Abstract Following the submission of dossier GMFF‐2023‐21253 under Regulation (EC) No 1829/2003 from Bayer CropScience LP, the Panel on Genetically Modified Organisms of the European Food Safety Authority was asked to deliver a scientific risk assessment on the data submitted in the context of the renewal of authorisation application for the stearidonic acid producing genetically modified soybean MON 87769, for food and feed uses, excluding cultivation within the European Union. The data received in the context of this renewal application contained post‐market environmental monitoring reports, post‐market monitoring reports, an evaluation of the literature retrieved by a scoping review, a search for additional studies performed by or on behalf of the applicant and updated bioinformatics analyses. The GMO Panel assessed these data for possible new hazards, modified exposure or new scientific uncertainties identified during the authorisation period and not previously assessed in the context of the original application. Under the assumption that the DNA sequence of the event in soybean MON 87769 considered for renewal is identical to the sequence of the originally assessed event, the GMO Panel concludes that there is no evidence in renewal dossier GMFF‐2023‐21253 for new hazards, modified exposure or scientific uncertainties that would change the conclusions of the original risk assessment on soybean MON 87769.

Genetically modified soybean MON 94313 was developed to confer tolerance to dicamba, glufosinate, 2,4-D and mesotrione-based herbicides. These properties were achieved by introducing the dmo, pat, ft_t.1 and tdo expression cassettes. The molecular characterisation data and bioinformatics analyses do not identify issues requiring food/feed safety assessment. None of the identified differences in the agronomic/phenotypic and compositional characteristics tested between soybean MON 94313 and its conventional counterpart need further assessment, except for methionine and Gly m Bd 28K, which underwent additional evaluation and were found to not raise any safety or nutritional concerns. The GMO Panel does not identify safety concerns regarding the toxicity and allergenicity of the DMO, PAT, FT_T.1 and TDO proteins as expressed in soybean MON 94313 and finds no evidence that the genetic modification would change the overall safety of soybean MON 94313. In the context of this application, the consumption of food and feed from soybean MON 94313 does not represent a nutritional concern in humans and animals, and no post-market monitoring of food/feed is considered necessary. In the case of release of processed soybean MON 94313 material, or accidental spillage of viable GM soybean seeds into the environment, this would not raise environmental safety concerns. The post-market environmental monitoring plan and reporting intervals are in line with the intended uses of soybean MON 94313. The GMO Panel concludes that soybean MON 94313 is as safe as its conventional counterpart and the tested non-GM soybean varieties with respect to potential effects on human and animal health and the environment.

Following a mandate from EFSA, the EFSA Panel on Genetically Modified Organisms (GMO Panel) addressed the food and feed risk assessment of genetically modified plants containing stacked transformation events ('stacks'). The GMO Panel examined the experience gained in the assessment of stacks in the last 20 years. Based on this, the GMO Panel concluded that under specific conditions, field trials for comparative analysis may not always be required for the assessment of stacks and a derogation may be considered. The conditions are: all the events combined in the stack should express traits through newly expressed proteins (NEPs) and these should not be metabolic modifiers. Under the same conditions and in the absence of interactions affecting NEP expression levels, a derogation from current requirements for dietary exposure assessment may also be considered. The GMO Panel also proposes improvements for applicants regarding the presentation of molecular characterisation data for stacks.

Narcolepsy type 1 is a sleep-wake disorder characterized by hypocretin deficiency. It has been considered an autoimmune disorder for decades due to the strong associating with the HLA-DQB1*06:02 allele and possible relations to the H1N1 pandemic in 2009. However, the pathophysiological mechanisms underlying the loss of hypocretin neurons is not understood. We hypothesize that a hypocretin neuron-specific antigen, other than hypocretin itself but sharing an expression pattern, may be the target of the autoimmune response leading to the development in individuals with narcolepsy type 1. In this study, we employed an in silico method to identify novel candidate antigens for an autoimmune response leading to the destruction of hypocretin cells. A combination of multiple publicly available datasets, based on human brain tissue from healthy individuals, was used to map the expression profile of hypocretin. Genes were categorized based on their expression pattern and its association with hypocretin expression. 15 candidate genes were identified as potentially relevant targets in the development of NT1, with varying degrees of confidence regarding the likelihood of their involvement. Six candidate genes also showed higher expression within hypocretin cells compared to other cells in the hypothalamus of which NPVF seems most promising. This study provides important new directions and potential targets for investigating and understanding the pathophysiology of narcolepsy type 1.

Abstract Genetically modified soybean GMB151 × DAS‐44406‐6 was developed by crossing to combine two single events: GMB151 and DAS‐44406‐6. The two‐event stack soybean expresses the Cry14Ab‐1, HPPD‐4, PAT, AAD‐12 and 2mEPSPS proteins to confer herbicide tolerance and resistance to plant parasitic nematodes. The GMO Panel previously assessed the two single soybean events and did not identify safety concerns. No new data on the single soybean events were identified that could lead to modification of the original conclusions on their safety. The molecular characterisation, comparative analysis (agronomic, phenotypic and compositional characteristics) and the outcome of the toxicological, allergenicity and nutritional assessment indicate that the combination of the single soybean events and of the newly expressed proteins in the two‐event stack soybean does not give rise to food and feed safety and nutritional concerns. The GMO Panel concludes that two‐event stack soybean, as described in this application, is as safe as the comparator and non‐GM reference soybean varieties tested and no post‐market monitoring of food/feed is considered necessary. In the case of accidental release of GM two‐event stack soybean material into the environment, this would not raise environmental safety concerns. The post‐market environmental monitoring plan and reporting intervals are in line with the intended uses of soybean GMB151 × DAS‐44406‐6. Post‐market monitoring of food/feed is not considered necessary. The GMO Panel concludes that two‐event stack soybean is as safe as its comparator and the tested non‐GM reference varieties with respect to potential effects on human and animal health and the environment.

Objectives:Refractory celiac disease type II (RCDII) is an intestinal tumor of aberrant intra-epithelial T-lymphocytes (IEL). The severe enteropathy found in RCDII is caused by aberrant IEL that exert cytotoxicity against enterocytes. In this study, we investigated the cell death mechanism responsible for villous atrophy in RCDII. Methods:Aberrant IEL were isolated from duodenal biopsies of RCDII patients. Enterocyte and RCDII patient-derived cell lines and human small intestinal organoids were used. mRNA expression was determined with reverse transcriptase-multiplex ligation-dependent probe amplification. Protein expression, degranulation and enterocyte killing were measured using flow cytometry, immunofluorescence or bright field microscopy. Secretion of granzyme-B was detected by enzyme immunoassay. Results:Levels of granzyme-B expression were significantly upregulated in aberrant IEL of RCDII patients compared to patients with celiac disease (CD) on gluten-free diet (P = 0.0001) and correlated with severity of villous atrophy and clinical response to therapy. Killing of intestinal epithelial cells was caused by granzyme-B. For granzyme-B degranulation and subsequent cytotoxicity, cell-cell binding via the CD103-receptor, which was upregulated on aberrant IEL, was essential. In a preclinical model, aberrant IEL migrated to the intestinal organoids and induced organoid disintegration and CD103-dependent cell death. Targeting CD103-heterodimeric partner β7 with therapeutic monoclonal antibody etrolizumab prevented enterocyte cell killing and resulted in survival of organoids. Conclusion:Killing of enterocytes in RCDII patients depends on degranulation of granzyme-B by aberrant IEL through CD103-β7 binding. By blocking this interaction, etrolizumab restores the intestinal epithelium and therefore should be considered as potential therapy for RCDII patients.

Following the submission of dossier GMFF-2025-33580 under Regulation (EC) No 1829/2003 from Syngenta Crop Protection AG, the Panel on Genetically Modified Organisms of the EFSA was asked to deliver a scientific risk assessment on the data submitted in the context of the renewal of authorisation application for the herbicide-tolerant genetically modified soybean FG72, for food and feed uses, excluding cultivation within the European Union. The data received in the context of this renewal application contained post-market environmental monitoring reports, an evaluation of the literature retrieved by a scoping review, additional studies performed by or on behalf of the applicant and updated bioinformatics analyses. The GMO Panel assessed these data for possible new hazards, modified exposure or new scientific uncertainties identified during the authorisation period and not previously assessed in the context of the original application. Assuming that the DNA sequence of the event in soybean FG72 considered for renewal is identical to the sequence of the originally assessed event, the GMO Panel concludes that there is no evidence in renewal dossier GMFF-2025-33580 for new hazards, modified exposure or scientific uncertainties that would change the conclusions of the original risk assessment on soybean FG72.

CD4+ T helper (Th) cell responses to commensal microbiota are linked to Inflammatory Bowel Disease (IBD), yet how Th programs coexist and evolve in human tissues remains poorly defined. Here, we profiled CD4+ memory T cells in intestinal biopsies using immunological and histological approaches to map phenotypes, functional states, and spatial relationships across disease states. A marked expansion of CD4+ T cells concomitant with a RORγt+ Th population with elevated T-bet expression was linked to the progression of inflammation. Moreover, Foxp3+ cells co-expressing RORγt emerged within the inflamed niche, indicating regulatory-Th17 plasticity. Trajectory visualization revealed a potential branched differentiation path toward regulatory or tissue-resident Th17-like fates, with both termini expressing activation and proliferation markers. Correlation network analysis connected pro-inflammatory CD4+ states to T-bet+Granzyme-B+ CD8+ subsets, indicating coordination between helper and cytotoxic lineages. Histology revealed increased T-cell infiltration and spatial segregation of tissue-resident subsets, with CD103+CD4+ T cells localized mainly in the lamina propria and CD103+CD8+ T cells near the epithelium. TCR stimulation during active disease revealed broad suppression of CD4+ pro-inflammatory cytokines alongside Foxp3+ expansion. Conversely, HLA-DR+CD38+ memory subset retained multifunctionality, producing elevated levels of pro-inflammatory cytokines. Together, these results define a dynamic, tissue-embedded CD4 T-cell landscape in IBD.

Abstract Primarily recognized as the site for T cell development, the thymus supports a complex interplay between thymic stromal cells and developing thymocytes, which is essential for T cell maturation and the establishment of central tolerance. Emerging evidence indicates that thymic B cells contribute to tolerance induction by functioning as antigen-presenting cells. However, their developmental pathways and functional roles remain poorly understood. Using tissue mass cytometry, we localized B cells in the thymus and their orientation towards other cells in the medulla. We characterized the heterogeneity of thymic B cells using single-cell RNA sequencing of cells isolated from human thymi, identifying naive, germinal center-like, plasma cell, and multiple memory B cell populations. We identified a distinct pre-B cell subset with local thymic B cell development potential, that can develop due to the inhibition of Notch signaling by Deltex1, a Notch antagonist. Using BCR repertoire analysis, we explored clonal diversity, somatic hypermutation patterns and class switch recombination of thymic B cells. Spectral flow cytometry further validated the surface phenotype of thymic B cell populations and confirmed the presence of distinct CD21 - CD27 - memory compartments with heterogeneous surface immunoglobulin isotype usage. In doing so we provide novel insights into the unique biology of human thymic B cells, their development, and their differentiation in the human thymus. We conclude that the human thymus supports local B cell development and differentiation into medullary memory-like populations that undergo class switching with limited somatic hypermutation, suggesting secondary lymphoid-like B cell programs adapted to central tolerance induction. One Sentence Summary The human thymus is not only a primary lymphoid organ for T cell development, but also a secondary site for the development and maturation of unique populations of B cells.

Abstract Genetically modified soybean DAS‐44406‐6 × FG72 was developed by conventional crossing to combine two single events: DAS‐44406‐6 and FG72. The soybean DAS‐44406‐6 × FG72 expresses the AAD‐12, 2mEPSPS, PAT and HPPD W336 proteins to confer herbicide tolerance to 2,4‐D‐, glyphosate‐, glufosinate‐containing and HPPD‐inhibiting herbicide products, respectively. The GMO Panel previously assessed the two single soybean events and did not identify safety concerns. No new data on the single soybean events were identified that could lead to modification of the original conclusions on their safety. The molecular characterisation, comparative analysis (agronomic, phenotypic and compositional characteristics) and the outcome of the toxicological, allergenicity and nutritional assessment indicate that the combination of the single soybean events and of the newly expressed proteins in the soybean DAS‐44406‐6 × FG72 does not give rise to food and feed safety or nutritional concerns. The GMO Panel concludes that the DAS‐44406‐6 × FG72 stack soybean, as described in this application, is as safe as the non‐GM comparator and non‐GM reference varieties tested, and no post‐market monitoring of food and feed is considered necessary. In the case of release of processed soybean DAS‐44406‐6 × FG72 or accidental spillage of viable GM soybean seeds into the environment, this would not raise environmental safety concerns. The post market environmental monitoring plan and reporting intervals are in line with the intended uses of soybean DAS‐44406‐6 × FG72. The GMO Panel concludes that soybean DAS‐44406‐6 × FG72 is as safe as its non‐GM comparator and the tested non‐GM reference varieties with respect to potential effects on human and animal health and the environment.

Horse-derived anti-thymocyte globulin (ATGAM) in combination with long-term ciclosporin is the first-line treatment for most immune-mediated aplastic anemia (AA) patients. The exact impact of this immunosuppressive therapy (IST) on hematologic recovery and the immune landscape, however, remains poorly understood. We report a longitudinal analysis of the pharmacodynamic effects of ATGAM-based IST in a cohort of 44 AA patients. We used flow cytometry to quantify plasma levels of lymphocyte-binding ATGAM, which is believed to mediate the therapeutic effect. Population pharmacokinetic modeling revealed substantial between-patient variability in ATGAM exposure, with higher exposure levels associating with earlier hematologic recovery. ATGAM bound all lymphoid lineages and profoundly depleted T and natural killer cells at high plasma concentrations. Strikingly, ATGAM did not deplete B cells but instead induced an increase in CD27+ B cells. Deep immunophenotyping on series of peripheral blood samples collected up to three years after start of IST demonstrated that ATGAM induced rapid depletion of T cells, including KLRG1+ terminally differentiated CD8+ T cells and Th17-like CCR6+CD4+ T cells. Although naïve and pathogen-specific T cells were also depleted, they recovered quickly, indicating preservation of protective immunity. Notably, CCR6++ B cells, implicated in AA pathogenesis, escaped ATGAM depletion but reduced gradually over time along with residual potentially pathogenic T cells, including the CCR6+CD4+ T cells. This could explain the crucial contribution of long-term ciclosporin to successful IST. Collectively, our results identify ATGAM exposure as a factor influencing hematologic recovery and indicate that the therapeutic effect of IST goes beyond total lymphodepletion but is rather the result of selective depletion and suppression of key lymphocyte subpopulations.

Following the submission of application GMFF-2023-21236 under Regulation (EC) No 1829/2003 from Bayer CropScience LP, the Panel on Genetically Modified Organisms of the European Food Safety Authority was asked to deliver a scientific risk assessment on the data submitted in the context of the renewal of authorisation application for the herbicide-tolerant, increased oleic acid genetically modified soybean MON 87705, for food and feed uses, excluding cultivation within the European Union. The data received in the context of this renewal application contained post-market environmental monitoring reports, post-market monitoring reports, an evaluation of the literature retrieved by a scoping review, a search for additional studies performed by or on behalf of the applicant and updated bioinformatics analyses. The GMO Panel assessed these data for possible new hazards, modified exposure or new scientific uncertainties identified during the authorisation period and not previously assessed in the context of the original application. Under the assumption that the DNA sequence of the event in soybean MON 87705 considered for renewal is identical to the sequence of the originally assessed event, the GMO Panel concludes that there is no evidence in renewal application GMFF-2023-21236 for new hazards, modified exposure or scientific uncertainties that would change the conclusions of the original risk assessment on soybean MON 87705.

Following the submission of dossier GMFF-2024-23010 Regulation (EC) No 1829/2003 from BASF Agricultural Solutions Seed US LLC, the Panel on Genetically Modified Organisms of the European Food Safety Authority was asked to deliver a scientific risk assessment on the data submitted in the context of the renewal of authorisation application for the insect resistant and herbicide tolerant genetically modified cotton T304-40, for food and feed uses, excluding cultivation within the European Union. The data received in the context of this renewal application contained post-market environmental monitoring reports, an evaluation of the literature retrieved by a scoping review, a search for additional studies performed by or on behalf of the applicant and updated bioinformatics analyses. The GMO Panel assessed these data for possible new hazards, modified exposure or new scientific uncertainties identified during the authorisation period and not previously assessed in the context of the original application. Under the assumption that the DNA sequence of the event in cotton T304-40 considered for renewal is identical to the sequence of the originally assessed event, the GMO Panel concludes that there is no evidence in renewal dossier GMFF-2024-23010 for new hazards, modified exposure or scientific uncertainties that would change the conclusions of the original risk assessment on cotton T304-40.

Abstract Genetically modified cotton GHB614 × T304‐40 × GHB119 × COT102 was developed by crossing to combine four single events: GHB614, T304‐40, GHB119 and COT102. The four‐event‐stack cotton expresses 2mEPSPS, Cry1Ab, Cry2Ae, Vip3Aa19 and PAT/bar to confer herbicide tolerance and insect resistance. Furthermore, event COT102 expresses the antimicrobial APH4 protein used during its molecular development. The GMO Panel previously assessed the four single cotton events and did not identify safety concerns. Since then, no new data on the single cotton events were identified that would require modification of the original conclusions on their safety. The molecular characterisation, comparative analysis (agronomic, phenotypic and compositional characteristics) and the outcome of the toxicological, allergenicity and nutritional assessment does not indicate interactions which would give rise to new food and feed safety and nutritional concerns. The GMO Panel concludes that the four‐event stack cotton, as described in this application, is as safe as its non‐GM comparator and non‐GM cotton varieties tested, and no post‐market monitoring of food/feed is considered necessary. In the case of release of processed cotton GHB614 × T304‐40 × GHB119 × COT102 or accidental spillage of viable GM cotton seeds into the environment, this would not raise environmental safety concerns. The post‐market environmental monitoring plan and reporting intervals are in line with the intended uses of cotton GHB614 × T304‐40 × GHB119 × COT102. The GMO Panel concludes that four‐event stack cotton is as safe as its non‐GM comparator and the tested non‐GM cotton varieties with respect to potential effects on human and animal health and the environment.

Abstract Following the submission of dossier GMFF‐2023‐21252 under Regulation (EC) No 1829/2003 from Bayer CropScience LP, the Panel on Genetically Modified Organisms of the European Food Safety Authority was asked to deliver a scientific risk assessment on the data submitted in the context of the renewal of authorisation application for the herbicide‐tolerant genetically modified maize NK603 × T25, for food and feed uses, excluding cultivation within the European Union. The data received in the context of this renewal application contained post‐market environmental monitoring reports, an evaluation of the literature retrieved by a scoping review, a search for additional studies performed by or on behalf of the applicant and updated bioinformatics analyses. The GMO Panel assessed these data for possible new hazards, modified exposure or new scientific uncertainties identified during the authorisation period and not previously assessed in the context of the original application. Under the assumption that the DNA sequences of the events in maize NK603 × T25 considered for renewal are identical to the sequences of the originally assessed events, the GMO Panel concludes that there is no evidence in renewal dossier GMFF‐2023‐21252 for new hazards, modified exposure or scientific uncertainties that would change the conclusions of the original risk assessment on maize NK603 × T25.

This study provides a detailed protocol to visualize the codevelopment of structural and immune cells in the human fetal lung through imaging mass cytometry (IMC). Using IMC, spatial relationships between lung epithelial cells and myeloid cells can be visualized, which may contribute to unraveling cellular interactions important for lung maturation.

Abstract Following the submission of dossier GMFF‐2024‐21890 under Regulation (EC) No 1829/2003 from BASF Agricultural Solutions Seeds US LLC, the Panel on Genetically Modified Organisms of the European Food Safety Authority was asked to deliver a scientific risk assessment on the data submitted in the context of the renewal of authorisation application for the herbicide‐tolerant genetically modified cotton GHB614 × LLCotton25, for food and feed uses, excluding cultivation within the European Union. The data received in the context of this renewal application contained post‐market environmental monitoring reports, an evaluation of the literature retrieved by a scoping review, a search for additional studies performed by or on behalf of the applicant and updated bioinformatics analyses. The GMO Panel assessed these data for possible new hazards, modified exposure or new scientific uncertainties identified during the authorisation period and not previously assessed in the context of the original application. Under the assumption that the DNA sequences of the events in cotton GHB614 × LLCotton25 considered for renewal are identical to the sequences of the originally assessed events, the GMO Panel concludes that there is no evidence in renewal dossier GMFF‐2024‐21890 for new hazards, modified exposure or scientific uncertainties that would change the conclusions of the original risk assessment on cotton GHB614 x LLCotton25.

Genetically modified soybean DBN9004 was developed to confer tolerance to glufosinate-ammonium- and glyphosate-containing herbicides. These properties were achieved by introducing the cp4 epsps and pat expression cassettes. The molecular characterisation data and bioinformatic analyses do not identify issues requiring food/feed safety assessment. None of the identified differences in the agronomic/phenotypic and compositional characteristics tested between soybean DBN9004 and its conventional counterpart needs further assessment. The GMO Panel does not identify safety concerns regarding the toxicity and allergenicity of the CP4 EPSPS and PAT proteins as expressed in soybean DBN9004 and finds no evidence that the genetic modification would change the overall safety of soybean DBN9004, as food and feed. In the context of this application, the consumption of food and feed from soybean DBN9004 does not represent a nutritional concern in humans and animals. The GMO Panel concludes that soybean DBN9004 is as safe as the conventional counterpart and non-GM soybean varieties tested, and no post-market monitoring of food/feed is considered necessary. In the case of release of soybean DBN9004 material, including viable grains, into the environment, this would not raise environmental safety concerns. The post-market environmental monitoring plan and reporting intervals are in line with the intended uses of soybean DBN9004. The GMO Panel concludes that soybean DBN9004 is as safe as its conventional counterpart and the tested non-GM soybean varieties with respect to potential effects on human and animal health, and the environment.

Following the submission of dossier GMFF-2024-22651 under Regulation (EC) No 1829/2003 from BASF Agricultural Solutions Seed US LLC, the Panel on genetically modified organisms of the European Food Safety Authority was asked to deliver a scientific risk assessment on the data submitted in the context of the renewal of authorisation application for the herbicide-tolerant genetically modified maize T25, for food and feed uses, excluding cultivation within the European Union. The data received in the context of this renewal application contained post-market environmental monitoring reports, an evaluation of the literature retrieved by a scoping review, a search for additional studies performed by or on behalf of the applicant and updated bioinformatics analyses. The GMO Panel assessed these data for possible new hazards, modified exposure or new scientific uncertainties identified during the authorisation period and not previously assessed in the context of the original application. Under the assumption that the DNA sequence of the event in maize T25 considered for renewal is identical to the sequence of the originally assessed event, the GMO Panel concludes that there is no evidence in renewal dossier GMFF-2024-22651 for new hazards, modified exposure or scientific uncertainties that would change the conclusions of the original risk assessment on maize T25.