Synergistic anticancer effects of ginsenoside CK and gefitinib against gefitinib-resistant NSCLC by regulating the balance of angiogenic factors through HIF-1α/VEGF.

Drug resistance is a serious problem for gefitinib in the treatment of lung cancer. Ginsenoside CK, a metabolite of diol ginsenosides, have many excellent pharmacological activities, but whether ginsenoside CK can overcome gefitinib resistance remains unclear. In our study, the sensitizing activity of ginsenoside CK on gefitinib-resistant non-small cell lung cancer (NSCLC) in vitro and in vivo was investigated. Ginsenoside CK was confirmed to enhance the anti-proliferation, pro-apoptotic and anti-migration effects of gefitinib in primary and acquired resistant NSCLC. Furthermore, the combined administration of CK and gefitinib effectively promoted the sensitivity of lung cancer xenograft to gefitinib in vivo, and the tumor inhibition rate reached 70.97% (vs. gefitinib monotherapy 32.65%). Subsequently, tubule formation experiment and western blot results showed that co-treatment of ginsenoside CK inhibited the angiogenesis ability of HUVEC cells, and inhibited the expression of HIF-1α, VEGF, FGF and MMP2/9. More interestingly, ginsenoside CK co-treatment enhanced the expression of anti-angiogenic factor PF4, increased pericellular envelope, and promoted the normalization of vascular structure. In conclusion, ginsenoside CK improved the resistance of gefitinib by regulating the balance of angiogenic factors through down-regulating the HIF-1α/VEGF signaling pathway, providing a theoretical basis for improving the clinical efficacy of gefitinib and applying combined strategies to overcome drug resistance.

Processing, characterization and hemostatic mechanism of a ultraporous collagen/ORC biodegradable composite with excellent biological effectiveness.

Collagen, one of the most biocompatible materials in nature, is widely used in wound healing and organ repair. However, the limited mechanical strength and biological effectiveness of collagen restrain its application as a hemostasis and filling material in medicine. To overcome these limitations, ultraporous collagen/oxidized regenerated cellulose (Col/ORC) composites were prepared. The results showed that the Col-0.25%ORC composite had optimal wettability, porosity, and water absorption. An MTT assay proved that the Col and Col/ORC composites possessed no cytotoxicity in living cells. Evaluation of the hemostatic time in vivo and the amount of bleeding in two injury models revealed that the Col-0.25%ORC composite has the most outstanding biological effectiveness and could be biodegraded completely without any inflammatory reaction after 3 weeks. The SEM micrographs showed that the fasciculate ORC fibers were evenly dispersed into the reticulate structure of the Col sponge. The FT-IR spectra of the Col-ORC composites were completely different from that of neat ORC, but similar to Col spectra. Moreover, a possible hemostasis mechanism was discussed based on ELISA analysis, coagulation function, and physicochemical properties.

Development of a Reduced Chemical Reaction Mechanism for n-Pentanol Based on Combined Reduction Methods and Genetic Algorithm.

To gradually reduce the demand for fossil energy and accelerate energy transformation, alcohol fuels are being vigorously developed and utilized in the world. n-Pentanol as a common alcohol fuel has attracted increasing attention in recent years owing to its many advantages. In this study, a reduced mechanism of n-pentanol containing 148 species and 575 reactions was established based on combined reduction methods including the direct relationship graph with error propagation, reaction pathway analysis, rate of production analysis, and temperature sensitivity analysis methods. Then, the reaction rate parameters were optimized using the nondominated sorting genetic algorithm II. A verification experiment for the oxidation of n-pentanol was conducted in a jet-stirred reactor (JSR) with gas chromatography-mass spectrometry. The main species mole fractions were quantitatively analyzed in the temperature range 700-1100 K, equivalence ratios of 0.5-2.0, and a pressure of 1 atm. Extensive validations were performed over wide experimental conditions by comparing the experimental data of the ignition delay time, species concentration profiles in the JSR, and laminar flame speed. It was found that the predicted values were in good agreement with the experimental values. Therefore, the reduced mechanism developed in this study can accurately predict the experimental results, which is capable of reasonably applying to the simulation of combustion behaviors of n-pentanol in internal combustion engines.

Body Composition as a Predictor of Toxicity and Prognosis in Patients with Diffuse Large B-Cell Lymphoma Receiving R-CHOP Immunochemotherapy.

BACKGROUND: Our study measured the body composition of Diffuse large B-cell lymphoma (DLBCL) patients receiving rituximab with cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) regimen by computed tomographic (CT) and assessed their correlation with treatment-related toxicity and other adverse outcomes. METHODS: We retrospectively analyzed 201 DLBCL patients who underwent pre-treatment abdominal CT examination. CT images were used to assess body composition metrics at the third lumbar vertebrae including fat tissues and muscle. Based on the skeletal muscle area (SMA) and density (SMD), skeletal muscle index (SMI), skeletal muscle gauge (SMG = SMI × SMD) and lean body mass (LBM) were calculated. Also analyzed were the toxicity, adverse events and survival. RESULTS: We found that SMG, SMD, SMI and LBM were correlated with any grade 3-4 toxicity, dose reduction, hospitalization or termination of the treatment due to immunochemotherapy and worse survival. However, multivariate analysis demonstrated SMG [progression-free survival (PFS): hazard ratio (HR), 2.889; 95% CI, 1.401-5.959; p = 0.004; overall survival (OS): HR, 2.655; 95% CI, 1.218-5.787; p = 0.014] was the best predictor of poor prognosis. CONCLUSIONS: SMG, SMD, SMI and LBM were identified as predictors of adverse reactions and poor survival. SMG was an innovative and valuable indicator of immunochemotherapy toxicity and other adverse outcomes. Additionally, it can be used to individualize antineoplastic drug dosing.

Additional possibilities of chimeric antigen receptor T-cells in B-cell lymphoma: combination therapy.

B-cell non-Hodgkin's lymphoma (B-NHL) is a lymphoproliferative disorder that affects B lymphocytes. Chimeric antigen receptor (CAR) T-cell immunotherapy is a new type of immunotherapy that uses genetic engineering techniques to modify and expand the patient's autoimmune cells in vitro, after which these cells are reinfused into the patient. CAR-T cell immunotherapy has the potential to treat different types of B-cell lymphoma. Many clinical studies have shown that CAR-T cell therapy has significant antitumor effects on B-cell lymphoma. Although much work has been carried out to improve the efficacy of CAR-T cell therapy and to reduce associated side effects, there are still many issues to address. CAR-T cell therapy shows significant promise in treating B-NHL, but some patients still have a poor initial response to this therapy where the infused CAR-T cells show insufficient persistence. With the rapid development of immunological therapy, combination therapy has been certified to improve the efficacy of CAR-T cell therapy. Targeted drugs such as programmed death-1 (PD-1) inhibitors, programmed cell death-ligand 1 (PD-L1) inhibitors, and Bruton's tyrosine kinase (BTK) inhibitors may further enhance the efficacy and reduce the side effects of CAR-T cell treatment. This article reviews the rationale and relevant clinical research on combination therapy based on CAR-T cell therapy for B-cell lymphoma treatment.

Prognostic Roles of Blood Inflammatory Markers in Hepatocellular Carcinoma Patients Taking Sorafenib. A Systematic Review and Meta-Analysis.

Objective: The purpose of this meta-analysis is to investigate the effectiveness of the prognostic roles of blood inflammatory markers in hepatocellular carcinoma (HCC) patients receiving sorafenib. Methods: We carried out a comprehensive literature search in four databases. Study endpoints, hazard ratios (HRs) and the associated 95% confidence intervals (CI) for clinical outcomes, which were to assess therapeutic efficacy, were extracted. This meta-analysis was conducted by Review Manager 5.3. Results: We summarized the available evidence from 18 studies with a total of 2,745 cases. The pooled results showed that the synthesized HR favored patients with low pretreatment NLR (neutrophil-to-lymphocyte ratio), which also indicated that HCC patients with a lower baseline NLR may have a better response to sorafenib than those with higher NLR (HR = 1.76, 95% CI [1.44, 2.15], P < 0.00001, I 2 = 68%). Significance was also observed for the prognostic function of the PLR (platelet-to-lymphocyte ratio) of HCC patients treated with sorafenib (HR = 1.49, 95% CI [1.16, 1.93], P = 0.002, I 2 = 0%, P = 0.65). The subgroup analysis revealed that different gene backgrounds play a prominent role in the source of heterogeneity. Interestingly, the predictive effect on OS (overall survival) was more pronounced as the NLR cutoff value increased. Notably, a significant predictive effect of NLR on the clinical outcome was detected in HCC patients treated with sorafenib compared to those treated with tivantinib. Conclusion: In conclusion, the present study reported promising predictive biomarkers for HCC patients and notably indicated that HCC patients with a lower baseline NLR and PLR may have a better response to sorafenib than those with higher ones. Further large-scale prospective studies are required to determine the optimal NLR and PLR cutoff values, which are important for identifying the dominant populations for sorafenib treatment.

Lignocellulose utilization and bacterial communities of millet straw based mushroom (Agaricus bisporus) production.

Agaricus bisporus is in general cultivated on wheat and rice straw in China. However, millet straw is a potential alternative resource for Agaricus bisporus cultivation, but this has hardly been studied. In the present study, the feasibility of millet straw based mushroom production was analyzed by three successive trials. Mature compost demonstrated high quality with total nitrogen, pH, and C/N ratio of 2.0%, 7.5, and 18:1 respectively, which was suitable for mushroom mycelia growth. During composting, 47-50% of cellulose, 63-65% of hemicellulose, and 8-17% lignin were degraded, while 22-27% of cellulose, 14-16% of hemicellulose, and 15-21% of lignin were consumed by A. bisporus mycelia during cultivation. The highest FPUase and CMCase were observed during mushroom flushes. Endo-xylanase had the key role in hemicellulose degradation with high enzyme activity during cultivation stages. Laccase participated in lignin degradation with the highest enzyme activity in Pinning stage followed by a sharp decline at the first flush. Yield was up to 20 kg/m2, as this is similar to growth on wheat straw, this shows that millet straw is an effective resource for mushroom cultivation. Actinobacteria, Bacteroidetes, Chloroflexi, Deinococcus-Thermus, Firmicutes, and Proteobacteria were the dominant phyla, based on 16S rRNA gene sequencing during composting. The key environmental factors dominating bacterial communities of the samples were determined to be pH value, cellulose content, and hemicellulose content for prewetting and premixed phase of basic mixture (P0); moisture content for phase I (PI); and nitrogen content, lignin content, and ash content for phase II (PII), respectively.

Incorporation of bacteriophages in polycaprolactone/collagen fibers for antibacterial hemostatic dual-function.

Effective and affordable, antibacterial and hemostatic materials are of great interests in clinical wound care practices. Herein, Enterobacteria phage T4 were incorporated in polycaprolactone/collagen I (PCL-ColI) nanofibers via electrospinning in order to eradicate Escherichia coli infection and meanwhile establish hemostasis. Tensile strength of the membrane was significantly enhanced with increased PCL ratio. Those with a collagen component above 70% were demonstrated to be more hemostatic with shorter hemostatic time and smaller amount of bleeding. On the other hand, the T4 phage incorporated PCL-ColI membrane (PCL:ColI = 30%/70%, w/w) exhibited the optimal antibacterial efficiency (above 90%). The in vivo evaluation indicated that the PCL-ColI B (30%:70%, w/w) membrane fully degraded in 8 weeks and no obvious pathological reaction to muscle and subcutaneous layer tissues in the back of rabbit was found. The novel fibrous hemostatic materials coupled with phage therapy hold great promise in designing novel antibacterial, hemostatic wound dressings that addresses concerns of antibiotic resistance. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2588-2595, 2018.

Comparison of loop-mediated isothermal amplification with hyperbranched rolling circle amplification as a simple detection method for Heterosigma akashiwo.

The fish-killing alga Heterosigma akashiwo is a globally distributed, toxic, and bloom-forming raphidophyte that has caused great losses to the fishing industry in many coastal countries. Therefore, rapid and sensitive detection methods should be developed to present timely warning of harmful algal blooms. In this study, hyperbranched rolling circle amplification (HRCA) was established for the detection of H. akashiwo and compared with loop-mediated isothermal amplification (LAMP) in terms of specificity and sensitivity. The partial D1-D2 sequence of the large subunit (LSU) of rDNA of H. akashiwo was used to design a specific padlock probe for HRCA and two pairs of specific primers for LAMP. The parameters for HRCA were optimized. Cross-reactivity tests showed that the specificity of the developed HRCA for H. akashiwo was greater than that of LAMP in this study. The sensitivities of HRCA and LAMP were comparable and were 10-fold higher than that of regular PCR. These methods also yielded a detection limit of 20 fg/µL for the recombinant plasmid containing the target LSU D1-D2 and 1 cell for target species. The test with the simulated field samples indicated that the developed HRCA obtained a detection limit of 5 cells mL-1, which was lower than the warning cell density (100 cells mL-1) of H. akashiwo. The visual detection of positive HRCA could be achieved via coloration reaction with the addition of fluorescent SYBR Green I dye to the amplification products. The developed HRCA was also efficient for field samples with target cell densities ranging from 10 cells mL-1 to 1000 cells mL-1. Therefore, the proposed HRCA detection protocols are possibly applicable to the field monitoring of H. akashiwo.

Effect of ultrasound assisted extraction on the physicochemical and functional properties of collagen from soft-shelled turtle calipash.

The aim of the present study was to evaluate the physicochemical and functional properties of acid-soluble collagen by ultrasound assisted extraction (UASC) from calipash of soft-shelled turtle (Pelodiscus sinensis). The results showed the collagen content was increased by 16.3% in UASC over the collagen from the conventional extraction (ASC). Both ASC and UASC contained a moderate amount of imino acid (197 and 216 residues/1000 residues, respectively) and hydrophobic amino acid (353 and 391 residues/1000 residues, respectively) in amino acid composition. Fourier transform infrared (FTIR) spectroscopy and X-ray diffraction (XRD) analyses confirmed that the ultrasound treatment did not disrupt the triple-stranded helical structures in UASC. UASC had higher thermal stability compared with ASC by viscosity and differential scanning calorimetry (DSC) measurements, therefore, UASC might have the advantage to be used. In dynamic elastic behavior measurement, UASC showed a larger elasticity than ASC. With a mild modification by ultrasound, UASC had superior functional properties to ASC, including water/oil absorption capacity, water-holding capacity, emulsifying properties and foaming properties. These results suggested that UASC from the soft-shelled turtle calipash had a potential to be used widely in food, medicine, cosmetics and biomedical materials.

Comparison between paricalcitol and active non-selective vitamin D receptor activator for secondary hyperparathyroidism in chronic kidney disease: a systematic review and meta-analysis of randomized controlled trials.

PURPOSE: The goal of this systematic review is to evaluate the efficacy and safety of paricalcitol versus active non-selective vitamin D receptor activators (VDRAs) for secondary hyperparathyroidism (SHPT) management in chronic kidney disease (CKD) patients. METHODS: PubMed, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), clinicaltrials.gov (inception to September 2015), and ASN Web site were searched for relevant studies. A meta-analysis of randomized controlled trials (RCTs) and quasi-RCTs that assessed the effects and adverse events of paricalcitol and active non-selective VDRA in adult CKD patients with SHPT was performed using Review Manager 5.2. RESULTS: A total of 10 trials involving 734 patients were identified for this review. The quality of included trials was limited, and very few trials reported all-cause mortality or cardiovascular calcification without any differences between two groups. Compared with active non-selective VDRAs, paricalcitol showed no significant difference in both PTH reduction (MD -7.78, 95% CI -28.59-13.03, P = 0.46) and the proportion of patients who achieved the target reduction of PTH (OR 1.27, 95% CI 0.87-1.85, P = 0.22). In addition, no statistical differences were found in terms of serum calcium, episodes of hypercalcemia, serum phosphorus, calcium × phosphorus products, and bone metabolism index. CONCLUSIONS: Current evidence is insufficient, showing paricalcitol is superior to active non-selective VDRAs in lowering PTH or reducing the burden of mineral loading. Further trials are required to prove the tissue-selective effect of paricalcitol and to overcome the limitation of current research.