bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ungual Keratoacanthoma With Features of Regression
Authors: Fernandez-Flores Angel , García-Paíno Luis , Perón Águeda Santos , Cassarino David 
Published: January 2023

Abstract:
Ungual keratoacanthoma (UKA) is an infrequent tumor. Different from keratoacanthoma in other parts of the skin, UKA rarely regresses, and grows aggressively with common destruction of the subjacent phalanx. Reported cases of UKA with features of regression are exceptional, and even dermatopathologists with reputed experience in nail pathology admit to having seen very few cases. We herein report a case of a 77-year-old man who presented a painful subungual lesion on the second finger of the right hand. An x-ray showed evidence of erosion of the subjacent distal phalanx. The patient was highly concerned about the lesion and rejected conservative treatment preferring amputation of the distal phalanx. The histopathologic examination revealed a UKA with features of regression.
Injection Site Reaction to Various Insulins as Type III Allergy With Urticarial Vasculitis in a Patient With Type I Diabetes Mellitus
Authors: Müller Cornelia S. L. , Bourg Catherine , Schweitzer Luca Filomena , Friesenhahn-Ochs Bettina , Pföhler Claudia 
Published: January 2023

Abstract:
Injection site reactions are defined as skin reactions at the injection site to drugs administered subcutaneously. Pathophysiologically, these reactions are based on different immunological mechanisms. We report the case of a 49-year-old patient with type 1 diabetes mellitus (first diagnosis in 1994 at the age of 23 years). Continuous subcutaneous insulin infusion using an insulin pump has been used for many years. The patient presented to the department of dermatology with progressive symptoms in the area of the insulin injection sites on the lower abdomen, accompanied by pain, burning, erythema, tenderness, and the formation of subcutaneous nodules. Previous attempts to use different insulins and to change the injection sites did not improve his symptoms. Furthermore, the symptoms appeared within hours after the insulin pump was attached, so that the injection site has to be changed as soon as every 48 hours. No anaphylactic shock was reported at any time. Multiple histological specimens were obtained from an older lesion on the abdomen as well as from test sites after standard allergological tests (prick and intradermal tests) of various insulins. Histologically, these biopsies showed the image of an extensive deep-reaching small vessel vasculitis with the aspect of an urticarial vasculitis and confirmed the diagnosis of an injection-site reaction that can be characterized as a type III hypersensitivity reaction.
Intrahepatic osteopontin signaling by CREBZF defines a checkpoint for steatosis-to-NASH progression
Authors: Ma Fengguang , Liu Yuxiao , Hu Zhimin , Xue Yaqian , Liu Zhengshuai , Cai Genxiang , Su Weitong , Zheng Zengpeng , Fang Xia , Yan Xi , Ding Dong , Sun Xiaoyang , Jiang Yang , Wei Shuang , Li Wenjing , Zhao Jiuxiang , Zhang Haibing , Li Hong , Xiao Dongguang , Zhang Cuiying , Ying Hao , Qin Jun , Gao Xin , Dai Xiaozhen , Fu Wenguang , Xu Yong , Li Yu , Cui Aoyuan 
Published: January 2023

Background and Aims:
NASH has emerged as a leading cause of chronic liver disease. However, the mechanisms that govern NASH fibrosis remain largely unknown. CREBZF is a CREB/ATF bZIP transcription factor that causes hepatic steatosis and metabolic defects in obesity.

Approach and Results:
Here, we show that CREBZF is a key mechanism of liver fibrosis checkpoint that promotes hepatocyte injury and exacerbates diet-induced NASH in mice. CREBZF deficiency attenuated liver injury, fibrosis, and inflammation in diet-induced mouse models of NASH. CREBZF increases HSC activation and fibrosis in a hepatocyte-autonomous manner by stimulating an extracellular matrix protein osteopontin, a key regulator of fibrosis. The inhibition of miR-6964-3p mediates CREBZF-induced production and secretion of osteopontin in hepatocytes. Adeno-associated virus –mediated rescue of osteopontin restored HSC activation, liver fibrosis, and NASH progression in CREBZF-deficient mice. Importantly, expression levels of CREBZF are increased in livers of diet-induced NASH mouse models and humans with NASH.

Conclusions:
Osteopontin signaling by CREBZF represents a previously unrecognized intrahepatic mechanism that triggers liver fibrosis and contributes to the severity of NASH.
STRICT PRO RE NATA VERSUS TREAT-AND-EXTEND REGIMENS IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION
Authors: Fang Hwa-Shin , Bai Chyi-Huey , Cheng Cheng-Kuo 
Published: January 2023

Purpose:
To compare the visual and anatomical outcomes between strict pro re nata (strict PRN) and treat-and-extend (T&E) anti–vascular endothelial growth factor (anti-VEGF) regimens for neovascular age-related macular degeneration (nAMD).

Methods:
A meta-analysis of 1-year and 2-year changes between strict PRN and T&E anti-VEGF regimens were conducted in both randomized controlled trials (RCTs) and real-world studies (RWSs). The best-corrected visual acuity (BCVA), central retinal thickness (CRT), and weighted mean numbers of visits and injections were evaluated.

Results:
A total of 19 RCTs and 23 RWSs (2,530 eyes in strict PRN and 4,399 eyes in T&E) were included. Mean BCVA change in strict PRN group in both 1-year and 2-year (5.95 and 5.78, respectively) was noninferior to the T&E group (7.85 and 5.96, respectively). Mean CRT changes were also similar in both strict PRN and T&E groups. Mean number of visits were significantly more in the strict PRN group, whereas mean number of injections was significantly more in the T&E group.

Conclusion:
The strict PRN regimen demonstrates a noninferior BCVA improvement to the T&E regimen, achieving fewer injections, and may be both economically and medically beneficial. Both selections should be provided to patients with an overall consideration.
Machine learning augmentation reduces prediction error in collective forecasting: development and validation across prediction markets
Authors: Gruen Alexander , Mattingly Karl R , Morwitch Ellen , Bossaerts Frederik , Clifford Manning , Nash Chad , Ioannidis John P A , Ponsonby Anne-Louise 
Published: January 2023

AbstractThe recent COVID-19 crisis highlighted the inadequacy of human forecasting. We aim to leverage human prediction markets with real-time machine weighting of likely higher accuracy trades to improve performance. The crowd sourced Almanis prediction market longitudinal platform (n=1822) and Next Generation Social Science (NGS2) platform (n=103) were utilised. A 43-feature model predicted top quintile relative Brier accuracy scores in two out-of-sample datasets (pboth<1×10−9). Trades graded as high machine accuracy quality vs. other trades had a greater AUC temporal gain from before to after trade. Hybrid human-machine forecasts had higher accuracy than human forecasts alone, particularly when the two systems disagreed by 5% or more for binary event prediction: the hybrid system demonstrating substantial AUC gains of 13.2%, p=1.35×10−14and 13.8%, p=0.003 in the out-of-sample Almanis B and NGS2 datasets respectively. When discordant, the hybrid model was correct for COVID-19 event occurrence 72.7% of the time vs 27.3% for human-only models, p=0.007. This net classification benefit was replicated in the separate Almanis B dataset, p=2.4×10−7. Real-time machine classification followed by weighting human trades according to likely accuracy improves collective forecasting performance. Implementation may allow improved anticipation of and response to emerging risks and improved human collective efforts generally.Significance StatementHuman-machine hybrid approaches have been identified as a new frontier for event prediction and decision making in the artificial intelligence and collective human intelligence fields. For the first time, we present the successful development and validation of a human-machine hybrid prediction market approach and demonstrate its superior accuracy when compared to prediction markets based on human forecasting alone. The advantages of this new hybrid system are demonstrated in the context of COVID-19-related event prediction.
The ChAMP App: A Scalable mHealth Technology for Detecting Digital Phenotypes of Early Childhood Mental Health
Authors: Loftness Bryn C. , Halvorson-Phelan Julia , O’Leary Aisling , Bradshaw Carter , Prytherch Shania , Berman Isabel , Torous John , Copeland William L. , Cheney Nick , McGinnis Ryan S. , McGinnis Ellen W. 
Published: January 2023

AbstractChildhood mental health problems are common, impairing, and can become chronic if left untreated. Children are not reliable reporters of their emotional and behavioral health, and caregivers often unintentionally under-or over-report child symptoms, making assessment challenging. Objective physiological and behavioral measures of emotional and behavioral health are emerging. However, these methods typically require specialized equipment and expertise in data and sensor engineering to administer and analyze. To address this challenge, we have developed the ChAMP (Childhood Assessment and Management of digital Phenotypes) System, which includes a mobile application for collecting movement and audio data during a battery of mood induction tasks and an open-source platform for extracting digital biomarkers. As proof of principle, we present ChAMP System data from 101 children 4-8 years old, with and without diagnosed mental health disorders. Machine learning models trained on these data detect the presence of specific disorders with 70-73% balanced accuracy, with similar results to clinical thresholds on established parent-report measures (63-82% balanced accuracy). Features favored in model architectures are described using Shapley Additive Explanations (SHAP). Canonical Correlation Analysis reveals moderate to strong associations between predictors of each disorder and associated symptom severity (r = .51-.83). The open-source ChAMP System provides clinically-relevant digital biomarkers that may later complement parent-report measures of emotional and behavioral health for detecting kids with underlying mental health conditions and lowers the barrier to entry for researchers interested in exploring digital phenotyping of childhood mental health.
Comparison of gene set scoring methods for reproducible evaluation of multiple tuberculosis gene signatures
Authors: Wang Xutao , VanValkenberg Arthur , Odom-Mabey Aubrey R. , Ellner Jerrold J. , Hochberg Natasha S. , Salgame Padmini , Patil Prasad , Johnson W. Evan 
Published: January 2023

ABSTRACTRationaleMany blood-based transcriptional gene signatures for tuberculosis (TB) have been developed with potential use to diagnose disease, predict risk of progression from infection to disease, and monitor TB treatment outcomes. However, an unresolved issue is whether gene set enrichment analysis (GSEA) of the signature transcripts alone is sufficient for prediction and differentiation, or whether it is necessary to use the original statistical model created when the signature was derived. Intra-method comparison is complicated by the unavailability of original training data, missing details about the original trained model, and inadequate publicly-available software tools or source code implementing models. To facilitate these signatures’ replicability and appropriate utilization in TB research, comprehensive comparisons between gene set scoring methods with cross-data validation of original model implementations are needed.ObjectivesWe compared the performance of 19 TB gene signatures across 24 transcriptomic datasets using both re-rebuilt original models and gene set scoring methods to evaluate whether gene set scoring is a reasonable proxy to the performance of the original trained model. We have provided an open-access software implementation of the original models for all 19 signatures for future use.MethodsWe considered existing gene set scoring and machine learning methods, including ssGSEA, GSVA, PLAGE, Singscore, and Zscore, as alternative approaches to profile gene signature performance. The sample-size-weighted mean area under the curve (AUC) value was computed to measure each signature’s performance across datasets. Correlation analysis and Wilcoxon paired tests were used to analyze the performance of enrichment methods with the original models.Measurement and Main ResultsFor many signatures, the predictions from gene set scoring methods were highly correlated and statistically equivalent to the results given by the original diagnostic models. PLAGE outperformed all other gene scoring methods. In some cases, PLAGE outperformed the original models when considering signatures’ weighted mean AUC values and the AUC results within individual studies.ConclusionGene set enrichment scoring of existing blood-based biomarker gene sets can distinguish patients with active TB disease from latent TB infection and other clinical conditions with equivalent or improved accuracy compared to the original methods and models. These data justify using gene set scoring methods of published TB gene signatures for predicting TB risk and treatment outcomes, especially when original models are difficult to apply or implement.
FcyRIIB is a novel immune checkpoint in the tumor microenvironment limiting activity of Treg-targeting antibodies
Authors: Knorr David , Leidner Rom , Jensen Shawn , Meng Ryan , Jones Andrew , Ballesteros-Merino Carmen , Bell R. Bryan , Baez Maria , Sprott David , Bifulco Carlo , Piening Brian , Dahan Rony , Fox Bernard A. , Ravetch Jeffrey 
Published: January 2023

SummaryDespite pre-clinical murine data supporting T regulatory (Treg) cell depletion as a major mechanism by which anti-CTLA-4 antibodies function in vivo, the two main antibodies tested in patients (ipilimumab and tremelimumab) have failed to demonstrate similar effects. We report analogous findings in an immunocompetent murine model humanized for CTLA-4 and Fcy receptors (hCTLA-4/hFcyR mice), where both ipilimumab and tremelimumab fail to show appreciable Treg depletion. Immune profiling of the tumor microenvironment (TME) in both mice and human samples revealed upregulation of the inhibitory Fcy receptor, FcyRIIB, which limits the ability of the antibody Fc fragment of human anti-CTLA-4 antibodies to induce effective antibody dependent cellular cytotoxicty/phagocytosis (ADCC/ADCP). Blocking FcyRIIB in humanized mice rescues Treg depleting capacity and anti-tumor activity of ipilimumab. For another target, CC motif chemokine receptor 8 (CCR8), which is selectively expressed on tumor infiltrating Tregs, we show that Fc engineering to enhance binding to activating Fc receptors, while limiting binding to the inhibitory Fc receptor, leads to consistent Treg depletion and single-agent activity across multiple tumor models, including B16, MC38 and MB49. These data reveal the importance of reducing engagement to the inhibitory Fc receptor to optimize Treg depletion by TME targeting antibodies. Our results define the inhibitory FcyRIIB receptor as a novel immune checkpoint limiting antibody-mediated Treg depletion in tumors, and demonstrate Fc variant engineering as a means to overcome this limitation and augment efficacy for a repertoire of antibodies currently in use or under clinical evaluation in oncology.Highlights-Fully human anti-CTLA-4 antibodies are limited in their capacity to deplete T regulatory cells and drive durable anti-tumor immunity in humanized FcyR/hCTLA-4 mice-The inhibitory Fcy receptor, FcyRIIB, is upregulated in the tumor microenvironment in patients and in humanized FcyR/hCTLA-4 mice-Blocking FcyRIIB leads to rescue of Treg depletion in humanized murine models-Fc engineering can improve the depleting capacity and in vivo anti-tumor activity of anti-CTLA and anti-CCR8 antibodies targeting tumor infiltrating Tregs
T helper cells exhibit a dynamic and reversible 3’UTR landscape
Authors: Seyres Denis , Gorka Oliver , Schmidt Ralf , Marone Romina , Zavolan Mihaela , Jeker Lukas T. 
Published: January 2023

Abstract3’ untranslated regions (3’UTRs) are critical elements of messenger RNAs, as they contain binding sites for RNA-binding proteins (RBP) and microRNAs that affect various aspects of the RNA life cycle including transcript stability and cellular localisation. In response to T cell receptor activation, T cells undergo massive expansion during the effector phase of the immune response and dynamically modify their 3’UTRs. Whether this serves to directly regulate the abundance of specific mRNAs or is a secondary effect of proliferation remains unclear. To study 3’UTR dynamics in T helper cells we investigated division-dependent alternative polyadenylation (APA). We generated 3’ end UTR sequencing data from naïve, activated, memory and regulatory CD4+ T cells. 3’UTR length changes were estimated using a non-negative matrix factorization approach and were compared with those inferred from long-read PacBio sequencing. We found that APA events were transient and reverted after effector phase expansion. Using an orthogonal bulk RNAseq dataset, we did not find evidence of APA association with differential gene expression or transcript usage, indicating that APA has only a marginal effect on transcript abundance. 3’UTR sequence analysis revealed conserved binding sites for T cell-relevant microRNAs and RBPs in the alternative 3’UTRs. These results indicate that polyA site usage could play an important role in the control of cell fate decisions and homeostasis.
Functional synapses between small cell lung cancer and glutamatergic neurons
Authors: Schmitt Anna , Sakthivelu Vignesh , Ndoci Kristiano , Wani Gulzar A , Touet Marian , Pintelon Isabel , Kisis Ilmars , Ibruli Olta , Weber Julia , Maresch Roman , Bebber Christina M , Goergens Jonas , Jevtic Milica , Odenthal Franka , Placzek Aleksandra , Hennrich Alexandru A , Conzelmann Karl-Klaus , Boecker Maike , Heimsoeth Alena , Gülcüler Gülce S , Jachimowicz Ron D , George Julie , Brägelmann Johannes , von Karstedt Silvia , Peifer Martin , Persigehl Thorsten , Grüll Holger , Sos Martin L , Brüning Jens , Reifenberger Guido , Fischer Matthias , Adriaensen Dirk , Büttner Reinhard , Brouns Inge , Rad Roland , Thomas Roman K , Bergami Matteo , Motori Elisa , Reinhardt Hans Christian , Beleggia Filippo 
Published: January 2023

AbstractSmall cell lung cancer (SCLC) is a highly aggressive type of lung cancer, characterized by rapid proliferation, early metastatic spread, clinical recurrence and high rate of mortality. Usingin vivoinsertional mutagenesis screening in conjunction with cross-species genomic and transcriptomic validation, we identified a strong and consistent signal for neuronal, synaptic, and glutamatergic signaling gene sets in murine and human SCLC. We show that SCLC cells have the ability to develop intimate contacts with neuronal glutamatergic terminalsin vitro, in autochthonous primary lung tumors and in brain-engrafted tumors. These contacts can develop intobona fidesynapses, allowing SCLC cells to receive glutamatergic inputs. Fitting with a potential oncogenic role of neuron-SCLC interactions, we show that SCLC cells derive a robust proliferation advantage when co-cultured with neurons. Moreover, the repression of glutamate release and the stimulation of the inhibitory glutamate receptor GRM8 displayed therapeutic efficacy in an autochthonous mouse model of SCLC. Therefore, following malignant transformation, SCLC cells appear to hijack glutamatergic signaling to sustain tumor growth, thereby exposing a novel entry route for therapeutic intervention.
A novel method for characterising the inter- and intra-lake variability of CH4emissions: validation and application across a latitudinal transect in the Alpine region
Authors: Tomelleri Enrico , Scholz Katharina , Pighini Sylvie , Carotenuto Federico , Gioli Beniamino , Miglietta Franco , Sommaruga Ruben , Tonon Giustino , Zaldei Alessandro , Wohlfahrt Georg 
Published: January 2023

AbstractLakes in the Alpine region are recognised as critical CH4 emitters, but a robust characterisation of the magnitude and variability of CH4 fluxes is still needed. We developed a mobile platform for CH4 eddy covariance (EC) flux measurements to tackle this gap. Our approach was shown to be well suited to catch all CH4 emission pathways and overcome the limitations of other methods (e.g., gradient-based). This is by surpassing their local nature and thus being suited for characterising the variability of the within-lake emissions, primarily because of CH4 emissions by ebullition stochasticity. The mobile system was deployed at nine lakes across a latitudinal transect in the Alps and validated by comparing the measured fluxes with a fixed EC station and to chambers and boundary layer estimates. Methane fluxes were explained by water turbidity, dissolved organic carbon, dissolved nitrogen, elevation, particulate organic carbon, and total phosphorus. The highest fluxes and most substantial seasonal variability were found in a shallow low-altitude lake in the Southern Alps. Additionally, the mobile EC permitted to resolve the spatial structure of fluxes at the selected lakes. Finally, we demonstrated the usability of our novel mobile system to characterise intra- and inter-lake variability of fluxes. We suggest that characterising the intra-lake emission heterogeneity and a deeper understanding of inter-lake emission magnitude differences is fundamental for a solid estimate of freshwater CH4 budgets.Key PointsCH4 emissions from alpine lakes are recognised to be an important component to the global methane budget but they are poorly characterizedWe developed and validated a mobile eddy covariance platform for capturing CH4 fluxes across lakes in the alpine region for two yearsA robust statistical model based on a fewin-situphysicochemical and biological parameters can be generally used to predict CH4 fluxes
Extracellular matrices of bone marrow stroma regulate cell phenotype and contribute to distinct stromal nichesin vivo
Authors: Stone Andrew , Rand Emma , Thornes Gabriel , Kay Alasdair , Barnes Amanda , Hitchcock Ian , Genever Paul 
Published: January 2023

AbstractThe heterogeneity of bone marrow stromal cells (BMSCs) has been revealed more in recent years through the advent of single cell RNA sequencing. However, protein level characterisation is likely to provide a deeper understanding of the functions of individual subsets and may reveal insights into the co-ordination of the cell phenotype maintaining niche.Here, by analysing heterogeneity in BMSC populations using human stromal cell lines to model extremes of cell morphology and migration characteristics, we identified plastic cell phenotypes that can be modified through secreted proteins. Transfer of secreted signals from a differentiation-competent stem cell phenotype was able to stimulate migration in a slow-moving stromal cell, observed via label-free ptychography. Subsequent untargeted proteomic interrogation of the secreted factors from these cell lines identified a highly significant enrichment of extracellular matrix (ECM) protein production by the differentiation-competent cells compared to non-stem cells. The most highly enriched proteins, aggrecan and periostin, were identified on the endosteal surfaces of mouse and human bone, underlying CD271+ stromal cells in the latter, indicating that they may represent key non-cellular niche-components important for cell maintenance and phenotype. ECM from stem cells was further capable of enhancing migration in non-stem cells in a focal adhesion kinase-dependent manner.Overall, we demonstrate the importance of the ECM in co-ordination of cellular phenotype and highlight how non-cellular components of the BMSC niche may provide insights into the role of BMSCs in health and disease.