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Two new carbon skeleton compounds, identified as 2-(1-(3-hydroxy-2,2,6-trimethyl-6-vinyltetrahydro-2H-pyran-3-yl)-2-methylpropoxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol named Olerapyran A (1), and (E)-3-(6-acetyl-2-methyl-5-((3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)cyclooctylidene)butan-2-one named Oleraoctyl (2), were first isolated from Portulaca oleracea L., then their structures were determined using spectroscopic methods, including UHPLC-ESI-QTOF/MS, 1D and 2D NMR. In addition, the activities of Olerapyran A and Oleraoctyl inhibiting nitric oxide (NO) were studied.
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Molecular property prediction faces the challenge of limited labeled data as it necessitates a series of specialized experiments to annotate target molecules. Data augmentation techniques can effectively address the issue of data scarcity. In recent years, Mixup has achieved significant success in traditional domains such as image processing. However, its application in molecular property prediction is relatively limited due to the irregular, non-Euclidean nature of graphs and the fact that minor variations in molecular structures can lead to alterations in their properties. To address these challenges, we propose a novel data augmentation method called Mix-Key tailored for molecular property prediction. Mix-Key aims to capture crucial features of molecular graphs, focusing separately on the molecular scaffolds and functional groups. By generating isomers that are relatively invariant to the scaffolds or functional groups, we effectively preserve the core information of molecules. Additionally, to capture interactive information between the scaffolds and functional groups while ensuring correlation between the original and augmented graphs, we introduce molecular fingerprint similarity and node similarity. Through these steps, Mix-Key determines the mixup ratio between the original graph and two isomers, thus generating more informative augmented molecular graphs. We extensively validate our approach on molecular datasets of different scales with several Graph Neural Network architectures. The results demonstrate that Mix-Key consistently outperforms other data augmentation methods in enhancing molecular property prediction on several datasets.
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Algoritmos , Estrutura Molecular , Biologia Computacional/métodos , SoftwareRESUMO
Garnet-type solid-state Li metal batteries (SSLMBs) are viewed as hopeful next-generation batteries due to their high energy density and safety. However, the major obstacle to the development of garnet-type SSLMBs is the lithiophobicity of Li6.75La3Zr1.75Ta0.25O12 (LLZTO), resulting in a large interfacial impedance. Herein, a LiI/ZnLix mixed ion/electron conductive buffer layer is constructed at the interface by an in situ reaction of molten Li metal with ZnI2 film. This mixed buffer layer ensures close contact between the Li metal and garnet, significantly reducing interfacial impedance. As a result, the Li symmetrical cell with the LiI/ZnLix buffer layer shows an interface impedance of 10.3 Ω cm2, much lower than that of the cell with bare LLZTO (1173.4 Ω cm2). The critical current density (CCD) is up to 2.3 mA cm-2, and the symmetric cells present a long cycle life of 2000 h at 0.1 mA cm-2 and 800 h at 1.0 mA cm-2. In addition, the full cells assembled with the LiFePO4 cathode show a capacity of 143.9 mA h g-1 after 200 cycles at 0.5C with a low-capacity decay of 0.021% per cycle. This work reveals a simple, feasible, and practical interface modification strategy for solid-state Li metal batteries.
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Compared to transition metal dichalcogenide (TMD) monolayers, rhombohedral-stacked (R-stacked) TMD bilayers exhibit remarkable electrical performance, enhanced nonlinear optical response, giant piezo-photovoltaic effect and intrinsic interfacial ferroelectricity. However, from a thermodynamics perspective, the formation energies of R-stacked and hexagonal-stacked (H-stacked) TMD bilayers are nearly identical, leading to mixed stacking of both H- and R-stacked bilayers in epitaxial films. Here, we report the remote epitaxy of centimetre-scale single-crystal R-stacked WS2 bilayer films on sapphire substrates. The bilayer growth is realized by a high flux feeding of the tungsten source at high temperature on substrates. The R-stacked configuration is achieved by the symmetry breaking in a-plane sapphire, where the influence of atomic steps passes through the lower TMD layer and controls the R-stacking of the upper layer. The as-grown R-stacked bilayers show up-to-30-fold enhancements in carrier mobility (34 cm2V-1s-1), nearly doubled circular helicity (61%) and interfacial ferroelectricity, in contrast to monolayer films. Our work reveals a growth mechanism to obtain stacking-controlled bilayer TMD single crystals, and promotes large-scale applications of R-stacked TMD.
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[This corrects the article DOI: 10.1371/journal.pone.0049468.].
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Two new alkaloids identified as 2-(((S,Z)-1-(1H-azirin-1-yl)-5-methylhex-1-en-3-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol and (S,Z)-1-(1H-azirin-1-yl)-5-methylhex-1-en-3-ol, named olerazirin A (1), olerazirin B (2), together with five known alkaloids, identified as cyclo (L-Val-L-Ala) (3), cyclo-(glycyl-L-leucine) (4), cyclo-(Gly-Phe) (5), cyclo (Ser-Phe) (6), (3S,6S)-3-[(1R)-1-hydroxyethyl]-6-(phenyl-methyl)-2,5-piperazinedione (7) were obtained from Portulaca oleracea L. using a range of chromatographic techniques, 1D and 2D NMR, and high-resolution electrospray ionisation time-of-flight mass spectroscopic methods, in which the compounds 3-7 were isolated from P. oleracea for the first time. In addition, the results showed that the compounds 1 and 2 have anti-inflammatory activities and compounds 1-3 and 5-7 exhibit the anticholinesterase activities.
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PURPOSE: Prostate cancer (PCa) is often considered as a "cold" tumor with low responsiveness to immunotherapy. Recent evidence suggests the activation of specific immune cells, such as tumor-associated macrophages (TAMs), could potentially influence the efficacy of immunotherapy in PCa. However, the relationship between TAMs and PD-L1, a significant regulator in immunotherapy, within PCa remains unexplored. METHODS: In this study, we assessed TAM infiltration and PD-L1 expression levels in a local cohort of 95 PCa tissue samples and two publicly available PCa datasets. We employed a combination of bioinformatics and experimental techniques, including gene set enrichment analysis, CIBERSORTx, tissue microarray, immunohistochemistry staining, and analysis of single-cell sequencing datasets, to provide a comprehensive understanding of the association between PD-L1 and TAMs in the PCa microenvironment. RESULTS: The study showed that CD68+ TAMs and CD163+ TAMs (M2-TAMs) were more abundant in the tumor microenvironment than in non-cancerous surrounding tissues. The infiltration of CD163+ TAMs was significantly associated with the Gleason score and risk stratification of PCa. Importantly, elevated PD-L1 expression correlated significantly with high infiltration of CD163+ TAMs. Furthermore, patients displaying high levels of CD163+ TAMs and PD-L1 expression exhibited shorter times to biochemical recurrence-free survival. CONCLUSION: Our study suggests that CD163+ TAMs are closely associated with PD-L1 expression and can act as a valuable prognostic indicator for PCa. The high infiltration of M2-TAMs, coupled with the overexpression of PD-L1, may contribute to immune escape mechanisms in PCa, thereby influencing disease prognosis.
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Neoplasias da Próstata , Macrófagos Associados a Tumor , Humanos , Masculino , Antígeno B7-H1/metabolismo , Imunoterapia , Macrófagos/metabolismo , Prognóstico , Neoplasias da Próstata/patologia , Microambiente Tumoral , Macrófagos Associados a Tumor/metabolismoRESUMO
Two novel alkaloids were identified as (E)-N-(4-3,4-dihydroxy-6-(hydroxymethyl)-5-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)-2,5-dihydroxyphenyl)-3-(4-hydroxyphenyl)acrylamide (1), named Oleracrylimide D, (E)-N-(4-3,4-dihydroxy-6-(hydroxymethyl)-5-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)-2,5-dihydroxyphenyl)-3-(4-hydroxy-3-methoxyphenyl)acrylamide (2), named Oleracrylimide E, isolated from Portulaca oleracea L. The structures were identified by spectroscopic methods, including 1D NMR, 2D NMR, and UHPLC-ESI-QTOF/MS methods, also, the anti-inflammatory bioactivities of the compounds were studied by ELISA method.
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OBJECTIVES: This study evaluated the benefits and risks of patients with refractory or relapsed acute lymphocytic leukemia (R/R ALL) treated with anti-CD19 chimeric antigen receptor (CAR) T-cell therapy and blinatumomab. METHODS: PubMed, Web of Science, Embase, and the Cochrane Library were searched for relevant studies. RESULTS: The pooled complete remission (CR) rate and minimal residual disease (MRD) negative rate were 48%, 31% for blinatumomab, and 86% and 80% for CAR T-cell therapy. CONCLUSIONS: The CAR T-cell therapy group exhibited a higher likelihood of CR rate than the blinatumomab group in every analysis regardless of adjustment subgroups. CAR T-cell therapy was associated with a significantly prolonged overall survival (OS) and relapse-free survival (RFS) compared with blinatumomab (2-year OS 55% vs 25%; 2-year RFS 40% vs 22%). CAR T-cell therapy was more effective for achieving CR and bridging to allogeneic hematopoietic stem cell transplantation (allo-SCT) than blinatumomab (2-year OS 75% vs. 57%). An emerging role for blinatumomab is as a bridging agent pre-SCT, and for patients who achieve an MRD-negative state pre-SCT, post-SCT outcomes are expected to be the same as CAR-T. For adverse effects (AEs), blinatumomab was associated with a lower rate of grade ≥3 hematological toxicity, CRS, and neurological events.
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Anticorpos Biespecíficos , Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Imunoterapia Adotiva/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Anticorpos Biespecíficos/efeitos adversos , Recidiva , Antígenos CD19RESUMO
BACKGROUND: To determine the predictive value of serum abnormal prothrombin (PIVKA-II) and alpha-fetoprotein (AFP) for the non-objective response of HBV-associated hepatocellular carcinoma (HCC) after transarterial chemoembolization (TACE). METHODS: This prospective study included HBV-associated HCC patients who underwent TACE at the Fourth People's Hospital of Qinghai Province between December 2021 and July 2022. According to contrast-enhanced ultrasound and upper abdomen contrast-enhanced MRI, the patients were divided into the objective response group and the non-objective response group 3 months after TACE. RESULTS: There were 54 patients, of whom 31 experienced non-objective responses. The PIVKA-II levels in the objective response group were significantly lower than in the non-objective response group at 1 month [352.00 (142.16-722.54) vs. 528.58(241.32-1681.23) mAU/ml, Pâ =â 0.005] and 3 months [28.96 (20.01-42.49) vs. 2082.55 (52.63-10 057.30) mAU/ml, Pâ =â 0.016] after TACE. The Spearman rank correlation analysis showed no significant correlation between PIVKA-II and AFP (râ =â 0.315, Pâ >â 0.05). The areas under the curve (AUCs) of AFP and PIVKA-II before TACE were 0.632 and 0.529. One month after TACE, the AUC of PIVKA-II combined with AFP (AUCâ =â 0.787) was higher than for PIVKA-II (AUCâ =â 0.658) and AFP (AUCâ =â 0.749). CONCLUSION: PIVKA-II does not outperform AFP in predicting non-objective response after TACE in HCC patients. The combination of PIVKA-II and AFP might improve the diagnosis of HCC non-objective response after TACE.
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Carcinoma Hepatocelular , Quimioembolização Terapêutica , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/diagnóstico , alfa-Fetoproteínas/análise , Protrombina , Vírus da Hepatite B , Estudos Prospectivos , Neoplasias Hepáticas/diagnóstico , Curva ROC , Quimioembolização Terapêutica/efeitos adversos , Biomarcadores , Biomarcadores TumoraisRESUMO
INTRODUCTION AND OBJECTIVES: Hepatocellular carcinoma (HCC), a malignancy with a very dismal prognosis, has drawn a lot of attention, particularly in East Asia, where morbidity and mortality are higher. Although new information about the role of fatty acids (FAs) in HCC is constantly being discovered, it is still vital to investigate how FA metabolism affects the prognosis, immune microenvironment, and responsiveness of HCC to immunotherapy as a whole. MATERIALS AND METHODS: To determine the significance of FA metabolism in HCC immunotherapy, we first evaluated HCC samples from the single-cell dataset GSE151530. The TCGA-LIHC cohort and GSE140901 were further studied to identify the impact of FA metabolism on prognosis, immune microenvironment, drug sensitivity, and immunotherapy response by developing a fatty acid prediction index (FPI). The heterogeneity and similarity of the involvement of FA metabolism in pan-cancer is also investigated. RESULTS: Combining single-cell and bulk analyses, we confirmed that FA metabolism regulates tumor malignancy, prognosis, immune microenvironment, drug sensitivity, and immunotherapy response in patients with HCC. Moreover, it can have a considerable impact on the physiological activities of hepatocellular cancer. In addition, we demonstrate that FA metabolism has a comparable or same role in many malignancies. CONCLUSIONS: Our investigation shows the crucial regulatory role of FA metabolism in HCC and suggests a potential therapeutic method for HCC patients, which may improve their survival.
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[This corrects the article DOI: 10.3389/fgene.2022.1092678.].
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Background: The diffuse large B-cell lymphoma (DLBCL) is a heterogeneous lymphoma with a dismal outcome, due to approximately 40% patients will be relapsed or refractory to the standard therapy of rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). Therefore, we need urgently to explore the approach to classify the risk of DLBCL patients accurately and accurately targeting therapy. The ribosome is a vital cellular organelle that is mainly responsible for translation mRNA into protein, moreover, more and more reports revealed that ribosome was associated with cellular proliferation and tumorigenesis. Therefore, our study aimed to construct a prognostic model of DLBCL patients using ribosome-related genes (RibGs). Method: We screened differentially expressed RibGs between healthy donors' B cells and DLBCL patients' malignant B cells in GSE56315 dataset. Next, we performed analyses of univariate Cox regression, the least absolute shrinkage and selection operator (LASSO) regression and multivariate Cox regression analyses to establish the prognostic model consisting of 15 RibGs in GSE10846 training set. Then, we validated the model by a range of analyses including Cox regression, Kaplan-Meier survival, ROC curve, and nomogram in training and validation cohorts. Results: The RibGs model showed a reliably predictive capability. We found the upregulated pathways in high-risk group most associated with innate immune reaction such as interferon response, complement and inflammatory responses. In addition, a nomogram including age, gender, IPI score and risk score was constructed to help explain the prognostic model. We also discovered the high-risk patients were more sensitive to some certain drugs. Finally, knocking out the NLE1 could inhibit the proliferation of DLBCL cell lines. Conclusion: As far as we know, it is the first time to predict the prognosis of DLBCL using the RibGs and give a new sight for DLBCL treatment. Importantly, the RibGs model could be acted as a supplementary to the IPI in classifying the risk of DLBCL patients.
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OBJECTIVE: Mortality rate is a general indicator which can be used to measure care and management of schizophrenia. This cohort study evaluated the standardized mortality ratios (SMRs) of all-cause mortality and life-years lost (LYLs) in patients with schizophrenia under a community care program in China. METHODS: Data were obtained from the National Community Care Program System for Severe Mental Disorders. A total of 99,214 patients diagnosed with schizophrenia were enrolled before December 2014 and followed between 2015 and 2019. A total of 9,483 patients died. Crude mortality rates (CMRs) and SMRs were then stratified by natural vs. unnatural causes, and major groups of death were standardized according to the 2010 National Population SMRs. The corresponding LYLs at birth were also calculated by gender and age. RESULTS: The SMRs of patients with schizophrenia were significantly elevated during the study period, with an overall SMR of 4.98 (95%CI 2.67-7.32). Neoplasms, cardiovascular diseases, cerebrovascular diseases, external injuries, and poisonings were the most significant causes of death among patients with schizophrenia compared to the general population. The mean LYLs of patients with schizophrenia were 15.28 (95%CI 13.26-17.30). Males with schizophrenia lost 15.82 life-years (95%CI 13.48-18.16), and females lost 14.59 life-years (95%CI 13.12-16.06). CONCLUSIONS: Patients with schizophrenia under community care had a high mortality rate in our study, even though mental health services have been integrated into the general healthcare system in China to narrow treatment gaps in mental health for > 10 years. In terms of mortality outcome indicators, effective and quality mental health services still have a long way to go. The current study demonstrates the potential for improved prevention and treatment of individuals with schizophrenia under community care.
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Esquizofrenia , Masculino , Feminino , Recém-Nascido , Humanos , Esquizofrenia/terapia , Seguimentos , Estudos de Coortes , Causas de Morte , Saúde MentalRESUMO
The great challenge for the growth of non-centrosymmetric 2D single crystals is to break the equivalence of antiparallel grains. Even though this pursuit has been partially achieved in boron nitride and transition metal dichalcogenides (TMDs) growth, the key factors that determine the epitaxy of non-centrosymmetric 2D single crystals are still unclear. Here we report a universal methodology for the epitaxy of non-centrosymmetric 2D metal dichalcogenides enabled by accurate time sequence control of the simultaneous formation of grain nuclei and substrate steps. With this methodology, we have demonstrated the epitaxy of unidirectionally aligned MoS2 grains on a, c, m, n, r and v plane Al2O3 as well as MgO and TiO2 substrates. This approach is also applicable to many TMDs, such as WS2, NbS2, MoSe2, WSe2 and NbSe2. This study reveals a robust mechanism for the growth of various 2D single crystals and thus paves the way for their potential applications.
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Competing endogenous RNA (ceRNA)-mediated signaling pathway dysregulation provides great insight into comprehensively understanding the molecular mechanism and combined targeted therapy for glioblastoma. circRNA is characterized by high stability, tissue/developmental stage-specific expression and abundance in brain and plays significant roles in the initiation and progression of cancer. Our previous published data have demonstrated that RPN2 was significantly upregulated in glioma and promoted tumor progression via the activation of the Wnt/ß-catenin pathway. Furthermore, we proved that miR-422a regulated the Wnt/ß-catenin signaling pathway by directly targeting RPN2. In this study, based on the glioblastoma microarray profiles, we identified the upstream circTOP2A, which completely bound to miR-422a and was co-expressed with the RPN2. circTOP2A was significantly overexpressed in glioma and conferred a poor prognosis. circTOP2A could regulate RPN2 expression by sponging miR-422a, verified by western blot, dual-luciferase reporter gene assay, and RNA pull-down assay. Functional assays including CCK8, transwell and FITC-annexin V were performed to explore the RPN2-mediated role of the circTOP2A effect on the glioma malignant phenotype. Additionally, TOP/FOP and immunofluorescence analysis were used to confirm that sh-circTOP2A could suppress the Wnt/ß-catenin pathway partly through RPN2. Finally, a tumor xenograft model was applied to validate the biological function of circTOP2A in vivo. Taken together, our findings reveal the critical role of circTOP2A in promoting glioma proliferation and invasion via a ceRNA mechanism and provide an exploitable biomarker and therapeutic target for glioma patients.
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Neoplasias Encefálicas , Glioblastoma , Glioma , Hexosiltransferases , MicroRNAs , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Glioblastoma/genética , beta Catenina/genética , Glioma/patologia , Neoplasias Encefálicas/patologia , Proliferação de Células/genética , Linhagem Celular Tumoral , Via de Sinalização Wnt/genética , Regulação Neoplásica da Expressão Gênica , Hexosiltransferases/genética , Hexosiltransferases/metabolismo , Complexo de Endopeptidases do Proteassoma/genética , Complexo de Endopeptidases do Proteassoma/metabolismoRESUMO
Objective: Mortality rate is a general indicator which can be used to measure care and management of schizophrenia. This cohort study evaluated the standardized mortality ratios (SMRs) of all-cause mortality and life-years lost (LYLs) in patients with schizophrenia under a community care program in China. Methods: Data were obtained from the National Community Care Program System for Severe Mental Disorders. A total of 99,214 patients diagnosed with schizophrenia were enrolled before December 2014 and followed between 2015 and 2019. A total of 9,483 patients died. Crude mortality rates (CMRs) and SMRs were then stratified by natural vs. unnatural causes, and major groups of death were standardized according to the 2010 National Population SMRs. The corresponding LYLs at birth were also calculated by gender and age. Results: The SMRs of patients with schizophrenia were significantly elevated during the study period, with an overall SMR of 4.98 (95%CI 2.67-7.32). Neoplasms, cardiovascular diseases, cerebrovascular diseases, external injuries, and poisonings were the most significant causes of death among patients with schizophrenia compared to the general population. The mean LYLs of patients with schizophrenia were 15.28 (95%CI 13.26-17.30). Males with schizophrenia lost 15.82 life-years (95%CI 13.48-18.16), and females lost 14.59 life-years (95%CI 13.12-16.06). Conclusions: Patients with schizophrenia under community care had a high mortality rate in our study, even though mental health services have been integrated into the general healthcare system in China to narrow treatment gaps in mental health for > 10 years. In terms of mortality outcome indicators, effective and quality mental health services still have a long way to go. The current study demonstrates the potential for improved prevention and treatment of individuals with schizophrenia under community care.
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Gastric cancer (GC) is the fourth most common cancer worldwide, with overall 5-year survival rate of approximate 20%. Although multimodal treatments that combine surgery with chemotherapy and immunotherapy have been shown to improve survival, pathological complete response (pCR) is rare in advanced GC patients with liver metastases. Pre-clinical studies and clinical trials have demonstrated the antitumor efficacy of invariant natural killer T (iNKT) cells in various malignancies, including GC. While multimodal therapy comprised of chemotherapy, anti-programmed cell death-1 (PD-1) therapy, and iNKT cell immunotherapy have not been reported in GC patients. This case report describes the treatment of an early 60s patient diagnosed with advanced stage IVB (T1N1M1) adenocarcinomas of gastric cardia with liver metastases who received multimodal therapy comprised of SOX chemotherapy, anti-programmed cell death-1 (PD-1) therapy, and iNKT cell immunotherapy followed by surgical resection. Dramatic decreases in tumor area were observed in both the primary tumor and metastatic lesions following six cycles of SOX chemotherapy and iNKT cell immunotherapy, and four cycles of anti-PD-1 therapy. This combined treatment resulted in the transformation of a remarkably large, unresectable liver metastases into a resectable tumor, and the patient received total gastrectomy with D2 lymph node dissection and liver metastasectomy. Subsequent pathological examination detected no cancer cells in either the primary site or liver metastatic lesions, supporting the likelihood that this treatment achieved pCR. To our knowledge, this report represents the first case of a metastatic gastric cancer patient displaying pCR after six months of multimodal therapy, thus supporting that a SOX chemotherapy, anti-PD-1 therapy, and iNKT cell immunotherapy combination strategy may be effective for treating, and potentially curing, patients with advanced gastric adenocarcinoma.