| 1. |
- Abbassi, Fariba, et al.
(författare)
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Novel Benchmark Values for Redo Liver Transplantation Does the Outcome Justify the Effort?
- 2022
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Ingår i: Annals of Surgery. - : Lippincott Williams & Wilkins. - 0003-4932 .- 1528-1140. ; 276:5, s. 860-867
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To define benchmark cutoffs for redo liver transplantation (redo-LT). Background: In the era of organ shortage, redo-LT is frequently discussed in terms of expected poor outcome and wasteful resources. However, there is a lack of benchmark data to reliably evaluate outcomes after redo-LT. Methods: We collected data on redo-LT between January 2010 and December 2018 from 22 high-volume transplant centers. Benchmark cases were defined as recipients with model of end stage liver disease (MELD) score <= 25, absence of portal vein thrombosis, no mechanical ventilation at the time of surgery, receiving a graft from a donor after brain death. Also, high-urgent priority and early redo-LT including those for primary nonfunction (PNF) or hepatic artery thrombosis were excluded. Benchmark cutoffs were derived from the 75th percentile of the medians of all benchmark centers. Results: Of 1110 redo-LT, 373 (34%) cases qualified as benchmark cases. Among these cases, the rate of postoperative complications until discharge was 76%, and increased up to 87% at 1-year, respectively. One-year overall survival rate was excellent with 90%. Benchmark cutoffs included Comprehensive Complication Index CCI (R) at 1-year of <= 72, and in-hospital and 1-year mortality rates of <= 13% and <= 15%, respectively. In contrast, patients who received a redo-LT for PNF showed worse outcomes with some values dramatically outside the redoLT benchmarks. Conclusion: This study shows that redo-LT achieves good outcome when looking at benchmark scenarios. However, this figure changes in high-risk redo-LT, as for example in PNF. This analysis objectifies for the first-time results and efforts for redo-LT and can serve as a basis for discussion about the use of scarce resources.
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| 2. |
- Desai, Trishna A., et al.
(författare)
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Identifying proteomic risk factors for overall, aggressive, and early onset prostate cancer using Mendelian Randomisation and tumour spatial transcriptomics
- 2024
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Ingår i: EBioMedicine. - : Elsevier. - 2352-3964. ; 105
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Tidskriftsartikel (refereegranskat)abstract
- Background Understanding the role of circulating proteins in prostate cancer risk can reveal key biological pathways and identify novel targets for cancer prevention. Methods We investigated the association of 2002 genetically predicted circulating protein levels with risk of prostate cancer overall, and of aggressive and early onset disease, using cis- pQTL Mendelian randomisation (MR) and colocalisation. Findings for proteins with support from both MR, after correction for multiple -testing, and colocalisation were replicated using two independent cancer GWAS, one of European and one of African ancestry. Proteins with evidence of prostate -speci fi c tissue expression were additionally investigated using spatial transcriptomic data in prostate tumour tissue to assess their role in tumour aggressiveness. Finally, we mapped risk proteins to drug and ongoing clinical trials targets. Findings We identi fi ed 20 proteins genetically linked to prostate cancer risk (14 for overall [8 speci fi c], 7 for aggressive [3 speci fi c], and 8 for early onset disease [2 speci fi c]), of which the majority replicated where data were available. Among these were proteins associated with aggressive disease, such as PPA2 [Odds Ratio (OR) per 1 SD increment = 2.13, 95% CI: 1.54 - 2.93], PYY [OR = 1.87, 95% CI: 1.43 - 2.44] and PRSS3 [OR = 0.80, 95% CI: 0.73 - 0.89], and those associated with early onset disease, including EHPB1 [OR = 2.89, 95% CI: 1.99 - 4.21], POGLUT3 [OR = 0.76, 95% CI: 0.67 - 0.86] and TPM3 [OR = 0.47, 95% CI: 0.34 - 0.64]. We con fi rmed an inverse association of MSMB with prostate cancer overall [OR = 0.81, 95% CI: 0.80 - 0.82], and also found an inverse association with both aggressive [OR = 0.84, 95% CI: 0.82 - 0.86] and early onset disease [OR = 0.71, 95% CI: 0.68 - 0.74]. Using spatial transcriptomics data, we identi fi ed MSMB as the genome-wide top -most predictive gene to distinguish benign regions from high grade cancer regions that comparatively had fi ve -fold lower MSMB expression. Additionally, ten proteins that were associated with prostate cancer risk also mapped to existing therapeutic interventions. Interpretation Our fi ndings emphasise the importance of proteomics for improving our understanding of prostate cancer aetiology and of opportunities for novel therapeutic interventions. Additionally, we demonstrate the added bene fi t of in-depth functional analyses to triangulate the role of risk proteins in the clinical aggressiveness of prostate tumours. Using these integrated methods, we identify a subset of risk proteins associated with aggressive and early onset disease as priorities for investigation for the future prevention and treatment of prostate cancer.
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| 3. |
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| 4. |
- Figiel, Sandy, et al.
(författare)
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Spatial transcriptomic analysis of virtual prostate biopsy reveals confounding effect of tissue heterogeneity on genomic signatures
- 2023
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Ingår i: Molecular Cancer. - : Springer Nature. - 1476-4598. ; 22:1, s. 162-
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Genetic signatures have added a molecular dimension to prognostics and therapeutic decision-making. However, tumour heterogeneity in prostate cancer and current sampling methods could confound accurate assessment. Based on previously published spatial transcriptomic data from multifocal prostate cancer, we created virtual biopsy models that mimic conventional biopsy placement and core size. We then analysed the gene expression of different prognostic signatures (OncotypeDx®, Decipher®, Prostadiag®) using a step-wise approach with increasing resolution from pseudo-bulk analysis of the whole biopsy, to differentiation by tissue subtype (benign, stroma, tumour), followed by distinct tumour grade and finally clonal resolution. The gene expression profile of virtual tumour biopsies revealed clear differences between grade groups and tumour clones, compared to a benign control, which were not reflected in bulk analyses. This suggests that bulk analyses of whole biopsies or tumour-only areas, as used in clinical practice, may provide an inaccurate assessment of gene profiles. The type of tissue, the grade of the tumour and the clonal composition all influence the gene expression in a biopsy. Clinical decision making based on biopsy genomics should be made with caution while we await more precise targeting and cost-effective spatial analyses.
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| 5. |
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| 6. |
- Gapińska, Marta, et al.
(författare)
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Structure-functional characterization of Lactococcus AbiA phage defense system
- 2024
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Ingår i: Nucleic Acids Research. - 1362-4962. ; 52:8, s. 4723-4738
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Tidskriftsartikel (refereegranskat)abstract
- Bacterial reverse transcriptases (RTs) are a large and diverse enzyme family. AbiA, AbiK and Abi-P2 are abortive infection system (Abi) RTs that mediate defense against bacteriophages. What sets Abi RTs apart from other RT enzymes is their ability to synthesize long DNA products of random sequences in a template- and primer-independent manner. Structures of AbiK and Abi-P2 representatives have recently been determined, but there are no structural data available for AbiA. Here, we report the crystal structure of Lactococcus AbiA polymerase in complex with a single-stranded polymerization product. AbiA comprises three domains: an RT-like domain, a helical domain that is typical for Abi polymerases, and a higher eukaryotes and prokaryotes nucleotide-binding (HEPN) domain that is common for many antiviral proteins. AbiA forms a dimer that distinguishes it from AbiK and Abi-P2, which form trimers/hexamers. We show the DNA polymerase activity of AbiA in an in vitro assay and demonstrate that it requires the presence of the HEPN domain which is enzymatically inactive. We validate our biochemical and structural results in vivo through bacteriophage infection assays. Finally, our in vivo results suggest that AbiA-mediated phage defense may not rely on AbiA-mediated cell death.
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