Use of monoclonal anti-EGFR antibody in the radioimmunotherapy of malignant gliomas in the context of EGFR expression in grade III and IV tumors

We investigated the putative benefits of simultaneous teleradiotherapy and anti-epidermal growth factor receptor (EGFR) 125I monoclonal antibody (MAb) 425 radioimmunotherapy, when applied after neurosurgery in high-grade gliomas, over teleradiotherapy alone. In comparison to previous studies which have reported good results with this type of radioimmunotherapy, we advanced the adjuvant radioimmunotherapy step, that is, gave it during, not after, teleradiotherapy. The randomized prospective study examined two groups: simultaneous postoperative teleradiotherapy and radioimmunotherapy (TRT + RIT; eight patients) versus teleradiotherapy alone (TRT; 10 patients). Patients who after primary operation of grade III (6 cases) or IV glioma (12 cases), showed no or less than 2 mL of remnant tumor on post-operative magnetic resonance (MR) study and were not treated postoperatively by chemotherapy were enrolled and randomized. Anti-EGFR 125IMAb 425 RIT was started during week 4 of radiotherapy, not later than 8 weeks after neurosurgery, and was repeated three times at 1-week intervals. Total activity given was 5026 + 739 MBq/patient. The tolerance of TRT was good. No immediate side effects of concomitant anti-EGRF 125I RIT were observed. Observation showed a median total survival (as evaluated from the primary neurosurgical treatment) of 14 months (range 3.5-28 months). There was no improvement in disease-free or total survival in the group of patients treated by TRT + RIT after neurosurgery. In addition, an immunohistochemical analysis of EGFR expression in gliomas was performed in a group of 100 cases and was distinctly positive in 50% grade IV gliomas and 68% grade III gliomas. We conclude that simultaneous radiotherapy and radioimmunotherapy with anti-EGFR 125I-MAb 425 is not beneficial over radiotherapy alone in adjuvant treatment of high-grade gliomas after neurosurgery. We also recommend individual confirmation of EGFR expression in further anti-EGFR radioimmunotherapy trials.     

Antidepressants and Changes in Concentration of Endocannabinoids and N-Acylethanolamines in Rat Brain Structures

The endocannabinoid (eCB) system has recently been implicated in both the pathogenesis of depression and the action of antidepressants. Here, we investigated the effect of acutely or chronically administering antidepressants [imipramine (IMI) (15 mg/kg), escitalopram (ESC) (10 mg/kg), and tianeptine (10 mg/kg)] on the levels of both eCBs [anandamide (AEA) and 2-arachidonoylglycerol (2-AG)] and N-acylethanolamines (NAEs) [palmitoylethanolamide (PEA) and oleoylethanolamide (OEA)] in various rat brain regions. We also examined the ability of the acute and chronic administration of N-acetylcysteine (NAC) (a mucolytic drug; 100 mg/kg) or URB597 (a fatty acid amide hydrolase inhibitor; 0.3 mg/kg), which have both elicited antidepressant activity in preclinical studies, to affect eCB and NAE levels. Next, we determined whether the observed effects are stable 10 days after the chronic administration of these drugs was halted. We report that the chronic administration of all investigated drugs increased AEA levels in the hippocampus and also increased both AEA and 2-AG levels in the dorsal striatum. NAE levels in limbic regions also increased after treatment with IMI (PEA/OEA), ESC (PEA), and NAC (PEA/OEA). Removing chronic ESC treatment for 10 days affected eCB and NAE levels in the frontal cortex, hippocampus, dorsal striatum, and cerebellum, while a similar tianeptine-free period enhanced accumbal NAE levels. All other drugs maintained their effects after the 10-day washout period. Therefore, the eCB system appears to play a significant role in the mechanism of action of clinically effective and potential antidepressants and may serve as a target for drug design and discovery.     

The effect of iron and zinc supplementation and its discontinuation on liver antioxidant status in rats fed deficient diets

Purpose

The aim was to investigate the effect of iron or combined iron/zinc supplementation on rat liver antioxidant status.

Methods

The 6-week male Wistar rats were examined in 3 stages: (1) 4-week adaptation to the diets (C—control AIN-93M diet, D—iron deficient and R—with 50 % reduction in all vitamin and mineral amounts); (2) 4-week supplementation with the same regimen enriched with tenfold more iron or iron/zinc; (3) 2-week post-supplementation period (the same diets as in the stage I).

Results

Combined iron/zinc supplementation similarly to iron supplementation alone significantly (p values ≤ 0.05) increased the iron content in the liver in D and R rats after stages II and III. Moreover, iron/zinc supplementation compared to iron supplementation alone significantly decreased the liver concentration of 8-isoprostane (after stage II in D and after stage III in R rats), protein carbonyl groups (only after stage III in R rats) and 8-hydroxy-2-deoxyguanosine (after stage II in R and after stage III in D and R rats). In rats fed R-type of diets after stage II hepatic superoxide dismutase (SOD) and catalase (CAT) activity, but not glutathione peroxidation activity and total antioxidant capacity, was lower in iron and iron/zinc supplemented than in non-supplemented rats, whereas after stage III in iron/zinc supplemented SOD was lower and CAT activity was higher in comparison with non-supplemented and iron supplemented rats.

Conclusions

The simultaneous iron/zinc supplementation can protect liver against peroxidative damage induced by high doses of iron during and after the intervention in rats fed iron-deficient diet and diet with reduced amounts of vitamins and minerals. The post-intervention observation is relevant because the effect may be delayed and visible only after this period.     

Adaptive mechanisms following antidepressant drugs: Focus on serotonin 5-HT2A receptors

BackgroundThere is a strong support for the role of serotonin (5-HT) neurotransmission in depression and in the mechanism of action of antidepressants. Among 5-HT receptors, 5-HT_2A receptor subtype seems to be an important target implicated in the above disorder.MethodsThe aim of the study was to investigate the effects of antidepressants, such as imipramine (15 mg/kg), escitalopram (10 mg/kg) and tianeptine (10 mg/kg) as well as drugs with antidepressant activity, including N-acetylcysteine (100 mg/kg) and URB597 (a fatty acid amide hydrolase inhibitor, 0.3 mg/kg) on the 5-HT_2A receptor labeling pattern in selected rat brain regions. Following acute or chronic (14 days) drug administration, rat brains were analyzed by using autoradiography with the 5-HT_2A receptor antagonist [³H]ketanserin.ResultsSingle dose or chronic administration of imipramine decreased the radioligand binding in the claustrum and cortical subregions. The [³H]ketanserin binding either increased or decreased in cortical areas after acute N-acetylcysteine and URB597 administration, respectively. A similar shift towards reduction of the [³H]ketanserin binding was detected in the nucleus accumbens shell following either acute treatment with imipramine, escitalopram, N-acetylcysteine and URB597 or repeated administration of imipramine, tianeptine and URB597.ConclusionsIn conclusion, the present result indicate different sensitivity of brain 5-HT_2A receptors to antidepressant drugs depending on schedule of drug administration and rat brain regions. The decrease of accumbal shell 5-HT_2A receptor labeling by antidepressant drugs exhibiting different primary mechanism of action seems to be a common targeting mechanism associated with the outcome of depression treatment.     

Pressure-assisted solvent- and catalyst-free production of well-defined poly(1-vinyl-2-pyrrolidone) for biomedical applications

In this work, we developed a fast, highly efficient, and environmentally friendly catalytic system for classical free-radical polymerization (FRP) utilizing a high-pressure (HP) approach. The application of HP for thermally-induced, bulk FRP of 1-vinyl-2-pyrrolidone (VP) allowed to eliminate the current limitation of ambient-pressure polymerization of ‘less-activated’ monomer (LAM), characterized by the lack of temporal control yielding polymers of unacceptably large disperisites and poor result reproducibility. By a simple manipulation of thermodynamic conditions (p = 125–500 MPa, T = 323–333 K) and reaction composition (two-component system: monomer and low content of thermoinitiator) well-defined poly(1-vinyl-2-pyrrolidone)s (PVP) in a wide range of molecular weights and low/moderate dispersities (M_n = 16.2–280.5 kg mol⁻¹, Đ = 1.27–1.45) have been produced. We have found that HP can act as an ‘external’ controlling factor that warrants the first-order polymerization kinetics for classical FRP, something that was possible so far only for reversible deactivation radical polymerization (RDRP) systems. Importantly, our synthetic strategy adopted for VP FRP enabled us to obtain polymers of very high M_n in a very short time-frame (0.5 h). It has also been confirmed that VP bulk polymerization yields polymers with significantly lower glass transition temperatures (T_g) and different solubility properties in comparison to macromolecules obtained during the solvent-assisted reaction.

High-pressure classical free-radical polymerization allowed to eliminate the current limitation of the ambient-pressure synthesis of 1-vinyl-2-pyrrolidone and production of well-defined polymers.     

Dietary Supplement Use in Relation to Socio-Demographic and Lifestyle Factors,including Adherence to Mediterranean-Style Diet in University Students

The study aimed to examine socio-demographic and lifestyle determinants, including diet quality, of dietary supplement (DS) use among 2545 students who attended public universities in Warsaw. The data was collected using a self-administered health and lifestyle questionnaire and a 5-day dietary record method. Diet quality was assessed using a Mediterranean Diet Score. To determine the covariates of DS use, multivariate-adjusted logistic regression models with an estimation of odds ratios (ORs) and 95% confidence intervals (95% CIs) were used. The results showed that 41% of participants were DS users. The following predictors of DS use were identified: gender (male vs. female; OR:0.62, 95% CI:0.50–0.79), physical activity (high vs. low; OR:1.79, 95% CI:1.45–2.20), BMI (≥25 vs. 18.5–24.9 kg/m²; OR:0.77, 95% CI:0.61–0.98), cigarette smoking (yes vs. no; OR:0.67, 95% CI:0.52–0.86), and presence of chronic diseases (yes vs. no; OR:2.37, 95% CI:1.89–2.98). Moreover, higher nutritional knowledge, special diet usage, eating more meals/day, and fortified food consumption were determinants of DS use. Adherence to the Mediterranean-style diet was positively associated with DS use, a 1-score increment was associated with a 10% (p-trend = 0.011) higher probability of DS usage. Given that the use of vitamins and/or minerals is common among university students and their users are characterized by eating a higher quality diet, investigating the contribution of DS in overall dietary nutrient intake warrants further study.