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Esipuhe Käsillä olevassa julkaisussa tuomme esiin Perheen erossaolon ylisukupolvinen muistaminen -tutkimushankkeen (Suomen Akatemia, 2019–2023, päätösnumero 344527) keskeisimpiä tuloksia. Kiitämme lämpimästi jokaista tähän tutkimukseen osallistunutta inkeriläistaustaista kyselyyn vastannutta ja elämäkerralliseen haastatteluun osallistunutta. Ilman heidän panostaan tämä inkeriläisten jälkeläisten hyvinvointiin ja perhemuisteluun keskittynyt hanke olisi ollut mahdoton toteuttaa. Hankkeessa kerätty tutkimusaineisto on avannut uusia väyliä inkeriläisten piiloon jääneiden kokemusten ja laajemmin heidän sosiaalihistoriansa tutkimukselle. Perhemuistojen kerääminen on mahdollistanut inkeriläisten historian tarkastelun heidän omista lähtökohdistaan. Tämä näkökulma on aiemmassa tutkimuksessa jäänyt monilta osin huomiotta, koska tutkimus on pitkälti nojautunut suomalaisten viranomaisten tuottamaan materiaaliin. Perhemuistojen tutkimus tuo esiin inkeriläisten 1900-luvun historian vaiherikkauden ja inkeriläistaustaisen yhteisön moninaisuuden. Nämä ovat jääneet jossain määrin varjoon myös inkeriläisten muistelmakirjallisuudessa ja heidän lähettämiensä kirjeiden tutkimuksessa. Monia inkeriläistaustaisia yhdistää perheitä koetellut vaino ja syrjintä. Eri maissa asuvat inkeriläiset ovat joutuneet piilottamaan etnisen taustansa, syntyperänsä tai kansalaisuutensa selviytyäkseen arkielämässä, sopeutuakseen uuteen yhteiskuntaan tai jopa pysyäkseen hengissä. Tutkimuksemme osoittaa, että tällaisilla perheissä sanallisesti tai sanattomasti jaetuilla kokemuksilla, tai niistä vaikenemisella, on ylisukupolvisia vaikutuksia jälkipolvien hyvinvointiin. Nämä kokemukset vaikuttavat monella tapaa myös eri maissa asuvien perheenjäsenien yhteydenpitoon. Venäjän hyökkäyssota Ukrainassa, poliittisesti kiristynyt tilanne Venäjällä sekä Venäjää ja sen kansalaisia koskevien asenteiden koveneminen ovat tuoneet esiin, miten tärkeää on tutkia ennakkoluulojen pitkiä jälkiä ja perheiden pakotettua hajoamista sodan, vainojen ja pakolaisuuden seurauksena. Moni inkeriläistaustainen toivoo, että inkeriläisten perheiden historiaa tunnettaisiin paremmin ja sitä myös käsiteltäisiin julkisesti. Tässä hankkeessa jaetut inkeriläisten kokemukset havainnollistavat jokaisen inhimillistä tarvetta tulla nähdyksi ja muistetuksi omalla tarinallaan. Osa tutkimuksen haastatteluista arkistoidaan Suomalaisen Kirjallisuuden Seuran (SKS) arkistoon vuoden 2023 aikana. Kiitämme SKS:n yhteistyökumppaneita, erityisesti Maiju Kortetta, hankkeemme tukemisesta. Kiitämme Taisto Raudalaista avusta kyselyaineiston keruussa Virossa ja Kristel Edelmania, jonka työpanos ja asiantuntemus mahdollistivat tutkimuksen vironkielisten haastatteluiden ja kyselyiden toteutuksen. Kyselyaineisto arkistoidaan Tietoarkistoon. Toivomme, että inkeriläisyyden tutkimus jatkuu arkistoaineistoja hyödyntämällä myös tämän hankkeen päätyttyä. Kiitokset myös Aleksi Huhdalle tärkeästä panoksesta hankkeen suunnitteluvaiheessa, hankkeen ohjausryhmälle sekä Oulun yliopiston ja Siirtolaisuusinstituutin kollegoille tuesta läpi hankkeen toteutuksen. Lopuksi haluamme osoittaa lämpimät kiitoksemme Sarianna Kranzille ja Pertti Alanteelle, jotka ovat antaneet taidettaan julkaisun kuvitukseksi.

The project Postmemory of Family Separation: An Intergenerational Perspective (Academy of Finland, 2019–2023) has gathered information about the mental health of Ingrian descendants whose family history include forced migration, ethnic persecution, and family separation. This research report presents the results of the survey. The data was collected through a mail and online survey in Finland in 2021. Two archival sources were used to reach the target group: the Ingrian refugee congregation’s list of children born in 1919–1950 and the list of Soviet citizens in Finland in 1955. The address information was obtained from the population register for those descendants who were over 15 years old and had a permanent address in Finland at the time. The invitation to participate in the research was sent to 1227 descendants, i.e., children and grandchildren of Ingrians who had experienced forced migration in the first half of the 20th century. The survey response rate was 52. The survey data consists of 650 respondents, of which 282 are children (i.e., second generation) and 368 grandchildren (i.e., third generation) of displaced Ingrians. All second-generation participants are children of Ingrians who were transferred from the Soviet Union to Finland during the Second World War. Their average age was 65 years. Of the third-generation respondents, 209 are grandchildren of these forcibly displaced Ingrians (average age 38 years). In addition, 159 of the third-generation participants are descendants of Ingrian refugees who came to Finland during the First World War (average age 66 years). Traumatic experiences related to war and persecution were common in the respondents’ family history and were reported especially among the second-generation respondents. More than half of the respondents (58%) felt that their parents had been open about their Ingrian background. The descendants’ experience that the parents had kept quiet or concealed things related to their Ingrian background was, however, common. Almost half of the second-generation respondents (45%) felt that their parents had avoided talking about their Ingrian background. Regarding mental health, the study looked at the general quality of life, loneliness, sense of coherence, and psychological strain. The results show that mental health is generally lowest among the youngest respondents, who are under the age of 40. Tiivistelmä Perheen erossaolon ylisukupolvinen muistaminen -tutkimushankkeessa (Suomen Akatemia, 2019–2023) on kerätty tietoa pakkomuuttoja, etnistä vainoa ja perheen hajaantumista kokeneiden inkeriläisten jälkeläisten mielen hyvinvoinnista Suomessa tänä päivänä. Tässä tutkimusraportissa esitellään kyselytutkimuksen perustuloksia. Tutkimuksen aineisto kerättiin posti- ja verkkokyselynä kesällä 2021. Tutkittavien tavoittamiseksi hyödynnettiin kahta arkistolähdettä: Inkerin pakolaisseurakunnan vuonna 1919–1950 syntyneiden lasten luetteloa ja Neuvostoliiton kansalaiset Suomessa vuonna 1955 -luetteloa. Tutkimuksen perusjoukko koostuu näistä luetteloista poimittujen inkeriläisten yli 15-vuotiaista jälkeläisistä, joilla oli poiminta-ajankohtana vakinainen osoite Suomessa. Heidän osoitetietonsa saatiin väestörekisteristä. Kyselykutsu lähetettiin 1227 inkeriläisen jälkeläiselle eli pakkomuuttoja 1900-luvun alkupuolella kokeneiden inkeriläisten lapsille ja lapsenlapsille. Kyselyn vastausprosentti oli 52. Tutkimukseen osallistui 650 henkilöä, joista 282 on pakkomuuttoja kokeneiden inkeriläisten lapsia (toinen sukupolvi) ja 368 lapsenlapsia (kolmas sukupolvi). Toisen sukupolven vastaajista kaikki kuuluvat siirtoväkenä toisen maailmansodan aikana Suomeen tulleiden inkeriläisten jälkeläisiin. Heidän keski-ikänsä oli keruuajankohtana 65 vuotta. Kolmannen sukupolven vastaajista 159 on ensimmäisen maailmansodan aikoihin Suomeen tulleiden Inkerin pakolaisten jälkeläisiä (keski-ikä 66 vuotta) ja 209 siirtoväkenä tulleiden lapsenlapsia (keski-ikä 38 vuotta). Sotaan ja vainoon liittyvät traumaattiset kokemukset olivat vastaajien perhehistoriassa yleisiä ja niistä raportoitiin erityisesti toisessa sukupolvessa. Yli puolet vastaajista (58 %) koki vanhempiensa olleen avoimia inkeriläistaustastaan. Jälkeläisten kokemus siitä, että vanhemmat olivat vaienneet tai salanneet inkeriläistaustaansa liittyviä asioita, oli kuitenkin yleinen. Toisen sukupolven vastaajista lähes joka toinen (45 %) koki vanhempiensa vältelleen inkeriläistaustastaan puhumista. Mielen hyvinvoinnin osalta tutkimuksessa tarkasteltiin yleistä elämänlaatua, yksinäisyyden kokemusta, koherenssin tunnetta ja psyykkistä kuormittuneisuutta. Tulokset osoittavat mielen hyvinvoinnin olevan yleisesti heikointa nuorimpien, alle 40-vuotiaiden vastaajien keskuudessa.

Supplementary Methods PDF file - 98K, Supplementary materials and methods

Supplementary Table S2 PDF file - 90K, Ingenuity transcription factor analysis of CIP2A depleted cells

Supplementary Table S3 PDF file - 64K, Sequences of siRNAS, RT-PCR primers and ChIP primers

Supplementary Figure 5 PDF file - 82K, Prognostic value of CIP2A in advanced human breast cancer patient material and characterization of vinorelbine effects

Supplementary Figure 4 PDF file - 269K, Characterization of hypomorphic CIP2A HOZ mice

Supplementary Figure 3 PDF file - 114K, RB expression is not needed for CIP2A-depletion induced senescence

Supplementary Table S1 PDF file - 71K, CIP2A overexpression frequencies and clinical relevance in human cancer types

Supplementary Figure 2 PDF file - 96K, Transcriptional regulation and functional role for CIP2A in response to p53 reactivation

Background Changes in the incidence of melanoma in children and adolescents have been reported in Europe and in the USA in the recent decades. Aims The aim of this study was to examine the incidence of paediatric and adolescent melanomas in Finland in 1990-2014, and the associated clinical and histopathological characteristics to reveal temporal trends, such as changes in diagnostic sensitivity of Spitzoid melanomas. Methods Information on 122 patients diagnosed with cutaneous melanoma at 0-19 years of age in Finland in 1990-2014 were retrieved from the Finnish Cancer Registry. 73 primary melanoma archival samples were re-evaluated by two dermatopathologists to allow comparability over time. Results A 5.6% annual increase was observed in the incidence of melanoma among children and adolescents during the study period. Fifty-six tumours were confirmed as malignant melanomas in the re-evaluation. After correction for tumour misclassification in the Cancer Registry, the age-adjusted annual incidence was estimated to have increased from 1.4/1 000 000 in 1990-1994 to 5.8/1 000 000 in 2010-2014. The change in incidence was most prominent among adolescents and in Spitzoid melanoma subtype. Melanomas diagnosed 1990-2002 and 2003-2014 did not differ in terms of their clinicopathological characteristics or prognosis (hazard ratio for melanoma-related death 1.53, 95% CI 0.30 to 7.88). Spitzoid melanomas were diagnosed at a younger age, were of higher stage and had higher Clark level than other melanomas, yet the hazard ratio for death was 0.52 (95% CI 0.10 to 2.58) for Spitzoid versus other melanomas. Conclusions The incidence of cutaneous melanoma has clearly increased among the young in Finland, especially among adolescents. No evidence for overdiagnosis of Spitzoid melanomas as the underlying cause of the increased incidence was observed. Key message A nationwide retrospective re-evaluation of the cutaneous melanomas recorded in the Finnish Cancer Registry among patients aged 0-19 years in Finland in 1990-2014 revealed an approximately 4-fold increase in the incidence. The increase in the incidence was most prominent among adolescents and in the Spitzoid melanoma subtype. Our results contrast those reported in other countries, where the incidence of melanoma among adolescents has declined.

Supplementary tables S1-S5 and supplementary figures S1-S5

Purpose:Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncoprotein that inhibits the tumor suppressor PP2A-B56α. However, CIP2A mRNA variants remain uncharacterized. Here, we report the discovery of a CIP2A splicing variant, novel CIP2A variant (NOCIVA).Experimental Design:Characterization of CIP2A variants was performed by both 3′ and 5′ rapid amplification of cDNA ends from cancer cells. The function of NOCIVA was assessed by structural and molecular biology approaches. Its clinical relevance was studied in an acute myeloid leukemia (AML) patient cohort and two independent chronic myeloid leukemia (CML) cohorts.Results:NOCIVA contains CIP2A exons 1 to 13 fused to 349 nucleotides from CIP2A intron 13. Intriguingly, the first 39 nucleotides of the NOCIVA-specific sequence are in the coding frame with exon 13 of CIP2A and code for a 13-amino acid peptide tail nonhomologous to any known human protein sequence. Therefore, NOCIVA translates to a unique human protein. NOCIVA retains the capacity to bind to B56α, but, whereas CIP2A is predominantly a cytoplasmic protein, NOCIVA translocates to the nucleus. Indicative of prevalent alternative splicing from CIP2A to NOCIVA in myeloid malignancies, AML and CML patient samples overexpress NOCIVA, but not CIP2A mRNA. In AML, a high NOCIVA/CIP2A mRNA expression ratio is a marker for adverse overall survival. In CML, high NOCIVA expression is associated with inferior event-free survival among imatinib-treated patients, but not among patients treated with dasatinib or nilotinib.Conclusions:We discovered a novel variant of the oncoprotein CIP2A and its clinical relevance in predicting tyrosine kinase inhibitor therapy resistance in myeloid leukemias.

Oncolytic viruses have gained attention as a novel form of cancer treatment. Many viral vectors in use today have been rendered safe by deletion of genes encoding viral structural proteins, thus making them unable to spread beyond the first infected cells. Hence, such replication-deficient constructs may lack efficacy. Here, we analyzed the oncolytic potential of the replication-competent vector VA7-EGFP, based on the avirulent Semliki Forest virus (SFV) strain A7(74), to kill cancer cells in culture as well as to target s.c. human melanoma xenografts in severe combined immunodeficient (SCID) mice. VA7-EGFP was able to infect most cancer cell lines studied, leading to complete lysis of the cells within 72 hours after infection. In SCID mice grafted with A2058 human melanoma, marked regression of the xenografts was observed following a single injection of 106 plaque-forming units of virus given either i.p., i.v., or intratumorally. Histologic analysis revealed the presence of virus not only in all treated tumors but also in the brains of the treated mice, causing progressing neuropathology beginning at day 16 after infection. Following initial oncolysis, clusters of viable tumor cells were observed embedded in connective tissue, and at later stages, encapsulated tumor nodules had formed. Infection of melanoma cells from explant cultures of these nodules revealed that a portion of the cells were resistant to virus. To be eligible for use in virotherapy, the ability of avirulent SFV to spread within tumor tissue may have to be improved and the biological safety of the virus may have to be addressed thoroughly in higher animals. (Cancer Res 2006; 66(14): 7185-94)

Supplementary Table 1 from Hypoxic Conversion of SMAD7 Function from an Inhibitor into a Promoter of Cell Invasion

Supplementary Figures 1-8 from Hypoxic Conversion of SMAD7 Function from an Inhibitor into a Promoter of Cell Invasion

Supplementary Figures 1-3 from Oncolytic Capacity of Attenuated Replicative Semliki Forest Virus in Human Melanoma Xenografts in Severe Combined Immunodeficient Mice

Supplementary Figure Legends 1-8 from Hypoxic Conversion of SMAD7 Function from an Inhibitor into a Promoter of Cell Invasion

Smad7 is an inhibitor of the transforming growth factor-β–activated signaling pathway. Under well-oxygenated conditions, Smad7 is a potent inhibitor of carcinoma cell invasion. Paradoxically, however, the expression of Smad7 is upregulated across several cancers and may promote cancer progression. Hypoxia, which is frequently met in solid tumors, is an enhancer of carcinoma cell invasion and cancer progression. Here, we report that hypoxia activates the expression of Smad7 in a hypoxia-inducible factor– and von Hippel-Lindau protein–dependent manner. As expected, in normoxia, the forced expression of Smad7 inhibited carcinoma cell invasion. In contrast with the normoxic condition, the inhibitory effect of Smad7 was lost under hypoxia. The block in carcinoma cell invasion by forced expression of Smad7 was released by hypoxia in two invasive carcinoma cell lines. Moreover, the noninvasive HaCaT keratinocytes become invasive upon simultaneous hypoxia and transforming growth factor-β stimulus. The hypoxia-activated invasion was attenuated by inhibiting Smad7 expression by short interfering RNA. Finally, the increased Smad7 expression in human carcinomas correlated with hypoxic gene expression. The data provide evidence that hypoxia could convert Smad7 function from an invasion inhibitor into an activator of invasion. Furthermore, they might shed light as to why increased Smad7 expression is detected in cancers. Cancer Res; 70(14); 5984–93. ©2010 AACR.

How has international business (IB) research evolved to account for the politicization of the context in which multinational corporations (MNCs) operate? To address this question, we review research at the nexus of location, politics, and the MNC from 2000 through 2021. Rooted in classic IB theories, our review reveals three directions in current IB research: (i) expansion of MNC agency in shaping the political environment, (ii) a wider diversity of actors involved in the business–government–society interface, and (iii) extension of the levels of analysis from country level to sub- and supra-national levels. This three-fold evolution has moved IB research closer to the field of political geography, but the shift has remained largely implicit and its theoretical linkages are few. Drawing on key theoretical insights from political geography, we discuss the opportunities and challenges of bringing political geography into IB research.

PurposePrevious research has shown that in contemporary societies, women have a healthier dietary intake than men. However, no research has examined how this gender gap develops over the long term. The present study examined how gender differences in fresh vegetable intake frequency have evolved from 1979 to 2017 in Finland and whether differences are affected by age or educational level.Design/methodology/approachThe data were derived from annually repeated, nationally representative “Health Behaviour and Health among the Finnish Adult Population” and “Regional Health and Well-being (RHW)” surveys on the health habits of the Finnish population. The dataset is a time series of repeated cross-sectional surveys. In total, the data sample comprised 161,996 Finns aged 20–64 years. Descriptive methods and logistic regression were used for the analysis.FindingsDuring 1979–2017, the prevalence of daily vegetable intake increased from 12 to 35% among men and from 18 to 56% among women. Thus, the magnitude of the gap between genders doubled across the study period. The increased vegetable intake was partly explained by the changing education and age structures of society. Potential explanations and avenues for future research are also discussed. Policy implications depend on whether the findings are interpreted as a case of health differences or health inequality.Originality/valueThis study used a long time series to analyse how gender differences in vegetable intake have evolved in a Nordic welfare state context. It showed that the gap in fresh vegetable intake between men and women has widened.

The aim was to assess the risk of hyperacusis in relation to occupational noise exposure among female workers in general, and among women working in preschool specifically.A retrospective longitudinal study was performed. Survey data were collected in 2013 and 2014 from two cohorts: randomly selected women from the population in region Västra Götaland, Sweden, and women selected based on having received a preschool teacher degree from universities in the same region. The final study sample included n = 8328 women born between 1948 and 1989. Occupational noise exposure was objectively assigned to all time periods from the first to the last reported occupation throughout working life, using the Swedish Job-Exposure Matrix (JEM) with three exposure intervals:75 dB(A), 75 to 85 dB(A), and85 dB(A). The JEM assigns preschool teachers to the 75 to 85 dB(A) exposure interval. The outcome hyperacusis was assessed by self-report using one question addressing discomfort or pain from everyday sounds. In the main analysis, a hyperacusis event was defined by the reported year of onset, if reported to occur at least a few times each week. Additional sensitivity analyses were performed using more strict definitions: (a) at least several times each week and (b) every day. The risk (hazard ratio, HR) of hyperacusis was analyzed in relation to years of occupational noise exposure, using survival analysis with frailty regression modeling accounting for individual variation in survival times which reflect, for example, noise exposure during years prior to onset. Occupational noise exposure was defined by the occupation held at year of hyperacusis onset, or the occupation held at the survey year if no event occurred. Models were adjusted for confounders including age, education, income, family history of hearing loss, and change of jobs due to noise.In total, n = 1966 hyperacusis events between 1960 and 2014 were analyzed in the main analysis. A significantly increased risk of hyperacusis was found among women working in any occupation assigned to the 75 to 85 dB(A) noise exposure group [HR: 2.6, 95% confidence interval (CI): 2.4-2.9], compared with the reference group75 dB(A). The risk was tripled among preschool teachers specifically (HR: 3.4, 95% CI: 3.0-3.7), with the crude Kaplan-Meier curve showing a higher rate of onset early in the working life in preschool teachers compared with all the other exposure groups. The risk was increased, but not statistically significant in the main analysis, for the highest exposure group85 dB(A), where only six hyperacusis events were identified (HR: 1.4, 95% CI: 0.6-3.1). In the sensitivity analysis, where hyperacusis was defined as occurring every day, the HR was significant also in the highest exposure group (HR: 3.8, 95% CI: 1.4-10.3), and generally slightly higher in the other exposure groups compared to the main analysis.This study indicates increased risk of hyperacusis already below the permissible occupational noise exposure limit in Sweden (85 dB LAeq,8h) among female workers in general, and in particular among preschool teachers. Prospective studies and less wide exposure intervals could confirm causal effects and assess dose-response relationships, respectively, although this study at present suggest a need for risk assessment, improved hearing prevention measures, and noise abatement measures in occupations with noise levels from 75 dB(A). The results could also have implications for management of occupational disability claims.

Long non-coding RNAs (lncRNAs) have emerged as important regulators of cancer progression. Super enhancers (SE) play a role in tumorigenesis and regulate the expression of specific lncRNAs. We examined the role of BRD3OS, also named LINC00094, in cutaneous squamous cell carcinoma (cSCC). Elevated BRD3OS (LINC00094) expression was detected in cSCC cells, and expression was downregulated by SE inhibitors THZ1 and JQ1 and via the MEK1/ERK1/2 pathway. Increased expression of BRD3OS (LINC00094) was noted in tumor cells in cSCCs and their metastases compared to normal skin, actinic keratoses, and cSCCs in situ. Higher BRD3OS (LINC00094) expression was noted in metastatic cSCCs than in non-metastatic cSCCs. RNA-seq analysis after BRD3OS (LINC00094) knockdown revealed significantly regulated GO terms Cell-matrix adhesion, Basement membrane, Metalloendopeptidase activity, and KEGG pathway Extracellular matrix–receptor interaction. Among the top-regulated genes were MMP1, MMP10, and MMP13. Knockdown of BRD3OS (LINC00094) resulted in decreased production of MMP-1 and MMP-13 by cSCC cells, suppressed invasion of cSCC cells through collagen I, and growth of human cSCC xenografts in vivo. Based on these observations, BRD3OS (LINC00094) was named SERLOC (super enhancer and ERK1/2-Regulated Long Intergenic non-protein coding transcript Overexpressed in Carcinomas). These results reveal the role of SERLOC in cSCC invasion and identify it as a potential therapeutic target in advanced cSCC.

Long non-coding RNAs (lncRNAs) have emerged as important regulators of cancer progression. Super enhancers (SE) play a role in tumorigenesis and regulate the expression of specific lncRNAs. We examined the role of

PurposeThis study investigates how the consumption of sugar products and non-alcoholic beverages has changed across birth cohorts. In addition, this study examines how the socio-economic gaps in the consumption of said products have evolved across birth cohorts.Design/methodology/approachThe research data are drawn from the Finnish household expenditure surveys covering the period 1985–2016 (n = 44,286). An age-period-cohort methodology is utilised through the age-period-cohort-trended lag model. The model assumes that the linear long-term component of change is caused by generations replacing one-another, and that the age effect is similar across cohorts.FindingsSugar products and non-alcoholic beverages occupied a larger portion of more recent birth cohorts' food baskets. Cohort differences were larger in beverage consumption. Lower income was associated with a higher food expenditure share of sugar products in several cohorts. A higher education level was linked to a higher food expenditure share of sugar products in more cohorts than a lower education level. In cohorts born before the 1950s, non-alcoholic beverages occupied a larger portion of the food baskets of the high socio-economic status groups. This gap reversed over time, leading to larger food expenditure shares of non-alcoholic beverages in low socio-economic status groups.Originality/valueThis study assessed how the consumption of sugar products and non-alcoholic beverages has changed across birth cohorts. In addition, this study assessed how socio-economic differences in the consumption of said products have changed. The results highlight that sugar products and non-alcoholic beverages occupy larger portions of more recent birth cohorts’ food baskets. The results also highlight a reversal of socioeconomic differences in non-alcoholic beverage consumption.

Purpose: Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncoprotein that inhibits the tumor suppressor PP2A-B56α. However, CIP2A mRNA variants remain uncharacterized. Here, we report the discovery of a CIP2A splicing variant, novel CIP2A variant (NOCIVA). Experimental Design: Characterization of CIP2A variants was performed by both 3′ and 5′ rapid amplification of cDNA ends from cancer cells. The function of NOCIVA was assessed by structural and molecular biology approaches. Its clinical relevance was studied in an acute myeloid leukemia (AML) patient cohort and two independent chronic myeloid leukemia (CML) cohorts. Results: NOCIVA contains CIP2A exons 1 to 13 fused to 349 nucleotides from CIP2A intron 13. Intriguingly, the first 39 nucleotides of the NOCIVA-specific sequence are in the coding frame with exon 13 of CIP2A and code for a 13-amino acid peptide tail nonhomologous to any known human protein sequence. Therefore, NOCIVA translates to a unique human protein. NOCIVA retains the capacity to bind to B56α, but, whereas CIP2A is predominantly a cytoplasmic protein, NOCIVA translocates to the nucleus. Indicative of prevalent alternative splicing from CIP2A to NOCIVA in myeloid malignancies, AML and CML patient samples overexpress NOCIVA, but not CIP2A mRNA. In AML, a high NOCIVA/CIP2A mRNA expression ratio is a marker for adverse overall survival. In CML, high NOCIVA expression is associated with inferior event-free survival among imatinib-treated patients, but not among patients treated with dasatinib or nilotinib. Conclusions: We discovered a novel variant of the oncoprotein CIP2A and its clinical relevance in predicting tyrosine kinase inhibitor therapy resistance in myeloid leukemias.

Little is known about the signaling pathways involved in the differentiation of human osteoclasts. The present study evaluated the roles of the Ras/PI3K/Akt/mTOR, Ras/Raf/MEK1/2/ERK1/2, calcium-PKC, and p38 signaling pathways in human osteoclast differentiation. Mononuclear cells were isolated from the peripheral blood of control persons and patients with neurofibromatosis 1 (NF1), and the cells were differentiated into osteoclasts in the presence of signaling pathway inhibitors. Osteoclast differentiation was assessed using tartrate-resistant acid phosphatase 5B. Inhibition of most signaling pathways with chemical inhibitors decreased the number of human osteoclasts and disrupted F-actin ring formation, while the inhibition of p38 resulted in an increased number of osteoclasts, which is a finding contradictory to previous murine studies. However, the p38 inhibition did not increase the bone resorption capacity of the cells. Ras-inhibitor FTS increased osteoclastogenesis in samples from control persons, but an inhibitory effect was observed in NF1 samples. Inhibition of MEK, PI3K, and mTOR reduced markedly the number of NF1-deficient osteoclasts, but no effect was observed in control samples. Western blot analyses showed that the changes in the phosphorylation of ERK1/2 correlated with the number of osteoclasts. Our results highlight the fact that osteoclastogenesis is regulated by multiple interacting signaling pathways and emphasize that murine and human findings related to osteoclastogenesis are not necessarily equivalent.

Most cases of keratinocyte cancer can be treated effectively with surgery. However, survival is reduced in patients with advanced disease. This retrospective cohort study evaluated overall survival of patients with invasive keratinocyte cancers, and high-risk features for progression of the disease and mortality in Finnish patients in a real-world setting. A total of 43,143 patients with keratinocyte cancer types of basal cell carcinoma and 10,380 with cutaneous squamous cell carcinoma were identified nationwide. More detailed patient records were available for a subset of patients (basal cell carcinoma n = 5,020 and cutaneous squamous cell carcinoma n = 1,482) from a regional database. Fifty percent of patients with advanced cutaneous squamous cell carcinoma died approximately 4.5 years after diagnosis. Multivariable models suggested that risk factors for keratinocyte cancer progression were male sex, presence of comorbidities, immunosuppression, and pre-cancerous lesions, while risk factors for disease-specific mortality were advanced disease stage with immunosuppression, other malignancies, and consecutive surgical excisions. These results suggest that identifying patient and tumour factors associated with poor disease outcome could be important when determining appropriate treatment and follow-up; however, further studies are necessary.

Background Cutaneous squamous cell carcinoma (cSCC) is a common cancer that invades the dermis through the basement membrane. The role of the basement membrane in poorly differentiated cSCC is not well understood. Objectives To study the effect that loss of the laminin subunit alpha-3 (α3) chain from the tumour microenvironment has on tumour invasion and inflammatory cell recruitment. Methods We examined the role of the basement membrane proteins laminin subunits α3, β3 and γ2 in SCC invasion and inflammatory cell recruitment using immunohistochemistry, short hairpin RNA knockdown, RNA-Seq, mouse xenograft models and patient tumour samples. Results Analysis of SCC tumours and cell lines using antibodies specific to laminin chains α3, β3 and γ2 identified a link between poorly differentiated SCC and reduced expression of laminin α3 but not the other laminin subunits investigated. Knockdown of laminin α3 increased tumour invasion both in vitro and in vivo. Western blot and immunohistochemical staining identified increased phosphorylated myosin light chain with loss of laminin α3. Inhibition of ROCK (rho-associated protein kinase) but not Rac1 significantly reduced the invasive potential of laminin α3 knockdown cells. Knockdown of laminin subunits α3 and γ2 increased monocyte recruitment to the tumour microenvironment. However, only the loss of laminin α3 correlated with increased tumour-associated macrophages both in xenografted tumours and in patient tumour samples. Conclusions These data provide evidence that loss of the laminin α3 chain in cSCC has an effect on both the epithelial and immune components of cSCC, resulting in an aggressive tumour microenvironment.

Long non-coding RNAs (lncRNAs) are a largely uncharacterized group of non-coding RNAs with diverse regulatory roles in various biological processes. Recent observations have elucidated the functional roles of lncRNAs in cutaneous biology, e.g. in proliferation and differentiation of epidermal keratinocytes and in cutaneous wound repair. Furthermore, the role of lncRNAs in keratinocyte-derived skin cancers is emerging, especially in cutaneous squamous cell carcinoma (cSCC), which presents a significant burden to health care services worldwide and causes high mortality as metastatic disease. Elucidation of the functions of keratinocyte-specific lncRNAs will improve understanding of the molecular pathogenesis of epidermal disorders and skin cancers and can be exploited in development of new diagnostic and therapeutic applications for keratinocyte carcinomas. In this review, we summarize the current evidence of functionally important lncRNAs in cutaneous biology and in keratinocyte carcinomas.

All leukocytes can get entrance into the draining lymph nodes via the afferent lymphatics but only lymphoid cells can leave the nodes. The molecular mechanisms behind this phenomenon have remained unknown. We employed genome wide microarray analyses of the subcapsular sinus and lymphatic sinus (LS) endothelial cells and found Robo4 to be selectively expressed on LS lymphatics. Further analyses showed high Robo4 expression in lymphatic vessels of Peyer’s patches, which only have efferent lymphatic vessels. In functional assays, Robo4-deficient animals showed accumulation of naive B cells (CD19+/CD62Lhi/CD44lo) in Peyer’s patches, whereas no difference was seen within other lymphocyte subtypes. Short-term lymphocyte homing via high endothelial venules to peripheral and mesenteric lymph nodes and Peyer’s patches was also slightly impaired in Robo4 knockout animals. These results show for the first time, selective expression of Robo4 in the efferent arm of the lymphatics and its role in controlling the turnover of a subset of B lymphocytes from Peyer’s patches.

Mallipohjaisessa tuotemäärittelyssä (Model-based Definition, MBD) tuotteen geometria ja vaatimusmäärittely esitetään digitaalisena 3D-mallina. MBD-tuotemalliin voidaan linkittää myös muuta dataa, kuten asiakirjoja ja ohjeita. MBD-tuotemalli korvaa perinteisen piirustuksen kokonaan tai osittain. MBD:n kantavana ajatuksena on käyttää samaa digitaalista tuotemallia koko arvoketjussa. Tuotteen arvoketjun voidaan tässä yhteydessä katsoa sisältävän kaikki yrityksen sekä sen toimitusverkon toiminnot ja mukaan luettuna jopa loppuasiakas. Jokaisella arvoketjun toimijalla on oma näkökulmansa tuotemalliin ja he voivat jalostaa tuotemallia edelleen oman prosessinsa osalta. Tuotemallissa olevaa tietoa voidaan suodattaa, rajata ja visualisoida toimijan näkökulmaan sopivalla tavalla. MBD-toimintatavan pyrkimyksinä ovat esimerkiksi täsmällisempi ja täydellisempi vaatimusmäärittely CAx-sovelluksen ohjaamana, ajansäästö suunnittelu- ja valmistusprosessien eri vaiheissa, kaikkialla ajantasainen ja ristiriidaton tietomalli, virheetön ja mahdollisimman automaattinen tiedonsiirto tietojärjestelmien ja eri toimijoiden välillä sekä muutosprosessien luotettava hallinta. Tiedonsiirrossa MBD-tuotemallin koneluettavuutta pyritään hyödyntämään mahdollisimman paljon. Näin siis teoriassa. Käytännössä rajoituksia ja haasteita on sekä CAx-ohjelmistojen toiminnallisuuksissa, MBD-tietomallin luomisessa, sen jakamisessa eteenpäin arvoketjussa ja mahdollisten ohjelmistorajapintojen läpi, tiedon koneluettavuudessa, eri osastojen ja alihankkijoiden nykyisissä toimintatavoissa, koulutuksessa ja tietämyksessä sekä asenteissa. Kaikkia lueteltuja osa-alueita olisi kyettävä kehittämään eteenpäin, mutta ei pelkästään yrityksen sisällä. Kaikille toimitusketjussa oleville olisi tarjottava toimiva ja luonteva tapa käyttää MBD-dataa. Toimintatapojen olisi lisäksi oltava yhteisiä ja standardisoituja. ISO onkin julkaissut viime vuosina useita MBD-toimintamallia tukevia standardeja, tärkeimpinä mainittakoon ISO 16792, ISO 1101 ja ISO 10303-242. Suomessa METSTA on pyrkinyt lisäämään tietoisuutta eri tavoilla. Tässä oppaassa pyritään antamaan ohjeistusta MBD:n käyttöönottoon ja hyödyntämiseen. Opas ei ole sisällöiltään millään tavalla tyhjentävä, vaan toimii lähinnä hyvänä ohjenuorana ja muistilistana huomioon otettavien asioiden osalta. Aihealueen laajuuden vuoksi käsiteltäviä aiheita on jouduttu rajaamaan. Esimerkiksi MBD:n suhdetta yrityksen muihin tietojärjestelmiin ja yleisempiä tietoteknisiä vaatimuksia käsitellään varsin suppeasti.Yksityiskohtaisempi kuvaus MBD:n perusteista on esimerkiksi METSTAn julkaisemassa MBD-raportissa [ks. 13.1, [4]). Myös internetistä löytyy paljon aiheitta koskevia julkaisuja.

The incidence of cutaneous squamous cell carcinoma (cSCC) is increasing globally. Here, we have studied the functional role of complement factor I (CFI) in the progression of cSCC. CFI was knocked down in cSCC cells, and RNA-seq analysis was performed. Significant downregulation of genes in IPA biofunction categories Proliferation of cells and Growth of malignant tumor, in Gene Ontology (GO) terms Metallopeptidase activity and Extracellular matrix component, as well as Reactome Degradation of extracellular matrix was detected after CFI knockdown. Further analysis of the latter three networks, revealed downregulation of several genes coding for invasion-associated matrix metalloproteinases (MMPs) after CFI knockdown. The downregulation of MMP-13 and MMP-2 was confirmed at mRNA, protein and tissue levels by qRT-qPCR, Western blot and immunohistochemistry, respectively. Knockdown of CFI decreased the invasion of cSCC cells through type I collagen. Overexpression of CFI in cSCC cells resulted in enhanced production of MMP-13 and MMP-2 and increased invasion through type I collagen and Matrigel, and in increased ERK1/2 activation and cell proliferation. Altogether, these findings identify a novel mechanism of action of CFI in upregulation of MMP-13 and MMP-2 expression and cSCC invasion. These results identify CFI as a prospective molecular marker for invasion and metastasis of cSCC.

Simple Summary Skin cancers are the most common types of cancer worldwide, and their incidence is increasing. Epidermal keratinocyte-derived cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer, and it is associated with poor prognosis in the advanced stage. The most important risk factor for cSCC is long-term exposure to solar ultraviolet radiation, which induces oncogenic mutations in epidermal keratinocytes. The most common mutations are inactivating mutations in tumor suppressor p53, which result in accumulation of additional mutations. Recently, the role of p53 in the progression and invasion of cSCC has also been elucidated. In this review we will discuss the role of p53 in development of cSCC and as a potential new therapeutic target in advanced cSCC. Abstract Skin cancers are the most common types of cancer worldwide, and their incidence is increasing. Melanoma, basal cell carcinoma (BCC), and cutaneous squamous cell carcinoma (cSCC) are the three major types of skin cancer. Melanoma originates from melanocytes, whereas BCC and cSCC originate from epidermal keratinocytes and are therefore called keratinocyte carcinomas. Chronic exposure to ultraviolet radiation (UVR) is a common risk factor for skin cancers, but they differ with respect to oncogenic mutational profiles and alterations in cellular signaling pathways. cSCC is the most common metastatic skin cancer, and it is associated with poor prognosis in the advanced stage. An important early event in cSCC development is mutation of the TP53 gene and inactivation of the tumor suppressor function of the tumor protein 53 gene (TP53) in epidermal keratinocytes, which then leads to accumulation of additional oncogenic mutations. Additional genomic and proteomic alterations are required for the progression of premalignant lesion, actinic keratosis, to invasive and metastatic cSCC. Recently, the role of p53 in the invasion of cSCC has also been elucidated. In this review, the role of p53 in the progression of cSCC and as potential new therapeutic target for cSCC will be discussed.

Purpose To assess whether working in preschools increases the risk of hearing-related symptoms and whether age, occupational noise, and stressful working conditions affect the risk. Methods Questionnaire data on hearing-related symptoms were analysed in women aged 24–65 (4718 preschool teachers, and 4122 randomly selected general population controls). Prevalence and risk ratio (RR) of self-reported hearing loss, tinnitus, difficulty perceiving speech, hyperacusis and sound-induced auditory fatigue were assessed by comparing the cohorts in relation to age and self-reported occupational noise and stressful working conditions (effort–reward imbalance and emotional demands). RR was calculated using log-binomial regression models adjusted for age, education, income, smoking, hearing protection, and leisure noise. Incidence rates and incidence rate ratios (IRR) were calculated for retrospectively reported onset of all symptoms except sound-induced auditory fatigue. Results Compared to the controls, preschool teachers had overall more than twofold RR of sound-induced auditory fatigue (RR 2.4, 95% confidence interval 2.2–2.5) and hyperacusis (RR 2.3, 2.1–2.5) and almost twofold for difficulty perceiving speech (RR 1.9, 1.7–2.0). Preschool teachers had a threefold IRR of hyperacusis (IRR 3.1, 2.8–3.4) and twofold for difficulty perceiving speech (IRR 2.4, 2.2–2.6). Significantly although slightly less increased RR and IRR were observed for hearing loss and tinnitus. RR and IRR were generally still increased for preschool teachers when stratified by age and occupational exposure to noise and stress. Conclusions This large cohort study showed that working as preschool teacher increases the risk of self-reported hearing-related symptoms, indicating a need of preventative measures. Electronic supplementary material The online version of this article (10.1007/s00420-019-01453-0) contains supplementary material, which is available to authorized users.

Summary Background The incidence of epidermal keratinocyte‐derived cutaneous squamous cell carcinoma (cSCC) is increasing worldwide. Objectives To study the role of the complement classical pathway components C1q, C1r and C1s in the progression of cSCC. Methods The mRNA levels of C1Q subunits and C1R and C1S in cSCC cell lines, normal human epidermal keratinocytes, cSCC tumours in vivo and normal skin were analysed with quantitative real‐time polymerase chain reaction. The production of C1r and C1s was determined with Western blotting. The expression of C1r and C1s in tissue samples in vivo was analysed with immunohistochemistry and further investigated in human cSCC xenografts by knocking down C1r and C1s. Results Significantly elevated C1R and C1S mRNA levels and production of C1r and C1s were detected in cSCC cells, compared with normal human epidermal keratinocytes. The mRNA levels of C1R and C1S were markedly elevated in cSCC tumours in vivo compared with normal skin. Abundant expression of C1r and C1s by tumour cells was detected in invasive sporadic cSCCs and recessive dystrophic epidermolysis bullosa‐associated cSCCs, whereas the expression of C1r and C1s was lower in cSCC in situ, actinic keratosis and normal skin. Knockdown of C1r and C1s expression in cSCC cells inhibited activation of extracellular signal‐related kinase 1/2 and Akt, promoted apoptosis of cSCC cells and significantly suppressed growth and vascularization of human cSCC xenograft tumours in vivo. Conclusions These results provide evidence for the role of tumour‐cell‐derived C1r and C1s in the progression of cSCC and identify them as biomarkers and putative therapeutic targets in cSCC. What's already known about this topic? The incidences of actinic keratosis, cutaneous squamous cell carcinoma (cSCC) in situ and invasive cSCC are increasing globally.Few specific biomarkers for progression of cSCC have been identified, and no biological markers are in clinical use to predict the aggressiveness of actinic keratosis, cSCC in situ and invasive cSCC. What does this study add? Our results provide novel evidence for the role of complement classical pathway components C1r and C1s in the progression of cSCC. What is the translational message? Our results identify complement classical pathway components C1r and C1s as biomarkers and putative therapeutic targets in cSCC., Linked Comment: https://doi.org/10.1111/bjd.18419. https://doi.org/10.1111/bjd.18821 available online