FNH-like nodules: Possible precursor lesions in patients with focal nodular hyperplasia (FNH)

BACKGROUND: The typical lesion of focal nodular hyperplasia (FNH) is a benign tumor-like mass characterized by hepatocytic nodules separated by fibrous bands. The solitary central artery with high flow and the absent portal vein give the lesions their characteristic radiological appearance. The great majority of cases seen in daily practice conform to the above description. Additional small nodules (from 1-2 up to 15-20 mm in diameter) detected by imaging techniques or on macroscopic examination may be difficult to identify as representing FNH if they lack the key features of FNH as defined in larger lesions. The aim of this study was to characterize these small nodules, and to compare their characteristics with those of typical lesions of FNH present in the same specimens. RESULTS: Eight patients underwent hepatic resections for the removal of a mass lesion ("nodule") diagnosed as: FNH (1 patient); nodules of unknown nature (5 patients); or nodules thought to be adenoma or hepatocellular carcinoma (2 patients). Six nodules out of 9 discovered by imaging techniques met histopathological criteria for the diagnosis of typical FNH, at least in parts of the nodule; 2 nodules corresponded to a minor form of FNH ("subtle FNH") and one nodule to a steatotic area. Although FNH was thought to be found in a normal or nearly normal liver, this study revealed that, in addition, there were various types of small FNH-like nodules and vascular abnormalities in the liver with typical FNH nodule. The various types of small FNH-like nodules (n = 8, diameter 2 to 20 mm) consisted of the association to various degrees of numerous and/or enlarged arteries in portal tracts or in septa, with hyperplastic foci, slight ductular reaction, and regions of sinusoidal dilatation, accompanied by thin fibrous bands. Vascular abnormalities consisted of unpaired arteries, portal tracts with arteries larger than the associated bile duct, and regions of sinusoidal dilatation. CONCLUSIONS: Although these small nodules can be considered as insufficient type or abortive forms of FNH, or adenoma, they can be precursors of the large mass lesions in which FNH was recognized and defined

Neutral particle Mass Spectrometry with Nanomechanical Systems

Current approaches to Mass Spectrometry (MS) require ionization of the analytes of interest. For high-mass species, the resulting charge state distribution can be complex and difficult to interpret correctly. In this article, using a setup comprising both conventional time-of-flight MS (TOF-MS) and Nano-Electro-Mechanical-Systems-based MS (NEMS-MS) in situ, we show directly that NEMS-MS analysis is insensitive to charge state: the spectrum consists of a single peak whatever the species charge state, making it significantly clearer than existing MS analysis. In subsequent tests, all charged particles are electrostatically removed from the beam, and unlike TOF-MS, NEMS-MS can still measure masses. This demonstrates the possibility to measure mass spectra for neutral particles. Thus, it is possible to envisage MS-based studies of analytes that are incompatible with current ionization techniques and the way is now open for the development of cutting edge system architectures with unique analytical capability

Association of adenoma and focal nodular hyperplasia: experience of a single French academic center

BACKGROUND: We report our experience of the simultaneous occurrence of adenoma and focal nodular hyperplasia (FNH). Liver cell adenoma together with FNH was found in five out of 30 cases of "multiple benign hepatocytic nodules" collected in our files of the Department of Pathology of the University Hospital of Bordeaux, during the last 12 years. All five cases were women on oral contraceptives. In all cases, the reason for surgery was the discovery, by imaging techniques, of an adenoma (4 cases) or of an unidentified benign tumor, possibly an adenoma. RESULTS: Four cases of FNH were discovered by imaging techniques, prior to surgery. Additional small nodules were diagnosed either during surgery or during the slicing of the specimen in 3 cases. Adenoma and the FNH cases identified by imaging techniques were confirmed as such by light microscopy. Some small nodules could not be categorized with certainty because they contained biliary structures without ductular reaction. In one case, the non-nodular liver was abnormal around the area in which there were multiple nodules: there was approximation of portal tracts with portal and hepatic venous thromboses, and portal tract remnants with arteries surrounded with a rim of fibrosis. In two cases, some large hepatic veins had thickened walls. CONCLUSIONS: The association of FNH and adenoma could be coincidental or secondary to shared causal mechanisms: a) systemic and local angiogenic abnormalities induced by oral contraceptives; b) tumor-induced growth factors; c) thrombosis and local arterio-venous shunting. A better recognition of the association of adenoma and FNH, particularly in the context of multiple nodules, could be useful in clinical practice

JDLL: A library to run Deep Learning models on Java bioimage informatics platforms

We present JDLL, an agile Java library that offers a comprehensive toolset/API to unify the development of high-end applications of DL for bioimage analysis and to streamline their installation and maintenance. JDLL provides all the functions required to consume DL models seamlessly, without being burdened by the configuration of the Python-based DL frameworks, within Java bioimage informatics platforms. Moreover, it allows the deployment of pre-trained models in the Bioimage Model Zoo (BMZ) by shipping the logic to connect to the BMZ website, download and run a selected model inference

Hepatocellular adenoma: what is new in 2008

Patients (85%) with hepatocellular adenoma (HCA) are women taking oral contraceptives. They can be divided into four subgroups according to their genotype/phenotype features. (1) Hepatocyte nuclear factor 1α (HNF1α) biallelic somatic mutations are observed in 35% of the HCA cases. It occurs in almost all cases in women. HNF1α-mutated HCA are most of the time, highly steatotic, with a lack of expression of liver fatty acid binding protein (LFABP) in immunohistochemistry analyses. Adenomatosis is frequently detected in this context. An HNF1α germline mutation is observed in less than 5% of HCA cases and can be associated with MODY 3 diabetes. (2) An activating β-catenin mutation was found in 10% of HCA. These β-catenin activated HCAs are observed in men and women, and specific risk factors, such as male hormone administration or glycogenosis, are associated with their development. Immunohistochemistry studies show that these HCAs overexpress β-catenin (nuclear and cytoplasmic) and glutamine synthetase. This group of tumours has a higher risk of malignant transformation into hepatocellular carcinoma. (3) Inflammatory HCAs are observed in 40% of the cases, and they are most frequent in women but are also found in men. Lesions are characterised by inflammatory infiltrates, dystrophic arteries, sinusoidal dilatation and ductular reaction. They express serum amyloid A and C-reactive protein. In this group, GGT is frequently elevated, with a biological inflammatory syndrome present. Also, there are more overweight patients in this group. An additional 10% of inflammatory HCAs express β-catenin, and are also at risk of malignant transformation. (4) Currently, less than 10% of HCAs are unclassified. It is hoped that in the near future it will be possible with clinical, biological and imaging data to predict in which of the 2 major groups (HNF1α-mutated HCA and inflammatory HCA) the patient belongs and to propose better guidelines in terms of surveillance and treatment

SPARC Deficiency Results in Improved Surgical Survival in a Novel Mouse Model of Glaucoma Filtration Surgery

Glaucoma is a disease frequently associated with elevated intraocular pressure that can be alleviated by filtration surgery. However, the post-operative subconjunctival scarring response which blocks filtration efficiency is a major hurdle to the achievement of long-term surgical success. Current application of anti-proliferatives to modulate the scarring response is not ideal as these often give rise to sight-threatening complications. SPARC (secreted protein, acidic and rich in cysteine) is a matricellular protein involved in extracellular matrix (ECM) production and organization. In this study, we investigated post-operative surgical wound survival in an experimental glaucoma filtration model in SPARC-null mice. Loss of SPARC resulted in a marked (87.5%) surgical wound survival rate compared to 0% in wild-type (WT) counterparts. The larger SPARC-null wounds implied that aqueous filtration through the subconjunctival space was more efficient in comparison to WT wounds. The pronounced increase in both surgical survival and filtration efficiency was associated with a less collagenous ECM, smaller collagen fibril diameter, and a loosely-organized subconjunctival matrix in the SPARC-null wounds. In contrast, WT wounds exhibited a densely packed collagenous ECM with no evidence of filtration capacity. Immunolocalization assays confirmed the accumulation of ECM proteins in the WT but not in the SPARC-null wounds. The observations in vivo were corroborated by complementary data performed on WT and SPARC-null conjunctival fibroblasts in vitro. These findings indicate that depletion of SPARC bestows an inherent change in post-operative ECM remodeling to favor wound maintenance. The evidence presented in this report is strongly supportive for the targeting of SPARC to increase the success of glaucoma filtration surgery

Development of a Multivariate Prediction Model for Early-Onset Bronchiolitis Obliterans Syndrome and Restrictive Allograft Syndrome in Lung Transplantation.

Chronic lung allograft dysfunction and its main phenotypes, bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS), are major causes of mortality after lung transplantation (LT). RAS and early-onset BOS, developing within 3 years after LT, are associated with particularly inferior clinical outcomes. Prediction models for early-onset BOS and RAS have not been previously described. LT recipients of the French and Swiss transplant cohorts were eligible for inclusion in the SysCLAD cohort if they were alive with at least 2 years of follow-up but less than 3 years, or if they died or were retransplanted at any time less than 3 years. These patients were assessed for early-onset BOS, RAS, or stable allograft function by an adjudication committee. Baseline characteristics, data on surgery, immunosuppression, and year-1 follow-up were collected. Prediction models for BOS and RAS were developed using multivariate logistic regression and multivariate multinomial analysis. Among patients fulfilling the eligibility criteria, we identified 149 stable, 51 BOS, and 30 RAS subjects. The best prediction model for early-onset BOS and RAS included the underlying diagnosis, induction treatment, immunosuppression, and year-1 class II donor-specific antibodies (DSAs). Within this model, class II DSAs were associated with BOS and RAS, whereas pre-LT diagnoses of interstitial lung disease and chronic obstructive pulmonary disease were associated with RAS. Although these findings need further validation, results indicate that specific baseline and year-1 parameters may serve as predictors of BOS or RAS by 3 years post-LT. Their identification may allow intervention or guide risk stratification, aiming for an individualized patient management approach

ASS1 Overexpression:A Hallmark of Sonic Hedgehog Hepatocellular Adenomas; Recommendations for Clinical Practice

Until recently, 10% of hepatocellular adenomas (HCAs) remained unclassified (UHCA). Among the UHCAs, the sonic hedgehog HCA (shHCA) was defined by focal deletions that fuse the promoter of Inhibin beta E chain with GLI1. Prostaglandin D2 synthase was proposed as immunomarker. In parallel, our previous work using proteomic analysis showed that most UHCAs constitute a homogeneous subtype associated with overexpression of argininosuccinate synthase (ASS1). To clarify the use of ASS1 in the HCA classification and avoid misinterpretations of the immunohistochemical staining, the aims of this work were to study (1) the link between shHCA and ASS1 overexpression and (2) the clinical relevance of ASS1 overexpression for diagnosis. Molecular, proteomic, and immunohistochemical analyses were performed in UHCA cases of the Bordeaux series. The clinico-pathological features, including ASS1 immunohistochemical labeling, were analyzed on a large international series of 67 cases. ASS1 overexpression and the shHCA subgroup were superimposed in 15 cases studied by molecular analysis, establishing ASS1 overexpression as a hallmark of shHCA. Moreover, the ASS1 immunomarker was better than prostaglandin D2 synthase and only found positive in 7 of 22 shHCAs. Of the 67 UHCA cases, 58 (85.3%) overexpressed ASS1, four cases were ASS1 negative, and in five cases ASS1 was noncontributory. Proteomic analysis performed in the case of doubtful interpretation of ASS1 overexpression, especially on biopsies, can be a support to interpret such cases. ASS1 overexpression is a specific hallmark of shHCA known to be at high risk of bleeding. Therefore, ASS1 is an additional tool for HCA classification and clinical diagnosis

MicroRNA-21 Exhibits Antiangiogenic Function by Targeting RhoB Expression in Endothelial Cells

BACKGROUND: MicroRNAs (miRNAs) are endogenously expressed small non-coding RNAs that regulate gene expression at post-transcriptional level. The recent discovery of the involvement of these RNAs in the control of angiogenesis renders them very attractive in the development of new approaches for restoring the angiogenic balance. Whereas miRNA-21 has been demonstrated to be highly expressed in endothelial cells, the potential function of this miRNA in angiogenesis has never been investigated. METHODOLOGY/PRINCIPAL FINDINGS: We first observed in endothelial cells a negative regulation of miR-21 expression by serum and bFGF, two pro-angiogenic factors. Then using in vitro angiogenic assays, we observed that miR-21 acts as a negative modulator of angiogenesis. miR-21 overexpression reduced endothelial cell proliferation, migration and the ability of these cells to form tubes whereas miR-21 inhibition using a LNA-anti-miR led to opposite effects. Expression of miR-21 in endothelial cells also led to a reduction in the organization of actin into stress fibers, which may explain the decrease in cell migration. Further mechanistic studies showed that miR-21 targets RhoB, as revealed by a decrease in RhoB expression and activity in miR-21 overexpressing cells. RhoB silencing impairs endothelial cell migration and tubulogenesis, thus providing a possible mechanism for miR-21 to inhibit angiogenesis. Finally, the therapeutic potential of miR-21 as an angiogenesis inhibitor was demonstrated in vivo in a mouse model of choroidal neovascularization. CONCLUSIONS/SIGNIFICANCE: Our results identify miR-21 as a new angiogenesis inhibitor and suggest that inhibition of cell migration and tubulogenesis is mediated through repression of RhoB

Reinforcement selection acting on the European house mouse hybrid zone

Behavioural isolation may lead to complete speciation when partial postzygotic isolation acts in the presence of divergent‐specific mate‐recognition systems. These conditions exist where Mus musculus musculus and M. m. domesticus come into contact and hybridize. We studied two mate‐recognition signal systems, based on urinary and salivary proteins, across a Central European portion of the mouse hybrid zone. Introgression of the genomic regions responsible for these signals: the major urinary proteins (MUPs) and androgen binding proteins (ABPs), respectively, was compared to introgression at loci assumed to be nearly neutral and those under selection against hybridization. The preference of individuals taken from across the zone regarding these signals was measured in Y mazes, and we develop a model for the analysis of the transition of such traits under reinforcement selection. The strongest assortative preferences were found in males for urine and females for ABP. Clinal analyses confirm nearly neutral introgression of an Abp locus and two loci closely linked to the Abp gene cluster, whereas two markers flanking the Mup gene region reveal unexpected introgression. Geographic change in the preference traits matches our reinforcement selection model significantly better than standard cline models. Our study confirms that behavioural barriers are important components of reproductive isolation between the house mouse subspecies.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/86873/1/j.1365-294X.2011.05106.x.pd