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  1. Article ; Online: Prognostic impact of kallikrein-related peptidase transcript levels in prostate cancer.

    Lehto, Timo-Pekka K / Kovanen, Ruusu-Maaria / Lintula, Susanna / Malén, Adrian / Stürenberg, Carolin / Erickson, Andrew / Pulkka, Olli-Pekka / Stenman, Ulf-Håkan / Diamandis, Eleftherios P / Rannikko, Antti / Mirtti, Tuomas / Koistinen, Hannu

    International journal of cancer

    2023  Volume 153, Issue 4, Page(s) 867–881

    Abstract: We aimed to study mRNA levels and prognostic impact of all 15 human kallikrein-related peptidases (KLKs) and their targets, proteinase-activated receptors (PARs), in surgically treated prostate cancer (PCa). Seventy-nine patients with localized grade ... ...

    Abstract We aimed to study mRNA levels and prognostic impact of all 15 human kallikrein-related peptidases (KLKs) and their targets, proteinase-activated receptors (PARs), in surgically treated prostate cancer (PCa). Seventy-nine patients with localized grade group 2-4 PCas represented aggressive cases, based on metastatic progression during median follow-up of 11 years. Eighty-six patients with similar baseline characteristics, but no metastasis during follow-up, were assigned as controls. Transcript counts were detected with nCounter technology. KLK12 protein expression was investigated with immunohistochemistry. The effects of KLK12 and KLK15 were studied in LNCaP cells using RNA interference. KLK3, -2, -4, -11, -15, -10 and -12 mRNA, in decreasing order, were expressed over limit of detection (LOD). The expression of KLK2, -3, -4 and -15 was decreased and KLK12 increased in aggressive cancers, compared to controls (P < .05). Low KLK2, -3 and -15 expression was associated with short metastasis-free survival (P < .05) in Kaplan-Meier analysis. PAR1 and -2 were expressed over LOD, and PAR1 expression was higher, and PAR2 lower, in aggressive cases than controls. Together, KLKs and PARs improved classification of metastatic and lethal disease over grade, pathological stage and prostate-specific antigen combined, in random forest analyses. Strong KLK12 immunohistochemical staining was associated with short metastasis-free and PCa-specific survival in Kaplan-Meier analysis (P < .05). Knock-down of KLK15 reduced colony formation of LNCaP cells grown on Matrigel basement membrane preparation. These results support the involvement of several KLKs in PCa progression, highlighting, that they may serve as prognostic PCa biomarkers.
    MeSH term(s) Male ; Humans ; Prognosis ; Receptor, PAR-1/genetics ; Kallikreins/genetics ; Kallikreins/metabolism ; Prostatic Neoplasms/genetics ; Prostatic Neoplasms/surgery ; Prostatic Neoplasms/metabolism ; Prostate-Specific Antigen ; RNA, Messenger/genetics
    Chemical Substances Receptor, PAR-1 ; Kallikreins (EC 3.4.21.-) ; Prostate-Specific Antigen (EC 3.4.21.77) ; RNA, Messenger
    Language English
    Publishing date 2023-05-04
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 218257-9
    ISSN 1097-0215 ; 0020-7136
    ISSN (online) 1097-0215
    ISSN 0020-7136
    DOI 10.1002/ijc.34551
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 478: Show issues Location:
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    ab Jg. 2022: Lesesaal (EG)
    Zs.MO 576: Show issues

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  2. Article ; Online: Fibrinogen-like protein 2 in gastrointestinal stromal tumour.

    Pulkka, Olli-Pekka / Viisanen, Leevi / Tynninen, Olli / Laaksonen, Maria / Reichardt, Peter / Reichardt, Annette / Eriksson, Mikael / Hall, Kirsten Sundby / Wardelmann, Eva / Nilsson, Bengt / Sihto, Harri / Joensuu, Heikki

    Journal of cellular and molecular medicine

    2022  Volume 26, Issue 4, Page(s) 1083–1094

    Abstract: Gastrointestinal stromal tumour (GIST), the most common sarcoma of the gastrointestinal tract, can be treated effectively with tyrosine kinase inhibitors, such as imatinib. Cancer immune therapy has limited efficacy, and little is known about the immune ... ...

    Abstract Gastrointestinal stromal tumour (GIST), the most common sarcoma of the gastrointestinal tract, can be treated effectively with tyrosine kinase inhibitors, such as imatinib. Cancer immune therapy has limited efficacy, and little is known about the immune suppressive factors in GISTs. Fibrinogen-like protein 2 (FGL2) is expressed either as a membrane-associated protein or as a secreted soluble protein that has immune suppressive functions. We found that GISTs expressed FGL2 mRNA highly compared to other types of cancer in a large human cancer transcriptome database. GIST expressed FGL2 frequently also when studied using immunohistochemistry in two large clinical series, where 333 (78%) out of the 425 GISTs were FGL2 positive. The interstitial cells of Cajal, from which GISTs may originate, expressed FGL2. FGL2 expression was associated with small GIST size, low mitotic counts and low tumour-infiltrating lymphocyte (TIL) counts. Patients whose GIST expressed FGL2 had better recurrence-free survival than patients whose GIST lacked expression. Imatinib upregulated FGL2 in GIST cell lines, and the patients with FGL2-negative GIST appeared to benefit most from long duration of adjuvant imatinib. We conclude that GISTs express FGL2 frequently and that FGL2 expression is associated with low TIL counts and favourable survival outcomes.
    MeSH term(s) Antineoplastic Agents/therapeutic use ; Benzamides ; Fibrinogen/genetics ; Gastrointestinal Neoplasms/drug therapy ; Gastrointestinal Stromal Tumors/drug therapy ; Gastrointestinal Stromal Tumors/genetics ; Gastrointestinal Stromal Tumors/pathology ; Humans ; Piperazines/pharmacology ; Proto-Oncogene Proteins c-kit/metabolism ; Pyrimidines/pharmacology
    Chemical Substances Antineoplastic Agents ; Benzamides ; FGL2 protein, human ; Piperazines ; Pyrimidines ; Fibrinogen (9001-32-5) ; Proto-Oncogene Proteins c-kit (EC 2.7.10.1)
    Language English
    Publishing date 2022-01-14
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2074559-X
    ISSN 1582-4934 ; 1582-4934 ; 1582-1838
    ISSN (online) 1582-4934
    ISSN 1582-4934 ; 1582-1838
    DOI 10.1111/jcmm.17163
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 5752: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  3. Article ; Online: Clinical relevance of integrin alpha 4 in gastrointestinal stromal tumours.

    Pulkka, Olli-Pekka / Mpindi, John-Patrick / Tynninen, Olli / Nilsson, Bengt / Kallioniemi, Olli / Sihto, Harri / Joensuu, Heikki

    Journal of cellular and molecular medicine

    2018  Volume 22, Issue 4, Page(s) 2220–2230

    Abstract: The molecular mechanisms for the dissemination and metastasis of gastrointestinal stromal tumours (GIST) are incompletely understood. The purpose of the study was to investigate the clinical relevance of integrin alpha 4 (ITGA4) expression in GIST. GIST ... ...

    Abstract The molecular mechanisms for the dissemination and metastasis of gastrointestinal stromal tumours (GIST) are incompletely understood. The purpose of the study was to investigate the clinical relevance of integrin alpha 4 (ITGA4) expression in GIST. GIST transcriptomes were first compared with transcriptomes of other types of cancer and histologically normal gastrointestinal tract tissue in the MediSapiens in silico database. ITGA4 was identified as an unusually highly expressed gene in GIST. Therefore, the effects of ITGA4 knock-down and selective integrin alpha 4 beta 1 (VLA-4) inhibitors on tumour cell proliferation and invasion were investigated in three GIST cell lines. In addition, the prognostic role of ITGA4 expression in cancer cells was investigated in a series of 147 GIST patients with immunohistochemistry. Inhibition of ITGA4-related signalling decreased GIST cell invasion in all investigated GIST cell lines. ITGA4 protein was expressed in 62 (42.2%) of the 147 GISTs examined, and expression was significantly associated with distant metastases during the course of the disease and several adverse prognostic features. Patients whose GIST expressed strongly ITGA4 had unfavourable GIST-specific survival and overall survival compared to patients with low or no ITGA4 expression. Taken together, ITGA4 is an important integrin in the molecular pathogenesis of GIST and may influence their clinical behaviour.
    MeSH term(s) Adult ; Aged ; Aged, 80 and over ; Cell Line, Tumor ; Cell Proliferation ; Female ; Gastrointestinal Stromal Tumors/genetics ; Gastrointestinal Stromal Tumors/metabolism ; Gastrointestinal Stromal Tumors/pathology ; Gene Expression Regulation, Neoplastic ; Humans ; Integrin alpha4/genetics ; Integrin alpha4/metabolism ; Male ; Middle Aged ; Neoplasm Invasiveness ; Proto-Oncogene Proteins c-kit/metabolism
    Chemical Substances Integrin alpha4 (143198-26-9) ; Proto-Oncogene Proteins c-kit (EC 2.7.10.1)
    Language English
    Publishing date 2018-01-29
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2074559-X
    ISSN 1582-4934 ; 1582-4934 ; 1582-1838
    ISSN (online) 1582-4934
    ISSN 1582-4934 ; 1582-1838
    DOI 10.1111/jcmm.13502
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5752: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
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    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  4. Article: Anagrelide for Gastrointestinal Stromal Tumor.

    Pulkka, Olli-Pekka / Gebreyohannes, Yemarshet K / Wozniak, Agnieszka / Mpindi, John-Patrick / Tynninen, Olli / Icay, Katherine / Cervera, Alejandra / Keskitalo, Salla / Murumägi, Astrid / Kulesskiy, Evgeny / Laaksonen, Maria / Wennerberg, Krister / Varjosalo, Markku / Laakkonen, Pirjo / Lehtonen, Rainer / Hautaniemi, Sampsa / Kallioniemi, Olli / Schöffski, Patrick / Sihto, Harri /
    Joensuu, Heikki

    Clinical cancer research : an official journal of the American Association for Cancer Research

    2018  Volume 25, Issue 5, Page(s) 1676–1687

    Abstract: Purpose: Gastrointestinal stromal tumor (GIST) is a common type of soft-tissue sarcoma. Imatinib, an inhibitor of KIT, platelet-derived growth factor receptor alpha (PDGFRA), and a few other tyrosine kinases, is highly effective for GIST, but advanced ... ...

    Abstract Purpose: Gastrointestinal stromal tumor (GIST) is a common type of soft-tissue sarcoma. Imatinib, an inhibitor of KIT, platelet-derived growth factor receptor alpha (PDGFRA), and a few other tyrosine kinases, is highly effective for GIST, but advanced GISTs frequently progress on imatinib and other approved tyrosine kinase inhibitors. We investigated phosphodiesterase 3 (PDE3) as a potential therapeutic target in GIST cell lines and xenograft models.
    Experimental design: The GIST gene expression profile was interrogated in the MediSapiens IST Online transcriptome database comprising human tissue and cancer samples, and PDE3A and PDE3B expression was studied using IHC on tissue microarrays (TMA) consisting of 630 formalin-fixed human tissue samples. GIST cell lines were screened for sensitivity to 217 anticancer compounds, and the efficacy of PDE inhibitors on GIST was further studied in GIST cell lines and patient-derived mouse xenograft models.
    Results: GISTs expressed PDE3A and PDE3B frequently compared with other human normal or cancerous tissues both in the
    Conclusions: PDE3A and PDE3B are frequently expressed in GIST. Anagrelide had anticancer efficacy in GIST xenograft models and warrants further testing in clinical trials.
    MeSH term(s) Animals ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Cell Line, Tumor ; Cell Survival/drug effects ; Cyclic Nucleotide Phosphodiesterases, Type 3/genetics ; Cyclic Nucleotide Phosphodiesterases, Type 3/metabolism ; Disease Models, Animal ; Drug Resistance, Neoplasm ; Drug Screening Assays, Antitumor ; Gastrointestinal Stromal Tumors/drug therapy ; Gastrointestinal Stromal Tumors/genetics ; Gastrointestinal Stromal Tumors/mortality ; Gastrointestinal Stromal Tumors/pathology ; High-Throughput Screening Assays ; Humans ; Mice ; Platelet Aggregation Inhibitors/pharmacology ; Platelet Aggregation Inhibitors/therapeutic use ; Quinazolines/pharmacology ; Quinazolines/therapeutic use ; Signal Transduction/drug effects ; Xenograft Model Antitumor Assays
    Chemical Substances Antineoplastic Agents ; Platelet Aggregation Inhibitors ; Quinazolines ; Cyclic Nucleotide Phosphodiesterases, Type 3 (EC 3.1.4.17) ; anagrelide (K9X45X0051)
    Language English
    Publishing date 2018-12-07
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1225457-5
    ISSN 1557-3265 ; 1078-0432
    ISSN (online) 1557-3265
    ISSN 1078-0432
    DOI 10.1158/1078-0432.CCR-18-0815
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 4223: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  5. Article ; Online: SLUG transcription factor: a pro-survival and prognostic factor in gastrointestinal stromal tumour.

    Pulkka, Olli-Pekka / Nilsson, Bengt / Sarlomo-Rikala, Maarit / Reichardt, Peter / Eriksson, Mikael / Hall, Kirsten Sundby / Wardelmann, Eva / Vehtari, Aki / Joensuu, Heikki / Sihto, Harri

    British journal of cancer

    2017  Volume 116, Issue 9, Page(s) 1195–1202

    Abstract: Background: The SLUG transcription factor has been linked with the KIT signalling pathway that is important for gastrointestinal stromal tumour (GIST) tumourigenesis. Its clinical significance in GIST is unknown.: Methods: Influence of SLUG ... ...

    Abstract Background: The SLUG transcription factor has been linked with the KIT signalling pathway that is important for gastrointestinal stromal tumour (GIST) tumourigenesis. Its clinical significance in GIST is unknown.
    Methods: Influence of SLUG expression on cell proliferation and viability were investigated in GIST48 and GIST882 cell lines. The association between tumour SLUG expression in immunohistochemistry and recurrence-free survival (RFS) was studied in two clinical GIST series, one with 187 patients treated with surgery alone, and another one with 313 patients treated with surgery and adjuvant imatinib.
    Results: SLUG downregulation inhibited cell proliferation, induced cell death in both cell lines, and sensitised GIST882 cells to lower imatinib concentrations. SLUG was expressed in 125 (25.0%) of the 500 clinical GISTs evaluated, and expression was associated with several factors linked with unfavourable prognosis. SLUG expression was associated with unfavourable RFS both when patients were treated with surgery alone (HR=3.40, 95% CI=1.67-6.89, P=0.001) and when treated with surgery plus adjuvant imatinib (HR=1.83, 95% CI=1.29-2.60, P=0.001).
    Conclusions: GIST patients with high tumour SLUG expression have unfavourable RFS. SLUG may mediate pro-survival signalling in GISTs.
    MeSH term(s) Adult ; Aged ; Aged, 80 and over ; Carcinogenesis/genetics ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Disease-Free Survival ; Drug Resistance, Neoplasm/genetics ; Female ; Gastrointestinal Stromal Tumors/drug therapy ; Gastrointestinal Stromal Tumors/genetics ; Gastrointestinal Stromal Tumors/pathology ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Imatinib Mesylate/administration & dosage ; Male ; Middle Aged ; Prognosis ; Signal Transduction/drug effects ; Snail Family Transcription Factors/biosynthesis ; Snail Family Transcription Factors/genetics
    Chemical Substances SNAI1 protein, human ; Snail Family Transcription Factors ; Imatinib Mesylate (8A1O1M485B)
    Language English
    Publishing date 2017-04-25
    Publishing country England
    Document type Journal Article
    ZDB-ID 80075-2
    ISSN 1532-1827 ; 0007-0920
    ISSN (online) 1532-1827
    ISSN 0007-0920
    DOI 10.1038/bjc.2017.82
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Uh III Zs.142: Show issues Location:
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