| 1. |
- 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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| 2. |
- Barucca, G., et al.
(författare)
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The potential of Λ and Ξ- studies with PANDA at FAIR
- 2021
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Ingår i: European Physical Journal A. - : Springer Nature. - 1434-6001 .- 1434-601X. ; 57:4
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Tidskriftsartikel (refereegranskat)abstract
- The antiproton experiment PANDA at FAIR is designed to bring hadron physics to a new level in terms of scope, precision and accuracy. In this work, its unique capability for studies of hyperons is outlined. We discuss ground-state hyperons as diagnostic tools to study non-perturbative aspects of the strong interaction, and fundamental symmetries. New simulation studies have been carried out for two benchmark hyperon-antihyperon production channels: p¯ p→ Λ¯ Λ and p¯ p→ Ξ¯ +Ξ-. The results, presented in detail in this paper, show that hyperon-antihyperon pairs from these reactions can be exclusively reconstructed with high efficiency and very low background contamination. In addition, the polarisation and spin correlations have been studied, exploiting the weak, self-analysing decay of hyperons and antihyperons. Two independent approaches to the finite efficiency have been applied and evaluated: one standard multidimensional efficiency correction approach, and one efficiency independent approach. The applicability of the latter was thoroughly evaluated for all channels, beam momenta and observables. The standard method yields good results in all cases, and shows that spin observables can be studied with high precision and accuracy already in the first phase of data taking with PANDA.
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| 3. |
- Barucca, G., et al.
(författare)
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Study of excited Ξ baryons with the P¯ ANDA detector
- 2021
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Ingår i: European Physical Journal A. - : Springer Nature. - 1434-6001 .- 1434-601X. ; 57:4
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Tidskriftsartikel (refereegranskat)abstract
- The study of baryon excitation spectra provides insight into the inner structure of baryons. So far, most of the world-wide efforts have been directed towards N∗ and Δ spectroscopy. Nevertheless, the study of the double and triple strange baryon spectrum provides independent information to the N∗ and Δ spectra. The future antiproton experiment P¯ANDA will provide direct access to final states containing a Ξ¯ Ξ pair, for which production cross sections up to μb are expected in p¯p reactions. With a luminosity of L= 10 31 cm- 2 s- 1 in the first phase of the experiment, the expected cross sections correspond to a production rate of ∼106events/day. With a nearly 4 π detector acceptance, P¯ANDA will thus be a hyperon factory. In this study, reactions of the type p¯p → Ξ¯ +Ξ∗ - as well as p¯p → Ξ¯ ∗ +Ξ- with various decay modes are investigated. For the exclusive reconstruction of the signal events a full decay tree fit is used, resulting in reconstruction efficiencies between 3 and 5%. This allows high statistics data to be collected within a few weeks of data taking.
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| 4. |
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| 5. |
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| 6. |
- Buntgen, U., et al.
(författare)
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Tree rings reveal globally coherent signature of cosmogenic radiocarbon events in 774 and 993 CE
- 2018
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Though tree-ring chronologies are annually resolved, their dating has never been independently validated at the global scale. Moreover, it is unknown if atmospheric radiocarbon enrichment events of cosmogenic origin leave spatiotemporally consistent fingerprints. Here we measure the 14C content in 484 individual tree rings formed in the periods 770–780 and 990–1000 CE. Distinct 14C excursions starting in the boreal summer of 774 and the boreal spring of 993 ensure the precise dating of 44 tree-ring records from five continents. We also identify a meridional decline of 11-year mean atmospheric radiocarbon concentrations across both hemispheres. Corroborated by historical eye-witness accounts of red auroras, our results suggest a global exposure to strong solar proton radiation. To improve understanding of the return frequency and intensity of past cosmic events, which is particularly important for assessing the potential threat of space weather on our society, further annually resolved 14C measurements are needed.
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| 7. |
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| 8. |
- Darzentas, N., et al.
(författare)
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A different ontogenesis for chronic lymphocytic leukemia cases carrying stereotyped antigen receptors : molecular and computational evidence
- 2010
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 0887-6924 .- 1476-5551. ; 24:1, s. 125-132
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Tidskriftsartikel (refereegranskat)abstract
- Chronic lymphocytic leukemia (CLL) is uniquely characterized by the existence of subsets of cases with quasi-identical, 'stereotyped' B-cell receptors (BCRs). Herein we investigate this stereotypy in 2662 patients with CLL, the largest series yet, using purpose-built bioinformatics methods based on sequence pattern discovery. Besides improving the identification of 'stereotyped' cases, we demonstrate that CLL actually consists of two different categories, based on the BCR repertoire, with important biological and ontogenetic differences. The first ( approximately 30% of cases) shows a very restricted repertoire and is characterized by BCR stereotypy (clustered cases), whereas the second includes cases with heterogeneous BCRs (nonclustered cases). Eleven major CLL clusters were identified with antigen-binding sites defined by just a few critically positioned residues, regardless of the actual immunoglobulin (IG) variable gene used. This situation is closely reminiscent of the receptors expressed by cells participating in innate immune responses. On these grounds, we argue that whereas CLL cases with heterogeneous BCRs likely derive from the conventional B-cell pool, cases with stereotyped BCRs could derive from progenitor cells evolutionarily adapted to particular antigenic challenges, perhaps intermediate between a true innate immune system and the conventional adaptive B-cell immune system, functionally similar to what has been suggested previously for mouse B1 cells.
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| 9. |
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| 10. |
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| 11. |
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| 12. |
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| 13. |
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| 14. |
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| 15. |
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| 16. |
- Björklund, J., et al.
(författare)
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Scientific Merits and Analytical Challenges of Tree-Ring Densitometry
- 2019
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Ingår i: Reviews of geophysics. - 8755-1209 .- 1944-9208. ; 57:4, s. 1224-1264
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Forskningsöversikt (refereegranskat)abstract
- X-ray microdensitometry on annually resolved tree-ring samples has gained an exceptional position in last-millennium paleoclimatology through the maximum latewood density (MXD) parameter, but also increasingly through other density parameters. For 50 years, X-ray based measurement techniques have been the de facto standard. However, studies report offsets in the mean levels for MXD measurements derived from different laboratories, indicating challenges of accuracy and precision. Moreover, reflected visible light-based techniques are becoming increasingly popular, and wood anatomical techniques are emerging as a potentially powerful pathway to extract density information at the highest resolution. Here we review the current understanding and merits of wood density for tree-ring research, associated microdensitometric techniques, and analytical measurement challenges. The review is further complemented with a careful comparison of new measurements derived at 17 laboratories, using several different techniques. The new experiment allowed us to corroborate and refresh long-standing wisdom but also provide new insights. Key outcomes include (i) a demonstration of the need for mass/volume-based recalibration to accurately estimate average ring density; (ii) a substantiation of systematic differences in MXD measurements that cautions for great care when combining density data sets for climate reconstructions; and (iii) insights into the relevance of analytical measurement resolution in signals derived from tree-ring density data. Finally, we provide recommendations expected to facilitate futureinter-comparability and interpretations for global change research.
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| 17. |
- Björklund, Jesper, 1979, et al.
(författare)
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Scientific Merits and Analytical Challenges ofTree-Ring Densitometry
- 2019
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Ingår i: Reviews of Geophysics. - : American Geophysical Union (AGU). - 8755-1209 .- 1944-9208. ; 57:4, s. 1224-1264
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Tidskriftsartikel (refereegranskat)abstract
- X-ray microdensitometry on annually resolved tree-ring samples has gained an exceptional position in last-millennium paleoclimatology through the maximum latewood density (MXD) parameter, but also increasingly through other density parameters. For 50 years, X-ray based measurement techniques have been the de facto standard. However, studies report offsets in the mean levels for MXD measurements derived from different laboratories, indicating challenges of accuracy and precision. Moreover, reflected visible light-based techniques are becoming increasingly popular, and wood anatomical techniques are emerging as a potentially powerful pathway to extract density information at the highest resolution. Here we review the current understanding and merits of wood density for tree-ring research, associated microdensitometric techniques, and analytical measurement challenges. The review is further complemented with a careful comparison of new measurements derived at 17 laboratories, using several different techniques. The new experiment allowed us to corroborate and refresh "long-standing wisdom" but also provide new insights. Key outcomes include (i) a demonstration of the need for mass/volume-based recalibration to accurately estimate average ring density; (ii) a substantiation of systematic differences in MXD measurements that cautions for great care when combining density data sets for climate reconstructions; and (iii) insights into the relevance of analytical measurement resolution in signals derived from tree-ring density data. Finally, we provide recommendations expected to facilitate futureinter-comparability and interpretations for global change research.
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| 18. |
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| 19. |
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| 20. |
- Rao, M. P., et al.
(författare)
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European and Mediterranean hydroclimate responses to tropical volcanic forcing over the last millennimum
- 2017
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Ingår i: Geophysical Research Letters. - 0094-8276 .- 1944-8007. ; 44:10, s. 5104-5112
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Tidskriftsartikel (refereegranskat)abstract
- Volcanic eruptions have global climate impacts, but their effect on the hydrologic cycle is poorly understood. We use a modified version of superposed epoch analysis, an eruption year list collated from multiple data sets, and seasonal paleoclimate reconstructions ( soil moisture, precipitation, geopotential heights, and temperature) to investigate volcanic forcing of spring and summer hydroclimate over Europe and the Mediterranean over the last millennium. In the western Mediterranean, wet conditions occur in the eruption year and the following 3 years. Conversely, northwestern Europe and the British Isles experience dry conditions in response to volcanic eruptions, with the largest moisture deficits in posteruption years 2 and 3. The precipitation response occurs primarily in late spring and early summer (April-July), a pattern that strongly resembles the negative phase of the East Atlantic Pattern. Modulated by this mode of climate variability, eruptions force significant, widespread, and heterogeneous hydroclimate responses across Europe and the Mediterranean.
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| 21. |
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| 22. |
- Ravelli, A, et al.
(författare)
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2016 Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis: A European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organisation Collaborative Initiative
- 2016
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Ingår i: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 75:3, s. 481-489
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Tidskriftsartikel (refereegranskat)abstract
- To develop criteria for the classification of macrophage activation syndrome (MAS) in patients with systemic juvenile idiopathic arthritis (JIA). A multistep process, based on a combination of expert consensus and analysis of real patient data, was conducted. A panel of 28 experts was first asked to classify 428 patient profiles as having or not having MAS, based on clinical and laboratory features at the time of disease onset. The 428 profiles comprised 161 patients with systemic JIA—associated MAS and 267 patients with a condition that could potentially be confused with MAS (active systemic JIA without evidence of MAS, or systemic infection). Next, the ability of candidate criteria to classify individual patients as having MAS or not having MAS was assessed by evaluating the agreement between the classification yielded using the criteria and the consensus classification of the experts. The final criteria were selected in a consensus conference. Experts achieved consensus on the classification of 391 of the 428 patient profiles (91.4%). A total of 982 candidate criteria were tested statistically. The 37 best-performing criteria and 8 criteria obtained from the literature were evaluated at the consensus conference. During the conference, 82% consensus among experts was reached on the final MAS classification criteria. In validation analyses, these criteria had a sensitivity of 0.73 and a specificity of 0.99. Agreement between the classification (MAS or not MAS) obtained using the criteria and the original diagnosis made by the treating physician was high (κ=0.76). We have developed a set of classification criteria for MAS complicating systemic JIA and provided preliminary evidence of its validity. Use of these criteria will potentially improve understanding of MAS in systemic JIA and enhance efforts to discover effective therapies, by ensuring appropriate patient enrollment in studies.
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| 23. |
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| 24. |
- Sofou, E, et al.
(författare)
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Evidence of somatic hypermutation in the antigen binding sites of patients with CLL harboring IGHV genes with 100% germline identity
- 2022
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Ingår i: Frontiers in oncology. - : Frontiers Media SA. - 2234-943X. ; 12, s. 1079772-
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Tidskriftsartikel (refereegranskat)abstract
- Classification of patients with chronic lymphocytic leukemia (CLL) based on the somatic hypermutation (SHM) status of the clonotypic immunoglobulin heavy variable (IGHV) gene has established predictive and prognostic relevance. The SHM status is assessed based on the number of mutations within the IG heavy variable domain sequence, albeit only over the rearranged IGHV gene excluding the variable heavy complementarity determining region 3 (VH CDR3). This may lead to an underestimation of the actual impact of SHM, in fact overlooking the most critical region for antigen-antibody interactions, i.e. the VH CDR3. Here we investigated whether SHM may be present within the VH CDR3 of cases bearing ‘truly unmutated’ IGHV genes (i.e. 100% germline identity across VH FR1-VH FR3) employing Next Generation Sequencing. We studied 16 patients bearing a ‘truly unmutated’ CLL clone assigned to stereotyped subsets #1 (n=12) and #6 (n=4). We report the existence of SHM within the germline-encoded 3’IGHV, IGHD, 5’IGHJ regions of the VH CDR3 in both the main IGHV-IGHD-IGHJ gene clonotype and its variants. Recurrent somatic mutations were identified between different patients of the same subset, supporting the notion that they represent true mutational events rather than technical artefacts; moreover, they were located adjacent to/within AID hotspots, pointing to SHM as the underlying mechanism. In conclusion, we provide immunogenetic evidence for intra-VH CDR3 variations, attributed to SHM, in CLL patients carrying ‘truly unmutated’ IGHV genes. Although the clinical implications of this observation remain to be defined, our findings offer a new perspective into the immunobiology of CLL, alluding to the operation of VH CDR3-restricted SHM in U-CLL.
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| 25. |
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| 26. |
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| 27. |
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| 28. |
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| 29. |
- Kaufman, M, et al.
(författare)
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Impact of the Types and Relative Quantities of IGHV Gene Mutations in Predicting Prognosis of Patients With Chronic Lymphocytic Leukemia
- 2022
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Ingår i: Frontiers in oncology. - : Frontiers Media SA. - 2234-943X. ; 12, s. 897280-
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Tidskriftsartikel (refereegranskat)abstract
- Patients with CLL with mutated IGHV genes (M-CLL) have better outcomes than patients with unmutated IGHVs (U-CLL). Since U-CLL usually express immunoglobulins (IGs) that are more autoreactive and more effectively transduce signals to leukemic B cells, B-cell receptor (BCR) signaling is likely at the heart of the worse outcomes of CLL cases without/few IGHV mutations. A corollary of this conclusion is that M-CLL follow less aggressive clinical courses because somatic IGHV mutations have altered BCR structures and no longer bind stimulatory (auto)antigens and so cannot deliver trophic signals to leukemic B cells. However, the latter assumption has not been confirmed in a large patient cohort. We tried to address the latter by measuring the relative numbers of replacement (R) mutations that lead to non-conservative amino acid changes (Rnc) to the combined numbers of conservative (Rc) and silent (S) amino acid R mutations that likely do not or cannot change amino acids, “(S+Rc) to Rnc IGHV mutation ratio”. When comparing time-to-first-treatment (TTFT) of patients with (S+Rc)/Rnc ≤ 1 and >1, TTFTs were similar, even after matching groups for equal numbers of samples and identical numbers of mutations per sample. Thus, BCR structural change might not be the main reason for better outcomes for M-CLL. Since the total number of IGHV mutations associated better with longer TTFT, better clinical courses appear due to the biologic state of a B cell having undergone many stimulatory events leading to IGHV mutations. Analyses of larger patient cohorts will be needed to definitively answer this question.
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| 30. |
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| 31. |
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| 32. |
- Langerak, A. W., et al.
(författare)
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Immunoglobulin sequence analysis and prognostication in CLL : guidelines from the ERIC review board for reliable interpretation of problematic cases
- 2011
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 0887-6924 .- 1476-5551. ; 25:6, s. 979-984
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Tidskriftsartikel (refereegranskat)abstract
- prognostication in chronic lymphocytic leukemia (CLL) and the definition of standardized procedures has allowed reliable and reproducible results. Occasionally, a straightforward interpretation of the sequences is not possible because of the so-called 'problematic sequences' that do not fit the 'classic' interpretation and pose scientific questions at the cross-road between hematology and immunology. Thanks to a dedicated effort within the European Research Initiative on CLL (ERIC), we have now the possibility to present such cases, offer a scientific explanation and propose recommendations in terms of prognostication.
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| 33. |
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| 34. |
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| 35. |
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| 36. |
- Minoia, F, et al.
(författare)
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Development and initial validation of the MS score for diagnosis of macrophage activation syndrome in systemic juvenile idiopathic arthritis
- 2019
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Ingår i: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 78:10, s. 1357-1362
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Tidskriftsartikel (refereegranskat)abstract
- To develop and validate a diagnostic score that aids in identifying macrophage activation syndrome (MAS) in patients with systemic juvenile idiopathic arthritis (sJIA).MethodsThe clinical and laboratory features of 362 patients with sJIA-associated MAS and 404 patients with active sJIA without evidence of MAS were collected in a multinational collaborative project. Eighty percent of the study population was used to develop the score and the remaining 20% constituted the validation sample. A Bayesian Model Averaging approach was used to assess the role of each clinical and laboratory variables in the diagnosis of MAS and to obtain the coefficients of selected variables. The final score, named MAS/sJIA (MS) score, resulted from the linear combination of these coefficients multiplied by the values of each variable. The cut-off that best discriminated MAS from active sJIA was calculated by means of receiver operating characteristic (ROC) curve analysis. Score performance was evaluated in both developmental and validation samples.ResultsThe MS score ranges from −8.4 to 41.8 and comprises seven variables: central nervous system dysfunction, haemorrhagic manifestations, active arthritis, platelet count, fibrinogen, lactate dehydrogenase and ferritin. A cut-off value ≥−2.1 revealed the best performance in discriminating MAS from active sJIA, with a sensitivity of 0.85, a specificity of 0.95 and a kappa value of 0.80. The good performance of the MS score was confirmed in the validation sample.ConclusionThe MS score is a powerful and feasible tool that may assist practitioners in making a timely diagnosis of MAS in patients with sJIA.
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| 37. |
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| 38. |
- Minoia, F, et al.
(författare)
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Dissecting the heterogeneity of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis
- 2015
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Ingår i: The Journal of rheumatology. - : The Journal of Rheumatology. - 0315-162X .- 1499-2752. ; 42:6, s. 994-1001
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Tidskriftsartikel (refereegranskat)abstract
- To seek insights into the heterogeneity of macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (sJIA) through the analysis of a large patient sample collected in a multinational survey.Methods.International pediatric rheumatologists and hemato-oncologists entered their patient data, collected retrospectively, in a Web-based database. The demographic, clinical, laboratory, histopathologic, therapeutic, and outcome data were analyzed in relation to (1) geographic location of caring hospital, (2) subspecialty of attending physician, (3) demonstration of hemophagocytosis, and (4) severity of clinical course.Results.A total of 362 patients were included by 95 investigators from 33 countries. Demographic, clinical, laboratory, and histopathologic features were comparable among patients seen in diverse geographic areas or by different pediatric specialists. Patients seen in North America were given biologics more frequently. Patients entered by pediatric hemato-oncologists were treated more commonly with biologics and etoposide, whereas patients seen by pediatric rheumatologists more frequently received cyclosporine. Patients with demonstration of hemophagocytosis had shorter duration of sJIA at MAS onset, higher prevalence of hepatosplenomegaly, lower levels of platelets and fibrinogen, and were more frequently administered cyclosporine, intravenous immunoglobulin (IVIG), and etoposide. Patients with severe course were older, had longer duration of sJIA at MAS onset, had more full-blown clinical picture, and were more commonly given cyclosporine, IVIG, and etoposide.Conclusion.The clinical spectrum of MAS is comparable across patients seen in different geographic settings or by diverse pediatric subspecialists. There was a disparity in the therapeutic choices among physicians that underscores the need to establish uniform therapeutic protocols.
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| 39. |
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| 40. |
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| 41. |
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| 42. |
- Strefford, J. C., et al.
(författare)
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Distinct patterns of novel gene mutations in poor-prognostic stereotyped subsets of chronic lymphocytic leukemia : the case of SF3B1 and subset #2
- 2013
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 0887-6924 .- 1476-5551. ; 27:11, s. 2196-2199
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Tidskriftsartikel (refereegranskat)abstract
- Recent studies have revealed recurrent mutations of the NOTCH1, SF3B1 and BIRC3 genes in chronic lymphocytic leukemia (CLL), especially among aggressive, chemorefractory cases. Nevertheless, it is currently unknown whether their presence may differ in subsets of patients carrying stereotyped B-cell receptors and also exhibiting distinct prognoses. Here, we analyzed the mutation status of NOTCH1, SF3B1 and BIRC3 in three subsets with particularly poor prognosis, that is, subset # 1, # 2 and # 8, aiming to explore links between genetic aberrations and immune signaling. A remarkably higher frequency of SF3B1 mutations was revealed in subset # 2 (44%) versus subset # 1 and # 8 (4.6% and 0%, respectively; P<0.001). In contrast, the frequency of NOTCH1 mutations in subset # 2 was only 8%, lower than the frequency observed in either subset # 1 or # 8 (19% and 14%, respectively; P 0.04 for subset # 1 versus # 2). No associations were found for BIRC3 mutations that overall were rare. The apparent non-random association of certain mutations with stereotyped CLL subsets alludes to subset-biased acquisition of genomic aberrations, perhaps consistent with particular antigen/antibody interactions. These novel findings assist in unraveling specific mechanisms underlying clinical aggressiveness in poor-prognostic stereotyped subsets, with far-reaching implications for understanding their clonal evolution and implementing biologically oriented therapy.
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| 43. |
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| 44. |
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| 45. |
- Wilson, R., et al.
(författare)
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Improved dendroclimatic calibration using blue intensity in the southern Yukon
- 2019
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Ingår i: The Holocene. - : SAGE Publications. - 0959-6836 .- 1477-0911. ; 29:11, s. 1817-1830
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Tidskriftsartikel (refereegranskat)abstract
- In north-western North America, the so-called divergence problem (DP) is expressed in tree ring width (RW) as an unstable temperature signal in recent decades. Maximum latewood density (MXD), from the same region, shows minimal evidence of DP. While MXD is a superior proxy for summer temperatures, there are very few long MXD records from North America. Latewood blue intensity (LWB) measures similar wood properties as MXD, expresses a similar climate response, is much cheaper to generate and thereby could provide the means to profoundly expand the extant network of temperature sensitive tree-ring (TR) chronologies in North America. In this study, LWB is measured from 17 white spruce sites (Picea glauca) in south-western Yukon to test whether LWB is immune to the temporal calibration instabilities observed in RW. A number of detrending methodologies are examined. The strongest calibration results for both RW and LWB are consistently returned using age-dependent spline (ADS) detrending within the signal-free (SF) framework. RW data calibrate best with June-July maximum temperatures (Tmax), explaining up to 28% variance, but all models fail validation and residual analysis. In comparison, LWB calibrates strongly (explaining 43-51% of May-August Tmax) and validates well. The reconstruction extends to 1337 CE, but uncertainties increase substantially before the early 17th century because of low replication. RW-, MXD- and LWB-based summer temperature reconstructions from the Gulf of Alaska, the Wrangell Mountains and Northern Alaska display good agreement at multi-decadal and higher frequencies, but the Yukon LWB reconstruction appears potentially limited in its expression of centennial-scale variation. While LWB improves dendroclimatic calibration, future work must focus on suitably preserved sub-fossil material to increase replication prior to 1650 CE.
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