Dietary phytochemicals as the potential protectors against carcinogenesis and their role in cancer chemoprevention.

Health-threatening consequences of carcinogen exposure are mediated via occurrence of electrophiles or reactive oxygen species. As a result, the accumulation of biomolecular damage leads to the cancer initiation, promotion or progression. Accordingly, there is an association between lifestyle factors including inappropriate diet or carcinogen formation during food processing, mainstream, second or third-hand tobacco smoke and other environmental or occupational carcinogens and malignant transformation. Nevertheless, increasing evidence supports the protective effects of naturally occurring phytochemicals against carcinogen exposure as well as carcinogenesis in general. Isolated phytochemicals or their mixtures present in the whole plant food demonstrate efficacy against malignancy induced by carcinogens widely spread in our environment. Phytochemicals also minimize the generation of carcinogenic substances during the processing of meat and meat products. Based on numerous data, selected phytochemicals or plant foods should be highly recommended to become a stable and regular part of the diet as the protectors against carcinogenesis.

Colposcopic scoring indexes in the evaluation of cervical lesions with the cytological result of atypical squamous cells, cannot exclude high-grade lesion.

AIM: Colposcopic indexes including Reid index and Swede score were developed to make the colposcopy more objective. The aim of our study was to evaluate the significance of colposcopic indexes in the evaluation of ASC-H cervical lesions. METHODS: We carried out a cross-sectional study in the Clinic of Obstetrics and Gynecology between January 2013 and December 2018. The study included 535 women, from which 66 women had a cytological result ASC-H. Scoring of all colposcopic findings was assessed according to Reid modified index and Swede score and a composite score was determined. Frequency distributions were compared using χ2 /Fisher exact test. Spearman rank correlation coefficient was computed between RCI and Swede score. RESULTS: Sensitivity, specificity, positive and negative predictive value and positive likelihood ratio of modified Reid colposcopic index at a cutoff of ≥4 for the detection of HSIL+ lesions were: 86.11% (95% CI: 70.5-95.3), 83.33% (95% CI: 65.3-94.4), 86.11% (95% CI: 69.7-94.8), 83.33% (95% CI: 64.5-93.7) and 5.17 (95% CI: 2.3-11.6). Swede score with the cutoff value ≥5 showed comparable results to modified Reid index with the increased sensitivity: 94.44% (95% CI: 81.3-99.3). CONCLUSION: ASC-H category represents the trickiest cytological diagnosis as it is underlined with the high risk of severe cervical dysplasia. Evaluating the cervical lesion by the use of colposcopic indices helps the gynecologist to objectively evaluate all the pathologies of uterine cervix. Swede score with the cutoff value 8 also enables a 'see and treat' option in management of atypical squamous cells, cannot exclude high-grade lesions.

DNA Methylation Status in Cancer Disease: Modulations by Plant-Derived Natural Compounds and Dietary Interventions.

The modulation of the activity of DNA methyltransferases (DNMTs) represents a crucial epigenetic mechanism affecting gene expressions or DNA repair mechanisms in the cells. Aberrant modifications in the function of DNMTs are a fundamental event and part of the pathogenesis of human cancer. Phytochemicals, which are biosynthesized in plants in the form of secondary metabolites, represent an important source of biomolecules with pleiotropic effects and thus provide a wide range of possible clinical applications. It is well documented that phytochemicals demonstrate significant anticancer properties, and in this regard, rapid development within preclinical research is encouraging. Phytochemicals affect several epigenetic molecular mechanisms, including DNA methylation patterns such as the hypermethylation of tumor-suppressor genes and the global hypomethylation of oncogenes, that are specific cellular signs of cancer development and progression. This review will focus on the latest achievements in using plant-derived compounds and plant-based diets targeting epigenetic regulators and modulators of gene transcription in preclinical and clinical research in order to generate novel anticancer drugs as sensitizers for conventional therapy or compounds suitable for the chemoprevention clinical setting in at-risk individuals. In conclusion, indisputable anticancer activities of dietary phytochemicals linked with proper regulation of DNA methylation status have been described. However, precisely designed and well-controlled clinical studies are needed to confirm their beneficial epigenetic effects after long-term consumption in humans.

Why the Gold Standard Approach by Mammography Demands Extension by Multiomics? Application of Liquid Biopsy miRNA Profiles to Breast Cancer Disease Management.

In the global context, the epidemic of breast cancer (BC) is evident for the early 21st century. Evidence shows that national mammography screening programs have sufficiently reduced BC related mortality. Therefore, the great utility of the mammography-based screening is not an issue. However, both false positive and false negative BC diagnosis, excessive biopsies, and irradiation linked to mammography application, as well as sub-optimal mammography-based screening, such as in the case of high-dense breast tissue in young females, altogether increase awareness among the experts regarding the limitations of mammography-based screening. Severe concerns regarding the mammography as the "golden standard" approach demanding complementary tools to cover the evident deficits led the authors to present innovative strategies, which would sufficiently improve the quality of the BC management and services to the patient. Contextually, this article provides insights into mammography deficits and current clinical data demonstrating the great potential of non-invasive diagnostic tools utilizing circulating miRNA profiles as an adjunct to conventional mammography for the population screening and personalization of BC management.

The role of dietary phytochemicals in the carcinogenesis via the modulation of miRNA expression.

PURPOSE: Phytochemicals are naturally occurring plant-derived compounds and some of them have the potential to serve as anticancer drugs. Based on recent evidence, aberrantly regulated expression of microRNAs (miRNAs) is closely associated with malignancy. MicroRNAs are characterized as small non-coding RNAs functioning as posttranscriptional regulators of gene expression. Accordingly, miRNAs regulate various target genes, some of which are involved in the process of carcinogenesis. RESULTS: This comprehensive review emphasizes the anticancer potential of phytochemicals, either isolated or in combination, mediated by miRNAs. The ability to modulate the expression of miRNAs demonstrates their importance as regulators of tumorigenesis. Phytochemicals as anticancer agents targeting miRNAs are widely studied in preclinical in vitro and in vivo research. Unfortunately, their anticancer efficacy in targeting miRNAs is less investigated in clinical research. CONCLUSIONS: Significant anticancer properties of phytochemicals as regulators of miRNA expression have been proven, but more studies investigating their clinical relevance are needed.

Vaginal dryness: individualised patient profiles, risks and mitigating measures.

Vaginal dryness (VD) affects both pre- and postmenopausal women at any age. Since the hormonal regulation changes during the climacteric period are considered as being the main course of the VD, affected women prefer not to talk about the problem. However, the problem does exist, and unfortunately if any, relatively minor group in the population possesses the health literacy at sufficient level to understand that VD is a suboptimal health condition which carries a multi-factorial character. Thereby, some of the contributing factors are clearly preventable and, therefore, if treated properly, have a potential to milden the VD. Current chapter demonstrates specific signs and symptoms of Flammer syndrome in women suffering from vaginal dryness, although individualised patient profiles clearly discriminate between pre- and postmenopausal women regarding the subgroup-specific symptoms. Noteworthy, about 20% of the VD patients involved in the study notify a delayed or even impaired wound healing observed for themselves over a couple of years. Optimising modifiable risk factors accompanying FS phenotype at the level of primary prevention is strongly recommended. Individualised patient profiles provide important information for VD mitigating measures tailored to the person. Further, future projects should essentially deal with the complexity of vulvar-vaginal dryness as part of the Sicca syndrome in individuals with FS phenotype, in order to prevent genital female cancers which may occur at any age. In contrast to the human papilloma virus as possible trigger of the disease, the role of the vulvar-vaginal dryness as an important risk factor is strongly underestimated in currently applied diagnostic and treatment approaches.

Dietary Phytochemicals Targeting Cancer Stem Cells.

There is an increasing awareness of the importance of a diet rich in fruits and vegetables for human health. Cancer stem cells (CSCs) are characterized as a subpopulation of cancer cells with aberrant regulation of self-renewal, proliferation or apoptosis leading to cancer progression, invasiveness, metastasis formation, and therapy resistance. Anticancer effects of phytochemicals are also directed to target CSCs. Here we provide a comprehensive review of dietary phytochemicals targeting CSCs. Moreover, we evaluate and summarize studies dealing with effects of dietary phytochemicals on CSCs of various malignancies in preclinical and clinical research. Dietary phytochemicals have a significant impact on CSCs which may be applied in cancer prevention and treatment. However, anticancer effects of plant derived compounds have not yet been fully investigated in clinical research.

Methylation of CADM1 and MAL together with HPV status in cytological cervical specimens serves an important role in the progression of cervical intraepithelial neoplasia.

Cervical cancer (CC) is the second most common type of cancer affecting the female population. The development of CC takes several years, and involves a precancerous stage known as cervical intraepithelial neoplasia (CIN). A key factor in the development of disease is the human papillomavirus (HPV) infection, which initiates carcinogenesis. Furthermore, CC is also impacted by epigenetic changes such as DNA methylation, which causes activation or exclusion of certain genes, and the hypermethylation of cytosines in promoters, thereby switching off previously active genes. The majority of DNA methylation events occur at cytosine-guanine nucleotides, which in the human genome are known as CpG islands. The aim of the present study was to investigate the methylation levels in intronic sequences of the two tumor suppressor genes cell adhesion molecule 1 (CADM1) and T-lymphocyte maturation associated protein (MAL) using cytological samples and to identify potential biomarkers involved in CIN by pyrosequencing. DNA was isolated from cervical smears from patients with CINs, with healthy patients serving as a control group. Samples were converted by treatment with sodium bisulfite and subsequent pyrosequencing to detect the methylation status of the selected genes. The presence of HPV DNA infection analyzed by the polymerase chain reaction, was detected in each sample. Of the total number of samples (n=91), the present study confirmed the presence of one or two high-risk subtypes of HPV in 39 cases (42.85%) and HPV infection was significantly associated with CIN2+ lesions. For the two genes (MAL and CADM1) the present study confirmed that the median methylation was significantly higher in HPV positive patients [P=0.0097, 95% confidence interval (CI): (-0.030, -0.003)/P=0.0024, 95% CI: (-0.06, -0.01)] when compared with patients negative for HPV DNA infection, and the average methylation was demonstrated to be increased with the degree of cervical lesion. The present study used logistical regression to model the dependence between the case/control statuses (control group vs. Dg. 1-4). The area under the curve values for MAL were: 84% for cervical inflammation, 71% for CIN1, 73.4% for CIN2+ and 77% for squamous cell carcinoma (SCC); and for CADM1 were: 88.6% for cervical inflammation, 68% for CIN1, 80% for CIN2+ and 89% for SCC. The present study confirmed that there were statistically significant differences between the methylation levels of individual CpGs and significantly higher median methylation in patients positive for HPV16/18. CADM1 exhibited higher levels of methylation in almost every study group when compared with MAL during the transition of CIN and appeared to be a promising biomarker for future study.

Current approaches in the clinical management of pregnancy-associated breast cancer-pros and cons.

Malignancies are one of the leading causes of mortality in women during their reproductive life. Treatment of gynecological malignant tumors during pregnancy is possible but not simple, since it creates a conflict between care of the mother and the fetus. BC is the most prevalent malignancy diagnosed in pregnancy, ranking up to 21% of all pregnancy-related malignancies. Due to its stets increasing prevalence, aggressive cancer subtype, and severe ethical and psychological aspects linked to the disease, experts raise an alarm for an acute necessity to improve the overall management of the PABC-the issue which has strongly motivated our current paper. Comprehensive research data and clinical experience accumulated in recent years have advanced our understanding of the disease complexity. PABC treatment must be individualized with an emphasis on optimal care of the mother, while observing standard treatment protocols with regard to safety of the fetus. Treatment protocols should be elaborated based on the individualized patient profile, bearing in mind the acute danger to the mother, maximizing the therapy efficacy and minimizing harmful effects to the fetus. Complex consulting on treatment options, their impacts on pregnancy and potential teratogenic effects requires tight "doctor-patient" collaboration. Complications that may arise due to the treatment of breast cancer in pregnancy require a multiprofessional expertise including oncologists, neonatologists, perinatologists, obstetricians, teratologists, and toxicologists, and an extensive psychological support throughout the pregnancy and after giving birth. Thereby, specifically psychological aspects of PABC diagnosis and follow-up are frequently neglected, being not yet adequately explored in the entire disease management approach. Herewith, we update the status quo regarding the currently available diagnostic modalities, complex treatment algorithms, and novel clinical approaches which altogether argue for an urgent necessity of a paradigm shift moving away from reactive to predictive, preventive, and personalized medical approach in the overall management of PABC meeting the needs of young populations, persons at high risk, affected patients, and families as the society at large.

Methylation status of KLF4 and HS3ST2 genes as predictors of endometrial cancer and hyperplastic endometrial lesions.

Endometrial carcinoma is one of the most common tumours in developed countries. In addition to the active role of genetic factors, epigenetic changes also have an important effect. The present study analysed the methylation status of kruppel like factor 4 (KLF4) and heparan sulfate­glucosamine 3­sulfotransferase 2 (HS3ST2) genes in three endometrial tissue types for carcinoma prediction. The sample comprised 91 women with histologically­confirmed endometrial carcinoma (64.16±9.64 years old), 36 women with hyperplasia (53.39±9.64 years old) and 45 with no signs or symptoms of malignancy (48.53±11.11 years old). The CpG dinucleotide methylation levels were examined by quantitative pyrosequencing, and the discrimination accuracy of the model was calculated using the Random Forest classification algorithm of the area under the ROC curve (AUC). The mean values of KLF4 and HS3ST2 methylation indices were 23.83±11.39 and 8.52±2.57 in the control samples; 30.40±8.52 and 33.76±20.66 in hyperplasia and 34.72±10.79 and 34.49±18.39 in the cancerous tissues. Multinomial logistic regression indicated that the HS3ST2 CpG1 methylation status is a predictor of hyperplasia (P<0.05) and that the KLF4 CpG2 dinucleotide can predict carcinoma formation (P<0.001). The AUC value of 0.95 indicates high discrimination accuracy of the CpG nucleotides methylation status model between the controls and the two other diagnoses. The results of the present study establish the likelihood that aberrations in KLF4 and HS3ST2 gene methylation levels are important in the development of endometrial hyperplasia and carcinoma, with hyperplasia an intermediate step between healthy and tumour tissues.