Polymorphisms in TS,MTHFR and ERCC1 genes as predictive markers in first-line platinum and pemetrexed therapy in NSCLC patients

Purpose

We presented retrospective analysis of up to five polymorphisms in TS, MTHFR and ERCC1 genes as molecular predictive markers for homogeneous Caucasian, non-squamous NSCLC patients treated with pemetrexed and platinum front-line chemotherapy.

Methods

The following polymorphisms in DNA isolated from 115 patients were analyzed: various number of 28-bp tandem repeats in 5′-UTR region of TS gene, single nucleotide polymorphism (SNP) within the second tandem repeat of TS gene (G>C); 6-bp deletion in 3′-UTR region of the TS (1494del6); 677C>T SNP in MTHFR; 19007C>T SNP in ERCC1. Molecular examinations’ results were correlated with disease control rate, progression-free survival (PFS) and overall survival.

Results

Polymorphic tandem repeat sequence (2R, 3R) in the enhancer region of TS gene and G>C SNP within the second repeat of 3R allele seem to be important for the effectiveness of platinum and pemetrexed in first-line chemotherapy. The insignificant shortening of PFS in 3R/3R homozygotes as compared to 2R/2R and 2R/3R genotypes were observed, while it was significantly shorter in patients carrying synchronous 3R allele and G nucleotide. The combined analysis of TS VNTR and MTHFR 677C>T SNP revealed shortening of PFS in synchronous carriers of 3R allele in TS and two C alleles in MTHFR. The strongest factors increased the risk of progression were poor PS, weight loss, anemia and synchronous presence of 3R allele and G nucleotide in the second repeat of 3R allele in TS. Moreover, lack of application of second-line chemotherapy, weight loss and poor performance status and above-mentioned genotype of TS gene increased risk of early mortality.

Conclusion

The examined polymorphisms should be accounted as molecular predictor factors for pemetrexed- and platinum-based front-line chemotherapy in non-squamous NSCLC patients.     

Impact of advanced age on myocardial perfusion, distal embolization, and mortality patients with ST-segment elevation myocardial infarction treated by primary angioplasty and glycoprotein IIb–IIIa inhibitors

Despite mechanical reperfusion, the outcome is still unsatisfactory in elderly patients with ST-segment elevation myocardial infarction (STEMI). The vast majority of studies have been conducted without extensive use of glycoprotein (Gp) IIb–IIIa inhibitors, which have been associated with improved perfusion and survival. Thus the aim of the current study was to evaluate the impact of age on the angiographic and clinical outcome patients with STEMI undergoing primary angioplasty with Gp IIb–IIIa inhibitors. Our population is represented by a total of 1,662 patients undergoing primary angioplasty for STEMI included in 11 randomized trials comparing early versus late administration of Gp IIb–IIIa inhibitors. Myocardial perfusion was evaluated by myocardial blush grade and ST-segment resolution. Follow-up data were collected between 30 days and 1 year after primary angioplasty. A total of 231 (13.9 %) patients were older than 75 years. Elderly patients showed a larger prevalence of female gender, hypertension, and diabetes, more advanced Killip class at presentation and longer time to treatment, but a smaller prevalence of smoking. All patients were treated with GP IIb–IIIa inhibitors. Elderly patients showed a significantly impaired postprocedural thrombolysis in myocardial infarction (TIMI) flow (TIMI 0–2: 17.7 vs 10.3 %, P = 0.002) and myocardial perfusion (myocardial blush grade 0–1: 38.3 vs 26.5 %, P = 0.001), and higher prevalence of distal embolization (19.2 vs 9.8 %, P < 0.001), whereas no difference was observed in terms of ST-segment resolution. At follow-up, elderly patients showed a significantly higher mortality (3.2 vs 11.0 %, hazard ratio (HR) (95 % confidence interval (CI)) = 3.78 (2.31–6.16), P < 0.001), which was confirmed after adjustment for baseline confounding factors (HR (95 % CI) = 5.01 (2.63–9.55), P < 0.0001). This study showed that among patients with STEMI undergoing primary angioplasty, advanced age is an independent predictor of mortality after primary angioplasty. Higher rates of distal embolization and poor myocardial perfusion, in addition to the worse risk profile, contribute toward explaining the impact of aging on mortality.     

Synthesis,structural studies and biological properties of some phosphono-perfluorophenylalanine derivatives formed by SNAr reactions

Several novel phosphono-perfluorophenylalanine derivatives, as mimetics of phenylalanine, were synthesized by subjecting diethyl (2-(perfluorophenyl)-1-(phenylamino)ethyl)-phosphonate to S_NAr reactions with different types of nucleophiles such as thiols, amines and phenols. The structure of the products was confirmed using spectroscopic and spectrometric techniques. For two compounds X-ray single crystal diffraction analysis and DFT investigations were performed providing information in regard to the preferable conformation, hydrogen bonds and other interactions. The antiproliferative potency of some of the new phosphono-perfluorophenylalanine derivatives obtained as well as representatives of previously synthesized perfluorophenyl phosphonate analogues of phenylalanine was studied on selected glioma cell lines. Preliminary evaluation of the compounds drug likeness was examined with respect to Lipinski''s and Veber''s rules, and showed that they meet the criteria perfectly. MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide) assay results demonstrated that the compounds exhibit moderate activity against the glioblastoma multiforme cell lines (T98G and U-118 MG). Moreover most of the studied S_NAr reaction products displayed significantly higher inhibitory activity against both cancer cell lines than the parent diethyl (2-(perfluorophenyl)-1-(phenylamino)ethyl)phosphonate.

Several novel phosphono-perfluorophenylalanine derivatives, as mimetics of phenylalanine, were synthesized by subjecting diethyl (2-(perfluorophenyl)-1-(phenylamino)ethyl)-phosphonate to S_NAr reactions with thiols, amines and phenols.     

The prospects of brain — computer interface applications in children

The restoring of motor functions in adults through brain-computer interface applications is widely studied in the contemporary literature. But there is a lack of similar analyses and research on the application of brain-computer interfaces in the neurorehabilitation of children. There is a need for expanded knowledge in the aforementioned area. This article aims at investigating the extent to which the available opportunities in the area of neurorehabilitation and neurological physiotherapy of children with severe neurological deficits using brain-computer interfaces are being applied, including our own concepts, research and observations.     

Bioreactor Study Employing Bacteria with Enhanced Activity toward Cyanobacterial Toxins Microcystins

An important aim of white (grey) biotechnology is bioremediation, where microbes are employed to remove unwanted chemicals. Microcystins (MCs) and other cyanobacterial toxins are not industrial or agricultural pollutants; however, their occurrence as a consequence of human activity and water reservoir eutrophication is regarded as anthropogenic. Microbial degradation of microcystins is suggested as an alternative to chemical and physical methods of their elimination. This paper describes a possible technique of the practical application of the biodegradation process. The idea relies on the utilization of bacteria with a significantly enhanced MC-degradation ability (in comparison with wild strains). The cells of an Escherichia coli laboratory strain expressing microcystinase (MlrA) responsible for the detoxification of MCs were immobilized in alginate beads. The degradation potency of the tested bioreactors was monitored by HPLC detection of linear microcystin LR (MC-LR) as the MlrA degradation product. An open system based on a column filled with alginate-entrapped cells was shown to operate more efficiently than a closed system (alginate beads shaken in a glass container). The maximal degradation rate calculated per one liter of carrier was 219.9 µg h⁻¹ of degraded MC-LR. A comparison of the efficiency of the described system with other biological and chemo-physical proposals suggests that this new idea presents several advantages and is worth investigating in future studies.     

Oral mucosa in children with Prader–Willi syndrome

J Oral Pathol Med (2011) 40 : 778–784 Prader–Willi syndrome is a genetic disorder. Abnormal saliva secretion, emotional and behaviour problems, may affect the health status of the oral mucousa. Objectives: To assess the impact of self‐destructive behaviour and abnormal saliva secretion on the oral mucosa in children with Prader–Willi syndrome (PWS). Materials and methods: Fifteen PWS’s children (mean age 9.8 ± 4.4 years) and 15 healthy children (mean age 11.5 ± 3.5 years) were assessed for self‐destructive behaviours, such as picking at the skin, physical and chemical saliva characteristics, mycology, and the clinical status of the oral mucosa. Results: Picking at the skin was only in children with PWS (n = 12). In contrast to the control group, the moistening rate of the lower lip mucosa was slower, and the mean pH of the resting saliva was reduced in the affected subjects. Sticky frothy or frothy saliva, decreased secretion rate of the stimulated saliva, and a reduced buffer capacity were more frequently in PWS’s children; Candida spp. and oral candidiasis were also more common. Injurious lesions in the oral mucosa were found in one control child, and in eight PWS’s subjects. In affected children, the lesions were concurrent with picking at the skin. A statistical correlation was noted between the presence of Candida spp. and oral candidiasis, and unfavourable saliva properties, and between injurious lesions and a slow moistening rate of the lower lip mucosa, and oral candidiasis. Conclusions: Abnormal saliva secretion and self‐destructive behaviours in children with Prader–Willi syndrome predispose them to injurious lesions in the oral mucosa, and possibly, to oral candidiosis.