Wirginia Likus

Cancer stem cells, cancer-initiating cells and methods for their detection.

The cancer stem cell (CSC) hypothesis considers CSCs as the main culprits of tumor initiation, propagation, metastasis and therapy failure. CSCs represent a minority subpopulation of cells within a tumor. Their detection, characterization and monitoring are crucial steps toward a better understanding of the biological roles of these special cells in the development and propagation of tumors which, in turn, improves clinical reasoning and treatment options. Nowadays, in vitro and in vivo assays are available that address the self-renewal and differentiation potential of CSCs, and advanced in vivo molecular imaging technology facilitates the detection and provides an unprecedented in vivo observation platform to study the behavior of CSCs in their natural environment. Here, we provide a brief overview of CSCs and describe modern cellular models and labeling techniques to study and trace CSCs.

Could drugs inhibiting the mevalonate pathway also target cancer stem cells

Understanding the connection between metabolic pathways and cancer is very important for the development of new therapeutic approaches based on regulatory enzymes in pathways associated with tumorigenesis. The mevalonate cascade and its rate-liming enzyme HMG CoA-reductase has recently drawn the attention of cancer researchers because strong evidences arising mostly from epidemiologic studies, show that it could promote transformation. Hence, these studies pinpoint HMG CoA-reductase as a candidate proto-oncogene. Several recent epidemiological studies, in different populations, have proven that statins are beneficial for the treatment-outcome of various cancers, and may improve common cancer therapy strategies involving alkylating agents, and antimetabolites. Cancer stem cells/cancer initiating cells (CSC) are key to cancer progression and metastasis. Therefore, in the current review we address the different effects of statins on cancer stem cells. The mevalonate cascade is among the most pleiotropic, and highly interconnected signaling pathways. Through G-protein-coupled receptors (GRCP), it integrates extra-, and intracellular signals. The mevalonate pathway is implicated in cell stemness, cell proliferation, and organ size regulation through the Hippo pathway (e.g. Yap/Taz signaling axis). This pathway is a prime preventive target through the administration of statins for the prophylaxis of obesity-related cardiovascular diseases. Its prominent role in regulation of cell growth and stemness also invokes its role in cancer development and progression. The mevalonate pathway affects cancer metastasis in several ways by: (i) affecting epithelial-to-mesenchymal transition (EMT), (ii) affecting remodeling of the cytoskeleton as well as cell motility, (iii) affecting cell polarity (non-canonical Wnt/planar pathway), and (iv) modulation of mesenchymal-to-epithelial transition (MET). Herein we provide an overview of the mevalonate signaling network. We then briefly highlight diverse functions of various elements of this mevalonate pathway. We further discuss in detail the role of elements of the mevalonate cascade in stemness, carcinogenesis, cancer progression, metastasis and maintenance of cancer stem cells.

Glioblastoma and chemoresistance to alkylating agents: Involvement of apoptosis, autophagy, and unfolded protein response

ABSTRACT Despite advances in neurosurgical techniques and radio‐/chemotherapy, the treatment of brain tumors remains a challenge. This is particularly true for the most frequent and fatal adult brain tumor, glioblastoma (GB). Upon diagnosis, the average survival time of GB patients remains only approximately 15 months. The alkylating drug temozolomide (TMZ) is routinely used in brain tumor patients and induces apoptosis, autophagy and unfolded protein response (UPR). Here, we review these cellular mechanisms and their contributions to TMZ chemoresistance in brain tumors, with a particular emphasis on TMZ chemoresistance in glioma stem cells and GB.

CYP3A5∗3 and C3435T MDR1 Polymorphisms in Prognostication of Drug-Resistant Epilepsy in Children and Adolescents

Drug-resistant epilepsies still remain one of the most profound problems of contemporary epileptology. Several mechanisms of drug resistance are possible; among them, genetic factors have a prominent place. Much importance is attached to genes, which encode enzymes that metabolize antiepileptic drugs CYP 3A, which belong to the family of cytochromes P450 and the genome of multidrug resistance, such as multidrug resistance 1 (MDR1) that expresses P-glycoprotein (P-gp), a drug transporter protein. The aim of the study was to assess the relation between polymorphism of gene CYP3A5 and polymorphism C3435T of MDR1 gene with the occurrence of focal, drug-resistant epilepsy in children and youths up to 18 years of age. The study comprised 85 patients, and their age range was from 33 months to 18 years of age, suffering from epilepsy, partly responding well to treatment, partly drug resistant. The polymorphism of both genes has been analysed using the PCR-RFLP method. The study failed to corroborate association between polymorphism CYP3A5∗3 and C3435T polymorphism in MDR1 gene and pharmacoresistant epilepsy. The results of our research do not confirm the prognostic value of the polymorphisms examined in the prognostication of drug resistance in epilepsies.

Cephalic Index in the First Three Years of Life: Study of Children with Normal Brain Development Based on Computed Tomography

Cephalic index is a highly useful method for planning surgical procedures, as well as assessing their effectiveness in correcting cranial deformations in children. There are relatively very few studies measuring cephalic index in healthy Caucasian young children. The aim of our study was to develop a classification of current cephalic index for healthy Caucasian children up to 3 years of age with normal brain development, using axial slice computer tomography performed with very thin slices (0.5 mm) resulting in more accurate measurements. 180 healthy infants (83 females and 97 males) were divided into 5 age categories: 0–3, 4–6, 7–12, 13–24, and 25–36 months. The average value of cephalic index in children up to 3 years of age amounted to 81.45 ± 7.06. The index value in case of children under 3 months was 80.19, 4 to 6 months was 81.45, 7 to 12 months was 83.15, in children under 2 years was 81.05, and in children under 3 years was 79.76. Mesocephaly is the dominating skull shape in children. In this study, we formulated a classification of current cephalic indices of children with normal brain development. Our date appears to be of utmost importance in anthropology, anatomy forensic medicine, and genetics.

Polymorphism of ABCB1/MDR1 C3435T in Children and Adolescents with Partial Epilepsy is due to Different Criteria for Drug Resistance – Preliminary Results

Background The diagnosis of “drug resistance” in epilepsy can be defined and interpreted in various ways. This may be due to discrepant definitions of drug resistance to pharmacotherapy. The aim of our study was to investigate the relationship between C3435T polymorphism of the MDR1 gene and drug resistance in epilepsy with the consideration of 4 different criteria for qualification to groups sensitive and resistant to applied pharmacotherapy. Material/Methods Evaluation of C3435T polymorphism of MDR1/ABCB1 gene was conducted on a group of 82 white children and young adolescents up to 18 years old. While qualifying the patients to the group of sensitive or drug resistant, the following 4 definitions of drug resistance were applied: the ILAE’s, Appleton’s, Siddiqui’s, and Berg’s. Results A detailed analysis of genotypes of the MDR1 gene did not show any significant discrepancies between the groups of patients resistant and sensitive to antiepileptic drugs (AEDs) in 4 consecutive comparisons taking into consideration various criteria of sensitivity and resistance to pharmacotherapy. Conclusions The obtained results clearly confirm the lack of a connection between the occurrence of drug-resistant epilepsy and C435T polymorphism of the MDR1 gene irrespective of the definition of drug resistance applied to the patient.

Nasal Region Dimensions in Children: A CT Study and Clinical Implications

Atresias of nasal cavity, especially in young children, pose an essential problem in childrens otolaryngology. Only a few morphometric studies of nasal cavity concerning healthy neonates and young infants without nasal stenosis are available. Multislice computed tomography is a perfect tool enabling a precise evaluation of anatomic structures. The aim of this study was a complex morphometric evaluation of clinically important bone and mucosal structures of nasal cavity and examination of their dependence on age and sex in children up to 3 years of age. 180 children, age range 0–3 years, were divided into 5 age groups, and measurements of 18 distances between skeletal structures and between mucosal structures of nasal cavity were performed on their CT scans. A correlation between the widths of selected bone structures was examined. There were no statistically significant differences in analyzed morphometric parameters between adjacent age groups. The differences were statistically significant only between extreme age groups. There was a correlation between evaluated structures and age. Our results are a valuable supplement of nasal cavity morphometric data of young children. They may be useful in setting reference values of evaluated parameters in children and in diagnosis and planning of surgical treatment in childrens otolaryngology.

Inhibition of miR301 enhances Akt-mediated cell proliferation by accumulation of PTEN in nucleus and its effects on cell-cycle regulatory proteins

Micro-RNAs (miRs) represent an innovative class of genes that act as regulators of gene expression. Recently, the aberrant expression of several miRs has been associated with different types of cancers. In this study, we show that miR301 inhibition influences PI3K-Akt pathway activity. Akt overexpression in MCF7 and MDAMB468 cells caused downregulation of miR301 expression. This effect was confirmed by co-transfection of miR301-modulators in the presence of Akt. Cells overexpressing miR301-inhibitor and Akt, exhibited increased migration and proliferation. Experimental results also confirmed PI3K, PTEN and FoxF2 as regulatory targets for miR301. Furthermore, Akt expression in conjunction with miR301-inhibitor increased nuclear accumulation of PTEN, thus preventing it from downregulating the PI3K-signalling. In summary, our data emphasize the importance of miR301 inhibition on PI3K-Akt pathway-mediated cellular functions. Hence, it opens new avenues for the development of new anti-cancer agents preferentially targeting PI3K-Akt pathway.

Medical Aspects of Nanomaterial Toxicity

Nanosilver is the most popular and most studied nanomaterial, however, a family of nanomaterials is rapidly enlarging. They are used in various branches of industry and everyday life. In medicine new nanomaterials can be used either alone or in combi‐ nation with other “classical” drugs, e.g. cytostatic drugs or antibiotics. They can be also used as diagnostic agents. A development of nanoparticles has led to a new combination of diagnostic and therapy theranostic. Size of a particle makes a difference not only between bulk material and nanomaterial, but also in their properties and toxicity. Nanomaterials can have beneficial properties, but can also be toxic. New issues concerning nanomaterials arise an industrial exposure and environmental pollution. They can enter human body in various ways. Cellular mechanisms of nanomaterial toxicity comprise mainly a generation of reactive oxygen species and genotoxicity. The differences between toxicity of fine particles and nanoparticles have led to an origin of a new branch of science, nanotoxicology.

Fungal Colonization of the Respiratory Tract in Allogeneic and Autologous Hematopoietic Stem Cell Transplant Recipients: A Study of 573 Transplanted Patients

Background Fungal colonization and infections remain a major cause of infection morbidity and mortality following hematopoietic stem cell transplantation (HSCT) in patients with hematological malignancies. The aim of this study was to analyze the spectrum of fungal microflora of the respiratory tract (oral cavity, pharynx, epiglottis, and sputum) in patients undergoing HSCT and to evaluate the relationship between HSCT type and incidence of mycotic colonization and infections. Material/Methods Retrospective analysis of fungal isolates collected from the respiratory tract (oral cavity, pharynx, epiglottis, and sputum) of 573 patients undergoing HSCT was performed. Results The overall rate of fungal colonization in patients undergoing HSCT was 8.7%. Patients undergoing allogeneic HSCT were statistically significantly more often colonized (12.95%) compared to autologous HSCT recipients (4.7%). Colonizing cultures were mainly C. albicans and C. krusei, and sporadically C. glabrata, C. famata, Aspergillus spp. and Saccharomyces cerevisiae. C. albicans was the most frequent species found in isolates from the pharynx, sputum, and oral cavity collected from patients undergoing HSCT. Aspergillosis was more common after allogeneic than after autologous HSCT. The pharynx was the most frequently colonized site. Conclusions Allogeneic HSCT recipients are more susceptible to fungal infections compared to the autologous group. Selection of species during prophylaxis and antifungal therapy requires developing more effective prevention and treatment strategies based on new antifungal drugs and microbe-specific diagnoses.