A randomized phase III trial comparing adjuvant single-agent S1, S-1 with oxaliplatin, and postoperative chemoradiation with S-1 and oxaliplatin in patients with node-positive gastric cancer after D2 resection: the ARTIST 2 trial☆.

BACKGROUND: Adjuvant chemotherapy and chemoradiotherapy are some of the standards of care for gastric cancer (GC). The Adjuvant chemoRadioTherapy In Stomach Tumors (ARTIST) 2 trial compares two adjuvant chemotherapy regimens and chemoradiotherapy in patients with D2-resected, stage II or III, node-positive GC. PATIENTS AND METHODS: The ARTIST 2 compared, in a 1:1:1 ratio, three adjuvant regimens: oral S-1 (40-60 mg twice daily 4 weeks on/2 weeks off) for 1 year, S-1 (2 weeks on/1 week off) plus oxaliplatin 130 mg/m2 every 3 weeks (SOX) for 6 months, and SOX plus chemoradiotherapy 45 Gy (SOXRT). Randomization was stratified according to surgery type (total or subtotal gastrectomy), pathologic stage (II or III), and Lauren histologic classification (diffuse or intestinal/mixed). The primary endpoint was disease-free survival (DFS) at 3 years; a reduction of 33% in the hazard ratio (HR) for DFS with SOX or SOXRT, when compared with S-1, was considered clinically meaningful. The trial is registered at clinicaltrials.gov (NCT0176146). RESULTS: A total of 546 patients were recruited between February 2013 and January 2018 with 182, 181, and 183 patients in the S-1, SOX, and SOXRT arms, respectively. Median follow-up period was 47 months, with 178 DFS events observed. Estimated 3-year DFS rates were 64.8%, 74.3%, and 72.8% in the S-1, SOX, and SOXRT arms, respectively. HR for DFS in the control arm (S-1) was shorter than that in the SOX and SOXRT arms: S-1 versus SOX, 0.692 (P = 0.042) and S-1 versus SOXRT, 0.724 (P = 0.074). No difference in DFS was found between SOX and SOXRT (HR 0.971; P = 0.879). Adverse events were as anticipated in each arm, and were generally well-tolerated and manageable. CONCLUSIONS: In patients with curatively D2-resected, stage II/III, node-positive GC, adjuvant SOX or SOXRT was effective in prolonging DFS, when compared with S-1 monotherapy. The addition of radiotherapy to SOX did not significantly reduce the rate of recurrence after D2 gastrectomy.

Treatment with QiBaoMeiRan, a Chinese herbal formula, prevents bone loss in ovariectomized rat.

OBJECTIVE: Hormone replacement therapy has been used as an effective treatment for the prevention of bone loss in postmenopausal women. In our previous study, QiBaoMeiRan formula (QBMR) had estrogenic activity and could relieve symptoms of hot flushes and body weight increase induced by estrogen decline. However, no evidence base links QBMR to preventing bone loss. The aim of this study is to investigate the effect of QBMR on bone loss. METHODS: The ovariectomized rat model was established, and ovariectomized rats were treated with QBMR at doses of 0.875, 1.75, and 3.5 g/kg per day for 8 weeks. Biochemical parameters, bone mineral density, structural morphometric traits and histological characteristics of trabecular bone were assessed. RESULTS: QBMR treatment significantly decreased the increase in serum alkaline phosphatase, bone Gla-protein and C-telopeptide fragments of type I collagen and decreased the decline of serum calcium and phosphorus in the circulation of ovariectomized rats. QBMR completely corrected the decrease in bone mineral density in lumbar vertebrae (L4-L6) comparable to the sham group. In addition, QBMR treatment also significantly ameliorated the decrease of structural parameters of femur trabecular bone, bone volume fraction, trabecular number, trabecular thickness and bone mineral density as well as the increase in trabecular separation by micro-computerized tomography scanning. These were also confirmed by bone histological results that showed its protective action. CONCLUSIONS: Our results indicated that QBMR had a definite anti-bone loss effect and will have potential to be used for the treatment of postmenopausal osteoporosis.

The effects of germacrone on lipopolysaccharide-induced acute lung injury in neonatal rats.

Germacrone is one of the main bioactive components in the traditional Chinese medicine Rhizoma curcuma and has been shown to possess an anti-inflammatory activity. Our present study aimed to investigate the protective effects of germacrone on lipopolysaccharide (LPS)-induced acute lung injury in neonatal rats. Results showed that germacrone treatment significantly decreased the expression of pro-inflammatory cytokines IL-6 and TNF-α. Meanwhile, the expression of anti-inflammatory mediators TGF-ß1 and IL-10 was obviously increased following germacrone administration. The LPS-induced pathological changes in neonatal rats were also attenuated by germacrone treatment. In vitro, MTT and EdU incorporation assay indicated that germacrone administration significantly increased the A549 cell viabilities in a dose-dependent manner. Besides, flow cytometry and TUNEL analysis showed that the cell apoptosis rate was significantly reduced in a concentration-dependent manner after germacrone injection. At the molecular level, we found that germacrone treatment promoted the expression of claudin-4 both in vivo and in vitro as shown by real time PCR and western blot. Collectively, our study demonstrated that germacrone protected neonatal rats against LPS-induced ALI partially by modulation of claudin-4.

Antibacterial and synergy of a flavanonol rhamnoside with antibiotics against clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA).

The in vitro antibacterial activity of taxifolin-7-O-α-L-rhamnopyranoside (TR) and its synergy with four conventional antibiotics (ampicillin (AMP), levofloxacin (LEV), ceftazidime (CAZ) and azithromycin (AZM)) against ten clinical isolates of methicillin-resistant staphylococcus aureus (MRSA) were evaluated, respectively. Individual MICs and MBCs were determined by microdilution methods following the CLSI guidelines. Anti-MRSA synergy effects were measured using the chequerboard and time-kill curve tests. MICs/MBCs (µg/ml) ranges were 32-64/64-128 for TR alone against all 10 MRSA isolates. Chequerboard method showed that significant synergies were observed for the TR/CAZ and TR/LEV combinations with FICI ranged 0.187-0.375 and 0.25-0.5, respectively. Some synergy and additivity effects were also observed for TR/AMP and TR/AZM combinations. In the time-kill dynamic confirmation test, synergy results kept by the TR/CAZ combination (2.186 log10 cfu/ml increase in killing), but the TR/LEV combination changed to additivity (1.839 log10 cfu/ml increase in killing). These results demonstrated that TR enhanced the efficacy of CAZ and LEV in vitro, which had potential for combinatory therapy of patients infected with MRSA.

Comparison of hyperkalemic cardioplegia with altered [CaCl2] and [MgCl2] on [Ca2+]i transients and function after warm global ischemia in isolated hearts.

AIM: [MgCl(2)] and [CaCl(2)] may modify the cardioprotective effects of hyperkalemic cardioplegia (CP). We changed [MgCl(2)] and [CaCl(2)] in a CP solution to examine their effects on [Ca(2+)]i transients and cardiac function before and after global normothermic ischemia. METHODS: After stabilization and loading of indo 1-AM in Kreb's solution (KR), each heart was perfused with either KR or 1 of 4 CP solutions before 37 degrees C, 30 min ischemia followed by reperfusion with KR. The KR solution contained, in mM, 4.5 KCl, 2.4 MgCl(2) and 2.5 CaCl(2); the CP solutions had in addition to 18 KCl: CP 1 (control CP): 2.4 MgCl(2), 2.5 CaCl(2); CP 2: 7.2 MgCl(2), 2.5 CaCl(2); CP 3, 7.2 MgCl(2), 1.25 CaCl(2); CP 4: 2.4 MgCl(2), 1.25 CaCl(2). RESULTS: In the KR group [Ca(2+)]i markedly increased on early reperfusion while functional return (LVP, dLVP/dt((max and min))) was much reduced; each CP group led to reduced [Ca(2+)]i loading and improved function. The rates of cytosolic Ca(2+) fluxes (d[Ca(2+)]/dt(max) and d[Ca(2+)]/dt(min)) increased significantly compared to baseline in the KR group, but were mostly suppressed in the CP groups, and d[Ca(2+)]/dt(min) was lower after CP 4 compared to CP 1 on reperfusion. At 60 min reperfusion, LVP area to [Ca(2+)] area and cardiac efficiency to phasic [Ca(2+)] relationships were shifted after KR, but not after CP 1-4. With similar functional recovery, [Ca(2+)] transient and [Ca(2+)] area were significantly lower after CP 4 than after CP 1. CONCLUSION: Increasing [MgCl(2)] (CP 2 and 3) did not improve cardiac function or reduce Ca(2+) transients on reperfusion better than the other CP groups, but reducing [CaCl(2)] (CP 3 and 4) was more effective in reducing [Ca(2+)] transients on reperfusion after global ischemia.

Utility of the Arabidopsis FAE1 and yeast SLC1-1 genes for improvements in erucic acid and oil content in rapeseed.

High-erucic acid (HEA) Brassica napus cultivars are regaining interest in industrial contexts. Erucic acid and its derivatives are important renewable raw materials utilized in the manufacture of plastic films, in the synthesis of Nylon 13,13, and in the lubricant and emollient industries. Theoretically, the highest level of erucic acid that can be achieved by means of classical breeding is 66 mol%; however, using new approaches on the basis of genetic engineering, it might be possible to develop a B. napus cultivar containing levels of erucic acid significantly above 66 mol% (>80 mol%). In an attempt to increase the amounts of very-long-chain fatty acids (VLCFAs), and erucic acid in particular, in Canadian HEA B. napus cultivars, we have focused on two targets using a transgenic approach. We examined both the role/function of the Arabidopsis thaliana FAE1 (fatty acid elongase) gene by expressing it under the control of the seed-specific napin promoter in B. napus germplasm with analysis of the changes in VLCFA content in the seed oil of transgenic lines, and the performance of the yeast SLC1-1 (sphingolipid compensation mutant) in B. napus cv. Hero transgenic progeny in the field. Here, we report analyses of the contents of 22:1, total VLCFAand oil in the seed oil, as well as seed yield of the field-grown FAE1 and SLC1-1 B. napus cv. Hero progeny.

Isolation and structural characterization of endo-rhamnogalacturonase-generated fragments of the backbone of rhamnogalacturonan I.

A combination of commercially available preparations of Aspergillus niger beta-D-galactosidase, endo-alpha-L-arabinanase, alpha-L-arabinosidase, and endo-beta-D-galactanase has been used to generate oligoglycosyl fragments of the backbone of rhamnogalacturonan I (RG-I) that had been isolated from the walls of suspension-cultured sycamore cells. The backbone-cleaving enzyme, which is present in the beta-D-galactosidase preparation, only fragments the RG-I backbone when many of the neutral oligoglycosyl side chains have been removed by the other exo- and endo- glycanases. The oligosaccharides released from the backbone were separated from the partially fragmented RG-I and then purified, as their oligoglycosyl aldonic acids, by HPAEC-PAD. Those backbone fragments with degrees of polymerization (dp's) between 2 and 11 were characterized using one- and two-dimensional 1H NMR spectroscopy, electrospray mass spectrometry, and glycosyl-residue and glycosyl-linkage composition analyses. Two series of oligoglycosyl fragments were identified. The quantitatively predominant series has the structure alpha-D-GalpA-(1 --> 2)- alpha-L-Rhap-[ --> 4)-alpha-D-GalpA-(1 --> 2)-alpha-L-Rhap-(1 --> ]n-4-D-GalpA, and the quantitatively minor series has the structure alpha-L-Rhap-[ --> 4)-alpha-D-GalpA-(1 --> 2)-alpha-L-Rhap-(1 --> ]n-4-D- GalpA (n = 1-5). Thus, the enzyme preparations contain an alpha-L-rhamnosidase in addition to the endo- rhamnogalacturonase. The products of the endo-rhamnogalacturonase provide additional evidence that the backbone of RG-I is composed of the diglycosyl repeating unit: --> 4)-alpha-D-GalpA-(1 --> 2)-alpha-L-Rhap- (1 -->. The endo-rhamnogalacturonase from the A. niger beta-D-galactosidase preparation and the endo- rhamnogalacturonase secreted by Aspergillus aculeatus [H.A. Schols et al. Carbohydr. Res., 206 (1990) 117-129] have the same substrate specificities and generate similar oligoglycosyl fragments.

Studies on the chelation of hypocrellin A with aluminium ion and the photodynamic action of the resulting complex.

Hypocrellin A (HA), a perylenoquinone derivative, is an efficient phototherapeutic agent. The chelation of HA with aluminium ion (Al3+) results in the formation of a 1:1 complex (Al(3+)-HA). The probable structure for this complex has been proposed. Compared with HA, this complex has a much higher solubility in water. In addition, Al(3+)-HA preserves the 1O2-generating function of HA as demonstrated by diphenylanthracene photo-bleaching experiments. In irradiated oxygen-saturated solutions of Al(3+)-HA superoxide radical anion and hydroxyl radical are formed as verified using 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) as the electron spin resonance (ESR) spin trapping agent. The production of superoxide radical anion is enhanced significantly in the presence of electron donors such as 1-benzyl-1,4-dihydronicotinamide (BNAH). These results suggest that the photodynamic action of Al(3+)-HA proceeds via both type 1 and type 2 reactions.

Isolation and structural characterization of beta-D-glucosyluronic acid and 4-O-methyl beta-D-glucosyluronic acid-containing oligosaccharides from the cell-wall pectic polysaccharide, rhamnogalacturonan I.

Rhamnogalacturonan I (RG-I), a pectic polysaccharide isolated from the walls of suspension-cultured sycamore cells, was shown by glycosyl-residue composition analysis to contain D-glucosyluronic acid (GlcpA) residues (1 mol%) and 4-O-methyl-D-glucosyluronic acid (4-O-Me-GlcpA) residues (0.5 mol%). These monosaccharides were shown, by glycosyl-linkage analysis, to be present in RG-I as terminal nonreducing residues. The glycosyl sequences containing GlcpA and 4-O-Me-GlcpA were determined by structurally characterizing the acidic oligosaccharides released by partial acid hydrolysis of RG-I. Six acidic oligosaccharides were purified by semipreparative high-performance anion-exchange chromatography with pulsed amperometric detection (HPAEC-PAD) and characterized by glycosyl-residue and glycosyl-linkage composition analyses, GLC-CIMS, GLC-EIMS, electrospray MS (ESMS), and 1H NMR spectroscopy. We propose that three of the acidic oligosaccharides characterized, 4-O-Me-beta-D-GlcpA-(1-->6)-D-Gal, beta-D-GlcpA-(1-->6)-D-Gal, and beta-D-GlcpA-(1-->4)-D-Gal, originate from the galactosyl-containing side chains of RG-I. The three other acidic oligosaccharides characterized, alpha-D-GalpA-(1-->2)-L-Rha, alpha-D-GalpA-(1-->2)-alpha-L-Rhap-(1-->4)-alpha-D-GalpA+ ++-(1-->2)-alpha-L-Rha, and alpha-D-GalpA-(1-->2)-alpha-L-Rhap-(1-->4)-alpha-D-GalpA+ ++-(1-->2)-alpha-L- Rhap-(1-->4)-alpha-D-GalpA-(1-->2)-alpha-L-Rha, were generated by partial hydrolysis of the RG-I backbone. No evidence was obtained for the presence of galactosyluronic acid in the side chains of RG-I.(ABSTRACT TRUNCATED AT 250 WORDS)

[Effect of Na2SeO3 on the damages of genetic materials induced by MNNG in children's foreskin fibroblasts in vitro].

In order to study the effect of selenium on anticarcinogenesis, micronuclei (MN) and chromosome aberrations (CA) were used as the indexes to reflect the damages on the genetic materials induced by MNNG in children's foreskin fibroblasts in vitro. In the MN test, the final concentrations of Na2SeO3 were 10(-7), 10(-6), 10(-5) and 10(-4) M and MNNG, 10(-5)M. In the CA test, Na2SeO3 were used in 10(-7), 10(-6) and 10(-5)M and MNNG, 10(-6)M as the final concentrations. Relative to the time of MNNG treatment, the cells were exposed to Na2SeO3 4 hours before and at the same time as with the carcinogen. The results showed that the MN% (number of cells out of one thousand MN) was reduced from 4.31 +/- 0.91% to 1.55 +/- 0.54% and 1.54 +/- 0.54% (P less than 0.05), respectively. The CA% (the percentage of the cell with CA) was reduced from 86 +/- 7% to 34 +/- 9% and 33 +/- 9% (P less than 0.05), respectively. However there was no like results when the cells were treated with Na2SeO3 and MNNG simultaneously. Na2SeO3 had no significant protective effects on the cells when the concentration was 10(-7)M. If the dose was 10(-4)M or more, Na2SeO3 became toxic to the cells. The results suggested that the protection of Na2SeO3 on the damages of genetic materials induced by MNNG be time and dose dependent.

Circular dichroism of bilirubin-amine association complexes: insights into bilirubin-albumin binding.

Bichromophoric (4Z, 15Z)-bilirubin-IX alpha, the yellow-orange cytotoxic pigment of jaundice, adopts either of two intramolecularly hydrogen-bonded enantiomeric conformations that are in dynamic equilibrium in solution. The addition of optically active amines induces the pigment solutions to exhibit intense bisignate circular dichroism in the region of the bilirubin long wavelength uv-visible absorption band. The most intense circular dichroism Cotton effects, (delta epsilon) approximately equal to 130, are induced by beta-arylamines and are comparable to those exhibited by bilirubin complexes with serum albumin and other proteins. Like serum albumin and other proteins, the optically active base acts as a chiral complexation agent to induce an asymmetric transformation of bilirubin, whose induced bisignate circular dichroism Cotton effect is characteristic of exciton splitting of the component pyrromethenone chromophores. The amines thus serve as chiral templates for molecular recognition, and the complementary action of the amine complexation sites provides insight into the binding forces important in protein-bilirubin heteroassociation.