Showing papers by "Gdańsk Medical University published in 2005"

Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501).

Abstract: Background. In 2004, level I evidence was estab- lished for the postoperative adjuvant treatment of patients with selected high-risk locally advanced head and neck cancers, with the publication of the results of two trials conducted in Europe

Gender-Selective Interaction Between Aging, Blood Pressure, and Sympathetic Nerve Activity

Abstract: The mechanisms mediating the more striking age related increase in cardiovascular disease in women than in men are poorly understood. We tested the hypothesis that aging has a greater impact on sympathetic traffic in women than in men. Muscle sympathetic nerve activity (MSNA), blood pressure, and heart rate were measured in 120 healthy males and 96 healthy females aged 20 to 72 years. MSNA increased with age in both sexes, but age explained 53% of MSNA variance in female subjects and only 8% of MSNA variance in male subjects. Both the slope and intercept of the regression lines were significantly different between male and female groups (P<0.01 and P<0.001, respectively). For each decade of life, women showed an increase of 6.5 bursts/min in comparison to an increase of 2.6 bursts/min in males. Menopause did not explain the age-related increase in sympathetic traffic. For every 10-burst/min increment in MSNA in subjects older than 40, mean blood pressure increased by 2.7 mm Hg in men and by 6.1 mm Hg in women. Aging is accompanied by a greater increase in sympathetic traffic in women than in men, independent of menopausal status. Sympathetic neural mechanisms may contribute importantly to the more marked influence of age on blood pressure and cardiovascular disease in women.

On the role of melatonin in skin physiology and pathology

Abstract: Melatonin has been experimentally implicated in skin functions such as hair growth cycling, fur pigmentation, and melanoma control, and melatonin receptors are expressed in several skin cells including normal and malignant keratinocytes, melanocytes, and fibroblasts. Melatonin is also able to suppress ultraviolet (U)-induced damage to skin cells and shows strong antioxidant activity in Uexposed cells. Moreover, we recently uncovered expression in the skin of the biochemical machinery involved in the sequential transformation of l-tryptophan to serotonin and melatonin. Existence of the biosynthetic pathway was confirmed by detection of the corresponding genes and proteins with actual demonstration of enzymatic activities for tryptophan hydroxylase, serotonin N-acetyl-transferase, and hydroxyindole-O-methyltransferase in extracts from skin and skin cells. Initial evidence for in vivo synthesis of melatonin and its metabolism was obtained in hamster skin organ culture and in one melanoma line. Therefore, we propose that melatonin (synthesized locally or delivered topically)could counteract or buffer external (environmental)or internal stresses to preserve the biological integrity of the organ and to maintain its homeostasis. Furthermore, melatonin could have a role in protection against solar radiation or even in the management of skin diseases.

Anion–π Interactions in Cyanuric Acids: A Combined Crystallographic and Computational Study

Abstract: Several structures of π complexes of isocyanuric acid and of several thio derivatives with anions have been computed by using high level ab initio calculations. The nature of the complexes has been studied by means of the method of molecular interaction potential with polarization (MIPp) and Bader's theory of atoms-in-molecules. These molecules form favorable complexes with anions and can be used as binding units for building receptors for the molecular recognition of anions. In several cases, the anion–π interaction has been demonstrated experimentally by means of X-ray crystallography.

The diverse signaling network of EGFR, HER2, HER3 and HER4 tyrosine kinase receptors and the consequences for therapeutic approaches.

Abstract: The HER family of receptor tyrosine kinase couples binding of extracellular growth factor ligands to intracellular signal transduction pathways, contributing in this fashion to the ability of the cell to respond correctly to its environment. The HER family and its ligands are critically involved in the carcinogenesis of the mammary gland. Abnormal function of the members of HER family resulting in receptor hyper-activation (due to gene amplification, protein overexpression or abnormal transcriptional regulation) has been linked with breast cancer prognosis. It is also extensively studied as the predictive factor and target for therapy. There are clinical indications supporting the concept that none of the receptors: EGFR, HER2, HER3 and HER4 can be considered as the stand-alone receptor in breast cancer development and clinical course of the disease. There is a growing body of evidence that cooperation between them contributes to more aggressive tumor phenotype and influences the response to therapy. This underlines the importance of quantification of all HER family members and indicates the urgent need for implementation of methods that can efficiently and reliably examine four HER receptors as a whole panel in breast cancer patients.

Ectopic expression of anthocyanin 5-o-glucosyltransferase in potato tuber causes increased resistance to bacteria.

Abstract: The principal goal of this paper was to investigate the significance of anthocyanin 5-O-glucosyltransferase (5-UGT) for potato tuber metabolism. The ectopic expression of a 5-UGT cDNA in the tuber improved the plant's defense against pathogen infection. The resistance of transgenic lines against Erwinia carotovora subsp. carotovora was about 2-fold higher than for nontransformed plants. In most cases the pathogen resistance was accompanied by a significant increase in tuber yield. To investigate the molecular basis of transgenic potato resistance, metabolic profiling of the plant was performed. In tuber extracts, the anthocyanin 3,5-O-substituted level was significantly increased when compared to that of the control plant. Of six anthocyanin compounds identified, the highest quantity for pelargonidin 3-rutinoside-5-glucoside acylated with p-coumaric acid and peonidin 3-rutinoside-5-glucoside acylated with p-coumaric acid was detected. A significant increase in starch and a decrease in sucrose level in transgenic tubers have been detected. The level of all other metabolites (amino acids, organic acids, polyamines, and fatty acids) was quite the same as in nontransformants. The plant resistance to bacterial infection correlates with anthocyanin content and sucrose level. The properties of recombinant glucosyltransferase were analyzed in in vitro experiments. The enzyme kinetics and its biochemical properties were similar to those from other sources.

Recent advances in studies on biochemical and structural properties of equilibrative and concentrative nucleoside transporters

Abstract: Nucleoside transporters (NT) facilitate the movement of nucleosides and nucleobases across cell membranes. NT-mediated transport is vital for the synthesis of nucleic acids in cells that lack de novo purine synthesis. Some nucleosides display biological activity and act as signalling molecules. For example, adenosine exerts a potent action on many physiological processes including vasodilatation, hormone and neurotransmitter release, platelet aggregation, and lipolysis. Therefore, carrier-mediated transport of this nucleoside plays an important role in modulating cell function, because the efficiency of the transport processes determines adenosine availability to its receptors or to metabolizing enzymes. Nucleoside transporters are also key elements in anticancer and antiviral therapy with the use of nucleoside analogues. Mammalian cells possess two major nucleoside transporter families: equilibrative (ENT) and concentrative (CNT) Na(+)-dependent ones. This review characterizes gene loci, substrate specificity, tissue distribution, membrane topology and structure of ENT and CNT proteins. Regulation of nucleoside transporters by various factors is also presented.

Circulating clonal CLA+ and CD4+ T cells in Sézary syndrome express the skin-homing chemokine receptors CCR4 and CCR10 as well as the lymph node-homing chemokine receptor CCR7

Abstract: Summary Background Adhesion molecules and chemokine receptors are involved in tissue-specific homing of T cells to the skin and play an important role in the pathophysiology of cutaneous lymphoma. It has recently been reported that the chemokine CCL27 expressed by keratinocytes attracts lymphocytes bearing the chemokine receptor CCR10. Objectives To investigate the expression of CCR4, CCR7 and CCR10 on skin-homing CLA+ and CD4+ T cells in the peripheral blood of patients with Sezary syndrome (SS), a rare leukaemic variant of cutaneous T-cell lymphoma. Methods Lymphocytes from five patients with SS, six patients with mycosis fungoides and four healthy volunteers were isolated and analysed using flow cytometry. Additionally, the T-cell receptor (TCR)-Vβ CDR3 regions were cloned and sequenced in two patients. Results We found that CCR4 is expressed on almost all CLA+ and CD4+ memory T cells. Using monoclonal antibodies specific for single TCR-Vβ chains we identified malignant T cells in four patients with SS. Importantly, we found that most but not all malignant Sezary cells expressed the skin-homing chemokine receptor CCR10. Additionally, we found that a significant proportion of these cells also expressed the lymph node-homing chemokine receptor CCR7. Conclusions Our results support the concept that chemokine receptors play an important role in the pathophysiology of SS and suggest that the malignant clone may represent an expansion of skin-homing cutaneous ‘central’ memory T cells in the peripheral blood of these patients.

The second to fourth digit ratio in elite and non-elite female athletes

Abstract: Contests in the animal world to determine social status almost exclusively involve males, which points out that androgens may be indispensable in the development of competitive instincts. In animal studies, it has been shown that prenatal exposure to androgens may produce permanent changes toward more aggressive behavior in adulthood. Thus, there is a strong suspicion that women involved in competitive activities, such as sports, may have been exposed to high androgen levels in utero. There is strong evidence that the ratio between the second to fourth digits ratio (2D:4D ratio) correlates negatively with intrauterine androgen concentrations and could potentially be used as a marker for prenatal androgen exposure. Therefore, the purpose of our study was to test the hypothesis that women engaged in sports have lower 2D:4D ratio—a marker of high prenatal androgen exposure. We measured the 2D:4D ratios in elite and non-elite female athletes and compared them with female individuals not engaged in any sport activities. Our results showed that elite female athletes have significantly lower left hand 2D:4D ratios compared to the control group (P < 0.05). Therefore, we can speculate that low 2D:4D ratio may be a positive correlate of sports potential in females. Am. J. Hum. Biol. 17:796–800, 2005. © 2005 Wiley-Liss, Inc.

Prediction of peptide retention at different HPLC conditions from multiple linear regression models.

Abstract: To quantitatively characterize the structure of a peptide and to predict its gradient retention time at given HPLC conditions three structural descriptors are used: (i) logarithm of the sum of retention times of the amino acids composing the peptide, log SumAA, (ii) logarithm of the van der Waals volume of the peptide, log VDW(Vol), (iii) and the logarithm of the peptide's calculated n-octanol-water partition coefficient, clog P. The log SumAA descriptor is obtained from empirical data for 20 natural amino acids, determined in a given HPLC system. The two other descriptors are calculated from the peptides' structural formulas using molecular modeling methods. The quantitative structure-retention relationships (QSRR), build by multiple linear regression, describe HPLC retention of peptide on a given chromatographic system on which the retention of the 20 amino acids was predetermined. A structurally diversified series of 98 peptides was employed. The predicted gradient retention times on several chromatographic systems were in good agreement with the experimental data. The QSRR equations, derived for a given system operated at variable gradient times and temperatures allowed for the prediction of peptide retention in that system. Matching the experimental HPLC retention to the theoretically predicted for a presumed peptide could facilitate original protein identification in proteomics. In conjunction with MS data, prediction of the retention time for a given peptide might be used to improve the confidence of peptide identifications and to increase the number of correctly identified peptides.

Enhanced Citrate Synthase Activity in Human Pancreatic Cancer

Abstract: Objectives:Assuming that a high flux of carbohydrate is strictly connected with lipid synthesis in neoplastic cells, one can hypothesize that the activity of citrate synthase, which plays an important role in glucose to lipid conversion, is enhanced in pancreatic cancer. The aim of the present study

Synthesis and antibacterial activity of 1H-pyrazolo[3,4-b]pyrazine and -pyridine derivatives

Abstract: The investigations of new pyrazine and pyridine derivatives showing an antibacterial activity have been made. Upon treatment of 3-chloro-2-cyanopyrazine [1] and 2-chloro-3-cyanopyridine with 1,1-dimethyl-hydrazine, 1-aminopiperidine and 1-amino-4-methylpiperazine, either the pyrazolo-pyrazine ( 1 ), and -pyridine ( 2 ) derivatives, or ammonium salts ( 3 – 8 ) were obtained, according to the reaction conditions. Compound 1 was obtained in the reaction of the initial nitrile with methylhydrazine as well. The reactions of 1 gave the following derivatives: acylation—( 9 ), that with p -chlorobenzoic aldehyde—( 10 ), and with phenyl-isothiocyanate—( 11 ). 3-Chloro-2-cyanopyrazine treated with hydrazine hydrate gave amidrazone ( 12 ), which upon condensation with p -chlorobenzoic aldehyde produced ( 13 ). The compounds obtained were tested in vitro for their tuberculostatic activity. The minimal inhibitory concentration (MIC) values were within 22–100 μg/cm 3 . Compounds 1 , 5 and 6 were also tested in vitro for their activity towards 25 strains of anaerobic, and 25 strains of aerobic bacteria. They appeared to be of elevated activity towards the anaerobes and of low one towards the aerobes (Table 2).

Region-specific alterations of adenosine receptors expression level in kidney of diabetic rat

Abstract: Pathological alterations of renal function in insulin-dependent diabetes have been attributed to numerous factors, including adenosine. This study examined the expression levels of adenosine receptors (ARs) in the kidney of the streptozotocin-induced diabetic rat. In the diabetic kidney A1-AR mRNA levels increased 1.7- and 2.8-fold in cortex and medulla, respectively. This was accompanied by increased A1-AR protein levels in membranes of kidney cortex (1.5-fold) and medulla (threefold). A1-AR immunoreactivity increased strongly along medullar tubules especially in the collecting duct. The levels of A2a-AR mRNA increased twofold in diabetic kidney cortex but remained unchanged in medulla; however, A2a-AR protein levels increased more than threefold in cortex. Immunohistochemistry showed increased A2a-AR immunoreactivity in luminal membranes of cortical collecting ducts and in epithelial cells of preglomerular vessels. There were no significant changes in A2b-AR expression in diabetic kidney except in medullar membranes, where the receptor protein content decreased by 60%. A3-AR mRNA levels in diabetic kidney remained unchanged, but membrane-associated A3-AR protein levels increased by 70% in diabetic kidney cortex and decreased by 80% in medulla. These changes in ARs genes expression, receptor protein content, and cellular and tissue distribution, correspond to abnormalities characteristic of the diabetic kidney, suggesting involvement in pathogenesis of diabetic nephropathy.

Prognostic impact of BRCA1 pathogenic and BRCA1/BRCA2 unclassified variant mutations in patients with ovarian carcinoma.

Abstract: BACKGROUND The clinical relevance of BRCA1/2 alterations in ovarian carcinoma patients is debatable. Our aim was to determine factors influencing the risk of recurrence and death in ovarian carcinoma patients with BRCA pathogenic and unclassified variant mutations. METHODS A consecutive series of 205 women with primary ovarian carcinoma were screened for mutations in BRCA1 and BRCA2 genes using a conformational sensitive gel electrophoresis and direct sequencing. Data regarding medical and familial history were collected using questionnaires. Clinical and pathologic data were extracted from medical records. RESULTS Unclassified variant mutations in BRCA1 or BRCA2 genes were found in 16 (8%) patients, and BRCA1 pathogenic mutations were found in 18 (9%) patients. No pathogenic mutation was found in BRCA2 gene. Multivariate analysis showed that BRCA1 pathogenic mutation was an independent predictor of reduced risk of relapse and death (Hazard ratios [HR] 0.52 [confidence interval {CI} 0.28–0.98] and 0.38 [CI 0.10–0.96], respectively). Unclassified variant mutation did not affect recurrence and survival (HR 0.84 [CI 0.43–1.66] and 0.94 [CI 0.48–1.82], respectively). Other factors associated with reduced risk of relapse and death were complete pathologic remission at second-look laparotomy and family history of breast and ovarian carcinoma, respectively. Recurrence and death outcomes among unclassified variant mutation carriers did not differ significantly from those in sporadic cases. CONCLUSIONS Patients with BRCA1 pathogenic mutation seem to have reduced risk of recurrence and death. These results should be interpreted with caution as they may be influenced by more intensive treatment, better response to cisplatin, and younger age of mutation carriers. Clinical relevance of BRCA1/2 unclassified variant mutations warrants further studies. Cancer 2005. © 2005 American Cancer Society.

A prospective, randomised study to compare two palliative radiotherapy schedules for non-small-cell lung cancer (NSCLC).

Abstract: A prospective randomised study compared two palliative radiotherapy schedules for inoperable symptomatic non-small-cell lung cancer (NSCLC). After stratification, 100 patients were randomly assigned to 20 Gy/5 fractions (fr)/5 days (arm A) or 16 Gy/2 fr/day 1 and 8 (arm B). There were 90 men and 10 women aged 47–81 years (mean 66), performance status 1–4 (median 2). The major clinical characteristics and incidence and degree of initial disease-related symptoms were similar in both groups. Treatment effects were assessed using patient's chart, doctor's scoring of symptomatic change and chest X-ray. Study end points included degree and duration of symptomatic relief, treatment side effects, objective response rates and overall survival. A total of 55 patients were assigned to arm A and 45 to arm B. In all, 98 patients received assigned treatment, whereas two patients died before its termination. Treatment tolerance was good and did not differ between study arms. No significant differences between study arms were observed in the degree of relief of all analysed symptoms. Overall survival time differed significantly in favour of arm B (median 8.0 vs 5.3 months; P=0.016). Both irradiation schedules provided comparable, effective palliation of tumour-related symptoms. The improved overall survival and treatment convenience of 2-fraction schedule suggest its usefulness in the routine management of symptomatic inoperable NSCLC.

Prediction of high-performance liquid chromatography retention of peptides with the use of quantitative structure-retention relationships.

Abstract: Quantitative structure retention relationships (QSRR) were derived allowing prediction of reversed-phase high-performance liquid chromatography (HPLC) retention of peptides. To quantitatively characterize the structure of a peptide, and then to predict its gradient retention time under given HPLC conditions, the following descriptors are employed: logarithm of the sum of retention times of the amino acids composing the peptide, log Sum(AA), logarithm of Van der Waals volume of the peptide, log VDW(Vol), and logarithm of its calculated n-octanol-water partition coefficient, clog P. The first descriptor is based on a set of empirical data for 20 natural amino acids. The next two descriptors are easily calculated from a structural formula. The predicted gradient retention times are in excellent agreement with the experimental data, determined for a structurally diversified series of 101 peptides. The QSRR equation obtained predicts in a convenient and reliable manner the retention times for any peptide in a once characterized HPLC system.

Association between SLC11A1 (formerly NRAMP1) and the risk of sarcoidosis in Poland

Abstract: Sarcoidosis (SA) is a systemic granulomatous disorder of unknown etiology characterized by T helper 1-type inflammatory responses at sites of disease with signs of B cell hyperactivity. Like rheumatoid arthritis and diabetes, an infectious etiology has frequently been postulated but no single infectious trigger definitively identified. Polymorphic alleles at SLC11A1 have previously been associated with susceptibility to both the putative infectious agents and to these autoimmune disorders. We therefore investigated its candidacy as a genetic determinant of SA in Poland in an association-based study comparing 86 SA patients with 85 tuberculosis (TB) patients and 93 control subjects. The functional promoter (GT)n polymorphism and four of 10 other single nucleotide or insertion/deletion polymorphisms genotyped across SLC11A1 were informative in our sample. Consistent with previous autoimmune disease studies, allele 3 at the functional (GT)n promoter region repeat polymorphism was significantly associated with SA when compared with healthy controls (odds ratio 1.68; 95% CI: 1.01–2.81; P=0.04) or with TB patients (odds ratio 1.69; 95% CI: 1.042–0.78; P=0.03).