Donor Atheromatous Disease is a Risk Factor for Hepatic Artery Thrombosis After Liver Transplantation.

The increasing age of liver donors and transplant candidates, together with the growing prevalence of metabolic comorbidities, could impact the risk of vascular complications after liver transplantation. We enrolled a consecutive cohort of adult patients undergoing liver transplantation from 2012 to 2021 who had a blinded pathological assessment of atherosclerosis in the donor and recipient hepatic arteries (HA). Patients receiving partial or reduced grafts, retransplantation, or combined organ transplantation were excluded. The relationship between HA atherosclerosis and HA thrombosis after liver transplantation was evaluated using logistic regression in the whole study cohort and in a propensity score-matched subpopulation. Among 443 eligible patients, 272 had a full pathological evaluation of the donor and recipient HA and were included in the study. HA atheroma was present in 51.5% of donors and in 11.4% of recipients. HA thrombosis occurred in 16 patients (5.9%), being more likely in patients who received a donor with HA atherosclerosis than in those without (10.7% vs. 0.8%; p < 0.001). Donor HA atherosclerosis was an independent risk factor of HA thrombosis (OR = 17.79; p = 0.008), and this finding was consistent in the propensity score-matched analysis according to age, sex, complex arterial anastomosis, and alcoholic liver disease (OR = 19.29; p = 0.007). Atheromatous disease in the recipient had no influence on the risk of HA thrombosis (OR = 1.70; p = 0.55). In conclusion, patients receiving donors with HA atherosclerosis are at increased risk for HA thrombosis after liver transplantation. The evaluation of the donor graft vasculature could guide antiplatelet therapy in the postoperative period.

Single-cell ICP-MS for studying the association of inorganic nanoparticles with cell lines derived from aquaculture species.

The current research deals with the use of single-cell inductively coupled plasma-mass spectrometry (scICP-MS) for the assessment of titanium dioxide nanoparticle (TiO2 NP) and silver nanoparticle (Ag NP) associations in cell lines derived from aquaculture species (sea bass, sea bream, and clams). The optimization studies have considered the avoidance of high dissolved background, multi-cell peak coincidence, and possible spectral interferences. Optimum operating conditions were found when using a dwell time of 50 µs for silver and 100 µs for titanium. The assessment of associated TiO2 NPs by scICP-MS required the use of ammonia as a reaction gas (flow rate at 0.75 mL min-1) for interference-free titanium determinations (measurements at an m/z ratio of 131 from the 48Ti(NH)(NH3)4 adduct). The influence of other parameters such as the number of washing cycles and the cell concentration on accurate determinations by scICP-MS was also fully investigated. Cell exposure trials were performed using PVP-Ag NPs (15 and 100 nm, nominal diameter) and citrate-TiO2 NPs (5, 25, and 45 nm, nominal diameter) at nominal concentrations of 10 and 50 µg mL-1 for citrate-TiO2 NPs and 5.0 and 50 µg mL-1 for PVP-Ag NPs. Results have shown that citrate-TiO2 NPs interact with the outer cell membranes, being quite low in the number of citrate-TiO2 NPs that enters the cells (the high degree of aggregation is the main factor which leads to the aggregates being in the extracellular medium). In contrast, PVP-Ag NPs have been found to enter the cells.

Quantitative titanium imaging in fish tissues exposed to titanium dioxide nanoparticles by laser ablation-inductively coupled plasma-mass spectrometry.

Imaging studies by laser ablation-inductively coupled plasma mass spectrometry have been successfully developed to obtain qualitative and quantitative information on the presence/distribution of titanium (ionic titanium and/or titanium dioxide nanoparticles) in sea bream tissues (kidney, liver, and muscle) after exposure assays with 45-nm citrate-coated titanium dioxide nanoparticles. Laboratory-produced gelatine standards containing ionic titanium were used as a calibration strategy for obtaining laser ablation-based images using quantitative (titanium concentrations) data. The best calibration strategy consisted of using gelatine-based titanium standards (from 0.1 to 2.0 µg g-1) by placing 5.0-µL drops of the liquid gelatine standards onto microscope glass sample holders. After air drying at room temperature good homogeneity of the placed drops was obtained, which led to good repeatability of measurements (calibration slope of 4.21 × 104 ± 0.39 × 104, n = 3) and good linearity (coefficient of determination higher than 0.990). Under the optimised conditions, a limit of detection of 0.087 µg g-1 titanium was assessed. This strategy allowed to locate prominent areas of titanium in the tissues as well as to quantify the bioaccumulated titanium and a better understanding of titanium dioxide nanoparticle spatial distribution in sea bream tissues.

Bioaccumulation of titanium dioxide nanoparticles in green (Ulva sp.) and red (Palmaria palmata) seaweed.

A bioaccumulation study in red (Palmaria palmata) and green (Ulva sp.) seaweed has been carried out after exposure to different concentrations of citrate-coated titanium dioxide nanoparticles (5 and 25 nm) for 28 days. The concentration of total titanium and the number and size of accumulated nanoparticles in the seaweeds has been determined throughout the study by inductively coupled plasma mass spectrometry (ICP-MS) and single particle-ICP-MS (SP-ICP-MS), respectively. Ammonia was used as a reaction gas to minimize the effect of the interferences in the 48Ti determination by ICP-MS. Titanium concentrations measured in Ulva sp. were higher than those found in Palmaria palmata for the same exposure conditions. The maximum concentration of titanium (61.96 ± 15.49 µg g-1) was found in Ulva sp. after 28 days of exposure to 1.0 mg L-1 of 5 nm TiO2NPs. The concentration and sizes of TiO2NPs determined by SP-ICP-MS in alkaline seaweed extracts were similar for both seaweeds exposed to 5 and 25 nm TiO2NPs, which indicates that probably the element is accumulated in Ulva sp. mainly as ionic titanium or nanoparticles smaller than the limit of detection in size (27 nm). The implementation of TiO2NPs in Ulva sp. was confirmed by electron microscopy (TEM/STEM) in combination with energy dispersive X-Ray analysis (EDX).

Experimental and Computational Studies on the Interaction of a Dansyl-Based Fluorescent Schiff Base Ligand with Cu2+ Ions and CuO NPs.

We studied the interaction of Cu2+ ions and CuO nanoparticles with the fluorescent Schiff base ligand H3L, which derives from the condensation of 4-formyl-3-hydroxybenzoic acid with N-(2-aminobenzyl)-5-(dimethylamino)naphthalene-1-sulfonamide (DsA). A detailed assignment of the most significant bands of the electronic and infrared spectra of H3L and DsA was performed using DFT methods, based on both crystal structures. The affinity of H3L to react with Cu2+ ions in solution (KB = 9.01 103 L mol-1) is similar to that found for the Cu2+ ions present on the surface of CuO NPs (KB = 9.84 103 L mol-1). Fluorescence spectroscopic measurements suggest five binding sites for H3L on the surface of the CuO NPs used. The µ-XRF analysis indicates that a polycrystalline sample of CuO-H3L NPs contains 15:1 Cu:S molar ratio (CuO:H3L). ATR-FTIR spectroscopy, supported by DFT calculations, showed that the HL2- (as a phenolate and sulfonamide anion) is coordinated to superficial Cu2+ ions of the CuO NPs through their azomethine, sulphonamide, and phenolic groups. A solution of H3L (126 ppb) shows sensitive responses to CuO NPs, with a limit of detection (LOD) of 330 ppb. The working range for detection of CuO NPs with [H3L] = 126 ppb was 1.1-9.5 ppm. Common metal ions in water, such as Na+, K+, Mg2+, Ca2+, Fe3+, and Al3+ species, do not interfere significantly with the detection of CuO NPs.

Synthesis and application of a surface ionic imprinting polymer on silica-coated Mn-doped ZnS quantum dots as a chemosensor for the selective quantification of inorganic arsenic in fish.

A novel room temperature phosphorescence chemosensor probe has been successfully developed and applied to the selective detection and quantification of inorganic arsenic (As(III) plus As(V)) in fish samples. The prepared material (IIP@ZnS:Mn QDs) was based on Mn-doped ZnS quantum dots coated with (3-aminopropyl) triethoxysilane and an As(III) ionic imprinted polymer. The novel use of vinyl imidazole as a complexing reagent when synthesizing the ionic imprinted polymer guarantees that both inorganic arsenic species (As(III) and As(V)) can interact with the recognition cavities in the ionic imprinted polymer. After characterization, several studies were performed to enhance the interaction between the targets (As(III) and As(V) ions) and the IIP@ZnS:Mn QDs nanoparticles. The optimization and validation process showed that the composite material offers high selectivity (high imprinting factor) for inorganic arsenic species. The limit of quantification for total inorganic As was 29.6 µg kg-1, value lower than the EU/EC regulation limits proposed for other foodstuffs than fish, such as rice. The proposed method is therefore simple, requires short analysis times and offers good sensitivity, precision (inter-day relative standard deviations lower than 10%), and quantitative analytical recoveries. The method has been successfully applied to assess total inorganic arsenic in several fishery products, showing good agreement with the total inorganic arsenic concentration (As(III) plus As(V)) found after applying other advanced and expensive methods such those based on high-performance liquid chromatography hyphenated to inductively coupled plasma-mass spectrometry. Graphical abstract.

The bioavailability of arsenic species in rice.

Rice is the principal food in many countries for billions of people and one of the most consumed cereals in the world. The rice plant has the ability to bioaccumulate essential and toxic trace elements such as arsenic. The toxicity of the elements depends not only on their concentration but also on their chemical form and their bioavailability. The inorganic forms of arsenic are more toxic than the organic forms and the toxicity increases with decreasing oxidation states. The consumers of rice in Europe who are the most exposed to inorganic arsenic are children under three, thorough diet (rice-based food). Recently, the European Commission established the maximum levels of inorganic arsenic in foodstuffs. This regulation establishes a maximum level of inorganic arsenic of 100 µg kg-1 in rice destined for the production of food for infants and young children. In order to know the relation between the As ingested and the arsenic absorbed, studies of bioavailability are necessary. We proposed an in vitro digestion method with dialysis to estimate this relation. Furthermore, a bioavailability study of As species in rice was performed in order to know if a change in As species occurred during the gastrointestinal digestion process. Arsenic species were determined in rice and in the dialysate fraction by high-performance liquid chromatography coupled to inductively coupled plasma mass spectrometry (HPLC-ICP-MS). The proposed method has been applied to different rice samples acquired in the local Spanish market. Graphical abstract.

Combining ultrasound-assisted extraction and vortex-assisted liquid-liquid microextraction for the sensitive assessment of aflatoxins in aquaculture fish species.

Although aflatoxins contamination in feedstuff is a well-known problem, and hence these residues are controlled in poultry products, there is scarce information regarding the presence of these toxic substances in aquaculture fish, facilities that use several feedstuff for fish breeding. A simple, rapid, and sensitive method has been therefore developed for aflatoxins (B1, B2, G1, and G2) assessment in aquaculture products by combining ultrasound probe-assisted extraction and vortex-assisted liquid-liquid microextraction as a sample pretreatment, and high-performance liquid chromatography-tandem mass spectrometry as a separation/detection system. Aflatoxins were extracted from fish flesh/liver with a 60:40 acetonitrile/aqueous phosphate buffer (pH 7.0) mixture before preconcentration and clean-up by vortex-assisted liquid-liquid microextraction under the following optimized conditions: 5.0 mL of fish extract at pH 7.0 and NaCl at 0.5% (w/v), 400 µL of chloroform as extracting solvent, and vortex shaking at 2000 rpm for 1 min. The proposed method is shown to be precise and accurate, and the limit of quantitations (from 0.20 to 1.10 µg kg-1 ) were lower than the value established by the European Commission Regulation for aflatoxins in foodstuff. Results have shown that fish flesh is free of aflatoxins, but aflatoxins B2 and G1 were quantified in fish liver.

Selenium and All-cause Mortality in End-Stage Renal Disease. Retrospective Observational Cohort Study.

OBJECTIVE: The objectives of the study were to determine whether low plasma selenium levels (<63 µg/L according to population-based reference interval) were associated with poorer survival among adult patients with end-stage renal disease (ESRD) on dialysis treatment and to study whether plasma selenium behaved as a biomarker of mortality risk independent of other monitored biochemical markers. METHODS: This is a retrospective observational cohort study that included 85 patients with ESRD on 3 modalities of dialysis, with a plasma selenium test performed 5-6 years before the study. RESULTS: Patients with low selenium showed an increased risk of all-cause mortality (hazard ratio = 2.952, 95% CI 1.402-6.217) compared with patients with normal or high selenium (>118 µg/L), according to a Cox multivariate model that included age and history of cardiovascular disease as covariates. Patients with low selenium had an increased risk of all-cause mortality (hazard ratio = 2.894, 95% CI 1.457-5.751) according to a model that included age, anemia, and low albumin as covariates. Low albumin patients had an increased risk of having low plasma selenium (odds ratio = 5.778, 95% CI 2.212-15.098). CONCLUSIONS: Low plasma selenium group's survival was significantly lower than that of the group with normoselenemia or hyperselenemia. Plasma selenium behaved as a biomarker of mortality risk independent of other biochemical markers usually monitored in patients with ESRD.

Small bowel enteroscopy - A joint clinical guideline by the Spanish and Portuguese small-bowel study groups.

The present evidence-based guidelines are focused on the use of device-assisted enteroscopy in the management of small-bowel diseases. A panel of experts selected by the Spanish and Portuguese small-bowel study groups reviewed the available evidence focusing on the main indications of this technique, its role in the management algorithm of each indication, and its diagnostic and therapeutic yield. A set of recommendations was issued accordingly.

mTOR Expression in Liver Transplant Candidates with Hepatocellular Carcinoma: Impact on Histological Features and Tumour Recurrence.

(1) Background: The mammalian target of rapamycin (mTOR) pathway activation is critical for hepatocellular carcinoma (HCC) progression. We aimed to evaluate the mTOR tissue expression in liver transplant (LT) patients and to analyse its influence on post-LT outcomes. (2) Methods: Prospective study including a cohort of HCC patients who underwent LT (2012⁻2015). MTOR pathway expression was evaluated in the explanted liver by using the "PathScan Intracellular Signalling Array Kit" (Cell Signalling). Kaplan-Meier and Cox regression analyses were performed to evaluate post-LT HCC recurrence. (3) Results: Forty-nine patients were included (average age 56.4 ± 6, 14.3% females). Phospho-mTOR (Ser2448) was over-expressed in peritumoral tissue as compared with tumoral tissue (ΔSignal 22.2%; p < 0.001). The mTOR activators were also increased in peritumoral tissue (phospho-Akt (Thr308) ΔSignal 18.2%, p = 0.004; phospho-AMPKa (Thr172) ΔSignal 56.3%, p < 0.001), as they were the downstream effectors responsible for cell growth/survival (phospho-p70S6K (Thr389) ΔSignal 33.3%, p < 0.001 and phospho-S6RP (Ser235/236) ΔSignal 54.6%, p < 0.001). MTOR expression was increased in patients with multinodular HCC (tumoral p = 0.01; peritumoral p = 0.001). Increased phospho-mTOR in tumoral tissue was associated with higher HCC recurrence rates after LT (23.8% vs. 5.9% at 24 months, p = 0.04). (4) Conclusion: mTOR pathway is over-expressed in patients with multinodular HCC and is it associated with increased post-LT tumour recurrence rates.

Role of capsule endoscopy in alarm features and non-responsive celiac disease: A European multicenter study.

BACKGROUND AND AIM: The role of capsule endoscopy (CE) in established celiac disease (CD) remains unclear. Our objective was to analyze the usefulness of CE in the suspicion of complicated CD. METHODS: This was a retrospective multicenter study. One hundred and eighty-nine celiac patients (mean age: 46.6 ± 16.6, 30.2% males) who underwent CE for alarm symptoms (n = 86, 45.5%) or non-responsive CD (n = 103, 54.5%) were included. Diagnostic yield (DY), therapeutic impact and safety were analyzed. RESULTS: Capsule endoscopy was completed in 95.2% of patients (small bowel transit time: 270.5 ± 100.2 min). Global DY was 67.2%, detecting atrophic mucosa (n = 92, 48.7%), ulcerative jejunoileitis (n = 21, 11.1%), intestinal lymphoma (n = 7, 3.7%) and other enteropathies (n = 7, 3.7%, six Crohn's disease cases and one neuroendocrine tumor). The DY of CE was significantly higher in patients presenting with non-responsive disease compared to patients with alarm symptoms (73.8% vs 59.3%, P = 0.035). The new findings of the CE modified management in 59.3% of the cases. There were no major complications. CONCLUSION: Capsule endoscopy may be a moderately helpful and safe diagnostic tool in the suspicion of complicated CD, modifying the clinical course of these patients.

In vivo and in vitro testing for selenium and selenium compounds bioavailability assessment in foodstuff.

The assessment of selenium and selenium species bioavailability in foodstuff is of special concern on the context of human nutrition. In vivo (human and animal), and in vitro tests are important approaches for estimating the bioavailability of toxic and essential compounds to humans. An overview on in vivo and in vitro bioavailability assays for releasing selenium and selenium species in foodstuffs is summarized. Se and Se species content in a foodstuff critically influence Se bioavailability and bioactivity to humans and animals. Se bioavailability is affected by foodstuff-matrix major composition and minor components. Foodstuffs processing and/or treatments could enhancement or decrease Se bioavailability. Experimental conditions such as the selection of healthy status of examined people (in in vivo humans approaches), the selection of animal model (in vivo animals approaches), or the selection of GI conditions (in in vitro tests) could determines the results. Thus, international standardized protocol for in vivo and in vitro approaches assessment is mandatory.

Cannabinoids assessment in plasma and urine by high performance liquid chromatography-tandem mass spectrometry after molecularly imprinted polymer microsolid-phase extraction.

A molecularly imprinted polymer (MIP) selective for cannabinoids [Δ9-tetrahydrocannabinol (Δ9-THC), 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (Δ9-THC-COOH), and 11-hydroxy-Δ9-tetrahydrocannabinol (Δ9-THC-OH)] has been synthesized, fully characterized, and applied to the assessment of plasma and urine analysis of marijuana abuse by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Δ9-THC-COOH was used as a template molecule, whereas ethylene glycol dimethacrylate (EGDMA) was used as a functional monomer, divinylbenzene (DVB) as a cross-linker, and 2,2'-azobisisobutyronitrile (AIBN) as an initiator. The prepared MIP was found to be highly selective for cannabinoids typically found in blood and urine, and also for cannabinol (CBN) and cannabidiol (CBD). MIP beads (50 mg) were loaded inside a cone-shaped device made of a polypropylene (PP) membrane for microsolid-phase extraction (µ-SPE) in batch mode. Optimum retention of analytes (0.1 to 1.0 mL of plasma/urine) was achieved by fixing plasma/urine pH at 6.5 and assisting the procedure by mechanical shaking (150 rpm, 40 °C, 12 min). Optimum elution conditions implied 2 mL of a 90:10 methanol/acetic acid and ultrasound extraction (35 kHz, 325 W) for 6 min. Good precision was assessed by intra-day and inter-day assays. In addition, the method was found to be accurate after intra-day and inter-day analytical recovery assays and after analyzing control serum and urine control samples. The limits of quantification were in the range of 0.36-0.49 ng L-1 (plasma analysis) and 0.47-0.57 ng L-1 (urine analysis). These values are low enough for confirmative conclusions regarding marijuana abuse through blood and urine analysis. Graphical Abstract ᅟ.

Simple and Sensitive Molecularly Imprinted Polymer - Mn-Doped ZnS Quantum Dots Based Fluorescence Probe for Cocaine and Metabolites Determination in Urine.

A new molecularly imprinted polymer (MIP)-based fluorescent artificial receptor has been prepared by anchoring a selective MIP for cocaine (COC) on the surface of polyethylene glycol (PEG) modified Mn-doped ZnS quantum dots (QDs). The prepared material combines the high selectivity attributed to MIPs and the sensitive fluorescent property of the Mn-doped ZnS QDs. Simple and low cost methods have therefore been optimized for assessing cocaine abuse in urine by monitoring the fluorescence quenching when the template (COC) and also metabolites from COC [benzoylecgonine (BZE) and ecgonine methyl ester (EME)] are present. Fluorescence quenching was not observed when performing experiments with other drugs of abuse (and their metabolites) or when using nonimprinted polymer (NIP)-coated QDs. Under optimized operating conditions (1.5 mL of 200 mg L(-1) MIP-coated QDs solution, pH 5.5, and 15 min before fluorescence scanning) two analytical methods were developed/validated. One of the procedures (direct method) consisted of urine sample 1:20 dilution before fluorescence measurements. The method has been found to be fast, precise, and accurate, but the standard addition technique for performing the analysis was required because of the existence of matrix effect. The second procedure performed a solid phase extraction (SPE) first, avoiding matrix effect and allowing external calibration. The limits of detection of the methods were 0.076 mg L(-1) (direct method) and 0.0042 mg L(-1) (SPE based method), which are lower than the cutoff values for confirmative conclusions regarding cocaine abuse.

Evaluation of number concentration quantification by single-particle inductively coupled plasma mass spectrometry: microsecond vs. millisecond dwell times.

The quality of the quantitative information in single-particle inductively coupled plasma mass spectrometry (SP-ICP-MS) depends directly on the number concentration of the nanoparticles in the sample analyzed, which is proportional to the flux of nanoparticles through the plasma. Particle number concentrations must be selected in accordance with the data acquisition frequency, to control the precision from counting statistics and the bias, which is produced by the occurrence of multiple-particle events recorded as single-particle events. With quadrupole mass spectrometers, the frequency of data acquisition is directly controlled by the dwell time. The effect of dwell times from milli- to microseconds (10 ms, 5 ms, 100 µs, and 50 µs) on the quality of the quantitative data has been studied. Working with dwell times in the millisecond range, precision figures about 5 % were achieved, whereas using microsecond dwell times, the suitable fluxes of nanoparticles are higher and precision was reduced down to 1 %; this was independent of the dwell time selected. Moreover, due to the lower occurrence of multiple-nanoparticle events, linear ranges are wider when dwell times equal to or shorter than 100 µs are used. A calculation tool is provided to determine the optimal concentration for any instrument or experimental conditions selected. On the other hand, the use of dwell times in the microsecond range reduces significantly the contribution of the background and/or the presence of dissolved species, in comparison with the use of millisecond dwell times. Although the use of dwell times equal to or shorter than 100 µs offers improved performance working in single-particle mode, the use of conventional dwell times (3-10 ms) should not be discarded, once their limitations are known.

Solid phase microextraction and gas chromatography-mass spectrometry methods for residual solvent assessment in seized cocaine and heroin.

A simple sample pre-treatment method based on solid phase microextraction (SPME) and gas chromatography-mass spectrometry (GC-MS) has been optimized and validated for the assessment of 15 residual solvents (2-propanol, 2-methylpentane, 3-methylpentane, acetone, ethyl acetate, benzene, hexane, methylcyclohexane, methylcyclopentane, m-xylene, propyl acetate, toluene, 1,2,4-trimethylbenzene, dichloromethane, and ethylbenzene) in seized illicit cocaine and heroin. DMSO and DMF as sample diluents were found to offer the best residual solvent transference to the head space for further adsorption onto the SPME fiber, and the developed method therefore showed high sensitivity and analytical recovery. Variables affecting SPME were fully evaluated by applying an experimental design approach. Best conditions were found when using an equilibration time of 5 min at 70 °C and headspace sampling of residual solvents at the same temperature for 15 min. Method validation, performed within the requirements of international guidelines, showed excellent sensitivity, as well as intra- and inter-day precision and accuracy. The proposed methodology was applied to 96 cocaine samples and 14 heroin samples seized in Galicia (northwestern Spain) within 2013 and 2014.

Lack of agreement for defining 'clinical suspicion of rejection' in liver transplantation: a model to select candidates for liver biopsy.

The gold standard to diagnose acute cellular rejection (ACR) after liver transplantation (LT) is histological evaluation, but there is no consensus to select patients for liver biopsy. We aimed to evaluate the agreement among clinicians to select candidates for liver biopsy early after LT. From a protocol biopsy population (n = 690), we randomly selected 100 LT patients in whom the biopsy was taken 7-10 days after LT. The clinical information between LT and protocol biopsy was given to nine clinicians from three transplant centres who decided whether a liver biopsy was needed. The agreement among clinicians to select candidates for liver biopsy was poor: κ = 0.06-0.62, being κ < 0.40 in 76% of comparisons. The concordance between indication for liver biopsy and moderate-severe ACR in the protocol biopsy was κ < 0.30 in all cases. A multivariate model based on the product age-by-MELD (OR = 0.81; P = 0.013), delta eosinophils (OR = 1.5; P = 0.002) and mean tacrolimus trough concentrations <6 ng/ml within the prior 4 days (OR = 11.4; P = 0.047) had an AUROC = 0.84 to diagnose moderate-severe histological ACR. In conclusion, the agreement among clinicians to select patients for liver biopsy is very poor. If further validated the proposed model would provide an objective method to select candidates for liver biopsy after LT.

Assessing the Effect of Surface Coating on the Stability, Degradation, Toxicity and Cell Endocytosis/Exocytosis of Upconverting Nanoparticles.

Lanthanide-doped up-converting nanoparticles (UCNPs) have emerged as promising biomedical tools in recent years. Most research efforts were devoted to the synthesis of inorganic cores with the optimal physicochemical properties. However, the careful design of UCNPs with the adequate surface coating to optimize their biological performance still remains a significant challenge. Here, we propose the functionalization of UCNPs with four distinct types of surface coatings, which were compared in terms of the provided colloidal stability and resistance to degradation in different biological-relevant media, including commonly avoided analysis in acidic lysosomal-mimicking fluids. Moreover, the influence of the type of particle surface coating on cell cytotoxicity and endocytosis/exocytosis was also evaluated. The obtained results demonstrated that the functionalization of UCNPs with poly(isobutylene-alt-maleic anhydride) grafted with dodecylamine (PMA-g-dodecyl) constitutes an outstanding strategy for their subsequent biomedical application, whereas poly(ethylene glycol) (PEG) coating, although suitable for colloidal stability purposes, hinders extensive cell internalization. Conversely, surface coating with small ligand were found not to be suitable, leading to large degradation degrees of UCNPs. The analysis of particle' behavior in different biological media and in vitro conditions here performed pretends to help researchers to improve the design and implementation of UCNPs as theranostic nanotools.

A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C.

BACKGROUND & AIMS: Tremelimumab is a monoclonal antibody that blocks cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), an inhibitory co-receptor that interferes with T cell activation and proliferation. The purpose of this pilot clinical trial was to test the antitumor and antiviral effect of tremelimumab in patients with hepatocellular carcinoma (HCC) and chronic hepatitis C virus (HCV) infection; and to study the safety of its administration to cirrhotic patients. METHODS: Tremelimumab at a dose of 15 mg/kg IV every 90 days was administered until tumor progression or severe toxicity. Twenty patients were assessable for toxicity and viral response and 17 were assessable for tumor response. Most patients were in the advanced stage and 43% had an altered liver function (Child-Pugh class B). RESULTS: A good safety profile was recorded and no patient needed steroids because of severe immune-mediated adverse events. Some patients had a transient albeit intense elevation of transaminases after the first dose, but not following subsequent cycles. Partial response rate was 17.6% and disease control rate was 76.4%. Time to progression was 6.48 months (95% CI 3.95-9.14). A significant drop in viral load was observed while new emerging variants of the hypervariable region 1 of HCV replaced the predominant variants present before therapy, particularly in those patients with a more prominent drop in viral load. This antiviral effect was associated with an enhanced specific anti-HCV immune response. CONCLUSIONS: Tremelimumab safety profile and antitumor and antiviral activity, in patients with advanced HCC developed on HCV-induced liver cirrhosis, support further investigation.