| 1. |
- Abbafati, Cristiana, et al.
(författare)
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- 2020
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Tidskriftsartikel (refereegranskat)
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| 2. |
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| 3. |
- Blattner, Mirjam, et al.
(författare)
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SPOP Mutations in Prostate Cancer across Demographically Diverse Patient Cohorts
- 2014
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Ingår i: Neoplasia. - New York : Elsevier. - 1522-8002 .- 1476-5586. ; 16:1, s. 14-U34
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Recurrent mutations in the Speckle-Type POZ Protein (SPOP) gene occur in up to 15% of prostate cancers. However, the frequency and features of cancers with these mutations across different populations is unknown.OBJECTIVE: To investigate SPOP mutations across diverse cohorts and validate a series of assays employing high-resolution melting (HRM) analysis and Sanger sequencing for mutational analysis of formalin-fixed paraffin-embedded material.DESIGN, SETTING, AND PARTICIPANTS: 720 prostate cancer samples from six international cohorts spanning Caucasian, African American, and Asian patients, including both prostate-specific antigen-screened and unscreened populations, were screened for their SPOP mutation status. Status of SPOP was correlated to molecular features (ERG rearrangement, PTEN deletion, and CHD1 deletion) as well as clinical and pathologic features.RESULTS AND LIMITATIONS: Overall frequency of SPOP mutations was 8.1% (4.6% to 14.4%), SPOP mutation was inversely associated with ERG rearrangement (P < .01), and SPOP mutant (SPOPmut) cancers had higher rates of CHD1 deletions (P < .01). There were no significant differences in biochemical recurrence in SPOPmut cancers. Limitations of this study include missing mutational data due to sample quality and lack of power to identify a difference in clinical outcomes.CONCLUSION: SPOP is mutated in 4.6% to 14.4% of patients with prostate cancer across different ethnic and demographic backgrounds. There was no significant association between SPOP mutations with ethnicity, clinical, or pathologic parameters. Mutual exclusivity of SPOP mutation with ERG rearrangement as well as a high association with CHD1 deletion reinforces SPOP mutation as defining a distinct molecular subclass of prostate cancer.
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| 5. |
- O'Regan, Matthew, et al.
(författare)
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Plio-Pleistocene trends in ice rafted debris on the Lomonosov Ridge
- 2010
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Ingår i: Quaternary International. - : Elsevier BV. - 1040-6182 .- 1873-4553. ; 19:1-2, s. 168-176
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Tidskriftsartikel (refereegranskat)abstract
- Although more than 700 sediment cores exist from the Arctic Ocean, the Plio-Pleistocene evolution of the basin and its marginal seas remains virtually unknown. This is largely due the shallow penetration of most of these records, and difficulties associated with deriving chronologies for the recovered material. The Integrated Ocean Drilling Program's (IODP) Expedition 302 (Arctic Coring Expedition, ACEX) recovered 197 m of Neogene/Quaternary sediment from the circumpolar regions of the Lomonosov Ridge. As detailed analyses of this material emerge, research is beginning to formulate a long-term picture of paleoceanographic changes in the central Arctic Ocean. This paper reviews the ACEX Plio-Pleistocene age model, identifies uncertainties, and addresses ways in which these may be eliminated. Within the established stratigraphic framework, a notable reduction in the abundance of ice rafted debris (IRD) occurs in the early part of the Pleistocene and persists until Marine Isotope Stage 6 (MIS 6). Therefore, while global oceanographic proxies indicate the gradual growth of terrestrial ice-sheets during this time, IRD delivery to the central Arctic Ocean remained comparatively low and stable. Within the resolution of existing data, the Pleistocene reduction in IRD is synchronous with predicted changes in both the inflow of North Atlantic and Pacific waters, which in modern times are known to exert a strong influence on sea ice stability.
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| 6. |
- Walsh, Louise, et al.
(författare)
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BET Inhibition as a Rational Therapeutic Strategy for Invasive Lobular Breast Cancer
- 2019
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Ingår i: Clinical cancer research : an official journal of the American Association for Cancer Research. - 1078-0432. ; 25:23, s. 7139-7150
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Invasive lobular carcinoma (ILC) is a subtype of breast cancer accounting for 10% of breast tumors. The majority of patients are treated with endocrine therapy; however, endocrine resistance is common in estrogen receptor-positive breast cancer and new therapeutic strategies are needed. Bromodomain and extraterminal inhibitors (BETi) are effective in diverse types of breast cancer but they have not yet been assessed in ILC.EXPERIMENTAL DESIGN: We assessed whether targeting the BET proteins with JQ1 could serve as an effective therapeutic strategy in ILC in both 2D and 3D models. We used dynamic BH3 profiling and RNA-sequencing (RNA-seq) to identify transcriptional reprograming enabling resistance to JQ1-induced apoptosis. As part of the RATHER study, we obtained copy-number alterations and RNA-seq on 61 ILC patient samples.RESULTS: Certain ILC cell lines were sensitive to JQ1, while others were intrinsically resistant to JQ1-induced apoptosis. JQ1 treatment led to an enhanced dependence on antiapoptotic proteins and a transcriptional rewiring inducing fibroblast growth factor receptor 1 (FGFR1). This increase in FGFR1 was also evident in invasive ductal carcinoma (IDC) cell lines. The combination of JQ1 and FGFR1 inhibitors was highly effective at inhibiting growth in both 2D and 3D models of ILC and IDC. Interestingly, we found in the RATHER cohort of 61 ILC patients that 20% had FGFR1 amplification and we showed that high BRD3 mRNA expression was associated with poor survival specifically in ILC.CONCLUSIONS: We provide evidence that BETi either alone or in combination with FGFR1 inhibitors or BH3 mimetics may be a useful therapeutic strategy for recurrent ILC patients.
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