The adapter protein Shc is a ubiquitously expressed Src homology 2 (SH2) domain protein implicated in the transmission of activation signals to Ras. She proteins become phosphorylated on tyrosine in cells stimulated with a variety of growth factors and in v-𝘴𝘳𝘤 transformed cells and are able to transform fibroblasts and differentiate PC12 cells in a Ras-dependent fashion. To assess the transforming ability of Shc in the mouse mammary gland, I generated transgenic mice harbouring the p52ˢʰᶜ cDNA under the transcriptional control of the mouse mammary tumor virus long terminal repeat (MMTV LTR). While p52ˢʰᶜ expression was correlated with multiple enlarged terminal end buds in virgin mouse mammary glands, multiparous mice developed mammary hyperplasias and mammary carcinomas. The frequency, latency and focal nature with which these tumors arose suggests that additional events are necessary to induce malignant conversion of primary mammary epithelial cells. To directly test the role of Shc in established mammary tumor models, I have generated two strains of bigenic mice. When Shc was overexpressed with NDL 1-2, a constitutively activated form of the Neu receptor tyrosine kinase, latency of tumor onset was decreased over that of parental MMTV/NDL 1-2 mice. Polyomavirus middle T antigen (PyV MT) mutants with a functionally inactive Shc binding site (MT Y250F) are debilitated in mammary tumor formation compared to wild-type PyV MT transgenic animals. Concurrent overexpression of Shc with MT Y250F accelerated tumor kinetics and increased the propensity for metastasis to the lungs of bigenic animals. / Thesis / Master of Science (MSc)

We investigated the role of Shc¡BPYK2¡BGrb2-sos binding complex¡BRas and Raf proteins at the rostral ventrolateral medulla (RVLM), the origin of sympathetic neurogenic vasomotor tone, in mevinphos (Mev) intoxication. Adult Sprague-Dawley rats anesthetized by sodium pentobarbital (45 mg/kg) and maintained by propofol (20-25 mg/kg/hr) were used. Bilateral microinjection of Mev (10 nmol) into the RVLM elicited two distinct phases of cardiovascular responses, designated Phase I (sympathoexcitatory) and Phase II (sympathoinhibitory) Mev intoxication. Pretreatment with microinjection of a phospho-Shc-tyrosine 317, phospho-PYK2-tyrosine 402, phospho-PYK2-tyrosine 579/580 antibody (1:20), Grb2-sos complex inhibitor (SH3b-p), Ras specific inhibitors (manumycin A or FTA) or Raf specific inhibitor (GW5074) into the bilateral RVLM blunted the magnitude of the Mev-elicited sympathoexcitatory cardiovascular effect without affecting the duration. The Mev-elicited sympathoinhibitory cardiovascular effect was not influenced. Our results suggest that signaling pathways that involve Shc, PYK2, Grb2-sos complex, Ras or Raf protein in the RVLM participate in the sympathoexcitatory phase of Mev intoxication.

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The majority of Swedish boys and girls have good psychosomatic health. Despite that the risk of mental health problems such as nervousness, feeling low and sleeping difficulties has increased steadily in recent decades. Moreover, previous surveys on health and well-being indicate that boys and girls of foreign extraction in Sweden are at increased risk of ill health compared to boys and girls of Swedish background.   The main aim of this thesis was to analyse health and social determinants among boys and girls of foreign extraction in Sweden. The factors explored in papers I–IV include parental background, family affluence and gender and their associations with subjective health complaints, psychosomatic problems or health risk behaviours. Other included risk factors for ill health were involvement in bullying, low participation and discrimination at school. This thesis takes an intersectional perspective, with ambitions to be able to emphasize the interplay between different power relations (i.e. gender, social class and parental background).   Two sets of cross-sectional data were used. Three papers were based on the Swedish part of the World Health Organization’s Health Behaviour in School-Aged Children. The sample consisted of 11,972 children (boys n = 6054; girls n = 5918) in grades five, seven and nine from the measurement years 1997/98, 2001/02 and 2005/06. The response rate varied between 85 and 90%. About one fifth of the included children were of foreign extraction. For the fourth paper regional data from Northern Sweden were used. Boys (n = 729) and girls (n = 798) in grades six to nine answered a questionnaire in 2011 and the response rate was 80%. About 14% of the included children were of foreign extraction. Statistical methods used were chi-square test, correlation analyses, logistic regression analyses, cluster analyses and test of mediating factor.   The results showed that girls of foreign background were at increased risk of subjective health complaints (SHC) and boys of mixed background were at increased risk of psychosomatic problems (PSP). Increased risk of allocation to the cluster profile of multiple risk behaviour was shown in boys and girls of mixed background, in girls of foreign background and in girls of low family affluence. Increased risk of allocation to the cluster profile of inadequate tooth brushing was shown in boys and girls of foreign background and in girls of low family affluence. General risk factors for increased risk of ill health for boys and girls in Sweden were: any form of bullying involvement, low family affluence, low participation and discrimination at school, of which the latter also was a mediating factor for ill health. Living with a single parent was a risk factor for ill health among girls.   The results can function as a basis for developing health promotion programmes at schools that focus on social consequences of foreign extraction, family affluence, participation as well as health risk behaviours and gender. / Majoriteten av flickorna och pojkarna i Sverige har en god psykosomatisk hälsa. Trots det har risken för psykiska hälsosymptom såsom nervositet, att känna sig nere och sömnsvårigheter ökat successivt de senaste årtiondena. Dessutom indikerar tidigare forskning angående hälsa och välmående att flickor och pojkar med utländsk härkomst har ökad risk för ohälsa jämfört med flickor och pojkar med svensk härkomst.   Denna avhandlings huvudsyfte var att analysera hälsa och sociala bestämningsfaktorer bland flickor och pojkar i Sverige, med fokus på föräldrabakgrund. Artiklarnas (I–IV) syften inkluderar föräldrahärkomst, familjens materiella tillgångar och genus samt dess samband med subjektiva hälsobesvär, psykosomatiska problem eller hälsoriskbeteenden. Andra riskfaktorer för ohälsa som inkluderades var inblandning i mobbning, lågt deltagande och förekomst av diskriminering på skolan. Denna avhandling beaktar ett intersektionellt perspektiv med ambitionen att kunna tydliggöra samspelet mellan olika maktordningar (dvs. genus, social klass och föräldrabakgrund).   Två dataset från tvärsnittsstudier har använts. I de tre första artiklarna användes World Health Organization – Health Behaviour in School-Aged Children, som i Sverige heter Svenska skolbarns hälsovanor. Studiepopulationen bestod av 11 972 barn (flickor n = 5918; pojkar n = 6054) i årskurserna fem, sju och nio undersöknings år 1997/98, 2001/02 och 2005/06. Svarsfrekvensen var mellan 85 och 90 %. Ungefär en femtedel av barnen som deltog hade utländsk härkomst. I den fjärde artikeln användes regional data från norra Sverige. Flickor (n = 798) och pojkar (n = 729) i årskurserna sex till nio deltog i studien år 2011, svarsfrekvensen var 80 %. Omkring 14 % av barnen hade utländsk härkomst. De statistiska metoder som användes var sambandstest (chi-två), test av linjära samband så kallade korrelationsanalyser, logistisk regressionsanalys, klusteranalys och test av medierande faktor.   Resultaten visade att flickor med utländsk bakgrund hade ökad risk för subjektiva hälsobesvär (SHC) och pojkar av mixbakgrund hade ökad risk för psykosomatiska problem (PSP). Ökad risk för att hamna i klusterprofilen multipelt hälsoriskbeteende hade flickor och pojkar med mixbakgrund, flickor med utländsk bakgrund samt flickor i familjer med låg nivå av materiella tillgångar. Ökad risk för att hamna i klusterprofilen bristande tandborstning hade flickor och pojkar med utländsk bakgrund och flickor i familjer med låg nivå av materiella tillgångar. Generella riskfaktorer för ohälsa bland flickor och pojkar i Sverige var: alla former av inblandning i mobbning, låg nivå av materiella tillgångar i familjen, lågt deltagande och förekomst av diskriminering på skolan, vilken den senare även var en medierande faktor för ohälsa. Att leva med en ensamstående förälder var en riskfaktor för ohälsa bland flickor.   Avhandlingens resultat kan ligga till grund för utformande av hälsofrämjande interventioner inom elevhälsan, till exempel interventioner som fokuserar på sociala konsekvenser av utländsk härkomst, familjens materiella tillgångar, deltagande och diskriminering samt hälsoriskbeteenden och genus.

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