| 1. |
- Niemi, MEK, et al.
(author)
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- 2021
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swepub:Mat__t
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| 2. |
- Kanai, M, et al.
(author)
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- 2023
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swepub:Mat__t
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| 3. |
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| 4. |
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| 5. |
- Das, A., et al.
(author)
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Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency
- 2022
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In: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 28:1, s. 125-135
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Journal article (peer-reviewed)abstract
- Cancers arising from germline DNA mismatch repair deficiency or polymerase proofreading deficiency (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion–deletion (MS-indel) burden in humans. MMRD and PPD cancers are commonly lethal due to the inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICIs) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI treatment in these patients. Using an international consortium registry study, we report on the ICI treatment of 45 progressive or recurrent tumors from 38 patients. Durable objective responses were observed in most patients, culminating in a 3 year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations per Mb) enriched for combined MMRD + PPD, while MS-indels predicted response in MMRD tumors with lower mutation burden (10–100 mutations per Mb). Furthermore, both mechanisms were associated with increased immune infiltration even in ‘immunologically cold’ tumors such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and was associated with immune activation in the tumor microenvironment and systemically. Furthermore, patients with flare who continued ICI treatment achieved durable responses. This study demonstrates improved survival for patients with tumors not previously known to respond to ICI treatment, including central nervous system and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained response to immunotherapy. © 2022, The Author(s).
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| 6. |
- Furukawa, T. A., et al.
(author)
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Dismantling, optimising, and personalising internet cognitive behavioural therapy for depression: a systematic review and component network meta-analysis using individual data
- 2021
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In: Lancet Psychiatry. - : Elsevier BV. - 2215-0374 .- 2215-0366. ; 8:6, s. 500-511
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Journal article (peer-reviewed)abstract
- Findings We identified 76 RCTs, including 48 trials contributing individual participant data (11 704 participants) and 28 trials with aggregate data (6474 participants). The participants' weighted mean age was 42.0 years and 12 406 (71%) of 17 521 reported were women. There was suggestive evidence that behavioural activation might be beneficial (iMD -1.83 [95% credible interval (CrI) -2.90 to -0.80]) and that relaxation might be harmful (1.20 [95% CrI 0.17 to 2.27]). Baseline severity emerged as the strongest prognostic factor for endpoint depression. Combining human and automated encouragement reduced dropouts from treatment (incremental odds ratio, 0.32 [95% CrI 0.13 to 0.93]). The risk of bias was low for the randomisation process, missing outcome data, or selection of reported results in most of the included studies, uncertain for deviation from intended interventions, and high for measurement of outcomes. There was moderate to high heterogeneity among the studies and their components. 511
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| 7. |
- Chen, Zhishan, et al.
(author)
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Fine-mapping analysis including over 254 000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes
- 2024
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In: Nature Communications. - : Springer Nature. - 2041-1723. ; 15:1
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Journal article (peer-reviewed)abstract
- Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.
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| 8. |
- Toreti, A, et al.
(author)
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Narrowing uncertainties in the effects of elevated CO2 on crops
- 2020
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In: Nature Food. - : Springer Science and Business Media LLC. - 2662-1355. ; 1, s. 775-782
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Journal article (peer-reviewed)abstract
- Plant responses to rising atmospheric carbon dioxide (CO2) concentrations, together with projected variations in temperature and precipitation will determine future agricultural production. Estimates of the impacts of climate change on agriculture provide essential information to design effective adaptation strategies, and develop sustainable food systems. Here, we review the current experimental evidence and crop models on the effects of elevated CO2 concentrations. Recent concerted efforts have narrowed the uncertainties in CO2-induced crop responses so that climate change impact simulations omitting CO2 can now be eliminated. To address remaining knowledge gaps and uncertainties in estimating the effects of elevated CO2 and climate change on crops, future research should expand experiments on more crop species under a wider range of growing conditions, improve the representation of responses to climate extremes in crop models, and simulate additional crop physiological processes related to nutritional quality.
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| 9. |
- Asuk, Sijeh A., et al.
(author)
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Impact of human foraging on tree diversity, composition, and abundance in a tropical rainforest
- 2023
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In: Biotropica. - : Wiley. - 0006-3606 .- 1744-7429. ; 55:1, s. 232-245
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Journal article (peer-reviewed)abstract
- Tropical forest tree communities are structured by a range of large-scale drivers including elevation, certain high-impact anthropogenic activities (e.g., deforestation), and fires. However, low-impact human activities such as foraging may also be subtly but notably altering the composition of tropical forest tree communities. The study assessed the (i) differences in species diversity, patterns of relative abundance, and pairwise beta diversity between trees with edible and inedible fruits and seeds along an elevation gradient, and (ii) impact of human foraging on the forest tree communities in Oban Division of Cross River National Park, Nigeria. Fifteen permanent 40 by 40 m plots were established along an elevational gradient (120–460 m above mean sea level). All trees of 0.1 m diameter at breast height (dbh) and above were measured, identified, and, with the aid of structured questionnaires, classified into those with edible and inedible fruits/seeds. A total of 35 edible species with density of 128 stems/hectare and basal area of 11.99 m2/hectare, and 109 inedible species with density of 364 stems/hectare and basal area of 22.42 m2/hectare were sampled. However, the evenness of edible and inedible species was similar at pooled and plot levels. For inedible species, there was a positive relationship between pairwise beta diversity and elevation, and this was driven mainly by turnover. In contrast, edible species exhibited a non-significant trend between elevation and beta diversity. Thus, the study showed that human foraging of edible fruits may have subtly influenced patterns of species diversity and community structure in this tropical forest.
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| 10. |
- Das, Anirban, et al.
(author)
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Combined immunotherapy improves outcome for replication repair deficient (RRD) high-grade glioma failing anti-PD1 monotherapy: A report from the International RRD Consortium.
- 2024
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In: Cancer discovery. - 2159-8290. ; 14:2, s. 258-273
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Journal article (peer-reviewed)abstract
- Immune-checkpoint inhibition (ICI) is effective for replication-repair deficient, high-grade gliomas (RRD-HGG). Clinical/biologic impact of immune-directed approaches after failing ICI-monotherapy are unknown. We performed an international study on 75 patients treated with anti-PD1; 20 are progression-free (median follow-up: 3.7-years). After 2nd-progression/recurrence (n=55), continuing ICI-based salvage prolonged survival to 11.6-months (n=38; p<0.001), particularly for those with extreme mutation burden (p=0.03). Delayed, sustained responses were observed, associated with changes in mutational spectra and immune-microenvironment. Response to re-irradiation was explained by an absence of deleterious post-radiation indel signatures (ID8). Increased CTLA4-expression over time, and subsequent CTLA4-inhibition resulted in response/stable disease in 75%. RAS-MAPK-pathway inhibition led to reinvigoration of peripheral immune and radiological responses. Local (flare) and systemic immune adverse events were frequent (biallelic mismatch-repair deficiency > Lynch syndrome). We provide mechanistic rationale for the sustained benefit in RRD-HGG from immune-directed/ synergistic salvage therapies. Future approaches need to be tailored to patient and tumor biology.
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