tbuckley/cabot-search huggingface dataset:
Direct neuronal reprogramming of mouse astrocytes is associated with multiscale epigenome remodeling and requires Yy1
Authors: Allwyn Pereira, Jeisimhan Diwakar, Giacomo Masserdotti, Sude Beşkardeş, Tatiana Simon, Younju So, Lucía Martín-Loarte, Franziska Bergemann, Lakshmy Vasan, Tamas Schauer, Anna Danese, Riccardo Bocchi, Maria Colomé-Tatché, Carol Schuurmans, Anna Philpott, Tobias Straub, Boyan Bonev, Magdalena Götz
Journal: Nature Neuroscience (2024)

Abstract Direct neuronal reprogramming is a promising approach to regenerate neurons from local glial cells. However, mechanisms of epigenome remodeling and co-factors facilitating this process are unclear. In this study, we combined single-cell multiomics with genome-wide profiling of three-dimensional nuclear architecture and DNA methylation in mouse astrocyte-to-neuron reprogramming mediated by Neurogenin2 (Ngn2) and its phosphorylation-resistant form (PmutNgn2), respectively. We show that Ngn2 drives multilayered chromatin remodeling at dynamic enhancer–gene interaction sites. PmutNgn2 leads to higher reprogramming efficiency and enhances epigenetic remodeling associated with neuronal maturation. However, the differences in binding sites or downstream gene activation cannot fully explain this effect. Instead, we identified Yy1, a transcriptional co-factor recruited by direct interaction with Ngn2 to its target sites. Upon deletion of Yy1, activation of neuronal enhancers, genes and ultimately reprogramming are impaired without affecting Ngn2 binding. Thus, our work highlights the key role of interactors of proneural factors in direct neuronal reprogramming.
Detecting haplotype-specific transcript variation in long reads with FLAIR2
Authors: Alison D. Tang, Colette Felton, Eva Hrabeta-Robinson, Roger Volden, Christopher Vollmers, Angela N. Brooks
Journal: Genome biology (2024)

Abstract Background RNA-seq has brought forth significant discoveries regarding aberrations in RNA processing, implicating these RNA variants in a variety of diseases. Aberrant splicing and single nucleotide variants (SNVs) in RNA have been demonstrated to alter transcript stability, localization, and function. In particular, the upregulation of ADAR, an enzyme that mediates adenosine-to-inosine editing, has been previously linked to an increase in the invasiveness of lung adenocarcinoma cells and associated with splicing regulation. Despite the functional importance of studying splicing and SNVs, the use of short-read RNA-seq has limited the community’s ability to interrogate both forms of RNA variation simultaneously. Results We employ long-read sequencing technology to obtain full-length transcript sequences, elucidating cis-effects of variants on splicing changes at a single molecule level. We develop a computational workflow that augments FLAIR, a tool that calls isoform models expressed in long-read data, to integrate RNA variant calls with the associated isoforms that bear them. We generate nanopore data with high sequence accuracy from H1975 lung adenocarcinoma cells with and without knockdown of ADAR . We apply our workflow to identify key inosine isoform associations to help clarify the prominence of ADAR in tumorigenesis. Conclusions Ultimately, we find that a long-read approach provides valuable insight toward characterizing the relationship between RNA variants and splicing patterns.
Identifying behaviour-related and physiological risk factors for suicide attempts in the UK Biobank
Authors: Bei Zhang, Jia You, Edmund T Rolls, Xiang Wang, Jujiao Kang, Yuzhu Li, Ruohan Zhang, Wei Zhang, Huifu Wang, Shitong Xiang, Chun Shen, Yuchao Jiang, Chao Xie, Jintai Yu, Wei Cheng, Jianfeng Feng
Journal: Nature Human Behaviour (2024)
How can regulation and reimbursement better accommodate flexible suites of digital health technologies?
Authors: Rebecca Mathias, Peter McCulloch, Anastasia Chalkidou, Stephen Gilbert
Journal: npj Digital Medicine (2024)

Individual digital health devices are increasingly being bundled together as interacting, multicomponent suites, to deliver clinical services (e.g., teleconsultation and 'hospital-at-home services'). In the first article of this two-article series we described the challenges in implementation and the current limitations in frameworks for the regulation, health technology assessment, and reimbursement of these device suites and linked novel care pathways. A flexible and fit-for-purpose evaluation framework that can analyze the strengths and weaknesses of digital technology suites is needed. In this second article we describe adaptations that could enable this new technological paradigm while maintaining patient safety and fair value.
Effects of intermittent senolytic therapy on bone metabolism in postmenopausal women: a phase 2 randomized controlled trial
Authors: Joshua N. Farr, Elizabeth J. Atkinson, Sara J. Achenbach, Tammie L. Volkman, Amanda J. Tweed, Stephanie J. Vos, Ming Ruan, Jad Sfeir, Matthew T. Drake, Dominik Saul, Madison L. Doolittle, Irina Bancos, Kai Yu, Tamara Tchkonia, Nathan K. LeBrasseur, James L. Kirkland, David G. Monroe, Sundeep Khosla
Journal: Nature Medicine (2024)
Neoadjuvant chemotherapy with or without camrelizumab in resectable esophageal squamous cell carcinoma: the randomized phase 3 ESCORT-NEO/NCCES01 trial
Authors: Jianjun Qin, Liyan Xue, Anlin Hao, Xiaofeng Guo, Tao Jiang, Yunfeng Ni, Shuoyan Liu, Yujie Chen, Hongjing Jiang, Chen Zhang, Mingqiang Kang, Jihong Lin, Hecheng Li, Chengqiang Li, Hui Tian, Lin Li, Junke Fu, Yong Zhang, Jianqun Ma, Xiaoyuan Wang, Maoyong Fu, Hao Yang, Zhaoyang Yang, Yongtao Han, Longqi Chen, Lijie Tan, Tianyang Dai, Yongde Liao, Weiguo Zhang, Bin Li, Qixun Chen, Shiping Guo, Yu Qi, Li Wei, Zhigang Li, Ziqiang Tian, Xiaozheng Kang, Ruixiang Zhang, Yong Li, Zhen Wang, Xiankai Chen, Zhiguo Hou, Rongrong Zheng, Wenqing Zhu, Jie He, Yin Li
Journal: Nature Medicine (2024)

Recent single-arm studies involving neoadjuvant camrelizumab, a PD-1 inhibitor, plus chemotherapy for resectable locally advanced esophageal squamous cell carcinoma (LA-ESCC) have shown promising results. This multicenter, randomized, open-label phase 3 trial aimed to further assess the efficacy and safety of neoadjuvant camrelizumab plus chemotherapy followed by adjuvant camrelizumab, compared to neoadjuvant chemotherapy alone. A total of 391 patients with resectable thoracic LA-ESCC (T1b-3N1-3M0 or T3N0M0) were stratified by clinical stage (I/II, III or IVA) and randomized in a 1:1:1 ratio to undergo two cycles of neoadjuvant therapy. Treatments included camrelizumab, albumin-bound paclitaxel and cisplatin (Cam+nab-TP group; n = 132); camrelizumab, paclitaxel and cisplatin (Cam+TP group; n = 130); and paclitaxel with cisplatin (TP group; n = 129), followed by surgical resection. Both the Cam+nab-TP and Cam+TP groups also received adjuvant camrelizumab. The dual primary endpoints were the rate of pathological complete response (pCR), as evaluated by a blind independent review committee, and event-free survival (EFS), as assessed by investigators. This study reports the final analysis of pCR rates. In the intention-to-treat population, the Cam+nab-TP and Cam+TP groups exhibited significantly higher pCR rates of 28.0% and 15.4%, respectively, compared to 4.7% in the TP group (Cam+nab-TP versus TP: difference 23.5%, 95% confidence interval (CI) 15.1-32.0, P < 0.0001; Cam+TP versus TP: difference 10.9%, 95% CI 3.7-18.1, P = 0.0034). The study met its primary endpoint of pCR; however, EFS is not yet mature. The incidence of grade ≥3 treatment-related adverse events during neoadjuvant treatment was 34.1% for the Cam+nab-TP group, 29.2% for the Cam+TP group and 28.8% for the TP group; the postoperative complication rates were 34.2%, 38.8% and 32.0%, respectively. Neoadjuvant camrelizumab plus chemotherapy demonstrated superior pCR rates compared to chemotherapy alone for LA-ESCC, with a tolerable safety profile. Chinese Clinical Trial Registry identifier: ChiCTR2000040034 .
Benefits for children with suspected cancer from routine whole-genome sequencing
Authors: Angus Hodder, Sarah M. Leiter, Jonathan Kennedy, Dilys Addy, Munaza Ahmed, Thankamma Ajithkumar, Kieren Allinson, Phil Ancliff, Shivani Bailey, Gemma Barnard, G. A. Amos Burke, Charlotte Burns, Julian Cano-Flanagan, Jane Chalker, Nicholas Coleman, Danny Cheng, Yasmin Clinch, Caryl Dryden, Sara Ghorashian, Blanche Griffin, Gail Horan, Michael Hubank, Phillippa May, Joanna McDerra, Rajvi Nagrecha, James Nicholson, David O’Connor, Vesna Pavasovic, Annelies Quaegebeur, Anupama Rao, Thomas Roberts, Sujith Samarasinghe, Iryna Stasevich, John A. Tadross, Claire Trayers, Jamie Trotman, Ajay Vora, James Watkins, Lyn S. Chitty, Sarah Bowdin, Ruth Armstrong, Matthew J. Murray, Catherine E. Hook, Patrick Tarpey, Aditi Vedi, Jack Bartram, Sam Behjati
Journal: Nature Medicine (2024)

Clinical whole-genome sequencing (WGS) has been shown to deliver potential benefits to children with cancer and to alter treatment in high-risk patient groups. It remains unknown whether offering WGS to every child with suspected cancer can change patient management. We collected WGS variant calls and clinical and diagnostic information from 281 children (282 tumors) across two English units (n = 152 from a hematology center, n = 130 from a solid tumor center) where WGS had become a routine test. Our key finding was that variants uniquely attributable to WGS changed the management in ~7% (20 out of 282) of cases while providing additional disease-relevant findings, beyond standard-of-care molecular tests, in 108 instances for 83 (29%) cases. Furthermore, WGS faithfully reproduced every standard-of-care molecular test (n = 738) and revealed several previously unknown genomic features of childhood tumors. We show that WGS can be delivered as part of routine clinical care to children with suspected cancer and can change clinical management by delivering unexpected genomic insights. Our experience portrays WGS as a clinically impactful assay for routine practice, providing opportunities for assay consolidation and for delivery of molecularly informed patient care.
High-dimensional single-cell analysis of human natural killer cell heterogeneity
Authors: Lucas Rebuffet, Janine E. Melsen, Bertrand Escalière, Daniela Basurto-Lozada, Avinash Bhandoola, Niklas K. Björkström, Yenan T. Bryceson, Roberta Castriconi, Frank Cichocki, Marco Colonna, Daniel M. Davis, Andreas Diefenbach, Yi Ding, Muzlifah Haniffa, Amir Horowitz, Lewis L. Lanier, Karl-Johan Malmberg, Jeffrey S. Miller, Lorenzo Moretta, Emilie Narni-Mancinelli, Luke A. J. O’Neill, Chiara Romagnani, Dylan G. Ryan, Simona Sivori, Dan Sun, Constance Vagne, Eric Vivier
Journal: Nature Immunology (2024)

Abstract Natural killer (NK) cells are innate lymphoid cells (ILCs) contributing to immune responses to microbes and tumors. Historically, their classification hinged on a limited array of surface protein markers. Here, we used single-cell RNA sequencing (scRNA-seq) and cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) to dissect the heterogeneity of NK cells. We identified three prominent NK cell subsets in healthy human blood: NK1, NK2 and NK3, further differentiated into six distinct subgroups. Our findings delineate the molecular characteristics, key transcription factors, biological functions, metabolic traits and cytokine responses of each subgroup. These data also suggest two separate ontogenetic origins for NK cells, leading to divergent transcriptional trajectories. Furthermore, we analyzed the distribution of NK cell subsets in the lung, tonsils and intraepithelial lymphocytes isolated from healthy individuals and in 22 tumor types. This standardized terminology aims at fostering clarity and consistency in future research, thereby improving cross-study comparisons.
Twenty percent human albumin solution fluid bolus administration therapy in patients after cardiac surgery-II: a multicentre randomised controlled trial
Authors: Geoffrey J. Wigmore, Adam M. Deane, Jeffrey J. Presneill, Glenn Eastwood, Ary Serpa Neto, Matthew J. Maiden, Shailesh Bihari, Robert A. Baker, Jayme S. Bennetts, Rashmi Ghanpur, James R. Anstey, Jaishankar Raman, Rinaldo Bellomo, Leah Peck, Helen Young, Will Dovenya, Xu K, Akinori Maeda, Ke Xu, Sofia Spano, Fumitaka Yanase, Helen Young, Michelle Horton, Stephanie Pearce, Paul Power, Jemma Trickey, Deborah Barge, Kathleen Byrne, Michael Haeusler, Chris MacIsaac, Madeleina Snowdon
Journal: Intensive Care Medicine (2024)

After cardiac surgery, fluid bolus therapy (FBT) with 20% human albumin may facilitate less fluid and vasopressor administration than FBT with crystalloids. We aimed to determine whether, after cardiac surgery, FBT with 20% albumin reduces the duration of vasopressor therapy compared with crystalloid FBT. We conducted a multicentre, parallel-group, open-label, randomised clinical trial in six intensive care units (ICUs) involving cardiac surgery patients deemed to require FBT. We randomised 240 patients to receive up to 400 mL of 20% albumin/day as FBT, followed by 4% albumin for any subsequent FBT on that day, or to crystalloid FBT for at least the first 1000 mL, with use of crystalloid or 4% albumin FBT thereafter. The primary outcome was the cumulative duration of vasopressor therapy. Secondary outcomes included fluid balance. Of 480 randomised patients, 466 provided consent and contributed to the primary outcome (mean age 65 years; median EuroSCORE II 1.4). The cumulative median duration of vasopressor therapy was 7 (interquartile range [IQR] 0–19.6) hours with 20% albumin and 10.8 (IQR 0–22.8) hours with crystalloids (difference − 3.8 h, 95% confidence interval [CI] − 8 to 0.4; P = 0.08). Day one fluid balance was less with 20% albumin FBT (mean difference − 701 mL, 95% CI − 872 to − 530). In patients after cardiac surgery, when compared to a crystalloid-based FBT, 20% albumin FBT was associated with a reduced positive fluid balance but did not significantly reduce the duration of vasopressor therapy.
From biogenesis to aptasensors: advancements in analysis for tumor-derived extracellular vesicles research
Authors: Gaojian Yang, Zhiyang Li, Rabia Usman, Yuan Liu, Song Li, Zhu Chen, Hui Chen, Yan Deng, Yile Fang, Nongyue He
Journal: Theranostics (2024)

Extracellular vesicles (EVs) are enclosed by a nanoscale phospholipid bilayer membrane and typically range in size from 30 to 200 nm.They contain a high concentration of specific proteins, nucleic acids, and lipids, reflecting but not identical to the composition of the parent cell.The inherent characteristics and variety of EVs give them extensive and unique advantages in the field of cancer identification and treatment.Recently, EVs have been recognized as potential tumor markers for the detection of cancer.Aptamers, which are molecules of single-stranded DNA or RNA, demonstrate remarkable specificity and affinity for their targets by adopting distinct tertiary structures.Aptamers offer various advantages over their protein counterparts, such as reduced immunogenicity, the ability for convenient large-scale synthesis, and straightforward chemical modification.In this review, we summarized EVs biogenesis, sample collection, isolation, storage and characterization, and finally provided a comprehensive survey of analysis techniques for EVs detection that are based on aptamers.
Bioinspired soft-hard combined system with mild photothermal therapeutic activity promotes diabetic bone defect healing via synergetic effects of immune activation and angiogenesis
Authors: Minhao Wu, Huifan Liu, Yufan Zhu, Ping Wu, Yun Chen, Zhouming Deng, Xiaobin Zhu, Lin Cai
Journal: Theranostics (2024)

Background:The comprehensive management of diabetic bone defects remains a substantial clinical challenge due to the hostile regenerative microenvironment characterized by aggravated inflammation, excessive reactive oxygen species (ROS), bacterial infection, impaired angiogenesis, and unbalanced bone homeostasis.Thus, an advanced multifunctional therapeutic platform capable of simultaneously achieving immune regulation, bacterial elimination, and tissue regeneration is urgently designed for augmented bone regeneration under diabetic pathological milieu.Methods and Results: Herein, a photoactivated soft-hard combined scaffold system (PGCZ) was engineered by introducing polydopamine-modified zeolitic imidazolate framework-8-loaded double-network hydrogel (soft matrix component) into 3D-printed poly(ε-caprolactone) (PCL) scaffold (hard matrix component).The versatile PGCZ scaffold based on double-network hydrogel and 3D-printed PCL was thus prepared and features highly extracellular matrix-mimicking microstructure, suitable biodegradability and mechanical properties, and excellent photothermal performance, allowing long-term structural stability and mechanical support for bone regeneration.Under periodic near-infrared (NIR) irradiation, the localized photothermal effect of PGCZ triggers the on-demand release of Zn 2+ , which, together with repeated mild hyperthermia, collectively accelerates the proliferation and osteogenic differentiation of preosteoblasts and potently inhibits bacterial growth and biofilm formation.Additionally, the photoactivated PGCZ system also presents outstanding immunomodulatory and ROS scavenging capacities, which regulate M2 polarization of macrophages and drive functional cytokine secretion, thus leading to a pro-regenerative microenvironment in situ with enhanced vascularization.In vivo experiments further demonstrated that the PGCZ platform in conjunction with mild photothermal therapeutic activity remarkably attenuated the local inflammatory cascade, initiated endogenous stem cell recruitment and neovascularization, and orchestrated the osteoblast/osteoclast balance, ultimately accelerating diabetic bone regeneration. Ivyspring
The emerging role of Piezo1 in the musculoskeletal system and disease
Authors: Lei Lei, Zhenkang Wen, Mingde Cao, Haozhi Zhang, Samuel Ka-Kin Ling, Bruma Sai-Chuen Fu, Ling Qin, Jiankun Xu, Patrick Shu-Hang Yung
Journal: Theranostics (2024)

Piezo1, a mechanosensitive ion channel, has emerged as a key player in translating mechanical stimuli into biological signaling. Its involvement extends beyond physiological and pathological processes such as lymphatic vessel development, axon growth, vascular development, immunoregulation, and blood pressure regulation. The musculoskeletal system, responsible for structural support, movement, and homeostasis, has recently attracted attention regarding the significance of Piezo1. This review aims to provide a comprehensive summary of the current research on Piezo1 in the musculoskeletal system, highlighting its impact on bone formation, myogenesis, chondrogenesis, intervertebral disc homeostasis, tendon matrix cross-linking, and physical activity. Additionally, we explore the potential of targeting Piezo1 as a therapeutic approach for musculoskeletal disorders, including osteoporosis, muscle atrophy, intervertebral disc degeneration, and osteoarthritis.
Intraductal photothermal ablation: a noninvasive approach for early breast cancer treatment and prevention
Authors: Jianhua Liu, Biao Huang, Yan Rao, Liantao Guo, Cheguo Cai, Dongcheng Gao, Deguang Kong, Guannan Wang, Yao Xiong, Ran Cui, Mingxi Zhang, Chuang Chen
Journal: Theranostics (2024)

Background: Innovative treatment strategies for early-stage breast cancer (BC) are urgently needed.Tumors originating from mammary ductal cells present an opportunity for targeted intervention.Methods: We explored intraductal therapy via natural nipple openings as a promising non-invasive approach for early BC.Using functional Near-infrared II (NIR-II) nanomaterials, specifically NIR-IIb quantum dots conjugated with Epep polypeptide for ductal cell targeting, we conducted in situ imaging and photothermal ablation of mammary ducts.Intraductal administration was followed by stimulation with an 808 nm laser.Results: This method achieved precise ductal destruction and heightened immunological responses in the microenvironment.The technique was validated in mouse models of triple-negative BC and a rat model of ductal carcinoma in situ, demonstrating promising therapeutic potential for localized BC treatment and prevention.Conclusion: Our study demonstrated the effectiveness of NIR-II nanoprobes in guiding non-invasive photothermal ablation of mammary ducts, offering a compelling avenue for early-stage BC therapy.
Biomarker-driven molecular imaging probes in radiotherapy
Authors: Haonan Li, Qiyong Gong, Kui Luo
Journal: Theranostics (2024)

Biomarker-driven molecular imaging has emerged as an integral part of cancer precision radiotherapy. The use of molecular imaging probes, including nanoprobes, have been explored in radiotherapy imaging to precisely and noninvasively monitor spatiotemporal distribution of biomarkers, potentially revealing tumor-killing mechanisms and therapy-induced adverse effects during radiation treatment.
Targeted opening of the blood-brain barrier using VCAM-1 functionalised microbubbles and “whole brain” ultrasound
Authors: Vanessa A. Johanssen, Jia-Ling Ruan, Oliver Vince, Alec Thomas, Sarah Peeters, Manuel Sarmiento Soto, Jessica Buck, Michael Gray, Eleanor Stride, Nicola R. Sibson
Journal: Theranostics (2024)

Metastatic tumours in the brain now represent one of the leading causes of death from cancer. Current treatments are largely ineffective owing to the combination of late diagnosis and poor delivery of therapies across the blood-brain barrier (BBB). Conjugating magnetic resonance imaging (MRI) contrast agents with a monoclonal antibody for VCAM-1 (anti-VCAM1) has been shown to enable detection of micrometastases, two to three orders of magnitude smaller in volume than those currently detectable clinically. The aim of this study was to exploit this targeting approach to enable localised and temporary BBB opening at the site of early-stage metastases using functionalised microbubbles and ultrasound.