Biomedical subjects

W Nowak

Publications and source records attributed to W Nowak.

At least 19 recordsLinked to original sources

PubMed2006

Inhibitory effect of antipsychotic drugs on the Con A- and LPS-induced proliferative activity of mouse splenocytes: a possible mechanism of action.

Antipsychotic drugs are widely used to alleviate a number of psychic disorders and have been found to modulate some immune parameters, but the molecular mechanism of their action on the proliferative activity has been poorly recognized. In the present study, we investigated effects of various antipsychotics on the proliferative activity of lymphocytes stimulated by concanavalin A (Con A) and lipopolysaccharide (LPS). Chlorpromazine (3 x 10(-6)-10(-4) M) showed the most potent effect in inhibiting 3H-thymidine incorporation into C57BL/6 mouse spleen cells stimulated by Con A and LPS. Treatment of the cells with thioridazine (10(-5)-10(-4) M), promazine (10(-5)-10(-4) M), haloperidol (10(-5)-10(-4) M), risperidone (10(-5)-10(-4) M), raclopride (3 x 10(-5) - 10(-4) M), remoxipride (3 x 10(-5)-10(-4) M) and clozapine ( 3 x 10(-5)-10(-4) M), but not with sulpiride (10(-7)-10(-4) M), suppressed proliferative activity of splenocytes after Con A stimulation. On the other hand, LPS-induced proliferation of splenocytes was inhibited by clozapine, promazine, thioridazine and haloperidol, but not by risperidone, remoxipride, sulpiride and raclopride. In the next part of the study, the influence of some kinase modulators on chlorpromazine- and clozapine-evoked inhibition of the proliferative activity of splenocytes was determined. Wortmannin, a selective phosphatidylinositol 3-kinase (PI3-K) inhibitor, blocked chlorpromazine and clozapine inhibitory effect on the mitogen-stimulated splenocyte proliferation. The involvement of PI 3-K /protein kinase B (PKB, Akt) pathway was confirmed by the results of the Western blot study, which showed that both drugs increased the level of active phospho-Ser-473 Akt, without changing the total Akt level, and decreased the level of active, nonphosphorylated glycogen synthase kinase-3 (GSK-3beta). Additionally, we have found that chlorpromazine action was also attenuated by a selective p-38-MAPK inhibitor, while clozapine effect was suppressed by a protein kinase C (PKC) activator. The obtained results indicated that atypical antipsychotic drugs markedly inhibited the proliferative activity of splenocytes only after ConA stimulation. Inhibition of the proliferative capability of splenocytes by chlorpromazine and clozapine resulted mainly from the activation of PI3-K/Akt pathway.

Androstadienes↗

PubMed2005

Genes involved in biosynthesis and signalisation of ethylene in Brassica oleracea and Arabidopsis thaliana: identification and genome comparative mapping of specific gene homologues.

The study reported was aimed at the identification and determination of the chromosomal organisation of genes involved in the ethylene biosynthesis and signalling pathways in Brassica oleracea, on the basis of the Arabidopsis thaliana DNA probes and in silico genome analysis. Because of its polyploidal origin, the B. oleracea genome is characterised by extensive gene redundancy. Therefore, an important aspect of gene expression in B. oleracea response to environmental stimuli is to identify the specific gene copy involved. This aspect should also be taken into consideration while studying the genetic basis of biosynthesis and signal transduction in relation to basic phytohormones. Our present work concerns the identification of homologue genes involved in ethylene biosynthesis such as SAM, ACS and ACO, as well as those involved in the ethylene signalling pathway, mainly ETR1, CTR1, MKK4, MKK5, EIN2, EIN3, EREBP, ERF5 and ERF7 on the basis of the restriction fragment length polymorphism (RFLP) and PCR mapping. In the case of ACC synthases, (ACSs) the in silico analysis of gene variants in the genome of A. thaliana was followed by the identification of homologues to ACS2, ACS6 and ACS7 in the B. oleracea database. In total, 22 loci with sequence homology to the genes under analysis were included in the existing B. oleracea RFLP chromosomal map. Based on the stress responsiveness of most of the A. thaliana genes analysed in this study, we performed initial functional analysis of some gene homologues mapped. With the use of the RT-PCR approach the conservation of differential transcriptional induction of ACS homologues in the B. oleracea and A. thaliana was demonstrated during ozone stress.

Arabidopsis↗

PubMed2003

Incidence of thyroid cancer in the selected areas of iodine deficiency in Poland.

The aim of the study was to evaluate the incidence rate (IR), trend and histotype of the differentiated thyroid cancer in the selected areas with varying iodine deficiency. The study was carried out in three areas: Krakow, (Carpathian endemic goiter area with 1.99 million mixed rural and urban population), Gliwice (Upper Silesia--moderate iodine deficiency area mostly industrial with 4.89 million inhabitants) and Olsztyn (slight iodine deficiency area, mainly rural with 0.77 million inhabitants). Between 1990 and 2001, in the study area 2691 newly diagnosed cases of malignant neoplasms of the thyroid gland were registered. In over 80% of patients it was differentiated thyroid cancer: mainly in women over 40 years, with F/M ratio 5.8. The highest percentage of papillary cancer 72.9% was observed in Olsztyn and lowest--50.0%--in Krakow and Nowy Sacz districts. In this period of time incidence rate of differentiated thyroid cancer in women increased in Kraków, Gliwice, and Olsztyn from 1.51 to 9.34 in 1998 1.27 to 5.74 in 1999 and from 2.52 to 11.35 in 2001 respectively. In the youngest (0-20 years) age group no significant increase of IR was observed. Between 1998 and 2001 the dynamics of increase of the thyroid cancer incidence markedly diminished. In conclusion it was hypothesised that an increase in IR of differentiated thyroid cancer in the study area was caused mainly by the suspension of iodine prophylaxis in 1980 and was diminished by the introduction of an obligatory model of iodine prophylaxis in 1996/1997. It was modified in terms of histotype and dynamics of increase by exposure to ionizing radiation. A very specific group at risk on the population level were women aged 20-40 years in the reproductive age exposed to iodine deficiency after suspension of iodine prophylaxis in 1980 and to radiation after the Chernobyl accident in 1986.

Adult↗

PubMed2001

Cellular and molecular actions of adrenomedullin in glomerular mesangial cells.

Adrenomedullin (AM), a potent vasodilatory and hypotensive peptide produces several biological outcomes in glomerular mesangial cells. Mesangial cells are important in the pathogenesis of glomerulonephritis, and therefore the actions of AM on mesangial cells have important clinical and therapeutic implications. This minireview describes the various actions of AM on mesangial cell function and the signal transduction mechanisms involved. As in other systems, most actions of AM can be explained by increase in cAMP levels in the cell, although a few exceptions remain. The fact that most data obtained to date has been in culture, the physiological significance of the actions of AM in mesangial cells is discussed.

Adrenomedullin↗

PubMed2001

Cladribine combined with cyclophosphamide and mitoxantrone as front-line therapy in chronic lymphocytic leukemia.

The objective of the study was to determine the effectiveness and the toxicity of a combined chemotherapy consisting of cladribine (2-CdA), mitoxantrone and cyclophosphamide (CMC regimen) in the treatment of previously untreated B cell chronic lymphocytic leukemia (B-CLL). From August 1998 to December 2000 2-CdA was administered at a dosage of 0.12 mg/kg for 3 (CMC3) or 5 (CMC5) consecutive days, mitoxantrone at 10 mg/m2 on day 1 and cyclophosphamide at 650 mg/m2 on day 1 to 62 patients with advanced or progressive B-CLL. The cycles were repeated at 4 week intervals or longer if severe myelosuppression occurred. Twenty patients received CMC5 and 42 patients CMC3. Within the analyzed group an overall response (OR) rate (CR+PR) of 64.5% (95% CI: 52.7-76.3%) was reported, including 29.0% CR. There was no difference in the CR rate between the patients treated with CMC5 (30%) and CMC3 (28.6%) (P = 0.9), nor in the OR rate (55.0% and 69.0%, respectively, P = 0.3). Residual disease was identified in seven out of 18 (38.9%) patients who were in CR, including two treated with CMC5 and five treated with CMC3 protocols. CMC-induced grade III or IV thrombocytopenia occurred in 12 (19.4%) of patients, including four (20%) CMC5-treated and eight (19%) CMC3-treated patients (P= 0.8). Neutropenia grade III or IV was observed in seven (35%) and 11 (26.2%) patients, respectively (P = 0.8). Severe infections, including pneumonia and sepsis, occurred more frequently after CMC5 (11 patients, 55.0%) than CMC3 (10 patients, 28.6%) (P = 0.03) Fourteen patients died, including six treated with CMC5 and eight treated with CMC3 (30% and 19%, respectively). Infections were the cause of death in nine patients, including four in the CMC5 group and five in the CMC3 group. In conclusion, our results indicate that the CMC programme is an active combined regimen in previously untreated B-CLL patients; its efficiency seems to be similar to that observed earlier in B-CLL patients treated with 2-CdA as a single agent. However, toxicity, especially after CMC5 administration, is significant. Therefore, we recommend the CMC3 but not the CMC5 programme for further evaluation.

Adult↗

PubMed2001

[Thyroid carcinoma--contemporary diagnostic principles and treatment].

Thyroid cancer, which is a rare neoplasm, is still controversial issue. References approved in Poland in 1995 caused unification of the extension of thyroid surgery to total resection of thyroid gland in case of cancer. For many surgeons such a radical treatment is still doubtful. On the other hand thyroid cancer is an object of many studies because of its heterogenous clinical course and prognosis depending of histological type. This article focuses on modern principles of diagnosis, treatment and follow-up according to obligatory references in Poland. The authors show current epidemiological data, prognosis according to histological type of cancer and explain pathogenesis of the disease. Preoperative diagnostic model has been described including role of ultrasound examination, biopsy, cytology and histology examination. Special interest was taken to follow-up patients after total thyroidectomy emphasising the role of thyreglobin in early detection of cancer recurrence. It is also important to observed patients for the rest of their life because cancer recurrences have been reported even 40 years after surgery. Preoperative diagnosis and treatment is a typical example of multi-disciplinary procedure which should be held in specialistic centres with proper equipment and experience.

Humans↗

PubMed2001

Effect of nuclear matrix attachment regions on transgene expression in tobacco plants.

Matrix attachment regions (MARs) are thought to participate in the organization and segregation of independent chromosomal loop domains. Although there are several reports on the action of natural MARs in the context of heterologous genes in transgenic plants, in our study we tested a synthetic MAR (sMAR) with the special property of unpairing when under superhelical strain, for its effect on reporter gene expression in tobacco plants. The synthetic MAR was a multimer of a short sequence from the MAR 3' end of the immunoglobulin heavy chain (IgH) enhancer. This sMAR sequence was used to flank the beta-glucuronidase (GUS) reporter gene within the T-DNA of the binary vector pBI121. Vectors with or without the sMARs were then used to transform tobacco plants by Agrobacterium tumefaciens. Transgenic plants containing the sMAR sequences flanking the GUS gene exhibited higher levels of transgene expression compared with transgenic plants which lacked the sMARs. This effect was observed independently of the position of the sMAR at the 5' side of the reporter gene. However, variation of the detected transgene expression was significant in all transformed plant populations, irrespective of the construct used.

Agrobacterium tumefaciens↗

PubMed2001

Computer modeling studies of the structural role of NADPH binding to active site mutants of human dihydrofolate reductase in complex with piritrexim.

Dihydrofolate reductase (DHFR, EC 1.5.1.3) is one of the enzymes active in the folate cycle which plays an important role in DNA synthesis. Inhibition of DHFR is a key element in the treatment of many diseases, including cancer and AIDS related infections. A search for new selective inhibitors is motivated by the resistance to common drugs observed in the course of treatment. In this paper, results of a detailed computer analysis of human DHFR interactions with the lipophilic inhibitor piritrexim (PTX) are presented. It was found that the NADPH cofactor contributes 30% of the total PTX-enzyme interaction energy. Substitution of the highly conserved Glu30 with alanine does not lead to the release of the inhibitor from the hDHFR pocket. The important L22F point mutation does affect PTX orientation but does not changethe binding energy. Simulations of the dynamics of binary hDHFR-PTX complexes were performed with the use of Extensible Systematic Force Field (ESFF) and the results indicate structural changes in the enzyme induced by NADPH binding.

Antineoplastic Agents↗

PubMed2001

[Radical surgical treatment of differentiated thyroid cancer--necessity or over-enthusiasm?].

The extent of surgical treatment of well differentiated thyroid cancer has been controversial and widely discussed for years. Although the recommendations defining the strategy of thyroid surgery were approved in 1995, a lot of questions remained. The aim of this retrospective study was to analyse long-term results of surgical treatment of thyroid cancer according to the type of applied surgical procedure. The study group consisted of 206 patients surgically treated for well differentiated thyroid cancer with the minimal follow-up period of 5 years. The median age patients was 49.1 years. 159 patients (77.2%) have still remained in the follow-up programme, 23 died because of thyroid cancer (11.1%) and the remaining 24 have either refused to participate in the programme or died of other causes. Median follow-up period was 10.7 years. Total thyroidectomy was performed in 90 patients (43.7%) and less extensive procedures in 106 (51.4%). The remaining patients were qualified for palliative reduction of the tumour mass and they were not included in this study. The comparison of the patients with I and II stage of the disease according to the type of surgical procedure did not show differences in 10-year survival. In stage III the difference was very close to statistical significance. The same results were observed with regard to disease recurrence. Long-time survival in low risk patients was not related to the extent of surgical procedure. The risk of recurrence and death was higher in the patients with advanced disease in stage III who underwent less radical procedures like total resection of involved lobe with isthmus and subtotal resection of contralateral lobe.

Antineoplastic Protocols↗

PubMed2001

[Poorly differentiated carcinoma of the thyroid--immunohistochemical evaluation of p53 and p27 protein expression].

Thyroid carcinomas represent a broad spectrum of tumours with different biologic behaviours. The gap between the indolent course of well-differentiated papillary and follicular carcinomas and the very aggressive behaviour of anaplastic carcinomas is filled by variants of thyroid carcinoma with intermediate prognosis, designated in the literature as poorly differentiated (with insular, trabecular and solid patterns) and tall/columnar cell variant of papillary carcinoma. The study has been carried out in 103 patients who had thyroid cancer with various grade of differentiation. The diagnostic significance of p53 and p27 expression in tumor cells has been investigated by immunohistochemical analysis. Well differentiated carcinomas have exhibited the lowest p53 staining frequency, the expression has been higher in poorly differentiated carcinomas and 100% of anaplastic carcinomas have been positive p27 immunohistochemistry has been positive in 80% of investigated carcinomas (in 15% strong positive reaction). In the group of poorly differentiated tumours positive reaction has been observed in 75% cases (in 15% strong positive reaction). Our data suggest that expression of p53 and p27 seems to have limited routine diagnostic significance, but p53 positivity is a good marker of tumour progression.

Adenocarcinoma, Follicular↗

PubMed2001

[Expression of protein p53: the marker of low neoplastic cell differentiation in thyroid carcinoma].

UNLABELLED: The aim of the study was to evaluate the frequency of positive staining of p53 protein in the course of thyroid carcinoma and to establish the prognostic value of such expression. MATERIAL AND METHOD: Immunohistochemical staining of frozen sections was performed in 159 patients with thyroid carcinoma (139 females and 29 males). The average age was 50.4 years. All patients have been followed-up for at least 5 years and the average time of observation was 10.7 years. There were 46% patients with papillary carcinoma, 39% with follicular carcinoma and 15% with poorly differentiated thyroid carcinoma in the study group. Additionally, staining was performed in 6 cases of anaplastic carcinoma. The expression of p53 protein was assessed by two-degree scale: a medium (10% of cells with positive staining) and strong (50% of positive staining). RESULTS: In the group of 135 patients with well differentiated thyroid carcinoma the expression of p53 protein has been found in 55 cases (40.1%) but significantly more often in medium (69.1%) than in strong degree (30.9%). Significantly more often in expression has occurred among patients with poorly differentiated carcinoma (66%) and anaplastic carcinoma (100% of patients with strong expression in all cases). Comparing the frequency of p53 protein expression on every stage of disease, no significant difference has been found. The presence of p53 protein has not correlated with reduced changes in survival. In multivariate analyses the expression of p53 protein have not shown prognostic value. CONCLUSION: The expression of p53 protein has concerned the poorly differentiated carcinomas of thyroid and has not correlated with the stage of disease. No influence of expression on clinical course of the well differentiated thyroid carcinoma has been found. Worse prognoses have correlated with poor differentiated thyroid cancer cases and with strong expression of p53 protein.

Adenocarcinoma, Follicular↗

PubMed2000

Cladribine with prednisone versus chlorambucil with prednisone as first-line therapy in chronic lymphocytic leukemia: report of a prospective, randomized, multicenter trial.

The efficacy and toxicity of cladribine (2-CdA) + prednisone (P) versus chlorambucil (Chl) + P were compared in previously untreated patients with progressive or symptomatic chronic lymphocytic leukemia (CLL) in a randomized, multicenter prospective trial. Eligible patients were assigned to either 2-CdA 0.12 mg/kg per day in 2-hour infusions and P 30 mg/m(2) per day for 5 consecutive days or Chl 12 mg/m(2) per day and P 30 mg/m(2) per day for 7 consecutive days. Three courses were administered at 28-day intervals or longer if myelosuppression developed. The therapy was finished if complete response (CR) was achieved. Of 229 available patients 126 received 2-CdA+P and 103 received Chl+P as a first-line treatment. CR and overall response rates were significantly higher in the patients treated with 2-CdA+P (47% and 87%, respectively) than in the patients treated with Chl+P (12% and 57%, respectively) (P = .001). Progression-free survival was significantly longer in the 2-CdA-treated group (P = .01), but event-free survival was not statistically different. Thirteen percent of patients were refractory to 2-CdA+P and 43% to Chl+P (P = .001). Drug-induced neutropenia was more frequently observed during 2-CdA+P (23%) than Chl+P therapy (11%) (P = .02), but thrombocytopenia occurred with similar frequency in both groups (36% and 27%, respectively). Infections were seen more frequently in the 2-CdA+P-treated group (56%) than in the Chl+P-treated group (40%; P = .02). Death rates have so far been similar in patients treated with 2-CdA (20%) and with Chl (17%). The probability of overall survival calculated from Kaplan-Meier curves at 24 months was also similar for both groups (78% and 82%, respectively). (Blood. 2000;96:2723-2729)

Adult↗

PubMed2000

Measurement of the spin asymmetry in the photoproduction of pairs of high- p(T) hadrons at HERMES

We present a measurement of the longitudinal spin asymmetry A(||) in photoproduction of pairs of hadrons with high transverse momentum p(T). Data were accumulated by the HERMES experiment using a 27.5 GeV polarized positron beam and a polarized hydrogen target internal to the HERA storage ring. For h(+)h(-) pairs with p(h(1))(T)>1.5 GeV/c and p(h(2))(T)>1.0 GeV/c, the measured asymmetry is A(||) = -0. 28+/-0.12(stat)+/-0.02(syst). This negative value is in contrast to the positive asymmetries typically measured in deep inelastic scattering from protons, and is interpreted to arise from a positive gluon polarization.

Journal Article↗

PubMed2000

Cladribine with or without prednisone in the treatment of previously treated and untreated B-cell chronic lymphocytic leukaemia - updated results of the multicentre study of 378 patients.

Between January 1992 and January 1999, we treated 378 B-chronic lymphocytic leukaemia (CLL) patients with cladribine (2-CdA), and 255 of the patients were also treated with prednisone. A total of 194 patients were previously untreated, and 184 had relapsed or refractory disease after previous other therapy. Complete response (CR) was obtained in 111 (29.4%) and partial response (PR) in 138 (36.5%) patients, giving an overall response (OR) rate of 65.9%. CR and OR were achieved more frequently in patients in whom 2-CdA was a first-line treatment (45.4% and 82.5% respectively) than in the pretreated group (12.5% and 48.4% respectively) (P < 0.0001). The median duration of OR for previously untreated patients was 14.7 months and for pretreated patients 13.5 months (P = 0.09). The median survival evaluated from the beginning of 2-CdA treatment was shorter in the pretreated group (16.3 months) than in the untreated group (19.4 months) (P < 0.0001). A total of 117 (63.9%) patients died in the pretreated group and 63 (32.6%) in the untreated group. In pretreated patients, 2-CdA + prednisone (P) and 2-CdA alone resulted in similar OR (51.0% and 45.0% respectively; P = 0.4). In contrast, in untreated patients, 2-CdA + P produced a higher OR (85.4%) than 2-CdA alone (72.1%) (P = 0.04). Infections and fever of unknown origin, observed in 91 (49.4%) pretreated and 74 (38.1%) untreated patients (P = 0.03), were the most frequent toxic effects. Our results indicate that 2-CdA is an effective, relatively well-tolerated drug, especially in previously untreated CLL.

2-Chloroadenosine↗

PubMed1999

Nesidioblastosis in an adult man--case report.

We report a case of nesidioblastosis in a 66-year-old man with chronic alcohol-induced pancreatitis manifested by attacks of hypoglycemia for several years. The state of the patient improved after subtotal pancreatectomy.

Aged↗

PubMed1999

[General characteristics, basis and procedures for high dose chemotherapy procedures supported by hemopoietic stem cell transplantation].

Indications for autologous and allogeneic bone marrow transplantation in hematological malignancies and solid tumours are summarised. AML treatment protocol including induction and consolidation chemotherapy followed by conventional maintenance chemotherapy or high dose chemotherapy with subsequent autologous or allogeneic stem cell transplant are presented. We compared elements and targets of autologous and allogeneic procedures pointing out the major differences regarding transplant related mortality, disease free survival and relapse rates.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1999

[Non Hodgkin's lymphoma--treatment of choice and the role of high dose chemotherapy].

Non Hodgkin's Lymphomas protocols currently used at the CMUJ Department of Haematology in Cracow based on updated results of randomised trials are summarised. High dose chemotherapy with hematopoietic blood stem cell support is only one of the elements of modern NHL therapy; it's effectiveness depends on optimal indications and timing of the procedure.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1998

Computer modelling of dynamics of Ser92X deoxymyoglobin mutants.

The hydrogen bond between His93 and Ser92, recently discovered in crystal structures of myoglobins (Mbs), may contribute to the oxygen storage capacity of the heme proteins through a stabilization of the proximal ligand. The possible influence of this H-bond on the geometry of the heme proximal side and ligand binding properties of Mb were computationally studied using model proteins with point mutations affecting this bond. The results of the computer modelling of Ser92X (X = Ala, Ile, Thr, Val) mutants of human (H) and sperm whale (SW) Mbs are presented. The OPLS-AMBER-CHARMM forcefield was used in the calculations. Several 10-50 ps molecular dynamics simulations (300 K, in vacuo) were performed. Our results show that the Ser92X mutants are stable molecules. In the wild types and Ser92Thr mutants, the H-bond studied is observed only for a relatively short period of time. It is expected that in both HMb and SW Mb molecules the impact of the proximal histidine interaction with the Ser92(F7) residue on the iron reactivity is rather low. However, the limited torsional flexibility of the proximal histidine imidazole ring was found in hydrogen bonding mutants. This effect may be attributed to the specific long range electrostatic interactions.

Alanine↗