julilili42/papers huggingface dataset:
Validation of HLA presented tumor-exclusive peptides in an independent cohort of head and neck squamous cell carcinoma.
2024-06-01

6047 Background: Response rates to anti-PD1 antibodies in head and neck squamous cell carcinoma (HNSCC) range from 13-20% in recurrent / metastatic disease and up to 50% in locoregionally advanced disease. Vaccines composed of tumor-exclusive antigens may increase response rates to immunotherapy. We have previously identified HLA-presented tumor-exclusive peptides (TEP) in a cohort of 40 oropharyngeal HNSCC (UL dataset) and defined a warehouse of HLA allotype specific TEP (EP2023/071063, patent pending) for semipersonalized vaccine composition for 15 HLA allotypes. Methods: The HLA-bound immunopeptidome of a validation cohort of 40 HNSCC from Tübingen University was analyzed by tandem mass spectrometry (TÜ dataset). Data were processed as previously described to identify TEP. The TÜ dataset was queried for TEP from the previously defined warehouse containing 48 TEP for the respective 15 HLA allotypes in a cohort of 40 oropharyngeal HNSCC (UL dataset) patient samles. Coverage was defined as the fraction of patients presenting at least one of the TEP for a certain HLA allotype. Results: Among all 80 patients, 75 had at least one of the 15 HLA allotypes (36 in the TÜ cohort and 39 in the UL cohort). Of the 48 TEP, 28 TEP for 11/15 HLA allotypes were found in the TÜ validation cohort. The best coverages with the warehouse TEP were found for the following four HLA allotypes: HLA-A*01:01 (TÜ: 91%; UL: 79%), A*02:01 (TÜ: 81%; UL: 52%), B*40:01 (TÜ: 63%; UL: 100%) and A*24:02 (TÜ: 60%; 44%.). Based on a semipersonalized TEP selection by HLA allotype, 27/40 patients in the TÜ cohort presented at least one of the TEP selected (range: 0-10), whereas 28/40 patients in the UL cohort presented at least one of the TEP (range: 0-7). Thus, the total cohort coverage based on a semipersonalized peptide selection was 55/80 patients (68.8%). Conclusions: We validated previously identified TEP from oropharyngeal HNSCC for frequently occurring HLA allotypes in an independent, equally sized cohort of HNSCC patients. A semipersonalized vaccine composition strategy using a warehouse / off-the-shelve approach for immunotherapy trials seems feasible.
Intralesional administration of L19IL2/L19TNF in high-risk locally advanced basal cell carcinoma or cutaneous squamous cell carcinoma.
2024-06-01

TPS9617 Background: Basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC) account for 99% of skin neoplasms, with a rising incidence due to increased sun exposure and growing life expectancy. Approximately 0.8-5% of patients (pts) develop high-risk locally advanced (LA) disease, which is treated with surgery, radiotherapy, sonic hedgehog inhibitors, PD1-based immune checkpoint blockade, or chemotherapy. While surgery offers high cure rates, factors such as location, functional and cosmetic impairment, or patient factors including age, comorbidities, and personal preferences may preclude surgery. Intralesional treatment with immunostimulatory drugs represents an attractive therapeutic approach to treat LA BCC and LA cSCC. Here, we investigate a combination of two immunocytokines (Bifikafusp alfa (L19IL2) and Onfekafusp alfa (L19TNF)) targeting the extradomain B of fibronectin (EDB) for the treatment of high-risk locally advanced BCC and cSCC. EDB is an oncofetal antigen that is undetectable in virtually all healthy adult tissues but becomes highly expressed in tumors, including BCC and cSCC. Methods: In a single-arm phase II study (NCT04362722), pts with locally advanced, non-metastatic, node-negative, single, or multifocal BCC or cSCC not eligible for surgery or radiotherapy are treated with four weekly intratumoral administrations of L19IL2/L19TNF. The study is divided into two parts: a first exploratory part with a total of 40 pts with laBCC or lacSCC, and a second part where the laBCC cohort has been expanded to up to 72 pts not eligible for surgery or radiotherapy. The first part of the trial has been completed with 28 laBCC pts and 12 lacSCC pts evaluable for safety and efficacy. The pre-specified activity goal for the first stage of accrual was met, and the second stage of accrual began in September 2023, with a total of 39 BCC and 18 cSCC pts enrolled so far. Clinical trial information: NCT04362722 .
Early detection of side effects in patients with metastatic melanoma receiving immune checkpoint inhibitors by investigation of CD8+ immune infiltrate with [89Zr] crefmirlimab berdoxam PET.
2024-06-01

TPS9601 Background: Immune checkpoint inhibitors (ICI) improved outcomes of patients (pts) with advanced melanoma. Nevertheless, a significant number have immune-mediated adverse event (iAE). Due to the impact on quality of life and other therapeutic options, early identification of pts with increased risk of iAE is needed. CD8 immuno-PET with [ 89 Zr] crefmirlimab berdoxam (Zr-Df-IAB22M2C) has shown to be a specific tool to visualize CD8+ T cells mediating both anti-tumor immune response and inflammatory adverse effects rendering this an innovative evaluation method in the field of immuno-oncology. Methods: Trial design: Open-label, single-arm, single center study to determine if CD8+ T-cell infiltration evaluated by immune-PET provides diagnostic gain in early detection of severe iAE. Pts with irresectable stage III/IV melanoma receiving nivolumab + ipilimumab (NIVO+IPI) may be included. Primary objective: Feasibility of early detection of iAE by semiquantitative assessment of CD8+ T-cell infiltration using immune-PET. Secondary objectives: 1) Prediction of iAE using immuno-PET for semiquantitative assessment of CD8+ T-cell infiltration; 2) Correlation between CD8+ T-cell infiltration in metastasis and lymphoid organs and response. Baseline Imaging. To assess glucose metabolism in metastases, primary and secondary lymphatic organs [ 18 F] FDG PET/CT (60 min p.i. 1.5 MBq/KG/BW) is performed on a high sensitivity PET/CT with large field of view (Siemens Vision Quadra). Immediately after PET/CT data acquisition, pts are injected with [ 89 Zr] crefmirlimab berdoxam (37 MBq ±20%) and undergo immuno-PET/CT 24 hours p.i. to detect CD8+ T-cells in metastases and lymphoid organs. NIVO+IPI is administered immediately after completion of [ 89 Zr] crefmirlimab berdoxam-PET/CT. Blood samples are taken for immune cell composition analysis, activation state, proteomic investigation (cytokine/chemokines) as well as metabolic profile. Therapy Phase Imaging: Three weeks after first ICI cycle and before second cycle, follow-up PET/CT are performed with both radiotracers [ 18 F]FDG and [ 89 Zr] crefmirlimab berdoxam following the identical protocol described above. Clinical trial information: EudraCT number - 2021-004328-13 .
Scoping Review of Qualitative Evaluation Methods for Mono- and Interprofessional Consultations – What Needs to Be Known and Considered?
2024-06-01

Jasmin Bossert,1 Helena DÃ1⁄4rsch,1 Bianca Korus,1 Ursula Boltenhagen,2 Mette Stie,3,4 Nadja Klafke1 1Department of General Practice and Health Service Research, University Hospital Heidelberg, Heidelberg, Germany; 2Department of Nursing Science, University Hospital Tuebingen, Tuebingen, Germany; 3Department of Oncology, Lillebaelt Hospital, University Hospital of Southern Denmark, Vejle, Denmark; 4Department of Regional Health Research, Faculty of Health Sciences, University of Southern Denmark, Odense, DenmarkCorrespondence: Jasmin Bossert, Email JasminBossert@gmx.deAbstract: Qualitative evaluation of healthcare consultations offers a profound understanding of the communication dynamics between healthcare providers and patients, fostering active patient involvement in their treatment. This scoping review aims to provide an overview of existing qualitative evaluation methods used in the context of monoprofessional as well as interprofessional consultations. Studies including qualitative and mixed-methods approaches published between 1990 and 2020 were examined across PubMed, PsycINFO, EBSCO CINAHL, Cochrane, and PEDro databases. Utilizing the JBI appraisal checklist for quality assessment, 54 studies were included (51 mono professional, 3 interprofessional consultations). Furthermore, this review identified 58 diverse qualitative methods, with content analysis emerging as the most prevalent. Qualitative methods pose both challenges and opportunities, urging researchers to carefully consider their suitability for specific research objectives. By presenting various qualitative assessment methods, it is possible to evaluate consultations in depth and thereby strengthen communication between patients and providers.Keywords: consultations, content analysis, interprofessional collaboration, patient-oriented communication, qualitative methods, evaluation
FusionVAC22_01: A phase I clinical trial evaluating a DNAJB1-PRKACA fusion transcript-based peptide vaccine combined with immune checkpoint inhibition for fibrolamellar hepatocellular carcinoma and other tumor entities carrying the oncogenic driver fusion.
2024-06-01

TPS2702 Background: The DNAJB1-PRKACA fusion transcript is the driving force behind tumor development in fibrolamellar hepatocellular carcinoma (FL-HCC) and other tumor types, such as oncocytic neoplasms of the pancreas and bile ducts. Consequently, it serves as a versatile target for innovative cancer therapies. Recently, the DNAJB1-PRKACA fusion protein was recognized as a source of HLA-presented neoepitopes targetable by to T cell-based immunotherapy (1). The FusionVAC-22 neoepitope, derived from DNAJB1-PRKACA fusion, is computationally predicted to bind to 1,290 different HLA class II alleles. Furthermore, it includes embedded HLA class I ligands for 13 out of the 20 most common HLA class I alleles, covering 93.8% of the global population This broad coverage enables the widespread application of FusionVAC-22-based immunotherapies. The initial use of FusionVAC-22-based peptide vaccines, adjuvanted with the TLR1/2 agonist XS15 emulsified in Montanide ISA 51 VG, in two FL-HCC patients was well-tolerated and demonstrated the induction of robust and long-lasting T cell responses. Notably, T cell responses coincided with 32 months and 13 months of progression-free survival for the respective patients. Methods: Building on these promising outcomes, we have initiated a Phase I open-label, multicentric clinical trial to assess the immunogenicity, safety, toxicity, and initial signs of efficacy of the FusionVAC-22-based peptide vaccine combined with the immune checkpoint inhibitor (ICI) atezolizumab. The trial includes 20 patients with locally advanced or metastatic FL-HCC or other malignancies carrying the DNAJB1-PRKACA fusion transcript without available standard therapy. Key eligibility criteria involve the absence of autoimmune phenomena due to prior immunotherapy agents (≥ grade 3) and no history of tissue or organ allografts. The FusionVAC-22-based peptide vaccine is administered twice with a 4-week interval, with an option for a booster vaccination after 11 months. ICI administration begins on day 15 after the first vaccination and continues every 4 weeks for 1 year, followed by a 6-month follow-up. Primary trial objectives include assessing immunogenicity in terms of peptide-specific T cell responses up to 28 days after the second vaccination, as well as evaluating the safety and toxicity of the peptide vaccine in combination with ICI. Safety assessment is based on the frequency of adverse events according to CTCAE v5.0. Clinical efficacy is determined through iRECIST assessment on imaging. Additionally, disease control rate, quality of life, and overall and progression-free survival will be evaluated. So far, 3 out of 20 planned patients have been enrolled. 1. Bauer et al., Nat. Commun, 2022. Clinical trial information: NCT05937295 .
Overall survival in patients with BRCA-mutated platinum-sensitive relapsed ovarian cancer (PSROC) treated with olaparib maintenance: Real-world data of the C-PATROL study.
2024-06-01

e17542 Background: Maintenance monotherapy with PARP-inhibitor (PARPi), olaparib has previously shown good effectiveness and tolerability in total population of patients with PSROC who were in response to platinum-based chemotherapy (PBC) in the C-PATROL study. Here we present the overall survival (OS) data in different subgroups. Methods: The prospective German non-interventional study C-PATROL (NCT02503436) captured routine clinical data of olaparib maintenance according to label in patients with BRCA-mutated PSROC treated with PBC. The primary endpoint was PFS, relevant secondary endpoints included OS and safety. Data were analyzed by descriptive statistics. Results: Between 10/2015 and 10/2019, 277 patients were enrolled. The ITT set (study selection criteria fulfilled) comprised 267 patients (median age: 60 yrs; ECOG ≤1: 93%; ≥2 relapses: 32%; ≥3 prior PBC: 29%). Median follow-up was 23.5 months (range 0.0–80.5) and median olaparib treatment duration was 13.6 months (0.1–80.9). 10% of patients received olaparib for ≥ 5 years and 8% of patients received further PARPi also as subsequent treatment. Median OS was 35.4 months (95% CI 29.2–49.9). The longest median OS was observed in patients with a complete debulking after the surgery at current relapse, a complete response (CR) to the current PBC and a BRCA2 mutation. Adverse events (AEs) were consistent with the known tolerability profile of olaparib (safety set: n=274; any AE: 95%, AE of CTCAE grade ≥ 3: 40%, olaparib discontinuation due to AE: 11%; most common AE any CTCAE: nausea (46%), fatigue (39%), anaemia (31%), and vomiting (17%); most common AE CTCAE grade ≥ 3: anaemia (14%)). Conclusions: Olaparib is effective and safe in the real-world setting. In olaparib-treated patients with BRCA-mutated PSROC longer OS was observed mainly with respect to resection status after debulking surgery at current relapse, to tumor burden at the therapy start and BRCA mutation type. Our data underline the role of cytoreduction and platinum response in the context of PARPi maintenance therapy. Clinical trial information: NCT02503436 . [Table: see text]
X. Das Ringen um die presbyterial-synodale Kirchenordnung im preußischen Westen und die Relevanz demokratischer Gedanken
2024-06-01

Summary In Jülich-Cleve-Berg-Mark, the Reformed and Lutheran churches had been governed almost independently by synods since the 17 th century. With the establishment of the Prussian western provinces in 1815, however, consistories were installed alongside, whose legal claims competed with those of the existing synods; these, however, tried tenaciously to preserve their traditional rights. Considerations that this ecclesiastical demand correlated with contemporary democratic thought and its demand for a state constitution were vehemently rejected in the Prussian West for theological reasons.
Causal definitions versus casual estimation: Reply to Valente et al. (2022).
2024-06-01

In this response to Valente et al. (2022), I am discussing the plausibility and applicability of the proposed mediation model and its causal effects estimation for single case experimental designs (SCEDs). I will focus on the underlying assumptions that the authors use to identify the causal effects. These assumptions include the particularly problematic assumption of sequential ignorability or no-unmeasured confounders. First, I will discuss the plausibility of the assumption in general and then particularly for SCEDs by providing an analytic argument and a reanalysis of the empirical example in Valente et al. (2022). Second, I will provide a simulation that reproduces the design by Valente et al. (2022) with the exception that, for a more realistic depiction of empirical data, an unmeasured confounder affects the mediator and outcome variables. The results of this simulation study indicate that even minor violations will lead to Type I error rates up to 100% and coverage rates as low as 0% for the defined causal direct and indirect effects. Third, using historical data on the effect of birth control on stork population and birth rates, I will show that mediation models like the proposed method can lead to surprising artifacts. These artifacts can hardly be identified with statistically means including methods such as sensitivity analyses. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
Deep Learning in the Detection of Rare Fractures – Development of a “Deep Learning Convolutional Network” Model for Detecting Acetabular Fractures
2024-06-01

Abstract Background Fracture detection by artificial intelligence and especially Deep Convolutional Neural Networks (DCNN) is a topic of growing interest in current orthopaedic and radiological research. As learning a DCNN usually needs a large amount of training data, mostly frequent fractures as well as conventional X-ray are used. Therefore, less common fractures like acetabular fractures (AF) are underrepresented in the literature. The aim of this pilot study was to establish a DCNN for detection of AF using computer tomography (CT) scans. Methods Patients with an acetabular fracture were identified from the monocentric consecutive pelvic injury registry at the BG Trauma Center XXX from 01/2003–12/2019. All patients with unilateral AF and CT scans available in DICOM-format were included for further processing. All datasets were automatically anonymised and digitally post-processed. Extraction of the relevant region of interests was performed and the technique of data augmentation (DA) was implemented to artificially increase the number of training samples. A DCNN based on Med3D was used for autonomous fracture detection, using global average pooling (GAP) to reduce overfitting. Results From a total of 2,340 patients with a pelvic fracture, 654 patients suffered from an AF. After screening and post-processing of the datasets, a total of 159 datasets were enrolled for training of the algorithm. A random assignment into training datasets (80%) and test datasets (20%) was performed. The technique of bone area extraction, DA and GAP increased the accuracy of fracture detection from 58.8% (native DCNN) up to an accuracy of 82.8% despite the low number of datasets. Conclusion The accuracy of fracture detection of our trained DCNN is comparable to published values despite the low number of training datasets. The techniques of bone extraction, DA and GAP are useful for increasing the detection rates of rare fractures by a DCNN. Based on the used DCNN in combination with the described techniques from this pilot study, the possibility of an automatic fracture classification of AF is under investigation in a multicentre study.
Liturgical Order, Cultura Dei and the Normative Function of Ritual Power: Considerations on the Effective Forces of the Cultura Dei in the Coronation of King Charles III
2024-06-01

Abstract This article examines the coronation ritual of King Charles III as an aspect of the cultura Dei using Jürgen Bolten’s cultural theory, particularly his concept of ‘fuzzy culture’. The coronation shows how the normative force of the cultura Dei can be used to promote religious pluralism beyond the Judeo-Christian traditions of the Church of England. Using the concept of cultura Dei, as discussed by Bolten, frames the discussion of the coronation as an essentially Judeo-Christian ritual of transformation within the broader context of a multi-religious, non-religious, political, and social context. The analysis offered here is a theological one, framed by the discipline of liturgical theology within the Latin Rite (Roman) Catholic theological tradition, thus providing a particular view of the cultura Dei. The uniqueness of the analysis offered throughout is its German Catholic liturgical viewpoint, which provides the non-German reader with the opportunity to consider German-language sources and a non-British perspective of the use of ritual and symbol in the coronation liturgy and their relationship to the cultura Dei.
TIMS2Rescore: A DDA-PASEF optimized data-driven rescoring pipeline based on MS2Rescore
2024-06-02

Abstract The high throughput analysis of proteins with mass spectrometry (MS) is highly valuable for understanding human biology, discovering disease biomarkers, identifying therapeutic targets, and exploring pathogen interactions. To achieve these goals, specialized proteomics subfields – such as plasma proteomics, immunopeptidomics, and metaproteomics – must tackle specific analytical challenges, such as an increased identification ambiguity compared to routine proteomics experiments. Technical advancements in MS instrumentation can counter these issues by acquiring more discerning information at higher sensitivity levels, as is exemplified by the incorporation of ion mobility and parallel accumulation - serial fragmentation (PASEF) technologies in timsTOF instruments. In addition, AI-based bioinformatics solutions can help overcome ambiguity issues by integrating more data into the identification workflow. Here, we introduce TIMS 2 Rescore, a data-driven rescoring workflow optimized for DDA-PASEF data from timsTOF instruments. This platform includes new timsTOF MS 2 PIP spectrum prediction models and IM2Deep, a new deep learning-based peptide ion mobility predictor. Furthermore, to fully streamline data throughput, TIMS 2 Rescore directly accepts Bruker raw mass spectrometry data, and search results from ProteoScape and many other search engines, including MS Amanda and PEAKS. We showcase TIMS 2 Rescore performance on plasma proteomics, immunopeptidomics (HLA class I and II), and metaproteomics data sets. TIMS 2 Rescore is open-source and freely available at https://github.com/compomics/tims2rescore .
The expansion of basic education during ‘deskilling’ technological change in England and Wales, c. 1780–1830
2024-06-02

Abstract The first country to industrialize – England – ostensibly did so without expanding investment in the basic education of its workforce. The empirical evidence underpinning this argument for England rests largely on signature rates at marriage. These are not a perfect indication of educational achievement, particularly as many children never learned to write. More problematically, I argue signatures are likely to have systematically underestimated human capital in industrial districts. In place of signature data, I propose age heaping, a measure widely understood as a proxy for numeracy but shown here to be closely related to both reading and writing abilities. In contrast to signatures, this measure suggests that ‘deskilling’ industrialization induced human capital accumulation. I argue that this occurred not because human capital was directly productive, but rather because schools provided a valuable signal. Sunday school attendance signalled low leisure‐preference among child workers and were popularly attended in industrial districts. Further, such schools taught children to read but not write, which they considered inappropriate for the Sabbath, accounting for the discrepancy between these two measures of human capital.