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Spiny keratoderma is a rare entity characterized by filiform keratotic lesions on palms and soles. Although there are some inherited cases the majority are acquired. This last variant can be idiopathic or associated with neoplasms and chronic systemic diseases. We report a new case of spiny keratoderma associated with endometrial carcinoma.

Screening for social determinants of health (SDOH) has been mandated by health systems nationwide. However, a gap exists in closed-loop referral for care coordination between health care and social services. This article presents the framework of a technology-based project to facilitate closed-loop referral between health care and social service agencies in Greater Houston by leveraging and connecting the existing care coordination technology infrastructure. Ten health care and social service organizations in Greater Houston participated in the demonstration project initiated in January 2023. The authors leveraged and linked regional health information exchange (HIE) technology with a master patient index of >18 million, and sector-specific care coordination platforms to build closed-loop referral capacity between HIE-participating health care organizations and social service organizations to meet patient SDOH needs. Evaluation efforts will assess the reach, adoption, implementation, and the effectiveness of the closed-loop framework in improving social and health outcomes. The framework comprised the following 4 components: (1) establishment of collaborative governance for shared decision-making processes, fostering trust, alignment, and transparency among organizations; (2) development of technology linkages between existing platforms to facilitate seamless referrals between organizations and ensure visibility of referral outcomes; (3) integration of regional resource directories into technology infrastructure to ensure resource accessibility/quality; and (4) evaluation of the system's impact on health equity, efficiency, and cost reduction. This project aimed to close the loop for care coordination between health care and social service agencies, enable data evaluation to determine care coordination effectiveness, and lay the foundation for SDOH-related research/practice equitably.

In severe skeletal muscle damage, muscle tissue regeneration process has to face the loss of resident muscle stem cells (MuSCs) and the lack of connective tissue necessary to guide the regeneration process. Biocompatible and standardized 3D structures that can be injected to the muscle injury site, conforming to the defect shape while actively guiding the repair process, holds great promise for skeletal muscle tissue regeneration. In this study, we explore the use of an injectable and porous lysine dendrimer/polyethylene glycol (DGL/PEG) hydrogel as an acellular support for skeletal muscle regeneration. We adjusted the DGL/PEG composition to achieve a stiffness conducive to the attachment and proliferation of murine immortalized myoblasts and human primary muscle stems cells, sustaining the formation and maturation of muscle fibers in vitro . We then evaluated the potential of one selected "myogenic-porous hydrogel" as a supportive structure for muscle repair in a large tibialis anterior muscle defect in rats. This injectable and porous formulation filled the defect, promoting rapid cellularization with the presence of endothelial cells, macrophages, and myoblasts, thereby supporting neo-myogenesis more specifically at the interface between the wound edges and the hydrogel. The selected porous DGL/PEG hydrogel acted as a guiding scaffold at the periphery of the defect, facilitating the formation and anchorage of aligned muscle fibers 21 days after injury. Overall, our results indicate DGL/PEG porous injectable hydrogel potential to create a pro-regenerative environment for muscle cells after large skeletal muscle injuries, paving the way for acellular treatment in regenerative muscle medicine., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Background: Glycosphingolipids (GSLs) are membrane lipids composed of a ceramide backbone linked to a glycan moiety. Ganglioside biosynthesis is a part of the GSL metabolism, which involves sequential reactions catalyzed by specific enzymes that in part have a poor substrate specificity. GSLs are deregulated in cancer, thus playing a role as potential biomarkers for personalized therapy or subtype classification. However, the analysis of GSL profiles is complex and requires dedicated technologies, that are currently not included in the commonly utilized high-throughput assays adopted in contexts such as molecular tumor boards., Methods: In this study, we developed a method to discriminate the enzyme activity among the four series of the ganglioside metabolism pathway by incorporating transcriptome data and topological information of the metabolic network. We introduced three adjustment options for reaction activity scores (RAS) and demonstrated their application in both exploratory and comparative analyses by applying the method on neuroblastic tumors (NTs), encompassing neuroblastoma (NB), ganglioneuroblastoma (GNB), and ganglioneuroma (GN). Furthermore, we interpreted the results in the context of earlier published GSL measurements in the same tumors., Results: By adjusting RAS values using a weighting scheme based on network topology and transition probabilities (TPs), the individual series of ganglioside metabolism can be differentiated, enabling a refined analysis of the GSL profile in NT entities. Notably, the adjustment method we propose reveals the differential engagement of the ganglioside series between NB and GNB. Moreover, MYCN gene expression, a well-known prognostic marker in NTs, appears to correlate with the expression of therapeutically relevant gangliosides, such as GD2. Using unsupervised learning, we identified subclusters within NB based on altered GSL metabolism., Conclusion: Our study demonstrates the utility of adjusting RAS values in discriminating ganglioside metabolism subtypes, highlighting the potential for identifying novel cancer subgroups based on sphingolipid profiles. These findings contribute to a better understanding of ganglioside dysregulation in NT and may have implications for stratification and targeted therapeutic strategies in these tumors and other tumor entities with a deregulated GSL metabolism., (© 2024. The Author(s).)

The sharing of human neuroimaging data has great potential to accelerate the development of imaging biomarkers in neurological and psychiatric disorders; however, major obstacles remain in terms of how and why to share data in the Open Science context. In this Health Policy by the European Cluster for Imaging Biomarkers, we outline the current main opportunities and challenges based on the results of an online survey disseminated among senior scientists in the field. Although the scientific community fully recognises the importance of data sharing, technical, legal, and motivational aspects often prevent active adoption. Therefore, we provide practical advice on how to overcome the technical barriers. We also call for a harmonised application of the General Data Protection Regulation across EU countries. Finally, we suggest the development of a system that makes data count by recognising the generation and sharing of data as a highly valuable contribution to the community., Competing Interests: Declaration of interests H-JM is supported by the Dutch Heart Foundation (03-004-2020-T049), by the Eurostars-2 joint programme with cofunding from the EU Horizon 2020 Research and Innovation Programme (ASPIRE E!113701), provided by the Netherlands Enterprise Agency, and by the EU Joint Program for Neurodegenerative Disease Research, provided by the Netherlands Organisation for Health Research and Development and Alzheimer Nederland (DEBBIE JPND2020-568-106). FB is supported by the National Institute for Health and Care Research biomedical research centre at University College London Hospitals. He is part of the steering committee or Data Safety Monitoring Board member for Biogen, Merck, Alzheimer's Therapeutic Research Institute and Alzheimer's Clinical Trials Consortium, and Prothena. He is a consultant for Roche, Celltrion, Rewind Therapeutics, Merck, IXICO, Jansen, and Combinostics, has research agreements with Merck, Biogen, GE Healthcare, and Roche, and is a cofounder and shareholder of Queen Square Analytics. SC is supported by the EU Horizon 2020 Research and Innovation Programme under grant agreement number 945539 (HBP SGA3). GC has received research support from the EU Horizon 2020 Research and Innovation Programme under grant agreement number 667696, support from Fondation d'entreprise MMA des Entrepreneurs du Futur, Fondation Alzheimer, Programme Hospitalier de Recherche Clinique, Agence Nationale de la Recherche, Région Normandie, Association France Alzheimer et maladies apparentées, Fondation Vaincre Alzheimer, Fondation Recherche Alzheimer, and Fondation pour la Recherche Médicale (all to Institut National de la Santé et de la Recherche Médicale), and personal fees from Institut National de la Santé et de la Recherche Médicale (salary), Eisai, and Fondation Alzheimer. SM received speaker honoraria from GE Healthcare, Eli Lilly, and Life Molecular Imaging. PR acknowledges support by Virtual Research Environment at Charité Berlin – a node of EBRAINS Health Data Cloud, the EU Horizon Europe programme Horizon EBRAINS2.0 (101147319), Virtual Brain Twin (101137289), EBRAINS-PREP 101079717, AISN – 101057655, EBRAIN-Health101058516, Digital Europe TEF-Health 101100700, EU H2020 Virtual Brain Cloud 826421, Human Brain Project SGA2 785907; Human Brain Project SGA3 945539, ERC Consolidator 683049; German Research Foundation SFB 1436 (project ID 425899996); SFB 1315 (project ID 327654276); SFB 936 (project ID 178316478); SFB-TRR 295 (project ID 424778381); SPP Computational Connectomics RI 2073/6-1, RI 2073/10-2, RI 2073/9-1; DFG Clinical Research Group BECAUSE-Y 504745852, PHRASE Horizon EIC grant 101058240; Berlin Institute of Health & Foundation Charité, Johanna Quandt Excellence Initiative; and ERAPerMed Pattern-Cog2522FSB904. BS is supported by the María de Maeztu Unit of Excellence (Institute of Neurosciences, University of Barcelona) CEX2021-001159-M Ministry of Science, Innovation and Universities and by Generalitat de Catalunya 2021SGR0080 and the CERCA Programme/Generalitat de Catalunya. LEMW is supported by MultiPark, a strategic research area at Lund University, an National Institutes of Health grant (R01-AG070952), an Alzheimerfonden project grant (AF-980872), and a Vetenskapsradet project grant (2022-00900). TvE is a civil servant of North Rhine-Westphalia and employee of the University Hospital of Cologne, Germany. In the last 2 years, he has received honoraria, stipends, or speaker fees from the Lundbeck Foundation, Gain Therapeutics, Orion Pharma, Lundbeck Pharma, Atheneum, and the International Movement Disorders Society. He receives materials from Life Molecular Imaging and Lilly Pharma. He owns stocks of the corporations NVIDIA, Microsoft, and IBM. Multiple unrelated research projects are currently supported by the German Research Foundation. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: The modulation of brain circuits of emotion is a promising pathway to treat borderline personality disorder (BPD). Precise and scalable approaches have yet to be established. Two studies investigating the amygdala-related electrical fingerprint (Amyg-EFP) in BPD are presented: one study addressing the deep-brain correlates of Amyg-EFP, and a second study investigating neurofeedback (NF) as a means to improve brain self-regulation., Methods: Study 1 combined electroencephalography (EEG) and simultaneous functional magnetic resonance imaging to investigate the replicability of Amyg-EFP-related brain activation found in the reference dataset ( N = 24 healthy subjects, 8 female; re-analysis of published data) in the replication dataset ( N = 16 female individuals with BPD). In the replication dataset, we additionally explored how the Amyg-EFP would map to neural circuits defined by the research domain criteria. Study 2 investigated a 10-session Amyg-EFP NF training in parallel to a 12-weeks residential dialectical behavior therapy (DBT) program. Fifteen patients with BPD completed the training, N = 15 matched patients served as DBT-only controls., Results: Study 1 replicated previous findings and showed significant amygdala blood oxygenation level dependent activation in a whole-brain regression analysis with the Amyg-EFP. Neurocircuitry activation (negative affect, salience, and cognitive control) was correlated with the Amyg-EFP signal. Study 2 showed Amyg-EFP modulation with NF training, but patients received reversed feedback for technical reasons, which limited interpretation of results., Conclusions: Recorded via scalp EEG, the Amyg-EFP picks up brain activation of high relevance for emotion. Administering Amyg-EFP NF in addition to standardized BPD treatment was shown to be feasible. Clinical utility remains to be investigated.

Congenital defects of the erythrocyte membrane are common in northern Europe and all over the world. The resulting diseases, for example, hereditary spherocytosis (HS), are often underdiagnosed, partly due to their sometimes mild and asymptomatic courses. In addition to a broad clinical spectrum, this is also due to the occasionally complex diagnostics that are not available to every patient. To test whether next-generation sequencing (NGS) could replace time-consuming spherocytosis-specific functional tests, 22 consecutive patients with suspected red cell membranopathy underwent functional blood tests. We were able to identify the causative genetic defect in all patients with suspected HS who underwent genetic testing ( n = 17). The sensitivity of the NGS approach, which tests five genes ( ANK1 (gene product: ankyrin1), EPB42 (erythrocyte membrane protein band4.2), SLC4A1 (band3), SPTA1 (α-spectrin), and SPTB (β-spectrin)), was 100% (95% confidence interval: 81.5-100.0%). The major advantage of genetic testing in the paediatric setting is the small amount of blood required (<200 µL), and compared to functional assays, sample stability is not an issue. The combination of medical history, basic laboratory parameters, and an NGS panel with five genes is sufficient for diagnosis in most cases. Only in rare cases, a more comprehensive functional screening is required.

H3K27M mutant (mut) diffuse midline glioma (DMG) is a lethal cancer with no effective cure. The glycosphingolipids (GSL) metabolism is altered in these tumors and could be exploited to develop new therapies. We tested the effect of the glucosylceramide synthase inhibitors (GSI) miglustat and eliglustat on cell proliferation, alone or in combination with temozolomide or ionizing radiation. Miglustat was included in the therapy protocol of two pediatric patients. The effect of H3.3K27 trimethylation on GSL composition was analyzed in ependymoma. GSI reduced the expression of the ganglioside GD2 in a concentration and time-dependent manner and increased the expression of ceramide, ceramide 1-phosphate, sphingosine, and sphingomyelin but not of sphingosine 1-phosphate. Miglustat significantly increased the efficacy of irradiation. Treatment with miglustat according to dose recommendations for patients with Niemann-Pick disease was well tolerated with manageable toxicities. One patient showed a mixed response. In ependymoma, a high concentration of GD2 was found only in the presence of the loss of H3.3K27 trimethylation. In conclusion, treatment with miglustat and, in general, targeting GSL metabolism may offer a new therapeutic opportunity and can be administered in close proximity to radiation therapy. Alterations in H3K27 could be useful to identify patients with a deregulated GSL metabolism.

Despite massive improvements in the treatment of B-ALL through CART-19 immunotherapy, a large number of patients suffer a relapse due to loss of the targeted epitope. Mutations in the CD19 locus and aberrant splicing events are known to account for the absence of surface antigen. However, early molecular determinants suggesting therapy resistance as well as the time point when first signs of epitope loss appear to be detectable are not enlightened so far. By deep sequencing of the CD19 locus, we identified a blast-specific 2-nucleotide deletion in intron 2 that exists in 35% of B-ALL samples at initial diagnosis. This deletion overlaps with the binding site of RNA binding proteins (RBPs) including PTBP1 and might thereby affect CD19 splicing. Moreover, we could identify a number of other RBPs that are predicted to bind to the CD19 locus being deregulated in leukemic blasts, including NONO. Their expression is highly heterogeneous across B-ALL molecular subtypes as shown by analyzing 706 B-ALL samples accessed via the St. Jude Cloud. Mechanistically, we show that downregulation of PTBP1, but not of NONO, in 697 cells reduces CD19 total protein by increasing intron 2 retention. Isoform analysis in patient samples revealed that blasts, at diagnosis, express increased amounts of CD19 intron 2 retention compared to normal B cells. Our data suggest that loss of RBP functionality by mutations altering their binding motifs or by deregulated expression might harbor the potential for the disease-associated accumulation of therapy-resistant CD19 isoforms., Competing Interests: The authors declare no competing financial interests. This project has been funded by the NMFZ program of the University of Mainz and the Gilead funding program, the foundation “Kinderkrebsforschung Mainz”, the Walter Schulz foundation and the DFG., (© 2023 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Neuroblastoma (NBL) and medulloblastoma (MB) are aggressive pediatric cancers which can benefit from therapies targeting gangliosides. Therefore, we compared the ganglioside profile of 9 MB and 14 NBL samples by thin layer chromatography and mass spectrometry. NBL had the highest expression of GD2 (median 0.54 nmol GD2/mg protein), and also expressed complex gangliosides. GD2-low samples expressed GD1a and were more differentiated. MB mainly expressed GD2 (median 0.032 nmol GD2/mg protein) or GM3. Four sonic hedgehog-activated (SHH) as well as one group 4 and one group 3 MBs were GD2-positive. Two group 3 MB samples were GD2-negative but GM3-positive. N-glycolyl neuraminic acid-containing GM3 was neither detected in NBL nor MB by mass spectrometry. Furthermore, a GD2-phenotype predicting two-gene signature ( ST8SIA1 and B4GALNT1 ) was applied to RNA-Seq datasets, including 86 MBs and validated by qRT-PCR. The signature values were decreased in group 3 and wingless-activated (WNT) compared to SHH and group 4 MBs. These results suggest that while NBL is GD2-positive, only some MB patients can benefit from a GD2-directed therapy. The expression of genes involved in the ganglioside synthesis may allow the identification of GD2-positive MBs. Finally, the ganglioside profile may reflect the differentiation status in NBL and could help to define MB subtypes.

Abnormal emotional processing in major depressive disorder (MDD) has been associated with increased activation to negative stimuli in cortico-limbic brain regions. The authors investigated whether treatment with BI 1358894, a small-molecule inhibitor of the transient receptor potential cation channel subfamily C leads to attenuated activity in these areas in MDD patients. 73 MDD patients were randomized to receive a single oral dose of BI 1358894 (100 mg), citalopram (20 mg), or matching placebo. Brain responses to emotional faces and scenes were investigated using functional magnetic resonance imaging. Primary endpoints were BOLD signal changes in response to negative faces in cortico-limbic brain regions, i.e. bilateral amygdala (AMY), dorsolateral prefrontal cortex, anterior insula (AI), and anterior cingulate cortex. Secondary endpoints were BOLD signal changes in response to negative scenes. For each region, separate ANOVA models were computed for the comparison of treatments (BI 1358894 or citalopram) vs. placebo. The adjusted treatment differences in the % BOLD signal changes in the faces task showed that BI 1358894 induced signal reduction in bilateral AMY and left AI. In the scenes task, BI 1358894 demonstrated significant signal reduction in bilateral AMY, AI, anterior cingulate cortex and left dorsolateral prefrontal cortex. Citalopram failed to induce any significant reductions in BOLD signal in both tasks. BI 1358894-mediated inhibition of the transient receptor potential cation channel subfamily resulted in strong signal reduction in cortico-limbic brain regions, thereby supporting development of this mechanism of action for MDD patients., Competing Interests: Declaration of Competing Interest SJ, VS, RF, SM, CT, CSchu and AWun are employees of Boehringer Ingelheim International GmbH. SG and CSschm have served as consultants to and received research support from Boehringer Ingelheim International GmbH. CP and LH are consultants for Boehringer Ingelheim International GmbH. CB and MM are employees of SBGneuro contracted to perform the blinded analysis. CK, IN, CB, MM, and AWei have no conflicts to disclose., (Copyright © 2022. Published by Elsevier B.V.)

Following CART-19 immunotherapy for B-cell acute lymphoblastic leukaemia (B-ALL), many patients relapse due to loss of the cognate CD19 epitope. Since epitope loss can be caused by aberrant CD19 exon 2 processing, we herein investigate the regulatory code that controls CD19 splicing. We combine high-throughput mutagenesis with mathematical modelling to quantitatively disentangle the effects of all mutations in the region comprising CD19 exons 1-3. Thereupon, we identify ~200 single point mutations that alter CD19 splicing and thus could predispose B-ALL patients to developing CART-19 resistance. Furthermore, we report almost 100 previously unknown splice isoforms that emerge from cryptic splice sites and likely encode non-functional CD19 proteins. We further identify cis-regulatory elements and trans-acting RNA-binding proteins that control CD19 splicing (e.g., PTBP1 and SF3B4) and validate that loss of these factors leads to pervasive CD19 mis-splicing. Our dataset represents a comprehensive resource for identifying predictive biomarkers for CART-19 therapy., (© 2022. The Author(s).)

Replicability and reproducibility of scientific findings is paramount for sustainable progress in neuroscience. Preregistration of the hypotheses and methods of an empirical study before analysis, the sharing of primary research data, and compliance with data standards such as the Brain Imaging Data Structure (BIDS), are considered effective practices to secure progress and to substantiate quality of research. We investigated the current level of adoption of open science practices in neuroimaging and the difficulties that prevent researchers from using them. Email invitations to participate in the survey were sent to addresses received through a PubMed search of human functional magnetic resonance imaging studies that were published between 2010 and 2020. 283 persons completed the questionnaire. Although half of the participants were experienced with preregistration, the willingness to preregister studies in the future was modest. The majority of participants had experience with the sharing of primary neuroimaging data. Most of the participants were interested in implementing a standardized data structure such as BIDS in their labs. Based on demographic variables, we compared participants on seven subscales, which had been generated through factor analysis. Exploratory analyses found that experienced researchers at lower career level had higher fear of being transparent and researchers with residence in the EU had a higher need for data governance. Additionally, researchers at medical faculties as compared to other university faculties reported a more unsupportive supervisor with regards to open science practices and a higher need for data governance. The results suggest growing adoption of open science practices but also highlight a number of important impediments., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2022. Published by Elsevier Inc.)

Predicting the consequences of one's own decisions is crucial for organizing future behavior. However, when reward contingencies vary frequently, flexible adaptation of decisions is likely to depend on the situation. We examined the effects of an instructed threat context on choice behavior (i.e., reversal learning) and its electrocortical correlates. In a probabilistic decision-making task, 30 participants had to choose between two options that were either contingent on monetary gains or losses. Reward contingencies were reversed after reaching a probabilistic threshold. Decision-making and reversal learning were examined with two contextual background colors, which were instructed as signals for threat-of-shock or safety. Self-report data confirmed the threat context as more unpleasant, arousing, and threatening relative to safety condition. However, against our expectations, behavioral performance was comparable during the threat and safety conditions (i.e., errors-to-criterion, number of reversal, error rates, and choice times). Regarding electrocortical activity, feedback processing changed throughout the visual processing stream. The feedback-related negativity (FRN) reflected expectancy-driven processing (unexpected vs. congruent losses and gains), and the threat-selective P3 component revealed non-specific discrimination of gains vs. losses. Finally, the late positive potentials (LPP) showed strongly valence-specific processing (unexpected and congruent losses vs. gains). Thus, regardless of contextual threat, early and late cortical activity reflects an attentional shift from expectation- to outcome-based feedback processing. Findings are discussed in terms of reward, threat, and reversal-learning mechanisms with implications for emotion regulation and anxiety disorders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bublatzky, Schellhaas and Paret.)

Despite decades of experimental and clinical practice, the neuropsychological mechanisms underlying neurofeedback (NF) training remain obscure. NF is a unique form of reinforcement learning (RL) task, during which participants are provided with rewarding feedback regarding desired changes in neural patterns. However, key RL considerations - including choices during practice, prediction errors, credit-assignment problems, or the exploration-exploitation tradeoff - have infrequently been considered in the context of NF. We offer an RL-based framework for NF, describing different internal states, actions, and rewards in common NF protocols, thus fashioning new proposals for characterizing, predicting, and hastening the course of learning. In this way we hope to advance current understanding of neural regulation via NF, and ultimately to promote its effectiveness, personalization, and clinical utility., Competing Interests: Declaration of interests T.H. is a chief medical scientist of Graymatters Health. The other authors declare no conflicts of interest in relation to this work., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Amygdala NeuroFeedback (NF) have the potential of being a valuable non-invasive intervention tool in many psychiatric disporders. However, the feasibility and best practices of this method have not been systematically examined. The current article presents a review of amygdala-NF studies, an analytic summary of study design parameters, and examination of brain mechanisms related to successful amygdala-NF performance. A meta-analysis of 33 publications showed that real amygdala-NF facilitates learned modulation compared to control conditions. In addition, while variability in study dsign parameters is high, these design choices are implicitly organized by the targeted valence domain (positive or negative). However, in most cases the neuro-behavioral effects of targeting such domains were not directly assessed. Lastly, re-analyzing six data sets of amygdala-fMRI-NF revealed that successful amygdala down-modulation is coupled with deactivation of the posterior insula and nodes in the Default-Mode-Network. Our findings suggest that amygdala self-modulation can be acquired using NF. Yet, additional controlled studies, relevant behavioral tasks before and after NF intervention, and neural 'target engagement' measures are critically needed to establish efficacy and specificity. In addition, the fMRI analysis presented here suggest that common accounts regarding the brain network involved in amygdala NF might reflect unsuccessful modulation attempts rather than successful modulation., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Non-conventional T cells, such as γδ T and invariant natural killer T (iNKT) cells, are emerging players in fighting cancer. Alpha-galactosylceramide (α-GalCer) is used as an exogenous ligand to activate iNKT cells. Human cells don't have a direct pathway producing α-GalCer, which, however, can be produced by bacteria. We searched the literature for bacteria strains that are able to produce α-GalCer and used available sequencing data to analyze their presence in human tumor tissues and their association with survival. The modulatory effect of antibiotics on the concentration of α-GalCer was analyzed in mice. The human gut bacteria Bacteroides fragilis , Bacteroides vulgatus, and Prevotella copri produce α-GalCer structures that are able to activate iNKT cells. In mice, α-GalCer was depleted upon treatment with vancomycin. The three species were detected in colon adenocarcinoma (COAD) and rectum adenocarcinoma tissues, and Prevotella copri was also detected in bone tumors and glioblastoma tissues. Bacteroides vulgatus in COAD tissues correlated with better survival. In conclusion, α-GalCer-producing bacteria are part of the human gut microbiome and can infiltrate tumor tissues. These results suggest a new mechanism of interaction between bacteria and immune cells: α-GalCer produced by bacteria may activate non-conventional T cells in tumor tissues, where they can exert a direct or indirect anti-tumor activity.

While exercise and physical activity have been suggested to reduce mortality and symptoms in cancer, knowledge on these associations in patients with childhood cancer (CCPs) is sparse. Anti-inflammatory properties of exercise might mediate these beneficial effects. We investigated the influence of exercise on the inflammation markers neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and systemic-immune-inflammation index (SII) and associations to patient-reported-outcomes in CCPs in a randomized-controlled trial. Results show associations between inflammation markers and patient-reported outcomes. Compared to the control group, SII was significantly reduced following exercise (p=0.036). Anti-inflammatory effects of exercise are also present in CCPs and may underlie exercise-induced benefits on symptoms. Clinical Trial Registration Number: NCT02612025., (© 2021. The Author(s).)

Awareness theory posits that individuals connected to a brain-computer interface can learn to estimate and discriminate their brain states. We used the amygdala Electrical Fingerprint (amyg-EFP) - a functional Magnetic Resonance Imaging-inspired Electroencephalogram surrogate of deep brain activation - to investigate whether participants could accurately estimate their own brain activation. Ten participants completed up to 20 neurofeedback runs and estimated their amygdala-EFP activation (depicted as a thermometer) and confidence in this rating during each trial. We analysed data using multilevel models, predicting the real thermometer position with participant rated position and adjusted for activation during the previous trial. Hypotheses on learning regulation and improvement of estimation were not confirmed. However, participant ratings were significantly associated with the amyg-EFP signal. Higher rating accuracy also predicted higher subjective confidence in the rating. This proof-of-concept study introduces an approach to study awareness with fMRI-informed neurofeedback and provides initial evidence for metacognition in neurofeedback., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Extensive sequencing of tumor tissues has greatly improved our understanding of cancer biology over the past years. The integration of genomic and clinical data is increasingly used to select personalized therapies in dedicated tumor boards (Molecular Tumor Boards) or to identify patients for basket studies. Genomic alterations and clinical information can be stored, integrated and visualized in the open-access resource cBioPortal for Cancer Genomics. cBioPortal can be run as a local instance enabling storage and analysis of patient data in single institutions, in the respect of data privacy. However, uploading clinical input data and genetic aberrations requires the elaboration of multiple data files and specific data formats, which makes it difficult to integrate this system into clinical practice. To solve this problem, we developed cbpManager., Results: cbpManager is an R package providing a web-based interactive graphical user interface intended to facilitate the maintenance of mutations data and clinical data, including patient and sample information, as well as timeline data. cbpManager enables a large spectrum of researchers and physicians, regardless of their informatics skills to intuitively create data files ready for upload in cBioPortal for Cancer Genomics on a daily basis or in batch. Due to its modular structure based on R Shiny, further data formats such as copy number and fusion data can be covered in future versions. Further, we provide cbpManager as a containerized solution, enabling a straightforward large-scale deployment in clinical systems and secure access in combination with ShinyProxy. cbpManager is freely available via the Bioconductor project at https://bioconductor.org/packages/cbpManager/ under the AGPL-3 license. It is already used at six University Hospitals in Germany (Mainz, Gießen, Lübeck, Halle, Freiburg, and Marburg)., Conclusion: In summary, our package cbpManager is currently a unique software solution in the workflow with cBioPortal for Cancer Genomics, to assist the user in the interactive generation and management of study files suited for the later upload in cBioPortal., (© 2021. The Author(s).)

Medulloblastoma is the most common malignant brain tumor in children. Immunotherapy is yet to demonstrate dramatic results in medulloblastoma, one reason being the low rate of mutations creating new antigens in this entity. In tumors with low mutational burden, gene fusions may represent a source of tumor-specific neoantigens. Here, we reviewed the landscape of fusions in medulloblastoma and analyzed their predicted immunogenicity. Furthermore, we described a new in-frame fusion protein identified by RNA-Seq. The fusion involved two genes on chromosome 2 coding for the enhancer of polycomb homolog 2 (EPC2) and GULP PTB domain containing engulfment adaptor 1 (GULP1) respectively. By qRT-PCR analysis, the fusion was detected in 3 out of 11 medulloblastoma samples, whereby 2 samples were from the same patients obtained at 2 different time points (initial diagnosis and relapse), but not in other pediatric brain tumor entities. Cloning of the full-length sequence indicated that the fusion protein contains the N-terminal enhancer of polycomb-like domain A (EPcA) of EPC2 and the coiled-coil domain of GULP1. In silico analyses predicted binding of the neoantigen-derived peptide to HLA-A*0201. A total of 50% of the fusions described in the literature were also predicted to produce an immunogenic peptide. The EPC2-GULP1 fusion peptide was able to induce a de novo T cell response characterized by interferon gamma release of CD8 + cytotoxic T cells in vitro. While the functional relevance of this fusion in medulloblastoma biology remains to be clarified, our data support an immunotherapeutic approach for pediatric medulloblastoma patients carrying the EPC2-GULP1 fusion and other immunogenic fusions.

Background: Psychiatric medication that has a soothing effect on limbic responses to affective stimuli could improve affective instability symptoms as observed in borderline personality disorder (BPD). The objective of this study was to investigate whether citalopram versus placebo reduces the response of the affective neural circuitry during an emotional challenge., Methods: A total of 30 female individuals with a BPD diagnosis participated in a placebo-controlled, double-blind crossover trial design. Three hours after oral drug intake, individuals with BPD viewed affective pictures while undergoing functional magnetic resonance imaging. Blood oxygen level-dependent responses to images of negative affective scenes and faces showing negative emotional expressions were assessed in regions of interest (amygdala, anterior cingulate cortex, anterior insula, dorsolateral prefrontal cortex). Blood perfusion at rest was assessed with arterial spin labeling., Results: The neural response to pictures showing negative affective scenes was not significantly affected by citalopram (n = 23). Citalopram significantly reduced the amygdala response to pictures of faces with negative affective expressions (n = 25, treatment difference left hemisphere: -0.06 ± 0.16, p < .05; right hemisphere: -0.06 ± 0.17, p < .05). We observed no significant effects of citalopram on the other regions. The drug did not significantly alter blood perfusion at rest., Conclusions: Citalopram can alter the amygdala response to affective stimuli in BPD, which is characterized by overly responsive affective neural circuitry., (Copyright © 2021 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

The ganglioside GD2 is an important target in childhood cancer. Nevertheless, the only therapy targeting GD2 that is approved to date is the monoclonal antibody dinutuximab, which is used in the therapy of neuroblastoma. The relevance of GD2 as a target in other tumor entities remains to be elucidated. Here, we analyzed the expression of GD2 in different pediatric tumor entities by flow cytometry and tested two approaches for targeting GD2. H3K27M-mutant diffuse midline glioma (H3K27M-mutant DMG) samples showed the highest expression of GD2 with all cells strongly positive for the antigen. Ewing's sarcoma (ES) samples also showed high expression, but displayed intra- and intertumor heterogeneity. Osteosarcoma had low to intermediate expression with a high percentage of GD2-negative cells. Dinutuximab beta in combination with irinotecan and temozolomide was used to treat a five-year-old girl with refractory ES. Disease control lasted over 12 months until a single partially GD2-negative intracranial metastasis was detected. In order to target GD2 in H3K27M-mutant DMG, we blocked ganglioside synthesis via eliglustat, since dinutuximab cannot cross the blood-brain barrier. Eliglustat is an inhibitor of glucosylceramide synthase, and it is used for treating children with Gaucher's disease. Eliglustat completely inhibited the proliferation of primary H3K27M-mutant DMG cells in vitro. In summary, our data provide evidence that dinutuximab might be effective in tumors with high GD2 expression. Moreover, disrupting the ganglioside metabolism in H3K27M-mutant DMG could open up a new therapeutic option for this highly fatal cancer.

Papillary renal cell carcinoma (PRCC) is a rare entity in children with no established therapy protocols for advanced diseases. Immunotherapy is emerging as an important therapeutic tool for childhood cancer. Tumor cells can be recognized and killed by conventional and unconventional T cells. Unconventional T cells are able to recognize lipid antigens presented via CD1 molecules independently from major histocompatibility complex, which offers new alternatives for cancer immunotherapies. The nature of those lipids is largely unknown and α-galactosylceramide is currently used as a synthetic model antigen. In this work, we analyzed infiltrating lymphocytes of two pediatric PRCCs using flow cytometry, immunohistochemistry and qRT-PCR. Moreover, we analyzed the CD1d expression within both tumors. Tumor lipids of PRCC samples and three normal kidney samples were fractionated and the recognition of tumor own lipid fractions by unconventional T cells was analyzed in an in vitro assay. We identified infiltrating lymphocytes including γδ T cells and iNKT cells, as well as CD1d expression in both samples. One lipid fraction, containing ceramides and monoacylglycerides amongst others, was able to induce the proliferation of iNKT cells isolated from peripheral blood mononuclear cells (PBMCs) of healthy donors and of one matched PRCC patient. Furthermore, CD1d tetramer stainings revealed that a subset of iNKT cells is able to bind lipids being present in fraction 2 via CD1d. We conclude that PRCCs are infiltrated by conventional and unconventional T cells and express CD1d. Moreover, certain lipids, present in pediatric PRCC, are able to stimulate unconventional T cells. Manipulating these lipids and T cells may open new strategies for therapy of pediatric PRCCs., (Copyright © 2020 Lehmann, Paret, El Malki, Russo, Neu, Wingerter, Seidmann, Foersch, Ziegler, Roth, Backes, Sandhoff and Faber.)

The analysis of tumours using biomarkers in blood is transforming cancer diagnosis and therapy. Cancers are characterised by evolving genetic alterations, making it difficult to develop reliable and broadly applicable DNA-based biomarkers for liquid biopsy. In contrast to the variability in gene mutations, the methylation pattern remains generally constant during carcinogenesis. Thus, methylation more than mutation analysis may be exploited to recognise tumour features in the blood of patients. In this work, we investigated the possibility of using global CpG (CpG means a CG motif in the context of methylation. The p represents the phosphate. This is used to distinguish CG sites meant for methylation from other CG motifs or from mentions of CG content) island methylation profiles as a basis for the prediction of cancer state of patients utilising liquid biopsy samples. We retrieved existing GEO methylation datasets on hepatocellular carcinoma (HCC) and cell-free DNA (cfDNA) from HCC patients and healthy donors, as well as healthy whole blood and purified peripheral blood mononuclear cell (PBMC) samples, and used a random forest classifier as a predictor. Additionally, we tested three different feature selection techniques in combination. When using cfDNA samples together with solid tumour samples and healthy blood samples of different origin, we could achieve an average accuracy of 0.98 in a 10-fold cross-validation. In this setting, all the feature selection methods we tested in this work showed promising results. We could also show that it is possible to use solid tumour samples and purified PBMCs as a training set and correctly predict a cfDNA sample as cancerous or healthy. In contrast to the complete set of samples, the feature selections led to varying results of the respective random forests. ANOVA feature selection worked well with this training set, and the selected features allowed the random forest to predict all cfDNA samples correctly. Feature selection based on mutual information could also lead to better than random results, but LASSO feature selection would not lead to a confident prediction. Our results show the relevance of CpG islands as tumour markers in blood.