Impact of metabolic dysfunction-associated steatotic liver disease on the efficacy of immunotherapy in patients with chronic hepatitis B-related hepatocellular carcinoma.

OBJECTIVE: To investigate the impact of metabolic dysfunction-associated steatotic liver disease (MASLD) on the efficacy of immune checkpoint inhibitor (ICI)-based therapy in patients with chronic hepatitis B (CHB)-related hepatocellular carcinoma (HCC). METHODS: A total of 155 patients with CHB-related HCC who received ICI-based therapy (in the Department of Hepatology, Tianjin Second People's Hospital and Department of Hepatobiliary Oncology, Tianjin Medical University Cancer Institute & Hospital) between April 2021 and December 2023 were evaluated. Patients were divided into two groups: MASLD concurrent with CHB [MASLD-CHB] (n = 38), and CHB (n = 117). RESULTS: The median progression-free survival (PFS, 6.9 months vs. 9.3 months; P = 0.001), progressive disease (57.89% vs. 37.61%; P = 0.028), and disease control rate (42.11% vs. 62.39%; P = 0. 028) in the MASLD-CHB group were significantly worse than the CHB group. The median overall survival was not attained. The percentage of CD4+PD1+ (17. 56% vs. 8.89%; P < 0.001) and CD8+PD1+ T cells (10.50% vs. 7.42%; P = 0.005) in patient samples from the MASLD-CHB group were significantly higher than the CHB group. Concurrent MASLD [hazard ratio (HR) = 1.921; 95% CI, 1.138-3.245; P = 0.015] and alpha-fetoprotein levels after 3 months of treatment (HR = 2.412; 95% CI, 1.360-4.279; P = 0.003) were independent risk factors for PFS in all patients. CONCLUSIONS: ICI-based therapy in patients with CHB-related HCC and concurrent MASLD resulted in poorer efficacy and shorter PFS compared to patients with CHB-related HCC alone.

Noninvasive tests maintain high accuracy for advanced fibrosis in chronic hepatitis B patients with different nomenclatures of steatotic liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a new nomenclature proposed in 2023. We aimed to compare the diagnostic efficacy of noninvasive tests (NITs) for advanced fibrosis under different nomenclatures in patients with chronic hepatitis B (CHB). A total of 844 patients diagnosed with CHB and concurrent steatotic liver disease (SLD) by liver biopsy were retrospectively enrolled and divided into four groups. The performances of fibrosis-4 (FIB-4), gamma-glutamyl transpeptidase to platelet ratio index (GPRI), aspartate aminotransferase to platelet ratio index (APRI), and liver stiffness measurement (LSM) were compared among the four groups. The four NITs showed similar diagnostic efficacy for nonalcoholic fatty liver disease (NAFLD), MASLD, and metabolic dysfunction-associated fatty liver disease (MAFLD) in patients with CHB with advanced fibrosis. LSM showed the most stable accuracy for NAFLD (AUC = 0.842), MASLD (AUC = 0.846), and MAFLD (AUC = 0.863) compared with other NITs (p < 0.05). Among the four NITs, APRI (AUC = 0.841) and GPRI (AUC = 0.844) performed best in patients with CHB & MetALD (p < 0.05). The cutoff value for GPRI in patients with CHB & MetALD was higher than that in the other three groups, while further comparisons of NITs at different fibrosis stages showed that the median GPRI of CHB & MetALD (1.113) at F3-4 was higher than that in the CHB & MASLD group (0.508) (p < 0.05). Current NITs perform adequately in patients with CHB and SLD; however, alterations in cutoff values for CHB & MetALD need to be noted.

Derivatization reagent-assisted enantioseparation of 3-hydroxyaspartate with two chiral centers in rat cerebrospinal fluid by capillary electrophoresis-mass spectrometry.

A new analytical method based on capillary zone electrophoresis-mass spectrometry (CZE-MS) was proposed and validated for the simultaneous determination of four stereoisomers of 3-hydroxyaspartate with two chiral centers in rat cerebrospinal fluid (CSF) in absence of optically pure single enantiomer standards. The derivatization reagent 9-fluorenylmethyl chloroformate (FMOC-Cl) was found to assist chiral separation and the derivatized enantiomers of 3-hydroxyaspartate can achieve enantioseparation with a lower concentration (6 mM) of ß-cyclodextrin (ß-CD), while underivatized 3-hydroxyaspartate cannot be separated. The enhanced interactions between derivatized analytes and ß-CD were demonstrated by proton nuclear magnetic resonance (1H NMR). The four stereoisomers of FMOC-3-hydroxyaspartate were identified successfully using a new method based on experimental and calculated electronic circular dichroism (ECD) spectra combined with the comparison of CE peak areas. Large volume sample stacking with polarity switching (LVSS-PS) was used to increase sensitivity and the detection limit of 356 nM was achieved for L-THA, which was around 10-fold improvement compared to the normal CE-MS analysis. The composition of the background electrolyte (BGE) was optimized by response surface methodology (RSM). Under the optimal conditions, satisfactory results of L-THA were obtained in terms of linearity over the range of 2-80 µM (R2 > 0.99) and precision (RSD below 1.43% and 2.56% for migration time and peak area, respectively). The recoveries for all four stereoisomers in spiked rat CSF ranged from 91.2% to 99.5%. The method has been successfully applied to rat CSF analysis and D-erythro-3-hydroxyaspartate (D-EHA) was detected.

High-symmetry tubular Ta@B183-, Ta2@B18, and Ta2@B27+ as embryos of α-boronanotubes with a transition-metal wire coordinated inside.

Transition-metal doping leads to dramatic structural changes and results in novel bonding patterns in small boron clusters. Based on the experimentally derived mono-ring planar C9v Ta©B92- (1) and extensive first-principles theory calculations, we present herein the possibility of high-symmetry double-ring tubular D9d Ta@B183- (2) and C9v Ta2@B18 (3) and triple-ring tubular D9h Ta2@B27+ (4), which may serve as embryos of single-walled metalloboronanotube α-Ta3@B48(3,0) (5) wrapped up from the recently observed most stable free-standing boron α-sheet on a Ag(111) substrate with a transition-metal wire (-Ta-Ta-) coordinated inside. Detailed bonding analyses indicate that, with an effective dz2-dz2 overlap on the Ta-Ta dimer along the C9 molecular axis, both Ta2@B18 (3) and Ta2@B27+ (4) follow the universal bonding pattern of σ + π double delocalization with each Ta center conforming to the 18-electron rule, providing tubular aromaticity to these Ta-doped boron complexes with magnetically induced ring currents. The IR, Raman, and UV-vis spectra of 3 and 4 are computationally simulated to facilitate their future experimental characterization.

A Key Factor Dominating the Competition between Photolysis and Photoracemization of [Ru(bipy)3]2+ and [Ru(phen)3]2+ Complexes.

Photolysis and photoracemization are two important photochemical phenomena of the prototype complexes [Ru(bipy)3]2+ and [Ru(phen)3]2+ (bipy = 2,2'-bipyridine, phen = 1,10-phenanthroline), but little is known about their relations. To solve this issue, the photoinduced chiral inversion Δâ‡ŒΛ of the complexes was analyzed theoretically. The results indicated that the photoracemization reaction proceeds on the lowest triplet potential energy surface in three steps 3CTΔ↔3MCΔ, 3MCΔ↔3MCΛ, and 3MCΛ↔3CTΛ (CT = charge transfer state; MC = metal-centered state). Where the first and third steps are fast processes of picoseconds, the second is the rate-determining step (RDS) of microseconds. Such a slow step for the racemization leads to the excited molecule lingering around the bottom of 3MC state after the first step and, therefore, greatly enhances the possibility of deexcitation and photolysis mostly at the triplet-singlet crossing point. In other words, the photoracemization and photolysis of the complexes have a competition relation, not a slave relation as assumed by the photoracemization model suggested in literature. They are dominated by the RDS. This conclusion is also consistent with the Δ(δ S)⇌Λ(δ S) chiral inversion of the [Ru(bipy)2(L-ser)]+ series complexes, which is reversible with no detectable photolysis, as its second step is a fast one. Note that, although the photoracemization of the prototype complexes is very slow, it passes through the three steps reversibly and ends with a photon emitting, which could be detected with the time-resolved circularly polarized luminescence and related techniques. These findings are helpful to understand and control the photochemical behavior of the complexes in practice.

Triplet Ground-State-Bridged Photochemical Process: Understanding the Photoinduced Chiral Inversion at the Metal Center of [Ru(phen)2(l-ser)]+ and Its Bipy Analogues.

One of the main concerns in the photochemistry and photophysics of ruthenium complexes is the de-excitation of the triplet metal centered ligand-field state 3MC. To understand the mechanism by which the 3MC states in some reversible photochemical reactions could avoid the fate of fast decay and ligand dissociations, the photoinduced chiral inversion at the metal center of the complexes [Ru(diimine)2(l-ser)]+ (diimine = 1,10-phenanthroline or 2,2'-bipyridine, l-ser = l-serine) has been analyzed at the first principle level of theory. The calculated equilibrium constants and ECD curves for the photoinduced equilibrium mixtures are in agreement with the observed ones. The results showed that the reversible photochemical process Δ(δS) ⇌ Λ(δS) on the potential surface of the lowest triplet excited state proceeds in three steps: 3CTΔ â†” 3MCΔ, 3MCΔ â†” 3MCΛ, 3MCΛ â†” 3CTΛ, where the first and the third steps involve mainly the elongation and compression of the octahedral core of the reactant Δ(δS) and product Λ(δS), respectively. The chiral inversion Δ â†” Λ takes place in the second step through a much distorted square-pyramid-like transition state, and actually proceeds on the triplet ground state 3MC due to the crossover of the triplet T1 and singlet S0 states. Inspecting the transient structures at the crossing points, we found that they become less distorted and their lowest or imaginary-frequency displacement vectors in triplet state still dominate the reaction path, which makes the reaction reversible without ligand release. Thus, the triplet ground-state-bridged photoinduced mechanism offers a new angle of view to understand the related reversible photochemical reactions.

Structural transition in metal-centered boron clusters: from tubular molecular rotors Ta@B21 and Ta@B22+ to cage-like endohedral metalloborospherene Ta@B22.

Inspired by the recent discovery of the metal-centered tubular molecular rotor Cs B2-Ta@B18- with the record coordination number of CN = 20 and based on extensive first-principles theory calculations, we present herein the possibility of the largest tubular molecular rotors Cs B3-Ta@B18 (1) and C3v B4-Ta@B18+ (2) and smallest axially chiral endohedral metalloborospherenes D2 Ta@B22- (3 and 3'), unveiling a tubular-to-cage-like structural transition in metal-centered boron clusters at Ta@B22-via effective spherical coordination interactions. The highly stable Ta@B22- (3) as an elegant superatom, which features two equivalent corner-sharing B10 boron double chains interconnected by two B2 units with four equivalent B7 heptagons evenly distributed on the cage surface, conforms to the 18-electron configuration with a bonding pattern of σ + π double delocalization and follows the 2(n + 1)2 electron counting rule for spherical aromaticity (n = 2). Its calculated adiabatic detachment energy of ADE = 3.88 eV represents the electron affinity of the cage-like neutral D2 Ta@B22 which can be viewed as a superhalogen. The infrared, Raman, VCD, and UV-vis spectra of the concerned species are computationally simulated to facilitate their spectral characterizations.

Theoretical Analysis on the Importance of Achiral Unidentate Ligands to Electronic Circular Dichroism of cis-Bis(ethylenediamine) Cobalt(III) Complexes.

Compared with the importance of didentate ligands to chiral chelates, little is known about the influence of unidentate ligands on the chiroptical properties of related chelates. To assess the importance of achiral unidentate ligands to electronic circular dichroism (ECD) spectra, calculations of the excitation energies and oscillator and rotational strengths for all the Λ-enantiomers of bis(ethylenediamine) cobalt(III) complexes cis-[Co(en)2(X)2](n+) (X = Cl(-), CN(-), NH3, N3(-), NO2(-), H2O; n = 1, 3) were performed at the TDDFT/B3LYP/6-311++G(2d,p)//DFT/B3LYP/6-311++G(2d,p) level of theory, including solvent effects. The individual contributions of the chiral arrays, Δ/Λ octahedral core, δ/λ twists of the en ligands, and δ/λ relative orientations of the unidentate ligands to the rotational strengths of related transitions were quantitatively determined and graphically presented. It was found that, for the chelates with nonaxially symmetric unidentate ligands (N3(-), NO2(-), H2O), the chiral orientation (δ/λ) of the unidentate ligands not only dominates the ECD spectra of the Λ-diastereoisomers but also dominates the relative energies in solution with the δ-orientation preferred. For those complexes with axially symmetric unidentate ligands (Cl(-), CN(-), NH3), the inherent dissymmetry within the metal ion-donor atom cluster was found to be unidentate ligand-dependent. The Boltzmann-weighted averaged ECD spectra of the complexes with Λ-octahedral core are in excellent agreement with the observed ones, except that for the diazido complex, they are opposite in sign. This demonstrates that the absolute configuration of the complex cis-(-)-[Co(en)2(N3)2](+) is Δ, not the Λ-form assigned by McCaffery et al. in 1965. These findings not only reveal the importance of unidentate ligands to the ECD spectra of related chelates but also provide an insight for the influence of unidentate ligands on both the inherent dissymmetry and the distributional chirality.

Theoretical analysis of the influence of chelate-ring size and vicinal effects on electronic circular dichroism spectra of cobalt(III) EDDA-type complexes.

To assess the contributions of configurational and vicinal effects as well as chelate-ring size to rotational strengths, the geometries of a series of cobalt(III) complexes [Co(EDDA-type)(L)](±) with the tetradentate EDDA-type ligands, EDDA (ethylenediamine-N,N'-diacetate), DMEDDA (N,N'-dimethylethylenediamine-N,N'-diacetate), DEEDDA (N,N'-diethylethylenediamine-N,N'-diacetate), and a bidentate ancillary ligand L (L = ethylenediamine, oxalate, carbonate, (S)-alanine, and malonate) in aqueous solution have been optimized at the DFT/B3LYP/6-311++G(2d,p) level of theory. Based on the optimized geometries, the excitation energies and oscillator and rotational strengths have been calculated using the time-dependent density functional theory (TDDFT) method with the same functional and basis set. The calculated circular dichroism (CD) curves are in excellent agreement with the observed ones except for some small red or blue shifts in peak wavelengths. For the influence of chelate-ring size of the bidentate ligands on the CD intensities, a qualitative analysis together with the quantitative TDDFT calculation reveal that it depends on the symmetry of the cobalt-EDDA backbone. For the s-cis-isomers, the influence is negligible due to the perturbation is symmetric. For the uns-cis-isomers, the perturbation is unsymmetric. Since a small ring size means a large perturbation, this leads to the integral CD intensities decreasing with increasing the chelate ring size. The vicinal effects of asymmetric nitrogens incorporate both the substitutent effects and conformational relaxation effects, with the former being dominant. By analyzing the contributions of chiral arrays to rotational strengths, we found that the part of contributions dominated by the S-type chiral nitrogens could be considered as a good measure for the vicinal effects of chiral nitrogens. In addition, we found that the twist form (δ/λ) of the backbone ethylenediamine ring (E-ring) of the coordinated EDDA-type ligands is a key factor to understand the properties of these chelates, because it not only dominates the relative stabilities of the s-cis-Λ(SS)-diastereoisomers with the result that λ > δ but also affects the major CD band by changing the order of the first two transitions. Moreover, the twist angle of E-ring is inversely related to the vicinal effect of chiral nitrogens. These findings may help us to understand the chelate ring size as well as vicinal effect related chiroptical phenomenon of the cobalt EDDA-type chelates.

Synthesis of a novel cyclodextrin-derived chiral stationary phase with multiple urea linkages and enantioseparation toward chiral osmabenzene complex.

A novel chiral stationary phase was synthesized by immobilizing heptakis(6-azido-6-deoxy-2,3-di-O-p-chlorophenylcarbamoylated)-ß-cyclodextrin onto silica gel surface via Staudinger reaction, and applied in enantiomeric separation of a pair of osmabenzene complexes, {Os[CHC(PPh3)CHC(PPh3)CH](C9H6NO)2}Cl (1), which is the first report for enantioseparation of the chiral-only-at-metal osmabenzene complex till now. The effects of separation conditions including salt additives, organic modifiers, pH values, and column temperature on the retention and resolution of the complex have been investigated in detail. Meanwhile, possible chiral recognition mechanism was presented. Chiral complex 1 was well resolved via semi-preparative chiral HPLC technique under optimization conditions and two pure enantiomers were further characterized by analytical HPLC, NMR spectra and solution circular dichroism (CD) spectra, respectively. Furthermore, absolute configuration of the enantiomer was confirmed by theoretical investigation of CD spectra.

Pyridinium tetra-kis-(1,1,1-trifluoro-pentane-2,4-dionato)dysprosate.

In the anion of the title compound, (C(5)H(6)N)[Dy(C(5)H(4)F(3)O(2))(4)], the central metal ion, Dy(3+), is coordinated by four bidentate 1,1,1-trifluoro-pentane-2,4-dionate (TAA) ligands, forming an approximate square-anti-prismatic configuration. The pyridin-ium cation is connected to the complex ion by an N-H⋯O hydrogen bond and electrostatic inter-actions in the crystal. There are two kinds of disorder in the structure, one involving rotational disorder of a CF(3) group [occupancy ratio 0.560 (15):0.440 (15)] and the other involving an exchange between a CF(3) group and CH(3) group within a given bidentate ligand (occupancy ratio 0.64:0.36).

Chiral magnetic metal-organic frameworks of Mn(II) with achiral tetrazolate-based ligands by spontaneous resolution.

The enantiomers of complex 1 (1a and 1b) have been obtained by spontaneous resolution upon crystallization in the absence of a chiral source. The enantiomeric nature of 1a and 1b was confirmed by circular dichroism (CD) spectra and theoretical investigation.

Hoveyda-Grubbs catalyst confined in the nanocages of SBA-1: enhanced recyclability for olefin metathesis.

Via a simple adsorption, the second generation Hoveyda-Grubbs catalyst was successfully immobilized on a mesoporous material SBA-1, leading to a highly recyclable solid catalyst for olefin metathesis.

Theoretical analysis of the individual contributions of chiral arrays to the chiroptical properties of tris-diamine ruthenium chelates.

Calculations of the excitation energies, oscillator and rotational strengths, and the CD spectra of 16 diastereoisomers of the tris-diamine ruthenium chelates [Ru(en)(3)](2+), [Ru(pn)(3)](2+), and [Ru(bn)(3)](2+) have been performed at the TDDFT/B3LYP/LanL2DZ+6-31G* level including solvent effects. The individual contributions of the chiral arrays, Delta/Lambda octahedral core, delta/lambda twists of the ligand rings, and R/S chiral carbons to the rotational strengths of related transitions have been quantitatively determined and graphically presented. It was found that the three chiral arrays Delta, delta and S each make their contributions to the CD spectra of the chelates with the sign alternated between negative and positive from long wavelength to short, but the intensities of the extrema are different for different chiral arrays. By simply combining the contributions of related chiral arrays in the chelates, all CD spectra of the 16 isomers obtained at the TDDFT level can be well reproduced, and those of the other conformers can also be well predicted, as expected. These findings not only make it possible to determine the absolute configurations and conformations of related chelates in solution from their CD spectra but also provide a deep insight into the chiroptical properties of the chelates.

Hydrogen-bond network and local structure of liquid water: An atoms-in-molecules perspective.

The nearly linear relationship between hydrogen-bond strength at the CCSD(T)/Aug-cc-pVTZ level and the electron density at the bond critical point in the atoms-in-molecules theory provides a practical means of calculating the hydrogen-bond strength in liquid water. A statistical analysis of the hydrogen-bonds obtained from Car-Parrinello molecular dynamics simulations shows that the strengths of hydrogen bonds in liquid water conform to a Gaussian distribution. Considering supercooled (250 K) water to have a fully coordinated (icelike) local tetrahedral configuration, we show that the local structure of liquid water is partly distorted tetrahedral in normal liquid water and even in superheated water.

Theoretical analysis of the porphyrin-porphyrin exciton interaction in circular dichroism spectra of dimeric tetraarylporphyrins.

Chiral bis-porphyrins are currently the subject of intense interest as chiral receptors and as probes in the determination of structure and stereochemistry. To provide an improved framework for interpreting the circular dichroism (CD) spectra of bis-porphyrins, we have calculated the CD spectra of chiral bis-porphyrins from three classes: I, where porphyrins can adopt a relatively wide range of orientations relative to each other; II, porphyrins have a fixed relative orientation; III, porphyrins undergo pi-stacking. The calculations primarily utilized the classical polarizability theory of DeVoe, but were supplemented by the quantum mechanical matrix method. Class I was represented by three isomers of the diester of 5alpha-cholestane-3,17-diol with 5-(4'-carboxyphenyl)-10,15,20-triphenylporphin (2-alphabeta, 2-betaalpha, 2-betabeta). Careful analysis of the torsional degrees of freedom led to two to four minimum-energy conformers for each isomer, in each of which the phenyl-porphyrin bonds had torsional angles near 90 degrees. Libration about these bonds is relatively unrestricted over a range of +/-45 degrees. CD spectra in the Soret region were calculated as Boltzmann-weighted averages over the low-energy conformers for each isomer. Three models were used: the effective transition moment model, in which only one of the degenerate Soret components is considered, along the 5-15 direction; the circular oscillator model, in which both Soret components are given equal weight; and the hybrid model, in which the 10-20 oscillator is given half the weight of the 5-15 oscillator, to mimic the effect of extensive librational averaging about the 5-15 direction. All three models predict Soret exciton couplets with signs in agreement with experiment. Quantitatively, the best results are given by the hybrid and circular oscillator models. These results validate the widely used effective transition moment model for qualitative assignments of bis-porphyrin chirality and thus permit application of the exciton chirality model. However, for quantitative studies, the circular oscillator or hybrid models should be used. The simplified effective transition moment and hybrid models are justified by the librational averaging in the class I bis-porphyrins and should only be used with such systems. Two class II bis-porphyrins were also studied by DeVoe method calculations in the circular oscillator model, which yielded good agreement with experiment. Class III bis-porphyrins were represented by 2-alphaalpha, for which the calculations gave qualitative agreement. However, limitations in the conformational analysis with the close contacts and dynamic effects in these pi-stacked systems preclude quantitative results.

Determination of the absolute configuration of rubroflavin by comparison of measured and calculated CD spectra of its thermolysis product 3-methanesulfinyl-5-methylmercaptophenol.

The absolute configuration of rubroflavin has been determined indirectly by comparison of the measured and the calculated CD spectrum of its thermal decomposition product 3-methanesulfinyl-5-methylmercaptophenol. Performing geometry optimizations at the HF/6-31+G* level we found fifteen local minima for the (R)-isomer of 3-methanesulfinyl-5-methylmercaptophenol. The CD spectrum of the compound was then obtained as a superposition of the Boltzmann-weighted spectra for each structure calculated with the non-empirical CIS method. The corresponding Boltzmann factors have been calculated employing the relative energies of these minima determined at the ZPE + MP2/6-31+G*//HF/6-31+G* level of ab initio theory. Comparing the signs of the observed and calculated longest wave length Cotton effect we assign an absolute configuration to the thermolysis product. Since additional calculations revealed that the tricoordinate sulfur atom in rubroflavin and in its decomposition product is configurationally stable under the conditions of thermolysis we conclude that the absolute configuation at the corresponding sulfur atom of rubroflavin is the same.

Conformational analysis and TDDFT calculations of the chiroptical properties of tris [1,2-propanediolato(2-)-kappaO,kappaO'] selenium/tellurium and related compounds.

The tris(didentate) chelates [E(OCR1R2CR3R4O)3], with E = Se and Te, display both configurational (delta or lambda; R or S) and conformational (delta or lambda) chirality. In order to assess the contributions of these three chiral arrays to the Cotton effects of the chelates and to elucidate their stereochemistry in the gas phase and in solution, calculations of the UV and CD spectra (down to 180 nm), and also of the relative stability of the chelates, have been performed at the TDDFT/TZVP/B-P86 level. An extensive conformational analysis has supplied additional information on the relevant conformers in the conformational manifold. It was found that the dominant CD effect reflects mostly the delta/lambda twists of the three five-membered ligand rings, and less so the influence of the A/A core configuration, while the contributions of any R/S chiral carbon atoms of the ligand rings are negligible. The sign, the intensity, and the energy of this dominant CD band are found to depend on the stereochemistry of the chelates in a predictable way. Among the conformers, those with equatorially disposed methyl substituents are much preferred. These results make it possible to determine the absolute configuration (A/A) and conformation (delta/lambda) of the chelates from the CD data.