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Article ; Online: Impact of epithelial organization on Myc expression and activity--letter.

Partanen, Johanna I / Klefstrom, Juha

2012 Volume 72, Issue 4, Page(s) 1035; author reply 1036

MeSH term(s)	Epithelial Cells/physiology ; Humans ; Proto-Oncogene Proteins c-myc/antagonists & inhibitors
Chemical Substances	Proto-Oncogene Proteins c-myc
Language	English
Publishing date	2012-02-15
Publishing country	United States
Document type	Comment ; Letter
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
DOI	10.1158/0008-5472.CAN-11-2201
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Article ; Online: How Communicating Polygenic and Clinical Risk for Atherosclerotic Cardiovascular Disease Impacts Health Behavior: an Observational Follow-up Study.

Widén, Elisabeth / Junna, Nella / Ruotsalainen, Sanni / Surakka, Ida / Mars, Nina / Ripatti, Pietari / Partanen, Juulia J / Aro, Johanna / Mustonen, Pekka / Tuomi, Tiinamaija / Palotie, Aarno / Salomaa, Veikko / Kaprio, Jaakko / Partanen, Jukka / Hotakainen, Kristina / Pöllänen, Pasi / Ripatti, Samuli

Circulation. Genomic and precision medicine

2022 Volume 15, Issue 2, Page(s) e003459

Abstract: Background: Prediction tools that combine polygenic risk scores with clinical factors provide a new opportunity for improved prediction and prevention of atherosclerotic cardiovascular disease, but the clinical utility of polygenic risk score has ... ...

Abstract	Background: Prediction tools that combine polygenic risk scores with clinical factors provide a new opportunity for improved prediction and prevention of atherosclerotic cardiovascular disease, but the clinical utility of polygenic risk score has remained unclear. Methods: We collected a prospective cohort of 7342 individuals (64% women, mean age 56 years) and estimated their 10-year risk for atherosclerotic cardiovascular disease both by a traditional risk score and a composite score combining the effect of a polygenic risk score and clinical risk factors. We then tested how returning the personal risk information with an interactive web-tool impacted on the participants' health behavior. Results: When reassessed after 1.5 years by a clinical visit and questionnaires, 20.8% of individuals at high (>10%) 10-year atherosclerotic cardiovascular disease risk had seen a doctor, 12.4% reported weight loss, 14.2% of smokers had quit smoking, and 15.4% had signed up for health coaching online. Altogether, 42.6% of persons at high risk had made one or more health behavioral changes versus 33.5% of persons at low/average risk such that higher baseline risk predicted a favorable change (OR [CI], 1.53 [1.37-1.72] for persons at high risk versus the rest, Conclusions: Web-based communication of personal atherosclerotic cardiovascular disease risk-data including polygenic risk to middle-aged persons motivates positive changes in health behavior and the propensity to seek care. It supports integration of genomic information into clinical risk calculators as a feasible approach to enhance disease prevention.
MeSH term(s)	Atherosclerosis/genetics ; Cardiovascular Diseases/genetics ; Female ; Follow-Up Studies ; Health Behavior ; Humans ; Male ; Middle Aged ; Prospective Studies ; Risk Factors
Language	English
Publishing date	2022-02-07
Publishing country	United States
Document type	Journal Article ; Observational Study
ISSN	2574-8300
ISSN (online)	2574-8300
DOI	10.1161/CIRCGEN.121.003459
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Article ; Online: Ex vivo

Kuusanmäki, Heikki / Kytölä, Sari / Vänttinen, Ida / Ruokoranta, Tanja / Ranta, Amanda / Huuhtanen, Jani / Suvela, Minna / Parsons, Alun / Holopainen, Annasofia / Partanen, Anu / Kuusisto, Milla E L / Koskela, Sirpa / Räty, Riikka / Itälä-Remes, Maija / Västrik, Imre / Dufva, Olli / Siitonen, Sanna / Porkka, Kimmo / Wennerberg, Krister /

Heckman, Caroline A / Ettala, Pia / Pyörälä, Marja / Rimpiläinen, Johanna / Siitonen, Timo / Kontro, Mika

Haematologica

2023 Volume 108, Issue 7, Page(s) 1768–1781

Abstract: The BCL-2 inhibitor venetoclax has revolutionized the treatment of acute myeloid leukemia (AML) in patients not benefiting from intensive chemotherapy. Nevertheless, treatment failure remains a challenge, and predictive markers are needed, particularly ... ...

Abstract	The BCL-2 inhibitor venetoclax has revolutionized the treatment of acute myeloid leukemia (AML) in patients not benefiting from intensive chemotherapy. Nevertheless, treatment failure remains a challenge, and predictive markers are needed, particularly for relapsed or refractory AML. Ex vivo drug sensitivity testing may correlate with outcomes, but its prospective predictive value remains unexplored. Here we report the results of the first stage of the prospective phase II VenEx trial evaluating the utility and predictiveness of venetoclax sensitivity testing using different cell culture conditions and cell viability assays in patients receiving venetoclax-azacitidine. Participants with de novo AML ineligible for intensive chemotherapy, relapsed or refractory AML, or secondary AML were included. The primary endpoint was the treatment response in participants showing ex vivo sensitivity and the key secondary endpoints were the correlation of sensitivity with responses and survival. Venetoclax sensitivity testing was successful in 38/39 participants. Experimental conditions significantly influenced the predictive accuracy. Blast-specific venetoclax sensitivity measured in conditioned medium most accurately correlated with treatment outcomes; 88% of sensitive participants achieved a treatment response. The median survival was significantly longer for participants who were ex vivo-sensitive to venetoclax (14.6 months for venetoclax-sensitive patients vs. 3.5 for venetoclax-insensitive patients, P<0.001). This analysis illustrates the feasibility of integrating drug-response profiling into clinical practice and demonstrates excellent predictivity. This trial is registered with ClinicalTrials.gov identifier: NCT04267081.
MeSH term(s)	Humans ; Prospective Studies ; Leukemia, Myeloid, Acute/diagnosis ; Leukemia, Myeloid, Acute/drug therapy ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Bridged Bicyclo Compounds, Heterocyclic/pharmacology ; Bridged Bicyclo Compounds, Heterocyclic/therapeutic use ; Antineoplastic Combined Chemotherapy Protocols/pharmacology ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use
Chemical Substances	venetoclax (N54AIC43PW) ; Antineoplastic Agents ; Bridged Bicyclo Compounds, Heterocyclic
Language	English
Publishing date	2023-07-01
Publishing country	Italy
Document type	Journal Article
ZDB-ID	2333-4
ISSN	1592-8721 ; 0017-6567 ; 0390-6078
ISSN (online)	1592-8721
ISSN	0017-6567 ; 0390-6078
DOI	10.3324/haematol.2022.281692
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Article ; Online: Breaking the epithelial polarity barrier in cancer: the strange case of LKB1/PAR-4.

Partanen, Johanna I / Tervonen, Topi A / Klefström, Juha

Philosophical transactions of the Royal Society of London. Series B, Biological sciences

2013 Volume 368, Issue 1629, Page(s) 20130111

Abstract: The PAR clan of polarity regulating genes was initially discovered in a genetic screen searching for genes involved in asymmetric cell divisions in the Caenorhabditis elegans embryo. Today, investigations in worms, flies and mammals have established PAR ... ...

Abstract	The PAR clan of polarity regulating genes was initially discovered in a genetic screen searching for genes involved in asymmetric cell divisions in the Caenorhabditis elegans embryo. Today, investigations in worms, flies and mammals have established PAR proteins as conserved and fundamental regulators of animal cell polarization in a broad range of biological phenomena requiring cellular asymmetries. The human homologue of invertebrate PAR-4, a serine-threonine kinase LKB1/STK11, has caught attention as a gene behind Peutz-Jeghers polyposis syndrome and as a bona fide tumour suppressor gene commonly mutated in sporadic cancer. LKB1 functions as a master regulator of AMP-activated protein kinase (AMPK) and 12 other kinases referred to as the AMPK-related kinases, including four human homologues of PAR-1. The role of LKB1 as part of the energy sensing LKB1-AMPK module has been intensively studied, whereas the polarity function of LKB1, in the context of homoeostasis or cancer, has gained less attention. Here, we focus on the PAR-4 identity of LKB1, discussing the weight of evidence indicating a role for LKB1 in regulation of cell polarity and epithelial integrity across species and highlight recent investigations providing new insight into the old question: does the PAR-4 identity of LKB1 matter in cancer?
MeSH term(s)	AMP-Activated Protein Kinases/metabolism ; Cell Polarity/physiology ; Epithelial Cells/physiology ; Humans ; Models, Biological ; Morphogenesis/physiology ; Neoplasms/physiopathology ; Protein-Serine-Threonine Kinases/metabolism
Chemical Substances	STK11 protein, human (EC 2.7.1.-) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; AMP-Activated Protein Kinases (EC 2.7.11.31)
Language	English
Publishing date	2013-09-23
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	208382-6
ISSN	1471-2970 ; 0080-4622 ; 0264-3839 ; 0962-8436
ISSN (online)	1471-2970
ISSN	0080-4622 ; 0264-3839 ; 0962-8436
DOI	10.1098/rstb.2013.0111
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Article ; Online: Low ferritin levels appear to be associated with worsened health in male repeat blood donors.

Palokangas, Elina / Lobier, Muriel / Partanen, Jukka / Castrén, Johanna / Arvas, Mikko

Vox sanguinis

2021 Volume 116, Issue 10, Page(s) 1042–1050

Abstract: Background and objectives: Frequent blood donation depletes iron stores of blood donors. Iron depletion may lead to anaemia, but the health effects of iron depletion without anaemia in healthy blood donors are not well understood. We studied in the ... ...

Abstract	Background and objectives: Frequent blood donation depletes iron stores of blood donors. Iron depletion may lead to anaemia, but the health effects of iron depletion without anaemia in healthy blood donors are not well understood. We studied in the FinDonor cohort whether worsening of self-rated health of blood donors during the study period was associated with biomarkers for iron levels or other self-reported changes in lifestyle. Materials and methods: We included 1416 participants from the cohort who answered an 89-item questionnaire on their health and lifestyle during their enrolment visit and again at the end of the study. We performed multivariate logistic regression to test if blood donation-related factors affected the probability of reporting worsened health. To set these findings into a more holistic context of health, we subsequently analysed all other questionnaire items with a data-driven exploratory analysis. Results: We found that donation frequency in men and post-menopausal women and ferritin level only in men was associated negatively with worsened health between questionnaires. In the exploratory analysis, stable physical condition was the only questionnaire item that was associated negatively with worsened health in both women and men. Conclusion: Our results suggest that low ferritin level is associated with worsened health even in non-anaemic repeat donors, although we find that when health is analysed more holistically, ferritin and other factors primarily related to blood donation lose their importance.
MeSH term(s)	Anemia, Iron-Deficiency ; Blood Donors ; Cohort Studies ; Female ; Ferritins ; Humans ; Iron ; Male
Chemical Substances	Ferritins (9007-73-2) ; Iron (E1UOL152H7)
Language	English
Publishing date	2021-04-14
Publishing country	England
Document type	Journal Article
ZDB-ID	80313-3
ISSN	1423-0410 ; 0042-9007
ISSN (online)	1423-0410
ISSN	0042-9007
DOI	10.1111/vox.13104
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Article ; Online: Sequential high-sensitivity mutational and chimerism analyses predict responses to post-transplant salvage therapies in MDS.

Ebeling, Freja / Illman, Johanna / Kankainen, Matti / Kontro, Mika / Partanen, Anu / Sahlstedt, Leila / Myllymäki, Mikko / Niittyvuopio, Riitta / Kytölä, Soili

Bone marrow transplantation

2022 Volume 58, Issue 1, Page(s) 100–102

MeSH term(s)	Humans ; Chimerism ; Salvage Therapy ; Hematopoietic Stem Cell Transplantation ; Graft vs Host Disease ; Transplantation Chimera
Language	English
Publishing date	2022-10-17
Publishing country	England
Document type	Letter ; Research Support, Non-U.S. Gov't
ZDB-ID	632854-4
ISSN	1476-5365 ; 0268-3369 ; 0951-3078
ISSN (online)	1476-5365
ISSN	0268-3369 ; 0951-3078
DOI	10.1038/s41409-022-01847-8
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Article ; Online: 3D view to tumor suppression: Lkb1, polarity and the arrest of oncogenic c-Myc.

Partanen, Johanna I / Nieminen, Anni I / Klefstrom, Juha

Cell cycle (Georgetown, Tex.)

2009 Volume 8, Issue 5, Page(s) 716–724

Abstract: Machiavelli wrote, in his famous political treatise Il Principe, about disrupting organization by planting seeds of dissension or by eliminating necessary support elements. Tumor cells do exactly that by disrupting the organized architecture of ... ...

Abstract	Machiavelli wrote, in his famous political treatise Il Principe, about disrupting organization by planting seeds of dissension or by eliminating necessary support elements. Tumor cells do exactly that by disrupting the organized architecture of epithelial cell layers during progression from contained benign tumor to full-blown invasive cancer. However, it is still unclear whether tumor cells primarily break free by activating oncogenes powerful enough to cause chaos or by eliminating tumor suppressor genes guarding the order of the epithelial organization. Studies in Drosophila have exposed genes that encode key regulators of the epithelial apicobasal polarity and which, upon inactivation, cause disorganization of the epithelial layers and promote unscheduled cell proliferation. These polarity regulator/tumor suppressor proteins, which include products of neoplastic tumor suppressor genes (nTSGs), are carefully positioned in polarized epithelial cells to maintain the order of epithelial structures and to impose a restraint on cell proliferation. In this review, we have explored the presence and prevalence of somatic mutations in the human counterparts of Drosophila polarity regulator/tumor suppressor genes across the human cancers. The screen points out LKB1, which is a causal genetic lesion in Peutz-Jeghers cancer syndrome, a gene mutated in certain sporadic cancers and a human homologue of the fly polarity gene par-4. We review the evidence linking Lkb1 protein to polarity regulation in the scope of our recent results suggesting a coupled role for Lkb1 as an architect of organized acinar structures and a suppressor of oncogenic c-Myc. We finally present models to explain how Lkb1-dependent formation of epithelial architecture is coupled to suppression of normal and oncogene-induced proliferation.
MeSH term(s)	Animals ; Cell Cycle ; Cell Polarity ; Drosophila Proteins/genetics ; Drosophila Proteins/metabolism ; Drosophila melanogaster/genetics ; Drosophila melanogaster/metabolism ; Genes, Tumor Suppressor ; Glycogen Synthase Kinase 3 ; Humans ; Oncogenes ; Protein Kinases/genetics ; Protein Kinases/metabolism ; Protein-Serine-Threonine Kinases/genetics ; Protein-Serine-Threonine Kinases/metabolism ; Proto-Oncogene Proteins c-myc/genetics ; Proto-Oncogene Proteins c-myc/metabolism
Chemical Substances	Drosophila Proteins ; Proto-Oncogene Proteins c-myc ; Protein Kinases (EC 2.7.-) ; STK11 protein, human (EC 2.7.1.-) ; LKB1 protein, Drosophila (EC 2.7.11.1) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; Glycogen Synthase Kinase 3 (EC 2.7.11.26) ; Par-1 protein, Drosophila (EC 2.7.11.26)
Language	English
Publishing date	2009-03-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2146183-1
ISSN	1551-4005 ; 1538-4101 ; 1554-8627
ISSN (online)	1551-4005
ISSN	1538-4101 ; 1554-8627
DOI	10.4161/cc.8.5.7786
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Article ; Online: c-Myc blazing a trail of death: coupling of the mitochondrial and death receptor apoptosis pathways by c-Myc.

Nieminen, Anni I / Partanen, Johanna I / Klefstrom, Juha

Cell cycle (Georgetown, Tex.)

2007 Volume 6, Issue 20, Page(s) 2464–2472

Abstract: TRAIL ligand induces selectively apoptosis in tumor cells by binding to two death receptors (DR4 and DR5) and holds promise as a potential therapeutic agent against cancer. While it has been known for long time that TRAIL receptors are commonly expressed ...

Abstract	TRAIL ligand induces selectively apoptosis in tumor cells by binding to two death receptors (DR4 and DR5) and holds promise as a potential therapeutic agent against cancer. While it has been known for long time that TRAIL receptors are commonly expressed in wide variety of normal tissues, it is not well understood why TRAIL kills tumor cells but leaves normal cells unharmed. The prototypic oncogene c-Myc promotes the cell cycle and simultaneously primes activation of the Bcl-2 family controlled mitochondria apoptosis pathway. A striking reflection of the c-Myc-dependent apoptotic sensitization is the dramatic c-Myc-induced vulnerability of cells to TRAIL and other death receptor ligands. Here we summarize the recent findings regarding the death mechanisms of TRAIL/TRAIL receptor system and the connection of c-Myc to the mitochondrial apoptosis pathway, focusing on our work that couples c-Myc via Bak to the TRAIL death receptor pathway. Finally, we present a mitochondria-priming model to explain how c-Myc-Bak interaction amplifies the TRAIL-induced caspase 8-Bid pathway to induce full-blown apoptosis. We discuss the implications of these findings for understanding the selective cytotoxicity of TRAIL and for the therapeutic exploitation of the death receptor pathway.
MeSH term(s)	Animals ; Apoptosis ; Humans ; Mitochondria/metabolism ; Protein Binding ; Proto-Oncogene Proteins c-myc/metabolism ; Receptors, Death Domain/metabolism ; Signal Transduction
Chemical Substances	Proto-Oncogene Proteins c-myc ; Receptors, Death Domain
Language	English
Publishing date	2007-08-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2146183-1
ISSN	1551-4005 ; 1538-4101 ; 1554-8627
ISSN (online)	1551-4005
ISSN	1538-4101 ; 1554-8627
DOI	10.4161/cc.6.20.4917
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Article ; Online: Long-term antidepressant use in general practice: a qualitative study of GPs' views on discontinuation.

Donald, Maria / Partanen, Riitta / Sharman, Leah / Lynch, Johanna / Dingle, Genevieve A / Haslam, Catherine / van Driel, Mieke

The British journal of general practice : the journal of the Royal College of General Practitioners

2021 Volume 71, Issue 708, Page(s) e508–e516

Abstract: Background: There is considerable concern about increasing antidepressant use, with Australians among the highest users in the world. Evidence suggests this is driven by patients on long-term use, rather than new prescriptions. Most antidepressant ... ...

Abstract	Background: There is considerable concern about increasing antidepressant use, with Australians among the highest users in the world. Evidence suggests this is driven by patients on long-term use, rather than new prescriptions. Most antidepressant prescriptions are generated in general practice, and it is likely that attempts to discontinue are either not occurring or are proving unsuccessful. Aim: To explore GPs' insights about long-term antidepressant prescribing and discontinuation. Design and setting: A qualitative interview study with Australian GPs. Method: Semi-structured interviews explored GPs' discontinuation experiences, decision-making, perceived risks and benefits, and support for patients. Data were analysed using reflexive thematic analysis. Results: Three overarching themes were identified from interviews with 22 GPs. The first, 'not a simple deprescribing decision', spoke to the complex decision-making GPs undertake in determining whether a patient is ready to discontinue. The second, 'a journey taken together', captured a set of steps GPs take together with their patients to initiate and set-up adequate support before, during, and after discontinuation. The third, 'supporting change in GPs' prescribing practices', described what GPs would like to see change to better support them and their patients to discontinue antidepressants. Conclusion: GPs see discontinuation of long-term antidepressant use as more than a simple deprescribing decision. It begins with considering a patient's social and relational context, and is a journey involving careful preparation, tailored care, and regular review. These insights suggest interventions to redress long-term use will need to take these considerations into account and be placed in a wider discussion about the use of antidepressants.
MeSH term(s)	Antidepressive Agents/therapeutic use ; Attitude of Health Personnel ; Australia ; General Practice ; General Practitioners ; Humans ; Practice Patterns, Physicians' ; Qualitative Research
Chemical Substances	Antidepressive Agents
Language	English
Publishing date	2021-06-24
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1043148-2
ISSN	1478-5242 ; 0035-8797 ; 0960-1643
ISSN (online)	1478-5242
ISSN	0035-8797 ; 0960-1643
DOI	10.3399/BJGP.2020.0913
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Article: c-Myc primed mitochondria determine cellular sensitivity to TRAIL-induced apoptosis.

Nieminen, Anni I / Partanen, Johanna I / Hau, Annika / Klefstrom, Juha

The EMBO journal

2007 Volume 26, Issue 4, Page(s) 1055–1067

Abstract: Oncogenic c-Myc renders cells sensitive to TRAIL-induced apoptosis, and existing data suggest that c-Myc sensitizes cells to apoptosis by promoting activation of the mitochondrial apoptosis pathway. However, the molecular mechanisms linking the ... ...

Abstract	Oncogenic c-Myc renders cells sensitive to TRAIL-induced apoptosis, and existing data suggest that c-Myc sensitizes cells to apoptosis by promoting activation of the mitochondrial apoptosis pathway. However, the molecular mechanisms linking the mitochondrial effects of c-Myc to the c-Myc-dependent sensitization to TRAIL have remained unresolved. Here, we show that TRAIL induces a weak activation of procaspase-8 but fails to activate mitochondrial proapoptotic effectors Bax and Bak, cytochrome c release or downstream effector caspase-3 in non-transformed human fibroblasts or mammary epithelial cells. Our data is consistent with the model that activation of oncogenic c-Myc primes mitochondria through a mechanism involving activation of Bak and this priming enables weak TRAIL-induced caspase-8 signals to activate Bax. This results in cytochrome c release, activation of downstream caspases and postmitochondrial death-inducing signaling complex -independent augmentation of caspase-8-Bid activity. In conclusion, c-Myc-dependent priming of the mitochondrial pathway is critical for the capacity of TRAIL-induced caspase-8 signals to activate effector caspases and for the establishment of lethal caspase feedback amplification loop in human cells.
MeSH term(s)	Apoptosis/genetics ; Apoptosis/physiology ; Blotting, Western ; Caspase 8/metabolism ; Cell Line ; Humans ; Microscopy, Fluorescence ; Mitochondria/metabolism ; Models, Biological ; Proto-Oncogene Proteins c-myc/metabolism ; Signal Transduction/genetics ; Signal Transduction/physiology ; TNF-Related Apoptosis-Inducing Ligand/genetics ; TNF-Related Apoptosis-Inducing Ligand/metabolism ; bcl-2-Associated X Protein/metabolism
Chemical Substances	BAX protein, human ; MYC protein, human ; Proto-Oncogene Proteins c-myc ; TNF-Related Apoptosis-Inducing Ligand ; TNFSF10 protein, human ; bcl-2-Associated X Protein ; Caspase 8 (EC 3.4.22.-)
Language	English
Publishing date	2007-02-21
Publishing country	England
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	586044-1
ISSN	1460-2075 ; 0261-4189
ISSN (online)	1460-2075
ISSN	0261-4189
DOI	10.1038/sj.emboj.7601551
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