Clinical outcomes in patients switching from agalsidase beta to migalastat: A Fabry Registry analysis.

Fabry Registry data were analyzed among 83 agalsidase beta-treated patients with Fabry disease who switched to migalastat. Outcomes (estimated glomerular filtration rate [eGFR], urine protein-creatinine ratio [UPCR], plasma globotriaosylceramide [GL-3], plasma globotriaosylsphingosine [lyso-GL-3], interventricular septal wall thickness [IVST], left posterior wall thickness [LPWT], left ventricular mass index [LVMI]) were assessed using linear mixed models to estimate annual change over time in the pre- and postswitch periods. eGFR decreased throughout both periods (preswitch: -0.85 mL/min/1.73 m2/year; postswitch: -1.96 mL/min/1.73 m2/year; both p < 0.0001), with steeper decline postswitch (ppre/post = 0.01) in both classic and late-onset patients. UPCR increased significantly postswitch (ppre/post = 0.003) among classic patients and was stable in both periods among late-onset patients. GL-3 trajectories worsened postswitch across phenotypes (ppre/post = 0.0005 classic, 0.02 late-onset). LPWT was stable preswitch (0.07 mm/year, p = 0.25) and decreased postswitch (-0.51 mm/year, p = 0.0005; ppre/post = 0.0009), primarily among late-onset patients. IVST and LVMI slopes varied significantly by phenotype. Among classic patients, IVST and LVMI were stable and decreasing, respectively preswitch and increasing postswitch (ppre/post = 0.02 IVST, 0.01 LVMI). Among late-onset patients, IVST significantly decreased postswitch (ppre/post = 0.0003); LVMI was stable over time (ppre/post = 0.89). Ultimately, eGFR and GL-3 trajectories worsened postswitch across phenotypes, while UPCR and cardiac measures worsened among classic and stabilized/improved among late-onset patients. These findings indicate variability in long-term outcomes after switching from ERT to migalastat, underscoring the importance of careful monitoring.

Pea Seed Priming with Pluronic P85-Grafted Single-Walled Carbon Nanotubes Affects Photosynthetic Gas Exchange but Not Photosynthetic Light Reactions.

Nanotechnology is rapidly advancing towards the development of applications for sustainable plant growth and photosynthesis optimization. The nanomaterial/plant interaction has been intensively investigated; however, there is still a gap in knowledge regarding their effect on crop seed development and photosynthetic performance. In the present work, we apply a priming procedure with 10 and 50 mg/L Pluronic-P85-grafted single-walled carbon nanotubes (P85-SWCNT) on garden pea seeds and examine the germination, development, and photosynthetic activity of young seedlings grown on soil substrate. The applied treatments result in a distorted topology of the seed surface and suppressed (by 10-19%) shoot emergence. No priming-induced alterations in the structural and functional features of the photosynthetic apparatus in 14-day-old plants are found. However, photosynthetic gas exchange measurements reveal reduced stomatal conductance (by up to 15%) and increased intrinsic water use efficiency (by 12-15%), as compared to hydro-primed variants, suggesting the better ability of plants to cope with drought stress-an assumption that needs further verification. Our study prompts further research on the stomatal behavior and dark reactions of photosynthesis in order to gain new insights into the effect of carbon nanotubes on plant performance.

Thiopurine adherence: a high prevalence with low impact on UC outcomes.

INTRODUCTION: thiopurines are used as maintenance therapy in patients with ulcerative colitis (UC). There are contradictory results regarding the relationship between adherence to treatment and risk of relapse. OBJECTIVES: to quantify and evaluate the trends in thiopurine prescription rates, and to determine the impact and risk factors of non-adherence. METHODS: analytical, observational, retrospective study of UC patients taking thiopurines included in the ENEIDA single-center registry from October 2017 to October 2019. Adult patients in clinical remission at the beginning of the study on thiopurines maintenance treatment for at least 6 months before recruitment were included. Adherence was evaluated with an electronic pharmaceutical prescription system. Adherence was considered when 80 % or more of the prescribed medication was dispensed at the pharmacy. Kaplan-Meier curves and a regression model were used to examine year-to-year treatment dispensation, and to identify factors associated with non-adherence. RESULTS: a total of 41 patients were included, of whom 71 % were males with a mean age of 44 (14), and 26.8 % were concomitantly managed with biological therapy. Overall, 22 % were non-adherent to thiopurines. No predictive factors of non-adherence were identified. Adherence rate did not correlate with disease activity during two years of follow-up (OR 1.6; 95 % CI = 0.3-9.1). Left-sided colitis and concomitant biological treatment were related with disease relapse (p ≤ 0.01). CONCLUSION: adherence to thiopurines in UC patients is high (78 %). Non-adherence is not related to clinical or pharmacological factors. Adherence rate was not associated with disease activity.

First Report of Cucurbit chlorotic yellows virus infecting Cucumber Plants in Spain.

During the winter 2018, symptoms of leaf chlorotic spots (Figure 1) followed by symptoms of leaf interveinal chlorosis (Figure 2) and severe chlorosis in basal leaves were observed in cucumber cv Laredo (Cucumis sativus) plants in three separated greenhouses, sited in distinct locations in southern Spain. In all cases, Bemisia tabaci populations were observed on infected plants. The symptomology observed was similar to that caused by whitefly transmitted Cucurbit yellow stunting disorder virus (CYSDV, genus Crinivirus, family Closteroviridae), which is usually found infecting cucumber plants in this geographical area (1). Samples from four different cucumber plants of distinct greenhouses were collected and tested for the presence of CYSDV. Total RNA was extracted from the samples using the NucleoSpin RNA Plant kit (Macherey-Nagel, Germany). Molecular detection of CYSDV was performed using the multiplex and degenerate primer RT-PCR method (2), specific to the region of the highly conserved RNA-dependent RNA polymerase (RdRp) gene of criniviruses, which also detects other criniviruses such as Lettuce infectious yellows virus (LIYV) and Beet pseudo-yellows virus (BPYV). Results indicated that the viral species CYSDV, LIYV and BPYV were not detected in the four cucurbit plant samples. In 2004, an emergent crinivirus (Cucurbit chlorotic yellows virus, CCYV), inducing symptoms similar to those caused by CYSDV, was described infecting cucurbits in Japan (3). Recently, CCYV was detected in 2011 in Greece (4) and in 2014 in Egypt (5) and Saudi Arabia (6). Therefore, the four RNA samples were tested for the presence of the CCYV by a RT-PCR method previously described (7). Specific primers were designed to amplify 336 nt of the capsid protein (CP) gene and 680 nt of the RdRp gene, located on CCYV genomic RNA 1 and RNA 2, respectively. In all cases, clear cDNA bands of both expected sizes were detected for each cucumber sample that were then purified and sequenced via Sanger technology. BLAST analysis of those sequences showed 99% identity with the nucleotide sequence of the CP and RpRd genes from the CCYV isolates from Greece (LT992911, LT992910), China (KY400633.1, KX118632) and Taiwan (JF502222). To our knowledge, this is the first report of CCYV infecting cucurbits in Spain. Probably CCYV has been spread throughout the Mediterranean basin, remaining undetected due to the yellowing symptom similarities between CYSDV and CCYV. Detection of the emergent virus CCYV in Spain represents a new threat for the horticultural area of southern Europe.

Pultruded FRP Beams with Embedded Fibre Bragg Grating Optical Sensors for Strain Measurement and Failure Detection.

Composites have added new dimensions to the design and construction of buildings and structures. One of the wider spread composite applications in the construction industry is composite beams or pillars, which can be manufactured through pultrusion processes. These types of construction elements are usually used to withstand the weight of large loads, so their integrity must be guaranteed. Due to optical sensors' advantages over their electrical counterparts-small sizes, low weight, non-conductive, and immunity to electromagnetic interference-and FBGs having an outstanding position among optical fibre sensors-due to their multiplexation capability and relatively easy monitoring-in this study, we propose the integration of FBG sensors for the observation and analysis of the integrity of structures made with composite beams over time. The validation test results showed the successful embedding integration of FBG-based fibre optical sensors in an FRP pultrusion beam and strain transmission up to 7500 µÉ› from the composite test piece to the sensor. Additionally, we were able to anticipate the piece failure by the FBG spectrum deformation.

Chronic Venous Insufficiency as a Predisposing Factor for Basal Cell Carcinoma on Legs.

BACKGROUND: The main risk factor associated with basal cell carcinomas (BCCs) is believed to be exposure to ultraviolet radiation (UVR). In the case of lower limb BCC, the frequency is higher in women, possibly because of greater exposure of the leg to UVR. Chronic venous insufficiency (CVI), also more common in women, may have some association with leg BCCs. METHODS: We retrospectively evaluated the histopathological features of leg BCCs removed between 1993 and 2017 in a tertiary referral center. The patients' clinical data were obtained from medical records, considering, in particular, CVI. RESULTS: We selected 149 patients with leg BCCs, predominately occurring in elderly Caucasian women. Of those, 71 had a clinical diagnosis of CVI in whom the clinical tumor size and frequency of recurrences were significantly higher than patients without CVI. There was an association between clinical diagnosis of CVI and histological findings of (1) follicular induction in epidermis and (2) distal sweat duct hyperplasia. CONCLUSIONS: CVI, besides the already known UVR exposure, is probably associated with leg BCCs and may determine a worse BCC course.

Environment and host identity structure communities of green algal symbionts in lichens.

An understanding of how biotic interactions shape species' distributions is central to predicting host-symbiont responses under climate change. Switches to locally adapted algae have been proposed to be an adaptive strategy of lichen-forming fungi to cope with environmental change. However, it is unclear how lichen photobionts respond to environmental gradients, and whether they play a role in determining the fungal host's upper and lower elevational limits. Deep-coverage Illumina DNA metabarcoding was used to track changes in the community composition of Trebouxia algae associated with two phylogenetically closely related, but ecologically divergent fungal hosts along a steep altitudinal gradient in the Mediterranean region. We detected the presence of multiple Trebouxia species in the majority of thalli. Both altitude and host genetic identity were strong predictors of photobiont community assembly in these two species. The predominantly clonally dispersing fungus showed stronger altitudinal structuring of photobiont communities than the sexually reproducing host. Elevation ranges of the host were not limited by the lack of compatible photobionts. Our study sheds light on the processes guiding the formation and distribution of specific fungal-algal combinations in the lichen symbiosis. The effect of environmental filtering acting on both symbiotic partners appears to shape the distribution of lichens.

Fungal-algal association patterns in lichen symbiosis linked to macroclimate.

Both macroclimate and evolutionary events may influence symbiont association and diversity patterns. Here we assess how climatic factors and evolutionary events shape fungal-algal association patterns in the widely distributed lichen-forming fungal genus Protoparmelia. Multilocus phylogenies of fungal and algal partners were generated using 174 specimens. Coalescent-based species delimitation analysis suggested that 23 fungal hosts are associating with 20 algal species. Principal component analysis (PCA) was performed to infer how fungal-algal association patterns varied with climate. Fungi associated with one to three algal partners whereas algae accepted one to five fungal partners. Both fungi and algae were more specific, associating with fewer partners, in the warmer climates. Interaction with more than one partner was more frequent in cooler climates for both the partners. Cophylogenetic analyses suggest congruent fungal-algal phylogenies. Host switch was a more common event in warm climates, whereas failure of the photobiont to diverge with its fungal host was more frequent in cooler climates. We conclude that both environmental factors and evolutionary events drive fungal and algal evolution in Protoparmelia. The processes leading to phylogenetic congruence of fungi and algae are different in different macrohabitats in our study system. Hence, closely related species inhabiting diverse habitats may follow different evolutionary pathways.

In vitro neuroprotective potential of lichen metabolite fumarprotocetraric acid via intracellular redox modulation.

The lichen-forming fungi Cetraria islandica has been largely used in folk medicines, and it has recently showed promising in vitro antioxidant effects in glial-like cells. Current work aimed at investigating the neuroprotective potential of its major isolated secondary metabolite: the depsidone fumarprotocetraric acid (FUM). H2O2 was used herein to induce oxidative stress (OS)-mediated cytotoxicity in two models of neurons and astrocytes cells (SH-SY5Y and U373-MG cell lines). We found that a pre-treatment with FUM significantly enhanced cell viability compared to H2O2-treated cells, and we selected the optimal concentrations in each model (1 and 25µg/ml, respectively) for assessing its cytoprotective mechanisms. FUM, which exerted effective peroxyl radical scavenging effect in the chemical oxygen radical antioxidant capacity (ORAC) assay, alleviated the alterations in OS markers provoked by H2O2. It attenuated intracellular ROS formation, lipid peroxidation and GSH depletion. At mitochondrial level, FUM prevented from the dissipation of mitochondrial membrane potential and the increase in mitochondrial calcium, implying a protective role against oxidative damage in mitochondrial membrane. Similarly, FUM pre-treatment diminished H2O2-induced apoptosis, as evidenced by the reduction in caspase-3 activity and expression; inmunoblot analysis also revealed a decrease in Bax and an increase in Bcl-2 proteins levels. Furthermore, FUM up-regulated the expression of the antioxidant enzymes catalase, superoxide dismutase-1, and hemeoxigenase-1. These findings and the activation of Nrf2 binding activity in nuclear extracts suggest a plausible involvement of Nrf2 signaling pathway in the cytoprotection by FUM. In conclusion, FUM emerges as a potential drug candidate in the therapy of OS-related diseases, such as the neurodegenerative disorders.

Large-scale impact of climate change vs. land-use change on future biome shifts in Latin America.

Climate change and land-use change are two major drivers of biome shifts causing habitat and biodiversity loss. What is missing is a continental-scale future projection of the estimated relative impacts of both drivers on biome shifts over the course of this century. Here, we provide such a projection for the biodiverse region of Latin America under four socio-economic development scenarios. We find that across all scenarios 5-6% of the total area will undergo biome shifts that can be attributed to climate change until 2099. The relative impact of climate change on biome shifts may overtake land-use change even under an optimistic climate scenario, if land-use expansion is halted by the mid-century. We suggest that constraining land-use change and preserving the remaining natural vegetation early during this century creates opportunities to mitigate climate-change impacts during the second half of this century. Our results may guide the evaluation of socio-economic scenarios in terms of their potential for biome conservation under global change.

Antioxidant potential of lichen species and their secondary metabolites. A systematic review.

CONTEXT: Pharmacological interest of lichens lies in their capacity to produce bioactive secondary metabolites, being most of them phenolic compounds with reactive hydroxyl groups that confer antioxidant potential through various mechanisms. Increasing incidence and impact of oxidative stress-related diseases (i.e., neurodegenerative disorders) has encouraged the search of new pharmacological strategies to face them. Lichens appear to be a promising source of phenolic compounds in the discovery of natural products exerting antioxidant activity. OBJECTIVE: The present review thoroughly discusses the available knowledge on antioxidant properties of lichens, including both in vitro and in vivo studies and the parameters assessed so far on lichen constituents. METHODS: Literature survey was performed by using as main databases PubMed, Google Scholar, Scopus, Science Direct, and Recent Literature on Lichens. We reviewed 98 highlighted research articles without date restriction. RESULTS: Current report collects data related to antioxidant activities of more than 75 lichen species (from 18 botanical families) and 65 isolated metabolites. Much information comes from in vitro investigations, such as chemical assays evaluating radical scavenging properties, lipid peroxidation inhibition, and reducing power of lichen species and compounds; similarly, research on cellular substrates and animal models generally measures antioxidant enzymes levels and other antioxidant markers, such as glutathione levels or tissue peroxidation. CONCLUSION: Since consistent evidence demonstrated the contribution of oxidative stress on the development and progression of several human diseases, reviewed data suggest that some lichen compounds are worthy of further investigation and better understanding of their antioxidant and neuroprotective potentials.

Evolution of complex symbiotic relationships in a morphologically derived family of lichen-forming fungi.

We studied the evolutionary history of the Parmeliaceae (Lecanoromycetes, Ascomycota), one of the largest families of lichen-forming fungi with complex and variable morphologies, also including several lichenicolous fungi. We assembled a six-locus data set including nuclear, mitochondrial and low-copy protein-coding genes from 293 operational taxonomic units (OTUs). The lichenicolous lifestyle originated independently three times in lichenized ancestors within Parmeliaceae, and a new generic name is introduced for one of these fungi. In all cases, the independent origins occurred c. 24 million yr ago. Further, we show that the Paleocene, Eocene and Oligocene were key periods when diversification of major lineages within Parmeliaceae occurred, with subsequent radiations occurring primarily during the Oligocene and Miocene. Our phylogenetic hypothesis supports the independent origin of lichenicolous fungi associated with climatic shifts at the Oligocene-Miocene boundary. Moreover, diversification bursts at different times may be crucial factors driving the diversification of Parmeliaceae. Additionally, our study provides novel insight into evolutionary relationships in this large and diverse family of lichen-forming ascomycetes.

Fungal specificity and selectivity for algae play a major role in determining lichen partnerships across diverse ecogeographic regions in the lichen-forming family Parmeliaceae (Ascomycota).

Microbial symbionts are instrumental to the ecological and long-term evolutionary success of their hosts, and the central role of symbiotic interactions is increasingly recognized across the vast majority of life. Lichens provide an iconic group for investigating patterns in species interactions; however, relationships among lichen symbionts are often masked by uncertain species boundaries or an inability to reliably identify symbionts. The species-rich lichen-forming fungal family Parmeliaceae provides a diverse group for assessing patterns of interactions of algal symbionts, and our study addresses patterns of lichen symbiont interactions at the largest geographic and taxonomic scales attempted to date. We analysed a total of 2356 algal internal transcribed spacer (ITS) region sequences collected from lichens representing ten mycobiont genera in Parmeliaceae, two genera in Lecanoraceae and 26 cultured Trebouxia strains. Algal ITS sequences were grouped into operational taxonomic units (OTUs); we attempted to validate the evolutionary independence of a subset of the inferred OTUs using chloroplast and mitochondrial loci. We explored the patterns of symbiont interactions in these lichens based on ecogeographic distributions and mycobiont taxonomy. We found high levels of undescribed diversity in Trebouxia, broad distributions across distinct ecoregions for many photobiont OTUs and varying levels of mycobiont selectivity and specificity towards the photobiont. Based on these results, we conclude that fungal specificity and selectivity for algal partners play a major role in determining lichen partnerships, potentially superseding ecology, at least at the ecogeographic scale investigated here. To facilitate effective communication and consistency across future studies, we propose a provisional naming system for Trebouxia photobionts and provide representative sequences for each OTU circumscribed in this study.

Insights into intrathalline genetic diversity of the cosmopolitan lichen symbiotic green alga Trebouxia decolorans Ahmadjian using microsatellite markers.

Trebouxia decolorans is a widespread and common symbiotic green alga that is found in association with different species of lichen-forming fungi. By applying T. decolorans-specific microsatellite markers, we investigated the within-thallus diversity of T. decolorans in thalli of Xanthoria parietina and Anaptychia ciliaris. We found several algal strains in most of the thalli of both hosts. High genetic differentiation among thalli suggests that algal diversity is generated de novo via mutation in both fungal hosts. Rarefied allelic richness of the algae was higher in thalli of X. parietina. Our results indicate that in X. parietina intrathalline algal diversity is additionally created by environmental uptake of algae either at the start of the symbiotic association or during the lifetime of the thallus. This study indicates that promiscuous host-symbiont associations in lichen symbioses with Trebouxia spp. may be more common than currently recognized.

The First Miniature, Small Foliose, Brown Xanthoparmelia in the Northern Hemisphere.

The genus Xanthoparmelia includes several subcrustose, squamulose, small foliose, and small subfruticose species, primarily in the Southern Hemisphere. Here, we report on the first small foliose species lacking usnic acid in the genus occurring in the Holarctic. The species has been previously known as Lecanora olivascens Nyl., but subsequent studies of the morphology, secondary chemistry, and molecular data of the nuITS rDNA indicate that this species instead belongs to Xanthoparmelia. Consequently, the new combination Xanthoparmelia olivascens (Nyl.) V.J. Rico and G. Amo is proposed, and an epitype is designated here. We discuss the unique presence of a subcrustose Xanthoparmelia species lacking cortical usnic acid in the Northern Hemisphere. This species fits phylogenetically into a clade that was previously only known from the Southern Hemisphere, and hence represents another example of N-S disjunction in lichenized fungi.

Osteoblastic Cell Sheet Engineering Using P(VCL-HEMA)-Based Thermosensitive Hydrogels Doped with pVCL@Icariin Nanoparticles Obtained with Supercritical CO2-SAS.

New clinical strategies for treating severe bone and cartilage injuries are required, especially for use in combination with implant procedures. For this purpose, p(VCL-co-HEMA) thermosensitive hydrogels have been activated with icariin-loaded nanoparticles to be used as bone-cell-harvesting platforms. Supercritical CO2-SAS technology has been applied to encapsulate icariin, a small molecule that is involved in osteoblastic differentiation. Thus, physical-chemical analysis, including swelling and transmittance, showed the impact of HEMA groups in hydrogel composition. Moreover, icariin (ICA) release from p(VCL-co-HEMA) platforms, including pVCL@ICA nanoparticles, has been studied to evaluate their efficacy in relevant conditions. Finally, the thermosensitive hydrogels' cell compatibility, transplant efficiency, and bone differentiation capacity were tested. This study identifies the optimal formulations for icariin-activated hydrogels for both control and HEMA formulations. Using this technique, osteoblastic sheets that were rich in collagen type I were successfully transplanted and recultivated, maintaining an optimal extracellular matrix (ECM) composition. These findings suggest a new cell-sheet-based therapy for bone regeneration purposes using customized and NP-activated pVCL-based cell platforms.

Testing the use of ITS rDNA and protein-coding genes in the generic and species delimitation of the lichen genus Usnea (Parmeliaceae, Ascomycota).

In lichen-forming fungi, traditional taxonomical concepts are frequently in conflict with molecular data, and identifying appropriate taxonomic characters to describe phylogenetic clades remains challenging in many groups. The selection of suitable markers for the reconstruction of solid phylogenetic hypotheses is therefore fundamental. The lichen genus Usnea is highly diverse, with more than 350 estimated species, distributed in polar, temperate and tropical regions. The phylogeny and classification of Usnea have been a matter of debate, given the lack of phenotypic characters to describe phylogenetic clades and the low degree of resolution of phylogenetic trees. In this study, we investigated the phylogenetic relationships of 52 Usnea species from across the genus, based on ITS rDNA, nuLSU, and two protein-coding genes RPB1 and MCM7. ITS comprised several highly variable regions, containing substantial genetic signal, but also susceptible to causing bias in the generation of the alignment. We compared several methods of alignment of ITS and found that a simultaneous optimization of alignment and phylogeny (using BAli-phy) improved significantly both the topology and the resolution of the phylogenetic tree. However the resolution was even better when using protein-coding genes, especially RPB1 although it is less variable. The phylogeny based on the concatenated dataset revealed that the genus Usnea is subdivided into four highly-supported clades, corresponding to the traditionally circumscribed subgenera Eumitria, Dolichousnea, Neuropogon and Usnea. However, characters that have been used to describe these clades are often homoplasious within the phylogeny and their parallel evolution is suggested. On the other hand, most of the species were reconstructed as monophyletic, indicating that combinations of phenotypic characters are suitable discriminators for delimitating species, but are inadequate to describe generic subdivisions.

Reference-Based Restriction-Site-Associated DNA Sequencing Data Are Useful for Species Delineation in a Recently Diverged Asexually Reproducing Species Complex (Parmeliaceae, Ascomycota).

Cryptic species are common in lichen-forming fungi and have been reported from different genera in the most speciose family, Parmeliaceae. Herein, we address species delimitation in a group of mainly asexually reproducing Parmelina species. The morphologically distinct P. pastillifera was previously found nested within a morphologically circumscribed P. tiliacea based on several loci. However, these studies demonstrated a relatively high genetic diversity within P. tiliacea sensu lato. Here, we revisit the species delimitation in the group by analyzing single-nucleotide polymorphisms (SNPs) through genome-wide assessment using Restriction-Site-Associated sequencing and population genomic methods. Our data support previous studies and provide further insight into the phylogenetic relationships of the four clades found within the complex. Based on the evidence suggesting a lack of gene flow among the clades, we recognize the four clades as distinct species, P. pastillifera and P. tiliacea sensu stricto, and two new species, P. clandestina sp. nov. and P. mediterranea sp. nov.

Targeting shared molecular etiologies to accelerate drug development for rare diseases.

Rare diseases affect over 400 million people worldwide and less than 5% of rare diseases have an approved treatment. Fortunately, the number of underlying disease etiologies is far less than the number of diseases, because many rare diseases share a common molecular etiology. Moreover, many of these shared molecular etiologies are therapeutically actionable. Grouping rare disease patients for clinical trials based on the underlying molecular etiology, rather than the traditional, symptom-based definition of disease, has the potential to greatly increase the number of patients gaining access to clinical trials. Basket clinical trials based on a shared molecular drug target have become common in the field of oncology and have been accepted by regulatory agencies as a basis for drug approvals. Implementation of basket clinical trials in the field of rare diseases is seen by multiple stakeholders-patients, researchers, clinicians, industry, regulators, and funders-as a solution to accelerate the identification of new therapies and address patient's unmet needs.

Pancreatic steatosis and iron overload increases cardiovascular risk in non-alcoholic fatty liver disease.

Objective: To assess the prevalence of pancreatic steatosis and iron overload in non-alcoholic fatty liver disease (NAFLD) and their correlation with liver histology severity and the risk of cardiometabolic diseases. Method: A prospective, multicenter study including NAFLD patients with biopsy and paired Magnetic Resonance Imaging (MRI) was performed. Liver biopsies were evaluated according to NASH Clinical Research Network, hepatic iron storages were scored, and digital pathology quantified the tissue proportionate areas of fat and iron. MRI-biomarkers of fat fraction (PDFF) and iron accumulation (R2*) were obtained from the liver and pancreas. Different metabolic traits were evaluated, cardiovascular disease (CVD) risk was estimated with the atherosclerotic CVD score, and the severity of iron metabolism alteration was determined by grading metabolic hiperferritinemia (MHF). Associations between CVD, histology and MRI were investigated. Results: In total, 324 patients were included. MRI-determined pancreatic iron overload and moderate-to severe steatosis were present in 45% and 25%, respectively. Liver and pancreatic MRI-biomarkers showed a weak correlation (r=0.32 for PDFF, r=0.17 for R2*). Pancreatic PDFF increased with hepatic histologic steatosis grades and NASH diagnosis (p<0.001). Prevalence of pancreatic steatosis and iron overload increased with the number of metabolic traits (p<0.001). Liver R2* significantly correlated with MHF (AUC=0.77 [0.72-0.82]). MRI-determined pancreatic steatosis (OR=3.15 [1.63-6.09]), and iron overload (OR=2.39 [1.32-4.37]) were independently associated with high-risk CVD. Histologic diagnosis of NASH and advanced fibrosis were also associated with high-risk CVD. Conclusion: Pancreatic steatosis and iron overload could be of utility in clinical decision-making and prognostication of NAFLD.