tbuckley/cabot-search huggingface dataset:
Proteomic and phenotypic characteristics of memory-like natural killer cells for cancer immunotherapy
Authors: Helena Arellano-Ballestero, Agnieszka Zubiak, Chris Dally, Kim Orchard, Aljawharah Alrubayyi, Xenia Charalambous, Melina Michael, Robert Torrance, Trinity Eales, Kushal Das, Maxine G. B. Tran, May Sabry, Dimitra Peppa, Mark W. Lowdell
Journal: Journal for ImmunoTherapy of Cancer (2024)

Human and mouse natural killer (NK) cells have been shown to develop memory-like function after short-term exposure to the cocktail of IL-12/15/18 or to overnight co-culture with some tumor cell lines. The resulting cells retain enhanced lytic ability for up to 7 days as well as after cryopreservation, and memory-like NK cells (mlNK) have been shown to induce complete remissions in patients with hematological malignancies. No single phenotype has been described for mlNK and the physiological changes induced by the short-term cytokine or tumor-priming which are responsible for these enhanced functions have not been fully characterized. Here, we have generated mlNK by cytokine and tumor-priming to find commonalities to better define the nature of NK cell "memory" in vitro and, for the first time, in vivo. We initiated mlNK in vitro from healthy donors with cytokines (initiated cytokine-induced memory-like (iCIML)-NK) and by tumor priming (TpNK) overnight and compared them by high-dimensional flow cytometry, proteomic and metabolomic profiling. As a potential mechanism of enhanced cytolytic function, we analyzed the avidity of binding of the mlNK to NK-resistant tumors (z-Movi). We generated TpNK from healthy donors and from cancer patients to determine whether mlNK generated by interaction with a single tumor type could enhance lytic activity. Finally, we used a replication-incompetent tumor cell line (INKmune) to treat patients with myeloid leukaemias to potentiate NK cell function in vivo. Tumor-primed mlNK from healthy donors and patients with cancer showed increased cytotoxicity against multiple tumor cell lines in vitro, analogous to iCIML-NK cells. Multidimensional cytometry identified distinct memory-like profiles of subsets of cells with memory-like characteristics; upregulation of CD57, CD69, CD25 and ICAM1. Proteomic profiling identified 41 proteins restricted to mlNK cells and we identified candidate molecules for the basis of NK memory which can explain how mlNK overcome inhibition by resistant tumors. Finally, of five patients with myelodysplastic syndrome or refractory acute myeloid leukemia treated with INKmune, three responded to treatment with measurable increases in NK lytic function and systemic cytokines. NK cell "memory" is a physiological state associated with resistance to MHC-mediated inhibition, increased metabolic function, mitochondrial fitness and avidity to NK-resistant target cells.
Faecal proteomics links neutrophil degranulation with mortality in patients with alcohol-associated hepatitis
Authors: Henriette Kreimeyer, Carlos G Gonzalez, Marcos F Fondevila, Cynthia L Hsu, Phillipp Hartmann, Xinlian Zhang, Peter Stärkel, Francisco Bosques-Padilla, Elizabeth C Verna, Juan G Abraldes, Robert S Brown, Victor Vargas, Jose Altamirano, Juan Caballería, Debbie L Shawcross, Alexandre Louvet, Michael R Lucey, Philippe Mathurin, Guadalupe Garcia-Tsao, Ramón Bataller, AlcHepNet Investigators, David J Gonzalez, Bernd Schnabl
Journal: Gut (2024)

Patients with alcohol-associated hepatitis (AH) have a high mortality. Alcohol exacerbates liver damage by inducing gut dysbiosis, bacterial translocation and inflammation, which is characterised by increased numbers of circulating and hepatic neutrophils. In this study, we performed tandem mass tag (TMT) proteomics to analyse proteins in the faeces of controls (n=19), patients with alcohol-use disorder (AUD; n=20) and AH (n=80) from a multicentre cohort (InTeam). To identify protein groups that are disproportionately represented, we conducted over-representation analysis using Reactome pathway analysis and Gene Ontology to determine the proteins with the most significant impact. A faecal biomarker and its prognostic effect were validated by ELISA in faecal samples from patients with AH (n=70), who were recruited in a second and independent multicentre cohort (AlcHepNet). Faecal proteomic profiles were overall significantly different between controls, patients with AUD and AH (principal component analysis p=0.001, dissimilarity index calculated by the method of Bray-Curtis). Proteins that showed notable differences across all three groups and displayed a progressive increase in accordance with the severity of alcohol-associated liver disease were predominantly those located in neutrophil granules. Over-representation and Reactome analyses confirmed that differentially regulated proteins are part of granules in neutrophils and the neutrophil degranulation pathway. Myeloperoxidase (MPO), the marker protein of neutrophil granules, correlates with disease severity and predicts 60-day mortality. Using an independent validation cohort, we confirmed that faecal MPO levels can predict short-term survival at 60 days. We found an increased abundance of faecal proteins linked to neutrophil degranulation in patients with AH, which is predictive of short-term survival and could serve as a prognostic non-invasive marker.
A combined EEG motor and speech imagery paradigm with automated successive halving for customizable command selection
Authors: Natasha Padfield, Tracey Camilleri, Simon Fabri, Marvin Bugeja, Kenneth Camilleri
Journal: Brain-Computer Interfaces (2024)

The classification performance of endogenous electroencephalogram (EEG) brain-computer interfaces (BCIs) can be improved by hybridizing the paradigm through the use of commands from multiple paradigms. Hybrid paradigms using motor imagery (MI) and speech imagery (SI) have shown promise, but there is a lack of research into: i) their effectiveness when compared to pure MI and SI for multiclass problems, and ii) automated command selection. This study investigates multiclass MI and SI hybrid paradigms and compares the results to those obtained using pure MI and SI. Performance was assessed using F1 score and accuracy. The performances of all possible hybrid paradigm designs were assessed. The analysis indicated that hybridization does not always guarantee improved performance when compared to the pure paradigms, and there is inter-subject variation in the best paradigm. This confirmed the need for automated subject-specific hybrid paradigm designs. An automated hybrid paradigm selection technique using successive halving (SH) for expedited computational times was developed and results were compared to those obtained using a standard grid search. The SH approach resulted in an improvement in F1 score of 21.09% and 36.86% compared to MI and SI and led to a reduction in computational times of 82.80% compared to grid search.
A history of repeated antibiotic usage leads to microbiota-dependent mucus defects
Authors: Kertu Liis Krigul, Rachel H. Feeney, Supapit Wongkuna, Oliver Aasmets, Sandra M. Holmberg, Reidar Andreson, Fabiola Puértolas-Balint, Kateryna Pantiukh, Linda Sootak, Tõnis Org, Tanel Tenson, Elin Org, Bjoern O. Schroeder
Journal: Gut Microbes (2024)

Recent evidence indicates that repeated antibiotic usage lowers microbial diversity and ultimately changes the gut microbiota community. However, the physiological effects of repeated - but not recent - antibiotic usage on microbiota-mediated mucosal barrier function are largely unknown. By selecting human individuals from the deeply phenotyped Estonian Microbiome Cohort (EstMB), we here utilized human-to-mouse fecal microbiota transplantation to explore long-term impacts of repeated antibiotic use on intestinal mucus function. While a healthy mucus layer protects the intestinal epithelium against infection and inflammation, using
TGF-β1 mediates hypoxia-preconditioned olfactory mucosa mesenchymal stem cells improved neural functional recovery in Parkinson’s disease models and patients
Authors: Yi Zhuo, Wen-Shui Li, Wen Lu, Xuan Li, Li-Te Ge, Yan Huang, Qing-Tao Gao, Yu-Jia Deng, Xin-Chen Jiang, Zi-Wei Lan, Que Deng, Yong-Heng Chen, Yi Xiao, Shuo Lu, Feng Jiang, Zuo Liu, Li Hu, Yu Liu, Yu Ding, Zheng-Wen He, De-An Tan, Da Duan, Ming Lu
Journal: Military Medical Research (2024)

Abstract Background Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the degeneration of dopaminergic neurons in the substantia nigra (SN). Activation of the neuroinflammatory response has a pivotal role in PD. Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic approach for various nerve injuries, but there are limited reports on their use in PD and the underlying mechanisms remain unclear. Methods We investigated the effects of clinical-grade hypoxia-preconditioned olfactory mucosa (hOM)-MSCs on neural functional recovery in both PD models and patients, as well as the preventive effects on mouse models of PD. To assess improvement in neuroinflammatory response and neural functional recovery induced by hOM-MSCs exposure, we employed single-cell RNA sequencing (scRNA-seq), assay for transposase accessible chromatin with high-throughput sequencing (ATAC-seq) combined with full-length transcriptome isoform-sequencing (ISO-seq), and functional assay. Furthermore, we present the findings from an initial cohort of patients enrolled in a phase I first-in-human clinical trial evaluating the safety and efficacy of intraspinal transplantation of hOM-MSC transplantation into severe PD patients. Results A functional assay identified that transforming growth factor-β1 (TGF-β1), secreted from hOM-MSCs, played a critical role in modulating mitochondrial function recovery in dopaminergic neurons. This effect was achieved through improving microglia immune regulation and autophagy homeostasis in the SN, which are closely associated with neuroinflammatory responses. Mechanistically, exposure to hOM-MSCs led to an improvement in neuroinflammation and neural function recovery partially mediated by TGF-β1 via activation of the anaplastic lymphoma kinase/phosphatidylinositol-3-kinase/protein kinase B (ALK/PI3K/Akt) signaling pathway in microglia located in the SN of PD patients. Furthermore, intraspinal transplantation of hOM-MSCs improved the recovery of neurologic function and regulated the neuroinflammatory response without any adverse reactions observed in patients with PD. Conclusions These findings provide compelling evidence for the involvement of TGF-β1 in mediating the beneficial effects of hOM-MSCs on neural functional recovery in PD. Treatment and prevention of hOM-MSCs could be a promising and effective neuroprotective strategy for PD. Additionally, TGF-β1 may be used alone or combined with hOM-MSCs therapy for treating PD.
Risk assessment of hepatitis B virus-related hepatocellular carcinoma development using vibration-controlled transient elastography: Systematic review and meta-analysis
Authors: Young-Joo Jin, Hee Yeon Kim, Young Ju Suh, Chae Hyeon Lee, Jung Hwan Yu, Mi Na Kim, Ji Won Han, Han Ah Lee, Jihyun An, Young Eun Chon, Dae Won Jun, Miyoung Choi, Seung Up Kim
Journal: Clinical and Molecular Hepatology (2024)

Backgrounds/Aims: Liver stiffness measurement (LSM) using vibration-controlled transient elastography (VCTE) can assess fibrotic burden in chronic liver diseases. The systematic review and meta-analysis was conducted to determine whether LSM using VCTE can predict the risk of development of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients.Methods: A systematic literature search of the Ovid-Medline, EMBASE, Cochrane, and KoreaMed databases (from January 2010 to June 2023) was conducted. Of the 1,345 individual studies identified, 10 studies that used VCTE were finally registered. Hazard ratios (HRs) and the 95% confidence intervals (CIs) were considered summary estimates of treatment effect sizes of ≥11 kilopascal (kPa) standard for HCC development. Meta-analysis was performed using the restricted Maximum Likelihood random effects model.Results: Among the ten studies, data for risk ratios for HCC development could be obtained from nine studies. When analyzed for the nine studies, the HR for HCC development was high at 3.33 (95% CI, 2.45–4.54) in CHB patients with a baseline LSM of ≥11 kPa compared to patients who did not. In ten studies included, LSM of ≥11 kPa showed the sensitivity and specificity for predicting HCC development were 61% (95% CI, 50–71%) and 78% (95% CI, 66–86%), respectively, and the diagnostic accuracy was 0.74 (95% CI, 0.70–0.77).Conclusions: The risk of HCC development was elevated in CHB patients with VCTE-determined LSM of ≥11 kPa. This finding suggests that VCTE-determined LSM values may aid the risk prediction of HCC development in CHB patients.
Incretin-based therapy in the management of metabolic dysfunction-associated steatotic liver disease (MASLD): one piece of the puzzle: Editorial on “Comparison of glucagon-like peptide-1 receptor agonists and thiazolidinediones on treating nonalcoholic fatty liver disease: A network meta-analysis”
Authors: Tian-Yi Ren, Mohammed Eslam, Jian-Gao Fan
Journal: Clinical and Molecular Hepatology (2024)
Genomic biomarkers to predict response to atezolizumab plus bevacizumab immunotherapy in hepatocellular carcinoma: Insights from the IMbrave150 trial
Authors: Sun Young Yim, Sung Hwan Lee, Seung-Woo Baek, Bohwa Sohn, Yun Seong Jeong, Sang-Hee Kang, Kena Park, Hyewon Park, Sunyoung S. Lee, Ahmed O. Kaseb, Young Nyun Park, Sun-Hee Leem, Michael A. Curran, Ji Hoon Kim, Ju-Seog Lee
Journal: Clinical and Molecular Hepatology (2024)

Combination immunotherapy, exemplified by atezolizumab plus bevacizumab, has become the standard of care for inoperable hepatocellular carcinoma (HCC). However, the lack of predictive biomarkers and limited understanding of response mechanisms remain a challenge. Using data from the IMbrave150plus cohort, we applied an immune signature score (ISS) predictor to stratify HCC patients treated with atezolizumab plus bevacizumab or with sorafenib alone into potential high and low response groups. By applying multiple statistical approaches including a Bayesian covariate prediction algorithm, we refined the signature to 10 key genes (ISS10) for clinical use while maintaining similar predictive power to the full model. We further validated ISS10 in an independent HCC cohort treated with nivolumab plus ipilimumab. The study identified a significant association between the ISS and treatment response. Among patients classified as high responders, those treated with the atezolizumab plus bevacizumab combination exhibited improved overall and progression-free survival as well as better objective response rate compared to those treated with sorafenib. We also observed a significant correlation between ISS10 and response to nivolumab plus ipilimumab treatment. Analysis of immune cell subpopulations revealed distinct characteristics associated with ISS subtypes. In particular, the ISS10 high subtype displayed a more favorable immune environment with higher proportions of antitumor macrophages and activated T-cells, potentially explaining its better response. Our study suggests that ISS and ISS10 are promising predictive biomarkers for enhanced therapeutic outcomes in HCC patients undergoing combination immunotherapy. These markers are crucial for refining patient stratification and personalized treatment approaches to advance the effectiveness of standard-of-care regimens.
Cross-species single-cell RNA sequencing reveals divergent phenotypes and activation states of adaptive immunity in human carotid and experimental murine atherosclerosis
Authors: Hauke Horstmann, Nathaly Anto Michel, Xia Sheng, Sophie Hansen, Alexandra Lindau, Katharina Pfeil, Marbely C Fernández, Timoteo Marchini, Holger Winkels, Lucia Sol Mitre, Tijani Abogunloko, Xiaowei Li, Timothy Bon-Nawul Mwinyella, Mark Colin Gissler, Heiko Bugger, Timo Heidt, Konrad Buscher, Ingo Hilgendorf, Peter Stachon, Sven Piepenburg, Nicolas Verheyen, Thomas Rathner, Teresa Gerhardt, Patrick Malcolm Siegel, Wolfgang Kurt Oswald, Tina Cohnert, Alma Zernecke, Josef Madl, Peter Kohl, Amanda C Foks, Constantin von zur Muehlen, Dirk Westermann, Andreas Zirlik, Dennis Wolf
Journal: Cardiovascular Research (2024)

Abstract Aims The distinct functions of immune cells in atherosclerosis have been mostly defined by pre-clinical mouse studies. Contrastingly, the immune cell composition of human atherosclerotic plaques and their contribution to disease progression are only poorly understood. It remains uncertain whether genetic animal models allow for valuable translational approaches. Methods and results Single-cell RNA-sequencing (scRNA-seq) was performed to define the immune cell landscape in human carotid atherosclerotic plaques. The human immune cell repertoire demonstrated an unexpectedly high heterogeneity and was dominated by cells of the T-cell lineage, a finding confirmed by immunohistochemistry. Bioinformatical integration with 7 mouse scRNA-seq data sets from adventitial and atherosclerotic vascular tissue revealed a total of 51 identities of cell types and differentiation states, of which some were only poorly conserved between species and exclusively found in humans. Locations, frequencies, and transcriptional programmes of immune cells in mouse models did not resemble the immune cell landscape in human carotid atherosclerosis. In contrast to standard mouse models of atherosclerosis, human plaque leucocytes were dominated by several T-cell phenotypes with transcriptional hallmarks of T-cell activation and memory formation, T-cell receptor, and pro-inflammatory signalling. Only mice at the age of 22 months partially resembled the activated T-cell phenotype. In a validation cohort of 43 patients undergoing carotid endarterectomy, the abundance of activated immune cell subsets in the plaque defined by multi-colour flow cytometry associated with the extent of clinical atherosclerosis. Conclusion Integrative scRNA-seq reveals a substantial difference in the immune cell composition of murine and human carotid atherosclerosis—a finding that questions the translational value of standard mouse models for adaptive immune cell studies. Clinical associations suggest a specific role for T-cell driven (auto-)immunity in human plaque formation and instability.
Impact of immediate release film coating on the disintegration process of tablets
Authors: Mingrui Ma, Daniel Powell, Marwa Nassar, Jason Teckoe, Daniel Markl, J. Axel Zeitler
Journal: Journal of Controlled Release (2024)

Pharmaceutical tablets are often coated with a layer of polymeric material to protect the drug from environmental degradation, facilitate the packaging process, and enhance patient compliance. However, the detailed effects of such coating layers on drug release are not well understood. To investigate this, flat-faced pure microcrystalline cellulose tablets with a diameter of 13 mm and a thickness between 1.5 mm to 1.6 mm were directly compressed, and a film coating layer with a thickness of 80 μm to 120 μm was applied to one face of these tablets. This tablet geometry and immediate release film coating were chosen as a model system to understand how the film coating interacts with the tablet core. The coating hydration and dissolution process was studied using terahertz pulsed imaging, while optical coherence tomography was used to capture further details on the swelling process of the polymer in the coated tablet. The study investigated the film coating polymer dissolution process and found the gelling of dissolving polymer restricted the capillary liquid transport in the core. These findings can help predict the dissolution of film coating within the typical range of thickness (30 μm to 40 μm) and potentially be extended to understand modified release coating formulations.
Cobalt(III) prodrug-based nanomedicine for inducing immunogenic cell death and enhancing chemo-immunotherapy
Authors: Kun Shang, Nicolás Montesdeoca, Hanchen Zhang, Elizaveta Efanova, Ganghao Liang, Jasmine Ochs, Johannes Karges, Haiqin Song, Lingpu Zhang
Journal: Journal of Controlled Release (2024)
Experimental evolution in a warming world – the <i>omics</i> era
Authors: Marta A Santos, Ana Carromeu-Santos, Ana S Quina, Marta A Antunes, Torsten N Kristensen, Mauro Santos, Margarida Matos, Inês Fragata, Pedro Simões
Journal: Molecular Biology and Evolution (2024)

A comprehensive understanding of the genetic mechanisms that shape species responses to thermal variation is essential for more accurate predictions of the impacts of climate change on biodiversity. Experimental evolution with high-throughput resequencing approaches (evolve and resequence) is a highly effective tool that has been increasingly employed to elucidate the genetic basis of adaptation. The number of thermal evolve and resequence studies is rising, yet there is a dearth of efforts to integrate this new wealth of knowledge. Here, we review this literature showing how these studies have contributed to increase our understanding on the genetic basis of thermal adaptation. We identify two major trends: highly polygenic basis of thermal adaptation and general lack of consistency in candidate targets of selection between studies. These findings indicate that the adaptive responses to specific environments are rather independent. A review of the literature reveals several gaps in the existing research. Firstly, there is a paucity of studies done with organisms of diverse taxa. Secondly, there is a need to apply more dynamic and ecologically relevant thermal environments. Thirdly, there is a lack of studies that integrate genomic changes with changes in life history and behavioral traits. Addressing these issues would allow a more in-depth understanding of the relationship between genotype and phenotype. We highlight key methodological aspects that can address some of the limitations and omissions identified. These include the need for greater standardization of methodologies and the utilization of new technologies focusing on the integration of genomic and phenotypic variation in the context of thermal adaptation.