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  • 1. Baumeister, Sebastian E.
    et al.
    Schlesinger, Sabrina
    Aleksandrova, Krasimira
    Jochem, Carmen
    Jenab, Mazda
    Gunter, Marc J.
    Overvad, Kim
    Tjonneland, Anne
    Boutron-Ruault, Marie-Christine
    Carbonnel, Franck
    Fournier, Agnes
    Kuehn, Tilman
    Kaaks, Rudolf
    Pischon, Tobias
    Boeing, Heiner
    Trichopoulou, Antonia
    Bamia, Christina
    La Vecchia, Carlo
    Masala, Giovanna
    Panico, Salvatore
    Fasanelli, Francesca
    Tumino, Rosario
    Grioni, Sara
    de Mesquita, Bas Bueno
    Vermeulen, Roel
    May, Anne M.
    Borch, Kristin B.
    Oyeyemi, Sunday O.
    Ardanaz, Eva
    Rodriguez-Barranco, Miguel
    Chirlaque Lopez, Maria Dolores
    Felez-Nobrega, Mireia
    Sonestedt, Emily
    Ohlsson, Bodil
    Hemmingsson, Oskar
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Werner, Mårten
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Perez-Cornago, Aurora
    Ferrari, Pietro
    Stepien, Magdalena
    Freisling, Heinz
    Tsilidis, Konstantinos K.
    Ward, Heather
    Riboli, Elio
    Weiderpass, Elisabete
    Leitzmann, Michael F.
    Association between physical activity and risk of hepatobiliary cancers: A multinational cohort study2019Ingår i: Journal of Hepatology, ISSN 0168-8278, E-ISSN 1600-0641, Vol. 70, nr 5, s. 885-892Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background & Aims: To date, evidence on the association between physical activity and risk of hepatobiliary cancers has been inconclusive. We examined this association in the European Prospective Investigation into Cancer and Nutrition cohort (EPIC).

    Methods: We identified 275 hepatocellular carcinoma (HCC) cases, 93 intrahepatic bile duct cancers (IHBCs), and 164 non-gallbladder extrahepatic bile duct cancers (NGBCs) among 467,336 EPIC participants (median follow-up 14.9 years). We estimated cause-specific hazard ratios (HRs) for total physical activity and vigorous physical activity and performed mediation analysis and secondary analyses to assess robustness to confounding (e.g. due to hepatitis virus infection).

    Results: In the EPIC cohort, the multivariable-adjusted HR of HCC was 0.55 (95% CI 0.38–0.80) comparing active and inactive individuals. Regarding vigorous physical activity, for those reporting >2 hours/week compared to those with no vigorous activity, the HR for HCC was 0.50 (95% CI 0.33–0.76). Estimates were similar in sensitivity analyses for confounding. Total and vigorous physical activity were unrelated to IHBC and NGBC. In mediation analysis, waist circumference explained about 40% and body mass index 30% of the overall association of total physical activity and HCC.

    Conclusions: These findings suggest an inverse association between physical activity and risk of HCC, which is potentially mediated by obesity.

    Lay summary: In a pan-European study of 467,336 men and women, we found that physical activity is associated with a reduced risk of developing liver cancers over the next decade. This risk was independent of other liver cancer risk factors, and did not vary by age, gender, smoking status, body weight, and alcohol consumption.

  • 2. Boussemart, Lise
    et al.
    Malka-Mahieu, Hélène
    Girault, Isabelle
    Allard, Delphine
    Hemmingsson, Oskar
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi. Inserm UMR981, F-94805 Villejuif, France.
    Tomasic, Gorana
    Thomas, Marina
    Basmadjian, Christine
    Ribeiro, Nigel
    Thuaud, Frédéric
    Mateus, Christina
    Routier, Emilie
    Kamsu-Kom, Nyam
    Agoussi, Sandrine
    Eggermont, Alexander M
    Désaubry, Laurent
    Robert, Caroline
    Vagner, Stéphan
    eIF4F is a nexus of resistance to anti-BRAF and anti-MEK cancer therapies2014Ingår i: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 513, nr 7516, s. 105-109Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In BRAF(V600)-mutant tumours, most mechanisms of resistance to drugs that target the BRAF and/or MEK kinases rely on reactivation of the RAS-RAF-MEK-ERK mitogen-activated protein kinase (MAPK) signal transduction pathway, on activation of the alternative, PI(3)K-AKT-mTOR, pathway (which is ERK independent) or on modulation of the caspase-dependent apoptotic cascade. All three pathways converge to regulate the formation of the eIF4F eukaryotic translation initiation complex, which binds to the 7-methylguanylate cap (m(7)G) at the 5' end of messenger RNA, thereby modulating the translation of specific mRNAs. Here we show that the persistent formation of the eIF4F complex, comprising the eIF4E cap-binding protein, the eIF4G scaffolding protein and the eIF4A RNA helicase, is associated with resistance to anti-BRAF, anti-MEK and anti-BRAF plus anti-MEK drug combinations in BRAF(V600)-mutant melanoma, colon and thyroid cancer cell lines. Resistance to treatment and maintenance of eIF4F complex formation is associated with one of three mechanisms: reactivation of MAPK signalling, persistent ERK-independent phosphorylation of the inhibitory eIF4E-binding protein 4EBP1 or increased pro-apoptotic BCL-2-modifying factor (BMF)-dependent degradation of eIF4G. The development of an in situ method to detect the eIF4E-eIF4G interactions shows that eIF4F complex formation is decreased in tumours that respond to anti-BRAF therapy and increased in resistant metastases compared to tumours before treatment. Strikingly, inhibiting the eIF4F complex, either by blocking the eIF4E-eIF4G interaction or by targeting eIF4A, synergizes with inhibiting BRAF(V600) to kill the cancer cells. eIF4F not only appears to be an indicator of both innate and acquired resistance but also is a promising therapeutic target. Combinations of drugs targeting BRAF (and/or MEK) and eIF4F may overcome most of the resistance mechanisms arising in BRAF(V600)-mutant cancers.

  • 3. Bradbury, Kathryn E.
    et al.
    Appleby, Paul N.
    Tipper, Sarah J.
    Travis, Ruth C.
    Allen, Naomi E
    Kvaskoff, Marina
    Overvad, Kim
    Tjønneland, Anne
    Halkjaer, Jytte
    Cervenka, Iris
    Mahamat-Saleh, Yahya
    Bonnet, Fabrice
    Kaaks, Rudolf
    Fortner, Renée T.
    Boeing, Heiner
    Trichopoulou, Antonia
    La Vecchia, Carlo
    Stratigos, Alexander J.
    Palli, Domenico
    Grioni, Sara
    Matullo, Giuseppe
    Panico, Salvatore
    Tumino, Rosario
    Peeters, Petra H.
    Bueno-de-Mesquita, H Bas
    Ghiasvand, Reza
    Veierød, Marit B.
    Weiderpass, Elisabete
    Bonet, Catalina
    Molina, Elena
    Huerta, José M.
    Larrañaga, Nerea
    Barricarte, Aurelio
    Merino, Susana
    Isaksson, Karolin
    Stocks, Tanja
    Ljuslinder, Ingrid
    Hemmingsson, Oskar
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap.
    Wareham, Nick
    Khaw, Kay-Tee
    Gunter, Marc J.
    Rinaldi, Sabina
    Tsilidis, Konstantinos K.
    Aune, Dagfinn
    Riboli, Elio
    Key, Timothy J.
    Circulating insulin-like growth factor I in relation to melanoma risk in the European prospective investigation into cancer and nutrition2019Ingår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 144, nr 5, s. 957-966Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Insulin-like growth factor-I (IGF-I) regulates cell proliferation and apoptosis, and is thought to play a role in tumour development. Previous prospective studies have shown that higher circulating concentrations of IGF-I are associated with a higher risk of cancers at specific sites, including breast and prostate. No prospective study has examined the association between circulating IGF-I concentrations and melanoma risk. A nested case-control study of 1,221 melanoma cases and 1,221 controls was performed in the European Prospective Investigation into Cancer and Nutrition cohort, a prospective cohort of 520,000 participants recruited from 10 European countries. Conditional logistic regression was used to estimate odds ratios (ORs) for incident melanoma in relation to circulating IGF-I concentrations, measured by immunoassay. Analyses were conditioned on the matching factors and further adjusted for age at blood collection, education, height, BMI, smoking status, alcohol intake, marital status, physical activity and in women only, use of menopausal hormone therapy. There was no significant association between circulating IGF-I concentration and melanoma risk (OR for highest vs lowest fifth = 0.93 [95% confidence interval [CI]: 0.71 to 1.22]). There was no significant heterogeneity in the association between IGF-I concentrations and melanoma risk when subdivided by gender, age at blood collection, BMI, height, age at diagnosis, time between blood collection and diagnosis, or by anatomical site or histological subtype of the tumour (Pheterogeneity≥0.078). We found no evidence for an association between circulating concentrations of IGF-I measured in adulthood and the risk of melanoma.

  • 4. Caini, Saverio
    et al.
    Masala, Giovanna
    Saieva, Calogero
    Kvaskoff, Marina
    Sacerdote, Carlotta
    Savoye, Isabelle
    Hemmingsson, Oskar
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Bech, Bodil Hammer
    Overvad, Kim
    Tjonneland, Anne
    Petersen, Kristina E. N.
    Mancini, Francesca Romana
    Boutron-Ruault, Marie-Christine
    Cervenka, Iris
    Kaaks, Rudolf
    Kuehn, Tilman
    Boeing, Heiner
    Floegel, Anna
    Trichopoulou, Antonia
    Valanou, Elisavet
    Kritikou, Maria
    Tagliabue, Giovanna
    Panico, Salvatore
    Tumino, Rosario
    Bueno-de-Mesquita, H. B(as)
    Peeters, Petra H.
    Veierod, Marit B.
    Ghiasvand, Reza
    Lukic, Marko
    Ramon Quiros, Jose
    Chirlaque, Maria-Dolores
    Ardanaz, Eva
    Salamanca Fernandez, Elena
    Larranaga, Nerea
    Zamora-Ros, Raul
    Nilsson, Lena Maria
    Umeå universitet, Arktiskt centrum vid Umeå universitet (Arcum). Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Ljuslinder, Ingrid
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Jirstrom, Karin
    Sonestedt, Emily
    Key, Timothy J.
    Wareham, Nick
    Khaw, Kay-Tee
    Gunter, Marc
    Huybrechts, Inge
    Murphy, Neil
    Tsilidis, Konstantinos K.
    Weiderpass, Elisabete
    Palli, Domenico
    Coffee, tea and melanoma risk: findings from the European Prospective Investigation into Cancer and Nutrition2017Ingår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 140, nr 10, s. 2246-2255Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    What's new? Laboratory studies suggest that coffee and tea protect against melanoma, but epidemiological findings are inconsistent. Here the authors studied more than 400,000 participants within the European Prospective Investigation into Cancer and Nutrition (EPIC) and confirmed an inverse association between caffeinated coffee consumption and melanoma risk. No association was found with decaffeinated coffee or tea. Interestingly, drinking coffee only protected men, but not women, from developing the often fatal skin cancer, raising interesting questions about gender-specific hormones or coffee habits influencing this association. In vitro and animal studies suggest that bioactive constituents of coffee and tea may have anticarcinogenic effects against cutaneous melanoma; however, epidemiological evidence is limited to date. We examined the relationships between coffee (total, caffeinated or decaffeinated) and tea consumption and risk of melanoma in the European Prospective Investigation into Cancer and Nutrition (EPIC). EPIC is a multicentre prospective study that enrolled over 500,000 participants aged 25-70 years from ten European countries in 1992-2000. Information on coffee and tea drinking was collected at baseline using validated country-specific dietary questionnaires. We used adjusted Cox proportional hazards regression models to calculate hazard ratios (HR) and 95% confidence intervals (95% CI) for the associations between coffee and tea consumption and melanoma risk. Overall, 2,712 melanoma cases were identified during a median follow-up of 14.9 years among 476,160 study participants. Consumption of caffeinated coffee was inversely associated with melanoma risk among men (HR for highest quartile of consumption vs. non-consumers 0.31, 95% CI 0.14-0.69) but not among women (HR 0.96, 95% CI 0.62-1.47). There were no statistically significant associations between consumption of decaffeinated coffee or tea and the risk of melanoma among both men and women. The consumption of caffeinated coffee was inversely associated with melanoma risk among men in this large cohort study. Further investigations are warranted to confirm our findings and clarify the possible role of caffeine and other coffee compounds in reducing the risk of melanoma.

  • 5. Duarte-Salles, Talita
    et al.
    Misra, Sandeep
    Stepien, Magdalena
    Plymoth, Amelie
    Muller, David
    Overvad, Kim
    Olsen, Anja
    Tjonneland, Anne
    Baglietto, Laura
    Severi, Gianluca
    Boutron-Ruault, Marie-Christine
    Turzanski-Fortner, Renee
    Kaaks, Rudolf
    Boeing, Heiner
    Aleksandrova, Krasimira
    Trichopoulou, Antonia
    Lagiou, Pagona
    Bamia, Christina
    Pala, Valeria
    Palli, Domenico
    Mattiello, Amalia
    Tumino, Rosario
    Naccarati, Alessio
    Bueno-de-Mesquita, H. B(as).
    Peeters, Petra H.
    Weiderpass, Elisabete
    Quiros, J. Ramon
    Agudo, Antonio
    Sanchez-Cantalejo, Emilio
    Ardanaz, Eva
    Gavrila, Diana
    Dorronsoro, Miren
    Werner, Mårten
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Hemmingsson, Oskar
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Ohlsson, Bodil
    Sjoberg, Klas
    Wareham, Nicholas J.
    Khaw, Kay-Tee
    Bradbury, Kathryn E.
    Gunter, Marc J.
    Cross, Amanda J.
    Riboli, Elio
    Jenab, Mazda
    Hainaut, Pierre
    Beretta, Laura
    Circulating Osteopontin and Prediction of Hepatocellular Carcinoma Development in a Large European Population2016Ingår i: Cancer Prevention Research, ISSN 1940-6207, E-ISSN 1940-6215, Vol. 9, nr 9, s. 758-765Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We previously identified osteopontin (OPN) as a promising marker for the early detection of hepatocellular carcinoma (HCC). In this study, we investigated the association between prediagnostic circulating OPN levels and HCC incidence in a large population-based cohort. A nested case-control study was conducted within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. During a mean follow-up of 4.8 years, 100 HCC cases were identified. Each case was matched to two controls and OPN levels were measured in baseline plasma samples. Viral hepatitis, liver function, and a-fetoprotein (AFP) tests were also conducted. Conditional logistic regression models were used to calculate multivariable odds ratio (OR) and 95% confidence intervals (95% CI) for OPN levels in relation to HCC. Receiver operating characteristics curves were constructed to determine the discriminatory accuracy of OPN alone or in combination with other liver biomarkers in the prediction of HCC. OPN levels were positively associated with HCC risk (per 10% increment, ORmultivariable = 1.30; 95% CI, 1.14-1.48). The association was stronger among cases diagnosed within 2 years of follow-up. Adding liver function tests to OPN improved the discriminatory performance for subjects who developed HCC (AUC = 0.86). For cases diagnosed within 2 years, the combination of OPN and AFP was best able to predict HCC risk (AUC = 0.88). The best predictive model for HCC in this low-risk population is OPN in combination with liver function tests. Within 2 years of diagnosis, the combination of OPN and AFP best predicted HCC development, suggesting that measuring OPN and AFP could identify high-risk groups independently of a liver disease diagnosis.

  • 6. Fedirko, Veronika
    et al.
    Tran, Hao Quang
    Gewirtz, Andrew T
    Stepien, Magdalena
    Trichopoulou, Antonia
    Aleksandrova, Krasimira
    Olsen, Anja
    Tjønneland, Anne
    Overvad, Kim
    Carbonnel, Franck
    Boutron-Ruault, Marie-Christine
    Severi, Gianluca
    Kühn, Tilman
    Kaaks, Rudolf
    Boeing, Heiner
    Bamia, Christina
    Lagiou, Pagona
    Grioni, Sara
    Panico, Salvatore
    Palli, Domenico
    Tumino, Rosario
    Naccarati, Alessio
    Peeters, Petra H
    Bueno-de-Mesquita, H B
    Weiderpass, Elisabete
    Castaño, José María Huerta
    Barricarte, Aurelio
    Sánchez, María-José
    Dorronsoro, Miren
    Quirós, J Ramón
    Agudo, Antonio
    Sjöberg, Klas
    Ohlsson, Bodil
    Hemmingsson, Oskar
    Department of Surgical and Perioperative Sciences, Kirurgcentrum, Norrlands Universitetssjukhus, Umeå, Sweden.
    Werner, Mårten
    Department of Medicine Sections for Hepatology and Gastroenterology, Umeå University Hospital, SE-90185 Umeå, Sweden.
    Bradbury, Kathryn E
    Khaw, Kay-Tee
    Wareham, Nick
    Tsilidis, Konstantinos K
    Aune, Dagfinn
    Scalbert, Augustin
    Romieu, Isabelle
    Riboli, Elio
    Jenab, Mazda
    Exposure to bacterial products lipopolysaccharide and flagellin and hepatocellular carcinoma: a nested case-control study2017Ingår i: BMC Medicine, ISSN 1741-7015, E-ISSN 1741-7015, Vol. 72, nr 15Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Leakage of bacterial products across the gut barrier may play a role in liver diseases which often precede the development of liver cancer. However, human studies, particularly from prospective settings, are lacking.

    METHODS: We used a case-control study design nested within a large prospective cohort to assess the association between circulating levels of anti-lipopolysaccharide (LPS) and anti-flagellin immunoglobulin A (IgA) and G (IgG) (reflecting long-term exposures to LPS and flagellin, respectively) and risk of hepatocellular carcinoma. A total of 139 men and women diagnosed with hepatocellular carcinoma between 1992 and 2010 were matched to 139 control subjects. Multivariable rate ratios (RRs), including adjustment for potential confounders, hepatitis B/C positivity, and degree of liver dysfunction, were calculated with conditional logistic regression.

    RESULTS:  = 0.021). This finding did not vary substantially by time from enrollment to diagnosis, and did not change after adjustment for chronic infection with hepatitis B and C viruses.

    CONCLUSIONS: These novel findings, based on exposures up to several years prior to diagnosis, support a role for gut-derived bacterial products in hepatocellular carcinoma development. Further study into the role of gut barrier failure and exposure to bacterial products in liver diseases is warranted.

  • 7.
    Hemmingsson, Oskar
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    ASNA1 and cisplatin resistance: studies in C. elegans and in human tumor cells2010Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Platinum based chemotherapy is widely used to treat cancer. Cisplatin (diamminedichloroplatinum) combination treatments provide cure for metastatic testicular cancer and prolong survival for patients suffering from ovarian, head and neck, bladder and non small cell lung cancer. Tumors that initially respond to treatment may eventually acquire resistance, resulting in treatment failure. Cisplatin resistant cells are crossresistant to arsenite and antimonite and these metalloids are exported from bacteria by the ars-operon.

    In this thesis, we describe the human ArsA homolog, ASNA1, as a protein involved in a novel resistance mechanism to cisplatin, arsenite and antimonite. ASNA1 was downregulated by antisense and siRNA techniques in human melanoma and ovarian carcinoma cell lines. These cells displayed increased sensitivity to arsenite and the platinum based drugs cisplatin, carboplatin and oxaliplatin. In both melanoma and ovarian carcinoma, cisplatin resistant cells overexpressed ASNA1.

    Blockage of ASNA1 resulted in increased apoptosis and retarded growth, complicating further characterization of ASNA1 in human cell lines. ASNA1 also promotes insulin signaling and mediates membrane insertion of tail-anchored proteins. To explore different aspects of ASNA1 function with respect to cisplatin resistance, we used the model organism C. elegans.

    In the nematode C. elegans, asna-1 (rnai) treated larvae were hypersensitive to cisplatin, arsenite and antimonite. Adult asna-1 mutant worms were cisplatin sensitive and this hypersensitivity was seen even when apoptosis was blocked. Expression of human ASNA1 rescued the cisplatin hypersensitivity in asna-1 mutants, showing conservation of function. Transgene expression of mutated forms of asna-1 separated the cisplatin hypersensitivity phenotype from the insulin signaling phenotype of asna-1 mutants. Three ASNA-1 residues, His164, Cys285 and Cys288 were identified as essential for ASNA-1 promoted cisplatin resistance but not for insulin signaling. Finally, studies of the C. elegans germline revealed increased numbers of apoptotic cells in asna-1 mutants.

    In conclusion, C. elegans is a suitable model organism to identify and characterize cisplatin response mechanisms. A targeted therapy against ASNA1 could sensitize cisplatin resistant cells and improve outcome for cancer patients.

  • 8.
    Hemmingsson, Oskar
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Kao, Gautam
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Still, Maria
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Naredi, Peter
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    ASNA-1 activity modulates sensitivity to cisplatin2010Ingår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 70, nr 24, s. 10321-10328Artikel i tidskrift (Refereegranskat)
    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.

  • 9.
    Hemmingsson, Oskar
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Nöjd, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Kao, Gautam
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Naredi, Peter
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Increased sensitivity to platinating agents and arsenite in human ovarian cancer by downregulation of ASNA12009Ingår i: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 22, nr 4, s. 869-875Artikel i tidskrift (Refereegranskat)
    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.

  • 10.
    Hemmingsson, Oskar
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Zhang, Youyi
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Still, Maria
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Naredi, Peter
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    ASNA1, an ATPase targeting tail-anchored proteins, regulates melanoma cell growth and sensitivity to cisplatin and arsenite2009Ingår i: Cancer Chemotherapy and Pharmacology, ISSN 0344-5704, E-ISSN 1432-0843, Vol. 63, nr 3, s. 491-499Artikel i tidskrift (Refereegranskat)
    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.

  • 11. Hughes, David J.
    et al.
    Duarte-Salles, Talita
    Hybsier, Sandra
    Trichopoulou, Antonia
    Stepien, Magdalena
    Aleksandrova, Krasimira
    Overvad, Kim
    Tjonneland, Anne
    Olsen, Anja
    Affret, Aurelie
    Fagherazzi, Guy
    Boutron-Ruault, Marie-Christine
    Katzke, Verena
    Kaaks, Rudolf
    Boeing, Heiner
    Bamia, Christina
    Lagiou, Pagona
    Peppa, Eleni
    Palli, Domenico
    Krogh, Vittorio
    Panico, Salvatore
    Tumino, Rosario
    Sacerdote, Carlotta
    Bueno-de-Mesquita, Hendrik Bastiaan
    Peeters, Petra H.
    Engeset, Dagrun
    Weiderpass, Elisabete
    Lasheras, Cristina
    Agudo, Antonio
    Sanchez, Maria-Jose
    Navarro, Carmen
    Ardanaz, Eva
    Dorronsoro, Miren
    Hemmingsson, Oskar
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Wareham, Nicholas J.
    Khaw, Kay-Tee
    Bradbury, Kathryn E.
    Cross, Amanda J.
    Gunter, Marc
    Riboli, Elio
    Romieu, Isabelle
    Schomburg, Lutz
    Jenab, Mazda
    Prediagnostic selenium status and hepatobiliary cancer risk in the European Prospective Investigation into Cancer and Nutrition cohort2016Ingår i: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 104, nr 2, s. 406-414Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Selenium status is suboptimal in many Europeans and may be a risk factor for the development of various cancers, including those of the liver and biliary tract.

    Objective: We wished to examine whether selenium status in advance of cancer onset is associated with hepatobiliary cancers in the EPIC (European Prospective Investigation into Cancer and Nutrition) study.

    Design: We assessed prediagnostic selenium status by measuring serum concentrations of selenium and selenoprotein P (SePP; the major circulating selenium transfer protein) and examined the association with hepatocellular carcinoma (HCC; n = 121), gallbladder and biliary tract cancers (GBTCs; n = 100), and intrahepatic bile duct cancer (IHBC; n = 40) risk in a nested case-control design within the EPIC study. Selenium was measured by total reflection X-ray fluorescence, and SePP was determined by a colorimetric sandwich ELISA. Multivariable ORs and 95% CIs were calculated by using conditional logistic regression.

    Results: HCC and GBTC cases, but not IHBC cases, showed significantly lower circulating selenium and SePP concentrations than their matched controls. Higher circulating selenium was associated with a significantly lower HCC risk (OR per 20-mg/L increase: 0.41; 95% CI: 0.23, 0.72) but not with the risk of GBTC or IHBC. Similarly, higher SePP concentrations were associated with lowered HCC risk only in both the categorical and continuous analyses (HCC: P-trend <= 0.0001; OR per 1.5-mg/L increase: 0.37; 95% CI: 0.21, 0.63).

    Conclusion: These findings from a large prospective cohort provide evidence that suboptimal selenium status in Europeans may be associated with an appreciably increased risk of HCC development.

  • 12.
    Kao, Gautam
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Hemmingsson, Oskar
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Chitturi, Jyothsna
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap.
    Naredi, Peter
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    ­ASNA-1 influence on apoptosis in C. elegansManuskript (preprint) (Övrigt vetenskapligt)
  • 13.
    Natarajan, Balasubramanian
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Gaur, Rahul
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Hemmingsson, Oskar
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Kao, Gautam
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Naredi, Peter
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap.
    Depletion of the ER chaperone ENPL-1 sensitizes C. elegans to the anticancer drug cisplatin2013Ingår i: Worm, ISSN 2162-4046, Vol. 2, nr 1, artikel-id e24059Artikel i tidskrift (Refereegranskat)
    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.

  • 14.
    Natarajan, Balasubramanian
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Hemmingsson, Oskar
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Kao, Gautam
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Naredi, Peter
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Unfolded protein response and enpl-1 depletion sensitize C. elegans to the anti-cancer drug cisplatinManuskript (preprint) (Övrigt vetenskapligt)
  • 15.
    Rutegård, Martin
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Hassmén, N
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap.
    Hemmingsson, Oskar
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Haapamäki, Markku M
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Matthiessen, P
    Rutegård, Jörgen
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Anterior Resection for Rectal Cancer and Visceral Blood Flow: An Explorative Study2016Ingår i: Scandinavian Journal of Surgery, ISSN 1457-4969, E-ISSN 1799-7267, Vol. 105, nr 2, s. 78-83Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND AND AIMS: Impaired blood perfusion may be implicated in anastomotic leakage after anterior resection for rectal cancer. We investigated whether high ligation of the inferior mesenteric artery or total mesorectal excision compromises visceral blood flow in the colonic limb and the rectal stump, respectively.

    MATERIAL AND METHODS: A prospective cohort study was conducted in a university hospital setting. We used Laser Doppler flowmetry to evaluate the impact of level of tie on colonic limb perfusion and the extent of the mesorectal excision on the rectal blood flow. In the rectum, different quadrants were also assessed. The Mann-Whitney U test was used to compare mean blood flow ratios between groups.

    RESULTS: Some 23 patients were recruited in a convenience sample during a period in 2012-2013. The mean blood flow ratio was not decreased after high tie compared to low tie surgery (1.71 vs 1.19; p = 0.28). Total mesorectal excision reduced the mean blood flow ratio in the rectum, as compared with partial mesorectal excision (0.76 vs 1.28; p = 0.14). This was especially pronounced in the posterior aspect of the rectum (0.66 vs 1.68; p = 0.02).

    CONCLUSION: High tie ligation did not seem to decrease colonic limb perfusion, while total mesorectal excision may decrease rectal blood flow. The posterior quadrant of the rectum might be particularly vulnerable to the dissection involved in total mesorectal excision.

  • 16.
    Rutegård, Martin
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Hemmingsson, Oskar
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Matthiessen, P.
    Rutegård, Jörgen
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    High tie in anterior resection for rectal cancer confers no increased risk of anastomotic leakage2012Ingår i: British Journal of Surgery, ISSN 0007-1323, E-ISSN 1365-2168, Vol. 99, nr 1, s. 127-132Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: It is controversial whether division of the inferior mesenteric artery close to the aorta influences the risk of anastomotic leakage, especially in the elderly and unfit. This population-based study was carried out to evaluate the independent association between a high arterial ligation and anastomotic leakage in anterior resection for rectal cancer. Methods: All patients who had anterior resection for rectal cancer from 2007 to 2009 inclusive were identified in the Swedish Colorectal Cancer Registry. The association between high tie and anastomotic leakage was evaluated in a logistic regression model, with adjustment for confounders. Stratification was performed for co-morbidity as judged by the American Society of Anesthesiologists (ASA) classification. Results: Symptomatic anastomotic leakage occurred in 81 (9.9 per cent) of 818 patients with a high tie and 108 (9.8 per cent) of 1101 without. Overall, the use of a high tie was not associated with a higher risk of anastomotic leakage (odds ratio (OR) 1.00, 95 per cent confidence interval 0.72 to 1.39). There was no increased risk in patients classifed as ASA grade I or II (OR 0.97, 0.69 to 1.35), or in those graded ASA III or IV (OR 1.26, 0.58 to 2.75). Conclusion: In the present population-based setting, use of a high tie was not associated with an increased rate of symptomatic anastomotic leakage.

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