Development and validation of novel interpretable survival prediction models based on drug exposures for severe heart failure during vulnerable period.

BACKGROUND: Severe heart failure (HF) has a higher mortality during vulnerable period while targeted predictive tools, especially based on drug exposures, to accurately assess its prognoses remain largely unexplored. Therefore, this study aimed to utilize drug information as the main predictor to develop and validate survival models for severe HF patients during this period. METHODS: We extracted severe HF patients from the MIMIC-IV database (as training and internal validation cohorts) as well as from the MIMIC-III database and local hospital (as external validation cohorts). Three algorithms, including Cox proportional hazards model (CoxPH), random survival forest (RSF), and deep learning survival prediction (DeepSurv), were applied to incorporate the parameters (partial hospitalization information and exposure durations of drugs) for constructing survival prediction models. The model performance was assessed mainly using area under the receiver operator characteristic curve (AUC), brier score (BS), and decision curve analysis (DCA). The model interpretability was determined by the permutation importance and Shapley additive explanations values. RESULTS: A total of 11,590 patients were included in this study. Among the 3 models, the CoxPH model ultimately included 10 variables, while RSF and DeepSurv models incorporated 24 variables, respectively. All of the 3 models achieved respectable performance metrics while the DeepSurv model exhibited the highest AUC values and relatively lower BS among these models. The DCA also verified that the DeepSurv model had the best clinical practicality. CONCLUSIONS: The survival prediction tools established in this study can be applied to severe HF patients during vulnerable period by mainly inputting drug treatment duration, thus contributing to optimal clinical decisions prospectively.

Short-term usage of proton pump inhibitors during admission was associated with increased risk of rehospitalization in critically ill patients with myocardial infarction: a cohort study.

PURPOSE: Previous studies showed that long-term use of proton pump inhibitors (PPIs) was associated with cardiovascular events. However, the impact of short-term PPI exposure on intensive care unit (ICU) patients with myocardial infarction (MI) remains largely unknown. This study aims to determine the precise correlation between short-term PPI usage during hospitalization and prognostic outcomes of ICU-admitted MI patients using Medical Information Mart for Intensive Care IV database (MIMIC-IV). METHODS: Propensity score matching (PSM) was applied to adjust confounding factors. The primary study outcome was rehospitalization with mortality and length of stay as secondary outcomes. Binary logistic, multivariable Cox, and linear regression analyses were employed to estimate the impact of short-term PPI exposure on ICU-admitted MI patients. RESULTS: A total of 7249 patients were included, involving 3628 PPI users and 3621 non-PPI users. After PSM, 2687 pairs of patients were matched. The results demonstrated a significant association between PPI exposure and increased risk of rehospitalization for MI in both univariate and multivariate [odds ratio (OR) = 1.157, 95% confidence interval (CI) 1.020-1.313] analyses through logistic regression after PSM. Furthermore, this risk was also observed in patients using PPIs > 7 days, despite decreased risk of all-cause mortality among these patients. It was also found that pantoprazole increased the risk of rehospitalization, whereas omeprazole did not. CONCLUSION: Short-term PPI usage during hospitalization was still associated with higher risk of rehospitalization for MI in ICU-admitted MI patients. Furthermore, omeprazole might be superior to pantoprazole regarding the risk of rehospitalization in ICU-admitted MI patients.

A strategy to comprehensively analyze the bioactivity of complex herbal prescriptions via peak-by-peak cutting and knock-out chromatography: Qiliqiangxin capsule as an example.

An herbal prescription is usually composed of several herbal medicines. The complex and diverse components bring great challenges to its bioactivity study. To comprehensively analyze the bioactivity of an herbal prescription, a new strategy based on peak-by-peak cutting and knock-out chromatography was proposed. In this strategy, active compounds were screened out via peak-by-peak cutting from an herbal extract, and the influence of a compound on the overall activity of the herbal extract was evaluated by knock-out chromatography. Qiliqiangxin capsule is an herbal prescription composed of 11 herbal medicines for the treatment of chronic heart failure. A total of 71 peaks were collected through peak-by-peak cutting, and each peak was identified by a high-resolution mass spectrum. The bioassay against 1,1-diphenyl-2-picrylhydrazyl showed that two types of compounds namely salvianolic acids and caffeoylquinic acids were potent scavengers. Knock-out chromatography suggested that the removal of one single compound had no obvious influence on the overall activity of the Qiliqiangxin capsule. After all the main peaks in the Qiliqiangxin capsule were knocked out, the remaining part still exhibited a potent activity, indicating high activity stability of the Qiliqiangxin capsule. The proposed strategy is helpful for the comprehensive analysis of the bioactivity of other herbal prescriptions.

Two new sesquiterpene aryl esters from Armillaria gallica 012m.

Two new sesquiterpene aryl esters, armimelleolides A and B (1 and 2), and four known ones, were isolated from the EtOAc extract of Armillaria gallica 012 m by column chromatography on silica gel, reversed-phase C18 silica gel and semi-preparative HPLC. Their structures were elucidated on the basis of spectroscopic methods, including extensive 1 D NMR, 2 D NMR and MS. All these compounds showed potential antitumor activities against at least one of the human cancer cell lines (A549, HCT-116, M231 and W256), with IC50 ranging from 2.57 to 19.94 µM.

Three new diphenyl ether derivatives from the fermentation products of an endophytic fungus Phomopsis fukushii.

Three new diphenyl ethers (1-3), together with four known isopentylated diphenyl ethers derivatives (4-7), were isolated from the fermentation products of an endophytic fungus Phomopsis fukushii. Their structures were elucidated by spectroscopic methods, including extensive 1D and 2D NMR techniques. Compounds 1-3 were evaluated for their anti-methicillin-resistant Staphylococcus aureus (anti-MRSA) activity. The results revealed that compounds 1 and 2 showed strong inhibitions with inhibition zone diameters (IZD) of 20.2 ± 2.5 mm and 17.9 ± 2.2 mm, respectively. Compound 3 also showed good inhibition with IZD 15.2 ± 1.8 mm. The IZD data of compound 1 is close to that of positive control with IZD 21.9 ± 2.1 mm.

Antiviral and Cytotoxic Isocoumarin Derivatives from an Endophytic Fungus Aspergillus oryzae.

Oryzaeins A-D (1-4), four new isocoumarin derivatives, along with five known ones (5-9) were isolated from solid cultures of an endophytic fungus Aspergillus oryzae. Their structures were elucidated by detailed spectroscopic analysis and by comparison with reported data of related derivatives. Among them, compounds 1 and 2 represent the first examples of isocoumarins possessing an unusual 2-oxopropyl group and a rare 3-hydroxypropyl group. Compounds 1 and 2 displayed moderate anti-tobacco mosaic virus activities with inhibition rates of 28.4% and 30.6%, respectively, at the concentration of 20 µM. The new compounds showed moderate inhibitory activities against several human tumor cell lines with IC50 values in the range of 2.8-8.8 µM. Supporting information available online at http://www.thieme-connect.de/products.

[A new cytotoxic isocoumarin from endophytic fungus Aspergillus versicolor].

A new isocoumarin, along with five known ones,were isolated from the fermentation products of an endophytic fungus Aspergillus versicolorby using various chromatographic techniques.Their structures were elucidated on the basis of extensivespectroscopic analysis, including 1D-and 2D-NMR techniques. Compound 1 was evaluated for cytotoxicity against five human tumor cell lines. The results showed that 1 exhibited weak cytotoxicityagainst NB4, SHSY5Y and MCF7 cells with IC50 values of 6.8, 4.3,8.8 µmol•L⁻¹, respectively.

Antiviral butyrolactones from the endophytic fungus Aspergillus versicolor.

Versicolactones A-D (1-4), four new butyrolactones, along with four known butyrolactones (5-8) were isolated from the fermentation products of the endophytic fungus Aspergillus versicolor. The structures of compounds 1-4, including absolute configuration, were elucidated by interpretation of the NMR and CD data. Compound 2 was further confirmed by single-crystal X-ray diffraction analysis. In particular, compound 1 is the first naturally occurring butyrolactone possessing an unusual 2-oxopropyl group. More importantly, compounds 1 and 8 displayed significant antitobacco mosaic virus activities with inhibition rates of 46.4 % and 35.4 %, even more potent than the positive control ningnanmycin (30.8 %). Compound 1 also showed moderate cytotoxicity against A549 and MCF7 cells with IC50 values of 3.2 and 2.5 µM, respectively.

Isocoumarins from the fermentation products of a plant entophytic fungus Penicillium oxalicum.

Three new isocoumarins, terrecoumarins A-C (1-3), together with six known isocoumarins (4-9) were isolated from the fermentation products of the fungus Penicillium oxalicum 0403. Their structures were elucidated by spectroscopic methods, including extensive 1D and 2D NMR techniques. The anti-tobacco mosaic virus (anti-TMV) activities of 1-9 were evaluated. The results revealed that compound 1 showed high anti-TMV activity with inhibition rate 25.4 ± 3.5%. Other compounds also showed weak activity with inhibition rate in the range of 11.3-18.9%.

Dihydroxanthenones from the fermentation product of an endophytic fungus Gliomastix murorum.

Three new dihydroxanthones, muroxanthenones A-C (1-3), together with three known dihydroxanthones (4-6) were isolated from the fermentation products of an endophytic fungus Gliomastix murorum. Their structures were elucidated by spectroscopic methods, including extensive 1D and 2D NMR techniques. Compound 3 showed high cytotoxicities against NB4 and PC3 cell with IC(50) values of 2.2 and 2.8 µM. The other compounds also showed moderate cytotoxicities for some tested cell lines with IC(50) values between 4.1 and 9.5 µM.

[The evaluation of efflux transporter model based on RNA interference technology in vitro].

In the present study, the specifically knockdown models of P-gp or MRP2 were constructed by using a series of chemically synthesized small interfering RNA (siRNA) in vitro. The expression of P-gp and MRP2 was measured by real-time PCR and Western blot, and the function was evaluated by applying P-gp and MRP2 substrate, rhodamine and methotrexate. The results showed that MRP2 siRNA-3 or P-gp siRNA-2 significantly decreased the mRNA expression of MRP2 or P-gp, the inhibition ratio was 68% or 84%; MRP2 siRNA-3 or P-gp siRNA-2 at a dose of 80 nmol x L(-1) significantly reduced the protein expression of MRP2 or P-gp at 48 h after treatment, the inhibition ratio was 62% or 70%. Meanwhile, other transporters were not influenced by siRNA. When pretreatment with MRP2 siRNA-3 or P-gp siRNA-2, the efflux of methotrexate or rhodamine decreased significantly and the intra-cellular concentration increased. The results suggested that chemically synthesized siRNA could significantly inhibit the expression and function of MRP2 and P-gp, and the model of RNAi in vitro could be used to evaluate the role of efflux transporters in transportation of drugs.

The anti-TMV potency of the tobacco-derived fungus Aspergillus versicolor and its active alkaloids, as anti-TMV activity inhibitors.

Nicotiana tabacum (tobacco) has attracted interest as one of the most economically important industrial crops widely cultivated in China, whose dried leaves are popularly consumed medicinally and recreationally by human societies. In this study, five undescribed alkaloids derivatives, isoaspergillines A-E, together with eight known alkaloids, notoamide D, (1R,4S)-4-benzyl-1-isopropyl-2,4-dihydro-1H-pyrazino-[2,1-b]quinazoline-3,6-dione, protuboxepin K, notoamide C, notoamide M, deoxybrevianamide E, cyclo (D-Pro-L-Trp), and versicolamide B, were obtained from the culture of the Nicotiana tabacum-derived fungus Aspergillus versicolor. Their structures were mainly elucidated through comprehensive analyses of spectroscopic data. Bioactivity evaluation of all isolated compounds revealed that isoaspergilline A and notoamide M exhibited anti-TMV activities with IC50 values of 20.0 and 22.8 µM, respectively. Molecular docking suggested that isoaspergilline A and notoamide M were well located into the active site of anti-TMV by interacting with SER138, SER143, and ASN73 residues. This study enlightens the therapeutic potential of the endophytic fungus A. versicolor and it is helpful to find undescribed anti-TMV activity inhibitors, as well as searching for new anti-TMV candidates from natural sources.

[Analyzing the Chinese medicine pathogenesis of stroke].

Both ischemic and hemorrhage stroke pertain to the category of wind stroke in Chinese medicine (CM). Up to date, it is deemed that the etiology and pathogenesis of wind stroke are wind, fire, sputum, qi, stasis, and deficiency. Among them, it is regarded that wind and fire are the key factors triggering wind stroke. By analyzing the time order and causality, it is found that wind stroke is prior to the onset of wind and fire, wind and fire are the secondary outcomes of wind stroke. By parallel comparing stroke with thromboembolism and hemorrhagic diseases in other Zang-organs, it can be comprehended that the reason why wind symptoms appear in stroke is due to its physiological feature of brain itself. Based on Neijing, the pathogenesis of wind stroke is proposed as follows. Tunnels of viscera (vessels) get lesions. The old pathogenic factors of sputum and stasis or the stasis formed by bleeding inside viscera consume qi, and blood of viscera and damage the spirits hidden in them. The damage of Gan-spirit causes symptoms of stroke, such as hemiplegia, deviation of eyes and mouth, and so on. Wind and fire symptoms are caused by the injury of Gan blood and yin, and/or the stagnation of fire in pericardium (the pathway organ) due to obstruction by old pathogenic factors and stasis (formed by bleeding).

Measles virus infection in adults induces production of IL-10 and is associated with increased CD4+ CD25+ regulatory T cells.

Despite steady progress in elimination of measles virus globally, measles infection still causes 500,000 annual deaths, mostly in developing countries where endemic measles strains still circulate. Many adults are infected every year in China, with symptoms more severe than those observed in children. In this study, we have used blood samples from adult measles patients in Shanghai and age-matched healthy controls to gain an understanding of the immune status of adult measles patients. IFN-alpha mRNA was reduced in patient PBMC compared with healthy controls. In contrast, gene expression and plasma production of IL-2, IL-10, and IFN-gamma were elevated in patient blood. A similar cytokine profile was observed at early times when cultured PBMC were infected with a clinical isolate of measles virus. In contrast to previous studies in pediatric patients, we did not find a reduction in total CD4(+) and CD8(+) T cells in patient PBMC. Interestingly, we found that CD4(+)CD25(+)CD127(low) regulatory T cells were significantly increased in patient PBMC compared with controls. Using intracellular cytokine staining we also show that the measles virus induces IL-10-producing CD14(+) and CD4(+)CD25(+) cells in PBMC. Our results show that adult measles patients in the acute phase of the disease have a mixed Th1/Th2 type response, accompanied with severe immunosuppression of both innate and adaptive responses including suppression of type I IFN. Both regulatory T cells and plasma IL-10 may contribute to the immunosuppression.

Basal expression of metallothionein suppresses butenolide-induced oxidative stress in liver homogenates in vitro.

Butenolide (4-acetamido-4-hydroxy-2-butenoic acid gamma-lactone) is a Fusarium mycotoxin which is frequently detected in foodstuffs and feedstuffs for human and animal consumption. It can evoke a broad spectrum of toxicities, thus posing a potential health risk to both humans and animals. Previous study showed that this mycotoxin produced a significant oxidative stress, and several antioxidants abated this effect. Metallothionein (MT) has been proposed as a potent antioxidant, therefore, this study attempts to determine whether endogenous expression of MT protects against butenolide-induced hepatic oxidative stress by using an in vitro incubation system of liver homogenates prepared from MT-I/II null (MT-/-) mice, and the corresponding wild type (MT+/+) mice. The results showed that butenolide elicited significant oxidative stress in both MT-/- mice and MT+/+ mice; however, MT-/- mice were more sensitive than MT+/+ mice to butenolide-induced hepatic oxidative stress, as evidenced by more production of thiobarbituric acid reactive substances and nitric oxide, and by more severe reductions of glutathione, superoxide dismutase and glutathione peroxidase in the liver homogenates of MT-/- mice than those of MT+/+ mice. These findings implicated the antioxidant potency of basal expression of MT in suppression of the oxidative stress of butenolide.

[Studies on chemical constituents of Swertia mussotii].

OBJECTIVE: To study the chemical constituents of Swertia mussotii. METHODS: The constituents were isolated by various column chromatography methods, and their structures were identified by physico-chemical properties and spectral analysis. RESULTS: Eleven compounds were isolated and identified as 1,3, 8-trihydroxy-7-methoxyxanthone (I), 2,8-dihydroxy-1,6-dimethyoxyxanthone (II), 1,8-dihydroxy-2,6-dimethoxyxanthone (III), 1,2,8-trimethoxyxanthone (IV), 1,3,5,6-tetrohyroxyxanthone (V), 1,8-dihydroxy-3,7-dimethoxyxanthone (VI), beta-daucosterol (VII), clerosterol 3beta-O-[6'-o-hydro-benzene-beta-D-glucoside] (VIII), ursolicacid (IX), 3beta,28-dihydroxylup-20 (29) -ene (X), erythrocentaurin (XI). CONCLUSION: Compounds VIII, IX and X are isolated from Swertia mussotii for the first time.

Lymph node metastasis in Chinese patients with clinical T1 non-small cell lung cancer: A multicenter real-world observational study.

BACKGROUND: Approximately 8.3-15.9% of patients with clinical stage I non-small cell lung cancer are subsequently shown to have lymph node metastasis. However, the clinical characteristics of patients with lymph node metastasis in China are not fully understood. METHODS: This is a multicenter retrospective analysis of pathological T1 non-small cell lung cancer patients who underwent surgical resection from 2 January 2014 to 27 December 2017. Clinical and pathological information was collected with the assistance of the Large-scale Data Analysis Center of Cancer Precision Medicine-LinkDoc database. The clinical and pathological factors associated with lymph node metastasis were analyzed by univariate and multivariate logistic regression. RESULTS: A total of 10 885 participants (51.6% women; 15.3% squamous cell carcinoma) were included in the analysis. The median age was 60.0 years (range 12.9-86.6 years). A total of 1159 patients (10.6%) had metastases in mediastinal nodes (N2), and 640 patients (5.9%) had metastasis in pulmonary lymph nodes (N1). Most patients had T1b lung cancer (4766, 43.8%). Of the patients, 3260 (29.9%) were current or former smokers. The univariate and multivariate analyses showed that younger age, squamous cell carcinoma, poor differentiation, larger tumor size, carcinoembryonic antigen level ≥5 ng/mL, and vascular invasion (+) were significantly associated with higher percentages of lymph node metastases (P < 0.001 for all). CONCLUSION: This real-world study showed the significant association of lymph node metastasis with age, tumor size, histology and differentiation, carcinoembryonic antigen levels, and status of vascular invasion. Female patients with T1a adenocarcinoma in the right upper lobe barely had lymph node metastasis.

Isopentylated diphenyl ether derivatives from the fermentation products of an endophytic fungus Phomopsis fukushii.

Three new isopentylated diphenyl ethers, (1-3), together with two known isopentylated diphenyl ethers derivatives (4 and 5) were isolated from the fermentation products of an endophytic fungus Phomopsis fukushii. Their structures were elucidated by spectroscopic methods, including extensive 1D- and 2D NMR techniques. Compounds 1-3 were evaluated for their anti-methicillin-resistant Staphylococcus aureus (anti-MRSA) activity. The results showed that compounds 1-3 showed strong activity with diameter of inhibition zone (IZD) of 21.8 ± 2.4 mm, 16.8 ± 2.2 mm, and 15.6 ± 2.0 mm, respectively.

Toxic effects of Fusarium mycotoxin butenolide on rat myocardium and primary culture of cardiac myocytes.

Mycotoxin toxicosis has been implicated in the etiopathogenesis of Keshan disease (KD), an endemic cardiomyopathy prevailing in some regions of China. Butenolide (4-acetamido-4-hydroxy-2-butenoic acid gamma-lactone, CAS No. 16275-44-8), a mycotoxin produced by several Fusarium species such as Fusarium tricinctum and Fusarium graminearum, is frequently detected from the cereals in the endemic areas of KD. The present study is undertaken to investigate whether this mycotoxin can induce myocardial damage. Exposure of primary culture of cardiac myocytes to butenolide resulted in significant cytotoxicity, manifested by changes in cell morphology and decreases in cell viability. Consistent with the in vitro findings, distinct myocardial toxicity in vivo was observed after administration of rats by gavage with butenolide (10 and 20 mg/kg/day) for 2 months, and the myocardial injuries were characterized by focal necrosis of myocardium and fragmentation of myofiber. Butenolide also induced significant oxidative damage to the myocardium in vitro evidenced by a concentration-dependent lipid peroxidation in the myocardial homogenates, whereas antioxidants superoxide dismutase (SOD), N-acetylcysteine (NAC) and glutathione (GSH) provided significant protections against this oxidative effect. Taken together, these results clearly reveal that butenolide possesses the potential to induce myocardial toxicity. The present findings may reinforce the hypothesis that toxicosis by mycotoxins is one of the etiological factors for KD.

The oxidative damage of butenolide to isolated erythrocyte membranes.

Butenolide (CAS No. 16275-44-8), a mycotoxin produced by several Fusarium species, has been shown to be a potential risk factor for animal and human health. This study was undertaken to investigate the potential oxidative damage of butenolide to biomembranes in vitro using the erythrocyte membrane model. Following exposure of isolated rat erythrocyte membranes to butenolide, the extent of oxidative damage was assessed by measuring lipid peroxidation, -SH groups content, Ca2+/Mg2+-ATPase and Na+/K+-ATPase activities, and conformational changes in membrane proteins. It was observed that butenolide resulted in a significant lipid peroxidation, revealed by a concentration-dependent increase in the level of thiobarbituric acid reactive substances (TBARS). Similarly, this toxin induced a concentration-dependent decrease in the content of membrane total -SH groups, as well as free -SH groups. Membrane-bound enzymes were also impaired by the toxin, demonstrated by the marked inhibition of the activities of Na+/K+-ATPase and Ca2+/Mg2+-ATPase. Conformational changes in membrane proteins were determined using electron paramagnetic resonance (EPR) spin labeling. Butenolide caused an increase in the ratio of weakly to strongly immobilized components (W/S ratio) in a manner of concentration-dependent, indicating conformational changes in membrane proteins occurred. In conclusion, these findings indicate that butenolide is capable of inducing significant oxidative damage to membrane lipids and proteins.