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  • 4951.
    Zhang, Hong
    et al.
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Wang, Da-Wei
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre. Department of Stomatology, The Third Hospital of Hebei Medical University, Hebei, China.
    Adell, Gunnar
    Department of Oncology, Karolinska University Hospital, Karolinska, Sweden.
    Sun, Xiao-Feng
    Division of Oncology, Department of Clinical and Experimental Medicine, Faculty of Heath Science, Linköping University, Sweden .
    WRAP53 is an independent prognostic factor in rectal cancer- a study of Swedish clinical trial of preoperative radiotherapy in rectal cancer patients2012In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 12, p. 294-Article in journal (Refereed)
    Abstract [en]

    Background: Expression of WRAP53 protein has oncogenic properties and it is up regulated in several types of tumors. Methods: We examined expression of WRAP53 protein in rectal cancers and analyzed its relationship to the response to preoperative radiotherapy and patient survival. The WRAP53 protein was examined by immunohistochemistry in normal mucosa, primary tumors and lymph node metastases from 143 rectal cancer patients participated in a Swedish clinical trial of preoperative radiotherapy. Results: Frequency of WRAP53 protein expression was increased in primary rectal cancer compared to the normal mucosa (p < 0.05). In non-radiotherapy group positive WRAP53 in primary tumors (p = 0.03, RR, 3.73, 95% CI, 1.13-11.89) or metastases (p = 0.01, RR, 4.11, 95% CI, 1.25-13.14), was associated with poor prognosis independently of stages and differentiations. In radiotherapy group, positive WRAP53 in the metastasis correlated with better survival (p = 0.04). An interaction analysis showed that the correlations of WRAP53 with the prognostic significance with and without radiotherapy in the metastasis differed (p = 0.01). In the radiotherapy group, expression of WRAP53 in metastases gave a better outcome (p = 0.02, RR, 0.32, 95% CI, 0.13-0.84), and an interaction analysis showed significance between the two groups (p = 0.01). Conclusion: WRAP53 may be a new biomarker used to predict prognosis and to select suitable patients for preoperative radiotherapy.

  • 4952.
    Zhang, Hong
    et al.
    Örebro University, School of Medical Sciences.
    Zhu, Zhen-Long
    Department of Pathology, The First Hospital of Hebei Medical University, Shijiazhuang, China.
    Wang, Da-Wei
    Department of Stomatology, The Third Hospital of Hebei Medical University, Shijiazhuang, China.
    Yang, Yan-Hong
    Department of Pathology, The First Hospital of Hebei Medical University, Shijiazhuang, China.
    Wang, Hao
    Department of Stomatology, The Third Hospital of Hebei Medical University, Shijiazhuang, China.
    Sun, Xiao-Feng
    Division of Oncology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, University of Linköping, Linköping, Sweden.
    Upregulation of nucleoporin 88 is associated with nodal metastasis and poor differentiation in oral squamous cell carcinoma2016In: International Journal of Clinical and Experimental Medicine, ISSN 1940-5901, E-ISSN 1940-5901, Vol. 9, no 5, p. 8399-8404Article in journal (Refereed)
    Abstract [en]

    Nucleoporin 88 (Nup 88) is a component of the nuclear pore complexes (NPCs) that mediates nucleocytoplasmic trafficking of macromolecules, Nup 88 has been reported to be up-regulated in a wide variety of malignancies. Studies show that overexpression of this antigen is associated with the development, agressiveness, differentiation and prognosis in some tumours. Since no study has been carried out in the relationship between the Nup 88 expression and clinicopathological features in the patients with oral squamous cell carcinoma (OSCC), this study aimed to determine Nup 88 expression in OSCC and its clinicopathological significance. Nup 88 expression was examined by immunohistochemistry in 20 normal oral mucosa specimens and 83 OSCC tissues. The frequency of positive Nup 88 expression was gradually increased from normal oral mucosa (10%) to primary OSCC (40%, P=0.012). The Nup 88 positive rate in OSCC patient with nodal metastasis was significantly higher than those without nodal metastasis (64% vs. 21%, P=0.000085). The frequency of positive Nup 88 expression was significantly different between worse and better differentiation (80 vs. 27%, P=0.000024). Nup 88 expression was not related to the patients' gender, age, location and tumour size (P>0.05). In conclusion, Nup 88 may play an important role in tumorigenesis in oral squamous cell carcinoma. Upregulation of Nup 88 is associated with nodal metastasis and poor differentiation in oral squamous cell carcinoma.

  • 4953.
    Zhang, Jiao
    et al.
    West China Hospital, Sichuan University, Chengdu, China.
    Zhou, Bin
    IWest China Hospital, Sichuan University, Chengdu, China.
    Liu, Yinghua
    DWest China Hospital, Sichuan University, Chengdu, China.
    Chen, Keling
    West China Hospital, Sichuan University, Chengdu, China.
    Bao, Pingqian
    West China Hospital, Sichuan University, Chengdu, China.
    Wang, Yi
    West China Hospital, Sichuan University, Chengdu, China.
    Wang, Jiaxiang
    First Affiliated Hospital of Zhengzhou University, Henan, China.
    Zhou, Zongguang
    West China Hospital, Sichuan University, Chengdu, China.
    Sun, Xiao-Feng
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology. nstitute of Digestive Surgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
    Li, Yuan
    West China Hospital, Sichuan University, Chengdu, China.
    Wnt inhibitory factor-1 functions as a tumor suppressor through modulating Wnt/β-catenin signaling in neuroblastoma2014In: Cancer Letters, ISSN 0304-3835, E-ISSN 1872-7980, Vol. 348, no 1–2, p. 12-19Article in journal (Refereed)
    Abstract [en]

    Neuroblastoma is the most common extracranial solid tumor in childhood and is associated with serious morbidity and mortality. The effective treatment of neuroblastoma remains one of the major challenges in pediatric oncology. The Wnt signaling pathway has been shown to play a significant role in the pathogenesis of adult and pediatric tumors. WIF-1 has been identified as an important Wnt antagonist which inhibits Wnt/β-catenin signaling by directly binding to Wnt proteins. However, the expression and function of WIF-1 in neuroblastoma remains unknown. The present study showed that WIF-1 was downregulated with high level promoter methylation in neuroblastoma cells, and was significantly upregulated after exposure to demethylating agent. This finding suggests that downregulation of WIF-1 was associated with its promoter methylation in neuroblastoma. To further study the potential function of WIF-1 in neuroblastoma, we constructed a plasmid that over-expressed WIF-1 and transfected the plasmid into one neuroblastoma cell line SK-N-SH. We found that restoration of WIF-1 inhibited the growth and proliferation of neuroblastoma cells in vitro. Morever, Wnt/β-catenin signaling activity and target genes expression were reduced by WIF-1 restoration. These results provide support that WIF-1 is downregulated and functions as a tumor suppressor by antagonizing Wnt/β-catenin signaling in neuroblastoma, suggesting a potential role as a therapeutic target in neuroblastoma.

  • 4954.
    Zhang, Lei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Molecular Regulation of Vascular Abnormalization and Its Role in Glioma2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Glioblastoma, grade IV glioma, is the one of the deadliest cancers, with a median survival of only 12-15 months despite aggressive treatment including surgery, chemotherapy and radiation. One hallmark of glioblastoma is the morphological and functional abnormalization of tumor blood vessels. The molecular mechanisms involved in this process and their functional and pathological implications are not yet fully understood. Indentification of molecular mechanisms that underlie vascular abnormalization in GBM is necessary to develop efficient treatment regimens for normalizing vascular function.

    By analyzing the RNA-content of laser microdissected vessels from human biobank specimens using affymetrix microarray analysis, we found that the abnormal glioblastoma vessels have a distinct gene expression signature. We found 95 genes which were differentially expressed in grade IV glioma vessels as compared to vessels in low grade tumors and control brain. 78 of which were up-regulated while 17 were down-regulated. Many of these genes are regulated by VEGFA or TGFβ signaling. In addition, we show a significant increase in Smad signaling complexes in the vasculature of human glioblastoma in situ, suggesting that TGFβ signaling may play important role in vessel abnormalization.

    CD93 is a single-pass transmembrane glycoprotein, which we found to be up-regulated in high grade glioma. Vascular expression of CD93 correlates to tumor grade in human glioma. Moreover, high grade glioma patients with high CD93 expression in the vasculature are associate with poor prognosis. We found that knocking down CD93 in endothelial cells with siRNA clearly impaired endothelial cell adhesion, migration and tube formation due to defects in cytoskeletal rearrangement. In addition, tumor growth was severely delayed in the CD93-/- mice.

    Pleiotrophin, a multi-functional heparin-binding growth factor, promotes glioma growth in several ways. Here, we identify pleiotrophin as a driver of vascular abnormalization in glioma. We found that high pleiotrophin expression correlates with poor survival of patients with astrocytomas. Pleiotrophin overexpression in orthotopic GL261 gliomas increases microvessel density, enhances tumour growth and decreases survival. Vessels in pleiotrophin-expressing gliomas are poorly perfused and display a high degree of abnormality, coinciding with elevated levels of vascular endothelial growth factor (VEGF) deposited in direct proximity to the vasculature. In addition to its role in vessel abnormalization, pleiotrophin enhanced PDGF-B-induced gliomagenesis. Taken together, our results indicate that PTN has an important role in glioma initiation and establishment of the characteristic abnormal tumor vasculature in glioblastoma, identifying PTN as a potential target for therapy.

  • 4955.
    Zhang, Lei
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab. Shaanxi Normal Univ, Natl Engn Lab Resource Developing Endangered Chin, Coll Life Sci, Key Lab, Minist Educ Med Plant Resource & Nat Phar, Xian, Shaanxi, Peoples R China.
    He, Liqun
    Tianjin Med Univ Gen Hosp, Key Lab Postneuroinjury Neurorepair & Regenerat C, Tianjin Neurol Inst, Dept Neurosurg, Minist Educ & Tianjin City, Tianjin, Peoples R China.
    Lugano, Roberta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Roodakker, Kenney Roy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Bergqvist, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg. Umeå Univ Hosp, Dept Radiat Sci & Oncol, Umeå, Sweden.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    IDH mutation status is associated with distinct vascular gene expression signatures in lower-grade gliomas2018In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 20, no 11, p. 1505-1516Article in journal (Refereed)
    Abstract [en]

    Background: Vascular gene expression patterns in lower-grade gliomas (LGGs; diffuse World Health Organization [WHO] grades II–III gliomas) have not been thoroughly investigated. The aim of this study was to molecularly characterize LGG vessels and determine if tumor isocitrate dehydrogenase (IDH) mutation status affects vascular phenotype.

    Methods: Gene expression was analyzed using an in-house dataset derived from microdissected vessels and total tumor samples from human glioma in combination with expression data from 289 LGG samples available in the database of The Cancer Genome Atlas. Vascular protein expression was examined by immunohistochemistry in human brain tumor tissue microarrays (TMAs) representing WHO grades II–IV gliomas and nonmalignant brain samples. Regulation of gene expression was examined in primary endothelial cells in vitro.

    Results: Gene expression analysis of WHO grade II glioma indicated an intermediate stage of vascular abnormality, less severe than that of glioblastoma vessels but distinct from normal vessels. Enhanced expression of laminin subunit alpha 4 (LAMA4) and angiopoietin 2 (ANGPT2) in WHO grade II glioma was confirmed by staining of human TMAs. IDH wild-type LGGs displayed a specific angiogenic gene expression signature, including upregulation of ANGPT2 and serpin family H (SERPINH1), connected to enhanced endothelial cell migration and matrix remodeling. Transcription factor analysis indicated increased transforming growth factor beta (TGFβ) and hypoxia signaling in IDH wild-type LGGs. A subset of genes specifically induced in IDH wild-type LGG vessels was upregulated by stimulation of endothelial cells with TGFβ2, vascular endothelial growth factor, or cobalt chloride in vitro.

    Conclusion: IDH wild-type LGG vessels are molecularly distinct from the vasculature of IDH-mutated LGGs. TGFβ and hypoxia-related signaling pathways may be potential targets for anti-angiogenic therapy of IDH wild-type LGG.

  • 4956. Zhang, Lei
    et al.
    Kundu, Soumi
    Feenstra, Tjerk
    Li, Xiujuan
    Jin, Chuan
    Elsir, Tamador
    Ohlin, K. Elisabet
    Yu, Di
    Olofsson, Tommie
    Olsson, Anna-Karin
    Pontén, Fredrik
    Magnusson, Peetra U.
    Forsberg Nilsson, Karin
    Essand, Magnus
    Smits, Anja
    Dieterich, Lothar C.
    Dimberg, Anna
    Pleiotrophin promotes vascular abnormalization in glioma and correlates withpoor survival in human astrocytomasArticle in journal (Other academic)
  • 4957.
    Zhang, Lei
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Laaniste, Liisi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab. Imperial Coll, Fac Med, Div Brain Sci, London, England..
    Jiang, Yiwen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Mol Biochem & Biophys, Solna, Sweden..
    Alafuzoff, Irina
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Uhrbom, Lene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pleiotrophin enhances PDGFB-induced gliomagenesis through increased proliferation of neural progenitor cells2016In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 49, p. 80382-80390Article in journal (Refereed)
    Abstract [en]

    Pleiotrophin (PTN) augments tumor growth by increasing proliferation of tumor cells and promoting vascular abnormalization, but its role in early gliomagenesis has not been evaluated. Through analysis of publically available datasets, we demonstrate that increased PTN mRNA expression is associated with amplification of chromosome 7, identified as one of the earliest steps in glioblastoma development. To elucidate the role of PTN in tumor initiation we employed the RCAS/tv-a model that allows glioma induction by RCAS-virus mediated expression of oncogenes in neural progenitor cells. Intracranial injection of RCAS-PTN did not induce glioma formation when administrated alone, but significantly enhanced RCAS-platelet derived growth factor (PDGF) B-induced gliomagenesis. PTN co-treatment augmented PDGFBinduced Akt activation in neural progenitor cells in vitro, and enhanced neural sphere size associated with increased proliferation. Our data indicates that PTN expression is associated with chromosome 7 gain, and that PTN enhances PDGFB-induced gliomagenesis by stimulating proliferation of neural progenitor cells.

  • 4958. Zhang, Lei
    et al.
    Laaniste, Liisi
    Jiang, Yiwen
    Uhrbom, Lene
    Dimberg, Anna
    Pleiotrophin enhances PDGF-B-induced gliomagenesis and promotesangiogenesis in high-grade tumors in mouse experimental gliomaManuscript (preprint) (Other academic)
  • 4959. Zhang, Mingfeng
    et al.
    Wang, Zhaoming
    Obazee, Ofure
    Jia, Jinping
    Childs, Erica J.
    Hoskins, Jason
    Figlioli, Gisella
    Mocci, Evelina
    Collins, Irene
    Chung, Charles C.
    Hautman, Christopher
    Arslan, Alan A.
    Beane-Freeman, Laura
    Bracci, Paige M.
    Buring, Julie
    Duell, Eric J.
    Gallinger, Steven
    Giles, Graham G.
    Goodman, Gary E.
    Goodman, Phyllis J.
    Kamineni, Aruna
    Kolonel, Laurence N.
    Kulke, Matthew H.
    Malats, Nuria
    Olson, Sara H.
    Sesso, Howard D.
    Visvanathan, Kala
    White, Emily
    Zheng, Wei
    Abnet, Christian C.
    Albanes, Demetrius
    Andreotti, Gabriella
    Brais, Lauren
    Bueno-de-Mesquita, H. Bas
    Basso, Daniela
    Berndt, Sonja I.
    Boutron-Ruault, Marie-Christine
    Bijlsma, Maarten F.
    Brenner, Hermann
    Burdette, Laurie
    Campa, Daniele
    Caporaso, Neil E.
    Capurso, Gabriele
    Cavestro, Giulia Martina
    Cotterchio, Michelle
    Costello, Eithne
    Elena, Joanne
    Boggi, Ugo
    Gaziano, J. Michael
    Gazouli, Maria
    Giovannucci, Edward L.
    Goggins, Michael
    Gross, Myron
    Haiman, Christopher A.
    Hassan, Manal
    Helzlsouer, Kathy J.
    Hu, Nan
    Hunter, David J.
    Iskierka-Jazdzewska, Elzbieta
    Jenab, Mazda
    Kaaks, Rudolf
    Key, Timothy J.
    Khaw, Kay-Tee
    Klein, Eric A.
    Kogevinas, Manolis
    Krogh, Vittorio
    Kupcinskas, Juozas
    Kurtz, Robert C.
    Landi, Maria T.
    Landi, Stefano
    Le Marchand, Loic
    Mambrini, Andrea
    Mannisto, Satu
    Milne, Roger L.
    Neale, Rachel E.
    Oberg, Ann L.
    Panico, Salvatore
    Patel, Alpa V.
    Peeters, Petra H. M.
    Peters, Ulrike
    Pezzilli, Raffaele
    Porta, Miquel
    Purdue, Mark
    Ramon Quiros, J.
    Riboli, Elio
    Rothman, Nathaniel
    Scarpa, Aldo
    Scelo, Ghislaine
    Shu, Xiao-Ou
    Silverman, Debra T.
    Soucek, Pavel
    Strobel, Oliver
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Malecka-Panas, Ewa
    Taylor, Philip R.
    Tavano, Francesca
    Travis, Ruth C.
    Thornquist, Mark
    Tjonneland, Anne
    Tobias, Geoffrey S.
    Trichopoulos, Dimitrios
    Vashist, Yogesh
    Vodicka, Pavel
    Wactawski-Wende, Jean
    Wentzensen, Nicolas
    Yu, Herbert
    Yu, Kai
    Zeleniuch-Jacquotte, Anne
    Kooperberg, Charles
    Risch, Harvey A.
    Jacobs, Eric J.
    Li, Donghui
    Fuchs, Charles
    Hoover, Robert
    Hartge, Patricia
    Chanock, Stephen J.
    Petersen, Gloria M.
    Stolzenberg-Solomon, Rachael S.
    Wolpin, Brian M.
    Kraft, Peter
    Klein, Alison P.
    Canzian, Federico
    Amundadottir, Laufey T.
    Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.212016In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 41, p. 66328-66343Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies (GWAS) have identified common pancreatic cancer susceptibility variants at 13 chromosomal loci in individuals of European descent. To identify new susceptibility variants, we performed imputation based on 1000 Genomes (1000G) Project data and association analysis using 5,107 case and 8,845 control subjects from 27 cohort and case-control studies that participated in the PanScan I-III GWAS. This analysis, in combination with a two-staged replication in an additional 6,076 case and 7,555 control subjects from the PANcreatic Disease ReseArch (PANDoRA) and Pancreatic Cancer Case-Control (PanC4) Consortia uncovered 3 new pancreatic cancer risk signals marked by single nucleotide polymorphisms (SNPs) rs2816938 at chromosome 1q32.1 (per allele odds ratio (OR) = 1.20, P = 4.88x10(-15)), rs10094872 at 8q24.21 (OR = 1.15, P = 3.22x10(-9)) and rs35226131 at 5p15.33 (OR = 0.71, P = 1.70x10(-8)). These SNPs represent independent risk variants at previously identified pancreatic cancer risk loci on chr1q32.1 (NR5A2), chr8q24.21 (MYC) and chr5p15.33 (CLPTM1L-TERT) as per analyses conditioned on previously reported susceptibility variants. We assessed expression of candidate genes at the three risk loci in histologically normal (n = 10) and tumor (n = 8) derived pancreatic tissue samples and observed a marked reduction of NR5A2 expression (chr1q32.1) in the tumors (fold change -7.6, P = 5.7x10(-8)). This finding was validated in a second set of paired (n = 20) histologically normal and tumor derived pancreatic tissue samples (average fold change for three NR5A2 isoforms -31.3 to -95.7, P = 7.5x10(-4)-2.0x10(-3)). Our study has identified new susceptibility variants independently conferring pancreatic cancer risk that merit functional follow-up to identify target genes and explain the underlying biology.

  • 4960.
    Zhang, Ming-Ran
    et al.
    Sichuan University, Peoples R China; Sichuan University, Peoples R China; Sichuan University, Peoples R China.
    Xie, Tian-Hang
    Sichuan University, Peoples R China.
    Chi, Jun-Lin
    Sichuan University, Peoples R China.
    Li, Yuan
    Sichuan University, Peoples R China.
    Yang, Lie
    Sichuan University, Peoples R China.
    Yu, Yong-Yang
    Sichuan University, Peoples R China.
    Sun, Xiao-Feng
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology. Sichuan University, Peoples R China.
    Zhou, Zong-Guang
    Sichuan University, Peoples R China.
    Prognostic role of the lymph node ratio in node positive colorectal cancer: a meta-analysis2016In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 45, p. 72898-72907Article in journal (Refereed)
    Abstract [en]

    The lymph node ratio (LNR) (i. e. the number of metastatic lymph nodes divided by the number of totally resected lymph nodes) has recently emerged as an important prognostic factor in colorectal cancer (CRC). However, the tumor node metastasis (TNM) staging system for colorectal cancer does not consider it as a prognostic parameter. Therefore, we conducted a meta-analysis to evaluate the prognostic role of the LNR in node positive CRC. A systematic search was performed in PubMed, Embase and the Cochrane Library for relevant studies up to November 2015. As a result, a total of 75,838 node positive patients in 33 studies were included in this meta-analysis. Higher LNR was significantly associated with shorter overall survival (OS) (HR = 1.91; 95% CI 1.71-2.14; P = 0.0000) and disease free survival (DFS) (HR = 2.75; 95% CI: 2.14-3.53; P = 0.0000). Subgroup analysis showed similar results. Based on these results, LNR was an independent predictor of survival in colorectal cancer patients and should be considered as a parameter in future oncologic staging systems.

  • 4961. Zhang, Xiangwei
    et al.
    Wang, Yang
    Li, Cheng
    Helmersson, Jing
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Jiang, Yuanzhu
    Ma, Guoyuan
    Wang, Guanghui
    Dong, Wei
    Sang, Shaowei
    Du, Jiajun
    The prognostic value of tumor length to resectable esophageal squamous cell carcinoma: a retrospective study2017In: PeerJ, ISSN 2167-8359, E-ISSN 2167-8359, Vol. 5, article id e2943Article in journal (Refereed)
    Abstract [en]

    Background: The current TNM classification system does not consider tumor length for patients with esophageal carcinoma (EC). This study explored the effect of tumor length, in addition to tumor depth and lymph node involvement, on survival in patients with esophageal squamous cell carcinoma (ESCC).

    Methods: A total of 498 ESCC patients who underwent surgical resection as the primary treatment were selected in the retrospective study. Pathological details were collected, which included tumor type, TNM stage, differentiation. Other collected information were: the types of esophageal resection, ABO blood group, family history and demographic and lifestyle factors. A time-dependent receiver operating characteristic (ROC) curve and a regression tree for survival were used to identify the cut-off point of tumor length, which was 3 cm. Univariate and multivariate Cox proportional hazard regression models were used to identify the prognostic factors to ESCC.

    Results & Discussion: The 1-, 3-, 5-year overall survival rates were found to be 82.5%, 55.6%, and 35.1%, respectively. Patients who had larger tumor length (>3 cm) had a higher risk for death than the rest patients. From the univariate Cox proportional hazards regression model, the overall survival rate was significantly influenced by the depth of the tumor and lymph node involvement (either as dummy or continuous variables), Sex, and tumor length. Using these four variables in the multivariate Cox proportional hazard regression model, we found that the overall survival was significantly influenced by all variables except Sex. Therefore, in addition to the depth of the tumor and lymph node involvement (as either dummy or continuous variables), the tumor length is also an independent prognostic factor for ESCC. The overall survival rate was higher in a group with smaller tumor length (≤3 cm) than those patients with larger tumor length (>3 cm), no matter what the tumor stage was.

    Conclusion: The tumor length was found to be an important prognostic factor for ESCC patients without receiving neoadjuvant therapy. The modification of EC staging system may consider tumor length to better predict ESCC survival and identify higher risk patients for postoperative therapy.

  • 4962. Zhang, Xiangwei
    et al.
    Wang, Yang
    Qu, Pengfei
    Liu-Helmersson, Jing
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Zhao, Linping
    Zhang, Lin
    Sang, Shaowei
    The Prognostic Value of Tumor Length for Cause-Specific Mortality in Resectable Esophageal Cancer.2018In: Annals of Thoracic Surgery, ISSN 0003-4975, E-ISSN 1552-6259, Vol. 106, no 4, p. 1038-1046Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The current esophageal cancer AJCC-TNM staging system may not capture the full prognostic implications of the primary tumor. A study is needed to explore the prognostic value of tumor size on esophageal cancer-specific mortality.

    METHODS: Patients who underwent surgical resection for non-metastatic esophageal cancer were selected from the Surveillance, Epidemiology and End Results Program database (United States, 1988 - 2014). Using statistics methods - maximally selected rank and two hazard models (Cox model and Fine-Gray model) - the optimum cutoff point for tumor length in each T classification was estimated and the prognostic value of tumor size on esophageal cancer-specific mortality was analyzed.

    RESULTS: 4,447 patients were identified. The median tumor size was significantly correlated with T classification, with the correlation coefficient of 0.43 (p < 0.001). Patients in the T1-T3 classifications who had larger tumor size showed a larger probability of cancer-specific mortality. The multivariate Cox model showed that tumor size was significantly associated with an increase in cancer-specific mortality in T1 (2.15, 95% CI [1.72, 2.69]) and T2 (1.31, 95% CI [1.06, 1.62]), but marginally significantly in T3 (1.12, 95% CI [1.00, 1.27]) and insignificantly in T4 classification (p > 0.1). Similar results were found using the multivariate Fine-Gray model.

    CONCLUSIONS: We have found that combining T classification with tumor size can increase the precision in identifying the high-risk groups in T1-T2 classification. Based on esophageal cancer-specific mortality our study is the first to explore the prognostic cutoff point of tumor size by T classification.

  • 4963.
    Zhang, Xueli
    et al.
    Orebro Univ, Sweden; Soochow Univ, Peoples R China.
    Sun, Xiao-Feng
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Shen, Bairong
    Soochow Univ, Peoples R China.
    Zhang, Hong
    Orebro Univ, Sweden.
    Potential Applications of DNA, RNA and Protein Biomarkers in Diagnosis, Therapy and Prognosis for Colorectal Cancer: A Study from Databases to AI-Assisted Verification2019In: Cancers, ISSN 2072-6694, Vol. 11, no 2, article id 172Article in journal (Refereed)
    Abstract [en]

    In order to find out the most valuable biomarkers and pathways for diagnosis, therapy and prognosis in colorectal cancer (CRC) we have collected the published CRC biomarkers and established a CRC biomarker database (CBD: http://sysbio.suda.edu.cn/CBD/index.html). In this study, we analysed the single and multiple DNA, RNA and protein biomarkers as well as their positions in cancer related pathways and protein-protein interaction (PPI) networks to describe their potential applications in diagnosis, therapy and prognosis. CRC biomarkers were collected from the CBD. The RNA and protein biomarkers were matched to their corresponding DNAs by the miRDB database and the PubMed Gene database, respectively. The PPI networks were used to investigate the relationships between protein biomarkers and further detect the multiple biomarkers. The Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment analysis and Gene Ontology (GO) annotation were used to analyse biological functions of the biomarkers. AI classification techniques were utilized to further verify the significances of the multiple biomarkers in diagnosis and prognosis for CRC. We showed that a large number of the DNA, RNA and protein biomarkers were associated with the diagnosis, therapy and prognosis in various degrees in the CRC biomarker networks. The CRC biomarkers were closely related to the CRC initiation and progression. Moreover, the biomarkers played critical roles in cellular proliferation, apoptosis and angiogenesis and they were involved in Ras, p53 and PI3K pathways. There were overlaps among the DNA, RNA and protein biomarkers. AI classification verifications showed that the combined multiple protein biomarkers played important roles to accurate early diagnosis and predict outcome for CRC. There were several single and multiple CRC protein biomarkers which were associated with diagnosis, therapy and prognosis in CRC. Further, AI-assisted analysis revealed that multiple biomarkers had potential applications for diagnosis and prognosis in CRC.

  • 4964.
    Zhang, Yanyu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Platelets – Multifaceted players in tumor progression and vascular function2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Platelets play a crucial role for blood hemostasis, the process that prevents bleeding. In addition, platelets have been demonstrated to promote cancer progression and cancer related complications like metastasis and thrombosis. Platelets can affect cancer related diseases either directly or by interacting with other blood cells or molecules in the circulation of individuals with cancer. The current thesis addresses the role of platelets in tumor progression and tumor-induced systemic effects of cancer, with a special focus on the effects on the vasculature.

    In the first paper, the role of platelets in tumor progression in histidine-rich glycoprotein (HRG)-deficient mice was addressed. We report that HRG-deficient mice show enhanced tumor growth, epithelial to mesenchymal transition (EMT) and metastasis. The enhanced platelet activity in the absence of HRG is responsible for the accelerated tumor progression.

    In the second paper, we demonstrate that platelet-derived PDGFB is a central player to keep the tumor vessels functional. Moreover, in a pancreatic neuroendocrine carcinoma model with PDGFB-deficient platelets, spontaneous liver metastasis was enhanced. With this finding we identify a previously unknown role of platelet derived PDGFB.

    In the third paper, we found that TBK1 mediates platelet-induced EMT by activation of NF-kB signaling, which suggest that TBK1 contributes to tumor invasiveness in mammary epithelial tumors.

    In the last paper, we report that the vascular function in organs that are neither affected by the primary tumor, nor represent metastatic sites, is impaired in mice with cancer. We show that tumor-induced formation of intravascular neutrophil extracellular traps (NETs), a fibril matrix consisting of neutrophils with externalized DNA and histones, granule proteases and platelets, are responsible for the impaired peripheral vessel function.

  • 4965.
    Zhang, Yanyu
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Valsala Madhavan Unnithan, Ragaseema
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Caja, Laia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Saupe, Falk
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Siegbahn, Agneta
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Moustakas, Aristidis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Cedervall, Jessica
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    TBK1, an NF-κB activating kinase, is required for platelet-induced EMTManuscript (preprint) (Other academic)
    Abstract [en]

    Platelets can promote several steps during the metastatic process, and hence

    contribute to malignant progression. During early stages of metastasis, platelets

    promote invasive properties of tumor cells by induction of epithelial to mesenchymal transition (EMT). In this study we show that TANK binding kinase-1 (TBK1) is a previously unknown mediator of platelet-induced EMT - a finding that suggests a possible role of TBK1 as a potential driver of metastatic disease. Using the two mammary epithelial cell lines Ep5 and MCF10A (M2), we show that co-culture with isolated platelets induced morphological as well as molecular features indicative of EMT, and that this is paralleled with activation of TBK1. Inhibiting TBK1 using siRNA suppressed platelet induced EMT in both Ep5 and MCF10A (M2) cells. Furthermore, platelet induced NF-κB signaling was suppressed after TBK1 knock down, suggesting that TBK1 is a crucial mediator of platelet-induced NF-κB signaling and subsequent EMT. Altogether, these results suggest that TBK1 contribute to tumor invasiveness and may hence be a driver of metastatic spread in mammary epithelial tumors.

  • 4966.
    Zhang, Yanyu
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Valsala Madhavan Unnithan, Ragaseema
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Govt Arts Coll, Thiruvananthapuram, Kerala, India.
    Hamidi, Anahita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Caja, Laia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Saupe, Falk
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Moustakas, Aristidis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Cedervall, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    TANK-binding kinase 1 is a mediator of platelet-induced EMT in mammary carcinoma cells2019In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 33, no 7, p. 7822-7832Article in journal (Refereed)
    Abstract [en]

    Platelets can promote several stages of the metastatic process and thus contribute to malignant progression. As an example, platelets promote invasive properties of tumor cells by induction of epithelial to mesenchymal transition (EMT). In this study, we show that tumor necrosis factor receptor-associated factor (TRAF) family member-associated NF-kappa B activator (TANK)-binding kinase 1 (TBK1) is a previously unknown mediator of platelet-induced EMT in mammary carcinoma cells. Coculture of 2 mammary carcinoma cell lines, Ep5 from mice and MCF10A(MII) from humans, with isolated platelets induced morphologic as well as molecular changes characteristic of EMT, which was paralleled with activation of TBK1. TBK1 depletion using small interfering RNA impaired platelet-induced EMT in both Ep5 and MCF10A(MII) cells. Furthermore, platelet-induced activation of the NF-kappa B subunit p65 was suppressed after TBK1 knockdown, demonstrating that TBK1 mediates platelet-induced NF-kappa B signaling and EMT. Using an in vivo metastasis assay, we found that depletion of TBK1 from mammary carcinoma cells during in vitro preconditioning with platelets subsequently suppressed the formation of lung metastases in mice. Altogether, these results suggest that TBK1 contributes to tumor invasiveness and may be a driver of metastatic spread in breast cancer.-Zhang, Y., Unnithan, R. V. M., Hamidi, A., Caja, L., Saupe, F., Moustakas, A., Cedervall, J., Olsson, A.-K. TANK-binding kinase 1 is a mediator of platelet-induced EMT in mammary carcinoma cells.

  • 4967.
    Zhang, Yi
    et al.
    Capital Med Univ, Beijing Hosp Tradit Chinese Med, Dept Oncol, 23 Back Rd Art Gallery, Beijing 100010, Peoples R China..
    Sun, Xu
    Capital Med Univ, Beijing Hosp Tradit Chinese Med, Dept Oncol, 23 Back Rd Art Gallery, Beijing 100010, Peoples R China..
    Nan, Nan
    Capital Med Univ, Beijing Hosp Tradit Chinese Med, Dept Oncol, 23 Back Rd Art Gallery, Beijing 100010, Peoples R China..
    Cao, Ke-Xin
    Capital Med Univ, Beijing Hosp Tradit Chinese Med, Dept Oncol, 23 Back Rd Art Gallery, Beijing 100010, Peoples R China..
    Ma, Cong
    Capital Med Univ, Beijing Hosp Tradit Chinese Med, Dept Oncol, 23 Back Rd Art Gallery, Beijing 100010, Peoples R China..
    Yang, Guo-Wang
    Capital Med Univ, Beijing Hosp Tradit Chinese Med, Dept Oncol, 23 Back Rd Art Gallery, Beijing 100010, Peoples R China..
    Yu, Ming-Wei
    Capital Med Univ, Beijing Hosp Tradit Chinese Med, Dept Oncol, 23 Back Rd Art Gallery, Beijing 100010, Peoples R China..
    Yang, Lin
    Capital Med Univ, Beijing Hosp Tradit Chinese Med, Dept Oncol, 23 Back Rd Art Gallery, Beijing 100010, Peoples R China..
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Capital Med Univ, Beijing Hosp Tradit Chinese Med, Dept Oncol, 23 Back Rd Art Gallery, Beijing 100010, Peoples R China.
    Wang, Xiao-Min
    Capital Med Univ, Beijing Hosp Tradit Chinese Med, Dept Oncol, 23 Back Rd Art Gallery, Beijing 100010, Peoples R China..
    Zhang, Gan-Lin
    Capital Med Univ, Beijing Hosp Tradit Chinese Med, Dept Oncol, 23 Back Rd Art Gallery, Beijing 100010, Peoples R China..
    Elemene inhibits the migration and invasion of 4T1 murine breast cancer cells via heparanase2017In: Molecular Medicine Reports, ISSN 1791-2997, E-ISSN 1791-3004, Vol. 16, no 1, p. 794-800Article in journal (Refereed)
    Abstract [en]

    Elemene (ELE), a natural plant drug extracted from Curcumae Rhizoma, has been widely used for cancer treatment in China for more than 20 years. Although it is reported to be a broad-spectrum anticancer drug, the mechanism underlying the action of ELE in the treatment of breast cancer remains to be fully elucidated. Heparanase, a mammalian endo-D-glucuronidase, is involved in degradation of the extracellular matrix (ECM), and thus promotes tumor progression and metastasis. The downregulation of heparanase can effectively reduce tumor malignant behaviors. In the present study, the inhibitory effects of ELE were evaluated in breast cancer cells using a Cell Counting kit 8 assay. The migratory and invasive capabilities of cancer cells were investigated using a wound healing assay, real-time cell analysis and a Transwell assay. In addition, western blot analysis was used to assess alterations in the expression levels of key proteins. The present results confirmed the antiproliferative and antimetastatic effects of ELE, using low-molecular weight heparin (LMWH) as a positive control. In addition, ELE was demonstrated to downregulate the expression of heparanase, and decrease the phosphorylation of extracellular signal-regulated kinase and AKT. These findings suggested that ELE may be a promising agent targeting heparanase in the treatment of breast cancer.

  • 4968.
    Zhao, Qinghai
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Targeting to EGF receptors: Preparation and experimental analysis of end-end coupled mEGF-dextran conjugates1998Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Targeted tumor therapy is to deliver cytotoxic agents selectively to tumor cells. By such delivery, normal tissues receive minimal damage while a therapeutical effect is achieved in tumor. A targetingsystem can be constructed by conjugating a tumor-seeking molecule and toxic agents via a carrier. In this thesis, mouse epidermal growth factor, mEGF, was the tumor-seeking molecule for targeting against malignancies that overexpress EGF receptors. Dextran was attached to mEGF by different methods and used as a carrier. Preparation of different mEGF-dextran conjugates, effects of different conjugation methods on cellular intenalization and the biodistribution of the conjugates in vivo were studied in the planning for future clinic trials.

    Two end-end coupling methods have been developed in this thesis. One is direct reductive amination by which the terminal amino group of mEGF reacts with the aldehyde group on rhe reducting end of dextran. The other end-end coupling methods is glutaraldehyde mediated cross-linking, in which a few glutaraldehyde molecules act as a linker between the amino terminus of mEGF and the end-aminated dextran.

    The end-end coupled mEGF-dextran conjugates were investigated together with a randomly coupled mEGF-dextran conjugate, for cellular binding ptterns using cultured glioma cells. The time for maximal binding and the intracellular retention of the conjugates were analysed. The intracellular radioactivity associated with free mEGF had a fast turnover whereas all three conjugates gave long half-lives for the intracellular retention.

    The end-end coupled mEGF-dextran, type A prepared by reductive amination, had a dissociation constant of 7.1 x 10-9 M and free mEGF had a value of 6.6 x 10-10 M. The end-end coupled intermediate was further activated by the cyanopyridinium agent CDAP and tyrosines were introduced to the dextran part of the conjugate. The iodinated conjugate could to a large extent be internalized in test cells and the radioactivity was retained intracellularly better than when the radioactivity only was on the mEGF part of the conjugate.

    Dextranated mEGF had a slower clearance in blood and liver than mEGF as seen in positron emission tomography on rats. Dextranated mEGF also had a lower uptake in kidney than free mEGF. There was an "unknown mEGF complex" in the blood circulation which was formed after mEGF was injected but this complex did not appear in urine samples.

  • 4969.
    Zhao, Senlin
    et al.
    Shanghai Jiao Tong University, Peoples R China.
    Sun, Hongcheng
    Shanghai Jiao Tong University, Peoples R China.
    Jiang, Weiliang
    Shanghai Jiao Tong University, Peoples R China.
    Mi, Yushuai
    Shanghai Jiao Tong University, Peoples R China.
    Zhang, Dongyuan
    Shanghai Jiao Tong University, Peoples R China.
    Wen, Yugang
    Shanghai Jiao Tong University, Peoples R China.
    Cheng, Dantong
    Shanghai Jiao Tong University, Peoples R China.
    Tang, Huamei
    Shanghai Jiao Tong University, Peoples R China.
    Wu, Shaohan
    Jiaxing Coll, Peoples R China.
    Yu, Yang
    Shanghai Jiao Tong University, Peoples R China.
    Liu, Xisheng
    Shanghai Jiao Tong University, Peoples R China.
    Cui, Weiyingqi
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Zhang, Meng
    Fudan University, Peoples R China.
    Sun, Xiao-Feng
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Zhou, Zongguang
    Sichuan University, Peoples R China.
    Peng, Zhihai
    Shanghai Jiao Tong University, Peoples R China.
    Yan, Dongwang
    Shanghai Jiao Tong University, Peoples R China.
    miR-4775 promotes colorectal cancer invasion and metastasis via the Smad7/TGF beta-mediated epithelial to mesenchymal transition2017In: Molecular Cancer, ISSN 1476-4598, E-ISSN 1476-4598, Vol. 16, article id 12Article in journal (Refereed)
    Abstract [en]

    Background: Despite advancements in the diagnosis and treatment of colorectal cancer (CRC), many patients die because of tumor metastasis or recurrence. Therefore, identifying new prognostic markers and elucidating the mechanisms of CRC metastasis and recurrence will help to improve the prognosis of the disease. As dysregulation of microRNAs is strongly related to cancer progression, the aim of this study was to identify the role of miR-4775 in the prognosis of CRC patients and the underling mechanisms involved in CRC progression. Methods: qPCR and in situ hybridization were used to evaluate the expression of miR-4775 in 544 pairs of paraffin-embedded normal and CRC tissues. Kaplan-Meier analysis with the log-rank test was used for survival analyses. Immunohistochemical staining was applied to investigate the expression of miR-4775-regulated Smad7/TGF beta pathway-associated markers. In vitro and in vivo invasion and metastasis assays were used to explore the function of miR-4775 in the progression of CRC. Results: miR-4775 was identified as a high-risk factor for CRC metastasis and recurrence, with high levels predicting poor survival among the 544 studied CRC patients. Furthermore, high miR-4775 expression promoted the invasion of CRC cells as well as metastasis and the epithelial to mesenchymal transition (EMT) via Smad7-mediated activation of TGF beta signaling both in vitro and in vivo. Downregulating miR-4775 or overexpressing Smad7 reversed the tumor-promoting roles of miR-4775/ Smad7/TGF beta in vitro and in vivo. Conclusion: miR-4775 promotes CRC metastasis and recurrence in a Smad7/TGF beta signaling-dependent manner, providing a new therapeutic target for inhibiting the metastasis or recurrence of the disease.

  • 4970.
    Zheng, Daoshan
    et al.
    Mayo Clin, Dept Canc Biol, 4500 San Pablo Rd,Griffin 210, Jacksonville, FL 32224 USA..
    Trynda, Justyna
    Mayo Clin, Dept Canc Biol, 4500 San Pablo Rd,Griffin 210, Jacksonville, FL 32224 USA..
    Williams, Cecilia
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Vold, Jeremy A.
    Mayo Clin, Mayo Canc Registry, 4500 San Pablo Rd, Jacksonville, FL 32224 USA..
    Nguyen, Justin H.
    Mayo Clin, Dept Surg, 4500 San Pablo Rd, Jacksonville, FL 32224 USA.;Mayo Clin, Ctr Canc, 4500 San Pablo Rd, Jacksonville, FL 32224 USA..
    Harnois, Denise M.
    Mayo Clin, Dept Surg, 4500 San Pablo Rd, Jacksonville, FL 32224 USA.;Mayo Clin, Ctr Canc, 4500 San Pablo Rd, Jacksonville, FL 32224 USA..
    Bagaria, Sanjay P.
    Mayo Clin, Dept Surg, 4500 San Pablo Rd, Jacksonville, FL 32224 USA.;Mayo Clin, Ctr Canc, 4500 San Pablo Rd, Jacksonville, FL 32224 USA..
    McLaughlin, Sarah A.
    Mayo Clin, Dept Surg, 4500 San Pablo Rd, Jacksonville, FL 32224 USA.;Mayo Clin, Ctr Canc, 4500 San Pablo Rd, Jacksonville, FL 32224 USA..
    Li, Zhaoyu
    Mayo Clin, Dept Canc Biol, 4500 San Pablo Rd,Griffin 210, Jacksonville, FL 32224 USA..
    Sexual dimorphism in the incidence of human cancers2019In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 19, no 1, article id 684Article in journal (Refereed)
    Abstract [en]

    BackgroundSex differences in the incidences of cancers become a critical issue in both cancer research and the development of precision medicine. However, details in these differences have not been well reported. We provide a comprehensive analysis of sexual dimorphism in human cancers.MethodsWe analyzed four sets of cancer incidence data from the SEER (USA, 1975-2015), from the Cancer Registry at Mayo Clinic (1970-2015), from Sweden (1970-2015), and from the World Cancer Report in 2012.ResultsWe found that all human cancers had statistically significant sexual dimorphism with male dominance in the United States and mostly significant in the Mayo Clinic, Sweden, and the world data, except for thyroid cancer, which is female-dominant.ConclusionsSexual dimorphism is a clear but mostly neglected phenotype for most human cancers regarding the clinical practice of cancer. We expect that our study will facilitate the mechanistic studies of sexual dimorphism in human cancers. We believe that fully addressing the mechanisms of sexual dimorphism in human cancers will greatly benefit current development of individualized precision medicine beginning from the sex-specific diagnosis, prognosis, and treatment.

  • 4971.
    Zheng, Daoshan
    et al.
    Dept Canc Biol, 4500 San Pablo Rd, Jacksonville, FL 32224 USA..
    Williams, Cecilia
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Cellular and Clinical Proteomics. KTH, Centres, Science for Life Laboratory, SciLifeLab. Karolinska Institute.
    Vold, Jeremy A.
    Mayo Canc Registry, 4500 San Pablo Rd, Jacksonville, FL 32224 USA..
    Nguyen, Justin H.
    Mayo Clin, Dept Surg, 4500 San Pablo Rd, Jacksonville, FL 32224 USA.;Mayo Clin, Mayo Clin Canc Ctr, 4500 San Pablo Rd, Jacksonville, FL 32224 USA..
    Harnois, Denise M.
    Mayo Clin, Dept Surg, 4500 San Pablo Rd, Jacksonville, FL 32224 USA.;Mayo Clin, Mayo Clin Canc Ctr, 4500 San Pablo Rd, Jacksonville, FL 32224 USA..
    Bagaria, Sanjay P.
    Mayo Clin, Dept Surg, 4500 San Pablo Rd, Jacksonville, FL 32224 USA.;Mayo Clin, Mayo Clin Canc Ctr, 4500 San Pablo Rd, Jacksonville, FL 32224 USA..
    McLaughlin, Sarah A.
    Mayo Clin, Dept Surg, 4500 San Pablo Rd, Jacksonville, FL 32224 USA.;Mayo Clin, Mayo Clin Canc Ctr, 4500 San Pablo Rd, Jacksonville, FL 32224 USA..
    Li, Zhaoyu
    Dept Canc Biol, 4500 San Pablo Rd, Jacksonville, FL 32224 USA..
    Regulation of sex hormone receptors in sexual dimorphism of human cancers2018In: Cancer Letters, ISSN 0304-3835, E-ISSN 1872-7980, Vol. 438, p. 24-31Article, review/survey (Refereed)
    Abstract [en]

    Gender differences in the incidences of cancers have been found in almost all human cancers. However, the mechanisms that underlie gender disparities in most human cancer types have been under-investigated. Here, we provide a comprehensive overview of potential mechanisms underlying sexual dimorphism of each cancer regarding sex hormone signaling. Fully addressing the mechanisms of sexual dimorphism in human cancers will greatly benefit current development of precision medicine. Our discussions of potential mechanisms underlying sexual dimorphism in each cancer will be instructive for future cancer research on gender disparities.

  • 4972. Zheng, Jiaojiao
    et al.
    Rutegård, Martin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Santoni, Giola
    Wallner, Bengt
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology, School of Dentistry.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Xie, Shao-Hua
    Lagergren, Jesper
    Prediabetes and diabetes in relation to risk of gastric adenocarcinoma2019In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 120, no 12, p. 1147-1152Article in journal (Refereed)
    Abstract [en]

    Background: Whether prediabetes or diabetes increases the risk of gastric adenocarcinoma is not clear.

    Methods: This cohort study included 111,198 participants in the Northern Swedish Health and Disease Study. The participants were followed up from November 1985 to April 2017. The exposure to prediabetes or diabetes was assessed by oral glucose tolerance tests and self-reports. The incidence of the outcome gastric adenocarcinoma was identified from the Swedish Cancer Registry. Multivariable Cox regressions were used to analyse the associations between prediabetes or diabetes and the risk of gastric adenocarcinoma, providing hazard ratios (HR) with 95% confidence intervals (CI), with adjustment for sex, age, calendar year, body mass index, tobacco smoking and education level.

    Results: Compared with normoglycaemic participants, the risk of gastric adenocarcinoma was not increased among participants with prediabetes (HR 1.07, 95% CI 0.79–1.44), diabetes (HR 0.77, 95% CI 0.46–1.29) or any of these exposures (HR 0.96, 95% CI 0.73–1.27). No associations were identified between prediabetes or diabetes and the risk of gastric adenocarcinoma in stratified analyses or in analyses separating cardia and non-cardia gastric adenocarcinoma.

    Conclusions: This study does not support the hypothesis that prediabetes or diabetes increases the risk of gastric adenocarcinoma.

  • 4973. Zheng, S. Lilly
    et al.
    Stevens, Victoria L.
    Wiklund, Fredrik
    Isaacs, Sarah D.
    Sun, Jielin
    Smith, Shelly
    Pruett, Kristen
    Wiley, Kathleen E.
    Kim, Seong-Tae
    Zhu, Yi
    Zhang, Zheng
    Hsu, Fang-Chi
    Turner, Aubrey R.
    Johansson, Jan-Erik
    Örebro University, School of Health and Medical Sciences.
    Liu, Wennuan
    Kim, Jin Woo
    Chang, Bao-Li
    Duggan, David
    Carpten, John
    Rodriguez, Carmen
    Isaacs, William
    Grönberg, Henrik
    Xu, Jianfeng
    Two independent prostate cancer risk-associated Loci at 11q132009In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 18, no 6, p. 1815-1820Article in journal (Refereed)
    Abstract [en]

    Single nucleotide polymorphisms (SNP) at 11q13 were recently implicated in prostate cancer risk by two genome-wide association studies and were consistently replicated in multiple study populations. To explore prostate cancer association in the regions flanking these SNPs, we genotyped 31 tagging SNPs in a approximately 110 kb region at 11q13 in a Swedish case-control study (Cancer of the Prostate in Sweden), including 2,899 cases and 1,722 controls. We found evidence of prostate cancer association for the previously implicated SNPs including rs10896449, which we termed locus 1. In addition, multiple SNPs on the centromeric side of the region, including rs12418451, were also significantly associated with prostate cancer risk (termed locus 2). The two groups of SNPs were separated by a recombination hotspot. We then evaluated these two representative SNPs in an additional approximately 4,000 cases and approximately 3,000 controls from three study populations and confirmed both loci at 11q13. In the combined allelic test of all four populations, P = 4.0 x 10(-11) for rs10896449 at locus 1 and P = 1.2 x 10(-6) for rs12418451 at locus 2, and both remained significant after adjusting for the other locus and study population. The prostate cancer association at these two 11q13 loci was unlikely confounded by prostate-specific antigen (PSA) detection bias because neither SNP was associated with PSA levels in controls. Unlike locus 1, in which no known gene is located, several putative mRNAs are in close proximity to locus 2. Additional confirmation studies at locus 2 and functional studies for both loci are needed to advance our knowledge on the etiology of prostate cancer.

  • 4974. Zheng, S. Lilly
    et al.
    Sun, Jielin
    Wiklund, Fredrik
    Gao, Zhengrong
    Stattin, Pär
    Purcell, Lina D.
    Adami, Hans-Olov
    Hsu, Fang-Chi
    Zhu, Yi
    Adolfsson, Jan
    Johansson, Jan-Erik
    Örebro University, School of Health and Medical Sciences.
    Turner, Aubrey R.
    Adams, Tamara S.
    Liu, Wennuan
    Duggan, David
    Carpten, John D.
    Chang, Bao-Li
    Isaacs, William B.
    Xu, Jianfeng
    Grönberg, Henrik
    Genetic variants and family history predict prostate cancer similar to prostate-specific antigen2009In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 15, no 3, p. 1105-1111Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Although prostate-specific antigen (PSA) is the best biomarker for predicting prostate cancer, its predictive performance needs to be improved. Results from the Prostate Cancer Prevention Trial revealed the overall performance measured by the areas under curve of the receiver operating characteristic at 0.68. The goal of the present study is to assess the ability of genetic variants as a PSA-independent method to predict prostate cancer risk. EXPERIMENTAL DESIGN: We systematically evaluated all prostate cancer risk variants that were identified from genome-wide association studies during the past year in a large population-based prostate cancer case-control study population in Sweden, including 2,893 prostate cancer patients and 1,781 men without prostate cancer. RESULTS: Twelve single nucleotide polymorphisms were independently associated with prostate cancer risk in this Swedish study population. Using a cutoff of any 11 risk alleles or family history, the sensitivity and specificity for predicting prostate cancer were 0.25 and 0.86, respectively. The overall predictive performance of prostate cancer using genetic variants, family history, and age, measured by areas under curve was 0.65 (95% confidence interval, 0.63-0.66), significantly improved over that of family history and age (0.61%; 95% confidence interval, 0.59-0.62; P = 2.3 x 10(-10)). CONCLUSION: The predictive performance for prostate cancer using genetic variants and family history is similar to that of PSA. The utility of genetic testing, alone and in combination with PSA levels, should be evaluated in large studies such as the European Randomized Study for Prostate Cancer trial and Prostate Cancer Prevention Trial.

  • 4975.
    Zhou, Wenjing
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Aspects of Progression in Breast Carcinoma: from ductal carcinoma in situ to invasive cancer2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In the past decades our knowledge concerning breast cancer progression from ductal carcinoma in situ (DCIS) to invasive cancer has grown rapidly. However, molecular factors driving the progression are still largely unknown.

    In the first study, we investigated tumor evolution in breast cancer by analyzing TP53 mutation status in tumors from various stages of the disease. Presence of the same TP53 mutations in both DCIS and invasive components from the same tumor indicates same cellular origin. The role of mutant TP53 in the progression of breast cancer is less clear and may vary between subtypes.

    In the second study, we studied the prognosis of basal-like DCIS in a large population-based cohort. Basal-like DCIS was associated with about doubled but not statistically significant risk for local recurrence compared with the other molecular subtypes. Molecular subtype was a better prognostic parameter than histopathological grade.

    In the third study, we studied markers in primary DCIS in relation to type of recurrence. Interestingly, recurrences after an ER-/HER2+, ER negative or EGFR positive primary DCIS were more often of the in situ type. The molecular subtype ER+/HER2+, FOXA1 positivity and FOXC1 positivity were risk factors for any recurrence.

    In the fourth study, we proposed a histological classification system for a new entity: neoductgenesis. We also evaluated histologic criteria for neoductgenesis. According to our criteria, good agreements among pathologists were achieved. Neoductgenesis was related to more aggressive tumor biology and to mammographic features. The result indicates potential benefits for women earlier considered having pure DCIS but later diagnosed as breast carcinoma with neoductgenesis, suggesting a need to develop appropriate treatment regiments. Our findings have to be repeated and the relation to prognosis warrants further studies.

  • 4976.
    Zhou, Wenjing
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Johansson, Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Jirström, Karin
    Department of Clinical Sciences, Pathology, Lund University.
    Ringberg, Anita
    Department of Plastic and Reconstructive Surgery, Malmö Hospital.
    Blomqvist, Carl
    Department of Oncology, Helsinki University Central Hospital.
    Amini, Rose Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Fjällskog, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Wärnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Tumor Markers Predicting Type of Recurrence after a Primary Ductal Carcinoma In Situ2012In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542XArticle in journal (Other academic)
    Abstract [en]

    Introduction:

    About half of all recurrences after a primary ductal carcinoma in situ (DCIS) are invasive. The determinants for type of recurrence, in situ or invasive, are not known. We studied markers in primary DCIS in relation to type of recurrence.

    Methods:

    Two hundred and sixty six primary DCIS with a known recurrence were included. One hundred were from a population based cohort with 458 women diagnosed 1986-2004 in Uppland/Västmanland region, Sweden, and all 166 women with a recurrence from the randomized nationwide SweDCIS Trial (1987-1999). The 358 women without a recurrence were used as a reference group. TMA-blocks were constructed and estrogen receptor- (ER), progesterone receptor- (PR), HER2, EGFR, cytokeratin 5/6, Ki67, FOXA1, FOXC1, GATA-3 and CD10 status were evaluated in the primary tumors. Logistic regression was used to calculate odd ratios and 95% confidence intervals in univariate and multivariate analyses (adjusted for age, free margin, surgical method and molecular subtype).

    Results:

    One hundred and thirty of the recurrences were in situ and 136 invasive. In multivariate analyses, a recurrence was more often invasive if the primary was ER positive (OR 2.5, CI 95 1.2 – 5.1). Primaries being HER2 positive (OR 0.5, CI 95 0.3-0.9), EGFR positive (OR 0.4, CI 95 0.2-0.9) and ER-/HER2+ (OR 0.2, CI 95 0.1-0.6) had a lower risk of the recurrence being invasive. Primaries of the molecular subtype ER+/HER2+ had higher risk of any recurrence (OR 1.9, CI 95 1.1-3.4) as did primaries expressing FOXA1 (OR 3.1, CI 95 1.5-6.2) and FOXC1 (OR 2.9, CI 95 1.7-5.0).

    Conclusions:

    Surprisingly, recurrences after an ER-/HER2+, ER negative or EGFR positive primary DCIS were more often of the in situ type. The molecular subtype ER+/HER2+, FOXA1 positivity and FOXC1 positivity were risk factors for any recurrence.

  • 4977.
    Zhou, Wenjing
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Sollie, Thomas
    Univ Örebro, Dept Pathol, Örebro, Sweden..
    Tot, Tibor
    Falun Cent Hosp, Dept Pathol, Falun, Sweden..
    Blomqvist, Carl
    Univ Helsinki, Cent Hosp, Dept Oncol, Helsinki, Finland..
    Abdsaleh, Shahin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Liljegren, Göran
    Univ Örebro, Dept Surg, Örebro, Sweden..
    Wärnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Ductal Breast Carcinoma In Situ: Mammographic Features and Its Relation to Prognosis and Tumour Biology in a Population Based Cohort2017In: International Journal of Breast Cancer, ISSN 2090-3170, E-ISSN 2090-3189, article id 4351319Article in journal (Refereed)
    Abstract [en]

    Casting-type calcifications and a histopathological picture with cancer-filled duct-like structures have been presented as breast cancer with neoductgenesis. We correlated mammographic features and histopathological neoductgenesis with prognosis in a DCIS cohort with long follow-up. Mammographic features were classified into seven groups according to Tabar. Histopathological neoductgenesis was defined by concentration of ducts, lymphocyte infiltration, and periductal fibrosis. Endpoints were ipsilateral (IBE) in situ and invasive events. Casting-type calcifications and neoductgenesis were both related to high nuclear grade, ER-and PR-negativity, and HER2 overexpression but not to each other. Casting-type calcifications and neoductgenesis were both related to a nonsignificant lower risk of invasive IBE, HR 0.38 (0.13-1.08) and 0.82 (0.29-2.27), respectively, and the HR of an in situ IBE was 0.90 (0.41-1.95) and 1.60 (0.75-3.39), respectively. Casting-type calcifications could not be related to a worse prognosis in DCIS. We cannot explain why a more aggressive phenotype of DCIS did not correspond to a worse prognosis. Further studies on how the progression from in situ to invasive carcinoma is driven are needed.

  • 4978.
    Zhou, Wenjing
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Tot, Tibor
    Department of Pathology, Falun Central Hospital.
    Tabár, László
    Department of Mammography, Falun Central Hospital.
    Pinder, Sarah
    Department of Pathology, King´s College, London.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Blomqvist, Carl
    Department of Oncology, Helsinki University Central Hospital.
    Fjällskog, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science.
    Gunilla, Christensson
    Department of Surgery, Falun Central Hospital.
    Abdsaleh, Shahin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science.
    Sollie, Thomas
    Department of Pathology, Örebro University.
    Wärnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Breast carcinoma with neoductgenesis: a new subgroup of breast cancerManuscript (preprint) (Other academic)
    Abstract [en]

    Background: A new subgroup of breast cancer has been proposed: breast carcinoma with neoductgenesis. Cases presenting with casting type calcifications on the mammogram, histologically high grade DCIS with an abnormal number of ducts, periductal desmoplastic reaction and lymphocyte infiltration has been suggested to represent a more aggressive form of breast cancer. Treatment decision based on traditional histopathology showing DCIS might be challenged if neoductgenesis is diagnosed. We evaluated a histological classification system proposed for neoductgenesis and studied tumor biology in cases with and without neoductgenesis.

     

    Material and Method: Seventy-four tumors with DCIS grade 2-3, with or without an invasive component, were blocked in TMAs. A classification system based on a pathological evaluation and Tenascin-C (Tn-C) expression was used to categorize tumors as showing neoductgenesis or not. Immunohistochemical staining for known tumor markers and correlation with mammographic features was performed. Logistic regression model was use to evaluate the correlation between breast carcinoma with neoductgenesis and molecular- and mammographic features.

     

    Results: Four pathologists could categorize cases as “possible neoductgenesis” with an overall correlation of 72% and a kappa value of 0.44. Adding Tn-C staining resulted in a group with neoductgenesis (n=37) and one without (n=31). Neoductgenesis correlated significantly with mammographic casting- and crushed stone microcalcifications and estrogen receptor status (p-values 0.04 and 0.03, respectively). High nuclear grade, HER2 positivity, progesterone receptor negativity and high proliferation were also more often seen in the group with neoductgenesis, but this was not statistically significant (0.10, 0.07, 0.20 and 0.29).

     

    Discussion: We developed reproducible histologic criteria for a new entity: breast carcinoma with neoductgenesis. The system seemed to be useful in receiving reproducibility between pathologists making the diagnosis. Neoductgenesis was related to more aggressive tumor biology and to the mammographic features. Our findings have to be repeated and the relation to prognosis further studied. However, we can already predict a potential benefit for women earlier considered having a pure DCIS but now diagnosed as breast carcinoma with neoductgenesis and a need to develop appropriate treatment regiments.

  • 4979.
    Zhu, Jianwei
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Fang, Fang
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Sjölander, Arvid
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Fall, Katja
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Adami, Hans Olov
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, USA; Clinical Effectiveness Research Group, Institute of Health and Society, University of Oslo, Oslo, Norway .
    Valdimarsdottir, Unnur Anna
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, USA; Center of Public Health Sciences, School of Health Sciences, Faculty of Medicine, University of Iceland, Reykjavík, Iceland.
    First-onset mental disorders after cancer diagnosis and cancer-specific mortality: a nationwide cohort study2017In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 28, no 8, p. 1964-1969Article in journal (Refereed)
    Abstract [en]

    Background: The diagnosis of cancer is strongly associated with the risk of mental disorders even in patients with no previous history of mental disorders. Accumulating data suggest that mental distress may accelerate tumor progression. We hypothesized therefore that mental disorders after a cancer diagnosis may increase the risk of cancer-specific mortality.

    Patients and methods: We conducted a nationwide cohort study including 244 261 cancer patients diagnosed in Sweden during 2004-2009 and followed them through 2010. Through the Swedish Patient Register, we obtained clinical diagnoses of all mental disorders and focused on mood-, anxiety-, and substance abuse disorders (ICD10: F10-F16, F18-F19, F32-F33, F40-F41, and F43-45) that are commonly diagnosed among patients with cancer. We further classified the studied mental disorders into first-onset or recurrent mental disorders. We used Cox regression to estimate multivariable hazard ratios (HRs) with 95% confidence intervals (CIs) as a measure of the association between mental disorders after cancer diagnosis and cancer-specific mortality, adjusting for age, sex, calendar period, educational level, cancer stage, and cancer type at diagnosis.

    Results: After cancer diagnosis, 11 457 patients were diagnosed with mood-, anxiety-, and substance abuse disorders; of which 7236 were first-onset mental disorders. Patients with a first-onset mental disorder were at increased risk of cancer-specific mortality (HR: 1.82, 95% CI: 1.71-1.92) while patients with a recurrent mental disorder had much lower risk elevation (HR: 1.14, 95% CI: 1.05-1.24). The increased cancer-specific mortality by first-onset mental disorders was observed for almost all cancer sites/groups and the association was stronger for localized cancers (HR: 2.00, 95% CI: 1.73-2.31) than for advanced cancers (HR: 1.49, 95% CI: 1.32-1.69).

    Conclusions: Patients with a first-onset common mood-, anxiety-, or substance abuse disorder after cancer diagnosis may be at increased risk of cancer-specific death.

  • 4980.
    Zhu, Jianwei
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Orthopedics, Shandong Provincial Hospital, Shandong University, Jinan, China.
    Lu, Donghao
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Sveinsson, Olafur
    Department of Neurology, Karolinska University Hospital, Stockholm, Sweden.
    Wirdefeldt, Karin
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Fall, Katja
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Piehl, Fredrik
    Department of Neurology, Karolinska University Hospital, Stockholm, Sweden.
    Valdimarsdóttir, Unnur
    Center of Public Health, University of Iceland, Reykjavík, Iceland.
    Fang, Fang
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Is a cancer diagnosis associated with subsequent risk of transient global amnesia?2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 4, article id e0122960Article in journal (Refereed)
    Abstract [en]

    Background: Psychological stress has been associated with transient global amnesia (TGA). Whether a cancer diagnosis, a severely stressful life event, is associated with subsequent risk of TGA has not been studied.

    Methods: Based on the Swedish Cancer Register and Patient Register, we conducted a prospective cohort study including 5,365,608 Swedes at age 30 and above during 2001-2009 to examine the relative risk of TGA among cancer patients, as compared to cancer-free individuals. Incidence rate ratios (IRRs) and their 95% confidence intervals (CIs) derived from Poisson regression were used as estimates of the association between cancer diagnosis and the risk of TGA.

    Results: During the study 322,558 individuals (6.01%) received a first diagnosis of cancer. We identified 210 cases of TGA among the cancer patients (incidence rate, 0.22 per 1000 person-years) and 4,887 TGA cases among the cancer-free individuals (incidence rate, 0.12 per 1000 person-years). Overall, after adjustment for age, sex, calendar year, socioeconomic status, education and civil status, cancer patients had no increased risk of TGA than the cancer-free individuals (IRR, 0.99; 95% CI, 0.86-1.13). The IRRs did not differ over time since cancer diagnosis or across individual cancer types. The null association was neither modified by sex, calendar period or age.

    Conclusion: Our study did not provide support for the hypothesis that patients with a new diagnosis of cancer display a higher risk of TGA than cancer-free individuals.

  • 4981.
    Zhu, Jianwei
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Sjölander, Arvid
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Fall, Katja
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Valdimarsdottir, Unnur
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston MA, USA; Faculty of Medicine, Center of Public Health Sciences, School of Health Sciences, University of Iceland, Reykjavík, Iceland.
    Fall, Katja
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Mental disorders around cancer diagnosis and increased hospital admission rate: a nationwide cohort study of Swedish cancer patients2018In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 18, no 1, article id 322Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Whether the emotional distress around cancer diagnosis is associated with the long-term outcomes and care utilization is unknown. We aimed to examine the association of mental disorders around cancer diagnosis with the hospital admission rates of cancer patients thereafter.

    METHODS: We conducted a nationwide cohort study including 218,508 cancer patients diagnosed in Sweden during 2004-2009 and followed them from 90 days after cancer through 2010. We used a clinical diagnosis of stress-related mental disorders from 90 days before to 90 days after cancer diagnosis as the exposure. We studied first all hospital admissions and then separately three common admissions, including external injuries, infections, and cardiovascular diseases. The Cox model was used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs).

    RESULTS: Four thousand one hundred five patients received a diagnosis of stress-related mental disorders around the cancer diagnosis, and experienced a 35% increased rate of any hospital admission during follow-up (HR: 1.35, 95%CI: 1.28-1.41) as well as hospital admissions for external injuries (HR: 1.89, 95%CI: 1.67-2.14), infections (HR: 1.28, 95%CI: 1.08-1.52), and cardiovascular diseases (HR: 1.16, 95%CI: 1.03-1.30). Similar association was noted for most common cancer types.

    CONCLUSIONS: These data suggest that cancer patients diagnosed with a stress-related mental disorder immediately before or after cancer diagnosis are subsequently at increased risk of hospital admissions for major comorbidities of cancer.

  • 4982.
    Zhu, Yanping
    et al.
    Binzhou Med Univ, Precis Med Res Ctr, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China.
    Qi, Xiaoying
    Binzhou Med Univ, Precis Med Res Ctr, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China.
    Yu, Cuicui
    Qing Dao Univ, Affiliated Yantai Yuhuangding Hosp, Dept Anesthesiol, 20 Yudong Rd, Yantai S264009, Shandong, Peoples R China.
    Yu, Shoujun
    Binzhou Med Univ, Yantai Affiliated Hosp, Dept Ultrasound, 717 Jinfu Rd, Binzhou 264100, Shandong, Peoples R China.
    Zhang, Chao
    Binzhou Med Univ, Precis Med Res Ctr, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China.
    Zhang, Yuan
    Binzhou Med Univ, Precis Med Res Ctr, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China.
    Liu, Xiuxiu
    Binzhou Med Univ, Precis Med Res Ctr, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China.
    Xu, Yuxue
    Binzhou Med Univ, Precis Med Res Ctr, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China.
    Yang, Chunhua
    Binzhou Med Univ, Precis Med Res Ctr, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China.
    Jiang, Wenguo
    Binzhou Med Univ, Precis Med Res Ctr, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China.
    Tian, Geng
    Binzhou Med Univ, Precis Med Res Ctr, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China.
    Li, Xuri
    Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, State Key Lab Ophthalmol, Guangzhou 510060, Guangdong, Peoples R China.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Binzhou Med Univ, Precis Med Res Ctr, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China.
    Zhang, Jiandi
    Binzhou Med Univ, Precis Med Res Ctr, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China;Yantai Zestern Biotech Co LTD, 39 Keji Ave Bioasis, Yantai, Peoples R China.
    Wang, Lei
    Harbin Med Univ, Affiliated Hosp 1, Dept Thorac Surg, 23 Youzheng St, Harbin 150000, Heilongjiang, Peoples R China.
    Mi, Jia
    Binzhou Med Univ, Precis Med Res Ctr, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China.
    Identification of prothymosin alpha (PTMA) as a biomarker for esophageal squamous cell carcinoma (ESCC) by label-free quantitative proteomics and Quantitative Dot Blot (QDB)2019In: Clinical Proteomics, ISSN 1542-6416, E-ISSN 1559-0275, Vol. 16, article id 12Article in journal (Refereed)
    Abstract [en]

    Background: Esophageal cancer (EC) is one of the malignant tumors with a poor prognosis. The early stage of EC is asymptomatic, so identification of cancer biomarkers is important for early detection and clinical practice.

    Methods: In this study, we compared the protein expression profiles in esophageal squamous cell carcinoma (ESCC) tissues and adjacent normal esophageal tissues from five patients through high-resolution label-free mass spectrometry. Through bioinformatics analysis, we found the differentially expressed proteins of ESCC. To perform the rapid identification of biomarkers, we adopted a high-throughput protein identification technique of Quantitative Dot Blot (QDB). Meanwhile, the QDB results were verified by classical immunohistochemistry.

    Results: In total 2297 proteins were identified, out of which 308 proteins were differentially expressed between ESCC tissues and normal tissues. By bioinformatics analysis, the four up-regulated proteins (PTMA, PAK2, PPP1CA, HMGB2) and the five down-regulated proteins (Caveolin, Integrin beta-1, Collagen alpha-2(VI), Leiomodin-1 and Vinculin) were selected and validated in ESCC by Western Blot. Furthermore, we performed the QDB and IHC analysis in 64 patients and 117 patients, respectively. The PTMA expression was up-regulated gradually along the progression of ESCC, and the PTMA expression ratio between tumor and adjacent normal tissue was significantly increased along with the progression. Therefore, we suggest that PTMA might be a potential candidate biomarker for ESCC.

    Conclusion: In this study, label-free quantitative proteomics combined with QDB revealed that PTMA expression was up-regulated in ESCC tissues, and PTMA might be a potential candidate for ESCC. Since Western Blot cannot achieve rapid and high-throughput screening of mass spectrometry results, the emergence of QDB meets this demand and provides an effective method for the identification of biomarkers.

  • 4983. Zhu, Ying
    et al.
    Wei, Yongyue
    Zhang, Ruyang
    Dong, Xuesi
    Shen, Sipeng
    Zhao, Yang
    Bai, Jianling
    Albanes, Demetrius
    Caporaso, Neil E.
    Landi, Maria Teresa
    Zhu, Bin
    Chanock, Stephen J.
    Gu, Fangyi
    Lam, Stephen
    Tsao, Ming-Sound
    Shepherd, Frances A.
    Tardon, Adonina
    Fernandez-Somoano, Ana
    Fernandez-Tardon, Guillermo
    Chen, Chu
    Barnett, Matthew J.
    Doherty, Jennifer
    Bojesen, Stig E.
    Johansson, Mattias
    Brennan, Paul
    Mckay, James D.
    Carreras-Torres, Robert
    Muley, Thomas
    Risch, Angela
    Wichmann, Heunz-Erich
    Bickeboeller, Heike
    Rosenberger, Albert
    Rennert, Gad
    Saliba, Walid
    Arnold, Susanne M.
    Field, John K.
    Davies, Michael P. A.
    Marcus, Michael W.
    Wu, Xifeng
    Ye, Yuanqing
    Le Marchand, Loic
    Wilkens, Lynne R.
    Melander, Olle
    Manjer, Jonas
    Brunnstrom, Hans
    Hung, Rayjean J.
    Liu, Geoffrey
    Brhane, Yonathan
    Kachuri, Linda
    Andrew, Angeline S.
    Duell, Eric J.
    Kiemeney, Lambertus A.
    van der Heijden, Erik H. F. M.
    Haugen, Aage
    Zienolddiny, Shanbeh
    Skaug, Vidar
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Woll, Penella J.
    Cox, Angela
    Taylor, Fiona
    Teare, Dawn M.
    Lazarus, Philip
    Schabath, Matthew B.
    Aldrich, Melinda C.
    Houlston, Richard S.
    McLaughlin, John
    Stevens, Victoria L.
    Shen, Hongbing
    Hu, Zhibin
    Dai, Juncheng
    Amos, Christopher I.
    Han, Younghun
    Zhu, Dakai
    Goodman, Gary E.
    Chen, Feng
    Christiani, David C.
    Elevated Platelet Count Appears to Be Causally Associated with Increased Risk of Lung Cancer: A Mendelian Randomization Analysis2019In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 28, no 5, p. 935-942Article in journal (Refereed)
    Abstract [en]

    Background: Platelets are a critical element in coagulation and inflammation, and activated platelets are linked to cancer risk through diverse mechanisms. However, a causal relationship between platelets and risk of lung cancer remains unclear. Methods: We performed single and combined multiple instrumental variable Mendelian randomization analysis by an inverse-weighted method, in addition to a series of sensitivity analyses. Summary data for associations between SNPs and platelet count are from a recent publication that included 48,666 Caucasian Europeans, and the International Lung Cancer Consortium and Transdisciplinary Research in Cancer of the Lung data consisting of 29,266 cases and 56,450 controls to analyze associations between candidate SNPs and lung cancer risk. Results: Multiple instrumental variable analysis incorporating six SNPs showed a 62% increased risk of overall nonsmall cell lung cancer [NSCLC; OR, 1.62; 95% confidence interval (CI), 1.15-2.27; P = 0.005] and a 200% increased risk for small-cell lung cancer (OR, 3.00; 95% CI, 1.27-7.06; P = 0.01). Results showed only a trending association with NSCLC histologic subtypes, which may be due to insufficient sample size and/or weak effect size. A series of sensitivity analysis retained these findings. Conclusions: Our findings suggest a causal relationship between elevated platelet count and increased risk of lung cancer and provide evidence of possible antiplatelet interventions for lung cancer prevention. Impact: These findings provide a better understanding of lung cancer etiology and potential evidence for antiplatelet interventions for lung cancer prevention.

  • 4984. Zhukova, Nataliya
    et al.
    Ramaswamy, Vijay
    Remke, Marc
    Martin, Dianna C
    Castelo-Branco, Pedro
    Zhang, Cindy H
    Fraser, Michael
    Tse, Ken
    Poon, Raymond
    Shih, David J H
    Baskin, Berivan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ray, Peter N
    Bouffet, Eric
    Dirks, Peter
    von Bueren, Andre O
    Pfaff, Elke
    Korshunov, Andrey
    Jones, David T W
    Northcott, Paul A
    Kool, Marcel
    Pugh, Trevor J
    Pomeroy, Scott L
    Cho, Yoon-Jae
    Pietsch, Torsten
    Gessi, Marco
    Rutkowski, Stefan
    Bognar, Laszlo
    Cho, Byung-Kyu
    Eberhart, Charles G
    Conter, Cecile Faure
    Fouladi, Maryam
    French, Pim J
    Grajkowska, Wieslawa A
    Gupta, Nalin
    Hauser, Peter
    Jabado, Nada
    Vasiljevic, Alexandre
    Jung, Shin
    Kim, Seung-Ki
    Klekner, Almos
    Kumabe, Toshihiro
    Lach, Boleslaw
    Leonard, Jeffrey R
    Liau, Linda M
    Massimi, Luca
    Pollack, Ian F
    Ra, Young Shin
    Rubin, Joshua B
    Van Meir, Erwin G
    Wang, Kyu-Chang
    Weiss, William A
    Zitterbart, Karel
    Bristow, Robert G
    Alman, Benjamin
    Hawkins, Cynthia E
    Malkin, David
    Clifford, Steven C
    Pfister, Stefan M
    Taylor, Michael D
    Tabori, Uri
    WNT activation by lithium abrogates TP53 mutation associated radiation resistance in medulloblastoma2014In: Acta neuropathologica communications, ISSN 2051-5960, Vol. 2, article id 174Article in journal (Refereed)
    Abstract [en]

    TP53 mutations confer subgroup specific poor survival for children with medulloblastoma. We hypothesized that WNT activation which is associated with improved survival for such children abrogates TP53 related radioresistance and can be used to sensitize TP53 mutant tumors for radiation. We examined the subgroup-specific role of TP53 mutations in a cohort of 314 patients treated with radiation. TP53 wild-type or mutant human medulloblastoma cell-lines and normal neural stem cells were used to test radioresistance of TP53 mutations and the radiosensitizing effect of WNT activation on tumors and the developing brain. Children with WNT/TP53 mutant medulloblastoma had higher 5-year survival than those with SHH/TP53 mutant tumours (100% and 36.6%±8.7%, respectively (p<0.001)). Introduction of TP53 mutation into medulloblastoma cells induced radioresistance (survival fractions at 2Gy (SF2) of 89%±2% vs. 57.4%±1.8% (p<0.01)). In contrast, beta-catenin mutation sensitized TP53 mutant cells to radiation (p<0.05). Lithium, an activator of the WNT pathway, sensitized TP53 mutant medulloblastoma to radiation (SF2 of 43.5%±1.5% in lithium treated cells vs. 56.6±3% (p<0.01)) accompanied by increased number of gammaH2AX foci. Normal neural stem cells were protected from lithium induced radiation damage (SF2 of 33%±8% for lithium treated cells vs. 27%±3% for untreated controls (p=0.05). Poor survival of patients with TP53 mutant medulloblastoma may be related to radiation resistance. Since constitutive activation of the WNT pathway by lithium sensitizes TP53 mutant medulloblastoma cells and protect normal neural stem cells from radiation, this oral drug may represent an attractive novel therapy for high-risk medulloblastomas.

  • 4985.
    Zieba, Agata
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Application of Proximity Ligation Assay for Multidirectional Studies on Transforming Growth Factor-β Pathway2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    A comprehensive understanding of how the body and all its components function is essential when this knowledge is exploited for medical purposes. The achievements in biological and medical research during last decades has provided us with the complete human genome and identified signaling pathways that governs the cellular processes that facilitates the development and maintenance of higher order organisms. This has brought about the realization that diseases such as cancer is a consequence of genomic aberrations that effects these signaling pathways, endowing cancer cells with the capacity to circumvent homeostasis by acquiring features like self-sustained proliferation and insensitivity to apoptosis. The increased understanding of biology and medicine has been made possible by the development of advanced methods to carry out biological and clinical analyses. The demands of a method often differ regarding in what context it will be applied. It may be acceptable for method to be laborious and time consuming if it is used in basic research, but for medical purposes molecular methods need to be fast and straightforward to perform. Innovative technologies should preferentially address the demands of both researchers and clinicians and provide data not possible to obtain by other methods. An example of such a method is the in situ proximity ligation assay (in situ PLA). In this thesis I have used this method to determine the activity status, at the single-cell level, of the transforming growth factor-β (TGF-β) signaling pathway and activating protein-1 (AP-1) family of transcription factors.  Both of these pathways are frequently involved in cancer development and progression. In addition to this research I herein also present further modifications of in situ PLA, and analyses thereof, to increase the utility and resolution of this assay.

  • 4986.
    Zirakzadeh, A. Ali
    et al.
    Karolinska Inst, Unit Immunol & Allergy, Dept Med, Stockholm, Sweden.
    Kinn, Johan
    Karolinska Inst, Unit Immunol & Allergy, Dept Med, Stockholm, Sweden.
    Krantz, David
    Karolinska Inst, Unit Immunol & Allergy, Dept Med, Stockholm, Sweden.
    Rosenblatt, Robert
    Umeå Univ Hosp, Dept Surg & Perioperat Sci Urol & Androl, Umeå, Sweden; Karolinska Inst, Stockholm South Gen Hosp, Dept Urol, Stockholm, Sweden.
    Winerdal, Malin E.
    Karolinska Inst, Unit Immunol & Allergy, Dept Med, Stockholm, Sweden.
    Hu, Jin
    Karolinska Inst, Unit Immunol & Allergy, Dept Med, Stockholm, Sweden.
    Hartana, Ciputra Adijaya
    Karolinska Inst, Unit Immunol & Allergy, Dept Med, Stockholm, Sweden.
    Lundgren, Christian
    Karolinska Inst, Unit Immunol & Allergy, Dept Med, Stockholm, Sweden.
    Bergman, Emma Ahlén
    Karolinska Inst, Unit Immunol & Allergy, Dept Med, Stockholm, Sweden.
    Johansson, Markus
    Sundsvall Hosp, Dept Urol, Sundsvall, Sweden.
    Holmström, Benny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Hansson, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg.
    Sidikii, Alexander
    Länssjukhuset Ryhov, Dept Urol, Region Jonköping, Sweden.
    Vasko, Janos
    Umeå Univ, Dept Med Biosci, Pathol, Umeå, Sweden.
    Marits, Per
    Karolinska Inst, Unit Immunol & Allergy, Dept Med, Stockholm, Sweden.
    Sherif, Amir
    Umeå Univ Hosp, Dept Surg & Perioperat Sci Urol & Androl, Umeå, Sweden.
    Winqvist, Ola
    Karolinska Inst, Unit Immunol & Allergy, Dept Med, Stockholm, Sweden.
    Doxorubicin enhances the capacity of B cells to activate T cells in urothelial urinary bladder cancer2017In: Clinical Immunology, ISSN 1521-6616, E-ISSN 1521-7035, Vol. 176, p. 63-70Article in journal (Refereed)
    Abstract [en]

    Cancer is currently treated by a combination of therapies, including chemotherapy which is believed to suppress the immune system. Combination of immunotherapy and chemotherapy correlates with improved survival but needs careful planning in order to achieve a synergistic effect. In this study, we have demonstrated that doxorubicin treatment of B cells resulted in increased expression of CD86 and concordantly increased CD4(+) T cell activation in the presence of superantigen, an effect that was inhibited by the addition of a CD86 blocking antibody. Furthermore, doxorubicin resulted in decreased expression of the anti-inflammatory cytokines IL-10 and TNF-alpha. Finally, B cells from urinary bladder cancer patients, treated with a neoadjuvant regiment containing doxorubicin, displayed increased CD86-expression. We conclude that doxorubicin induces CD86 expression on B cells and hence enhances their antigen-presenting ability in vitro, a finding verified in patients. Development of tailored time and dose schedules may increase the effectiveness of combining chemotherapy and immunotherapy.

  • 4987. Zirakzadeh, A. Ali
    et al.
    Marits, Per
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Winqvist, Ola
    Multiplex B Cell Characterization in Blood, Lymph Nodes, and Tumors from Patients with Malignancies2013In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 190, no 11, p. 5847-5855Article in journal (Refereed)
    Abstract [en]

    B lymphocytes contribute to immune surveillance, by tumor-specific Abs and Ag presentation to T lymphocytes, but are insufficiently studied in humans. In this article, we report a flow cytometric investigation of B lymphocyte subpopulations in blood, lymph nodes (LNs), and malignant tissues from 20 patients operated on because of advanced solid tumors. The CD19(+) compartment in peripheral blood was essentially unaltered in patients, as compared with healthy control subjects. In metastatic LNs, signs of B lymphocyte activation were observed, as evidenced by increased proportions of plasmablasts and CD86-expressing cells. In tumor-infiltrating B lymphocytes (TIL-B), both switched memory cells and plasmablasts were expanded, as compared with nonmalignant epithelium. Moreover, pronounced skewing of Ig lambda/Ig kappa ratio was evident among TIL-Bs. By spectratype analysis on IgH, we confirmed a monoclonal expansion of the Vh7 family in TIL-B, also present in a tumor-associated LN. Sequencing the clonally expanded Vh7 revealed signs of somatic hypermutation. In conclusion, B lymphocytes in cancer patients exhibit signs of activation in tumor-associated tissues, likely induced by recognition of tumor Ags. Increased numbers of switched memory cells and plasmablasts in combination with clonal expansion and signs of somatic hypermutation suggest a CD4(+) T lymphocyte-dependent antitumoral response, which may be exploited for immunotherapy.

  • 4988. Zolochevska, Olga
    et al.
    Halin Bergström, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Comeaux, Brennen
    Emrick, Todd
    Figueiredo, Marxa L
    Novel antitumor strategies using cytokine PEDF for prostate cancer therapy2012In: Current Angiogenesis, ISSN 2211-5528 (print), 2211-5536 (online), Vol. 1, no 4, p. 277-298Article in journal (Refereed)
    Abstract [en]

    Prostate cancer is the most common solid tumor affecting men in the United States and Western Europe. Currently, therapeutic options remain limited and novel therapies are needed that can provide low toxicity and high therapeutic index. One promising new agent is a potent inhibitor of angiogenesis with anti-metastatic activities, the pigment epithelium- derived factor (PEDF). Some additional functions of PEDF that augment its promise as a new therapeutic include its pro-apoptosis (tumor cells and tumor-associated endothelial cells) and potential pro-immunogenic (cytotoxic macrophages) activities. We will discuss findings by several groups using PEDF as an efficient therapeutic following many delivery strategies including gene, protein, peptide, or cell-based therapy. PEDF also has potential to serve as a proteomics biomarker for prostate cancer progression, as downregulated levels could help predict metastatic potential of tumors. We will provide an overview of the potential and promise for achieving translation of PEDF therapeutics for the treatment of advanced prostate cancer.

  • 4989.
    Zorzan, Eleonora
    et al.
    Univ Padua, Dept Comparat Biomed & Food Sci, Padua, Italy.
    Elgendy, Ramy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Univ Padua, Dept Comparat Biomed & Food Sci, Padua, Italy.
    Giantin, Mery
    Univ Padua, Dept Comparat Biomed & Food Sci, Padua, Italy.
    Dacasto, Mauro
    Univ Padua, Dept Comparat Biomed & Food Sci, Padua, Italy.
    Sissi, Claudia
    Univ Padua, Dept Pharmaceut & Pharmacol Sci, Padua, Italy.
    Whole-Transcriptome Profiling of Canine and Human in Vitro Models Exposed to a G-Quadruplex Binding Small Molecule2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 17107Article in journal (Refereed)
    Abstract [en]

    G-quadruplexes (G4) are secondary nucleic acid structures that have been associated with genomic instability and cancer progression. When present in the promoter of some oncogenes, G4 structures can affect gene regulation and, hence, represent a possible therapeutic target. In this study, RNA-Seq was used to explore the effect of a G4-binding anthraquinone derivative, named AQ1, on the whole-transcriptome profiles of two common cell models for the study of KIT pathways; the human mast cell leukemia (HMC1.2) and the canine mast cell tumor (C2). The highest non-cytotoxic dose of AQ1 (2 mu M) resulted in 5441 and 1201 differentially expressed genes in the HMC1.2 and C2 cells, respectively. In both cell lines, major pathways such as cell cycle progression, KIT- and MYC-related pathways were negatively enriched in the AQ1-treated group, while other pathways such as p53, apoptosis and hypoxia-related were positively enriched. These findings suggest that AQ1 treatment induces a similar functional response in the human and canine cell models, and provide news insights into using dogs as a reliable translational model for studying G4-binding compounds.

  • 4990. Zovko, Ana
    et al.
    Viktorsson, Kristina
    Haag, Petra
    Kovalerchick, Dimitry
    Farnegardh, Katarina
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Alimonti, Andrea
    Ilan, Micha
    Carmeli, Shmuel
    Lewensohn, Rolf
    Marine Sponge Cribrochalina vasculum Compounds Activate Intrinsic Apoptotic Signaling and Inhibit Growth Factor Signaling Cascades in Non-Small Cell Lung Carcinoma2014In: Molecular Cancer Therapeutics, ISSN 1535-7163, E-ISSN 1538-8514, Vol. 13, no 12, p. 2941-2954Article in journal (Refereed)
    Abstract [en]

    Marine-derived compounds have been explored and considered as possible antitumor agents. In this study, we analyzed extracts of the sponge Cribrochalina vasculum for their ability to inhibit tumor cell proliferation. Screening identified two acetylenic compounds of similar structure that showed strong tumor-specific toxicity in non-small cell lung carcinoma (NSCLC) cells and small-cell lung carcinoma cells, and less prominent toxicity in ovarian carcinoma, while having no effect on normal cells. These acetylenic compounds were found to cause a time-dependent increase in activation of apoptotic signaling involving cleavage of caspase-9, caspase-3, and PARP, as well as apoptotic cell morphology in NSCLC cells, but not in normal fibroblasts. Further analysis demonstrated that these compounds caused conformational change in Bak and Bax, and resulted in loss of mitochondrial potential and cytochrome c release in NSCLC cells. Moreover, a decreased phosphorylation of the growth factor signaling kinases Akt, mTOR, and ERK was evident and an increased phosphorylation of JNK was observed. Thus, these acetylenic compounds hold potential as novel therapeutic agents that should be further explored for NSCLC and other tumor malignancies.

  • 4991. Zovko, Ana
    et al.
    Yektaei-Karin, Elham
    Salamon, Daniel
    Nilsson, Anders
    Wallvik, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Stenke, Leif
    Montelukast, a cysteinyl leukotriene receptor antagonist, inhibits the growth of chronic myeloid leukemia cells through apoptosis2018In: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 40, no 2, p. 902-908Article in journal (Refereed)
    Abstract [en]

    The clinical outcome for patients with chronic myeloid leukemia (CML) has improved significantly with the introduction of tyrosine kinase inhibitors (TKIs). However, their curative potential appears limited, probably as a consequence of TKI-resistant leukemic stem cells (LSCs) that persist as a result of aberrant pathways independent of the well-established oncoprotein Bcr-Abl. One such pathway involves signaling through leukotrienes (LTs), bioactive compounds that have been suggested to play a role in several other malignancies. Cysteinyl LT1 receptor (CysLT1R) has been reported to be overexpressed in a number of solid cancers, and blocking of this receptor with the antagonist montelukast (treatment approved for bronchial asthma) has resulted in the killing of cancer cells. We recently demonstrated that montelukast, alone or in combination with imatinib, can effectively reduce the growth of CML cells, while normal bone marrow cells were left unaffected. Herein, we further investigated the importance of CysLT1R for the survival of CML cells and the mechanisms by which montelukast induces cell death. Knockdown of the CysLT1R of K562 cells with siRNA reduced their growth by 25%. Montelukast had no effect on these cells, while it killed more than 50% of CysLT1R-expressing cells. Growth inhibition exerted by imatinib was unaffected by CysLT1R status. Montelukast-induced killing of K562/JURL-MK1 CML cells was paralleled by Bax overexpression, cytochrome c release, PARP-1 cleavage, and caspase-3 activation, an event further increased in a setting where montelukast was added to imatinib. Wnt/-catenin signaling was activated by CysLT1R and we observed that montelukast could induce proteins in this pathway, a finding of relevance for LSC survival. Thus, montelukast, employed at in vivo-like concentrations, induces the killing of CML cells through apoptotic pathways and may provide an additional, novel therapeutic possibility in CML.

  • 4992. Zuo, H.
    et al.
    Ueland, P. M.
    Midttun, O.
    Tell, G. S.
    Fanidi, A.
    Zheng, W.
    Shu, X.
    Xiang, Y.
    Wu, J.
    Prentice, R.
    Pettinger, M.
    Thomson, C. A.
    Giles, G. G.
    Hodge, A.
    Cai, Q.
    Blot, W. J.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Stevens, V. L.
    McCullough, M. L.
    Weinstein, S. J.
    Albanes, D.
    Ziegler, R. G.
    Freedman, N. D.
    Caporaso, N. E.
    Langhammer, A.
    Hveem, K.
    Naess, M.
    Buring, J. E.
    Lee, I.
    Gaziano, J. M.
    Severi, G.
    Zhang, X.
    Stampfer, M. J.
    Han, J.
    Zeleniuch-Jacquotte, A.
    Marchand, L. L.
    Yuan, J.
    Wang, R.
    Koh, W.
    Gao, Y.
    Ericson, U.
    Visvanathan, K.
    Jones, M. R.
    Relton, C.
    Brennan, P.
    Ulvik, A.
    Vitamin B6 catabolism and lung cancer risk: results from the Lung Cancer Cohort Consortium (LC3)2019In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 30, no 3, p. 478-485Article in journal (Refereed)
    Abstract [en]

    Background: Increased vitamin B6 catabolism related to inflammation, as measured by the PAr index (the ratio of 4-pyridoxic acid over the sum of pyridoxal and pyridoxal-5'-phosphate), has been positively associated with lung cancer risk in two prospective European studies. However, the extent to which this association translates to more diverse populations is not known.

    Materials and methods: For this study, we included 5323 incident lung cancer cases and 5323 controls individually matched by age, sex, and smoking status within each of 20 prospective cohorts from the Lung Cancer Cohort Consortium. Cohort-specific odds ratios (ORs) and 95% confidence intervals (CIs) for the association between PAr and lung cancer risk were calculated using conditional logistic regression and pooled using random-effects models.

    Results: PAr was positively associated with lung cancer risk in a dose-response fashion. Comparing the fourth versus first quartiles of PAr resulted in an OR of 1.38 (95% CI: 1.19-1.59) for overall lung cancer risk. The association between PAr and lung cancer risk was most prominent in former smokers (OR: 1.69, 95% CI: 1.36-2.10), men (OR: 1.60, 95% CI: 1.28-2.00), and for cancers diagnosed within 3years of blood draw (OR: 1.73, 95% CI: 1.34-2.23).

    Conclusion: Based on pre-diagnostic data from 20 cohorts across 4 continents, this study confirms that increased vitamin B6 catabolism related to inflammation and immune activation is associated with a higher risk of developing lung cancer. Moreover, PAr may be a pre-diagnostic marker of lung cancer rather than a causal factor.

  • 4993. Zuo, Hui
    et al.
    Ueland, Per Magne
    Midttun, Øivind
    Vollset, Stein E
    Tell, Grethe S
    Theofylaktopoulou, Despoina
    Travis, Ruth C
    Boutron-Ruault, Marie-Christine
    Fournier, Agnes
    Severi, Gianluca
    Kvaskoff, Marina
    Boeing, Heiner
    Bergmann, Manuela
    Fortner, Renée Turzanski
    Kaaks, Rudolf
    Trichopoulou, Antonia
    Kotanidou, Anastasia
    Lagiou, Pagona
    Palli, Domenico
    Sieri, Sabina
    Panico, Salvatore
    Bueno-de-Mesquita, H B As
    Peeters, Petra H
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Agudo, Antonio
    Quirós Garcia, Jose Ramón
    Larrañaga, Nerea
    Sanchez, Maria-Jose
    Chirlaque, Maria-Dolores
    Ardanaz, Eva
    Chuang, Shu-Chun
    Gallo, Valentina
    Brennan, Paul
    Johansson, Mattias
    Ulvik, Arve
    Results from the European Prospective Investigation into Cancer and Nutrition Link Vitamin B6 Catabolism and Lung Cancer Risk2018In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 78, no 1, p. 302-308Article in journal (Refereed)
    Abstract [en]

    Circulating pyridoxal-5′-phosphate (PLP) has been linked to lung cancer risk. The PAr index, defined as the ratio 4-pyridoxic acid/(pyridoxal + PLP), reflects increased vitamin B6 catabolism during inflammation. PAr has been defined as a marker of lung cancer risk in a prospective cohort study, but analysis of a larger numbers of cases are needed to deepen the significance of this study. Here, we conducted a nested case–control study within the European Prospective Investigation into Cancer and Nutrition (EPIC, n = 521,330), which included 892 incident lung cancer cases and 1,748 controls matched by center, gender, date of blood collection, and date of birth. The association of PAr with risk of lung cancer was evaluated by using conditional logistic regression. Study participants with elevated PAr experienced higher risk of lung cancer in a dose–response fashion, with a doubling in PAr levels associated with 52% higher odds of lung cancer after adjustment for tobacco smoking, serum cotinine levels, educational attainment, and BMI [OR, 1.52; 95% confidence interval (CI) 1.27–1.81; P < 0.001]. Additional adjustment for intake of vegetables and fruits and physical activity did not materially affect risk association. The association of PAr with lung cancer risk was similar in both genders but slightly stronger in former smokers and in participants diagnosed with squamous cell carcinoma. This study provides robust evidence that increased vitamin B6 catabolism is independently associated with a higher risk of future lung cancer.

  • 4994.
    Zuse, Ann
    et al.
    Institute of Medicinal and Pharmaceutical Chemistry, Westphalian Wilhelms-University, Hittorfstrasse 58-62, D-48149 Münster, Germany; Manitoba Institute of Cell Biology, CancerCare Manitoba, Department of Biochemistry and Medical Genetics, Winnipeg, Canada.
    Prinz, Helge
    Institute of Medicinal and Pharmaceutical Chemistry, Westphalian Wilhelms-University, Hittorfstrasse 58-62, D-48149 Münster, Germany.
    Müller, Klaus
    Institute of Medicinal and Pharmaceutical Chemistry, Westphalian Wilhelms-University, Hittorfstrasse 58-62, D-48149 Münster, Germany.
    Schmidt, Peter
    Zentaris GmbH, Weismüllerstrasse 50, D-60314 Frankfurt, Germany.
    Günther, Eckhard G.
    Zentaris GmbH, Weismüllerstrasse 50, D-60314 Frankfurt, Germany.
    Schweizer, Frank
    Department of Chemistry, Univ. Manitoba, Winnipeg, Canada.
    Prehn, Jochen H.M.
    Department of Physiology and RCSI Research Institute, St. Stephen's Green, Dublin, Ireland.
    Los, Marek Jan
    Manitoba Institute of Cell Biology, Cancer Care Manitoba; Manitoba Institute of Child Health; Department of Biochemistry and Medical Genetics; Department of Human Anatomy and Cell Science, University Manitoba, Winnipeg, Canada, .
    9-benzylidene-naphtho[2,3-b]thiophen-4-ones and benzylidene-9(10H)-anthracenones as novel tubulin interacting agents with high apoptosis-inducing activity2007In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 575, no 1-3, p. 34-45Article in journal (Refereed)
    Abstract [en]

    Tubulin-binding 9-benzylidene-naphtho[2,3-b]thiophen-4-ones 1a and 1b and benzylidene-9(10H)-anthracenone 2 were evaluated for their ability to induce cell death. We examined the effect of the molecules on cell cycle progression, organization of microtubule networks, and apoptosis induction. As determined by flow cytometry, cancer cells were predominantly arrested in metaphase with 4N DNA before cell death occurred. By using indirect immunofluorescence techniques we visualized microtubule depolymerization recognizable by short microtubule fragments scattered around the nucleus. The incubation with 1a and 2 resulted in chromatin condensation, nuclear fragmentation, and cell shrinkage, which are, among others, typical features of apoptotic cell death. Furthermore, time- and dose-dependent induction of apoptosis in SH-SY5Y cells was detected via cleavage of Ac-DEVD-AMC, a fluorigenic substrate for caspase-3. We observed a lower apoptotic activity in neuroblastoma cells overexpressing Bcl-xL, suggesting activation of the mitochondrial apoptosis pathway. Western blot analysis demonstrated that caspase-3, an apoptosis mediator, was activated in a time-dependent manner after exposure of SH-SY5Y cells to drugs 1a and 2. Taken together, the agents investigated in the present study display strong apoptosis-inducing activity and therefore show promise for the development of novel chemotherapeutics.

  • 4995.
    Åberg, Malin
    et al.
    University of Skövde, School of Health and Education.
    Joelsson, Josefine
    University of Skövde, School of Health and Education.
    Kvinnliga patienters upplevelse under pågående behandling av bröstcancer.: En kvalitativ studie av bloggar2016Independent thesis Basic level (university diploma), 10 credits / 15 HE creditsStudent thesis
  • 4996.
    Åkerstedt, Torbjörn
    et al.
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.
    Knutsson, Anders
    Mid Sweden University, Faculty of Human Sciences, Department of Health Sciences.
    Narusyte, Jurgita
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.
    Svedberg, Pia
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.
    Kecklund, Goran
    Radboud Univ Nijmegen, Behav Sci Inst, NL-6525 ED Nijmegen, Netherlands.
    Alexanderson, Kristina
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.
    Night work and breast cancer in women: a Swedish cohort study2015In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 5, no 4, article id e008127Article in journal (Refereed)
    Abstract [en]

    Objectives: Recent research has suggested a moderate link between night work and breast cancer in women, mainly through case-control studies, but nonsignificant studies are also common and cohort studies are few. The purpose of the present study was to provide new information from cohort data through investigating the association between the number of years with night work and breast cancer among women. Design: Cohort study of individuals exposed to night shift work in relation to incidence of breast cancer in women. Setting: Individuals in the Swedish Twin registry, with follow-up in the Swedish Cancer Registry. Participants: 13 656 women from the Swedish Twin Registry, with 3404 exposed to night work. Outcome measures: Breast cancer from the Swedish Cancer Registry (463 cases) during a follow-up time of 12 years. Results: A Cox proportional hazards regression analysis with control for a large number of confounders showed that the HR was HR=1.68 (95% CI 0.98 to 2.88) for the group with >20 years of night work. When the follow-up time was limited to ages below 60 years, those exposed >20 years showed a HR=1.77 (95% CI 1.03 to 3.04). Shorter exposure to night work showed no significant effects. Conclusions: The present results, together with previous work, suggest that night work is associated with an increased risk of breast cancer in women, but only after relatively long-term exposure.

  • 4997.
    Åkerstedt, Torbjörn
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Narusyte, Jurgita
    Svedberg, Pia
    Kecklund, Göran
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Radboud University, The Netherlands .
    Alexanderson, Kristina
    Night work and prostate cancer in men: a Swedish prospective cohort study2017In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 7, no 6, article id e015751Article in journal (Refereed)
    Abstract [en]

    Objectives Prostate cancer is the most common cancer and the second leading cause of cancer-related deaths among men, but the contributing factors are unclear. One such may be night work because of the day/night alternation of work and the resulting disturbance of the circadian system. The purpose of the present study was to investigate the prospective relation between number of years with night work and prostate cancer in men.

    Design Cohort study comparing night and day working twins with respect to incident prostate cancer in 12 322 men.

    Setting Individuals in the Swedish Twin Registry.

    Participants 12 322 male twins.

    Outcome measures Prostate cancer diagnoses obtained from the Swedish Cancer Registry with a follow-up time of 12 years, with a total number of cases=454.

    Results Multiple Cox proportional hazard regression analysis, adjusted for a number of covariates, showed no association between ever night work and prostate cancer, nor for duration of night work and prostate cancer. Analysis of twin pairs discordant for prostate cancer (n=332) showed no significant association between night work and prostate cancer.

    Conclusions The results, together with previous studies, suggest that night work does not seem to constitute a risk factor for prostate cancer.

  • 4998.
    Åkerström, Göran
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Surgical management of pancreatico-duodenal tumors in multiple endocrine neoplasia syndrome type 12012In: Clinics, ISSN 1807-5932, E-ISSN 1980-5322, Vol. 67, no S 1, p. 173-178Article, review/survey (Refereed)
    Abstract [en]

    Pancreatico-duodenal tumors are the second most common endocrinopathy in multiple endocrine neoplasia syndrome type 1, and have a pronounced effect on life expectancy as the principal cause of disease-related death. Previous discussions about surgical management have focused mainly on syndromes of hormone excess and, in particular, the management of multiple endocrine neoplasia syndrome type 1-related Zollinger-Ellison syndrome. Since hormonal syndromes tend to occur late and indicate the presence of metastases, screening with biochemical markers and endoscopic ultrasound is recommended for early detection of pancreatico-duodenal tumors, and with early surgery before metastases have developed. Surgery is recommended in patients with or without hormonal syndromes in the absence of disseminated liver metastases. The suggested operation includes distal 80% subtotal pancreatic resection together with enucleation of tumors in the head of the pancreas, and in cases with Zollinger-Ellison syndrome, excision of duodenal gastrinomas together with clearance of regional lymph node metastases. This strategy, with early and aggressive surgery before metastases have developed, is believed to reduce the risks for tumor recurrence and malignant progression.

  • 4999.
    Ångstrom-Brännström, Charlotte
    et al.
    Umeå University, Faculty of Medicine, Department of Nursing.
    Engvall, G.
    Mullaney, T.
    Nilsson, K.
    Wickart-Johansson, G.
    Svärd, A. M.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Nyholm, Tufve
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Lindh, Jack
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Lindh, Viveca
    Umeå University, Faculty of Medicine, Department of Nursing.
    Facilitating Radiotherapy for Children: Technique, Design and Professional Care in Synergy, a Multicenter Intervention Study2016In: Pediatric Blood & Cancer, ISSN 1545-5009, E-ISSN 1545-5017, Vol. 63, p. S213-S213Article in journal (Other academic)
  • 5000.
    Ångström-Brännström, C.
    et al.
    Umea Univ, Dept Nursing, Umea, Sweden..
    Engvall, Gunn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Mullaney, T.
    Umea Univ, Umea Inst Design, Umea, Sweden..
    Nilsson, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Wickart-Johansson, G.
    Karolinska Univ Hosp, Dept Oncol Radiumhemmet, Stockholm, Sweden..
    Svärd, A. M.
    Umea Univ, Dept Radiat Sci, Umea, Sweden..
    Nyholm, T.
    Umea Univ, Dept Radiat Sci, Umea, Sweden..
    Lindh, J.
    Umea Univ, Dept Radiat Sci, Umea, Sweden..
    Lindh, V.
    Umea Univ, Dept Nursing, Umea, Sweden..
    Facilitating Radiotherapy for Children: Technique, Design and Professional Care in Synergy, a Multicenter Intervention Study2016In: Pediatric Blood & Cancer, ISSN 1545-5009, E-ISSN 1545-5017, Vol. 63, p. S213-S213Article in journal (Refereed)
979899100101 4951 - 5000 of 5047
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