Donor-Derived Cell-Free DNA: Attractive Biomarker Seeks a Context of Use

Donor-derived cell-free DNA; Post-transplant monitoring; Predictive valuesADN libre de células derivado de donantes; Seguimiento postrasplante; Valores predictivosADN lliure de cèl·lules derivat de donants; Seguiment posttrasplantament; Valors predictiusMN is the senior clinical investigator of the Research Foundation Flanders (F.W.O.) (1844019N). AP is supported by a PhD Fellowship grant from the Research Foundation Flanders (F.W.O.) (1S93023N)

Synthesis and biological evaluation of novel (thio)semicarbazone-based benzimidazoles as antiviral agents against human respiratory viruses

Respiratory RNA viruses are responsible for recurrent acute respiratory illnesses that stillrepresent a major medical need. Previously we developed a large variety of benzimidazole derivativesable to inhibit these viruses. Herein, two series of (thio)semicarbazone- and hydrazone-basedbenzimidazoles have been explored, by derivatizing 5-acetyl benzimidazoles previously reported by us,thereby evaluating the influence of the modification on the antiviral activity. Compounds6,8,16and17,bearing the 5-(thio)semicarbazone and 5-hydrazone functionalities in combination with the 2-benzylring on the benzimidazole core structure, acted as dual inhibitors of influenza A virus and humancoronavirus. For respiratory syncytial virus (RSV), activity is limited to the 5-thiosemicarbazone(25) and 5-hydrazone (22) compounds carrying the 2-[(benzotriazol-1/2-yl)methyl]benzimidazolescaffold. These molecules proved to be the most effective antiviral agents, able to reach the potencyprofile of the licensed drug ribavirin. The molecular docking analysis explained the SAR of thesecompounds around their binding mode to the target RSV F protein, revealing the key contacts forfurther assessment. The herein-investigated benzimidazole-based derivatives may represent valuablehit compounds, deserving subsequent structural improvements towards more efficient antiviralagents for the treatment of pathologies caused by these human respiratory viruses

Evolution of the Definition of Rejection in Kidney Transplantation and Its Use as an Endpoint in Clinical Trials

T cell-mediated rejection; Biopsy; Subclinical rejectionRechazo mediado por células T; Biopsia; Rechazo subclínicoRebuig mediat per cèl·lules T; Biòpsia; Rebuig subclínicThis article outlines the evolving definition of rejection following kidney transplantation. The viewpoints and evidence presented were included in documentation prepared for a Broad Scientific Advice request to the European Medicines Agency (EMA), relating to clinical trial endpoints in kidney transplantation. This request was initiated by the European Society for Organ Transplantation (ESOT) in 2016 and finalized following discussions between the EMA and ESOT in 2020. In ESOT’s opinion, the use of “biopsy-proven acute rejection” as an endpoint for clinical trials in kidney transplantation is no longer accurate, although it is still the approved histopathological endpoint. The spectrum of rejection is now divided into the phenotypes of borderline changes, T cell-mediated rejection, and antibody-mediated rejection, with the latter two phenotypes having further subclassifications. Rejection is also described in relation to graft (dys)function, diagnosed because of protocol (surveillance) or indication (for-cause) biopsies. The ongoing use of outdated terminology has become a potential barrier to clinical research in kidney transplantation. This article presents these perspectives and issues, and provides a foundation on which subsequent articles within this Special Issue of Transplant International build.This initiative was supported by the European Society for Organ Transplantation

Synthesis and Antiviral Evaluation of Bisnoradamantane Sulfites and Related Compounds

The reaction of a series of 1,2-diols with thionyl chloride led to bisnoradamantane sulfites in very good yields. The reaction has also been applied to related polycyclic scaffolds. The compounds have been tested for antiviral activity but none of them showed to be active. Several attempts to generate and trap SO from these polycyclic sulfites have been unsuccessful

Anti-influenza virus activity of benzo[d]thiazoles that target heat shock protein 90

Seasonal or pandemic influenza virus infections are a worldwide health problem requiring antiviral therapy. Since virus resistance to the established neuraminidase inhibitors and novel polymerase inhibitors is growing, new drug targets are needed. Heat shock protein 90 (Hsp90) is associated with several aspects of the influenza virus life cycle, and is considered a relevant host cell target. We report here on a series of benzo[d]thiazole and 4,5,6,7-tetrahydrobenzo [d]thiazole derivatives with robust and selective activities against influenza A (H1N1, H3N2) and influenza B viruses. Two compounds, 1 and 4, have low micromolar EC50 values and show high binding affinities for Hsp90, which suggests that inhibition of Hsp90 is the mechanism underlying their antiviral effects. These compounds represent suitable scaffolds for designing novel Hsp90 inhibitors with favourable activities against influenza virus.Peer reviewe

European Guideline for the Management of Kidney Transplant Patients With HLA Antibodies: By the European Society for Organ Transplantation Working Group

HLA antibodies; Guidelines; IncompatibleAnticuerpos HLA; Pautas; IncompatibleAnticossos HLA; Directrius; IncompatibleThis guideline, from a European Society of Organ Transplantation (ESOT) working group, concerns the management of kidney transplant patients with HLA antibodies. Sensitization should be defined using a virtual parameter such as calculated Reaction Frequency (cRF), which assesses HLA antibodies derived from the actual organ donor population. Highly sensitized patients should be prioritized in kidney allocation schemes and linking allocation schemes may increase opportunities. The use of the ENGAGE 5 ((Bestard et al., Transpl Int, 2021, 34: 1005–1018) system and online calculators for assessing risk is recommended. The Eurotransplant Acceptable Mismatch program should be extended. If strategies for finding a compatible kidney are very unlikely to yield a transplant, desensitization may be considered and should be performed with plasma exchange or immunoadsorption, supplemented with IViG and/or anti-CD20 antibody. Newer therapies, such as imlifidase, may offer alternatives. Few studies compare HLA incompatible transplantation with remaining on the waiting list, and comparisons of morbidity or quality of life do not exist. Kidney paired exchange programs (KEP) should be more widely used and should include unspecified and deceased donors, as well as compatible living donor pairs. The use of a KEP is preferred to desensitization, but highly sensitized patients should not be left on a KEP list indefinitely if the option of a direct incompatible transplant exists.The authors declare that this study received funding from Hansa Biopharma. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication. Medical writing support was provided by Linda Edmondson and Rebecca Mant, independent medical writers, funded by the European Society of Organ Transplantation

Metal-Chelating 2‑Hydroxyphenyl Amide Pharmacophore for Inhibition of Influenza Virus Endonuclease

The influenza virus PA endonuclease is an attractive target for development of novel anti-influenza virus therapeutics. Reported PA inhibitors chelate the divalent metal ion(s) in the enzyme’s catalytic site, which is located in the Nterminal part of PA (PA-Nter). In this work, a series of 2- hydroxybenzamide-based compounds have been synthesized and biologically evaluated in order to identify the essential pharmacophoric motif, which could be involved in functional sequestration of the metal ions (probably Mg2+) in the catalytic site of PA. By using HL1, H2L2, and HL3 as model ligands with Mg2+ ions, we isolated and fully characterized a series of complexes and tested them for inhibitory activity toward PA-Nter endonuclease. H2L2 and the corresponding Mg2+ complex showed an interesting inhibition of the endonuclease activity. The crystal structures of the uncomplexed HL1 and H2L2 and of the isolated magnesium complex [Mg(L3)2(MeOH)2]·2MeOH were solved by X-ray diffraction analysis. Furthermore, the speciation models for HL1, H2L2, and HL3 with Mg2+ were obtained, and the formation constants of the complexes were measured. Preliminary docking calculations were conducted to investigate the interactions of the title compounds with essential amino acids in the PANter active site. These findings supported the “two-metal” coordination of divalent ions by a donor triad atoms chemotype as a powerful strategy to develop more potent PA endonuclease inhibitors

The EKiTE network (epidemiology in kidney transplantation - a European validated database): an initiative epidemiological and translational European collaborative research

Background: Kidney transplantation is considered to be the treatment of choice for people with end-stage renal disease (ESRD). However, due to the shortage of available organs and the increase in the ESRD prevalence in Europe, it is essential to improve transplantation outcomes by studying the related prognostic factors. Today, there is no European registry collecting data to perform such clinical epidemiology studies. Main body: Entitled EKiTE, for European cohort for Kidney Transplantation Epidemiology, this prospective and multicentric cohort includes patients from Spanish (Barcelona), Belgian (Leuven), Norwegian (Oslo) and French (Paris Necker, Lyon, Nantes, Nancy, Montpellier, Nice and Paris Saint Louis) transplantation centers and currently contains 13, 394 adult recipients of kidney (only) transplantation from 2005 and updated annually. A large set of parameters collected from transplantation until graft failure or death with numbers of post-transplantation outcomes. The long-term follow-up and the collected data enable a wide range of possible survival and longitudinal analyses. Conclusion: EKiTE is a multicentric cohort aiming to better assess the natural history of the ESRD in European kidney transplant recipients and perform benchmarking of clinical practices. The data are available for clinical epidemiology studies and open for external investigators upon request to the scientific council. Short-term perspectives are to extend EKITE network to other European countries and collect additional parameters in respect of the common thesaurus