tbuckley/cabot-search huggingface dataset:
Elucidating the genomic basis of rare pediatric neurological diseases in Central Asia and Transcaucasia
Authors: Rauan Kaiyrzhanov, Nazira Zharkinbekova, Ulviyya Guliyeva, Manizha Ganieva, Zaruhi Tavadyan, Tamar Gachechiladze, Kamran Salayev, Sughra Guliyeva, Mariam Isayan, Mariam Kekenadze, Biayna Sukhudyan, Ani Gevorgyan, Artsruni Hakobyan, Rima Ibadova, Nazi Tabatadze, Ekaterina Kurua, Teona Shatirishvili, Nigara Yerkhojayeva, Kairgali Koneev, Dauren Zhumakhanov, Askhat Mukushev, Altynshash Jaxybayeva, Alissa Nauryzbayeva, Maksudjon Isrofilov, Saadat Badalova, Naila Zeyniyeva, Ilaha Hajiyeva, Leyla Alakbarov, Aynur Zeynalova, Viorica Chelban, Jana Vandrovcova, Valentina Turchetti, David Murphy, Stephanie Efthymiou, Shahryar Alavi, Rahema Mohammad, Tinatin Tkemaladze, Chingiz Shashkin, Nana Nino Tatishvili, Maia Beridze, Samson G. Khachatryan, Gia Melikishvili, John Hardy, Reza Maroofian, Henry Houlden
Journal: Nature Genetics (2024)
Spatial and single-nucleus transcriptomic analysis of genetic and sporadic forms of Alzheimer’s disease
Authors: Emily Miyoshi, Samuel Morabito, Caden M. Henningfield, Sudeshna Das, Negin Rahimzadeh, Sepideh Kiani Shabestari, Neethu Michael, Nora Emerson, Fairlie Reese, Zechuan Shi, Zhenkun Cao, Shushrruth Sai Srinivasan, Vanessa M. Scarfone, Miguel A. Arreola, Jackie Lu, Sierra Wright, Justine Silva, Kelsey Leavy, Ira T. Lott, Eric Doran, William H. Yong, Saba Shahin, Mari Perez-Rosendahl, Elizabeth Head, Kim N. Green, Vivek Swarup
Journal: Nature Genetics (2024)

Abstract The pathogenesis of Alzheimer’s disease (AD) depends on environmental and heritable factors, with its molecular etiology still unclear. Here we present a spatial transcriptomic (ST) and single-nucleus transcriptomic survey of late-onset sporadic AD and AD in Down syndrome (DSAD). Studying DSAD provides an opportunity to enhance our understanding of the AD transcriptome, potentially bridging the gap between genetic mouse models and sporadic AD. We identified transcriptomic changes that may underlie cortical layer-preferential pathology accumulation. Spatial co-expression network analyses revealed transient and regionally restricted disease processes, including a glial inflammatory program dysregulated in upper cortical layers and implicated in AD genetic risk and amyloid-associated processes. Cell–cell communication analysis further contextualized this gene program in dysregulated signaling networks. Finally, we generated ST data from an amyloid AD mouse model to identify cross-species amyloid-proximal transcriptomic changes with conformational context.
Optimization of the activity and biodegradability of ionizable lipids for mRNA delivery via directed chemical evolution
Authors: Xuexiang Han, Mohamad-Gabriel Alameh, Ying Xu, Rohan Palanki, Rakan El-Mayta, Garima Dwivedi, Kelsey L. Swingle, Junchao Xu, Ningqiang Gong, Lulu Xue, Qiangqiang Shi, Il-Chul Yoon, Claude C. Warzecha, James M. Wilson, Drew Weissman, Michael J. Mitchell
Journal: Nature Biomedical Engineering (2024)
Mapping in silico genetic networks of the KMT2D tumour suppressor gene to uncover novel functional associations and cancer cell vulnerabilities
Authors: Yuka Takemon, Erin D. Pleasance, Alessia Gagliardi, Christopher S. Hughes, Veronika Csizmok, Kathleen Wee, Diane L. Trinh, Ryan D. Huff, Andrew J. Mungall, Richard A. Moore, Eric Chuah, Karen L. Mungall, Eleanor Lewis, Jessica Nelson, Howard J. Lim, Daniel J. Renouf, Steven JM. Jones, Janessa Laskin, Marco A. Marra
Journal: Genome Medicine (2024)

Abstract Background Loss-of-function (LOF) alterations in tumour suppressor genes cannot be directly targeted. Approaches characterising gene function and vulnerabilities conferred by such mutations are required. Methods Here, we computationally map genetic networks of KMT2D , a tumour suppressor gene frequently mutated in several cancer types. Using KMT2D loss-of-function ( KMT2D LOF ) mutations as a model, we illustrate the utility of in silico genetic networks in uncovering novel functional associations and vulnerabilities in cancer cells with LOF alterations affecting tumour suppressor genes. Results We revealed genetic interactors with functions in histone modification, metabolism, and immune response and synthetic lethal (SL) candidates, including some encoding existing therapeutic targets. Notably, we predicted WRN as a novel SL interactor and, using recently available WRN inhibitor (HRO761 and VVD-133214) treatment response data, we observed that KMT2D mutational status significantly distinguishes treatment-sensitive MSI cell lines from treatment-insensitive MSI cell lines. Conclusions Our study thus illustrates how tumour suppressor gene LOF alterations can be exploited to reveal potentially targetable cancer cell vulnerabilities.
Epigenetic age and long-term cancer risk following a stroke
Authors: Antoni Suárez-Pérez, Adrià Macias-Gómez, Isabel Fernández-Pérez, Marta Vallverdú-Prats, Elisa Cuadrado-Godia, Eva Giralt-Steinhauer, Maia Campanale, Daniel Guisado-Alonso, Ana Rodríguez-Campello, Joan Jiménez-Balado, Jordi Jiménez-Conde, Angel Ois
Journal: Genome Medicine (2024)

The association between increased cancer risk following a cerebrovascular event (CVE) has been previously reported. We hypothesize that biological age (B-age) acceleration is involved in this association. Our study aims to examine B-age as a novel contributing factor to cancer development post-CVE. From our prospective stroke registry (BasicMar), we selected 940 cases with epigenetic data. For this study, we specifically analyzed 648 of these patients who had available data, no prior history of cancer, and a minimum follow-up of 3 months. The primary outcome was cancer incidence. B-age was estimated using DNA methylation data derived from whole blood samples obtained within 24 h of stroke onset, employing various epigenetic clocks (including Hannum, Horvath, PhenoAge, ZhangBLUP, ZhangEN, and the mitotic epiTOC). Extrinsic epigenetic age acceleration (EEAA) was calculated as the residuals from the regression of B-age against chronological age (C-age). For epiTOC, the age-adjusted values were obtained by regressing out the effect of age from the raw epiTOC measurements. Estimated white cell counts were derived from DNA methylation data, and these cell fractions were used to compute the intrinsic epigenetic age acceleration (IEAA). Subsequently, we evaluated the independent association between EEAA, IEAA, and cancer incidence while controlling for potential confounding variables. Among 648 patients with a median follow-up of 8.15 years, 83 (12.8%) developed cancer. Cox multivariable analyses indicated significant associations between Hannum, Zhang, and epiTOC EEAA and the risk of cancer after CVE. After adjusting for multiple testing and competing risks, EEAA measured by Hannum clock maintained an independent association with cancer risk. Specifically, for each year increase in Hannum's EEAA, we observed a 6.0% increased incidence of cancer (HR 1.06 [1.02–1.10], p value = 0.002). Our findings suggest that epigenetic accelerated aging, as indicated by Hannum's EEAA, may play a significant role in the increased cancer risk observed in CVE survivors.
Agile, on-demand wastewater surveillance of virus infections to support pandemic and outbreak response in Rotterdam-Rijnmond, the Netherlands, 2020 to 2022
Authors: Emma Besijn, Jane Whelan, Paul Bijkerk, Gregorius J Sips, Jeroen Langeveld, Ray W Izquierdo-Lara, Elvira van Baarle, Remy Schilperoort, Marion P G Koopmans, Miranda de Graaf, Gertjan Medema, Ewout Fanoy
Journal: Eurosurveillance (2024)

Background Wastewater surveillance may support early and comprehensive detection of infectious diseases’ community transmission, particularly in settings where other health surveillance systems provide biased or limited information. Amid the SARS-CoV-2 pandemic, deploying passive samplers to monitor targeted populations gained importance. Evaluation of the added public health value of this approach in the field can support its broader adoption. Aim We aimed to assess the feasibility and utility of on-demand wastewater surveillance, employing passive samplers, for SARS-CoV-2 and monkeypox virus (MPXV) in small/targeted populations, also considering ethical aspects. Methods Pilot case studies in the Rotterdam-Rijnmond region were used for a systematic assessment of the feasibility and utility of wastewater monitoring of SARS-CoV-2 (variants) and MPXV using passive sampling. Each case study was instigated by actual questions from the Public Health Service about disease transmission. Results Case study results demonstrated the feasibility and utility of on-demand wastewater surveillance with successful identification of a local peak in SARS-CoV-2 transmission, early detection of wider Omicron variant transmission after the first case was reported, as well as indication of no emerging local MPXV transmission. Ethical considerations led to the abandonment of one case study involving a displaced population. Conclusions The study confirms the feasibility and utility of passive sampling for real-time infectious disease surveillance, at desired spatiotemporal resolution. Ethical concerns and operational challenges were identified, highlighting the need for early stakeholder engagement and ethical guideline adherence. The method could be used to study under-surveyed populations and be extended beyond SARS-CoV-2 and MPXV to other pathogens.
Escherichia coli from six European countries reveals differences in profile and distribution of critical antimicrobial resistance determinants within One Health compartments, 2013 to 2020
Authors: Håkon P Kaspersen, Michael SM Brouwer, Javier Nunez-Garcia, Ingrid Cárdenas-Rey, Manal AbuOun, Nicholas Duggett, Nicholas Ellaby, Jose Delgado-Blas, Jens A Hammerl, Maria Getino, Carlos Serna, Thierry Naas, Kees T Veldman, Alex Bossers, Marianne Sunde, Solveig S Mo, Silje B Jørgensen, Matthew Ellington, Bruno Gonzalez-Zorn, Roberto La Ragione, Philippe Glaser, Muna F Anjum
Journal: Eurosurveillance (2024)

Background Antimicrobial resistance (AMR) is a global threat. Monitoring using an integrated One Health approach is essential to detect changes in AMR occurrence. Aim We aimed to detect AMR genes in pathogenic and commensal Escherichia coli collected 2013–2020 within monitoring programmes and research from food animals, food (fresh retail raw meat) and humans in six European countries, to compare vertical and horizontal transmission. Methods We whole genome sequenced (WGS) 3,745 E. coli isolates , detected AMR genes using ResFinder and performed phylogenetic analysis to determine isolate relatedness and transmission. A BLASTn-based bioinformatic method compared draft IncI1 genomes to conserved plasmid references from Europe. Results Resistance genes to medically important antimicrobials (MIA) such as extended-spectrum cephalosporins (ESC) were widespread but predicted resistance to MIAs authorised for human use (carbapenem, tigecycline) was detected only in two human and three cattle isolates. Phylogenetic analysis clustered E. coli according to phylogroups; commensal animal isolates showed greater diversity than those from human patients. Only 18 vertical animal-food and human-animal transmission events of E. coli clones were detected. However, IncI1 plasmids from different sources and/or countries carrying resistance to ESCs were conserved and widely distributed, although these variants were rarely detected in human pathogens. Conclusion Using WGS we demonstrated AMR is driven vertically and horizontally. Human clinical isolates were more closely related, but their IncI1 plasmids were more diverse, while animal or food isolates were less similar with more conserved IncI1 plasmids. These differences likely arose from variations in selective pressure, influencing AMR evolution and transmission.
Genomic surveillance detects interregional spread of New Delhi metallo-beta-lactamase-1-producing Providencia stuartii in hospitals, Romania, December 2021 to September 2023
Authors: Marius Linkevicius, Sandra Witteveen, Mariana Buzea, Mirela Flonta, Marina Indreas, Maria Nica, Edit Székely, Daniela Tălăpan, Olov Svartström, Erik Alm, Daniel Palm, Dominique L Monnet, Antoni PA Hendrickx, Anke Kohlenberg, Gabriel Adrian Popescu
Journal: Eurosurveillance (2024)

Background New Delhi metallo-beta-lactamase (NDM)-producing Providencia stuartii has been reported from European Union/European Economic Area (EU/EEA) countries with increasing frequency. During 2018 to 2022, 355 cases of NDM-producing P. stuartii were detected in seven hospitals reporting on NDM-production in Enterobacterales in Romania. Aim Our aim was to determine the extent of spread of NDM-producing P. stuartii in hospitals in Romania. Methods We analysed whole genome sequences and epidemiological data of 74 P. stuartii isolates collected in six hospitals from December 2021 to September 2023. Results We identified four multi-hospital clusters including isolates detected over more than a year, indicating sustained spread of bla NDM-1 -carrying P. stuartii within the healthcare system. These clusters consisted of isolates from up to four hospitals and three regions. Three multi-hospital clusters were caused by a specific multidrug-resistant P. stuartii sequence type 46 lineage carrying bla NDM-1 and a large set of additional resistance markers. Investigation in an international context showed that this lineage had already been detected in nine countries (Bulgaria, France, Germany, Ireland, the Netherlands, Romania, Switzerland, United Kingdom, United States) since 2015. Conclusion Our results alert about the risk of carbapenem-resistant P. stuartii transmission in healthcare settings. Enhanced infection prevention and control measures should be instituted as soon as cases are detected in healthcare facilities. National surveillance systems in EU/EEA countries should, in addition to carbapenem-resistant and/or carbapenemase-producing Klebsiella pneumoniae and Escherichia coli , consider reporting carbapenem-resistant and/or carbapenemase-producing P. stuartii and other Enterobacterales where relevant.
Expert consensus on antimicrobial resistance research priorities to focus development and implementation of antibacterial vaccines and monoclonal antibodies
Authors: Nasreen Hassoun-Kheir, Mariana Guedes, Fabiana Arieti, Maria Diletta Pezzani, Beryl Primrose Gladstone, Julie V Robotham, Koen B Pouwels, Rhys Kingston, Yehuda Carmeli, Alessandro Cassini, Michele Cecchini, Francis Drobniewski, Isabel Frost, Jeroen Geurtsen, Andreas Kronenberg, Mila Nu Nu Htay, Mical Paul, Nuno Rocha-Pereira, Jesús Rodríguez-Baño, Luigia Scudeller, Andrew J Stewardson, Evelina Tacconelli, Stephan Harbarth, Venanzio Vella, Marlieke EA de Kraker
Journal: Eurosurveillance (2024)

To reduce antimicrobial resistance (AMR), pathogen-specific AMR burden data are crucial to guide target selection for research and development of vaccines and monoclonal antibodies (mAbs). We identified knowledge gaps through previously conducted systematic reviews, which informed a Delphi expert consultation on future AMR research priorities and harmonisation strategies to support data-driven decision-making. Consensus (≥80% agreement) on importance and feasibility of research topics was achieved in two rounds, involving 24 of 39 and 19 of 24 invited experts, respectively. Priority pathogens and resistance profiles for future research were identified: third generation cephalosporin-resistant Klebsiella pneumoniae and Escherichia coli, for bloodstream and urinary tract infections, respectively, and meticillin-resistant Staphylococcus aureus for surgical-site infections. Prioritised high-risk populations included surgical, haemato-oncological and transplant patients. Mortality and resource use were prioritised as health-economic outcomes. The importance of age-stratified data and inclusion of a non-infected comparator group were highlighted. This agenda provides guidance for future research to fill knowledge gaps and support data-driven selection of target pathogens and populations for new preventive and treatment strategies, specifically vaccines and mAbs, to effectively address the AMR burden in Europe. These research priorities are also relevant to improve the evidence base for future AMR burden estimates.
Autochthonous dengue outbreak in Marche Region, Central Italy, August to October 2024
Authors: Chiara Sacco, Augusto Liverani, Giulietta Venturi, Stefano Gavaudan, Flavia Riccardo, Giovanna Salvoni, Claudia Fortuna, Katia Marinelli, Giulia Marsili, Alessia Pesaresi, Carla Molina Grané, Irene Mercuri, Mattia Manica, Sara Caucci, Daniela Morelli, Lolita Sebastianelli, Maurilia Marcacci, Federica Ferraro, Marco Di Luca, Ilaria Pascucci, Christina Merakou, Anna Duranti, Ilaria Pati, Letizia Lombardini, Daniel Fiacchini, Giorgio Filipponi, Francesco Maraglino, Anna Teresa Palamara, Piero Poletti, Patrizio Pezzotti, Fabio Filippetti, Stefano Merler, Martina Del Manso, Stefano Menzo
Journal: Eurosurveillance (2024)

Between August and 28 October 2024, 199 autochthonous cases of dengue virus serotype 2 were notified in the city of Fano, central Italy. We describe the ongoing epidemiological and microbiological investigation and public health measures implemented to contain the outbreak. The high transmissibility and the extension of the outbreak suggest that dengue should be expected in temperate regions during favourable seasons, highlighting the need for heightened awareness among healthcare providers and the public to ensure timely detection and response.
Emergence of Escherichia coli ST131 carrying carbapenemase genes, European Union/European Economic Area, August 2012 to May 2024
Authors: Anke Kohlenberg, Olov Svartström, Petra Apfalter, Rainer Hartl, Pierre Bogaerts, Te-Din Huang, Katerina Chudejova, Lucia Malisova, Jessica Eisfeld, Mirco Sandfort, Anette M Hammerum, Louise Roer, Kati Räisänen, Laurent Dortet, Rémy A Bonnin, Ákos Tóth, Kinga Tóth, Christina Clarke, Martin Cormican, Algirdas Griškevičius, Kirstin Khonyongwa, Marie Meo, Baiba Niedre-Otomere, Reinis Vangravs, Antoni PA Hendrickx, Daan W Notermans, Ørjan Samuelsen, Manuela Caniça, Vera Manageiro, Vilhelm Müller, Barbro Mäkitalo, Urška Kramar, Mateja Pirs, Daniel Palm, Dominique L Monnet, Erik Alm, Marius Linkevicius
Journal: Eurosurveillance (2024)

Analysis of 594 isolates of Escherichia coli sequence type (ST)131 and its single locus variants carrying carbapenemase genes from 17 European Union/European Economic Area countries revealed acquisition of 18 carbapenemase variants, mainly in ST131 clades A and C. Most frequent were bla OXA-244 (n = 230) and bla OXA-48 (n = 224), detected in 14 and 12 countries, respectively. Isolates carrying bla OXA-244 have increased rapidly since 2021. The increasing detection of carbapenemase genes in the E. coli high-risk lineage ST131 is a public health concern.
‘Antimicrobial resistance is invisible. I am not.’
Authors: Guido Werner, Muna Abu Sin
Journal: Eurosurveillance (2024)

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Experiences of gender-affirming healthcare among transgender and gender diverse (TGD) people during the COVID-19 pandemic: an explanatory sequential mixed methods study
Authors: Ashley Lacombe-Duncan, Kaitrin Doll, Manvinder Gill, Viveka Ichikawa, Suchon Tepjan, Charmaine C. Williams, Notisha Massaquoi, Peter A. Newman
Journal: International Journal of Transgender Health (2024)

Background: Access to timely, gender affirming healthcare (GAH) for transgender and gender diverse (TGD) people is lifesaving. Yet, little is known about the GAH experiences of TGD people during the height of the COVID-19 pandemic. Methods: Utilizing an explanatory sequential mixed methods design, and applying critical transgender and intersectional theories, we examined baseline survey data (n = 44) and follow-up semi-structured interview data (n = 18 qualitative sub-sample from quantitative participants) with a cohort of TGD persons from a COVID-19 eHealth intervention (#SafeHandsSafeHearts) in Toronto, Canada. Results: One-sixth (n = 6/39, 15.4%) of the survey sample reported reduced access to GAH because of COVID-19. Qualitative participants described widespread barriers to access and negative mental health impacts given de-prioritization of TGD health during the pandemic. The cessation of gender affirming surgeries, deemed nonessential, was of greatest concern, along with fear that substantial progress made in improving access to GAH was being unraveled. Nevertheless, community resilience was highlighted through discussion of community support, particularly the development of TGD communities of care to compensate for the lack of institutional support. Despite these struggles, participants embodied trans joy, an act of resistance, refusing to be erased by a system that devalues their healthcare needs. Conclusions: Results inform recommendations for TGD healthcare and improvements that reprioritize TGD community health.
A 3D Pancreatic Cancer Model with Integrated Optical Sensors for Noninvasive Metabolism Monitoring and Drug Screening (Adv. Healthcare Mater. 29/2024)
Authors: Anna Chiara Siciliano, Stefania Forciniti, Valentina Onesto, Helena Iuele, Donatella Delle Cave, Federica Carnevali, Giuseppe Gigli, Enza Lonardo, Loretta L. del Mercato
Journal: Advanced Healthcare Materials (2024)
An Endocellulase‐Triggered NO Targeted‐Release Enzyme‐Prodrug Therapy System and Its Application in Ischemia Injury (Adv. Healthcare Mater. 29/2024)
Authors: Bo He, Yating Zhang, Huaping Liu, Manuel Tang, Ke Yang, Silian Cheng, Jie Shen, Yongzhen Wei, Weiliang Deng, Qiang Zhao, Guang‐Yu Yang
Journal: Advanced Healthcare Materials (2024)
Sintilimab plus decitabine for higher-risk treatment-naïve myelodysplastic syndromes: efficacy, safety, and biomarker analysis of a phase II, single-arm trial
Authors: Jing Wang, Siqi Li, Hao Jiang, Ying-Jun Chang, Xiaosu Zhao, Jinsong Jia, Xiaolu Zhu, Lizhong Gong, Xiaohong Liu, Wenjing Yu, Xiaojun Huang
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Immunotherapy combined with azacitidine was feasible in higher-risk myelodysplastic syndromes (MDSs) with limited sample size of treatment-naïve patients, while the optimization of treatment strategies, including the optimal immune checkpoint inhibitor and hypomethylating agent and possible benefiting population, remained undefined. This study first evaluates the efficacy and safety of sintilimab, a PD-1 blockade, plus decitabine in treatment-naïve higher-risk MDS patients and investigates biomarkers for predicting treatment response. Methods In this phase II, single-arm trial (ChiCTR2100044393), treatment-naïve higher-risk MDS patients with an International Prognostic Scoring System-Revised score &gt;3.5 received sintilimab (200 mg, days 1 and 22) and decitabine (20 mg/m 2 , day 1–5) over 6-week cycles. The primary endpoint was the overall response rate (ORR), including complete remission (CR), partial remission (PR) or marrow CR. Results A total of 54 eligible patients were enrolled and treated, with 25 (46.3%) having very high-risk MDS. Among 53 evaluable patients, the ORR was 77.4% (n=41), including 26.4% CR (n=14). The overall clinical improvement rate (CR, PR, marrow CR or hematological improvement) reached 81.1%. With a median follow-up of 20.0 months, the median event-free survival was 23 months with 12 progressing to acute myeloid leukemia. Median overall survival was not reached. Treatment was generally well tolerated, with hematologic toxicities being the most common adverse events. Biomarker analysis highlighted a negative correlation between T cell exhaustion markers, particularly TIM-3 and PD-1, with ORR. Conclusions The combination of sintilimab and decitabine shows promise efficacy for higher-risk MDS, with a favorable safety profile. The potential predictive value of T cell exhaustion biomarkers might help screen the possible benefiting population. Trial registration number ChiCTR210044393.