Cytoreductive surgery offers prognostic benefits in metastatic gastrointestinal stromal tumors with generalized progression following imatinib therapy: a single institute retrospective study.

BACKGROUND: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Distant metastasis has been detected in approximately 50% of GIST patients at the first diagnosis. The surgical strategy for metastatic GIST with generalized progression (GP) after imatinib therapy remains unclear. METHODS: We recruited 15 patients with imatinib-resistant metastatic GIST. They received cytoreductive surgery (CRS) for tumor rupture, intestinal obstruction and gastrointestinal bleeding. We collected clinical, pathological and prognostic data for analyses. RESULTS: OS and PFS after R0/1 CRS were 56.88 ± 3.47 and 26.7 ± 4.12 months, respectively, when compared with 26 ± 5.35 and 5 ± 2.78 months after R2 CRS (P = 0.002 and P < 0.001, respectively). The OS of patients from the initiation of imatinib in the R0/1 group was 133.90 ± 15.40 months when compared with 59.80 ± 10.98 months in the R2 CRS group. There were two significant grade III complications after 15 operations (13.3%). No patient underwent reoperation. In addition, no perioperative death occurred. CONCLUSIONS: R0/1 CRS is highly probable to provide prognostic benefits for patients with metastatic GIST who experience GP following imatinib treatment. An aggressive surgical strategy for achieving R0/1 CRS can be deemed safe. If applicable, R0/1 CRS should be carefully considered in imatinib-treated patients with GP metastatic GIST.

Multi-compound and drug-combination pharmacokinetic research on Chinese herbal medicines.

Traditional medicine has provided a basis for health care and disease treatment to Chinese people for millennia, and herbal medicines are regulated as drug products in China. Chinese herbal medicines have two features. They normally possess very complex chemical composition. This makes the identification of the constituents that are together responsible for the therapeutic action of an herbal medicine challenging, because how to select compounds from an herbal medicine for pharmacodynamic study has been a big hurdle in such identification efforts. To this end, a multi-compound pharmacokinetic approach was established to identify potentially important compounds (bioavailable at the action loci with significant exposure levels after dosing an herbal medicine) and to characterize their pharmacokinetics and disposition. Another feature of Chinese herbal medicines is their typical use as or in combination therapies. Coadministration of complex natural products and conventional synthetic drugs is prevalent worldwide, even though it remains very controversial. Natural product-drug interactions have raised wide concerns about reduced drug efficacy or safety. However, growing evidence shows that incorporating Chinese herbal medicines into synthetic drug-based therapies delivers benefits in the treatment of many multifactorial diseases. To address this issue, a drug-combination pharmacokinetic approach was established to assess drug-drug interaction potential of herbal medicines and degree of pharmacokinetic compatibility for multi-herb combination and herbal medicine-synthetic drug combination therapies. In this review we describe the methodology, techniques, requirements, and applications of multi-compound and drug-combination pharmacokinetic research on Chinese herbal medicines and to discuss further development for these two types of pharmacokinetic research.

[Mahuang (herbaceous stem of Ephedra spp.): chemistry, pharmacodynamics, and pharmacokinetics].

The Chinese medicinal herb Mahuang is herbaceous stem of Ephedra sinica, E. intermedia, or E. equisetina(Family, Ephedraceae). In China, Mahuang has been used, all the way over a millennium, as a key component herb of many herbal medicines for management of epidemics of acute respiratory illness and is also used in officially recommended herbal medicines for COVID-19. Mahuang is the first-line medicinal herb for cold and wheezing and also an effective diuretic herb for edema. However, Mahuang can also exert significant adverse effects. The key to safety and effectiveness is rational and precise use of the herb. In this review article, we comprehensively summarize chemical composition of Mahuang and associated differences in pharmacognosy, pharmacodynamics and pharmacokinetics of Mahuang compounds, along with the adverse effects of Mahuang compounds and products. Based on full understanding of how Mahuang is used in Chinese traditional medicine, systematic research on Mahuang in line with contemporary standards of pharmaceutical sciences will facilitate promoting Chinese herbal medicines to become more efficient in management of epidemic illnesses, such as COVID-19. To this end, we recommend research on Mahuang of two aspects, i.e., pharmacological investigation for its multicompound-involved therapeutic effects and toxicological investigation for clinical manifestation of the adverse effects, chemicals responsible for the adverse effects, and conditions for safe use of the herb and the herb-containing medicines.

Pharmacokinetics-based identification of pseudoaldosterogenic compounds originating from Glycyrrhiza uralensis roots (Gancao) after dosing LianhuaQingwen capsule.

LianhuaQingwen capsule, prepared from an herbal combination, is officially recommended as treatment for COVID-19 in China. Of the serial pharmacokinetic investigations we designed to facilitate identifying LianhuaQingwen compounds that are likely to be therapeutically important, the current investigation focused on the component Glycyrrhiza uralensis roots (Gancao). Besides its function in COVID-19 treatment, Gancao is able to induce pseudoaldosteronism by inhibiting renal 11ß-HSD2. Systemic and colon-luminal exposure to Gancao compounds were characterized in volunteers receiving LianhuaQingwen and by in vitro metabolism studies. Access of Gancao compounds to 11ß-HSD2 was characterized using human/rat, in vitro transport, and plasma protein binding studies, while 11ß-HSD2 inhibition was assessed using human kidney microsomes. LianhuaQingwen contained a total of 41 Gancao constituents (0.01-8.56 µmol/day). Although glycyrrhizin (1), licorice saponin G2 (2), and liquiritin/liquiritin apioside (21/22) were the major Gancao constituents in LianhuaQingwen, their poor intestinal absorption and access to colonic microbiota resulted in significant levels of their respective deglycosylated metabolites glycyrrhetic acid (8), 24-hydroxyglycyrrhetic acid (M2D; a new Gancao metabolite), and liquiritigenin (27) in human plasma and feces after dosing. These circulating metabolites were glucuronized/sulfated in the liver and then excreted into bile. Hepatic oxidation of 8 also yielded M2D. Circulating 8 and M2D, having good membrane permeability, could access (via passive tubular reabsorption) and inhibit renal 11ß-HSD2. Collectively, 1 and 2 were metabolically activated to the pseudoaldosterogenic compounds 8 and M2D. This investigation, together with such investigations of other components, has implications for precisely defining therapeutic benefit of LianhuaQingwen and conditions for its safe use.

Human pharmacokinetics of ginkgo terpene lactones and impact of carboxylation in blood on their platelet-activating factor antagonistic activity.

Terpene lactones are a class of bioactive constituents of standardized preparations of Ginkgo biloba leaf extract, extensively used as add-on therapies in patients with ischemic cardiovascular and cerebrovascular diseases. This investigation evaluated human pharmacokinetics of ginkgo terpene lactones and impact of their carboxylation in blood. Human subjects received oral YinXing-TongZhi tablet or intravenous ShuXueNing, two standardized ginkgo preparations. Their plasma protein-binding and platelet-activating factor antagonistic activity were assessed in vitro. Their carboxylation was assessed in phosphate-buffered saline (pH 7.4) and in human plasma. After dosing YinXing-TongZhi tablet, ginkgolides A and B and bilobalide exhibited significantly higher systemic exposure levels than ginkgolides C and J; after dosing ShuXueNing, ginkgolides A, B, C, and J exhibited high exposure levels. The compounds' unbound fractions in plasma were 45-92%. Apparent oral bioavailability of ginkgolides A and B was mostly >100%, while that of ginkgolides C and J was 6-15%. Bilobalide's bioavailability was probably high but lower than that of ginkgolides A/B. Terminal half-lives of ginkgolides A, B, and C (4-7 h) after dosing ShuXueNing were shorter than their respective values (6-13 h) after dosing YinXing-TongZhi tablet. Half-life of bilobalide after dosing the tablet was around 5 h. Terpene lactones were roughly evenly distributed in various body fluids and tissues; glomerular-filtration-based renal excretion was the predominant elimination route for the ginkgolides and a major route for bilobalide. Terpene lactones circulated as trilactones and monocarboxylates. Carboxylation reduced platelet-activating factor antagonistic activity of ginkgolides A, B, and C. Ginkgolide J, bilobalide, and ginkgo flavonoids exhibited no such bioactivity. Collectively, differences in terpene lactones' exposure between the two preparations and influence of their carboxylation in blood should be considered in investigating the relative contributions of terpene lactones to ginkgo preparations' therapeutic effects. The results here will inform rational clinical use of ginkgo preparations.

Pharmacokinetics and disposition of anlotinib, an oral tyrosine kinase inhibitor, in experimental animal species.

Anlotinib is a new oral tyrosine kinase inhibitor; this study was designed to characterize its pharmacokinetics and disposition. Anlotinib was evaluated in rats, tumor-bearing mice, and dogs and also assessed in vitro to characterize its pharmacokinetics and disposition and drug interaction potential. Samples were analyzed by liquid chromatography/mass spectrometry. Anlotinib, having good membrane permeability, was rapidly absorbed with oral bioavailability of 28%-58% in rats and 41%-77% in dogs. Terminal half-life of anlotinib in dogs (22.8±11.0 h) was longer than that in rats (5.1±1.6 h). This difference appeared to be mainly associated with an interspecies difference in total plasma clearance (rats, 5.35±1.31 L·h-1·kg-1; dogs, 0.40±0.06 L·h-1/kg-1). Cytochrome P450-mediated metabolism was probably the major elimination pathway. Human CYP3A had the greatest metabolic capability with other human P450s playing minor roles. Anlotinib exhibited large apparent volumes of distribution in rats (27.6±3.1 L/kg) and dogs (6.6±2.5 L/kg) and was highly bound in rat (97%), dog (96%), and human plasma (93%). In human plasma, anlotinib was predominantly bound to albumin and lipoproteins, rather than to α1-acid glycoprotein or γ-globulins. Concentrations of anlotinib in various tissue homogenates of rat and in those of tumor-bearing mouse were significantly higher than the associated plasma concentrations. Anlotinib exhibited limited in vitro potency to inhibit many human P450s, UDP-glucuronosyltransferases, and transporters, except for CYP3A4 and CYP2C9 (in vitro half maximum inhibitory concentrations, <1 µmol/L). Based on early reported human pharmacokinetics, drug interaction indices were 0.16 for CYP3A4 and 0.02 for CYP2C9, suggesting that anlotinib had a low propensity to precipitate drug interactions on these enzymes. Anlotinib exhibits many pharmacokinetic characteristics similar to other tyrosine kinase inhibitors, except for terminal half-life, interactions with drug metabolizing enzymes and transporters, and plasma protein binding.

Pharmacokinetics and disposition of monoterpene glycosides derived from Paeonia lactiflora roots (Chishao) after intravenous dosing of antiseptic XueBiJing injection in human subjects and rats.

AIM: Monoterpene glycosides derived from Paeonia lactiflora roots (Chishao) are believed to be pharmacologically important for the antiseptic herbal injection XueBiJing. This study was designed to characterize the pharmacokinetics and disposition of monoterpene glycosides. METHODS: Systemic exposure to Chishao monoterpene glycosides was assessed in human subjects receiving an intravenous infusion and multiple infusions of XueBiJing injection, followed by assessment of the pharmacokinetics of the major circulating compounds. Supportive rat studies were also performed. Membrane permeability and plasma-protein binding were assessed in vitro. RESULTS: A total of 18 monoterpene glycosides were detected in XueBiJing injection (content levels, 0.001-2.47 mmol/L), and paeoniflorin accounted for 85.5% of the total dose of monoterpene glycosides detected. In human subjects, unchanged paeoniflorin exhibited considerable levels of systemic exposure with elimination half-lives of 1.2-1.3 h; no significant metabolite was detected. Oxypaeoniflorin and albiflorin exhibited low exposure levels, and the remaining minor monoterpene glycosides were negligible or undetected. Glomerular-filtration-based renal excretion was the major elimination pathway of paeoniflorin, which was poorly bound to plasma protein. In rats, the systemic exposure level of paeoniflorin increased proportionally as the dose was increased. Rat lung, heart, and liver exposure levels of paeoniflorin were lower than the plasma level, with the exception of the kidney level, which was 4.3-fold greater than the plasma level; brain penetration was limited by the poor membrane permeability. CONCLUSION: Due to its significant systemic exposure and appropriate pharmacokinetic profile, as well as previously reported antiseptic properties, paeoniflorin is a promising XueBiJing constituent of therapeutic importance.

Methylation and its role in the disposition of tanshinol, a cardiovascular carboxylic catechol from Salvia miltiorrhiza roots (Danshen).

AIM: Tanshinol is an important catechol in the antianginal herb Salvia miltiorrhiza roots (Danshen). This study aimed to characterize tanshinol methylation. METHODS: Metabolites of tanshinol were analyzed by liquid chromatography/mass spectrometry. Metabolism was assessed in vitro with rat and human enzymes. The major metabolites were synthesized for studying their interactions with drug metabolizing enzymes and transporters and their vasodilatory properties. Dose-related tanshinol methylation and its influences on tanshinol pharmacokinetics were also studied in rats. RESULTS: Methylation, preferentially in the 3-hydroxyl group, was the major metabolic pathway of tanshinol. In rats, tanshinol also underwent considerable 3-O-sulfation, which appeared to be poor in human liver. These metabolites were mainly eliminated via renal excretion, which involved tubular secretion mainly by organic anion transporter (OAT) 1. The methylated metabolites had no vasodilatory activity. Entacapone-impaired methylation did not considerably increase systemic exposure to tanshinol in rats. The saturation of tanshinol methylation in rat liver could be predicted from the Michaelis constant of tanshinol for catechol-O-methyltransferase (COMT). Tanshinol had low affinity for human COMT and OATs; its methylated metabolites also had low affinity for the transporters. Tanshinol and its major human metabolite (3-O-methyltanshinol) exhibited negligible inhibitory activities against human cytochrome P450 enzymes, organic anion transporting polypeptides 1B1/1B3, multidrug resistance protein 1, multidrug resistance-associated protein 2, and breast cancer resistance protein. CONCLUSION: Tanshinol is mainly metabolized via methylation. Tanshinol and its major human metabolite have low potential for pharmacokinetic interactions with synthetic antianginal agents. This study will help define the risk of hyperhomocysteinemia related to tanshinol methylation.

Construction of universal equations for knot attributes of three coniferous species.

We constructed base model, dummy variable model, and mixture model with three variables including knot diameter, loose knot length, and sound knot length with three typical coniferous species, Pinus koraiensis, Larix olgensis, and Pinus sylvestris var. mongolica, from the Linkou Forestry Bureau and Mengjiagang forest farm in Heilongjiang Province in 2020. We analyzed the differences in knot properties among different tree species and simplified the modeling work. Firstly, we collected relevant knot property data through the sectioning method based on relevant literature, transformation of the model form and substitution of related variables to conduct a base model. We transformed the species into dummy variables as qualitative factors, and introduced the dummy variable model of the relevant attributes into the base model. We introduced the random effects of sample trees and sample plots when constructing the mixture model. By comparing evaluation indicators, such as Akaike Information Criterion (AIC) and Bayesian Information Criterion (BIC), the mixture model with the best fitting effect was selected. We selected the optimal universal equation by comparing the fitting accuracy of the base model, dummy variable model and mixture model. The fitting accuracy of the dummy variable model and mixture model was higher than that of the basic model. The evaluation indicators (AIC and BIC) showed that the mixture model had a better fitting effect on knot properties than the dummy variable model. In the model comparison results, R2 of mixture models for sound knot length, the loose knot length, and knot diameter increased by 13.2%, 84.8% and 40.3%, respectively. The predictive accuracy of the three base models for different tree species' knot attributes was above 90%, and both the prediction accuracy of the dummy variable model and mixture model were above 94%, indicating that the constructed models could well predict knot-related properties. From the perspective of tree species, the sound knot length, knot diameter, and loose knot length was in order of P. sylvestris var. mongolica > P. koraiensis > L. olgensis. Fitted results of the dummy variable model and the mixture model were superior to the basic model, with higher accuracy.

Mechanistic analysis of resveratrol in cardiac hypertrophy by network pharmacology and animal experiments.

Resveratrol (Res) serves a protective role in hepatic, cardiovascular and autoimmune hypertrophic disease. However, the mechanisms by which Res ameliorates cardiac hypertrophy have not yet been fully elucidated. In the present study, network pharmacology was used to construct a network and perform enrichment analysis to evaluate the effect of Res on cardiac hypertrophy. Experimental validation was performed using 40 Sprague­Dawley rats administered intragastric 80 mg/kg/day Res and 20 mg/kg/day 3­methyladenine (3­MA) for 4 weeks. A total of 444 targets associated with cardiac hypertrophy and 229 potential disease­associated targets of Res were identified, from which 8 overlapping genes were demonstrated. Gene Ontology function and 'Kyoto Encyclopedia of Genes and Genomes' pathway enrichment analysis demonstrated that Res affected STAT3 and was associated with autophagy signaling pathways, including 'negative regulation of autophagy for hypertrophic cardiomyopathy'. Furthermore, Res ameliorated isoprenaline­induced cardiac hypertrophy, significantly improving cardiac dysfunction in vivo experiment (echocardiography, the degree of ventricular hypertrophy, etc.); this effect may be associated with regulation of autophagy and apoptosis. The autophagy inhibitor 3­MA markedly reversed the anti­cardiac hypertrophy effects of Res. In conclusion, Res inhibited cardiac hypertrophy via downregulation of the apoptosis signaling pathway and upregulating the autophagy pathway.

Molecular Basis Underlying Hepatobiliary and Renal Excretion of Phenolic Acids of Salvia miltiorrhiza Roots (Danshen).

Phenolic acids are cardiovascular constituents (originating from the Chinese medicinal herb Salvia miltiorrhiza root/Danshen) of DanHong and many other Danshen-containing injections. Our earlier pharmacokinetic investigation of DanHong suggested that hepatic and/or renal uptake of the Danshen compounds was the crucial steps in their systemic elimination. This investigation was designed to survey the molecular basis underlying hepatobiliary and renal excretion of the Danshen compounds, i.e., protocatechuic acid, tanshinol, rosmarinic acid, salvianolic acid D, salvianolic acid A, lithospermic acid, and salvianolic acid B. A large battery of human hepatic and renal transporters were screened for transporting the Danshen compounds and then characterized for the uptake kinetics and also compared with associated rat transporters. The samples were analyzed by liquid chromatography/mass spectrometry. Because the Danshen phenolic acids are of poor or fairly good membrane permeability, their elimination via the liver or kidneys necessitates transporter-mediated hepatic or renal uptake from blood. Several human transporters were found to mediate hepatic and/or renal uptake of the Danshen compounds in a compound-molecular-mass-related manner. Lithospermic acid and salvianolic acid B (both >500 Da) underwent systemic elimination, initiated by organic anion-transporting polypeptide (OATP)1B1/OATP1B3-mediated hepatic uptake. Rosmarinic acid and salvianolic acids D (350-450 Da) underwent systemic elimination, initiated by OATP1B1/OATP1B3/organic anion transporter (OAT)2-mediated hepatic uptake and by OAT1/OAT2-mediated renal uptake. Protocatechuic acid and tanshinol (both <200 Da) underwent systemic elimination, initiated by OAT1/OAT2-mediated renal uptake and OAT2-mediated hepatic uptake. A similar scenario was observed with the rat orthologs. The investigation findings advance our understanding of the disposition of the Danshen phenolic acids and could facilitate pharmacokinetic research on other Danshen-containing injections.

Emerging blood exosome-based biomarkers for preclinical and clinical Alzheimer's disease: a meta-analysis and systematic review.

Blood exosomes, which are extracellular vesicles secreted by living cells into the circulating blood, are regarded as a relatively noninvasive novel tool for monitoring brain physiology and disease states. An increasing number of blood cargo-loaded exosomes are emerging as potential biomarkers for preclinical and clinical Alzheimer's disease. Therefore, we conducted a meta-analysis and systematic review of molecular biomarkers derived from blood exosomes to comprehensively analyze their diagnostic performance in preclinical Alzheimer's disease, mild cognitive impairment, and Alzheimer's disease. We performed a literature search in PubMed, Web of Science, Embase, and Cochrane Library from their inception to August 15, 2020. The research subjects mainly included Alzheimer's disease, mild cognitive impairment, and preclinical Alzheimer's disease. We identified 34 observational studies, of which 15 were included in the quantitative analysis (Newcastle-Ottawa Scale score 5.87 points) and 19 were used in the qualitative analysis. The meta-analysis results showed that core biomarkers including Aß1-42, P-T181-tau, P-S396-tau, and T-tau were increased in blood neuron-derived exosomes of preclinical Alzheimer's disease, mild cognitive impairment, and Alzheimer's disease patients. Molecules related to additional risk factors that are involved in neuroinflammation (C1q), metabolism disorder (P-S312-IRS-1), neurotrophic deficiency (HGF), vascular injury (VEGF-D), and autophagy-lysosomal system dysfunction (cathepsin D) were also increased. At the gene level, the differential expression of transcription-related factors (REST) and microRNAs (miR-132) also affects RNA splicing, transport, and translation. These pathological changes contribute to neural loss and synaptic dysfunction. The data confirm that the above-mentioned core molecules and additional risk-related factors in blood exosomes can serve as candidate biomarkers for preclinical and clinical Alzheimer's disease. These findings support further development of exosome biomarkers for a clinical blood test for Alzheimer's disease. This meta-analysis was registered at the International Prospective Register of Systematic Reviews (Registration No. CRD4200173498, 28/04/2020).

[Construction of the additive model system for heartwood, sapwoodand bark taper of Pinus koraiensis plantation in different regions of Heilongjiang Province, China]. / é»‘é¾™æ±Ÿä¸åŒåŒºåŸŸäººå·¥çº¢æ¾å¿ƒè¾¹æåŠæ ‘çš®å‰Šåº¦å¯åŠ æ€§æ¨¡åž‹ç³»ç»Ÿæž„å»º.

With the commonly used variable-exponent taper models developed by Kozak (1988), Muhairwe (1999), Lee (2003) and Kozak (2004), we aimed to develop taper functions of diameter outside bark (DOB), heartwood diameter (HD), sapwood width (SW), and bark thickness (BT) based on the data of 2977 discs from 103 sample trees of Pinus koraiensis plantations under different conditions in Mengjiagang Forest Farm, Dongjingcheng and Linkou Forestry Bureau in Heilongjiang Province. We selected the optimal basic model after comparison. By using seemingly unrelated regression (SUR) method in the PROC MODEL of SAS software, we established an additive model system for the taper equations of DOB, HD, SW and BT. By introducing the region as a dummy variable, the models were evaluated by coefficient determination (Radj2), root mean square error (RMSE), Akaike information criterion (AIC) and Bayesian information criterion (BIC). The results showed that the taper model developed by Kozak (2004) was the optimal one for the DOB, HD, SW and BT. When satisfying the additivity of each component and total amount, the additivity model system got better prediction effect, with a prediction precision of more than 98%. The additive model system with dummy variables improved the prediction ability to varying degrees, especially the prediction precision of HD and SW models. Minor differences existed in DOB and BT among different regions, while enormous differences in HD and SW. The additive model system with dummy variables not only had high prediction accuracy but also satisfied the additive logic of DOB, HD, SW and BT, which provided a basis for accurate estimation of heartwood, sapwood and bark volume of P. koraiensis.

Extraction of branch factors and model construction for Larix plantation using terrestrial laser scanning (TLS).

Forest parameters could be estimated without damage using terrestrial laser scanning (TLS). In this study, 1266 sets of branch parameters, including branch height, branch chord length, branch length, branch angle, branch diameter and the branch arc height, of 26 Larix trees were extracted based on TLS using point cloud processing software in the way of human-computer interaction. The average of extracted maximum relative height of the branches was 0.83. The accuracy of the extracted branch attributes followed the order of branch height > branch chord length > branch length > branchdiameter (with the branch diameter >20 mm) > branch arc height. After dividing the crown into four parts, it proved that the density of the branches increased while the extraction ratio and precision of branches decreased with the increase of crown height. Due to the low accuracy of branch diameter extraction, we developed a base diameter prediction model using the branch chord length, the height of branch, diameter at breast height and tree height as independent variables. The measured, extracted and model predicted values of different base diameter were compared, and discovered that accuracy of model prediction was greater than that of extraction by TLS. For timber production, the most worthy wood was the middle and lower section of the tree. The method could accurately extract tree height, diameter at breast height (DBH) and the branch attributes with the relative branch height of less than 0.8, providing the parameters that are necessary to develop a wood quality model.

Difluoromethylornithine attenuates isoproterenol-induced cardiac hypertrophy by regulating apoptosis, autophagy and the mitochondria-associated membranes pathway.

Myocardial hypertrophy is an independent risk factor of cardiovascular diseases and is closely associated with the incidence of heart failure. In the present study, we hypothesized that difluoromethylornithine (DFMO) could attenuate cardiac hypertrophy through mitochondria-associated membranes (MAM) and autophagy. Cardiac hypertrophy was induced in male rats by intravenous administration of isoproterenol (ISO; 5 mg/kg/day) for 1, 3,7 and 14 days. For DFMO treatment group, rats were given ISO (5 mg/kg/day) for 14 days and 2% DFMO in their water for 4 weeks. The expression of atrial natriuretic peptide (ANP) mRNA,heart parameters, apoptosis rate, fibrotic area and protein expressions of cleaved caspase3/9, GRP75, Mfn2, CypD and VDAC1 were measured to confirm the development of cardiac hypertrophy, apoptosis and autophagy induced by ISO. ANP mRNA and MAM protein expression levels were assessed by reverse transcription-quantitative PCR and western blotting to evaluate hypertrophy and the effects of DFMO oral administration. The results demonstrated that heart parameters, ANP mRNA levels, fibrotic area and apoptosis rate were significantly increased in the heart tissue for ISO 7 and 14 day groups compared with the control group. Furthermore, treatment with DFMO significantly inhibited these indicators, and DFMO downregulated the MAM signaling pathway and upregulated the autophagy pathway in heart tissue compared with the ISO 14 day group. Overall, all ISO-induced changes analyzed in the present study were attenuated following treatment with DFMO. The findings form this study suggested that DFMO treatment may be considered as a potential strategy for preventing ISO-induced cardiac hypertrophy.

Therapy for Apnoea of Prematurity: A Retrospective Study on Effects of Standard Dose and Genetic Variability on Clinical Response to Caffeine Citrate in Chinese Preterm Infants.

INTRODUCTION: Apnoea of prematurity (AOP) is among the most common diagnoses in the neonatal intensive care unit. Caffeine treatment is a preferred treatment choice. However, neonatal caffeine therapy results in significant intersubject variability. This study aimed to determine the effects of plasma caffeine levels based on standard dose and genetic variability on clinical response to caffeine citrate in Chinese preterm infants. METHODS: This single-center and retrospective study examined data from 112 preterm infants (< 35 weeks gestational age) between July 2017 and July 2018. Subjects were divided into apnoea-free (n = 48) and apnoeic (n = 64) groups, and their clinical outcomes were summarized. Liquid chromatography-tandem mass spectrometry was used to measure levels of caffeine and its primary metabolites. Eighty-eight single-nucleotide polymorphisms were chosen for genotyping by a MassARRAY system. RESULTS: Preterm infants in the apnoea-free group were associated with a reduction in the incidence of bronchopulmonary dysplasia and a reduced requirement for patent ductus arteriosus ligation. No significant association was observed between plasma-trough-concentration-to-dose (C0/D) ratio and birth weight, gestational age, or postnatal age in either group. Polymorphisms in CYP1A2 and aryl hydrocarbon receptor (AHR) genes did not affect plasma caffeine levels. Polymorphisms in adenosine receptor genes ADORA1 (rs10920568 and rs12744240), ADORA2A (rs34923252 and rs5996696), and ADORA3 (rs10776727 and rs2298191), especially in AHR (rs4410790) and adenosine deaminase (rs521704), play critical roles in the interindividual response to caffeine therapy. CONCLUSIONS: Genetic polymorphisms in caffeine's target receptors, but not the exposure levels based on the standard dosing, were associated with variable responses to caffeine therapy in preterm neonates. Future studies are needed to uncover how these genetic variants affect responses to caffeine therapy in this patient population.

[Prediction models of knot volume inside the stem for Korean pine plantation]. / äººå·¥çº¢æ¾æ ‘å¹²å† éƒ¨èŠ‚å­ä½“ç§¯é¢„æµ‹æ¨¡åž‹.

Based on 1207 knots from 49 sample trees of 29 standard plots of Korean pine plantations in Linkou and Dongjingcheng Forest Bureau of Heilongjiang Province, China, we extracted longitudinal sections of knots using the image processing software Digimizer and represented the shape of knots using two-dimensional scatter plots. According to the two-dimensional scatter plots, knots of Korean pine plantation were divided into three types: 1) alive knots (whole knot contained only sound knot portion); 2) non-occluded dead knots (whole knot contained both sound and loose knot portions); 3) occluded dead knots (the sound and loose portion of the knot were partially occluded by the bark). For all the three types of knots, the volume of sound knot was calculated by mathematical integral of the sound knot shape equation. The volume of loose knot was calculated using the volume equation of a cylinder. The total volume of knots was calculated as the sum of sound and loose knot volume. Finally, based on knot variables (diameter, relative height and total length of knots) and tree variable (diameter at breast height), we established the prediction models for sound knot volume, loose knot volume, and total volume of knot using the linear mixed model at plot level and tree level. Compared with fixed-effects model, the mixed effects models of the volume of sound knot, loose knot, and total knots provided more accurate parameter estimation, more uniform residual distribution, and higher model fitting precision. The validation results showed that prediction precision of each fixed-effect model was higher than 90%, while that of the mixed models with plot and tree effect was above 93%, indicating that the established model could well predict the volume of knot for Korean pine plantation.

Prediction model system with dummy variables for carbon storage of larch plantation in Heilongjiang Province, China.

Based on monitoring data from fixed plots of larch plantation in Heilongjiang Province obtained in 2005 and 2010, we analyzed the relationship among stand variables of larch plantation in Heilongjiang Province and established site class index curve model and stand density index model. A two-stage least square method was used to establish a simultaneous equations system for predicting average basal area and carbon storage of stands. Together, they were called prediction model system for carbon storage of larch plantation in Heilongjiang Province. The system included two dummy variables of age group and region. Results showed that the determination coefficients of those models were all greater than 0.98, and the root mean square errors were less than 4, except for the site class index curve model. The model with dummy variables increased the determination coefficient, and the root mean square error was less than 3, indicating that the model had good stability with accutrate estimated parameters. The average relative error of all models was less than 2%, the absolute value of the average relative error of most models was less than 15%, and the accuracy of all models was above 95%, indicating that the models could be used to accurately predict the carbon storage of larch plantations in different regions and age groups in Heilongjiang Pro-vince. According to the analysis of the site class index curve model and the estimated parameters of the simultaneous equations, the greater stand age, the larger stand average height, average basal area and carbon storage when the survey plots were located in the same area, which fitted natural growth rules. Under the same stand but different regions, the stand average height decreased in the order of plain area, southern slope area of Xiao-xing'anling, eastern slope area of Zhangguangcai-ling, Wandashan area, western slope area of Zhangguangcailing, and northern slope area of Xiao-xing'anling, while the order of stand basal area and carbon storage was eastern slope area of Zhangguangcailing, northern slope area of Xiaoxing'anling, western slope area of Zhangguangcailing, southern slope area of Xiaoxing'anling, Wandashan area, and plain area.

[Change pattern of heartwood of Larix olgensis plantation.] / 长白落叶松人工林心材变化规律.

Based on the data of 1179 discs and whorls of 49 trees from larch (Larix olgensis) plantations located in Mengjiagang forest farm in Heilongjiang Province, China, we analyzed the longitudinal variation pattern of heartwood radius. The results showed that the heartwood radius decreased with the increases of tree height, which was basically the same as the trunk shape. The relationship between the xylem radius (XR), diameter at breast height (DBH) and cambial age (CA) with the heartwood radius was significant. The stepwise regression analysis was used to develop heartwood radius (HR) and heartwood area (HA) models: HR=b1+b2XR2+b3CA+b4XR, HA=b1+b2DBH·XR+b3CA+b4DBH·XR2. We used the evaluation statistics such as AIC, BIC, Log Likelihood and Likelihood ratio test to compare the heartwood radius and heartwood area models which fitted with the plot effect and tree effect. The heartwood radius and heartwood area models with parameters b1, b2, b3 as mixed effects performed best when the tree effect was considered. The prediction accuracy of the mixed model was better than that of the basic model. In the application, the total heartwood radius and area could be predicted by the mixed model. Beta regression model was used to simulate the heartwood proportion. In this model, all parameters were significant, and the coefficients of determination were relatively high, with a good simulation effect.

[Knot attributes of Korean pine plantation based on mixed effect model.] / 基于混合效应模型的人工红松节子属性.

Based on 1534 knot data from 60 sample trees in a Korean pine plantation in Mengjiagang Forest Farm, Heilongjiang Province, China, mixed effect model of knot attributefactors (knot diameter, sound knot length, year of death of knot and knot angle) of Korean pine plantation was established using NLMIXED and GLIMMIX procedures of SAS software. The prediction accuracy of models was compared using evaluation statistics, such as Akaike information criterion (AIC), Bayesian information criterion (BIC), -2Log likelihood(-2LL), and likelihood ratio test (LRT). Results showed that all of the mixed effect models that considered tree effect performed better than conventional fixed-effect models. For knot diameter models, the model with random parameter combination of b1, b2 had the best performance. For sound knot length models, the model with random parameter combination of b1, b3 had the best performance. For the models of year of death of knot, the model with random variables of knot diameter was proved to be the optimal generalized linear mixed model. For the models of knot angle, the model with randomvariables of intercept, knot diameter, sound knot length was proved to be the optimal generalized linear mixed model. Mixed effect model was more effective than conventional fixed-effect model for describing knot attributes. The combination of knot attributes models and reasonable prunning schemes could improve timber quality of Korean pine which is one of the main commercial tree species in Northeast China.