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Aim: We aimed to establish and validate a simple and sensitive UPLC–MS/MS method for the determination of UNC1999, a dual inhibitor against EZH1 and EZH2 in plasma samples. Materials & methods: UNC1999 in rat plasma was processed with protein precipitation method and then separated on a C18column and detected under positive ionization mode. The method presented good linearity over the range of 1.0–2000 ng/ml with good accuracy and precision. UNC1999 was absorbed slowly and achieved a maximum concentration of 118.8 ± 12.0 ng/ml 1.5 h after oral administration. Conclusion: The method provides a favorable character in selectivity, linearity, accuracy, precision, recovery, matrix effects and stabilities and was suitable for describing the pharmacokinetic profile of UNC1999.

Multisystem inflammatory syndrome in children (MIS-C) associated with coronavirus disease 2019 (COVID-19) has been described to partially overlap with Kawasaki disease (KD) with regard to clinical symptoms, but they are unlikely to share the same disease entity. We conducted a systematic review and meta-analysis to characterize the laboratory parameters of MIS-C compared with those of KD and Kawasaki disease shock syndrome (KDSS). Databases were searched for studies on laboratory parameters of MIS-C (hematology, inflammatory markers, cardiac markers, and biochemistry) through May 31, 2021. Twelve studies with 3073 participants yielded 969 MIS-C patients. In terms of hematology, MIS-C patients had lower levels of leukocytes, absolute lymphocyte count and platelet count (PLT) than KD patients and had similar absolute neutrophil count (ANC) and hemoglobin (Hb) levels. In terms of inflammatory markers, MIS-C patients had higher levels of C-reactive protein, D-dimer and ferritin than KD patients and had similar levels of procalcitonin and erythrocyte sedimentation rate (ESR). In terms of cardiac markers, MIS-C patients had higher CPK levels than KD patients. The levels of N-terminal pro-brain natriuretic peptide, troponin and aspartate aminotransferase were not significantly different between MIS-C and KD patients. In terms of biochemistry, MIS-C patients had lower levels of albumin, sodium and alanine aminotransferase and higher levels of creatinine than KD patients. In addition, MIS-C patients had lower levels of PLT, Hb and ESR and higher levels of ANC than KDSS patients. Measurement of laboratory parameters might assist clinicians with accurate evaluation of MIS-C and further mechanistic research.

VS-5584 is a small-molecular compound that showed equivalent activity against mTOR and all class I PI3K isoforms and demonstrated preclinical activity in diverse cancer cell lines and xenograft tumor model, and rational combination of VS-5584 and other target therapies achieved promising outcomes in oncology. In the present study, we established and validated a simple and sensitive UPLC-MS/MS method for the determination of VS-5584 in plasma samples. VS-5584 was separated via an Acquity UPLC BEH C18 column, with a mobile phase composed of acetonitrile and 0.2% formic acid in water (40 : 60). The calibration curve displayed a good linearity in the range of 1.0–1000 ng/mL, with satisfactory accuracy (−13.6%

Aim: GW788388 is a selective and orally active TGF-β1 receptor inhibitor that shows potent activity in renal fibrosis. We aimed to establish and validate a simple and sensitive ultra-performance LC–MS/MS method for the determination of GW788388 in plasma samples. Methodology & results: GW788388 in rat plasma was processed with protein precipitation method and then separated on a C18 column. The calibration curve presented a good linearity in the range of 1.0–1200 ng/ml, with satisfactory accuracy (relative error, [-17.5% < relative error

Aim: Capmatinib is an orally bioavailable mesenchymal-epithelial transition factor inhibitor with anticancer activity, which has proved preclinical activity in multiple cancer trials. The present study aimed to develop a fast and reliable assay approach to quantify capmatinib in rat plasma. Methodology & results: After protein precipitation with acetonitrile, the chromatographic separation was achieved with an Acquity UPLC BEH C18 column, and subsequently detected with positive electrospray ionization via a triple quadrupole tandem mass spectrometer. The target quantitative ion pairs m/z 412.99 → 381.84 for capmatinib and 387.00 → 355.81 for the internal standard, respectively. The calibration curve for the assay was linear over the range of 1.0–4000 ng/ml. Conclusion: The method shows an excellent performance in linearity, accuracy, precision, stability, and has been successfully applied to a pharmacokinetic study after oral administration of capmatinib at three doses (5, 10 and 20 mg/kg) in rats.

The short flowering period of ornamental cherry trees is the main factor limiting their use in gardens. Determining the secondary flowering characteristics of ornamental cherry trees is required to prolong their flowering period. In this experiment, Cerasus subhirtella ‘Autumnalis’ was used as the experimental material. The phenological differences in their annual growth cycle were observed using the BBCH coding system. The cooling requirements of the flower buds were evaluated by the chilling hours model (temperature between 0 and 7.2 °C) and the Utah model. The expression of the core gene involved in bud dormancy regulation DAM (dormancy-associated MADS-box) from the completion of flower bud differentiation in one year until the following year was measured by performing real-time fluorescence-based quantitative PCR. The results showed that the flowering duration of C. subhirtella ‘Autumnalis’ from November to December was longer than that of C. yedoensis ‘Somei Yoshino’, which was from March to April. The progress from seed bud-break to flower bud opening took about 10 days for C. subhirtella ‘Autumnalis’, while the same stage for C. yedoensis ‘Somei Yoshino’ took around 20 days. Additionally, the flower buds of C. subhirtella ‘Autumnalis’ needed only the chilling temperature unit of 54.08 to satisfy the chilling requirement, while C. yedoensis ‘Somei Yoshino’ required a chilling temperature unit of 596.75. After the completion of flower bud differentiation, during low-temperature storage, the expression of DAM4 and DAM5 genes first increased and then decreased, whereas, the expression of the DAM6 gene continued to decrease, and the expression of DAM4, DAM5, and DAM6 in C. yedoensis ‘Somei Yoshino’ increased rapidly and was maintained at a high level. This showed that the upregulation of the expression of the DAM4, DAM5, and DAM6 genes can inhibit the flower bud germination of Cherry Blossom. The relative expression of the DAM gene of C. subhirtella ‘Autumnalis’ was significantly lower than that of the DAM gene of C. yedoensis ‘Somei Yoshino’ from the end of October to the beginning of December, leading to its secondary flowering in autumn. These results might elucidate why the flower buds of C. subhirtella ‘Autumnalis’ can break their internal dormancy and bloom in the autumn and then again in the following year. Our findings might provide a reference for conducting further studies on the mechanisms of secondary flowering and bud dormancy in cherries.

Greening can usually have a cooling effect on urban space; but is this law also applicable to coastal sloping urban space? The coastal urban space of Qingdao Haizhifeng Square, with a sloping topography, was the area we selected to study. The study area contained two parts: a coastal green space and a residential area. ENVI-met was used to create six scenarios. Different lawns, black pine and ash were planted in the two areas to study the cooling effect. The results showed that the closer the area was to the sea, the better the thermal comfort. In both the coastal green area and the residential area, trees increased the PET of the site, and the higher the LAI of the trees, the more obvious the thermal effect. At 15:00, the hottest time during the summer, the highest PET at pedestrian height was lowest in the scenario without trees, reaching 28.3 °C, and the highest was with full ash, reaching 34.3 °C. At the same time, the average difference in PET between the two scenarios was 1.4 °C. The highest PET at pedestrian height was generated in the area of the building away from the sea breeze, especially in the case of the sloping topography behind it or dense street trees on the urban road. Finally, it was concluded that, in urban spaces with a coastal slope topography, lawns should be planted in the coastal green part and low LAI trees in residential areas, and shade trees should not be planted on the coastal walkway. This afforestation strategy can provide a basis to formulate a strategy for promoting the design of regions with similar geographical and climatic conditions in the future.

Purpose To investigate the frailty status in Chinese cancer patients through establishing a novel prediction algorithm. Methods The percentage of frailty in various age groups, locations, and tumor types in Chinese cancer patients was investigated. The prediction capacity of frailty on mortality of Chinese cancer patients was analysed by the frailty index composing of routine laboratory data (FI‐LAB) accessible from a blood test and calculated as the ratio of abnormal factors to 22 total variables. The establishment of a novel algorithm, MCP (mortality of cancer patients), to predict the 5‐year mortality in Chinese cancer patients was accomplished and the algorithm's prediction capacity was tested in the training and validation sets using receiver operating characteristic (ROC) analysis. Results We found that the risk of death in cancer patients can be successfully identified through FI‐LAB. The univariable and multivariable Cox regression were used to evaluate the effect of frailty on death. In the 5‐year follow‐up, 20.6% of the 2959 participants (age = 55.8 ± 11.7 years; 43.5% female) died, while the mean FI‐LAB score in baseline was 0.23 (standard deviation = 0.13; range = 0–0.73). Frailty (after adjusting for gender, age, and other confounders) directly correlated with an increased risk of death, hazard ratio of 12.67 (95% confidence interval [CI]: 7.19, 22.31), compared to those without frailty. In addition, the MCP algorithm (MCP) = 3.678 × FI‐LAB + 1.575 × sex + 1.779 × first tumor node metastasis staging, presented an area under the ROC (AUC) of 0.691 (95% CI: 0.656–0.726) and 0.648 (95% CI: 0.613–0.684) in the training and validation sets, respectively. Conclusion Frailty as defined by FI‐LAB was common and indicated a significant death risk in cancer patients. Our novel developed algorithm MCP had a passable prediction capacity on 5‐year MCP., To investigate the frailty status in Chinese cancer patients through establishing a novel prediction algorithm. Frailty as defined by FI‐LAB (frailty index composing of routine laboratory data) was common and indicated a significant death risk in cancer patients. Our novel developed algorithm mortality of cancer patients had a passable prediction capacity on 5‐year mortality of cancer patients.

Purpose To investigate the prediction capacity and status of frailty in Chinese cancer patients in national level, through establishing a novel prediction algorithm. Methods The percentage of frailty in different ages, provinces and tumor type groups of Chinese cancer patients were revealed. The predictioncapacity of frailty on mortality of Chinese cancer patients was analyzed by FI-LAB that is composed of routine laboratory data from accessible blood test and calculated as the ratio of abnormal factors in 22 variables. Establishment of a novel algorithm MCP(mortality of cancer patients)to predict the five-year mortality in Chinese cancer patients was accomplished and its prediction capacity was tested in the training and validation sets using ROC analysis. ResultsWe found that the increased risk of death in cancer patients can be successfully identified through FI-LAB. The univariable and multivariable Cox regression were used to evaluate the effect of frailty on death. In the 5-year follow-up, 20.6% of the 2959 participants (age = 55.8 ± 11.7 years; 43.5% female) were dead while the mean FI-LAB score in baseline was 0.23 (standard deviation = 0.13; range = 0 to 0.73).Frailty (after adjusting for gender, age, and other confounders) could be directly correlated with increased risk of death, with a hazard ratio of 12.67 (95% confidence interval CI: 7.19, 22.31) in comparison with those without frailty. In addition, MCP algorithm presented an area under the ROC (AUC) of 0.691 (95% CI: 0.659-0.684) and 0.648 (95% CI: 0.613-0.684) in the training and validation set, respectively. Conclusion Frailty is common in cancer patients and FI-LAB has high prediction capacity on mortality. The MCP algorithm is a good supplement for frailty evaluation and mortality prediction in cancer patients.

Light-sheet microscopy has attracted considerable attention because it is a fluorescence imaging technique with rapid optical sectioning capability for transparent samples. In this study, we report ...

Biotrophic fungi have to infect their host to obtain nutrients and must establish an interaction with the host to complete their life cycle. In this process, effectors play important roles in manipulating the host’s immune system to avoid being attacked. Sporisorium scitamineum is the causative agent of sugarcane smut, the most important disease in sugarcane-producing regions worldwide. In this work, we functionally characterized the conserved effector PEP1 in S. scitamineum. The mating process and the expression of genes in the MAPK signaling pathway and the a and b loci were adversely affected in Sspep1-null mutants. The requirement for SsPEP1 in pathogenicity and symptom development was allele dosage-dependent, i.e., deleting one Sspep1 allele in the mating pair turned a normal black whip with abundant teliospores into a white whip with few teliospores, however, deleting both alleles almost abolished infectivity and whip development. ΔSspep1 mutants produced significantly less mycelium mass within infected plants. Additionally, SsPEP1 was identified as a potent inhibitor of sugarcane POD-1a peroxidase activity, implying that SsPEP1 may function to relieve reactive oxygen species-related stress within the host plant. Taken together, our work demonstrated that SsPEP1 is a multifaceted effector essential for S. scitamineum growth, development, and pathogenicity.

Since October 2010, porcine epidemic diarrhea (PED) caused by variant porcine epidemic diarrhea virus (PEDV) has led great economic losses to the global pig industry, especially in China. To study the genetic characteristics of PEDV strains in Chinese mainland, a total of 603 clinical samples from nine provinces/districts of Chinese mainland from January 2014 to December 2015 were collected for RT-PCR detection and 1-1323bp of S gene of 91 isolates and ORF3 gene of 46 isolates were sequenced. The results showed that the variant PEDV were the dominant pathogens of viral diarrhea diseases in these areas. Six novel variant PEDV strains (FJAX1, FJAX2, HeNPDS1, HeNPDS2, HeNPY3, and HeNPY4) with two amino acids (aa) deletion at the 56-57 aa of S protein were identified. A total of 405 Chinese PEDV strains were subjected to phylogenetic and phylogeographic analysis. The results revealed that the subgroup Va in variant PEDV group were the dominant subgroup and the spread trend of variant PEDV strains seemed to be from the southeast coastal districts to other coastal districts and interior districts. The N-terminal of S gene (1-750bp), to some extent, could represent S1 or full length S gene for phylogenetic, similarity, antigen index, hydrophilicity plot, and differentiation analyses. The 404-472bp of S gene contained the three genetic markers, i.e., "TAA" insertion at 404-405bp, "ACAGGT" deletion at 430-435bp, and "ATA" deletion at 455-457bp can be used to differentiate the classical and variant virulent parental/attenuated PEDV strains and help us to learn the infectious and genetic characteristics of PEDV strains more convenient and cheaper. This study has important implication for understanding the infectious, genetic, and evolutionary aspects of PEDV strains in Chinese mainland.

Esophageal cancer is the fourth most common cause of cancer death in China. Patients with esophageal cancer are more likely to suffer from malnutrition. The purpose of this study is to assess nutritional status of patients with esophageal cancer from multiple perspectives and analyze the risk factors.A total of 1482 esophageal cancer patients were enrolled in the study. We investigated the Scored Patient Generated Subjective Global Assessment (PG-SGA) scores, NRS-2002 scores, Karnofsky performance status scores, anthropometric, and laboratory indicators of patients. Unconditional logistic regression analysis was applied to identify the risk factors of nutritional status.PG-SGA (≥4) and NRS-2002 (≥3) showed the incidence of malnutrition were 76% and 50%, respectively. In the patients with PG-SGA score ≥4, the proportion of patients who did not receive any nutritional support was 60%. The incidence of malnutrition in females was significantly higher than that in males. Besides, abnormality rates of Red blood cell (P0.001), MAC (P = 0.037), and MAMC (P0.001) in males was significantly higher than that in females, while abnormality rates of TSF (P0.001) was lower than that in females. After adjusted with the other potential risk factors listed, unconditional logistic regression analysis indicated smoking (odds ratio: 2.868, 95% confidence interval: 1.660-4.954), drinking (OR: 1.726, 95% CI: 1.099-2.712), family history (OR: 1.840, 95% CI: 1.132-2.992), radiotherapy or chemotherapy (OR: 1.594, 95% CI: 1.065-2.387), and pathological stage (OR: 2.263, 95% CI: 1.084-4.726) might be the risk factors of nutritional status, while nutritional support can reduce the risk of malnutrition.Effective nutritional risk assessment methods and nutritional intervention measures can be adopted according to the research data to improve quality of life of esophageal cancer patients.

Background: Malnutrition is common in patients with cancer, which adversely affects the survival and quality of life of cancer patients. However, there is no national data on the prevalence of malnutrition in Chinese cancer patients. This study aims to evaluate the prevalence of malnutrition and quality of life (QOL) of Chinese patients with local regional, recurrent or metastatic cancer, to address the prognostic value of nutritional status and QOL on the survival of cancer patients in China and to validate the patient-generated subjective global assessment (PG-SGA) questionnaire in Chinese cancer patients.Methods: This is an observational, multi-centered, and hospital-based prospective cohort study. We aimed to recruit 50,000 cancer patients (age 18 and above) over an 8-year period. Data collection will occur within 48 hr after patients are admitted to hospital, 30-days after hospital admission, and the follow-up will be conducted 1-8 years after enrolment. The primary outcome is overall survival, and secondary outcomes are length of hospital stay and hospital costs. Factors measured are demographic characteristics, tumor characteristics, anthropometry measurements, hematological measurement, body composition, PG-SGA scores, Karnofsky performance status scores, and QLQ C30 scores. This protocol was approved by local ethical committees of all the participant hospitals.Conclusions: This multi-centered, large-scale, long-time follow-up prospective study will help diagnose malnutrition in cancer patients in China, and identify the related risk factors associated with the negative outcomes. The anticipated results will highlight the need for a truly scientific appraisal of nutrition therapy, and help to improve outcomes among cancer patients in China.Trial Registration: The trial has been registered with the Chinese Clinical Trial Registry, ChiCTR1800020329. Registered on 19 December 2018.

PH-797804 is a selective p38 MAPK inhibitor currently evaluated in clinical trials. This study described a validated UPLC-MS/MS combined with one-step protein precipitation extraction method for determination of PH-797804 in rat plasma. After protein precipitation with acetonitrile, the plasma sample was analyzed by a Waters Acquity UPLC BEH C18 column, with acetonitrile/0.1% formic acid (70:30) as the mobile phase. Mass spectrometric detection was conducted with a Waters TQ-S mass spectrometer via electrospray, positive-mode ionization, with target quantitative ion pairs of m/z 476.895 → 126.860 for PH-797804, and 482.726 → 269.707 for regorafenib (internal standard). The assay showed a good linearity over the range of 1.0–1600 ng/mL, with acceptable accuracy (RE from −7.8% to 8.5%) and precision (RSD within 8.4%) values. Recovery from plasma was 81.4–90.2% and matrix effect was negligible (93.3–95.4%). The validated method presented a quantification method of PH-797804 in detail for the first time and utilized for a pharmacokinetic study at three dose concentrations after oral administration in Wistar rats. The pharmacokinetic profiles of PH-797804 showed a linear relationship between drug concentration and dose, which provided dosage and safety information on further clinical studies.

Allergic conjunctivitis (AC) is an inflammatory disease of the conjunctiva, which is characterized by antigen challenge and toll-like receptor 2 (TLR2) activation. Here, a designed small peptide ZY12 was found to contain therapeutic potential in staphylococcal enterotoxin B (SEB)-induced AC model. ZY12 treatment showed the remission of clinical signs, plasma total IgE levels, number of mast cells and the proportion of degranulated mast cell in AC mice. Levels of Th2 cytokines (IL-4, IL-5, IL-13) in the lymph nodes or spleen were significantly decreased while those of Th1 cytokine (IFN-γ) were increased in ZY12 treated group, suggesting a protective role of ZY12 in AC by mediating the balance of Th1/Th2 cytokines. Importantly, ZY12 significantly inhibited TLR2 expression in conjunctival tissue. Combined its therapeutic effects with TLR2 inhibitory function, ZY12 might be an ideal candidate for the development of new therapeutic agent for allergic disease.

Spiders are the most successful insect predators given that they use their venom containing insecticidal peptides as biochemical weapons for preying. Due to the high specificity and potency of peptidic toxins, discoveries of insecticidal toxins from spider venom have provided an opportunity to obtain natural compounds for agricultural applications without affecting human health. In this study, a novel insecticidal toxin (μ-NPTX-Nc1a) was identified and characterized from the venom of Nephila clavata. Its primary sequence is GCNPDCTGIQCGWPRCPGGQNPVMDKCVSCCPFCPPKSAQG which was determined by automated Edman degradation, cDNA cloning, and MS/MS analysis. BLAST search indicated that Nc1a shows no similarity with known peptides or proteins, indicating that Nc1a belongs to a novel family of insecticidal peptide. Nc1a displayed inhibitory effects on NaV and KV channels in cockroach dorsal unpaired median neurons. The median lethal dose (LD50) of Nc1a on cockroach was 573 ng/g. Herein, a study that identifies a novel insecticidal toxin, which can be a potential candidate and/or template for the development of bioinsecticides, is presented.

We report the development and validation of a rapid, specific, and sensitive liquid chromatographic–tandem mass spectrometric (LC–MS–MS) method for analysis and pharmacokinetic study, in rats, of hyperoside and isoquercitrin, two bioactive structural isomers present in the leaves of Apocynum venetum L. After simple deproteinization by addition of acetonitrile, the analytes were separated on a C18 column. Detection was by tandem mass spectrometry in multiple reaction monitoring mode. The method was linear over the concentration range 3.9–195 ng mL−1 for both hyperoside and isoquercitrin. Intra-day and inter-day precision for both hyperoside and isoquercitrin were

A sensitive fluorescence liquid chromatographic analytical method was developed for the simultaneous determination of carnosine enantiomers in rat plasma. The method was applied to pharmacokinetic studies. Chiral separation of carnosine enantiomers was achieved by pre-column derivatization with o-phthaldialdehyde and the thiol N-acety-l-cysteine as derivating reagents. They were separated on an ODS column and detected by fluorescence detection (λex = 350 nm, λem = 450 nm). γ-Aminobutyric acid was used as internal standard. The method was linear up to 6,000 ng mL−1 for l-carnosine, 4,000 ng mL−1 for d-carnosine. Low limit of quantitation (LLOQ) was 40 ng mL−1 for each isomer. The relative standard deviations obtained for intra- and inter-day precision were lower than 12% and the recoveries were higher than 75% for both enantiomers. The method was applied to a stereoselective study on the pharmacokinetics of carnosine after oral administration with a single dose (carnosine, 75 mg kg−1 for each isomer) to a rat. The initial data indicated that l-carnosine had a larger value of the highest plasma concentration than d-carnosine (C max 5,344 vs. 1,914 ng mL−1), and that of l-carnosine had a lower value of AUC(0−∞) and t 1/2(h) (AUC(0−∞) 5,306 vs. 6,321 ng h mL−1, t 1/2 1.43 vs. 3.37 h). Our results indicated that the pharmacokinetic of l-carnosine and d-carnosine revealed enantioselective properties significantly.

Multicast communication involves transmitting information from a single source node to multiple destination nodes, and is becoming an important requirement in high-performance networks. We study multicast communication in a class of optical WDM networks with regular topologies such as linear arrays, rings, meshes, tori and hypercubes. For each type of network, we derive the necessary and sufficient conditions on the minimum number of wavelengths required for a WDM network to be wide-sense nonblocking for multicast communication under some commonly used routing algorithms.

Objective To determine whether a relationship exists between performance-based physical assessments and pre-diabetes/diabetes in an older Chinese population. Methods Our study population comprised 976 subjects (mean ± SD age: 67.6±6.0 years; 44.5% men) from the Hangu area of Tianjin, China. Diabetes was defined by self-reporting of a physician's diagnosis, or a fasting plasma glucose level ≥126 mg/dL; and pre-diabetes was defined as a fasting plasma glucose level ≥100 mg/dL and

An oxygen isotope temperature record from 381 to 166 kaB. P. (230Th/234U dating and tuned ages) has been obtained by combining data on the isotopic composition of calcites with that of fluid inclusions trapped in a stalagmite from a limestone cave in which a fossil cranium deposited. Several laminae in microsequence of the stalagmite represent climatic events or shifts. The Nanjing man fossil was older than 381 kaB. P.

Multicast communication involves transmitting information from a single source node to multiple destination nodes, and is becoming an important requirement in high-performance networks. In this paper, we study multicast communication in a class of optical WDM networks with direct interconnects such as linear arrays, rings, meshes, tori and hypercubes. For each type of network, we derive the necessary and sufficient conditions on the minimum number of wavelengths required for a network to be wide-sense nonblocking for arbitrary multicast communication.