Improving Pathological Assessment of Breast Cancer by Employing Array-Based Transcriptome Analysis

Breast cancer research has paved the way of personalized oncology with the introduction of hormonal therapy and the measurement of estrogen receptor as the first widely accepted clinical biomarker. The expression of another receptor—HER2/ERBB2/neu—was initially a sign of worse prognosis, but targeted therapy has granted improved outcome for these patients so that today HER2 positive patients have better prognosis than HER2 negative patients. Later, the introduction of multigene assays provided the pathologists with an unbiased assessment of the tumors’ molecular fingerprint. The recent FDA approval of complete microarray pipelines has opened new possibilities for the objective classification of breast cancer samples. Here we review the applications of microarrays for determining ER and HER2 status, molecular subtypes as well as predicting prognosis and grade for breast cancer patients. An open question remains the role of single genes within such signatures. Openly available microarray datasets enable the execution of an independent cross-validation of new marker and signature candidates. In summary, we review the current state regarding clinical applications of microarrays in breast cancer molecular pathology

YB-1 dependent oncolytic adenovirus efficiently inhibits tumor growth of glioma cancer stem like cells

Background: The brain cancer stem cell (CSC) model describes a small subset of glioma cells as being responsible for tumor initiation, conferring therapy resistance and tumor recurrence. In brain CSC, the PI3-K/AKT and the RAS/mitogen activated protein kinase (MAPK) pathways are found to be activated. In consequence, the human transcription factor YB-1, knowing to be responsible for the emergence of drug resistance and driving adenoviral replication, is phosphorylated and activated. With this knowledge, YB-1 was established in the past as a biomarker for disease progression and prognosis. This study determines the expression of YB-1 in glioblastoma (GBM) specimen in vivo and in brain CSC lines. In addition, the capacity of Ad-Delo3-RGD, an YB-1 dependent oncolytic adenovirus, to eradicate CSC was evaluated both in vitro and in vivo. Methods: YB-1 expression was investigated by immunoblot and immuno-histochemistry. In vitro, viral replication as well as the capacity of Ad-Delo3-RGD to replicate in and, in consequence, to kill CSC was determined by real-time PCR and clonogenic dilution assays. In vivo, Ad-Delo3-RGD-mediated tumor growth inhibition was evaluated in an orthotopic mouse GBM model. Safety and specificity of Ad-Delo3-RGD were investigated in immortalized human astrocytes and by siRNA-mediated downregulation of YB-1. Results: YB-1 is highly expressed in brain CSC lines and in GBM specimen. Efficient viral replication in and virus-mediated lysis of CSC was observed in vitro. Experiments addressing safety aspects of Ad-Delo3-RGD showed that (i) virus production in human astrocytes was significantly reduced compared to wild type adenovirus (Ad-WT) and (ii) knockdown of YB-1 significantly reduced virus replication. Mice harboring othotopic GBM developed from a temozolomide (TMZ)-resistant GBM derived CSC line which was intratumorally injected with Ad-Delo3-RGD survived significantly longer than mice receiving PBS-injections or TMZ treatment. Conclusion: The results of this study supported YB-1 based virotherapy as an attractive therapeutic strategy for GBM treatment which will be exploited further in multimodal treatment concepts

Daily rhythm of synapse turnover in mouse somatosensory cortex

The whisker representations in the somatosensory barrel cortex of mice are modulated by sensory inputs associated with animal motor behavior which shows circadian rhythmicity. In a C57/BL mouse strain kept under a light/dark (LD 12:12) regime, we observed daily structural changes in the barrel cortex, correlated with the locomotor activity level. Stereological analysis of serial electron microscopic sections of the barrel cortex of mice sacrificed during their active or rest period, revealed an increase in the total numerical density of synapses and in the density of excitatory synapses located on dendritic spines during the rest, as well as an increase in the density of inhibitory synapses located on double-synapse spines during the active period. This is the first report demonstrating a daily rhythm in remodeling of the mammalian somatosensory cortex, manifested by changes in the density of synapses and dendritic spines. Moreover, we have found that the excitatory and inhibitory synapses are differently regulated during the day/night cycle

Prediction of the response to chemotherapy in ovarian cancers

Ovarian cancer represents the fifth most frequent cause of death as a result of malignant processes after cancers of the breast, large intestine, lung and stomach. Owing to the localisation of ovarian cancer, approximately 75% of cases are diagnosed at the III and IV stages of advancement according to FIGO. Because of the advanced stage of the disease surgery has to be followed by chemotherapy in most cases of ovarian cancer and therefore resistance to cytostatic drugs represents a major clinical problem. The potential to predict the response to therapy with the use of cytostatic drugs would enable the most effective drugs to be applied in individual cases, thus improving the efficiency of the treatment and restricting the development of resistance to cytostatic drugs. In the present paper the progress made so far in the prediction of the clinical course of ovarian cancer is reviewed. The significance of the expression of the ATP-binding cassette (ABC) transporters is described, including P-glycoprotein and MRP2, the principal representatives of the protein group. The importance of disturbed control of apoptosis and the overexpression of HER-2 and topoisomerase 1A are also discussed. Two sections are devoted to the most recent studies in the biology of ovarian cancer, pangenomic studies on gene expression using DNA microarrays and aberrations of DNA methylation

Evaluation of transfection effectiveness using fluorescein-labelled oligonucleotides and various liposomes

Silencing of genes using siRNA represents a generally used technique aimed at inhibiting expression of proteins in cells. Results have frequently not met expectations and this has posed problems in association with this technique. The phenomenon might reflect an incorrect sequence of RNAi, poor penetration of the cells by the nucleotides or insufficient knowledge of the protein in question. The present study is aimed at evaluating the effectiveness of the transfection of selected cell lines using various liposomes. The studies were performed using 9 cell lines: EPG 257/85 RNOV, EPG 257/85 RDB, W 181/A17, A 2780P, A 2780 RCIS, MEWO CIS, 181 RDB, 181 P and MCF-7/MX. The lines were transfected with fluorescently labelled oligonucleotides. Two parallel experiments were performed. In one oligofectamin and in the other DMRI were used as oligonucleotide carriers. The studies demonstrated that in every case nucleotides penetrated more than 90% of the cells. In 4 cell lines the signal was stronger when oligofectamin was used, in 4 cell lines when DMRI was employed and in one case the signal strength was comparable using any carrier. The studies showed that various liposomes demonstrated distinct transfection efficiency, depending on the cell line used, and that application of fluorescently labelled nucleotides may be helpful in the optimisation of transfection conditions

O kobietach, które „rozbojem się bawiły”. Katarzyna Włodkowa Skrzyńska i Barbara Rusinowska – zapomniane zbójniczki z XV wieku

Historiographic sources contain the memory of two 15th-century female rob­bers: Katarzyna Włodkowa Skrzyńska and Barbara Rusinowska. The former was the wife of Włodek from Skrzynów of the Swan coat of arms, who lived in Barwałd Castle in the area of Zator and reigned terror in the whole region. We are concerned here with a peculiar phenomenon, that is, a husband–wife duo of robbers, and the fact that they were both of noble birth only spices up this story. Barbara Rusinowska, who was active in the Świętokrzyskie Moun­tains, was also from a noble family. She attacked manor houses and merchant wagons, and her characteristic trait was her men’s attire. Both bandits were finally captured and executed. The article introduces the life story of these women and compares various (often contradictory) information about their brigandage that has survived in ancient chronicles. In the nineteenth cen­tury, Rusinowska became the heroine of a stage drama written by Aleksander Ładnowski.O kobietach, które „rozbojem się bawiły”. Katarzyna Włodkowa Skrzyńska i Barbara Rusinowska – zapomniane zbójniczki z XV wieku W źródłach historiograficznych oraz legendach przechowywana jest pamięć o dwóch XV-wiecznych zbójniczkach – Katarzynie Włodkowej Skrzyń­skiej i Barbarze Rusinowskiej. Pierwsza była żoną Włodka ze Skrzynna herbu Łabędź, który mieszkał na zamku Barwałd w ziemi zatorskiej i siał postrach w całej okolicy. Mamy więc do czynienia ze swoistym fenomenem, jakim było małżeństwo zbójników, a dodatkowego kolorytu nadaje tej histo­rii fakt, że były to osoby wysoko urodzone. Ze stanu szlacheckiego pocho­dziła także Barbara Rusinowska, która działała w Górach Świętokrzyskich. Napadała na dwory i wozy kupieckie, a jej cechą charakterystyczną był męski strój. Obie zbójniczki zostały w końcu pojmane i stracone. Artykuł przybliża dzieje życia tych kobiet, a także zestawia różne (często sprzeczne) informacje na temat ich rozbójniczej działalności, które zachowały się w dawnych kroni­kach. W XIX w. Rusinowska stała się bohaterką dramatu scenicznego autor­stwa Aleksandra Ładnowskiego

Kwercetyna hamuje proliferację i zwiększa wrażliwość komórek raka jajnika na cisplatynę i paklitaksel

Introduction: Due to frequent diagnosis of ovarian cancer at an advanced clinical stage, in most cases surgical debulking is followed by chemotherapy. The principal cause of therapeutic failure involves incomplete surgery and resistance of neoplastic cells to chemotherapy. A search continues for substances which would overcome resistance to treatment and, as a result, would increase efficacy of the applied treatment. Quercetin represents one of more interesting compounds, which at present in subjected to several tests. Material and methods: Studies were performed on in vitro sensitivity of human ovarian cancer cell lines, SKOV-3, EFO27, OVCAR-3 and A2780P to low doses of quercetin and on the effect exerted by quercetin on sensitivity of the cell lines to cisplatin and pactitaxel. Results: The experiments proved that the studied cells of ovarian cancer manifest a similar sensitivity to quercetin. Following incubation of the cells with two distinct concentrations of quercetin and the studied cytostatic agents all the cells lines were found to significantly increase their sensitivity to pactitaxel In cases of two cell lines, OVCAR-2 and A2780P, they also significantly increased their sensitivity to cisplatin. Discussion: Our results demonstrated suitability of low quercetin doses (achievable using oral administration) as a substance which increases sensitivity of ovarian cancer cells to cisplatin and paclitaxel. The value of quercetin include its wide accessibility, efficacy and a broad range of activity but also its low toxicity, as compared to other examined compounds. Conclusions: Used in low doses, quercetin increases chemosensitivity of ovarian cancer cells.Wstęp: Ze względu na częste rozpoznawanie raków jajnika w zaawansowanym stadium klinicznym w większości przypadków po przeprowadzeniu zabiegu operacyjnego stosowana jest chemioterapia. Podstawową przyczyną niepowodzeń stosowanej terapii jest nieradykalność leczenia operacyjnego oraz oporność komórek nowotworowych na chemioterapię. Poszukuje się substancji, które pozwolą zwalczyć oporność na leczenie i w efekcie zwiększyć skuteczność stosowanej terapii. Jednym z ciekawszych związków poddawanych obecnie szeregowi badań jest kwercetyna. Materiał i metody: Przeprowadzono badania in vitro wrażliwości linii komórkowych ludzkiego raka jajnika SKOV-3, EFO27, OVCAR-3 i A2780P na niskie dawki kwercetyny oraz ocenę wpływu kwercetyny na wrażliwość linii komórkowych na cisplatynę i paklitaksel. Wyniki: Przeprowadzone doświadczenia wykazały, że badane komórki raka jajnika wykazują zbliżoną wrażliwość na kwercetynę. W wyniku inkubacji badanych komórek z dwoma różnymi stężeniami kwercetyny i z badanymi cytostatykami wykazaliśmy, że wszystkie linie istotnie zwiększyły swoją wrażliwość na paklitaksel. W przypadku dwóch linii – OVCAR-2 i A2780P uzyskaliśmy również istotny wzrost wrażliwości na cisplatynę. Dyskusja: Nasze badania wykazały przydatność niskich dawek kwercetyny (osiągalnych przy podaży doustnej), jako substancji zwiększającej wrażliwość komórek raka jajnika na cisplatynę i paklitaksel. Jej walory podkreśla nie tylko łatwa dostępność, skuteczność i szeroki zakres działania, ale również mała, w porównaniu z innymi badanymi substancjami, toksyczność. Wnioski: Kwercetyna zastosowana w niskich dawkach powoduje wzrost chemiowrażliwości komórek raka jajnika

Multiferroic materials for sensors, transducers and memory devices

Chemical compositions and basic properties of smart materials (ferroics, biferroics, multiferroics) are introduced in this paper. Single phase and composite ferroelectromagnetics are characterized in detail. Multiferroic ferroelectromagnetics are materials which are both ferromagnetic/ferrimagnetic/antiferromagnetic and ferroelectric/ferrielectric, antiferrolectric in the same phase. As a result they have a spontaneous magnetization which can be switched by an applied magnetic field, a spontaneous polarization which can be switched by an applied electric field, and often there is some coupling between those fields. The physical mechanisms of the coupling process were analyzed. In the case of the ferroelectromagnetics in general the transitions method d electrons, which are essential for magnetism, reduce the tendency for off-center ferroelectric distortion. Such materials have all the potential applications of both their parent ferroelectric and ferromagnetic materials

Walka z „morowym powietrzem” na terenach dawnej Rzeczypospolitej w świetle żywieckiej kroniki z XVIII wieku

The article presents the problem of dealing with the pestilence (pol. morowe powietrze, “pestilent air”) on the territory of the old Republic of Poland, with particular focus on the Żywiec County in the 16th to 8th century. The paper attempts to answer the questions of how the medics of that time dealt with epidemics, what actions were taken by ordinary people for whom the raging plague was often the result of the interference of demonic forces, and finally, what preventive measures against the plague were proposed to the faithful by the Church. The source for the considerations is the Chronografia albo Dziejopis żywiecki [Chronography or the Żywiec Chronicle], the account of history of the town of Żywiec and the surrounding area covering the years 1400–1728, written by the mayor, Andrzej Komoniecki (1659–1729). The Chronicle brings back an extraordinarily colorful picture of old customs, beliefs and superstitions, as well as paramedical practices, which to our contemporary cultural sensitivity may appear bizarre, gruesome and terrifying. In preparing the article, the author also used extensive literature, primarily in the history of medicine.Among the research methods used in the study, it is worth mentioning, first of all: the explicative method, the method of document research, the method of analysis and criticism of sources, the method of cultural analysis and the method of stylistic-rhetorical analysis. In contemporary socio-cultural reality, the reading of the Chronografia takes on new meanings. In the context of the pandemic that struck the world in the 21st century, the extremely accurate accounts of the Żywiec chronicler seem particularly interesting, as they allow us to compare the attitude of our old Polish ancestors and ourselves in the face of a similar threat. This comparative leads us to believe that some of the measures taken to prevent the spread of infections, such as keeping a distance, limiting the number of participants at funerals, or not letting strangers into towns, are still taken today, while others, such as locking the sick up in huts, setting fire to infected houses, burying plague victims under fences, drowning them in rivers, or desecrating the bodies of the dead suspected of having caused the plague, are now happily forgotten.Artykuł przybliża problem walki z „morowym powietrzem” na obszarze dawnej Rzeczypospolitej, ze szczególnym uwzględnieniem Państwa Żywieckiego, w XVI–VIII wieku. Autorka stara się odpowiedzieć na pytania, jak ówcześni medycy radzili sobie z epidemiami, jakie działania podejmowali zwykli ludzie, dla których szalejąca zaraza była często wynikiem ingerencji sił demonicznych, i wreszcie, jakie formy walki z zarazą zostały zaproponowane wiernym przez Kościół. Źródłem rozważań jest „Chronografia albo Dziejopis Żywiecki”, opis dzie- jów miasta Żywca i okolic z lat 1400–1728, spisany przez wójta Andrzeja Komonieckiego (1659–1729). Kronika przywołuje niezwykle barwny obraz dawnych obyczajów, wierzeń i przesądów oraz praktyk paramedycznych, które dla naszej współczesnej wrażliwości kulturowej mogą wydawać się dziwaczne, przerażające lub makabryczne. Autorka wykorzystała obszerną literaturę przedmiotu, przede wszystkim z zakresu historii medycyny. Wśród metod badawczych zastosowanych w opracowaniu warto wymienić przede wszystkim: metodę eksplikatywną, metodę badania dokumentów, metodę analizy i krytyki źródeł, metodę analizy kulturowej oraz metodę analizy stylistyczno-retorycznej. We współczesnej rzeczywistości społeczno-kulturowej czytanie „Chronografii” nabiera nowych znaczeń. W kontekście pandemii, która nawiedziła świat w XXI wieku, szczególnie interesujące wydają się niezwykle trafne relacje żywieckiego kronikarza, które pozwalają porównać postawę naszych dawnych polskich przodków i nas samych w obliczu podobnego zagrożenia. To porównanie prowadzi do przekonania, że niektóre środki podjęte w celu powstrzymania rozprzestrzeniania się infekcji, takie jak zachowanie dystansu, ograniczenie liczby uczestników pogrzebów czy niewpuszczanie obcych do miast, są podejmowane do dziś, podczas gdy inne, takie jak: zamykanie chorych w chatach, podpalanie zarażonych domów, grzebanie ofiar dżumy pod płotami, topienie ich w rzekach czy bezczeszczenie ciał zmarłych podejrzanych o spowodowanie dżumy, są teraz szczęśliwie zapomniane