| 1. |
- Tanskanen, T., et al.
(författare)
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Genome-wide association study and meta-analysis in Northern European populations replicate multiple colorectal cancer risk loci
- 2018
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Ingår i: International Journal of Cancer. - Stockholm : Wiley. - 0020-7136 .- 1097-0215. ; 142:3, s. 540-546
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies have been successful in elucidating the genetic basis of colorectal cancer (CRC), but there remains unexplained variability in genetic risk. To identify new risk variants and to confirm reported associations, we conducted a genome-wide association study in 1,701 CRC cases and 14,082 cancer-free controls from the Finnish population. A total of 9,068,015 genetic variants were imputed and tested, and 30 promising variants were studied in additional 11,647 cases and 12,356 controls of European ancestry. The previously reported association between the single-nucleotide polymorphism (SNP) rs992157 (2q35) and CRC was independently replicated (p=2.08 x 10(-4); OR, 1.14; 95% CI, 1.06-1.23), and it was genome-wide significant in combined analysis (p=1.50 x 10(-9); OR, 1.12; 95% CI, 1.08-1.16). Variants at 2q35, 6p21.2, 8q23.3, 8q24.21, 10q22.3, 10q24.2, 11q13.4, 11q23.1, 14q22.2, 15q13.3, 18q21.1, 20p12.3 and 20q13.33 were associated with CRC in the Finnish population (false discovery rate<0.1), but new risk loci were not found. These results replicate the effects of multiple loci on the risk of CRC and identify shared risk alleles between the Finnish population isolate and outbred populations.
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| 2. |
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| 3. |
- Carreras-Puigvert, Jordi, et al.
(författare)
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A comprehensive structural, biochemical and biological profiling of the human NUDIX hydrolase family
- 2017
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Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- The NUDIX enzymes are involved in cellular metabolism and homeostasis, as well as mRNA processing. Although highly conserved throughout all organisms, their biological roles and biochemical redundancies remain largely unclear. To address this, we globally resolve their individual properties and inter-relationships. We purify 18 of the human NUDIX proteins and screen 52 substrates, providing a substrate redundancy map. Using crystal structures, we generate sequence alignment analyses revealing four major structural classes. To a certain extent, their substrate preference redundancies correlate with structural classes, thus linking structure and activity relationships. To elucidate interdependence among the NUDIX hydrolases, we pairwise deplete them generating an epistatic interaction map, evaluate cell cycle perturbations upon knockdown in normal and cancer cells, and analyse their protein and mRNA expression in normal and cancer tissues. Using a novel FUSION algorithm, we integrate all data creating a comprehensive NUDIX enzyme profile map, which will prove fundamental to understanding their biological functionality.
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| 4. |
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| 5. |
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| 6. |
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| 7. |
- Eklund, Jörgen, et al.
(författare)
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Lean implementation, work environment and sustainability
- 2015
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Ingår i: Sustainable Development in Organizations. - : Edward Elgar Publishing. - 9781784716882 ; , s. 29-41
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Bokkapitel (refereegranskat)abstract
- Lean is introduced in industry as well as in the public sector. Previous research has criticized Lean for creating bad working conditions. Also sustainability of organizational changes is claimed to be low. The aim of this chapter is to describe consequences for working conditions and sustainability as a result of implementations of Lean in manufacturing industry and in the public sector. A second aim is to give examples of the type of knowledge produced in an interactive research approach and to discuss the use of interactive research when implementing Lean. Two programs for implementing Lean were assessed through interactive research. The research showed that there is a huge variation between organizations regarding how Lean is interpreted, how it is implemented, and also regarding the outcomes. The majority of the employees in the manufacturing companies experienced that Lean meant improved working conditions, e.g. more participation, learning and development. However they also experienced more stress and repetitive work. For the public organizations, the employees experienced on average that the working conditions had deteriorated. Sustainability of the changes was also substantially lower than for the manufacturing companies. The interactive research approach enabled deep access to a broad sample of organizations and contributed to better relevance and validity of the research results.
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| 8. |
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| 9. |
- Hamsten, C., et al.
(författare)
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Protein profiles of CCL5, HPGDS, and NPSR1 in plasma reveal association with childhood asthma
- 2016
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Ingår i: Allergy. European Journal of Allergy and Clinical Immunology. - : Blackwell Publishing. - 0105-4538 .- 1398-9995. ; 71:9, s. 1357-1361
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Tidskriftsartikel (refereegranskat)abstract
- Asthma is a common chronic childhood disease with many different phenotypes that need to be identified. We analyzed a broad range of plasma proteins in children with well-characterized asthma phenotypes to identify potential markers of childhood asthma. Using an affinity proteomics approach, plasma levels of 362 proteins covered by antibodies from the Human Protein Atlas were investigated in a total of 154 children with persistent or intermittent asthma and controls. After screening, chemokine ligand 5 (CCL5) hematopoietic prostaglandin D synthase (HPGDS) and neuropeptide S receptor 1 (NPSR1) were selected for further investigation. Significantly lower levels of both CCL5 and HPGDS were found in children with persistent asthma, while NPSR1 was found at higher levels in children with mild intermittent asthma compared to healthy controls. In addition, the protein levels were investigated in another respiratory disease, sarcoidosis, showing significantly higher NPSR1 levels in sera from sarcoidosis patients compared to healthy controls. Immunohistochemical staining of healthy tissues revealed high cytoplasmic expression of HPGDS in mast cells, present in stroma of both airway epithelia, lung as well as in other organs. High expression of NPSR1 was observed in neuroendocrine tissues, while no expression was observed in airway epithelia or lung. In conclusion, we have utilized a broad-scaled affinity proteomics approach to identify three proteins with altered plasma levels in asthmatic children, representing one of the first evaluations of HPGDS and NPSR1 protein levels in plasma.
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| 10. |
- Iwaya, Leonardo H., et al.
(författare)
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Firewall Usability and Visualization : A Systematic Literature Review
- 2016
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Rapport (refereegranskat)abstract
- Firewalls are network security components that allow administrators to handle incoming and outgoing traffic based on a set of rules. Such security appliances are typically the first line of defense, creating a barrier between organization’s internal network and the outside network (e.g., Internet). The process of correctly configuring a firewall is complex and error prone, and it only gets worse as the complexity of the network grows. A vulnerable firewall configuration will very likely result in major threats to the organization’s security. In this report we aim to investigate how to make administrator task of planning and implementing firewall solutions easier, from the stand points of usability and visualization. Our scientific investigation starts with the understanding of the state-of-the-art on this specific field. To do so, we conducted a Systematic Literature Review (SLR), a strict methodology to plan a literature review, to gather relevant information, to synthesize and compare approaches, and to report findings. During the initial search process thousands of papers were screened, leading us to 125 papers carefully selected for further readings. In the secondary study, ten relevant works were identified and assessed, in which authors tackled the issues of usability and visualization for Firewalls and Personal Firewalls. Among the main findings, we perceive that there is a lack (or even absence) of user studies to validate the proposed models. This leads us to a series of unwarranted solutions, that need to be prototyped and tested with real users. We also see an huge opportunity for integrative approaches, that could combine firewall research areas, such as automatic anomaly detection, advisory systems, and varying visualization schemes.
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| 11. |
- Jounger, SL, et al.
(författare)
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Repeated buffered acidic saline infusion in the human masseter muscle as a putative experimental pain model
- 2019
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1, s. 15474-
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Tidskriftsartikel (refereegranskat)abstract
- This study investigated if repeated buffered acidic saline infusions into the masseter muscles induced muscle pain and mechanical sensitization. Fourteen healthy men participated in this double-blind, randomized, and placebo-controlled study. Two repeated infusions (day 1 and 3) were given in the masseter muscles with either a buffered acidic saline solution (pH 5.2) or an isotonic saline solution (pH 6) as control. After 10 days of wash-out, the experiment was repeated with the other substance. Pressure pain thresholds (PPT), pain intensity, maximum unassisted mouth opening (MUO), and pain drawings were assessed before, directly following, and after each infusion at 5, 15, and 30 min and on day 4 and 7. Fatigue and pain intensity were assessed after a one-minute chewing test 30 min after infusions and day 4 and 7. Acidic saline induced higher pain intensity than control day 3 up to 5 min after infusions, but did not affect PPT. The chewing test did not evoke higher fatigue during chewing or MUO or after acidic saline infusion compared to control. Repeated acidic saline infusions in the masseter muscles induced a short-lasting muscle pain without mechanical hyperalgesia or functional pain. Hence, this model might not be superior to already existing experimental muscle pain models.
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| 12. |
- Lindskog, Anders, et al.
(författare)
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Dating of sedimentary rock intervals using visual comparison of carbon isotope records : a comment on the recent paper by Bergström et al. concerning the age of the Winneshiek Shale
- 2019
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Ingår i: Lethaia. - : Scandinavian University Press / Universitetsforlaget AS. - 0024-1164 .- 1502-3931. ; 52:3, s. 299-303
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Tidskriftsartikel (refereegranskat)abstract
- The recently published Lethaia paper by Bergström et al. (https://doi.org/10.1111/let.12269) on the age of the Ordovician Winneshiek Shale (Iowa, USA), and the impact that formed the Decorah crater which hosts this rock unit, is an interesting scientific contribution, although there are a number of problems with the interpretations and data presentation that merit comment. Due mainly to a lack of adequate critical assessment of δ13C data and biostratigraphical control, we contend that the conclusions of Bergström et al. are poorly founded and should not be cursorily accepted and propagated in future scientific literature.
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| 13. |
- Lindskog, Anders, et al.
(författare)
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Lower–Middle Ordovician carbon and oxygen isotope chemostratigraphy at Hällekis, Sweden : implications for regional to global correlation and palaeoenvironmental development
- 2019
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Ingår i: Lethaia. - : Scandinavian University Press / Universitetsforlaget AS. - 0024-1164 .- 1502-3931. ; 52:2, s. 204-219
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Tidskriftsartikel (refereegranskat)abstract
- A high-resolution chemostratigraphical (coupled δ13Ccarb and δ18Ocarb) study of the topmost Floian through the middle Darriwilian (Ordovician) succession at the Hällekis quarry, Kinnekulle, southern Sweden, shows relatively steady isotopic values with overall minor changes, although some notable short- and long-term shifts are discernible. A pronounced positive shift in δ13C in the uppermost part of the study succession is identified as the Middle Darriwilian Isotopic Carbon Excursion (MDICE), representing the only named global isotopic excursion in the data set. Regional and global comparisons suggest that few details in the different carbon and oxygen isotope curves can be confidently correlated, but longer-term patterns appear quite consistent. Trends in the isotope data are in agreement with palaeogeographical reconstructions. Differences in stratigraphical patterns of both carbon and oxygen isotopes between localities suggest strong secular development at several spatiotemporal scales; any global signal involving relatively minor isotopic shifts is often masked/subdued by local and regional overprinting and care should be taken not to overinterpret data sets. Collectively, the data suggest rising sea levels and cooling climates through the studied time interval, but detailed interpretations remain problematic.
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| 14. |
- Lindskog, A., et al.
(författare)
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Refined Ordovician timescale reveals no link between asteroid breakup and biodiversification
- 2017
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- The catastrophic disruption of the L chondrite parent body in the asteroid belt c. 470 Ma initiated a prolonged meteorite bombardment of Earth that started in the Ordovician and continues today. Abundant L chondrite meteorites in Middle Ordovician strata have been interpreted to be the consequence of the asteroid breakup event. Here we report a zircon U-Pb date of 467.50±0.28 Ma from a distinct bed within the meteorite-bearing interval of southern Sweden that, combined with published cosmic-ray exposure ages of co-occurring meteoritic material, provides a precise age for the L chondrite breakup at 468.0±0.3 Ma. The new zircon date requires significant revision of the Ordovician timescale that has implications for the understanding of the astrogeobiologic development during this period. It has been suggested that the Middle Ordovician meteorite bombardment played a crucial role in the Great Ordovician Biodiversification Event, but this study shows that the two phenomena were unrelated.
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| 15. |
- Lindskog, Cecilia, et al.
(författare)
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The human cardiac and skeletal muscle proteomes defined by transcriptomics and antibody-based profiling
- 2015
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Ingår i: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- Background: To understand cardiac and skeletal muscle function, it is important to define and explore their molecular constituents and also to identify similarities and differences in the gene expression in these two different striated muscle tissues. Here, we have investigated the genes and proteins with elevated expression in cardiac and skeletal muscle in relation to all other major human tissues and organs using a global transcriptomics analysis complemented with antibody-based profiling to localize the corresponding proteins on a single cell level. Results: Our study identified a comprehensive list of genes expressed in cardiac and skeletal muscle. The genes with elevated expression were further stratified according to their global expression pattern across the human body as well as their precise localization in the muscle tissues. The functions of the proteins encoded by the elevated genes are well in line with the physiological functions of cardiac and skeletal muscle, such as contraction, ion transport, regulation of membrane potential and actomyosin structure organization. A large fraction of the transcripts in both cardiac and skeletal muscle correspond to mitochondrial proteins involved in energy metabolism, which demonstrates the extreme specialization of these muscle tissues to provide energy for contraction. Conclusions: Our results provide a comprehensive list of genes and proteins elevated in striated muscles. A number of proteins not previously characterized in cardiac and skeletal muscle were identified and localized to specific cellular subcompartments. These proteins represent an interesting starting point for further functional analysis of their role in muscle biology and disease.
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| 16. |
- Malipatlolla, Dilip, 1990, et al.
(författare)
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Long-term mucosal injury and repair in a murine model of pelvic radiotherapy
- 2019
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Chronic intestinal injury after pelvic radiotherapy affects countless cancer survivors worldwide. A comprehensive understanding of the long-term injury dynamics is prevented in available animal models. With linear accelerators that are used to treat cancer in patients, we irradiated a small volume encompassing the colorectum in mice with four fractions of 8 Gy per fraction. We then determined the long-term dynamics of mucosal injury, repair, and the duration of inflammation. We show that crypt fission, not cell proliferation, is the main long-term mechanism for rescuing crypt density after irradiation, and provides a potentially wide window for clinical interventions. Persisting macrophage aggregations indicate a chronic mucosal inflammation. A better understanding as to how crypt fission is triggered and why it fails to repair fully the mucosa may help restore bowel health after pelvic radiotherapy. Moreover, anti-inflammatory interventions, even if implemented long after completed radiotherapy, could promote bowel health in pelvic cancer survivors.
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| 17. |
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| 18. |
- Rasmussen, Christian, et al.
(författare)
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Onset of main Phanerozoic marine radiation sparked by emerging Mid Ordovician icehouse.
- 2016
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- The Great Ordovician Biodiversification Event (GOBE) was the most rapid and sustained increase in marine Phanerozoic biodiversity. What generated this biotic response across Palaeozoic seascapes is a matter of debate; several intrinsic and extrinsic drivers have been suggested. One is Ordovician climate, which in recent years has undergone a paradigm shift from a text-book example of an extended greenhouse to an interval with transient cooling intervals - at least during the Late Ordovician. Here, we show the first unambiguous evidence for a sudden Mid Ordovician icehouse, comparable in magnitude to the Quaternary glaciations. We further demonstrate the initiation of this icehouse to coincide with the onset of the GOBE. This finding is based on both abiotic and biotic proxies obtained from the most comprehensive geochemical and palaeobiological dataset yet collected through this interval. We argue that the icehouse conditions increased latitudinal and bathymetrical temperature and oxygen gradients initiating an Early Palaeozoic Great Ocean Conveyor Belt. This fuelled the GOBE, as upwelling zones created new ecospace for the primary producers. A subsequent rise in δ(13)C ratios known as the Middle Darriwilian Isotopic Carbon Excursion (MDICE) may reflect a global response to increased bioproductivity encouraged by the onset of the GOBE.
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| 19. |
- Thul, Peter J., et al.
(författare)
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A subcellular map of the human proteome
- 2017
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Ingår i: Science. - : American Association for the Advancement of Science. - 0036-8075 .- 1095-9203. ; 356:6340
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Tidskriftsartikel (refereegranskat)abstract
- Resolving the spatial distribution of the human proteome at a subcellular level can greatly increase our understanding of human biology and disease. Here we present a comprehensive image-based map of subcellular protein distribution, the Cell Atlas, built by integrating transcriptomics and antibody-based immunofluorescence microscopy with validation by mass spectrometry. Mapping the in situ localization of 12,003 human proteins at a single-cell level to 30 subcellular structures enabled the definition of the proteomes of 13 major organelles. Exploration of the proteomes revealed single-cell variations in abundance or spatial distribution and localization of about half of the proteins to multiple compartments. This subcellular map can be used to refine existing protein-protein interaction networks and provides an important resource to deconvolute the highly complex architecture of the human cell.
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| 20. |
- Zhao, Ziran, et al.
(författare)
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PPP2R2A prostate cancer haploinsufficiency is associated with worse prognosis and a high vulnerability to B55 alpha/PP2A reconstitution that triggers centrosome destabilization
- 2019
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Ingår i: Oncogenesis. - : NATURE PUBLISHING GROUP. - 2157-9024. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- The PPP2R2A gene encodes the B55 alpha regulatory subunit of PP2A. Here, we report that PPP2R2A is hemizygously lost in similar to 42% of prostate adenocarcinomas, correlating with reduced expression, poorer prognosis, and an increased incidence of hemizygous loss (>75%) in metastatic disease. Of note, PPP2R2A homozygous loss is less common (5%) and not increased at later tumor stages. Reduced expression of B55 alpha is also seen in prostate tumor tissue and cell lines. Consistent with the possibility that complete loss of PPP2R2A is detrimental in prostate tumors, PPP2R2A deletion in cells with reduced but present B55 alpha reduces cell proliferation by slowing progression through the cell cycle. Remarkably, B55 alpha-low cells also appear addicted to lower B55 alpha expression, as even moderate increases in B55 alpha expression are toxic. Reconstitution of B55 alpha expression in prostate cancer (PCa) cell lines with low B55 alpha expression reduces proliferation, inhibits transformation and blocks xenograft tumorigenicity. Mechanistically, we show B55 alpha reconstitution reduces phosphorylation of proteins essential for centrosomal maintenance, and induces centrosome collapse and chromosome segregation failure; a first reported link between B55 alpha/PP2A and the vertebrate centrosome. These effects are dependent on a prolonged metaphase/anaphase checkpoint and are lethal to PCa cells addicted to low levels of B55 alpha. Thus, we propose the reduction in B55 alpha levels associated with hemizygous loss is necessary for centrosomal integrity in PCa cells, leading to selective lethality of B55 alpha reconstitution. Such a vulnerability could be targeted therapeutically in the large pool of patients with hemizygous PPP2R2A deletions, using pharmacologic approaches that enhance PP2A/B55 alpha activity.
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