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BackgroundModulation of adaptive immunity may underscore the efficacy of trans-arterial chemoembolization (TACE). We evaluated the influence of TACE on T-cell function by phenotypic lymphocyte characterization in samples of patients undergoing surgery with (T+) or without (T-) prior-TACE treatment.MethodsWe profiled intratumoral (IT), peritumoral (PT) and non-tumoral (NT) background tissue to evaluate regulatory CD4+/FOXP3+ (T-reg) and immune-exhausted CD8+/PD-1+ T-cells across T+ (n=58) and T− (n=61). We performed targeted transcriptomics and T-cell receptor sequencing in a restricted subset of samples (n=24) evaluated in relationship with the expression of actionable drivers of anti-cancer immunity including PD-L1, indoleamine 2,3 dehydrogenase (IDO-1), cytotoxic T-lymphocyte associated protein 4 (CTLA-4), Lag-3, Tim-3 and CD163.ResultsWe analyzed 119 patients resected (n=25, 21%) or transplanted (n=94, 79%) for Child-Pugh A (n=65, 55%) and Barcelona Clinic Liver Cancer stage A (n=92, 77%) hepatocellular carcinoma. T+ samples displayed lower IT CD4+/FOXP3+ (p=0.006), CD8+ (p=0.002) and CD8+/PD-1+ and NT CD8+/PD-1+ (p<0.001) compared with T−. Lower IT (p=0.005) and NT CD4+/FOXP3+ (p=0.03) predicted for improved recurrence-free survival. In a subset of samples (n=24), transcriptomic analysis revealed upregulation of a pro-inflammatory response in T+. T+ samples were enriched for IRF2 expression (p=0.01), an interferon-regulated transcription factor implicated in cancer immune-evasion. T-cell clonality and expression of PD-L1, IDO-1, CTLA-4, Lag-3, Tim-3 and CD163 was similar in T+ versus T−.ConclusionsTACE is associated with lower IT density of immune-exhausted effector cytotoxic and T-regs, with significant upregulation of pro-inflammatory pathways. This highlights the pleiotropic effects of TACE in modulating the tumor microenvironment and strengthens the rationale for developing immunotherapy alongside TACE.

ObjectiveMicroRNAs (miRNAs) are well-known regulators of disease pathogenesis and have great potential as biomarkers and therapeutic targets. We aimed at profiling miRNAs in alcoholic hepatitis (AH) and identifying miRNAs potentially involved in liver injury.DesignMiRNA profiling was performed in liver samples from patients with AH, alcohol liver disease, non-alcoholic steatohepatitis, HCV disease and normal liver tissue. Expression of miRNAs was assessed in liver and serum from patients with AH and animal models. Mimic and decoy miR-182 were used in vitro and in vivo to evaluate miR-182's biological functions.ResultsMiRNA expression profile in liver was highly altered in AH and distinctive from alcohol-induced cirrhotic livers. Moreover, we identified a set of 18 miRNAs predominantly expressed in AH as compared with other chronic liver conditions. Integrative miRNA-mRNA functional analysis revealed the association of AH-altered miRNAs with nuclear receptors, IGF-1 signalling and cholestasis. Interestingly, miR-182 was the most highly expressed miRNA in AH, which correlated with degree of ductular reaction, disease severity and short-term mortality. MiR-182 mimic induced an upregulation of inflammatory mediators in biliary cells. At experimental level, miR-182 was increased in biliary cells in mice fed with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet but not upregulated by alcohol intake or fibrosis. Inhibition of miR-182 in DDC-fed mice reduced liver damage, bile acid accumulation and inflammatory response.ConclusionsAH is characterised by a deregulated miRNA profile, including miR-182, which is associated with disease severity and liver injury. These results highlight the potential of miRNAs as therapeutic targets and biomarkers in AH.

ObjectiveTo determine the diagnostic accuracy and predictive value of gadoxetic acid liver MRI (Gd-EOB-DTPA MRI) alone or in combination with diffusion-weighted imaging (DWI) as a second-line tool for detecting early hepatocellular carcinoma (HCC) recurrence in cirrhotic patients with previous HCC treated with resection or ablation.MethodsBetween 2014 and 2017, we prospectively included 34 cirrhotic patients with complete response to resection and/or ablation of early HCC in whom a new focal lesion enhancing in the arterial phase without washout was detected during follow-up with EC-MRI. After signing the informed consent, all patients underwent DWI and Gd-EOB-DTPA MRI; two readers analyzed signal intensities on each phase of dynamic study and on DWI. The final diagnosis was established by histology or follow-up EC-MRI. We used cross-tabulation to calculate indices of diagnostic accuracy.ResultsWe evaluated 34 patients (7 women; 73.5% with hepatitis C virus) with a total of 53 new arterial-phase-enhancing foci (median size, 10 [IQR 9–14] mm). The final diagnosis, reached by histopathology in 15 (35.7%) lesions and EC-MR follow-up in 27 (64.3%), was HCC in 42 (79.2%) and benign conditions in 11 (21.8%). Hepatobiliary-phase hypointensity on Gd-EOB-DTPA MRI plus hyperintensity on DWI yielded 54.8% sensitivity, 90.9% specificity, 95.8% positive predictive value, and 34.5% negative predictive value for diagnosing HCC recurrence.ConclusionAmong potential indices, combining hypointensity on hepatobiliary-phase Gd-EOB-DTPA MRI and hyperintensity on DWI has the highest specificity and positive predictive value to optimally detect HCC recurrence prior to confident diagnosis by conventional imaging criteria on EC-MRI in cirrhotic liver.Key Points• In patients at risk of HCC recurrence, the use of gadoxetic acid liver MRI and DWI may improve the differentiation of unspecific new arterial-enhancing foci from early hypervascular HCC recurrence in patients with non-conclusive findings on extracellular liver MRI.• Combined findings on hepatobiliary-phase gadoxetic acid–enhanced liver MRI and DWI had high specificity (90.9%) and positive predictive value (95.8%) for detecting early hypervascular HCC recurrence, but limited sensitivity.• Combining hepatobiliary-phase hypointensity on gadoxetic acid MRI and hyperintensity on diffusion-weighted imaging allows early diagnosis of hypervascular hepatocellular carcinoma and may help select patients for salvage therapy.

Many people living with rare disease (RD) report a difficult diagnostic process from the symptom onset until they obtain the definitive diagnosis. The aim of this study was thus to ascertain the diagnostic process in RDs, and explore the determinants related with having to wait for more than one year in this process (defined as “diagnostic delay”). We conducted a case–control study, using a purpose-designed form from the Spanish Rare Diseases Patient Registry for data-collection purposes. A descriptive analysis was performed and multivariate backward logistic regression models fitted. Based on data on 1216 patients living with RDs, we identified a series of determinants associated with experiencing diagnostic delay. These included: having to travel to see a specialist other than that usually consulted in the patient’s home province (OR 2.1; 95%CI 1.6–2.9); visiting more than 10 specialists (OR 2.6; 95%CI 1.7–4.0); being diagnosed in a region other than that of the patient’s residence at the date of symptom onset (OR 2.3; 95%CI 1.5–3.6); suffering from a RD of the nervous system (OR 1.4; 95%CI 1.0–1.8). In terms of time taken to see a specialist, waiting more than 6 months to be referred from the first medical visit was the period of time which most contributed to diagnostic delay (PAR 30.2%). In conclusion, this is the first paper to use a collaborative study based on a nationwide registry to address the diagnostic process of patients living with RDs. While the evidence shows that the diagnostic process experienced by these persons is complex, more studies are needed to determine the implications that this has for their lives and those of their families at a social, educational, occupational, psychological, and financial level.

Introduction Diffuse midline glioma (DMG) H3 K27-altered is a type of high-grade gliomas first recognized as a new entity in the 2016 World Health Organization Classification of Central Nervous System (CNS) Tumors as DMG H3 K27M-mutant, recently renamed in the new 2021 WHO classification. The aim of this review is to describe the characteristics of diffuse midline gliomas H3 K27-altered in the adult population. Methods We performed a review of the current literature regarding the genetic, clinical, imaging characteristics and management of diffuse midline gliomas H3 K27-altered in adult patients. Results The 2021 WHO classification now designates the previously recognized DMG H3K27M-mutant as DMG H3 K27-altered, recognizing the alternative mechanisms by which the pathogenic pathway can be altered. Thus, the diagnostic criteria for this entity consist of diffuse growth pattern, midline anatomic location, and H3 K27-specific neuroglial mutations. DMGs’ characteristic midline location makes them difficult to surgically resect and biopsy, carrying high mortality and morbidity rates, with median survival ranging from 9 to 12 months in adult patients. Conclusion The diagnosis of DMGs H3 K27-altered in adult patients should be considered upon neurological symptoms associated with an infiltrative midline brain tumor detected on imaging. Future studies are necessary to continue refining their characteristics in this age group.

This research was funded by \"Consejeria de Economia, Conocimiento, Empresas y Universidad\", Junta de Andalucia (Spain) (PAI-EXCEL-06-FQM-02075) and by \"Fomento e Impulso de la Investigacion y de la Transferencia\" Programme, Universidad de Cadiz (Spain) (PR2020-013).

Electromagnetic induction (EMI) techniques are widely used in geophysical surveying. Their success is mainly due to their easy and fast data acquisition, but the effectiveness of data inversion is strongly influenced by the quality of sensed data, resulting from suiting the device configuration to the physical features of the survey site. Forward modelling is an essential tool to optimize this aspect and design a successful surveying campaign. In this paper, a new software tool for forward EMI modelling is introduced. It extends and complements an existing open-source package for EMI data inversion, and includes an interactive graphical user interface. Its use is explained by a theoretical introduction and demonstrated through a simulated case study. The nonlinear data inversion issue is briefly discussed and the inversion module of the package is extended by a new regularized minimal-norm algorithm.

The identification of noninvasive biomarkers for monitoring liver transplant (LT) recipients is crucial for the early detection of graft dysfunction and rejection. Donor-derived cell-free DNA (dd-cfDNA) and microRNAs (miRNAs) have been identified as promising biomarkers for assessing graft integrity. While the levels of dd-cfDNA have been validated for this use in kidney and heart transplantation, there are limited data regarding its potential in liver graft monitoring. Similarly, the expression levels of miRNAs, key regulators of immune responses and liver injury, have potential utility in distinguishing between rejection and other causes of graft dysfunction. In this prospective, observational study, we monitored the levels of dd-cfDNA and miRNAs by analyzing 437 plasma samples from 64 LT recipients over a 12-month period, measuring the levels of dd-cfDNA and signature miRNAs at predefined time points and during episodes of graft dysfunction. The diagnostic performance of the levels of dd-cfDNA and signature miRNAs was assessed through receiver operating characteristic (ROC) curve analysis and logistic regression models. dd-cfDNA levels were significantly elevated during acute rejection (AR) episodes, with a median 3.9-fold increase over those in stable patients. A diagnostic cut-off value of 9.88% yielded an area under the ROC curve (AUROC) of 0.812, a sensitivity of 100%, a specificity of 66.7%, a positive predictive value (PPV) of 17.5% and a negative predictive value (NPV) of 100%. Interestingly, patients with cholestasis also exhibited increased dd-cfDNA levels (3.0-fold vs. stable patients), suggesting that it could serve as a potential confounder in the diagnosis of transplant rejection. Plasma miRNA analysis demonstrated significant upregulation of the expression levels of miR-155-5p, miR-122-5p, and miR-181a-5p during rejection episodes, and the incorporation of these factors improved diagnostic accuracy when combined with the level of dd-cfDNA. dd-cfDNA and miRNA profiling represent promising noninvasive biomarkers for diagnosing liver graft rejection and dysfunction. The combined use of these biomarkers may result in increased diagnostic accuracy, reduce unnecessary biopsies, and allow personalized immunosuppressive management. Further studies in larger cohorts are needed to validate the clinical applicability of these compounds as diagnostic biomarkers.

REPI is a pivotal point enzyme in plant benzylisoquinoline alkaloid metabolism as it promotes the evolution of the biosynthetic branch of morphinan alkaloids. Experimental studies of its activity led to the identification of two modules (DRS and DRR) that catalyze two sequential steps of the epimerization of (S)- to (R)-reticuline. Recently, special attention has been paid to its genetic characterization and evolutionary history, but no structural analyses of the REPI protein have been conducted to date. We present here a computational structural characterization of REPI with heme and NADP cofactors in the apo state and in three complexes with substrate (S)-reticuline in DRS and intermediate 1,2-dehydroreticuline in DRS and in DRR. Since no experimental structure exists for REPI, we used its AlphaFold model as a scaffold to build up these four systems, which were submitted to all-atom molecular dynamics (MD) simulations. A comparison of MD results for the four systems revealed key dynamic changes associated with cofactor and ligand binding and provided a dynamic picture of the evolution of their structures and interactions. We also explored the possible dynamic occurrence of tunnels and electrostatic highways potentially involved in alternative mechanisms for channeling the intermediate from DRS to DRR.

The histone demethylase lysine-specific demethylase 1 (LSD1 or KDM1A) has emerged as a candidate therapeutic target in acute myeloid leukaemia (AML); tranylcypromine-derivative inhibitors induce loss of clonogenic activity and promote differentiation, in particular in the MLL-translocated molecular subtype of AML. In AML, the use of drugs in combination often delivers superior clinical activity. To identify genes and cellular pathways that collaborate with LSD1 to maintain the leukaemic phenotype, and which could be targeted by combination therapies, we performed a genome-wide CRISPR-Cas9 dropout screen. We identified multiple components of the amino acid sensing arm of mTORC1 signalling—RRAGA, MLST8, WDR24 and LAMTOR2—as cellular sensitizers to LSD1 inhibition. Knockdown of mTORC1 components, or mTORC1 pharmacologic inhibition, in combination with LSD1 inhibition enhanced differentiation in both cell line and primary cell settings, in vitro and in vivo, and substantially reduced the frequency of clonogenic primary human AML cells in a modelled minimal residual disease setting. Synergistic upregulation of a set of transcription factor genes associated with terminal monocytic lineage differentiation was observed. Thus, dual mTORC1 and LSD1 inhibition represents a candidate combination approach for enhanced differentiation in MLL-translocated AML which could be evaluated in early phase clinical trials.