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

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

VTT-006, an anti-mitotic compound, binds to the Ndc80 complex and suppresses cancer cell growth <i>in vitro</i>.

Hec1 (Highly expressed in cancer 1) resides in the outer kinetochore where it works to facilitate proper kinetochore-microtubule interactions during mitosis. Hec1 is overexpressed in various cancers and its expression shows correlation with high tumour grade and poor patient prognosis. Chemical perturbation of Hec1 is anticipated to impair kinetochore-microtubule binding, activate the spindle assembly checkpoint (spindle checkpoint) and thereby suppress cell proliferation. In this study, we performed high-throughput screen to identify novel small molecules that target the Hec1 calponin homology domain (CHD), which is needed for normal microtubule attachments. 4 million compounds were first virtually fitted against the CHD, and the best hit molecules were evaluated in vitro. These approaches led to the identification of VTT-006, a 1,2-disubstituted-tetrahydro-beta-carboline derivative, which showed binding to recombinant Ndc80 complex and modulated Hec1 association with microtubules in vitro. VTT-006 treatment resulted in chromosome congression defects, reduced chromosome oscillations and induced loss of inter-kinetochore tension. Cells remained arrested in mitosis with an active spindle checkpoint for several hours before undergoing cell death. VTT-006 suppressed the growth of several cancer cell lines and enhanced the sensitivity of HeLa cells to Taxol. Our findings propose that VTT-006 is a potential anti-mitotic compound that disrupts M phase, impairs kinetochore-microtubule interactions, and activates the spindle checkpoint

ASIC-E4: Interplay of Beta-Amyloid, Synaptic Density and Neuroinflammation in Cognitively Normal Volunteers With Three Levels of Genetic Risk for Late-Onset Alzheimer's Disease - Study Protocol and Baseline Characteristics

Background:& nbsp;Detailed characterization of early pathophysiological changes in preclinical Alzheimer's disease (AD) is necessary to enable development of correctly targeted and timed disease-modifying treatments. ASIC-E4 study ( "Beta-Amyloid, Synaptic loss, Inflammation and Cognition in healthy APOE epsilon 4 carriers ") combines state-of-the-art neuroimaging and fluid-based biomarker measurements to study the early interplay of three key pathological features of AD, i.e., beta-amyloid (A beta) deposition, neuroinflammation and synaptic dysfunction and loss in cognitively normal volunteers with three different levels of genetic (APOE-related) risk for late-onset AD.& nbsp;Objective:& nbsp;Here, our objective is to describe the study design, used protocols and baseline demographics of the ASIC-E4 study.& nbsp;Methods/Design:& nbsp;ASIC-E4 is a prospective observational multimodal imaging study performed in Turku PET Centre in collaboration with University of Gothenburg. Cognitively normal 60-75-year-old-individuals with known APOE epsilon 4/epsilon 4 genotype were recruited via local Auria Biobank (Turku, Finland). Recruitment of the project has been completed in July 2020 and 63 individuals were enrolled to three study groups (Group 1: APOE epsilon 4/epsilon 4, N = 19; Group 2: APOE epsilon 4/epsilon 3, N = 22; Group 3: APOE epsilon 3/epsilon 3, N = 22). At baseline, all participants will undergo positron emission tomography imaging with tracers targeted against A beta deposition (C-11-PIB), activated glia (C-11-PK11195) and synaptic vesicle glycoprotein 2A (C-11-UCB-J), two brain magnetic resonance imaging scans, and extensive cognitive testing. In addition, blood samples are collected for various laboratory measurements and blood biomarker analysis and cerebrospinal fluid samples are collected from a subset of participants based on additional voluntary informed consent. To evaluate the predictive value of the early neuroimaging findings, neuropsychological evaluation and blood biomarker measurements will be repeated after a 4-year follow-up period.& nbsp;Discussion:& nbsp;Results of the ASIC-E4 project will bridge the gap related to limited knowledge of the synaptic and inflammatory changes and their association with each other and A beta in "at-risk " individuals. Thorough in vivo characterization of the biomarker profiles in this population will produce valuable information for diagnostic purposes and future drug development, where the field has already started to look beyond A beta

Recontacting biobank participants to collect lifestyle, behavioural and cognitive information via online questionnaires : lessons from a pilot study within FinnGen

OBJECTIVES: To recontact biobank participants and collect cognitive, behavioural and lifestyle information via a secure online platform. DESIGN: Biobank-based recontacting pilot study. SETTING: Three Finnish biobanks (Helsinki, Auria, Tampere) recruiting participants from February 2021 to July 2021. PARTICIPANTS: All eligible invitees were enrolled in FinnGen by their biobanks (Helsinki, Auria, Tampere), had available genetic data and were >18 years old. Individuals with severe neuropsychiatric disease or cognitive or physical disabilities were excluded. Lastly, 5995 participants were selected based on their polygenic score for cognitive abilities and invited to the study. Among invitees, 1115 had successfully participated and completed the study questionnaire(s). OUTCOME MEASURES: The primary outcome was the participation rate among study invitees. Secondary outcomes included questionnaire completion rate, quality of data collected and comparison of participation rate boosting strategies. RESULTS: The overall participation rate was 18.6% among all invitees and 23.1% among individuals aged 18-69. A second reminder letter yielded an additional 9.7% participation rate in those who did not respond to the first invitation. Recontacting participants via an online healthcare portal yielded lower participation than recontacting via physical letter. The completion rate of the questionnaire and cognitive tests was high (92% and 85%, respectively), and measurements were overall reliable among participants. For example, the correlation (r) between self-reported body mass index and that collected by the biobanks was 0.92. CONCLUSION: In summary, this pilot suggests that recontacting FinnGen participants with the goal to collect a wide range of cognitive, behavioural and lifestyle information without additional engagement results in a low participation rate, but with reliable data. We suggest that such information be collected at enrolment, if possible, rather than via post hoc recontacting.publishedVersionPeer reviewe

The Purpose Limitation Principle in the Context of Big Data

Tämä pro gradu -tutkielma analysoi yleisen tietosuoja-asetuksen (GDPR) käyttötarkoitussidonnaisuuden periaatteen ja massadata-ilmiön yhteensopivuutta. Käyttötarkoitussidonnaisuuden periaate on ollut yksi eurooppalaisen tietosuojalainsäädännön kulmakiviä 70-luvulta alkaen. Käyttötarkoitussidonnaisuuden periaatteen mukaan henkilötiedot on kerättävä tiettyä, nimenomaista ja laillista tarkoitusta varten, eikä niitä saa käsitellä myöhemmin näiden tarkoitusten kanssa yhteensopimattomalla tavalla. Massadata-ilmiöön kuuluu tietomäärän valtaisa kasvaminen ja sen automatisoitu käsitteleminen, mikä on johtanut merkittäviin muutoksiin tietojenkäsittelykäytännöissä. Tutkimuksen päämääränä on tarkastella käyttötarkoitussidonnaisuuden periaatteen merkitystä ja sisältöä sekä analysoida sen tavoitteita massadata-ilmiön kontekstissa. Menetelmälliseltä lähestymistavaltaan tutkielma on lainopillinen. Tutkielmassa kuvataan ensinnäkin vaatimusta, jonka mukaan henkilötiedot on kerättävä tiettyä tarkoitusta varten, käyttäen apuna tietosuojatyöryhmä WP 29:n lausuntoja. Tutkielma tarkastelee massadata-analytiikan ominaisuutta, jossa tietomassasta voidaan analyysin avulla löytää korrelaatioita ja tietämystä, joiden avulla dataa voidaan käyttää uusiin tarkoituksiin. Tutkielma tarkastelee tämän ominaisuuden ja GDPR:n välille syntyvää ristiriitaa. Tutkielman päätelmänä on, että vaatimusta on käytännössä vaikeata soveltaa, kun otetaan huomioon massadata-analytiikan ominaisuudet. Toiseksi, tutkielma tarkastelee käyttötarkoitussidonnaisuuden periaatteen sisältämää yhteensopivuuden arviointia massadatan kontekstissa. Tietosuojatyöryhmä WP 29 on kehittänyt lausunnoissaan yhteensopivuuden arviointiperusteita, jotka tuotu GDPR:n säädöstekstiin. Tutkielma tarkastelee yhteensopivuuden arvioinnin vaatimuksia suhteessa massadata-ilmiön ominaisuuteen, jossa dataa käytetään uudella tavalla eri käyttötarkoituksiin kuin mihin se alun perin kerättiin. Tutkielma tulee siihen johtopäätökseen, että massadatan käyttäminen uuteen käyttötarkoitukseen ilmiölle ominaisella tavalla on GDPR:n näkökulmasta haastavaa, kun ottaa huomioon yhteensopivuuden arvioinnin kriteerit. Käyttötarkoitussidonnaisuuden periaate ja massadata-ilmiö vaikuttavat olevan perustavanlaatuisessa ristiriidassa keskenään. On kyseenalaista, täyttääkö käyttötarkoitussidonnaisuuden periaate edelleen tavoitteensa ja onko se edelleen tehokas tapa suojata henkilötietoja.The subject of this Master’s Thesis is to analyze the compatibility of the purpose limitation principle of the General Data Protection Regulation (GDPR) and the big data phenomenon. The purpose limitation principle has been one of the core principles of European data protection law since 1970s and it requires personal data to be collected for specified, explicit and legitimate purposes and not further processed in a manner that is incompatible with those purposes. The big data phenomenon consists of an enormous increase of information and the automated use of it that has led to a considerable change in data processing practices. The focus of the research is on examining the meaning and content of the purpose limitation principle and analyzing its objectives in the context of big data. The research method of this research is legal dogmatic. Firstly, the thesis describes the purpose specification requirement as developed in the opinions of the Article 29 Working Party and examines the conflict between the requirement and the characteristic of big data in which data are analyzed to find correlations and trends that may reveal new uses for the data. The thesis concludes that in practice it is very difficult to apply the requirement in the context of data discovery. Secondly, the thesis examines the compatibility assessment of the purpose limitation principle in the context of big data. The Article 29 Working Party has developed in its opinions certain criteria for the compatibility assessment that have now been introduced in the legislative text of the GDPR. The thesis examines the requirements of the compatibility assessment in light of the characteristic of big data in which value is derived from data by re-purposing them in novel ways. The thesis concludes that the criteria of the compatibility assessment can be hard to fulfil when considering the characteristics of big data. There seems to be an inherent conflict between the purpose limitation principle and the big data phenomenon. It is questionable whether the principle of purpose limitation can still meet the objectives it was created to fulfil and whether it is still a viable way of protecting personal data

Law and digitalization : an agenda for the future

The current state of affairs shows a strong need for action regarding legal digitalization. Even though the legal field is undergoing a transformation, there is not much research on digitalization and law. The lack of information needs to be remedied and The Legal Tech Lab aims to fulfill this need. The first steps are: 1) to define the phenomenon, 2) to establish best practices and 3) to actively create tools to facilitate navigating the legal system. The steps are recursive and should be advanced jointly. The main objective of the work is to improve access to justice

Altered TUBB3 expression contributes to the epothilone response of mitotic cells

BACKGROUND: Epothilones are a novel group of microtubule (mt) targeting cancer drugs that bind to the β-subunit of the αβ-tubulin dimer. Epothilones inhibit cell proliferation and induce cell death by interfering with the normal mt function. In this study, we examined the consequences of altered expression of human β-tubulin isotypes in terms of the epothilone drug response in human lung and breast cancer cell lines. METHODS: The β-tubulin isotypes TUBB2A–C, TUBB3 and TUBB were silenced or overexpressed in A549, A549EpoB40 and MCF7 cell lines in the presence or absence of epothilones. The drug effects on cell proliferation, mitosis and mt dynamics were determined using live cell microscopy and immunofluorescence assays. RESULTS: Loss of TUBB3 enhanced the action of epothilones. TUBB3 knockdown increased the severity of drug-induced mitotic defects and resulted in stabilisation of the mt dynamics in cells. Moreover, exogenous expression of TUBB3 in the epothilone resistant cell line conferred the response to drug treatments. In contrast, reduced levels of TUBB2A–C or TUBB had not apparent effect on the cells' response to epothilones. CONCLUSION: Our results show that the expression of TUBB3 contributes to the cellular response to epothilones, putatively by having an impact on the mt dynamics