SwePub - search: WFRF:(Johansson Ann Charlotte)

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1.	Thålin, Charlotte, et al. (author) Elevated Troponin Levels in Acute Stroke Patients Predict Long-term Mortality 2015 In: Journal of Stroke & Cerebrovascular Diseases. - : Elsevier BV. - 1052-3057 .- 1532-8511. ; 10, s. 285-286 Research review (peer-reviewed)abstract Background: Elevated plasma levels of troponin in acute stroke patients are common and have in several studies been shown to predict in-hospital and short-term mortality. Little is, however, known about the long-term prognosis of these patients. The aim of this study was to determine patient characteristics and 5-year mortality in patients with acute stroke and troponin elevation on admission. Methods: A retrospective cohort study of all consecutive patients with acute stroke and a plasma troponin I (TnI) analyzed on admission to Danderyd Hospital between January 1, 2005, and January 1, 2006 (n = 247). Patient characteristics were obtained from the Swedish National Stroke Register, Riksstroke, as well as hospital records. Mortality data were obtained from the Swedish Cause of Death Register. Results: There were 133 patients (54%) with TnI less than .03 mu g/L (normal), 74 patients (30%) with TnI .03-.11 mu g/L (low elevation), and 40 patients (16%) with TnI greater than .11 mu g/L (high elevation). TnI elevations were associated with a higher age, prior ischemic stroke, chronic heart failure, renal insufficiency, stroke severity, and ST segment elevation or depression on admission. The rate of hyperlipidemia decreased with increasing TnI. Adjusted for age and comorbidity, elevated TnI values on admission had a significantly and sustained increased mortality over the 5-year follow-up, with a hazard ratio of 1.90 (95% confidence interval, 1.33-2.70). Conclusions: Troponin elevation in patients with acute stroke, even when adjusted for several possible confounders, is associated with an almost 2-fold increased risk of 5-year mortality.
2.	Appelqvist, Hanna, et al. (author) Lysosome-Mediated Apoptosis is Associated with Cathepsin D-Specific Processing of Bid at Phe24,Trp48, and Phe183 2012 In: Annals of Clinical and Laboratory Science. - : Institute for Clinical Science. - 0091-7370 .- 1550-8080. ; 42:3, s. 231-242 Journal article (peer-reviewed)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.
3.	Danared, Håkan, et al. (author) Preface 2017 In: IPAC 2018 : Proceedings of the 8th International Particle Accelerator Conference - Proceedings of the 8th International Particle Accelerator Conference. - 9783954501823 Journal article (other academic/artistic)
4.	Gerhardt, Karin, et al. (author) Nog nu, politiker – ta klimatkrisen på allvar 2022 In: Aftonbladet. - Stockholm : Aftonbladet Hierta. ; 25 August Journal article (pop. science, debate, etc.)
5.	Johansson, Ann-Charlotte, et al. (author) Cathepsin D-mediated processing of Bid at Phe24, Trp48, and Phe183 2008 In: International Journal of Experimental Pathology. Journal article (peer-reviewed)
6.	Kågedal, Katarina, et al. (author) Lysosomal membrane permeabilization during apoptosis : Involvement of Bax? 2005 In: International journal of experimental pathology (Print). - : John Wiley & Sons. - 0959-9673 .- 1365-2613. ; 86:5, s. 309-321 Journal article (peer-reviewed)abstract Bcl-2 family members have long been known to control permeabilization of the mitochondrial membrane during apoptosis, but involvement of these proteins in lysosomal membrane permeabilization (LMP) was not considered until recently. The aim of this study was to investigate the mechanism underlying the release of lysosomal proteases to the cytosol seen during apoptosis, with special emphasis on the role of Bax. In human fibroblasts, exposed to the apoptosis-inducing drug staurosporine (STS), the release of the lysosomal protease cathepsin D to the cytosol was observed by immunocytochemistry. In response to STS treatment, there was a shift in Bax immunostaining from a diffuse to a punctate pattern. Confocal microscopy showed co-localization of Bax with both lysosomes and mitochondria in dying cells. Presence of Bax at the lysosomal membrane was confirmed by immuno-electron microscopy. Furthermore, when recombinant Bax was incubated with pure lysosomal fractions, Bax inserted into the lysosomal membrane and induced the release of lysosomal enzymes. Thus, we suggest that Bax is a mediator of LMP, possibly promoting the release of lysosomal enzymes to the cytosol during apoptosis.
7.	Nilsson, Cathrine, 1978-, et al. (author) Cytosolic acidification and lysosomal alkalinization during TNF-α induced apoptosis in U937 cells 2006 In: Apoptosis (London). - : Springer Netherlands. - 1360-8185 .- 1573-675X. ; 11:7, s. 1149-1159 Journal article (peer-reviewed)abstract Apoptosis is often associated with acidification of the cytosol and since loss of lysosomal proton gradient and release of lysosomal content are early events during apoptosis, we investigated if the lysosomal compartment could contribute to cytosolic acidification. After exposure of U937 cells to tumor necrosis factor-α, three populations; healthy, pre-apoptotic, and apoptotic cells, were identified by flow cytometry. These populations were investigated regarding intra-cellular pH and apoptosis-associated events. There was a drop in cytosolic pH from 7.2 ± 0.1 in healthy cells to 6.8 ± 0.1 in pre-apoptotic, caspase-negative cells. In apoptotic, caspase-positive cells, the pH was further decreased to 5.7 ± 0.04. The cytosolic acidification was not affected by addition of specific inhibitors towards caspases or the mitochondrial F0F1-ATPase. In parallel to the cytosolic acidification, a rise in lysosomal pH from 4.3 ± 0.3, in the healthy population, to 4.8 ± 0.3 and 5.5 ± 0.3 in the pre-apoptotic- and apoptotic populations, respectively, was detected. In addition, lysosomal membrane permeability increased as detected as release of cathepsin D from lysosomes to the cytosol in pre-apoptotic and apoptotic cells. We, thus, suggest that lysosomal proton release is the cause of the cytosolic acidification of U937 cells exposed to TNF-α.
8.	Nilsson, Jan, 1963-, et al. (author) Development and validation of a new tool measuring nurses self-reported professional competence — The nurse professional competence (NPC) Scale 2014 In: Nurse Education Today. - Midlothian, Scotland : Elsevier BV. - 0260-6917 .- 1532-2793. ; 34:4, s. 574-580 Journal article (peer-reviewed)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.
9.	Nilsson, Jan, 1963-, et al. (author) Nursing in a globalized world : Nursing students with international study experience report higher competence at graduation 2014 In: Open Journal of Nursing. - : Scientific Research Publishing, Inc.. - 2162-5336 .- 2162-5344. ; :4, s. 848-858 Journal article (peer-reviewed)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.
10.	Alevronta, Eleftheria, et al. (author) Dose-response relationships for an atomized symptom of fecal incontinence after gynecological radiotherapy. 2013 In: Acta oncologica (Stockholm, Sweden). - : Taylor & Francis. - 1651-226X .- 0284-186X. ; 52:4, s. 719-26 Journal article (peer-reviewed)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.
11.	Andrén Ann-Charlotte, Johansson Åsa. (author) Anorexia Nervosa - olika behandlingsmodeller i Sverige Del 2 (Seminarieuppgift inom kursen Dietetik C. 1996 In: Dietistaktuellt 1996 (?):?-?.. Journal article (other academic/artistic)
12.	Ansell, Anna, et al. (author) Epidermal growth factor is a biomarker for poor cetuximab response in tongue cancer cells 2016 In: Journal of Oral Pathology & Medicine. - : Wiley-Blackwell. - 0904-2512 .- 1600-0714. ; 45:1, s. 9-16 Journal article (peer-reviewed)abstract Background: Epidermal growth factor receptor (EGFR) is a target for treatment in tongue cancer. Here, EGFR ligands were evaluated for their potential uses as predictive biomarkers of cetuximab treatment response.Methods: In three tongue cancer cell lines the influences of epidermal growth factor (EGF), amphiregulin (AR), and epiregulin (EPR) on tumour cell proliferation and cetuximab response were evaluated by the addition of recombinant human (rh) proteins or the siRNA-mediated downregulation of endogenous ligand production.Results: EGF or AR downregulation suppressed the proliferation of all investigated cell lines. Furthermore, all cell lines displayed increased cetuximab resistance upon the addition of rhEGF, whereas EGF silencing resulted in an improved cetuximab response in one cell line.Conclusions: Our data suggest that EGF and AR are critical components of the EGFR signalling network required for full proliferative potential. Moreover, EGF is a potential predictive biomarker of poor cetuximab response and a possible treatment target.
13.	Ansell, Anna, 1983- (author) Identification of Tumor Cell- and Stroma Derived Biomarkers of Treatment Response in Head and Neck Cancer 2013 Doctoral thesis (other academic/artistic)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.
14.	Ansell, Anna, et al. (author) Molecular cross-talk between head and neck squamous cell carcinoma cells and cancer-associated fibroblasts 2013 Other publication (other academic/artistic)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.
15.	Arvidsson, Ida, et al. (author) Apyrase decreases phage induction and Shiga toxin release from E. coli O157:H7 and has a protective effect during infection 2022 In: Gut microbes. - : Informa UK Limited. - 1949-0976 .- 1949-0984. ; 14:1 Journal article (peer-reviewed)abstract Shiga toxin (Stx)-producing enterohemorrhagic Escherichia coli (EHEC) cause gastrointestinal infection and, in severe cases, hemolytic uremic syndrome which may lead to death. There is, to-date, no therapy for this infection. Stx induces ATP release from host cells and ATP signaling mediates its cytotoxic effects. Apyrase cleaves and neutralizes ATP and its effect on Stx and EHEC infection was therefore investigated. Apyrase decreased bacterial RecA and dose-dependently decreased toxin release from E. coli O157:H7 in vitro, demonstrated by reduced phage DNA and protein levels. The effect was investigated in a mouse model of E. coli O157:H7 infection. BALB/c mice infected with Stx2-producing E. coli O157:H7 were treated with apyrase intraperitoneally, on days 0 and 2 post-infection, and monitored for 11 days. Apyrase-treated mice developed disease two days later than untreated mice. Untreated infected mice lost significantly more weight than those treated with apyrase. Apyrase-treated mice exhibited less colonic goblet cell depletion and apoptotic cells, as well as lower fecal ATP and Stx2, compared to untreated mice. Apyrase also decreased platelet aggregation induced by co-incubation of human platelet-rich-plasma with Stx2 and E. coli O157 lipopolysaccharide in the presence of collagen. Thus, apyrase had multiple protective effects, reducing RecA levels, stx2 and toxin release from EHEC, reducing fecal Stx2 and protecting mouse intestinal cells, as well as decreasing platelet activation, and could thereby delay the development of disease.
16.	Bergengren, Oskar, et al. (author) Satisfaction with Nurse-led Follow-up in Prostate Cancer Patients-A Nationwide Population-based Study 2022 In: European Urology Open Science. - : Elsevier. - 2666-1691 .- 2666-1683. ; 38, s. 25-31 Journal article (peer-reviewed)abstract Background: Satisfaction with nurse-led follow-up among men with prostate can-cer is high. However, it is unclear whether all men are satisfied or whether there are men who would benefit from being followed by a urologist or a nurse.Objective: To investigate the follow-up distribution between urologists and nurses, and whether the high self-reported satisfaction with nurse-led follow-up is inde-pendent of other factors such as age or comorbidity.Design, setting, and participants: All Swedish men, <= 70 yr of age, with a low-risk prostate cancer diagnosis in 2008, answered a questionnaire 7 yr after diagnosis. The extensive questionnaire included a question on satisfaction with care, answered on a seven-point scale. Participants were divided based on whether they were followed up by a nurse, a urologist, or both.Outcome measurements and statistical analysis: Factors that could influence the level of satisfaction were identified as age, edu-cation, comorbidity, treatment, disease progression, urinary bother, level of infor-mation, and participation in treatment decision. Likelihood ratio tests from ordinal regression were used to test the null hypothesis of similar satisfaction between groups.Results and limitations: Out of 1288 men, 1137 (88%) answered both the question on who performed the follow-up and the question regarding satisfaction. In all, 350 men reported that they were followed up by nurses (31%), 598 (52%) by urologists, and 189 (17%) by both. No differences in satisfaction where seen between the groups. Approximately 50% were satisfied completely, regardless of who performed the follow-up. Results were not affected by age, educational level, comorbidity, treatment, disease progression, urinary bother, information, or participation in treatment decision. Limitations include the nonrandomized, retrospective design and a potential recall bias.Conclusions: Satisfaction with nurse-led follow-up is high, regardless of factors such as age, level of education, comorbidity, and treatment.Patient summary: Men with prostate cancer can be offered nurse-led follow-up on a regular basis and still maintain their satisfaction with health care.
17.	Bergh, Jonas C. S., et al. (author) Docetaxel, trastuzumab, pertuzumab versus trastuzumab emtansine as neoadjuvant treatment of HER2-positive breast cancer : results from the Swedish PREDIX HER2 trial identifying a new potential de-escalation standard? 2019 In: Journal of Clinical Oncology. - : American Society of Clinical Oncology. - 0732-183X .- 1527-7755. ; 37:15, s. 501-501 Journal article (other academic/artistic)abstract Background: Neoadjuvant therapy produces high rates of pathological complete response (pCR) and is the standard of care in HER2 positive breast cancer; however, the optimal treatment regimen remains to be established. Methods: In this randomized phase II study patients ≥18 years with HER2 positive breast cancer > 20mm or verified lymph node metastases were randomized to 6 courses of docetaxel, trastuzumab and pertuzumab (DTP, group A) or trastuzumab emtansine (T-DM1, group B), q 21 days. The protocol allowed switch to the competing treatment upon lack of response or drug-related severe toxicity. Patients received postoperative epirubicin+cyclophosphamide, trastuzumab for a total of one year and endocrine therapy. Accrual was completed in October 2018 after randomization of 202 patients, data on pCR were available for 190 at the time for this abstract submission. Median age, 52 years (26-74), menopausal status, histological type and grade were well balanced between the treatment groups. 62.6% of the tumors were hormone receptor (HR) positive. Results: Primary endpoint was pathological objective response. 190 patients completed the protocol-specified preoperative treatment. pCR was achieved in 45.3% of patients, 46.4% in patients treated with DTP and 44.1% with T-DM1 (chi-sq., p = 0.75). In HR-positive tumors, pCR was obtained in 35.3% of patients, 35.9% in group A vs. 34.6% in group B (p = 0.87); in HR-negative tumors, the overall pCR rate was 62.0%, 66.7% in group A vs. 57.9% in group B (p = 0.45). Severe (grade 3/4) toxicity was reported at 68 occasions related to DTP, compared with 16 related to T-DM1, 26 vs. 3 caused by febrile neutropenia. Significantly better quality of life was reported by patients treated with T-DM1. Conclusions: Our data on TDM-1 demonstrates similar efficacy and less toxicity, in particular for patients with HER2 and HR positive cancers, being a potential new standard for neoadjuvant therapy. Clinical trial information: NCT02568839.
18.	Bertilsson, Ann-Sofie, et al. (author) A client-centred ADL intervention: three-month follow-up of a randomized controlled trial 2014 In: Scandinavian Journal of Occupational Therapy. - : Informa UK Limited. - 1103-8128 .- 1651-2014. ; 21, s. 377-391 Journal article (peer-reviewed)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.
19.	Brandberg, Yvonne, et al. (author) Health-related quality of life in the Swedish PREDIX HER2 trial, evaluating docetaxel, trastuzumab, pertuzumab versus trastuzumab emtansine as neoadjuvant treatment of HER2-positive breast cancer. 2019 In: Journal of Clinical Oncology. - : American Society of Clinical Oncology. - 0732-183X .- 1527-7755. ; 37:15, s. 583-583 Journal article (other academic/artistic)abstract Background: Neoadjuvant therapy combining docetaxel, trastuzumab and pertuzumab (DTP) was compared to trastuzumab emtansine (T-DM1) in the randomized phase 2 PREDIX HER2 trial. Patients, ≥18 years with HER2 positive breast cancer, ≥20mm or with verified lymph node metastases, were randomized to six courses of DTP (Standard arm) or T-DM1 (Experimental arm). Primary endpoint was pathological objective response to primary medical therapy at post-treatment surgery. Health related quality of life (HRQoL) was a secondary outcome, and is of specific interest as there was no difference between the randomization groups regarding the main endpoint (results presented in a separate abstract sent to ASCO 2019, Bergh et al.). Methods: Of 202 randomized patients, 190 are available for evaluation at this point. HRQoL was measured, using EORTC QLQ-C30 + EORTC QLQ-BR23, at baseline before randomization and after six courses. Results: No differences between the randomization arms were found at baseline. Results after six courses, based on 163 patients (86%) and adjusted to baseline values, revealed statistical significant differences (p≤0.01), favoring the experimental T-DM1 arm on 7 out of 15 of the EORTC QLQ-C30 variables (Physical functioning, Role functioning, Social functioning, Global quality of Life, Fatigue, Dyspnea, and Diarrhea). For the breast cancer specific questionnaire (EORTC-BR23), the experimental arm scored statistically significantly better on 5 out of 7 subscales (Body image, Sexual functioning, Sexual enjoyment, Systemic therapy side effects and Upset by hair loss). All of the statistical significant differences were of moderate or large clinical significance (≥10 scale scores). No differences between the randomization arms were found for the remaining HRQoL variables. Conclusions: The experimental arm reported better HRQoL than the control arm after six courses. Trastuzumab emtansine may be a useful treatment alternative due to better HRQoL and lower toxicity. Clinical trial information: NCT02568839.
20.	Brandstrom, Josef, et al. (author) CD-Sens and Component Resolved Diagnostics In Diagnosing Hazelnut Allergy 2014 In: Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 0091-6749 .- 1097-6825. ; 133:2, s. AB111-AB111 Journal article (other academic/artistic)
21.	Brandström, Josef, et al. (author) Individually dosed omalizumab facilitates peanut oral immunotherapy in peanut allergic adolescents 2019 In: Clinical and Experimental Allergy. - : Wiley. - 0954-7894 .- 1365-2222. ; 49:10, s. 1328-1341 Journal article (peer-reviewed)abstract Background: Peanut oral immunotherapy (pOIT) has showed good short-term outcomes, but allergic reactions may prevent effective up-dosing and is a major cause of stopping OIT. In placebo-controlled trials, omalizumab has been shown to facilitate allergen immunotherapy and increase tolerance to peanut.Objective: We hypothesized that by combining omalizumab with pOIT, and monitor treatment effects with basophil allergen threshold sensitivity tests (CD-sens), peanut allergic patients could safely initiate pOIT and thereafter slowly withdraw omalizumab.Methods: This is the 2nd part of a one-armed open phase-2 study where peanut allergic adolescents (n = 23) started pOIT after an individualized omalizumab treatment. The pOIT dose was increased from 280 to 2800 mg peanut protein in 8 weeks followed by an individualized step-wise withdrawal of omalizumab, based on clinical symptoms and CD-sens levels. pOIT continued for 12 weeks followed by an open peanut challenge. Peanut CD-sens and allergen-binding activity (ABA) and IgE-ab, IgG-ab and IgG4-ab to peanut and its components were measured during the study.Results: All 23 patients successfully reached the 2800 mg maintenance dose. Moderate/systemic allergic reactions were rare while receiving full-dose omalizumab. Eleven of 23 (48%) successfully continued with pOIT after omalizumab was stopped. Compared to treatment failures, median baseline IgE-ab to peanut components Ara h 1-3 and CD-sens to peanut were significantly lower among successfully treated patients and IgG4-ab to peanut, Ara h 2 and 6 increased significantly more during treatment.Conclusions and clinical relevance: This study indicates that omalizumab is an effective adjunctive therapy for initiation and rapid up-dosing of pOIT; however, adverse events from pOIT become more frequent as omalizumab doses are decreased.
22.	Bråred Christensson, Johanna, 1965, et al. (author) Limonene hydroperoxide analogues differ in allergenic activity 2008 In: Contact Dermatitis. - : Wiley. - 0105-1873 .- 1600-0536. ; 59:6, s. 344-352 Journal article (peer-reviewed)abstract Background: The fragrance terpene R-limonene is a very weak sensitizer but forms allergenic oxidation products upon contact with air. Oxidized (ox.) limonene is a frequent cause of contact allergy in clinical testing. Objectives: This study investigates the sensitizing potencies of ox. and non-ox. limonene and of structurally closely related limonene hydroperoxides. The clinical importance of the difference in sensitizing potency of two hydroperoxides in autoxidized limonene was studied. Patients/Methods: Ox. and non-ox. limonene were investigated in the murine local lymph node assay (LLNA). Limonene hydroperoxides were investigated using a modified LLNA involving non-pooled lymph nodes and statistical calculations; patch testing of patients with known contact allergy to ox. limonene was performed. Results: A marked increase in the sensitizing potency of ox. limonene compared with that of pure limonene was observed in the LLNA. One analogue, limonene-1-hydroperoxide, was a significantly more potent sensitizer than the other hydroperoxides and gave more positive test reactions in the allergic patients. Conclusions: The results support that hydroperoxides have a specific reactivity indicating that oxygen-centred radicals are important in hapten–protein complex formation of hydroperoxides. The primary oxidation products of ox. limonene, the hydroperoxides, have an important impact on the sensitizing capacity of the oxidation mixture.
23.	Bäckman, Karin, et al. (author) Vårdens alltför svåra val? : kartläggning av prioriteringsarbete och analys av riksdagens principer och riktlinjer för prioriteringar i hälso- och sjukvården 2007 Reports (other academic/artistic)abstract PrioriteringsCentrum har på uppdrag av Socialstyrelsen genomfört en kartläggning av på vilket sätt hälso- och sjukvårdens huvudmän och andra centrala aktörer arbetar med prioriteringar och har utvärderat hur detta arbete överensstämmer med intentionerna i riksdagens beslut om prioriteringar. Vi har även analyserat innehållet i och tillämpningen av riksdagens riktlinjer för prioriteringar i hälso- och sjukvården. Det har skett genom en etisk analys och mot bakgrund av ett stort antal intervjuer i landsting och kommuner samt med representanter för statliga myndigheter och yrkesorganisationer och med ledning av vad som framkommit i tidigare uppföljningar. Vi föreslår i rapporten ett anta förändringar och förtydliganden av riktlinjerna.Vi kan konstatera att sättet att arbeta med prioriteringar i landsting och kommuner inte är helt olikt det som gällde när Prioriteringsdelegationen redovisade en motsvarande uppföljning år 2001. Fortfarande finns knappast några öppna beslut om fördelning och prioritering av resurser om man med öppenhet avser att beslutsfattaren medvetet överväger flera alternativ och att grunderna för besluten är kända för dem som önskar ta del av dem.I situationer då tillgängliga resurser inte befinner sig i paritet med önskvärda ambitioner får sjukvårdspersonalen ta det största ansvaret för att besluta om och genomföra ransonering av vården. Förutom på chefsnivå tycks dock sjukvårdpersonal fortfarande i liten utsträckning vara medveten om de etiska principer som enligt riksdagsbeslutet ska styra prioriteringar i vården. Få känner till den etiska plattformen med de tre etiska principerna. Lokala mallar eller styrdokument för prioriteringar är ovanliga. Det saknas nödvändiga förutsättningar för att tillämpa riksdagens prioriteringsbeslut och det finns inte heller några tydliga strategier för hur man vill skapa sådana förutsättningar inom landstingen.Den kommunala vård- och omsorgsverksamheten upplever sig fortfarande i ringa utsträckning berörd av den etiska plattformen och prioriteringsprinciperna. Någon gemensam prioritering mellan huvudmännen sker knappast alls.Medborgarna är i mycket liten utsträckning involverade i prioriteringsarbetet. Den ökade öppenheten gentemot brukare innebär oftast att viss information om prioriteringar sker genom traditionella kanaler som patientorganisationer, pensionärsråd och handikappråd och synpunkter inhämtas via allmänna patientenkäter medan klagomål hanteras genom patientnämnder.Vi har också funnit tydliga skillnader när det gäller hur arbetet med prioriteringar bedrivs idag jämfört med för sex år sedan. Genom Socialstyrelsen och Läkemedelsförmånsnämnden har staten tagit ledningen när det gäller att visa hur prioriteringar kan göras på ett systematiskt och öppet sätt. Detta arbete har resulterat i en tydlig metodutveckling. Idag finns det dessutom flera exempel på konkret utvecklingsarbete och samverkan mellan huvudmän kring det vidare begreppet kunskapsstyrd vård till vilket systematiska prioriteringar är starkt relaterat. Vi kan också notera olika initiativ till vertikala prioriteringar i verksamheten där det framförallt är läkarkåren som engagerat sig; men också enstaka försök med systematiska politiska prioriteringar. Det finns dessutom flera lovande utvecklingsprojekt rörande prioriteringar som initierats av och drivs av sjukvårdspersonal både lokalt och nationellt. Yrkesförbunden är också mer aktiva idag när det gäller att sprida kunskap om prioriteringar....
24.	Dabrosin, Charlotta, 1961-, et al. (author) Decreased secretion of Cathepsin D in breast cancer in vivo by tamoxifen : Mediated by the mannose-6-phosphate/IGF-II receptor? 2004 In: Breast Cancer Research and Treatment. - 0167-6806 .- 1573-7217. ; 85:3, s. 229-238 Journal article (peer-reviewed)abstract The lysosomal protease Catliepsin D (Cath D) is associated with increased invasiveness and metastasis in breast cancer. Both estrogen and tamoxifen have been reported to increase Cath D, which seems to contradict the efficacy of tamoxifen as an adjuvant for estrogen dependent breast cancer. Cath D is bioactive in the extracellular space but very little is known about hormonal regulation of secreted Cath D in vivo. In this study we used microdialysis to sample the extracellular fluid in estrogen receptor positive MCF-7 tumors in nude mice. We show that tamoxifen in combination with estradiol decreased secreted Cath D compared with estradiol treatment only in solid tumors in situ. Cell culture of MCF-7 cells revealed that estradiol and tamoxifen increased intracellular proteolytic activity of Cath D in a similar fashion whereas secretion of Cath D was increased by estradiol and inhibited by tamoxifen. Immunofluorescence showed that estradiol located Cath D to the cell surface, while tamoxifen accumulated Cath D to dense lysosomes in perinuclear regions. Moreover, tamoxifen increased the intracellular transporter of Cath D, the mannose 6-phosphate/IGF-II receptor (M6P/IGF2R). In contrast, estradiol decreased the levels of this receptor. Thus, secretion of Cath D is hormone dependent and may be mediated by altered expression of the M6P/IGF2R. Our results highlight the importance of measurements of proteins in all compartments where they are biological active and show that microdialysis is a viable technique for sampling of Cath D in vivo.
25.	Dahlbäck, Ann-Charlotte, et al. (author) Utmaningar när hemmet involveras i läsningen 2021 In: Svenskläraren. - : Svensklärarföreningen. - 0346-2412. ; :1/2, s. 26-28 Journal article (pop. science, debate, etc.)abstract Läsprojekt ihop med vårdnadshavare kan ge guldstunder, men i värsta fall även öka kunskapsklyftorna. Här berättar lärare, från två F-3 skolor i Piteå, om sina erfarenheter efter att ha genomfört ett läsprojekt med forskares hjälp.
26.	de Oliveira, Kelin Gonçalves, et al. (author) Decoding of the surfaceome and endocytome in primary glioblastoma cells identifies potential target antigens in the hypoxic tumor niche 2024 In: Acta Neuropathologica Communications. - : BioMed Central (BMC). - 2051-5960. ; 12:1 Journal article (peer-reviewed)abstract Immunotherapies with antibody-drug-conjugates (ADC) and CAR-T cells, targeted at tumor surface antigens (surfaceome), currently revolutionize clinical oncology. However, target identification warrants a better understanding of the surfaceome and how it is modulated by the tumor microenvironment. Here, we decode the surfaceome and endocytome and its remodeling by hypoxic stress in glioblastoma (GBM), the most common and aggressive brain tumor in adults. We employed a comprehensive approach for global and dynamic profiling of the surfaceome and endocytosed (endocytome) proteins and their regulation by hypoxia in patient-derived GBM cultures. We found a heterogeneous surface-endocytome profile and a divergent response to hypoxia across GBM cultures. We provide a quantitative ranking of more than 600 surface resident and endocytosed proteins, and their regulation by hypoxia, serving as a resource to the cancer research community. As proof-of-concept, the established target antigen CD44 was identified as a commonly and abundantly expressed surface protein with high endocytic activity. Among hypoxia induced proteins, we reveal CXADR, CD47, CD81, BSG, and FXYD6 as potential targets of the stressed GBM niche. We could validate these findings by immunofluorescence analyses in patient tumors and by increased expression in the hypoxic core of GBM spheroids. Selected candidates were finally confronted by treatment studies, showing their high capacity for internalization and ADC delivery. Importantly, we highlight the limited correlation between transcriptomics and proteomics, emphasizing the critical role of membrane protein enrichment strategies and quantitative mass spectrometry. Our findings provide a comprehensive understanding of the surface-endocytome and its remodeling by hypoxia in GBM as a resource for exploration of targets for immunotherapeutic approaches in GBM.
27.	Engström, Gunnar, et al. (author) The Swedish CArdioPulmonary BioImage Study : objectives and design 2015 In: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 278:6, s. 645-659 Journal article (peer-reviewed)abstract Cardiopulmonary diseases are major causes of death worldwide, but currently recommended strategies for diagnosis and prevention may be outdated because of recent changes in risk factor patterns. The Swedish CArdioPulmonarybioImage Study (SCAPIS) combines the use of new imaging technologies, advances in large-scale 'omics' and epidemiological analyses to extensively characterize a Swedish cohort of 30 000 men and women aged between 50 and 64 years. The information obtained will be used to improve risk prediction of cardiopulmonary diseases and optimize the ability to study disease mechanisms. A comprehensive pilot study in 1111 individuals, which was completed in 2012, demonstrated the feasibility and financial and ethical consequences of SCAPIS. Recruitment to the national, multicentre study has recently started.
28.	Eriksson, Lennart, et al. (author) Beskogning av jordbruksmark : stora möjligheter men också risker 2013 In: Fakta. Skog. - 1400-7789. Other publication (pop. science, debate, etc.)
29.	Eriksson, Lennart, et al. (author) Skog på jordbruksmark – erfarenheter från de senaste decennierna 2011 Reports (other academic/artistic)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
30.	Ewerhard, Ann Charlotte, et al. (author) Consumer decision-making of slow moving consumer goods in the age of multi-channels 2019 In: International Review of Retail, Distribution and Consumer Research. - : Informa UK Limited. - 0959-3969 .- 1466-4402. ; 29:1, s. 1-22 Journal article (peer-reviewed)abstract Currently, consumer decision-making is influenced by the spread of technology that has made multi-channel retailing possible. Multi-channel retailing can be defined as a retailer using a combination of separate and independent channels without any overlap for promoting and selling products and services. This study contributes to three research streams: consumer decision-making, multi-channel retailing and slow-moving consumer goods (SMCG). A theoretical framework is developed to examine the decision-making processes of two groups of consumers, Millennials and Mothers. As the aim of the study was to gain insight into consumer decision-making in the context of multi-channels it was designed to be exploratory and used an abductive approach. The empirical material was mainly collected via interviews in store and consumers’ homes. The interview data are complemented by in-store observations. Our findings show that multi-channels influence consumers’ decision-making and that there are differences between Millennials and Mothers. Different devices and channels are used at different stages of the decision-making process and we claim that they complement, rather than conflict with each other. Retailers need to understand that customers expect omni-channelling, which has a positive impact on brand and sales. We argue that retailers who want to remain competitive will need to move toward omni-channelling.
31.	Farnebo, Lovisa, et al. (author) Combining factors on protein and gene level to predict radioresponse in head and neck cancer cell lines 2011 In: Journal of Oral Pathology & Medicine. - : John Wiley and sons. - 0904-2512 .- 1600-0714. ; 40:10, s. 739-746 Journal article (peer-reviewed)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.
32.	Farnebo, Lovisa (author) Predictive markers : for treatment sensitivity in head and neck squamous cell carcinoma 2010 Doctoral thesis (other academic/artistic)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.
33.	Farnebo, Lovisa, et al. (author) Proteins and single nucleotide polymorphisms involved in apoptosis, growth control, and DNA repair predict cisplatin sensitivity in head and neck cancer cell lines 2009 In: International Journal of Molecular Medicine. - : Spandidos Publications. - 1107-3756 .- 1791-244X. ; 24:4, s. 549-556 Journal article (peer-reviewed)abstract The present study was undertaken to evaluate the possibility of using a panel of proteins and single nucleotide polymorphisms (SNPs) involved in apoptosis, growth control, and DNA repair as predictive markers for cisplatin sensitivity. For this purpose the intrinsic cisplatin sensitivity (ICS) was determined in 39 cell lines derived from squamous cell carcinomas of the head and neck using a colony-forming assay. In these cell lines and in normal oral keratinocytes (NOK), the expression of epidermal growth factor receptor (EGFR), Hsp70, Bax, Bcl-2, Bcl-XL, survivin, and COX-2 was determined. Moreover, the p53, MDM2, FGFR4, XPC, XPD, XRCC1, and XRCC3 genes were analyzed for the presence of specific single nucleotide polymorphisms (SNPs). Pearsons correlation test showed that EGFR was the only protein that was significantly correlated to the ICS (r=0.388, p=0.015). The combination of EGFR, Hsp70, Bax, and Bcl-2 gave the strongest correlation (r=0.566, p andlt;= 0.001), whereas Bax alone had the second highest influence on the ICS. Furthermore, all four SNPs within genes involved in DNA repair, i.e. XPC, XPD, XRCC1, and XRCC3, tended to influence the ICS. In order to find the combination of factors, on both protein and gene levels, with the highest correlation to ICS, a multivariate statistical calculation was performed. Our results indicate that SNPs in DNA repair genes (XRCC3(241) and XPD751) influence the ICS and together with the expression of EGFR, Hsp70, Bax, and Bcl-2, they could predict the cisplatin sensitivity of head and neck cancer cell lines (r=0.614, p andlt;= 0.001).
34.	Gluch, Pernilla, 1968, et al. (author) Environmental attitudes, management and performance 2010 In: Performance Improvement in Construction Management (eds. Atkin and Borgbrant). ; , s. 158-172 Book chapter (other academic/artistic)
35.	Gluch, Pernilla, 1968, et al. (author) Miljöbarometern för bygg- och fastighetssektorn 2006 - en kartläggning av sektorns miljöarbete 2007 Reports (other academic/artistic)abstract Studien har kartlagt företagens syn på miljöutmaningen, responsen på densamma samt resultatet av genomfört miljöarbete. Enkätstudien som genomfördes under hösten 2006 riktades till miljöansvariga i inom svensk bygg- och fastighetssektor, av totalt 542 företag svarade 246. Resultaten visar att företagen upplever att miljöproblemen minskat något eller varit oförändrade under den senaste fyraårsperioden, men också att sektorn fortfarande kämpar med energifrågan och bruk av ej förnyelsebara material. Företagen fortsätter dessutom att lägga resurser på avfallshantering och miljöledningssystem. Företagen uppskattar att de främst uppnått resultat inom källsortering och kemikalieanvändning. I grova drag har bygg- och fastighetsföretagen under den senaste perioden satsat ännu mer på det man redan satsat mycket på. Resultaten visar att hindren för att göra gröna affärer idag upplevs mer framträdande, vilket lett till att fler tappat tron på marknadsmekanismer som lösning på problemen. Istället har lagstiftande åtgärder som främsta lösning stärkts. Under perioden har konceptet hållbar utveckling fått genomslag, även om det hittills inte påverkat organiseringen av arbetet i företagen. Slutsatsen som dras är att företagen inom bygg- och fastighetssektorn har ett aktivt miljöarbete men att utvecklingen på området uppvisar en viss utvecklingströghet. Studien identifierar sex möjliga orsaker till denna tröghet vilka presenteras i rapporten.
36.	Gluch, Pernilla, 1968, et al. (author) What makes it slow? A questionnaire survey of environmental attitudes, management and performance 2007 In: 4th Nordic Conference on Construction Economics and Organisation, 14th-15th June 2007, Luleå, Sweden. Conference paper (peer-reviewed)abstract Over the last two decades the Swedish building industry has made much effort to develop green building practices. Researchers within the field have provided theoretical knowledge on how to design green buildings and analytical environmental management tools have been developed to guide practitioners. Information campaigns have raised the general environmental awareness among building practitioners. In spite of these efforts, mainstream building practices do not seem to have undergone any marked changes. This raises the question of how environmental issues actually are dealt with in the building industry. Has the development stagnated and, if so, why? What causes green innovation inertia in the Swedish building industry? What makes it slow? This paper provides some answers to these questions by empirically examining environmental attitudes, management and performance in the industry. The paper is based on a structured questionnaire survey directed to environmental managers at all companies in Sweden with at least 50 employees within technical consultants, building constructors, and property owners and managers and companies with at least 20 employees within architecture. The response rate was 45.4% which corresponds to 246 respondents. The study detects possible causes to deficiencies and creates larger understanding as to why the development, despite much effort, sometimes does not go in the direction as intended by top management. Focusing on relations between the definition of environmental challenge, measures adopted and results from measures, the paper identifies trends and institutionalising processes that hinder sustainable development within the building industry.
37.	Governa, Valeria, et al. (author) Landscape of surfaceome and endocytome in human glioma is divergent and depends on cellular spatial organization 2022 In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences (PNAS). - 0027-8424 .- 1091-6490. ; 119:9 Journal article (peer-reviewed)abstract Therapeutic strategies directed at the tumor surfaceome (TS), including checkpoint inhibitor blocking antibodies, antibody drug conjugates (ADCs), and chimeric antigen receptor T (CAR-T) cells, provide a new armament to fight cancer. However, a remaining bottleneck is the lack of strategies to comprehensively interrogate patient tumors for potential TS targets. Here, we have developed a platform (tumor surfaceome mapping [TS-MAP]) integrated with a newly curated TS classifier (SURFME) that allows profiling of primary 3D cultures and intact patient glioma tumors with preserved tissue architecture. Moreover, TS-MAP specifically identifies proteins capable of endocytosis as tractable targets for ADCs and other modalities requiring toxic payload internalization. In high-grade gliomas that remain among the most aggressive forms of cancer, we show that cellular spatial organization (2D vs. 3D) fundamentally transforms the surfaceome and endocytome (e.g., integrins, proteoglycans, semaphorins, and cancer stem cell markers) with general implications for target screening approaches, as exemplified by an ADC targeting EGFR. The TS-MAP platform was further applied to profile the surfaceome and endocytome landscape in a cohort of freshly resected gliomas. We found a highly diverse TS repertoire between patient tumors, not directly associated with grade and histology, which highlights the need for individualized approaches. Our data provide additional layers of understanding fundamental to the future development of immunotherapy strategies, as well as procedures for proteomics-based target identification and selection. The TS-MAP platform should be widely applicable in efforts aiming at a better understanding of how to harness the TS for personalized immunotherapy.
38.	Gånemo, Agneta, et al. (author) Usefulness of Rajka and Langeland Eczema Severity Score in Clinical Practice. 2016 In: Acta Dermato-Venereologica. - : Medical Journals Sweden AB. - 1651-2057 .- 0001-5555. ; 96:4, s. 521-524 Journal article (peer-reviewed)abstract Simple, validated eczema severity scores are required for the evaluation of interventions. The Rajka and Langeland (R and L) scale is based on 3 domains (extent, course, and intensity); however, its validity is not yet confirmed. The aim of this study was to investigate the quality aspects of the R and L scale in clinical practice. In the first part of the study, experts and consumers judged the content validity of the scale. The second part of the study was performed with 87 children during a 4-month eczema school. Construct validity, internal consistency, sensitivity to change, time consumption and health-related quality of life variables were investigated. The content of the R and L scale was considered valid by 45 panellists. Inter- and intra-observer reliability was very good. Divergent construct validity was adequate, while convergent construct validity and internal consistency were inadequate. The R and L scale was able to define a significant improvement in eczema during the eczema school. The time required for completing the R and L assessment was significantly shorter than for objective Severity Scoring of Atopic Dermatitis (SCORAD). The R and L scale is a simple, fast, valid, reliable and sensitive tool for scoring of atopic dermatitis in everyday clinical practice.
39.	Hatschek, Thomas, et al. (author) Neoadjuvant Trastuzumab, Pertuzumab, and Docetaxel vs Trastuzumab Emtansine in Patients With ERBB2-Positive Breast Cancer A Phase 2 Randomized Clinical Trial 2021 In: JAMA Oncology. - : American Medical Association. - 2374-2437 .- 2374-2445. ; 7:9, s. 1360-1367 Journal article (peer-reviewed)abstract IMPORTANCE: Trastuzumab emtansine (T-DM1) is presently approved for treatment of advanced breast cancer and after incomplete response to neoadjuvant therapy, but the potential of T-DM1 as monotherapy is so far unknown.OBJECTIVE: To assess pathologic complete response (pCR) to standard neoadjuvant therapy of combination docetaxel, trastuzumab, and pertuzumab (DTP) vs T-DM1 monotherapy in patients with ERBB2 (formerly HER2)-positive breast cancer.DESIGN, SETTING, AND PARTICIPANTS: This randomized phase 2 trial, conducted at 9 sites in Sweden, enrolled 202 patients between December 1, 2014, and October 31, 2018. Participants were 18 years or older, with ERBB2-positive tumors larger than 20 mm and/or verified lymph node metastases. Analysis was performed on an intention-to-treat basis.INTERVENTIONS: Patients were randomized to receive 6 cycles of DTP (standard group) or T-DM1 (investigational group). Crossover was recommended at lack of response or occurrence of intolerable toxic effects. Assessment with fluorine 18-labeled fluorodeoxyglucose (F-18-FDG) positron emission tomography combined with computed tomography (PET-CT) was performed at baseline and after 2 and 6 treatment cycles.MAIN OUTCOME AND MEASURES: Pathologic complete response, defined as ypT0 or Tis ypN0. Secondary end points were clinical and radiologic objective response; event-free survival, invasive disease-free survival, distant disease-free survival, and overall survival; safety; health-related quality of life (HRQoL); functional and biological tumor characteristics; and frequency of breast-conserving surgery.RESULTS: Overall, 202 patients were randomized; 197 (99 women in the standard group [median age, 51 years (range, 26-73 years)] and 98 women in the investigational group [median age, 53 years (range, 28-74 years)]) were evaluable for the primary end point. Pathologic complete response was achieved in 45 patients in the standard group (45.5%; 95% CI 35.4%-55.8%) and 43 patients in the investigational group (43.9%; 95% CI 33.9%-54.3%). The difference was not statistically significant (P = .82). In a subgroup analysis, the pCR rate was higher in hormone receptor-negative tumors than in hormone receptor-positive tumors in both treatment groups (45 of 72 [62.5%] vs 45 of 125 [36.0%]). Three patients in the T-DM1 group experienced progression during therapy. In an exploratory analysis, tumor-infiltrating lymphocytes at 10% or more (median) estimated pCR significantly (odds ratio, 2.76; 95% CI, 1.42-5.36; P = .003). Response evaluation with F-18-FDG PET-CT revealed a relative decrease of maximum standardized uptake value by more than 31.3% (median) was associated with pCR (odds ratio, 6.67, 95% CI, 2.38-20.00; P < .001).CONCLUSIONS AND RELEVANCE: In this study, treatment with standard neoadjuvant combination DTP was equal to T-DM1.
40.	Hatschek, T., et al. (author) PREDIX HER2 trial : Event-free survival and pathologic complete response in clinical subgroups and stromal TILs levels 2020 In: Annals of Oncology. - : Elsevier. - 0923-7534 .- 1569-8041. ; 31:Suppl. 2, s. S49-S49 Journal article (other academic/artistic)abstract Background: Neoadjuvant treatment with Trastuzumab-emtansine was associated with similar rates of pathological complete remission (pCR) as standard therapy withd ocetaxel, trastuzumab and pertuzumab in the PREDIX HER2 trial. Here, results of event-free survival (EFS), and pCR rates in key clinical-pathological subgroups and biomarkers including the abundance of stromal tumor infiltrating lymphocytes (TILs) are presented.Methods: PREDIX HER2 is a randomized, multicenter, open-label, phase 2 study involving 9 Swedish sites. Patients with HER2 positive breast cancer, verified by ISH, T>20 mm and/or verified lymph node metastases were randomized to six three-weekly courses of either docetaxel, trastuzumab SC and pertuzumab (group A), or trastuzumab emtansine (T-DM1, group B). Switch of treatment to the opposite arm was allowed in case of lack of response or severe toxicity. Radiological evaluation included 18F-FDG PET/CT. Patients in both groups received adjuvant chemotherapy with epirubicin and cyclophosphamide. TILs were evaluated using standard methodology, median 10%.Results: In total 197 pts. were evaluable, 99 in group A, and 98 in group B. pCR (ypT0/is ypN0) was achieved in 90 pts, 45.7%, with no significant difference between the two treatment groups. pCR rates were lower in the group of patients with hormone receptor (HR)epositive compared with HR-negative tumors but similar in both treatment groups. pCR rates did not differ between the two treatments in subgroups defined by age, menopausal status, tumor grade, T size, node status, HR-status, HER2 status and Ki67. Progressive disease was observed in 3 pts. (3%) during treatment with T-DM1, none in group A. After a median follow-up of 2.4 years 13 EFS events occurred, with no significant differences between the treatment groups. The presence of 10% TILs predicted pCR significantly (p¼0.009), similar in both treatment groups. We also found that a decrease of SUVmax by more than 80% was highly predictive of pCR. HRQoL was significantly better in pts. receiving T-DM1.Conclusions: Our data suggest that neoadjuvant T-DM1 may be as effective as standard neoadjuvant treatment in all clinical subgroups evaluated. Both TILs and PET/CT showed potential to predict pCR.Clinical trial identification: NCT02568839.
41.	Hosnijeh, Fatemeh Saberi, et al. (author) Prediagnostic telomere length and risk of B-cell lymphoma-Results from the EPIC cohort study 2014 In: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 135:12, s. 2910-2917 Journal article (peer-reviewed)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.
42.	Indira Chandran, Vineesh, et al. (author) Global extracellular vesicle proteomic signature defines U87-MG glioma cell hypoxic status with potential implications for non-invasive diagnostics 2019 In: Journal of Neuro-Oncology. - : SPRINGER. - 0167-594X .- 1573-7373. ; 144:3, s. 477-488 Journal article (peer-reviewed)abstract Purpose Glioblastoma multiforme (GBM) is the most common and lethal of primary malignant brain tumors. Hypoxia constitutes a major determining factor for the poor prognosis of high-grade glioma patients, and is known to contribute to the development of treatment resistance. Therefore, new strategies to comprehensively profile and monitor the hypoxic status of gliomas are of high clinical relevance. Here, we have explored how the proteome of secreted extracellular vesicles (EVs) at the global level may reflect hypoxic glioma cells. Methods We have employed shotgun proteomics and label free quantification to profile EVs isolated from human high-grade glioma U87-MG cells cultured at normoxia or hypoxia. Parallel reaction monitoring was used to quantify the identified, hypoxia-associated EV proteins. To determine the potential biological significance of hypoxia-associated proteins, the cumulative Z score of identified EV proteins was compared with GBM subtypes from HGCC and TCGA databases. Results In total, 2928 proteins were identified in EVs, out of which 1654 proteins overlapped with the ExoCarta EV-specific database. We found 1034 proteins in EVs that were unique to the hypoxic status of U87-MG cells. We subsequently identified an EV protein signature, "HYPSIGNATURE", encompassing nine proteins that strongly represented the hypoxic situation and exhibited close proximity to the mesenchymal GBM subtype. Conclusions We propose, for the first time, an EV protein signature that could comprehensively reflect the hypoxic status of high-grade glioma cells. The presented data provide proof-of-concept for targeted proteomic profiling of glioma derived EVs, which should motivate future studies exploring its utility in non-invasive diagnosis and monitoring of brain tumor patients.
43.	Indira Chandran, Vineesh, et al. (author) Ultrasensitive Immunoprofiling of Plasma Extracellular Vesicles Identifies Syndecan-1 as a Potential Tool for Minimally Invasive Diagnosis of Glioma 2019 In: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 25:10, s. 3115-3127 Journal article (peer-reviewed)abstract Purpose: Liquid biopsy has great potential to improve the management of brain tumor patients at high risk of surgery-associated complications. Here, the aim was to explore plasma extracellular vesicle (plEV) immunoprofiling as a tool for noninvasive diagnosis of glioma.Experimental Design: PlEV isolation and analysis were optimized using advanced mass spectrometry, nanoparticle tracking analysis, and electron microscopy. We then established a new procedure that combines size exclusion chromatography isolation and proximity extension assay-based ultrasensitive immunoprofiling of plEV proteins that was applied on a well-defined glioma study cohort (n = 82).Results: Among potential candidates, we for the first time identify syndecan-1 (SDC1) as a plEV constituent that can discriminate between high-grade glioblastoma multiforme (GBM, WHO grade IV) and low-grade glioma [LGG, WHO grade II; area under the ROC curve (AUC): 0.81; sensitivity: 71%; specificity: 91%]. These findings were independently validated by ELISA. Tumor SDC1 mRNA expression similarly discriminated between GBM and LGG in an independent glioma patient population from The Cancer Genome Atlas cohort (AUC: 0.91; sensitivity: 79%; specificity: 91%). In experimental studies with GBM cells, we show that SDC1 is efficiently sorted to secreted EVs. Importantly, we found strong support of plEVSDC1 originating from GBM tumors, as plEVSDC1 correlated with SDC1 protein expression in matched patient tumors, and plEVSDC1 was decreased postoperatively depending on the extent of surgery.Conclusions: Our studies support the concept of circulating plEVs as a tool for noninvasive diagnosis and monitoring of gliomas and should move this field closer to the goal of improving the management of cancer patients.
44.	Jedlinski, Adam, 1978-, et al. (author) Cetuximab sensitivity of head and neck squamous cell carcinoma xenografts is associated with treatment-induced reduction in EGFR, pEGFR, and pSrc. 2017 In: Journal of Oral Pathology & Medicine. - : Wiley. - 0904-2512 .- 1600-0714. ; 46:9, s. 717-724 Journal article (peer-reviewed)abstract BACKGROUND: The aims of this study were to validate in vitro drug sensitivity testing of head and neck squamous cell carcinoma (HNSCC) cell lines in an in vivo xenograft model and to identify treatment-induced changes in the epidermal growth factor receptor (EGFR) signaling pathway that could be used as markers for cetuximab treatment response.MATERIALS AND METHODS: The in vitro and in vivo cetuximab sensitivity of two HNSCC cell lines, UT-SCC-14 and UT-SCC-45, was assessed using a crystal violet assay and xenografts in nude mice, respectively. The expression of EGFR, phosphorylated EGFR (pEGFR), phosphorylated Src (pSrc), and Ki-67 was investigated by immunohistochemistry. To verify these results, the in vitro expression of EGFR and pEGFR was analyzed with ELISA in a panel of 10 HNSCC cell lines.RESULTS: A close correlation was found between in vitro and in vivo cetuximab sensitivity data in the two investigated HNSCC cell lines. In treatment sensitive UT-SCC-14 xenografts, there was a decrease in EGFR, pEGFR, and pSrc upon cetuximab treatment. Interestingly, in insensitive UT-SCC-45 xenografts, an increased expression of these three proteins was found. The change in EGFR and pEGFR expression in vivo was confirmed in cetuximab-sensitive and cetuximab-insensitive HNSCC cell lines using ELISA.CONCLUSION: High sensitivity to cetuximab was strongly associated with a treatment-induced reduction in pEGFR both in vivo and in vitro in a panel of HNSCC cell lines, suggesting that EGFR and pEGFR dynamics could be used as a predictive biomarker for cetuximab treatment response.
45.	Jedlinski, Adam, et al. (author) EGFR status and EGFR ligand expression influence the treatment response of head and neck cancer cell lines 2013 In: Journal of Oral Pathology & Medicine. - : John Wiley and Sons. - 0904-2512 .- 1600-0714. ; 42:1, s. 26-36 Journal article (peer-reviewed)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.
46.	Jedliński, Adam (author) Understanding the Role of EGFR in the Treatment of Head and Neck Squamous Cell Carcinoma 2015 Doctoral thesis (other academic/artistic)abstract Head and neck squamous cell carcinoma (HNSCC) originates from the epithelial lining of the upper aerodigestive tract. It accounts for over 90 % of the malignancies found in the head and neck region. 600,000 new cases of HNSCC occur each year worldwide. Apart from causing painful lesions, HNSCC directly impacts the patient’s fundamental functions such as breathing and eating and also can disrupt the patient’s senses such as smell, taste, speech and even vision. Most cases of HNSCC require a combination of different treatments such as surgery, chemotherapy (primarily cisplatin based), and radiotherapy. Treatment decisions are largely based on the size of the tumor, the involvement of local lymph nodes, and distant spread. Treatment resistance and local recurrence are significant problems and to date no form of clinical treatment sensitivity prediction is available.A majority of HNSCC tumors overexpresses the epidermal growth factor receptor (EGFR). This receptor is involved in proliferation and DNA repair and is the target of a monoclonal antibody named cetuximab that selectively binds and inhibits EGFR. It is the only targeted therapy available to HNSCC patients and reserved for late stage patients in Sweden.Numerous investigators have searched for predictive markers and we hypothesized that since HNSCC is a very heterogeneous disease a single factor would not be able to predict the treatment outcome. In paper I we explore a panel of predictive factors using a point system, called the number of negative points (NNP), in which we could combine both proteins and genetic variations in an attempt to find a set of markers that could predict the intrinsic cisplatin sensitivity (ICS). The expression level of EGFR, Hsp70, Bax, Bcl-XL, survivin, and COX-2 was determined in 39 HNSCC cell lines. Moreover, the p53, MDM2, FGFR4, XPC, XPD, XRCC1, and XRCC3 genes were analyzed for the presence of specific single nucleotide polymorphisms (SNPs). Pearson’s correlation tests showed that EGFR was the only protein that alone correlated to ICS (r=0.388, P=0.015). The strongest correlation to ICS was found when combining SNPs in XRCC3 and XPD with the expression of EGFR, Hsp70, Bax, and Bcl-2 using the NNP system (r=0.614 P≤0.001).In paper II we assess the intrinsic radiosensitivity (IR), the ICS, and the intrinsic cetuximab sensitivity (ICmabS) as well as their combinations in 25 HNSCC cell lines established from HNSCC biopsies taken at the Department of Otorhinolaryngology and Head and Neck Surgery at Linköping University Hospital. Furthermore we investigate the EGFR status (consisting of EGFR gene copy number, EGFR mRNA, EGFR protein, pEGFR), pAkt and mRNA levels of the seven known EGFR ligands. No correlation was found between the different treatment sensitivities. Cetuximab treatment response was significantly correlated to epiregulin (EREG) mRNA expression (r=-0.408, P=0.043). Cetuximab resistant cell lines tended to have low levels of pEGFR (P=0.13) while resistant cell lines had a significantly lower expression of EGFR protein (P=0.04) and tended to have decreased levels of pAkt (P=0.13) and amphiregulin (AREG) mRNA (p=0.18).In paper III the functional importance of EGFR ligands in relation to proliferation and cetuximab sensitivity was investigated. Here we tried to diminish the tumor heterogeneity by selecting three cell lines that are derived from the same anatomical location but display different ICmabS. Signaling through the EGFR was stimulated with recombinant EGF, AREG or EREG or reduced by siRNA-mediated silencing of the aforementioned EGFR ligands. EGF downregulation suppressed the proliferation of all investigated tumor cell lines whereas the response to an increased level of EGF differed between EGFR overexpressing and EGFR non-overexpressing cell lines. Furthermore, tumor cells consistently displayed increased cetuximab resistance upon the addition of EGF, whereas EGF silencing was associated with an improved cetuximab response. The data regarding AREG and EREG were inconclusive.In paper IV we wanted to validate in vitro drug sensitivity testing of HNSCC cell lines in an in vivo xenograft model, and to identify treatment-induced changes in the EGFR signaling pathway that could be used as markers for cetuximab treatment response. In vitro ICmabS for the HNSCC cell lines UT-SCC-14 and UT-SCC-45 was established using a crystal violet assay. In order to determine the corresponding in vivo sensitivity, UT-SCC-14 and UT-SCC-45 xenografts were generated in female BALB/c (nu/nu) nude mice. Mice were given three injections of intraperitoneal cetuximab or PBS and the tumor volume was recorded continuously. The expression of EGFR, pEGFR, pSrc, and Ki67 in the tumor tissue was investigated by immunohistochemistry. The in vitro sensitivity was reproduced in the in vivo model. Furthermore a clear reduction of EGFR, pEGFR, and pSrc after cetuximab treatment was noted in UT-SCC-14, the cetuximab sensitive cell line while the cetuximab resistant UT-SCC-45 showed a slight increase in EGFR, pEGFR and pSrc.In conclusion, the EGFR ligand EGF is a potential predictive marker of poor cetuximab response and a possible treatment target. Moreover, treatment-induced downregulation of EGFR and pEGFR is associated with a good cetuximab response.
47.	Jerhammar, Fredrik, et al. (author) YAP1 Gene Amplification is a Marker for Cetuximab Resistance in Head and Neck Cancer Other publication (other academic/artistic)abstract The epidermal growth factor receptor (EGFR) is commonly overexpressed in head and neck squamous cell carcinomas (HNSCC). The monoclonal antibody cetuximab (Erbitux®) inhibits its signaling and has been approved for treatment of HNSCC. However, since many patients do not benefit from cetuximab treatment, predictive biomarkers of cetuximab response are required. The present study aims at finding novel markers of cetuximab resistance. The intrinsic cetuximab sensitivity of 35 HNSCC cell lines was determined, and revealed a great variation in the response between cell lines. Five cell lines (14%) were cetuximab sensitive, and 12 (34%) were resistant. Interestingly, two cell lines proliferated after cetuximab treatment. 10 cell lines (five cetuximab sensitive and five cetuximab resistant) were selected for gene copy number array analysis on the Affymetrix SNP 6.0 platform. 39 protein coding genes were amplified in cetuximab resistant cells and normal in sensitive cells, all present on genomic regions 11q22.1 or 5p13-15. Five genes were selected for quantitative PCR verification, namely, YAP1 and TRPC6 (11q22.1) and PDCD6, TPPP, and PTGER4 (5p13-15). An extended panel of totally 10 cetuximab resistant and 10 sensitive cell lines verified that YAP1 amplified cells are cetuximab resistant. YAP1 gene amplification was highly correlated to the YAP1 mRNA expression, which was significantly higher in cetuximab resistant cells than in sensitive. YAP1 downregulation resulted in increased cetuximab sensitivity in one of two cetuximab resistant cell lines investigated and growth inhibition in another. We conclude that YAP1 is a marker for cetuximab resistance in head and neck cancer.
48.	Jerhammar, Fredrik, et al. (author) YAP1 is a potential biomarker for cetuximab resistance in head and neck cancer 2014 In: Oral Oncology. - : Elsevier. - 1368-8375 .- 1879-0593. ; 50:9, s. 832-839 Journal article (peer-reviewed)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.
49.	Johansson, Ann-Charlotte (author) Assessment and measurement of drum sound 2004 Conference paper (peer-reviewed)
50.	Johansson, Ann-Charlotte, et al. (author) Cancer-Associated Fibroblasts Induce Matrix Metalloproteinase-Mediated Cetuximab Resistance in Head and Neck Squamous Cell Carcinoma Cells 2012 In: Molecular Cancer Research. - : American Association for Cancer Research. - 1541-7786 .- 1557-3125. ; 10:9, s. 1158-1168 Journal article (peer-reviewed)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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