The Diagnostic of Cervical Carcinoma: From Theory to Practice

Human papillomaviruses (HPV) are naked particles composed of 72 subunits, each formed by 2 structural proteins designated L1 and L2 (L = late). HPV does not grow outside of squamous epithelium cells, in which it infects the suprabasal prickle cell layer. The viral double-stranded DNA (vDNA) has about 8 kilobase pairs (kbp) and also encodes several non-structural polypeptides, designated E1–E7 (E = early). At least 3 early oncoproteins (E5, E6, and E7) induce host cell proliferation, driving them into permanent division. During long-term latency, the circularized HPV DNA may get integrated into the host cell DNA molecule. The circular HPV DNA is then interrupted, usually within the E2 open reading frame (ORF), which then cannot exert its regulatory (feedback) effect on the early gene expression. The increased expression of E6/E7 proteins seriously affects the regulation of host cell division mainly via dysregulation of the functions of p53 and Rp proteins. HPV infects the female genital tract representing the main cause of cervical dysplasia and subsequent squamous cell carcinoma (SCa). The HPV isolates exist mainly in the form of amplified DNAs; based on the similarity and/or variations (dissimilarity) of their L1 capsid polypeptide sequence, 96 human genotypes were included into five genera of the Papillomaviridae family. The clinically most important genotypes that cause lesions at mucosal membranes and/or on the skin, belong mainly to the Alphapapillomavirus genus. The genotypes, associated with severe dysplastic changes and/or cervical cancer, were designated as high risk (HR-HPV). The prevalence of the integrated HPV DNA sequence over the episomal molecules appears in a proportion smears-graded LSIL (low-grade squamous intraepithelial lesion). Later on, carrier cells revealing the integrated HPV genome expression the oncoproteins (E6/E7) clearly prevail especially in HSIL (high-grade squamous intraepithelial lesion) smears and in the cervical cancer itself. What is crucial for the modern diagnostic of cervical dysplasia, is the p16/INK4A (inhibitor kinase) polypeptide, which itself represents a form of cell defense against the viral oncogenic proteins. The p16 antigen shows a continuous parabasal staining in the CIN I lesion. If dysplastic cells occupy at least one half (or two thirds) of squamous epithelium, the designation CIN II/HSIL is correct, and at the stage of CIN III/HSIL, dysplastic cells replace the entire squamous epithelium. Another frequently used immunohistochemical marker of intraepithelial cervical dysplasia so far is the Ki-67 antigen, which occurs in the nuclei of proliferating and/or repeatedly dividing (immortalized) cells. Women revealing p16-positive ASCUS (atypical smear cells of unknown significance) as well as those showing LSIL (low-grade cytological changes) should be examined for the presence of the HPV DNA. The detection of HPV DNA alone, that is, in the absence of cytological screening, has a relatively lower prediction value, though the HR HPV positive DNA test in the absence of morphological alterations may in part predict the possible progression into malignancy. Nevertheless, only the combined cytological as well as molecular follow-up (cervical smear examined for cytology as well as for HPV DNA) is regarded for the most reliable diagnostic approach

Melatonin May Increase Anticancer Potential of Pleiotropic Drugs

Melatonin (N-acetyl-5-methoxytryptamine) is not only a pineal hormone, but also an ubiquitary molecule present in plants and part of our diet. Numerous preclinical and some clinical reports pointed to its multiple beneficial effects including oncostatic properties, and as such, it has become one of the most aspiring goals in cancer prevention/therapy. A link between cancer and inflammation and/or metabolic disorders has been well established and the therapy of these conditions with so-called pleiotropic drugs, which include non-steroidal anti-inflammatory drugs, statins and peroral antidiabetics, modulates a cancer risk too. Adjuvant therapy with melatonin may improve the oncostatic potential of these drugs. Results from preclinical studies are limited though support this hypothesis, which, however, remains to be verified by further research

Anticancer Activities of Thymus vulgaris L. in Experimental Breast Carcinoma In Vivo and In Vitro

Naturally-occurring mixtures of phytochemicals present in plant foods are proposed to possess tumor-suppressive activities. In this work, we aimed to evaluate the antitumor effects of Thymus vulgaris L. in in vivo and in vitro mammary carcinoma models. Dried T. vulgaris (as haulm) was continuously administered at two concentrations of 0.1% and 1% in the diet in a chemically-induced rat mammary carcinomas model and a syngeneic 4T1 mouse model. After autopsy, histopathological and molecular analyses of rodent mammary carcinomas were performed. In addition, in vitro evaluations using MCF-7 and MDA-MB-231 cells were carried out. In mice, T. vulgaris at both doses reduced the volume of 4T1 tumors by 85% (0.1%) and 84% (1%) compared to the control, respectively. Moreover, treated tumors showed a substantial decrease in necrosis/tumor area ratio and mitotic activity index. In the rat model, T. vulgaris (1%) decreased the tumor frequency by 53% compared to the control. Analysis of the mechanisms of anticancer action included well-described and validated diagnostic and prognostic markers that are used in both clinical approach and preclinical research. In this regard, the analyses of treated rat carcinoma cells showed a CD44 and ALDH1A1 expression decrease and Bax expression increase. Malondialdehyde (MDA) levels and VEGFR-2 expression were decreased in rat carcinomas in both the T. vulgaris treated groups. Regarding the evaluations of epigenetic changes in rat tumors, we found a decrease in the lysine methylation status of H3K4me3 in both treated groups (H3K9m3, H4K20m3, and H4K16ac were not changed); up-regulations of miR22, miR34a, and miR210 expressions (only at higher doses); and significant reductions in the methylation status of four gene promoters—ATM serin/threonine kinase, also known as the NPAT gene (ATM); Ras-association domain family 1, isoform A (RASSF1); phosphatase and tensin homolog (PTEN); and tissue inhibitor of metalloproteinase-3 (TIMP3) (the paired-like homeodomain transcription factor (PITX2) promoter was not changed). In vitro study revealed the antiproliferative and proapoptotic effects of essential oils of T. vulgaris in MCF-7 and MDA-MB-231 cells (analyses of 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) (MTS); 5-bromo-20-deoxyuridine (BrdU); cell cycle; annexin V/PI; caspase-3/7; Bcl-2; PARP; and mitochondrial membrane potential). T. vulgaris L. demonstrated significant chemopreventive and therapeutic activities against experimental breast carcinoma

Fatal alcohol intoxication in women: A forensic autopsy study from Slovakia

<p>Abstract</p> <p>Background</p> <p>Plenty of information related to alcoholism can be found in the literature, however, the studies have mostly dealt with the predominance of male alcoholism and data related to addiction in women are desperately scarce and difficult to find. Basic demographic data focusing on the impact of acute alcohol intoxication on the circumstances of death and social behaviour in the alcohol addicted female population are needed especially in the prevention of alcohol related mortality.</p> <p>Methods</p> <p>A retrospective forensic autopsy study of all accidental deaths due to alcohol intoxication over a 12-year period was performed in order to evaluate the locations, circumstances, mechanisms and causes of death.</p> <p>Results</p> <p>A sample of 171 cases of intoxicated women who died due to blood alcohol concentration (BAC) equal to or higher than 2 g/kg was selected. Among them 36.26% (62/171) of women died due to acute alcohol intoxication (AAI). We noted an increase in the number of deaths in women due to AAI from 2 in 1994 up to 5 in 2005 (an elevation of 150% between the years 1994-2005). The age structure of deaths in women due to BAC and AAI followed the Gaussian distribution with a dominant group of women aged 41-50 years (45.16% and 35.09% respectively). The most frequent place of death (98%) among women intoxicated by alcohol was their own home. The study suggests a close connection between AAI and violence against women.</p> <p>Conclusions</p> <p>The increasing number of cases of death of women suffering from AAI has drawn attention to the serious problem of alcoholism in women in the Slovak Republic during the process of integration into "western" lifestyle and culture.</p

Functional MRI and Diffusion Tensor Imaging of Brain Reorganization After Experimental Stroke

The potential of the adult brain to reorganize after ischemic injury is critical for functional recovery and provides a significant target for therapeutic strategies to promote brain repair. Despite the accumulating evidence of brain plasticity, the interaction and significance of morphological and physiological modifications in post-stroke brain tissue remain mostly unclear. Neuroimaging techniques such as functional MRI (fMRI) and diffusion tensor imaging (DTI) enable in vivo assessment of the spatial and temporal pattern of functional and structural changes inside and outside ischemic lesion areas. This can contribute to the elucidation of critical aspects in post-stroke brain remodeling. Task/stimulus-related fMRI, resting-state fMRI, or pharmacological MRI enables direct or indirect measurement of neuronal activation, functional connectivity, or neurotransmitter system responses, respectively. DTI allows estimation of the structural integrity and connectivity of white matter tracts. Together, these MRI methods provide an unprecedented means to (a) measure longitudinal changes in tissue structure and function close by and remote from ischemic lesion areas, (b) evaluate the organizational profile of neural networks after stroke, and (c) identify degenerative and restorative processes that affect post-stroke functional outcome. Besides, the availability of MRI in clinical institutions as well as research laboratories provides an optimal basis for translational research on stroke recovery. This review gives an overview of the current status and perspectives of fMRI and DTI applications to study brain reorganization in experimental stroke models

Ethnic disparities in breast cancer between Central Europe Caucasian women of Slavic origin and Middle East Turkish subjects

The biological, cultural, behavioral and sociodemographic differences across populations modulate breast cancer profile among races or ethnics. Following this, we aimed to identify differences in breast cancer epidemiology, histopathology, and clinical presentation from representatives of central Europe (Slovakia) and Middle-East countries (Turkey) to point on ethnic disparities in cancer biology