| 1. |
|
|
| 2. |
|
|
| 3. |
- Mourikis, TP, et al.
(författare)
-
Patient-specific cancer genes contribute to recurrently perturbed pathways and establish therapeutic vulnerabilities in esophageal adenocarcinoma
- 2019
-
Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 3101-
-
Tidskriftsartikel (refereegranskat)abstract
- The identification of cancer-promoting genetic alterations is challenging particularly in highly unstable and heterogeneous cancers, such as esophageal adenocarcinoma (EAC). Here we describe a machine learning algorithm to identify cancer genes in individual patients considering all types of damaging alterations simultaneously. Analysing 261 EACs from the OCCAMS Consortium, we discover helper genes that, alongside well-known drivers, promote cancer. We confirm the robustness of our approach in 107 additional EACs. Unlike recurrent alterations of known drivers, these cancer helper genes are rare or patient-specific. However, they converge towards perturbations of well-known cancer processes. Recurrence of the same process perturbations, rather than individual genes, divides EACs into six clusters differing in their molecular and clinical features. Experimentally mimicking the alterations of predicted helper genes in cancer and pre-cancer cells validates their contribution to disease progression, while reverting their alterations reveals EAC acquired dependencies that can be exploited in therapy.
|
|
| 4. |
|
|
| 5. |
|
|
| 6. |
|
|
| 7. |
- Turkington, RC, et al.
(författare)
-
Immune activation by DNA damage predicts response to chemotherapy and survival in oesophageal adenocarcinoma
- 2019
-
Ingår i: Gut. - : BMJ. - 1468-3288 .- 0017-5749. ; 68:11, s. 1918-1927
-
Tidskriftsartikel (refereegranskat)abstract
- Current strategies to guide selection of neoadjuvant therapy in oesophageal adenocarcinoma (OAC) are inadequate. We assessed the ability of a DNA damage immune response (DDIR) assay to predict response following neoadjuvant chemotherapy in OAC.DesignTranscriptional profiling of 273 formalin-fixed paraffin-embedded prechemotherapy endoscopic OAC biopsies was performed. All patients were treated with platinum-based neoadjuvant chemotherapy and resection between 2003 and 2014 at four centres in the Oesophageal Cancer Clinical and Molecular Stratification consortium. CD8 and programmed death ligand 1 (PD-L1) immunohistochemical staining was assessed in matched resection specimens from 126 cases. Kaplan-Meier and Cox proportional hazards regression analysis were applied according to DDIR status for recurrence-free survival (RFS) and overall survival (OS).ResultsA total of 66 OAC samples (24%) were DDIR positive with the remaining 207 samples (76%) being DDIR negative. DDIR assay positivity was associated with improved RFS (HR: 0.61; 95% CI 0.38 to 0.98; p=0.042) and OS (HR: 0.52; 95% CI 0.31 to 0.88; p=0.015) following multivariate analysis. DDIR-positive patients had a higher pathological response rate (p=0.033), lower nodal burden (p=0.026) and reduced circumferential margin involvement (p=0.007). No difference in OS was observed according to DDIR status in an independent surgery-alone dataset.DDIR-positive OAC tumours were also associated with the presence of CD8+ lymphocytes (intratumoural: p<0.001; stromal: p=0.026) as well as PD-L1 expression (intratumoural: p=0.047; stromal: p=0.025).ConclusionThe DDIR assay is strongly predictive of benefit from DNA-damaging neoadjuvant chemotherapy followed by surgical resection and is associated with a proinflammatory microenvironment in OAC.
|
|
| 8. |
- Wootton, K. P., et al.
(författare)
-
Storage ring lattice calibration using resonant spin depolarization
- 2013
-
Ingår i: Physical Review Special Topics. Accelerators and Beams. - 1098-4402. ; 16:7
-
Tidskriftsartikel (refereegranskat)abstract
- This paper presents measurements of the GeV-scale electron beam energy for the storage rings at the synchrotron light source facilities Australian Synchrotron (AS) and SPEAR3 at SLAC. Resonant spin depolarization was employed in the beam energy measurement, since it is presently the highest precision technique and an uncertainty of order 10(-6) was achieved at SPEAR3 and AS. Using the resonant depolarization technique, the beam energy was measured at various rf frequencies to measure the linear momentum compaction factor. This measured linear momentum compaction factor was used to evaluate models of the beam trajectory through combined-function bending magnets. The main bending magnets of both lattices are rectangular, horizontally defocusing gradient bending magnets. Four modeling approaches are compared for the beam trajectory through the bending magnet: a circular trajectory, linear and nonlinear hyperbolic cosine trajectories, and numerical evaluation of the trajectory through the measured magnetic field map. Within the uncertainty of the measurement the momentum compaction factor is shown to agree with the numerical model of the trajectory within the bending magnet, and disagree with the hyperbolic cosine approximation.
|
|
