| 1. |
- Appelqvist, Hanna, et al.
(författare)
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Lysosome-Mediated Apoptosis is Associated with Cathepsin D-Specific Processing of Bid at Phe24,Trp48, and Phe183
- 2012
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Ingår i: Annals of Clinical and Laboratory Science. - : Institute for Clinical Science. - 0091-7370 .- 1550-8080. ; 42:3, s. 231-242
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Tidskriftsartikel (refereegranskat)abstract
- Bax-mediated permeabilization of the outer mitochondrial membrane and release of apoptogenic factors into the cytosol are key events that occur during apoptosis. Likewise, apoptosis is associated with permeabilization of the lysosomal membrane and release of lysosomal cathepsins into the cytosol. This report identifies proteolytically active cathepsin D as an important component of apoptotic signaling following lysosomal membrane permeabilization in fibroblasts. Lysosome-mediated cell death is associated with degradation of Bax sequestering 14-3-3 proteins, cleavage of the Box activator Bid, and translocation of Box to mitochondria, all of which were cathepsin D-dependent. Processing of Bid could be reproduced by enforced lysosomal membrane permeabilization, using the lysosomotropic detergent O-methyl-serine dodecylamine hydrochloride (MSDH). We identified three cathepsin D-specific cleavage sites in Bid, Phe24, Trp48, and Phe183. Cathepsin D-cleaved Bid induced Bax-mediated release of cytochrome c from purified mitochondria, indicating that the fragments generated are functionally active. Moreover, apoptosis was associated with cytosolic acidification, thereby providing a more favorable environment for the cathepsin D-mediated cleavage of Bid. Our study suggests that cytosolic cathepsin D triggers Bax-mediated cytochrome c release by proteolytic activation of Bid.
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| 2. |
- Nilsson, Jan, 1963-, et al.
(författare)
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Development and validation of a new tool measuring nurses self-reported professional competence — The nurse professional competence (NPC) Scale
- 2014
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Ingår i: Nurse Education Today. - Midlothian, Scotland : Elsevier BV. - 0260-6917 .- 1532-2793. ; 34:4, s. 574-580
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To develop and validate a new tool intended for measuring self-reported professional competence among both nurse students prior to graduation and among practicing nurses. The new tool is based on formal competence requirements from the Swedish Board of Health and Welfare, which in turn are based on WHO guidelines. Design: A methodological study including construction of a new scale and evaluation of its psychometric properties. Participants and settings: 1086 newly graduated nurse students from 11 universities/university colleges. Results: The analyses resulted in a scale named the NPC (Nurse Professional Competence) Scale, consisting of 88 items and covering eight factors: “Nursing care”, “Value-based nursing care”, “Medical/technical care”, “Teaching/ learning and support”, “Documentation and information technology”, “Legislation in nursing and safety planning”, “Leadership in and development of nursing care” and “Education and supervision of staff/students”. All factors achieved Cronbach's alpha values greater than 0.70. A second-order exploratory analysis resulted in two main themes: “Patient-related nursing” and “Nursing care organisation and development”. In addition, evidence of known-group validity for the NPC Scale was obtained.
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| 3. |
- Nilsson, Jan, 1963-, et al.
(författare)
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Nursing in a globalized world : Nursing students with international study experience report higher competence at graduation
- 2014
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Ingår i: Open Journal of Nursing. - : Scientific Research Publishing, Inc.. - 2162-5336 .- 2162-5344. ; :4, s. 848-858
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Tidskriftsartikel (refereegranskat)abstract
- Due to globalization, there is a need for nurses with skills and competence in providing safe, competent and culturally appropriate care. The aim of the study was to investigate whether International Study Experiences (ISE) in other countries during basic nursing education had an impact on newly graduated nurses as regards to self-reported competence. Moreover, a second aim was to explore what background factors that facilitated or constituted a hindrance for nursing students to choose to conduct part of their basic nursing education abroad. At 11 Universities/University Colleges (henceforth called Higher Education Institutions [HEIs]) in Sweden, 565 nursing students responded to the Nurse Professional Competence (NPC) Scale. Students with ISE rated their competence significantly higher on three NPC competence areas; “Legislation in nursing and safety planning”, “Leadership and development of nursing” and “Education and supervision of staff/students”. Background factors that significantly seemed to enhance ISE were; living alone, not having children or other commitments, international focus at the HEI and previous international experience. Lack of financial means was reported to prevent students from choosing ISE. The study implies that several background factors are of importance whether students choose ISE or not. ISE during basic nursing education might result in better self-reported competence in leading and developing nursing care, including education of future nurses, and in providing safe care.
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| 4. |
- Alevronta, Eleftheria, et al.
(författare)
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Dose-response relationships for an atomized symptom of fecal incontinence after gynecological radiotherapy.
- 2013
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Ingår i: Acta oncologica (Stockholm, Sweden). - : Taylor & Francis. - 1651-226X .- 0284-186X. ; 52:4, s. 719-26
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Tidskriftsartikel (refereegranskat)abstract
- Purpose. The aim of this study was to investigate what bowel organ and delivered dose levels are most relevant for the development of 'emptying of all stools into clothing without forewarning' so that the related dose-responses could be derived as an aid in avoiding this distressing symptom in the future. Material and methods. Of the 77 gynecological cancer survivors treated with radiotherapy (RT) for gynecological cancer, 13 developed the symptom. The survivors were treated between 1991 and 2003. The anal-sphincter region, the rectum, the sigmoid and the small intestines were all delineated and the dose-volume histograms were exported for each patient. The dose-volume parameters were estimated fitting the data to the Relative Seriality (RS), the Lyman and the generalized Equivalent Uniform Dose (gEUD) model. Results. The dose-response parameters for all three models and four organs at risk (OARs) were estimated. The data from the sigmoid fits the studied models best: D50 was 58.8 and 59.5 Gy (RS, Lyman), γ50 was 1.60 and 1.57 (RS, Lyman), s was 0.32, n was 0.13 and a was 7.7 (RS, Lyman, gEUD). The estimated volume parameters indicate that the investigated OARs behave serially for this endpoint. Our results for the three models studied indicate that they have the same predictive power (similar LL values) for the symptom as a function of the dose for all investigated OARs. Conclusions. In our study, the anal-sphincter region and sigmoid fit our data best, but all OARs were found to have steep dose-responses for 'emptying of all stools into clothing without forewarning' and thus, the outcome can be predicted with an NTCP model. In addition, the dose to the four studied OARs may be considered when minimizing the risk of the symptom.
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| 5. |
- Ansell, Anna, 1983-
(författare)
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Identification of Tumor Cell- and Stroma Derived Biomarkers of Treatment Response in Head and Neck Cancer
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Head and neck squamous cell carcinoma (HNSCC) poses a major health problem in the world with approximately 600 000 new cases yearly. Treatment resistance is a major problem within this patient group and despite advances in treatment strategies the overall survival rate has unfortunately not increased.One of the major components of the tumor microenvironment is the cancer associated fibroblasts (CAFs) which can modulate the treatment sensitivity, tumor growth, and the invasive potential of tumor cells.The aim of this thesis was to identify predictive markers for treatment response in HNSCC and to study the crosstalk between tumor cells and CAFs that may underlie treatment resistance.In paper I, we identified gene expression differences between one cisplatin sensitive cell line and two cisplatin resistant cell lines, by microarray analysis, and found that a high expression of matrix metalloproteinase (MMP) -7 was associated with resistance to cisplatin. In paper II, the epidermal growth factor (EGF) receptor ligands EGF, amphiregulin, and epiregulin were evaluated regarding their potential use as predictive biomarkers for cetuximab treatment response in tongue cancer cell lines and it was shown that EGF may serve as a marker for poor cetuximab response. In paper III and IV, we investigated the influence of CAFs on the proliferation, migration, gene expression, and cetuximab response of tumor cells. It was found that CAFs induced resistance to cetuximab in a MMP-dependent manner. In addition, a microarray analysis, comparing tumor cells co-cultured with CAFs and tumor cells cultured alone, revealed that CAFs induced multiple gene expression changes in tumor cells some of which are related to epithelial to mesenchymal transition. Some of these changes were found to be dependent on cell-cell contact.Taken together, we here suggest MMP-7 and EGF to be predictive markers of cisplatin and cetuximab response, respectively. We also show that CAFs protect HNSCC cells from cetuximab treatment; however, the factor responsible for the protective effect is yet to be discovered.
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| 6. |
- Ansell, Anna, et al.
(författare)
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Molecular cross-talk between head and neck squamous cell carcinoma cells and cancer-associated fibroblasts
- 2013
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Cancer-associated fibroblasts (CAFs) are one of the main components of the tumor stroma and are known to increase tumor growth and stimulate invasion and metastasis. Increasing evidence suggests that CAFs may also be an important determinant of the response to various treatments. In this study we aimed to characterize the molecular cross-talk between CAFs and head and neck squamous cell carcinoma (HNSCC) cells.HNSCC cell lines were co-cultured with their patient-matched CAFs for seven days, after which the gene expression of tumor cells was investigated by Affymetrix microarray. 58 protein coding genes were found to be differentially expressed (Q≤0.05) in tumor cells cocultured with CAFs when compared to tumor cells cultured alone. The top functions of these genes were cancer, cellular movement, and embryonic development as analyzed by Ingenuity Pathway Analysis. Nine genes were upregulated by ≥1.5-fold while the expression of 35 genes was found to be reduced by ≤ 0.67-fold. Several of the differentially expressed genes have been associated with epithelial-to-mesenchymal transition (EMT). The change in the expression of POSTN, GREM1, COL1A2, VIM, and MMP7 was verified by qPCR analysis. Moreover, the influence of CAFs on the proliferation, migration and cetuximab sensitivity of tumor cells was investigated, and was found to vary among the tumor cell-CAF pairs.In conclusion, we demonstrate that CAF-derived signals cause changes in the expression of multiple genes, several of which are associated with an EMT phenotype of tumor cells. Furthermore, CAFs modulate the proliferation, migration and cetuximab treatment response of tumor cells.
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| 7. |
- Bertilsson, Ann-Sofie, et al.
(författare)
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A client-centred ADL intervention: three-month follow-up of a randomized controlled trial
- 2014
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Ingår i: Scandinavian Journal of Occupational Therapy. - : Informa UK Limited. - 1103-8128 .- 1651-2014. ; 21, s. 377-391
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The aim was to study a client-centred activities of daily living (ADL) intervention (CADL) compared with the usualADL intervention (UADL) in people with stroke regarding: independence in ADL, perceived participation, life satisfaction,use of home-help service, and satisfaction with training and, in their significant others, regarding: caregiver burden, lifesatisfaction, and informal care. Methods: In this multicentre study, 16 rehabilitation units were randomly assigned to deliverCADL or UADL. The occupational therapists who provided the CADL were specifically trained. Eligible for inclusion werepeople with stroke treated in a stroke unit £3 months after stroke, dependent in ‡two ADL, not diagnosed with dementia, andable to understand instructions. Data were collected at inclusion and three months thereafter. To detect a significant differencebetween the groups in the Stroke Impact Scale (SIS) domain “participation”, 280 participants were required. Intention-totreatanalysis was applied. Results: At three months, there was no difference in the outcomes between the CADL group(n = 129) and the UADL group (n = 151), or their significant others (n = 87/n = 93) except in the SIS domain “emotion” infavour of CADL (p = 0.04). Conclusion: The CADL does not appear to bring about short-term differences in outcomes andlonger follow-ups are required.
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| 8. |
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| 9. |
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| 10. |
- Eriksson, Lennart, et al.
(författare)
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Skog på jordbruksmark – erfarenheter från de senaste decennierna
- 2011
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Under senare delen av 1900-talet har stora arealer jordbruksmark tagits ur drift. En första större nedläggning, delvis följd av granplantering skedde under senare delen av 1960-talet. Under en andra period i decennieskiftet mellan 1980- och 90-talen utgick bidrag för att mark togs ur jordbruksdrift kombinerat med bidrag för plantering av lövträd. Den gran från 1960-talet som överlevt etableringen blev högproducerande och har gallrats och delvis slutavverkats. Historiskt såväl som för framtiden sker stora förändringar i Europas jordbrukspolitik. Nu är det möjligt att få gårdsstöd också för odling av energigrödor, till vilka räknas Salix, hybridasp och poppel förutsatt att avverkning sker inom 20 år. Gårdsstödet uppgår till 1 200-2 800 SEK/ha och år beroende på läge i landet. Stängsling kan också stödjas till en kostnad av 12 000 SEK/ha. Jordbruksstödet, vilket år 2007 utgjorde 50 % av EU:s budget, förväntas hamna på 40 % år 2013 och kanske ännu lägre i nya planen för 2014-2020. Det här redovisade projektet har som övergripande syfte att samla kunskap från redan genomförd skogsodling på svensk jordbruksmark och förmedla den till dem som avser att beskoga den bästa skogsodlingsmarken, den som blir över när jordbruket minskar sin areal. Den samlade arealen som blir tillgänglig för beskogning under en 30-årsperiod har av Jordbruksverket, Skogsstyrelsen och SLU gemensamt uppskattats till 400 000 ha. Arealerna är ofta fragmenterade vilket påkallar småskaliga lösningar. Kapitel 2 ”Åtgärder vid anläggning och skötsel” syftar till att beskriva åtgärder för bestånd på jordbruksmark, såsom de presenterats i inhemsk och övrig europeisk litteratur. Här behandlas åtgärderna var för sig, medan åtgärder sammankopplade till skötselsystem för omloppstider, tas upp i kapitel 8, ”Analyser av alternativ för beskogning av jordbruksmark”. Litteraturuppgifterna ställs mot utvärderingar av planteringar från Omställning-90, samt mot iakttagelser från exkursioner till bestånd från samma tid. Trädslagens ståndortskrav har uppmärksammats, speciellt där man i praktiken inte tillräckligt beaktat dessa krav. Andra exempel på brister vid Omställning-90 är försummad markbehandlig, ogräsbekämpning samt skydd mot vilt. Brist på litteratur som direkt berör beskogning av jordbruksmark har kompenserats med material omfattande hög bonitet på vanlig skogsmark. För flera av de exotiska trädslagen saknas det ofta inhemska erfarenheter och produktionssiffror. I kapitel 3, ”Plantmaterial, överlevnad och produktion i studerade planteringar” redovisas resultat från planteringar på 131 lokaler belägna framför allt i södra och mellersta Sverige. Dessa har inventerats under åren 2006-2009. Arter som studerats är: glasbjörk (Betula pubescens Ehrh.), vårtbjörk (Betula pendula Roth), gråal (Alnus incana (L.) Moench.), klibbal (Alnus glutinosa (L.) Gaertner), fågelbär (Prunus avium L.), hybridasp (Populus tremuloides Michx. x Populus tremula L.), hybridpoppel (Populus sp.), hybridlärk (Larix x eurolepis A. Henry) och gran (Picea abies (L.) Karst.). Även ett fåtal planteringar med lind (Tilia sp.) och tall (Pinus sylvestris L.) har inventerats. Resultat, från tidigare inventeringar av 157 granplanteringar, har tillförts studien. Spontan inväxt av lövträd (asp, björk och sälg) på nedlagd jordbruksmark har studerats i 7 bestånd. Många planteringar har uppvisat hög tillväxt samt är oskadade och välslutna. Överlevnaden har efter fem år varit mellan 70 och 90 % för björk- och alarterna samt granen. Hänsyn har dock inte kunnat tas till planteringar som helt gått ut och som därmed inte kommit med i studien. Hybridlärken har låg överlevnad, 20 %, huvudsakligen beroende på viltbetning. Volymtillväxten varierar starkt mellan olika arter. De mest högproducerande är hybridasp och poppel, 13-19 m3sk per år och ha samt gran, 13 m3sk per år och ha, medan övriga arter producerar mellan 3 och 7 m3sk per år och ha. Plantering av gran på jordbruksmark är idag en väl fungerande metod där det finns lämpliga provenienser samt utarbetade markbehandlings- och planteringsmetoder. Kapitel 4 ”Virkeskvalitet i studerade planteringar” tar upp ämnet kvalitets-påverkande faktorer. Sådana faktorer har utvärderats hos provträd i planteringar anlagda på tidigare jordbruksmark. Studien omfattar 10 trädslag (poppel, hybridasp, vårt- och glasbjörk, klibbal, lind, fågelbär, hybridlärk, gran och tall). Totalt ingår 141 planteringar i detta material. En majoritet av planteringarna är 20 år eller yngre. Brösthöjdsdiametern hos inmätta provträd varierar från 3 till knappt 50 cm beroende på trädslag, ålder och lokal. Objektens nuvarande status med avseende på stamskador (stambrott, flerstammighet och viltskador) och övriga virkeskvalitetsfel (stam- och rotkrok, sprötkvist, klyka och grengrovlek) har registrerats. Den totala andelen provträd med någon typ av stamskada och/eller kvalitetsfel var högre än 50 % för alla trädslag utom gran. Högst andel provträd med stamskador hade lind, följt av hybridasp, klibbal och poppel. Bland övriga trädslag hade mindre än 15 % av provträden någon typ av stamskada. Flerstammighet var den dominerande stamskadan hos lind och klibbal. Viltskador i form av älgbetning och fejning registrerades för alla trädslag utom fågelbär, gran och tall. Hybridaspen hade högst frekvens provträd med viltskador. Lind hade även högst andel kvalitetsfel. Bland alla trädslag utom hybridasp och gran hade mer än hälften av provträden ett eller flera kvalitetsfel. Slängkrok var den vanligaste typen av kvalitetsfel hos glasbjörk, klibbal, tall, fågelbär, hybridlärk och gran. Sprötkvist förekom i högst andel hos lind följt av glasbjörk. Klykor förekom endast hos en liten andel av provträden hos alla trädslag utom glasbjörk. Bland dessa registrerades klyka hos knappt vart tredje provträd. Variationen mellan planteringar med samma trädslag är dock stor, både vad gäller förekomst av olika typer av stamskador och kvalitetsfel. De varierande resultaten, både inom och mellan trädslag, pekar på att det finns potential att skapa god virkeskvalitet för flera olika trädslag på bördig mark i Sverige. Kunskap och engagemang, rätt plantmaterial, anpassad skötsel och inte minst väl underhållet viltskydd möjliggör produktion av olika sortiment. De inventerade planteringarna är idag dock relativt unga och uppföljande studier av skadebild och virkesegenskaper bör därför göras när stammarna nått gagnvirkesdimension. Kapitel 5 har titeln ”Teknik och ekonomi vid beskogning av jordbruksmark”. Tekniskt sett erbjuder tidigare jordbruksmark, som vanligen ligger på plana sediment, speciella möjligheter för avancerade system som inte alltid är tillämpbara på exempelvis normal sandig-moig morän. Planteringsplogen sänker anläggningskostnaden påtagligt, kostnaden för stängsling blir likaså lägre på jordbruksmark. Biomassaskörd av såväl hela stående träd som avverkningsrester och stubbar kan ofta drivas med god marknadsavsättning, med begränsade negativa tillväxteffekter samt mer rationellt jämfört med normal skogsmark. Drivarens ekonomiska fördelar ser ut att ofta komma till sin rätt på beskogad jordbruksmark. I framtiden kan man väl tänka sig att en mer utvecklad teknik och metodik för exempelvis stamkvistning samt produktionsoptimering och automation kommer att tillämpas långt tidigare än på den kuperade och mindre homogena normala skogsmarken. Ekonomin är viktig vid beskogning av jordbruksmark, inte minst på grund av de höga anläggningskostnaderna. Skogsbrukets speciella betingelser som beskattningen (reglerna för skogsdrift avviker i vissa avseenden starkt från annan beskattning), den långa tidshorisonten och produkternas mångsidiga användning måste beaktas vid analys av ekonomin när ny skog anläggs. Skogsägarens egen finansiella situation är avgörande för det kapital-avkastningskrav, som bör ställas på en investering i beståndsanläggning. Markvärde och årlig markersättning (vid jämförelse med jordbruksgröda) som beslutskriterier ger möjlighet att ställa utfallet från en specifik anläggning mot andra placeringsalternativ. Möjligheten till bioenergiuttag har förbättrat lönsamheten generellt och bidrar till att finansiera den intensiva skötseln av till exempel ädellövskog. Det vanligaste alternativet på lämnad jordbruksmark, att inget göra, ger både utmaningar inför en kostsam nyanläggning och möjligheter genom att befintlig naturlig föryngring både kan utgöra produktionsalternativ och skydd åt ett nytt underbestånd. ”Markägarnas attityder till beskogning av jordbruksmark”, som beskrivs i kapitel 6, har undersökts via litteraturstudier, intervjuer och diskussioner med forskare och handläggare samt 15 djupintervjuer med markägare. Planteringarna i samband med Omställning-90 blev ofta eftersatta, inte sällan beroende på att de initierades av finansiellt stöd snarare än av företagarintresse. Vid EU-inträdet 1995 återinfördes ett jordbruksstöd och mycket av den omställda marken återgick till jordbruksproduktion. Ägare av större fastigheter, aktiva lantbrukare i åldern 40-65 år och innehavare av stor andel egen mark (få arrenden) är de som främst tagit jordbruksmark ur produktion genom att plantera Salix. Regelverket kring utarrendering av jordbruksmark utgör genom sin konstruktion ett hinder för beskogning, vilket blir kännbart eftersom ca 45 % av jordbruksmarken är utarrenderad. Markägarna har löst sitt rådgivningsbehov dels via olika organisationer och företag dels via Internet, som uppgavs fungera bra enligt ca hälften av respondenterna. Argument för plantering som nämnts vid intervjuerna är: önskan att skapa bättre arrondering ge
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| 11. |
- Farnebo, Lovisa, et al.
(författare)
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Combining factors on protein and gene level to predict radioresponse in head and neck cancer cell lines
- 2011
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Ingår i: Journal of Oral Pathology & Medicine. - : John Wiley and sons. - 0904-2512 .- 1600-0714. ; 40:10, s. 739-746
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Radiotherapy is the main therapy for head and neck squamous cell carcinoma (HNSCC); however, treatment resistance and local recurrence are significant problems, highlighting the need for predictive markers. In this study, we evaluated selected proteins, mutations, and single nucleotide polymorphisms (SNPs) involved in apoptosis, cell proliferation, and DNA repair alone or combined as predictive markers for radioresponse in 42 HNSCC cell lines. METHODS: The expression of epidermal growth factor receptor, survivin, Bax, Bcl-2, Bcl-XL, cyclooxygenase-2, and heat shock protein 70 was analyzed by ELISA. Furthermore, mutations and SNPs in the p53 gene as well as SNPs in the MDM2, XRCC1, and XRCC3 genes were analyzed for their relation to radioresponse. To enable the evaluation of the predictive value of several factors combined, each cell line was allocated points based on the number of negative points (NNP) system, and the NNP sum was correlated with radioresponse. RESULTS: Survivin was the only factor that alone was significantly correlated with the intrinsic radiosensitivity (r=0.36, p=0.02). The combination of survivin, Bax, Bcl-2, Bcl-XL, cyclooxygenase-2, and the p53 Arg72Pro polymorphism was found to most strongly correlate with radioresponse (r=0.553, p<0.001). CONCLUSION: These data indicate that the intrinsic radiosensitivity of 42 HNSCC cell lines can be predicted by a panel of factors on both the protein and gene levels. Moreover, among the investigated factors, survivin was the most promising biomarker of radioresponse.
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| 12. |
- Farnebo, Lovisa
(författare)
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Predictive markers : for treatment sensitivity in head and neck squamous cell carcinoma
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Head and neck cancer is the sixth most common cancer world wide. In Sweden approximately 850 new cases are diagnosed each year, and two thirds are men. The past decades of improved treatment strategies have unfortunately not significantly improved the five-year survival rates for this group of patients. Therefore, it is important to rapidly find combinations of new and strong predictive markers for treatment response. Different predictive markers have been investigated for decades, without succeeding in finding means to securely predict response to treatment. Models to combine markers are called for.The aim of this thesis was to test multiple predictive markers on both gene and protein level to evaluate their predictive value for radiotherapy and cisplatin response. Furthermore, to combine, and correlate them to treatment response in order to extract the panel of markers that strongest correlated to the investigated treatment. Cell lines derived from 42 patients with head and neck squamous cell carcinoma (HNSCC) were used for protein quantification with Western blot and ELISA of the proteins survivin, Epidermal Growth Factor Receptor, Bcl-2, Bcl-XL, Bax, Bad, Bak, PUMA, Heat shock protein 70, MDM2, p53, SMAD4, Cyclooxygenase-2, and Cyclin D1. The expression of the selected proteins was related to the mean expression of normal oral keratinocytes (NOK) from healthy individuals. Furthermore, mutations in the p53 gene, along with single nucleotide polymorphisms in the genes of p53, MDM2, FGFR4, XRCC1, XRCC3, XPD, and XPC were analysed. To allow a large number of predictive markers on both protein and gene level to be combined and correlated to treatment response, the number of negative points (NNP) model was introduced. Both correlations of sensitivity to radiotherapy and to cisplatin treatment was analysed among the cell lines. In the first paper, including nine cell lines, the panel of EGFR, survivin, and splice site/missense p53 mutations correlated strongest to radioresponse. In paper II, 42 cell lines were used and the combination of survivin, Bcl-2, Bcl-XL, Bax, COX-2, and the p53 Arg72Pro polymorphism was found to most strongly correlate with radioresponse. In paper IV, the panel correlating strongest with cisplatin sensitivity consisted of EGFR, Hsp70, Bax, and Bcl-2 in combination with SNPs in the DNA-repair genes XRCC3 and XPD.The predisposition of the FGFR4 Gly388Arg polymorphism for the development of HNSCC was investigated in paper III. DNA was isolated from 110 tumour biopsies, and restriction fragment length polymorphism analysis showed that 58% of the individuals in the control group carried the FGFR4 Arg388 allele, whereas the frequency in the tumour group was 45%. The Gly388 allele gave a significantly higher risk of developing HNSCC, suggesting Gly388 to be the risk allele for cancer development. Furthermore, a novel mutation was found in the FGFR4 gene. The influence of this new mutation is however unknown.In conclusion, predictive markers for treatment sensitivity need to be combined to receive an accurate prediction of treatment response.
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| 13. |
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| 14. |
- Hosnijeh, Fatemeh Saberi, et al.
(författare)
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Prediagnostic telomere length and risk of B-cell lymphoma-Results from the EPIC cohort study
- 2014
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 135:12, s. 2910-2917
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Tidskriftsartikel (refereegranskat)abstract
- Recent epidemiological investigations have reported on the association between telomere length (TL) and a number of malignancies, including B-cell lymphoma (BCL). The reported results for BCLs are however inconsistent. We carried out a nested case-control study to determine whether TL is associated with future risk of BCL. Using quantitative polymerase chain reaction, the relative TL (i.e. the ratio of telomere repeat copy number to single gene copy number) was measured in mononuclear cell DNA of prediagnostic peripheral blood samples of 464 lymphoma cases and 464 matched controls (median time between blood collection and diagnosis, 4.6 years). Conditional logistic regression was used to analyze the association between TL and the risk of developing lymphoma and histologic subtypes. TL was significantly longer in cases compared to controls (p 5 0.01). Multivariable models showed a significantly increased risk of BCL [odds ratio (OR) = 1.66, 1.80 and 3.20 for quartiles 2-4, respectively, p-trend = 0.001], diffuse large B-cell lymphoma (DLBCL) (OR = 1.20, 2.48 and 2.36 for quartiles 2-4, respectively, p-trend = 0.03) and follicular lymphoma (FL) (OR = 1.39, 1.90 and 2.69 for quartiles 2-4, respectively, p-trend = 0.02) with increasing TL. This study suggests an association between longer leucocyte TL and increased risk of BCL which was most pronounced for DLBCL and FL.
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| 15. |
- Jedlinski, Adam, et al.
(författare)
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EGFR status and EGFR ligand expression influence the treatment response of head and neck cancer cell lines
- 2013
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Ingår i: Journal of Oral Pathology & Medicine. - : John Wiley and Sons. - 0904-2512 .- 1600-0714. ; 42:1, s. 26-36
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Tidskriftsartikel (refereegranskat)abstract
- Background: Combination treatment (chemoradiotherapy) is the standard treatment for locally advanced head and neck squamous cell carcinoma (HNSCC); however, treatment resistance and local recurrence are significant problems. A high level of epidermal growth factor receptor (EGFR) has been associated with a more aggressive phenotype as well as decreased responsiveness to radio- or chemotherapy. We examined the role of EGFR status and EGFR ligand expression for the treatment response. Methods: Intrinsic sensitivity to radiotherapy, cisplatin, and cetuximab treatments was investigated in 25 HNSCC cell lines. EGFR gene copy number, mRNA and protein expression, EGFR and Akt phosphorylation status, and mRNA expression of the EGFR ligands were analyzed using quantitative PCR and ELISA and assessed for their impact on treatment sensitivity. Results: Different treatment modalities yielded great diversity in outcome; of note, cetuximab treatment stimulated growth in one cell line. When treatments were combined primarily additive effects were observed. While radioresistance tended to be associated with a high level of phosphorylated EGFR (pEGFR; P = 0.09), cetuximab-resistant cells had low levels of pEGFR (P = 0.13). The three most cetuximab-sensitive cell lines had high EGFR gene copy numbers. Furthermore, cetuximab treatment response was significantly correlated with epiregulin mRNA expression (r = -0.408, P = 0.043). Cisplatin-resistant tumor cells expressed significantly lower levels of EGFR protein (P = 0.04) compared to cisplatin-sensitive cells and tended to have lower levels of phosphorylated Akt (pAkt; P = 0.13) and lower expression levels of amphiregulin (P = 0.18). Conclusions: Epidermal growth factor receptor status and ligand expression influence the treatment sensitivity of HNSCC cells and may be useful as predictive markers.
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| 16. |
- Jerhammar, Fredrik, et al.
(författare)
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YAP1 is a potential biomarker for cetuximab resistance in head and neck cancer
- 2014
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Ingår i: Oral Oncology. - : Elsevier. - 1368-8375 .- 1879-0593. ; 50:9, s. 832-839
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Targeted therapy against the epidermal growth factor receptor (EGFR) only variably represents a therapeutic advance in head and neck squamous cell carcinoma (HNSCC). This study addresses the need of biomarkers of treatment response to the EGFR-targeting antibody cetuximab (Erbitux (R)). Materials and Methods: The intrinsic cetuximab sensitivity of HNSCC cell lines was assessed by a crystal violet assay. Gene copy number analysis of five resistant and five sensitive cell lines was performed using the Affymetrix SNP 6.0 platform. Quantitative real-time PCR was used for verification of selected copy number alterations and assessment of mRNA expression. The functional importance of the findings on the gene and mRNA level was investigated employing siRNA technology. The data was statistically evaluated using Mann-Whitney U-test and Spearmans correlation test. Results: Analysis of the intrinsic cetuximab sensitivity of 32 HNSCC cell lines characterized five and nine lines as cetuximab sensitive or resistant, respectively. Gene copy number analysis of five resistant versus five sensitive cell lines identified 39 amplified protein-coding genes, including YAP1, in the genomic regions 11q22.1 or 5p13-15. Assessment using qPCR verified that YAP1 amplification associated with cetuximab resistance. Amplification of YAP1 correlated to higher mRNA levels, and RNA knockdown resulted in increased cetuximab sensitivity. Assessment of several independent clinical data sets in the public domain confirmed YAP1 amplifications in multiple tumor types including HNSCC, along with highly differential expression in a subset of HNSCC patients. Conclusion: Taken together, we provide evidence that YAP1 could represent a novel biomarker gene of cetuximab resistance in HNSCC cell lines.
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| 17. |
- Johansson, Ann-Charlotte, et al.
(författare)
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Cancer-Associated Fibroblasts Induce Matrix Metalloproteinase-Mediated Cetuximab Resistance in Head and Neck Squamous Cell Carcinoma Cells
- 2012
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Ingår i: Molecular Cancer Research. - : American Association for Cancer Research. - 1541-7786 .- 1557-3125. ; 10:9, s. 1158-1168
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Tidskriftsartikel (refereegranskat)abstract
- A growing body of evidence suggests that components of the tumor microenvironment, including cancer-associated fibroblasts (CAF), may modulate the treatment sensitivity of tumor cells. Here, we investigated the possible influence of CAFs on the sensitivity of head and neck squamous cell carcinoma (HNSCC) cell lines to cetuximab, an antagonistic epidermal growth factor receptor (EGFR) antibody. Cetuximab treatment caused a reduction in the proliferation rate of HNSCC cell lines, whereas the growth of HNSCC-derived CAF cultures was unaffected. When tumor cells were cocultured with CAFs in a transwell system, the cetuximab-induced growth inhibition was reduced, and a complete protection from growth inhibition was observed in one of the tumor cell lines investigated. Media that had been conditioned by CAFs offered protection from cetuximab treatment in a concentration-dependent manner, suggesting that the resistance to treatment was mediated by CAF-derived soluble factors. The coculture of HNSCC cell lines with CAFs resulted in an elevated expression of matrix metalloproteinase-1 (MMP-1) in both the tumor cells and CAFs. Moreover, the CAF-induced resistance was partly abolished by the presence of an MMP inhibitor. However, CAFs treated with siRNA targeting MMP-1 still protected tumor cells from cetuximab treatment, suggesting that several MMPs may cooperate to facilitate resistance or that the protective effect is mediated by another member of the MMP family. These results identify a novel CAF-dependent modulation of cetuximab sensitivity and suggest that inhibiting MMPs may improve the effects of EGFR-targeted therapy.
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| 18. |
- Johansson, Ann-Charlotte, et al.
(författare)
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Regulation of apoptosis-associated lysosomal membrane permeabilization
- 2010
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Ingår i: APOPTOSIS. - : Springer Science Business Media. - 1360-8185 .- 1573-675X. ; 15:5, s. 527-540
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Tidskriftsartikel (refereegranskat)abstract
- Lysosomal membrane permeabilization (LMP) occurs in response to a large variety of cell death stimuli causing release of cathepsins from the lysosomal lumen into the cytosol where they participate in apoptosis signaling. In some settings, apoptosis induction is dependent on an early release of cathepsins, while under other circumstances LMP occurs late in the cell death process and contributes to amplification of the death signal. The mechanism underlying LMP is still incompletely understood; however, a growing body of evidence suggests that LMP may be governed by several distinct mechanisms that are likely engaged in a death stimulus- and cell-type-dependent fashion. In this review, factors contributing to permeabilization of the lysosomal membrane including reactive oxygen species, lysosomal membrane lipid composition, proteases, p53, and Bcl-2 family proteins, are described. Potential mechanisms to safeguard lysosomal integrity and confer resistance to lysosome-dependent cell death are also discussed.
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| 19. |
- La Fleur, Linnea, et al.
(författare)
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A CD44(high)/EGFR(low) Subpopulation within Head and Neck Cancer Cell Lines Shows an Epithelial-Mesenchymal Transition Phenotype and Resistance to Treatment
- 2012
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Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 7:9
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Tidskriftsartikel (refereegranskat)abstract
- Mortality in head and neck squamous cell carcinoma (HNSCC) is high due to emergence of therapy resistance which results in local and regional recurrences that may have their origin in resistant cancer stem cells (CSCs) or cells with an epithelial-mesenchymal transition (EMT) phenotype. In the present study, we investigate the possibility of using the cell surface expression of CD44 and epidermal growth factor receptor (EGFR), both of which have been used as stem cell markers, to identify subpopulations within HNSCC cell lines that differ with respect to phenotype and treatment sensitivity. Three subpopulations, consisting of CD44(high)/EGFR(low), CD44(high)/EGFR(high) and CD44(low) cells, respectively, were collected by fluorescence-activated cell sorting. The CD44(high)/EGFR(low) population showed a spindle-shaped EMT-like morphology, while the CD44(low) population was dominated by cobblestone-shaped cells. The CD44(high)/EGFR(low) population was enriched with cells in G0/G1 and showed a relatively low proliferation rate and a high plating efficiency. Using a real time PCR array, 27 genes, of which 14 were related to an EMT phenotype and two with stemness, were found to be differentially expressed in CD44(high)/EGFR(low) cells in comparison to CD44(low) cells. Moreover, CD44(high)/EGFR(low) cells showed a low sensitivity to radiation, cisplatin, cetuximab and gefitinib, and a high sensitivity to dasatinib relative to its CD44(high)/EGFR(high) and CD44(low) counterparts. In conclusion, our results show that the combination of CD44 (high) and EGFR (low) cell surface expression can be used to identify a treatment resistant subpopulation with an EMT phenotype in HNSCC cell lines.
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| 20. |
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| 21. |
- Nedlund, Ann-Charlotte
(författare)
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Designing for Legitimacy : Policy Work and the Art of Juggling When Setting Limits in Health Care
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Limit-setting in publicly funded healthcare is unavoidable, and increasingly important in the governance and management of the demand for health services. The work of limit-setting takes place in the organising of the provision of health services, where various health workers (professionals, administrators, unit managers, politicians) collectively exercise their skills. Limit-setting often creates tensions which impose the quest for legitimacy; it involves norms and values which are related to the interests of the health workers, and moreover to society at large. In that sense, limit-setting is related to internal processes of legitimacy within the healthcare organisation, i.e. internal legitimacy, and external processes of legitimacy where citizens are legitimating the activities in the healthcare organisation, i.e. external legitimacy.The purpose of this thesis was to discover, and increase the understanding of the dilemma associated with sustaining, generating and designing internal legitimacy, when working with a policy of limit-setting in healthcare, in relation to the provision of Assistive Technologies (AT). It has explored what health workers do when they are working with a policy, and in particular how they work out what they should be doing. Finally the role of mediating institutions in supporting and designing internal legitimacy, was explored in the thesis.Following a case-study design and a qualitative approach, where fifty-seven semi-structured open-ended interviews were conducted, data allowed the exploration of internal legitimacy in a context of complex interaction and construction of policy work in two Swedish county councils.This research produced a number of key findings; in an environment of finite resources health workers encountered situations that were characterised by conflicting pressures, and handled these by way of interaction, sense making, presenting arguments, negotiating and seeking support for an appropriate course of action and practices. The policy work with limit-setting can therefore be regarded as a dynamic interactive process, which incorporates several actors in different situations and locations, together negotiating and institutionalising the policy. Various policy sites, which had the role of mediating institutions, were identified, and were important in the interactive processes of forming a shared collective meaning in order to reach an appropriate act. Hence, designing legitimacy has to acknowledge the interactive policy work, and its contextual character, taking place at the different levels of a healthcare system.
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| 22. |
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| 23. |
- Sartz, Lisa, et al.
(författare)
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A novel C3 mutation causing increased formation of the C3 convertase in familial atypical hemolytic uremic syndrome.
- 2012
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 188:4, s. 2030-2037
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Forskningsöversikt (refereegranskat)abstract
- Atypical hemolytic uremic syndrome has been associated with dysregulation of the alternative complement pathway. In this study, a novel heterozygous C3 mutation was identified in a factor B-binding region in exon 41, V1636A (4973 T > C). The mutation was found in three family members affected with late-onset atypical hemolytic uremic syndrome and symptoms of glomerulonephritis. All three patients exhibited increased complement activation detected by decreased C3 levels and glomerular C3 deposits. Platelets from two of the patients had C3 and C9 deposits on the cell surface. Patient sera exhibited more C3 cleavage and higher levels of C3a. The C3 mutation resulted in increased C3 binding to factor B and increased net formation of the C3 convertase, even after decay induced by decay-accelerating factor and factor H, as assayed by surface plasmon resonance. Patient sera incubated with washed human platelets induced more C3 and C9 deposition on the cell surface in comparison with normal sera. More C3a was released into serum over time when washed platelets were exposed to patient sera. Results regarding C3 and C9 deposition on washed platelets were confirmed using purified patient C3 in C3-depleted serum. The results indicated enhanced convertase formation leading to increased complement activation on cell surfaces. Previously described C3 mutations showed loss of function with regard to C3 binding to complement regulators. To our knowledge, this study presents the first known C3 mutation inducing increased formation of the C3 convertase, thus explaining enhanced activation of the alternative pathway of complement.
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| 24. |
- Waldenström, Ann-Charlotte, 1950, et al.
(författare)
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Pain and mean absorbed dose to the pubic bone after radiotherapy among gynecological cancer survivors.
- 2011
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Ingår i: International journal of radiation oncology, biology, physics. - : Elsevier. - 1879-355X .- 0360-3016. ; 80:4, s. 1171-1180
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To analyze the relationship between mean absorbed dose to the pubic bone after pelvic radiotherapy for gynecological cancer and occurrence of pubic bone pain among long-term survivors.METHODS AND MATERIALS: In an unselected, population-based study, we identified 823 long-term gynecological cancer survivors treated with pelvic radiotherapy during 1991-2003. For comparison, we used a non-radiation-treated control population of 478 matched women from the Swedish Population Register. Pain, intensity of pain, and functional impairment due to pain in the pubic bone were assessed with a study-specific postal questionnaire.RESULTS: We analyzed data from 650 survivors (participation rate 79%) with median follow-up of 6.3 years (range, 2.3-15.0 years) along with 344 control women (participation rate, 72 %). Ten percent of the survivors were treated with radiotherapy; ninety percent with surgery plus radiotherapy. Brachytherapy was added in 81%. Complete treatment records were recovered for 538/650 survivors, with dose distribution data including dose-volume histograms over the pubic bone. Pubic bone pain was reported by 73 survivors (11%); 59/517 (11%) had been exposed to mean absorbed external beam doses <52.5 Gy to the pubic bone and 5/12 (42%) to mean absorbed external beam doses ≥ 52.5 Gy. Thirty-three survivors reported pain affecting sleep, a 13-fold increased prevalence compared with control women. Forty-nine survivors reported functional impairment measured as pain walking indoors, a 10-fold increased prevalence.CONCLUSIONS: Mean absorbed external beam dose above 52.5 Gy to the pubic bone increases the occurrence of pain in the pubic bone and may affect daily life of long-term survivors treated with radiotherapy for gynecological cancer.
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| 25. |
- Waldenström, Ann-Charlotte, 1950, et al.
(författare)
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Relative importance of hip and sacral pain among long-term gynecological cancer survivors treated with pelvic radiotherapy and their relationships to mean absorbed doses.
- 2012
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Ingår i: International Journal of Radiation Oncology, Biology, Physics. - : Elsevier. - 0360-3016 .- 1879-355X. ; 84:2, s. 428-436
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To investigate the relative importance of patient-reported hip and sacral pain after pelvic radiotherapy (RT) for gynecological cancer and its relationship to the absorbed doses in these organs.METHODS AND MATERIALS: We used data from a population-based study that included 650 long-term gynecological cancer survivors treated with pelvic RT in the Gothenburg and Stockholm areas in Sweden with a median follow-up of 6 years (range, 2-15) and 344 population controls. Symptoms were assessed through a study-specific postal questionnaire. We also analyzed the hip and sacral dose-volume histogram data for 358 of the survivors.RESULTS: Of the survivors, one in three reported having or having had hip pain after completing RT. Daily pain when walking was four times as common among the survivors compared to controls. Symptoms increased in frequency with a mean absorbed dose >37.5 Gy. Also, two in five survivors reported pain in the sacrum. Sacral pain also affected their walking ability and tended to increase with a mean absorbed dose >42.5 Gy.CONCLUSIONS: Long-term survivors of gynecological cancer treated with pelvic RT experience hip and sacral pain when walking. The mean absorbed dose was significantly related to hip pain and was borderline significantly related to sacral pain. Keeping the total mean absorbed hip dose below 37.5 Gy during treatment might lower the occurrence of long-lasting pain. In relation to the controls, the survivors had a lower occurrence of pain and pain-related symptoms from the hips and sacrum compared with what has previously been reported for the pubic bone.
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| 26. |
- Waldenström, Ann-Charlotte, 1950, et al.
(författare)
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Variation in position and volume of organs at risk in the small pelvis.
- 2010
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Ingår i: Acta oncologica (Stockholm, Sweden). - : Informa UK Limited. - 1651-226X .- 0284-186X. ; 49:4, s. 491-9
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Tidskriftsartikel (refereegranskat)abstract
- In preparation for studies of dose volume of ionizing radiation and long-term side effects, we assessed both variation in position and volume of organs at risk in the small pelvis.
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