julilili42/papers huggingface dataset:
Visualizing incompatibilities in phylogenetic trees using consensus outlines
2023-06-01

Phylogenetic analysis frequently leads to the creation of many phylogenetic trees, either from using multiple genes or methods, or through bootstrapping or Bayesian analysis. A consensus tree is often used to summarize what the trees have in common. Consensus networks were introduced to also allow the visualization of the main incompatibilities among the trees. However, in practice, such networks often contain a large number of nodes and edges, and can be non-planar, making them difficult to interpret. Here, we introduce the new concept of a phylogenetic consensus outline, which provides a planar visualization of incompatibilities in the input trees, without the complexities of a consensus network. Furthermore, we present an effective algorithm for its computation. We demonstrate its usage and explore how it compares to other methods on a Bayesian phylogenetic analysis of languages using data from a published database and on multiple gene trees from a published study on water lilies.
CONSOLIDATIVE HCT‐ASCT IS SUPERIOR TO NON‐MYELOABLATIVE CHEMO‐IMMUNOTHERAPY IN NEWLY‐DIAGNOSED PCNSL ‐ UPDATED RESULTS OF THE RANDOMIZED PHASE III MATRIX/IELSG43 TRIAL
2023-06-01

Background: Current treatment options for patients with primary central nervous system lymphoma (PCNSL) eligible for intensive treatment approaches comprise high-dose methotrexate (HD-MTX) based immuno-chemotherapy (IT) followed by consolidating high-dose chemotherapy and ASCT (HDC-ASCT). To clarify, whether minimal residual disease may also be eliminated by non-myeloablative IT, comprising non-cross resistant cytotoxic agents, the MATRix/IELSG43 trial, an international randomised phase III trial comparing HDC-ASCT with non-myeloablative consolidation in patients with newly diagnosed PCNSL (NCT02531841) was conducted. This is an updated report on the main study endpoints. Methods: This randomized phase III trial was conducted in 79 centers in five countries. Immuno-competent patients with untreated PCNSL, aged 18–65 years irrespective of ECOG PS or 66–70 years with ECOG PS ≤ 2 were considered eligible. Induction comprised four cycles MATRix (rituximab 375 mg/m2/d days(d) 0,5; methotrexate 3.5 g/m2 d1; cytarabine 2 × 2 g/m2/d d2,3; thiotepa 30 mg/m2 d4, every three weeks. Stem cell harvest following cycle 2. Randomization was performed for patients achieving at least partial response (PR) following induction therapy. Arm A consisted of two cycles R-DeVIC (375 mg/m2 d0; dexamethasone 40 mg/d d1–3; etoposide 100 mg/m2/d d1–3; ifosfamide 1500 mg/m2/d d1–3; carboplatin 300 mg/m2 d1); Arm B, consisted of HDC-ASCT (BCNU 400 mg/m2 (d-6) and thiotepa 2 × 5 mg/kg/d d-5,-4)). The primary endpoint progression-free survival (PFS) was analyzed with a Cox proportional hazards model. Results: 368 pts were registered between July 2014 and August 2019, 230/346 pts (67%) were randomly assigned to arm A and arm B, respectively. 116 patients discontinued induction treatment, mainly due to toxicity (15%) or progressive disease (12%). Median age of the randomized pts was 59 years (range 21–70) with 22% being ≥65 years. Overall response rate (ORR) following induction treatment was 69% (52% PR, 27% CR). Thirteen pts died due to treatment-related toxicity, comprising mainly infectious complications. Following consolidation CR rate increased substantially to 65% in arm A and 68% in arm B. Six patients died of toxicity during consolidation treatment (2 in arm A and 4 in arm B), Median follow-up was 45 months (range 0.2–86). The 3-year PFS and OS rates were 79% (95% CI 71–86) and 86% (95% CI 78–91) following HDC-ASCT and 53% (95% CI 44–62%) and 71% (95% CI 61–78) after R-DeVIC (HR 0.41; p = 0.0002). The evaluation of neurocognitive functions showed no difference between arms. The research was funded by: Riemser, Roche Keywords: aggressive B-cell non-Hodgkin lymphoma, stem cell transplant Conflicts of interests pertinent to the abstract G. Illerhaus Consultant or advisory role: Roche, Gilead, Incyte Educational grants: Roche, Gilead
The Yet Underestimated Importance of Communicating Findings from Educational Trials to Teachers, Schools, School Authorities, or Policy Makers (Comment on Brady et al. (2023))
2023-06-01

Abstract This article is a comment on Brady et al. ( Educational Psychology Review 35:36–37, 2023) with which we largely agree. We add to this important discussion by pointing to the underestimated importance of communicating findings to stakeholders, which is important because recommendations are derived from them, and a correct understanding is essential for stakeholders to evaluate the usefulness of recommendations and strengthen stakeholders’ beliefs in their added value. Moreover, we suggest that in addition to an effect size, responder rates may be communicated so that stakeholders can better understand the consequences of implementing a treatment.
ProSperA: Phase I study to evaluate safety, tolerability and preliminary efficacy of a bispecific PSMAxCD3 antibody in men with biochemical recurrence of prostate cancer.
2023-06-01

TPS5114 Background: Bispecific antibodies (bsAbs), alike CAR T cells, are not yet successful in solid tumors. Recently we developed a PSMAxCD3 bsAb termed CC-1 in an IgG-based format mediating fully target cell-restricted T cell activation and potent antitumor activity (Zekri et al, EMBO Mol Med, 2020). In prostate cancer (PC), PSMA is not only expressed on the malignant cells themselves, but also on tumor vessels. Targeting the latter improves accessibility of the tumor site for immune effector cells, a critical prerequisite for success. CC-1 is under evaluation in a First in Human trial enrolling patients with castration resistant prostate carcinoma (NCT04104607) and, in combination with checkpoint inhibition, in a phase I trial enrolling patients with squamous cell carcinoma of the lung (NCT04104607). On the basis of the meanwhile available very favorable safety and preliminary efficacy data, CC-1 is now being evaluated as first line treatment in patients with biochemical recurrence (BCR) of PC (NCT05646550), where tumor burden is low and accordingly further reduced side effects and sustained efficacy are expected. Methods: This is an ongoing open label, single center phase I clinical trial evaluating CC-1 without androgen deprivation therapy as first line treatment in men with BCR of PC. Key eligibility criteria include low risk of disease progression (PSA-Doubling time &gt; 1 year after prostatectomy or interval to BCR &gt; 18 months after radiation; ISUP grade &lt; 4; PSA ≥ 0.2 ng/ml and &lt; 5 ng/ml) and no androgen deprivation therapy except in a neoadjuvant/adjuvant setting. The clinical trial consists of (i) a dose escalation part (24-42 patients) using a 3+3 design to determine overall safety, tolerability as well as maximum tolerated dose (MTD) and (ii) a dose expansion part, in which 14 patients are treated at the MTD. CC-1 is applied twice-weekly over 21 days as three-hour infusion in up to six 28-day cycles. In the first cycle, step dosing (day 1: 10μg, day 2: 28μg, day 3 and thereafter: target dose) is performed, and 7 patient cohorts receiving dose levels from 78μg to 600μg are evaluated. Premedication includes acetaminophen, dimetindene and cortisone to minimize the risk of infusion reactions and cytokine release syndrome (CRS). The primary objectives are definition of MTD and recommended phase II dose. Assessment of safety is based on the frequency of adverse events according to CTCAE v5.0. Dose limiting toxicities are defined as ≥ 3° adverse drug reactions (e.g. CRS) with predefined exceptions (e.g. temporary laboratory abnormalities). Efficacy is determined by serial PSA-measurements (PSA-response: ≥50% decrease compared to baseline). Furthermore, percentage of patients with no clinical relapse, no salvage and no subsequent antineoplastic therapy will be assessed. Clinical trial information: NCT05646550 .
GO‐Compass: Visual Navigation of Multiple Lists of GO terms
2023-06-01

Abstract Analysis pipelines in genomics, transcriptomics, and proteomics commonly produce lists of genes, e.g., differentially expressed genes. Often these lists overlap only partly or not at all and contain too many genes for manual comparison. However, using background knowledge, such as the functional annotations of the genes, the lists can be abstracted to functional terms. One approach is to run Gene Ontology (GO) enrichment analyses to determine over‐ and/or underrepresented functions for every list of genes. Due to the hierarchical structure of the Gene Ontology, lists of enriched GO terms can contain many closely related terms, rendering the lists still long, redundant, and difficult to interpret for researchers. In this paper, we present GO‐Compass (Gene Ontology list comparison using Semantic Similarity), a visual analytics tool for the dispensability reduction and visual comparison of lists of GO terms. For dispensability reduction, we adapted the RE‐VIGO algorithm, a summarization method based on the semantic similarity of GO terms, to perform hierarchical dispensability clustering on multiple lists. In an interactive dashboard, GO‐Compass offers several visualizations for the comparison and improved interpretability of GO terms lists. The hierarchical dispensability clustering is visualized as a tree, where users can interactively filter out dispensable GO terms and create flat clusters by cutting the tree at a chosen dispensability. The flat clusters are visualized in animated treemaps and are compared using a correlation heatmap, UpSet plots, and bar charts. With two use cases on published datasets from different omics domains, we demonstrate the general applicability and effectiveness of our approach. In the first use case, we show how the tool can be used to compare lists of differentially expressed genes from a transcriptomics pipeline and incorporate gene information into the analysis. In the second use case using genomics data, we show how GO‐Compass facilitates the analysis of many hundreds of GO terms. For qualitative evaluation of the tool, we conducted feedback sessions with five domain experts and received positive comments. GO‐Compass is part of the Tue‐Vis Visualization Server as a web application available at https://go‐compass‐tuevis.cs.uni‐tuebingen.de/
COmic: convolutional kernel networks for interpretable end-to-end learning on (multi-)omics data
2023-06-01

Abstract Motivation The size of available omics datasets is steadily increasing with technological advancement in recent years. While this increase in sample size can be used to improve the performance of relevant prediction tasks in healthcare, models that are optimized for large datasets usually operate as black boxes. In high-stakes scenarios, like healthcare, using a black-box model poses safety and security issues. Without an explanation about molecular factors and phenotypes that affected the prediction, healthcare providers are left with no choice but to blindly trust the models. We propose a new type of artificial neural network, named Convolutional Omics Kernel Network (COmic). By combining convolutional kernel networks with pathway-induced kernels, our method enables robust and interpretable end-to-end learning on omics datasets ranging in size from a few hundred to several hundreds of thousands of samples. Furthermore, COmic can be easily adapted to utilize multiomics data. Results We evaluated the performance capabilities of COmic on six different breast cancer cohorts. Additionally, we trained COmic models on multiomics data using the METABRIC cohort. Our models performed either better or similar to competitors on both tasks. We show how the use of pathway-induced Laplacian kernels opens the black-box nature of neural networks and results in intrinsically interpretable models that eliminate the need for post hoc explanation models. Availability and implementation Datasets, labels, and pathway-induced graph Laplacians used for the single-omics tasks can be downloaded at https://ibm.ent.box.com/s/ac2ilhyn7xjj27r0xiwtom4crccuobst/folder/48027287036. While datasets and graph Laplacians for the METABRIC cohort can be downloaded from the above mentioned repository, the labels have to be downloaded from cBioPortal at https://www.cbioportal.org/study/clinicalData?id=brca\\_metabric. COmic source code as well as all scripts necessary to reproduce the experiments and analysis are publicly available at https://github.com/jditz/comics.
Compact sample environment for in situ X-ray scattering during spin-coating
2023-06-01

We demonstrate a compact sample environment for the in situ study of crystallization kinetics of thin films on synchrotron beamlines, featuring atmospheric control, automated deposition, spin-coating, and annealing stages. The setup is suitable for studying thin film growth in real time using grazing-incidence X-ray diffraction techniques. Humidity and oxygen levels are being detected by sensors. The spinning stage exhibits low vertical oscillation amplitude (∼3μm at speeds up to 10 000 rpm) and can optionally be employed for antisolvent application or gas quenching to investigate the impact of these techniques, which are often used to assist thin film growth. Differential reflectance spectroscopy is implemented in the spin-coater environment for inspecting thin film thickness and optical properties. The infrared radiation-based annealing system consists of a halogen lamp and a holder with an adjustable lamp-to-sample distance, while the sample surface temperature is monitored by a pyrometer. All features of the sample environment can be controlled remotely by the control software at synchrotron beamlines. In order to test and demonstrate the performance, the crystallization pathway of the antisolvent-assisted MAPbI3 (MA = methylammonium) perovskite thin film during the spinning and annealing stages is monitored and discussed.
Anti-PD1 plus BRAF/MEK inhibitors (triplet therapy) after failure of standard therapy in patients (pts) with advanced melanoma.
2023-06-01

9528 Background: Preclinical models support the combination of immune checkpoint inhibitors (ICI) with targeted therapy (TT), suggesting a synergistic effect; however, clinical trials evaluating the efficacy of triplet combination in first-line setting showed limited advantage compared to TT only. Early data from the phase II TRIDeNT (NCT02910700) study showed promising clinical activity in anti-PD1 refractory pts. We sought to evaluate the efficacy of combined TT plus anti-PD1 after the failure of standard therapy in pts with advanced melanoma. Methods: This retrospective, multicenter study included pts with advanced melanoma who were treated with a BRAF inhibitor and a MEK inhibitor in combination with a PD1 inhibitor after failure of a minimum of one standard therapy in seven major melanoma centers between February 2016 and July 2022. Demographics, disease characteristics, therapy details, and outcome data were evaluated. Results: 59 pts were identified; med age was 48 yrs (range, 24-80), 32 pts (54.2%) were males, 20 pts (33.9%) had ECOG PS 1, 46 pts (78%) had 3 or more metastatic sites, 40 pts (67.8%) had brain metastases, and 25 (42.2%) had LDH levels above the upper limit of normal before initiation of triple therapy. Median follow-up time was 16.2 months (IQR, 6.02-20.81). Median number of previous treatment lines was 2 (range, 1-6); 40 pts (67.8%) were pretreated with at least one line of ICI and TT in any sequence. Of 55 pts who received ICI (n = 41 CTLA4 plus PD1; n = 9 PD1 mono; n = 2 CTLA4 mono; n = 3 PD1-based therapy) prior to triplet therapy, 44 pts (80%) were primary resistant (progressive disease (PD); stable disease (SD) for &lt; 6 months), and 11 pts (20%) secondary resistant (complete response (CR), partial response (PR), SD for &gt; 6 months) to the ICI therapy. Treatment with triplet therapy resulted in an overall response rate (ORR) of 44.1% (n = 26) and a disease control rate (DCR) of 55.9% (n = 33) with a median duration of response of 13.7 months (range, 5.4-33.2). Median PFS for the entire cohort was 6 months (95% CI, 3.88-8.08), with a 12-month PFS of 29.4% (95% CI, 17.8-42.1) and a 24-month PFS of 20.2% (95% CI, 11.0-32.8). Median OS was 15.7 months (95% CI, 8.1-23.3 months), with a 12-month OS of 52.7% (95% CI, 39.1-65.7) and a 24-month OS of 43.2% (95% CI, 29.6-55.9). Pts with extracerebral PD prior to triplet therapy (40.7%, n = 24) showed an ORR of 50%, pts with intracerebral PD (32.2%, n = 19) of 47.4%, and pts with global PD (27.1%, N = 16) of 31.3%. Treatment-related adverse events (TRAE) of grade ≥3 occurred in 17 of 59 pts (28.8%), of which cytokine release syndrome (n = 7) and hepatitis (n = 3) were the most common. In 16.9% (n = 10) of pts, TRAEs led to treatment discontinuation. Conclusions: Triple therapy has shown promising efficacy in heavily pretreated pts with advanced melanoma and may represent a treatment option after failure of standard therapy with ICI and TT.
Association between pCR, TILs, and Ki-67 at baseline and after 2 weeks in patients with triple-negative breast cancer (TNBC) treated with atezolizumab and chemotherapy +/- a preceding atezolizumab monotherapy window: A translational analysis of the neoMono trial.
2023-06-01

595 Background: neoMono randomized patients (pts) with triple negative breast cancer (TNBC) to receive (Arm A) or not to receive (Arm B) 2-week Atezolizumab monotherapy prior to neoadjuvant 24-week Atezolizumab + chemotherapy. In prespecified interim analysis, no difference regarding pathological complete response (pCR) was observed among all pts. However, in regard to pCR rates, pts with PD-L1 positive TNBC seem to benefit from addition of the monotherapy window. Here we analyze the association between central TILs and Ki-67 at baseline (BL) / after 2 weeks (2w) and pCR. Methods: Ki-67 expression (% positive tumor cells) was analyzed using immunohistochemistry. Analysis of stromal TILs was performed according to the International TILs Working Group. Differences from BL at the 2w time point were denoted as Ki-67-diff and TIL-diff, respectively. Associations between pCR and BL/2w measurements were analyzed using logistic regression. Akaike information criterion (AIC) was used to evaluate goodness-of-fit between models. Since the a priori chosen biomarker thresholds ( &lt; = 30% [Ki-67] and &lt; = 60% [TILs]) resulted in very low subgroup sizes, k-means clustering analysis was performed and association of the cluster labels with pCR was then investigated. Results: The analysis included 50 (Arm A) and 51 (Arm B) pts. The threshold of Ki-67 ( &lt; = 30%) was reached in 98% (BL) and 92% (2w), that of TILs ( &lt; = 60%) in 11% (BL) and 18% (2w), respectively. PD-L1 (BL) was &lt; = 1 in 26%. In separate logistic regression models (including BL and change), both BL-Ki-67 and BL-TILs were significantly though moderately associated with pCR. A combined model using both biomarkers yielded the best AIC. BL-Ki-67 and BL-TILs, as well as TIL-diff were highly significantly though again moderately associated with pCR. Cluster analysis I (using BL-Ki-67, Ki-67-diff, and PD-L1) yielded cluster 1 (medium BL-Ki-67 and subsequent increase) with a pCR rate of 50% compared to 77% in cluster 2 (high BL-Ki-67 and decreasing Ki-67). Similarly, cluster analysis II (using BL-TILS, TILS-diff and PD-L1) yielded cluster 3 (low BL-TILs/non-essential TILs change) with a low pCR rate of 55% compared to 84.4% and 85.7% for clusters 4 (low BL-TILs /substantial increase) and 5 (high BL-TILs/non-essential change), respectively. In a combined regression model of all clusters above, clusters 2 and 4 had the highest pCR probability. Conclusions: Our results demonstrate that while BL-Ki-67 and BL-TILs are highly informative of pCR probability, Ki-67-diff and even more so TIL-diff added further significant information. Analysis of the full neoMono dataset will allow us to investigate this association further and to potentially develop a predictive algorithm regarding pCR based on baseline and dynamic biomarkers.
German Firms in International Trade: Evidence from Recent Microdata
2023-06-01

Abstract In this paper, we zoom in on the firm level of German merchandise foreign trade, using a novel data base with information on the export and import value by firm, country, product and year for the period 2011–2019. Problems arising from the consolidated reporting of taxable entities and the reporting thresholds present in intra-EU trade have been largely eliminated through redistributions conducted by DESTATIS. Using the data, we examine how global German firms are by looking at the joint distribution of the number of products they trade and the number of countries they trade with. Moreover, we examine the importance of firms mainly engaged in trade intermediation, as opposed to production. Most importantly, we provide a rich description of heterogeneity among German firms by decomposing their trade relationships into intensive margins (value of trade) and extensive margins (number of firms, products and countries). We describe the distributions for each margin, distinguishing intra-EU and extra-EU trade as well as different firm types (producers, wholesalers, retailers). Finally, we reveal strong positive correlations between and within importing and exporting margins, supporting the presence of firm-level complementarities implied by recent theory.