tbuckley/cabot-search huggingface dataset:
Palladium-103 (<sup>103</sup>Pd/<sup>103m</sup>Rh), a promising Auger-electron emitter for targeted radionuclide therapy of disseminated tumor cells - absorbed doses in single cells and clusters, with comparison to <sup>177</sup>Lu and <sup>161</sup>Tb
Authors: Elif Hindié, Alexandre Larouze, Mario Alcocer-Ávila, Clément Morgat, Christophe Champion
Journal: Theranostics (2024)

Early use of targeted radionuclide therapy (TRT) to eradicate disseminated tumor cells (DTCs) might offer cure.Selection of appropriate radionuclides is required.This work highlights the potential of 103 Pd (T1/2 = 16.991d) which decays to 103m Rh (T1/2 = 56.12min) then to stable 103 Rh with emission of Auger and conversion electrons.Methods: The Monte Carlo track structure code CELLDOSE was used to assess absorbed doses in single cells (14-μm diameter; 10-μm nucleus) and clusters of 19 cells.The radionuclide was distributed on the cell surface, within the cytoplasm, or in the nucleus.Absorbed doses from 103 Pd, 177 Lu and 161 Tb were compared after energy normalization.The impact of non-uniform cell targeting, and the potential benefit from dual-targeting was investigated.Additional results related to 103m Rh, if used directly, are provided.Results: In the single cell, and depending on radionuclide distribution, 103 Pd delivered 7-to 10-fold higher nuclear absorbed dose and 9-to 25-fold higher membrane dose than 177 Lu.In the 19-cell clusters, 103 Pd absorbed doses also largely exceeded 177 Lu.In both situations, 161 Tb stood in-between 103 Pd and 177 Lu.Non-uniform targeting, considering four unlabeled cells within the cluster, resulted in moderate-to-severe dose heterogeneity.For example, with intranuclear 103 Pd, unlabeled cells received only 14% of the expected nuclear dose.Targeting with two 103 Pd-labeled radiopharmaceuticals minimized dose heterogeneity.Conclusion: 103 Pd, a next-generation Auger emitter, can deliver substantially higher absorbed doses than 177 Lu to single tumor cells and cell clusters.This may open new horizons for the use of TRT in adjuvant or neoadjuvant settings, or for targeting minimal residual disease.
Methyl-CpG-binding 2 K271 lactylation-mediated M2 macrophage polarization inhibits atherosclerosis
Authors: Liangqi Chen, Meiju Zhang, Xueyan Yang, Yanan Wang, Tuo Huang, Xin Li, Yunting Ban, Qifeng Li, Qingyuan Yang, Yongxiang Zhang, Yang Zheng, Di Wang, Xiaoqi Wang, Xiujie Shi, Maomao Zhang, Yong Sun, Jian Wu
Journal: Theranostics (2024)

Rationale: Posttranslational modifications of proteins have not been addressed in studies aimed at elucidating the cardioprotective effect of exercise in atherosclerotic cardiovascular disease (ASCVD).In this study, we reveal a novel mechanism by which exercise ameliorates atherosclerosis via lactylation.Methods: Using ApoE -/-mice in an exercise model, proteomics analysis was used to identify exercise-induced specific lactylation of MeCP2 at lysine 271 (K271).Mutation of the MeCP2 K271 lactylation site in aortic plaque macrophages was achieved by recombinant adenoviral transfection.Explore the molecular mechanisms by which motility drives MeCP2 K271 lactylation to improve plaque stability using ATAC-Seq, CUT &Tag and molecular biology.Validation of the potential target RUNX1 for exercise therapy using Ro5-3335 pharmacological inhibition.Results: we showed that in ApoE -/-mice, methyl-CpG-binding protein 2 (MeCP2) K271 lactylation was observed in aortic root plaque macrophages, promoting pro-repair M2 macrophage polarization, reducing the plaque area, shrinking necrotic cores, reducing plaque lipid deposition, and increasing collagen content.Adenoviral transfection, by introducing a mutant at lysine 271, overexpressed MeCP2 K271 lactylation, which enhanced exercise-induced M2 macrophage polarization and increased plaque stability.Mechanistically, the exercise-induced atheroprotective effect requires an interaction between MeCP2 K271 lactylation and H3K36me3, leading to increased chromatin accessibility and transcriptional repression of RUNX1.In addition, the pharmacological inhibition of the transcription factor RUNX1 exerts atheroprotective effects by promoting the polarization of plaque macrophages towards the pro-repair M2 phenotype.Conclusions: These findings reveal a novel mechanism by which exercise ameliorates atherosclerosis via MeCP2 K271 lactylation-H3K36me3/RUNX1.Interventions that enhance MeCP2 K271 lactylation have been shown to increase pro-repair M2 macrophage infiltration, thereby promoting plaque stabilization and reducing the risk of atherosclerotic cardiovascular disease.We also established RUNX1 as a potential drug target for exercise therapy, thereby providing guidance for the discovery of new targets.
Multifunctional hydrogel-based engineered extracellular vesicles delivery for complicated wound healing
Authors: Zuhao Li, Jinlong Liu, Jian Song, Zhifeng Yin, Fengjin Zhou, Hao Shen, Guangchao Wang, Jiacan Su
Journal: Theranostics (2024)

The utilization of extracellular vesicles (EVs) in wound healing has been well-documented.However, the direct administration of free EVs via subcutaneous injection at wound sites may result in the rapid dissipation of bioactive components and diminished therapeutic efficacy.Functionalized hydrogels provide effective protection, as well as ensure the sustained release and bioactivity of EVs during the wound healing process, making them an ideal candidate material for delivering EVs.In this review, we introduce the mechanisms by which EVs accelerate wound healing, and then elaborate on the construction strategies for engineered EVs.Subsequently, we discuss the synthesis strategies and application of hydrogels as delivery systems for the sustained release of EVs to enhance complicated wound healing.Furthermore, in the face of complicated wounds, functionalized hydrogels with specific wound microenvironment regulation capabilities, such as antimicrobial, anti-inflammatory, and immune regulation, used for loading engineered EVs, provide potential approaches to addressing these healing challenges.Ultimately, we deliberate on potential future trajectories and outlooks, offering a fresh viewpoint on the advancement of artificial intelligence (AI)-energized materials and 3D bio-printed multifunctional hydrogel-based engineered EVs delivery dressings for biomedical applications.
<sup>68</sup>Ga-labeled fibroblast activation protein inhibitor (FAPI) PET/CT for locally advanced or recurrent pancreatic cancer staging and restaging after chemoradiotherapy
Authors: Giulia Metzger, Christian Bayerl, Julian MM Rogasch, Christian Furth, Christoph Wetz, Marcus Beck, Felix Mehrhof, Holger Amthauer, Pirus Ghadjar, Christopher Neumann, Uwe Pelzer, Daniel Zips, Frank Hofheinz, Jane Grabowski, Imke Schatka, Sebastian Zschaeck
Journal: Theranostics (2024)

Purpose: 68 Ga-labeled fibroblast activation protein inhibitor (FAPI) is a novel PET tracer with great potential for staging pancreatic cancer.Data on locally advanced or recurrent disease is sparse, especially on tracer uptake before and after high dose chemoradiotherapy (CRT).The aim of this study was to evaluate [ 68 Ga]Ga-FAPI-46 PET/CT staging in this setting.Methods: Twenty-seven patients with locally recurrent or locally advanced pancreatic adenocarcinoma (LRPAC n = 15, LAPAC n = 12) in stable disease or partial remission after chemotherapy underwent FAPI PET/CT and received consolidation CRT in stage M0 with follow-up FAPI PET/CT every three months until systemic progression.Quantitative PET parameters SUVmax, SUVmean, FAPI-derived tumor volume and total lesion FAPI-uptake were measured in baseline and follow-up PET/CT scans.Contrast-enhanced CT (ceCT) and PET/CT data were evaluated blinded and staged according to TNM classification.Results: FAPI PET/CT modified staging compared to ceCT alone in 23 of 27 patients in baseline, resulting in major treatment alterations in 52% of all patients (30%: target volume adjustment due to N downstaging, 15%: switch to palliative systemic chemotherapy only due to diffuse metastases, 7%: abortion of radiotherapy due to other reasons).Regarding follow-up scans, major treatment alterations after performing FAPI PET/CT were noted in eleven of 24 follow-up scans (46%) with switch to systemic chemotherapy or best supportive care due to M upstaging and ablative radiotherapy of distant lymph node and oligometastasis.Unexpectedly, in more than 90 % of the follow-up scans, radiotherapy did not induce local fibrosis related FAPI uptake.During the first follow-up, all quantitative PET metrics decreased, and irradiated lesions showed significantly lower FAPI uptake in locally controlled disease (SUVmax p = 0.047, SUVmean p = 0.0092) compared to local failure. Ivyspring
Astrocyte-derived lactate aggravates brain injury of ischemic stroke in mice by promoting the formation of protein lactylation
Authors: Xiao-Yi Xiong, Xin-Ru Pan, Xia-Xia Luo, Yu-Fei Wang, Xin-Xiao Zhang, Su-Hao Yang, Zhan-Qiong Zhong, Chang Liu, Qiong Chen, Peng-Fei Wang, Xiao-Wei Chen, Shu-Guang Yu, Qing-Wu Yang
Journal: Theranostics (2024)

Aim:Although lactate supplementation at the reperfusion stage of ischemic stroke has been shown to offer neuroprotection, whether the role of accumulated lactate at the ischemia phase is neuroprotection or not remains largely unknown.Thus, in this study, we aimed to investigate the roles and mechanisms of accumulated brain lactate at the ischemia stage in regulating brain injury of ischemic stroke.Methods and Results: Pharmacological inhibition of lactate production by either inhibiting LDHA or glycolysis markedly attenuated the mouse brain injury of ischemic stroke.In contrast, additional lactate supplement further aggravates brain injury, which may be closely related to the induction of neuronal death and A1 astrocytes.The contributing roles of increased lactate at the ischemic stage may be related to the promotive formation of protein lysine lactylation (Kla), while the post-treatment of lactate at the reperfusion stage did not influence the brain protein Kla levels with neuroprotection.Increased protein Kla levels were found mainly in neurons by the HPLC-MS/MS analysis and immunofluorescent staining.Then, pharmacological inhibition of lactate production or blocking the lactate shuttle to neurons showed markedly decreased protein Kla levels in the ischemic brains.Additionally, Ldha specific knockout in astrocytes (Aldh1l1 CreERT2 ; Ldha fl/fl mice, cKO) mice with MCAO were constructed and the results showed that the protein Kla level was decreased accompanied by a decrease in the volume of cerebral infarction in cKO mice compared to the control groups.Furthermore, blocking the protein Kla formation by inhibiting the writer p300 with its antagonist A-485 significantly alleviates neuronal death and glial activation of cerebral ischemia with a reduction in the protein Kla level, resulting in extending reperfusion window and improving functional recovery for ischemic stroke.Conclusion: Collectively, increased brain lactate derived from astrocytes aggravates ischemic brain injury by promoting the protein Kla formation, suggesting that inhibiting lactate production or the formation of protein Kla at the ischemia stage presents new therapeutic targets for the treatment of ischemic stroke.
Aryl hydrocarbon receptor confers protection against macrophage pyroptosis and intestinal inflammation through regulating polyamine biosynthesis
Authors: Yajing Gao, Kwei-Yan Liu, Wenfeng Xiao, Xueru Xie, Qiuyan Liang, Zikun Tu, Lan Yang, Hongmiao Yu, Haiyan Guo, Saihua Huang, Xiao Han, Jinrong Fu, Yufeng Zhou
Journal: Theranostics (2024)

Rationale:The aryl hydrocarbon receptor (AhR) functions in the regulation of intestinal inflammation, but knowledge of the underlying mechanisms in innate immune cells is limited.Here, we investigated the role of AhR in modulating the functions of macrophages in inflammatory bowel disease pathogenesis.Methods: The cellular composition of intestinal lamina propria CD45 + leukocytes in a dextran sulfate sodium (DSS)-induced mouse colitis model was determined by single-cell RNA sequencing.Macrophage pyroptosis was quantified by analysis of lactate dehydrogenase release, propidium iodide staining, enzyme-linked immunosorbent assay, western blot, and flow cytometry.Differentially expressed genes were confirmed by RNA-seq, RT-qPCR, luciferase assay, chromatin immunoprecipitation, and immunofluorescence staining.Results: AhR deficiency mediated dynamic remodeling of the cellular composition of intestinal lamina propria (LP) CD45 + immune cells in a colitis model, with a significant increase in monocyte-macrophage lineage.Mice with AhR deficiency in myeloid cells developed more severe dextran sulfate sodium induced colitis, with concomitant increased macrophage pyroptosis.Dietary supplementation with an AhR pre-ligand, indole-3-carbinol, conferred protection against colitis while protection failed in mice lacking AhR in myeloid cells.Mechanistically, AhR signaling inhibited macrophage pyroptosis by promoting ornithine decarboxylase 1 (Odc1) transcription, to enhance polyamine biosynthesis.The increased polyamine, particularly spermine, inhibited NLRP3 inflammasome assembly and subsequent pyroptosis by suppressing K + efflux.AHR expression was positively correlated with ODC1 in intestinal mucosal biopsies from patients with ulcerative colitis.Conclusions: These findings suggest a functional role for the AhR/ODC1/polyamine axis in maintaining intestinal homeostasis, providing potential targets for treatment of inflammatory bowel disease.
Tumor evolution metrics predict recurrence beyond 10 years in locally advanced prostate cancer
Authors: Javier Fernandez-Mateos, George D. Cresswell, Nicholas Trahearn, Katharine Webb, Chirine Sakr, Andrea Lampis, Christine Stuttle, Catherine M. Corbishley, Vasilis Stavrinides, Luis Zapata, Inmaculada Spiteri, Timon Heide, Lewis Gallagher, Chela James, Daniele Ramazzotti, Annie Gao, Zsofia Kote-Jarai, Ahmet Acar, Lesley Truelove, Paula Proszek, Julia Murray, Alison Reid, Anna Wilkins, Michael Hubank, Ros Eeles, David Dearnaley, Andrea Sottoriva
Journal: Nature Cancer (2024)

Abstract Cancer evolution lays the groundwork for predictive oncology. Testing evolutionary metrics requires quantitative measurements in controlled clinical trials. We mapped genomic intratumor heterogeneity in locally advanced prostate cancer using 642 samples from 114 individuals enrolled in clinical trials with a 12-year median follow-up. We concomitantly assessed morphological heterogeneity using deep learning in 1,923 histological sections from 250 individuals. Genetic and morphological (Gleason) diversity were independent predictors of recurrence (hazard ratio (HR) = 3.12 and 95% confidence interval (95% CI) = 1.34–7.3; HR = 2.24 and 95% CI = 1.28–3.92). Combined, they identified a group with half the median time to recurrence. Spatial segregation of clones was also an independent marker of recurrence (HR = 2.3 and 95% CI = 1.11–4.8). We identified copy number changes associated with Gleason grade and found that chromosome 6p loss correlated with reduced immune infiltration. Matched profiling of relapse, decades after diagnosis, confirmed that genomic instability is a driving force in prostate cancer progression. This study shows that combining genomics with artificial intelligence-aided histopathology leads to the identification of clinical biomarkers of evolution.
Disruption of neural periodicity predicts clinical response after deep brain stimulation for obsessive-compulsive disorder
Authors: Nicole R. Provenza, Sandesh Reddy, Anthony K. Allam, Sameer V. Rajesh, Nabeel Diab, Gabriel Reyes, Rose M. Caston, Kalman A. Katlowitz, Ajay D. Gandhi, Raphael A. Bechtold, Huy Q. Dang, Ricardo A. Najera, Nisha Giridharan, Katherine E. Kabotyanski, Faiza Momin, Mohammed Hasen, Garrett P. Banks, Brian J. Mickey, Brent M. Kious, Ben Shofty, Benjamin Y. Hayden, Jeffrey A. Herron, Eric A. Storch, Ankit B. Patel, Wayne K. Goodman, Sameer A. Sheth
Journal: Nature Medicine (2024)

Recent advances in surgical neuromodulation have enabled chronic and continuous intracranial monitoring during everyday life. We used this opportunity to identify neural predictors of clinical state in 12 individuals with treatment-resistant obsessive-compulsive disorder (OCD) receiving deep brain stimulation (DBS) therapy ( NCT05915741 ). We developed our neurobehavioral models based on continuous neural recordings in the region of the ventral striatum in an initial cohort of five patients and tested and validated them in a held-out cohort of seven additional patients. Before DBS activation, in the most symptomatic state, theta/alpha (9 Hz) power evidenced a prominent circadian pattern and a high degree of predictability. In patients with persistent symptoms (non-responders), predictability of the neural data remained consistently high. On the other hand, in patients who improved symptomatically (responders), predictability of the neural data was significantly diminished. This neural feature accurately classified clinical status even in patients with limited duration recordings, indicating generalizability that could facilitate therapeutic decision-making.
Marked increase in cryptosporidiosis cases, Spain, 2023
Authors: Marina Peñuelas Martinez, David Carmena, Bernardo R Guzmán Herrador, Margarita Palau Miguel, Gabriela Saravia Campelli, Rosa María García Álvarez, María Guerrero-Vadillo, Alejandro Dashti, Pamela C Köster, Esperanza Guevara Alemany, Fernando Simón Soria, Isabel Fuentes Corripio, Carmen Varela Martínez, María José Sierra Moros
Journal: Eurosurveillance (2024)

Background By mid-September 2023, several event notifications related to cryptosporidiosis had been identified from different regions in Spain. Therefore, a request for urgent notification of cryptosporidiosis cases to the National Surveillance Network was launched. Aim We aimed at assessing the extent of the increase in cases, the epidemiological characteristics and the transmission modes and compared to previous years. Methods We analysed data on case notifications, outbreak reports and genotypes focusing on June–October 2023 and compared the results to 2016–2022. Results In 2023, 4,061 cryptosporidiosis cases were notified in Spain, which is an increase compared to 2016–2022. The cumulative incidence was 8.3 cases per 100,000 inhabitants in 2023, sixfold higher than the median of 1.4 cases per 100,000 inhabitants 2016–2022. Almost 80% of the cases were notified between June and October. The largest outbreaks were related to contaminated drinking water or swimming pools. Cryptosporidium hominis was the most common species in the characterised samples (115/122), and the C. hominis IfA12G1R5 subtype, previously unusual in Spain, was detected from 76 (62.3%) of the 122 characterised samples. Conclusions A substantial increase in cryptosporidiosis cases was observed in 2023. Strengthening surveillance of Cryptosporidium is essential for prevention of cases, to better understand trends and subtypes circulating and the impact of adverse meteorological events.
An evidence-based screening tool for heart failure with preserved ejection fraction: the HFpEF-ABA score
Authors: Yogesh N V Reddy, Rickey E Carter, Varun Sundaram, David M Kaye, M Louis Handoko, Ryan J Tedford, Mads J Andersen, Kavita Sharma, Masaru Obokata, Frederik H Verbrugge, Barry A Borlaug
Journal: Nature Medicine (2024)
Author Correction: Micropillar arrays as a high-throughput screening platform for therapeutics in multiple sclerosis
Authors: Feng Mei, Stephen P J Fancy, Yun-An A Shen, Jianqin Niu, Chao Zhao, Bryan Presley, Edna Miao, Seonok Lee, Sonia R Mayoral, Stephanie A Redmond, Ainhoa Etxeberria, Lan Xiao, Robin J M Franklin, Ari Green, Stephen L Hauser, Jonah R Chan
Journal: Nature Medicine (2024)
Evaluation of the sensitivity of a measles diagnostic real-time RT-PCR assay incorporating recently observed priming mismatch variants, 2024
Authors: Andrew S Beck, Elena N Lopareva, Hyun Hwang, Derek Hart, Marcos de Almeida, Raydel Anderson, Paul A Rota, Bettina Bankamp
Journal: Eurosurveillance (2024)

We investigated a variant of measles virus that encodes three mismatches to the reverse priming site for a widely used diagnostic real-time RT-PCR assay; reduction of sensitivity was hypothesised. We examined performance of the assay in context of the variant using in silico data, synthetic RNA templates and clinical specimens. Sensitivity was reduced observed at low copy numbers for templates encoding the variant sequence. We designed and tested an alternate priming strategy, rescuing the sensitivity of the assay.
First detection of a Mycobacterium tuberculosis XDR clinical isolate harbouring an RpoB I491F mutation in a Ukrainian patient treated in Germany, October 2023
Authors: Inna Friesen, Viola Dreyer, Angela Klingmüller, Sylvia Zuber, Ada M Hoffmann, Isabelle Suárez, Beatrice Schütz, Tim Preßel, Sönke Andres, Stefan Niemann, Jan Rybniker
Journal: Eurosurveillance (2024)

This report documents the case of a Ukrainian patient infected with an extensively drug-resistant (XDR) lineage 2 Mycobacterium tuberculosis strain harbouring the rifampicin resistance mutation RpoB I491F. This mutation is not detected by routine molecular WHO-recommended rapid diagnostics, complicating the detection and treatment of these strains. The occurrence of such mutations underscores the need for enhanced diagnostic techniques and tailored treatment regimens, especially in eastern Europe where lineage 2 strains and XDR-tuberculosis are prevalent.
Nosocomial transmission of tet(x3), blaNDM-1 and blaOXA-97-carrying Acinetobacter baumannii conferring resistance to eravacycline and omadacycline, the Netherlands, March to August 2021
Authors: Ditmer T Talsma, Rodrigo Monteiro, Rosario del Carmen Flores-Vallejo, Maarten Heuvelmans, Thuy-Nga Le, Antoni PA Hendrickx, Sigrid Rosema, Ianthe Maat, Jan Maarten van Dijl, Erik Bathoorn
Journal: Eurosurveillance (2024)

Carbapenem-resistant Acinetobacter baumannii (CRAb) is an important pathogen causing serious nosocomial infections. We describe an outbreak of CRAb in an intensive care unit in the Netherlands in 2021. During an outbreak of non-resistant A. baumannii , while infection control measures were in place, CRAb isolates carrying highly similar bla NDM-1 - and tet(x3)- encoding plasmids were isolated from three patients over a period of several months. The chromosomal and plasmid sequences of the CRAb and non-carbapenemase-carrying A. baumannii isolates cultured from patient materials were analysed using hybrid assemblies of short-read and long-read sequences. The CRAb isolates revealed that the CRAb outbreak consisted of two different strains, carrying similar plasmids. The plasmids contained multiple antibiotic resistance genes including the tetracycline resistance gene tet(x3) , and the bla NDM-1 and bla OXA-97 carbapenemase genes. We determined minimal inhibitory concentrations (MICs) for 13 antibiotics, including the newly registered tetracycline antibiotics eravacycline and omadacycline. The CRAb isolates showed high MICs for tetracycline antibiotics including eravacycline and omadacycline, except for minocycline which had a low MIC. In this study we show the value of sequencing multidrug-resistant A. baumannii for outbreak tracking and guiding outbreak mitigation measures.