The Incidences and Related CT Features of Vascular Lake Phenomenon on Angiography Before Chemoembolization.

PURPOSE: To elucidate incidence rates of vascular lake phenomenon (VLP) in hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), hepatic metastasis (HMT) on transarterial angiography before chemoembolization, and to identity CT features predictive for it. MATERIALS AND METHODS: A comprehensive evaluation involved 665 subjects for incidence analysis, comprising 527 of HCC, 33 of ICC and 105 of HMT. VLP was characterized as intratumoral contrast material pool persisting late into venous phase. Incidences were cataloged on both super-selective and common hepatic artery angiography. For CT features analysis, a subset of 182 cases were analyzed. Enhancement ratio served as an index for comparative analysis of nodule enhancement degrees. RESULTS: In HCC, incidence of VLP ascertained via super-selective angiography was 13.5%, whereas it as 7.8% on common hepatic artery angiography. Remarkably, no incidences of VLP were recorded in either ICC or HMT cases. On pre-interventional CT, the prevalence of pseudocapsule was statistically greater in VLP group than Non-VLP group (66.6% vs. 37.6%, P = 0.015). The Houndsfield units (HU) of tumors in plain scan (P = 0.007), arterial phase (P = 0.001), venous phase (P = 0.041), arterial phase enhancement ratio (P < 0.001) were statistically higher in VLP group compared to Non-VLP group. Arterial phase enhancement ratio (P = 0.025), presence of pseudocapsule (P = 0.001), HU of tumor in plain scan (P = 0.035) serve as independent risk factors for VLP manifestation. CONCLUSION: VLP is a distinct angiography phenomenon uniquely associated with HCC. High arterial phase enhancement ratio, presence of pseudocapsule, high HU of tumor in plain scan are independent risk factors for VLP.

Gas-to-ionic liquid partition: QSPR modeling and mechanistic interpretation.

The present work was devoted to explore the quantitative structure-property relationships for gas-to-ionic liquid partition coefficients (log KILA ). A series of linear models were first established for the representative dataset (IL01). The optimal model was a four-parameter equation (1Ed) consisting of two electrostatic potential-based descriptors ( Σ V s , i n d - ${{\rm { \Sigma }}{V}_{s,ind}^{-}}$ and Vs,max ), one 2D matrix-based descriptor (J_D/Dt) and dipole moment (µ). All of the four descriptors introduced in the model can find the corresponding parameters, directly or indirectly, from Abraham's linear solvation energy relationship (LSER) or its theoretical alternatives, which endows the model good interpretability. Gaussian process was utilized to build the nonlinear model. Systematical validations, including 5-fold cross-validation for the training set, the validation for test set, as well as a more rigorous Monte Carlo cross-validation were performed to verify the reliability of the constructed models. Applicability domain of the model was evaluated, and the Williams plot revealed that the model can be used to predict the log KILA values of structurally diverse solutes. The other 13 datasets were also processed in the same way, and all of the linear models with expressions similar to equation 1Ed were obtained. These models, whether linear of nonlinear, represent satisfactory statistical results, which confirms the universality of the method adopted in this study in QSPR modeling of gas-to-IL partition.

Molecularly engineered AIEgens with enhanced quantum and singlet-oxygen yield for mitochondria-targeted imaging and photodynamic therapy.

Luminogens characteristic of aggregation-induced emission (AIEgens) have been extensively exploited for the development of imaging-guided photodynamic therapeutic (PDT) agents. However, intramolecular rotation of donor-acceptor (D-A) type AIEgens favors non-radiative decay of photonic energy which results in unsatisfactory fluorescence quantum and singlet oxygen yields. To address this issue, we developed several molecularly engineered AIEgens with partially "locked" molecular structures enhancing both fluorescence emission and the production of triplet excitons. A triphenylphosphine group was introduced to form a D-A conjugate, improving water solubility and the capacity for mitochondrial localization of the resulting probes. Experimental and theoretical analyses suggest that the much higher quantum and singlet oxygen yield of a structurally "significantly-locked" probe (LOCK-2) than its "partially locked" (LOCK-1) and "unlocked" equivalent (LOCK-0) is a result of suppressed AIE and twisted intramolecular charge transfer. LOCK-2 was also used for the mitochondrial-targeting, fluorescence image-guided PDT of liver cancer cells.

QSPR study on Hydrophobicity of Pt(II) complexes with surface electrostatic potential-based descriptors.

Pt(II) complexes play an important role in bioinorganic chemistry due to their antitumor activities. In the present study, we focused on building predictive models for the hydrophobicity of Pt(II) complexes. A five-parameter model, integrating frontier orbital energies (EHOMO, ELUMO) and descriptors derived from electrostatic potentials on molecular surface, was firstly constructed by using multiple linear regression (MLR) method. Mechanistic interpretations of the introduced descriptors were elucidated in terms of intermolecular interactions in the n-octanol/water partition system. Then, four up-to-date modeling methods, including support vector machine (SVM), least-squares support vector machine (LSSVM), random forest (RF) and Gaussian process (GP), were utilized to build the nonlinear models. Systematical validations including leave-one-out cross-validation, the validation for test set, as well as a very rigorous Monte Carlo cross-validation (MCCV) were performed to verify the reliability of the constructed models. The peak, median and integralRext2 values of the best GP model are 0.88, 0.86 and 0.84, respectively. The root mean squared errors for the test set (RMSEP) of the MLR, SVM, LSSVM and GP models fall in the range of 0.62-0.71. Although they are not superior to prior models built with the use of a number of descriptors, the results are satisfactory. Applicability domain of the model was evaluated.

Water-soluble bright NIR AIEgens with hybrid ROS for wash-free mitochondrial "off-on" imaging and photodynamic therapy.

Several aggregation-induced emission luminogens (AIEgens) with excellent water-solubility and near-infrared emission were designed and synthesized for wash-free "off-on" mitochondrial imaging and photodynamic therapy of HeLa cells. The AIEgen TEPP exhibits both bright near-infrared emission (φF = 17.8%) and high hybrid ROS productivity (including OH˙ and 1O2).

Prediction of the hydrophobicity of platinum(IV) complexes based on molecular surface properties.

A quantitative structure-property relationship (QSPR) study was performed for predicting the hydrophobicity of Pt(IV) complexes. Two four-parameter equations, one based solely on structural descriptors derived from electrostatic potentials (ESPs) on molecular surface, and the other integrated ESP descriptors with molecular surface area (AS), were firstly constructed. Mechanistic interpretations of the structural descriptors introduced were elucidated in terms of solute-solvent intermolecular interactions. Subsequently, several up-to-date modeling techniques, including support vector machine (SVM), least-squares support vector machine (LSSVM), random forest (RF) and Gaussian process (GP), were utilized to build the nonlinear models. Systematical validations including leave-one-out cross-validation, the validation for test set, as well as a more rigorous Monte Carlo cross-validation were performed to verify the reliability of the constructed models. The predictive performances of the four different nonlinear modeling methods follow the order of LSSVM≈GP > RF > SVM. The pure-ESP-based models are generally inferior to the AS-integrated ones. Comparisons with previous results were made.

Multicolor Circularly Polarized Photoluminescence and Electroluminescence with 1,2-Diaminecyclohexane Enantiomers.

Development of simple chiral materials with tunable circularly polarized photoluminescence (CPPL) and circularly polarized electroluminescence (CPEL) for efficient circularly polarized organic light-emitting diodes (CP-OLEDs) is the key toward future 3D displays. In this study, four pairs of chiral 1,2-diaminocyclohexane-based fluorescence enantiomers were efficiently prepared with high yields (up to 92%) and enantiomeric excesses (ee >99%). By the introduction of N-methyl, carbazole, and diphenylamine-donating groups, these materials showed multicolor CPPL and CPEL from blue (420 nm) to red (610 nm) with good thermal and conformational stability. The multilayer CP-OLEDs based on these enantiomers show high external quantum efficiency of up to 5.5% with low-efficiency roll-off and microimage circularly polarized electroluminescence with a dissymmetry factor (gEL) of up to -1.4 × 10-3/+1.3 × 10-3. These results push forward the development of future multicolor circularly polarized electroluminescent materials.

Spontaneous regression of recurrent hepatocellular carcinoma with multiple lung metastases.

Spontaneous regression (SR) of hepatocellular carcinoma (HCC) is a rare phenomenon but its true incidence is much higher than expected. We report a recurrent HCC who experienced SR both in intrahepatic lesion and lung metastasis. Serum alpha-fetoprotein decreased dramatically from more than 1000 µg/L to normal range. In addition, we reviewed 11 similar case reports published in recent 5 years. We find that the interval from diagnosis to the recognition of SR is very short (4 m, 1-14 m). Therefore, we speculate the mechanism of SR should be a severe systemic reaction, and immune activation is the most likely conjecture.

Phosphorylation Mechanism of N-Acetyl-l-glutamate Kinase, a QM/MM Study.

In microorganisms and plants, N-acetyl-l-glutamate kinase (NAGK) catalyzes the second step in l-arginine synthesis, the phosphorylation of N-Acetyl-l-glutamate (NAG) to give N-acetyl-l-glutamate-5-phosphate. NAGK is only present in microorganisms and plants but absent in mammals, which makes it an attractive target for antimicrobial or biocidal development. Understanding the substrate binding mode and reaction mechanism of NAGK is crucial for targeting the kinase to develop potential therapies. Here, the substrate binding mode was studied by comparing the conformational change of NAGK in the presence and in the absence of the NAG substrate based on molecular dynamics simulations. We revealed that with substrate binding, the catalytic site of the kinase involving three loops in NAGK exhibits a closed conformation, which is predominantly controlled by an interaction between Arg98 and the α-COO- of NAG. Lys41 is found to guide phosphate transfer through the interactions with the ß-,γ-, and γ-phosphate oxygen atoms of adenosine 5'-triphosphate surrounded by two highly conserved glycine residues (Gly44 and Gly76), while Arg98 helps to position the NAG substrate in the catalytic site, which facilitates the phosphate transfer. Furthermore, we elucidated phosphate-transfer reaction mechanism using hybrid density functional theory-based quantum mechanics/molecular mechanics calculations (B97D/AMBER99) and found that the catalysis follows a dissociative mechanism.

Phosphorylation Mechanism of Phosphomevalonate Kinase: Implications for Rational Engineering of Isoprenoid Biosynthetic Pathway Enzymes.

The mevalonate pathway is of important clinical, pharmaceutical, and biotechnological relevance. However, lack of the understanding of the phosphorylation mechanism of the kinases in this pathway has limited rationally engineering the kinases in industry. Here the phosphorylation reaction mechanism of a representative kinase in the mevalonate pathway, phosphomevalonate kinase, was studied by using molecular dynamics and hybrid QM/MM methods. We find that a conserved residue (Ser106) is reorientated to anchor ATP via a stable H-bond interaction. In addition, Ser213 located on the α-helix at the catalytic site is repositioned to further approach the substrate, facilitating the proton transfer during the phosphorylation. Furthermore, we elucidate that Lys101 functions to neutralize the negative charge developed at the ß-, γ-bridging oxygen atom of ATP during phosphoryl transfer. We demonstrate that the dissociative catalytic reaction occurs via a direct phosphorylation pathway. This is the first study on the phosphorylation mechanism of a mevalonate pathway kinase. The elucidation of the catalytic mechanism not only sheds light on the common catalytic mechanism of the GHMP kinase superfamily but also provides the structural basis for engineering the mevalonate pathway kinases to further exploit their applications in the production of a wide range of fine chemicals such as biofuels or pharmaceuticals.

Interactions between pyrazole derived enantiomers and Chiralcel OJ: Prediction of enantiomer absolute configurations and elution order by molecular dynamics simulations.

The separation of enantiomers and confirmation of their absolute configurations is significant in the development of chiral drugs. The interactions between the enantiomers of chiral pyrazole derivative and polysaccharide-based chiral stationary phase cellulose tris(4-methylbenzoate) (Chiralcel OJ) in seven solvents and under different temperature were studied using molecular dynamics simulations. The results show that solvent effect has remarkable influence on the interactions. Structure analysis discloses that the different interactions between two isomers and chiral stationary phase are dependent on the nature of solvents, which may invert the elution order. The computational method in the present study can be used to predict the elution order and the absolute configurations of enantiomers in HPLC separations and therefore would be valuable in development of chiral drugs.

Quantitative structure-hydrophobicity relationships of molecular fragments and beyond.

Quantitative structure-property relationship (QSPR) models were firstly established for the hydrophobic substituent constant (πX) using the theoretical descriptors derived solely from electrostatic potentials (EPSs) at the substituent atoms. The descriptors introduced are found to be related to hydrogen-bond basicity, hydrogen-bond acidity, cavity, or dipolarity/polarizability terms in linear solvation energy relationship, which endows the models good interpretability. The predictive capabilities of the models constructed were also verified by rigorous Monte Carlo cross-validation. Then, eight groups of meta- or para-disubstituted benzenes and one group of substituted pyridines were investigated. QSPR models for individual systems were achieved with the ESP-derived descriptors. Additionally, two QSPR models were also established for Rekker's fragment constants (foct), which is a secondary-treatment quantity and reflects average contribution of the fragment to logP. It has been demonstrated that the descriptors derived from ESPs at the fragments, can be well used to quantitatively express the relationship between fragment structures and their hydrophobic properties, regardless of the attached parent structure or the valence state. Finally, the relations of Hammett σ constant and ESP quantities were explored. It implies that σ and π, which are essential in classic QSAR and represent different type of contributions to biological activities, are also complementary in interaction site.

Identification of Peptide Inhibitors of Enveloped Viruses Using Support Vector Machine.

The peptides derived from envelope proteins have been shown to inhibit the protein-protein interactions in the virus membrane fusion process and thus have a great potential to be developed into effective antiviral therapies. There are three types of envelope proteins each exhibiting distinct structure folds. Although the exact fusion mechanism remains elusive, it was suggested that the three classes of viral fusion proteins share a similar mechanism of membrane fusion. The common mechanism of action makes it possible to correlate the properties of self-derived peptide inhibitors with their activities. Here we developed a support vector machine model using sequence-based statistical scores of self-derived peptide inhibitors as input features to correlate with their activities. The model displayed 92% prediction accuracy with the Matthew's correlation coefficient of 0.84, obviously superior to those using physicochemical properties and amino acid decomposition as input. The predictive support vector machine model for self- derived peptides of envelope proteins would be useful in development of antiviral peptide inhibitors targeting the virus fusion process.

(R)-[(R)-3-Benzyl-2-oxooxazolidin-4-yl][4-(methyl-sulfon-yl)phen-yl]methyl acetate.

The structure of the title compound, C20H21NO6S, is of inter-est with respect to its anti-bacterial properties. The oxazolidine ring makes dihedral angles of 79.63 (14) and 56.16 (12)° with the phenyl and benzene rings, respectively, while the phenyl and benzene rings make a dihedral angle of 64.37 (13)°. In the crystal, non-classical C-H⋯O hydrogen bonds link adjacent mol-ecules along the c axis.

[Curative effects on standardized management of community patients with coronary heart disease complicated with chronic heart failure].

OBJECTIVE: To explore the effects on the standardized management of patients with coronary atherosclerotic heart disease complicated with chronic heart failure. METHODS: A total of 823 patients discharged from our department were randomly enrolled. Among 734 patients with follow-up consents, they were divided into management and control groups (n = 440, 294). The management group received standardized out-of-hospital management, regular health education and follow-ups of telephone and outpatient visits. RESULTS: Compared with the control group, the management group had lower rates of all-cause mortality, cardiac death and readmission due to cardiovascular events (CVE) declining by 26.5%, 32.2% and 57.0% respectively. Over a 4-year period, the annular survival rate of management group was 92%, 85%, 83% and 82% while that of control group 95%, 89%, 82% and 75% respectively. Patient compliance of digoxin and diuretics in the control group was inferior to that in the management group. CONCLUSION: Through standardized out-of-hospital management, the patients with coronary atherosclerotic heart disease plus chronic heart failure may achieve significant benefits through reducing the rates of all-cause mortality, cardiac death and readmission due to CVE and improving survival rate.

Role of Arg228 in the phosphorylation of galactokinase: the mechanism of GHMP kinases by quantum mechanics/molecular mechanics studies.

GHMP kinases are a group of structurally related small molecule kinases. They have been found in all kingdoms of life and are mostly responsible for catalyzing the ATP-dependent phosphorylation of intermediary metabolites. Although the GHMP kinases are of clinical, pharmaceutical, and biotechnological importance, the mechanism of GHMP kinases is controversial. A catalytic base mechanism was suggested for mevalonate kinase that has a structural feature of the γ-phosphate of ATP close to an aspartate residue; however, for one GHMP family member, homoserine kinase, where the residue acting as general base is absent, a direct phosphorylation mechanism was suggested. Furthermore, it was proposed by some authors that all the GHMP kinases function by a similar mechanism. This controversy in mechanism has limited our ability to exploit these enzymes as drug targets and in biotechnology. Here the phosphorylation reaction mechanism of the human galactokinase, a member of the GHMP kinase family, was investigated using molecular dynamics simulations and density functional theory-based quantum mechanics/molecular mechanics calculations (B3LYP-D/AMBER99). The reaction coordinates were localized by potential energy scan using an adiabatic mapping method. Our results indicate that a highly conserved Glu174 captures Arg105 in the proximity of the α-phosphate of ATP, forming a H-bond network; therefore, the mobility of ATP in the large oxyanion hole is restricted. Arg228 functions to stabilize the negative charge developed at the ß,γ-bridging oxygen of the ATP during bond cleavage. The reaction occurs via a direct phosphorylation mechanism, and the Asp186 in the proximity of ATP does not directly participate in the reaction pathway. Because Arg228 is not conserved among GHMP kinases, reagents which form interactions with Arg228, and therefore can interrupt its function in phosphorylation, may be developed into potential selective inhibitors for galactokinase.

A quantitative structure-property relationship analysis of soot-water partition coefficients for persistent organic pollutants.

Geometrical optimization and electrostatic potential calculations have been performed at the HF/6-31G level of theory for investigated persistent organic pollutants (POPs). A number of statistically based parameters have been obtained. Relationship between soot-water partition coefficients (logK(SC)) of POPs and the structural descriptors has been established by the multiple linear regression method. The result shows that the quantities derived from electrostatic potential V(s)(-)¯ and V(s,max), together with molecular surface area (A(S)) and the energy of the highest occupied molecular orbital (E(HOMO)) can be well used to express the quantitative relationship between structure and logK(SC) (QSPR) of POPs. Predictive capability of the model has been demonstrated by leave-one-out cross-validation with the cross-validated correlation coefficient of 0.9797. Furthermore, the predictive power of this model was further examined for the external test set with the correlation coefficient of 0.9811 between observed and predicted logK(SC), validating the robustness and good predictive ability of our model. Furthermore, in order to further investigate the applicability of these parameters derived from electrostatic potential in prediction of soot-water partition coefficient for organic pollutants, eleven polycyclic aromatic hydrocarbons (PAHs), eleven polychlorinated biphenyls (PCBs) and nine phenyl urea herbicides (PUHs) from other source have also been studied. The QSPR models established may provide a new powerful method for predicting soot-water partition coefficients (logK(SC)) of organic pollutants.

Effect of double mutations K214/A-E215/Q of FRATide on GSK3ß: insights from molecular dynamics simulation and normal mode analysis.

Glycogen synthase kinase 3ß (GSK3ß) is a multifunctional serine/threonine protein kinase that is involved in several biological processes including insulin and Wnt signaling pathways. The Wnt signaling via FRAT-mediated displacement of axin inhibits GSK3ß activity toward non-primed substrates without affecting its activity toward primed substrates. Herein, molecular dynamics simulation, molecular mechanics generalized Born/surface area (MM_GBSA) calculation, and normal mode analysis are performed to explore the structural influence of the double mutations K214/A-E215/Q of FRATide on the GSK3ß-FRATide complex. The results reveal that the priming phosphate-binding site, the primed substrate-binding site, the alignment of the critical active site residues in the ATP-binding site, as well as the periodic open-closed conformational change of the ATP-binding site, which are critical for the catalytic activity of GSK3ß, are negligibly influenced in the mutated system compared with the wild-type (WT) system. This indicates that FRATide does not inhibit the GSK3ß activity toward primed substrates. Additionally, MM_GBSA calculation indicates that the less energy-favorable GSK3ß-FRATide complex is observed in the mutant than in the WT complex.

Molecular modeling and molecular dynamics simulation studies on pyrrolopyrimidine-based α-helix mimetic as dual inhibitors of MDM2 and MDMX.

Inhibition of the interactions between the tumor suppressor protein p53 and its negative regulators, the MDM2 and MDMX oncogenic proteins, is increasingly gaining interest in cancer therapy and drug design. In this study, we carry out molecular docking, molecular dynamics (MD) simulations, and molecular mechanics Poisson-Boltzmann and generalized Born/surface area (MM-PB/GBSA) binding free energy calculations on an active compound 3a and an inactive compound NC-1, which share a common pyrrolopyrimidine-based scaffold. MD simulations and MM-PB/GBSA calculations show that the compound NC-1 may not bind to MDM2 and MDMX, in agreement with the experimental results. Detailed MM-PB/GBSA calculations on the MDM2-3a and MDMX-3a complexes unravel that the binding free energies are similar for the two complexes. Furthermore, the van der Waals energy is the largest component of the binding free energy for both complexes, which indicates that the interactions between the compound 3a and MDM2 and MDMX are dominated by shape complementarity. In addition, the analysis of individual residue contribution and protein-ligand binding mode show that the three functional groups on R1, R2, and R3 of the compound 3a can mimic the spatial orientation of the side chains of Phe19, Trp23, and Leu26 of p53, respectively. The obtained computational results suggest that the compound 3a can act as a dual inhibitor of MDM2-p53 and MDMX-p53 interactions, consistent with the experimental results.