tbuckley/cabot-search huggingface dataset:
The impact of ATP-binding cassette transporters in the diseased brain: Context matters
Authors: Chrysiida Baltira, Eleonora Aronica, William F. Elmquist, Oliver Langer, Wolfgang Löscher, Jann N. Sarkaria, Pieter Wesseling, Mark C. de Gooijer, Olaf van Tellingen
Journal: Cell Reports Medicine (2024)

ATP-binding cassette (ABC) transporters facilitate the movement of diverse molecules across cellular membranes, including those within the CNS. While most extensively studied in microvascular endothelial cells forming the blood-brain barrier (BBB), other CNS cell types also express these transporters. Importantly, disruptions in the CNS microenvironment during disease can alter transporter expression and function. Through this comprehensive review, we explore the modulation of ABC transporters in various brain pathologies and the context-dependent consequences of these changes. For instance, downregulation of ABCB1 may exacerbate amyloid beta plaque deposition in Alzheimer's disease and facilitate neurotoxic compound entry in Parkinson's disease. Upregulation may worsen neuroinflammation by aiding chemokine-mediated CD8 T cell influx into multiple sclerosis lesions. Overall, ABC transporters at the BBB hinder drug entry, presenting challenges for effective pharmacotherapy. Understanding the context-dependent changes in ABC transporter expression and function is crucial for elucidating the etiology and developing treatments for brain diseases.
Urolithin A promotes p62-dependent lysophagy to prevent acute retinal neurodegeneration
Authors: Juan Ignacio Jiménez-Loygorri, Álvaro Viedma-Poyatos, Raquel Gómez-Sintes, Patricia Boya
Journal: Molecular Neurodegeneration (2024)

Abstract Background Age-related macular degeneration (AMD) is the leading cause of blindness in elderly people in the developed world, and the number of people affected is expected to almost double by 2040. The retina presents one of the highest metabolic demands in our bodies that is partially or fully fulfilled by mitochondria in the neuroretina and retinal pigment epithelium (RPE), respectively. Together with its post-mitotic status and constant photooxidative damage from incoming light, the retina requires a tightly-regulated housekeeping system that involves autophagy. The natural polyphenol Urolithin A (UA) has shown neuroprotective benefits in several models of aging and age-associated disorders, mostly attributed to its ability to induce mitophagy and mitochondrial biogenesis. Sodium iodate (SI) administration recapitulates the late stages of AMD, including geographic atrophy and photoreceptor cell death. Methods A combination of in vitro, ex vivo and in vivo models were used to test the neuroprotective potential of UA in the SI model. Functional assays (OCT, ERGs), cellular analysis (flow cytometry, qPCR) and fine confocal microscopy (immunohistochemistry, tandem selective autophagy reporters) helped address this question. Results UA alleviated neurodegeneration and preserved visual function in SI-treated mice. Simultaneously, we observed severe proteostasis defects upon SI damage induction, including autophagosome accumulation, that were resolved in animals that received UA. Treatment with UA restored autophagic flux and triggered PINK1/Parkin-dependent mitophagy, as previously reported in the literature. Autophagy blockage caused by SI was caused by severe lysosomal membrane permeabilization. While UA did not induce lysosomal biogenesis, it did restore upcycling of permeabilized lysosomes through lysophagy. Knockdown of the lysophagy adaptor SQSTM1/p62 abrogated viability rescue by UA in SI-treated cells, exacerbated lysosomal defects and inhibited lysophagy. Conclusions Collectively, these data highlight a novel putative application of UA in the treatment of AMD whereby it bypasses lysosomal defects by promoting p62-dependent lysophagy to sustain proteostasis. Graphical Abstract
Endometriosis: Improvements and challenges in diagnosis and symptom management
Authors: Philippa T.K. Saunders, Lucy H.R. Whitaker, Andrew W. Horne
Journal: Cell Reports Medicine (2024)

Endometriosis is a chronic disorder with debilitating symptoms that is difficult to diagnose and treat. Advances in imaging technologies and strategies for the management of symptoms are improving the quality of life of patients by reducing the time taken for diagnosis and offering a more balanced approach to therapy. Endometriosis is a chronic disorder with debilitating symptoms that is difficult to diagnose and treat. Advances in imaging technologies and strategies for the management of symptoms are improving the quality of life of patients by reducing the time taken for diagnosis and offering a more balanced approach to therapy.
Non-invasive diagnosis of esophageal cancer by a simplified circulating cell-free DNA methylation assay targeting OTOP2 and KCNA3: a double-blinded, multicenter, prospective study
Authors: Yan Bian, Ye Gao, Han Lin, Chang Sun, Wei Wang, Siyu Sun, Xiuling Li, Zhijie Feng, Jianlin Ren, Hezhong Chen, Chaojing Lu, Jinfang Xu, Jun Zhou, Kangkang Wan, Lei Xin, Zhaoshen Li, Luowei Wang
Journal: Journal of Hematology & Oncology (2024)

Esophageal cancer (EC) is a highly lethal disease lacking early detection approaches. We previously identified that OTOP2 and KCNA3 were specifically hypermethylated in circulating cell-free DNA from patients with EC. We then developed a blood-based methylation assay targeting OTOP2 and KCNA3 (named "IEsohunter") for esophageal cancer noninvasive detection. This double-blinded, multicenter, prospective study aimed to comprehensively evaluate its clinical diagnostic performance.
Safe and effective liver-directed AAV-mediated homology-independent targeted integration in mouse models of inherited diseases
Authors: Federica Esposito, Fabio Dell’Aquila, Manuel Rhiel, Stefano Auricchio, Kay Ole Chmielewski, Geoffroy Andrieux, Rita Ferla, Paula Sureda Horrach, Arjun Padmanabhan, Roberto Di Cunto, Simone Notaro, Manel Llado Santeularia, Melanie Boerries, Margherita Dell’Anno, Edoardo Nusco, Agnese Padula, Sofia Nutarelli, Tatjana I. Cornu, Nicolina Cristina Sorrentino, Pasquale Piccolo, Ivana Trapani, Toni Cathomen, Alberto Auricchio
Journal: Cell Reports Medicine (2024)

Liver-directed adeno-associated viral (AAV) vector-mediated homology-independent targeted integration (AAV-HITI) by CRISPR-Cas9 at the highly transcribed albumin locus is under investigation to provide sustained transgene expression following neonatal treatment. We show that targeting the 3′ end of the albumin locus results in productive integration in about 15% of mouse hepatocytes achieving therapeutic levels of systemic proteins in two mouse models of inherited diseases. We demonstrate that full-length HITI donor DNA is preferentially integrated upon nuclease cleavage and that, despite partial AAV genome integrations in the target locus, no gross chromosomal rearrangements or insertions/deletions at off-target sites are found. In line with this, no evidence of hepatocellular carcinoma is observed within the 1-year follow-up. Finally, AAV-HITI is effective at vector doses considered safe if directly translated to humans providing therapeutic efficacy in the adult liver in addition to newborn. Overall, our data support the development of this liver-directed AAV-based knockin strategy.
The tissue-resident regulatory T cell pool is shaped by transient multi-tissue migration and a conserved residency program
Authors: Oliver T. Burton, Orian Bricard, Samar Tareen, Vaclav Gergelits, Simon Andrews, Laura Biggins, Carlos P. Roca, Carly Whyte, Steffie Junius, Aleksandra Brajic, Emanuela Pasciuto, Magda Ali, Pierre Lemaitre, Susan M. Schlenner, Harumichi Ishigame, Brian D. Brown, James Dooley, Adrian Liston
Journal: Immunity (2024)

The tissues are the site of many important immunological reactions, yet how the immune system is controlled at these sites remains opaque. Recent studies have identified Foxp3
Neoadjuvant sintilimab plus chemotherapy in EGFR-mutant NSCLC: Phase 2 trial interim results (NEOTIDE/CTONG2104)
Authors: Chao Zhang, Yu-Xuan Sun, Ding-Cheng Yi, Ben-Yuan Jiang, Li-Xu Yan, Ze-Dao Liu, Li-Shan Peng, Wen-Jie Zhang, Hao Sun, Zhi-Yong Chen, Dan-Hua Wang, Di Peng, Song-An Chen, Si-Qi Li, Ze Zhang, Xiao-Yue Tan, Jie Yang, Zhang-Yi Zhao, Wan-Ting Zhang, Jian Su, Yang-Si Li, Ri-Qiang Liao, Song Dong, Chong-Rui Xu, Qing Zhou, Xue-Ning Yang, Yi-Long Wu, Ze-Min Zhang, Wen-Zhao Zhong
Journal: Cell Reports Medicine (2024)

The clinical efficacy of neoadjuvant immunotherapy plus chemotherapy remains elusive in localized epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). Here, we report interim results of a Simon's two-stage design, phase 2 trial using neoadjuvant sintilimab with carboplatin and nab-paclitaxel in resectable EGFR-mutant NSCLC. All 18 patients undergo radical surgery, with one patient experiencing surgery delay. Fourteen patients exhibit confirmed radiological response, with 44% achieving major pathological response (MPR) and no pathological complete response (pCR). Similar genomic alterations are observed before and after treatment without influencing the efficacy of subsequent EGFR-tyrosine kinase inhibitors (TKIs) in vitro. Infiltration and T cell receptor (TCR) clonal expansion of CCR8+ regulatory T (Treg)hi/CXCL13+ exhausted T (Tex)lo cells define a subtype of EGFR-mutant NSCLC highly resistant to immunotherapy, with the phenotype potentially serving as a promising signature to predict immunotherapy efficacy. Informed circulating tumor DNA (ctDNA) detection in EGFR-mutant NSCLC could help identify patients nonresponsive to neoadjuvant immunochemotherapy. These findings provide supportive data for the utilization of neoadjuvant immunochemotherapy and insight into immune resistance in EGFR-mutant NSCLC.
Therapeutic potential of human microglia transplantation in a chimeric model of CSF1R-related leukoencephalopathy
Authors: Jean Paul Chadarevian, Jonathan Hasselmann, Alina Lahian, Joia K. Capocchi, Adrian Escobar, Tau En Lim, Lauren Le, Christina Tu, Jasmine Nguyen, Sepideh Kiani Shabestari, William Carlen-Jones, Sunil Gandhi, Guojun Bu, David A. Hume, Clare Pridans, Zbigniew K. Wszolek, Robert C. Spitale, Hayk Davtyan, Mathew Blurton-Jones
Journal: Neuron (2024)

Microglia replacement strategies are increasingly being considered for the treatment of primary microgliopathies like adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). However, available mouse models fail to recapitulate the diverse neuropathologies and reduced microglia numbers observed in patients. In this study, we generated a xenotolerant mouse model lacking the fms-intronic regulatory element (FIRE) enhancer within Csf1r, which develops nearly all the hallmark pathologies associated with ALSP. Remarkably, transplantation of human induced pluripotent stem cell (iPSC)-derived microglial (iMG) progenitors restores a homeostatic microglial signature and prevents the development of axonal spheroids, white matter abnormalities, reactive astrocytosis, and brain calcifications. Furthermore, transplantation of CRISPR-corrected ALSP-patient-derived iMG reverses pre-existing spheroids, astrogliosis, and calcification pathologies. Together with the accompanying study by Munro and colleagues, our results demonstrate the utility of FIRE mice to model ALSP and provide compelling evidence that iMG transplantation could offer a promising new therapeutic strategy for ALSP and perhaps other microglia-associated neurological disorders.
Combination of menin and kinase inhibitors as an effective treatment for leukemia with NUP98 translocations
Authors: Hongzhi Miao, Dong Chen, James Ropa, Trupta Purohit, EunGi Kim, Maria-Luisa Sulis, Adolfo Ferrando, Tomasz Cierpicki, Jolanta Grembecka
Journal: Leukemia (2024)
Pre-emptive detection and evolution of relapse in acute myeloid leukemia by flow cytometric measurable residual disease surveillance
Authors: Nicholas McCarthy, Gege Gui, Florent Dumezy, Christophe Roumier, Georgia Andrew, Sarah Green, Madeleine Jenkins, Alexandra Adams, Naeem Khan, Charles Craddock, Christopher S. Hourigan, Adriana Plesa, Sylvie Freeman
Journal: Leukemia (2024)

Measurable residual disease (MRD) surveillance in acute myeloid leukemia (AML) may identify patients destined for relapse and thus provide the option of pre-emptive therapy to improve their outcome. Whilst flow cytometric MRD (Flow-MRD) can be applied to high-risk AML/ myelodysplasia patients, its diagnostic performance for detecting impending relapse is unknown. We evaluated this in a cohort comprising 136 true positives (bone marrows preceding relapse by a median of 2.45 months) and 155 true negatives (bone marrows during sustained remission). At an optimal Flow-MRD threshold of 0.040%, clinical sensitivity and specificity for relapse was 74% and 87% respectively (51% and 98% for Flow-MRD ≥ 0.1%) by 'different-from-normal' analysis. Median relapse kinetics were 0.78 log10/month but significantly higher at 0.92 log10/month for FLT3-mutated AML. Computational (unsupervised) Flow-MRD (C-Flow-MRD) generated optimal MRD thresholds of 0.036% and 0.082% with equivalent clinical sensitivity to standard analysis. C-Flow-MRD-identified aberrancies in HLADRlow or CD34+CD38low (LSC-type) subpopulations contributed the greatest clinical accuracy (56% sensitivity, 90% specificity) and notably, by longitudinal profiling expanded rapidly within blasts in > 40% of 86 paired MRD and relapse samples. In conclusion, flow MRD surveillance can detect MRD relapse in high risk AML and its evaluation may be enhanced by computational analysis.
Recognition, diagnosis, and early management of suspected sepsis: summary of updated NICE guidance
Authors: Anthony Gildea, Caroline Mulvihill, Emma McFarlane, Alasdair Gray, Mervyn Singer
Journal: BMJ (2024)

### What you need to know Sepsis is defined as life threatening organ dysfunction caused by a dysregulated host response to infection.1 In 2016, the National Institute for Health and Care Excellence (NICE) first published guidance on recognising, diagnosing, and managing suspected sepsis. In May 2022, a statement published by the Academy of Medical Royal Colleges2 (and endorsed by NHS England) on use of the updated National Early Warning Score (NEWS2)3 sought to guide the urgency of antibiotic prescribing and source control. The statement was based on a narrative review of the literature and expert clinical consensus. As a result, in January 2024, NICE guidance was updated to include NEWS2 for stratifying risk of severe illness or death from sepsis.4 The updated guideline aims to ensure that early recognition of patient deterioration and treatment for sepsis becomes standardised nationally, and includes recommendations on the timing of antibiotic prescribing based on a person's risk level, while investigating the underlying infection source. NICE recommendations are based on systematic reviews of best available evidence and explicit consideration of cost effectiveness. When minimal evidence is available, recommendations are based on the guideline committee's expertise and opinion of what constitutes good practice. A subsequent consultation process with stakeholder bodies provides external confirmation. Evidence levels for the recommendations are given in italic in square brackets. ### GRADE Working Group grades of evidence
Nicotinamide metabolism face-off between macrophages and fibroblasts manipulates the microenvironment in gastric cancer
Authors: Yu Jiang, Yawen Wang, Guofeng Chen, Fei Sun, Qijing Wu, Qiong Huang, Dongqiang Zeng, Wenjun Qiu, Jiao Wang, Zhiqi Yao, Bishan Liang, Shaowei Li, Jianhua Wu, Na Huang, Yuanyuan Wang, Jingsong Chen, Xiaohui Zhai, Li Huang, Beibei Xu, Masami Yamamoto, Tetsuya Tsukamoto, Sachiyo Nomura, Wangjun Liao, Min Shi
Journal: Cell Metabolism (2024)

Immune checkpoint blockade has led to breakthroughs in the treatment of advanced gastric cancer. However, the prominent heterogeneity in gastric cancer, notably the heterogeneity of the tumor microenvironment, highlights the idea that the antitumor response is a reflection of multifactorial interactions. Through transcriptomic analysis and dynamic plasma sample analysis, we identified a metabolic "face-off" mechanism within the tumor microenvironment, as shown by the dual prognostic significance of nicotinamide metabolism. Specifically, macrophages and fibroblasts expressing the rate-limiting enzymes nicotinamide phosphoribosyltransferase and nicotinamide N-methyltransferase, respectively, regulate the nicotinamide/1-methylnicotinamide ratio and CD8
Head movement dynamics in dystonia: a multi-centre retrospective study using visual perceptive deep learning
Authors: Robert Peach, Maximilian Friedrich, Lara Fronemann, Muthuraman Muthuraman, Sebastian R. Schreglmann, Daniel Zeller, Christoph Schrader, Joachim K. Krauss, Alfons Schnitzler, Matthias Wittstock, Ann-Kristin Helmers, Steffen Paschen, Andrea Kühn, Inger Marie Skogseid, Wilhelm Eisner, Joerg Mueller, Cordula Matthies, Martin Reich, Jens Volkmann, Chi Wang Ip
Journal: npj Digital Medicine (2024)

Abstract Dystonia is a neurological movement disorder characterised by abnormal involuntary movements and postures, particularly affecting the head and neck. However, current clinical assessment methods for dystonia rely on simplified rating scales which lack the ability to capture the intricate spatiotemporal features of dystonic phenomena, hindering clinical management and limiting understanding of the underlying neurobiology. To address this, we developed a visual perceptive deep learning framework that utilizes standard clinical videos to comprehensively evaluate and quantify disease states and the impact of therapeutic interventions, specifically deep brain stimulation. This framework overcomes the limitations of traditional rating scales and offers an efficient and accurate method that is rater-independent for evaluating and monitoring dystonia patients. To evaluate the framework, we leveraged semi-standardized clinical video data collected in three retrospective, longitudinal cohort studies across seven academic centres. We extracted static head angle excursions for clinical validation and derived kinematic variables reflecting naturalistic head dynamics to predict dystonia severity, subtype, and neuromodulation effects. The framework was also applied to a fully independent cohort of generalised dystonia patients for comparison between dystonia sub-types. Computer vision-derived measurements of head angle excursions showed a strong correlation with clinically assigned scores. Across comparisons, we identified consistent kinematic features from full video assessments encoding information critical to disease severity, subtype, and effects of neural circuit interventions, independent of static head angle deviations used in scoring. Our visual perceptive machine learning framework reveals kinematic pathosignatures of dystonia, potentially augmenting clinical management, facilitating scientific translation, and informing personalized precision neurology approaches.
Pathogen‐Mimicking Nanoparticles Based on Rigid Nanomaterials as an Efficient Subunit Vaccine Delivery System for Intranasal Immunization
Authors: Hongping Wan, Kai Deng, Zhengqun Huang, Yunhan Yang, Bo Jing, Yumei Feng, Yuanfeng Li, Yong Liu, Mingqin Lu, Xinghong Zhao
Journal: Advanced Healthcare Materials (2024)

Despite the safety profile of subunit vaccines, the inferior immunogenicity hinders their application in the nasal cavity. This study introduces a novel antigen delivery and adjuvant system utilizing mucoadhesive chitosan-catechol (Chic) on silica spiky nanoparticles (Ssp) to enhance immunity through multiple mechanisms. The Chic functionalizes the Ssp surface and incorporates with SARS-CoV-2 spike protein receptor-binding domain (RBD) and toll-like receptor (TLR)9 agonist unmethylated cytosine-guanine (CpG) motif, forming uniform virus-like nanoparticles (Ssp-Chic-RBD-CpG) via electrostatic and covalent interactions. Ssp-Chic-RBD-CpG, mimicking the morphology and function of inactive virions, effectively prolongs the retention time of RBD in the nasal mucosa by 3.92-fold compared to RBD alone, enhances the maturation of dendritic cells (DCs), and facilitates the antigen trafficking to the draining lymph nodes, which subsequently induces a stronger mucosal immunity. Mechanistically, the enhanced chemokine chemokine (C-C motif) ligand 20 (CCL20)-driven DCs recruitment and maturation by Ssp-Chic-RBD-CpG are evidenced by a cell co-culture model. In addition, the overexpression of TLR4/9 and activation of MYD88/NF-κB signaling pathway in activation of DCs are observed. Proof of principle is obtained for RBD, but similar delivery mechanisms can be applied in other protein-based subunit vaccines as well when intranasal administration is needed.
Linda-Gail Bekker: Mentorship is critical for anyone in STEM
Authors: Lucie Van Emmenis
Journal: The Journal of Experimental Medicine (2024)

Linda-Gail Bekker is a professor, chief executive officer of the Desmond Tutu HIV Foundation, and director of the Desmond Tutu HIV Centre at the Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa. Her research interests include HIV treatment and prevention and tuberculosis, and she is active in developing community projects to promote education and research. We talked to Linda-Gail about her career, the importance of mentorship, and how rewarding it is to collaborate, mentor, and uplift other scientists.
Clonal evolution and blastic plasmacytoid dendritic cell neoplasm: malignancies of divergent hematopoietic lineages emerging from a common founding clone
Authors: Svenja Denker, Axel Künstner, Julian Schwarting, Hanno M. Witte, Veronica Bernard, Stephanie Stölting, Philipp Lohneis, Kathrin Kusch, Nikolas von Bubnoff, Hartmut Merz, Hauke Busch, Alfred C. Feller, Niklas Gebauer
Journal: Leukemia (2024)
Genomic, molecular, and cellular divergence of the human brain
Authors: Ralda Nehme, Olli Pietiläinen, Lindy E. Barrett
Journal: Trends in Neurosciences (2024)

While many core biological processes are conserved across species, the human brain has evolved with unique capacities. Current understanding of the neurobiological mechanisms that endow human traits as well as associated vulnerabilities remains limited. However, emerging data have illuminated species divergence in DNA elements and genome organization, in molecular, morphological, and functional features of conserved neural cell types, as well as temporal differences in brain development. Here, we summarize recent data on unique features of the human brain and their complex implications for the study and treatment of brain diseases. We also consider key outstanding questions in the field and discuss the technologies and foundational knowledge that will be required to accelerate understanding of human neurobiology.
Political courage needed to prevent the next pandemic
Authors: Helen Clark, Mauricio Cárdenas, Mark Dybul, Michel Kazatchkine, Joanne Liu, Henry E Mark, Rosemary McCarney, Christine McNab, David Miliband, Anders Nordström, Thoraya Ahmed Obaid, Raj Panjabi, Elizabeth Radin, George Werner, Ellen Johnson Sirleaf
Journal: The Lancet (2024)
Digital health technologies need regulation and reimbursement that enable flexible interactions and groupings
Authors: Rebecca Mathias, Peter McCulloch, Anastasia Chalkidou, Stephen Gilbert
Journal: npj Digital Medicine (2024)

Digital Health Technologies (DHTs) are being applied in a widening range of scenarios in medicine. We describe the emerging phenomenon of the grouping of individual DHTs, with a clinical use case and regulatory approval in their own right, into packages to perform specific clinical tasks in defined settings. Example groupings include suites of devices for remote monitoring, or for smart clinics. In this first article of a two-article series, we describe challenges in implementation and limitations in frameworks for the regulation, health technology assessment, and reimbursement of these device suites and linked novel care pathways.