The 2022 world health organization reevaluation of human and mammalian toxic equivalency factors for polychlorinated dioxins, dibenzofurans and biphenyls

In October 2022, the World Health Organization (WHO) convened an expert panel in Lisbon, Portugal in which the 2005 WHO TEFs for chlorinated dioxin-like compounds were reevaluated. In contrast to earlier panels that employed expert judgement and consensus-based assignment of TEF values, the present effort employed an update to the 2006 REP database, a consensus-based weighting scheme, a Bayesian dose response modeling and meta-analysis to derive "Best-Estimate" TEFs. The updated database contains almost double the number of datasets from the earlier version and includes metadata that informs the weighting scheme. The Bayesian analysis of this dataset results in an unbiased quantitative assessment of the congener-specific potencies with uncertainty estimates. The "Best-Estimate" TEF derived from the model was used to assign 2022 WHO-TEFs for almost all congeners and these values were not rounded to half-logs as was done previously. The exception was for the mono-ortho PCBs, for which the panel agreed to retain their 2005 WHO-TEFs due to limited and heterogenous data available for these compounds. Applying these new TEFs to a limited set of dioxin-like chemical concentrations measured in human milk and seafood indicates that the total toxic equivalents will tend to be lower than when using the 2005 TEFs

Polymorphisms of Dectin-1 and TLR2 Predispose to Invasive Fungal Disease in Patients with Acute Myeloid Leukemia.

Patients with acute myeloid leukemia (AML) who undergo induction chemotherapy are at high risk for invasive fungal disease (IFD). Dectin-1, a C-type lectin family member represents one of the most important pattern recognition receptors of the innate immune system and single nucleotide polymorphisms (SNPs) in the Dectin-1 gene have been associated with an increased risk of infectious complications. We sought to investigate the impact of three different Dectin-1 SNPs and one TLR2 SNP on developing IFD in 186 adult patients with newly diagnosed AML following anthracycline-based induction chemotherapy.Genotyping of Dectin-1 SNPs (rs16910526, rs3901533 and rs7309123) and TLR2 SNP (rs5743708) was performed by TaqMan method and pyrosequencing. IFD was defined according to the EORTC/MSG consensus guidelines. Multiple logistic regression analyses were applied to evaluate the association between the polymorphisms and the occurrence of pulmonary infections. Dectin-1 expression studies with SNP genotyped human monocytes were performed to elucidate susceptibility to IFD following chemotherapy.We could demonstrate that patients carrying the Dectin-1 SNP rs7309123 G/G (n = 47) or G/G and C/G (n = 133) genotype revealed a significant higher risk for developing both pneumonia in general (adjusted odds ratio (OR): 2.5; p = 0.014 and OR: 3.0, p = 0.004) and pulmonary IFD (OR: 2.6; p = 0.012 and OR: 2.4, p = 0.041, respectively). Patients carrying the TLR2 SNP rs5743708 (R753Q, GA/AA genotype, n = 12) also revealed a significantly higher susceptibility to pneumonia including IFD. Furthermore, Dectin-1 mRNA expression in human monocytes was lower following chemotherapy.To our best knowledge, this study represents the first analysis demonstrating that harbouring polymorphisms of Dectin-1 (rs7309123) or TLR2 (rs5743708) represents an independent risk factor of developing IFD in patients with AML undergoing induction chemotherapy

Cu-doped perovskite-type oxides: A structural deep dive and examination of their exsolution behaviour influenced by B-site doping

Perovskite-type oxides have gained significant attention in the scientific community due to their unique properties and potential applications. Their ability to exsolve reducible B-site cations (e.g. Co, Ni, Cu) combined with their flexibility regarding A-site and B-site composition allows for the tailoring of novel catalytic materials. This study focuses on B-site doped perovskite-type oxides with a general formula of Nd$_{0.6}$Ca$_{0.4}$Fe$_{1-x}$Cu$_x$O$_3$ and Pr$_{0.6}$Ca$_{0.4}$Fe$_{1-x}$Cu$_x$O$_3$ (x = 0.0, 0.03, 0.05, 0.10) for potential use as a catalyst for Methanol Steam Reforming via the exsolution of catalytically active Cu nanoparticles. The atomic and electronic structure, morphology, and exsolution behaviour of these materials were investigated experimentally and with density functional theory, with a specific emphasis on the impact of B-site doping with varying Cu content as well as choice of A-site element. Both parameters influenced the crystal structure, surface area, and morphology of the materials. The exsolution behaviour of the materials was observed using in-situ XRD at DESY beamline P02.1 at PETRA III, with nanoparticles forming after reductive treatments on the host oxide surface. The quantity and size of the nanoparticles were found to be adjustable by selecting the A-site ion, doping content at the B-site, and the choice of reducing agent. Materials with higher Cu content on the B-site exhibited facilitated exsolution. Furthermore, exsolution was promoted with Nd as the A-site element compared to Pr. In conclusion, the controlled exsolution of Cu nanoparticles introduces Cu-doped perovskite-type oxides as promising candidates for developing novel catalytic systems. The findings underscore the importance of fine-tuning the oxide composition (A-site element, amount of B-site dopant) to achieve tailored exsolution of nanoparticles, which is crucial for rational material design. By leveraging this knowledge, catalysts with finely tuned properties can be created for specific applications and operational environments

Chronic hepatitis E virus-induced spinal cord atrophy in a patient with chronic lymphatic leukemia: a case report and interdisciplinary management proposal

BackgroundThe hepatitis E virus (HEV) can cause acute viral hepatitis with or without neurological manifestations, and occasionally progresses to chronic infection in immunocompromised individuals. The management of chronic HEV infection in cancer patients may be challenging due to the complex immunological constellation. Furthermore, the diagnostic workflow and the impact on quality of life of neurological HEV manifestations in immunocompromised patients have not been sufficiently delineated previously.Case descriptionA 61-year-old male with systemically treated chronic lymphocytic leukemia (CLL) experienced a slowly progressive atrophy of the spinal cord due to a chronic HEV infection. Despite continuous antiviral treatment with ribavirin, the patient’s neurological condition continued to deteriorate, particularly following subsequent attempts to treat CLL. Treatment with obinutuzumab resulted in acute bowel and urinary retention and a further deterioration of motor skills, prompting the discontinuation of obinutuzumab. The patient’s neurological status improved after the administration of intravenous immunoglobulins.ConclusionThis case study provides a comprehensive long-term follow-up of a cancer patient with chronic HEV infection and associated CNS involvement, which resulted in progressive neurological disability over several years. The challenges faced in diagnosing new neurological symptoms in patients undergoing immunosuppressive cancer treatment underscore the need for an interdisciplinary diagnostic approach that includes HEV testing. We propose a diagnostic pathway for future validation in immunocompromised cohorts presenting with neurological symptoms, emphasizing its potential to enhance clinical outcomes

Perovskite-Type Oxide Catalysts in CO2 Utilization: A Principal Study of Novel Cu-Doped Perovskites for Methanol Synthesis

Six different perovskite-type oxides were investigated with respect to their ability for methanol synthesis via H2 and CO2: Fe-, Mn-, and Ti-based perovskites were prepared with and without Cu doping. For assessment, the catalysts were subjected to preliminary tests at atmospheric pressure to evaluate their ability to activate CO2. Additional catalytic tests with the doped versions of each catalyst type were carried out in a pressured reactor at 21 bar. After the measurements, the catalysts were characterized with X-ray diffraction (XRD) and scanning electron microscopy (SEM). All catalysts were able to produce methanol in the pressure tests. CO2 conversions between 14% and 23% were reached at 400 °C, with the highest methanol selectivity at the lower temperature of 250 °C. The combination of XRD and SEM revealed that the Fe-based and Ti-based perovskites were stable under reaction conditions and that catalytically highly active and stable nanoparticles had formed. The minor formation of CaCO3, which is a deactivating phase, was observed for one catalyst. These nanoparticles showed resistance to coking and sintering. However, the yield and selectivity for methanol need to be improved via the further tailoring of the perovskite composition

Impact of induction chemotherapy with intermediate-dosed cytarabine and subsequent allogeneic stem cell transplantation on the outcome of high-risk acute myeloid leukemia

Background!#!Acute myeloid leukemia (AML) with antecedent hematological disease (s-AML) and treatment-related AML (t-AML) predicts poor prognosis. Intensive treatment protocols of those high-risk patients should consider allogeneic stem cell transplantation (allo-HSCT) in first complete remission (CR). Despite allo-HSCT, relapse rate remains high. Induction chemotherapy with liposomal cytarabine and daunorubicin (CPX-351) has been approved for patients with AML with myeloid-related changes (AML-MRC) or t-AML based on improved survival and remission rates compared to standard 7 + 3 induction.!##!Patients and methods!#!110 patients with newly diagnosed s-AML or t-AML at a university hospital were analyzed retrospectively. Median age was 62 years (24-77 years). A total of 65 patients with s-AML after MDS (59%) and 23 patients (20.9%) with t-AML were included. Induction chemotherapy consisted of intermediate-dosed cytarabine (ID-AraC) in combination with idarubicin (patients up to 60 years) or mitoxantrone (patients over 60 years). In patients subsequently undergoing allo-HSCT, reduced conditioning regimens (RIC) were applied prior to transplantation in 47 of 62 patients (76%).!##!Results!#!Induction chemotherapy with ID-AraC resulted in an overall response rate of 83% including complete remission (CR/CRi) in 69 patients (63%) with a low rate of early death (2.7%). Most relevant non-hematologic toxicity consisted of infectious complications including sepsis with need of intensive care treatment in five patients (4.5%) and proven or probable invasive fungal disease in eight patients (7.2%). Relapse-free survival (RFS), event-free survival (EFS) and overall survival (OS) of the whole cohort were 19 months (0-167), 10 months (0-234) and 15 months (0-234), respectively (p < 0.0001). A significant improvement of OS was observed in patients who underwent allo-HSCT compared to those without subsequent allo-HSCT: 9 vs. 46 months, p < 0.0001. Rate of transplantation-related mortality (TRM) in the early phase post allo-HSCT was low (0.9% at day 30 and 1.8% at day 90, respectively). RIC conditioning results in OS rate of 60% after 60 months post allo-HSCT (median OS not reached).!##!Conclusion!#!S-AML and t-AML patients receiving induction chemotherapy with intermediate-dosed cytarabine showed satisfactory response rate and consolidation therapy with allo-HSCT after full or reduced-intensity conditioning further improved survival in these patients with similar outcome as reported for CPX-351

Outcome of patients with relapsed or refractory acute myeloid leukemia treated with Mito-FLAG salvage chemotherapy

Purpose!#!Curative intended treatment is challenging in patients with relapsed or refractory acute myeloid leukemia (r/r AML) and associated with a dismal prognosis for long-term survival. Despite novel treatment options, the majority of patients are treated with chemotherapy-based regimens. Although widely used, little data exist on the combination of fludarabine, cytarabine, granulocyte colony stimulating factor (FLAG) and mitoxantrone as salvage strategy for r/r AML.!##!Materials and methods!#!Sixty-six patients receiving Mito-FLAG for r/r AML treated at a German tertiary care center between 2009 and 2019 were analyzed with regard to response rates, survival and safety profile.!##!Results!#!Overall response rate was 75.8% with 56.1% of patients achieving complete remission (CR) and 19.7% partial remission (PR). After a median follow-up of 54 months, median overall survival (OS) was 13 months. Patients transitioned to allogeneic hematopoietic stem cell transplantation (alloHSCT) (75.8%) showed a significant improvement in OS with a median OS of 17 (95% CI 8.5-25.4) months vs 3 (95% CI 1.7-4.3) months (p < 0.001). 30- and 60-day mortality rates for all patients after the initial cycle of Mito-FLAG were 4.5% and 7.6%, respectively.!##!Conclusion!#!The Mito-FLAG salvage protocol represents an effective and feasible treatment regimen for r/r AML. Importantly, a high rate of transition to successful alloHSCT with the aim of long-term disease-free survival has been shown

Patients and clinical characteristics.

<p>Patients and clinical characteristics.</p

Multivariate analyses of the attributable risk of the TLR2 and Dectin-1 polymorphisms.

<p>Multivariate analyses of the attributable risk of the TLR2 and Dectin-1 polymorphisms.</p