Securin-related cell proliferation in breast cancer prognosis

Breast cancer is the most common malignancy among women. It remains a major cause of mortality among women, although the five-year survival of breast cancer patients is about 90%. To aid in the clinical treatment decisions, clinical factors and biomarkers are utilized to predict the behaviour and prognosis of breast cancer. Traditionally such prognostic factors have been the size and stage of the tumour, hormone receptor expression, the amplification status of Her2 oncogene and the proliferation activity of the tumour cells. The purpose of this study is to investigate regulatory proteins of the metaphase-anaphase transition of the cell division and evaluate their potential value in predicting the prognosis of breast carcinoma patients. The study is based on 1135 breast cancer patients with a maximum follow-up time of 22 years. The tissue material was collected into tissue microarrays and the protein expressions were analysed with immunohistochemical and immunofluorescence methods. Securin, PTTG1IP, separase and SA2 are proteins involved in the regulation of the cell cycle. In this study, the immunohistochemical expression of these proteins in breast cancer tissue was examined. The changes in the expression profile were then used to estimate their prognostic value. Securin overexpression alone predicted a 2.4-fold risk of breast cancer death (p>0.001). Combined with the other studied cell-cycle proteins, this risk was emphasized. A model combining securin, separase and axillary lymph node status increased the risk of breast cancer death 6.2-fold (p 0.0006, CI 3.2-82.6). In addition, cytoplasmic securin expression was associated with triple negative subtype of breast cancer. Based on this study securin-related cell cycle proteins are promising new candidates as biomarkers for breast cancer prognosis.Sekuriini ja siihen liittyvät säätelyproteiinit rintasyövän ennustetekijöinä Rintasyöpä on naisten yleisin syöpä. Viiden vuoden jälkeen sairastuneista naisista elossa on n. 90%. Hyvistä hoitotuloksista huolimatta rintasyöpään liittyy siis edelleen huomattavaa kuolleisuutta. Rintasyövän käyttäytymisen ennustaminen on perinteisesti perustunut kasvaimen kokoon, taudin levinneisyyteen, hormonireseptorien ja Her2-onkogeenin ilmentymiseen syöpäsoluissa sekä kasvainsolujen proliferaatioaktiivisuuteen. Tämän tutkimuksen tarkoituksena on selvittää uusia rintasyövän taudinkulkuun ja potilaiden ennusteeseen vaikuttavia tekijöitä. Tutkimus perustuu yhteensä 1135 rintasyöpäpotilaan aineistoon ja enimmillään 22 vuoden seuranta-aikaan. Potilaiden kudosnäytteistä valmistettiin monikudosblokit, joita tutkittiin immunohistokemiallisin ja immunofluoresenssi-menetelmin. Sekuriini, PTTG1IP, separaasi ja SA2 ovat solunjakautumisen säätelyyn osallistuvia proteiineja. Tutkimuksessa määritettiin näiden proteiinien immunohistokemiallista ilmentymistä rintasyöpäkudoksessa sekä värjäytymisprofiilin muutosten vaikutusta potilaiden ennusteeseen. Sekuriinin yli-ilmentyminen yksinään ennusti 2.4-kertaista rintasyöpäkuoleman riskiä (p>0.001). Yhdistettynä muihin solunjakautumisen säätelyyn osallistuviin proteiineihin riski korostui. Sekuriini, separaasi ja kainaloimusolmukestatus ennustivat 6.2-kertaista riskiä (p 0.0006, CI 3.2-82.6). Sekuriinin ilmentyminen solun sytoplasmassa liittyi voimakkaasti huonoennusteiseen kolmoisnegatiiviseen rintasyöpään. Tutkimuksen perusteella sekuriiniin liittyvät solunjakautumista säätelevät proteiinit ovat lupaavia tulevaisuuden biomarkkereita rintasyövän ennusteenarviointia ja yksilöllisiä hoitopäätöksiä varten

Silicon Surface Passivation by Al2O3: Effect of ALD Reactants

We have studied the surface passivation of p- and n-type silicon by thermal atomic layer deposited (ALD) Al2O3. The main emphasis is on different ALD reactant combinations and especially on using ozone as an oxidant. Thermal stability of Al2O3 will also be briefly addressed. Our results show that in p-type CZ-Si Al2O3 leads to much higher passivation than thermal oxidation, independent of the reactants. The best minority carrier lifetimes are measured when a combination of Al2O3 and TiO2 is used. In n-type CZ-Si similar results are obtained except the choice of reactants seems to be more crucial. However, the combination of Al2O3 and TiO2 results again in the best passivation with measured lifetimes well above 10 ms corresponding surface recombination velocities of ∼2 cm/s. Finally, we demonstrate that Al2O3 passivation is also applicable in high resistivity n-type FZ-Si and in ∼1 Ωcm p-type multicrystalline Si.Peer reviewe

Passivation of Detector-Grade Float Zone Silicon with Atomic Layer Deposited Aluminum Oxide

Silicon radiation and particle detectors are traditionally passivated with thermal silicon dioxide. It has been shown that aluminum oxide (Al2O3) films provide better surface passivation due to their high negative charge, but studies on Al2O3 surface passivation are usually performed on low-resistivity substrates. Herein, the passivation of high-resistivity, detector-grade float zone silicon (FZ-Si) with Al2O3 is studied, with a specific emphasis on the effect of post-annealing temperature on carrier lifetimes and film properties. It is confirmed that Al2O3 provides excellent surface passivation also on high-resistivity FZ-Si substrates, with a low interface defect density of around (2-4) x 10(11) cm(-2) eV(-1) and a high negative oxide charge of 1 x 10(12) to 3 x 10(12) q cm(-2), when post-annealed at temperatures of up to 450-500 degrees C. In addition, high-resistivity samples are studied for the phenomenon of bulk lifetime degradation occurring at typical post-annealing or metal sintering temperatures, which has been reported for low-resistivity FZ-Si. At post-annealing temperatures of >500 degrees C, reduced bulk lifetimes are observed if the substrates did not receive high-temperature treatment prior to surface passivation. Furthermore, it is noticed that n-type samples exhibit lower bulk lifetimes even when a high-temperature treatment is performed, which indicates a connection between FZ-Si bulk lifetime degradation and doping type.Peer reviewe

Effective Passivation of Black Silicon Surfaces by Atomic Layer Deposition

The poor charge-carrier transport properties attributed to nanostructured surfaces have been so far more detrimental for final device operation than the gain obtained from the reduced reflectance. Here, we demonstrate results that simultaneously show a huge improvement in the light absorption and in the surface passivation by applying atomic layer coating on highly absorbing silicon nanostructures. The results advance the development of photovoltaic applications, including high-efficiency solar cells or any devices, that require high-sensitivity light response.Peer reviewe

Varying outcomes of triple-negative breast cancer in different age groups-prognostic value of clinical features and proliferation

PurposeTriple-negative breast cancer (TNBC) is an aggressive disease lacking specific biomarkers to guide treatment decisions. We evaluated the combined prognostic impact of clinical features and novel biomarkers of cell cycle-progression in age-dependent subgroups of TNBC patients.MethodsOne hundred forty seven TNBC patients with complete clinical data and up to 18 year follow-up were collected from Turku University Hospital, Finland. Eight biomarkers for cell division were immunohistochemically detected to evaluate their clinical applicability in relation to patient and tumor characteristics.ResultsAge at diagnosis was the decisive factor predicting disease-specific mortality in TNBC (p = 0.002). The established prognostic features, nodal status and Ki-67, predicted survival only when combined with age. The outcome and prognostic features differed significantly between age groups, middle-aged patients showing the most favorable outcome. Among young patients, only lack of basal differentiation predicted disease outcome, indicating 4.5-fold mortality risk (p = 0.03). Among patients aged > 57, the established prognostic features predicted disease outcome with up to 3.0-fold mortality risk for tumor size ≥ 2 cm (p = 0.001). Concerning cell proliferation, Ki-67 alone was a significant prognosticator among patients aged > 57 years (p = 0.009). Among the studied cell cycle-specific biomarkers, only geminin predicted disease outcome, indicating up to 6.2-fold increased risk of mortality for tumor size p = 0.03).ConclusionTraditional clinical features do not provide optimal prognostic characterization for all TNBC patients. Young age should be considered as an additional adverse prognostic feature in therapeutic considerations. Increased proliferation, as evaluated using Ki-67 or geminin immunohistochemistry, showed potential in detecting survival differences in subgroups of TNBC.</p

A prognostic model based on cell-cycle control predicts outcome of breast cancer patients

Background A prognostic model combining biomarkers of metaphase-anaphase transition of the cell cycle was developed for invasive breast cancer. The prognostic value and clinical applicability of the model was evaluated in comparison with the routine prognosticators of invasive breast carcinoma. Methods The study comprised 1135 breast cancer patients with complete clinical data and up to 22-year follow-up. Regulators of metaphase-anaphase transition were detected immunohistochemically and the biomarkers with the strongest prognostic impacts were combined into a prognostic model. The prognostic value of the model was tested and evaluated in separate patient materials originating from two Finnish breast cancer centers. Results The designed model comprising immunoexpressions of Securin, Separase and Cdk1 identified 8.4-fold increased risk of breast cancer mortality (p 75%) of patients resulting with favorable as opposed to unfavorable outcome of the model. Along with nodal status, the model showed independent prognostic impact for all breast carcinomas and for subgroups of luminal, N+ and N- disease. Conclusions The impact of the proposed prognostic model in predicting breast cancer survival was comparable to nodal status. However, the model provided additional information in N- breast carcinoma in identifying patients with aggressive course of disease, potentially in need of adjuvant treatments. Concerning N+, in turn, the model could provide evidence for withholding chemotherapy from patients with favorable outcome.</div

Proliferation-associated miRNAs-494, -205, -21 and -126 detected by in situ hybridization: expression and prognostic potential in breast carcinoma patients

PurposeTo visualize by in situ hybridization (ISH) the levels of a set of proliferation-associated miRNAs and to evaluate their impact and clinical applicability in prognostication of invasive breast carcinoma.MethodsTissue specimen from breast carcinoma patients were investigated for miRNAs-494, -205, -21 and -126. Prognostic associations for levels of miRNAs were analyzed based on complete clinical data and up to 22.5-year follow-up of the patient material (n = 285). For detection of the miRNAs, an automated sensitive protocol applying in situ hybridization was developed.ResultsMiRNA-494 indicated prognostic value for patients with invasive breast carcinoma. Among node-negative disease reduced level of miRNA-494 predicted 8.5-fold risk of breast cancer death (p = 0.04). Altered levels and expression patterns of the studied miRNAs were observed in breast carcinomas as compared to benign breast tissue.ConclusionsThe present paper reports for the first time on the prognostic value of miRNA-494 in invasive breast cancer. Particularly, detection of miRNA-494 could benefit patients with node-negative breast cancer in identifying subgroups with aggressive disease. Based on our experience, the developed automatic ISH method to visualize altered levels of miRNAs-494, -205, -21 and -126 could be applied to routine pathology diagnostics providing that conditions of tissue treatment, especially fixation delays, are managed.</div

Formin Proteins FHOD1 and INF2 in Triple-Negative Breast Cancer: Association With Basal Markers and Functional Activities

Basal-like breast cancer is an aggressive form of breast cancer with limited treatment options. The subgroup can be identified immunohistochemically, by lack of hormone receptor expression combined with expression of basal markers such as CK5/6 and/or epidermal growth factor receptor (EGFR). In vitro, several regulators of the actin cytoskeleton are essential for efficient invasion of basal-like breast cancer cell lines. Whether these proteins are expressed in vivo determines the applicability of these findings in clinical settings. The actin-regulating formin protein FHOD1 participates in invasion of the triple-negative breast cancer cell line MDA-MB-231. Here, we measure the expression of FHOD1 protein in clinical triple-negative breast cancers by using immunohistochemistry and further characterize the expression of another formin protein, INF2. We report that basal-like breast cancers frequently overexpress formin proteins FHOD1 and INF2. In cell studies using basal-like breast cancer cell lines, we show that knockdown of FHOD1 or INF2 interferes with very similar processes: maintenance of cell shape, migration, invasion, and proliferation. Inhibition of EGFR, PI3K, or mitogen-activated protein kinase activity does not alter the expression of FHOD1 and INF2 in these cell lines. We conclude that the experimental studies on these formins have implications in the clinical behavior of basal-like breast cancer.</p

Tumor-infiltrating lymphocytes and CD8+ T cells predict survival of triple-negative breast cancer

PurposeTumor inflammatory response was evaluated as a prognostic feature in triple-negative breast cancer (TNBC) and compared with the clinical prognosticators of breast cancer and selected biomarkers of cancer cell proliferation.MethodsTNBC patients (n = 179) with complete clinical data and up to 18-year follow-up were obtained from Auria biobank, Turku University Hospital, Turku, Finland. Tumor-infiltrating lymphocytes (TILs) and several subtypes of inflammatory cells detected with immunohistochemistry were evaluated in different tumor compartments in full tissue sections and tissue microarrays.ResultsDeficiency of stromal TILs and low number of CD8+ T cells independently predicted mortality in TNBC (HR 2.4, p 0.02 and HR 2.1, p 0.02, respectively). Each 10% decrease in stromal TILs resulted in 20% increased risk of mortality. An average of 13.2-year survival difference was observed between the majority (> 75%) of patients with low (DiscussionTILs and CD8+ T cells provide additional prognostic value to the established clinical prognostic markers in TNBC. However, possible clinical applications would still benefit from systematic guidelines for evaluating tumor inflammatory response. Increasing understanding on the interactions between the regulation of cancer cell proliferation and inflammatory response may in future advance treatment of TNBC.</p

Minästä kiinni – Perusopetuksen oppimateriaali moninaisista identiteeteistä

Ota minästä kiinni, vahvista luokan yhteisöllisyyttä ja opasta oppilaasi kiehtovalle matkalle omiin identiteetteihinsä! Minästä kiinni ja Kielestä koppi -oppimateriaalipari sisältää toiminnallisia, yhteisöllisiä ja innostavia tehtäviä moninaisten identiteettien tarkasteluun, kielitietoiseen oppimiseen sekä monikielisten taitojen kehittämiseen. Tehtäviä tukee tiivis pedagoginen teoriaosuus. Tämän materiaalin avulla opettajan on helppo tuoda opetussuunnitelman edellyttämä kieli- ja kulttuuritietoisuus osaksi opetusta! Minästä kiinni -materiaali tarjoaa opettajalle välineitä jokaisen oppilaan moninaisuuden, identiteettien ja vahvuuksien esiintuomiseen. Lisäksi se herättelee keskustelua yksilön ja yhteiskunnan arvoista, eriarvoisuudesta sekä mahdollisuuksista. Oppimateriaalia voidaan käyttää kaikissa oppiaineissa sekä monialaisissa oppimiskokonaisuuksissa kaikilla perusopetuksen vuosiluokilla. Asioita lähestytään itseilmaisun ja yhdessä tekemisen kautta turvallisessa ilmapiirissä. Materiaali on kehitetty Turun yliopistolla yhteistyössä alan eri asiantuntijoiden ja opettajien kanssa.</p