julilili42/papers huggingface dataset:
170P EO2401 microbiome derived therapeutic vaccine + nivolumab +/- bevacizumab, in neoadjuvant, adjuvant and non-surgery linked treatment of recurrent glioblastoma: Phase I-II EOGBM1-18/ROSALIE study
2022-12-01

EO2401 was designed to activate memory T cells cross-reacting with tumor associated antigens and includes synthetically produced HLA-A2 peptides with molecular mimicry to antigens (IL13Rα2, BIRC5 and FOXM1) upregulated in glioblastoma, and the CD4 helper peptide UCP2. Patients with glioblastoma at first progression after radiotherapy/temozolomide received EO2401 (300 μg/peptide, q2w x4 then q4w) with nivolumab (3 mg/kg q2w; EN), or EN with bevacizumab (10 mg/kg q2w; ENB). In study part 2, low-dose bevacizumab (5 mg/kg q2w) could be used as symptom directed time-limited treatment of edema. In study part 3, 6 evaluable patients are to be treated with neoadjuvant EN, and 15 further patients with ENB (enrollment ongoing). Part 1 included 40 patients (EN = 29, ENB = 11). Part 2 enrolled 36 patients treated with EN. EN and ENB (n=76) were well tolerated with EO2401 associated tox limited to local administration site reactions (45% of patients; events 70% Grade 1, 26% Grade 2, and 4% Grade 3). The frequency and severity of nivolumab-/bevacizumab-tox was consistent with historical single-agent data. Immune monitoring demonstrated T cell responses against the 3 microbiome-derived peptides for 97% of patients investigated ex vivo or after in vitro stimulation (IVS). Cross-reactivity against the pool of 3 human target peptides was demonstrated in 96% of patients by IFN-γ ELISpot. The strength of the immune response correlated with clinical outcome (progression-free survival [PFS] and objective responses [OR]). For part 1, median PFS, and median survival for EN (n=29, median follow-up 20.1 months) were 1.8 and 10.6 months. Patients on ENB (n=11, median follow-up 13.1 months) had median PFS of 5.5 months and 55% of patients were alive beyond 12 months. OR rate / Disease Control Rate (DCR) (OR rate + stable disease) for EN and ENB were 14%/34% and 55%/82%. EO2401 was well tolerated and generated rapid and durable immune responses correlating with clinical outcome. Addition of standard bevacizumab to EN improved efficacy. Updated data from all parts of the trial will be presented. NCT04116658.
International Knowledge Transfer in subject-oriented didactics. The example of Religious Education
2022-12-01

Abstract Can there be international knowledge transfer in subject-related didactics which is not limited to psychological research results which have often been received internationally, and what are the presuppositions of such transfer? The starting point of this article is an international project with consultations and cooperation in the field of religion-related didactics. One of the most important questions in this project refers to the possibility of insights and research results achieved by subject-related didactics for which international validity can be claimed. This question is not limited to empirical research but refers to validity claims in subject-related didactics in general as well as to the more far- reaching question if subject-related didactics can be considered an academic discipline if international validity claims would be excluded. Moreover, the article discusses possible contents of the international knowledge transfer from teacher education. Finally, a number of suggestions for future work in subject- related didactics are offered.
Effective potential of the Polyakov loop in the Hamiltonian approach to QCD
2022-12-01

We investigate the effective potential of the Polyakov loop, which is the order parameter for the deconfinement phase transition in finite temperature QCD. Our work is based on the Hamiltonian approach in Coulomb gauge where finite temperature is introduced by compactifying one space direction. We briefly review this approach and extend earlier work in the Yang-Mills sector by including dynamical quarks. In a first approximation, we follow the usual functional approach and include only 1-loop contributions to the energy, with the finite temperature propagators replaced by their counterparts. It is found that this gives a poor description of the phase transition, in particular for the case of full QCD with light flavors. The physical reasons for this unexpected result are discussed, and pinned down to a relative weakness of gluon confinement compared to the deconfining tendency of the quarks. We attempt to overcome this issue by including the relevant gluon contributions from the 2-loop terms to the energy. We find that the 2-loop corrections have indeed a tendency to strengthen the gluon confinement and weaken the unphysical effects in the confining phase, while slightly increasing the (pseudo)critical temperature at the same time. To fully suppress artifacts in the confining phase, we must tune the parameters to rather large values, increasing the critical temperature to for .
Creation Rate of Dirac Particles at a Point Source
2022-12-01

Only recently has it been possible to construct a self-adjoint Hamiltonian that involves the creation of Dirac particles at a point source in 3d space. Its definition makes use of an interior-boundary condition. Here, we develop for this Hamiltonian a corresponding theory of the Bohmian configuration. That is, we construct a Markov jump process in the configuration space of a variable number of particles that is -distributed at every time and follows Bohmian trajectories between the jumps. The jumps correspond to particle creation or annihilation events and occur either to or from a configuration with a particle located at the source. The process is the natural analog of Bell's jump process, and a central piece in its construction is the determination of the rate of particle creation. The construction requires an analysis of the asymptotic behavior of the Bohmian trajectories near the source. We find that the particle reaches the source with radial speed 0, but orbits around the source infinitely many times in finite time before absorption (or after emission).
180P Recalling pre-existing microbiota-specific T cells to target tumors
2022-12-01

The gut microbiome has the singular property of shaping the immune system through a multitude of antigens that educate the T cell repertoire. Since microbial peptides can share similarities with tumor antigens, cross-reactive memory T cells that recognize both bacterial and tumor-derived peptides can thus emerge from the imprinting of the T cell repertoire by gut commensals. Harnessing the full potential of cross-reactive CD8+ T cells against tumor cells could therefore be achieved through the rational design of a microbiota-derived peptide vaccine. Enterome developed a novel peptide-based immunotherapy built on the principle of T cell cross-reactivity and molecular mimicry between bacterial-derived peptides called OncoMimicsTM peptides (OMP) and Tumor-Associated Antigens (TAA). HLA-A2-restricted OMP candidates targeting human TAA were first selected in silico from our proprietary metagenomic bank of human gut microbiota and then confirmed through in vitro binding assays, and in vivo evaluations of their immunogenicity and capacity to induce cross-reactive T cell responses against TAA in HLA-A2/DR1 humanized mice. Finally, the prevalence and functionality of OMP-specific T cells were assessed in human blood from healthy donors using tetramers, in vitro stimulation, and cytotoxicity assays. Selected OMPs could elicit cross-reactive cytotoxic T cell (CTL) responses against human TAA. This was demonstrated by the propensity of these CTL to secrete IFN-γ upon recognition of OMP or TAA peptides, reject TAA peptide-pulsed splenocytes as well as tumors ectopically expressing the selected TAA targets. We finally demonstrated that OMP-specific memory CD8+ T cells pre-exist in human blood, with high prevalence (>80% in the population), and harbor strong CTL functions against TAA when activated ex vivo with OMPs. We show that gut microbiota-derived peptides mimicking TAAs can elicit strong immune responses against tumors. The pre-existence of these cross-reactive CD8+ T cells in healthy donors exemplifies the strong promises of this innovative approach to develop efficient therapeutic cancer immunotherapies. To date, two OMP-based immunotherapies are evaluated in 3 clinical trials (Glioblastoma, Adrenal cancers, B lymphomas).
185P Interim analysis of the EOGBM1-18 study: Strong immune response to therapeutic vaccination with EO2401 microbiome derived therapeutic vaccine + nivolumab
2022-12-01

EO2401 is a therapeutic vaccine designed to activate memory commensal-specific T cells cross-reacting with tumor-associated antigens (TAAs). EO2401 includes synthetically produced HLA-A2 peptides with molecular mimicry to TAAs (IL13Rα2, BIRC5 and FOXM1) upregulated in glioblastoma, and the CD4 helper peptide UCP2. Patients with glioblastoma at first progression after radiotherapy/temozolomide received EO2401 (300μg/peptide, q2w x4 then q4w) with nivolumab (3 mg/kg q2w; EN), or EN with bevacizumab (10 mg/kg q2w; ENB) (NCT04116658). Blood collection was performed at baseline and then every 2-4 weeks. Immune responses were investigated on PBMCs ex vivo or in vitro stimulation (IVS) using tetramer staining, IFN-γ ELISpot and intracellular cytokine staining. Vaccination with EO2401 induces a strong and durable CD8+ T cell response against bacterial peptides and human TAAs. Immune monitoring using ELISpot demonstrated T cell responses against the 3 microbiome-derived peptides for 97% of patients investigated ex vivo or after IVS. Cross-reactivity against theTAA target peptides was demonstrated in 96% of patients by IFN-γ ELISpot. Frequency of CD8+ T cells against bacterial peptides after IVS is extremely high, with max value above 40% for EO2317 and EO2318. Ex vivo, CD8+ T cell against at least one of the EO2401 peptides or human peptides are detected in almost all evaluable patients with some patients exhibiting up to 5% of circulating specific CD8+ T cells. Polyfunctionality of CD8+ T cell induce upon vaccination was demontrated in most patients (CD107a,IFN-γ and TNF-α production after stimulation). Memory-specific CD8+ T cell response is found as early as 2 weeks after the 1st vaccination and maintenance of a strong immune response could be detected for more than 10 months. EO2401 vaccine demonstrates ability to generate fast and durable immune responses in patients treated with E02401/nivolumab +/- bevacizumab. Activation of specific T cells cross-reacting with commensal antigens and TAAs is thereby validated as an efficient approach to activate strong immune responses in a difficult to treat tumor. Updated immuno-monitoring data will be presented.
90P Long-term outcomes in melanoma patients achieving a complete response under immune checkpoint inhibition
2022-12-01

Immune checkpoint inhibition (ICI) has changed the landscape of melanoma therapy. However, not much is known about the long-term outcomes and durability of response in patients who experienced a complete response (CR) under ICI. It is important to monitor this patient population due to the financial toxicity and the immune-related adverse events (irAEs) associated with prolonged treatment. We evaluated unresectable stage IV melanoma patients treated with first-line ICI between 2013 and 2018 outside of a clinical trial. Overall survival (OS) and progression-free survival (PFS) were assessed. irAEs occurring after six months of treatment and response to ICI rechallenge were recorded. Additionally, the prognostic value of clinicopathologic features was investigated. 43 (12.1%) patients experienced CR. 40 (93%) patients discontinued therapy. Three (7%) patients are still receiving treatment without having a progressive disease (PD). The median age at the time of CR was 74 [IQR; 66-77] years old. 26 patients (65%) received anti-PD-1 monotherapy and 14 patients (35%) received nivolumab plus ipilimumab. The median follow-up (FUP) after CR was 49 [IQR; 43-57] months. The median treatment duration was 22 [IQR; 17–24] months, and the median time from CR to therapy ending was 10 [IQR; 1–17] months. Median PFS and OS were not reached (95% CI; NR-NR). 5-year PFS and OS after CR was 79% (95% CI; 62%-89%) and 83% (95% CI; 60%-93%), respectively. Age below 77 years at CR (p=0.043) was linked to a better prognosis in the univariable Cox regression. Neither the total length of treatment (p=0.754) nor the treatment duration after CR were associated with prognosis (p=0.398). Second-line ICI was administered to eight patients, and disease control was seen in 5 (64%). 10 (25%) of the patients experienced late toxicities, with two of them being severe. In our cohort, CR under ICI seems to be a surrogate marker for long-term survival. The duration of treatment was not associated with either PFS or OS, but the optimal duration of therapy in patients achieving CR is not established. Biomarkers are required to help identify patients at risk of relapse among complete responders but also patients who can safely stop therapy after CR.
Speed of cognitive decline in biomarker stratified SCD subgroups
2022-12-01

Abstract Background Subjective cognitive decline (SCD) is associated with an increased risk of cognitive decline and dementia, specifically in cases in the Alzheimer’s continuum (amyloid positive, A+). In the present study we tested, if further stratification with additional markers is useful for identifying fast progressors within SCD‐A+. Method The analysis is based on 170 SCD case of the multicenter memory clinic based DELCODE study in Germany. The following markers were used as predictors of cognitive decline: number of SCDplus criteria, CSF Aß42/Aß42, tTau, pTau181, APOE status and hippocampal volume. The outcome was the preclinical Alzheimer’s cognitive composite 5 (PACC5) over up to 5 years. Univariate and multivariate hierarchical regression models were calculated with continuous (a) and dichotomized (b) variables. Result In the univariate analyses significant or close to significant associations of Aß42/Aß42 (a:p = 0.012; b:p = 0.040), tTau (a:p = 0.034; b:p = 0.053) and pTau181 (a:p = 0.057; b:p = 0.019) with cognitive decline were observed. In the hierarchical model with continuous variables, only Aß42/Aß40 reached significance (p = 0.016); while dichotomized variables Aß42/Aß40 (p = 0,074) and pTau181 (p = 0.068) reached trend level significance. Conclusion Within SCD‐A+, those who are also pTau positive show greatest decline. This finding is in agreement with the concept of A+ and T+ indicating full Alzheimer’s disease pathology and is important for the design of clinical trials in SCD.
Genetic characterization of a Turkish dementia cohort: a focus on leukodystrophy genes
2022-12-01

Abstract Background Leukodystrophies broadly affect the brain white matter. As such, diseases including cerebral autosomal dominant/ recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL/CARASIL) are included in this group. NOTCH3 and HTRA1 variants are a known cause of CADASIL and CARASIL, respectively. Studies have reported NOTCH3 variants in Alzheimer’s disease, and heterozygous HTRA1 variants in cerebral small vessel disease. Therefore, there is growing evidence of leukodystrophy gene variants in neurodegenerative diseases. Method We screened a whole‐exome sequenced Turkish dementia cohort for rare variants in a panel of leukodystrophy genes. Where familial samples were available, we tested for segregation. We also consulted the exome data available from the Turkish Variome to gauge a better estimate of population frequency for candidate variants. Result We identified rare variants in leukodystrophy genes in individuals from this Turkish dementia cohort. Variants in NOTCH3 include a known pathogenic gain‐of‐cysteine variant in a family presenting with CADASIL (NOTCH3 p.Arg133Cys); a novel loss‐of‐cysteine variant (NOTCH3 p.Cys65Tyr) in an atypic dementia case, and a novel cysteine‐sparing missense variant (NOTCH3 p.Ala818Thr) in a family with Alzheimer’s disease and mild cognitive impairment. Conclusion Considering the increased consanguinity of the Turkish population we were expecting to identify bi‐allelic variants in HTRA1 with potential roles in disease. Instead, NOTCH3 presented a higher burden of variability, including known and novel variants expected to be involved in disease.
BACE inhibitor treatment at different stages of amyloid deposition
2022-12-01

Abstract Background We are interested in the link between Aβ deposition and neurodegeneration Method We analyzed the trajectories of Aβ deposition, Aβ seeding activity, and neurodegeneration in APP trangenic mice, and probed the linkage by impeding Aβ production at different amyloid stages using BACE1 inhibition. To extend the findings to humans, we studied key comparative trajectories of Aβ deposition and neurodegeneration markers in cases of familial AD. Result Outcome of BACE1 inhibition was dependent on the amyloid stage Conclusion We found a temporal uncoupling between Aβ deposition and neurodegeneration
Prognostic value of plasma Amyloid‐β 42/40 ratio in early and pre‐clinical AD
2022-12-01

Abstract Background In 2021 Adacanumab, the first antibody that might potentially treat causal neuropathology associated to Alzheimer’s disease (AD), was approved by the FDA. However, early, most likely pre‐cognitive treatment is required raising a high need for early and low‐invasive diagnostic biomarker. Here, we present plasma Amyoid‐beta (Aβ) measurements in a large longitudinal observational study from the German Center for Neurodegenerative Diseases (DZNE, DZNE‐Longitudinal Cognitive Impairment and Dementia (DELCODE) study). Method Plasma Aβ40 and Aβ42 of 1049 baseline samples from the DELCODE cohort were measured in a semi‐automated fashion according to our recently published protocol. Aβ immunoprecipitation and Mesoscale immuno‐measurement were controlled for batch effects. All samples were well balanced and Mesoscale Aβ measurements were performed in two technical replicates on the same assay plate. 41 samples with a coefficient of variation &gt; 10% between the two technical replicates were re‐measured. Corresponding CSF and plasma Aβ measurements were available for 377 samples for further downstream analysis. Result Interassay variability from a QC sample using 6 replicates was 8.3%, 8.0%, and 6.9% for Aβ40, Aβ42, and the Aβ42/40 ratio, respectively. CSF and plasma Aβ42 and Aβ42/40 ratio correlated with r=0.169 (p&lt;0.001) and r=0.466 (p&lt;0.0001), respectively. No correlation was observed for Aβ40. Plasma Aβ42/40 was able to distinguish samples from donors with a CSF Aβ42/40 ratio classified as pathological or normal with an AUC of 0.82. ApoE inclusion increased the AUC for plasma Aβ42/40 to 0.87 with a specificity of 0.73 and a sensitivity of 0.87. Importantly, plasma Aβ42/40 was not only able to differentiate participants with high vs. low CSF Aβ42/40 in general, but also predicted Aβ status in patients with milder or no cognitive impairments: in controls, the AUC for the plasma Aβ42/40 ratio was 0.78, in SCI 0.76, and in MCI 0.71. There was only one dementia case with a normal CSF Aβ profile, thus no further comparison could be performed for donors in dementia stage. Conclusion Plasma Aβ can differentiate CSF pathological vs normal AD patients. Further analysis including follow‐up data to identify the early predictive value of plasma Ab will be performed including neurocognitive measurements to include all plasma Aβ measurements.
Underlying clusters of NIA‐AA Research Framework stage 2 criteria and their relationship with AD biomarkers in the DELCODE study
2022-12-01

Abstract Background As part of the updated NIA‐AA Research Framework for Alzheimer’s disease (AD), a numeric clinical staging scheme, applicable only to individuals in the Alzheimer’s continuum, has been introduced. “Stage 2” is defined as a transitional stage, characterized by subtle or subjective decline in cognition or neuropsychiatric symptoms (NPS) that might reflect underlying AD pathology (Jack et al., Alzheimers Dement. 2018). Here, we aimed to cluster a sample of cognitively healthy participants based on stage 2 criteria and compare the emerging clusters with regard to differences in CSF biomarker status. Method For this analysis, we included baseline data of N = 349 cognitively healthy participants with available CSF biomarker information from the DZNE Longitudinal Cognitive Impairment and Dementia (DELCODE) study. A two‐step cluster analysis (TSCA) was applied based on CSF Aß42/40 status and stage 2 criteria, which included a) subtle objective cognitive impairment (&lt;0.5SD) in any of five factor scores from DELCODE’s neuropsychological test battery, b) subjective cognitive decline (SCD) with concern in any of the five SCD‐Interview domains and c) the presence of agitation, depression, anxiety, disinhibition, irritability or sleep disturbances on the Neuropsychiatric Inventory Questionnaire [NPI‐Q]. The TSCA identifies the optimal number of clusters by grouping cases into preclusters first and then clustering those using a hierarchical algorithm. Result The TSCA yielded three clusters. Cluster 1 ( n = 114) was characterized by subtle cognitive impairment in memory, language, executive function and working memory as well as SCD in the memory and language domain. In contrast, cluster 2 ( n = 104) was predominantly formed by participants that reported SCD and NPS without subtle objective impairment. In cluster 3 ( n = 121), none of the stage 2 criteria were prominent. In comparison to clusters 2 and 3, participants in cluster 1 had lower levels of Aß42/40 ( H (2) = 11.58, p = .003) and Aß42/ptau‐181 ( H (2) = 12.06, p = .002). We observed no significant differences between clusters 2 and 3. Conclusion Our analysis resulted in three distinct clusters of cognitively healthy participants with different distributions of stage 2 criteria. The criteria prominent in participants of cluster 1 seem most promising to identify individuals at risk of progression due to underlying AD pathology.