bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B047: Tertiary lymphoid structures and B cells signatures determine clinically relevant T cell phenotype in ovarian cancer
Authors: Moserova Irena Kusova , Kasikova Lenka , Rakova Jana , Tomankova Jana , Henser Michal , Lanickova Tereza , Mojzisova Katerina , Drozenova Jana , Laco Jan , Rob Lukas , Halaska Michael , Ryska Ales , Lischke Robert , Vachtenheim Jiri , Cibula David , Galluzzi Lorenzo , Spisek Radek , Fucikova Jitka 
Published: December 2023

Abstract
Tertiary lymphoid structures (TLSs) are ectopic lymphoid formations that arise at sites with persistent inflammatory conditions, including tumors. TLSs are composed predominantly of B cells, T cells, and CD21+ CD23+ follicular dendritic cells and exhibit different levels of the organization, ranging from locally concentrated aggregates of immune cells to well-defined B cell follicles to mature follicles with germinal center formation. Supporting key relevance for TLSs in natural and immunotherapy-driven immunosurveillance, intratumoral TLS density has been associated with improved disease outcome and response to cancer immunotherapy, mainly check-point inhibitors (ICIs) in solid carcinomas. Here, we demonstrate that compared to the immunologically hot tumors like non-small cell lung carcinoma (NSCLC), human high-grade serous ovarian carcinoma (HGSOC) contains only a limited number of TLS with germinal center formation. In parallel, TLS frequency and maturation positively correlate with progenitor stem-like CD8+ T cell phenotype. In line with this notion, B cell depletion in HGSOC biopsies promoted terminally exhausted, poorly ICI-sensitive CD8+ T cells, suggesting a critical role of intratumoral B cells in maintaining T cell effector functions. These findings point to key numerical and functional differences between mature TLSs in ICI-responsive vs ICI-irresponsive neoplasms that may guide the development of alternative ICI-based immunotherapies for patients with HGSOC.
Citation Format: Irena Kusova Moserova, Lenka Kasikova, Jana Rakova, Jana Tomankova, Michal Henser, Tereza Lanickova, Katerina Mojzisova, Jana Drozenova, Jan Laco, Lukas Rob, Michael Halaska, Ales Ryska, Robert Lischke, Jiri Vachtenheim, David Cibula, Lorenzo Galluzzi, Radek Spisek, Jitka Fucikova. Tertiary lymphoid structures and B cells signatures determine clinically relevant T cell phenotype in ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr B047.
Abstract PR01: Regulation of exhausted CD8+ T cell differentiation by IKZF transcription factors
Authors: Reading Sinead M , Munoz Isabelle , de Menezes Maria Nogueira , Saw Nicole Y.L , Ambani Krutika , Ahn Antonio , Nussing Simone , Roth Sara , Sampurno Shienny , Ramsbottom Kelly M , Trapani Joseph A , Good-Jacobson Kim L , Johnstone Ricky W , Goel Shom , Beavis Paul A , Parish Ian A 
Published: December 2023

Abstract
CD8+ T cells are indispensable for pathogen and tumor clearance, although can induce immunopathology if left unrestricted. T cell exhaustion, progressively programmed in the context of persistent antigen exposure, ensures partial control while mitigating immunopathological risk. However, exhaustion is characterized by curtailed proliferative capacity, cytokine production and cytotoxic functions, which tumors and chronic pathogens exploit to persist. As such, transiently disrupting exhaustion has emerged as a therapeutic strategy for treating cancer. Exhausted cells transition through a range of differentiation states, from stem-like progenitors that mediate response to checkpoint blockade, through to terminal effector or exhausted cells. Understanding the molecular pathways moderating the exhausted states and promoting terminal exhaustion is essential for augmenting cancer immunotherapy. We identify IKZF transcription factors, Ikaros (IKZF1), Helios (IKZF2) and Aiolos (IKZF3), as key mediators of T cell exhaustion, using gene knock-out mice and a CRISPR-mediated genetic knock-out system in both chronic infection and tumor models. IKZF1 and IKZF3 are critical regulators of exhausted subset expansion, retention, phenotype and cytokine function. Strikingly, dual IKZF1 and IKZF3 ablation boosts the response of anti-tumor and anti-viral exhausted T cells, potentially via the formation of atypical exhausted T cell populations and the enrichment of functional exhausted subsets. Cumulatively, our data highlight a novel role for IKZF transcription factors in biasing exhausted T cell differentiation and provides potentially important clinical implications, directing future cancer immunotherapies targeting T cell exhaustion.
Citation Format: Sinead M Reading, Isabelle Munoz, Maria Nogueira de Menezes, Nicole Y.L Saw, Krutika Ambani, Antonio Ahn, Simone Nussing, Sara Roth, Shienny Sampurno, Kelly M Ramsbottom, Joseph A Trapani, Kim L Good-Jacobson, Ricky W Johnstone, Shom Goel, Paul A Beavis, Ian A Parish. Regulation of exhausted CD8+ T cell differentiation by IKZF transcription factors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr PR01.
Gassendi and the Low Countries: Introduction
Authors: Bellis Delphine 
Published: December 2023

Abstract
This introduction summarises the nature of the strong intellectual links existing between the French philosopher Pierre Gassendi (1592–1655) and the Low Countries. It retraces the main steps of his trip to the Spanish Low Countries and the Dutch Republic in 1629, and the importance of this trip for the development of his philosophy, as well as the epistolary network with his correspondents from that area, especially in the field of astronomy. Scholars in the Low Countries were receptive to atomistic theories, empiricism, and anti-dogmatism, all of which are central to Gassendi’s philosophy. Gassendi’s philosophy also provided arguments against Descartes’s metaphysics, and helped disseminate Galileo’s mechanics in the Low Countries. Gassendi’s influence in the Low Countries lasted beyond his death, as can be seen in the philosophy of Spinoza and Bayle.
Atomism and Cartesianism: Gassendi and Gorlaeus (and More) in Utrecht Disputations in the 1650s
Authors: Bos Erik-Jan 
Published: December 2023

Abstract
In the 1650s, two professors of philosophy at the University of Utrecht defended atomism. Interestingly, one of them, Johannes de Bruyn, is considered to be a staunch Cartesian, while the other, Daniel Voet, was a neo-Aristotelian and strongly opposed to Descartes’s philosophy. This article examines this curious situation and analyses the theories of both professors. While converging with Gassendi on several crucial points, their theories relied mainly on other sources. Since De Bruyn’s atomistic view has never been studied before, the main part of the article is devoted to him and his sources. Surprisingly, it turns out that David Gorlaeus was a source of inspiration for De Bruyn’s development of a new type of Cartesianism.
Perseverare in (suo) Esse: Gassendi and Spinoza against Descartes
Authors: Le Gendre Samuel 
Published: December 2023

Abstract
This contribution focuses on the issue of creatures’ conservation in being. The aim is as follows: to demonstrate that the Cartesian position is significantly different from the positions adopted by Gassendi and then by Spinoza. Indeed, both, in contrast to Descartes, adopt a principle of metaphysical inertia, which parallels their principle of physical inertia. If Gassendi can conceive of this principle of metaphysical inertia, it is because he really distinguishes between creation and conservation. If Spinoza, who owes it to his reading of the 5th Objections and Replies, can conceive of his principle, it is because he distinguishes between ideal essence and actual essence.
AICAR Induces AMPK-Independent Cell Death in Adult T-Cell Leukemia/Lymphoma and Has Anti-Tumor Activity
Authors: Kozako Tomohiro , Aikawa Akiyoshi , Ohsugi Takeo , Honda Shin-Ichiro 
Published: December 2023

Introduction: Adult T-cell leukemia/lymphoma (ATL) is an aggressive T cell leukemia/lymphoma caused by human T-cell lymphotropic virus type I (HTLV-1) and has a poor outcome. Recently, we reported that AMPKα, the catalytic unit of AMP-activated protein kinase (AMPK), is highly expressed in cells from patients with ATL and that an AMPK inhibitor had anti-tumor activity in ATL mice 1. On the other hand, acadesine or 5-aminoimidazole-4-carboxamide riboside (AICAR) is anAMPK activator, and was recently shown to have tumor suppressive effects on B cell chronic lymphocytic leukemia via the activation of AMPK. However, the effect of AICAR on the death of ATL-related cell lines is unknown. This study evaluated the effects of AICAR on death in ATL-related cell lines and its anti-tumor activity.
Results: We demonstrated that AICAR inhibited the proliferation of ATL-related cell lines (S1T, MT-1 and MT-2) but not non-HTLV-1-infected Jurkat cells and peripheral blood mononuclear cells from healthy individuals. However, AICAR did not increase the phosphorylation levels of AMPKα. We found that AICAR increased annexin V-positive cell numbers in the sub-G0/G1 phase, and decreased the mitochondrial membrane potential and caspase-3/8/9 activation, which are hallmarks of apoptosis. However, AICAR did not increase the phosphorylation levels of AMPKα. On the other hand, HTLV-1 Tax, an HTLV-1-encoded oncogenic factor, expression did not affect AICAR-induced cell death. Moreover, AICAR induced the expression of death receptors (DR) DR4 and DR5 in vitro. Furthermore, AICAR inhibited the growth and infiltration of S1T cells transplanted subcutaneously in NOD/SCID/gamma mice.
Conclusion: This is the first evidence to demonstrate the AMPK-independent effects of AICAR on death in ATL-related cell lines and its anti-tumor activity. Thus, AICAR might be a candidate for the treatment of ATL.
Disclosures : No relevant conflicts of interest to declare.
1. Aikawa A, Kozako T, Uchida Y, et al. Cell death induced by dorsomorphin in adult T-cell leukemia/lymphoma is AMPK-independent. Febs j. 2020;287(18):4005-4015.
Single-Cell Genomics Details the Maturation Block in BCP-ALL and Identifies Therapeutic Vulnerabilities in DUX4-Rearranged Cases
Authors: Thorsson Hanna , Henningsson Rasmus , Puente-Moncada Noelia , Sjöström Ludvig , Ågerstam Helena , Peña-Martínez Pablo Enrique , Sandén Carl , Rissler Marianne , Castor Anders , Marquart Hanne Vibeke , Modvig Signe , Paulsson Kajsa , Pronk Cornelis , Schmiegelow Kjeld , Hyrenius Wittsten Axel , Orsmark-Pietras Christina , Lilljebjörn Henrik PhD , Fioretos Thoas 
Published: December 2023

B cell progenitor acute lymphoblastic leukemia (BCP-ALL) is the most common childhood malignancy. It is initiated by multiple genetic alterations, causing a maturation arrest and accumulation of abnormal progenitor B cells. Current treatment protocols with chemotherapy have led to favorable outcomes, but are associated with significant toxicity and risk of side effects, highlighting the necessity for highly effective, less toxic, targeted drugs that also show efficacy in children experiencing relapse.
We have used multimodal single-cell sequencing to delineate the transcriptional, epigenetic, and immunophenotypic characteristics of 23 childhood BCP-ALLs, including the BCR::ABL1-positive, ETV6::RUNX1-positive, high hyperdiploid, and recently discovered DUX4-rearranged subtypes. In total, 188,546 single cells derived from 23 BCP-ALLs and 9 normal bone marrow samples were profiled using the 10X Genomics platform. Cellranger multi and atac count (10X Genomics) were used to generate read count matrices. Further analysis was performed using Seurat and Signac. The in-house developed program SingleCellProjections was used to create a normal bone marrow reference graph onto which the BCP-ALL data was projected.
Projection of the ALL cells along the normal B cell differentiation axis, revealed a diversity in the maturation block between the different BCP-ALL subtypes. Whereas the BCR::ABL1-, ETV6::RUNX1-positive and high hyperdiploidy cells mainly showed similarities to normal pro-B cells, the DUX4-rearranged ALL cells also displayed a transcriptional signature resembling mature B cells. In addition, the blast population in DUX4-rearranged ALLs showed multilineage priming toward non-hematopoietic cells, myeloid and T cell lineages, but also an activation of PI3K/AKT signaling that sensitized the cells to PI3K inhibition. Finally, we show that chimeric antigen receptor T cell therapy targeting the upregulated myeloid receptor CD371 (CLL-1), effectively eliminates DUX4-rearranged ALL cells. Our results provide a detailed characterization of BCP-ALL at the single-cell level and reveal therapeutic vulnerabilities in the DUX4-rearranged subtype with important implications for the understanding of ALL biology and new therapeutic strategies.
Autoimmune Neutropenia of Infancy Is Almost Exclusively Caused By IgG Antibodies
Authors: Sachs Ulrich J. , Braun Matthias , Bein Gregor , Bayat Behnaz 
Published: December 2023

Background
The relevance of IgM antibodies in autoimmune mediated hemocytopenias remains a matter of debate. For autoimmune neutropenia, conflicting results were published. This study was performed as part of the Giessen Neutropenia Registry, which prospectively included children with suspected autoimmune neutropenia.
Methods
Children with suspected autoimmune neutropenia were prospectively enrolled and data central to their suspected diagnosis were collected over 3 years. Sera were tested for the presence of autoantibodies against neutrophils by granulocyte immunofluorescence test (GIFT) and granulocyte agglutination test (GAT). The presence of IgG and IgM antibodies was assessed in a subgroup of patients with positive initial GIFT in whom spontaneous remission of their neutropenia was documented.
Results
A total of 406 children were included in the study. A remission was reported for 114 patients during the study period. Of those, 96 children (84%) had an initial positive GIFT. Their median age at diagnosis was 11 months (7-17.5), and their mean neutrophil count was 293 (±267)/µL, ranging from 0 to 975. In total 75/96 (78%) of children had at least one documented infection at diagnosis. In 29/96 (30%), a bone marrow aspirate was available. At the documented time point of remission, children were 27 months (18-41) old. In the initial sample send for diagnosis, IgG antibodies against neutrophils were detected in 94/96 children (98%), and IgM antibodies were detected in 2/96 (2%). We did not observe children with autoantibodies of both Ig classes.
Conclusion
To our knowledge, this is the first study to demonstrate the contribution of IgG or IgM antibodies in a well-defined clinical cohort with a typical course including, spontaneous disease remission. IgG antibodies were present in 98%. Only very rarely, IgM antibodies can be detected. We conclude that in general, screening for IgG autoantibodies is appropriate as a first diagnostic step. In cases with strong clinical suspicion but negative GIFT with anti-IgG, anti-IgM testing may be considered.
Early M-Protein Immune Reconstitution after Autologous Hematopoietic Stem Cell Transplantation Is a Good Prognostic Marker for Patients with High-Risk Cytogenetic Multiple Myeloma
Authors: Zhu Huihui , Li Juan 
Published: December 2023

OBJECTIVE: The presence of transient abnormal protein banding (i.e. M-protein immune reconstitution) in serum immunofixation electrophoresis after autologous hematopoietic stem cell transplantation in patients with multiple myeloma has been reported, and patients with high-risk cytogenetics tend to have poor prognosis; the purpose of this paper is to investigate the impact of post-transplant M-protein immune reconstitution on the prognosis of patients with high-risk cytogenetic multiple myeloma;
METHODS: To retrospectively analyze the clinical data of 290 newly diagnosed multiple myeloma patients from August 1, 2008 to July 31, 2021 at the First Affiliated Hospital of Sun Yat-sen University, all of whom underwent sequential autologous hematopoietic stem cell transplantation after induction therapy, and to analyze and compare the clinical characteristics and prognostic survival of patients with and without M-protein immune reconstitution;
RESULTS: M-protein immune reconstitution was observed in 25.9% (75/290 patients), the most common type of immunoglobulin was IgG-λ. The median time to obtain M-protein immune reconstitution was 3 months (1-38 months) and the median duration was 4 months (1-39 months) after transplantation, and there were no statistical differences in disease stage, tumor load and cytogenetics between the M-protein immune reconstituted and non-M-protein immune reconstituted groups. The CR rate and MRD negativity were higher in the M-protein immune reconstitution group (85.3% vs 69.3%, p=0.013, 81.9% vs 66.5%, p=0.014), and although there were no statistical differences in PFS and OS between the M-protein immune reconstitution group and the group without M protein immune reconstruction, the overall median survival time was longer in the M protein immune reconstruction group (80 vs 72m, p=0.096. not reached vs 105m, p=0.344). Among patients in the cytogenetic high-risk group, access to M-protein immune reconstitution predicted better PFS and OS (80 vs 31m, p=0.010. not reached vs 79m, p=0.026). Also in R-ISS stage III patients, PFS and OS were better in patients who obtained M-protein immune reconstitution (80 vs 20m, p=0.034. 57 vs 32m, p=0.137).
CONCLUSION: Better prognosis in M-protein immune reconstitution patients may be associated with the acquisition of a deeper response, but in high-risk patients, early acquisition of M-protein immune reconstitution may suggest a better prognosis.
TBI/Ratg-Based Conditioning for Haploidentical Allogeneic Hematopoietic Stem Cell Transplantation in 11 Cases of Chemotherapy-Resistant Advanced-Stage Peripheral T-Cell Lymphoma
Authors: Zhu JUN , Xu Rong , Wang Chun , Zhao Chuxian , Jiang Ying , Wei Daolin , Shao Shan , Liu Huixia , Li Su 
Published: December 2023

Objectives: To evaluate the clinical outcomes and safety of haploidentical allogeneic hematopoietic stem cell transplantation(haplo-HSCT)with total body irradiation (TBI)/rabbit Anti-thymocyte globulin (rATG) based conditioning regimen in chemotherapy-resistant advanced-stage peripheral T-cell lymphoma (PTCL).
Methods: From September 2019 to December 2022, eleven chemotherapy-resistant advanced-stage PTCL patients who underwent haplo-HSCT were enrolled in our study. All of them received TBI/rATG-based conditioning regimen in our centers.
Results: ①Among 11 patients, there were 6 males and 5 females with a median age of 40(range：22~58) years old. Six cases of them are peripheral T-cell lymphoma not otherwise specified (PTCL NOS), 3 cases are angioimmunoblastic T-cell lymphoma (AITL), 1 case is large-cell transformation of mycosis fungoides (MF-LCT), and 1 case is T-cell large granular lymphocytic leukemia(T-LGLL). The Lugano stage was III or IV in all cases, and 8 patients had B symptoms. The median number of previous chemotherapy exposure before transplantation was 4 (range: 2~10) lines and the disease status before transplantation was progressive diseases (PD) in all cases. The median time from diagnosis to transplantation was 17(range：6~36) months.②The conditioning regimen consisted of TBI 2Gy d-8, 4Gy from day-7 to -6, rATG 2.5 mg/kg/d day-5 to -2, etoposide 15mg/kg/d day-5 to -4, cyclophosphamide (CTX) 50mg/kg/d, day-3 to -2. The patients with central nervous system involvement received a regimen of thiotepa 5 mg/kg/d， from day -5 to -4 instead of CTX and etoposide, and add 2.0 g/m2 of cytarabine twice a day, from day -3 to day -2 into the conditioning.③All patients were successfully engrafted. Only one patient developed Grade III-IV acute graft-vs-host disease (aGvHD). Among the 8 survivors, 4 cases developed chronic graft-vs-host disease (cGvHD).④After transplantation, CR was obtained in 9 patients. ⑤Regimen related toxicities: all were non-fatal. Hematopoietic suppression occurred in all patients after conditioning. Three patients had diarrhea and four had mucositis and three had elevated transaminase/bilirubin levels. Seven patients had infections.⑥The 1-year cumulative non-relapse mortality (NRM) and 1-year cumulative incidence of relapse (CIR) was 22.5±14.0% and 20.2±12.7%, respectively. The 1-year overall survival (OS) and 1-year disease-free survival (DFS) was 72.7±13.4% and 63.6±14.5%, respectively
Conclusions: TBIand rATG based conditioning regimen is effective and safe for haplo-HSCT in chemotherapy-resistant advanced-stage PTCL.
Haploidentical Hematopoietic Stem Cell Transplantation with Post-Transplant Cyclophosphamide in the Chilean National Health System. a Single Center Study
Authors: Puga Bárbara , Benavente Rafael , Bass Francisca , Molina M. Javiera , Andrade Alejandro , Majlis Alejandro , Cabrera Maria Elena , Undurraga Soledad 
Published: December 2023

Haploidentical peripheral blood stem cell transplantation with post-transplant cyclophosphamide (Haplo-PTCy) is the most common transplantation modality in low-and-middle-income countries (LMIC). Registry data has shown comparable outcomes when using haploidentical donors versus Matched Unrelated Donors (MUD) in patients with acute leukemias. In the Chilean Public Health System Haplo-PTCy was incorporated in 2016 for adults up to 60 years old.
We analyzed all adult patients who received an Haplo-PTCy at Hospital del Salvador, in a prospective registry study between 2016 and 2021. The primary outcome was overall survival (OS). Secondary outcomes were event-free survival (EFS), cumulative incidence of relapse, and incidence of grade II-IV acute graft-versus-host disease (aGVHD) at day +100. Overall survival and EFS were estimated using the Kaplan-Meier method. The cumulative incidence of relapse was calculated using relapse as the primary event and death without relapse as a competing event. Acute GVHD is shown as absolute incidence at day +100. All statistical analyses were performed with R. This study was done in compliance with the Helsinki Declaration and was approved by the Institutional Review Board.
Eighty-five Haplo-PTCy were performed in 82 patients (Table 1). Three-second Haplo-PTCy were excluded from this analysis. The median age was 25 years (range, 15-51), and 65% were male. Ninety-four percent of patients had a neoplastic disease (77/82), and the most common diagnosis was acute lymphoblastic leukemia (57%). Forty-seven percent proceeded to transplant in the first complete response. Most of the patients (76%) presented a low hematopoietic cell transplantation (HCT)-specific comorbidity index. Conditioning was mostly myeloablative (96%). The median dose of CD34+ cells infused was 8.1 x 106/kg (range, 2.4-10.0). No patient needed a desensitization regimen. Cytokine release syndrome (CRS) was common (86%) but no grade 3 CRS was observed. Primary graft failure was observed in one patient (1.2%). Poor graft function was observed in 11 patients (13%). Five patients (6.1%) died before engraftment. The incidence of grade II-IV aGVHD at day +100 was 29% (grade IV was not observed). With a median follow-up of 33 months (range 0-84), the estimated 3-year OS and EFS were 68.3% (95% CI 59-79%) and 64.6% (95% CI 55-76%), respectively (Figure 1). In patients with neoplastic disease (n=77), the 3-year cumulative incidence of relapse was 23% (95% CI 15-33%).
Haplo-PTCy is feasible in LMIC. This cohort of cases, mostly young patients with neoplastic disease, shows encouraging survival with an acceptable aGVHD and relapse incidence.