24 In HCC, CD44 is also an important marker used in combination w

24 In HCC, CD44 is also an important marker used in combination with other CSC markers to better define the surface phenotype of liver CSCs. For the aforementioned markers, including CD133 and CD90, cells co-expressing either of these markers and CD44

present a more aggressive phenotype than cells with a positive expression of either CD133 or CD90 alone. Yang et al. showed that CD44+ cells developed tumor nodules in immunodeficient mice faster than CD44- cells, whereas lung metastases were only observed in immunodeficient mice transplanted with CD90+CD44+ cells.23 In another study, CD44 was found to be preferentially expressed in a CD133+ population in four HCC cell lines, including Huh7, SMMC-7721, MHCC-LM3 and MHCC-97L. CD133+CD44+ cells exhibit enhanced PD98059 mw abilities to form tumors, are chemoresistant and express a higher level of “stemness”-associated genes, as compared with their CD133+CD44-

counterparts.25 EpCAM is present in the embryonic liver, bile duct epithelium and proliferating bile ductules in the cirrhotic liver, but it is absent in normal adult hepatocytes.26 An elevated expression of EpCAM was first identified in premalignant hepatic tissues; therefore, this surface protein was suggested to be an early biomarker for HCC.27 Following a cDNA microarray analysis on a clinical cohort of primary HCC tissue, EpCAM+ HCC was linked with the gene signature and the molecular pathway of hepatic progenitor

cells, whereas genes expressed in EpCAM- HCC cells were associated with mature hepatocyte functions.26 These two subtypes Natural Product Library cost of HCC were further stratified into four groups with features resembling different hepatic lineages, and they showed prognostic differences based on the expression of alpha fetoprotein (AFP).26,28 EpCAM+ HCC cells 上海皓元 have also been shown to be highly invasive and tumorigenic, in comparison with their EpCAM- counterparts.28 Recently, a novel cell surface marker, CD13, was identified for potentially dormant and semi-quiescent CSCs in HCC. Haraguchi et al. found that CD13 was commonly enriched in an SP population sorted from Huh7, PLC/PRF/5 and Hep3B cells by gene expression microarray analysis. CD13 was selected as a putative marker to enrich the semi-quiescent liver CSCs because of its predominant distribution during the G1/G0 phase.29 This result suggested that CD13+ cells represent the dormant or slow-growing population that is believed to account for the chemoresistant capacity in HCC. Researchers then assessed the tumorigenic potential of CD13 with two other liver CSC markers, CD133 and CD90. The results clearly showed that the CD13+CD133+ and CD13+CD90- fractions in Huh7 and PLC/PRF/5 cell lines, respectively, initiated tumor formation effectively in limiting-dilution and serial transplantation assays.

20 The extent to which these symptoms differ from

20 The extent to which these symptoms differ from http://www.selleckchem.com/products/apo866-fk866.html the nondisease population

and the interrelation with other symptom sets in PBC (most specifically fatigue) has not been comprehensively addressed to date. HADS is a validated anxiety and depression measure optimized for use in patients with chronic disease. It has previously been applied in PBC.20 Individual subscales reflecting anxiety and depression comprise seven items, each with a potential score of 0-21. Clinical cutoffs are variable. For the purposes of this study “caseness” for depression or anxiety was defined a score of 11 or greater for the subscale. Analysis was performed using the statistical analysis software Prism 3.0 (GraphPad Prism, San Diego, CA) and SPSS (IBM, Armonk, NY). It was determined whether data were normally distributed. Where data were normally distributed they are presented as mean ± standard deviation and comparison was made between groups using unpaired t tests. Where data were nonnormally distributed, they are presented as median and range and comparisons were made by Mann-Whitney U test. To determine whether the degree of functional impairment experienced by liver

transplant recipients was influenced by the symptoms they experienced, we explored the univariate relationship among functional capacity and the symptom assessment tools of cognitive symptoms, fatigue, and autonomic dysfunction. Univariate analysis was performed by correlations using Spearman and Pearson’s tests, where appropriate for parametric and nonparametric data. To determine Selleckchem Hydroxychloroquine whether the relation between perceived QOL and independent symptom domains were independent, a multivariate analysis was performed using the log-rank test. Differences in proportions were determined using chi-square tests. A statistically significant result was considered when P < 0.05. ESS Epworth Sleepiness Scale GWAS genome-wide association study HADS Hospital Anxiety

& Depression Scale OGS Orthostatic Grading Scale PBC primary biliary cirrhosis QOL quality MCE公司 of life UDCA ursodeoxycholic acid VAS Visual Analogue Scale In all, 2,402 PBC patients participated in the study, making this the largest study of the clinical expression of PBC. A total of 2,353 of the PBC patients returned analyzable measures and were suitable for inclusion in the study. The clinical characteristics of the UK-PBC study cohort has been reported previously, together with data relating to the clinical response to UDCA therapy16 and are summarized in Table 1. The demographic distribution of the PBC population reflected previous reports of disease epidemiology. As reported previously, 80% were treated with UDCA as recommended by treatment guidelines. Of those who had received UDCA for at least a year 79% (63% of the whole patient population) met the Paris criteria for adequate treatment response.

[18-20] Regions of interest were created using a semiautomated th

[18-20] Regions of interest were created using a semiautomated thresholding and region-growing technique described in a previous publication.[21] Additionally, a 5-mm-diameter spherical ROI was placed

within normal-appearing white matter (NAWM) in T2 or FLAIR images, respectively, to acquire CBF data for normalization of DSC and ASL values Panobinostat order in tumor regions. All images for each patient were registered to a high-resolution (1.0 mm isotropic), T1-weighted brain atlas (MNI152; Montreal Neurological Institute, Montreal, Canada) using a mutual information algorithm and a 12-degree of freedom transformation using FSL (FMRIB, Oxford, UK; http://www.fmrib.ox.ac.uk/fsl/). Fine registration (1-2 degrees and 1-2 voxels) was then MAPK Inhibitor Library chemical structure performed using a Fourier transform-based, six degrees of freedom, rigid body registration algorithm followed by visual inspection to ensure adequate alignment. DSC and ASL estimates of CBF in tumor ROIs were normalized to that of normal appearing white matter (NAWM) by dividing mean values for tumor ROIs by mean values for the respective modalities in NAWM. Linear regression

was performed for data extracted from tumor ROIs to determine if there was a significant linear relationship between DSC and ASL 上海皓元医药股份有限公司 CBF measurements. The voxel-wise correlation between DSC and ASL measurements of CBF was assessed for all voxels, for all patients. A linear correlation with no intercept was used as a model for the voxel-wise correlation between DSC and ASL estimates of CBF, which was tested for statistical significance using chi-squared goodness of fit using a reduced chi-squared value, χ2red, as the test statistic (ie, variance of the residuals). Although relative

CBV is the most common metric used to evaluate tumor vascularity, we chose to compare CBF estimates between DSC and ASL because ASL inherently provides quantification of absolute CBF. For most patients, DSC and ASL estimates of CBF were elevated within the areas of contrast-enhancement and the pattern of elevated CBF was similar between the two modalities. For example, Figure 1 illustrates a typical set perfusion images obtained in two different glioblastoma patients. In both these patients, the regions of contrast enhancement have the highest CBF; however, this elevated CBF is typically quite heterogeneous throughout the region of enhancement. As expected, both modalities show the lowest measured CBF within the central necrotic regions (hypointense on postcontrast T1-weighted images).

21 Human samples (five normal at 11 weeks of gestation [W], two A

21 Human samples (five normal at 11 weeks of gestation [W], two ARPKD at 13W, one ARPKD at 22W, and one patient with HNF1B mutation at 4 days after birth) were formalin-fixed and paraffin-embedded. Mouse liver preparation and immunofluorescence analysis of 5-μm-thick (human) or 9-μm-thick (mouse) sections were as described22 (Supporting Table 1). RNA from mouse liver was extracted

with Tripure RNA Isolation reagent (Roche, Vilvoorde, this website Belgium), and quantitative reverse-transcriptase polymerase chain reaction (Supporting Table 2) was performed with SYBR Green Master Mix Reagent (Invitrogen, Merelbeke, Belgium). For quantification of Sec63, Pkhd1, and Cys1, copy number for each messenger RNA (mRNA) was normalized to β-actin mRNA copy number using standard calibration curves, and reported by reference to control values set at 100%. To NVP-LDE225 cell line investigate how DPMs develop in the absence of HNF6 or HNF1β, we first determined the differentiation status of the ductal cells lining DPMs in livers of Hnf6−/− mice and of mice with liver-specific

inactivation of Hnf1b (Hnf1bloxP/loxP-Alfp-Cre). Because differentiation progresses from the hilum to the periphery, all livers were analyzed near the hilum. At E17.5, the cells lining biliary structures in Hnf6−/− mice did not express the biliary marker sex-determining region Y–related HMG box transcription factor 9 (SOX9), but most cells expressed the hepatocyte/hepatoblast marker

HNF4. Higher medchemexpress E-cadherin (Ecad) expression in biliary cells as compared to parenchymal cells is typical for mouse fetal liver (Fig. 1A). The ectopic expression of HNF4 in biliary structures (arrowheads) was in line with our earlier observation that the lack of HNF6 generates hybrid hepatobiliary cells.23 Such cells were observed on the portal and parenchymal sides of the biliary structures, which suggests that HNF6 is required for differentiation of the two biliary layers. In control mice, expression of the transforming growth factor receptor type II (TβRII) is absent from the portal side of PDS at E15.5 but is detected on their parenchymal side.3 At E17.5, the expression on the parenchymal side progressively waned, leading to ducts with a limited number TβRII-positive cells (open arrowheads, Supporting Fig. 1) and devoid of TβRII at E18.5.3 In the absence of HNF6, expression of TβRII persisted on both sides of the biliary structures at E17.5 (arrowheads, Supporting Fig. 1), and this was again in line with our earlier data at E15.5 which showed elevated expression of TβRII in the liver.23 In the absence of HNF1β at E17.5, differentiation of cells that lined the portal side of the DPM was normal throughout the liver: these cells were SOX9+/HNF4−/Ecadhigh.

The improvement of liver stiffness after dietary modification sug

The improvement of liver stiffness after dietary modification suggests a partially reversible pathologic picture that is alike to what was reported in patients with acute decompensated selleck chemicals llc heart failure,[3] although elastography is not validated in chronic liver diseases other than viral hepatitis.[4] The interconnections between the lymphatic system and blood circulation in portal hypertension have been recently suggested to play a role in the

pathogenesis of ascites and edema formation in cirrhosis.[5, 6] Ribera et al.[5] demonstrated an impaired lymphatic drainage in cirrhotic rats; hence, it might be reasonable to suppose that the complex interplay between the lymphatic and circulatory system could also justify a reverse mechanism for the BVD-523 supplier increased liver stiffness in a primary impairment of splanchnic lymphatic circulation. We thank Mrs. Bianca Ghisi for graphical assistance. Additional Supporting Information may be found in the online version of this article at the publisher’s website. “
“A 52-year-old male presented to our hospital with a focal hepatic mass that was incidentally detected on the screening ultrasound and computed tomography (CT). The patient did not have a relevant

medical history or any related complaints. All levels of serum tumor markers, including alfa-fetoprotein, carcinoembryonic antigen, carbohydrate antigen 125, and carbohydrate MCE公司 antigen 19-9 were within normal limits. CT, computed tomography; FDG, 2-fluoro-2-deoxy-D-glucose; PET, positron emission tomography. Ultrasonography revealed a well-encapsulated, hypoechoic round lesion in the left lobe of the liver.

On CT, a well-defined, hypoattenuating mass was indicated with enhancement of the capsule adjacent to the left portal vein (Fig. A). Positron emission tomography (PET) demonstrated increased 2-fluoro-2-deoxy-D-glucose (FDG) uptake in this lesion, suggesting a malignant tumor or inflammatory mass (Fig. B). The patient underwent lateral segmentectomy, and a cross-section of surgical specimen showed a well-demarcated, yellowish, solid round mass measuring 3 cm × 4.5 cm with minimal myxoid component and capsulation (Fig. C). A microscopic specimen obtained at the junction of the tumor and the liver (arrowhead), consisting of densely packed spindle cells (arrow) surrounded by a capsule, was compatible with the findings of schwannoma (Fig. D). An immunohistochemical study was performed on the mass. The tumor cells, which showed a whorl pattern, were positive for immunochemical staining with S-100 protein (Fig. E). However, the tumor cells were negative for smooth muscle actin, c-kit, and CD34.

[109] They are also low in abundance and difficult to detect[109

[109] They are also low in abundance and difficult to detect.[109] The pure arithmetic and subtlety of protein transformations and interactions has led to many semiofficial subcategories of proteomics that constrict their profiling domains to specific molecule classes, cellular functions, or PTMs, etc.[110-112] Simply put, the scale of the proteome is staggering. The constitution Ku-0059436 clinical trial of the metabolome meanwhile continues to be deliberated. From an original study of glucose processing in

E. coli under specific growth rates, the “metabolome” could be defined as “total complement of metabolites in a cell,” with an emphasis on representing the global metabolic processes of a cell by low-molecular weight compounds.[113] This definition was further expounded by successive metabolome studies, perpetuating a correlation between small molecule size (a metabolite weighs less than 15 kilodaltons[114]), with biochemical finality (“metabolites serve as direct signatures of biochemical activity”[21])

because a small molecule must be the result of many enzymatic processes from a gene-transcribed protein origin. While this may be true, it is inadequate in describing the important functional roles of metabolites in biology. The specific physiological functions of metabolites are appreciated and scrutinized in detail in metabolomic studies,[21, 115] but the widely accepted LY2606368 order definition of the metabolome, “the comprehensive study of naturally occurring small molecules,”[116] or some variation thereof,[21] does not generally take this into account. Metabolites may be end points of metabolism but they are not end points of physiological process, acting as catalysts, signaling molecules, and nutrients, among other

roles.[115, 117] The metabolome can perhaps be more comprehensively described as the study of the complete expression and biological function of molecules less than 25 kilodaltons within a given cell. This higher molecular mass inclusion takes medchemexpress into account the capability of NMR spectroscopy and MS in reliably resolving higher mass molecules in metabolomic studies than what some would consider a metabolite.[118] Molecule size runs along a continuum, and those not chemically or proportionally considered a metabolite or a protein may be important. This aspect is further discussed in this review. Fundamentally, reevaluations of what constitutes the proteome and metabolome illustrate the immense complexity of human biology and how “omics” have allowed us to understand this in a more complete way. The next challenge is in maneuvering this new expanse of information to unravel the mechanisms behind complex diseases such as the IBDs and build functional tools for their treatment and management. Some of the principles behind the novel ways in which the proteomic and metabolomic toolboxes are being used to these effects are discussed.

PT and MELD scores of patients in group A were markedly improved,

PT and MELD scores of patients in group A were markedly improved, compared with those in group

B, at week 3 after transplantation selleck screening library (Table 2; Fig. 2C,D). Furthermore, in both groups, there were no significant differences in PT or MELD scores between the cirrhosis and noncirrhosis subgroups (Table 3). Liver function comparisons from baseline to 48 weeks after transplantation (Table 4; Fig. 3) indicated that there were no marked differences in ALT levels between the two groups (Table 4(TBL4)). ALB levels of patients in group A were significantly superior to those in group B at 3-24 weeks after transplantation, and significant deviations were not found after 24 weeks (Table 4; Fig. 3A). The improvement in TBIL levels and PT scores of group A was markedly superior to those of group B only at 4-12 week after transplantation (Table 4; Fig. 3B,C). The improvement of MELD scores of group A was markedly superior to that of group B at 3-36 weeks after transplantation (Table 4; Fig. 3D). In regards to long-term prognosis, only one patient in group A developed HCC at 20 weeks after transplantation, and nine patients in group B developed ABT-263 chemical structure HCC throughout the 48-week follow-up; there were no significant deviations between these two groups (P = 0.107) (Fig. 4A). Furthermore, the survival rate of patients in group A was better than in group B, but significant deviations were not observed from 12 to 192 weeks of follow-up (P = 0.715) (Fig. 4B). No HCC

was found in the subgroup of patients with cirrhosis from group A, and only one incidence of HCC was observed at 20 weeks after transplantation in the subgroup of patients without cirrhosis from group A; significant deviations were not found. There were no significant deviations between these two subgroups for

survival rate (P = 0.915) (Fig. 4C). MMSCs demonstrate multipotentiality and can promote liver regeneration, secrete cytokines/growth factors, inhibit inflammation, inhibit activation of liver astrocytes, block the production of extracellular matrix (ECM), and facilitate the degradation of excessive ECM, leading to improvement of chronic hepatitis B, impediment of liver fibrosis, and repair of injured liver tissues.20 Great MCE公司 progress has been made in the treatment of liver diseases with the use of autologous MMSC transplantation and has included basic research and clinical studies.11-14, 21-24 Yet, there are still a number of problems requiring resolution in clinical practice, including the route of MMSC administration, the number of cells used for transplantation, and homing ability that may affect the efficacy of transplantation.25-27 In our previous research, we explored the bionomics of MMSCs from patients with hepatitis B.22, 28, 29 Based on these studies, we investigated the safety, short- and long-term therapeutic effects, and prognosis of a single transplantation of autologous MMSCs in patients with liver failure caused by hepatitis B.

For community health centers: The Health Resources and Services A

For community health centers: The Health Resources and Services Administration should BMN 673 cell line provide adequate resources to federally funded community health facilities for provision of comprehensive viral hepatitis services. For other settings that target at-risk populations, such as sexually transmitted disease and HIV clinics, shelter-based programs, and mobile health units: The Health Resources and Services Administration and CDC should provide resources and guidance to integrate comprehensive viral hepatitis services into those settings that serve

high-risk populations. The IOM committee believes that implementation of these and other recommendations in its report would lead to reductions in new HBV and HCV infections, fewer medical complications and deaths as a result of these viral infections of the liver, and lower total health costs. Advances will be needed: in knowledge and awareness about chronic viral hepatitis, in improvement of hepatitis B vaccine coverage, in improvement and find more better integration of viral hepatitis services, and in improvement of estimates of the burden of disease for resource-allocation purposes. The authors thank the members of the IOM’s

Committee on Prevention and Control of Viral Hepatitis Infections: Harvey J. Alter, Margaret L. Brandeau, Daniel R. Church, Alison A. Evans, Holly Hagan, Sandral Hullett, Stacene R. Maroushek, Randall R. Mayer, Brian J. McMahon, Martín Jose Sepúlveda, Samuel So, David L. Thomas, and Lester N. Wright. “
“Protease-activated receptor (PAR) 2 is a G-protein–coupled receptor that is activated after proteolytic cleavage by serine proteases, including mast cell tryptase and activated coagulation factors. PAR-2 activation augments inflammatory and profibrotic pathways through the induction of genes encoding proinflammatory cytokines and

extracellular matrix proteins. Thus, PAR-2 represents an important interface linking coagulation and inflammation. PAR-2 is widely expressed in cells of the gastrointestinal tract, including hepatic stellate 上海皓元医药股份有限公司 cells (HSCs), endothelial cells, and hepatic macrophages; however, its role in liver fibrosis has not been previously examined. We studied the development of CCl4-induced liver fibrosis in PAR-2 knockout mice, and showed that PAR-2 deficiency reduced the progression of liver fibrosis, hepatic collagen gene expression, and hydroxyproline content. Reduced fibrosis was associated with decreased transforming growth factor beta (TGFβ) gene and protein expression and decreased matrix metalloproteinase 2 and tissue inhibitor of matrix metalloproteinase 1 gene expression. In addition, PAR-2 stimulated activation, proliferation, collagen production, and TGFβ protein production by human stellate cells, indicating that hepatic PAR-2 activation increases profibrogenic cytokines and collagen production both in vivo and in vitro.

Addition of hTERT increased the anchorage independent growth of P

Addition of hTERT increased the anchorage independent growth of PHH. Transformed PHH harbored a dedifferentiated phenotype with decreased expression of hepatocytic markers, increased expression of some stemness markers and cancer stem cell self-renewal markers. Interestingly, transformed PHH showed an increased expression of Wnt/beta-catenin target genes in association with strong overexpression of upstream activators well known as Vadimezan implied in hepatocarcinogenesis such as Wnt3 ligand and Frizzled-7 receptor. Regarding the p53 family, TAp73 and DNp73 were strongly upregulated. We described for the first time a unique model

of in vitro transformation of human liver cells. We showed that both differentiated hepatocytes and bipotent progenitors are permissive to transformation. This process was accompanied by alteration of differentiation capabilities, and appearance of stemness markers in transformed PHH. Interestingly, some pathway deregulations previously described in human HCC tissues were also observed in our models : Wnt/beta-catenin and TP73. This could be an interesting tool for a better understanding of hepatocarcinogenesis and drug discovery. Disclosures: David Durantel – Grant/Research Support: Hoffmann-La Roche [Background] Liver cirrhosis is one of the most important risk factors for the development of liver cancer.

Various lineages of stromal cells including stellate cells, learn more activated myofibroblasts, and vascular endothelial cells as well as lymphocytes are known to emerge 上海皓元医药股份有限公司 in the cirrhotic liver. However, it is unclear how microenvironment alteration induced by these cells affects the process of liver cancer development. In this study, we evaluated the role of stromal cells on stemness of the tumor, which is closely associated with the

aggressiveness of liver cancer. [Methods]Primary hepatocellular carcinoma (HCC) cells obtained from surgically resected specimens as well as Huh7 cells were co-cultured with various stromal cells in vitro using cell culture inserts. Gene and protein expression was evaluated by qRT-PCR and Western blotting. Fluorescence-activated cell sorting (FACS) was used to evaluate the frequency of cancer stem cells expressing EpCAM/CD1 33. Cancer stem cell characteristics were evaluated by spheroid formation, invasion, and tumorigenicity in immune deficient mice. Time-lapse image analysis was performed to monitor cell motility affected by stromal cells. [Results] Co-culture of HCC cells with fibroblasts resulted in the enhanced cell motility, spheroid formation, and invasion capacities of HCC cells, whereas those co-cultured with vascular endothelial cells or stellate cells did not show such phenotypes. FACS analyses demonstrated the enrichment of EpCAM/CD1 33-positive cells when co-cultured with fibroblasts.

The following people have nothing to disclose: Claire Meyer, Sand

The following people have nothing to disclose: Claire Meyer, Sandeep K. Trip-athy Background. It is well known that liver and lung

injury can occur simultaneously during severe inflammation (e.g. multiple organ failure). However, whether these are parallel or interdependent (i.e. liver:lung axis) mechanisms is unclear. Previous studies have shown that chronic alcohol consumption greatly increases the risk of mortality caused by acute respiratory distress syndrome (ARDS). The potential contribution of subclini-cal liver disease driving this effect of ethanol on the lung has not been determined. Therefore, the purpose of this study was to develop a model of concomitant liver and lung injury in the setting of chronic alcohol exposure, followed by an acute inflammatory stimulus. Methods. Male mice were exposed to ethanol-containing Lieber-DeCarli diet or pair-fed control diet for 6w. At the end of the feeding period, some animals were administered LPS to induce MAPK inhibitor ARDS-like lung damage and sacrificed either 4 or 24 h after LPS exposure. The expression of cytokine mRNA in lung and liver tissue were determined by real-time PCR. Cytokine levels in the BAL and plasma were determined by Luminex assay. Changes in the ECM proteome of the liver and lung were determined by LC-MS. Results. As expected, the combination of EtOH and LPS caused liver injury, as indicated

by significantly increased levels of ALT/AST in the plasma. EtOH preexposure also increased the number and SB203580 mouse size of inflammatory foci in the liver tissue caused by LPS. In the lung, EtOH preexposure

enhanced pulmonary inflammation and alveolar hemorrhage caused by LPS exposure. The combination of EtOH and LPS resulted in a unique pro-inflammatory mRNA expression profile in the two organs. As expected, eth-anol preexposure significantly increased hepatic TNFα mRNA expression and increased TNFα levels in the systemic circulation. In contrast, EtOH preexposure significantly increased pulmonary mRNA expression of the TNFα responsive genes MIP-2 and KC in the lung in the absence of a significant increase in TNFα mRNA or protein in lung tissue or BAL fluid, respectively. Additionally, EtOH exposure caused dynamic, transitional changes in the expression of ECM components (e.g. fibrin and fibronectin) in both the liver 上海皓元医药股份有限公司 and lung. Conclusions. EtOH pre-exposure enhanced both liver and lung injury caused by LPS. Enhanced organ injury corresponded with unique changes in the expression of pro-inflammatory cytokines in the liver (i.e. TNFα) and the lung (i.e. MIP-2, KC). EtOH preexposure also contributed to transitional changes in the ECM profile and increased expression of extracellular matrices which may play direct role in enhanced inflammation and injury in the two organs. Jesse Roman – Advisory Committees or Review Panels: Cellgene; Grant/Research Support: Actelion, Intermune, Novartis The following people have nothing to disclose: Veronica L.