tbuckley/cabot-search huggingface dataset:
Macrophage-coated tumor cluster aggravates hepatoma invasion and immunotherapy resistance via generating local immune deprivation
Authors: Junya Ning, Yingnan Ye, Hongru Shen, Runjiao Zhang, Huikai Li, Tianqiang Song, Rui Zhang, Pengpeng Liu, Guidong Chen, Hailong Wang, Fenglin Zang, Xiangchun Li, Jinpu Yu
Journal: Cell Reports Medicine (2024)

Immune checkpoint inhibitors (ICIs) represent a promising treatment for hepatocellular carcinoma (HCC) due to their capacity for abundant lymphocyte infiltration. However, some patients with HCC respond poorly to ICI therapy due to the presence of various immunosuppressive factors in the tumor microenvironment. Our research reveals that a macrophage-coated tumor cluster (MCTC) signifies a unique spatial structural organization in HCC correlating with diminished recurrence-free survival and overall survival in a total of 572 HCC cases from 3 internal cohorts and 2 independent external validation cohorts. Mechanistically, tumor-derived macrophage-associated lectin Mac-2 binding protein (M2BP) induces MCTC formation and traps immunocompetent cells at the edge of MCTCs to induce intratumoral cytotoxic T cell exclusion and local immune deprivation. Blocking M2BP with a Mac-2 antagonist might provide an effective approach to prevent MCTC formation, enhance T cell infiltration, and thereby improve the efficacy of ICI therapy in HCC.
Application of the ERS/ATS Spirometry Standards and Race-Neutral Equations in the COPDGene Study
Authors: Enrico Schiavi, Min Hyung Ryu, Leonardo Martini, Aparna Balasubramanian, Meredith C McCormack, Spyridon Fortis, Elizabeth A Regan, Matteo Bonini, Craig P. Hersh
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

Rationale: The European Respiratory Society (ERS) and the American Thoracic Society (ATS) recommend using z-scores, and the ATS has recommended using Global Lung Initiative (GLI)- "Global" race-neutral reference equations for spirometry interpretation. However, these recommendations have been variably implemented and the impact has not been widely assessed, both in clinical and research settings. Objectives: We evaluated the ERS/ATS airflow obstruction severity classification. Methods: In the COPDGene Study (n = 10,108), airflow obstruction has been defined as a forced expiratory volume in one second to forced vital capacity (FEV1/FVC) ratio <0.70, with spirometry severity graded from class 1 to 4 based on race-specific percent predicted (pp) FEV1 cut-points as recommended by the Global Initiative for Chronic Obstructive Lung Disease (GOLD). We compared the GOLD approach, using NHANES III race-specific equations, to the application of GLI-Global equations using the ERS/ATS definition of airflow obstruction as FEV1/FVC ratio < lower limit of normal (LLN) and z-FEV1 cut-points of –1.645, –2.5, and –4 ("zGLI Global"). We tested the four-tier severity scheme for association with COPD outcomes. Measurements and Main Results: The lowest agreement between ERS/ATS with zGLI Global and the GOLD classification was observed in individuals with milder disease (56.9% and 42.5% in GOLD 1 and 2) and race was a major determinant of redistribution. After adjustment for relevant covariates, zGLI Global distinguished all-cause mortality risk between normal spirometry and the first grade of COPD (Hazard Ratio 1.23, 95% CI 1.04-1.44, p=0.014), and showed a linear increase in exacerbation rates with increasing disease severity, in comparison to GOLD. Conclusions: The zGLI Global severity classification outperformed GOLD in the discrimination of survival, exacerbations, and imaging characteristics.
Regulation of T helper cell differentiation by the interplay between histone modification and chromatin interaction
Authors: Shuai Liu, Yaqiang Cao, Kairong Cui, Gang Ren, Tingting Zhao, Xuezheng Wang, Danping Wei, Zuojia Chen, Rama Krishna Gurram, Chengyu Liu, Chuan Wu, Jinfang Zhu, Keji Zhao
Journal: Immunity (2024)
Microglial P2Y6 calcium signaling promotes phagocytosis and shapes neuroimmune responses in epileptogenesis
Authors: Anthony D. Umpierre, Bohan Li, Katayoun Ayasoufi, Whitney L. Simon, Shunyi Zhao, Manling Xie, Grace Thyen, Benjamin Hur, Jiaying Zheng, Yue Liang, Dale B. Bosco, Mark A. Maynes, Zhaofa Wu, Xinzhu Yu, Jaeyun Sung, Aaron J. Johnson, Yulong Li, Long-Jun Wu
Journal: Neuron (2024)
Arachidonic acid released by PIK3CA mutant tumor cells triggers malignant transformation of colonic epithelium by inducing chromatin remodeling
Authors: Baoyu He, Qingli Bie, Rou Zhao, Yugang Yan, Guanjun Dong, Baogui Zhang, Sen Wang, Wenrong Xu, Dongxing Tian, Yujun Hao, Yanhua Zhang, Mingsheng Zhao, Huabao Xiong, Bin Zhang
Journal: Cell Reports Medicine (2024)

Key gene mutations are essential for colorectal cancer (CRC) development; however, how the mutated tumor cells impact the surrounding normal cells to promote tumor progression has not been well defined. Here, we report that PIK3CA mutant tumor cells transmit oncogenic signals and result in malignant transformation of intestinal epithelial cells (IECs) via paracrine exosomal arachidonic acid (AA)-induced H3K4 trimethylation. Mechanistically, PIK3CA mutations sustain SGK3-FBW7-mediated stability of the cPLA2 protein, leading to the synthetic increase in AA, which is transported through exosome and accumulated in IECs. Transferred AA directly binds Menin and strengthens the interactions of Menin and MLL1/2 methyltransferase. Finally, the combination of VTP50469, an inhibitor of the Menin-MLL interaction, and alpelisib synergistically represses PDX tumors harboring PIK3CA mutations. Together, these findings unveil the metabolic link between PIK3CA mutant tumor cells and the IECs, highlighting AA as the potential target for the treatment of patients with CRC harboring PIK3CA mutations.
A comprehensive single-cell breast tumor atlas defines epithelial and immune heterogeneity and interactions predicting anti-PD-1 therapy response
Authors: Lily Xu, Kaitlyn Saunders, Shao-Po Huang, Hildur Knutsdottir, Kenneth Martinez-Algarin, Isabella Terrazas, Kenian Chen, Heather M. McArthur, Julia Maués, Christine Hodgdon, Sangeetha M. Reddy, Evanthia T. Roussos Torres, Lin Xu, Isaac S. Chan
Journal: Cell Reports Medicine (2024)

We present an integrated single-cell RNA sequencing atlas of the primary breast tumor microenvironment (TME) containing 236,363 cells from 119 biopsy samples across eight datasets. In this study, we leverage this resource for multiple analyses of immune and cancer epithelial cell heterogeneity. We define natural killer (NK) cell heterogeneity through six subsets in the breast TME. Because NK cell heterogeneity correlates with epithelial cell heterogeneity, we characterize epithelial cells at the level of single-gene expression, molecular subtype, and 10 categories reflecting intratumoral transcriptional heterogeneity. We develop InteractPrint, which considers how cancer epithelial cell heterogeneity influences cancer-immune interactions. We use T cell InteractPrint to predict response to immune checkpoint inhibition (ICI) in two breast cancer clinical trials testing neoadjuvant anti-PD-1 therapy. T cell InteractPrint was predictive of response in both trials versus PD-L1 (AUC = 0.82, 0.83 vs. 0.50, 0.72). This resource enables additional high-resolution investigations of the breast TME.
Prefrontal cortical dynorphin peptidergic transmission constrains threat-driven behavioral and network states
Authors: Huikun Wang, Rodolfo J. Flores, Hector E. Yarur, Aaron Limoges, Hector Bravo-Rivera, Sanne M. Casello, Niharika Loomba, Juan Enriquez-Traba, Miguel Arenivar, Queenie Wang, Robert Ganley, Charu Ramakrishnan, Lief E. Fenno, Yoon Kim, Karl Deisseroth, Grace Or, Chunyang Dong, Mark A. Hoon, Lin Tian, Hugo A. Tejeda
Journal: Neuron (2024)
Proteogenomic Characterization Reveals Estrogen Signaling as a Target for Never-Smoker Lung Adenocarcinoma Patients without <i>EGFR</i> or <i>ALK</i> Alterations
Authors: Seung-Jin Park, Shinyeong Ju, Sung-Ho Goh, Byoung-Ha Yoon, Jong-Lyul Park, Jeong-Hwan Kim, Seonjeong Lee, Sang-Jin Lee, Yumi Kwon, Wonyeop Lee, Kyung Chan Park, Geon Kook Lee, Seog Yun Park, Sunshin Kim, Seon-Young Kim, Ji-Youn Han, Cheolju Lee
Journal: Cancer Research (2024)

Abstract Never-smoker lung adenocarcinoma (NSLA) is prevalent in Asian populations, particularly in women. EGFR mutations and anaplastic lymphoma kinase (ALK) fusions are major genetic alterations observed in NSLA, and NSLA with these alterations have been well studied and can be treated with targeted therapies. To provide insights into the molecular profile of NSLA without EGFR and ALK alterations (NENA), we selected 141 NSLA tissues and performed proteogenomic characterization, including whole genome sequencing (WGS), transcriptomic, methylation EPIC array, total proteomic, and phosphoproteomic analyses. Forty patients with NSLA harboring EGFR and ALK alterations and seven patients with NENA with microsatellite instability were excluded. Genome analysis revealed that TP53 (25%), KRAS (22%), and SETD2 (11%) mutations and ROS1 fusions (14%) were the most frequent genetic alterations in NENA patients. Proteogenomic impact analysis revealed that STK11 and ERBB2 somatic mutations had broad effects on cancer-associated genes in NENA. DNA copy number alteration analysis identified 22 prognostic proteins that influenced transcriptomic and proteomic changes. Gene set enrichment analysis revealed estrogen signaling as the key pathway activated in NENA. Increased estrogen signaling was associated with proteogenomic alterations, such as copy number deletions in chromosomes 14 and 21, STK11 mutation, and DNA hypomethylation of LLGL2 and ST14. Finally, saracatinib, an Src inhibitor, was identified as a potential drug for targeting activated estrogen signaling in NENA and was experimentally validated in vitro. Collectively, this study enhanced our understanding of NENA NSLA by elucidating the proteogenomic landscape and proposed saracatinib as a potential treatment for this patient population that lacks effective targeted therapies. Significance: The proteogenomic landscape in never-smoker lung cancer without known driver mutations reveals prognostic proteins and enhanced estrogen signaling that can be targeted as a potential therapeutic strategy to improve patient outcomes.
Non–High-Density Lipoprotein Cholesterol Levels From Childhood to Adulthood and Cardiovascular Disease Events
Authors: Feitong Wu, David R. Jacobs, Stephen R. Daniels, Mika Kähönen, Jessica G. Woo, Alan R. Sinaiko, Jorma S. A. Viikari, Lydia A. Bazzano, Julia Steinberger, Elaine M. Urbina, Alison J. Venn, Olli T. Raitakari, Terence Dwyer, Markus Juonala, Costan G. Magnussen
Journal: JAMA (2024)

Importance Elevated non–high-density lipoprotein cholesterol (non–HDL-C; a recommended measure of lipid-related cardiovascular risk) is common in children and increases risk of adult cardiovascular disease (CVD). Whether resolution of elevated childhood non–HDL-C levels by adulthood is associated with reduced risk of clinical CVD events is unknown. Objective To examine the associations of non–HDL-C status between childhood and adulthood with incident CVD events. Design, Setting, and Participants Individual participant data from 6 prospective cohorts of children (mean age at baseline, 10.7 years) in the US and Finland. Recruitment took place between 1970 and 1996, with a final follow-up in 2019. Exposures Child (age 3-19 years) and adult (age 20-40 years) non–HDL-C age- and sex-specific z scores and categories according to clinical guideline–recommended cutoffs for dyslipidemia. Main Outcomes and Measures Incident fatal and nonfatal CVD events adjudicated by medical records. Results Over a mean length of follow-up of 8.9 years after age 40 years, 147 CVD events occurred among 5121 participants (60% women; 15% Black). Both childhood and adult non–HDL-C levels were associated with increased risk of CVD events (hazard ratio [HR], 1.42 [95% CI, 1.18-1.70] and HR, 1.50 [95% CI, 1.26-1.78] for a 1-unit increase in z score, respectively), but the association for childhood non–HDL-C was reduced when adjusted for adult levels (HR, 1.12 [95% CI, 0.89-1.41]). A complementary analysis showed that both childhood non–HDL-C levels and the change between childhood and adulthood were independently associated with the outcome, suggesting that from a preventive perspective, both childhood non–HDL-C levels and the change into adulthood are informative. Compared with those whose non-HDL-C levels remained within the guideline-recommended range in childhood and adulthood, participants who had incident non–HDL-C dyslipidemia from childhood to adulthood and those with persistent dyslipidemia had increased risks of CVD events (HR, 2.17 [95% CI, 1.00-4.69] and HR, 5.17 [95% CI, 2.80-9.56], respectively). Individuals who had dyslipidemic non–HDL-C in childhood but whose non-HDL-C levels were within the guideline-recommended range in adulthood did not have a significantly increased risk (HR, 1.13 [95% CI, 0.50-2.56]). Conclusions and Relevance Individuals with persistent non–HDL-C dyslipidemia from childhood to adulthood had an increased risk of CVD events, but those in whom dyslipidemic non–HDL-C levels resolve by adulthood have similar risk to individuals who were never dyslipidemic. These findings suggest that interventions to prevent and reduce elevated childhood non–HDL-C levels may help prevent premature CVD.
Simulation training of laparoscopic biliary-enteric anastomosis with a three-dimensional-printed model leads to better skill transfer: a randomized controlled trial
Authors: Jiliang Shen, Yaping Zhang, Bin Zhang, Chen Lu, Jiasheng Cao, Mingyu Chen, Bin Zheng, Jin Yang
Journal: International Journal of Surgery (2024)

A new simulation model and training curriculum for laparoscopic bilioenteric anastomosis has been developed. Currently, this concept lacks evidence for the transfer of skills from simulation to clinical settings. This study was conducted to determine whether training with a three-dimensional (3D) bilioenteric anastomosis model result in greater transfer of skills than traditional training methods involving video observation and a general suture model.
A modified endoscopic full-thickness resection technique: double traction-assisted resection
Authors: Yanjun Song, Xin Sun, Chang Ge, Ruyuan Li
Journal: Endoscopy (2024)

With the extensive use of gastrointestinal endoscopy and endoscopic ultrasonography (EUS), the diagnosis rate of gastric submucosal tumors (SMTs) has increased. While most SMTs are thought to be benign, up to 13% have malignant potential, especially those originating in the muscularis propria layer [1]. With the advance of endoscopic technology, endoscopic treatment for SMTs has proven to be an effective, safe, economical, and most importantly, minimally invasive method for both accurate histopathological evaluation and curative treatment. With advances in endoscopic techniques, exposed endoscopic full-thickness resection (EFTR) has been demonstrated to be an effective and minimally invasive method for gastric SMTs originating from the deep muscularis propria layer or those with extraluminal growth tumor [2]. It is however a time-consuming procedure and not easy to perform, particularly for some lesions >2.0 cm. We here report a modified exposed EFTR technique, in which we performed EFTR assisted by double floss traction ([Video 1]).
Airway remodelling in asthma and the epithelium: on the edge of a new era
Authors: Gilda Varricchi, Christopher E. Brightling, Christopher Grainge, Bart N. Lambrecht, Pascal Chanez
Journal: European Respiratory Journal (2024)

Asthma is a chronic, heterogeneous disease of the airways, often characterised by structural changes known collectively as airway remodelling. In response to environmental insults, including pathogens, allergens and pollutants, the epithelium can initiate remodelling via an inflammatory cascade involving a variety of mediators that have downstream effects on both structural and immune cells. These mediators include the epithelial cytokines thymic stromal lymphopoietin, interleukin (IL)-33 and IL-25, which facilitate airway remodelling through cross-talk between epithelial cells and fibroblasts, and between mast cells and airway smooth muscle cells, as well as through signalling with immune cells such as macrophages. The epithelium can also initiate airway remodelling independently of inflammation in response to the mechanical stress present during bronchoconstriction. Furthermore, genetic and epigenetic alterations to epithelial components are believed to influence remodelling. Here, we review recent advances in our understanding of the roles of the epithelium and epithelial cytokines in driving airway remodelling, facilitated by developments in genetic sequencing and imaging techniques. We also explore how new and existing therapeutics that target the epithelium and epithelial cytokines could modify airway remodelling.
The paradox of the safer cigarette: understanding the pulmonary effects of electronic cigarettes
Authors: Kassandra Allbright, John Villandre, Laura E. Crotty Alexander, Michael Zhang, Kambez H. Benam, John Evankovich, Melanie Königshoff, Divay Chandra
Journal: European Respiratory Journal (2024)

Electronic cigarette (e-cigarette) use continues to rise globally. E-cigarettes have been presented as safer alternatives to combustion cigarettes that can mitigate the harm associated with tobacco products; however, the degree to which e-cigarette use itself can lead to morbidity and mortality is not fully defined. Herein we describe how e-cigarettes function; discuss the current knowledge of the effects of e-cigarette aerosol on lung cell cytotoxicity, inflammation, antipathogen immune response, mucociliary clearance, oxidative stress, DNA damage, carcinogenesis, matrix remodelling and airway hyperresponsiveness; and summarise the impact on lung diseases, including COPD, respiratory infection, lung cancer and asthma. We highlight how the inclusion of nicotine or flavouring compounds in e-liquids can impact lung toxicity. Finally, we consider the paradox of the safer cigarette: the toxicities of e-cigarettes that can mitigate their potential to serve as a harm reduction tool in the fight against traditional cigarettes, and we summarise the research needed in this underinvestigated area.
Noninvasive Stratification of Colon Cancer by Multiplex PET Imaging
Authors: Gaurav Malviya, Tamsin R.M. Lannagan, Emma Johnson, Agata Mackintosh, Robert Bielik, Adam Peters, Dmitry Soloviev, Gavin Brown, Rene Jackstadt, Colin Nixon, Kathryn Gilroy, Andrew Campbell, Owen J. Sansom, David Y. Lewis
Journal: Clinical Cancer Research (2024)

Abstract Purpose: The current approach for molecular subtyping of colon cancer relies on gene expression profiling, which is invasive and has limited ability to reveal dynamics and spatial heterogeneity. Molecular imaging techniques, such as PET, present a noninvasive alternative for visualizing biological information from tumors. However, the factors influencing PET imaging phenotype, the suitable PET radiotracers for differentiating tumor subtypes, and the relationship between PET phenotypes and tumor genotype or gene expression–based subtyping remain unknown. Experimental Design: In this study, we conducted 126 PET scans using four different metabolic PET tracers, [18F]fluorodeoxy-D-glucose ([18F]FDG), O-(2-[18F]fluoroethyl)-l-tyrosine ([18F]FET), 3′-deoxy-3′-[18F]fluorothymidine ([18F]FLT), and [11C]acetate ([11C]ACE), using a spectrum of five preclinical colon cancer models with varying genetics (BMT, AKPN, AK, AKPT, KPN), at three sites (subcutaneous, orthograft, autochthonous) and at two tumor stages (primary vs. metastatic). Results: The results demonstrate that imaging signatures are influenced by genotype, tumor environment, and stage. PET imaging signatures exhibited significant heterogeneity, with each cancer model displaying distinct radiotracer profiles. Oncogenic Kras and Apc loss showed the most distinctive imaging features, with [18F]FLT and [18F]FET being particularly effective, respectively. The tissue environment notably impacted [18F]FDG uptake, and in a metastatic model, [18F]FET demonstrated higher uptake. Conclusions: By examining factors contributing to PET-imaging phenotype, this study establishes the feasibility of noninvasive molecular stratification using multiplex radiotracer PET. It lays the foundation for further exploration of PET-based subtyping in human cancer, thereby facilitating noninvasive molecular diagnosis.
A conserved complex lipid signature marks human muscle aging and responds to short-term exercise
Authors: Georges E. Janssens, Marte Molenaars, Katharina Herzog, Lotte Grevendonk, Carlijn M. E. Remie, Martin A. T. Vervaart, Hyung L. Elfrink, Eric J. M. Wever, Bauke V. Schomakers, Simone W. Denis, Hans R. Waterham, Mia L. Pras-Raves, Michel van Weeghel, Antoine H. C. van Kampen, Alessandra Tammaro, Loes M. Butter, Sanne van der Rijt, Sandrine Florquin, Aldo Jongejan, Perry D. Moerland, Joris Hoeks, Patrick Schrauwen, Frédéric M. Vaz, Riekelt H. Houtkooper
Journal: Nature Aging (2024)
Excess mortality in Europe coincides with peaks of COVID-19, influenza and respiratory syncytial virus (RSV), November 2023 to February 2024
Authors: Sarah K Nørgaard, Jens Nielsen, Anne Christine Nordholm, Lukas Richter, Alena Chalupka, Natalia Bustos Sierra, Toon Braeye, Maria Athanasiadou, Theodore Lytras, Gleb Denissov, Oskari Luomala, Anne Fouillet, Isabelle Pontais, Matthias an der Heiden, Benedikt Zacher, Alina Weigel, Ivo Foppa, Kassiani Gkolfinopoulou, Ioannis Panagoulias, Anna Paldy, Tibor Malnasi, Lisa Domegan, Eva Kelly, Naama Rotem, Oksana Rakhlin, Francesca K de'Donato, Chiara Di Blasi, Patrick Hoffmann, Telma Velez, Kathleen England, Neville Calleja, Liselotte van Asten, Femke Jongenotter, Ana Paula Rodrigues, Susana Silva, Petra Klepac, Diana Gomez-Barroso, Inmaculada Leon Gomez, Ilias Galanis, Ahmed Farah, Rolf Weitkunat, Katarina Fehst, Nick Andrews, Tom Clare, Declan T Bradley, Mark G O'Doherty, Naoma William, Mark Hamilton, Bolette Søborg, Tyra G Krause, Nick Bundle, Lasse S Vestergaard
Journal: Eurosurveillance (2024)

Since the end of November 2023, the European Mortality Monitoring Network (EuroMOMO) has observed excess mortality in Europe. During weeks 48 2023–6 2024, preliminary results show a substantially increased rate of 95.3 (95% CI: 91.7–98.9) excess all-cause deaths per 100,000 person-years for all ages. This excess mortality is seen in adults aged 45 years and older, and coincides with widespread presence of COVID-19, influenza and respiratory syncytial virus (RSV) observed in many European countries during the 2023/24 winter season.