István Ember

Differentiation-dependent expression of signal transducers and activators of transcription (STATs) might modify responses to growth factors in the cancers of the head and neck

Overexpression of the epidermal growth factor receptor (EGFR) in the cancers of the head and neck is well demonstrated. In addition, copy numbers of the EGFR mRNA were significantly higher in poorly differentiated tumors than in tumors that had a differentiated phenotype. Studies by others also showed that the constitutively activated signal transducer and activator of transcription-3 (STAT3), but not STAT1, is required for EGFR-mediated cell growth. Our aim was to reveal if STAT expression is differentiation-dependent and thus, might respond to exogenous stimuli in a differentiation-dependent manner. Both reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry revealed that expression of STAT1 was high in well/moderately differentiated tumors in vivo. In contrast, STAT3 was expressed in poorly differentiated tumors. In vitro experiments showed that differentiated primary oral keratinocytes expressed higher levels of STAT1, but lower levels of STAT3 than did their undifferentiated counterparts. Epidermal growth factor treatment of oral keratinocytes with various degrees of differentiation showed the maximal induction of cyclin D1 in undifferentiated cells. Our findings suggest that the level of differentiation might modulate the outcome of EGFR signaling (i.e. cyclin D1 transcription), due to the differentiation-associated intracellular balance of transcriptional regulators (STAT1 versus STAT3).

Investigation of c-myc and K-ras amplification in renal clear cell adenocarcinoma.

Tumour DNA samples isolated from 36 patients with renal clear cell carcinoma were investigated for c-myc and K-ras amplification, using a quantitative dot-blot hybridization. The characteristic clinical and histological parameters involved in the statistical analysis were age, sex, histological grade of the tumour, the TNM staging system, tumour size and weight, vascular invasion and the quality of life. The goal of the study was to estimate the prevalence as well as the prognostic value of the amplification of the oncogenes in question. Amplified c-myc (2.47-fold on the average) was found in three specimens (8.3%), showing slight correlation with intravasation (P > 0.05, n.s.). K-ras amplification (2.93-fold) detected in six tumours (16.6%) was shown to significantly correlate with both histological grade (2.2 vs. 1.8, P < 0.05) and tumour size (15 vs. 8 cm, P < 0.05). In cases with amplified K-ras also lymph node involvement was somewhat more frequent (P > 0.05, n.s.). No coamplification of these oncogenes was observed. The results of the study suggest that K-ras amplification may account for a more rapid progression of the disease.

The effect of an organized, nationwide breast cancer screening programme on non-organized mammography activities

Objectives To analyse the effect of an organized, nationwide breast cancer screening programme on non-organized mammography activities in Hungary. Setting The nationwide dataset of the Hungarian National Health Insurance Fund Administration covering the years 2000-2005. Methods Data derived from the nationwide database of the Hungarian National Health Insurance Fund Administration. The study includes all women undergoing mammography before (2000-2001) and after (2002-2003/2004-2005) the introduction of organized screening. Results The number of women having non-organized (opportunistic/diagnostic) mammograms was around 250,000 in 2000-2001, but increased to 350,000 in 2005. In the age group 45-64 years in 2000-2001, only 27.4% of all women undergoing mammography were examined within locally-organized programmes. After the introduction of the nationwide programme, this percentage increased to 61.0% in 2002-2003, and 56.3% in 2004-2005. After the introduction of the nationwide organized programme (2002-2003), the proportion of organized screening mammographics remained among the highest in county Hajdú-Bihar (78.4%) and Zala (88.3%) and increased significantly in county Vas (87.7%). Conclusion The introduction of an organized nationwide screening programme in Hungary resulted in increases in the number of screening mammographics, and also of non-organized mammographics. Although the ratio of organized screening versus non-organized mammography changed in favour of screening mammographics, there are large within-country differences between counties.

Allelic polymorphism of GSTM1 and NAT2 genes modifies dietary-induced DNA damage in colorectal mucosa.

Typically, cancer is caused by the interaction of genetic and environmental factors. In colorectal carcinogenesis, diet and nutritional habits are the most important external risk determinants. Allelic polymorphisms of certain metabolizing enzymes may have an influence on cancer risk by modifying the concentration of active carcinogenic compounds in the body. In the present study we investigated the interaction between nutritional and genetic susceptibility factors in human colon carcinogenesis. Healthy volunteers were divided into four groups, based on allelic polymorphisms of N-acetyltransferase 2 and glutathione-S-transferase M1 enzymes. Comet assay was used to determine the level of DNA strand breaks in exfoliated colorectal mucosal cells, following a 2-day vegetarian diet, and after switching to a 2-day ‘high-meat’ diet. The ‘high-meat’ diet statistically significantly increased the amount of single-strand breaks in rapid acetylators and among individuals with a GSMT1+ genotype, while it caused only a slight and not significant increase in the other groups. Our study emphasizes the importance of using susceptibility markers in cancer epidemiology, since environmental effects are strongly modified by these genetic factors.

Difficulties in the prevention of cervical cancer: Adults’ attitudes towards HPV vaccination 3 years after introducing the vaccine in Hungary

Cervical cancer is one of the most prevalent gynaecological malignancies worldwide. The Hungarian incidence and mortality of this disease take the 4th-5th places within the European Union. A survey including 785 male and female adults was conducted to assess the knowledge and attitudes concerning HPV vaccination. We focused on the difficulties of the primary and secondary prevention of cervical cancer and examined some potential sociodemographic predictors of HPV vaccine acceptability. Our findings have identified some important issues like: incomplete knowledge, intense distrust and financial concerns. Almost half of the college students (45.6%) are unaware of HPV infections. We confirmed previous findings that older age and female gender correlates with better knowledge on STDs, including HPV. We found that greater exposure to health information comes with better knowledge and more positive attitudes towards vaccination. One quarter of survey respondents do not believe that cervical cancer may be prevented by vaccination. More than half of the adults do not trust national health care system and the preparedness of Hungarian doctors. General attitudes towards vaccination are broadly positive, 80% of survey participants had expressed desire towards HPV vaccination, however if there was a need to pay for the vaccination the willingness would decrease by half. Primary prevention through HPV-focused educational programs, clear communication and financial support would be important for public health to reduce the high incidence and mortality of cervical cancer in Hungary in the future.

Suppression of growth by all-trans retinoic acid requires prolonged induction of interferon regulatory factor 1 in cervical squamous carcinoma (SiHa) cells.

ABSTRACT All-trans retinoic acid (ATRA) suppresses growth of cervical dysplasias in vivo, although the sensitivity to retinoids is frequently lost during cervical carcinogenesis. It has been suggested that prolonged treatment or use of higher doses of retinoids might offer favorable response rates. We found SiHa cervical squamous carcinoma cells that were virtually resistant to ATRA-induced growth-inhibitory effects at physiological doses (10−7 to 10−6 M) to be more responsive at pharmacological doses (10−5 to 10−4 M). The growth inhibition by high-dose (10−4 M) ATRA was associated with a sustained activation of interferon regulatory factor 1 (IRF-1), while a low dose (10−6 M) of ATRA activated IRF-1 only transiently. Antisense IRF-1 inhibited the high-dose (10−4 M), ATRA-mediated growth arrest; forced expression of IRF-1 caused a significant reduction in cell growth. High-dose (10−4 M) ATRA increased binding of NF-κB and STAT1 proteins to sequences that originated from the IRF-1 promoter region, while low-dose (10−6 M) ATRA induced only NF-κB binding. A delayed tyrosine phosphorylation of the signal transducer and activator of transcription-1 (STAT1) was observed after high-dose (10−4 M) but not low-dose (10−6 M) ATRA treatment. In agreement with this, induction of IRF-1 mRNA by ATRA was only modest and transient in a STAT1 knockout cell line, suggesting the importance of STAT1 in sustained IRF-1 expression. Our data showed that ATRA is capable of inducing dose-dependent cellular changes, which might be appropriate to overcome resistance to retinoids that frequently develops during cervical carcinogenesis.

Deuterium Depleted Water Effects on Survival of Lung Cancer Patients and Expression of Kras, Bcl2, and Myc Genes in Mouse Lung

Although advances in cancer therapies continue to develop, the shortness of the survival of lung cancer patients is still disappointing. Therefore, finding new adjuvant strategies is within the focus of cancer cure. Based on observations that deuterium depletion inhibits the growth of cancer cell lines and suppresses certain proto-oncogenes, we have conducted a clinical study in 129 patients with small cell and nonsmall cell lung cancers who consumed deuterium-depleted drinking water (DDW) as a nontoxic agent in addition to conventional chemotherapy and radiotherapy. Median survival time (MST) was 25.9 mo in males and 74.1 mo in female patients; the difference between genders was statistically significant (p < 0.05). Median survival of subjects with brain metastasis was 27.1 mo. Cumulative 5-yr survival probabilities were 19%, 52%, and 33% in males, females, and all patients with brain metastasis, respectively. Gene expression analysis in mouse lung indicated that DDW attenuates 7,12-dimethylbenz(a)anthracene (DMBA)-induced expression of Bcl2, Kras, and Myc in females. In conclusion, DDW counteracts the DMBA-induced overexpression of Bcl2, Kras and Myc genes in mouse lung, and it may extend survival of lung cancer patients as a nontoxic anticancer dietary supplement, especially for women with tumors overexpressing cancer-related genes, because MST of DDW-consuming group was 2–4 times longer than it is generally observed in lung cancer patients.

The effect of fenugreek on the gene expression of arachidonic acid metabolizing enzymes

The main bioactive compounds of Trigonella foenum graecum L. (fenugreek) seeds are protodioscin, trigoneoside, diosgenin and yamogenin, which have anticarcinogenic potency through inhibition of cell proliferation and inhibition of prostaglandin synthesis.

Chemopreventive Effect of Panax ginseng

Asian ginseng (Panax ginseng C. A. Meyer) has been used in Chinese medicine for two thousand years. The root of ginseng contains several saponins (ginsenosides) which are biologically active compounds. Individual ginsenosides suppress tumor cell growth, induce cell differentiation, regulate apoptosis and inhibit metastasis formation. The aim of this study was to evaluate its chemo‐preventive effects in an animal test model, through its regulatory effects on apoptosis and the cell cycle.

Effects of cytochrome P450 1A1 and uridine-diphosphate-glucuronosyltransferase 1A1 allelic polymorphisms on the risk of development and the prognosis of head and neck cancers.

We studied the effect of allelic polymorphisms of cytochrome P450 1A1 (CYP1A1) and uridine-diphosphate-glucuronosyltransferase 1A1 (UGT1A1) on the risk of development of head and neck cancers and overall survival. One hundred and forty-two head and neck cancer patients (48 with laryngeal, 42 with hypopharyngeal and 52 with mesopharyngeal tumours) were included in the study. The control group (150 individuals) included volunteers without malignant tumours. There was no statistically significant difference in age, sex distribution, or smoking habits between the two groups. The participants were genotyped for the CYP1A1 isoleucine/valine (Ile/Val) polymorphism in exon 7 and for the UGT1A1 thymine–adenine-repeat polymorphism (*1 and *28 alleles) in the promoter region of the gene. The effect of the allelic variants on survival was studied using the log-rank test, whereas the &khgr;2-test and odds ratios (OR) with 95% confidence intervals (CI) were used to compare the allelic frequencies between patients and controls. Our study revealed a significant link between the occurrence of the CYP1A1 Ile/Val, Val/Val (OR: 1.72, 95% CI: 1.02–2.96, P=0.044) and UGT1A1*28 alleles (OR: 2.74, 95% CI: 1.45–5.18, P=0.002) and an increased risk of head and neck cancers. These alleles decreased the duration of survival significantly (P=0.018 and 0.006). The survival was significantly more strongly reduced when the two high-risk alleles were carried simultaneously (OR: 2.149, 95% CI: 1.111–4.157, P=0.001). Our results suggest that the use of the CYP1A1 Ile/Val and Val/Val variants and UGT1A1*28 as biomarkers can aid risk assessment while their prognostic value can aid planning of individual therapy.