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Background A major challenge in neurodegenerative diseases concerns identifying biological disease signatures that track with disease progression or respond to an intervention. Several clinical trials in Huntington disease (HD), an inherited, progressive neurodegenerative disease, are currently ongoing. Therefore, we examine whether peripheral tissues can serve as a source of readily accessible biological signatures at the RNA and protein level in HD patients. Results We generate large, high-quality human datasets from skeletal muscle, skin and adipose tissue to probe molecular changes in human premanifest and early manifest HD patients—those most likely involved in clinical trials. The analysis of the transcriptomics and proteomics data shows robust, stage-dependent dysregulation. Gene ontology analysis confirms the involvement of inflammation and energy metabolism in peripheral HD pathogenesis. Furthermore, we observe changes in the homeostasis of extracellular vesicles, where we find consistent changes of genes and proteins involved in this process. In-depth single nucleotide polymorphism data across the HTT gene are derived from the generated primary cell lines. Conclusions Our ‘omics data document the involvement of inflammation, energy metabolism, and extracellular vesicle homeostasis. This demonstrates the potential to identify biological signatures from peripheral tissues in HD suitable as biomarkers in clinical trials. The generated data, complemented by the primary cell lines established from peripheral tissues, and a large panel of iPSC lines that can serve as human models of HD are a valuable and unique resource to advance the current understanding of molecular mechanisms driving HD pathogenesis.

Background: A major challenge in neurodegenerative diseases concerns identifying biological disease signatures that track with disease progression or respond to an intervention. Several clinical trials in Huntington disease (HD), an inherited, progressive neurodegenerative disease, are currently ongoing. Therefore, we examined whether peripheral tissues can serve as a source of readily accessible biological signatures at the RNA and protein level in HD patients. Results: We generated large, high-quality human datasets from skeletal muscle, skin and adipose tissue to probe molecular changes in human premanifest and early manifest HD patients - those most likely involved in clinical trials. In-depth single nucleotide polymorphism data across the HTT gene will facilitate the use of the generated primary- and iPSC cell lines in allele-specific targeting approaches. The analysis of the transcriptomics and proteomics data shows robust, stage-dependent dysregulation. Gene ontology analysis confirmed the involvement of inflammation and energy metabolism in peripheral HD pathogenesis. Furthermore, we observed changes in the homeostasis of extracellular vesicles, where we found consistent changes of genes and proteins involved in this process. Conclusions: Our 'omics data document the involvement of inflammation, energy metabolism and extracellular vesicle homeostasis. This demonstrates the potential to identify biological signatures from peripheral tissues in HD suitable as biomarkers in clinical trials. Together with the primary cell lines established from peripheral tissues and a large panel of iPSC lines that can serve as human models of HD, the generated data are a valuable and unique resource to advance the current understanding of molecular mechanisms driving HD pathogenesis. Competing Interest Statement J.M.L serves in the scientific advisory board of GenEdit, Inc. A.N. acts as a consultant for Triplet Therapeutics, Inc. In the past two years, through the offices of UCL Consultants Ltd, a wholly owned subsidiary of University College London, S.J.T. has undertaken consultancy services for Alnylam Pharmaceuticals Inc., Atalanta Pharmaceuticals, F. Hoffmann-La Roche Ltd, Genentech, Guidepoint, Horama, Locanobio, LoQus23 Therapeutics Ltd, Novartis Pharma, PTC Therapeutics, Sanofi, Spark Therapeutics, Takeda Pharmaceuticals Ltd, Triplet Therapeutics, University College Irvine and Vertex Pharmaceuticals Incorporated. All other authors declare no competing interests.

Alcohol Use Disorder (AUD) is associated with reductions in grey matter (GM) volume which can lead to changes in numerous brain functions. The results of previous studies on altered GM in AUD differ considerably in the regions identified. Three meta-analyses carried out between 2014 and 2017 yielded different results. The present study includes the considerable amount of newer research and delivers a state-of-the art meta-analysis in line with recently published guidelines. Additionally, we behaviorally characterized affected regions using fMRI metadata and identified related brain networks by determining their meta-analytic connectivity patterns. Twenty-seven studies with 1,045 AUD patients and 1,054 healthy controls were included in the analysis and analyzed by means of Anatomical Likelihood Estimation (ALE). GM alterations were identified in eight clusters covering different parts of the cingulate and medial frontal gyri, paracentral lobes, left post- and precentral gyri, left anterior and right posterior insulae and left superior frontal gyrus. The behavioral characterization associated these regions with specific cognitive, emotional, somatosensory and motor functions. Moreover, the clusters represent nodes within behaviorally relevant brain networks. Our results suggest that GM reduction in AUD could disrupt network communication responsible for the neurocognitive impairments associated with high chronic alcohol consumption.

Blinatumomab (BLN) is a bispecific T-cell engager that has revolutionized the treatment of B-cell precursor acute lymphoblastic leukemia (BCP-ALL), significantly improving outcomes in both adults and children. By simultaneously binding to CD19 on B cells and CD3 on T cells, BLN triggers target cell-dependent T-cell activation, resulting in the cytolysis of CD19 BCP-ALL cells. Despite the remarkable clinical advancements achieved with BLN, the immunological mechanisms underlying treatment response or failure remain poorly characterized. γδ T cells are attractive candidates for adoptive T-cell therapy due to potent cytotoxicity, capacity to present antigens, broad lysis of different tumor entities, and low alloreactivity. Because γδ T cells can also be redirected by BLN, we systematically studied BLN-driven effector functions in conventional αβ and unconventional γδ T cells from healthy donors. We evaluated cytotoxicity and cytokine/effector release in freshly isolated and -expanded αβ and γδ T cells from healthy adults against CD19 BCP-ALL cell lines (NALM-6, HAL-01), and profiled dynamic phenotypic alterations by multiparametric flow cytometry. CD19 targets were consistently reduced in the presence of BLN. Freshly isolated αβ, especially CD8 , displayed superior BLN-mediated effector functions as compared to γδ T cells, with donor-dependent variability in γδ killing. Notably, zoledronate-expanded Vγ9Vδ2 γδ T-cell lines achieved cytotoxicity comparable to PHA-expanded αβ cells. However, γδ T-cell-killing benefited from higher BLN concentration when challenged with high tumor load. In these healthy-donor T-cell cultures, BLN induced CD3 down-modulation in αβ T cells but not in γδ T cells, and αβ cultures released higher soluble Fas ligand, findings consistent with stronger early activation and suggestive of increased susceptibility to activation-associated apoptosis/AICD. Exploratory targeted single-cell transcriptomics (one donor) supported a pronounced activation/exhaustion program in αβ T cells and a comparatively stable effector-memory profile with low checkpoint expression in γδ T cells. Together, these data reveal subset-specific BLN responses and support the hypothesis that ex vivo-expanded Vγ9Vδ2 γδ T cells could complement BLN-mediated cytotoxicity, particularly under conditions of higher CD19 density and lower target burden. These findings provide a mechanistic framework for future testing of γδ T-cell/BLN combination strategies in patient-derived models and clinical studies.

Genetic integrity of induced pluripotent stem cells (iPSCs) is essential for their validity as disease models and for potential therapeutic use. We describe the comprehensive analysis in the ForIPS consortium: an iPSC collection from donors with neurological diseases and healthy controls. Characterization included pluripotency confirmation, fingerprinting, conventional and molecular karyotyping in all lines. In the majority, somatic copy number variants (CNVs) were identified. A subset with available matched donor DNA was selected for comparative exome sequencing. We identified single nucleotide variants (SNVs) at different allelic frequencies in each clone with high variability in mutational load. Low frequencies of variants in parental fibroblasts highlight the importance of germline samples. Somatic variant number was independent from reprogramming, cell type and passage. Comparison with disease genes and prediction scores suggest biological relevance for some variants. We show that high-throughput sequencing has value beyond SNV detection and the requirement to individually evaluate each clone.

In contrast to B-cell precursor acute lymphoblastic leukemia (ALL), molecular subgroups are less well defined in T-lineage ALL. Comprehensive studies on molecular T-ALL subgroups have been predominantly performed in pediatric ALL patients. Currently, molecular characteristics are rarely considered for risk stratification. Herein, we present a homogenously treated cohort of 230 adult T-ALL patients characterized on transcriptome, and partly on DNA methylation and gene mutation level in correlation with clinical outcome. We identified nine molecular subgroups based on aberrant oncogene expression correlating to four distinct DNA methylation patterns. The subgroup distribution differed from reported pediatric T-ALL cohorts with higher frequencies of prognostic unfavorable subgroups like HOXA or LYL1/LMO2. A small subset (3%) of HOXA adult T-ALL patients revealed restricted expression of posterior HOX genes with aberrant activation of lncRNA HOTTIP. With respect to outcome, TLX1 ( n  = 44) and NKX2-1 ( n  = 4) had an exceptionally favorable 3-year overall survival (3y-OS) of 94%. Within thymic T-ALL, the non TLX1 patients had an inferior but still good prognosis. To our knowledge this is the largest cohort of adult T-ALL patients characterized by transcriptome sequencing with meaningful clinical follow-up. Risk classification based on molecular subgroups might emerge and contribute to improvements in outcome.

OBJECTIVE:The aim of this study was to investigate the role of occupational and nonoccupational ultraviolet (UV)-exposure concerning the development of basal cell carcinoma (BCC). METHODS:We undertook a population-based multicenter case–control study. Patients with first incident BCC (n = 836) were propensity score matched by age and sex to controls without skin cancer (n = 836). Sociodemographic characteristics, clinical characteristics, and lifetime UV-exposure were assessed by trained investigators. The differential estimation of occupational and nonoccupational UV-exposure dosages was based on validated instruments and established reference values. Associations were assessed using multivariable-adjusted conditional logistic regression models. RESULTS:Individuals with high levels of occupational UV-exposure were at significantly increased BCC-risk compared with individuals with low [odds ratio (OR) 1.84; 95% confidence interval (95% CI) 1.19 to 2.83 and moderate (OR 1.97; 95% CI 1.20 to 3.22) occupational UV-exposure. Nonoccupational UV-exposure was not independently associated with BCC. CONCLUSION:Skin cancer prevention strategies should be expanded to the occupational setting.

Blinatumomab (BLN) is a bispecific T-cell engager that has revolutionized the treatment of B-cell precursor acute lymphoblastic leukemia (BCP-ALL), significantly improving outcomes in both adults and children. By simultaneously binding to CD19 on B cells and CD3 on T cells, BLN triggers target cell-dependent T-cell activation, resulting in the cytolysis of CD19+ BCP-ALL cells. Despite the remarkable clinical advancements achieved with BLN, the immunological mechanisms underlying treatment response or failure remain poorly characterized. γδ T cells are attractive candidates for adoptive T–cell therapy due to potent cytotoxicity, capacity to present antigens, broad lysis of different tumor entities, and low alloreactivity. Because γδ T cells can also be redirected by BLN, we systematically studied BLN–driven effector functions of conventional αβ and unconventional γδ T cells. We evaluated cytotoxicity and cytokine/effector release in freshly isolated and in vitro-expanded αβ and γδ T cells from healthy adults against CD19⁺ BCP-ALL lines (NALM-6, HAL-01), and profiled dynamic phenotypic alterations by multiparametric flow cytometry. CD19⁺ targets were consistently reduced in the presence of BLN. Freshly isolated αβ, especially CD8⁺, displayed superior BLN-mediated cytotoxicity as compared to γδ T cells, with donor-dependent variability in γδ killing. Notably, zoledronate-expanded Vγ9Vδ2 γδ T-cell lines achieved cytotoxicity comparable to PHA-expanded αβ cells. However, γδ T-cell-killing benefited from higher BLN concentration when challenged with high tumor load. BLN induced CD3 down-modulation in αβ T cells but not in γδ T cells, alongside higher soluble Fas ligand in αβ cultures, consistent with stronger early activation, preceding activation-induced cell death. γδ T cells showed no such changes, suggesting reduced susceptibility to activation-induced cell death. Single-cell RNA and flow analyses corroborated these findings, showing robust activation/exhaustion programs in αβ T cells and a stable effector-memory state with low checkpoint expression in γδ T cells. Together, these data reveal subset–specific BLN responses and support expanded Vγ9Vδ2 γδ T cells as a rational adoptive partner to BLN — particularly in settings of favorable antigen density/low tumor burden — providing complementary cytotoxicity with potentially reduced inflammatory liability. These findings provide a framework for combining γδ T-cell-based therapies in BLN-treated patients for improving BLN efficacy in BCP-ALL patients.

Genetic integrity of induced pluripotent stem cells (iPSCs) is essential for their validity as disease models and for potential therapeutic use. We describe the comprehensive analysis in the ForIPS consortium: an iPSC collection from donors with neurological diseases and healthy controls. Characterization included pluripotency confirmation, fingerprinting, conventional and molecular karyotyping in all lines. In the majority, somatic copy number variants (CNVs) were identified. A subset with available matched donor DNA was selected for comparative exome sequencing. We identified single nucleotide variants (SNVs) at different allelic frequencies in each clone with high variability in mutational load. Low frequencies of variants in parental fibroblasts highlight the importance of germline samples. Somatic variant number was independent from reprogramming, cell type and passage. Comparison with disease genes and prediction scores suggest biological relevance for some variants. We show that high-throughput sequencing has value beyond SNV detection and the requirement to individually evaluate each clone. Footnotes * --> We added the sentence \"Study approval including all iPSC procedures was granted by the local ethics committees (No. 4485 and 4120, FAU Erlangen-Nuernberg, Germany; and No StV I 1/09 Canton of Zurich) and all participants or their legal guardians gave written informed consent prior to inclusion into the study.\" to the methods section. --> We added the contributions of Martin Regensburger (M.R.) and Katharina Guenther (K.G.).