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  • 1. Agarwala, Sanjiv S
    et al.
    Hellstrand, Kristoffer
    Gehlsen, Kurt
    Naredi, Peter
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Surgery.
    Immunotherapy with histamine and interleukin 2 in malignant melanoma with liver metastasis.2004In: Cancer Immunol Immunother, ISSN 0340-7004, Vol. 53, no 9, p. 840-1Article in journal (Refereed)
  • 2.
    Billing, Ola
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Kao, Gautam
    Naredi, Peter
    ASNA-1 acts independently of its endoplasmic reticulum receptor WRB-1 to promote insulin/IGF signallingManuscript (preprint) (Other academic)
  • 3.
    Billing, Ola
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Kao, Gautam
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Mitochondrial function is required for secretion of DAF-28/insulin in C. elegans.2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 1, p. e14507-Article in journal (Refereed)
    Abstract [en]

    While insulin signaling has been extensively studied in Caenorhabditis elegans in the context of ageing and stress response, less is known about the factors underlying the secretion of insulin ligands upstream of the insulin receptor. Activation of the receptor governs the decision whether to progress through the reproductive lifecycle or to arrest growth and enter hibernation. We find that animals with reduced levels of the mitochondrial outer membrane translocase homologue TOMM-40 arrest growth as larvae and have decreased insulin signaling strength. TOMM-40 acts as a mitochondrial translocase in C. elegans and in its absence animals fail to import a mitochondrial protein reporter across the mitochondrial membrane(s). Inactivation of TOMM-40 evokes the mitochondrial unfolded protein response and causes a collapse of the proton gradient across the inner mitochondrial membrane. Consequently these broadly dysfunctional mitochondria render an inability to couple food abundance to secretion of DAF-28/insulin. The secretion defect is not general in nature since two other neuropeptides, ANF::GFP and INS-22::VENUS, are secreted normally. RNAi against two other putative members of the TOMM complex give similar phenotypes, implying that DAF-28 secretion is sensitive to mitochondrial dysfunction in general. We conclude that mitochondrial function is required for C. elegans to secrete DAF-28/insulin when food is abundant. This modulation of secretion likely represents an additional level of control over DAF-28/insulin function.

  • 4.
    Billing, Ola
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Natarajan, Balasubramanian
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Mohammed, Ateequrrahman
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Kao, Gautam
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    A directed RNAi screen based on larval growth arrest reveals new modifiers of C. elegans insulin signaling2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 4, p. e34507-Article in journal (Refereed)
    Abstract [en]

    Genes regulating Caenorhabditis elegans insulin/IGF signaling (IIS) have largely been identified on the basis of their involvement in dauer development or longevity. A third IIS phenotype is the first larval stage (L1) diapause, which is also influenced by asna-1, a regulator of DAF-28/insulin secretion. We reasoned that new regulators of IIS strength might be identified in screens based on the L1 diapause and the asna-1 phenotype. Eighty-six genes were selected for analysis by virtue of their predicted interaction with ASNA-1 and screened for asna-1-like larval arrest. ykt-6, mrps-2, mrps-10 and mrpl-43 were identified as genes which, when inactivated, caused larval arrest without any associated feeding defects. Several tests indicated that IIS strength was weaker and that insulin secretion was defective in these animals. This study highlights the role of the Golgi network and the mitochondria in insulin secretion and provides a new list of genes that modulate IIS in C. elegans.

  • 5.
    Björn, Erik
    et al.
    Umeå University, Faculty of Science and Technology, Chemistry.
    Nygren, Yvonne
    Umeå University, Faculty of Science and Technology, Chemistry.
    Nhu Nguyen, Tam Trinh Thi
    Umeå University, Faculty of Science and Technology, Chemistry.
    Ericson, Christer
    Umeå University, Faculty of Science and Technology, Chemistry.
    Nöjd, Mikael
    Kirurgi.
    Naredi, Peter
    Kirurgi.
    Determination of platinum in human subcellular microsamples by inductively coupled plasma mass spectrometry2007In: Analytical Biochemistry, Vol. 363, p. 135-42Article in journal (Refereed)
    Abstract [en]

    A fast and robust method for the determination of platinum in human subcellular microsamples by inductively coupled plasma mass spectrometry was developed, characterized, and validated. Samples of isolated DNA and exosome fractions from human ovarian (2008) and melanoma (T289) cancer cell lines were used. To keep the sample consumption to approximately 10 μl and obtain a high robustness of the system, a flow injection sample introduction system with a 4.6-μl sample loop was used in combination with a conventional pneumatic nebulizer and a spray chamber. The system was optimized with respect to signal/noise ratio using a multivariate experimental design. The system proved to be well suited for routine analysis of large sample series, and several hundreds of samples could be analyzed without maintenance or downtime. The detection limit of the method was 0.12 pg (26 pg/g) platinum. To avoid systematic errors from nonspectral interferences, it was necessary to use reagent matched calibration standards or isotope dilution analysis. An uncertainty budget was constructed to estimate the total expanded uncertainty of the method, giving a quantification limit of 2.3 pg (0.5 ng/g) platinum in DNA samples. The uncertainty was sufficiently low to study quantitative differences in the formation of Pt–DNA adducts after treatment with cisplatin using different exposure times and concentrations.

  • 6.
    Bodén, Ida
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery. Umeå University, Faculty of Science and Technology, Centre for Biomedical Engineering and Physics (CMTF).
    Larsson, William
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Nilsson, David
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Forssell, Erik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Lindholm-Sethson, Britta
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Science and Technology, Centre for Biomedical Engineering and Physics (CMTF).
    In vivo skin measurements with a novel probe head for simultaneous skin impedance and near-infrared spectroscopy2011In: Skin research and technology, ISSN 0909-752X, E-ISSN 1600-0846, Vol. 17, no 4, p. 494-504Article in journal (Refereed)
    Abstract [en]

    Background/purpose: Near-infrared (NIR) spectroscopy and skin impedance (IMP) measurements are useful techniques for objective diagnostics of various skin diseases. Here, we present a combined probe head for simultaneous, time-saving NIR spectroscopy and skin impedance measurements. The probe also ensures that both measurements are performed under equal conditions and at the same skin location.

    Methods: Finite element method simulations were performed for evaluation of the impedance. In vivo skin measurements were performed and combined NIR and impedance spectra were analysed by means of multivariate methods with respect to body location, age and gender. The classification rate was determined by a planar discriminant analysis. Reproducibility was investigated by calculation of scatter values and statistical significance between overlapping groups was assessed by the calculation of intra-model distances, q.

    Results: The novel probe yielded rapid reproducible results and was easy to manage. Significant differences between skin locations and to a lesser extent age groups and gender were demonstrated.

    Conclusion: With the novel probe, statistically significant differences between overlapping classes in score plots can be confirmed by calculating intra-model distances. The influence of molecular differences in the skin at different body locations is larger than the influence of gender or age and therefore relevant reference measurements are discussed.

  • 7.
    Bodén, Ida
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Nilsson, David
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Lindholm-Sethson, Britta
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Science and Technology, Centre for Biomedical Engineering and Physics (CMTF).
    Characterization of healthy skin using near infrared spectroscopy and skin impedance2008In: Medical and Biological Engineering and Computing, ISSN 0140-0118, E-ISSN 1741-0444, Vol. 46, no 10, p. 985-995Article in journal (Refereed)
    Abstract [en]

    Near infrared spectroscopy (NIR) and skin impedance (IMP) spectroscopy are two methods suggested for diagnoses of diseases inducing adverse effects in skin. The reproducibility of these methods and their potential value in non-invasive diagnostics were investigated. Measurements were performed in vivo on healthy skin at five anatomic body sites on eight young women. partial least squares discriminant analysis showed that both methods were useful for classification of the skin characteristics at the sites. Inter-individually the NIR model gave 100% correct classification while the IMP model provided 92%. Intra-individually the NIR model gave 88% correct classification whereas the IMP model did not provide any useful classification. The correct classification was increased to 93% when both datasets were combined, which demonstrates the value of adding information. Partial least squares discriminant analysis gave 72% correct predictions of skin sites while the combined model slightly improved to 73%.

  • 8.
    Bodén, Ida
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery. Umeå University, Faculty of Science and Technology, Centre for Biomedical Engineering and Physics (CMTF).
    Nyström, Josefina
    Swedish University of Agricultural Sciences, Unit of Biomass Technology and Chemistry.
    Geladi, Paul
    Swedish University of Agricultural Sciences, Unit of Biomass Technology and Chemistry.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Lindholm-Sethson, Britta
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    NIR and skin impedance spectroscopic measurements for studying the effect of coffee and alcohol on skin, and dysplastic naevi2012In: Skin research and technology, ISSN 0909-752X, E-ISSN 1600-0846, Vol. 18, no 4, p. 486-494Article in journal (Refereed)
    Abstract [en]

    Background/purpose: Near infrared (NIR) and impedance spectroscopy can be used for clinical skin measurements and need to be evaluated for possible confounding factors; (a) are skin conditions of the patient and the subsequent skin measurements influenced by alcohol and/or coffee consumption and (b) are measurements of dysplastic naevi (DN) reproducible over time and significantly different compared to reference skin.

    Methods: NIR and skin impedance spectroscopic data were analysed multivariately. In the first study, the skin characteristics of 15 healthy individuals were examined related to body location, gender, individual differences, and consumption of coffee or alcohol. The second study included five patients diagnosed with dysplastic naevi syndrome (DNS). Measurements were taken on DN and reference skin over time.

    Results: In the first study, body location and gender had a major influence on measurement scores. Inter-individual skin characteristics and coffee or alcohol effects on skin characteristics were of minor importance. In the second study, it was shown that DN can be differentiated from reference skin and the measurements are stable over time.

    Conclusions: Moderate consumption of alcohol and coffee did not influence the results of the measurements. It is possible to follow, stable or changed, characteristics of DN over time.

  • 9.
    Bodén, Ida
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Nyström, Josefina
    Swedish University of Agricultural Sciences, Unit of Biomass Technology and Chemistry.
    Lundskog, Bertil
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Zazo, Virginia
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Geladi, Paul
    Swedish University of Agricultural Sciences, Unit of Biomass Technology and Chemistry.
    Lindholm-Sethson, Britta
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Non-invasive identification of melanoma with near-infrared and skin impedance spectroscopy2013In: Skin research and technology, ISSN 0909-752X, E-ISSN 1600-0846, Vol. 19, no 1, p. e473-e478Article in journal (Refereed)
    Abstract [en]

    Background/purpose: An early diagnosis of cutaneous malignant melanoma is of high importance for good prognosis. An objective, non-invasive instrument could improve the diagnostic accuracy of melanoma and decrease unnecessary biopsies. The aim of this study was to investigate the use of Near infrared and skin impedance spectroscopy in combination as a tool to distinguish between malignant and benign skin tumours.

    Methods: Near infrared and skin impedance spectra were collected in vivo on 50 naevi or suspect melanomas prior to excision. Received data was analysed with multivariate techniques and the results were compared to histopathology analyses of the tumours. A total of 12 cutaneous malignant melanomas, 19 dysplastic naevi and 19 benign naevi were included in the study.

    Results: The observed sensitivity and specificity of the proposed method were 83% and 95%, respectively, for malignant melanoma.

    Conclusions: The results indicate that the combination of near infrared and skin impedance spectroscopy is a promising tool for non-invasive diagnosis of suspect cutaneous malignant melanomas. 

  • 10. Eriksson, H.
    et al.
    Lyth, J.
    Månsson-Brahme, E.
    Frohm-Nilsson, M.
    Ingvar, C.
    Lindholm, C.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Stierner, U.
    Wagenius, G.
    Carstensen, J.
    Hansson, J.
    Low level of education is associated with later stage at diagnosis and reduced survival in cutaneous malignant melanoma: a nationwide population-based study in Sweden2013In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 49, no 12, p. 2705-2716Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: A worse outcome has been reported for cutaneous malignant melanoma (CMM) patients with low socioeconomic status. We have investigated the association between level of education, clinical stage at diagnosis (stage at diagnosis) and CMM-specific survival in Sweden.

    METHODS: We identified 27,235 patients from the Swedish Melanoma Register diagnosed with a primary invasive CMM between 1990 and 2007 and linked data to nationwide, population-based, health and census registers with a follow-up to 2010.

    RESULTS: The odds ratio (OR) of higher disease stage at diagnosis was significantly increased in lower education groups (OR stage II versus I=1.6; 95% confidence interval (CI)=1.5-1.7. OR stage III-IV versus I=2.3; 95% CI=1.8-2.9). The risk of dying of CMM, was significantly increased in patients with low (hazard ratio (HR) low versus high=2.02; 95% CI=1.80-2.26; p<0.0001) and intermediate (HR intermediate versus high=1.35; 95% CI=1.20-1.51; p<0.0001) level of education. After adjustment for age, gender, stage at diagnosis and other known prognostic factors, the HRs remained significant for low versus high (HR=1.13; 95% CI=1.01-1.27; p=0.04) but not for intermediate versus high (HR=1.11; 95% CI=0.99-1.24; p=0.08) education. The HR associated with low level of education was significantly higher among female patients, patients <55years, patients with truncal tumours and during the first 5years after diagnosis.

    CONCLUSION: Lower level of education is associated with reduced CMM-specific survival, which may at least partially be attributed to a more advanced stage at diagnosis. These results emphasise the need for improved early detection strategies.

  • 11.
    Franklin, Oskar
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Öhlund, Daniel
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Lundin, Christina
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Öman, Mikael
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Wang, Wanzhong
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Combining conventional and stroma-derived tumour markers in pancreatic ductal adenocarcinoma2015In: Cancer Biomarkers, ISSN 1574-0153, Vol. 15, no 1, p. 1-10Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: A lack of disease-specific symptoms and good tumour markers makes early detection and diagnosis of pancreatic ductal adenocarcinoma (PDAC) challenging. OBJECTIVE: To analyse the tissue expression and circulating levels of four stroma-derived substances (type IV collagen, endostatin/type XVIII collagen, osteopontin and tenascin C) and four conventional tumour markers (CA 19-9, TPS, CEA and Ca 125) in a PDAC cohort.

    METHODS: Tissue expression of markers in normal pancreas and PDAC tissue was analysed with immunofluorescence. Plasma concentrations of markers were measured before and after surgery. Patients with non-malignant disorders served as controls.

    RESULTS: The conventional and stromal substances were expressed in the cancer cell compartment and the stroma, respectively. Although most patients had increased levels of many markers before surgery, 2/12 (17%) of patients had normal levels of Ca 19-9 at this stage. High preoperative endostatin/type XVIII collagen, and postoperative type IV collagen was associated with short survival. Neither the pre-nor postoperative levels of TPS, Ca 125 or CA 19-9 were associated to survival.

    CONCLUSIONS: PDAC is characterized by an abundant stroma. These initial observations indicate that the stroma can be a source of PDAC tumour markers that are found in different compartments of the cancer, thus reflecting different aspects of tumour biology.

  • 12.
    Goulley, Joan
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Surgery.
    Edlund, Helena
    Diabetes and β-cell hyperplasia in mice over-expressing the ATPase Asna-1Manuscript (Other (popular science, discussion, etc.))
  • 13. Gray, M.
    et al.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Bacon, N.
    Kerr, D. J.
    Better value cancer care for the 21st century2011In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 22, no 12, p. 2541-2545Article in journal (Other (popular science, discussion, etc.))
  • 14. Haglund, Ulf
    et al.
    Frisk, Jessica
    Ivarsson, Marie-Louise
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Rydén, Lisa
    Internship should give competence in medical science. The Surgical Association's curriculum proposal for all interns2008In: Läkartidningen, ISSN 0023-7205, Vol. 105, no 6, p. 369-72Article in journal (Refereed)
  • 15.
    Hamberg, Katarina
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Genusperspektiv i kirurgi2010In: Kirurgi / [ed] Bengt Jeppsson, Peter Naredi, Jörgen Nordenström, Bo Risberg, Studentlitteratur , 2010, p. 195-210Chapter in book (Other academic)
  • 16.
    Hammarström, Anne
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Dags att bryta den mansdominerade katedrala undervisningen2007In: Socialmedicinsk Tidskrift, ISSN 0037-833X, Vol. 84, no 6, p. 560-562Article in journal (Refereed)
    Abstract [en]

    Students at the medical programme at Umeå university point out the lack of female lecturers. The aim of this study was to see how many men respectively women our students meet as teachers in different teaching situations and to analyze the result from a student perspective. Students more often meet men than women in cathedral lectures. The male dominance is less obvious in group teaching and supervision. The medical programme should pay effort to have more women as cathedral lecturers.

  • 17.
    Hemmingsson, Oskar
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Kao, Gautam
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Still, Maria
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    ASNA-1 activity modulates sensitivity to cisplatin2010In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 70, no 24, p. 10321-10328Article in journal (Refereed)
    Abstract [en]

    Cancer can be cured by platinum based chemotherapy but resistance is a major cause of treatment failure. Here we present the nematode Caenorhabditis elegans as a model to study interactions between the platinum drug cisplatin and signaling pathways in vivo. Null mutations in a single gene, asna-1, makes worms hypersensitive to cisplatin. The metalloregulated ATPase ASNA-1 promotes insulin secretion and membrane insertion of tail-anchored proteins. Using structural data from ASNA-1 homologs, we identify specific ASNA-1 mutants that are sensitive to cisplatin while still able to promote insulin signaling. Mutational analysis reveals that hypersensitivity of ASNA-1 mutants to cisplatin remains in absence of CEP-1/p53 or apoptosis. Human ASNA1 can substitute for the worm gene, indicating a conserved function. Cisplatin sensitivity is not affected by decreased insulin signaling in wild type nematodes or restored insulin signaling in asna-1 mutants. These findings provide a functional insight into ASNA-1, demonstrate that C. elegans can be used to characterize cisplatin resistance mechanisms and propose that rationally designed drugs against ASNA-1 can sensitize cancer cells to cisplatin.

  • 18.
    Hemmingsson, Oskar
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Nöjd, Mikael
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Kao, Gautam
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Increased sensitivity to platinating agents and arsenite in human ovarian cancer by downregulation of ASNA12009In: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 22, no 4, p. 869-875Article in journal (Refereed)
    Abstract [en]

    Platinating agents constitute the first line treatment for ovarian cancer but treatment failure is common because of intrinsic and acquired resistance. Cancer cells develop the RASP-phenotype (cross resistance against arsenite, antimonite and platinum) associated with decreased accumulation of cisplatin and arsenite. ASNA1 is a possible subunit of a transport system for cisplatin and arsenite due to homology to arsA, an ATPase in the E. coli ars-complex responsible for efflux of arsenite and antimonite. Eukaryotic ASNA1 is a targeting factor for membrane insertion of tail-anchored proteins involved in the secretory pathway and cellular stress responses. The purpose with this study was to evaluate if ASNA1 expression influenced cisplatin, carboplatin, oxaliplatin or arsenite sensitivity in ovarian cancer. Human ovarian cancer cell line 2008 was transfected with a sense or an antisense ASNA1 construct. ASNA1 downregulated and overexpressing clones were identified by Western blots. Cell growth and chemosensitivity was determined by the MTT assay. Down-regulated ASNA1 expression was associated with retarded growth and increased sensitivity to cisplatin, carboplatin, oxaliplatin and arsenite whereas the cisplatin resistant 2008/A overexpresses ASNA1. These observations support the hypothesis that ASNA1 is a target to overcome platinum resistance in ovarian cancer.

  • 19.
    Hemmingsson, Oskar
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Zhang, Youyi
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Still, Maria
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    ASNA1, an ATPase targeting tail-anchored proteins, regulates melanoma cell growth and sensitivity to cisplatin and arsenite2009In: Cancer Chemotherapy and Pharmacology, ISSN 0344-5704, E-ISSN 1432-0843, Vol. 63, no 3, p. 491-499Article in journal (Refereed)
    Abstract [en]

    Purpose ASNA1 is homologous to E. coli ArsA, a well characterized ATPase involved in efflux of arsenite and antimonite. Cells resistant to arsenite and antimonite are cross-resistant to the chemotherapeutic drug cisplatin. ASNA1 is also an essential ATPase for the insertion of tail-anchored proteins into ER membranes and a novel regulator of insulin secretion. The aim of this study was to determine if altered ASNA1 levels influenced growth and sensitivity to arsenite and cisplatin in human melanoma cells.

    Methods Cultured melanoma T289 cells were transfected with plasmids containing sense or antisense ASNA1. Cells were exposed to cisplatin, arsenite and zinc. Cell growth and chemosensitivity were evaluated by the MTT assay and apoptosis by a TUNEL assay.

    Results ASNA1 expression was necessary for growth. T289 clones with decreased ASNA1 expression exhibited 51 ± 5% longer doubling times than wildtype T289 (P = 0.0091). After exposure to cisplatin, ASNA1 downregulated cells displayed a significant increase in apoptosis. The cisplatin IC50 in ASNA1 underexpressing cells was 41.7 ± 1.8% compared to wildtype (P = 0.00097) and the arsenite IC50 was 59.9 ± 3.2% of wildtype IC50 (P = 0.0067).

    Conclusions Reduced ASNA1 expression is associated with significant inhibition of cell growth, increased apoptosis and increased sensitivity to cisplatin and arsenite.

  • 20.
    Henriksson, Otto
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Lundgren, Peter J
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Kuklane, Kalev
    Holmér, Ingvar
    Giesbrecht, Gordon G
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Björnstig, Ulf
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Protection against cold in prehospital care: wet clothing removal or addition of a vapor barrier2015In: Wilderness & environmental medicine (Print), ISSN 1080-6032, E-ISSN 1545-1534, Vol. 26, no 1, p. 11-20Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The purpose of this study was to evaluate the effect of wet clothing removal or the addition of a vapor barrier in shivering subjects exposed to a cold environment with only limited insulation available.

    METHODS: Volunteer subjects (n = 8) wearing wet clothing were positioned on a spineboard in a climatic chamber (-18.5°C) and subjected to an initial 20 minutes of cooling followed by 30 minutes of 4 different insulation interventions in a crossover design: 1) 1 woolen blanket; 2) vapor barrier plus 1 woolen blanket; 3) wet clothing removal plus 1 woolen blanket; or 4) 2 woolen blankets. Metabolic rate, core body temperature, skin temperature, and heart rate were continuously monitored, and cold discomfort was evaluated at 5-minute intervals.

    RESULTS: Wet clothing removal or the addition of a vapor barrier significantly reduced metabolic rate (mean difference ± SE; 14 ± 4.7 W/m(2)) and increased skin temperature rewarming (1.0° ± 0.2°C). Increasing the insulation rendered a similar effect. There were, however, no significant differences in core body temperature or heart rate among any of the conditions. Cold discomfort (median; interquartile range) was significantly lower with the addition of a vapor barrier (4; 2-4.75) and with 2 woolen blankets (3.5; 1.5-4) compared with 1 woolen blanket alone (5; 3.25-6).

    CONCLUSIONS: In protracted rescue scenarios in cold environments with only limited insulation available, wet clothing removal or the use of a vapor barrier is advocated to limit the need for shivering thermogenesis and improve the patient's condition on admission to the emergency department.

  • 21.
    Henriksson, Otto
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Lundgren, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Kuklane, Kalev
    Lunds universitet, Insitutionen för designvetenskaper.
    Holmér, Ingvar
    Lunds universitet, Insitutionen för designvetenskaper.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Björnstig, Ulf
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Protection against cold in prehospital care: evaporative heat loss reduction by wet clothing removal or the addition of a vapour barrier - a thermal manikin study2012In: Prehospital and Disaster Medicine, ISSN 1049-023X, E-ISSN 1945-1938, Vol. 26, no 6, p. 1-6Article in journal (Refereed)
    Abstract [en]

    Introduction: In the prehospital care of a cold and wet person, early application of adequate insulation is of utmost importance to reduce cold stress, limit body core cooling, and prevent deterioration of the patient’s condition. Most prehospital guidelines on protection against cold recommend the removal of wet clothing prior to insulation, and some also recommend the use of a waterproof vapor barrier to reduce evaporative heat loss. However, there is little scientific evidence of the effectiveness of these measures.

    Objective: Using a thermal manikin with wet clothing, this study was conducted to determine the effect of wet clothing removal or the addition of a vapor barrier on thermal insulation and evaporative heat loss using different amounts of insulation in both warm and cold ambient conditions.

    Methods: A thermal manikin dressed in wet clothing was set up in accordance with the European Standard for assessing requirements of sleeping bags, modified for wet heat loss determination, and the climatic chamber was set to -15 degrees Celsius (°C) for cold conditions and +10°C for warm conditions. Three different insulation ensembles, one, two or seven woollen blankets, were chosen to provide different levels of insulation. Five different test conditions were evaluated for all three levels of insulation ensembles: (1) dry underwear; (2) dry underwear with a vapor barrier; (3) wet underwear; (4) wet underwear with a vapor barrier; and (5) no underwear. Dry and wet heat loss and thermal resistance were determined from continuous monitoring of ambient air temperature, manikin surface temperature, heat flux and evaporative mass loss rate.

    Results: Independent of insulation thickness or ambient temperature, the removal of wet clothing or the addition of a vapor barrier resulted in a reduction in total heat loss of 19-42%. The absolute heat loss reduction was greater, however, and thus clinically more important in cold environments when little insulation is available. A similar reduction in total heat loss was also achieved by increasing the insulation from one to two blankets or from two to seven blankets.

    Conclusion: Wet clothing removal or the addition of a vapor barrier effectively reduced evaporative heat loss and might thus be of great importance in prehospital rescue scenarios in cold environments with limited insulation available, such as in mass-casualty situations or during protracted evacuations in harsh conditions.

  • 22. Holzer, Alison K
    et al.
    Varki, Nissi M
    Le, Quynh T
    Gibson, Michael A
    Naredi, Peter
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Surgery.
    Howell, Stephen B
    Expression of the human copper influx transporter 1 in normal and malignant human tissues.2006In: J Histochem Cytochem, ISSN 0022-1554, Vol. 54, no 9, p. 1041-9Article in journal (Refereed)
  • 23.
    Kao, Gautam
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Hemmingsson, Oskar
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Chitturi, Jyothsna
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    ­ASNA-1 influence on apoptosis in C. elegansManuscript (preprint) (Other academic)
  • 24.
    Kao, Gautam
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine). Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Surgery.
    Nordenson, Cecilia
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Surgery.
    Still, Maria
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences.
    Rönnlund, Agneta
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Tuck, Simon
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Naredi, Peter
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Surgery.
    ASNA-1 positively regulates insulin secretion in C. elegans and mammalian cells.2007In: Cell, ISSN 0092-8674, Vol. 128, no 3, p. 577-87Article in journal (Refereed)
  • 25. Lindnér, Per
    et al.
    Rizell, Magnus
    Mattsson, Jan
    Hellstrand, Kristoffer
    Naredi, Peter
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Surgery.
    Combined treatment with histamine dihydrochloride, interleukin-2 and interferon-alpha in patients with metastatic melanoma.2004In: Anticancer Res, ISSN 0250-7005, Vol. 24, no 3b, p. 1837-42Article in journal (Refereed)
  • 26. Lindnér, Per
    et al.
    Tölli, Jukka
    Naredi, Peter
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Surgery.
    Öman, Mikael
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Surgery.
    Hafström, Larsolof
    Blood flow in liver tumors--effects of vasoactive drugs estimated with xenon (133Xe) clearance.2004In: Hepatogastroenterology, ISSN 0172-6390, Vol. 51, no 57, p. 781-6Article in journal (Refereed)
  • 27.
    Lundgren, Peter
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Henriksson, Otto
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Kuklane, Kalev
    Holmér, Ingvar
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Björnstig, Ulf
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Validity and reliability of the Cold Discomfort Scale: a subjective judgement scale for the assessment of patient thermal state in a cold environment.2014In: Journal of clinical monitoring and computing, ISSN 1387-1307, E-ISSN 1573-2614, Vol. 28, no 3, p. 287-291Article in journal (Refereed)
    Abstract [en]

    Complementary measures for the assessment of patient thermoregulatory state, such as subjective judgement scales, might be of considerable importance in field rescue scenarios where objective measures such as body core temperature, skin temperature, and oxygen consumption are difficult to obtain. The objective of this study was to evaluate, in healthy subjects, the reliability of the Cold Discomfort Scale (CDS), a subjective judgement scale for the assessment of patient thermal state in cold environments, defined as test-retest stability, and criterion validity, defined as the ability to detect a difference in cumulative cold stress over time. Twenty-two healthy subjects performed two consecutive trials (test-retest). Dressed in light clothing, the subjects remained in a climatic chamber set to -20 °C for 60 min. CDS ratings were obtained every 5 min. Reliability was analysed by test-retest stability using weighted kappa coefficient that was 0.84 including all the 5-min interval measurements. When analysed separately at each 5-min interval the weighted kappa coefficients were was 0.48-0.86. Criterion validity was analysed by comparing median CDS ratings of a moving time interval. The comparison revealed that CDS ratings were significantly increased for every interval of 10, 15, and 30 min (p < 0.001) but not for every interval of 5 min. In conclusion, in a prehospital scenario, subjective judgement scales might be a valuable measure for the assessment of patient thermal state. The results of this study indicated that, in concious patients, the CDS may be both reliable and valid for such purpose.

  • 28.
    Lundgren, Peter
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Henriksson, Otto
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Björnstig, Ulf
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    The effect of active external warming on cold discomfort in field treatment of trauma patients: a clinical randomized trialManuscript (preprint) (Other academic)
  • 29.
    Lundgren, Peter
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Henriksson, Otto
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Björnstig, Ulf
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    The effect of active warming in prehospital trauma care during road and air ambulance transportation: a clinical randomized trial2011In: Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine, ISSN 1757-7241, E-ISSN 1757-7241, Vol. 19, no 59Article in journal (Refereed)
    Abstract [en]

    Background: Prevention and treatment of hypothermia by active warming in prehospital trauma care is recommended but scientifical evidence of its effectiveness in a clinical setting is scarce. The objective of this study was to evaluate the effect of additional active warming during road or air ambulance transportation of trauma patients.

    Methods: Patients were assigned to either passive warming with blankets or passive warming with blankets with the addition of an active warming intervention using a large chemical heat pad applied to the upper torso. Ear canal temperature, subjective sensation of cold discomfort and vital signs were monitored.

    Results: Mean core temperatures increased from35.1°C(95% CI; 34.7–35.5 °C) to36.0°C(95% CI; 35.7–36.3 °C) (p<0.05) in patients assigned to passive warming only (n=22) and from35.6°C(95% CI; 35.2–36.0 °C) to36.4°C(95% CI; 36.1–36.7°C) (p<0.05) in patients assigned to additional active warming (n=26) with no significant differences between the groups. Cold discomfort decreased in 2/3 of patients assigned to passive warming only and in all patients assigned to additional active warming, the difference in cold discomfort change being statistically significant (p<0.05). Patients assigned to additional active warming also presented a statistically significant decrease in heart rate and respiratory frequency (p<0.05).

    Conclusions: In mildly hypothermic trauma patients, with preserved shivering capacity, adequate passive warming is an effective treatment to establish a slow rewarming rate and to reduce cold discomfort during prehospital transportation. However, the addition of active warming using a chemical heat pad applied to the torso will significantly improve thermal comfort even further and might also reduce the cold induced stress response.

  • 30.
    Lundgren, Peter
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Henriksson, Otto
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Björnstig, Ulf
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Validity and reliability of the cold discomfort scale: a subjective judgement scale for assesssment of the thermal state of the patient in a cold environmemtManuscript (preprint) (Other academic)
  • 31. Lyth, J.
    et al.
    Hansson, J.
    Ingvar, C.
    Mansson-Brahme, E.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Stierner, U.
    Wagenius, G.
    Lindholm, C.
    Prognostic subclassifications of T1 cutaneous melanomas based on ulceration, tumour thickness and Clark's level of invasion: results of a population-based study from the Swedish Melanoma Register2013In: British Journal of Dermatology, ISSN 0007-0963, E-ISSN 1365-2133, Vol. 168, no 4, p. 779-786Article in journal (Refereed)
    Abstract [en]

    Background Survival and prognostic factors for thin melanomas have been studied relatively little in population-based settings. This patient group accounts for the majority of melanomas diagnosed in western countries today, and better prognostic information is needed. Objectives The aim of this study was to use established prognostic factors such as ulceration, tumour thickness and Clark's level of invasion for risk stratification of T1 cutaneous melanoma. Methods From 1990 to 2008, the Swedish Melanoma Register included 97% of all melanomas diagnosed in Sweden. Altogether, 13 026 patients with T1 melanomas in clinical stage I were used for estimating melanoma-specific 10- and 15-year mortality rates. The Cox regression model was used for further survival analysis on 11 165 patients with complete data. Results Ulceration, tumour thickness and Clark's level of invasion all showed significant, independent, long-term prognostic information. By combining these factors the patients could be subdivided into three risk groups: a low-risk group (67.9% of T1 cases) with a 10-year melanoma-specific mortality rate of 1.5% (1.2-1.9%); an intermediate-risk group (28.6% of T1 cases) with a 10-year mortality rate of 6.1% (5.0-7.3%); and a high-risk group (3.5% of T1 cases) with a 10-year mortality rate of 15.6% (11.2-21.4%). The high-and intermediate-risk groups accounted for 66% of melanoma deaths within T1. Conclusions Using a population-based melanoma register, and combining ulceration, tumour thickness and Clark's level of invasion, three distinct prognostic subgroups were identified.

  • 32. Mattsson, Jan
    et al.
    Bergkvist, Leif
    Abdiu, Avni
    Aili Low, J F
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Ullberg, Karin
    Garpered, Ulf
    Håkansson, Annika
    Ingvar, Christian
    Sentinel node biopsy in malignant melanoma: Swedish experiences 1997-20052008In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 47, no 8, p. 1519-1525Article in journal (Refereed)
    Abstract [en]

    The sentinel node biopsy (SNB) procedure is a multidisciplinary technique, invented to gain prognostic information in different malignant tumors. The aim of the present study was to study the cohort of patients with malignant melanoma, operated with SNB, from the introduction of the technique in Sweden, concerning the prognostic information retrieved and the outcome of the procedures. In Sweden all patients with malignant melanoma are registered at regional Oncological Centers. From these databases ten centers were identified, treating malignant melanoma and performing sentinel node biopsy. Consecutive data concerning tumor characteristics, outcome of the procedure and disease related events during the follow-up time were collected from these ten centers. All cases from the very first in each centre were included. The SNB procedure was performed in 422 patients with a sentinel node (SN) detection rate of 97%, the mean Breslow thickness of the primary tumors was 3.2 mm (median 2.4 mm) and the proportion of ulcerated melanomas 38%. Metastasis in the SN was found in 19% of the patients but there was a wide range in the proportion of SN metastases between the different centers (5-52%). After a follow-up of median 12 months of 361 patients, SN negative patients had better disease-free survival than SN positive (p<0.0001). A false negative rate of 14% was found during the follow-up time. In this study the surgical technique seemed acceptable, but the non-centralized pathology work-up sub-optimal. However, SNB was still found to be a significant prognostic indicator, concerning disease free survival.

  • 33. Middleton, Mark
    et al.
    Hauschild, Axel
    Thomson, Damien
    Andersson, Ronny
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology. Onkologi.
    Burdette-Radoux, Susan
    Gehlsen, Kurt
    Hellstrand, Kristoffer
    Naredi, Peter
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Surgery.
    Results of a multicenter randomized study to evaluate the safety and efficacy of combined immunotherapy with interleukin-2, interferon-alpha2b and histamine dihydrochloride versus dacarbazine in patients with stage IV melanoma.2007In: Annals of Oncology, ISSN 0923-7534, Vol. 18, no 10, p. 1691-1697Article in journal (Refereed)
  • 34.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Surgery.
    Databases of hepatic resection for metastatic colorectal cancer--useful aids for clinical decision-making.2008In: Surg Oncol, ISSN 0960-7404, Vol. 17, no 1, p. 15-6Article in journal (Refereed)
  • 35.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Surgery.
    Improved cancer care puts focus on specialist education and training in surgical oncology2007In: European Oncological Disease, Vol. 1, p. 106-7Article in journal (Refereed)
  • 36.
    Naredi, Peter
    et al.
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Surgery.
    Audisio, Riccardo A
    Taylor, Irving
    Why do we need a core curriculum in surgical oncology in Europe?2008In: Surg Oncol, ISSN 0960-7404, Vol. 17, no 4, p. 267-9Article in journal (Refereed)
  • 37.
    Naredi, Peter
    et al.
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Surgery.
    Leidenius, Marjut
    Hocevar, Marko
    Roelofesen, Felicitas
    van de Velde, Cornelis
    Audisio, Riccardo A
    Recommended core curriculum for the specialist training in surgical oncology within Europe.2008In: Surg Oncol, ISSN 0960-7404, Vol. 17, p. 271-275Article in journal (Refereed)
  • 38.
    Natarajan, Balasubramanian
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Gaur, Rahul
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Hemmingsson, Oskar
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Kao, Gautam
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Depletion of the ER chaperone ENPL-1 sensitizes C. elegans to the anticancer drug cisplatin2013In: Worm, ISSN 2162-4046, Vol. 2, no 1, article id e24059Article in journal (Refereed)
    Abstract [en]

    Cisplatin is an essential chemotherapeutic drug in the treatment of many cancers. Its use, however, is limited by the development of resistance in many tumors. The ability to re-sensitize resistant tumors could significantly strengthen cisplatin therapy in patients. Caenorhabditis elegans is a suitable model for studying the cytoplasmic role of cisplatin in tumor cells. We have previously shown that the ATPase ASNA-1 has similar roles as a factor governing cisplatin sensitivity in mammalian tumor cells and C. elegans. Here we study the endoplasmic reticulum (ER) resident chaperone ENPL-1/GRP94 and find that its depletion makes worms sensitive to cisplatin. Elevated ER stress levels in enpl-1 mutants is the likely cause of this sensitivity because a correlation can be made between cisplatin sensitivity and the high ER stress levels. We also find that asna-1 mutants have elevated unfolded protein response (UPR) activity and that the intrinsically cisplatin resistant wild-type worms become sensitive when ER stress is high. We conclude that enpl-1 is a cisplatin sensitizing factor and suggest that manipulation of its levels or of UPR activity will enhance the effects of cisplatin based cancer therapy.

  • 39.
    Natarajan, Balasubramanian
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Hemmingsson, Oskar
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Kao, Gautam
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Unfolded protein response and enpl-1 depletion sensitize C. elegans to the anti-cancer drug cisplatinManuscript (preprint) (Other academic)
  • 40.
    Natarajan, Balasubramanian
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Mohammed, Ateequrrahman
    Kao, Gautam
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Survival motor neuron homolog SMN-1 activates insulin signaling and neuropeptide release in C. elegansManuscript (preprint) (Other academic)
  • 41.
    Natarajan, Balasubramanian
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Kao, Gautam
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    ENPL-1, a GRP94 homolog, interacts with ASNA-1 to promote Insulin/IGF secretion in Caenorhabditis elegansManuscript (preprint) (Other academic)
  • 42.
    Nygren, Yvonne
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Hemström, Petrus
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Åstot, Crister
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Björn, Erik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Hydrophilic interaction liquid chromatography (HILIC) coupled to inductively coupled plasma mass spectrometry (ICPMS) utilizing a mobile phase with a low-volatile organic modifier for the determination of cisplatin, and its monohydrolyzed metabolite2008In: Journal of Analytical Atomic Spectrometry, Vol. 23, no 7, p. 948-54Article in journal (Refereed)
    Abstract [en]

    This study demonstrates the on-line coupling of hydrophilic interaction liquid chromatography (HILIC) to inductively coupled plasma mass spectrometry (ICPMS). A low volatile organic solvent, dimethylformamide (DMF), was used as organic modifier of the mobile phase to minimize the solvent loading of the ICP and thereby improve analyte sensitivity and method robustness. The concept was illustrated by the selective determination of cisplatin (cis-DDP), and its mono-hydrolyzed metabolite (MH-DDP). Species were separated on a 2.1 × 150 mm ZIC-HILIC column and detected on-line by selective platinum (m/z 194 and 195) monitoring, giving a detection limit of 2 pg Pt (0.2 ng ml-1). Compared to the use of the conventional solvent acetonitrile (AcN), with DMF, cis-DDP sensitivity was enhanced as much as 36 times and no addition of oxygen to the plasma was needed to avoid carbon depositions on instrumental parts. Furthermore, several non-identified platinum containing compounds were observed when using AcN as a result of unwanted reactions between this solvent and the analytes. No such species were observed when DMF was used. The molecular structures of eluting compounds were verified by electrospray ionization mass spectrometry. Combined with a simple sample treatment protocol, the HILIC-ICPMS system allowed determination of free intracellular cis-DDP in in-vitro grown T289 human malignant melanoma cells up to 60 min after exposure to 50 g ml-1 cis-DDP for 1 h. This work shows that HILIC-ICPMS is a potent hyphenated technique for the analysis of hydrophilic metal compounds and that the use of chromatographic mobile phases with low-volatile organic solvents may be a generic approach to improve analyte sensitivity and system robustness of HPLC-ICPMS when mobile phases with high amount of organic solvent are used.

  • 43.
    Nyström, Hanna
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Lundin, Christina
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Björklund, Moa
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Nygren, Pia
    Department of Diagnosics and Oral Medicine, University of Oulu, Finland.
    Saalo, Tula
    Department of Diagnostics and Oral Medicine, University of Oulu, Finland.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Increased type IV collagen expression is a feature in liver metastases of epithelial origin and related to invasiveness of CRC cells in a novel organotypic liver metastatic modelArticle in journal (Other academic)
  • 44.
    Nyström, Hanna
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Berglund, Anette
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Tavelin, Björn
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Liver-metastatic potential of colorectal cancer is related to the stromal composition of the tumour2012In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 32, no 12, p. 5183-5191Article in journal (Refereed)
    Abstract [en]

    Background: The tumour stroma is an important modulator of cancer cell behaviour. The aim of this study was to compare the stromal composition between primary colorectal cancer (CRC) and colorectal liver metastases (CLM).

    Materials and Methods: The stromal composition in matched tissue sections of CRC and subsequent CLM was analysed, and related to clinical parameters.

    Results: Differences in the expression pattern of type I collagen and type IV collagen in CRC was related to a higher risk of CLM. Two types of CLM the desmoplastic and pushing type were identified. The time between CRC and diagnosis of CLM was shorter (p=0.047) for desmoplastic CLM. The mortality rate was higher for pushing CLM due to frequent extrahepatic disseminated disease. A difference in the overall survival rate between patients with desmoplastic and those with pushing CLM was seen at follow-up of more than 60 months (p=0.046).

    Conclusion: The liver-metastasizing potential is related to the stromal composition of primary CRC. There are distinct growth patterns in CLM with differences in stromal composition and clinical outcome.

  • 45.
    Nyström, Hanna
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Hafström, Larsolof
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Type IV collagen as a tumour marker for colorectal liver metastases2011In: European Journal of Surgical Oncology, ISSN 0748-7983, E-ISSN 1532-2157, Vol. 37, no 7, p. 611-617Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: About 50% of patients with primary colorectal cancer (CRC) will develop liver metastases (CLM). Currently, carcinoembryonic antigen (CEA) is the most common tumour marker for CRC and CLM. However, the sensitivity and specificity of this marker is not optimal, as almost 50% of patients have tumours that do not produce CEA. Therefore there is a need for better markers for CRC and CLM.

    METHODS: The circulating levels of type IV collagen were measured in patients with CLM, primary CRC and in healthy controls. The expression pattern of type IV collagen was studied by immunofluorescence in CLM and normal liver tissue. The metastatic volume of CLM in the liver was estimated from CT.

    RESULTS: In CLM tissue type IV collagen is highly expressed in the areas of desmoplasia. Patients with primary CRC (Dukes' A-C) did not show any increase in circulating type IV collagen compared to healthy controls. However, patients with CLM have significantly elevated levels of circulating type IV collagen when compared to patients with primary CRC and healthy controls. The levels of type IV collagen decreased during chemotherapy and increased at the time of disease progression. The circulating levels of type IV collagen seem to reflect the tumour burden in the liver.

    CONCLUSIONS: Type IV collagen has the potential to be used as tumour associated biomarker for CLM. These results indicate the importance of interaction between cancer cells and the stroma in the tumour microenvironment.

  • 46.
    Nyström, Hanna
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Tavelin, Björn
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Björklund, Moa
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Improved tumor marker sensitivity by combined type IV collagen and CEA measurement in colorectal liver metastasesArticle in journal (Other academic)
  • 47. Palm, Maria E
    et al.
    Weise, Christoph F
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Lundin, Christina
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Wingsle, Gunnar
    Nygren, Yvonne
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Björn, Erik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Wolf-Watz, Magnus
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Wittung-Stafshede, Pernilla
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Cisplatin binds human copper chaperone Atox1 and promotes unfolding in vitro2011In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 108, no 17, p. 6951-6956Article in journal (Refereed)
    Abstract [en]

    Cisplatin (cisPt), Pt(NH(3))(2)Cl(2), is a cancer drug believed to kill cells via DNA binding and damage. Recent work has implied that the cellular copper (Cu) transport machinery may be involved in cisPt cell export and drug resistance. Normally, the Cu chaperone Atox1 binds Cu(I) via two cysteines and delivers the metal to metal-binding domains of ATP7B; the ATP7B domains then transfer the metal to the Golgi lumen for loading on cuproenzymes. Here, we use spectroscopic methods to test if cisPt interacts with purified Atox1 in solution in vitro. We find that cisPt binds to Atox1's metal-binding site regardless of the presence of Cu or not: When Cu is bound to Atox1, the near-UV circular dichroism signals indicate Cu-Pt interactions. From NMR data, it is evident that cisPt binds to the folded protein. CisPt-bound Atox1 is however not stable over time and the protein begins to unfold and aggregate. The reaction rates are limited by slow cisPt dechlorination. CisPt-induced unfolding of Atox1 is specific because this effect was not observed for two unrelated proteins that also bind cisPt. Our study demonstrates that Atox1 is a candidate for cisPt drug resistance: By binding to Atox1 in the cytoplasm, cisPt transport to DNA may be blocked. In agreement with this model, cell line studies demonstrate a correlation between Atox1 expression levels, and cisplatin resistance.

  • 48.
    Palm-Espling, Maria
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Lundin, Christina
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Björn, Erik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Naredi, Peter
    Kirurgi, Sahlgrenska sjukhuset, Göteborgs universitet.
    Wittung-Stafshede, Pernilla
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Interaction between anticancer drug Cisplatin and copper chaperone Atox1 in human melanoma cells2014In: Protein peptide letters, ISSN 0929-8665, E-ISSN 1875-5305, Vol. 21, no 1, p. 63-68Article in journal (Refereed)
    Abstract [en]

    Cisplatin (CisPt) is one of the most common anticancer drugs used against many severe forms of cancers. However, treatment with this drug causes many side effects and often, it results in the development of cell resistance. A majority of side effects as well as cell resistance are thought to develop due to CisPt interactions with proteins prior to reaching the nucleus and the DNA target. The copper (Cu) transport proteins Ctr1 and ATP7A/B have been implicated in cellular resistance of CisPt, possibly exporting the drug out of the cell. Recent in vitro work demonstrated that CisPt also interacts with the cytoplasmic Cu-chaperone Atox1, binding in or near the Cu-binding site, without expulsion of bound Cu. Whereas Ctr1 and ATP7B interactions with CisPt have been shown in vivo or ex vivo, there is no such information for Atox1-CisPt interactions. To address this, we developed a method to probe if CisPt interacts with Atox1 in human melanoma cells. Atox1-specific antibodies were linked to magnetic beads and used to immune-precipitate Atox1 from melanoma cells that had been pre-exposed to CisPt. Analysis of extracted Atox1 with inductively coupled plasma mass spectrometry demonstrated the presence of Pt in the protein fraction. Thus, CisPt-exposed human melanoma cells contain Atox1 molecules that bind some derivative of CisPt. This study gives the first indication for the intracellular presence of Atox1-CisPt complexes ex vivo.

  • 49. Sullivan, Richard
    et al.
    Peppercorn, Jeffrey
    Sikora, Karol
    Zalcberg, John
    Meropol, Neal J.
    Amir, Eitan
    Khayat, David
    Boyle, Peter
    Autier, Philippe
    Tannock, Ian F.
    Fojo, Tito
    Siderov, Jim
    Williamson, Steve
    Camporesi, Silvia
    McVie, J. Gordon
    Purushotham, Arnie D.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Eggermont, Alexander
    Brennan, Murray F.
    Steinberg, Michael L.
    De Ridder, Mark
    McCloskey, Susan A.
    Verellen, Dirk
    Roberts, Terence
    Storme, Guy
    Hicks, Rodney J.
    Ell, Peter J.
    Hirsch, Bradford R.
    Carbone, David P.
    Schulman, Kevin A.
    Catchpole, Paul
    Taylor, David
    Geissler, Jan
    Brinker, Nancy G.
    Meltzer, David
    Kerr, David
    Aapro, Matti
    Delivering affordable cancer care in high-income countries2011In: The Lancet Oncology, ISSN 1470-2045, E-ISSN 1474-5488, Vol. 12, no 10, p. 933-980Article in journal (Refereed)
    Abstract [en]

    The burden of cancer is growing, and the disease is becoming a major economic expenditure for all developed countries. In 2008, the worldwide cost of cancer due to premature death and disability (not including direct medical costs) was estimated to be US$895 billion. This is not simply due to an increase in absolute numbers, but also the rate of increase of expenditure on cancer. What are the drivers and solutions to the so-called cancer-cost curve in developed countries? How are we going to afford to deliver high quality and equitable care? Here, expert opinion from health-care professionals, policy makers, and cancer survivors has been gathered to address the barriers and solutions to delivering affordable cancer care. Although many of the drivers and themes are specific to a particular field-eg, the huge development costs for cancer medicines-there is strong concordance running through each contribution. Several drivers of cost, such as over-use, rapid expansion, and shortening life cycles of cancer technologies (such as medicines and imaging modalities), and the lack of suitable clinical research and integrated health economic studies, have converged with more defensive medical practice, a less informed regulatory system, a lack of evidence-based sociopolitical debate, and a declining degree of fairness for all patients with cancer. Urgent solutions range from re-engineering of the macroeconomic basis of cancer costs (eg, value-based approaches to bend the cost curve and allow cost-saving technologies), greater education of policy makers, and an informed and transparent regulatory system. A radical shift in cancer policy is also required. Political toleration of unfairness in access to affordable cancer treatment is unacceptable. The cancer profession and industry should take responsibility and not accept a substandard evidence base and an ethos of very small benefit at whatever cost; rather, we need delivery of fair prices and real value from new technologies.

  • 50.
    Tran, Mai Quynh Thanh
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Nygren, Yvonne
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Lundin, Christina
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Björn, Erik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Evaluation of cell lysis methods for platinum metallomic studies of human malignant cells2010In: Analytical Biochemistry, ISSN 0003-2697, E-ISSN 1096-0309, Vol. 396, no 1, p. 76-82Article in journal (Refereed)
    Abstract [en]

    Three cell lysis methods-freeze-thaw, osmosis, and a chemical detergent-based method-were evaluated as sample treatment procedures for platinum metallomic studies of in vitro grown human malignant cells exposed to cisplatin. The lysis methods are relatively mild, resemble those commonly used in proteomic studies, and were selected because of the proven reactivity of platinum drug metabolites and indications that platinum in exposed cells and plasma is mainly associated with proteins. The chemical method gave an absolute lysis efficiency of greater than 80%, whereas the freeze-thaw and osmosis methods gave approximately 30% lower efficiency. The within- and between-batch lysis reproducibilities were, for all methods, better than 20 and 24% relative standard deviations, respectively. Total platinum concentration normalized to lysate protein content was statistically the same for all lysis methods. Reagents in the chemical lysis buffer did, however, react with platinum analyte compounds, making this method unsuitable for analysis of reactive compounds or for metallome profiling encompassing analytes with unknown reactivity. Of the lysis methods evaluated here, osmosis gave the highest cisplatin recovery, likely because this protocol is chemically inert and can be carried out at a constant low temperature. Therefore, it is the recommended cell lysis method for the determination of reactive and unknown intracellular platinum compounds.

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