Successful Lenvatinib Re-challenge following Atezolizumab Plus Bevacizumab Combination Therapy Failure for Unresectable Hepatocellular Carcinoma.

To our knowledge, there have been no reports of first-line lenvatinib (LEN) and LEN re-challenge following atezolizumab/bevacizumab (Atezo-Bev) failure in the same patient. We herein report a patient with advanced hepatocellular carcinoma who failed either 1st line LEN and 2nd line Atezo-Bev, and successfully achieved complete response to LEN rechallenge with sequencial transcatheter arterial chemoembolization (TACE). This patient had a poor response to TACE before immunotherapy and introduction of molecular-targeted drugs but showed a good response to selective TACE after LEN rechallenge. Our findings suggest the need to reconsider the use of molecular-targeted drugs and TACE with advances in immunotherapy.

New-onset atypical fulminant type 1 diabetes after COVID-19 vaccination: A case report.

Adverse reactions, including the onset of diabetes, after coronavirus disease 2019 (COVID-19) vaccination have been reported. Herein, we report a case of a man who developed anti-glutamic acid decarboxylase (GAD) antibody-positive fulminant type 1 diabetes 15 weeks after COVID-19 vaccination, atypical of the previously reported anti-GAD antibody-negative cases.

A Case Series of Ketoacidosis After Coronavirus Disease 2019 Vaccination in Patients With Type 1 Diabetes.

Introduction: We report a case series of severe ketoacidosis after COVID-19 vaccination in a type 1 diabetes patients treated with insulin and an SGLT-2 inhibitor. Case Report: We present two cases of type 1 diabetes mellitus. One patient was treated with insulin therapy and an SGLT-2 inhibitor, and the other patient was treated with insulin therapy alone. Both patients became ill after coronavirus disease-2019 vaccination, making it difficult to continue their diet or insulin injections. On admission, they developed severe diabetic ketoacidosis. This is the first report of ketoacidosis after coronavirus disease-2019 vaccination. Conclusion: The vaccine should be carefully administered to type 1 diabetes patients receiving intensive insulin therapy and a sodium-glucose transporter due to the high risk ketoacidosis. It is important to instruct patients to drink sufficient fluids and to continue insulin injections when they become sick.

Advanced hepatocellular carcinoma with response to lenvatinib after atezolizumab plus bevacizumab.

RATIONALE: Various treatments are available for treating hepatocellular carcinoma (HCC). The immune checkpoint inhibitor combination of atezolizumab plus bevacizumab was recently approved for the treatment of unresectable HCC, but there are few reports on the failure of the combination treatment. Here, we present a case of unresectable HCC with adrenal metastasis that was eventually operated on after lenvatinib (LEN) treatment that followed failed treatment with atezolizumab plus bevacizumab. PATIENT CONCERNS: A 68-year-old man was diagnosed with non-alcoholic steatohepatitis-based HCC with adrenal metastasis. DIAGNOSIS: Cirrhosis was classified as Child-Pugh score of 5. HCC was diagnosed as Barcelona Clinic Liver Cancer stage C. INTERVENTIONS: We initiated treatment with atezolizumab plus bevacizumab. Liver dysfunction appeared 2 days after the first administration but was improved by intravenous rehydration and did not appear after the second course. The HCC shrank, but the adrenal metastasis grew bigger after the fourth course, so we changed the therapy to LEN. After HCC and adrenal metastasis were necrotic by LEN, conversion surgery was performed. OUTCOMES: After successful conversion therapy, the general condition of the patient was good, and has been carefully followed for 4 months to date without any evidence of further recurrences. LESSONS: This case showed that even if atezolizumab plus bevacizumab is not effective, multidisciplinary treatment such as LEN and conversion surgery is possible. Given the efficacy of LEN after atezolizumab plus bevacizumab, it is important to consider that there is a possibility of cure even when first-line treatment is not effective for a patient with unresectable HCC.

Structure of the {U13} polyoxo cluster U13O8Cl x (MeO)38-x (x = 2.3, MeO = methoxide).

The structure of a new type of polyoxo cluster complex that contains thirteen uranium atoms, {U13}, is reported. The complex crystallized from methanol containing tetra-valent uranium (UIV) with a basic organic ligand, and was characterized as di-chloridoocta-cosa-µ2-methano-lato-octa-kis-(methano-lato)octa-µ4-oxido-trideca-uranium, [U13(CH3O)35.7Cl2.3O8] or [U13(µ4-Ooxo)8Cl x (MeO)38-x ] (x = 2.3, MeO = methoxide) (I), by single-crystal X-ray diffraction. The characterized {U13} polyoxo cluster complex (I) possesses a single cubic uranium polyhedron at the centre of the cluster core. To the best of our knowledge, this is the very first example of a polyoxo actinide complex that bears a single cubic polyhedron in its structure. The cubic polyhedron in I is well comparable in shape with those in bulk UO2. The U-O bonds in the cubic polyhedron of I are, however, significantly shorter than those not only in bulk UO2 but also in another analogue in the {U38} cluster. This shortening of U-O bonds, together with BVS calculations and the overall negative charge (2-) of I, suggests that the central uranium atom in I, which forms the single cubic coordination polyhedron, is presumably oxidized to the penta-valent state (UV) from the original tetra-valent state (UIV). Complex I is, hence, the first example of a polyoxo cluster possessing a single cubic coordination polyhedron of UV.

Systematic comparison of the structure of homoleptic tetradentate N2O2-type Schiff base complexes of tetravalent f-elements (M(IV) = Ce, Th, U, Np, and Pu) in solid state and in solution.

A series of tetradentate N2O2-type Schiff base complexes with tetravalent 4f- and 5f-block metals, [M(salpn)2] (H2salpn = N,N'-disalicylidene-1,3-diaminopropane; M = Ce, Th, U, Np, and Pu), were prepared to systematically investigate their solid state structure, and their complexation behaviour in solution with the goal to investigate the subtle differences between 4f- and 5f-elements. X-ray diffraction revealed that all investigated metal cations form [M(salpn)2] complexes. All the complexes show the same ligand arrangement with meridional conformation, amongst which only Ce(iv) exhibits unique behaviour upon crystallisation. [Ce(salpn)2] crystallises in two less symmetric systems (P1[combining macron] or P21/n), whilst all the other [M(salpn)2] crystallise in a more symmetric orthorhombic system (Pban). Quantum chemical calculations suggest that the observed structural peculiarity of Ce(iv) stems from the geometrical flexibility due to the more "ionic" nature of bonds to the 4f element. 1H NMR measurements revealed that [M(salpn)2] forms two different species in solution with and without an additional solvent molecule, where the relative distribution of the two species depends mainly on the ionic radius of the metal centre. Again, Ce(iv) behaves differently from the tetravalent actinides with a higher ratio of the solvent-molecule-coordinated species than the ratio expected from its ionic radius. Hence, this study is successful in observing subtle differences between 4f- (i.e. Ce) and 5f-elements (actinides; Th, U, Np, and Pu) both in the solid state and in solution on an analytically distinguishable level, and in relating the observed subtle differences to their electronic structure.

Solvent Extraction of Technetium(VII) and Rhenium(VII) Using a Hexaoctylnitrilotriacetamide Extractant.

Liquid-liquid extraction for the removal of pertechnetate (99TcO4-) and perrhenate (ReO4-) is reported based on using the tripodal extractant N,N,N',N',N″,N″-hexa-n-octylnitrilotriacetamide (HONTA) composed of three amide groups and a tertiary amine. The extraction behaviors were compared with those using alkyldiamideamines (ADAAM(Oct) and ADAAM(EH)), and the commercial amine-type extractant, trioctylamine (TOA). HONTA quantitatively extracted 99TcO4- and ReO4- in the pH range from 1.0 to 2.5 by the co-extraction of protons. The extraction performance of the extractants was improved in the order of HONTA > ADAAM(Oct) > ADAAM(EH) > TOA. 99TcO4- and ReO4- in the extracting phase were successfully stripped using neutral aqueous solutions as the receiving phase, and the extraction ability of HONTA was maintained after five repeated uses.

A Fragment of S38AA is a Novel Plasma Biomarker of Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease without a cure. The pathological process starts decades before clinical onset, and thus clinical trials of drugs aimed at treating AD should start at a presymptomatic stage. Therefore, it is critical to diagnose AD at an early stage. Tau, phosphorylated tau, and amyloid-ß peptide (Aß) in cerebrospinal fluid (CSF), and positron emission tomography (PET) imaging of Aß or tau accumulation are supportive biomarkers for AD diagnosis, but there is no reliable presymptomatic diagnostic marker. Since CSF sampling is invasive, and PET imaging is expensive and available only at specialized centers, a reliable blood biomarker has long been sought for. Here we describe a novel extramembrane fragment from solute carrier family 38 member 10 (SLC38A10, S38AA) that we found to be decreased in pyramidal neurons in AD cases by proteomics and immunohistochemical analysis. We detected a S38AA fragment in CSF and found the levels to correlate with severity of AD and APOE genotype. Importantly, the plasma levels of the fragment also showed a significant correlation with Mini-Mental State Examination scores in AD. Moreover, plasma from other neurodegenerative disease was analyzed and the fragment was found to be increased specifically in AD. Interestingly, the fragment is detected in mouse, rat, and monkey, and increases in amyloid precursor protein transgenic mice as the AD-like pathology progresses. We propose that the S38AA fragment in plasma could be a novel quantitative diagnostic marker for AD and potentially a marker of disease progression in AD.

The Year-Long Development of Microorganisms in Uncompacted Bavarian Bentonite Slurries at 30 and 60 °C.

In the multibarrier concept for the deep geological disposal of high-level radioactive waste (HLW), bentonite is proposed as a potential barrier and buffer material for sealing the space between the steel canister containing the HLW and the surrounding host rock. In order to broaden the spectra of appropriate bentonites, we investigated the metabolic activity and diversity of naturally occurring microorganisms as well as their time-dependent evolution within the industrial B25 Bavarian bentonite under repository-relevant conditions. We conducted anaerobic microcosm experiments containing the B25 bentonite and a synthetic Opalinus Clay pore water solution, which were incubated for one year at 30 and 60 °C. Metabolic activity was only stimulated by the addition of lactate, acetate, or H2. The majority of lactate- and H2-containing microcosms at 30 °C were dominated by strictly anaerobic, sulfate-reducing, and spore-forming microorganisms. The subsequent generation of hydrogen sulfide led to the formation of iron-sulfur precipitations. Independent from the availability of substrates, thermophilic bacteria dominated microcosms that were incubated at 60 °C. However, in the respective microcosms, no significant metabolic activity occurred, and there was no change in the analyzed biogeochemical parameters. Our findings show that indigenous microorganisms of B25 bentonite evolve in a temperature- and substrate-dependent manner.

Mixed-valent neptunium oligomer complexes based on cation-cation interactions.

Mixed-valent tri- and tetranuclear complexes of neptunium, [{NpIVCl4}{NpVO2Cl(THF)3}2]·THF and [{NpIVCl3}{NpVO2(µ2-Cl)(THF)2}3{µ3-Cl}] (THF = tetrahydrofuran), were synthesised and characterised. Both the complexes are formed via the cation-cation interactions between the Np(iv) centre and the axial oxygens of the neptunyl(v) unit (i.e. trans-dioxo NpO2+ cation), demonstrating the potential of cation-cation interactions for further exploring the oligomer/cluster chemistry of actinides.

Time-controlled synthesis of the 3D coordination polymer U(1,2,3-Hbtc)2 followed by the formation of molecular poly-oxo cluster {U14} containing hemimellitate uranium(iv).

Two coordination compounds bearing tetravalent uranium were synthesized in the presence of tritopic hemimellitic acid in acetonitrile with a controlled amount of water (H2O/U ≈ 8) and structurally characterized. Compound 1, [U(1,2,3-Hbtc)2]·0.5CH3CN is constructed around an eight-fold coordinated uranium cationic unit [UO8] linked by the poly-carboxylate ligands to form dimeric subunits, which are further connected to form infinite corrugated ribbons and a three-dimensional framework. Compound 2, [U14O8(OH)4Cl8(H2O)16(1,2,3-Hbtc)8(ox)4(ac)4] ({U14}) exhibits an unprecedented polynuclear {U14} poly-oxo uranium cluster surrounded by O-donor and chloride ligands. It is based on a central core of [U6O8] type surrounded by four dinuclear uranium-subunits {U2}. Compound 1 was synthesized by a direct reaction of hemimellitic acid with uranium tetrachloride in acetonitrile (+H2O), while the molecular species ({U14} (2)) crystallized from the supernatant solution after one month. The slow hydrolysis reaction together with the partial decomposition of the starting organic reactants into oxalate and acetate molecules induces the generation of such a large poly-oxo cluster with fourteen uranium centers. Structural comparisons with other closely related uranium-containing clusters, such as the {U12} cluster based on the association of inner core [U6O8] with three dinuclear sub-units {U2}, were performed.

Synthesis and Characterization of Heterometallic Iron-Uranium Complexes with a Bidentate N-Donor Ligand (2,2'-Bipyridine or 1,10-Phenanthroline).

The coordination chemistry of the diimine ligands, 2,2'-bipyridine (bipy) and 1,10-phenanthroline (phen), with d- and f-block metals has been extensively explored during the last century to yield many technological and industrial applications. Despite this long history, the chemistry of these diimine ligands in heterometallic systems containing multiple metals is poorly understood even to date. This study reports, for the first time, a systematic investigation into the coordination behavior bipy/phen in the heterometallic iron-uranium system covering all the combinations of the possible redox couples (i.e., Fe2+/Fe3+ and U4+/U6+) that are potentially relevant to the actual engineered or environmental systems. In total, 11 new compounds of pure uranium and heterometallic Fe-U complexes were successfully synthesized and structurally characterized. The synthesized compounds show an intriguing structural variety in terms of the nuclearity of the metal center (mono- and dinuclear arrangements for both Fe and U) and the manner of crystal packing based on different intra- and intermolecular interactions (e.g., π···π interactions, hydrogen bonding, etc.). The results also highlight the similarity of the fundamental coordination properties of bipy and phen toward Fe and U, regardless of the oxidation states of the metals, as well as the striking dissimilarity in their chemical behavior upon crystal packing.

Interaction of Uranium(VI) with α-Amylase and Its Implication for Enzyme Activity.

Because of its chemo- and radiotoxicity, the incorporation of uranium into human body via ingestion potentially poses a serious health risk. When ingested, the gastrointestinal fluids are the primary media to interact with uranium, eventually influencing and even determining its biochemical behavior in the gastrointestinal tract and thereafter. The chemical interactions between uranium and the components of gastrointestinal fluids are, however, poorly understood to date. In this study, the complexation of uranium(VI) (as the uranyl ion, UO22+) with the protein α-amylase, one of the major enzymes in saliva and pancreatic juices, was investigated over a wide range of pH or uranium/α-amylase concentrations covering physiological conditions. Macroscopic sorption experiments suggested a strong and fast complexation of UO22+ to α-amylase between pH 5 and 7. Potentiometric titration was employed to determine the complex stability constants for the relevant UO22+ α-amylase complexes, which is crucial for reliable thermochemical modeling to assess the potential health risk of uranium. Extended X-ray absorption fine structure (EXAFS) spectroscopy revealed that α-amylase is interacting with UO22+ primarily via its carboxylate groups presumably from the aspartic acid and glutamic acid side chains. The effect of UO22+ on the enzyme activity was also investigated to understand the potential implication of uranium for the in vivo functions of the digestive fluids, indicating that the presence of uranium inhibits the enzyme activity. This inhibitory effect can be, however, suppressed by an excess of calcium.

Impact of Haloarchaea on Speciation of Uranium-A Multispectroscopic Approach.

Haloarchaea represent a predominant part of the microbial community in rock salt, which can serve as host rock for the disposal of high level radioactive waste. However, knowledge is missing about how Haloarchaea interact with radionuclides. Here, we used a combination of spectroscopic and microscopic methods to study the interactions of an extremely halophilic archaeon with uranium, one of the major radionuclides in high level radioactive waste, on a molecular level. The obtained results show that Halobacterium noricense DSM 15987T influences uranium speciation as a function of uranium concentration and incubation time. X-ray absorption spectroscopy reveals the formation of U(VI) phosphate minerals, such as meta-autunite, as the major species at a lower uranium concentration of 30 µM, while U(VI) is mostly associated with carboxylate groups of the cell wall and extracellular polymeric substances at a higher uranium concentration of 85 µM. For the first time, we identified uranium biomineralization in the presence of Halobacterium noricense DSM 15987T cells. These findings highlight the potential importance of Archaea in geochemical cycling of uranium and their role in biomineralization in hypersaline environments, offering new insights into the microbe-actinide interactions in highly saline conditions relevant to the disposal of high-level radioactive waste as well as bioremediation.

{Np38} clusters: the missing link in the largest poly-oxo cluster series of tetravalent actinides.

Two poly-oxo cluster complexes of tetravalent neptunium (Np(iv)), Np38O56Cl18(bz)24(THF)8·nTHF and Np38O56Cl42(ipa)20·mipa (bz = benzoate, THF = tetrahydrofuran, and ipa = isopropanol), were obtained via solvothermal synthesis and structurally characterised by single-crystal X-ray diffraction. The {Np38} clusters are comparable to the analogous {U38} and {Pu38} motifs, filling the gap in this largest poly-oxo cluster series of tetravalent actinides.

Formation of a new type of uranium(iv) poly-oxo cluster {U38} based on a controlled release of water via esterification reaction.

A new strategy for the synthesis of large poly-oxo clusters bearing 38 tetravalent uranium atoms {U38} has been developed by controlling the water release from the esterification reaction between a carboxylic acid and an alcohol. The molecular entity [U38O56Cl40(H2O)2(ipa)20]·(ipa) x (ipa = isopropanol) was crystallized from the solvothermal reaction of a mixture of UCl4 and benzoic acid in isopropanol at temperature ranging from 70 to 130 °C. Its crystal structure reveals the molecular assembly of the UO2 fluorite-like inner core {U14} with oxo groups bridging the uranium centers. The {U14} core is further surrounded by six tetrameric sub-units of {U4} to form the {U38} cluster. Its surface is decorated by either bridging- and terminal chloride anions or terminal isopropanol molecules. Another synthesis using the same reactant mixture at room temperature resulted in the crystallization of a discrete dinuclear complex [U2Cl4(bz)4(ipa)4]·(ipa)0.5 (bz = benzoate), in which each uranium center is coordinated by two chlorine atoms, four oxygen atoms from carboxylate groups and two additional oxygen atoms from isopropanol. The slow production of water released from the esterification of isopropanol allows the formation of the giant cluster with oxo bridges linking the uranium atoms at a temperature above 70 °C, whereas no such oxo groups are present in the dinuclear complex formed at room temperature. The kinetics of {U38} crystallization as well as the ester formation are analyzed and discussed. SAXS experiments indicate that the {U38} species are not dominant in the supernatant, but hexanuclear entities which are closely related to the [U6O8] type are formed.

[UO2 Cl2 (phen)2 ], a Simple Uranium(VI) Compound with a Significantly Bent Uranyl Unit (phen=1,10-phenanthroline).

A simple synthesis based on UO2 Cl2 ⋅n H2 O and 1,10-phenanthroline (phen) resulted in the formation of a new uranyl(VI) complex [UO2 Cl2 (phen)2 ] (1), revealing a unique dodecadeltahedron coordination geometry around the uranium center with significant bending of the robust linear arrangement of the uranyl (O-U-O) unit. Quantum chemical calculations on complex 1 indicated that the weak but distinct interactions between the uranyl oxygens and the adjacent hydrogens of phen molecules play an important role in forming the dodecadeltahedron geometry that fits to the crystal structure of 1, resulting in the bending the uranyl unit. The uranyl oxygens in 1 are anticipated to be activated as compared with those in other linear uranyl(VI) compounds.

Speciation of the trivalent f-elements Eu(III) and Cm(III) in digestive media.

In case radioactive materials are released into the environment, their incorporation into our digestive system would be a significant concern. Trivalent f-elements, i.e., trivalent actinides and lanthanides, could potentially represent a serious health risk due to their chemo- and radiotoxicity, nevertheless the biochemical behavior of these elements are mostly unknown even to date. This study, therefore, focuses on the chemical speciation of trivalent f-elements in the human gastrointestinal tract. To simulate the digestive system artificial digestive juices (saliva, gastric juice, pancreatic juice and bile fluid) were prepared. The chemical speciation of lanthanides (as Eu(III)) and actinides (as Cm(III)) was determined experimentally by time-resolved laser-induced fluorescence spectroscopy (TRLFS) and the results were compared with thermodynamic modeling. The results indicate a dominant inorganic species with phosphate/carbonate in the mouth, while the aquo ion is predominantly formed with a minor contribution of the enzyme pepsin in the stomach. In the intestinal tract the most significant species are with the protein mucin. We demonstrated the first experimental results on the chemical speciation of trivalent f-elements in the digestive media by TRLFS. The results highlight a significant gap in chemical speciation between experiments and thermodynamic modeling due to the limited availability of thermodynamic stability constants particularly for organic species. Chemical speciation strongly influences the in vivo behavior of metal ions. Therefore, the results of this speciation study will help to enhance the assessment of health risks and to improve decorporation strategies after ingestion of these (radio-)toxic heavy metal ions.

Synthesis of Coordination Polymers of Tetravalent Actinides (Uranium and Neptunium) with a Phthalate or Mellitate Ligand in an Aqueous Medium.

Four metal-organic coordination polymers bearing uranium or neptunium have been hydrothermally synthesized from a tetravalent actinide chloride (AnCl4) and phthalic (1,2-H2bdc) or mellitic (H6mel) acid in aqueous media at 130 °C. With the phthalate ligand, two analogous assemblies ([AnO(H2O)(1,2-bdc)]2·H2O; An = U4+ (1) or Np4+ (2)) have been isolated, in which the square-antiprismatic polyhedra of AnO8 are linked to each other via µ3-oxo groups with an edge-sharing mode to materialize infinite zigzag ribbons. The phthalate molecules play a role in connecting the adjacent zigzag chains to build a two-dimensional (2D) network. Water molecules are bonded to the actinide center or found intercalated between the layers. With the mellitate ligand, two distinct structures have been identified. The uranium-based compound [U2(OH)2(H2O)2(mel)] (3) exhibits a three-dimensional (3D) structure composed of the dinuclear units of UO8 polyhedra (square antiprism), which are further linked via the µ2-hydroxo groups. The mellitate linkers use their carboxylate groups to connect the dinuclear units, eventually building a 3D framework. The compound obtained for the neptunium mellitate ([(NpO2)10(H2O)14(Hmel)2]·12H2O (4)) reveals oxidation of the initial NpIV to NpV under the applied hydrothermal synthetic conditions, yielding the neptunyl(V) (NpO2+) unit with a pentagonal-bipyramidal NpO7 environment. This further leads to the formation of a layered assembly of the square-frame NpO7 sheets via the bridging oxygen atoms from the neptunyl oxo groups, which further coordinate to the pentagonal equatorial coordination plane of the adjacent neptunium unit (i.e., cation-cation interactions). In compound 4, the mellitate molecules act as bridging linkers between the NpO7 sheets by using four of their carboxylage groups, eventually building up a 3D structure.