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Tässä raportissa tarkastellaan kansalliseen ja kansainväliseen kirjallisuuteen pohjautuen sitä, kuin- ka yksilöiden ja ryhmien urasuunnittelutaidot vahvistuvat eri elämänvaiheissa ja konteksteissa. Lisäksi kuvataan sitä, millaisilla julkisilla ja yksityisillä palveluilla voidaan tukea urasuunnittelutaitojen kehittymistä. Urasuunnittelutaidot nähdään monitahoisina, metakognitiivisina koko elämän ajan rakentuvina kompetensseina, joita yksilö kehittää vuorovaikutuksessa yhteiskunnan kanssa. Raportissa tarkastellaan eri maiden urasuunnittelutaitojen viitekehyksiä ja kootaan yhteen kansallisten ja kansainvälisten arviointien sekä kehittämishankkeiden kautta havaittuja urasuunnittelutaitojen osatekijöitä, jotka ovat osoittautuneet merkityksellisiksi riippumatta kansallisesta kontekstista tai ohjauspalvelujen järjestämistavoista. Tarkastelussa huomioidaan se, millaisessa yhteiskunnallisessa ja sosiokulttuurisessa kontekstissa viitekehykset on laadittu, ja arvioidaan, miltä osin esitetyillä viitekehyksillä voisi olla yhtymäpintaa Suomen kansalliseen kontekstiin. Lisäksi ra- portissa tarkastellaan ja arvioidaan sitä, millaisin eri menetelmin urasuunnittelutaitojen lähtötasoa ja kehittymistä voidaan mitata, millaisia nämä mittarit ovat tai voisivat olla ja mihin niillä pyritään. Raportti sisältää konkreettisia ehdotuksia urasuunnittelutaitojen viitekehyksen kehittämisen tueksi Suomessa. Tämä raportti on laadittu osana KEHA-keskuksen toteuttamaa Urasuunnittelutaitojen edistämishanketta. Hanke pohjautuu Elinikäisen ohjauksen strategian 2020–2023 tavoitteisiin sekä Jatkuvan oppimisen parlamentaarisen uudistuksen (2020) linjauksiin. Elinikäisen ohjauksen valtakunnalliseen kehittämiseen on saatu EU:n elpymis- ja palautumistukivälineestä rahoitusta Suomen kestävän kasvun ohjelman perusteella.

Despite the use of the highly specific anti-HER2 receptor (trastuzumab) therapy, HER2-positive breast cancers account for 20-30% of all breast cancer carcinomas, with HER2 status a challenge to treatment interventions. The heparan sulfate proteoglycans (HSPGs) are prominently expressed in the extracellular matrix (ECM), mediate breast cancer proliferation, development, and metastasis with most studies to date conducted in animal models. This study examined HSPGs in HER2-positive human breast cancer cell lines and their contribution to cancer cell proliferation. The study examined the cells following enhancement (via the addition of heparin) and knockdown (KD; using short interfering RNA, siRNA) of HSPG core proteins. The interaction of HSPG core proteins and AKT signalling molecules was examined to identify any influence of this signalling pathway on cancer cell proliferation. Our findings illustrated the HSPG syndecan-4 (SDC4) core protein significantly regulates cell proliferation with increased BC cell proliferation following heparin addition to cultures and decreased cell number following SDC4 KD. In addition, along with SDC4, significant changes in CK19/AKT signalling were identified as mediators of BC HER2-positive BC cell proliferation. This study provides evidence for a cell growth regulatory axis involving HSPGs/CK19 and AKT that represents a potential molecular target to prevent proliferation of HER2-positive breast cancer cells.

Tässä raportissa tarkastellaan lukiokoulutuksen ja ammatillisen koulutuksen opinto-ohjauksen saatavuutta ja riittävyyttä osana elinikäisen ohjauksen jatkumoa valtioneuvoston (2020) hyväksymän elinikäisen ohjauksen strategian 2020–2023 painopistealueiden mukaisesti. Kansallisessa elinikäisen ohjauksen strategiassa 2020–2023 korostetaan, että ohjauspalvelujen järjestämistä koskevassa päätöksenteossa tulee varmistaa palvelujen saatavuus, tasa-arvoisuus ja yhdenvertaisuus. Palvelujen tuottajien tulee varmistaa, että palvelut ovat saatavilla monikanavaisesti ja ne rakentuvat itsepalvelusta, avustetusta palvelusta sekä intensiivisestä ohjauksesta opiskelijoiden tarpeiden mukaisesti. Palvelujen järjestäjän tulisi arvioida, vastaavatko palvelut eri opiskelijaryhmien tarpeita ja että ne toteutetaan kustannus- ja resurssitehokkaasti.

Summer schools are an important element of universities’ international strategies. During the COVID-19 pandemic, however, they often had to be canceled due to health-related concerns and political guidelines. The partner universities A (Finland) and B (Germany) decided to offer their summer schools in a virtual format in 2021 to allow students to gain international experience from their home country and to maintain international relations during the pandemic. By evaluating the success of their summer schools and sharing their experiences, they found that virtual summer schools have great potential. For certain students (with jobs, limited financial resources, mobility impairments, families to care for, etc.), virtual summer schools are particularly suitable and might even represent the only possibility to gain international experience. For virtual summer schools to be successful, however, universities have to consider organizational and pedagogical questions. In this article, organizers from A and B share their lessons learned as an inspiration for other institutions planning virtual summer schools that are immersive and engaging.

The authors thank Markus Kyllönen for his help in running some of the bleaching experiments, and to Yibo Ma for his guidance on the hemicellulose extraction procedure with EMIM OAc. Open Access funding provided by Aalto University. This work was cofunded by Andritz Oy, Kemira Oyj, Metsä Group Oy, Stora Enso Oyj, UPM Kymmene Oyj, Suzano Pulp and Paper and Aalto University School of Chemical Engineering. The stoichiometry of ozone and hypochlorous acid reactions with lignin and hexenuronic acid (HexA) was measured in bleaching experiments of Eucalyptus sp. kraft pulp. The progress of the reactions was followed by UV Resonance Raman spectroscopy that can quantify lignin and HexA based on the Raman scattering intensities of the carbon–carbon double bond in HexA and the aromatic ring in lignin. Here, one mol of ozone converted 0.16 mol of lignin (C9 monomer units) and 0.28 mol of HexA, whereas 1 mol of hypochlorous acid converted 0.09 mol of lignin and 0.23 mol of HexA. The use of a tertiary amine catalyst with the hypochlorous acid treatments did not affect these stoichiometries. The stoichiometric ratios showed that ozone was more efficient in oxidizing lignin than hypochlorous acid, while both electrophiles reacted with HexA to a similar extent. HexA reaction by hypochlorous acid was concluded to involve initial electrophilic chlorination of the carbon–carbon double bond, contributing to significant organochlorine (OX) formation in the pulp. Evidence on this was the linear correlation between the initial HexA content and OX (0.59 mol OX per mol HexA) and the high OX content in the xylan extracted from the bleached pulp. The 2D NMR HSQC and TOCSY spectra of the isolated xylans showed the disappearance of HexA signals after the treatment with hypochlorous acid and the appearance of a new spin system, yet to be fully identified.

Earth’s orbit and rotation introduces systematic annual variations in geomagnetic activity, most notably via the changing orientation of the dayside magnetospheric magnetic field with respect to the heliospheric magnetic field (HMF). However, aside from these geometric effects, it is generally assumed that the solar wind is randomly sampled throughout the year. But systematic changes in the intrinsic solar wind conditions in near-Earth space could arise due to the variation in Earth heliocentric distance and heliographic latitude over the year. In this study we use 24 years of Advanced Composition Explorer (ACE) data to investigate the annual variations in the scalar properties of the solar wind, namely the solar wind proton density, the radial solar wind speed and the HMF intensity. All parameters do show some degree of systematic annual variation, with amplitudes of around 10 to 20%. For HMF intensity, the variation is in phase with the Earth’s heliocentric distance variation, and scaling observations for distance largely removes the variation. For proton density and solar wind speed, however, scaling for distance does not affect the variation and the annual phase is inconsistent with Earth’s heliocentric distance variation. Instead we attribute the annual variations to Earth’s heliographic latitude variation and systematic sampling of higher speed solar wind at higher latitude. These variations are most strongly ordered at solar minimum. Conversely, combining scalar solar wind parameters to produce dynamic pressure and potential power input to the magnetosphere estimates results in solar maximum exhibiting a greater annual variation, with an amplitude of around 40%. This suggests Earth’s position in the heliosphere makes a significant contribution to space weather, in addition to the well studied geometric effects.

Localized dynamic pressure enhancements - jets - are regularly observed downstream of the Earth’s bow shock. They drive enhanced particle acceleration, larger amplitude magnetic field variations and reconnecting current sheets. Various shock simulations have also exhibited jets, suggesting that they are not unique to Earth.In this study, we search for similar dynamic pressure pulses downstream of interplanetary shocks observed by the Wind spacecraft. We discuss how the jet selection criteria are adapted for such conditions. The interplanetary shocks where we have found jet candidates feature foreshock activity, a favourable condition for jet formation according to bow shock studies. We examine the properties of the candidate jets and compare them to those reported for magnetosheath jets. Widening the range of environments where downstream jets are observed can shed light on their dynamics and formation mechanisms.

The company ST1 Oy planned to construct an Enhanced Geothermal System (EGS) with two boreholes drilled down to ca. 6 km depth beneath the Aalto University campus in Otaniemi, Espoo, on the border of Helsinki. The company performed two stimulations, in June–July 2018 and in May 2020, with a goal of opening up a water reservoir and achieving water circulation between the boreholes. The stimulation periods, which induced thousands of earthquakes, and their immediate surroundings were monitored by both permanent and temporary seismic networks with over 100 stations located within a few tens of kilometers of the site. Between and after the stimulations, the site was and is still being monitored by a relatively dense, consisting in total of ca. 20 stations, regional surface station and company installed borehole station networks.We have developed a cross-correlation based event detector which uses the existing ISUH manually analysed catalogues primarily of the 2018 and 2020 stimulation period seismicity, complemented by automatically picked catalogues from IMS, to detect events from the collected continuous waveform database. The 4-step detector – templating, detecting, event filtering & relocating – can run on varying station configuration and is able to detect events down to ML -0.5 – -1.0 with the station-event geometry around the EGS. We present here the results of the detector run from the beginning of the dense stimulation monitoring in May 2018 to the end of 2022 providing a comprehensive anatomy of the EGS induced seismicity.

Magnetosheath jets are dynamic pressure enhancements that are frequently observed downstream of the Earth's bow shock. Earthward propagating jets are significantly more likely to occur downstream of the quasi-parallel shock than the quasi-perpendicular shock. However, as the quasi-perpendicular geometry is the more common configuration at the Earth's bow shock, quasi-perpendicular jets can constitute a significant fraction of jets observed at Earth. Moreover, at other more quasi-perpendicular shock environments, such as at interplanetary shocks or the bow shocks of outer planets, they would be expected to form an even more significant portion of jets. We study the solar wind influence on jet formation in the quasi-parallel and quasi-perpendicular regimes by investigating jets in the Earth’s subsolar magnetosheath separately during low and high IMF cone angles. We find that during low IMF cone angles (downstream of the quasi-parallel shock) jet occurrence near the bow shock is not sensitive to other solar wind parameters. However, during high IMF cone angles (downstream of the quasi-perpendicular shock) jet occurrence is higher during low B, low n, high beta, and high MA conditions. This suggests that quasi-perpendicular jet formation is related to shock dynamics amplified by higher beta and MA. These observations from a wide range of solar wind parameters also allow us to make predictions of jet occurrence at other planetary systems.

Combining cytotoxic chemotherapy or novel anticancer drugs with T-cell modulators holds great promise in treating advanced cancers. However, the response varies depending on the tumor immune microenvironment (TIME). Therefore, there is a clear need for pharmacologically tractable models of the TIME to dissect its influence on mono- and combination treatment response at the individual level. Here we establish a Patient-Derived Explant Culture (PDEC) model of breast cancer, which retains the immune contexture of the primary tumor, recapitulating cytokine profiles and CD8+ T cell cytotoxic activity. We explored the immunomodulatory action of a synthetic lethal BCL2 inhibitor venetoclax + metformin drug combinationex vivo, discovering metformin cannot overcome the lymphocyte-depleting action of venetoclax. Instead, metformin promotes dendritic cell maturation through inhibition of mitochondrial complex I, increasing their capacity to co-stimulate CD4+ T cells and thus facilitating anti-tumor immunity. Our results establish PDECs as a feasible model to identify immunomodulatory functions of anticancer drugs in the context of patient-specific TIME.

We study the point pair function in subdomains $G$ of $\mathbb{R}^n$. We prove that, for every domain $G\subsetneq\mathbb{R}^n$, the this function is a quasi-metric with the constant less than or equal to $\sqrt{5}\slash2$. Moreover, we show that it is a metric in the domain $G=\mathbb{R}^n\setminus\{0\}$ with $n\geq1$. We also consider generalized versions of the point pair function, depending on an arbitrary constant $\alpha>0$, and show that in some domains these generalizations are metrics if and only if $\alpha\leq12$., Comment: 21 pages, 3 figures

Background and Aims Diabetes is associated with advanced liver disease and predicts mortality regardless of the primary aetiology of the liver disease. Even a family history of diabetes has been linked to advanced liver fibrosis in non-alcoholic fatty liver disease (NAFLD). However, the fraction of liver-related outcomes in the general population that are attributable to diabetes remains unclear. Methods The population attributable fraction (PAF) of diabetes for liver disease as a time-dependent exposure was estimated in the Finnish FINRISK study (n = 28 787) and the British Whitehall II study (n = 7855). We also assessed the predictive ability of a family history of diabetes for liver-related outcomes. Incident diabetes data were from drug purchase/reimbursement and healthcare registries (FINRISK) or follow-up examinations (Whitehall II). Incident severe liver outcomes were identified through linkage with national healthcare registries. Results Diabetes was associated with a two-fold risk of liver-related outcomes in both the FINRISK (HR, 1.92; p < .001) and Whitehall II (HR, 2.37; p < .001) cohorts, and this remained significant after adjusting for multiple confounders. PAF analyses demonstrated that diabetes explained 12-14% of the risk for severe liver-related outcomes after 10 and 20 years of follow-up. Also, maternal diabetes increased the risk of liver-related outcomes in the FINRISK (HR, 1.43; p = .044) and Whitehall II (HR, 2.04; p = .051) cohorts. Conclusion Approximately 12%-14% of severe liver-related outcomes are attributable to diabetes at the population level. The association between maternal diabetes and liver disease might suggest a mitochondrial genetic mechanism.

Uncertainty surrounding the risk of developing and dying from Thrombosis and Thromobocytopenia Syndrome (TTS) associated with the AstraZeneca (AZ) COVID-19 vaccine may contribute to vaccine hesitancy. A model is urgently needed to combine and effectively communicate the existing evidence on the risks versus benefits of the AZ vaccine. We developed a Bayesian network to consolidate the existing evidence on risks and benefits of the AZ vaccine, and parameterised the model using data from a range of empirical studies, government reports, and expert advisory groups. Expert judgement was used to interpret the available evidence and determine the structure of the model, relevant variables, data to be included, and how these data were used to inform the model.The model can be used as a decision support tool to generate scenarios based on age, sex, virus variant and community transmission rates, making it a useful for individuals, clinicians, and researchers to assess the chances of different health outcomes. Model outputs include the risk of dying from TTS following the AZ COVID-19 vaccine, the risk of dying from COVID-19 or COVID-19-associated atypical severe blood clots under different scenarios. Although the model is focused on Australia, it can be easily adaptable to international settings by re-parameterising it with local data. This paper provides detailed description of the model-building methodology, which can used to expand the scope of the model to include other COVID-19 vaccines, booster doses, comorbidities and other health outcomes (e.g., long COVID) to ensure the model remains relevant in the face of constantly changing discussion on risks versus benefits of COVID-19 vaccination.

Sulfur(VI) fluorides (SFs) have emerged as valuable electrophiles for the design of 'beyond cysteine' covalent inhibitors, and offer potential for expansion of the liganded proteome. Since SFs target a broad range of nucleophilic amino acids, they deliver an approach for the covalent modification of proteins without requirement for a proximal cysteine residue. Further to this, libraries of reactive fragments present an innovative approach for the discovery of ligands and tools for proteins of interest by leveraging a breadth of mass spectrometry analytical approaches. Herein, we report a screening approach that exploits the unique properties of SFs for this purpose. Libraries of SF-containing reactive fragments were synthesised, and a direct-to-biology workflow was taken to efficiently identify hit compounds for CAII and BCL6. The most promising hits were further characterised to establish the site(s) of covalent modification, modification kinetics, and target engagement in cells. Crystallography was used to gain a detailed molecular understanding of how these reactive fragments bind to their target. It is anticipated that this screening protocol can be used for the accelerated discovery of ‘beyond cysteine’ covalent inhibitors.

The searching efficiency of predators depends on the balance between the adaptations of the predator and the counter-adaptations of the prey. In this evolutionary race, the prey should normally have the upper hand, as it can perform tradeoffs between efficiency in resource use and ability to avoid predators. In terrestrial predator–herbi-vore systems, however, the huge difference in food quality between prey and predators seems to give predators an advantage. In productive terrestrial ecosystems, predators thus chronically overexploit herbivores, i.e. regulate them at densities far below the point of maximum sustainable yield. Assuming type II functional response, this should result in violent limit cycle dynamics. In reality, however, such cycles are only common at high latitudes, whereas the herbivory-based food webs of species-rich ecosystems at middle and low latitudes are characterized by asymptotic dynamics, where numerical changes only occur in response to external forcing. One way or another, diversity thus seems to beget stability in terrestrial grazing webs. We propose that strong, donor-controlled energy flows from the detritus web and directly from plants to predators are the key for the prevalence of asymptotic dynamics at middle and low latitudes. These flows support generalists with type III functional response and, therefore, a capacity to curb budding outbreaks at an early stage. The ongoing extinction wave could critically weaken these stabilizing interactions, which could destabilize currently stable food webs. and result in violent limit cycle dynamics in ecosystems, where the dominating species have evolved under asymptotic dynamics. This could cause secondary extinc-tions and inflict large economic losses

USP28 expression in hepatocellular carcinoma and generation of an Usp28 knockout mouse.

Toll-like receptor 9 (TLR9) belongs to the innate immune system and recognizes microbial and vertebrate DNA. We showed previously that treatment with the TLR9-agonistic ODN M362 (a CpG sequence containing oligonucleotide) induces matrix metalloproteinase-13–mediated invasion in TLR9-expressing human cancer cell lines. Here, we further characterized the role of the TLR9 pathway in this process. We show that CpG oligonucleotides induce invasion in macrophages from wild-type C57/B6 and MyD88 knockout mice and in human MDA-MB-231 breast cancer cells lacking MyD88 expression. This effect was significantly inhibited in macrophages from TLR9 knockout mice and in human MDA-MB-231 breast cancer cells stably expressing TLR9 small interfering RNA or dominant-negative tumor necrosis factor receptor-associated factor 6 (TRAF6). Sequence modifications to the CpG oligonucleotides that targeted the stem loop and other secondary structures were shown to influence the invasion-inducing effect in MDA-MB-231 cells. In contrast, methylation of the cytosine residues of the parent CpG oligonucleotide did not affect the TLR9-mediated invasion compared with the unmethylated parent CpG oligonucleotide. Finally, expression of TLR9 was studied in clinical breast cancer samples and normal breast epithelium with immunohistochemistry. TLR9 staining localized in epithelial cells in both cancer and normal samples. The mean TLR9 staining intensity was significantly increased in the breast cancer cells compared with normal breast epithelial cells. In conclusion, our results suggest that TLR9 expression is increased in breast cancer and CpG oligonucleotide–induced cellular invasion is mediated via TLR9 and TRAF6, independent of MyD88. Further, our findings suggest that the structure and/or stability of DNA may influence the induction of TLR9-mediated invasion in breast cancer. (Mol Cancer Res 2008;6(10):1534–43)

Supplementary Figure S1 from Toll-Like Receptor 9 Mediates CpG Oligonucleotide–Induced Cellular Invasion

Knockdown of USP28 affects HIF-1a, c-Myc, c-Jun and Notch1 protein levels and enhances EMT markers in BT-549 cells.

Recent studies suggest that the ubiquitin-specific protease USP28 plays an important role in cellular repair and tissue remodeling, which implies that it has a direct role in carcinogenesis. The carcinogenic potential of USP28 was investigated in a comprehensive manner using patients, animal models, and cell culture. The findings demonstrate that overexpression of USP28 correlates with a better survival in patients with invasive ductal breast carcinoma. Mouse xenograft experiments with USP28-deficient breast cancer cells also support this view. Furthermore, lack of USP28 promotes a more malignant state of breast cancer cells, indicated by an epithelial-to-mesenchymal (EMT) transition, elevated proliferation, migration, and angiogenesis as well as a decreased adhesion. In addition to breast cancer, lack of USP28 in mice promoted an earlier onset and a more severe tumor formation in a chemical-induced liver cancer model. Mechanistically, the angio- and carcinogenic processes driven by the lack of USP28 appeared to be independent of HIF-1α, p53, and 53BP1.Implications: The findings of this study are not limited to one particular type of cancer but are rather applicable for carcinogenesis in a more general manner. The obtained data support the view that USP28 is involved in tumor suppression and has the potential to be a prognostic marker. Mol Cancer Res; 16(6); 1000–12. ©2018 AACR.

Overview of macroscopic changes in liver morphology.

Lack of USP28 does not affect p53 and 53BP1 protein levels in human cells or mouse tissue samples.

Knockdown of USP28 downregulates HIF-1a, c-Myc, c-Jun and Notch1 protein levels but enhances cell proliferation in MCF7 cells.

Primers used for qRT-PCR

The immunosuppressive microenvironment in glioblastoma (GBM) prevents an efficient antitumoral immune response and enables tumor formation and growth. Although an understanding of the nature of immunosuppression is still largely lacking, it is important for successful cancer treatment through immune system modulation. To gain insight into immunosuppression in GBM, we performed a computational analysis to model relative immune cell content and type of immune response in each GBM tumor sample from The Cancer Genome Atlas RNA-seq data set. We uncovered high variability in immune system–related responses and in the composition of the microenvironment across the cohort, suggesting immunologic diversity. Immune cell compositions were associated with typical alterations such as IDH mutation or inactivating NF1 mutation/deletion. Furthermore, our analysis identified three GBM subgroups presenting different adaptive immune responses: negative, humoral, and cellular-like. These subgroups were linked to transcriptional GBM subtypes and typical genetic alterations. All G-CIMP and IDH-mutated samples were in the negative group, which was also enriched by cases with focal amplification of CDK4 and MARCH9. IDH1-mutated samples showed lower expression and higher DNA methylation of MHC-I–type HLA genes. Overall, our analysis reveals heterogeneity in the immune microenvironment of GBM and identifies new markers for immunosuppression. Characterization of diverse immune responses will facilitate patient stratification and improve personalized immunotherapy in the future.Significance: This study utilizes a computational approach to characterize the immune environments in glioblastoma and shows that glioblastoma immune microenvironments can be classified into three major subgroups, which are linked to typical glioblastoma alterations such as IDH mutation, NF1 inactivation, and CDK4-MARCH9 locus amplification.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/19/5574/F1.large.jpg. Cancer Res; 78(19); 5574–85. ©2018 AACR.

PDF file, 70K, Availability of information on tumor morphology and receptor status for Europeans, by each included BCAC study.

Supplementary figures S2-S6. Supplementary Figure S2: A diagram depicting the location of the studied SNPs and miR-200a binding site in KEAP1 gene. Supplementary Figure S3: Association of KEAP1 rs11085735 with breast cancer survival among the KBCP and OBCS breast cancer cases. Supplementary Figure S4: Association of KEAP1 rs11085735 with breast cancer survival among the ER positive cases. Supplementary Figure S5: Association of KEAP1 rs11085735 with breast cancer survival among KBCP cases with lower (

File contains supplementary figures S1-S12. Figures include the concept, results and validation of the regression analysis, estimated cell proportions for all the non-malignant reference cells and tissues, validation of immune subgroups in separate GBM cohort, and different associations between GBM subgroups, genetic aberrations, relative cell proportions or cluster. Furthermore, figures showing gene expression of HLA genes in immune subgroups as well as HLA protein levels in glioma cell lines and patient-derived GBM cultures are included.

Tables contain immune system related Gene ontology and KEGG pathway enrichments for identified immune response related gene clusters.

Tables contain immune subgroup for each sample and results from statistical testing for all probes from Illumina Infinium Human DNA Methylation 450 array. Statistical testing was done between the following sample groups: IDH1 mutated sampels; IDH1 wild type samples with CDK4-MARCH9 locus amplification; Other IDH1 wild type samples.

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Table contains copy number variation of genes adjacent to CDK4 (AGAP2, MARCH9, TSPAN31) in samples with CDK4 amplification.

Supplementary tables S1-S10. S1. Significant associations of the KEAP1 protein expression and receptor statuses; S2. Association of the KEAP1 protein expression with NRF2 protein expression; S3. Analyzed polymorphisms in the KEAP1 gene; S4. Significant associations of the KEAP1 SNP genotypes with KEAP1 protein expression; S5. Associations of the KEAP1 SNP s11085735 genotypes with NRF2 protein expression; S6. Associations of the KEAP1 SNPs with breast cancer survival in multivariate analysis among invasive KBCP and OBCS breast cancer cases separately; S7. Variables significantly associated with breast cancer survival in multivariate analysis among invasive KBCP and OBCS breast cancer cases; S8. Significant associations with breast cancer survival in univariate analysis (Kaplan-Meier) according to KEAP1 SNP rs11085735 genotypes among KBCP and OBCS ER positive cases, KBCP ER positive cases and KBCP cases with low/negative ({less than or equal to}1.33) KEAP1 protein expression levelS9. Variables significantly associated with breast cancer survival in multivariate analysis among ER positive KBCP breast cancer cases; S10. Variables significantly associated with breast cancer survival in multivariate analysis among (KBCP) cases with lower KEAP1 protein expression

Purpose: Defective oxidative stress response may increase cancer susceptibility. In tumors, these rescue mechanisms may cause chemo- and radioresistance impacting patient outcome. We previously showed that genetic variation in the nuclear factor erythroid 2–related factor 2 (NFE2L2) is associated with breast cancer risk and prognosis. Here we further studied this pathway by investigating Kelch-like ECH-associated protein 1 (KEAP1).Experimental Design: Five tagging SNPs in the KEAP1 gene were genotyped in 996 breast cancer cases and 880 controls from two Finnish case–control sets. KEAP1 protein expression was studied in 373 invasive breast cancer tumors.Results: rs34197572 genotype TT was associated with increased risk of breast cancer in the KBCP samples [P = 1.8×10−4; OR, 7.314; confidence interval (CI), 2.185–24.478]. rs11085735 allele A was associated with lower KEAP1 protein expression (P = 0.040; OR,= 3.545) and high nuclear NRF2 expression (P = 0.009; OR, 2.445) and worse survival in all invasive cases (P = 0.023; HR, 1.634). When including treatment data, rs11085735 was associated with recurrence-free survival (RFS; P = 0.020; HR, 1.545) and breast cancer–specific survival (P = 0.016; HR, 1.683) and rs34197572 with overall survival (P = 0.045; HR, 1.304). rs11085735 associated with RFS also among tamoxifen-treated cases (P = 0.003; HR, 3.517). Among radiotherapy-treated cases, overall survival was associated with rs34197572 (P = 0.018; HR, 1.486) and rs8113472 (P = 0.025; HR, 1.455). RFS was associated with rs9676881 (P = 0.024; HR, 1.452) and rs1048290 (P = 0.020; HR, 1.468) among all invasive cases and among estrogen receptor (ER)-positive tamoxifen-treated cases (P = 0.018; HR, 2.407 and P = 0.015; HR, 2.476, respectively).Conclusions: The present findings suggest that the investigated SNPs have effects related to oxidative stress induced by cancer treatment, supporting involvement of the NRF2/KEAP1 pathway in breast cancer susceptibility and patient outcome. Clin Cancer Res; 21(7); 1591–601. ©2015 AACR.

Background: The single-nucleotide polymorphism (SNP) 5p12-rs10941679 has been found to be associated with risk of breast cancer, particularly estrogen receptor (ER)-positive disease. We aimed to further explore this association overall, and by tumor histopathology, in the Breast Cancer Association Consortium.Methods: Data were combined from 37 studies, including 40,972 invasive cases, 1,398 cases of ductal carcinoma in situ (DCIS), and 46,334 controls, all of white European ancestry, as well as 3,007 invasive cases and 2,337 controls of Asian ancestry. Associations overall and by tumor invasiveness and histopathology were assessed using logistic regression.Results: For white Europeans, the per-allele OR associated with 5p12-rs10941679 was 1.11 (95% CI = 1.08–1.14, P = 7 × 10−18) for invasive breast cancer and 1.10 (95% CI = 1.01–1.21, P = 0.03) for DCIS. For Asian women, the estimated OR for invasive disease was similar (OR = 1.07, 95%CI = 0.99–1.15, P = 0.09). Further analyses suggested that the association in white Europeans was largely limited to progesterone receptor (PR)-positive disease (per-allele OR = 1.16, 95% CI = 1.12–1.20, P = 1 × 10−18 vs. OR = 1.03, 95% CI = 0.99–1.07, P = 0.2 for PR-negative disease; Pheterogeneity = 2 × 10−7); heterogeneity by ER status was not observed (P = 0.2) once PR status was accounted for. The association was also stronger for lower grade tumors [per-allele OR (95% CI) = 1.20 (1.14–1.25), 1.13 (1.09–1.16), and 1.04 (0.99–1.08) for grade 1, 2, and 3/4, respectively; Ptrend = 5 × 10−7].Conclusion: 5p12 is a breast cancer susceptibility locus for PR-positive, lower grade breast cancer.Impact: Multicenter fine-mapping studies of this region are needed as a first step to identifying the causal variant or variants. Cancer Epidemiol Biomarkers Prev; 20(10); 2222–31. ©2011 AACR.

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Tables contain results from Ingenuity Pathway Analysis for immune system related gene clusters.

PDF file, 57K, Genotyping characteristics of each BCAC participating study.

Background: Our recent genome-wide association study identified a novel breast cancer susceptibility locus at 9q31.2 (rs865686).Methods: To further investigate the rs865686–breast cancer association, we conducted a replication study within the Breast Cancer Association Consortium, which comprises 37 case–control studies (48,394 cases, 50,836 controls).Results: This replication study provides additional strong evidence of an inverse association between rs865686 and breast cancer risk [study-adjusted per G-allele OR, 0.90; 95% confidence interval (CI), 0.88; 0.91, P = 2.01 × 10−29] among women of European ancestry. There were ethnic differences in the estimated minor (G)-allele frequency among controls [0.09, 0.30, and 0.38 among, respectively, Asians, Eastern Europeans, and other Europeans; P for heterogeneity (Phet) = 1.3 × 10−143], but no evidence of ethnic differences in per allele OR (Phet = 0.43). rs865686 was associated with estrogen receptor–positive (ER+) disease (per G-allele OR, 0.89; 95% CI, 0.86–0.91; P = 3.13 × 10−22) but less strongly, if at all, with ER-negative (ER−) disease (OR, 0.98; 95% CI, 0.94–1.02; P = 0.26; Phet = 1.16 × 10−6), with no evidence of independent heterogeneity by progesterone receptor or HER2 status. The strength of the breast cancer association decreased with increasing age at diagnosis, with case-only analysis showing a trend in the number of copies of the G allele with increasing age at diagnosis (P for linear trend = 0.0095), but only among women with ER+ tumors.Conclusions: This study is the first to show that rs865686 is a susceptibility marker for ER+ breast cancer.Impact: The findings further support the view that genetic susceptibility varies according to tumor subtype. Cancer Epidemiol Biomarkers Prev; 21(10); 1783–. ©2012 AACR.

Tables contain statistically significant associations between cluster activities and mutations or copy number variations in genes.