tbuckley/cabot-search huggingface dataset:
Intergenerational and genetic influences on physical activity: family data from the HUNT study, Norway
Authors: Mats Flaaten, Eivind Schjelderup Skarpsno, Atle Kongsvold, Bjørn Olav Åsvold, David Carslake, Paul Jarle Mork, Tom Ivar Lund Nilsen
Journal: British Journal of Sports Medicine (2024)

Objectives The objectives of this study are to examine the association of physical activity in parents with physical activity in their adult offspring and explore if the offspring’s genetic liability (ie, polygenic risk score) to physical activity influences this association. Methods The Trøndelag Health Study cohort is a population-based longitudinal study with data collected in 1984–1986, 1995–1997, 2006–2008 and 2017–2019. We calculated the odds ratio for being physically active and mean difference in physical activity levels according to parental physical activity (device-measured and self-reported) and own polygenic risk score. Results Compared with offspring with mothers in the lowest third of metabolic equivalent of task (MET)-min/day accumulated by vigorous physical activities, offspring with mothers in the upper third had an OR of 1.93 (95% CI 1.65 to 2.27) for accumulating ≥900 MET-min/week of vigorous physical activity. The OR for the corresponding father–offspring association was 1.78 (95% CI 1.48 to 2.14). Compared with offspring of parents not accumulating ≥900 MET-min/week, we found an OR of 1.89 (95% CI 1.45 to 2.44) for offspring to meet the same threshold if both parents accumulated ≥900 MET-min/week. Offspring with higher polygenic risk score to bephysically active and having physically active parents did more weekly physical activity, but we found no strong evidence of multiplicative synergistic effects between these two factors (all p values ≥0.01). Conclusion Both parental physical activity and offspring’s polygenic risk score were positively associated with physical activity levels in the adult offspring, but there was no evidence of effect modification between these factors. A family-based approach to promote physical activity may be effective from a public health perspective.
TCR-Engineered T Cells Directed against Ropporin-1 Constitute a Safe and Effective Treatment for Triple-Negative Breast Cancer
Authors: Dian Kortleve, Dora Hammerl, Mandy van Brakel, Rebecca Wijers, Daphne Roelofs, Kim Kroese, Mieke M. Timmermans, Chen-Yi Liao, Shaozhuo Huang, Anita Trapman-Jansen, Renée Foekens, Justine Michaux, Monique T.A. de Beijer, Sonja I. Buschow, Jeroen A.A. Demmers, Marleen Kok, Erik H.J. Danen, Michal Bassani-Sternberg, John W.M. Martens, Rachel J.M. Abbott, Reno Debets
Journal: Cancer Discovery (2024)

Abstract Triple-negative breast cancer (TNBC) has an urgent need for new therapies. We discovered Ropporin-1 (ROPN1) as a target to treat TNBC with T cells. ROPN1 showed high and homogenous expression in 90% of primary and metastatic TNBC but not in healthy tissues. Human leukocyte antigen-A2-binding peptides were detected via immunopeptidomics and predictions and used to retrieve T-cell receptors (TCR) from naïve repertoires. Following gene introduction into T cells and stringent selection, we retrieved a highly specific TCR directed against the epitope FLYTYIAKV that did not recognize noncognate epitopes from alternative source proteins. Notably, this TCR-mediated killing of three-dimensional (3D) tumoroids in vitro and tumor cells in vivo and outperformed standard-of-care drugs. Finally, the T-cell product expressing this TCR and manufactured using a clinical protocol fulfilled standard safety and efficacy assays. Collectively, we have identified and preclinically validated ROPN1 as a target and anti-ROPN1 TCR T cells as a treatment for the vast majority of patients with TNBC. Significance: Metastatic TNBC has a dismal prognosis. This study discovers Ropporin-1 as a target for T-cell therapy for most patients. The selected TCR is highly specific and sensitive in advanced models, and preclinical testing shows that the T-cell product expressing this TCR, manufactured according to good manufacturing practice, has favorable safety and potency.
Artificial intelligence applied to ‘omics data in liver disease: towards a personalised approach for diagnosis, prognosis and treatment
Authors: Soumita Ghosh, Xun Zhao, Mouaid Alim, Michael Brudno, Mamatha Bhat
Journal: Gut (2024)

Advancements in omics technologies and artificial intelligence (AI) methodologies are fuelling our progress towards personalised diagnosis, prognosis and treatment strategies in hepatology. This review provides a comprehensive overview of the current landscape of AI methods used for analysis of omics data in liver diseases. We present an overview of the prevalence of different omics levels across various liver diseases, as well as categorise the AI methodology used across the studies. Specifically, we highlight the predominance of transcriptomic and genomic profiling and the relatively sparse exploration of other levels such as the proteome and methylome, which represent untapped potential for novel insights. Publicly available database initiatives such as The Cancer Genome Atlas and The International Cancer Genome Consortium have paved the way for advancements in the diagnosis and treatment of hepatocellular carcinoma. However, the same availability of large omics datasets remains limited for other liver diseases. Furthermore, the application of sophisticated AI methods to handle the complexities of multiomics datasets requires substantial data to train and validate the models and faces challenges in achieving bias-free results with clinical utility. Strategies to address the paucity of data and capitalise on opportunities are discussed. Given the substantial global burden of chronic liver diseases, it is imperative that multicentre collaborations be established to generate large-scale omics data for early disease recognition and intervention. Exploring advanced AI methods is also necessary to maximise the potential of these datasets and improve early detection and personalised treatment strategies.
A 45-Year-Old With Multiple Skin Lesions on Sun-Protected Areas of the Body
Authors: Sheng-Wen Liu, Wei-Ming Wang
Journal: JAMA (2024)

A patient had multiple erythematous macules and patches on the trunk, hyperpigmented patches on the intergluteal cleft and subgluteal fold, and poikiloderma in the axillae; results of laboratory testing, including antinuclear antibody test, were unremarkable. What is the diagnosis and what would you do next?
Organismal metabolism regulates the expansion of oncogenic PIK3CA mutant clones in normal esophagus
Authors: Albert Herms, Bartomeu Colom, Gabriel Piedrafita, Argyro Kalogeropoulou, Ujjwal Banerjee, Charlotte King, Emilie Abby, Kasumi Murai, Irene Caseda, David Fernandez-Antoran, Swee Hoe Ong, Michael W. J. Hall, Christopher Bryant, Roshan K. Sood, Joanna C. Fowler, Albert Pol, Christian Frezza, Bart Vanhaesebroeck, Philip H. Jones
Journal: Nature Genetics (2024)

Oncogenic PIK3CA mutations generate large clones in aging human esophagus. Here we investigate the behavior of Pik3ca mutant clones in the normal esophageal epithelium of transgenic mice. Expression of a heterozygous Pik3ca
Mechanism for controlled assembly of transcriptional condensates by Aire
Authors: Yu-San Huoh, Qianxia Zhang, Ricarda Törner, Sylvan C. Baca, Haribabu Arthanari, Sun Hur
Journal: Nature Immunology (2024)

Abstract Transcriptional condensates play a crucial role in gene expression and regulation, yet their assembly mechanisms remain poorly understood. Here, we report a multi-layered mechanism for condensate assembly by autoimmune regulator (Aire), an essential transcriptional regulator that orchestrates gene expression reprogramming for central T cell tolerance. Aire condensates assemble on enhancers, stimulating local transcriptional activities and connecting disparate inter-chromosomal loci. This functional condensate formation hinges upon the coordination between three Aire domains: polymerization domain caspase activation recruitment domain (CARD), histone-binding domain (first plant homeodomain (PHD1)), and C-terminal tail (CTT). Specifically, CTT binds coactivators CBP/p300, recruiting Aire to CBP/p300-rich enhancers and promoting CARD-mediated condensate assembly. Conversely, PHD1 binds to the ubiquitous histone mark H3K4me0, keeping Aire dispersed throughout the genome until Aire nucleates on enhancers. Our findings showed that the balance between PHD1-mediated suppression and CTT-mediated stimulation of Aire polymerization is crucial to form transcriptionally active condensates at target sites, providing new insights into controlled polymerization of transcriptional regulators.
Tumor editing suppresses innate and adaptive antitumor immunity and is reversed by inhibiting DNA methylation
Authors: Ying Zhang, Pourya Naderi Yeganeh, Haiwei Zhang, Simon Yuan Wang, Zhouyihan Li, Bowen Gu, Dian-Jang Lee, Zhibin Zhang, Athanasios Ploumakis, Ming Shi, Hao Wu, Eric Lieberman Greer, Winston Hide, Judy Lieberman
Journal: Nature Immunology (2024)
A systematic review and meta-analysis of experimental methods for modulating intrusive memories following lab-analogue trauma exposure in non-clinical populations
Authors: Mohith M. Varma, Shengzi Zeng, Laura Singh, Emily A. Holmes, Jingyun Huang, Man Hey Chiu, Xiaoqing Hu
Journal: Nature Human Behaviour (2024)

Experiencing trauma leads to intrusive memories (IMs), a hallmark symptom of post-traumatic stress disorder (PTSD), which also occurs transdiagnostically. Understanding why IMs increase or decrease is pivotal in developing interventions to support mental health. In this preregistered meta-analysis (PROSPERO: CRD42021224835), we included 134 articles (131 techniques, 606 effect sizes and 12,074 non-clinical participants) to investigate how experimental techniques alter IM frequency, intrusion-related distress and symptoms arising from lab-analogue trauma exposure. Eligible articles were identified by searching eight databases until 12 December 2023. To test potential publication biases, we employed methods including Egger's test and three-parameter selection models. We employed three-level multilevel modelling and meta-regressions to examine whether and how experimental techniques would modulate IM frequency and associated outcomes. Results showed that techniques (behavioural, pharmacological, neuromodulation) significantly reduced intrusion frequency (g = 0.16, 95% confidence interval [0.09, 0.23]). Notably, techniques aimed to reduce IMs also ameliorated intrusion-related distress and symptoms, while techniques that increased IMs exacerbated these related outcomes, thus highlighting IM's centrality in PTSD-like symptoms. Techniques tapping into mental imagery processing (for example, trauma reminder followed by playing Tetris) reduced intrusions when administered immediately after, or at a delayed time after trauma. Although our meta-analysis is limited to symptoms induced by lab-analogue trauma exposure, some lab-based results have now generalized to real-world trauma and IMs, highlighting the promising utility of lab-analogue trauma paradigms for intervention development. Intrusive memories are a hallmark symptom of post-traumatic stress disorder (PTSD). This preregistered meta-analysis investigates how experimental techniques alter intrusive memory frequency, intrusion-related distress and symptoms arising from lab-analogue trauma exposure.
Effects of pregnancy and lactation prebiotics supplementation on infant allergic disease: a randomized controlled trial.
Authors: Debra J Palmer, Alana R Cuthbert, Thomas R Sullivan, Rachelle A Pretorius, Johan Garssen, Kristina Rueter, Maria C Jenmalm, Jeffrey A Keelan, Desiree Silva, Susan L Prescott
Journal: Journal of Allergy and Clinical Immunology (2024)

Ingestion of prebiotics during pregnancy and lactation may have immunomodulatory benefits for the developing fetal and infant immune system and provide a potential dietary strategy to reduce the risk of allergic diseases.
Influenza Vaccine Effectiveness and Progress Towards a Universal Influenza Vaccine
Authors: Benjamin J. Cowling, George N. Okoli
Journal: Drugs (2024)

At various times in recent decades, surges have occurred in optimism about the potential for universal influenza vaccines that provide strong, broad, and long-lasting protection and could substantially reduce the disease burden associated with seasonal influenza epidemics as well as the threat posed by pandemic influenza. Each year more than 500 million doses of seasonal influenza vaccine are administered around the world, with most doses being egg-grown inactivated subunit or split-virion vaccines. These vaccines tend to have moderate effectiveness against medically attended influenza for influenza A(H1N1) and influenza B, and somewhat lower for influenza A(H3N2) where differences between vaccine strains and circulating strains can occur more frequently due to antigenic drift and egg adaptations in the vaccine strains. Several enhanced influenza vaccine platforms have been developed including cell-grown antigen, the inclusion of adjuvants, or higher antigen doses, to improve immunogenicity and protection. During the COVID-19 pandemic there was unprecedented speed in development and roll-out of relatively new vaccine platforms, including mRNA vaccines and viral vector vaccines. These new platforms present opportunities to improve protection for influenza beyond existing products. Other approaches continue to be explored. Incremental improvements in influenza vaccine performance should be achievable in the short to medium term.
The treatment of latent tuberculosis infection in migrants in primary care<i>versus</i>secondary care
Authors: Matthew Burman, Dominik Zenner, Andrew J. Copas, Lara Goscé, Hassan Haghparast-Bidgoli, Peter J. White, Vicky Hickson, Opal Greyson, Duncan Trathen, Richard Ashcroft, Adrian R. Martineau, Ibrahim Abubakar, Christopher J. Griffiths, Heinke Kunst
Journal: European Respiratory Journal (2024)

Background Control of latent tuberculosis infection (LTBI) is a priority in the World Health Organization strategy to eliminate TB. Many high-income, low TB incidence countries have prioritised LTBI screening and treatment in recent migrants. We tested whether a novel model of care, based entirely within primary care, was effective and safe compared to secondary care. Methods This was a pragmatic cluster-randomised, parallel group, superiority trial ( ClinicalTrials.gov : NCT03069807 ) conducted in 34 general practices in London, UK, comparing LTBI treatment in recent migrants in primary care to secondary care. The primary outcome was treatment completion, defined as taking ≥90% of antibiotic doses. Secondary outcomes included treatment acceptance, adherence, adverse effects, patient satisfaction, TB incidence and a cost-effectiveness analysis. Analyses were performed on an intention-to-treat basis. Results Between September 2016 and May 2019, 362 recent migrants with LTBI were offered treatment and 276 accepted. Treatment completion was similar in primary and secondary care (82.6% versus 86.0%; adjusted OR (aOR) 0.64, 95% CI 0.31–1.29). There was no difference in drug-induced liver injury between primary and secondary care (0.7% versus 2.3%; aOR 0.29, 95% CI 0.03–2.84). Treatment acceptance was lower in primary care (65.2% (146/224) versus 94.2% (130/138); aOR 0.10, 95% CI 0.03–0.30). The estimated cost per patient completing treatment was lower in primary care, with an incremental saving of GBP 315.27 (95% CI 313.47–317.07). Conclusions The treatment of LTBI in recent migrants within primary care does not result in higher rates of treatment completion but is safe and costs less when compared to secondary care.
Optimal prognostic threshold for measurable residual disease positivity by multiparameter flow cytometry in acute myeloid leukemia (AML)
Authors: Eduardo Rodríguez-Arbolí, Megan Othus, Sylvie D. Freeman, Francesco Buccisano, Lok Lam Ngai, Ian Thomas, Raffaele Palmieri, Jacqueline Cloos, Sean Johnson, Elisa Meddi, Nigel H. Russell, Adriano Venditti, Patrycja Gradowska, Gert J. Ossenkoppele, Bob Löwenberg, Roland B. Walter
Journal: Leukemia (2024)
Making pandemic planning part of the everyday
Authors: Christina Pagel
Journal: BMJ (2024)

professor of operational researchThe UK Covid-19 inquiry's module 1 report on the resilience and preparedness of the UK had "no hesitation in concluding that the processes, planning and policy of the civil contingency structures within the UK government and devolved administrations and civil services failed their citizens." 1It calls for a "fundamental reform" of the way in which the UK plans for future emergencies.
Regulated and adaptive in vivo insulin secretion from islets only containing β-cells
Authors: Marta Perez-Frances, Eva Bru-Tari, Christian Cohrs, Maria Valentina Abate, Léon van Gurp, Kenichiro Furuyama, Stephan Speier, Fabrizio Thorel, Pedro L. Herrera
Journal: Nature Metabolism (2024)

Insulin-producing β-cells in pancreatic islets are regulated by systemic cues and, locally, by adjacent islet hormone-producing 'non-β-cells' (namely α-cells, δ-cells and γ-cells). Yet whether the non-β-cells are required for accurate insulin secretion is unclear. Here, we studied mice in which adult islets are exclusively composed of β-cells and human pseudoislets containing only primary β-cells. Mice lacking non-β-cells had optimal blood glucose regulation, enhanced glucose tolerance, insulin sensitivity and restricted body weight gain under a high-fat diet. The insulin secretion dynamics in islets composed of only β-cells was comparable to that in intact islets. Similarly, human β-cell pseudoislets retained the glucose-regulated mitochondrial respiration, insulin secretion and exendin-4 responses of entire islets. The findings indicate that non-β-cells are dispensable for blood glucose homeostasis and β-cell function. These results support efforts aimed at developing diabetes treatments by generating β-like clusters devoid of non-β-cells, such as from pluripotent stem cells differentiated in vitro or by reprograming non-β-cells into insulin producers in situ. Pancreatic islet β-cells can regulate insulin secretion in vivo, even in the absence of non-β-cells.
Pharmacological and pre-clinical safety profile of rSIV.F/HN, a hybrid lentiviral vector for cystic fibrosis gene therapy
Authors: Alena Moiseenko, Anthony Sinadinos, Ana Sergijenko, Kyriel Pineault, Aarash Saleh, Konradin Nekola, Nathalie Strang, Anastasia Eleftheraki, A Christopher Boyd, Jane C Davies, Deborah R Gill, Stephen C Hyde, Gerry McLachlan, Tim Rath, Michael Rothe, Axel Schambach, Silke Hobbie, Michael Schuler, Udo Maier, Matthew J Thomas, Detlev Mennerich, Manfred Schmidt, Uta Griesenbach, Eric W F W Alton, Sebastian Kreuz
Journal: European Respiratory Journal (2024)

Rationale and Objective Cystic fibrosis (CF) is caused by mutations in the CF Transmembrane Conductance Regulator (CFTR) gene. CFTR modulators offer significant improvements, but approximately 10% of patients remain nonresponsive or are intolerant. This study provides an analysis of rSIV.F/HN, a lentiviral vector optimized for lung delivery, including CFTR protein expression, functional correction of CFTR defects and genomic integration site analysis in preparation for a first-in-human clinical trial. Methods Air-liquid interface cultures of primary human bronchial epithelial cells (HBEC) from CF patients (F508del/F508del), as well as a CFTR-deficient immortalized human lung epithelial cell line mimicking Class I (CFTR-null) homozygous mutations, were used to assess transduction efficiency. Quantification methods included a novel proximity ligation assay (PLA) for CFTR protein expression. For assessment of CFTR channel activity, Ussing chamber studies were conducted. The safety profile was assessed using integration site analysis and in vitro insertional mutagenesis studies. Results rSIV.F/HN expressed CFTR and restored CFTR-mediated chloride currents to physiological levels in primary F508del/F508del HBECs as well as in a Class I cells. In contrast, the latter could not be achieved by small-molecule CFTR modulators, underscoring the potential of gene therapy for this mutation class. Combination of rSIV.F/HN-CFTR with the potentiator ivacaftor showed a greater than additive effect. The genomic integration pattern showed no site predominance (frequency of occurrence ≤10%), and a low risk of insertional mutagenesis was observed in an in vitro immortalization assay. Conclusions The results underscore rSIV.F/HN as a promising gene therapy vector for CF, providing a mutation-agnostic treatment option.
FDA launches health care at home initiative to drive equity in digital medical care
Authors: Stefanie Brückner, Celia Brightwell, Stephen Gilbert
Journal: npj Digital Medicine (2024)

A highly ambitious FDA initiative will explore, through a hub and ideas lab, how equitable healthcare at home can be delivered, recognizing that this is unlikely to come about without intervention. Market forces, as shaped by current regulations, are leading to digital health tools developed and operating in islands rather than enabling integrated digital care. Can the initiative, which adopts system-level regulatory thinking, solve this issue?
Reassessing Halm's clinical stability criteria in community-acquired pneumonia management
Authors: Simone Bastrup Israelsen, Markus Fally, Pernille Brok Nielsen, Lilian Kolte, Kasper Karmark Iversen, Pernille Ravn, Thomas Benfield
Journal: European Respiratory Journal (2024)

Background Halm's clinical stability criteria have long guided antibiotic treatment and hospital discharge decisions for patients hospitalised with community-acquired pneumonia (CAP). Originally introduced in 1998, these criteria were established based on a relatively small and select patient population. Consequently, our study aims to reassess their applicability in the management of CAP in a contemporary real-world setting. Methods This cohort study included 2918 immunocompetent patients hospitalised with CAP from three hospitals in Denmark between 2017 and 2020. The primary outcome was time to achieve clinical stability as defined by Halm's criteria. Additionally, we examined recurrence of clinical instability and severe complications. Cumulative incidence function or Kaplan–Meier survival curves were used to analyse these outcomes, considering competing risks. Results The study population primarily comprised elderly individuals (median age 75 years) with significant comorbidities. The median time to clinical stability according to Halm's criteria was 4 days, with one-fifth experiencing recurrence of instability after early clinical response (stability within 3 days). Severe complications within 30 days mainly comprised mortality, with rates of 5.1% (64/1257) overall in those with early clinical response, 1.7% (18/1045) in the subgroup without do-not-resuscitate orders and 17.3% (276/1595) among the rest. Conclusion Halm's clinical stability criteria effectively classify CAP patients with different disease courses, yet achieving stability required more time in this ageing population with substantial comorbidities and more severe disease. Early clinical response indicates reduced risk of complications, especially in those without do-not-resuscitate orders.