Modified screen printed (SPE) and carbon paste electrodes (CPE) with phenanthroline–tetraphenyl borate ionophore Phen:TPB were fabricated for the determination of copper(II). The modified electrodes ...have linear responses over a wide concentration range (1 × 10
−6
–1 × 10
−2
mol·L
−1
) of copper(II) ion at 25 °C with divalent cationic slopes of 29.85 ± 0.58 and 29.45 ± 0.81 mV·decade
−1
and exhibit a detection limit of 1 × 10
−6
mol·L
−1
for SPE and CPE. The selectivity coefficient was measured using the match potential method in acetate buffer of pH = 4.2. The modified SPE and CPE sensors show high selectivity and sensitivity for determination of copper(II) and also show stable and reproducible response over a period of five and three months for SPE and CPE sensors, respectively. This method can be used for determination of copper(II) in water, soil, plant and fish tissue samples and the results obtained agreed with those obtained with atomic absorption spectrometer (AAS).
IDH1 and IDH2 are hotspot mutations commonly identified in WHO-grade 4 astrocytomas. Their association with TAMs has never been investigated. We aim to explore the crosstalk between the IDH1/2 ...mutation metabolic effect and TAMs in tumour microenvironment and how this relationship affects the tumour recurrence.
The study included 20 samples of patients with WHO-grade 4 astrocytoma. The alteration hotspot in codon IDH1
and IDH2
was examined using direct sequencing. The protein expression of CD204 on TAM was detected through immunohistochemistry.
IDH1
and IDH2
were symmetrically identified as wildtype in 18/20 tumours (90%) and the remaining 2 tumours (10%) showed synonymous mutations on both codons. Tumours with IDH1/2-wildtype showed high expression of CD204
TAMs in 10 cases and low expression in 8 cases. Typical expression was seen equally in IDH1/2 mutant tumours. There was no significant association between IDH1/2 and CD204
TAM expression (p= 0.999). The association between the two groups was significantly observed among IDH-wildtype tumours (p=0.027). Highly expressed CD204 in IDH-wildtype tumours showed a median recurrence at 10 months compared to low CD204 expression, showed a median recurrence interval at 24 months.
IDH1
or IDH
has the same impact on the classification and prognosis of WHO-grade 4 astrocytoma. There was no crosstalk between IDH1/2 metabolic effect and CD204
TAM. However, IDH-wildtype glioblastomas with dense CD204
TAM are associated with early recurrence. Because the sample size is small, a larger study is recommended to determine the impact of IDH1/2 on TAMs.
In human and mouse, most imprinted genes are arranged in chromosomal clusters. Their linked organization suggests co-ordinated mechanisms controlling imprinting and gene expression. The ...identification of local and regional elements responsible for the epigenetic control of imprinted gene expression will be important in understanding the molecular basis of diseases associated with imprinting such as Beckwith-Wiedemann syndrome. We have established a complete contig of clones along the murine imprinting cluster on distal chromosome 7 syntenic with the human imprinting region at 11p15.5 associated with Beckwith-Wiedemann syndrome. The cluster comprises ∼1 Mb of DNA, contains at least eight imprinted genes and is demarcated by the two maternally expressed genes Tssc3 (Ipl) and H19 which are directly flanked by the non-imprinted genes Nap1l4 (Nap2) and Rpl23l (L23mrp), respectively. We also localized Kcnq1 (Kvlqt1) and Cd81 (Tapa-1) between Cdkn1c (p57Kip2) and Mash2. The mouse Kcnq1 gene is maternally expressed in most fetal but biallelically transcribed in most neonatal tissues, suggesting relaxation of imprinting during development. Our findings indicate conserved control mechanisms between mouse and human, but also reveal some structural and functional differences. Our study opens the way for a systematic analysis of the cluster by genetic manipulation in the mouse which will lead to animal models of Beckwith-Wiedemann syndrome and childhood tumours.
The construction, performance characteristics, and application of iron(III) sensors based on (5,5'- (propane-1,3-diylbis(sulfanediyl))bis(3-benzyl-4H-1,2,4-triazol-4-amine) (ionophore A), ...5,5'-(butane- 1,4-diylbis(sulfanediyl))bis(3-benzyl-4H-1,2,4-triazol-4-amine) (ionophore B), 7,8,16,17-tetrahydrodibenzoe,m 1,4,8,11dioxadiazacyclotetra-decine (ionophore C) and 3{(1E)-2-3-2-3- (1E)-2-aza-2-(3-carboxyphenyl)vinylphenoxy}-ethoxy)phenyl1-1-azavinyl} benzoic acid (ionophore D) are reported in this paper. The sensors are prepared by incorporating of A, B, C and D ionophores into a plasticized carbon paste electrodes to form electrodes I, II, III and IV, respectively. Under the optimized conditions, the electrodes reveal Nernstian slopes of 20±0.32, 20.3±0.46, 19.2±0.62 and 21±0.25 mV decade-1 over a wide concentration range from 1 × 10-6 to 1 × 10 2 mol L-1 with a detection limit of 6.4 × 10-7, 6.4 × 10-7, 1 × 10-6 and 4.8 × 10-7 mol L-1 at pH range from 1.8- 3, 1.8- 3, 2- 3.5 and 1.8- 3.5 for electrodes I, II, III and IV, respectively. The sensors are stable for 86, 74, 66 and 95 days for electrodes I, II, III and IV, respectively. without any measurable divergence in the potential characteristics and exhibit good selectivity with respect to alkali, alkaline earth and transition metal ions (e.g. Na(I), K(I), Ba(II), Ca(II), Zn(II), Cd(III), Co(II), Mn(II), Ni(II), Cu(II), Pb(II) and Al(III)). This method is successfully applied for potentiomertric determination of Fe(III) in water, soil and fish tissue samples, and the results obtained agreed with those obtained with atomic absorption spectrometer (AAS).
Abstract
BACKGROUND
Mutant isocitrate dehydrogenase (mIDH) enzymes produce the oncometabolite D-2-hydroxyglutarate (2-HG). Ivosidenib (IVO; AG-120) is a first-in-class oral inhibitor of mIDH1 being ...evaluated in 66 glioma patients (pts) in an ongoing phase 1 study (NCT02073994). Vorasidenib (VOR; AG-881) is an oral, potent, brain-penetrant inhibitor of mIDH1/2 being evaluated in 52 glioma pts in an ongoing phase 1 study (NCT02481154). In an orthotopic glioma model, IVO and VOR reduced 2-HG levels by 85% and 98%, respectively, despite different brain:plasma ratios (<0.04 vs 1.33).
MATERIAL AND METHODS
This is a phase 1, multicenter, open-label, perioperative study (NCT03343197). Pts with recurrent, nonenhancing WHO 2016 Grade (Gr) 2 or 3 mIDH1-R132H oligodendroglioma or astrocytoma undergoing craniotomy were randomized 2:2:1 to IVO 500 mg QD, VOR 50 mg QD, or no treatment (control) for 4 wk preoperatively in Cohort 1. Postoperatively, pts continued to receive IVO or VOR, and control pts were randomized 1:1 to IVO or VOR. Tumors were assessed for mIDH1 status, cellularity, 2-HG, and drug concentration. Treated samples were compared with control pts and mIDH1 and wild type (WT) banked reference (ref) samples. Plasma and CSF 2-HG were assessed. Primary endpoint: brain tumor 2-HG concentration with IVO or VOR treatment. Pts with nonevaluable tissue were replaced.
RESULTS
As of 29 Nov 2018, 26 pts (17 men, 9 women; 25 Gr 2, 1 Gr 3) were randomized preoperatively (IVO 10, VOR 11, control 5) and 25 received drug (IVO 12, VOR 13). At the data cut, 19 tumors were analyzed, with 16 evaluable. Treatment-emergent adverse events in >10% of patients (all Gr 1 or 2) were diarrhea (36%); hypocalcemia and constipation (each 20%); anemia, hyperglycemia, pruritus, headache, and nausea (each 16%); and hypokalemia and fatigue (each 12%). Mean brain:plasma ratio was 0.16 for IVO and 2.4 for VOR. Geometric mean (range) tumor 2-HG levels (μg/mL) were: IVO (n=6), 10 (2.2-104); VOR (n=6), 6.8 (3.9-10); control mIDH1 (n=65 4 pts, 61 ref), 141 (4.8-909); and WT ref (n=15), 2.7 (0.46-12). Mean changes (95% CI) in 2-HG level vs control were IVO -93% (74%, 98%) and VOR -95% (82%, 99%). Updated data from Cohort 1 will be presented.
CONCLUSION
In Cohort 1 of this phase 1 perioperative study, IVO and VOR were CNS penetrant and lowered tumor 2-HG levels compared with untreated samples. Cohort 2 is open and will evaluate IVO 250 mg BID and VOR 10 mg QD.
FUNDING
Agios Pharmaceuticals, Inc.
In vivo study was made for the coumpounds 3-(ocetyl Salicyloyl)-5,6-O-isoprpy lideneL-ascorbicocid,2,3-(acetyl Salicyloyl )-5,6-o- isopropylidene-L-ascorbic acid and 2,3,5,6(acetyl Salicyloyl ...)-L- ascorbic acid .And a measurement was mod for the concentration of the liberated aspirin in blood samples a fter (2,3,4,6,8,10) hours of the initial dose for the animal .The results showed that the highest concentration of aspirin was after four hours of giving the dose to the animal which is in accordance with pharmacokinetics studies
A prospectively randomized controlled clinical trial was performed comparing surgical resection and intraoperative radiotherapy (IORT) with conventional therapy in adenocarcinoma of the stomach. ...Patients in the experimental group underwent gastrectomy, and IORT was administered to their gastric bed (20 Gy using 11 to 15 MeV electrons). Patients in the control group underwent gastrectomy alone for early-stage lesions confined to the stomach (stages I to II) or resection and postoperative external beam radiotherapy to the upper abdomen (50 Gy using 6 to 10 mV photons) for advanced-stage lesions extending beyond the gastric wall (stages III to IV). One hundred patients were screened for the study, of whom 60 were randomized and underwent exploratory surgery. Nineteen patients were excluded intraoperatively because of unresectability or metastatic disease, leaving 41 patients in the study. Seven patients (17%) died of complications. The median survival for patients with tumors of all stages was 25 months for the IORT group and 21 months for the control group (p = 0.99). Locoregional disease failures occurred in 7 of 16 (44%) IORT patients and in 23 of 25 (92%) control patients (p < 0.001). Complication rates were similar between IORT and control patients. Although IORT failed to afford a significant advantage over conventional therapy in overall survival, IORT did significantly improve control of locoregional disease.
Growth and survival of seedlings were determined for 1 to 3 years following defoliation by black army cutworm, Actebia fennica (Tausch.). Ten data sets were collected on three sites and included four ...species of seedlings: interior Douglas-fir. Pseudotsuga menziesii var. glauca (Beissn.) Franco; lodgepole pine, Pinus contorta Dougl.; western larch, Larix occidentalis Nutt.; and Engelmann spruce, Picea engelmannii Parry. Mortality following defoliation cannot be assessed until after the flush in the next growing season because completely defoliated seedlings often regenerate new foliage and survive. More than 90% of the total mortality that did occur was detected at that time. Mortality of up to 39% occurred when seedlings were defoliated more than 60%; most of this occurred when planting was carried out concurrent with defoliation. Synergistic root stress effects caused by poor planting, dry sites, or drought significantly increased mortality. Height growth was significantly reduced when defoliation was greater than 60%; the greatest effects occurred when terminal bud destruction accompanied needle loss. Growth losses were greatest the year of defoliation; recovery of height growth of lodgepole pine was complete by the 2nd year on good growing sites. On poor sites, retardation of lodgepole pine height growth was still evident after 3 years.
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