Biology subjects

Westin, J.

Publications and source records attributed to Westin, J..

8 recordsLinked to original sources

bioRxiv2025

Proteomic analysis of bronchoalveolar lavage fluid after lung transplantation associates stable allograft function with less lung damage at 12 months

IntroductionFreedom from chronic lung allograft dysfunction (CLAD) is a key objective after lung transplantation, yet predicting its onset remains challenging. This study investigated whether early proteomic changes in bronchoalveolar lavage fluid (BALF) can differentiate between patients maintaining stable graft function at 36 months and those developing CLAD within the first year. Additionally, findings were compared to proteomic data from non-transplanted individuals. MethodsBALF samples were collected at one and twelve months post-transplant from 43 lung transplant recipients together with clinical parameters. Proteomic analysis was performed using mass spectrometry with label-free quantification for global protein profiling and heavy-labelled peptides for absolute quantification of mucins and related proteins. Differentially expressed proteins were identified and analyzed through pathway enrichment to explore biological mechanisms associated with CLAD. ResultsNo significant proteomic differences were detected at one month. By twelve months, 63 proteins were differentially expressed between patients who developed early CLAD and those with stable function. Mucin levels declined in stable patients but remained elevated in both groups compared to healthy controls. Cartilage acidic protein 1 was significantly higher in stable patients at twelve months and correlated with better pulmonary function. Pathway analysis linked several altered proteins in CLAD patients to networks associated with lung injury and remodelling. ConclusionProtein profiles in BALF that resemble those of healthy lungs are associated with sustained graft function, while persistent expression of lung injury markers is associated with early CLAD. This suggests an adaptive process is needed for long-term post-transplant success.

molecular biology↗

bioRxiv2023

CD8 T-cell dysfunction is linked with CAR T-cell failure and can be mitigated by a non-alpha IL-2 agonist, pegenzileukin

Chimeric antigen receptor (CAR) T-cell therapy has been a breakthrough for relapsed or refractory large B-cell lymphoma (rrLBCL). However, suboptimal CAR T-cell activity can lead to therapeutic failure and dismal outcome. Using single cell RNA-sequencing of rrLBCL tumors, we identify a prominent population of clonally expanded dysfunctional CAR+ CD8 T-cells indicative of ongoing tumor cell engagement, proliferation, and dysfunction at the time of progression from CAR T-cell therapy. Furthermore, we show that rrLBCL patient-derived CAR T-cells are more prone to dysfunction and loss of cytotoxicity compared to healthy donor-derived CAR T-cells. Using both antigen-driven and CAR-driven models of T-cell dysfunction, we show that pegenzileukin, a non-alpha IL2 agonist, can prevent T-cell dysfunction. In both in vitro and in vivo CAR T-cell models, pegenzileukin improved T-cell expansion and tumor control. This provides pre-clinical rational for use of pegenzileukin in combatting T-cell dysfunction, a central mechanism of CAR T-cell failure. HIGHLIGHTSO_LITumor-infiltrating CD8 CAR T-cells show clonal expansion and dysfunction at the time of progression. C_LIO_LIrrLBCL patient-derived CAR T-cells are more prone to dysfunction compared to healthy-donor-derived CAR T-cells. C_LIO_LIPegenzileukin, a non-alpha IL2 agonist, rescues antigen- and CAR-driven CD8 T-cell dysfunction and improves CAR T-cell responses in vivo. C_LI

immunology↗

bioRxiv2022

Teasing apart the joint effect of demography and natural selection in the birth of a contact zone

Vast population movements induced by recurrent climatic cycles have shaped the genetic structure of plant species. This is especially true in Scandinavia that was repeatedly glaciated. During glacial periods trees were confined to refugia, south and east of the ice sheet, from which they recolonized Scandinavia as the ice melted away. This multi-pronged recolonization led to large contact zones in most species. We leverage large genomic data from 5000 trees to reconstruct the demographic history of Norway spruce (Picea abies) and test for the presence of natural selection during the recolonization process and the establishment of the contact zone. Sweden is today made up of two large genetic clusters, a southern one originating from the Baltics and a Northern one originating from Northern Russia. The contact zone delineating these two clusters closely matches the limit between two major climatic regions. This suggests that natural selection contributed to the establishment and the maintenance of the contact zone. To test this hypothesis we first used Approximate Bayesian Computation; an Isolation-with migration model with genome-wide linked selection fits the data better than a purely neutral one. Secondly, we identified loci characterized by both extreme allele frequency differences between geographic regions and association to the variables defining the climatic zones. These loci, many of which are related to phenology, form clusters present on all linkage groups. Altogether, the current genetic structure reflects the joint effect of climatic cycles, recolonization and selection on the establishment of strong local adaptation and contact zones. Significance StatementUnderstanding how past climatic events, human actions and evolutionary forces contributed to the present distribution of genetic diversity is crucial to predict their reaction to the current climate crisis. Vast distribution shifts induced by past environmental changes, local ecological processes, natural selection and human transfers contributed to the current distribution of Norway spruce across Northern Europe. Genome-wide polymorphisms from thousands of individuals show that Scandinavia was recolonized after the Last Glacial from both south and north. This two-pronged recolonization established a contact zone between two genetic clusters that matches the limit between two major climate zones. The contact zone is shaped and maintained by natural selection on a large number of loci that form blocks of co-adapted loci spread genome-wide.

evolutionary biology↗

bioRxiv2021

Clonal hematopoiesis is associated with increased toxicity in large B-cell lymphoma patients treated with chimeric antigen receptor T cell therapy

To explore the role of clonal hematopoiesis (CH) on chimeric antigen receptor (CAR) T-cell therapy outcomes, we performed targeted deep-sequencing on 114 large B-cell lymphoma patients treated with anti-CD19 CAR T-cells. We detected CH in 42 (36.8%) pre-treatment patient samples, most frequently in PPM1D (19/114) and TP53 (13/114) genes. The incidence of grade [≥]3 immune-effector cell-associated neurotoxicity syndrome (ICANS) was higher in CH-positive patients compared to CH-negative patients (45.2% vs. 25.0%, p=0.038). Higher toxicities with CH were primarily driven by three CH genes, DNMT3A, TET2 and ASXL1 (DTA mutations). The incidence of grade [≥]3 ICANS [58.9% vs. 25%, p=0.02] and grade [≥]3 cytokine release syndrome [17.7% vs. 4.2%, p=0.08] were higher in patients with DTA mutations than those without CH. The estimated 24-month cumulative incidence of therapy-related myeloid neoplasms after CAR-T therapy was higher in patients with CH than those without CH (19% [95%CI: 5.5-38.7] vs. 4.2% [95%CI: 0.3-18.4], p=0.028). Statement of SignificanceOur study reveals that clonal hematopoiesis mutations, especially those associated with inflammation (DNMT3A, TET2, ASXL1), are associated with severe grade toxicities in lymphoma patients receiving anti-CD19 chimeric antigen receptor therapy. Further studies to investigate the mechanisms and interventions to improve toxicities in the context of CH are warranted.

genetics↗

bioRxiv2021

Immune microenvironment subtypes and association with tumor cell mutations and antigen expression in follicular lymphoma.

Follicular lymphoma (FL) is a B-cell lymphoma with a complex tumor microenvironment that is rich in non-malignant immune cells. We applied single-cell RNA-sequencing to characterize the diverse tumor and immune cell populations of FL and identified major phenotypic subsets of FL T-cells including a novel cytotoxic CD4 T-cell population. Their relative proportions of T-cells defined four major FL subtypes, characterized by differential representation or relative depletion of distinct T-cell subsets. By integrating exome sequencing, we observed that somatic mutations are associated with, but not definitive for, reduced antigen presentation on FL cells. In turn, expression of MHC class II genes by FL cells was associated with significant differences in the proportions and targetable immunophenotypic characteristics. This provides a classification framework of the FL microenvironment, their association with FL genotypes and antigen presentation, and informs different potential immunotherapeutic strategies based upon tumor cell MHC class II expression. Statement of significanceWe have characterized the FL-infiltrating T-cells, identified cytotoxic CD4 T-cells as an important component, showed that the abundance of these T-cell populations is associated with tumor-cell-intrinsic characteristics, and identified sets of targetable immune checkpoints on T-cells that differed between FLs with normal versus low antigen presentation.

cancer biology↗

bioRxiv2019

Pathognomonic and epistatic genetic alterations in B-cell non-Hodgkin lymphoma

B-cell non-Hodgkins lymphoma (B-NHL) encompasses multiple clinically and phenotypically distinct subtypes of malignancy with unique molecular etiologies. Common subtypes of B-NHL such as diffuse large B-cell lymphoma (DLBCL) have been comprehensively interrogated at the genomic level. But rarer subtypes such as mantle cell lymphoma (MCL) remain sparsely characterized. Furthermore, multiple B-NHL subtypes have thus far not been comprehensively compared using the same methodology to identify conserved or subtype-specific patterns of genomic alterations. Here, we employed a large targeted hybrid-capture sequencing approach encompassing 380 genes to interrogate the genomic landscapes of 685 B-NHL tumors at high depth; including DLBCL, MCL, follicular lymphoma (FL), and Burkitt lymphoma (BL). We identified conserved hallmarks of B-NHL that were deregulated in the majority of tumor from each subtype, including the frequent genetic deregulation of the ubiquitin proteasome system (UPS). In addition, we identified subtype-specific patterns of genetic alterations, including clusters of co-occurring mutations and DNA copy number alterations. The cumulative burden of mutations within a single cluster were more discriminatory of B-NHL subtypes than individual mutations, implicating likely patterns of genetic cooperation that contribute to disease etiology. We therefore provide the first cross-sectional analysis of mutations and DNA copy number alterations across major B-NHL subtypes and a framework of co-occurring genetic alterations that deregulate genetic hallmarks and likely cooperate in lymphomagenesis.

genomics↗

bioRxiv2018

Increased prediction ability in Norway spruce trials using a marker x environment interaction and non-additive genomic selection model

A genomic selection (GS) study of growth and wood quality traits is reported based on control-pollinated Norway spruce families established in two Northern Swedish trials at two locations using exome capture as a genotyping platform. Non-additive effects including dominance and first-order epistatic interactions (including additive by additive, dominance by dominance, and additive by dominance) and marker-by-environment interaction (MxE) effects were dissected in genomic and phenotypic selection models. GS models partitioned additive and non-additive genetic variances more precisely compared with pedigree-based models. In addition, predictive ability (PA) in GS was substantially increased by including dominance and slightly increased by including MxE effects when these effects are significant. For velocity, response to GS (RGS) per year increased 91.3/43.7%, 86.9/82.9%, and 78.9/80.8% compared with response to phenotypic selection (RPS) per year when GS was based on 1) main marker effects (M), 2) M + MxE effects (A), and 3) A + dominance effects (AD) for site 1/site 2, respectively. This indicates that including MxE and dominance effects not only improves genetic parameter estimates but also may improve the genetic gain when they are significant. For tree height, Pilodyn, and modulus of elasticity (MOE), RGS per year improved up to 84.2%, 91.3%, and 92.6% compared with RPS per year, respectively.

genetics↗

bioRxiv2018

Accuracy of genomic selection for growth and wood quality traits in two control-pollinated progeny trials using exome capture as genotyping platform in Norway spruce

BackgroundGenomic selection (GS) can increase genetic gain by reducing the length of breeding cycle in forest trees. Here we genotyped 1370 control-pollinated progeny trees from 128 full-sib families in Norway spruce (Picea abies (L.) Karst.), using exome capture as a genotyping platform. We used 116,765 high quality SNPs to develop genomic prediction models for tree height and wood quality traits. We assessed the impact of different genomic prediction methods, genotype-by-environment interaction (GxE), genetic composition, size of the training and validation set, relatedness, and the number of SNPs on the accuracy and predictive ability (PA) of GS.\n\nResultsUsing G matrix slightly altered heritability estimates relative to pedigree-based method. GS accuracies were about 11-14% lower than those based on pedigree-based selection. The efficiency of GS per year varied from 1.71 to 1.78, compared to that of the pedigree-based model if breeding cycle length was halved using GS. Height GS accuracy decreased more than 30% using one site as training for GS prediction to the second site, indicating that GxE for tree height should be accommodated in model fitting. Using half-sib family structure instead of full-sib led a significant reduction in GS accuracy and PA. The full-sib family structure only needed 750 makers to reach similar accuracy and PA as 100,000 markers required for half-sib family, indicating that maintaining the high relatedness in the model improves accuracy and PA. Using 4000-8000 markers in full-sib family structure was sufficient to obtain GS model accuracy and PA for tree height and wood quality traits, almost equivalent to that obtained with all makers.\n\nConclusionsThe study indicates GS would be efficient in reducing generation time of a breeding cycle in conifer tree breeding program that requires a long-term progeny testing. Sufficient number of trees within-family (16 for growth and 12 for wood quality traits) and number of SNPs (8000) are required for GS with full-sib family relationship. GS methods had little impact on GS efficiency for growth and wood quality traits. GS model should incorporate G x E effect when a strong GxE is detected.

genetics↗