julilili42/papers huggingface dataset:
CTNI-62. INTERIM DATA ON DUAL INHIBITION OF POST-RADIOGENIC ANGIO-VASCULOGENESIS BY OLAPTESED PEGOL (NOX-A12) AND BEVACIZUMAB IN GLIOBLASTOMA FROM THE FIRST EXPANSION ARM OF THE PHASE 1/2 GLORIA TRIAL
2023-11-01

Abstract BACKGROUND We recently reported favorable safety and preliminary efficacy signals for treatment with radiotherapy (RT), the CXCL12 neutralizing L-RNA aptamer olaptesed pegol (NOX-A12) and bevacizumab for glioblastoma (GBM) in the German multicenter phase 1/2 GLORIA trial (NCT04121455). Here, we report updated outcomes on dual inhibition of vasculogenesis (NOX-A12) and angiogenesis (bevacizumab). METHODS Six patients with incompletely resected, MGMT-unmethylated GBM, ECOG≤ 2 were enrolled, receiving standard RT (60 Gy in 30 fractions), continuous i.v. infusions of NOX-A12 (600 mg/week) and i.v. infusions of bevacizumab (10 mg/kg q2w). The primary endpoint was safety. Secondary endpoints included radiographic response according to modified RANO criteria (mRANO) as well as perfusion/diffusion imaging. RESULTS Combination treatment was well-tolerated and safe. Of all G≥2 AEs (n = 79), two G2 events (2.5%) were deemed related to NOX-A12 only. There were no dose-limiting toxicities and no treatment-related deaths. At a median follow-up of 14.6 months, one patient deceased due to distant leptomeningeal spread. Median overall survival (OS) has not yet been reached. With an overall response rate (ORR) of 83.3% under treatment, one patient achieved confirmed complete response (CR), four patients partial response (PR) and one patient stable disease (SD). The median best response under treatment was -68.9% (-53,8% to -100%) for target lesion sums and -100% (-99.9% to -100%) for non-target lesion (NTL) sums. In all three patients with NTLs at least one lesion disappeared. The median best change from baseline of the highly perfused-tumor fraction was -98.2% (-61.3% to -100%) and the median best change of the apparent diffusion coefficient was 24.9% (7.3% to 59.1%). CONCLUSIONS Interim data of the ongoing trial confirm the previously established safety profile of NOX-A12 for combinatory treatment with bevacizumab while demonstrating improved efficacy with deeper and longer-lasting responses and a higher ORR compared to treatment with RT and NOX-A12 only.
CTNI-74. ON-TRK: A NON-INTERVENTIONAL STUDY OF LAROTRECTINIB IN PATIENTS WITH TROPOMYOSIN RECEPTOR KINASE (TRK) FUSION SOLID TUMORS
2023-11-01

Abstract Increasingly, health authorities and the medical community are investing resources into evaluating real-world data (RWD) on precision biomarker-based treatments. Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are oncogenic drivers in various cancers. Larotrectinib is a highly selective, central nervous system (CNS)-active TRK inhibitor approved for tumor-agnostic use in pediatric and adult patients with various cancers. ON-TRK (NCT04142437) is an ongoing non-interventional post-approval study that is critical in gaining RWD on the treatment of patients with TRK fusion cancer and will contribute to the broader understanding of personalized therapy. This open-label, global, multi-cohort, prospective study will enroll up to 300 pediatric and adult patients with TRK fusion cancer scheduled to receive larotrectinib, including ≥ 30 pediatric patients. Patients with cancer harboring NTRK gene fusions, detected locally, are eligible. Patients who have had prior TRK inhibitor therapy and patients with NTRK genomic alterations other than functional gene fusions are excluded. Decisions on the dose and duration of treatment are at the discretion of the treating physician. The primary endpoint is safety, including specific long-term parameters in pediatric patients. Secondary endpoints include: efficacy (objective response rate, disease control rate, time to response, duration of response, progression-free survival, and overall survival), dosing patterns and long-term effects of larotrectinib in pediatric patients. The effects of larotrectinib on growth and developmental milestones in pediatric patients will be reported, including change in height and weight from baseline, age at adrenarche for males and menarche for females, number and percentage of patients with abnormal Tanner stages, and abnormal neurological assessments. All variables will be analyzed using descriptive statistics. Pediatric and adult patients will be followed for ≥ 5 years and ≥ 2 years, respectively, unless lost to follow-up, withdrawal, or death. Enrollment is ongoing worldwide; 24 patients with primary CNS cancer have been enrolled to date.
Platelet-derived microRNAs play a pivotal role in cardiac remodeling after myocardial ischemia and reperfusion
2023-11-01

Abstract Background Platelets can infiltrate ischemic myocardium and are increasingly recognized as critical regulators of inflammatory processes during myocardial ischemia and reperfusion (I/R). Platelets contain a broad repertoire of miRNAs, which, under certain conditions such as myocardial ischemia, may be transferred to surrounding cells or released into the microenvironment. Recent studies could demonstrate, that platelets contribute substantially to the circulating miRNA pool holding the potential for so far undiscovered regulatory functions. Purpose The present study aimed to determine the role of platelet-derived miRNAs in myocardial injury and repair following myocardial I/R. Methods and Results Combining an in vivo model of myocardial I/R, multimodal in vivo and ex vivo imaging approaches (LSFM, PET&amp;MRI, speckle-tracking echocardiography), in vitro immune cell migration assays and Next-generation deep sequencing analysis of platelet miRNA expression pattern in mice with a MK/platelet-specific knockout of pre-miRNA processing ribonuclease Dicer, the present study discloses a key role of platelet-derived miRNAs in the tightly regulated cellular processes orchestrating LV remodeling after myocardial I/R following transient LCA ligation. Disruption of the miRNA processing machinery in platelets by deletion of Dicer resulted in increased myocardial inflammation, impaired angiogenesis, and accelerated development of cardiac fibrosis, culminating in an increased infarct size by d7 that persisted through d28 of myocardial ischemia and reperfusion. Worsened cardiac remodeling after myocardial infarction (MI) in mice with a platelet-specific Dicer deletion (Dicer Pf4Δ/PfΔ4) resulted in an increased fibrotic scar formation and distinguishably increased perfusion defect of the apical and anterolateral wall at d28 post-MI. Altogether, these observations culminated in an impaired LV function and hampered long-term cardiac recovery after experimental MI and reperfusion therapy. Treatment with the P2Y12 antagonist ticagrelor completely reversed increased myocardial damage and adverse cardiac remodeling observed in Dicer Pf4Δ/Pf4Δ mice. Conclusions The present study discloses a critical role of platelet-derived miRNA in myocardial inflammation and structural remodeling processes following myocardial ischemia and reperfusion.
High efficacy and safety of pulsed electrical field ablation via contact force-controlled radiofrequency catheters for atrial fibrillation ablation with linear lesions in the left atrium
2023-11-01

Abstract Background Pulsed Field Ablation have been shown to be efficient and safe for Pulmonary vein isolation (PVI) in catheter ablation of atrial fibrillation (AF). The bipolar application of pulsed electrical energy for electroporation of myocardium has been established with specially designed catheters, which are not used for linear ablation. Purpose We evaluated a novel monophasic PEF ablation technique applied by commercially available CF-controlled catheters for linear ablation lines beyond PVI for treatment of complex AF patients. Methods Patients (n=31, age 64±12 years, 29% females, BMI 29±4) referred for re-ablation of AF and presented with recurrence of persistent AF (n=13) or atypical atrial flutter (n=14) after a PVI procedure, or patients with longstanding persistent AF and severe enlarged atrium (n=4) were included in our patient cohort for additional AF substrate ablation with PEF applications. After high density voltage mapping of the left atrium with multipolar microelectrode catheters, and PVI, or re-PVI was completed (8 patients), additional left atrial linear lesions were performed according to the atrial flutter mechanism or as fibrosis-guided substrate ablation. All but one patient showed low voltage areas (bipolar electrograms &amp;lt;0.5mV) in 35±31% of the left atrial surface. Using contact force sensing catheters, maximal PEF energy pulses were applied with a minimum of 5g contact force and an interlesion distance ≤6mm. Performed linear lesions were left atrial roof line, lateral mitral isthmus line, anterior mitral line, left posterior wall isolation, and cavotricuspid isthmus (CTI) line. Before PEF application close-by a coronary artery (lateral mitral line, CTI) nitroglycerie 0.2mg i.v. was injected. Results Complete lines with exclusively PEF applications and proofed bidirectional conduction block were 100% for roof lines (n=20), posterior wall isolation (n=8), anterior mitral lines (n=10). Exclusively endocardial PEF applications blocked the lateral mitral line in 14 out of 16 cases (88%). Only in two cases additional epicardial RF applications via coronary sinus and endocardial additional RF applications were necessary to complete the mitral isthmus block. In 7 out of 8 cases CTI were blocked by linear PEF applications (88%), however, in one case additional RF applications became necessary. No ECG ST segment elevation was recorded. No serious complications occurred throughout all procedures. Follow up will be available at presentation time. Conclusion Catheter ablation of complex AF patients with linear lesions is performd very efficient and safe with PEF applications by CF-sensing RF ablation catheters. Especially the high efficacy of exclusively endocardial PEF applications for creation of a lateral mitral isthmus block is very promising. However, the long term permanence of the linear lines have to be awaited.
Genotype-phenotype correlation in PRKN-associated Parkinson’s disease
2023-11-01

<h3></h3> Mutations in <i>PRKN</i> are the most common cause of early-onset autosomal recessive inherited PD, with over 140 different mutations spanning the entire gene described as being pathogenic. PD patients with bi-allelic pathogenic mutations in <i>PRKN</i> and with no pathogenic mutations in other genes known to result in monogenic PD were included. The type of mutation in <i>PRKN</i> was analysed for an association with the age at onset and motor severity, considering disease duration as a covariant. 644 patients were included for analysis [age at onset (31.4 ± 11.38 years), disease duration (18 ± 12.5 years)].Mean UPDRS part III (on) score at the time of disease onset was 12.6 ± 1.4 and increased by 3.85 ± 0.6 points every 10 years (n= 310, p= 3.6 e-09). Patients with 2 missense variants had a later age of onset (36.4± 12.3 years), compared to those with 2 structural variants (31.2±10.8 years) (p=0.004). Furthermore, variants located at the N-terminus of the protein (exon 1 – 3), were associated with an earlier age at onset of PD, 30.9 +/- 10.3 years, compared to variants located at the C-terminus (exons 7-12), 34.9 +/- 12.5 (p=0.05) We demonstrate that missense variants and variants located in the N-Ter of the protein are associated with a more benign progression of the disease, a finding which has never before been demonstrated in bi-allelic PRKN-PD.
A New Reconstruction of the Reigns of Adad-nārārī II and Tukultī-Ninurta II in Light of Five Unattributed Royal Inscriptions
2023-11-01

Abstract The reigns of Adad-nārārī II (911–891) and his son Tukultī-Ninurta II (890–884) are vital to understanding the rise of Neo-Assyria; yet, reconstruction of these is hampered by the scarce and fragmentary sources available. This study surveys the reigns of these two kings, and examines five fragmentary early Neo-Assyrian royal inscriptions from the city of Aššur published in 2009 by Frahm within Keilschrifttexte aus Assur literarischen Inhalts 3, providing solid ascriptions of three of these to Adad-nārārī II and two to Tukultī-Ninurta II on philological and historical grounds. These findings are then integrated into present knowledge of this period in order to present new portraits of these kings’ respective reigns. This results in a clearer historical articulation of Adad-nārārī II’s remarkably successful incumbency, particularly shedding light on his early victories. In turn, Tukultī-Ninurta II’s difficult reign spent consolidating his father’s territorial gains can also be better understood. Interestingly, various innovations can be ascribed to this latter king, not least the ‘calculated frightfulness’ for which his son would become so (in)famous within Assyriology. Finally, some repercussions of these findings for the study of 10th and 9th century royal inscriptions are explored .
Computational Prediction of Cyclic Peptide Structural Ensembles and Application to the Design of Keap1 Binders
2023-11-02

The Nrf2 transcription factor is a master regulator of the cellular response to oxidative stress, and Keap1 is its primary negative regulator. Activating Nrf2 by inhibiting the Nrf2-Keap1 protein-protein interaction has shown promise for treating cancer and inflammatory diseases. A loop derived from Nrf2 has been shown to inhibit Keap1 selectively, especially when cyclized, but there are no reliable design methods for predicting an optimal macrocyclization strategy. In this work, we employed all-atom, explicit-solvent molecular dynamics simulations with enhanced sampling methods to predict the relative degree of preorganization for a series of peptides cyclized with a set of bis-thioether "staples". We then correlated these predictions to experimentally measured binding affinities for Keap1 and crystal structures of the cyclic peptides bound to Keap1. This work showcases a computational method for designing cyclic peptides by simulating and comparing their entire solution-phase ensembles, providing key insights into designing cyclic peptides as selective inhibitors of protein-protein interactions.
Using weather data in energy time series forecasting: the benefit of input data transformations
2023-11-02

Abstract Renewable energy systems depend on the weather, and weather information, thus, plays a crucial role in forecasting time series within such renewable energy systems. However, while weather data are commonly used to improve forecast accuracy, it still has to be determined in which input shape this weather data benefits the forecasting models the most. In the present paper, we investigate how transformations for weather data inputs, i. e., station-based and grid-based weather data, influence the accuracy of energy time series forecasts. The selected weather data transformations are based on statistical features, dimensionality reduction, clustering, autoencoders, and interpolation. We evaluate the performance of these weather data transformations when forecasting three energy time series: electrical demand, solar power, and wind power. Additionally, we compare the best-performing weather data transformations for station-based and grid-based weather data. We show that transforming station-based or grid-based weather data improves the forecast accuracy compared to using the raw weather data between 3.7 and 5.2%, depending on the target energy time series, where statistical and dimensionality reduction data transformations are among the best.
Sex matters for the enhancement of cognitive training with transcranial direct current stimulation (tDCS)
2023-11-02

Abstract Background Transcranial direct current stimulation (tDCS) can influence brain network activity and associated cognitive and behavioural functions. In addition to the extensive variety in stimulation parameters, numerous biological factors drive these effects, however these are yet poorly understood. Here, we investigate one of the major biological factors by focusing on sex-dependent effects of tDCS on a challenging cognitive control task ( adaptive paced auditory serial addition task [PASAT]) in healthy humans. Methods This sex-specific re-analysis was performed on data of 163 subjects who underwent a 2-week cognitive control training (6 sessions in total). Subjects received either verum (anodal/cathodal) or sham tDCS. Electrodes were placed over the left or right dorsolateral prefrontal cortex and the respective contralateral deltoid muscle. Cognitive control was measured as performance in the PASAT and was analysed in respect to stimulation conditions (sham, anodal, cathodal) and sex. Results Regardless of stimulation condition, performance gains between the sexes were higher in females compared to males ( p = 0.0038). Female’s performance during anodal tDCS exceeded male’s ( p = 0.0070), yet no effects were found for cathodal or sham tDCS. Moreover, in females we found a superior effect for anodal tDCS over sham stimulation (f anodal : p = 0.0354; f cathodal : p = 0.6181), but no such effect in males (m anodal : p = 0.6882; m cathodal : p = 0.4822). Conclusions This study highlights the relevance of biological sex for the effects of tDCS on cognitive training. Thus, an increased attention to biological sex is advisable in future brain stimulation research to highlight and in consequence better understand potentially underlying sex-specific mechanisms. Considering biological sex will further advance customisation and individualisation of tDCS interventions. Trial registration ClinicalTrials.gov, NCT04108663.
Mutual benefits for research and practice: Randomized controlled trials in the Hector Children's Academy Program
2023-11-02

Abstract This article describes how a series of randomized controlled trials (RCTs) were implemented in the Hector Children's Academy Talent Development Program with the goal of generating mutual benefits for research and practice. The Hector Children's Academy Program, founded in 2010 and located in one of the largest states in Germany, Baden‐Württemberg, is a statewide enrichment program for talented primary school students, with a focus on STEMM topics. The program is financed by a private foundation, supervised by the Ministry of Education, and offered by 69 local sites that are hosted by local schools. About 15,000 primary school students (Grades 1–4) attend enrichment courses (more than 23,000 course participations) offered by the Hector Children's Academy Program every year. A unique element of the Hector Children's Academy Program is the role of empirical research in course development. The Hector Core Courses—offered by all local sites—undergo a strict quality assurance process in which RCTs are used to test their effectiveness with regard to central outcomes. After describing the Hector Children's Academy Program, we explain how the Hector Core Courses were developed and incorporated into the program, summarize key findings from the RCTs, and discuss mutual benefits for research and practice.
Computational charisma—A brick by brick blueprint for building charismatic artificial intelligence
2023-11-02

Charisma is considered as one's ability to attract and potentially influence others. Clearly, there can be considerable interest from an artificial intelligence's (AI) perspective to provide it with such skill. Beyond, a plethora of use cases opens up for computational measurement of human charisma, such as for tutoring humans in the acquisition of charisma, mediating human-to-human conversation, or identifying charismatic individuals in big social data. While charisma is a subject of research in its own right, a number of models exist that base it on various “pillars,” that is, dimensions, often following the idea that charisma is given if someone could and would help others. Examples of such pillars, therefore, include influence (could help) and affability (would help) in scientific studies, or power (could help), presence, and warmth (both would help) as a popular concept. Modeling high levels in these dimensions, i. e., high influence and high affability, or high power, presence, and warmth for charismatic AI of the future, e. g., for humanoid robots or virtual agents, seems accomplishable. Beyond, also automatic measurement appears quite feasible with the recent advances in the related fields of Affective Computing and Social Signal Processing. Here, we therefore present a brick by brick blueprint for building machines that can appear charismatic, but also analyse the charisma of others. We first approach the topic very broadly and discuss how the foundation of charisma is defined from a psychological perspective. Throughout the manuscript, the building blocks (bricks) then become more specific and provide concrete groundwork for capturing charisma through artificial intelligence (AI). Following the introduction of the concept of charisma, we switch to charisma in spoken language as an exemplary modality that is essential for human-human and human-computer conversations. The computational perspective then deals with the recognition and generation of charismatic behavior by AI. This includes an overview of the state of play in the field and the aforementioned blueprint. We then list exemplary use cases of computational charismatic skills. The building blocks of application domains and ethics conclude the article.