Oxidant/Antioxidant Status of Breast Cancer Patients in Pre- and Post-Operative Periods.

BACKGROUND AND OBJECTIVES: The purpose of this study is to evaluate the level of oxidative stress before and after breast cancer surgery. MATERIALS AND METHODS: Malondialdehyde (MDA) level was tested using a thiobarbituric acid (TBA) assay based on the release of a color complex due to TBA reaction with MDA. The glutathione S-transferase (GST) activity was evaluated by enzymatic conjugation of reduced glutathione (GSH) with 1-chloro-2,4-dinitrobenzene. The level of total glutathione (reduced GSH and oxidized GSSG) was detected using a recycling system by 5,5-dithiobis(2-nitrobenzoic acid). The levels of the indices were determined in the serum of 52 patients before surgery, two hours and five days after surgery, and in 42 healthy women. RESULTS: In the patients over 50 years old the level of MDA was higher after surgery in comparison with before surgery, and GST activity was lower in comparison with the control. The GSH + GSSG level in both ages groups after surgery was lower than in the control. Significant differences of MDA level were detected in patients with stage III after surgery compared to the control. The level of GSH + GSSG was significantly lower in the patients with I-III stages compared to the control. CONCLUSION: The most expressed changes demonstrate the significance of MDA as a marker to evaluate oxidative stress in breast cancer patients. The degree of oxidative stress depends on the patient's age and stage of disease.

Changes of reduced glutathione and glutathione S-transferase levels in colorectal cancer patients undergoing treatment.

PURPOSE:: The available data concerning reduced glutathione (GSH) and glutathione S-transferase (GST) levels in colorectal cancer patients during the treatment process are contradictory and insufficient. METHODS:: Forty patients with metastatic colorectal cancer receiving FOLFOX4 chemotherapy with or without bevacizumab and 40 healthy volunteers were included in the study. Blood samples were taken before treatment, after 2 months and at the end of treatment in the patient group and once in the healthy volunteer group. The levels of GSH and GST in blood serum were evaluated by enzyme-linked immunosorbent assay (ELISA) according to the manufacturer's instructions. RESULTS:: The serum level of GSH was significantly lower in colorectal cancer patients before treatment than in healthy volunteers (37.84 ± 19.39 µg/mL and 52.78 ± 19.39 µg/mL, respectively; p<0.001). After treatment, the level of GSH increased significantly, while the level of GST decreased significantly. These changes were observed only in the groups of patients with partial or complete response, having metastases only in the liver, receiving FOLFOX4 chemotherapy with bevacizumab, or undergoing resection or radiofrequency ablation of liver metastases. CONCLUSIONS:: GSH and GST levels change significantly during the treatment process and these changes depend on the response to treatment, treatment type, and site of metastases. Further analysis of the changes in GSH and GST levels during treatment would allow the assessment of the predictive potential of this molecular marker.

NOTCH signalinio kelio ir ginekologiniu piktybiniu naviku sasaja.

THE ASSOCIATION BETWEEN THE NOTCH SIGNALING PATHWAY AND GYNAECOLOGICAL MALIGNANCIES: Background. The body's cell behaviour is controlled by various signalling pathways, one of which is NOTCH. It has been found that a partial loss of the NOTCH function or abnormal strengthening of NOTCH signalling are related to various human diseases and developmental disorders. Materials and methods. PubMed was the main source of information for this paper. Results. The paper overviews the association between oncologic diseases and the participants of the NOTCH signalling pathway. In cancerogenesis, the NOTCH signalling pathway can act as a tumour suppressor or an oncogene. The mechanisms of such an effect are yet unknown. The NOTCH signalling pathway is an object of active research because its modulation by pharmacological and genetic approaches could be helpful in discovering new treatment methods of tumours. In this review more attention is paid to gynaecological malignancies, especially to uterine cancer. Conclusions. The findings of recently published studies show that the NOTCH signalling pathway is definitely important for the development of uterine cancer, therefore its components can be potential prognostic biomarkers and molecular therapeutic targets. However, further studies in this field are needed in order to clarify the role of the components of the NOTCH signalling pathway and their interaction with participants of other signalling pathways, which can be important in the development and progression of uterine cancer as well. Keywords: NOTCH signalling pathway, cancer, gynaecological malignancies.

Glutathione and glutathione S-transferase levels in patients with liver metastases of colorectal cancer and other hepatic disorders.

BACKGROUND/AIMS: Glutathione and glutathione S-transferases (GST) are involved in cell defence against reactive oxygen species, which induces oxidative stress and are associated with different chronic diseases. The aim of the present study was to determine the differences in reduced glutathione (GSH) and GST levels in patients with different liver diseases. MATERIALS AND METHODS: Overall, 114 patients were enrolled in this study: 58 patients with colorectal cancer (18 without and 40 with liver metastases), 27 with liver steatosis, 29 with alcoholic cirrhosis and a group of 40 healthy volunteers. The levels of GSH and GST in blood serum were evaluated by enzyme-linked immunosorbent assay (ELISA) according to the manufacturer's guidelines. RESULTS: Significant differences in GSH and GST levels were observed in most of the groups compared to the healthy volunteers (GSH: 52.72 µg/mL, GST: 0.53 ng/mL): with hepatic steatosis (GSH: 17.04 µg/mL, p < 0.001; GST: 5.89 ng/mL, p < 0.001), alcoholic cirrhosis (GSH: 62.04 µg/mL, p < 0.003; GST: 0.94 ng/mL, p < 0.001) and liver metastases (GSH: 37.84 µg/mL, p < 0.001, GST: 1.25 ng/mL, p=0.747). CONCLUSION: The different GSH and GST levels in patients with colorectal cancer liver metastases, liver steatosis and alcoholic cirrhosis indicate the differences in antioxidative system damage and its compensatory possibilities and could serve as potential biomarkers for its correction.

E3 ubiquitin ligases as drug targets and prognostic biomarkers in melanoma.

Melanomas are highly proliferative and invasive, and are most frequently metastatic. Despite many advances in cancer treatment over the last several decades, the prognosis for patients with advanced melanoma remains poor. New treatment methods and strategies are necessary. The main hallmark of cancer is uncontrolled cellular proliferation with alterations in the expression of proteins. Ubiquitin and ubiquitin-related proteins posttranslationally modify proteins and thereby alter their functions. The ubiquitination process is involved in various physiological responses, including cell growth, cell death, and DNA damage repair. E3 ligases, the most specific enzymes of ubiquitination system, participate in the turnover of many key regulatory proteins and in the development of cancer. E3 ligases are of interest as drug targets for their ability to regulate proteins stability and functions. Compared to the general proteasome inhibitor bortezomib, which blocks the entire protein degradation, drugs that target a particular E3 ligase are expected to have better selectivity with less associated toxicity. Components of different E3 ligases complexes (FBW7, MDM2, RBX1/ROC1, RBX2/ROC2, cullins and many others) are known as oncogenes or tumor suppressors in melanomagenesis. These proteins participate in regulation of different cellular pathways and such important proteins in cancer development as p53 and Notch. In this review we summarized published data on the role of known E3 ligases in the development of melanoma and discuss the inhibitors of E3 ligases as a novel approach for the treatment of malignant melanomas.

Significance of blood serum catalase activity and malondialdehyde level for survival prognosis of ovarian cancer patients.

BACKGROUND AND OBJECTIVE: Several markers were found to be potential prognostic factors in ovarian cancer. Among markers resembling systemic changes in the host's organism are markers of the oxidative stress. In this study we attempted to analyze the oxidant and antioxidant parameters of ovarian cancer patients. MATERIALS AND METHODS: A total of 42 patients with newly diagnosed stages I-IV primary ovary cancer were examined. Level of malondialdehyde (MDA) and catalytic activity catalase (CAT) were determined spectrophotometrically. RESULTS: Significantly lower CAT (28.2±15.5 vs. 36.1±14.6nmol/L/min, P=0.019) activity and higher MDA levels (8.7±3.0 vs. 6.7±2.7nmol/L, P=0.002) were observed in cancer patients compared with healthy volunteers. Both variables were not confirmed as prognostic factors according to Kaplan-Meier survival estimates. CONCLUSIONS: MDA and CAT demonstrate oxidative stress in cancer patients: CAT activity was significantly lower and MDA levels higher in cancer patients compared to healthy controls. These variables were not confirmed to be prognostic factors in ovarian cancer, possibly due to small size of the study group.

The significance of reduced glutathione and glutathione S-transferase during chemoradiotherapy of locally advanced cervical cancer.

BACKGROUND AND OBJECTIVE: To determine changes in reduced glutathione (GSH) and glutathione S-transferase (GST) during neoadjuvant chemotherapy followed by concurrent chemoradiation for patients with stage IIB-IIIB cervical cancer, and to evaluate their significance to the efficacy of the treatment. MATERIALS AND METHODS: According to the prospective phase II study protocol, 36 patients with stage IIB-IIIB cervical cancer were enrolled. A short course of intensive weekly neoadjuvant cisplatin and gemcitabine chemotherapy followed by concurrent weekly cisplatin and gemcitabine-based chemoradiation was administered. Blood samples for GSH, GST analysis were collected and analyzed before the start of the treatment, after neoadjuvant chemotherapy, and after the end of the chemoradiation. RESULTS: A statistically significant increase in the concentration of GSH after neoadjuvant chemotherapy was identified. After chemoradiation, values of this rate significantly decreased in contrast with GSH concentration after neoadjuvant chemotherapy in cases of stage IIB, regional metastases negative patients group, patients with a positive response to treatment, and patients who had no progression of the disease during the first 2 years after treatment. Statistically significant changes in GST during the treatment were not identified; the GST concentration after chemoradiation showed a statistically significant difference in GST concentrations in terms of the progression of the disease and disease without progression. CONCLUSIONS: The results suggest that changes in the concentration of GSH during the treatment of locally advanced cervical cancer might be important for the prediction of the efficacy of the treatment. Statistically significant changes in GST concentration levels during the treatment were not observed.

Relationship of MDA plasma concentrations to long-term survival of breast cancer patients.

AIMS AND BACKGROUND: Malondialdehyde (MDA) is a product of polyunsaturated fatty acid oxidation. Changes in MDA concentrations have been found in patients with various types of cancer. The aim of this study was to analyze the relationship of MDA plasma concentrations to the long-term survival of patients with breast cancer. METHODS AND STUDY DESIGN: We conducted a retrospective study which included 106 patients at various disease stages (I - n = 2; II - n = 30; III - n = 51; IV - n = 23). Plasma MDA concentrations were measured at the time of diagnosis. Study participants were divided into groups according to age (<55 years vs ≥55 years), disease stage, and MDA concentration (<9 mmol/L vs ≥9 mmol/L). Survival rates between groups were compared using the Kaplan-Meier method. RESULTS: We found that higher MDA concentrations were associated with lower survival rates in stage I and II breast cancer. No significant association was found in patients with stage III and IV disease. Multivariate analysis showed that the MDA level was the only independent prognostic factor for patient survival in the total study group (hazard ratio 1.57, P = 0.03). CONCLUSION: MDA can be used as a prognostic factor in early stages of breast cancer.

NOTCH1, NOTCH3, NOTCH4, and JAG2 protein levels in human endometrial cancer.

BACKGROUND AND OBJECTIVE: Notch signaling is a conserved developmental pathway, which plays an important role in the regulation of cell proliferation, differentiation and death. Deregulation of Notch pathway has been connected with the carcinogenesis in a variety of cancers. The aim of this study was to investigate the level of the Notch signaling pathway proteins (NOTCH1, 3, 4 and JAG2) in the samples from human endometrial cancer. MATERIALS AND METHODS: The amount of the Notch receptors NOTCH1, 3, 4 and ligand JAG2 protein was determined by Western blot analysis in the samples from stage I endometrial cancer and adjacent nontumor endometrial tissue of 22 patients. RESULTS: The level of NOTCH4 receptor was 1.7 times lower in stage I endometrial cancer as compared with the healthy tissue of the same patients (P=0.04). The protein level of ligand JAG2 was significantly reduced by 2.5 times in stage IB endometrial adenocarcinoma samples (P=0.01). It was reduced in the majority of stage IB adenocarcinomas. There were no significant changes in the protein amount of NOTCH1 and NOTCH3 receptors comparing stage I endometrial adenocarcinoma and healthy tissues. CONCLUSIONS: The reduced amount of NOTCH4 and JAG2 proteins and the decreased level of mRNA coding Notch proteins, as reported in our previous studies, supports the notion that Notch pathway has rather tumor-suppressive than oncogenic role in human endometrial cancer cells. It suggests that Notch pathway activation is a potential therapeutic target.

Down-regulated expression of Notch signaling molecules in human endometrial cancer.

Notch signaling pathway is a highly conserved developmental pathway, which plays an important role in the regulation of cellular proliferation, differentiation and apoptosis. Deregulation of Notch pathway has been connected with the carcinogenesis in a variety of cancers. In this study, we investigated the expression of Notch receptors (NOTCH1, NOTCH2, NOTCH3 and NOTCH4), ligands (JAG1, JAG2 and DLL1) and target gene HES1. Fifty paired samples of endometrial cancer and adjacent nontumor endometrial tissue from endometrial cancer patients were analyzed by quantitative PCR. The mRNA levels of all investigated molecules were lower in endometrial cancer compared to adjacent nontumor tissue. The expression of NOTCH1, NOTCH4 and DLL1 in IB stage adenocarcinoma was significantly lower (P < 0.05) than the expression in IA stage adenocarcinoma. Significant correlations were found between mRNA expression levels of Notch target gene HES1 and several Notch signaling molecules: NOTCH1, NOTCH3, DLL1 (P < 0.001) and NOTCH2, JAG2 (P < 0.05). This supports the notion that Notch pathway can function as tumor suppressor in human endometrial cancer.

Antioxidative system parameters and level of IL-18 after surgery in patients with renal cell carcinoma according to gender.

Functions of the antioxidative system and cytokines are important factors that can influence the development of cancer. The aim of this study was to determine gender-related differences in the concentration of inflammatory cytokine IL-18 and alterations of antioxidative system parameters after surgical treatment of renal cell carcinoma patients. The study comprised 40 patients (22 women and 18 men). The level of peroxidation product malonodialdehyde (MDA), the status of the antioxidative system and the concentration of interleukin-18 (IL-18) were analyzed. A significant difference in the changes of antioxidative system reflecting parameters was observed according to the gender. In the male group with higher IL-18 concentration after surgery the level of MDA was lower, while in the women group it did not change and the level of catalase activity was higher; superoxide dismutase activity was higher in both groups. It is important to notice that our previous study (where the data were not analyzed in respect of gender) showed that the level of IL-18 was significantly higher after surgical treatment if MDA content was increased. More detailed studies are required to confirm in which cases association between IL-18 concentration and MDA level is related to cancer progression and in which cases - to the better prognosis depending on the patients' gender.

Human papillomavirus infection in pregnant women.

INTRODUCTION: Human papillomavirus (HPV) is the most common sexually transmitted infection in the world. It has been established that about 70% of the sexually active population are exposed to this infection. The HPV prevalence rate among pregnant women ranges from 5.5 to 65.0%. Studies on HPV infection in pregnant women have yielded inconsistent results, including HPV prevalence, and HPV clearance. AIM: Our aim is to determine the prevalence of HPV infection in pregnant women, to identify the types of the virus, and to evaluate the changes of prevalence of HPV infection depending on the trimester of pregnancy in Lithuania. METHODS: Two hundred and thirteen pregnant women who were attending centres of the central outpatient clinic of Vilnius city (Lithuania) in 2008-2010 were studied. These women were examined for HPV infection and its type by polymerase chain reaction. Tests were performed on the first and third trimesters. The statistical analysis was done using SPSS17 and Excel software. RESULTS: At the beginning of the pregnancy (first trimester of pregnancy), HPV infection was detected in 17.8% of the pregnant women (38 from 213); high oncogenic risk HPV types were identified for 52.6% of the HPV-positive pregnant women. At the end of the pregnancy (third trimester of pregnancy), HPV was identified in 10.3% of the pregnant women (15 out of 146); high-risk HPV types were identified for 66.7%. CONCLUSION: Our study shows the high prevalence of HPV infection in pregnant women in Lithuania. The majority of pregnant women's HPV infection was cleared during the pregnancy. Only in a few cases a new HPV infection was detected.

[Tumor and immunity]. / Navikas ir imunitetas.

System of organism defense is an important complex of interrelated cellular, molecular, genetic, and other components, which regulate homeostasis of host. Experimental and clinical data show that immune system functions are significant, but also a complicated question in cancer development. It is very important to investigate and understood how immune system coordinates the response to cancer cells. Our understanding about innate and adaptive immunity functions and interaction with transformed cells is constantly changing. Different responses of these system components can promote, reduce, or inhibit tumor development. It is established that malignant cells develop into invasive cancer with interaction with tumor microenvironment, which is influenced by inflammation. Clinical and experimental studies have revealed the link between inflammation and cancer risk. Many cancers develop in the sites of inflammation. Activation of humoral and cellular immunity may predispose to neoplastic or cancer development. Despite the scientific progress, understanding of the immune system mechanisms responding to malignance remains insufficient.

Alterations of human immune system functions in relation to environmental contamination, gender and alcohol consumption intensity.

Environmental contamination and use of alcohol may be a cause of immune system disturbances and various diseases. The aim of this study was to evaluate changes of different alcohol consumption intensity on the immune condition of women and men living in a district contaminated with industrial siftings (Trakai) and in a relatively clean district (Sirvintos). The immune system parameters were investigated in 282 Trakai district inhabitants (127 males and 155 females) and in 282 Sirvintos district inhabitants (129 males and 153 females). Due to gender and alcohol consumption intensity the immune system functions were evaluated in the following groups: abstainers, light alcohol users, moderate alcohol users and alcohol abusers. Absolute number of CD5+, CD4+, concentration of IgA in blood serum and some other investigated indices of light alcohol users were significantly increased in the male group of Trakai district in comparison with females of this district. However, in the same group of light alcohol drinkers of Sirvintos district, males had lower indices (CD5+, CD4+, CD4+/CD8+, IgM) than females. Immune system parameters of males who were light and moderate alcohol users in Trakai district were stimulated in comparison with the same alcohol consumption groups of males in Sirvintos district. Our investigations showed that combination of environmental pollution and different intensity of alcohol consumption cause various alterations of immune system functions in males and females.

Disturbance of human immunohomeostasis by environmental pollution and alcohol consumption.

Environmental pollution and consumption of alcohol evoke various immunomodulations promoting the progress of different pathologies. The purpose of this study was to evaluate the influence of alcohol consumption intensity on the immune system functions of humans living in ecologically different regions, i.e. in a district polluted with industrial siftings (Trakai, n = 270) and in a relatively clean district (Sirvintos, n = 250). In the Trakai cohort 96% and in Sirvintos group 89% of persons consumed alcohol. With regard to alcohol consumption habits the immunohaematological indices were investigated in the following four groups: abstinents, light alcohol users, moderate alcohol users and alcohol abusers. We determined the compensatory mechanisms of immune system functions of moderate alcohol users and alcohol abusers in comparison with abstinents in the relatively clean Sirvintos district. In the Trakai district polluted with industrial siftings such compensatory reactions where not found. Thus, damage to the immune system functions is not only an endogenous risk factor for many diseases, but also an indicator of organism injury. This investigation stated, that immunity disturbance in humans depends on alcohol consumption intensity and place of residence.

[Changes in the parameters of immune and antioxidant systems in patients with cervical cancer]. / Serganciuju gimdos kaklelio veziu imunines ir antioksidacines sistemu bukle.

Taking into account the possibility of interaction of immune and antioxidant systems, the aim of this study was to investigate the changes in the parameters of immune and antioxidant systems in patients with cervical cancer and to compare them with the corresponding data obtained from healthy women. Ninety-four women with cervical cancer at II and III stage comprised the patient group and 69 healthy women were taken as the control group. The investigation results showed that the cellular immunity functions of patients with cervical cancer were suppressed in comparison with the same of healthy women. Though with respect to age, in 35-49-year-old women group with cervical cancer, some immune system indices were suppressed (quantity of T-, B-lymphocytes, NK); however in order to maintain the immune homeostasis of the organism other immune system functions were compensatorily stimulated (neutrophils and its phagocytic activity, CD8(+), IgG and IgA concentration were higher). The activity of the antioxidant system in patients with cervical cancer was impaired: the concentration of lipid peroxidation products was increased, the level of the endogenous antioxidant vitamin E and the activity of the antioxidant enzyme superoxide dismutase were decreased in comparison with the control group.