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Article ; Online: Virtual Screening Assisted Search for Inhibitors of the Translocated Intimin Receptor of Enteropathogenic Escherichia Coli.

Pylkkö, Tuomas / Tomašič, Tihomir / Poso, Antti / Tammela, Päivi

Chembiochem : a European journal of chemical biology

2023 Volume 25, Issue 2, Page(s) e202300638

Abstract: This study aimed to identify inhibitors of the translocated intimin receptor (Tir) of enteropathogenic Escherichia coli (EPEC). EPEC is an intestinal pathogen that causes diarrhea and is a major health concern worldwide. Because Tir is a key virulence ... ...

Abstract	This study aimed to identify inhibitors of the translocated intimin receptor (Tir) of enteropathogenic Escherichia coli (EPEC). EPEC is an intestinal pathogen that causes diarrhea and is a major health concern worldwide. Because Tir is a key virulence factor involved in EPEC pathogenesis, inhibiting its function is a potential strategy for controlling EPEC infections. Virtual screening was applied to chemical libraries to search for compounds that inhibit Tir-mediated bacterial adherence to host cells. Three sites were targeted using the cocrystal structure published earlier. A selection of compounds was then assessed in a cell-based infection model and fluorescence microscopy assay. The results of this study provide a basis for further optimization and testing of Tir inhibitors as potential therapeutic agents for EPEC infections.
MeSH term(s)	Humans ; Enteropathogenic Escherichia coli/metabolism ; Adhesins, Bacterial/metabolism ; Escherichia coli Proteins/metabolism ; Receptors, Cell Surface/chemistry ; Carrier Proteins ; Escherichia coli Infections/microbiology
Chemical Substances	Adhesins, Bacterial ; Escherichia coli Proteins ; Receptors, Cell Surface ; Carrier Proteins
Language	English
Publishing date	2023-11-27
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2020469-3
ISSN	1439-7633 ; 1439-4227
ISSN (online)	1439-7633
ISSN	1439-4227
DOI	10.1002/cbic.202300638
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Article ; Online: Association of exercise with pan-cancer incidence and overall survival.

Lavery, Jessica A / Boutros, Paul C / Knight, Daniel / Tammela, Tuomas / Moskowitz, Chaya S / Jones, Lee W

Cancer cell

2024 Volume 42, Issue 2, Page(s) 169–171

Abstract: Lavery et al. show that the association between exercise and risk of cancer varied as a function of organ site and amount of exercise. Exercise was also associated with a longevity benefit regardless of a cancer diagnosis or not. This study further ... ...

Abstract	Lavery et al. show that the association between exercise and risk of cancer varied as a function of organ site and amount of exercise. Exercise was also associated with a longevity benefit regardless of a cancer diagnosis or not. This study further highlights the importance of exercise as an effective cancer preventive strategy.
MeSH term(s)	Humans ; Incidence ; Exercise ; Neoplasms/epidemiology
Language	English
Publishing date	2024-01-04
Publishing country	United States
Document type	Letter ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2078448-X
ISSN	1878-3686 ; 1535-6108
ISSN (online)	1878-3686
ISSN	1535-6108
DOI	10.1016/j.ccell.2023.12.007
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Zs.A 5650: 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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Article ; Online: Early detection of clinically significant prostate cancer: protocol summary and statistical analysis plan for the ProScreen randomised trial.

Nevalainen, Jaakko / Raitanen, Jani / Natunen, Kari / Kilpeläinen, Tuomas / Rannikko, Antti / Tammela, Teuvo / Auvinen, Anssi

BMJ open

2024 Volume 14, Issue 1, Page(s) e075595

Abstract: Introduction: Evidence on the effectiveness of prostate cancer screening based on prostate-specific antigen is inconclusive and suggests a questionable balance between benefits and harms due to overdiagnosis, and complications from biopsies and ... ...

Abstract	Introduction: Evidence on the effectiveness of prostate cancer screening based on prostate-specific antigen is inconclusive and suggests a questionable balance between benefits and harms due to overdiagnosis, and complications from biopsies and overtreatment. However, diagnostic accuracy studies have shown that detection of clinically insignificant prostate cancer can be reduced by MRI combined with targeted biopsies.The aim of the paper is to describe the analysis of the ProScreen randomised trial to assess the performance of the novel screening algorithm in terms of the primary outcome, prostate cancer mortality and secondary outcomes as intermediate indicators of screening benefits and harms of screening. Methods: The trial aims to recruit at least 111 000 men to achieve sufficient statistical power for the primary outcome. Men will be allocated in a 1:3 ratio to the screening and control arms. Interim analysis is planned at 10 years of follow-up, and the final analysis at 15 years. Difference between the trial arms in prostate cancer mortality will be assessed by Gray's test using intention-to-screen analysis of randomised men. Secondary outcomes will be the incidence of prostate cancer by disease aggressiveness, progression to advanced prostate cancer, death due to any cause and cost-effectiveness of screening. Ethics and dissemination: The trial protocol was reviewed by the ethical committee of the Helsinki University Hospital (2910/2017). Results will be disseminated through publications in international peer-reviewed journals and at scientific meetings. Trial registration number: NCT03423303.
MeSH term(s)	Male ; Humans ; Prostatic Neoplasms/diagnosis ; Prostate-Specific Antigen ; Early Detection of Cancer ; Prostate ; Aggression ; Randomized Controlled Trials as Topic
Chemical Substances	Prostate-Specific Antigen (EC 3.4.21.77)
Language	English
Publishing date	2024-01-09
Publishing country	England
Document type	Clinical Trial Protocol ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2599832-8
ISSN	2044-6055 ; 2044-6055
ISSN (online)	2044-6055
ISSN	2044-6055
DOI	10.1136/bmjopen-2023-075595
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Article ; Online: A MASCOT for mosaic analysis.

Yan, Yan / Tammela, Tuomas

Proceedings of the National Academy of Sciences of the United States of America

2020 Volume 117, Issue 49, Page(s) 30876–30878

MeSH term(s)	Animals ; Integrases ; Mice ; Software
Chemical Substances	Cre recombinase (EC 2.7.7.-) ; Integrases (EC 2.7.7.-)
Language	English
Publishing date	2020-11-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Comment
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2021382117
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Article ; Online: Early detection of clinically significant prostate cancer

Jaakko Nevalainen / Anssi Auvinen / Antti Rannikko / Teuvo Tammela / Kari Natunen / Jani Raitanen / Tuomas Kilpeläinen

BMJ Open, Vol 14, Iss

protocol summary and statistical analysis plan for the ProScreen randomised trial

2024 Volume 1

Abstract: Introduction Evidence on the effectiveness of prostate cancer screening based on prostate-specific antigen is inconclusive and suggests a questionable balance between benefits and harms due to overdiagnosis, and complications from biopsies and ... ...

Abstract	Introduction Evidence on the effectiveness of prostate cancer screening based on prostate-specific antigen is inconclusive and suggests a questionable balance between benefits and harms due to overdiagnosis, and complications from biopsies and overtreatment. However, diagnostic accuracy studies have shown that detection of clinically insignificant prostate cancer can be reduced by MRI combined with targeted biopsies.The aim of the paper is to describe the analysis of the ProScreen randomised trial to assess the performance of the novel screening algorithm in terms of the primary outcome, prostate cancer mortality and secondary outcomes as intermediate indicators of screening benefits and harms of screening.Methods The trial aims to recruit at least 111 000 men to achieve sufficient statistical power for the primary outcome. Men will be allocated in a 1:3 ratio to the screening and control arms. Interim analysis is planned at 10 years of follow-up, and the final analysis at 15 years. Difference between the trial arms in prostate cancer mortality will be assessed by Gray’s test using intention-to-screen analysis of randomised men. Secondary outcomes will be the incidence of prostate cancer by disease aggressiveness, progression to advanced prostate cancer, death due to any cause and cost-effectiveness of screening.Ethics and dissemination The trial protocol was reviewed by the ethical committee of the Helsinki University Hospital (2910/2017). Results will be disseminated through publications in international peer-reviewed journals and at scientific meetings.Trial registration number NCT03423303
Keywords	Medicine ; R
Subject code	170
Language	English
Publishing date	2024-01-01T00:00:00Z
Publisher	BMJ Publishing Group
Document type	Article ; Online
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Article ; Online: Expected impact of MRI-targeted biopsy interreader variability among uropathologists on ProScreen prostate cancer screening trial: a pre-trial validation study.

Hietikko, Ronja / Mirtti, Tuomas / Kilpeläinen, Tuomas P / Tolonen, Teemu / Räisänen-Sokolowski, Anne / Nordling, Stig / Hannus, Jill / Laurila, Marita / Taari, Kimmo / Tammela, Teuvo L J / Autio, Reija / Natunen, Kari / Auvinen, Anssi / Rannikko, Antti

World journal of urology

2024 Volume 42, Issue 1, Page(s) 217

Abstract: Purpose: Prostate cancer (PCa) histology, particularly the Gleason score, is an independent prognostic predictor in PCa. Little is known about the inter-reader variability in grading of targeted prostate biopsy based on magnetic resonance imaging (MRI). ...

Abstract	Purpose: Prostate cancer (PCa) histology, particularly the Gleason score, is an independent prognostic predictor in PCa. Little is known about the inter-reader variability in grading of targeted prostate biopsy based on magnetic resonance imaging (MRI). The aim of this study was to assess inter-reader variability in Gleason grading of MRI-targeted biopsy among uropathologists and its potential impact on a population-based randomized PCa screening trial (ProScreen). Methods: From June 2014 to May 2018, 100 men with clinically suspected PCa were retrospectively selected. All men underwent prostate MRI and 86 underwent targeted prostate of the prostate. Six pathologists individually reviewed the pathology slides of the prostate biopsies. The five-tier ISUP (The International Society of Urological Pathology) grade grouping (GG) system was used. Fleiss' weighted kappa (κ) and Model-based kappa for associations were computed to estimate the combined agreement between individual pathologists. Results: GG reporting of targeted prostate was highly consistent among the trial pathologists. Inter-reader agreement for cancer (GG1-5) vs. benign was excellent (Model-based kappa 0.90, Fleiss' kappa κ = 0.90) and for clinically significant prostate cancer (csPCa) (GG2-5 vs. GG0 vs. GG1), it was good (Model-based kappa 0.70, Fleiss' kappa κ 0.67). Conclusions: Inter-reader agreement in grading of MRI-targeted biopsy was good to excellent, while it was fair to moderate for MRI in the same cohort, as previously shown. Importantly, there was wide consensus by pathologists in assigning the contemporary GG on MRI-targeted biopsy suggesting high reproducibility of pathology reporting in the ProScreen trial.
MeSH term(s)	Male ; Humans ; Prostatic Neoplasms/diagnostic imaging ; Prostatic Neoplasms/pathology ; Early Detection of Cancer ; Reproducibility of Results ; Retrospective Studies ; Prostate-Specific Antigen ; Biopsy ; Magnetic Resonance Imaging/methods ; Neoplasm Grading ; Image-Guided Biopsy
Chemical Substances	Prostate-Specific Antigen (EC 3.4.21.77)
Language	English
Publishing date	2024-04-06
Publishing country	Germany
Document type	Journal Article
ZDB-ID	380333-8
ISSN	1433-8726 ; 0724-4983
ISSN (online)	1433-8726
ISSN	0724-4983
DOI	10.1007/s00345-024-04898-2
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Article ; Online: Cellular and molecular mechanisms of plasticity in cancer.

Torborg, Stefan R / Li, Zhuxuan / Chan, Jason E / Tammela, Tuomas

Trends in cancer

2022 Volume 8, Issue 9, Page(s) 735–746

Abstract: Cancer cells are plastic - they can assume a wide range of distinct phenotypes. Plasticity is integral to cancer initiation and progression, as well as to the emergence and maintenance of intratumoral heterogeneity. Furthermore, plastic cells can rapidly ...

Abstract	Cancer cells are plastic - they can assume a wide range of distinct phenotypes. Plasticity is integral to cancer initiation and progression, as well as to the emergence and maintenance of intratumoral heterogeneity. Furthermore, plastic cells can rapidly adapt to and evade therapy, which poses a challenge for effective cancer treatment. As such, targeting plasticity in cancer holds tremendous promise. Yet, the principles governing plasticity in cancer cells remain poorly understood. Here, we provide an overview of the fundamental molecular and cellular mechanisms that underlie plasticity in cancer and in other biological contexts, including development and regeneration. We propose a key role for high-plasticity cell states (HPCSs) as crucial nodes for cell state transitions and enablers of intra-tumoral heterogeneity.
MeSH term(s)	Epithelial-Mesenchymal Transition/genetics ; Humans ; Neoplasms/genetics ; Neoplasms/therapy ; Neoplastic Stem Cells ; Phenotype ; Plastics
Chemical Substances	Plastics
Language	English
Publishing date	2022-05-23
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2852626-0
ISSN	2405-8025 ; 2405-8033 ; 2405-8033
ISSN (online)	2405-8025 ; 2405-8033
ISSN	2405-8033
DOI	10.1016/j.trecan.2022.04.007
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Article ; Online: WNT as a Driver and Dependency in Cancer.

Parsons, Marie J / Tammela, Tuomas / Dow, Lukas E

Cancer discovery

2021 Volume 11, Issue 10, Page(s) 2413–2429

Abstract: The WNT signaling pathway is a critical regulator of development and adult tissue homeostasis and becomes dysregulated in many cancer types. Although hyperactivation of WNT signaling is common, the type and frequency of genetic WNT pathway alterations ... ...

Abstract	The WNT signaling pathway is a critical regulator of development and adult tissue homeostasis and becomes dysregulated in many cancer types. Although hyperactivation of WNT signaling is common, the type and frequency of genetic WNT pathway alterations can vary dramatically between different cancers, highlighting possible cancer-specific mechanisms for WNT-driven disease. In this review, we discuss how WNT pathway disruption contributes to tumorigenesis in different organs and how WNT affects the tumor cell and immune microenvironment. Finally, we describe recent and ongoing efforts to target oncogenic WNT signaling as a therapeutic strategy. SIGNIFICANCE: WNT signaling is a fundamental regulator of tissue homeostasis and oncogenic driver in many cancer types. In this review, we highlight recent advances in our understanding of WNT signaling in cancer, particularly the complexities of WNT activation in distinct cancer types, its role in immune evasion, and the challenge of targeting the WNT pathway as a therapeutic strategy.
MeSH term(s)	Carcinogenesis ; Humans ; Neoplasms/genetics ; Tumor Microenvironment ; Wnt Signaling Pathway/genetics
Language	English
Publishing date	2021-09-13
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2625242-9
ISSN	2159-8290 ; 2159-8274
ISSN (online)	2159-8290
ISSN	2159-8274
DOI	10.1158/2159-8290.CD-21-0190
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Article: Investigating Tumor Heterogeneity in Mouse Models.

Tammela, Tuomas / Sage, Julien

Annual review of cancer biology

2019 Volume 4, Issue 1, Page(s) 99–119

Abstract: Cancer arises from a single cell through a series of acquired mutations and epigenetic alterations. Tumors gradually develop into a complex tissue comprised of phenotypically heterogeneous cancer cell populations, as well as noncancer cells that make up ... ...

Abstract	Cancer arises from a single cell through a series of acquired mutations and epigenetic alterations. Tumors gradually develop into a complex tissue comprised of phenotypically heterogeneous cancer cell populations, as well as noncancer cells that make up the tumor microenvironment. The phenotype, or state, of each cancer and stromal cell is influenced by a plethora of cell-intrinsic and cell-extrinsic factors. The diversity of these cellular states promotes tumor progression, enables metastasis, and poses a challenge for effective cancer treatments. Thus, the identification of strategies for the therapeutic manipulation of tumor heterogeneity would have significant clinical implications. A major barrier in the field is the difficulty in functionally investigating heterogeneity in tumors in cancer patients. Here we review how mouse models of human cancer can be leveraged to interrogate tumor heterogeneity and to help design better therapeutic strategies.
Language	English
Publishing date	2019-11-06
Publishing country	United States
Document type	Journal Article
ISSN	2472-3428
ISSN	2472-3428
DOI	10.1146/annurev-cancerbio-030419-033413
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Article ; Online: Development and validation of a high-content screening assay for inhibitors of enteropathogenic E. coli adhesion.

Pylkkö, Tuomas / Ilina, Polina / Tammela, Päivi

Journal of microbiological methods

2021 Volume 184, Page(s) 106201

Abstract: Enteropathogenic E. coli (EPEC) causes intestinal infections leading to severe diarrhea. EPEC attaches to the host cell causing lesions to the intestinal epithelium coupled with the effacement of microvilli. In the process, actin accumulates into a ... ...

Abstract	Enteropathogenic E. coli (EPEC) causes intestinal infections leading to severe diarrhea. EPEC attaches to the host cell causing lesions to the intestinal epithelium coupled with the effacement of microvilli. In the process, actin accumulates into a pedestal-like structure under bacterial microcolonies. We designed an automated fluorescence microscopy-based screening method for discovering compounds capable of inhibiting EPEC adhesion and virulence using aurodox, a type three secretion system (T3SS) inhibitor, as a positive control. The screening assay employs an EPEC strain (2348/69) expressing a fluorescent protein and actin staining for monitoring the bacteria and their pedestals respectively, analyzing these with a custom image analysis pipeline. The assay allows for the discovery of compounds capable of preventing the formation of pathogenic actin rearrangements. These compounds may be interfering with virulence-related molecular pathways relevant for developing antivirulence leads.
MeSH term(s)	Anti-Bacterial Agents/pharmacology ; Automation/methods ; Bacterial Adhesion/drug effects ; Drug Evaluation, Preclinical/methods ; Enteropathogenic Escherichia coli/drug effects ; Enteropathogenic Escherichia coli/genetics ; Enteropathogenic Escherichia coli/pathogenicity ; Enteropathogenic Escherichia coli/physiology ; Escherichia coli Infections/microbiology ; Escherichia coli Proteins/antagonists & inhibitors ; Escherichia coli Proteins/metabolism ; Humans ; Microscopy, Fluorescence/methods ; Type III Secretion Systems/antagonists & inhibitors ; Type III Secretion Systems/metabolism ; Virulence/drug effects
Chemical Substances	Anti-Bacterial Agents ; Escherichia coli Proteins ; Type III Secretion Systems
Language	English
Publishing date	2021-03-10
Publishing country	Netherlands
Document type	Evaluation Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	604916-3
ISSN	1872-8359 ; 0167-7012
ISSN (online)	1872-8359
ISSN	0167-7012
DOI	10.1016/j.mimet.2021.106201
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