Pharmacodynamic and Pharmacogenomic study of the nanoparticle conjugate of camptothecin CRLX101 for the treatment of cancer

CRLX101 is a nanopharmaceutical consisting of cyclodextrin-based polymer molecule and camptothecin. The CRLX101 nanoparticle is designed to concentrate and slowly release camptothecin in tumors over an extended period of time. Tumor biopsy and blood samples collected from patients with advanced solid malignancies before and after CRLX101 treatment are subjected to immunohistochemistry and pharmacogenomics. The expression of Topoisomerase-1, Ki-67, CaIX, CD31 and VEGF decreased after CRLX101 treatment. The expressions of these proteins are inversely proportional with survival duration of the patients. The Drug Metabolism Enzymes and Transporters (DMET) array shows an allele frequency in patients similar to global populations with none of the SNPs associated with toxicity. The results suggest that the observed lower toxicity is not likely be due to different genotypes in SNPs. CRLX101 demonstrates a promising anti-tumor activity in heavily pre-treated or treatment-refractory solid tumor malignancies presumably by inhibition of proliferation and angiogenesis correlating with tumor growth inhibition

Ferulic Acid against Cyclophosphamide-Induced Heart Toxicity in Mice by Inhibiting NF- κ

The purpose of the present study was to elucidate the protective effects of ferulic acid (FA) against cyclophosphamide- (CTX-) induced changes in mice. Forty-eight male ICR mice were divided into four groups. Control group was intraperitoneally (i.p.) injected with 200 μL of phosphate buffer saline (PBS). Model group was intraperitoneally injected with a single dose of CTX (200 mg/kg). FA (50 mg/kg) and FA (100 mg/kg) groups were intraperitoneally injected with a single dose of CTX (200 mg/kg) followed by the intragastric treatment with FA (50, 100 mg/kg) for 7 consecutive days. After 12 d, the mice were sacrificed to analyze the hematological, biochemical, histological parameters and mechanism research. The results indicated that FA significantly decreased the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatine kinase (CK), lactate dehydrogenase (LDH), interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-α (TNF-α) in CTX-injected mice. In addition, FA effectively reduced the total numbers of white blood cells (WBCs), red blood cells, platelets, and hemoglobin content. FA also obviously attenuated the histological changes of the heart tissues caused by CTX. Moreover, Western blot demonstrated that FA inhibited the phosphorylations of NF-κB signaling pathway in CTX-stimulated cardiac tissues. In conclusion, FA might be considered as an effective agent in the amelioration of the heart toxicity resulting from CTX treatment

De novo sequencing of circulating miRNAs identifies novel markers predicting clinical outcome of locally advanced breast cancer

<p>Abstract</p> <p>Background</p> <p>MicroRNAs (miRNAs) have been recently detected in the circulation of cancer patients, where they are associated with clinical parameters. Discovery profiling of circulating small RNAs has not been reported in breast cancer (BC), and was carried out in this study to identify blood-based small RNA markers of BC clinical outcome.</p> <p>Methods</p> <p>The pre-treatment sera of 42 stage II-III locally advanced and inflammatory BC patients who received neoadjuvant chemotherapy (NCT) followed by surgical tumor resection were analyzed for marker identification by deep sequencing all circulating small RNAs. An independent validation cohort of 26 stage II-III BC patients was used to assess the power of identified miRNA markers.</p> <p>Results</p> <p>More than 800 miRNA species were detected in the circulation, and observed patterns showed association with histopathological profiles of BC. Groups of circulating miRNAs differentially associated with ER/PR/HER2 status and inflammatory BC were identified. The relative levels of selected miRNAs measured by PCR showed consistency with their abundance determined by deep sequencing. Two circulating miRNAs, miR-375 and miR-122, exhibited strong correlations with clinical outcomes, including NCT response and relapse with metastatic disease. In the validation cohort, higher levels of circulating miR-122 specifically predicted metastatic recurrence in stage II-III BC patients.</p> <p>Conclusions</p> <p>Our study indicates that certain miRNAs can serve as potential blood-based biomarkers for NCT response, and that miR-122 prevalence in the circulation predicts BC metastasis in early-stage patients. These results may allow optimized chemotherapy treatments and preventive anti-metastasis interventions in future clinical applications.</p

Cancer-Secreted miR-105 Destroys Vascular Endothelial Barriers to Promote Metastasis

SummaryCancer-secreted microRNAs (miRNAs) are emerging mediators of cancer-host crosstalk. Here we show that miR-105, which is characteristically expressed and secreted by metastatic breast cancer cells, is a potent regulator of migration through targeting the tight junction protein ZO-1. In endothelial monolayers, exosome-mediated transfer of cancer-secreted miR-105 efficiently destroys tight junctions and the integrity of these natural barriers against metastasis. Overexpression of miR-105 in nonmetastatic cancer cells induces metastasis and vascular permeability in distant organs, whereas inhibition of miR-105 in highly metastatic tumors alleviates these effects. miR-105 can be detected in the circulation at the premetastatic stage, and its levels in the blood and tumor are associated with ZO-1 expression and metastatic progression in early-stage breast cancer

Comparative Pharmacokinetics and Preliminary Pharmacodynamics Evaluation of Piscidin 1 Against PRV and PEDV in Rats

Antimicrobial peptide (Piscidin-1) is an effective natural polypeptide, which has great influence and potential on porcine epidemic diarrhea virus (PEDV) and pseudorabies virus (PRV). As an alternative antibiotic substitute, Piscidin-1 was subjected for pharmacokinetics study with three administration routes (i.v, i.m, and p.o) after a single dose of 2 mg/kg in rats and preliminary pharmacodynamics including antiviral activity in cell against PEDV and PRV. Based on 50 percent tissue culture infective dose (TCID50), there were about 2 and 10% virus survived ratios for Piscidin-1 against PRV and PEDV, respectively. The plaque test showed 1 and 2 μg/ml Piscidin-1 could eliminate 95% PRV and 85% PEDV, respectively. The main pharmacokinetics parameters of Cmax, AUC0−∞, Ke, t1/2, Tmax, MRT, and Clb in plasma were not applicable value, 25.9 μg*h/ml, 0.041 h−1, 16.97 h, not available value, 22.77 h, 0.067 L/h*kg after i.v administration, 2.37 μg/ml, 18.95 μg*h/ml, 0.029 h−1, 23.50 h, 0.33 h, 30.12 h, 0.095 L/h*kg after i.m administration and 0.73 μg/ml, 9.63 μg*h/ml, 0.036 h−1, 19.46 h, 0.50 h, 26.76 h, 0.171 L/h*kg after p.o administration. The bioavailability values after i.m and p.o administrations were calculated as 73.17 and 37.18%, respectively. The i.m administration was selected for pharmacokinetics study in ileum content against PEDV. The main pharmacokinetic parameters of Cmax, AUC0−∞, Ke, t1/2, Tmax, MRT, and Clb in ileum content were 1.67 μg/ml, 78.40 μg*h/ml, 0.034 h−1, 20.16 h, 8.12 h, 36.45 h, 0.026 L/h*kg. The Cmax values in plasma (2.37 μg/ml) and ileum content (1.67 μg/ml) were higher than the effective inhibitory concentration determined in the plaque test, and this indicates that Piscidin-1 might have effective inhibition effect against PRV and PEDV after administration of 2 mg/kg i.m. The results of this study represent the first investigations toward the pharmacokinetic characteristics of piscidin-1 in plasma upon three different administration routes, among which i.m. resulted in the highest bioavailability (73.17%). Furthermore, the pharmacokinetics study of ileum content indicated Piscidin-1 might have good effect against PEDV and could be regarded as an alternative antibiotic in clinical veterinary in the future study

Agricultural Jiaosu Enhances the Stress Resistance of Pak Choi (<i>Brassica rapa</i> L. subsp. <i>chinensis</i>) by Recruiting Beneficial Rhizosphere Bacteria and Altering Metabolic Pathways

Agricultural Jiaosu (AJ) is a method of recycling agricultural wastes for improving soil properties, promoting plant growth, and enhancing plant stress resistance. However, the underlying mechanism by which AJ improves plant stress resistance needs to be determined. Therefore, in this study, two treatments of AJ spraying and water spraying were set up to determine the enzyme activities related to the stress resistance of pak choi after 30 days of growth, and the potential mechanism of AJ’s influence on the stress resistance of pak choi was revealed by transcriptome, metabolome, and rhizome microbiome analyses. Microbial community analysis revealed that the application of AJ does not alter microbial abundance in the rhizosphere; however, it can improve microbial diversity and enrich Actinobacteriota, Proteobacteria, and Firmicutes in the pak choi rhizosphere. Metabolomic analysis revealed that these phyla were significantly positively correlated, with highly upregulated metabolites. Our findings suggest that AJ recruits beneficial microorganisms (BMs) in the rhizosphere and stimulates the expression of genes and metabolites involved in phenylpropanoid and glucosinolate biosynthesis, as well as glutathione and alpha-linolenic acid metabolism pathways. The use of AJ could considerably minimise the use of pesticides and fertilisers and improve the quality of the ecological environment

THE APPLICATION OF PULSED LASER DEPOSITION IN PRODUCING BIOACTIVE CERAMIC FILMS

Pulsed laser deposition (PLD) is a relatively new technique for producing thin films. It presents unique advantages for the deposition of bioactive ceramics. The mechanism and characteristics of the technique PLD are introduced. Its applications and current research status in hydroxyapatite and bioglass thin films are reviewed. The effect of processing parameters of PLD, including atmosphere, substrate temperature, laser wavelength and target properties, on the structures and the properties of the hydroxyapatite film, is analyzed in detail. Future application trends are also analyzed.Pulsed laser deposition, bioactive ceramic, hydroxyapatite, bioglass

THE CURRENT TECHNIQUES FOR PREPARING BIOGLASS COATINGS

Bioglasses are promising alternatives as biomedical materials to repair or replace damaged parts of bones because of its good bioactivity and biocompatibility. It is possible to combine the bone-bonding ability of the bioglass surface with the high mechanical properties of the metallic substrate though the coating of metallic implants with bioglass. The principles and characteristics of some coating techniques, including sintering, plasma spray, sol-gel, electrophoresis deposition, ion beam assisted deposition and pulsed laser deposition, are introduced. Their current applications in preparing bioglass coatings are reviewed in detail. The future application trends are also reviewed.Bioglass, coating, bioactivity, techniques

STUDY ON STRESS INTENSITY FACTOR OF THREE DIMENSION MODEL OF TYPEⅠCRACK IN TYPICAL LUG JOINT

On the basis of two-dimension finite element analysis,the two-dimension stress intensity factor correction coefficients of typical lug joint were obtained; Three dimension elastic plastic contact finite element model of the typical lug joint was simulated and analyzed,and the lug thickness correction factor was introduced. Based on the results of two-dimension stress intensity factor correction and three-dimension finite element stress intensity factor simulation,the plug thickness correction factors were fitted,then get the expression of stress intensity factor of three-dimension model ofⅠtype crack in typical lug joint.Finally the corresponding stress intensity factor expression was carried out to verify the accuracy,which combined with the corresponding residual strength test. The results show that the stress intensity factor calculation formula is accurate