The optimal threshold of PD-L1 combined positive score to predict the benefit of PD-1 antibody plus chemotherapy for patients with HER2-negative gastric adenocarcinoma: a meta-analysis.

BACKGROUND: Immune checkpoint inhibitors (ICIs) combined with chemotherapy have become the first-line treatment of metastatic gastric and gastroesophageal adenocarcinomas (GEACs). This study aims to figure out the optimal combined positive score (CPS) cutoff value. METHODS: We searched for randomized phase III trials to investigate the efficacy of ICIs plus chemotherapy for metastatic GEACs compared with chemotherapy alone. Pooled analyses of hazard ratios (HRs) based on PD-L1 expression were performed. RESULTS: A total of six trials (KEYNOTE-062, KEYNOTE-590, KEYNOTE-859, ATTRACTION-04, CheckMate 649, and ORIENT-16) were included, comprising 5,242 patients. ICIs plus chemotherapy significantly improved OS (HR: 0.79, 95% CI 0.72-0.86 in global patients; HR: 0.75, 95% CI 0.57-0.98 in Asian patients) and PFS (HR: 0.74, 95% CI 0.68-0.82 in global patients; HR: 0.64, 95% CI 0.56-0.73 in Asian patients) compared with chemotherapy alone. The differences in OS (ratio of HR: 1.05, 95% CI 0.79-1.40; predictive value: - 5.1%) and PFS (ratio of HR: 1.16, 95% CI 0.98-1.36; predictive value: - 13.5%) were not statistically significant between the global and Asian patients. Subgroup analyses indicated that the optimal CPS threshold was at ≥ 5 for OS and ≥ 10 for PFS with the highest predictive values. CONCLUSIONS: The benefit derived from ICIs plus chemotherapy is similar between Asian and global GEAC patients. However, those with a PD-L1 CPS < 5 or CPS < 10 may not have significant benefits from ICIs therapy. Therefore, it is advisable to routinely assess PD-L1 expression in GEAC patients considered for ICIs treatment.

Heterodimeric diketopiperazine alkaloids from Penicillium expansum MA147 and their cytotoxicity.

Four previously undescribed heterodimeric diketopiperazine alkaloids, expansines A-D, were identified from the solid rice medium fermented by Penicillium expansum MA147, along with one new resorcylic acid derivative and five known compounds. Their structures and relative/absolute configurations were elucidated by interpretation of their spectroscopic data, quantum chemical calculations, and chemical conversion. Some obtained compounds were evaluated for the cytotoxicity against a triple-negative breast cancer cell line MDA-MB-231, and expansine C showed an IC50 value of 3.23 µM. In further mechanistic studies, we found that it might act by increasing the expression of ATP-binding cassette transporter A1 and reducing cellular cholesterol levels, suggesting its potential as a novel anti-cancer agent.

Enhancing Multi-species Liver Microsomal Stability Prediction through Artificial Intelligence.

Liver microsomal stability, a crucial aspect of metabolic stability, significantly impacts practical drug discovery. However, current models for predicting liver microsomal stability are based on limited molecular information from a single species. To address this limitation, we constructed the largest public database of compounds from three common species: human, rat, and mouse. Subsequently, we developed a series of classification models using both traditional descriptor-based and classic graph-based machine learning (ML) algorithms. Remarkably, the best-performing models for the three species achieved Matthews correlation coefficients (MCCs) of 0.616, 0.603, and 0.574, respectively, on the test set. Furthermore, through the construction of consensus models based on these individual models, we have demonstrated their superior predictive performance in comparison with the existing models of the same type. To explore the similarities and differences in the properties of liver microsomal stability among multispecies molecules, we conducted preliminary interpretative explorations using the Shapley additive explanations (SHAP) and atom heatmap approaches for the models and misclassified molecules. Additionally, we further investigated representative structural modifications and substructures that decrease the liver microsomal stability in different species using the matched molecule pair analysis (MMPA) method and substructure extraction techniques. The established prediction models, along with insightful interpretation information regarding liver microsomal stability, will significantly contribute to enhancing the efficiency of exploring practical drugs for development.

A Very Deep Graph Convolutional Network for 13C NMR Chemical Shift Calculations with Density Functional Theory Level Performance for Structure Assignment.

Nuclear magnetic resonance (NMR) chemical shift calculations are powerful tools for structure elucidation and have been extensively employed in both natural product and synthetic chemistry. However, density functional theory (DFT) NMR chemical shift calculations are usually time-consuming, while fast data-driven methods often lack reliability, making it challenging to apply them to computationally intensive tasks with a high requirement on quality. Herein, we have constructed a 54-layer-deep graph convolutional network for 13C NMR chemical shift calculations, which achieved high accuracy with low time-cost and performed competitively with DFT NMR chemical shift calculations on structure assignment benchmarks. Our model utilizes a semiempirical method, GFN2-xTB, and is compatible with a broad variety of organic systems, including those composed of hundreds of atoms or elements ranging from H to Rn. We used this model to resolve the controversial J/K ring junction problem of maitotoxin, which is the largest whole molecule assigned by NMR calculations to date. This model has been developed into user-friendly software, providing a useful tool for routine rapid structure validation and assignation as well as a new approach to elucidate the large structures that were previously unsuitable for NMR calculations.

A theoretical study on pseudo Mott phase transition of vanadium dioxide.

The structural phase transition (SPT) and metal-insulator phase transition (MIT) always occur simultaneously upon heating from the low-temperature insulator M1 phase to the high-temperature metal R phase in vanadium dioxide, and it is still unclear which one of Mott correlation and Peierls distortion plays a decisive role in the thermally induced phase transition (PT) since 1959. Our density functional theory (DFT)-based calculations revealed that the intermediate phase in the PT, the so-called monoclinic metal phase, is a zero indirect band gap semimetal (P21/c space group) with a pseudo gap (199 meV). From the M1 phase to the monoclinic metal phase, the band gap decreases gradually to zero, and the bonding lengths between vanadium-vanadium atoms remain nearly constant. The SPT and MIT from the intermediate structure to the R phase occur simultaneously with a sudden change of bonding lengths between vanadium-vanadium atoms, in which electrons can jump down rather than jump up to the conduction band minimum (CBM) from the valence band maximum (VBM) under thermal fluctuation in order to lower the total energy of the system to push forward the occurrence of PT. The electron jumping does not require additional energy from Coulomb repulsion between electrons even though it is always present. This SPT is a typical Peierls PT or a pseudo Mott PT rather than an actual Mott PT in the each of the two stages. Our conclusions provide a new understanding of SPT and MIT in vanadium dioxide that has been debated for more than 80 years.

Triterpenoids with antiproliferative activities from the twigs and leaves of Melaleuca linariifolia.

One new pentacyclic triterpenoid, urs-12,16-dien-3-one (1), together with twelve known pentacyclic triterpenoids (2‒13), were isolated from the twigs and leaves of Melaleuca linariifolia. Their structures were characterized by their 1D- and 2 D-NMR spectra analysis and mass spectra studies. Furthermore, all isolated compounds were tested the inhibitory effect on proliferation of six human cancer cell lines in vitro, including NCI-H441, NCI-H460, A549, SKOV3, hela, and caki-1 cells. Among them, compounds 3, 5, 7, 9, 12, and 13 exhibited moderate antiproliferative activities with IC50 values ranging from 3.85 to 33.31 µM.

[Condensed tannins from roots of Indigofera stachyodes].

Eleven condensed tannins were isolated from the roots of Indigofera stachyodes by various column chromatography techniques including silica gel, octadecyl silica(ODS), Sephadex LH-20, and semi-preparative high performance liquid chromatography(HPLC). These compounds were identified on the basis of physicochemical properties, nuclear magnetic resonance(NMR) and mass spectrometry(MS) data as stachyotannin A(1), epicatechin-(2ß→O→7,4ß→8)-epiafzelechin-(4ß→8)-catechin(2), cinnamtannin D1(3), cinnamtannin B1(4), epicatechin-(2ß→O→7,4ß→8)-epiafzelechin-(4α→8)-epicatechin(5), gambiriin C(6), proanthocyanidin A1(7), proanthocyanidin A2(8), aesculitannin B(9), proanthocyanidin A4(10), and procyanidin B5(11). Compound 1 is a new compound. Compounds 2-11 were isolated from Indigofera for the first time. Furthermore, compounds 1, 2, and 4-11 showed inhibitory effects on thrombin-induced ATP release in platelets.

GIAO 13C NMR Calculation with Sorted Training Sets Improves Accuracy and Reliability for Structural Assignation.

GIAO 13C NMR calculation plays important roles in structural assignment for small organic molecules. Especially, higher accuracy and confidence are required for the structural assignation of complex organic molecules. In this GIAO 13C NMR calculation strategy, carbons were sorted according to their type of hybridization, radii of solvation cavity, or solvent interactions. The calculated shielding tensors of carbons in each sorted training set were linear-regressed with experimental data separately, and the obtained linear parameters were used to convert calculated shielding tensors into calculated chemical shifts. This approach shows significantly improved accuracy, especially for sp2 carbons, compared to conventional GIAO 13C NMR calculation protocols. A statistic-based probability algorithm was proposed to quantify the reliability of structural assignation. With empirical linear parameters for three commonly used NMR solvents as well as an easy-to-use script and a spreadsheet, this 13C NMR calculation protocol provides a useful tool for structural validation or assignation of ambiguous organic structures.

Psathyrins: Antibacterial Diterpenoids from Psathyrella candolleana.

Two skeletally novel tetracyclic diterpenoids, psathyrins A (1) and B (2), have been characterized from cultures of the basidiomycete Psathyrella candolleana. Their structures including absolute configurations were established by means of spectroscopic methods, as well as ECD calculations. They possess a novel 5/5/4/6-fuesd ring system, for which the biosynthetic pathway is proposed. Compounds 1 and 2 inhibited the growth of Staphylococcus aureus and Salmonella enterica.

Amentotaxins C-V, Structurally Diverse Diterpenoids from the Leaves and Twigs of the Vulnerable Conifer Amentotaxus argotaenia and Their Cytotoxic Effects.

A phytochemical investigation of the MeOH extract of the leaves and twigs of Amentotaxus argotaenia, a relict vulnerable coniferous species endemic to China, led to the isolation and characterization of 35 diterpenoids/norditerpenoids. Twenty of these are new, including 11 ent-kaurane-type (amentotaxins C-M, 1-11, respectively), three icetexane-type [= 9(10→20)abeo-abietane-type (amentotaxins N-P, 12-14, respectively)], four ent-labdane-type (amentotaxins Q-T, 15-18, respectively), and two isopimarane-type [amentotaxins U (19) and V (20)] compounds. Their structures were elucidated on the basis of spectroscopic data, single-crystal X-ray diffraction, the modified Mosher's method, and electronic circular dichroism data analyses. Compounds 1-9 are rare 18-nor-ent-kaurane-type diterpenoids featuring a 4ß,19-epoxy ring. All the isolates were evaluated for their cytotoxic effects against a small panel of cultured human cancer cell lines (HeLa, A-549, MDA-MB-231, SKOV3, Huh-7, and HCT-116), and some of them exhibited cytotoxicities with IC50 values ranging from 1.5 to 10.0 µM.

Palhinosides A-H: Flavone Glucosidic Truxinate Esters with Neuroprotective Activities from Palhinhaea cernua.

Palhinosides A-H (1-8), new flavone glucosidic truxinate esters, including ß-truxinate and µ-truxinate forms, were isolated from Palhinhaea cernua. Their structures were elucidated by extensive spectroscopic methods and chemical analyses. The flavone glucoside cyclodimers possess a unique cyclobutane ring in their carbon scaffolds. Compounds 2-7 represent three pairs of stereoisomers (2/3, 4/5, 6/7). The protective effects of 1-8 against the damage of HT-22 cells induced by l-glutamate were evaluated, and compounds 4 and 5 showed better neuroprotective effects than the positive control, Trolox.

New prenylflavonol glycosides with xanthine oxidase inhibitory activity from the leaves of Cyclocarya paliurus.

Eight new prenylflavonol glycosides (1-8), along with five known analogues (9-13) were isolated from the n-butanol extract of the dried leaves of Cyclocarya paliurus (family Juglandaceae) for the first time. The structures of these compounds were characterized by comprehensive analysis of 1D, 2D NMR, HRESIMS, UV data and acid hydrolysis. In bioassay, all these thirteen prenylflavonol glycosides exhibited inhibitory effects on xanthine oxidase (XOD) activity. Especially compounds 2 and 7, showed outstanding IC50 values of 31.81 ± 2.20 and 29.71 ± 3.69 µM, respectively.

Influence of extending expansive open-door laminoplasty to C1 and C2 on cervical sagittal parameters.

BACKGROUND: For patients with spinal canal stenosis in the upper cervical spine who undergo C3-7 laminoplasty alone, it remains impossible to achieve full decompression due to its limited range. This study explores the extension of expansive open-door laminoplasty (EODL) to C1 and C2 for the treatment of cervical spinal stenosis of the upper cervical spine and its effects on cervical sagittal parameters. METHODS: A retrospective analysis of 33 patients presenting with symptoms of cervical spondylosis myelopathy (CSM) and ossification in the posterior longitudinal ligament (OPLL) of the upper cervical spine from February 2013 to December 2015 was performed. Furthermore, the changes in the C0-2 Cobb angle, C1-2 Cobb angle, C2-7 Cobb angle, C2-7 SVA, and T1-Slope in lateral X-rays of the cervical spine were measured before, immediately after, and 1 year after the operation. JOA and NDI scores were used to evaluate spinal cord function. RESULTS: The C0-2 and C1-2 Cobb angles did not significantly increase (P = 0.190 and P = 0.081), but the C2-7 Cobb angle (P = 0.001), C2-7 SVA (P < 0.001), and T1-Slope (P < 0.001) significantly increased from preoperative to 1 year postoperative. In addition, C2-7 SVA was significantly correlated with the T1-Slope (Pearson = 0.376, P < 0.001) and C0-2 Cobb angle (Pearson = 0.287, P = 0.004), and the C2-7 SVA was negatively correlated with the C2-7 Cobb angle (Pearson = - 0.295, P < 0.001). The average preoperative and postoperative JOA scores were 8.3 ± 1.6 and 14.6 ± 1.4 points, respectively, indicating in a postoperative neurological improvement rate of approximately 91.6%. The average preoperative and final follow-up NDI scores were 12.62 ± 2.34 and 7.61 ± 1.23. CONCLUSIONS: The sagittal parameters of patients who underwent EODL extended to C1 and C2 included loss of cervical curvature, increased cervical anteversion and compensatory posterior extension of the upper cervical spine to maintain visual balance in the field of vision. However, the changes in cervical spine parameters were far less substantial than the alarm thresholds reported in previous studies. We believe that EODL extended to C1 and C2 for the treatment of patients with spinal canal stenosis in the upper cervical spine is a feasible and safe procedure with excellent outcomes.

[Two new phenylpropanoid amide glycosides from whole plants of Corydalis racemosa].

Two new phenylpropanoid amide glycosides and ten analogues were isolated from the CH_2Cl_2 layer of 95% ethanol extract of the whole plants of Corydalis racemosa by using various chromatographic techniques, including silica gel, Sephadex LH-20, ODS column chromatographies, and semi-preparative HPLC. Their structures were identified on the basis of physicochemical properties, MS, NMR, and IR spectroscopic data as N-cis-sinapoyltyramine-4'-O-ß-glucoside(1), N-cis-sinapoyl-3-methoxytyramine-4'-O-ß-glucoside(2), N-cis-sinapoyltyramine(3), N-cis-feruloyltyramine(4), N-trans-cinnamoyltyramine(5), N-trans-feruloylphenethylamine(6), N-trans-p-methoxycinnamoyl-3-hydoxyoctopamine(7), N-cis-feruloyl-3-methoxytyramine(8), N-trans-feruloyltyramine(9), N-trans-feruloyl-3-methoxytyramine(10), N-trans-sinapoyltyramine(11), and N-trans-p-coumaroyltyramine(12). Compounds 1 and 2 are new compounds. Compounds 3-7 are obtained from the plants of Papaveraceae for the first time, and compounds 8-12 are firstly isolated from C. racemosa.

Curtachalasins, immunosuppressive agents from the endophytic fungus Xylaria cf. curta.

Eleven new cytochalasins, curtachalasins F-P (1-11), were isolated from the rice fermentation of endophytic fungus Xylaria cf. curta. Their structures were identified by extensive spectroscopic methods, X-ray diffraction, and quantum chemistry calculations. Curtachalasin P possesses a unique 5/6/6/7 fused ring system. In the bioactivity screening for curtachalasins F-P, A-C, and E (1-15), compounds 1, 3-6, 8-13, and 15 did not show obvious cytotoxicity against primary mouse splenocytes. Furthermore, the immunosuppressive assay against concanavalin A (ConA) induced T lymphocyte cell proliferation and lipopolysaccharide (LPS) induced B lymphocyte cell proliferation showed that compound 1 results in significant selective inhibition on B-cell proliferation (IC50 value of 2.42 µM) and compound 10 has selective inhibition on T-cell proliferation (IC50 value of 12.15 µM). These interesting immunosuppressive properties of this class of compounds provide new clues to fulfill the urgent demand for new immunosuppressive drugs.

Synthesis of difluoromethylated 2-oxindoles and quinoline-2,4-diones via visible light-induced tandem radical cyclization of N-arylacrylamides.

Visible light-induced difluoromethylation of N-arylacrylamides to afford difluoromethylated 2-oxindoles and quinoline-2,4-diones with difluoromethyl 2-pyridyl sulfones as radical precursors has been disclosed. This method provides convenient access to a variety of 2-oxindoles and quinoline-2,4-diones under mild conditions via a proposed tandem radical addition/cyclization process along with good tolerance to various functional groups. In addition, preliminary experimental studies have revealed that water is a key factor in difluoromethylation and the reaction involves an oxidative quenching cycle of the photocatalyst.

Vibralactones U-W, three vibralactone derivatives from cultures of the basidiomycete Boreostereum vibrans.

Three new vibralactone derivatives, namely vibralactones U-W (1-3), together with vibralactone (4), have been isolated from cultures of the basidiomycete Boreostereum vibrans. Their structures were determined on the basis of spectroscopic methods and literature data. All compounds showed no activities to five human cancer cell lines.

Accessing benzooxadiazepines via formal [4 + 3] cycloadditions of aza-o-quinone methides with nitrones.

An unprecedented and efficient [4 + 3] cycloaddition of N-(ortho-chloromethyl)aryl amides with nitrones has been developed. This approach provides easy access to a series of seven-membered benzooxadiazepine derivatives in good to excellent yields (up to 99% yield) under mild reaction conditions.

A Self-Assembled Oligopeptide as a Versatile NMR Alignment Medium for the Measurement of Residual Dipolar Couplings in Methanol.

Residual dipolar coupling (RDC) is a powerful structural parameter for the determination of the constitution, conformation, and configuration of organic molecules. Herein, we report the first liquid crystal-based orienting medium that is compatible with MeOH, thus enabling RDC acquisitions of a wide range of intermediate to polar organic molecules. The liquid crystals were produced from self-assembled oligopeptide nanotubes (AAKLVFF), which are stable at very low concentrations. The presented alignment medium is highly homogeneous, and the size of RDCs can be scaled with the concentration of the peptide. To assess the accuracy of the RDC measurement by employing this new medium, seven bioactive natural products from different classes were chosen and analyzed. The straightforward preparation of the anisotropic alignment sample will offer a versatile and robust protocol for the routine RDC measurement of natural products.

Antibacterial Azaphilones from an Endophytic Fungus, Colletotrichum sp. BS4.

Three new compounds, colletotrichones A-C (1-3), and one known compound, chermesinone B (4a), were isolated from an endophytic fungus, Colletotrichum sp. BS4, harbored in the leaves of Buxus sinica, a well-known boxwood plant used in traditional Chinese medicine (TCM). Their structures were determined by extensive spectroscopic analyses including 1D and 2D NMR, HRMS, ECD spectra, UV, and IR, as well as single-crystal X-ray diffraction, and shown to be azaphilones sharing a 3,6a-dimethyl-9-(2-methylbutanoyl)-9H-furo[2,3-h]isochromene-6,8-dione scaffold. Owing to the remarkable antibacterial potency of known azaphilones coupled to the usage of the host plant in TCM, we evaluated the antibacterial efficacy of the isolated compounds against two commonly dispersed environmental strains of Escherichia coli and Bacillus subtilis, as well as against two human pathogenic clinical strains of Staphylococcus aureus and Pseudomonas aeruginosa. Compound 1 exhibited marked antibacterial potencies against the environmental strains that were comparable to the standard antibiotics. Compound 3 was also active against E. coli. Finally, compound 2a exhibited the same efficacy as streptomycin against the clinically relevant bacterium S. aureus. The in vitro cytotoxicity of these compounds on a human acute monocytic leukemia cell line (THP-1) was also assessed. Our results provide a scientific rationale for further investigations into endophyte-mediated host chemical defense against specialist and generalist pathogens.