tbuckley/cabot-search huggingface dataset:
Trans-nasal brain delivery of anti-TB drugs by methyl-β-cyclodextrin microparticles show efficient mycobacterial clearance from central nervous system
Authors: Krishna Jadhav, Agrim Jhilta, Raghuraj Singh, Shweta Sharma, Swarnima Negi, Kailash Ahirwar, Rahul Shukla, Amit Kumar Singh, Rahul Kumar Verma
Journal: Journal of Controlled Release (2024)
Inferring Long-Term and Short-Term Determinants of Genetic Diversity in Honey Bees: Beekeeping Impact and Conservation Strategies
Authors: Thibault Leroy, Pierre Faux, Benjamin Basso, Sonia Eynard, David Wragg, Alain Vignal
Journal: Molecular Biology and Evolution (2024)

Abstract Bees are vital pollinators in natural and agricultural landscapes around the globe, playing a key role in maintaining flowering plant biodiversity and ensuring food security. Among the honey bee species, the Western honey bee (Apis mellifera) is particularly significant, not only for its extensive crop pollination services but also for producing economically valuable products such as honey. Here, we analyzed whole-genome sequence data from four Apis species to explore how honey bee evolution has shaped current diversity patterns. Using Approximate Bayesian Computation, we first reconstructed the demographic history of A. mellifera in Europe, finding support for postglacial secondary contacts, therefore predating human-mediated transfers linked to modern beekeeping. However, our analysis of recent demographic changes reveals significant bottlenecks due to beekeeping practices, which have notably affected genetic diversity. Black honey bee populations from conservatories, particularly those on islands, exhibit considerable genetic loss, highlighting the need to evaluate the long-term effectiveness of current conservation strategies. Additionally, we observed a high degree of conservation in the genomic landscapes of nucleotide diversity across the four species, despite a divergence gradient spanning over 15 million years, consistent with a long-term conservation of the recombination landscapes. Taken together, our results provide the most comprehensive assessment of diversity patterns in honey bees to date and offer insights into the optimal management of resources to ensure the long-term persistence of honey bees and their invaluable pollination services.
Radiofrequency Ablation Versus Stereotactic Body Radiotherapy for Recurrent Small Hepatocellular Carcinoma: A Randomized, Open-Label, Controlled Trial
Authors: Mian Xi, Zhoutian Yang, Li Hu, Yizhen Fu, Dandan Hu, Zhongguo Zhou, Mengzhong Liu, Jing Zhao, Jingxian Shen, Qiaoqiao Li, Baoqing Chen, Li Xu, Aiping Fang, Minshan Chen, Shiliang Liu, Yaojun Zhang
Journal: Journal of Clinical Oncology (2024)

PURPOSE To assess the efficacy and safety of radiofrequency ablation (RFA) versus stereotactic body radiotherapy (SBRT) in treating recurrent small hepatocellular carcinoma (HCC). METHODS In this trial, patients with recurrent small HCC (single lesion ≤5 cm) were randomly assigned to receive either SBRT or RFA. The primary end point was local progression-free survival (LPFS), and secondary end points were progression-free survival (PFS), overall survival (OS), local control rate, and safety. RESULTS Between August 2019 and April 2022, 166 patients were assigned to SBRT (n = 83) and RFA (n = 83) groups. After a median follow-up time of 42.8 and 42.9 months in the SBRT and RFA groups, respectively, SBRT demonstrated a significantly better LPFS than that of RFA (hazard ratio [HR], 0.45 [95% CI, 0.24 to 0.87]; P = .014). The 2-year LPFS rates were 92.7% (95% CI, 87.3 to 98.5) with SBRT and 75.8% (95% CI, 67.2 to 85.7) with RFA. The median PFS time of the SBRT and RFA groups was 37.6 (95% CI, 26.0 to 49.2) and 27.6 (95% CI, 20.3 to 34.8) months, respectively (HR, 0.76 [95% CI, 0.50 to 1.15]; P = .190). Nine patients in the SBRT group and 10 in the RFA group died during the follow-up. The 2-year OS rates were 97.6% (95% CI, 94.3 to 100.0) in the SBRT group and 93.9% (95% CI, 88.9 to 99.2) in the RFA group (HR, 0.91 [95% CI, 0.37 to 2.22]; P = .830). The incidences of both acute and late adverse events were comparable between the groups ( P = .436 and P = .715, respectively). CONCLUSION SBRT achieved better LPFS than that of RFA in patients with single recurrent HCC ≤5 cm, especially in HCC ≤2 cm, whereas PFS, OS, and safety were comparable between the two treatments.
LKB1 dictates sensitivity to immunotherapy through Skp2-mediated ubiquitination of PD-L1 protein in non-small cell lung cancer
Authors: Liting Lv, Qing Miao, Sutong Zhan, Peilin Chen, Wei Liu, Jiawen Lv, Wenjie Yan, Dong Wang, Hongbing Liu, Jie Yin, Jian Feng, Yong Song, Mingxiang Ye, Tangfeng Lv
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Loss-of-function mutations of liver kinase B ( LKB1 , also termed as STK11 ( serine/threonine kinase 11 )) are frequently detected in patients with non-small cell lung cancer (NSCLC). The LKB1 mutant NSCLC was refractory to almost all the antitumor treatments, including programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade therapy. Unfortunately, mechanisms underlying resistance to immunotherapy are not fully understood. In this study, we deciphered how LKB1 regulated sensitivity to anti-PD-1/PD-L1 immunotherapy. Methods We investigated the mutational landscape of LKB1 mutant NSCLC in next generation sequencing (NGS) data sets. Expression of LKB1, PD-L1 and S-phase kinase-associated protein 2 (Skp2) in NSCLC samples were assessed by immunohistochemistry (IHC). The tumor microenvironment (TME) profiling of LKB1 wild type (WT) and mutant NSCLC was performed using fluorescent multiplex IHC. Mass spectrometry and enrichment analysis were used to identify LKB1 interacting proteins. Mechanistic pathways were explored by immunoblotting, ubiquitination assay, cycloheximide chase assay and immunoprecipitation assay. Results By using NGS data sets and histological approaches, we demonstrated that LKB1 status was positively associated with PD-L1 protein expression and conferred a T cell-enriched “hot” TME in NSCLC. Patients with good responses to anti-PD-1/PD-L1 immunotherapy possessed a high level of LKB1 and PD-L1. Skp2 emerged as the molecular hub connecting LKB1 and PD-L1, by which Skp2 catalyzed K63-linked polyubiquitination on K136 and K280 residues to stabilize PD-L1 protein. Inhibition of Skp2 expression by short hairpin RNA or its E3 ligase activity by compound #25 abrogated intact expression of PD-L1 in vitro and generated a T cell-excluded “cold” TME in vivo. Thus, the LKB1-Skp2-PD-L1 regulatory loop was crucial for retaining PD-L1 protein expression and manipulation of this pathway would be a feasible approach for TME remodeling. Conclusion LKB1 and Skp2 are required for intact PD-L1 protein expression and TME remodeling in NSCLC. Inhibition of Skp2 resulted in a conversion from “hot” TME to “cold” TME and abrogated therapeutic outcomes of immunotherapy. Screening LKB1 and Skp2 status would be helpful to select recipients who may benefit from anti-PD-1/PD-L1 immunotherapy.
Do national cancer control plans address care and research for children, adolescents, and young adults? A review of status, priorities, and recommendations across 41 European countries
Authors: Joan Prades, Olga Kozhaeva, Maria Otth, Pamela Kearns, Ruth Ladenstein, Carmelo Rizzari, Delphine Heenen, Uta Dirksen, Cormac Owens, Deyan Lazarov, Ciara Sheehan, Josep M Borras, Gilles Vassal
Journal: The Lancet Regional Health - Europe (2024)
New Frontiers in Asthma Chest Imaging
Authors: Alexander M Matheson, Joseph Johnstone, Peter J Niedbalski, Jason C Woods, Mario Castro
Journal: Journal of Allergy and Clinical Immunology (2024)

Modern pulmonary imaging can reveal underlying pathological and pathophysiological changes in the lungs of people with asthma, with important clinical implications. A multitude of imaging modalities are now used to examine underlying structure/function relationships including computed tomography, magnetic resonance imaging, optical coherence tomography, and endobronchial ultrasound. Imaging-based biomarkers from these techniques, including airway dimensions, blood vessel volumes, mucus scores, ventilation defect extent and air trapping extent, often have increased sensitivity compared to traditional lung function measurements, and are increasingly used as endpoints in clinical trials. Imaging has been crucial to recent improvements in our understanding of relationships between T2-inflammation, eosinophilia, and mucus extent. With the advent of effective anti-T2 biologic therapies, computed tomography and magnetic resonance imaging techniques can identify not just which patients benefit from therapy, but why they benefit. Clinical trials have begun to assess the utility of imaging to prospectively plan airway therapy targets in bronchial thermoplasty and have potential to direct future bronchoscopic therapies. Together, imaging techniques provide a diverse set of tools to investigate how spatially-distributed airway, blood, and parenchymal abnormalities shape disease heterogeneity in patients with asthma.
Epidermal spongiotic Langerhans cell collections, but not eosinophils, are a clue to the diagnosis of allergic contact dermatitis: A series of 170 clinically- and patch test-confirmed cases
Authors: Peggy A Wu, Jiejun Wu, Regina Liu, Sydney Sullivan, Olivia Keller, Leah Caro-Chang, Yuden Pemba, Maxwell A Fung
Journal: Journal of the American Academy of Dermatology (2024)

Allergic contact dermatitis cannot be reliably differentiated from other forms of spongiotic/eczematous dermatitis by histology alone. Textbooks and recent studies have variably supported the specificity of dermal eosinophils, eosinophilic spongiosis, and Langerhans cell collections, among other features.
HGVS Nomenclature 2024: improvements to community engagement, usability, and computability
Authors: Reece K. Hart, Ivo F. A. C. Fokkema, Marina DiStefano, Ros Hastings, Jeroen F. J. Laros, Rachel Taylor, Alex H. Wagner, Johan T. den Dunnen
Journal: Genome Medicine (2024)

Abstract Background The Human Genome Variation Society (HGVS) Nomenclature is the global standard for describing and communicating variants in DNA, RNA, and protein sequences in clinical and research genomics. This manuscript details recent updates to the HGVS Nomenclature, highlighting improvements in governance, community engagement, website functionality, and underlying implementation of the standard. Methods The HGVS Variant Nomenclature Committee (HVNC) now operates under the Human Genome Organization (HUGO), facilitating broader community feedback and collaboration with related standards organizations. The website has been redesigned using modern documentation tools and practices. The specification was updated to include guidance for transcript selection and to align with recent cross-consortia recommendations for the representation of gene fusions. A formal computational grammar was introduced to improve the precision and consistency of variant descriptions. Results Major improvements in HGVS Nomenclature v. 21.1 include a redesigned website with enhanced navigation, search functionality, and mobile responsiveness; a new versioning policy aligned with software management practices; formal mechanisms for community feedback and change proposals; and adoption of Extended Backus-Naur Form (EBNF) for defining syntax. The specification now recommends MANE Select transcripts where appropriate and includes updated guidance for representing adjoined transcripts and gene fusions. All content is freely available under permissive licenses at hgvs-nomenclature.org. Conclusions These advancements establish a more sustainable foundation for maintaining and evolving the HGVS Nomenclature while improving its accessibility and utility. The introduction of formal computational grammar marks a crucial step toward unambiguous variant descriptions that can be reliably processed by both humans and machines. Combined with enhanced community engagement mechanisms and improved guidance, these changes position the HGVS Nomenclature to better serve the evolving needs of clinical and research genomics while maintaining the stability that users require.
In situ production and precise release of bioactive GM-CSF and siRNA by engineered bacteria for macrophage reprogramming in cancer immunotherapy
Authors: Yaxin Wang, Yali Fan, Xinyu Zhang, Jing Liu, Dawei Sun, Lianyue Li, Guijie Bai, Xinyu Liu, Jun Kang, Yingying Zhang, Hanjie Wang
Journal: Biomaterials (2024)
Ocular Manifestations and OCT Findings in Dengue: A Single-Arm Meta-Analysis
Authors: Mateus Pimenta Arruda, Rian Vilar Lima, Larissa Irigoyen Teixeira Barbosa, Sara Hira, Mariana Tosato Zinher, Giulia Steuernagel Del Valle, Valdez Melo Dos Anjos Filho, Heitor Santos Nogueira, Cristina Muccioli, Luiz H Lima
Journal: Ophthalmology (2024)
Dietary methionine supplementation promotes mice hematopoiesis after irradiation
Authors: Wei-Wei Zhang, Yang Xiang, Li Chen, Shao-Ting Liu, Chuan-Chuan Lin, Jiu-Xuan Li, Li-Xin Xiang, Nan-Xi Chen, Dong-Ling Shi, Yang-Yang Zhang, Xue-Ying Wang, Lan-Yue Hu, Sai Chen, Ya Luo, Cheng-Ning Tan, Pei-Pei Xue, Yang-Zhou Jiang, Sheng-Wen Calvin Li, Zhen-Xing Yang, Ji-Gang Dai, Zhong-Jun Li, Qian Ran
Journal: Military Medical Research (2024)

Abstract Background With the increasing risk of nuclear exposure, more attention has been paid to the prevention and treatment of acute radiation syndrome (ARS). Although amino acids are key nutrients involved in hematopoietic regulation, the impacts of amino acids on bone marrow hematopoiesis following irradiation and the associated mechanisms have not been fully elucidated. Hence, it is of paramount importance to study the changes in amino acid metabolism after irradiation and their effects on hematopoiesis as well as the related mechanisms. Methods The content of serum amino acids was analyzed using metabolomic sequencing. The survival rate and body weight of the irradiated mice were detected after altering the methionine content in the diet. Extracellular matrix (ECM) protein analysis was performed via proteomics analysis. Inflammatory factors were examined by enzyme-linked immunosorbent assay (ELISA). Flow cytometry, Western blotting, and immunofluorescence were employed to determine the mechanism by which S100 calcium-binding protein A4 (S100A4) regulates macrophage polarization. Results The survival time of irradiated mice was significantly associated with alterations in multiple amino acids, particularly methionine. A high methionine diet promoted irradiation tolerance, especially in the recovery of bone marrow hematopoiesis, yet with dose limitations. Folate metabolism could partially alleviate the dose bottleneck by reducing the accumulation of homocysteine. Mechanistically, high methionine levels maintained the abundance of ECM components, including collagens and glycoproteins, in the bone marrow post-irradiation, among which the level of S100A4 was significantly changed. S100A4 regulated macrophage polarization via the STAT3 pathway, inhibited bone marrow inflammation and facilitated the proliferation and differentiation of hematopoietic stem/progenitor cells. Conclusions We have demonstrated that an appropriate elevation in dietary methionine enhances irradiation tolerance in mice and explains the mechanism by which methionine regulates bone marrow hematopoiesis after irradiation.
AI-based classification of anticancer drugs reveals nucleolar condensation as a predictor of immunogenicity
Authors: Giulia Cerrato, Peng Liu, Liwei Zhao, Adriana Petrazzuolo, Juliette Humeau, Sophie Theresa Schmid, Mahmoud Abdellatif, Allan Sauvat, Guido Kroemer
Journal: Molecular Cancer (2024)

Immunogenic cell death (ICD) inducers are often identified in phenotypic screening campaigns by the release or surface exposure of various danger-associated molecular patterns (DAMPs) from malignant cells. This study aimed to streamline the identification of ICD inducers by leveraging cellular morphological correlates of ICD, specifically the condensation of nucleoli (CON). We applied artificial intelligence (AI)-based imaging analyses to Cell Paint-stained cells exposed to drug libraries, identifying CON as a marker for ICD. CON was characterized using SYTO 14 fluorescent staining and holotomographic microscopy, and visualized by AI-deconvoluted transmitted light microscopy. A neural network-based quantitative structure-activity relationship (QSAR) model was trained to link molecular descriptors of compounds to the CON phenotype, and the classifier was validated using an independent dataset from the NCI-curated mechanistic collection of anticancer agents. CON strongly correlated with the inhibition of DNA-to-RNA transcription. Cytotoxic drugs that inhibit RNA synthesis without causing DNA damage were as effective as conventional cytotoxicants in inducing ICD, as demonstrated by DAMPs release/exposure and vaccination efficacy in mice. The QSAR classifier successfully predicted drugs with a high likelihood of inducing CON. We developed AI-based algorithms for predicting CON-inducing drugs based on molecular descriptors and their validation using automated micrographs analysis, offering a new approach for screening ICD inducers with minimized adverse effects in cancer therapy.
Hydrogel-Based Nonwoven with Persistent Porosity for whole-stage Hypertonic Wound Healing by Regulating of Water Vaporization Enthalpy
Authors: Ying Gao, Shi Yin, Ying Guo, Guoyin Chen, Yanhong Wei, Jialei Yang, Hongyan Chen, Kai Hou, Meifang Zhu
Journal: Biomaterials (2024)
Brief Outpatient Rehabilitation Program for Post–COVID-19 Condition
Authors: Tom Farmen Nerli, Joel Selvakumar, Erin Cvejic, Ingar Heier, Maria Pedersen, Tone Langjordet Johnsen, Vegard Bruun Bratholm Wyller
Journal: JAMA Network Open (2024)

Post-COVID-19 condition (PCC) is emerging as a common and debilitating condition with few treatment options.
Uterus Transplant—Reply
Authors: Giuliano Testa, Anthony R. Gregg, Liza Johannesson
Journal: JAMA (2024)

In Reply We thank Drs Spillman and Sade for their comments on our article. The questions raised address 2 issues: (1) generalizability of uterus transplant and (2) inclusion and exclusion criteria stated by us and inferred from Spillman and Sade's questions.
Optimal Stopping Ages for Colorectal Cancer Screening
Authors: Matthias Harlass, Ronit R. Dalmat, Jessica Chubak, Rosita van den Puttelaar, Natalia Udaltsova, Douglas A. Corley, Christopher D. Jensen, Nicholson Collier, Jonathan Ozik, Iris Lansdorp-Vogelaar, Reinier G.S. Meester
Journal: JAMA Network Open (2024)

Prior studies have shown that the benefits, harms, and costs of colorectal cancer (CRC) screening at older ages are associated with a patient's sex, health, and screening history. However, these studies were hypothetical exercises and not directly informed by data on CRC risk.
Stereotactic Body Radiotherapy vs Sorafenib Alone in Hepatocellular Carcinoma
Authors: Laura A. Dawson, Kathryn A. Winter, Jennifer J. Knox, Andrew X. Zhu, Sunil Krishnan, Chandan Guha, Lisa A. Kachnic, Michael T. Gillin, Theodore S. Hong, Timothy D. Craig, Terence M. Williams, Ali Hosni, Eric Chen, Anne M. Noonan, Eugene J. Koay, Rishi Sinha, Michael I. Lock, Nitin Ohri, Jennifer A. Dorth, Guila Delouya, Anand Swaminath, Jennifer Moughan, Christopher H. Crane
Journal: JAMA Oncology (2024)

Importance Most patients with locally advanced hepatocellular carcinoma (HCC) recur within the liver following systemic therapy. Objective To determine whether stereotactic body radiation therapy (SBRT) improves outcomes in patients with locally advanced HCC compared with sorafenib alone. Design, Setting, and Participants This multicenter phase 3 randomized clinical trial randomized patients with HCC 1:1 to sorafenib or SBRT followed by sorafenib, stratified by performance status, liver function, degree of metastases, and macrovascular invasion. Eligible patients had HCC unsuitable for or refractory to standard local-regional therapies and were candidates for first-line systemic therapy. Data were collected from April 2013 to March 2021, and data were analyzed from July 2022 to August 2023. Intervention Personalized SBRT, 27.5 to 50 Gy in 5 fractions. Main Outcomes and Measures The primary end point was overall survival (OS). Secondary end points were progression-free survival (PFS), adverse events, and quality of life. Results Of 193 patients randomized, 177 were eligible. Accrual was stopped early due to a change in standard-of-care systemic therapy. Of 177 included patients, 150 (84.7%) were male, and the median (IQR) age was 66 (60-72) years. Macrovascular invasion was seen in 131 (74.0%). As of July 1, 2022, the median OS was 12.3 months (90% CI, 10.6-14.3) with sorafenib vs 15.8 months (90% CI, 11.4-19.2) following SBRT and sorafenib (hazard ratio [HR], 0.77; 90% CI, 0.59-1.01; 1-sided P = .06). Adjusting for stratification factors, OS was improved with SBRT (HR, 0.72; 95% CI, 0.52-0.99; 2-sided P = .04). Median PFS was improved from 5.5 months (95% CI, 3.4-6.3) with sorafenib to 9.2 months (95% CI, 7.5-11.9) with SBRT and sorafenib (HR, 0.55; 95% CI, 0.40-0.75; 2-sided P &amp;amp;lt; .001). Treatment-related grade 3 or higher adverse events were seen in 37 of 88 (42%) and 39 of 83 (47%) of patients treated with sorafenib vs SBRT and sorafenib, respectively ( P = .52). There were 2 treatment-related deaths in the sorafenib group (death not otherwise specified and liver failure) and 1 in the SBRT and sorafenib group (lung infection). At 6 months, improved quality of life was seen in 2 of 20 (10%) and 6 of 17 (35%) of patients treated with sorafenib and SBRT and sorafenib, respectively. Conclusions and Relevance In this phase 3 randomized clinical trial, among patients with locally advanced HCC, SBRT was associated with a clinically important but not statistically significant improved overall survival compared with sorafenib alone. Trial Registration ClinicalTrials.gov Identifier: NCT01730937