tbuckley/cabot-search huggingface dataset:
PET-CT-guided<i>versus</i>CT-guided biopsy in suspected malignant pleural thickening: a randomised trial
Authors: Duneesha de Fonseka, David T. Arnold, Helena J.M. Smartt, Lucy Culliford, Louise Stadon, Emma Tucker, Anna Morley, Natalie Zahan-Evans, Anna C. Bibby, Geraldine Lynch, Eleanor Mishra, Shahul Khan, Mohammed Haris, Henry Steer, Leon Lewis, Alina Ionescu, John Harvey, Kevin Blyth, Najib M. Rahman, Anthony E. Edey, Chris A. Rogers, Nick A. Maskell
Journal: European Respiratory Journal (2023)

Background Pleural biopsy is the gold standard for diagnosis of pleural malignancy but a significant proportion will have an inconclusive biopsy despite ongoing clinical suspicion of malignancy. We investigated whether positron emission tomography-computed tomography (PET-CT) targeted pleural biopsy is superior to standard CT-guided pleural biopsy following an initial non-diagnostic biopsy. Methods The TARGET trial was a multicentre, parallel group randomised trial. Patients with a previous inconclusive pleural biopsy but an ongoing suspicion of pleural malignancy were randomised (1:1) to receive either CT-guided biopsy (standard care) or PET-CT followed by a targeted CT biopsy (intervention). The primary outcome was pleural malignancy correctly identified from the trial biopsy. Results Between September 2015 and September 2018, 59 participants were randomised from eight UK hospital sites: 29 to CT-only followed by targeted biopsy and 30 to PET-CT followed by targeted biopsy. The proportion of pleural malignancy correctly identified was similar between the groups (risk ratio 1.03 (95% CI 0.83–1.29); p=0.77). The sensitivity of the trial biopsy to identify pleural malignancy was 79% (95% CI 54–94%) in the CT-only group versus 81% (95% CI 54–96%) in the PET-CT group. Conclusions The results do not support the practice of PET-CT to guide pleural biopsies in patients with a previous non-diagnostic biopsy. The diagnostic sensitivity in the CT-only group was higher than anticipated and supports the practice of repeating a CT-guided biopsy following an inconclusive result if clinical suspicion of malignancy persists.
Moving Forward with Reporting Back Individual Environmental Health Research Results
Authors: Katrina Smith Korfmacher, Julia Green Brody
Journal: Environmental Health Perspectives (2023)

Background: The practice of reporting back individual results to participants in environmental health research has evolved significantly over the past 20 years. Research findings support the potential of report-back to enhance the ethics, quality, and impact of environmental health research. Nonetheless, implementation of environmental health report-back practices is not yet routine. Objectives: We propose a framework for institutionalizing appropriate report-back to participants of their individual results across the environmental health research enterprise. We provide a brief overview of the rationales for report-back, social science research on report-back experiences over the past two decades, and recent efforts to synthesize guidance in this field. We also describe barriers to be addressed in moving toward widespread implementation of report-back. Discussion: Report-back of individual results is increasingly recognized as an ethical responsibility and essential component of impactful environmental health research. Experience shows that when personal results are returned with appropriate contextual information, report-back can increase environmental health literacy, promote individual actions, and enhance engagement in policy change. Therefore, report-back can promote environmental justice and reduce disparities in access to science. Despite this evidence base, report-back is not widely implemented. We recommend the collaborative development of guidelines, training, and resources to build capacity for appropriate report-back to study participants across the environmental health research enterprise, and we identify research priorities to advance the field. Development of tools and shared infrastructure for report-back holds promise for reducing barriers while ensuring high-quality personalized reports. Disseminating successful case studies could also advance excellence. We recommend including diverse scientific disciplines, community partners, representatives of study populations, clinicians, institutional review boards (IRBs), legal experts, public health professionals, and government officials in further developing this critical aspect of environmental health research. https://doi.org/10.1289/EHP12463
<i>Notes from the Field:</i> COVID-19 Pandemic-Related Changes in Blood Lead Screening — Chicago, Illinois, 2017–2022
Authors: Hillary Spencer, Emile Jorgensen, Jennifer Seo, Candice Robinson
Journal: MMWR Morbidity and Mortality Weekly Report (2023)

Lead is an environmental hazard that can cause serious harm to young children.Early childhood lead exposure can damage the brain and nervous system, slow growth and development, and cause hearing and speech problems (1).Screening for elevated blood lead levels (BLL) is essential for routine care of young children.At the onset of the COVID-19 pandemic, substantial disruptions to health care access occurred for routine, preventive care (2).At the onset of the pandemic (January-May 2020), 34% fewer U.S. children aged <6 years received blood lead level testing than during the same months in 2019 (3).The Chicago Department of Public Health (CDPH) characterized patterns of blood lead testing among young children in Chicago from the onset of the pandemic in 2019 through 2022.
Unintentional Firearm Injury Deaths Among Children and Adolescents Aged 0–17 Years — National Violent Death Reporting System, United States, 2003–2021
Authors: Rebecca F. Wilson, Sasha Mintz, Janet M. Blair, Carter J. Betz, Abby Collier, Katherine A. Fowler
Journal: MMWR Morbidity and Mortality Weekly Report (2023)

In the United States, unintentional injury is the fourth leading cause of death among infants (i.e., children aged <1 year) and is the top cause of death among children and adolescents aged 1-17 years; firearms are a leading injury method. Unsecured firearms (e.g., unlocked and loaded) are associated with risk for unintentional childhood firearm injury death. Data recorded during 2003-2021 by the National Violent Death Reporting System (NVDRS) from 49 states, the District of Columbia, and Puerto Rico were used to characterize unintentional firearm injury deaths of U.S. infants, children, and adolescents aged 0-17 years (referred to as children in this report). NVDRS identified 1,262 unintentional firearm injury deaths among children aged 0-17 years: the largest percentage (33%) of these deaths were among children aged 11-15 years, followed by 29% among those aged 0-5 years, 24% among those aged 16-17 years, and 14% among persons aged 6-10 years. Overall, 83% of unintentional firearm injury deaths occurred among boys. The majority (85%) of victims were fatally injured at a house or apartment, including 56% in their own home. Approximately one half (53%) of fatal unintentional firearm injuries to children were inflicted by others; 38% were self-inflicted. In 9% of incidents, it was unknown whether the injury was self- or other-inflicted. Approximately two thirds (67%) of shooters were playing with or showing the firearm to others when it discharged. Overall, firearms used in unintentional injury deaths were often stored loaded (74%) and unlocked (76%) and were most commonly accessed from nightstands and other sleeping areas (30%). Unintentional firearm injury deaths of children are preventable. Secured firearm storage practices (e.g., storing firearms locked, unloaded, and separate from ammunition) have been identified as protective factors against child firearm injuries and deaths, underscoring the importance of policymakers, health care professionals (e.g., pediatricians), and others partnering with parents, caregivers, and firearm owners to promote secure firearm storage.
<i>Notes from the Field:</i> Transmission of Mpox to Nonsexual Close Contacts — Two U.S. Jurisdictions, May 1–July 31, 2022
Authors: Ebony S. Thomas, Zachary J. Madewell, William L. Still, Julia Rowse, Brandon Shapiro, Emily Gately, Julie Shaffner, Anil T. Mangla, Jessica N. Ricaldi
Journal: MMWR Morbidity and Mortality Weekly Report (2023)
Harnessing p53 to Improve Immunotherapy for Lung Cancer Treatment
Authors: Xiaoteng Niu, Luis Martinez
Journal: Cancer Research (2023)

Immunotherapy, especially immune checkpoint blockade (ICB), has become a critical therapy for lung cancer treatment in recent years. Tumor mutational burden (TMB) is one of the decisive biomarkers for predicting ICB effect. Writing in Cancer Cell, Zhu and colleagues use autochthonous and syngeneic mouse models to show that p53 mutation and tumor heterogeneity may be responsible for resistance in patients with lung cancer. Pole-induced high TMB shows enhanced immunogenicity in KrasG12D mice, however, loss of p53 in KrasG12D PoleP286/+ mice can lead to an immune suppressive profile of lung tumors, which diminishes immune response to ICB. Moreover, high TMB causes high shared mutations, which helps promote immune protection and immune memory. Heterogeneity can drive immune escape to tumor cells causing resistance to ICB. Decreased cGAS/STING signaling may explain possible resistance to ICB. On the basis of the new model found by Zhu and colleagues for lung cancer, combined ICB with STING agonists or p53 inducers may be new therapeutic options to improve the efficacy of ICB for patients with lung cancer with high TMB.
Fimepinostat Impairs NF­κB and PI3K/AKT Signaling and Enhances Gemcitabine Efficacy in H3.3K27M-Diffuse Intrinsic Pontine Glioma
Authors: Dan Wang, Kun Yan, Hongxing Yu, Haocheng Li, Wei Zhou, Yaqiang Hong, Shuning Guo, Yi Wang, Cheng Xu, Changcun Pan, Yujie Tang, Nian Liu, Wei Wu, Liwei Zhang, Qiaoran Xi
Journal: Cancer Research (2023)

Abstract Diffuse intrinsic pontine glioma (DIPG) is the most aggressive pediatric brain tumor, and the oncohistone H3.3K27M mutation is associated with significantly worse clinical outcomes. Despite extensive research efforts, effective approaches for treating DIPG are lacking. Through drug screening, we identified the combination of gemcitabine and fimepinostat as a potent therapeutic intervention for H3.3K27M DIPG. H3.3K27M facilitated gemcitabine-induced apoptosis in DIPG, and gemcitabine stabilized and activated p53, including increasing chromatin accessibility for p53 at apoptosis-related loci. Gemcitabine simultaneously induced a prosurvival program in DIPG through activation of RELB-mediated NF­κB signaling. Specifically, gemcitabine induced the transcription of long terminal repeat elements, activated cGAS-STING signaling, and stimulated noncanonical NF­κB signaling. A drug screen in gemcitabine-treated DIPG cells revealed that fimepinostat, a dual inhibitor of HDAC and PI3K, effectively suppressed the gemcitabine-induced NF­κB signaling in addition to blocking PI3K/AKT activation. Combination therapy comprising gemcitabine and fimepinostat elicited synergistic antitumor effects in vitro and in orthotopic H3.3K27M DIPG xenograft models. Collectively, p53 activation using gemcitabine and suppression of RELB-mediated NF­κB activation and PI3K/AKT signaling using fimepinostat is a potential therapeutic strategy for treating H3.3K27M DIPG. Significance: Gemcitabine activates p53 and induces apoptosis to elicit antitumor effects in H3.3K27M DIPG, which can be enhanced by blocking NF­κB and PI3K/AKT signaling with fimepinostat, providing a synergistic combination therapy for DIPG.
Exploring the Role of Hyperinsulinemia in Obesity-Associated Tumor Development
Authors: Ericka Vélez-Bonet, Kristyn Gumpper-Fedus, Zobeida Cruz-Monserrate
Journal: Cancer Research (2023)

Abstract Although there has been a long-standing connection between hyperinsulinemia and cancer development, there is a lack of understanding of the role of the insulin receptor on cells that can become cancerous. In a recent issue of Cell Metabolism, Zhang and colleagues, using a diet-induced obesity mouse model, identified a direct function of insulin receptors on pancreatic acinar cells expressing a KRASG12D mutation in promoting obesity-associated pancreatic cancer. Furthermore, insulin receptor signaling from hyperinsulinemia promoted the secretion of digestive enzymes that contributed to acinar to ductal metaplasia. These findings highlight an important connection between obesity, diabetes, and pancreatic tumor development and suggest potential strategies for obesity-associated cancer prevention targeting the insulin receptor signaling pathways.
Osimertinib covalently binds to CD34 and eliminates myeloid leukemia stem/progenitor cells
Authors: Li Xia, Jie-Yang Liu, Meng-Ying Yang, Xue-Hong Zhang, Yue Jiang, Qian-Qian Yin, Chen-Hui Luo, Hong-Chen Liu, Zhi-Jie Kang, Cheng-Tao Zhang, Bei-Bei Gao, Ai-Wu Zhou, Hai-Yan Cai, Edmund K. Waller, Jin-Song Yan, Ying Lu
Journal: Cancer Research (2023)

Abstract Osimertinib is a third-generation covalent EGFR inhibitor that is used in treating non–small cell lung cancer. First-generation EGFR inhibitors were found to elicit pro-differentiation effect on acute myeloid leukemia (AML) cells in preclinical studies, but clinical trials yielded mostly negative results. Here, we report that osimertinib selectively induced apoptosis of CD34+ leukemia stem/progenitor cells but not CD34− cells in EGFR-negative AML and chronic myeloid leukemia (CML). Covalent binding of osimertinib to CD34 at cysteines 199 and 177 and suppression of Src family kinases (SFK) and downstream STAT3 activation contributed to osimertinib-induced cell death. SFK and STAT3 inhibition induced synthetic lethality with osimertinib in primary CD34+ cells. CD34 expression was elevated in AML cells compared with their normal counterparts. Genomic, transcriptomic, and proteomic profiling identified mutation and gene expression signatures of patients with AML with high CD34 expression, and univariate and multivariate analyses indicated the adverse prognostic significance of high expression of CD34. Osimertinib treatment induced responses in AML patient-derived xenograft models that correlated with CD34 expression while sparing normal CD34+ cells. Clinical responses were observed in two patients with CD34high AML who were treated with osimertinib on a compassionate-use basis. These findings reveal the therapeutic potential of osimertinib for treating CD34high AML and CML and describe an EGFR-independent mechanism of osimertinib-induced cell death in myeloid leukemia. Significance: Osimertinib binds CD34 and selectively kills CD34+ leukemia cells to induce remission in preclinical models and patients with AML with a high percentage of CD34+ blasts, providing therapeutic options for myeloid leukemia patients.
Suicide Rates by Industry and Occupation — National Vital Statistics System, United States, 2021
Authors: Aaron Sussell, Cora Peterson, Jia Li, Arialdi Miniño, Kenneth A. Scott, Deborah M. Stone
Journal: MMWR Morbidity and Mortality Weekly Report (2023)

The suicide rate among the U.S. working-age population has increased approximately 33% during the last 2 decades. To guide suicide prevention strategies, CDC analyzed suicide deaths by industry and occupation in 49 states, using data from the 2021 National Vital Statistics System. Industry (the business activity of a person's employer or, if self-employed, their own business) and occupation (a person's job or the type of work they do) are distinct ways to categorize employment. The overall suicide rates by sex in the civilian noninstitutionalized working population were 32.0 per 100,000 among males and 8.0 per 100,000 among females. Major industry groups with the highest suicide rates included Mining (males = 72.0); Construction (males = 56.0; females = 10.4); Other Services (e.g., automotive repair; males = 50.6; females = 10.4); Arts, Entertainment, and Recreation (males = 47.9; females = 15.0); and Agriculture, Forestry, Fishing, and Hunting (males = 47.9). Major occupation groups with the highest suicide rates included Construction and Extraction (males = 65.6; females = 25.3); Farming, Fishing, and Forestry (e.g., agricultural workers; males = 49.9); Personal Care and Service (males = 47.1; females = 15.9); Installation, Maintenance, and Repair (males = 46.0; females = 26.6); and Arts, Design, Entertainment, Sports, and Media (males = 44.5; females = 14.1). By integrating recommended programs, practices, and training into existing policies, workplaces can be important settings for suicide prevention. CDC provides evidence-based suicide prevention strategies in its Suicide Prevention Resource for Action and Critical Steps Your Workplace Can Take Today to Prevent Suicide, NIOSH Science Blog.
Metabolic GWAS-based dissection of genetic basis underlying nutrient quality variation and domestication of cassava storage root
Authors: Zehong Ding, Lili Fu, Bin Wang, Jianqiu Ye, Wenjun Ou, Yan Yan, Meiying Li, Liwang Zeng, Xuekui Dong, Weiwei Tie, Xiaoxue Ye, Jinghao Yang, Zhengnan Xie, Yu Wang, Jianchun Guo, Songbi Chen, Xinhui Xiao, Zhongqing Wan, Feifei An, Jiaming Zhang, Ming Peng, Jie Luo, Kaimian Li, Wei Hu
Journal: Genome biology (2023)

Abstract Background Metabolites play critical roles in regulating nutritional qualities of plants, thereby influencing their consumption and human health. However, the genetic basis underlying the metabolite-based nutrient quality and domestication of root and tuber crops remain largely unknown. Results We report a comprehensive study combining metabolic and phenotypic genome-wide association studies to dissect the genetic basis of metabolites in the storage root (SR) of cassava. We quantify 2,980 metabolic features in 299 cultivated cassava accessions. We detect 18,218 significant marker-metabolite associations via metabolic genome-wide association mapping and identify 12 candidate genes responsible for the levels of metabolites that are of potential nutritional importance. Me3GT , MeMYB4 , and UGT85K4 / UGT85K5 , which are involved in flavone, anthocyanin, and cyanogenic glucoside metabolism, respectively, are functionally validated through in vitro enzyme assays and in vivo gene silencing analyses. We identify a cluster of cyanogenic glucoside biosynthesis genes, among which CYP79D1 , CYP71E7b , and UGT85K5 are highly co-expressed and their allelic combination contributes to low linamarin content. We find MeMYB4 is responsible for variations in cyanidin 3-O-glucoside and delphinidin 3-O-rutinoside contents, thus controlling SR endothelium color. We find human selection affects quercetin 3-O-glucoside content and SR weight per plant. The candidate gene MeFLS1 is subject to selection during cassava domestication, leading to decreased quercetin 3-O-glucoside content and thus increased SR weight per plant. Conclusions These findings reveal the genetic basis of cassava SR metabolome variation, establish a linkage between metabolites and agronomic traits, and offer useful resources for genetically improving the nutrition of cassava and other root crops.
A time-resolved meta-analysis of consensus gene expression profiles during human T-cell activation
Authors: Michael Rade, Sebastian Böhlen, Vanessa Neuhaus, Dennis Löffler, Conny Blumert, Maximilian Merz, Ulrike Köhl, Susann Dehmel, Katherina Sewald, Kristin Reiche
Journal: Genome biology (2023)

Abstract Background The coordinated transcriptional regulation of activated T-cells is based on a complex dynamic behavior of signaling networks. Given an external stimulus, T-cell gene expression is characterized by impulse and sustained patterns over the course. Here, we analyze the temporal pattern of activation across different T-cell populations to develop consensus gene signatures for T-cell activation. Results Here, we identify and verify general biomarker signatures robustly evaluating T-cell activation in a time-resolved manner. We identify time-resolved gene expression profiles comprising 521 genes of up to 10 disjunct time points during activation and different polarization conditions. The gene signatures include central transcriptional regulators of T-cell activation, representing successive waves as well as sustained patterns of induction. They cover sustained repressed, intermediate, and late response expression rates across multiple T-cell populations, thus defining consensus biomarker signatures for T-cell activation. In addition, intermediate and late response activation signatures in CAR T-cell infusion products are correlated to immune effector cell-associated neurotoxicity syndrome. Conclusion This study is the first to describe temporally resolved gene expression patterns across T-cell populations. These biomarker signatures are a valuable source, e.g., monitoring transcriptional changes during T-cell activation with a reasonable number of genes, annotating T-cell states in single-cell transcriptome studies, or assessing dysregulated functions of human T-cell immunity.
Author Correction: Chromosome-level genomes of three key Allium crops and their trait evolution
Authors: Fei Hao, Xue Liu, Botong Zhou, Zunzhe Tian, Lina Zhou, Hang Zong, Jiyan Qi, Juan He, Yongting Zhang, Peng Zeng, Qiong Li, Kai Wang, Keke Xia, Xing Guo, Li Li, Wenwen Shao, Bohan Zhang, Shengkang Li, Haifeng Yang, Linchong Hui, Wei Chen, Lixin Peng, Feipeng Liu, Zi-Qiang Rong, Yingmei Peng, Wenbo Zhu, John A. McCallum, Zhen Li, Xun Xu, Hui Yang, Richard C. Macknight, Wen Wang, Jing Cai
Journal: Nature Genetics (2023)
Lysosomal destabilization: A missing link between pathological calcification and osteoarthritis
Authors: Tao Ye, Chenyu Wang, Jianfei Yan, Zixuan Qin, Wenpin Qin, Yuxuan Ma, Qianqian Wan, Weicheng Lu, Mian Zhang, Franklin R. Tay, Kai Jiao, Lina Niu
Journal: Bioactive Materials (2023)

Calcification of cartilage by hydroxyapatite is a hallmark of osteoarthritis and its deposition strongly correlates with the severity of osteoarthritis. However, no effective strategies are available to date on the prevention of hydroxyapatite deposition within the osteoarthritic cartilage and its role in the pathogenesis of this degenerative condition is still controversial. Therefore, the present work aims at uncovering the pathogenic mechanism of intra-cartilaginous hydroxyapatite in osteoarthritis and developing feasible strategies to counter its detrimental effects. With the use of