Anthracycline-induced cardiotoxicity and renin-angiotensin-aldosterone system—from molecular mechanisms to therapeutic applications

Heart Failure Reviews - Few millions of new cancer cases are diagnosed worldwide every year. Due to significant progress in understanding cancer biology and developing new therapies, the mortality...     

Polymorphism of the homologous recombination repair genes RAD51 and XRCC3 in breast cancer

The RAD51 protein and its paralog, XRCC3, play an important role in the repair of DNA double-strand breaks (DSBs) by homologous recombination. Since DSBs may contribute to the pathogenesis of breast cancer and variability in DNA repair genes may be linked with some cancers, we performed a case-control study (135 cases and 175 controls) to check the association between the genotypes of the Thr241Met polymorphism of the XRCC3 gene and the 135G>C polymorphism of the RAD51 gene and breast cancer occurrence and progression. Genotypes were determined in peripheral blood lymphocytes by RFLP-PCR. We did not find any association between either polymorphism singly and breast cancer occurrence. Both polymorphisms were not related to tumor size, estrogen and progesterone receptors status, cancer type and grade. However, the Thr241Met genotype of the XRCC3 polymorphism slightly increased the risk of local metastasis in breast cancer patients (OR 2.56, 95% CI 1.27-5.17). The combined Thr241Met/135G>C genotype decreased the risk of breast cancer occurrence (OR 0.22, 95% CI 0.08-0.59). Our results suggest that the variability of the DNA homologous recombination repair genes RAD51 and XRCC3 may play a role in breast cancer occurrence and progression, but this role may be underlined by a mutual interaction between these genes.     

Studies on the incidence and clinical significance of the metabolic syndrome in postmenopausal women in Lodz region

In menopausal period increased prevalence of lipid metabolism disorders, atherosclerosis, carbohydrate metabolism disorders, cardiovascular diseases is observed. AIM OF STUDY: Evaluation of prevalence of obesity, overweight, hypertension, carbohydrate and lipid metabolism disorders in population of women aged 45-65, treated in Menopause Diagnostic and Treatment Center Polish Mother's Memorial Hospital--Research Institute in Lodz. 2081 women, aged 45-65 were studied. In all of them diseases history, body mass index (BMI), blood pressure (twice), total cholesterol, triglycerides, fasting blood glucose levels were obtained. The highest percentage of obese women was noted in small villages (39%), whereas 21% of women from cities have BMI > or = 30 kg/m2. On the other side only 18.4% women living in cities have normal body weight, although in small villages there are 34.6% women from this group. Overweighted women percentage is similar among women living in small villages and cities. Hypertension prevalence did not depend on place of living, but obese women have hypertension more frequently. In study group diabetes mellitus was diagnosed in 4.8% of women and impaired glucose tolerance in 7%. Almost 2/3 of diabetes mellitus cases was first time diagnosed. Fasting blood glucose (FBG) level > or = 125 mg/dl was noted in 62 women (3%), values 111-124 mg/dl in 124 (6%), and in other 1895 women (91%) FBG was < or = 110 mg/dl. FBG level over 124 mg/dl and diabetes mellitus was more frequent in obese women. Women with hypercholesterolemia mostly (63.2%) have BMI > 25 kg/m2. Our study revealed that hypercholesterolemia prevalence did not differ with no statistical significance between women living in cities, towns and small villages. Elevated triglycerides level over 2.26 mmol/l was noted in 14.5% studied women, whereas there was no correlation between triglycerides level and body weight and place of living. Main health problem of women in perimenopausal period is obesity and lipid metabolism disorders detected in significant number of studied patients. Most cases of undiagnosed diabetes mellitus indicate that complex evaluation of health status of women in perimenopausal period is obligatory procedure.     

Dantrolene antagonizes the glycineB site of the NMDA receptor

In this study we tested the hypothesis that dantrolene, an established inhibitor of the skeletal muscle isoform of the ryanodine receptor, may interfere with activity of NMDA receptors in neurons. We assessed the effects of dantrolene on [(3)H]MK-801 and [(3)H]glycine binding to isolated rat cortical membranes. Dantrolene inhibited [(3)H]MK-801 binding in the presence of 100 microM NMDA with an IC(50) of 58.4 microM. The IC(50) value increased to 99.6, 343.0 and 364.6 microM in the presence of 10, 30 and 50 microM glycine, respectively, suggesting that dantrolene competes with glycine for binding site at the NMDA receptor complex. A binding assay using [(3)H]glycine confirmed this supposition: dantrolene inhibited strychnine-insensitive glycine binding in a dose-dependent way. Thus, our results show that dantrolene at concentrations of 50-100 microM and higher blocks the glycine binding site of the NMDA receptor complex and in this way inhibits activation of the NMDA ion channel. These data reveal a new mechanism of dantrolene action in neuronal tissue. Our results also suggest that the neuroprotective effect of dantrolene may be at least partly explained by its activity as a non-competitive antagonist of NMDA receptors.     

Evaluation of selected X syndrome factors during hormonal replacement therapy

Estrogen deficiency after menopause leads to characteristics changes in the hormonal profile, which may influence lipid carbohydrate and calcium-phosphate metabolism and some elements of homeostasis. AIM OF STUDY: To evaluate the influence of hormone replacement therapy with 2 mg estradiol valerate and 0,15 mg levonorgestrel on carbohydrate and lipid metabolism in women after menopause during 12 months of follow-up. We examined 101 women, mean age 52.9 +/- 4.6 years (range from 44 to 65). HRT was applied in 67 women whereas 34 women were without treatment. All of them had no carbohydrate disturbances. All women underwent clinical examination, and body mass index (BMI), fasting blood glucose, insulin, total cholesterol and triglycerides levels were obtained. At 1 and 2 hours after 75 g glucose challenge (75OGTT) glucose and insulin levels were obtained. During hormone replacement therapy all women noted release or significant decrease of climacteric symptoms. Total cholesterol level was decreased, whereas triglycerides did not change. After 12 months of treatment there was also a significant decrease of all factors relating to carbohydrate metabolism--fasting glucose and insulin, insulin/glucose ratio and area under glucose and insulin curves. In our study--after 6 months of follow-up fasting insulin level, area under glucose and insulin curves were increased whereas fasting blood glucose level remained unchanged. Among women without HRT there were no significant changes in selected lipid parameters and BMI. Triglyceride levels decreased (albeit insignificantly) but, total cholesterol levels did not change. After 12 months glucose level did not change, although other carbohydrate parameters were increased. 1) In the study group there was a statistically significant decrease in total cholesterol levels whereas triglycerides remained unchanged. 2) HRT we significantly decreased of insulin resistance and fasting blood glucose levels as compared with non-group HRT. 3) The present results indicate HRT-induced improvement of lipid and carbohydrate metabolism. 4) Long-term HRT is necessary to improve carbohydrate metabolism.     

Evaluation of endometrial biopsy in postmenopausal women before HRT

One of the reasons for not commencing or withdrawal of HRT in women is their fear for breast and endometrial cancers. Does ultrasonographic valuation guarantee sufficiently patient's safety? Most investigators do not recommend further endometrial diagnostics with endometrial thickness less than 4 mm. Endometrial biopsy is advised in cases of irregular uterine bleedings with normal endometrial image or when any endometrial pathology is suspected. In Poland the most frequently performed procedure of endometrial diagnostics is D&C. Our proposition was to offer endometrial biopsies to all patients who were taken HRT for more than 5 years or, despite having strong climacteric ailments, refused to take it because of their cancerophobia. AIM OF STUDY: To evaluate the usefulness of aspiration endometrial biopsy in women after menopause qualified for HRT. MATERIAL AND METHODS: In 84 females, being postmenopausal (amenorrhoeic for at least 12 months) and qualified for HRT, aspiration endometrial biopsies were performed in outpatient clinics. Age of women ranged 46-63 years, mean 57.3. Attained results were compared to ultrasonographic endometrial evaluation. Such factors as patient's age, menopausal age (years from last menstrual period) and previous administration of HRT were taken into our account (maintaining a 3-month wash-out interval). In 74% of women we have got a material being sufficient for histological evaluation. Form clinical point of view the most important for us was to exclude a proliferative or neoplastic process within endometrium. One of endometrial polyps was omitted in USG study, we were surprised also while detecting endometrial carcinoma cells in endometrium below 3.5 mm. In one postoperative slide the cells of endometrial ovarian carcinoma (with infiltrated Fallopian tube) were detected. CONCLUSION: Endometrial biopsy seems to be a useful, effective and cheap method of endometrial diagnostics also in women after menopause.     

Assessment of fat tissue distribution impact on selected prothrombin and fibrinolytic factors in pre- and postmenopausal women

OBJECTIVES: Objective was to examine the relationship of obesity, body fat distribution fasting plasma insulin concentrations and triglycerides of pro-thrombotic and fibrinolitics factors in pre and postmenopausal women. MATERIAL AND METHODS: We assessed 24 (13 nonobese and 11 obese) postmenopausal and 44 (15 obese and 29 non obese) premenopausal women. Plasma concentration of PAI-1 ag,PAI-1 activity, fibrinogen, tPA-1 akt, tPA ag, von Willebrand factor, fasting plasma insulin, and the lipid pattern (cholesterol, TG, HDL, LDL) was measured. The body fat distribution was assessed by waist-to-hip circumference measuring. RESULTS: Postmenopausal subjects had higher PAI-1 act. and PAI-1 ag (p < 0.05 and 0.001 respectively), vWf and lower ATIII. There was direct correlation between PAI-1 act., Fibrinogen and BMI in both groups of patients together and in premenopausal group PAI-1 act correlated directly and tPA ag/act. indirectly with plasma insulin concentrations. CONCLUSIONS: Plasma concentrations of the pro-thrombotic factors are increased in obese and postmenopausal women and correlate directly with BMI and indirectly with plasma insulin concentrations. Plasma concentrations of anti thrombotic factors indirectly correlated with WHR and with plasma insulin concentrations.     

Microsatellite instability (MSI) and MLH1 and MSH2 protein expression analysis in postmenopausal women with sporadic endometrial cancer

Microsatellite instability (MSI) seems to be important for the development of various human cancers including sporadic endometrial cancer. The aim of this study was evaluation of microsatellite instability in 60 postmenopausal women with endometrial cancer in DNA samples obtained from cancer tissue and blood of the same patients. Control DNA was obtained from normal endometrial tissue (n = 70). MSI was studied at five loci containing single- or dinucleotide repeat sequences and mapping to different chromosomal locations: BAT-25 (at locus 4q12), BAT-26 (2p16), D2S123 (2p16-p21), D5S346 (5q21-q22) and D17S250 (171q11.2-q12). No differences in the MSI frequencies between blood and cancer tissue obtained from patients were detected. The microsatellite instability status was significantly higher in endometrial cancer tissue [21/60 (35%)] compared to control [8/70 (11%)] (p < 0.05). There were significant differences between MSI presence in the subgroups assigned to the histological grades (p < 0.05). The lack of association between MLH1 and MSH2 protein expression and MSI in endometrial cancer samples was observed. The results suggest that the microsatellite instability seems to be important in the development of sporadic endometrial cancer.     

Polymorphisms of DNA Repair Genes in Endometrial Cancer

Endometrial cancer belongs to the commonest malignancy in females. Its development may be associated with the high exposure of endometrium to exo- and endogenous estrogens. Estrogens produce DNA bulky adducts and oxidative base damages which are removed in nucleotide excision repair (NER) and base excision repair (BER) pathways. The reaction of endometrial cells to DNA damage may be crucial for their susceptibility to cancer transformation. This reaction is executed mainly by DNA repair, which can be modulated by the variability in the genes encoding DNA repair proteins. In this report we genotyped 4 polymorphisms of 3 DNA repair genes in 94 endometrial cancer patients and 114 age-matched cancer-free women using RFLP-PCR. The following polymorphisms were studied: p.Arg194Trp, p.Arg399Gln of the XRCC1 gene, p.Ser326Cys of the hOGG1 gene and p.Lys751Gln of the ERCC2 gene. We found an association between the ERCC2 751Gln variant and endometrial cancer occurrence (OR 3.95; 95?% CI 1.88-8.31). Gene-gene interaction between the ERCC2 751Gln and XRCC1 194Trp variants also increased the risk of endometrial cancer (OR 4.41; 95?% CI 2.01-9.67). The risk in the carriers of the ERCC2 751Gln variant was increased by a positive cancer history in first degree relatives (OR 4.97; 95?% CI 1.98-12.48). The risk of endometrial cancer was not alter by polymorphism p.Ser326Cys of the hOGG1 gene. The 751 Lys/Gln polymorphism of the ERCC2 gene may be linked with endometrial cancer occurrence and its effect can be potentiated by variants of the XRCC1 gene or first degree relatives positive cancer history.     

New views on hyperplastic endometrial lesions classification--endometrial intraepithelial neoplasia (EIN)

The aim of the study was to present a new EIN classification of premalignant endometrial lesions. The diagnosis of precancerous disease of the endometrium remains non-standardized because the most widely used World Health Organisation classification is a poorly reproducible system, which does not specify objective architectural criteria for each category of hyperplasia and does not correspond to an appropriate clinical management (undertreatment, overtreatment of the lesions). The new proposed EIN diagnostic schema, based on integrated morphological, genetic molecular, objective histomorphometric (D-score) and clinical outcome studies, divides endometrial lesions into three categories: benign hyperplasia, endometrial intraepithelial neoplasia, and cancer.