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| 2. |
- Campbell, PJ, et al.
(författare)
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Pan-cancer analysis of whole genomes
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 578:7793, s. 82-
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Tidskriftsartikel (refereegranskat)abstract
- Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1–3. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10–18.
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| 4. |
- Mishra, A., et al.
(författare)
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Stroke genetics informs drug discovery and risk prediction across ancestries
- 2022
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 611, s. 115-123
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Tidskriftsartikel (refereegranskat)abstract
- Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.
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| 5. |
- Solmi, M, et al.
(författare)
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- 2022
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Ingår i: Journal of affective disorders. - : Elsevier BV. - 1573-2517 .- 0165-0327. ; 299, s. 367-376
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Tidskriftsartikel (refereegranskat)
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| 6. |
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| 7. |
- Esposito, Marco, 1965, et al.
(författare)
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MACHINED VERSUS CAST ABUTMENTS FOR DENTAL IMPLANTS: A 1-YEAR WITHIN-PATIENT MULTICENTRE RANDOMIZED CONTROLLED TRIAL ASSESSING MARGINAL SEAL CAPACITY AND OUTCOMES
- 2021
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Ingår i: Clinical Trials in Dentistry. - 2784-9015. ; 3:2, s. 19-31
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE To compare clinical outcomes of machined titanium abutments (machined group) versus cast cobalt-chrome abutments (cast group) and to evaluate in vitro their implant fit. MATERIALS AND METHODS This study comprised two parts. In the in vitro part, the im-plant–abutment fit of 5 cast abutments and 5 machined abutments screwed on with a torque of 30 Ncm was qualitatively and quantitatively evaluated using micro-computed tomography (µ-CT) and AgNO3 to reveal connection gaps. In the clinical part, 31 partially edentulous subjects received two single non-adjacent implant-supported crowns at three centres. At impression taking, three and a half months after implant placement, implants were randomized to receive a machined or cast abutment according to a wi-thin-patient study design. Unfortunately, four patients dropped out and one patient lost one implant before randomization, so only 26 patients had their implants randomized. Outcome measures were: prosthesis and implant failures, any complications, and radiographic peri-implant marginal bone level changes. Patients were followed up to 1 year after loading. RESULTS The fit of the implant–abutment connection was assessed in vitro using µ-CT scans. No gaps were revealed at any of the machined or cast abutments tested. In the clinical part, after randomization, three patients dropped out, no implant failed, but one crown on a cast abutment was replaced. The between-group difference in prosthesis failure was not statistically different (McNemar chi-square test P = 1.0; difference in proportions = 0.039). One complication occurred in each group, the difference not being statistically different (McNemar test P = 1.000; difference in proportions = 0; 95% CI 0.06 to 15.99). Both groups presented statistically significant peri-implant marginal bone loss from implant placement to 1 year after loading, respectively-0.76 ± 1.01 mm for machined and-0.69 ± 0.82 mm for cast abutments, with no statistically significant differences between the two groups (mean difference 0.07 mm; 95% CI-0.54 to 0.67; P = 0.828). Both groups gradually lost marginal peri-implant bone from loading to 1 year after loading but this was not significantly different, respectively-0.06 ± 0.56 mm for machined and-0.10 ± 0.29 mm for cast abutments, with no statistically significant differences between the two groups (P = 0.739; mean difference 0.07 mm; 95% CI-0.12 to 0.16; P = 0.739). CONCLUSIONS Our clinical data suggests that implant prognosis up to 1 year after loading is not affected by using machined or cast abutments. In support of these findings, in vitro analysis proved that both types of abutments allow a tight fit with no gaps. The-refore, for the time being dentists should feel free to choose whichever type they prefer. However, these preliminary results need to be confirmed by larger trials with at least 10 years of follow-up.
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| 9. |
- Menchon, JM, et al.
(författare)
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A prospective international multi-center study on safety and efficacy of deep brain stimulation for resistant obsessive-compulsive disorder
- 2021
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Ingår i: Molecular psychiatry. - : Springer Science and Business Media LLC. - 1476-5578 .- 1359-4184. ; 26:4, s. 1234-1247
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Tidskriftsartikel (refereegranskat)abstract
- Deep brain stimulation (DBS) has been proposed for severe, chronic, treatment-refractory obsessive-compulsive disorder (OCD) patients. Although serious adverse events can occur, only a few studies report on the safety profile of DBS for psychiatric disorders. In a prospective, open-label, interventional multi-center study, we examined the safety and efficacy of electrical stimulation in 30 patients with DBS electrodes bilaterally implanted in the anterior limb of the internal capsule. Safety, efficacy, and functionality assessments were performed at 3, 6, and 12 months post implant. An independent Clinical Events Committee classified and coded all adverse events (AEs) according to EN ISO14155:2011. All patients experienced AEs (195 in total), with the majority of these being mild (52% of all AEs) or moderate (37%). Median time to resolution was 22 days for all AEs and the etiology with the highest AE incidence was ‘programming/stimulation’ (in 26 patients), followed by ‘New illness, injury, condition’ (13 patients) and ‘pre-existing condition, worsening or exacerbation’ (11 patients). Sixteen patients reported a total of 36 serious AEs (eight of them in one single patient), mainly transient anxiety and affective symptoms worsening (20 SAEs). Regarding efficacy measures, Y-BOCS reduction was 42% at 12 months and the responder rate was 60%. Improvements in GAF, CGI, and EuroQol-5D index scores were also observed. In sum, although some severe AEs occurred, most AEs were mild or moderate, transient and related to programming/stimulation and tended to resolve by adjustment of stimulation. In a severely treatment-resistant population, this open-label study supports that the potential benefits outweigh the potential risks of DBS.
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| 10. |
- Baquero, JM, et al.
(författare)
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OGG1 Inhibition Triggers Synthetic Lethality and Enhances The Effect of PARP Inhibitor Olaparib in BRCA1-Deficient TNBC Cells
- 2022
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Ingår i: Frontiers in oncology. - : Frontiers Media SA. - 2234-943X. ; 12, s. 888810-
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Tidskriftsartikel (refereegranskat)abstract
- PARP1 plays a critical role in the base excision repair (BER) pathway, and PARP1 inhibition leads to specific cell death, through a synthetic lethal interaction, in the context of BRCA1/2 deficiency. To date, up to five different PARP inhibitors (PARPi), have been approved, nevertheless, the acquisition of resistance to PARPi is common and there is increasing interest in enhancing responses and expand their use to other tumour types.MethodsWe hypothesized that other BER members could be additional synthetic lethal partners with mutated BRCA genes. To test this, we decided to evaluate the glycosylase OGG1 as a potential candidate, by treating BRCA1 proficient and deficient breast cancer cells with PARPi olaparib and the OGG1 inhibitor TH5478.ResultsKnocking out BRCA1 in triple-negative breast cancer cell lines causes hypersensitivity to the OGG1 inhibitor TH5487. Besides, TH5487 enhances the sensitivity to the PARP inhibitor olaparib, especially in the context of BRCA1 deficiency, reflecting an additive interaction.DiscussionThese results provide the first evidence that OGG1 inhibition is a promising new synthetic lethality strategy in BRCA1-deficient cells, and could lead to a new framework for the treatment of hereditary breast and ovarian cancer.
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