotianae LAMP visual detection. “
“Degenerate Potyviridae primers were used to amplify and sequence the 3′-terminal regions of viruses from traditional and modern cultivars of sugarcane with mosaic disease growing in different areas of Yunnan province, China. Seven samples contained Sugarcane mosaic virus (SCMV), 11 contained Sorghum mosaic virus (SrMV) and two contained both viruses. SCMV was

only isolated from traditional cultivars. In a phylogenetic analysis of the partial NIb and complete coat protein coding regions, most SCMV isolates formed a distinctive phylogenetic cluster (named SO) that otherwise contained only three Vietnamese isolates. SCMV variation seems mostly related PLX4032 to host genotype. selleck chemical In the same analysis, the SrMV isolates formed three major groups, one of which is reported for the first time, but the significance of the grouping is unclear. “
“A field survey was conducted to determine the relationship between Ralstonia solanacearum diversity and severity of bacterial wilt

disease in tomato plants grown in plastic greenhouses. Both vegetative and reproductive stages of the plants were surveyed, and the symptoms were empirically categorized into five scales: 0 (asymptomatic): 1st, 2nd, 3rd and 4th. The bacterial wilt pathogen was isolated from infected plants at each disease scale; pathogenic characteristics and population densities of the Metalloexopeptidase bacterial strains were assessed. Two hundred and eighty-two isolates were identified as R. solanacearum, which were divided into three pathogenic types, virulent, avirulent and interim, using the attenuation index (AI) method and a plant inoculation bioassay. Ralstonia solanacearum was detected in all asymptomatic and symptomatic

tomato plants, with population numbers, ranging from 10.5 to 86.7 × 105 cfu/g. However, asymptomatic plants harboured only avirulent or interim R. solanacearum, whereas tomato plants displaying 1st or 2nd disease degree contained interim and virulent strains. Additionally, 3rd and 4th degree plants harboured only virulent strains. The disease was more severe in vegetative-stage plants (disease severity index (DSI) 0.20) with higher total numbers of interim and virulent R. solanacearum strains than those in reproductive-stage plants (DSI 0.12). Three pathotypes of R. solanacearum coexisted in a competitive growth system in the tomato field, and their distribution closely correlated with the severity of tomato bacterial wilt. “
“Evaluation of 130 accessions of rapeseed-mustard germplasm grown at the National Bureau of Plant Genetic Resources, New Delhi, India during the winter season (2011–2012) revealed the occurrence of a leaf curl disease in seven accessions. The occurrence of the disease was observed in another 62 of 525 accessions evaluated during 2012–2013.

, MD (AASLD Postgraduate Course, Parallel Session) Advisory Commi

, MD (AASLD Postgraduate Course, Parallel Session) Advisory Committees or Review Panels: Gilead Roberts, John P., MD, FACS (AASLD/ILTS Transplant Course)

Nothing to disclose Roberts, Lewis R., MB ChB, PhD (Parallel Session) Grant/Research Support: Bristol Myers Squibb, ARIAD Pharmaceuticals, BTG, Wako Diagnostics, Inova Diagnostics, Gilead Sciences Rockey, Don C., MD (Early Morning Workshops, Parallel Session) Grant/Research Support: Gilead, Actelion Rosen, Hugo R., MD (Advances for Practitioners) Nothing to disclose Rudnick, David A., MD, PhD (Early Morning Workshops, Parallel Session) Nothing to disclose Runyon, Bruce A., MD (Hepatology Associates Course) Nothing to disclose Russo, Mark W., MD, MPH (ABIM Maintenance of Certification, Career Development Workshop) Grant/Research Support: Vertex, selleck chemicals Merck Speaking and Teaching: Vertex, Gilead, BMS Sanchez, William, CP-673451 concentration MD (Competency Training Workshop) Nothing to disclose Sanyal, Arun J., MD (AASLD Postgraduate Course) Advisory Committees or Review Panels: Bristol Myers, Gilead, Abbott, Ikaria Consulting: Salix, Immuron, Exhalenz, Nimbus, Genentech, Echosens, Takeda Grant/Research Support: Salix, Genentech, Genfit, Intercept, Ikaria, Takeda, GalMed, Novartis, Gilead Independent Contractor: UpToDate, Elsevier Sarin, Shiv K., MD (Emerging Trends Symposium, Meet-the-Professor Luncheon) Nothing to disclose

Sass, David A., MD (Hepatology Associates Course) Nothing to disclose Schiff, Eugene R., MD (SIG Program) Advisory Committees or Review Panels: Bristol Myers Squibb, Gilead, Merck, Janssen, Salix Pharmaceutical, Pfizer Grant/Research Support: Bristol Myers Squibb, Abbott / AbbVee, Gilead, Merck, Conatus, Medmira, Roche, Janssen, Orasure Technologies, Discovery Life Sciences, Siemens Schinazi, Raymond F., PhD, DSc (SIG Program) Board Membership: RFS Pharma, LLC Stock Shareholder: RFS Pharma, LLC Schirmacher, Peter, MD (SIG Program)

Advisory Committees or Review Panels: Novartis Consulting: Novartis Grant/Research Support: Novartis Schnabl, Bernd, MD (Early Morning Workshops) Nothing Amisulpride to disclose Schuppan, Detlef, MD, PhD (Basic Research Workshop, Early Morning Workshops) Consulting: Boehringer Ingelheim, Aegerion, Gilead, Genzyme, GSK, Pfizer, Takeda, Sanofi Aventis, Silence Schwabe, Robert F., MD (Basic Research Workshop) Nothing to disclose Schwarz, Kathleen B., MD (Meet-the-Professor Luncheon) Consulting: Novartis, Novartis Grant/Research Support: Bristol-Myers Squibb, Gilead, Roche/ Genentech, Bristol-Myers Squibb, Vertex, Roche Seeff, Leonard B., MD (Early Morning Workshops) Nothing to disclose Seki, Ekihiro, MD, PhD (Basic Research Workshop) Grant/Research Support: Nippon Zoki Shah, Vijay, MD (AASLD Postgraduate Course, Early Morning Workshops) Nothing to disclose Sharma, Barjesh C.

Stepwise increase of total positive-area was observed according t

Stepwise increase of total positive-area was observed according to the ballooning hepatocyte score. Total positive-area was significantly greater in the liver tissues from the patients with nonalcoholic steatohepatitis (n=47) than those from the patients with nonalcoholic fatty liver (n=7). We next examined the role of S100A8

in a NAFLD mice model. LD-fed mice, but not ND-fed mice, displayed hepatitis with steatosis, lobular inflammation, ballooning and fibrosis. S100A8-positive cells were observed in a part of hepatic leukocytes, and significantly greater in number in the livers of LD-fed mice compared with ND-fed mice. Flow cytometric analyses revealed that more than 80% of S100A8 positive cells were CD11b+ Gr-1high myeloid lineage cells and significantly increased in the livers of LD-fed Erismodegib molecular weight mice compared with ND-fed mice. S100A8 positive cells also expressed CXCR2, a chemokine receptor. We studied chemokine gene expressions in the livers of LD- and ND-fed Gefitinib cost mice. The gene expressions of Cxcl1, Cxcl2, and Mcp1 significantly elevated in the livers of LD-fed mice compared with ND-fed mice. In vitro study, palmitic acid upregulated the gene expressions

of Cxcl1 and Mcp1 in CL2, murine hepatocyte cell line. Hepatic leukocytes from LD-fed mice, but not those from ND-fed mice, spontaneously produced substantial amounts of CXCL1 as well as TNF-α. Moreover, S100A8 significantly induced production of CXCL1 as well as TNF-α from normal hepatic leukocytes. Conclusion: The present study suggested that upregulated Cxcl1 expressions in the livers of LD-fed mice led to the accumulation

of S100A8 positive cells via CXCR2 and that S100A8 produced TNF-α and Cxcl1. Taken together with human results, the amplification of S100A8-CXCL1 loop via CXCR2 might be involved in the development of NAFLD. Disclosures: Tetsuo Takehara – Grant/Research Support: Chugai Pharmaceutical Co., MSD K.K. The following people have nothing to disclose: Kaori Mukai, Takuya Miyagi, Yoshinobu Yokoyama, Teppei Dynein Yoshioka, Kumiko Nishio, Akira Nishio, Yoshiki Onishi, Satoshi Aono, Yoshinobu Saito, Satoshi Tanaka, Hayato Hikita, Ryotaro Sakamori, Naoki Hiramatsu, Harumasa Yoshihara, Yasuharu Imai, Tomohide Tatsumi Background and Aim: Free fatty acids play a critical role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD), including non-alcoholic steatosis and steatohepatitis. Recent research has shown that apoptosis is a characteristic feature of hepatocytes in NAFLD. Meanwhile, a complex relationship is reported between apoptosis and autophagy in several disease models but not well established in NAFLD. In this study, we investigated the interplay between apoptosis and autophagy in NAFLD. Methods: HepG2 cells were cultured with saturated palmitic acid (PA). For in vivo studies, male C57BL/6J mice or Mx1-Cre mediated Atg7 knockout mice (Mx1-Cre Atg7 fl/fl), were fed high fat diet (HFD).

30 In the second part of our study we showed that αVEGFR2 treatme

30 In the second part of our study we showed that αVEGFR2 treatment prevents the progression of NASH by attenuating steatosis and inflammation, both in a preventive and therapeutic setting, thereby confirming our hypothesis that angiogenic factors play an early role in the disease progression from steatosis to NASH. The grade of steatosis and inflammation was significantly less in the liver of αVEGFR2-treated mice in a preventive setting. Moreover, αVEGFR2 treatment was able to block the progression to NASH in mice with steatosis and inflammation. This could indicate that αVEGFR2 treatment could temper the effect of angiogenic stimuli. Moreover, in vitro we

found that αVEGFR2 therapy significantly

decreased lipid accumulation in fat-laden primary hepatocytes. This is in line with previous studies that Palbociclib mw the VEGF/VEGFR2 pathway is critical for both angiogenesis and adipogenesis during de novo adipose tissue formation from preadipocytes.31 Moreover, previous studies CHIR-99021 ic50 showed that angiogenic, inflammatory, and lipogenic processes are tightly crosslinked and are capable of sustaining each other.32 The reason why αPlGF treatment did not have a significant effect on the liver histology of mice with NASH compared to untreated mice with NASH could probably lie in the fact that PlGF signals only through the VEGFR1 pathway and not by way of VEGFR2. To obtain a clear insight into the molecular events, we examined the transcript levels of lipogenic genes (Scd1 and L-fabp1). These experiments showed that αVEGFR2 treatment increased Scd1 gene expression

in both a preventive and therapeutic setting. Scd1 plays a key role in the prevention of steatohepatitis by partitioning excess lipid into monounsaturated fatty acids that can be safely stored.33 The literature confirms our results that MCD feeding causes a significant decrease in hepatic Scd1 gene expression as well as the down-regulation of L-fabp1 gene expression compared to mice fed a control diet.34, 35 Our study showed that αVEGFR2 increases Scd1 gene expression to a more normal Scd1 expression in the liver of mice treated in a therapeutic and preventive setting compared to untreated mice fed an Morin Hydrate MCD diet. This could suggest that αVEGFR2 therapy improves lipid metabolism in the liver. However, the exact molecular mechanism responsible for MCD diet-induced down-regulation of Scd1 as well as changes in Scd1 expression in human NAFLD, and its relation to liver damage and disease progression, remain unknown and will require further investigation. In summary, we demonstrated the role for VEGF in the pathophysiology in two mouse models for NASH. This study shows for the first time that αVEGFR2 treatment attenuates steatosis and inflammation in the liver of mice with NASH both in a preventive and therapeutic setting.

History has taught us that failure to preemptively develop a mora

History has taught us that failure to preemptively develop a moral framework to deal with problems of scarcity can lead to injustices to patients in need. Distributive justice is a moral principle that emphasizes “fair, equitable, and appropriate

distribution” of scarce www.selleckchem.com/products/17-AAG(Geldanamycin).html resources.13 Equality for all patients should be paramount, yet this should be carefully balanced with appropriate emphasis on medical need. With the arrival of DAA therapy, we will be unable to initially treat all patients requesting therapy, and we will once again be forced to allocate a scarce resource. Critical analysis of this problem has yielded two potential solutions for this allocation dilemma: a first-come, first-served approach and a needs-based approach. A conventional first-come, first-served approach, as the name implies, offers therapy, when appropriate, to patients in the order in buy NU7441 which they are seen in the clinic after DAA launch.

If (and when) the health care team becomes saturated, a waiting list will form, and patients on that list will be offered therapy when the health care team has more capacity. This approach has some advantages. It is the simplest plan and requires no planning prior to DAA availability. In fact, this approach will likely be a default system used by any center that has not enacted a preconceived DAA allocation system. First-come, first-served strictly adheres to the principle of justice, because all patients have an equal claim to therapy, and specific prioritizations are not made. However, it is inadequate because

it ignores the importance of medical need where the workforce available to treat is limited in relation to the need. We propose a needs-based allocation system. Much like the Model for End-Stage Liver Disease system, priority would be given to the sickest patients first in an effort to optimize outcomes for all patients with HCV. Prior to the launch of DAA therapy, treatment-eligible patients with HCV could be provided with an educational symposium outlining the natural progression of HCV and describing an allocation system, Smoothened which would stress the importance of expediting treatment for the sickest patients and the safety of waiting for therapy in patients with early stages of disease. Then, patients who have previously deferred therapy and new patients will be prioritized on the basis of need, with patients with cirrhosis at one end of the spectrum and asymptomatic patients with F0-F2 fibrosis at the other end of the spectrum. This system satisfies the principle of justice while placing appropriate emphasis on medical need. There will be inherent difficulties in this prioritization system.


“See Article on Page

1685 AFP, alpha-fetoprotein;


“See Article on Page

1685 AFP, alpha-fetoprotein; α-SMA, α-smooth muscle actin; EMT, epithelial-to-mesenchymal transition; FSP1, fibroblast-specific protein 1; HSC, hepatic stellate cell; TGF-β, transforming growth factor C646 price β. Fibrosis studies conducted in different organs including the liver have demonstrated that myofibroblasts are the primary source of extracellular matrix.2 Myofibroblasts are immunophenotypically characterized by a stellate shape, expression of abundant pericellular matrix, and fibrotic genes (α-smooth muscle actin [α-SMA], nonmuscle myosin, fibronectin, vimentin).3 Ultrastructurally, myofibroblasts are defined by prominent rough endoplasmic reticulum, a Golgi apparatus producing collagen,

peripheral myofilaments, fibronexus (no lamina), and gap junctions.3 Myofibroblasts are implicated in wound healing and fibroproliferative disorders.4-6 In response to fibrogenic stimuli, such as transforming growth factor β1 (TGF-β1), myofibroblasts express α-SMA, secrete extracellular matrix (fibronectin, collagen type I and III), obtain high contractility, and change phenotype (production of the stress fibers).7 But where do these myofibroblasts come from? Hepatic stellate cells (HSCs) are considered to be a major source of fibrogenic myofibroblasts in the injured liver.8 Hepatic myofibroblasts may also originate from portal fibroblasts,2 bone marrow–derived mesenchymal cells, and fibrocytes,9, 10 and by the transition of epithelial cells11 and endothelial cells12 to mesenchymal cells. What is the evidence for type 2 EMT being the etiology of the myofibroblasts in liver Venetoclax fibrosis? First, multiple studies in the kidney and in the lung were interpreted as showing EMT during fibrosis in those organs, and this concept was extrapolated to liver fibrosis (discussed in Zeisberg and Duffield13). Second, primary cell culture studies have clearly demonstrated that cholangiocytes and hepatocytes undergo a change in the phenotype and gene expression toward a mesenchymal cell, especially after

incubation with TGF-beta, which is the cytokine most closely associated with EMT.14 Third, immunohistochemical studies both in experimental and clinical liver fibrosis have reported the coexpression of mesenchymal markers (fibroblast-specific protein Exoribonuclease 1 [FSP1], α-SMA, vimentin, desmin) with the original epithelial markers (cytokeratin-19 for cholangiocytes and albumin for hepatocytes).15 These types of studies have been recently questioned, because the allegedly EMT-specific marker FSP1 (also called S100A4) has now been shown to be expressed by nonfibroblast cells in the liver, including by a subset of monocytes.16 Fourth, at least one study11 used lineage tracing in mouse liver (see description below) to demonstrate that cells that were originally hepatocytes (i.e., at one point expressed albumin) expressed FSP1 after a fibrogenic liver injury.