Barbara Zegarska

Frequent genetic differences between matched primary and metastatic breast cancer provide an approach to identification of biomarkers for disease progression.

Breast cancer is a major cause of morbidity and mortality in women and its metastatic spread is the principal reason behind the fatal outcome. Metastasis-related research of breast cancer is however underdeveloped when compared with the abundant literature on primary tumors. We applied an unexplored approach comparing at high resolution the genomic profiles of primary tumors and synchronous axillary lymph node metastases from 13 patients with breast cancer. Overall, primary tumors displayed 20% higher number of aberrations than metastases. In all but two patients, we detected in total 157 statistically significant differences between primary lesions and matched metastases. We further observed differences that can be linked to metastatic disease and there was also an overlapping pattern of changes between different patients. Many of the differences described here have been previously linked to poor patient survival, suggesting that this is a viable approach toward finding biomarkers for disease progression and definition of new targets useful for development of anticancer drugs. Frequent genetic differences between primary tumors and metastases in breast cancer also question, at least to some extent, the role of primary tumors as a surrogate subject of study for the systemic disease.

Chemoprevention of skin melanoma: facts and myths.

Melanoma is the most dangerous type of skin cancer. Despite the rise of public awareness, the incidence rate among the white population has been rising constantly for several decades. Systematic improvement in knowledge about the biology of pigment cells and molecular mechanisms of their neoplastic transformation has enhanced the possibility of melanoma chemoprevention. Hence, chemopreventive agents that prevent, inhibit, or reverse melanoma development are being investigated intensively. Among synthetic compounds, especially well studied are lipid-lowering drugs and cyclooxygenase inhibitors. Substances found in everyday diet, such as genistein, apigenin, quercetin, resveratrol, and curcumin may also have potential chemopreventive qualities. However, studies examining the chemopreventive activity of these compounds have shown widely varying results. Early reports on the possible chemopreventive activity of statins and fibrates were not proved by the results of randomized clinical trials. Similarly, case–control studies examining the influence of NSAIDs on the risk of melanoma do not confirm the antitumor activity of cyclooxygenase inhibitors. Further clinical trials involving carefully selected target populations as well as the identification of specific biomarkers of prognostic and predictive value seem to be essential for the evaluation of the chemopreventive activity of the studied substances.

Is mTOR inhibitor good enough for treatment all tumors in TSC patients

Tuberous sclerosis complex (TSC) is an autosomal dominant and multi-system genetic disorder in humans. TSC affects around 25,000 to 40,000 individuals in the United States and about 1 to 2 million individuals worldwide, with an estimated prevalence of one in 6,000 newborns. TSC occurs in all races and ethnic groups, and in both genders. TSC is caused by defects or mutations in two genes, TSC1 and TSC2. Loss of TSC1/TSC2 leads to dysregulation of mTOR, resulting in aberrant cell differentiation and development, and abnormal enlargement of cells. TSC is characterized by the development of benign and/or malignant tumors in several organs including renal/liver angiomyolipomas, facial angiofibroma, lymphangiomyomatosis, cardiac rhabdomyomas, retinal astrocytic, renal cell carcinoma, and brain subependymal giant cell astrocytomas (SEGA). In addition, TSC disease causes disabling neurologic disorders, including epilepsy, mental retardation and autism. Particularly problematic are the development of renal angiomyolipomas, which tend to be larger, bilateral, multifocal and present at a younger age compared with sporadic forms. In addition, SEGA block the flow of fluid within the brain, causing a buildup of fluid and pressure that leads to blurred vision and seizures. In the current review, we describe the pathology of TSC disease in key organs and summarize the use of mTOR inhibitors to treat tumors in TSC patients.

Transplantation of cultured autologous melanocytes: hope or danger?

Cultured human melanocytes are increasingly being used in the treatment of vitiligo. The growth media contain various types of mitogenic factors, both recombinant human (e.g., rhbFGF and rhSCF) and synthetic (e.g., TPA). High concentrations of mitogenic factors accelerate the cell cycle, and consequently may increase the risk of carcinogenesis of transplanted cells. Mutations of genes of the RAS/RAF/MEK/ERK signaling pathway are very often found in the early stages of the development of melanoma. TPA is considered to be an oncogenic factor, but so far there is no evidence to show that it is responsible for damage to the genetic material of cultured melanocytes. The aim of our study was to assess the risk of the development of mutations in selected genes of the RAS/RAF/MEK/ERK signaling pathway during the culturing of melanocytes in various growth media. Based on the results obtained, it can be concluded that TPA and high concentrations of other growth factors intensify the proliferation of melanocytes, without the risk of damage to the HRAS (exon 1 and 2), KRAS (exon 1 and 2), NRAS (exon 1 and 2), and BRAF (exon 11 and 15) genes. In order to assess the total safety of the transplantation of cultured melanocytes, it is necessary to carry out further studies on other signaling pathways as well as carry out biological tests on an animal model.

Use of Adipose-Derived Stem Cells to Support Topical Skin Adhesive for Wound Closure: A Preliminary Report from Animal In Vivo Study

The aim of this study was to determine the local and systemic effects of adipose-derived stem cells (ADSCs) as a component of topical skin adhesive in an animal artificial wound closure model. In presented study the cosmetic effects, histological analysis, mechanical properties, and cell migration have been assessed to evaluate the usefulness of ADSCs as supporting factor for octyl blend cyanoacrylate adhesive. The total of 40 rats were used and divided into six groups. In the Study Group, ADSCs were administered by multipoint injection of the six surrounding intrawound areas with additional freely leaving procedure of the cells between the skin flaps just before applying adhesive to close the wound. Five control groups without using ADSCs, utilizing different types of standard wound closure, were created in order to check efficiency of experimental stem cell therapy. In our study, we proved that ADSCs could be used effectively also as a supportive tool in topical skin adhesive for wound closure. However we did not achieve any spectacular differences related to such aspects as better mechanical properties or special biological breakthroughs in wound healing properties. The use of stem cells, especially ADSCs for wound closure can provide an inspiring development in plastic and dermatologic surgery.

Air pollution, UV irradiation and skin carcinogenesis: what we know, where we stand and what is likely to happen in the future?

The link between air pollution, UV irradiation and skin carcinogenesis has been demonstrated within a large number of epidemiological studies. Many have shown the detrimental effect that UV irradiation can have on human health as well as the long-term damage which can result from air pollution, the European ESCAPE project being a notable example. In total, at present around 2800 different chemical substances are systematically released into the air. This paper looks at the hazardous impact of air pollution and UV and discusses: 1) what we know; 2) where we stand; and 3) what is likely to happen in the future. Thereafter, we will argue that there is still insufficient evidence of how great direct air pollution and UV irradiation are as factors in the development of skin carcinogenesis. However, future prospects of progress are bright due to a number of encouraging diagnostic and preventive projects in progress at the moment.

Changes of Langerhans cells during skin ageing

Introduction During the process of skin ageing, changes occur in all skin layers and all cells, including the Langerhans cells. Aim To assess whether any quantitative difference in the number of CD1a+ LC cells/mm2 and HLA-DR+ LC cells/mm2 as well as in their morphological features can be observed during the course of different types of skin ageing. Material and methods The study was conducted in a group of 60 women, which was divided into three independent groups: group I with symptoms of menopausal skin ageing, group II with symptoms of photoageing, group III with symptoms of chronological ageing. Skin biopsy samples were taken from the pre-auricular region from all of the participants. The number of CD1a+ LC cells/mm2 and HLA-DR+ LC cells/mm2 as well as their morphological features were evaluated. Results The frequency of CD1a+ LC and HLA-DR+ LC in all the studied groups was diverse. In groups I and III, the LC with large cell bodies and long, multi-branched processes were the majority. In group II, the LC had small cell bodies and their processes were mainly short and unbranched. Conclusions The obtained results indicate the presence of quantitative and morphological changes of the CD1a+ LC and HLA-DR+ LC during the course of different types of skin ageing.

The prevalence of mutations in the gene encoding filaggrin in the population of Polish patients with atopic dermatitis

Introduction The genetic background of atopic dermatitis (AD) is complex, involves many genes and their participation varies in varied populations, and depends on the intensity and course of a disease. Changes in the nucleotide sequence of the FLG gene and a reduced number or a deficit of the functional product of processed profilaggrin can be one of risk factors for atopic dermatitis. Aim To determine the prevalence of R501X and 2282del4 mutations of the FLG gene in patients with AD. Material and methods The studied group included 60 patients with clinically diagnosed AD, and the control group included 61 healthy volunteers. The study protocol included collection of biological material for tests, DNA isolation and evaluation of its quality and quantity, and PCR amplification of the isolated genetic material. Results In the studied group, both changes in the nucleotide sequence of the FLG gene were detected and in the control group no tested mutations were detected. In 18 (30%) patients with AD, 22 mutations (4 heterozygous and 1 homozygous ones of R501X and 10 heterozygous and 7 homozygous ones of 2282del4) were detected. Conclusions A high rate of mutations of the FLG gene in patients with clinically diagnosed AD and pathologically dry skin was observed in the studied population. The 2282del4 mutation occurred more often than R501X.

Anti-proliferative and cytotoxic activity of rosuvastatin against melanoma cells

Introduction Statins are considered potential candidate agents for melanoma chemoprevention. Statin-induced mevalonate pathway inhibition leads to reduction of cholesterol synthesis and also to decreased cellular levels of non-steroidal isoprenoids, geranylgeranyl pyrophosphate and farnesyl pyrophosphate. This results in the impairment of protein prenylation which affects carcinogenesis. Aim To analyze anti-proliferative and cytotoxic activity of rosuvastatin against melanoma cells. Material and methods Melanoma cell lines (A375 and WM1552C) and normal fibroblasts (BJ) were used as the primary research material. Cells were treated with rosuvastatin at concentrations ranging from 0.01 µM to 10 µM. Cell viability was analyzed with the use of an MTT assay. Expression of proliferation marker Ki67 was assessed on the basis of immunofluorescence staining. Results Rosuvastatin reduced A375 and BJ cell viability in a time- and dose-dependent manner. After 72 h incubation, the IC50, half maximal inhibitory concentration, was 2.3 µM for melanoma cells and 7.4 µM for normal fibroblasts. In turn, rosuvastatin exhibited relatively lower activity against WM1552C cells. A significant reduction of Ki67 expression was also noted for BJ fibroblasts after prolonged incubation with the tested drug. Conclusions The results indicate that the anti-melanoma properties of rosuvastatin are highly dependent on the tumor cell line assessed. However, the concentrations required to decrease melanoma cell viability in vitro exceed the plasma concentrations reached in patients treated with rosuvastatin at well-tolerated doses. What is more disturbing, reduction of proliferation and viability observed in BJ fibroblasts indicated that rosuvastatin at high doses may be toxic for normal cells.

The possible role of diet in the pathogenesis of adult female acne

Acne in adults is a chronic, increasingly common disease, especially among women. It differs in pathogenesis and clinical presentation from adolescent acne. Acne in adults is associated with Western diet, defined as high consumption of milk, high glycemic load and high calorie intake. Metabolic signals of this diet result in a significant increase in insulin/insulin growth factor 1 serum level and consequently in the molecular interplay of mammalian target of rapamycin complex 1 kinase (mTORC1)/forkhead box protein 1 (FoxO1) mediated nutrient signaling, leading to increased proliferation of keratinocytes, increased lipogenesis and sebum production and finally to aggravation of acne.