Comments and illustrations of the WFUMB CEUS liver guidelines: Rare benign focal liver lesion, part II.

It is important to be familiar with the typical imaging features of the uncommon or even extremely rare focal liver lesions (FLL). Current guidelines of the World Federation for Ultrasound in Medicine and Biology (WFUMB) is aimed at assessing the usefulness of contrast enhanced ultrasound (CEUS) in the management of various FLL. In this review, we aim to summarize the ultrasound and CEUS characteristics with literature review of some extremely rare benign FLL, which might be helpful for improving diagnostic efficiency clinically

Epidemiology of surgery associated acute kidney injury (EPIS-AKI): a prospective international observational multi-center clinical study

Purpose: The incidence, patient features, risk factors and outcomes of surgery-associated postoperative acute kidney injury (PO-AKI) across different countries and health care systems is unclear. Methods: We conducted an international prospective, observational, multi-center study in 30 countries in patients undergoing major surgery (> 2-h duration and postoperative intensive care unit (ICU) or high dependency unit admission). The primary endpoint was the occurrence of PO-AKI within 72 h of surgery defined by the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Secondary endpoints included PO-AKI severity and duration, use of renal replacement therapy (RRT), mortality, and ICU and hospital length of stay. Results: We studied 10,568 patients and 1945 (18.4%) developed PO-AKI (1236 (63.5%) KDIGO stage 1500 (25.7%) KDIGO stage 2209 (10.7%) KDIGO stage 3). In 33.8% PO-AKI was persistent, and 170/1945 (8.7%) of patients with PO-AKI received RRT in the ICU. Patients with PO-AKI had greater ICU (6.3% vs. 0.7%) and hospital (8.6% vs. 1.4%) mortality, and longer ICU (median 2 (Q1-Q3, 1-3) days vs. 3 (Q1-Q3, 1-6) days) and hospital length of stay (median 14 (Q1-Q3, 9-24) days vs. 10 (Q1-Q3, 7-17) days). Risk factors for PO-AKI included older age, comorbidities (hypertension, diabetes, chronic kidney disease), type, duration and urgency of surgery as well as intraoperative vasopressors, and aminoglycosides administration. Conclusion: In a comprehensive multinational study, approximately one in five patients develop PO-AKI after major surgery. Increasing severity of PO-AKI is associated with a progressive increase in adverse outcomes. Our findings indicate that PO-AKI represents a significant burden for health care worldwide

Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches

Extracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year-on-year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non-vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its 'Minimal Information for Studies of Extracellular Vesicles', which was first published in 2014 and then in 2018 as MISEV2014 and MISEV2018, respectively. The goal of the current document, MISEV2023, is to provide researchers with an updated snapshot of available approaches and their advantages and limitations for production, separation and characterisation of EVs from multiple sources, including cell culture, body fluids and solid tissues. In addition to presenting the latest state of the art in basic principles of EV research, this document also covers advanced techniques and approaches that are currently expanding the boundaries of the field. MISEV2023 also includes new sections on EV release and uptake and a brief discussion of in vivo approaches to study EVs. Compiling feedback from ISEV expert task forces and more than 1000 researchers, this document conveys the current state of EV research to facilitate robust scientific discoveries and move the field forward even more rapidly

Sex differences in oncogenic mutational processes.

Sex differences have been observed in multiple facets of cancer epidemiology, treatment and biology, and in most cancers outside the sex organs. Efforts to link these clinical differences to specific molecular features have focused on somatic mutations within the coding regions of the genome. Here we report a pan-cancer analysis of sex differences in whole genomes of 1983 tumours of 28 subtypes as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We both confirm the results of exome studies, and also uncover previously undescribed sex differences. These include sex-biases in coding and non-coding cancer drivers, mutation prevalence and strikingly, in mutational signatures related to underlying mutational processes. These results underline the pervasiveness of molecular sex differences and strengthen the call for increased consideration of sex in molecular cancer research

Integration von ERP- und Umweltinformationssystemen – Status quo, Perspektiven und Anwendungsfelder

In den vergangenen 15 Jahren sind umfangreiche Anstrengungen im wissenschaftlichen Umfeld unternommen worden, betriebswirtschaftliche Anwendungssysteme (ERP-Systeme) mit Umweltinformationssystemen zu integrieren. Als Ergebnis dieser Arbeiten entstanden im Wesentlichen Konzepte, Referenzmodelle und prototypische Implementierungen. Eine flächendeckende Etablierung der entwickelten Konzepte in Unternehmen ist bislang ausgeblieben. Dieser Beitrag fasst die bisherigen Ergebnisse zusammen, stellt die Stoßrichtungen aktueller Projekte in diesem Umfeld dar und zeigt zukünftige Perspektiven und Anwendungsfelder auf

Unusual Reactivity of <i>N</i>,<i>N</i>,<i>N′</i>,<i>N</i>′-Tetramethylethylenediamine-Coordinated Neutral Nickel(II) Polymerization Catalysts

Tmeda-coordinated species [(N,O)NiCH3(tmeda)] (tmeda = N,N,N′,N′-tetramethylethylenediamine), obtained by reaction of [(tmeda)NiMe2] with salicylaldimines, (N̂O)H, are reactive and versatile intermediates for olefin polymerization catalysis. Solution NMR spectroscopic studies of 1-tmeda (N,O= 2,6-(3,5-(F3C)2C6H3)2C6H3-NCH-(3,5-I2-2-OC6H2)) revealed two major binding modes of the tmeda ligand, open κ1- and, unexpectedly, chelating κ2-fashion, which interconvert slowly on the NMR chemical shift time scale, and form equilibria with solvent complexes 1-L (L= dmso, methanol). Binding of tmeda is favored by 2−3 orders of magnitude at the temperatures studied (25 to 80 °C) over binding of solvent. Chelating κ2-coordination of tmeda renders the monoanionic bidentate salicylaldiminato ligand κ1-coordinate. Exposure of dmso solutions of 1-tmeda to excess ethylene in an NMR tube at 55 °C resulted in the very minor formation of propylene and an equilibrium mixture of Ni(II)-ethyl complexes 2-dmso and [(κ1-N,O)Ni(αCH2βCH3)(κ2-tmeda)] (2-κ2-tmeda). Ethylene is primarily dimerized to butenes, which qualitatively parallels the reactivity observed for tmeda-free solutions of 2-dmso, but tmeda-coordinated Ni(II)-alkyl complexes appeared unreactive, i.e., dormant, toward ethylene. Carrying out the aforementioned reaction under aqueous conditions revealed that hydrolysis of Ni(II)-Me species to methane is a relevant deactivation pathway of the catalyst precursor, which clearly contrasts the reactivity observed in the absence of tmeda. Observed pseudo-first-order rate constants of overall disappearance of 1-tmeda split into two independent contributions according to kobs,Me,1-tmeda= kins,Me,1-tmeda + khydr,1-tmeda[water], khydr,1-tmeda= 1.9 × 10−4 M−1 s−1, and kins,Me,1-tmeda ≈ 2.4 × 10−4 M−1 s−1 (∼0.1 M [C2H4]). Determination of activation parameters of the bimolecular elimination of ethane from 1-tmeda (ΔH⧧= 97 ± 7 kJ mol−1 and ΔS⧧ ≈ −5 J mol−1 K−1), a generally relevant deactivation mechanism of Ni(II)-methyl complexes, points out that tmeda-coordinated Ni(II)-methyl complexes, despite being inactive toward activation with ethylene, are actively involved in decomposition reactions

Treatment of a Patient with Refractory Non-Langerhans-Cell-Histiocytosis with the Tyrosine Kinase Inhibitor Sorafenib: Clinical and Genetic Implications

Abstract Abstract 4715 Non-Langerhans-cell-histiocytosis (Non-LCH) represents a rare disorder with a broad spectrum of clinical features and various outcome. We here report on a 61 years old man with Non-LCH with severe skin and bone marrow involvement. At the time of diagnosis in 2006, the patient presented with up to four centimeter large cutaneous papules involving face, stem, hands and feet. Since two years, the patient also developed an increasing tricytopenia due to an extensive bone marrow infiltration of histiocytes (80%). Since diagnosis, the patient received a large number of various therapies including daily glucocorticoids at different dosages (continuously since diagnosis), low-dose methotrexate (10-40mg s.c. per week; from may to september 2007), experimental treatment with lenalidomide (5-10mg per day; from february to june 2008), continous oral trofosfamide (100mg per day; from july to august 2008), cladribine monotherapy (2,1mg/m2 d1-5; 4 cycles; from December 2008 to march 2009) and the combination of cladribine (2.1mg/m2 d1-5) and cytarabine (40 mg s.c. d1-7; 3 cycles; from january to march 2010). The patient did not respond to any of these therapies. Due to the persistent distinctive clinical symptoms (massive skin involvement, tricytopenia), we started in July 2010 an experimental therapy with sorafenib at a dosage of 200mg per day for four days, followed by 400mg per day for another four days, and subsequently increased the dosage to 800mg daily. After four weeks, the marked skin papules flattened to skin level at all preferential sites. Small skin ulcers at the cheeks healed up. In parallel, there was a significant improvement of hematopoiesis since start of therapy with haemoglobin levels raising from 8,6g/dl to 12,2g/dl and normalization of leukocyte count (from 3.1/nl to 5.2/nl). Bone marrow rebiopsy is intended after three month of therapy, data on the actual grade of infiltration will be presented at the meeting. Based on the impressive clinical improvement under sorafenib, we analyzed selected target genes of the multityrosine kinase inhibitor: mutation screening was performed on the FLT3 (internal tandem duplication, point mutations of the tyrosine kinase domain) and KIT genes (exon 8 and exon 17) as well as for the recently described BRAF V600E mutation found in a significant number of patients with LCH (G. Badalian-Very et al., Blood prepublished online June 2, 2010; DOI 10.1182/blood-2010-04-279083). However, in none of these genes, mutations were found and further molecular analysis of the patient's bone marrow is currently under investigation. To our knowledge, this is the first report on the efficacy of sorafenib in a case of histiocytosis. However, the underlying genetic mechanisms of Non-LCH still have to be elucidated. Disclosures: Off Label Use: Sorafenib is approved for unresectable hepatocellular carcinoma and advanced renal cancer. We present an off-label use of sorafenib in a case of a severe orphan disease refractory to all standard therapies. Zenz:Roche: Honoraria; Boehringer: Honoraria; GSK: Honoraria; Celgene: Honoraria. </jats:sec

Polyglycidol-Based Prepolymers to Tune the Nanostructure of Microgels

The use of prepolymers for microgel synthesis via miniemulsification allows predefining the chemical functionality and the nanostructure of microgels. We report on tailor-made polyglycidol-based prepolymers using three protected glycidol monomers (allyl glycidyl ether, AGE; ethoxy ethyl glycidyl ether, EEGE; and <i>tert</i>-butyl glycidyl ether, tBGE). AGE with its pendant double bonds serves as site for cross-linking or functionalization, whereas the EEGE and tBGE building blocks represent precursors for hydroxyl functionalities. Following the prepolymer approach, we design statistical and block copolymers to control the nanostructure of the microgel. Cross-linking of the prepolymers is achieved in miniemulsions under UV irradiation in a thiol–ene click type reaction addressing the allyl groups with 2,2′-(ethylenedioxy)­diethanethiol. Analysis with cryo-TEM reveals that microgels derived from poly­(glycidol)-<i>block</i>-poly­(AGE) show larger hydrophobic domains than microgels derived from statistical copolymers. Additionally, the cross-linking of pH responsive tBGE/AGE prepolymers with different microstructures leads to microgels with nanostructures differing in local charge distributions

Mechanistic Insights on the Copolymerization of Polar Vinyl Monomers with Neutral Ni(II) Catalysts

The Ni(II) complexes [(N∧O)Ni(H)(PMe3)] (1) and [(N∧O)Ni(CH2CH3)(dmso)] (3) (N∧O = κ2-{(2,6-(3,5-(F3C)2C6H3)2C6H3)−NC(H)−(3,5-I2-2-O-C6H2)}) were found to be well-defined model compounds to study the reactivity of polymerization active neutral Ni(II) species toward polar vinyl monomers. Methyl acrylate (MA) insertion into the Ni(II)−hydride bond of 1 was monitored at T ≥ −40 °C by NMR spectroscopy. 2,1-Insertion yields the functionalized Ni(II) alkyl complex [(N∧O)Ni(CαH(CH3)Cβ(O)OCH3)(PMe3)] (4). Low-temperature 2D ROESY data indicate a weak Ni(II)···OCβ interaction in 4. This is supported by ab initio calculations at the gradient-corrected DFT (BP86/LACPV*) level of theory. Exposure of 1 to equal amounts of MA and ethylene afforded 4 and the Ni(II) ethyl complex 7 in a 9:1 ratio, which indicates that MA and ethylene effectively compete with each other for coordination and insertion. NMR spectroscopic monitoring revealed that 4 is stable in the absence of residual 1 at low temperatures but is subject to rapid bimolecular elimination of the functionalized alkyl moiety in the presence of free Ni(II) hydride species even at T = −40 °C. Isomerization into the 1,2-MA-insertion product was observed at T = 25 °C but occurred slowly compared to decomposition, which occurs at 0 °C by reaction of 4 with Ni(II) hydride formed by β-elimination from 4 itself at this temperature. Exposure of the higher Ni(II) alkyl complex 3 to MA in the presence of excess ethylene results in the immediate formation of methyl pentanoate as the ultimate decomposition product. Functionalized Ni(II) alkyl species formed from 2,1-insertion of MA into the metal−carbon bond of higher Ni(II) alkyls are subject to rapid hydrolysis in the presence of trace amounts of water in the reaction medium, which contrasts the stability of nonfunctionalized Ni(II) alkyls toward water. Exposure of 1 to vinyl acetate (VA) affords the kinetic 1,2-insertion product [(N∧O)Ni(CH2CH2OCγ′(O)CH3)(PMe3)] (5) at temperatures T ≥ −10 °C, which rearranges into the thermodynamically favored 2,1-insertion product [(N∧O)Ni(CH(CH3)OC(O)CH3)(PMe3)] (6). NMR data and ab initio calculations suggest a Ni(II)···OCγ′ interaction in 6. 5 decomposes via β-acetate elimination to yield ethylene and Ni(II) acetate species. Notably, VA does not undergo observable nickel−carbon bond insertion with 3, but reacted with Ni(II) hydride species in equilibrium with 3 to yield 5* which is subject to rapid decomposition via β-acetate elimination

Mechanistic Insights on the Copolymerization of Polar Vinyl Monomers with Neutral Ni(II) Catalysts

The Ni(II) complexes [(N∧O)Ni(H)(PMe3)] (1) and [(N∧O)Ni(CH2CH3)(dmso)] (3) (N∧O = κ2-{(2,6-(3,5-(F3C)2C6H3)2C6H3)−NC(H)−(3,5-I2-2-O-C6H2)}) were found to be well-defined model compounds to study the reactivity of polymerization active neutral Ni(II) species toward polar vinyl monomers. Methyl acrylate (MA) insertion into the Ni(II)−hydride bond of 1 was monitored at T ≥ −40 °C by NMR spectroscopy. 2,1-Insertion yields the functionalized Ni(II) alkyl complex [(N∧O)Ni(CαH(CH3)Cβ(O)OCH3)(PMe3)] (4). Low-temperature 2D ROESY data indicate a weak Ni(II)···OCβ interaction in 4. This is supported by ab initio calculations at the gradient-corrected DFT (BP86/LACPV*) level of theory. Exposure of 1 to equal amounts of MA and ethylene afforded 4 and the Ni(II) ethyl complex 7 in a 9:1 ratio, which indicates that MA and ethylene effectively compete with each other for coordination and insertion. NMR spectroscopic monitoring revealed that 4 is stable in the absence of residual 1 at low temperatures but is subject to rapid bimolecular elimination of the functionalized alkyl moiety in the presence of free Ni(II) hydride species even at T = −40 °C. Isomerization into the 1,2-MA-insertion product was observed at T = 25 °C but occurred slowly compared to decomposition, which occurs at 0 °C by reaction of 4 with Ni(II) hydride formed by β-elimination from 4 itself at this temperature. Exposure of the higher Ni(II) alkyl complex 3 to MA in the presence of excess ethylene results in the immediate formation of methyl pentanoate as the ultimate decomposition product. Functionalized Ni(II) alkyl species formed from 2,1-insertion of MA into the metal−carbon bond of higher Ni(II) alkyls are subject to rapid hydrolysis in the presence of trace amounts of water in the reaction medium, which contrasts the stability of nonfunctionalized Ni(II) alkyls toward water. Exposure of 1 to vinyl acetate (VA) affords the kinetic 1,2-insertion product [(N∧O)Ni(CH2CH2OCγ′(O)CH3)(PMe3)] (5) at temperatures T ≥ −10 °C, which rearranges into the thermodynamically favored 2,1-insertion product [(N∧O)Ni(CH(CH3)OC(O)CH3)(PMe3)] (6). NMR data and ab initio calculations suggest a Ni(II)···OCγ′ interaction in 6. 5 decomposes via β-acetate elimination to yield ethylene and Ni(II) acetate species. Notably, VA does not undergo observable nickel−carbon bond insertion with 3, but reacted with Ni(II) hydride species in equilibrium with 3 to yield 5* which is subject to rapid decomposition via β-acetate elimination