Heparin prevents caspase-11-dependent septic lethality independent of anticoagulant properties.

Heparin, a mammalian polysaccharide, is a widely used anticoagulant medicine to treat thrombotic disorders. It is also known to improve outcomes in sepsis, a leading cause of mortality resulted from infection-induced immune dysfunction. Whereas it is relatively clear how heparin exerts its anticoagulant effect, the immunomodulatory mechanisms enabled by heparin remain enigmatic. Here, we show that heparin prevented caspase-11-dependent immune responses and lethality in sepsis independent of its anticoagulant properties. Heparin or a chemically modified form of heparin without anticoagulant function inhibited the alarmin HMGB1-lipopolysaccharide (LPS) interaction and prevented the macrophage glycocalyx degradation by heparanase. These events blocked the cytosolic delivery of LPS in macrophages and the activation of caspase-11, a cytosolic LPS receptor that mediates lethality in sepsis. Survival was higher in septic patients treated with heparin than those without heparin treatment. The identification of this previously unrecognized heparin function establishes a link between innate immune responses and coagulation.

Integrative analysis of transcriptome and metabolome provides insights into the mechanisms of leaf variegation in Heliopsis helianthoides.

BACKGROUND: In the field of ornamental horticulture, phenotypic mutations, particularly in leaf color, are of great interest due to their potential in developing new plant varieties. The introduction of variegated leaf traits in plants like Heliopsis helianthoides, a perennial herbaceous species with ecological adaptability, provides a rich resource for molecular breeding and research on pigment metabolism and photosynthesis. We aimed to explore the mechanism of leaf variegation of Heliopsis helianthoides (using HY2021F1-0915 variegated mutant named HY, and green-leaf control check named CK in 2020 April, May and June) by analyzing the transcriptome and metabolome. RESULTS: Leaf color and physiological parameters were found to be significantly different between HY and CK types. Chlorophyll content of HY was lower than that of CK samples. Combined with the result of Weighted Gene Co-expression Network Analysis (WGCNA), 26 consistently downregulated differentially expressed genes (DEGs) were screened in HY compared to CK subtypes. Among the DEGs, 9 genes were verified to be downregulated in HY than CK by qRT-PCR. The reduction of chlorophyll content in HY might be due to the downregulation of FSD2. Low expression level of PFE2, annotated as ferritin-4, might also contribute to the interveinal chlorosis of HY. Based on metabolome data, differential metabolites (DEMs) between HY and CK samples were significantly enriched on ABC transporters in three months. By integrating DEGs and DEMs, they were enriched on carotenoids pathway. Downregulation of four carotenoid pigments might be one of the reasons for HY's light color. CONCLUSION: FSD2 and PFE2 (ferritin-4) were identified as key genes which likely contribute to the reduced chlorophyll content and interveinal chlorosis observed in HY. The differential metabolites were significantly enriched in ABC transporters. Carotenoid biosynthesis pathway was highlighted with decreased pigments in HY individuals. These findings not only enhance our understanding of leaf variegation mechanisms but also offer valuable insights for future plant breeding strategies aimed at preserving and enhancing variegated-leaf traits in ornamental plants.

METTL3-induced circ_0008345 contributes to the progression of colorectal cancer via the microRNA-182-5p/CYP1A2 pathway.

BACKGROUND: Circular RNA (circRNAs) have been found to play major roles in the progression of colorectal cancer (CRC). However, the functions of circ_0008345 (transcribed by PTK2) in regulating CRC development remain undefined. In this study, we aimed to explore the roles and underlying mechanisms of circ_0008345 in CRC. METHODS: RNase R-treated total cellular RNA was used to verify the circular structure of circ_0008345, and a subcellular fractionation assay was performed to detect the subcellular localization of circ_0008345. RNA pull-down and dual-luciferase assays were used to verify the binding relation between microRNA (miR)-182-5p and circ_0008345 and/or CYP1A2. Colony formation assay, EdU, and Transwell assays were performed to detect the biological behavior of CRC cells in vitro, and CRC cells were injected into mice to observe the tumor formation. m6A immunoprecipitation was used to detect the m6A modification of circ_0008345 in CRC cells. RESULTS: Circ_0008345, upregulated in CRC tissues and cells, was mainly present in the cytoplasm. Circ_0008345 bound to miR-182-5p, and miR-182-5p targeted CYP1A2, an oncogene in CRC. The colony formation, mobility, EdU-positive cell rate in vitro, and tumor growth in mice were inhibited after the knockdown of circ_0008345. However, the suppressing effects of sh-circ_0008345 on CRC and CYP1A2 expression were significantly reversed after further knockdown of miR-182-5p. METTL3 was the m6A modifier mediating circ_0008345 expression, and the suppression of METTL3 reduced the expression of circ_0008345. CONCLUSIONS: METTL3-dependent m6A methylation upregulated circ_0008345, which blocked the inhibitory effect of miR-182-5p on CYP1A2, thereby exacerbating the malignant phenotype of CRC cells.

MicroRNA-139-5p mediates BMSCs impairment in diabetes by targeting HOXA9/c-Fos.

The properties and functions of BMSCs were altered by the diabetic microenvironment, and its mechanism was not very clear. In recent years, the regulation of the function of BMSCs by microRNA has become a research hotspot, meanwhile, HOX genes also have been focused on and involved in multiple functions of stem cells. In this study, we investigated the role of miR-139-5p in diabetes-induced BMSC impairment. Since HOXA9 may be a target gene of miR-139-5p, we speculated that miR-139-5p/HOXA9 might be involved in regulating the biological characteristics and the function of BMSCs in diabetes. We demonstrated that the miR-139-5p expression was increased in BMSCs derived from STZ-induced diabetic rats. MiR-139-5p mimics were able to inhibit cell proliferation, and migration and promoted senescence and apoptosis in vitro. MiR-139-5p induced the down-regulated expression of HOXA9 and c-Fos in BMSCs derived from normal rats. Moreover, miR-139-5p inhibitors reversed the tendency in diabetic-derived BMSCs. Further, gain-and-loss function experiments indicated that miR-139-5p regulated the functions of BMSCs by targeting HOXA9 and c-Fos. In vivo wound model experiments showed that the downregulation of miR-139-5p further promoted the epithelialization and angiogenesis of diabetic BMSC-mediated skin. In conclusion, induction of miR-139-5p upregulation mediated the impairment of BMSCs through the HOXA9/c-Fos pathway in diabetic rats. Therefore, miR-139-5p/HOXA9 might be an important therapeutic target in treating diabetic BMSCs and diabetic complications in the future.

Meta-Analysis and Network Analysis Differentially Detect Various Pro-Inflammatory Mediators and Risk Factors for Type 2 Diabetes in the Elderly.

Type 2 diabetes (T2D) has a pathophysiological component that includes inflammation. Inflammation-sensitive marker measurement may be helpful in determining the risk of complications for both older T2D patients and the public. This study aimed to investigate the association between blood pro-inflammatory mediators and the characteristics of elderly patients with T2D using meta and network analyses. The Web of Science, Scopus, PubMed, and Cochrane Library databases were selected as study methodology. The Quality in Prognosis Studies (QUIPS) tool in the meta-analysis assessed the studies' methodological quality. The selected studies were statistically analyzed using the META-MAR tool based on the standardized mean difference (SMD). The selected studies included nine examinations involving 6399 old people [+>+55 years old, 65.9+±+4.09 (mean+±+SD)]. The meta-analysis showed that pro-inflammatory mediators (SMD 0.82) and patient-related variables [risk factors (SMD 0.71)] were significantly associated with T2D (p+<+0.05). Subgroup analysis revealed that tumor necrosis factor alpha (TNF-α; SMD 1.08), body mass index (SMD 0.64), high-density lipoprotein (HDL; SMD -0.61), body weight (SMD 0.50), and blood pressure (SMD 1.11) were factors significantly associated with T2D (p+<+0.05). Network analysis revealed that among patient characteristics, diastolic blood pressure and, among inflammatory mediators, leptin were the most closely associated factors with T2D in older adults. Moreover, network analysis showed that TNF-α and systolic blood pressure were most closely associated with leptin. Overall, alternate techniques, such as meta-analysis and network analysis, might identify different markers for T2D in older people. A therapeutic decision-making process needs to consider these differences in advance.

Recent Advances and Challenges in Protein Structure Prediction.

Artificial intelligence has made significant advances in the field of protein structure prediction in recent years. In particular, DeepMind's end-to-end model, AlphaFold2, has demonstrated the capability to predict three-dimensional structures of numerous unknown proteins with accuracy levels comparable to those of experimental methods. This breakthrough has opened up new possibilities for understanding protein structure and function as well as accelerating drug discovery and other applications in the field of biology and medicine. Despite the remarkable achievements of artificial intelligence in the field, there are still some challenges and limitations. In this Review, we discuss the recent progress and some of the challenges in protein structure prediction. These challenges include predicting multidomain protein structures, protein complex structures, multiple conformational states of proteins, and protein folding pathways. Furthermore, we highlight directions in which further improvements can be conducted.

Machine Learning for Predicting Risk and Prognosis of Acute Kidney Disease in Critically Ill Elderly Patients During Hospitalization: Internet-Based and Interpretable Model Study.

BACKGROUND: Acute kidney disease (AKD) affects more than half of critically ill elderly patients with acute kidney injury (AKI), which leads to worse short-term outcomes. OBJECTIVE: We aimed to establish 2 machine learning models to predict the risk and prognosis of AKD in the elderly and to deploy the models as online apps. METHODS: Data on elderly patients with AKI (n=3542) and AKD (n=2661) from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database were used to develop 2 models for predicting the AKD risk and in-hospital mortality, respectively. Data collected from Xiangya Hospital of Central South University were for external validation. A bootstrap method was used for internal validation to obtain relatively stable results. We extracted the indicators within 24 hours of the first diagnosis of AKI and the fluctuation range of some indicators, namely delta (day 3 after AKI minus day 1), as features. Six machine learning algorithms were used for modeling; the area under the receiver operating characteristic curve (AUROC), decision curve analysis, and calibration curve for evaluating; Shapley additive explanation (SHAP) analysis for visually interpreting; and the Heroku platform for deploying the best-performing models as web-based apps. RESULTS: For the model of predicting the risk of AKD in elderly patients with AKI during hospitalization, the Light Gradient Boosting Machine (LightGBM) showed the best overall performance in the training (AUROC=0.844, 95% CI 0.831-0.857), internal validation (AUROC=0.853, 95% CI 0.841-0.865), and external (AUROC=0.755, 95% CI 0.699-0.811) cohorts. In addition, LightGBM performed well for the AKD prognostic prediction in the training (AUROC=0.861, 95% CI 0.843-0.878), internal validation (AUROC=0.868, 95% CI 0.851-0.885), and external (AUROC=0.746, 95% CI 0.673-0.820) cohorts. The models deployed as online prediction apps allowed users to predict and provide feedback to submit new data for model iteration. In the importance ranking and correlation visualization of the model's top 10 influencing factors conducted based on the SHAP value, partial dependence plots revealed the optimal cutoff of some interventionable indicators. The top 5 factors predicting the risk of AKD were creatinine on day 3, sepsis, delta blood urea nitrogen (BUN), diastolic blood pressure (DBP), and heart rate, while the top 5 factors determining in-hospital mortality were age, BUN on day 1, vasopressor use, BUN on day 3, and partial pressure of carbon dioxide (PaCO2). CONCLUSIONS: We developed and validated 2 online apps for predicting the risk of AKD and its prognostic mortality in elderly patients, respectively. The top 10 factors that influenced the AKD risk and mortality during hospitalization were identified and explained visually, which might provide useful applications for intelligent management and suggestions for future prospective research.

Downregulation of circ-RAPGEF5 inhibits colorectal cancer progression by reducing the expression of polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3).

BACKGROUND: Circular RNA (circRNA) plays a crucial role in the pathogenesis and progression of colorectal cancer (CRC). However, the current understanding of the emerging function and mechanism of circ-RAPGEF5 in CRC remains poorly understood. METHODS: We first evaluated the expression level of circ-RAPGEF5 in CRC tissues and cells by quantitative real-time polymerase chain reaction (qRT-PCR). Then, we analyzed cell proliferation (EdU and colony formation assay), migration (cell wound healing assay), invasion (transwell assay), and apoptosis (flow cytometry assay). To further elucidate the mechanism of circ-RAPGEF5 in CRC, bioinformatics tools, Dual-luciferase reporter assay, Ago2 RNA immunoprecipitation assay, and RNA pull-down assay were employed. Moreover, we established a CRC transplantation tumor model to evaluate the effect of circ-RAPGEF5 on tumor growth in vivo. RESULTS: circ-RAPGEF5 was significantly upregulated in CRC tissues and CRC cells. Furthermore, the downregulation of circ-RAPGEF5 restrained CRC cell proliferation, migration, and invasion, and promoted cell apoptosis in vitro. Mechanistically, circ-RAPGEF5 accelerated the malignant behaviors of CRC cells by sponging miR-545-5p, which targeted polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3). In addition, we revealed that circ-RAPGEF5 silence curbed tumor growth in vivo. CONCLUSION: These findings revealed that circ-RAPGEF5 played an oncogenic role through the miR-545-5p/GALNT3 axis in CRC progression, providing potential therapeutic targets for the treatment of CRC.

Diterpenoids from the Aerial Parts of Isodon serra with Selective Cytotoxic Activity.

Four new diterpenoids, isodosins A-D (1-4), together with nine known compounds (5-13) were isolated and identified from the aerial parts of Isodon serra (Maxim.) Hara. The structures of the new diterpenoids were elucidated based on the analysis of HR-ESI-MS data, 1D/2D-NMR-spectroscopic data, and electronic circular dichroism (ECD) calculations. Cytotoxicities of compounds 2, 3, 5, 6, and 9 against the HepG2 and H1975 cell lines were evaluated with the MTT assay. As a result, compounds 2, 3, and 6 revealed higher levels of cytotoxicity against HepG2 cells than against H1975 cells. Moreover, compund 6 demonstrated the most efficacy in inhibiting the proliferation of HepG2 cells, with an IC50 value of 41.13 ± 3.49 µM. This effect was achieved by inducing apoptosis in a dose-dependent manner. Furthermore, the relationships between the structures and activities of these compounds are briefly discussed.

Microwave ablation versus laparoscopic resection as first-line therapy for solitary 3-5-cm HCC.

BACKGROUND AND AIMS: The study objective was to compare the effectiveness of microwave ablation (MWA) and laparoscopic liver resection (LLR) on solitary 3-5-cm HCC over time. APPROACH AND RESULTS: From 2008 to 2019, 1289 patients from 12 hospitals were enrolled in this retrospective study. Diagnosis of all lesions were based on histopathology. Propensity score matching was used to balance all baseline variables between the two groups in 2008-2019 (n = 335 in each group) and 2014-2019 (n = 257 in each group) cohorts, respectively. For cohort 2008-2019, during a median follow-up of 35.8 months, there were no differences in overall survival (OS) between MWA and LLR (HR: 0.88, 95% CI 0.65-1.19, p = 0.420), and MWA was inferior to LLR regarding disease-free survival (DFS) (HR 1.36, 95% CI 1.05-1.75, p = 0.017). For cohort 2014-2019, there was comparable OS (HR 0.85, 95% CI 0.56-1.30, p = 0.460) and approached statistical significance for DFS (HR 1.33, 95% CI 0.98-1.82, p = 0.071) between MWA and LLR. Subgroup analyses showed comparable OS in 3.1-4.0-cm HCCs (HR 0.88, 95% CI 0.53-1.47, p = 0.630) and 4.1-5.0-cm HCCs (HR 0.77, 95% CI 0.37-1.60, p = 0.483) between two modalities. For both cohorts, MWA shared comparable major complications (both p > 0.05), shorter hospitalization, and lower cost to LLR (all p < 0.001). CONCLUSIONS: MWA might be a first-line alternative to LLR for solitary 3-5-cm HCC in selected patients with technical advances, especially for patients unsuitable for LLR.

The vicious circle of UHRF1 down-regulation and KEAP1/NRF2/HO-1 pathway impairment promotes oxidative stress-induced endothelial cell apoptosis in diabetes.

BACKGROUND: Oxidative stress is recognized as a key factor in the induction of endothelial dysfunction in diabetes. However, the specific mechanisms have not been fully elucidated. We herein hypothesized that ubiquitin-like containing PHD and RING finger domains 1 (UHRF1) might have a role in oxidative stress-induced endothelial cell (EC) apoptosis in diabetes. METHODS: Western blot, qPCR, wound healing assay, apoptosis assay, reactive oxygen species (ROS) detection, dual-luciferase reporter assay, methylation-specific PCR, bisulfite sequencing PCR and chromatin immunoprecipitation assay were performed. RESULTS: UHRF1 expression levels were significantly decreased in endothelial colony-forming cells derived from peripheral blood of participants with type 2 diabetes compared with individuals without diabetes. ECs treated with high glucose, palmitate or hydrogen peroxide in vitro also exhibited decreased UHRF1 protein levels. Silencing of UHRF1 led to decreased migration ability and increased apoptosis and ROS production in ECs, which might be related to impaired Kelch-like ECH-associated protein 1 (KEAP1)/nuclear factor erythroid 2-related factor 2 (NRF2)/haeme oxygenase-1 pathway. Mechanistically, UHRF1 is closely implicated in epigenetic regulation of chromatin modification status at KEAP1 genomic locus via histone acetylation. NRF2 down-regulation in turn inhibits UHRF1 protein level, which might be due to increased ROS generation. CONCLUSION: Diabetes-induced oxidative stress can mediate down-regulation of UHRF1, which enhances ROS production by regulating KEAP1/p-NRF2 pathway through histone acetylation and might also form a self-perpetuating feedback loop with KEAP1/p-NRF2 to further promote oxidative stress-induced apoptosis of ECs in diabetes.

Coordination of sorbitol to Ga(OTf)3 in the liquid phase: an experimental and theoretical study.

In a solution of sorbitol (SBT) and Ga(OTf)3 compounds, the coordination of sorbitol (SBT) to [Ga(OTf)n]3-n (n = 0-3) has been investigated, using both ESI-MS spectra and density functional theory (DFT) calculations at the M06/6-311++g(d,p), aug-cc-pvtz level using a polarized continuum model (PCM-SMD). In sorbitol solution, the most stable conformer of sorbitol includes three intramolecular H-bonds, i.e., O2H⋯O4, O4H⋯O6, and O5H⋯O3. Through ESI-MS spectra, in a tetrahydrofuran solution of both SBT and Ga(OTf)3 compounds, five main species are observed, i.e., [Ga(SBT)]3+, [Ga(OTf)]2+, [Ga(SBT)2]3+, [Ga(OTf)(SBT)]2+, and [Ga(OTf)(SBT)2]2+. Through DFT calculations, in a solution of sorbitol (SBT) and Ga(OTf)3 compounds, the Ga3+ cation tends to form five six-coordination complexes, i.e., [Ga(η2O,O-OTf)3], [Ga(η3O2-O4-SBT)2]3+, [(η2O,O-OTf)Ga(η4O2-O5-SBT)]2+, [(η1O-OTf)(η2O2,O4-SBT)Ga(η3O3-O5-SBT)]2+, and [(η1O-OTf)(η2O,O-OTf)Ga(η3O3-O5-SBT)]+, which are in good agreement with the experimental observation of the ESI-MS spectra. For both [Ga(OTf)n]3-n (n = 1-3) and [Ga(SBT)m]3+ (m = 1, 2) complexes, the negative charge transfer from ligands to the Ga3+-center plays an important role in their stability, because of the strong polarization of the Ga3+ cation. For [Ga(OTf)n(SBT)m]3-n (n = 1, 2; m = 1, 2) complexes, the negative charge transfer from ligands to the Ga3+-center plays an essential role in their stability, accompanied by an electrostatic interaction between the Ga3+-center and ligands and/or spatial inclusion of ligands toward the Ga3+-center.

Cooperative Catalysis Mechanism of Brønsted and Lewis Acids from Al(OTf)3 with Methanol for ß-Cellobiose-to-Fructose Conversion: An Experimental and Theoretical Study.

Al-containing catalysts, e.g., Al(OTf)3, show good catalytic performance toward the conversion of cellulose to fructose in methanol solution. Here, we report the catalytic isomerization and alcoholysis mechanisms for the conversion of cellobiose to fructose at the PBE0/6-311++G(d,p), aug-cc-pVTZ theoretical level, combining the relevant experimental verifications of electrospray ionization mass spectrometry (ESI-MS), high-performance liquid chromatography (HPLC), and the attenuated total reflection-infrared (ATR-IR) spectra. From the alcoholysis of Al(OTf)3 in methanol solution, the catalytically active species involves both the [CH3OH2]+ Brønsted acid and the [Al(CH3O)(OTf)(CH3OH)4]+ Lewis acid. There are two reaction pathways, i.e., one through glucose (glycosidic bond cleavage followed by isomerization, w-G) and another through cellobiulose (isomerization followed by glycosidic bond cleavage, w-L). The Lewis acid ([Al(CH3O)(OTf)(CH3OH)4]+) is responsible for the aldose-ketose tautomerization, while the Brønsted acid ([CH3OH2]+) is in charge of ring-opening, ring-closure, and glycosidic bond cleavage. For both w-G and w-L, the rate-determining steps are related to the intramolecular [1,2]-H shift between C1-C2 for the aldose-ketose tautomerization catalyzed by the [Al(CH3O)(OTf)(CH3OH)4]+ species. The Lewis acid ([Al(CH3O)(OTf)(CH3OH)4]+) exhibits higher catalytic activity toward the aldose-ketose tautomerization of glycosyl-chain-glucose to glycosyl-chain-fructose than that of chain-glucose to chain-fructose. Besides, the Brønsted acid ([CH3OH2]+) shows higher catalytic activity toward the glycosidic bond cleavage of cellobiulose than that of cellobiose. Kinetically, the w-L pathway is predominant, whereas the w-G pathway is minor. The theoretically proposed mechanism has been experimentally testified. These insights may advance on the novel design of the catalytic system toward the conversion of cellulose to fructose.

Metronomic capecitabine as adjuvant therapy in locoregionally advanced nasopharyngeal carcinoma: a multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial.

BACKGROUND: Patients with locoregionally advanced nasopharyngeal carcinoma have a high risk of disease relapse, despite a high proportion of patients attaining complete clinical remission after receiving standard-of-care treatment (ie, definitive concurrent chemoradiotherapy with or without induction chemotherapy). Additional adjuvant therapies are needed to further reduce the risk of recurrence and death. However, the benefit of adjuvant chemotherapy for nasopharyngeal carcinoma remains controversial, highlighting the need for more effective adjuvant treatment options. METHODS: This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was done at 14 hospitals in China. Patients (aged 18-65 years) with histologically confirmed, high-risk locoregionally advanced nasopharyngeal carcinoma (stage III-IVA, excluding T3-4N0 and T3N1 disease), no locoregional disease or distant metastasis after definitive chemoradiotherapy, an Eastern Cooperative Oncology Group performance status of 0 or 1, sufficient haematological, renal, and hepatic function, and who had received their final radiotherapy dose 12-16 weeks before randomisation, were randomly assigned (1:1) to receive either oral metronomic capecitabine (650 mg/m2 body surface area twice daily for 1 year; metronomic capecitabine group) or observation (standard therapy group). Randomisation was done with a computer-generated sequence (block size of four), stratified by trial centre and receipt of induction chemotherapy (yes or no). The primary endpoint was failure-free survival, defined as the time from randomisation to disease recurrence (distant metastasis or locoregional recurrence) or death due to any cause, in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of capecitabine or who had commenced observation. This trial is registered with ClinicalTrials.gov, NCT02958111. FINDINGS: Between Jan 25, 2017, and Oct 25, 2018, 675 patients were screened, of whom 406 were enrolled and randomly assigned to the metronomic capecitabine group (n=204) or to the standard therapy group (n=202). After a median follow-up of 38 months (IQR 33-42), there were 29 (14%) events of recurrence or death in the metronomic capecitabine group and 53 (26%) events of recurrence or death in the standard therapy group. Failure-free survival at 3 years was significantly higher in the metronomic capecitabine group (85·3% [95% CI 80·4-90·6]) than in the standard therapy group (75·7% [69·9-81·9]), with a stratified hazard ratio of 0·50 (95% CI 0·32-0·79; p=0·0023). Grade 3 adverse events were reported in 35 (17%) of 201 patients in the metronomic capecitabine group and in 11 (6%) of 200 patients in the standard therapy group; hand-foot syndrome was the most common adverse event related to capecitabine (18 [9%] patients had grade 3 hand-foot syndrome). One (<1%) patient in the metronomic capecitabine group had grade 4 neutropenia. No treatment-related deaths were reported in either group. INTERPRETATION: The addition of metronomic adjuvant capecitabine to chemoradiotherapy significantly improved failure-free survival in patients with high-risk locoregionally advanced nasopharyngeal carcinoma, with a manageable safety profile. These results support a potential role for metronomic chemotherapy as an adjuvant therapy in the treatment of nasopharyngeal carcinoma. FUNDING: The National Natural Science Foundation of China, the Key-Area Research and Development Program of Guangdong Province, the Natural Science Foundation of Guangdong Province, the Innovation Team Development Plan of the Ministry of Education, and the Overseas Expertise Introduction Project for Discipline Innovation. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

C-X-C motif chemokine 16, modulated by microRNA-545, aggravates myocardial damage and affects the inflammatory responses in myocardial infarction.

BACKGROUND: Myocardial infarction (MI), a common type of coronary heart disease, is the major cause of morbidity and mortality around the world. Chemokine-mediated inflammatory cell infiltration and local inflammatory damage response are recent research hotspots. Hence, we attempted to examine the role of C-X-C motif chemokine 16 (CXCL16) as a potential candidate in MI. METHODS: Human cardiomyocytes were treated with hypoxia/reoxygenation (H/R) to establish an in vitro cell model. GEO database provided the clinical data of MI patients and GSEA verified the relationship of chemokine and MI. CCK-8 and flow cytometry analyses were used to measure cell viability and apoptosis. Bioinformatics analysis and luciferase reporter assay were conducted to determine the correlation between CXCL16 and miR-545. qRT-PCR and western blot assays were performed to investigate the expression level of the indicated genes. The activity of lactate dehydrogenase (LDH) and the levels of TNF-α, IL-6, IL-1ß, and IL-10 were explored using ELISA assay. RESULTS: CXCL16 was increased in MI. CXCL16 knockdown can reverse the inhibitory effect of H/R treatment on cell viability, while overexpression of CXCL16 showed the opposite trend. MiR-545 directly targeted CXCL16 and negatively regulated CXCL16 levels. MiR-545 promoted cell proliferation and inhibited apoptosis in the MI cell model, which attenuated the CXCL16-induced injury on cardiomyocytes. CONCLUSION: These findings demonstrated that CXCL16 aggravated MI damage through being directly targeted by miR-545 and mediating inflammatory responses, thereby providing potential therapeutic targets for MI therapy.

Proteasome inhibition for treatment of leishmaniasis, Chagas disease and sleeping sickness.

Chagas disease, leishmaniasis and sleeping sickness affect 20 million people worldwide and lead to more than 50,000 deaths annually. The diseases are caused by infection with the kinetoplastid parasites Trypanosoma cruzi, Leishmania spp. and Trypanosoma brucei spp., respectively. These parasites have similar biology and genomic sequence, suggesting that all three diseases could be cured with drugs that modulate the activity of a conserved parasite target. However, no such molecular targets or broad spectrum drugs have been identified to date. Here we describe a selective inhibitor of the kinetoplastid proteasome (GNF6702) with unprecedented in vivo efficacy, which cleared parasites from mice in all three models of infection. GNF6702 inhibits the kinetoplastid proteasome through a non-competitive mechanism, does not inhibit the mammalian proteasome or growth of mammalian cells, and is well-tolerated in mice. Our data provide genetic and chemical validation of the parasite proteasome as a promising therapeutic target for treatment of kinetoplastid infections, and underscore the possibility of developing a single class of drugs for these neglected diseases.

Double filtration plasmapheresis for hypertriglyceridemic acute pancreatitis caused by fat overload syndrome.

WHAT IS KNOWN AND OBJECTIVE: Severe hypertriglyceridemia (HTG) can cause acute pancreatitis (AP). CASE SUMMARY: We report a patient with acute lymphoblastic leukaemia who received long-term intravenous parenteral nutrition solution without monitoring of the serum triglyceride (TG) level, which resulted in fat overload syndrome and HTG-AP. WHAT IS NEW AND CONCLUSION: Double filtration plasmapheresis was performed to eliminate the TGs and treat the AP.

SMINBR: An Integrated Network and Chemoinformatics Tool Specialized for Prediction of Two-Component Crystal Formation.

Two-component crystals such as pharmaceutical cocrystals and salts have been proven as an effective strategy to improve physicochemical and biopharmaceutical properties of drugs. It is not easy to select proper molecular combinations to form two-component crystals. The network-based models have been successfully utilized to guide cocrystal design. Yet, the traditional social network-derived methods based on molecular-interaction topology information cannot directly predict interaction partners for new chemical entities (NCEs) that have not been observed to form two-component crystals. Herein, we proposed an effective tool, namely substructure-molecular-interaction network-based recommendation (SMINBR), to prioritize potential interaction partners for NCEs. This in silico tool incorporates network and chemoinformatics methods to bridge the gap between NCEs and known molecular-interaction network. The high performance of 10-fold cross validation and external validation shows the high accuracy and good generalization capability of the model. As a case study, top 10 recommended coformers for apatinib were all experimentally confirmed and a new apatinib cocrystal with paradioxybenzene was obtained. The predictive capability of the model attributes to its accordance with complementary patterns driving the formation of intermolecular interactions. SMINBR could automatically recommend new interaction partners for a target molecule, and would be an effective tool to guide cocrystal design. A free web server for SMINBR is available at http://lmmd.ecust.edu.cn/sminbr/.

Tailoring atomic 1T phase CrTe2forin situfabrication.

Controllable tailoring and understanding the phase-structure relationship of the 1T phase two-dimensional (2D) materials are critical for their applications in nanodevices. Thein situtransmission electron microscope (TEM) could regulate and monitor the evolution process of the nanostructure of 2D material with atomic resolution. In this work, a controllably tailoring 1T-CrTe2nanopore is carried out by thein situTEM. A preferred formation of the 1T-CrTe2border structure and nanopore healing process are studied at the atomic scale. The controllable tailoring of the 1T phase nanopore could be achieved by regulating the transformation of two types of low indices of crystal faces {101¯0} and {112¯0} at the nanopore border. Machine learning is applied to automatically process the TEM images with high efficiency. By adopting the deep-learning-based image segmentation method and augmenting the TEM images specifically, the nanopore of the TEM image could be automatically identified and the evaluation result of DICE metric reaches 93.17% on test set. This work presents the unique structure evolution of 1T phase 2D material and the computer aided high efficiency TEM data analysis based on deep learning. The techniques applied in this work could be generalized to other materials for controlled nanostructure regulation and automatic TEM image analyzation.

Glycemic control and neonatal outcomes in women with gestational diabetes mellitus treated using glyburide, metformin, or insulin: a pairwise and network meta-analysis.

AIMS: We aimed to assess the comparative efficiency and safety of the use of glyburide, metformin, and insulin in gestational diabetes mellitus (GDM). METHODS: We searched for randomized controlled trials that compared glyburide, metformin, and insulin in GDM. Data regarding glycemic control and neonatal safety were collected and analyzed in pairwise and network meta-analyses. RESULTS: A total of 4533 individuals from 23 trials were included. Compared with glyburide, metformin reduced 2-h postprandial blood glucose (2HPG) to a greater extent (standard mean difference (SMD) 0.18; 95% credible interval (CI) 0.01, 0.34). There were significantly lower prevalence of neonatal hypoglycemia (risk difference (RD) - 0.07; 95%CI - 0.11, - 0.02) and preeclampsia (RD - 0.03; 95%CI - 0.06, 0) in the metformin group than in the insulin group. The metformin group had significantly lower birth weight (SMD - 0.17; 95%CI - 0.25, - 0.08) and maternal weight gain (SMD - 0.61; 95%CI - 0.86,- 0.35) compared with the insulin group. Network meta-analysis suggested that metformin had the highest probability of successfully controlling glycemia and preventing neonatal complications. CONCLUSIONS: The present meta-analysis suggests that metformin may be as effective as insulin for glycemic control and is the most promising drug for the prevention of neonatal and maternal complications.