Three new indole alkaloid derivatives from Fissistigma oldhamii Levl. and their anti-inflammatory effects.

Three new indole alkaloid derivatives, fissindoalkas A-C (1-3) together with one known biogenetically related polysubstituted indole alkaloid (4) were isolated from the roots of Fissistigma oldhamii (Hemsl.) Merr. The structures of compounds 1-4 were elucidated using comprehensive spectroscopic methods. The inhibitory activities of compounds 1-4 against nitric oxide (NO) production induced by lipopolysaccharide (LPS) were evaluated in vitro using mouse macrophage RAW264.7 cells. Compounds 2 and 3 showed potent inhibitory activities on NO production with IC50 values of 2.52 ± 0.18 and 2.33 ± 0.16 µM. These results indicate that the discovery of indole alkaloid derivatives, from the roots of F. oldhamii, which show significant anti-inflammatory properties, could be of great importance to the research and for the development of novel natural anti-inflammatory agents.

Phenolic Acid Derivatives from Ficus esquiroliana Levl. and Their Anti-Inflammatory Effects.

One new mesomer, ficusnaph A (1), two new phenolic acid derivatives, ficusnaphs B and C (2 and 3) together with three known biogenetically related polysubstituted naphthalene derivatives (4-6) were isolated from the stems of Ficus esquiroliana Levl. The structures of these compounds were elucidated using comprehensive spectroscopic methods. Compounds 1-6 were evaluated the inhibitory activities against the nitric oxide (NO) production induced by lipopolysaccharide (LPS) in mouse macrophage RAW264.7 cells in vitro. Compounds 1 and 2 showed significant inhibitory activity with the IC50 value of 3.12±0.14 and 7.66±0.18 µM, respectively.

Rational design of wettability-patterned microchips for high-performance attomolar surface-enhanced Raman detection.

Recent progress in wettability-patterned microchips has facilitated the development of ultra-trace detection in multiple biomedical and food safety fields. The existence of a superhydrophilic trap can realize targeted deposition of the analyte. However, the wetting transition from the Cassie-Baxter state to the Wenzel state usually occurs during evaporation and leads to a larger deposition footprint, which has a strong impact on the detection sensitivity and uniformity. In this paper, we report an integrated design, fabrication, and evaporation strategy to avoid the transition for high-performance attomolar surface-enhanced Raman scattering (SERS) detection. An improved force balance model was proposed to design the microstructures of wettability-patterned microchips, which were fabricated by nanosecond laser direct writing and surface fluorination. The microchips were composed of superhydrophobic micro-grooves and superhydrophilic traps, by which the targeted deposition of Au nanoparticles and rhodamine 6G (R6G) onto a minimal area of ∼70 × 70 µm2 was realized after a two-step heated evaporation. Accordingly, the detection limit was down to the attomolar level (5 × 10-18 M) with SERS enhancement factors (EFs) exceeding 1010. More importantly, the Raman signals showed good uniformity (RSD of 11.5%) for the concentration of 2 × 10-17 M. A good linear relationship was obtained in the quantitative concentration range of 10-12 M to 5 × 10-18 M with a high correlation coefficient (R2) of 0.996. These wettability-patterned microchips exhibit high performance (that is, both good sensitivity and good uniformity) in the detection of ultra-trace molecules in aqueous solutions, avoiding the need for expensive equipment and considerable skill in operations. The proposed strategy could also be applied to other microfluidic devices for rapid and simple analyte pre-concentration.

Efficient isolation and purification of tissue-specific protoplasts from tea plants (Camellia sinensis (L.) O. Kuntze).

BACKGROUND: Plant protoplasts constitute unique single-cell systems that can be subjected to genomic, proteomic, and metabolomic analysis. An effective and sustainable method for preparing protoplasts from tea plants has yet to be established. The protoplasts were osmotically isolated, and the isolation and purification procedures were optimized. Various potential factors affecting protoplast preparation, including enzymatic composition and type, enzymatic hydrolysis duration, mannitol concentration in the enzyme solution, and iodixanol concentration, were evaluated. RESULTS: The optimal conditions were 1.5% (w/v) cellulase and 0.4-0.6% (w/v) macerozyme in a solution containing 0.4 M mannitol, enzymatic hydrolysis over 10 h, and an iodixanol concentration of 65%. The highest protoplast yield was 3.27 × 106 protoplasts g-1 fresh weight. As determined through fluorescein diacetate staining, maximal cell viability was 92.94%. The isolated protoplasts were round and regularly shaped without agglomeration, and they were less than 20 µm in diameter. Differences in preparation, with regard to yield and viability in the tissues (roots, branches, and leaves), cultivars, and cultivation method, were also observed. CONCLUSIONS: In summary, we reported on a simple, efficient method for preparing protoplasts of whole-organ tissue from tea plant. The findings are expected to contribute to the rapid development of tea plant biology.

Natural variations in a pectin acetylesterase gene, MdPAE10, contribute to prolonged apple fruit shelf life.

Room-temperature shelf life is a key factor in fresh market apple (Malus domestica Borkh.) quality and commercial value. To investigate the genetic and molecular mechanism underlying apple shelf life, quantitative trait loci (QTL) were identified using bulked segregant analysis via sequencing (BSA-seq). Ethylene emission, flesh firmness, or crispness of apple fruit from 1,273 F1 plants of M. asiatica Nakai 'Zisai Pearl' × M. domestica 'Golden Delicious' were phenotyped prior to and during 6 wk of room-temperature storage. Segregation of ethylene emission and the flesh firmness or crispness traits was detected in the population. Thirteen QTL, including three major ones, were identified on chromosome 03, 08, and 16. A candidate gene encoding pectin acetylesterase, MdPAE10, from the QTL Z16.1 negatively affected fruit shelf life. A 379-bp deletion in the coding sequence of MdPAE10 disrupted its function. A single nucleotide polymorphism (SNP) in the MdPAE10 promoter region reduced its transcription activity. These findings provided insight into the genetic control of fruit shelf life and can be potentially used in apple marker-assisted selection.

Fluoride absorption, transportation and tolerance mechanism in Camellia sinensis, and its bioavailability and health risk assessment: a systematic review.

Tea is the one of the most popular non-alcoholic caffeinated beverages in the world. Tea is produced from the tea plant (Camellia sinensis (L.) O. Kuntze), which is known to accumulate fluoride. This article systematically analyzes the literature concerning fluoride absorption, transportation and fluoride tolerance mechanisms in tea plants. Fluoride bioavailability and exposure levels in tea infusions are also reviewed. The circulation of fluoride within the tea plantation ecosystems is in a positive equilibrium, with greater amounts of fluoride introduced to tea orchards than removed. Water extractable fluoride and magnesium chloride (MgCl2 ) extractable fluoride in plantation soil are the main sources of absorption by tea plant root via active trans-membrane transport and anion channels. Most fluoride is readily transported through the xylem as F- /F-Al complexes to leaf cell walls and vacuole. The findings indicate that tea plants employ cell wall accumulation, vacuole compartmentalization, and F-Al complexes to co-detoxify fluoride and aluminum, a possible tolerance mechanism through which tea tolerates higher levels of fluoride than most plants. Furthermore, dietary and endogenous factors influence fluoride bioavailability and should be considered when exposure levels of fluoride in commercially available dried tea leaves are interpreted. The relevant current challenges and future perspectives are also discussed. © 2020 Society of Chemical Industry.

Metabolics and ionomics responses of tea leaves (Camellia sinensis (L.) O. Kuntze) to fluoride stress.

Tea plant (Camellia sinensis (L.) O. Kuntze) is known to accumulate high concentrations of fluoride (F) in its leaves; however, the underlying mechanism of F accumulation remains unclear. The main objective of this study was to investigate the homeostatic self-defense mechanisms of tea leaves to F supplementation (0, 5, 20, and 50 mgL-1) by metabolomics and ionomics. We identified a total of 96 up-regulated and 40 down-regulated metabolites in tea leaves treated with F. Of these different compounds, minor polypeptides, carbohydrates and amino acids played valuable roles in the F-tolerating mechanism of tea plant. After F treatments, the concentrations of sodium (Na), ferrum (Fe), manganese (Mn), and molybdenum (Mo) were significantly increased in tea leaves, whereas the aluminum (Al) was decreased. These findings suggest that the ionic balance and metabolites are attributable to the development of F tolerance, providing new insight into tea plant adaptation to F stress.

Stochastic radiative transfer in random media: Pure absorbing cases.

We study stochastic radiation transport through random media in one dimension, in particular for pure absorbing cases. The statistical model to calculate the ensemble-averaged transmission for a binary random mixture is derived based on the cumulative probability density function (PDF) of optical depth, which is numerically simulated for both Markovian and non-Markovian mixtures by Monte Carlo calculations. We present systematic results about the influence of mixtures' stochasticity on the radiation transport. It is found that mixing statistics affects the ensemble-averaged intensities mainly due to the distribution of cumulative PDF at small optical depths, which explains well why the ensemble-averaged transmission is observed to be sensitive to chord length distribution and its variances. The effect of the particle size is substantial when the mixtures' correlation length is comparable to the mean free path of photons, which imprints a moderately broad transition region into the cumulative PDF. With the mixing probability increasing, the intensity decreases nearly exponentially, from which the mixing zone length can be approximately estimated. The impact of mixed configuration is also discussed, which is in line with previous results.

Risk factors affecting prognosis in metachronous liver metastases from WHO classification G1 and G2 gastroenteropancreatic neuroendocrine tumors after initial R0 surgical resection.

BACKGROUND: Here we describe the treatments and prognosis for metachronous metastases from gastroenteropancreatic neuroendocrine tumors (GEP-NETs) after initial R0 surgical resection at a large center in China. METHODS: The clinicopathological data and survival outcomes for 108 patients (median age, 54.0 years) with metachronous hepatic metastatic GEP-NETs disease who were initially treated using R0 surgical resection between August 2003 and July 2014 were analyzed using one-way comparisons, survival analysis, and a predictive nomogram. RESULTS: Fifty-five (50.9%) patients had pancreatic NETs and 92 (85.2%) had G2 primary tumors. For treatment of the hepatic metastases, 48 (44.4%) patients received liver-directed local treatment (metastasectomy, radiofrequency ablation, transcatheter arterial chemoembolization, etc.), 15 (13.9%) received systemic treatment (interferon, somatostatin analogs, etc.), and 45 (41.7%) received both treatments. Multivariable analyses revealed that OS was associated with hepatic tumor number (P < 0.001), treatment modality (P = 0.045), and elevated Ki-67 index between the metastatic and primary lesions (P = 0.027). The predictive nomogram C-index was 0.63. CONCLUSIONS: A higher Ki-67 index in metastases compared to primary tumor was an independent factor for poor prognosis. Local treatment was associated with prolonged survival of hepatic metastatic GEP-NET patients. Optimal treatment strategies based on clinicopathological characteristics should be developed.

Distribution and re-transportation of sodium in three Malus species with different salt tolerance.

To further dissect the mechanism of salt tolerance in Malus, the comparison was made regarding the differences between the salt-tolerant and salt-sensitive species in sodium accumulation and extrusion capability in the roots and stem base as well as the sodium re-transportation from shoot to roots by using 22Na labeling-based feeding of leaves and roots-split experiments. The results demonstrated that the salt-tolerant Malus species could accumulate more 22Na in the main roots, lateral roots, stem base phloem and xylem, and extrude more sodium out than the salt-sensitive one. In addition, the salt-tolerant Malus species had the higher sodium re-transportation rate from shoot to roots. Altogether, it is concluded that the stronger sodium accumulation and extrusion in the roots and the stronger sodium re-transportation from shoot to roots in the salt-tolerant species play important roles in salt tolerance of Malus species.

Land use and land cover change in agro-pastoral ecotone in Northern China: A review.

Land use/cover change (LUCC) is the most direct manifestation of the interaction between human activities and natural ecosystems. In recent years, due to the increasing human activities, regional environment has been dramatically changed. As one of heavily influenced and fragile and vulnerable ecosystems, the agro-pastoral ecotone in Northern China is a "hot spot" for land use/cover change research. Based on a literature review of LUCC in the agro-pastoral ecotone in Northern China, we first systematically summarized the progress of the boundary definitions of the agro-pastoral ecotone, and then synthesized the current findings, methods, procedures, topics, environmental impacts and adaption of LUCC in the region. Finally, we proposed that few comprehensive, process-based ecosystem simulations and eco-environmental impact studies had been reported in the current LUCC research and called for more multi-disciplinary, multi-methods, and multi-scale researches in the future LULC research in this area.

Low birth weight contributed to increased serum IL-6 levels in infantile respiratory syncytial virus infection.

BACKGROUND: To evaluate the role of serum cytokines in the pathogenesis of respiratory syncytial virus (RSV) infection in infants with low birth weight (LBW). METHODS: A prospective observational study was performed, and hospitalized children with lower respiratory tract infection (LRTI) were recruited. Three hundred fifty-eight patients < 1 year met the inclusion criteria: 116 patients had only RSV infection (RSV group); 242 patients had no RSV or other specific pathogen (non-RSV group). Serum interleukin-2 (IL-2), IL-4, IL-6, IL-10, tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) were detected through flow cytometry. RESULTS: No significant differences in serum IL-2, 4, 6, 10, and IFN-γ levels were observed between the RSV and non-RSV groups. For RSV infected infants with or without wheezing, delivery mode had no obvious effect on the changes of serum cytokine levels. However, the level of IL-6 in the RSV-infected infants with LBW was significantly higher than that in infants with normal birth weight. CONCLUSIONS: Serum IL-6 level was significantly increased in RSV infected infants with LBW. It is likely that the specific serum cytokine pattern will contribute to our understanding of the pathogenesis of RSV infections, especially in RSV-infected infants with LBW.

miR156 switches on vegetative phase change under the regulation of redox signals in apple seedlings.

In higher plants, miR156 regulates the vegetative phase change via the target SBP/SPL genes. The regulation of miR156 during ontogenetic processes is not fully understood. In the apple genome, of 31 putative MdMIR156 genes that encode pre-miR156, seven were dominantly expressed. However, the transcript levels of only MdMIR156a5 and MdMIR156a12 decreased significantly during the vegetative phase change, which was consistent with the mature miR156 level, indicating that miR156 is under transcriptional regulation. Leaf H2O2 content was higher in the adult phase than in the juvenile phase because of excess H2O2 accumulation in chloroplasts. When in vitro shoots were treated with menadione, diphenyleneiodonium, L-2-oxothiazolidine-4-carboxylic acid or buthionine sulphoximine, the expressions of MdMIR156a5, MdMIR156a12, and as well miR156 were coordinated with reduced glutathione (GSH) contents and glutathione/glutathione disulfide ratio but not H2O2 contents. Alteration of miR156 expression level by MdMIR156a6-overexpressing or miR156-mimetic transgenic Nicotiana benthamiana did not cause a corresponding change in reactive oxygen species or GSH status. Collectively, the results indicate that the vegetative phase change in apple is controlled by the MdMIR156a5 and MdMIR156a12 transcriptional regulatory network in response to the plastid-nucleus redox signals, such as GSH.

Moscatilin induces apoptosis of pancreatic cancer cells via reactive oxygen species and the JNK/SAPK pathway.

Moscatilin is a bibenzyl derivative extracted from the Dendrobium aurantiacum var. denneanum, which has traditionally been used as an immunomodulatory treatment in China. The present study was designed to determine whether moscatilin is a pro­apoptotic agent in pancreatic cancer, and to elucidate the underlying mechanisms. The apoptotic and anti­proliferative effects of moscatilin on pancreatic cancer cells were determined in vitro using biochemical assays, such as the MTT assay, colony formation assay, Hoechst staining and DNA fragmentation assay, and in vivo using Panc­1 pancreatic cancer xenografts. Western blotting was also conducted to evaluate the expression levels of B­cell lymphoma 2 (Bcl2), Bcl2­associated X protein (Bax), Bcl2 homologous antagonist killer (Bak), caspase 3, cleaved­caspase 3, poly (ADP­ribose) polymerase, p­c­Jun N­terminal kinase (JNK)/stress­activated protein kinases (SAPK) and JNK/SAPK in response to moscatilin. We used DCFH­DA to detect the production of reactive oxygen species (ROS) induced by moscatilin. The present study demonstrated that moscatilin markedly inhibited pancreatic cancer cell viability and induced cell apoptosis in a concentration­dependent manner. Conversely, moscatilin did not affect the cell viability of human umbilical vein endothelial cells at the comparable dosage. Treatment with moscatilin suppressed clonogenicity of Panc­1 cells in a concentration­dependent manner. Furthermore, a decrease in Bcl2 expression, and an increase in the expression levels of Bak and Bax, was detected following treatment with moscatilin, resulting in an increase in the proapoptotic/anti­apoptotic expression ratio (Bax/Bcl2) in Panc­1 cells. Moscatilin also induced activation of the caspase­dependent mitochondrial apoptotic pathway. In addition, moscatilin enhanced cellular ROS production and induced activation of JNKSAPK signaling pathway. Conversely, pretreatment with the ROS scavenger N­acetylcysteine or the JNK/SAPK­specific inhibitor SP600125 prevented moscatilin­mediated reductions in cell viability. Furthermore, moscatilin inhibited tumor growth in nude mice bearing Panc­1 cells, without apparent toxicity. In conclusion, these results demonstrated that moscatilin may induce pancreatic cell apoptosis, and therefore may be considered a potential therapeutic agent for the treatment of pancreatic cancer.

SN38 increases IL-8 expression through the MAPK pathways in HCT8 cells.

The overexpression of interleukin-8 (IL-8) is closely associated with poor tumor differentiation, metastasis and tumor progression. This study aimed to examine the effects and mechanisms of action of SN38 (a metabolite of the camptothecin derivative, CPT-11) on IL-8 expression in HCT8 cells, using ELISA, CCK-8 and western blot analysis. Among jatrorrhizine, evodiamine, 5-fluorouracil and SN38, SN38 was found to inhibit the proliferation of HCT8 cells in a dose-dependent manner, but to increase IL-8 secretion from HCT8 cells. Of the other agents, evodiamine was found to inhibit both IL-8 secretion and cell proliferation, and jatrorrhizine was found to increase IL-8 secretion without any obvious inhibitory effect on cell proliferation. Further experiments revealed that the increased activation of p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK)1/2 and c-Jun N-terminal kinase (JNK) by SN38 contributed to the decreased cell proliferation and to the overexpression of IL-8 induced by SN38. Our results suggested that the MAPK pathways are activated by SN38, resulting in the upregulation of IL-8 expression and in the inhibition of cell proliferation in an IL-8-independent manner. Thus, the potential benefit of the use of a combination of camptothecin-11 with other chemical drugs with inhibitory effects on IL-8 expression, should be paid more attention in treating colon cancer.

Epigenetic changes in peripheral leucocytes as biomarkers in intrauterine growth retardation rat.

Epigenetics plays an important role in the fetal origins of adult disease. Intrauterine growth retardation (IUGR) can cause increased histone acetylation of the endothelin-1 (ET-1) gene from pulmonary vascular endothelial cells or the whole lung tissue and persist into later life, likely resulting in increased risk of pulmonary hypertension or asthma later in life. However, little is known regarding the correlation of epigenetic changes between specific tissue and peripheral leucocytes. In the present study, an IUGR rat model was established by maternal nutrient restriction. Peripheral blood leucocytes were isolated to detect the ET-1 expression level. Chromatin immunoprecipitation was used to analyze histone modification of the ET-1 gene promoter. The ET-1 protein expression of leucocytes from the 1-week IUGR group was similar to that from the 1-week control group. ET-1 protein expression of leucocytes from 10-week IUGR rats was obviously higher than that of the other groups (P<0.05). The levels of acetylated histone H3 in the ET-1 promoter of leucocytes from the 1-week IUGR rats were significantly higher than those from the age-matched control group (P=0.004). Furthermore, the trends continued ≤10 weeks after birth. In conclusion, epigenetic modifications of leucocytes can in part reflect the epigenetic changes of lung tissue in IUGR rats. Epigenetics of peripheral leucocytes may be used as a biomarker for predicting the risk of the development of disease, and may be used as a surrogate to investigate the subsequent development of pulmonary vascular disease or asthma.

Mass Spectrometry-based Proteomics in Acute Respiratory Distress Syndrome: A Powerful Modality for Pulmonary Precision Medicine.

OBJECTIVE: Acute respiratory distress syndrome (ARDS) is an acute and lethal clinical syndrome that is characterized by hypoxemic respiratory failure and diffuse alveolar inflammatory damage. This review aimed to search and discuss the mass spectrometry (MS)-based proteomic studies on different subsets of ARDS patients. DATA SOURCES: Original research articles were collected from the PubMed database published in English up to December 2015. STUDY SELECTION: The literature search was done using the term "(acute lung injury OR acute respiratory distress syndrome) AND (proteomics OR proteome OR mass spectrum OR differential in-gel electrophoresis OR two-dimensional polyacrylamide gel electrophoresis)". Related original research articles were included and were carefully analyzed. RESULTS: Eight original proteomic researches on ARDS patients were found. The common proteomic modalities were two-dimensional (2D) high-performance liquid chromatography-based electronic spray ion-MS/MS and 2D-polyacrylamide gel electrophoresis/differential in-gel electrophoresis-based matrix-assisted laser desorption ionization-time of flight/MS. They compared the proteome between ARDS patients and normal controls and analyzed the dynamic changes of proteome at different ARDS stages or severity. The disturbed proteome in ARDS patients includes plasma acute-phase proteins, inflammatory/immune-associated proteins, and coagulation proteins. CONCLUSIONS: Although several previous studies have provided some useful information about the lung proteome in ARDS patients and gained several interesting disease-associated biomarkers, clinical proteomic studies in ARDS patients are still in the initial stage. An increased cooperation is still needed to establish a global and faithful database containing disease-specific proteome from the largest ARDS subsets.

Serum cytokine profile contributes to discriminating M. pneumoniae pneumonia in children.

BACKGROUND: To evaluate the role of serum cytokines in discriminating M. pneumoniae infection in children with community-acquired pneumonia (CAP). METHODS: A prospective observational study was conducted. 385 hospitalized patients with CAP had only M. pneumoniae (MP group) infection; 321 hospitalized patients with CAP had no M. pneumoniae and other specific pathogen (control group) infections. Serum interleukin-2 (IL-2), IL-4, IL-6, IL-10, tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) were detected by flow cytometry. RESULTS: In children younger than 5years, serum IL-6, TNF-α, and IFN-γ levels from MP group were significantly higher than those from control group. However in children 5-15years, serum IL-6, IL-10, and IFN-γ levels from MP group were significantly higher than those from control group. In the final multivariate logistic regression model for serum cytokine, moderately elevated IL-6, IL-10, and IFN-γ shows a higher prediction of development of M. pneumoniae pneumonia among CAP patients. CONCLUSIONS: A specific cytokine pattern showed a higher prediction of M. pneumoniae pneumonia among CAP patients, further suggesting that serum cytokine pattern might be useful in differentiating infectious causative agents in children.

Value of apparent diffusion coefficient for predicting malignancy of intraductal papillary mucinous neoplasms of the pancreas.

PURPOSE: We aimed to explore the potential value of the whole tumor apparent diffusion coefficient (ADC) for discriminating between benign and malignant intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. METHODS: Forty-two patients underwent 1.5 T magnetic resonance imaging that included diffusion-weighted imaging (DWI, b=0.500 s/mm2). The mean, minimum, and maximum ADC values were measured for the whole tumor. The differences between benign and malignant IPMNs were calculated for the mean ADC, ADC-min, and ADC-max values. Receiver operating characteristics (ROC) analysis was conducted to evaluate their potential diagnostic performance. RESULTS: Fifteen of 25 benign IPMNs demonstrated low or iso-signal intensity on DWI with a b value of 500 s/mm2 compared with normal pancreatic parenchyma, whereas all malignant IPMNs demonstrated high signal intensity. The mean value of ADC was significantly higher in benign IPMNs compared with malignant IPMNs (3.39×10-3 mm2/s vs. 2.39×10-3 mm2/s, P < 0.001), with an area under the ROC curve (AUC) of 0.92 (95% confidence interval [CI], 0.79-0.98). The ADC-min value of malignant IPMNs was also significantly lower than that of benign IPMNs (1.24×10-3 mm2/s vs. 2.58×10-3 mm2/s, P < 0.001), with an AUC of 0.94 (95% CI, 0.82-0.99). No marked difference was found between benign and malignant IPMNs for the ADC-max value (3.89×10-3 mm2/s vs. 3.78×10-3 mm2/s, P = 0.299). CONCLUSION: Lower mean and minimum ADC values of the whole tumor might be potential predictors of malignant IPMNs of the pancreas.

Nab-Paclitaxel Plus S-1 Shows Increased Antitumor Activity in Patient-Derived Pancreatic Cancer Xenograft Mouse Models.

OBJECTIVES: To investigate the antitumor activity of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) plus S-1 in patient-derived pancreatic cancer xenograft mouse models and to explore biomarkers that could predict drug efficacy. METHODS: Ten patient-derived xenograft models were established. The third-generation tumor-bearing mice were randomized into 4 treatment groups: (1) control; (2) S-1; (3) nab-paclitaxel; (4) S-1 plus nab-paclitaxel. Resected tumors were tested by immunohistochemistry for the expression of thymidylate synthase, orotate phosphoribosyltransferase (OPRT), dihydropyrimidine dehydrogenase (DPD), secreted protein that is acidic and rich in cysteine, human epidermal growth factor receptor 2 (HER2), collagen-1, and CD31. RESULTS: Tumor growth inhibition of the S-1 group, nab-paclitaxel group, and combination group was 69.52%, 86.63%, 103.56%, respectively (P < 0.05). The efficacy of S-1 is better in thymidylate synthase-negative, OPRT-positive, and DPD-negative tumors. The efficacy of nab-paclitaxel is better in HER2-positive tumors. Collagen-1 was decreased and CD31 was increased in tumors treated with nab-paclitaxel and S-1 plus nab-paclitaxel compared with control or S-1. CONCLUSIONS: This preclinical study showed that S-1 plus nab-paclitaxel exerted significantly better antitumor activity than S-1 or nab-paclitaxel alone. Thymidylate synthase, OPRT, and DPD were possibly biomarkers of S-1 and HER2 of nab-paclitaxel.