Top read articles in the last 30 days
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Abstract
Over 200,000 individuals are diagnosed with lung cancer in the United States every year, with a growing proportion of cases, especially lung adenocarcinoma, occurring in individuals who have never smoked. Women over the age of 50 comprise the largest affected demographic. To understand the genomic drivers of lung adenocarcinoma and therapeutic response in this population, we performed whole genome and/or whole exome sequencing on 73 matched lung tumor/normal pairs from postmenopausal women who participated in the Women’s Health Initiative. Somatic copy number alterations showed little variation by smoking status, suggesting that aneuploidy may be a general characteristic of lung cancer regardless of smoke exposure. Similarly, clock-like and APOBEC mutation signatures were prevalent but did not differ in tumors from smokers and never-smokers. However, mutations in both EGFR and KRAS showed unique allelic differences determined by smoking status that are known to alter tumor response to targeted therapy. Mutations in the MYC-network member MGA were more prevalent in tumors from smokers. Fusion events in ALK, RET, and ROS1 were absent, likely due to age-related differences in fusion prevalence. Our work underscores the profound effect of smoking status, age, and sex on the tumor mutational landscape and identifies areas of unmet medical need.
Authors
Sitapriya Moorthi, Amy Paguirigan, Pushpa Itagi, Minjeong Ko, Mary Pettinger, Anna C.H. Hoge, Anwesha Nag, Neil A. Patel, Feinan Wu, Cassie Sather, Kevin M. Levine, Matthew P. Fitzgibbon, Aaron R. Thorner, Garnet L. Anderson, Gavin Ha, Alice H. Berger
Total views: 5087
Abstract
BACKGROUND After identifying 2 immunomarkers of acute injury, KIM-1 and LCN2, in all kidney biopsies from 31 patients with COVID-19 pneumonia and de novo kidney dysfunction, we investigated whether circulating markers of kidney epithelial injury are common in patients with laboratory-confirmed COVID-19 who require oxygen support but do not have critical illness.METHODS We studied 196 patients admitted to 15 hospitals with moderate to severe pneumonia who were enrolled in 2 independent randomized clinical trials. We measured 41 immune mediators and markers of kidney and endothelial injury in peripheral blood in these patients within 24 hours of randomization.RESULTS We constructed a generalized linear CORIMUNO model combining serum levels of KIM-1, LCN2, IL-10, and age at hospital admission that showed high discrimination for mortality (derivation cohort: AUC = 0.82, 95% CI: 0.73–0.92; validation cohort: AUC = 0.83, 95% CI: 0.74–0.92). An early rise in circulating kidney injury markers, in the absence of acute kidney injury criteria, was markedly associated with the risk of developing a severe form of COVID-19 and death within 3 months.CONCLUSION The CORIMUNO score may be a helpful tool for risk stratification, and for the first time to our knowledge, it identifies the overlooked impact of subclinical kidney injury on pneumonia outcomes.TRIAL REGISTRATION ClinicalTrials.gov NCT04324047, NCT04324073, and NCT04331808.FUNDING This research was funded by the French Ministry of Health, Programme Hospitalier de Recherche Clinique (PHRC COVID-19–20–0151, PHRC COVID-19–20–0029), Fondation de l’Assistance Publique Hôpitaux de Paris (Alliance Tous Unis Contre le Virus), Assistance Publique Hôpitaux de Paris, and grants from the Fondation pour la Recherche Médicale (FRM) (REA202010012514) and Agence Nationale de Recherches sur le Sida and emerging infectious diseases (ANRS) (ANRS0147) from the VINTED sponsorship.
Authors
Olivia Lenoir, Florence Morin, Anouk Walter-Petrich, Léa Resmini, Mohamad Zaidan, Nassim Mahtal, Sophie Ferlicot, Victor G. Puelles, Nicola Wanner, Julien Dang, Thibaut d’Izarny-Gargas, Jana Biermann, Benjamin Izar, Stéphanie Baron, Benjamin Terrier, Ziad A. Massy, Marie Essig, Aymeric Couturier, Olivia May, Xavier Belenfant, David Buob, Isabelle Brocheriou, Hassan Izzedine, Yannis Lombardi, Hélène François, Anissa Moktefi, Vincent Audard, Aurélie Sannier, Eric Daugas, Matthieu Jamme, Guylaine Henry, Isabelle Le Monnier de Gouville, Catherine Marie, Laurence Homyrda, Céline Verstuyft, Sarah Tubiana, Ouifiya Kafif, Valentine Piquard, Maxime Dougados, Tobias B. Huber, Marine Livrozet, Jean-Sébastien Hulot, Cedric Laouénan, Jade Ghosn, France Mentré, Alexandre Karras, Yazdan Yazdanpanah, Raphaël Porcher, Philippe Ravaud, Sophie Caillat-Zucman, Xavier Mariette, Olivier Hermine, Matthieu Resche-Rigon, Pierre-Louis Tharaux, CORIMUNO-19 collaborative group
Total views: 2235
Abstract
The human endometrium undergoes dynamic changes across the menstrual cycle to establish a receptive state for embryo implantation. Using bulk and single-cell RNA-Seq, we characterized gene expression dynamics in the cycling endometrium and the decidua from early pregnancy. We demonstrated that during the mid-secretory phase — the period encompassing the window of implantation — secretory glandular epithelial cells undergo notable transcriptional changes and alterations in cell-cell communication. Through comprehensive analyses, we identified the glandular epithelium receptivity module (GERM) signature, comprising 556 genes associated with endometrial receptivity. This GERM signature was consistently perturbed across datasets of endometrial samples from women with impaired fertility, validating its relevance as a marker of receptivity. In addition to epithelial changes, we observed shifts in stromal cell populations, notably involving decidual and senescent subsets, which also play key roles in modulating implantation. Together, these findings provide a high-resolution transcriptomic atlas of the receptive and early pregnant endometrium and shed light on key molecular pathways underlying successful implantation.
Authors
Gregory W. Burns, Emmanuel N. Paul, Manisha Persaud, Qingshi Zhao, Rong Li, Kristin Blackledge, Jessica Garcia de Paredes, Pratibha Shukla, Ripla Arora, Anat Chemerinski, Nataki C. Douglas
Total views: 2027
Abstract
Mucosal secretory IgA (sIgA) plays a central role in protecting against the invasion of respiratory pathogen via the upper respiratory tract. To understand how intranasal booster induces mucosal sIgA response in humans, we first used liquid chromatography–tandem mass spectrometry for peptide identification of immunoglobulin (MS Ig-seq) and single-cell B cell receptor sequencing (scBCR-seq) to identify 42 mucosal spike-specific sIgA monoclonal antibodies (mAbs) after intranasal booster. These mucosal sIgA mAbs exhibited enhanced neutralization up to 100-fold against SARS-CoV-2 variants compared with their monomeric IgG and IgA isotypes. Deep sequencing and longitudinal analysis of B cell receptor repertoires revealed that intranasal booster restimulates memory B cells primed by intramuscular vaccination to undergo IgA class switching, somatic hypermutation, and clonal expansion. Single-cell RNA-seq (scRNA-seq) revealed that intranasal booster upregulated the expression of mucosal homing receptors in spike-specific IgA-expressing B cells. This increase coincided with a transient increase of cytokines and chemokines that facilitate B cell recruitment in the nasal mucosa. Our findings demonstrate that intranasal booster can be an effective strategy for inducing upper respiratory mucosal sIgA and establishing mucosal immune protection.
Authors
Si Chen, Zhengyuan Zhang, Zihan Lin, Li Yin, Lishan Ning, Wenming Liu, Qian Wang, Chenchen Yang, Bo Feng, Ying Feng, Yongping Wang, Hengchun Li, Ping He, Huan Liang, Yichu Liu, Zhixia Li, Bo Liu, Yang Li, Diana Boraschi, Linbing Qu, Xuefeng Niu, Nanshan Zhong, Pingchao Li, Ling Chen
Total views: 2018
Abstract
Although well-differentiated thyroid carcinoma (WDTC) is characterized by a robust treatment response, aggressive subtypes, such as anaplastic thyroid carcinoma (ATC), remain highly lethal. To understand thyroid cancer evolution in both children and adults, we analyzed single-cell transcriptomes of 423,733 cells from 81 samples and spatially resolved key tumor and microenvironment populations across 28 tumors with spatial transcriptomics, including rare and unique composite WDTC/ATC tumors and pediatric diffuse sclerosing thyroid carcinomas. Additionally, we identified gene signatures of stromal cell populations in 5 large thyroid cancer bulk RNA-sequencing cohorts. Through this multi-institutional effort, we defined a population of POSTN+ myofibroblast cancer-associated fibroblasts (myCAFs) that are intimately associated with invasive tumor cells and correlate with poor prognosis, lymph node metastasis, and disease progression in thyroid carcinoma. We also revealed a population of inflammatory CAFs that are distant to tumor cells and are found in the inflammatory stromal microenvironment of autoimmune thyroiditis. Together, our study provides spatial profiling of thyroid cancer evolution in samples with mixed WDTC/ATC histopathology and identifies a prognostic myCAF subtype with potential clinical utility in predicting aggressive disease in both children and adults.
Authors
Matthew A. Loberg, George J. Xu, Sheau-Chiann Chen, Hua-Chang Chen, Claudia C. Wahoski, Kailey P. Caroland, Megan L. Tigue, Heather A. Hartmann, Jean-Nicolas Gallant, Courtney J. Phifer, Andres A. Ocampo, Dayle K. Wang, Reilly G. Fankhauser, Kirti A. Karunakaran, Chia-Chin Wu, Maxime Tarabichi, Sophia M. Shaddy, James L. Netterville, Sarah L. Rohde, Carmen C. Solórzano, Lindsay A. Bischoff, Naira Baregamian, Barbara A. Murphy, Jennifer H. Choe, Jennifer R. Wang, Eric C. Huang, Quanhu Sheng, Luciane T. Kagohara, Elizabeth M. Jaffee, Ryan H. Belcher, Ken S. Lau, Fei Ye, Ethan Lee, Vivian L. Weiss
Total views: 1951
Abstract
Recently, skeletal stem cells were shown to be present in the epiphyseal growth plate (epiphyseal skeletal stem cells, epSSCs), but their function in connection with linear bone growth remains unknown. Here, we explore the possibility that modulating the number of epSSCs can correct differences in leg length. First, we examined regulation of the number and activity of epSSCs by Hedgehog (Hh) signaling. Both systemic activation of Hh pathway with Smoothened agonist (SAG) and genetic activation of Hh pathway by Patched1 (Ptch1) ablation in Pthrp-creER Ptch1fl/fl tdTomato mice promoted proliferation of epSSCs and clonal enlargement. Transient intra-articular administration of SAG also elevated the number of epSSCs. When SAG-containing beads were implanted into the femoral secondary ossification center of 1 leg of rats, this leg was significantly longer 1 month later than the contralateral leg implanted with vehicle-containing beads, an effect that was even more pronounced 2 and 6 months after implantation. We conclude that Hh signaling activates growth plate epSSCs, which effectively leads to increased longitudinal growth of bones. This opens therapeutic possibilities for the treatment of differences in leg length.
Authors
Dana Trompet, Anastasiia D. Kurenkova, Baoyi Zhou, Lei Li, Ostap Dregval, Anna P. Usanova, Tsz Long Chu, Alexandra Are, Andrei A. Nedorubov, Maria Kasper, Andrei S. Chagin
Total views: 1944
Abstract
BACKGROUND Icotrokinra is the first and only targeted oral peptide that selectively binds the IL-23 receptor with high affinity to precisely inhibit IL-23 signaling. Icotrokinra demonstrated high rates of complete skin clearance and durable disease control in the phase IIb trial, FRONTIER-1, and its long-term extension, FRONTIER-2, in participants with moderate-to-severe plaque psoriasis. This study evaluated systemic and skin pharmacodynamic response of icotrokinra and its relationship to clinical response in FRONTIER participants.METHODS FRONTIER-1 participants received icotrokinra or placebo for 16 weeks. FRONTIER-2 followed participants for up to 1 year of treatment; placebo participants transitioned to icotrokinra after week 16. Systemic pharmacodynamic changes were assessed in serum through week 52. Skin pharmacodynamic changes were assessed using transcriptomic analysis of skin biopsies and protein quantification in tape-strip samples through week 16.RESULTS Icotrokinra dose-dependently reduced serum levels of the IL-23/IL-17 axis and psoriasis disease biomarkers through week 52, with maximal reductions observed with the highest 100 mg twice-daily dose. Proteomic analyses showed icotrokinra selectively blocked IL-23–driven inflammation without broader impacts on circulating proteins, including serum IL-23 levels. Sixteen weeks of icotrokinra, but not placebo, reduced expression of psoriasis-associated genes in lesional skin. Icotrokinra treatment also reduced psoriasis-relevant proteins in week 16 lesional skin tape-strips to levels comparable to nonlesional samples.CONCLUSION Icotrokinra induced a dose-dependent pharmacodynamic response, with early (week 4) and sustained (week 52) reductions in biomarkers of IL-23 pathway activation and psoriasis disease severity, which correlated with clinical response.TRIAL REGISTRATION ClinicalTrials.gov: NCT05223868, NCT05364554.FUNDING Johnson & Johnson.
Authors
David Strawn, James G. Krueger, Robert Bissonnette, Kilian Eyerich, Laura K. Ferris, Amy S. Paller, Andreas Pinter, Dylan Richards, Elizabeth Y. Chen, Kate Paget, Daniel Horowitz, Roohid Parast, Joshua J. Rusbuldt, Jocelyn Sendecki, Sunita Bhagat, Lynn P. Tomsho, Ching-Heng Chou, Marta E. Polak, Brice E. Keyes, Emily Bozenhardt, Yuan Xiong, Wangda Zhou, Cynthia DeKlotz, Paul Newbold, Dawn M. Waterworth, Megan Miller, Takayuki Ota, Ya-Wen Yang, Monica W.L. Leung, Lloyd S. Miller, Carolyn A. Cuff, Bradford McRae, Darren Ruane, Arun K. Kannan
Total views: 1819
Abstract
Small cell lung cancer (SCLC) transformation is an incompletely characterized mechanism of resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in EGFR-mutant cancers, limiting development of optimal treatment approaches. Through single-cell RNA sequencing of malignant pleural effusions from patients who underwent SCLC transformation, we identified heterogeneity and diversity, including distinct neuroendocrine (NE) and mesenchymal non-NE cancer cell subsets, which were maintained in patient-derived cell lines. We demonstrate that EZH2 regulates EGFR expression in NE cells where EGFR expression is silenced at baseline. Although neither epigenetic derepression nor exogenous overexpression of mutant EGFR sensitized the cells to EGFR inhibition, non-NE cells exhibited selective sensitivity to MEK inhibitors. Combined MEK inhibitor and chemotherapy effectively inhibited growth of both NE and non-NE cells in vitro and in vivo. Our findings demonstrate that EGFR-mutant SCLC is composed of mixed cell states with distinct therapeutic vulnerabilities and offer a therapeutic strategy to target tumor heterogeneity in highly plastic and treatment-resistant malignancies such as transformed SCLC.
Authors
Atsuko Ogino, Amir Vajdi, Xinmeng Jasmine Mu, Navin R. Mahadevan, Kenneth Ngo, Matthew A. Booker, Paloma Cejas, Jeffrey J. Okoro, Man Xu, Benjamin F. Springer, Benjamin K. Eschle, Cameron M. Messier, Stephen Wang, Sudeepa Syamala, Rubii M. Tamen, Anika E. Adeni, Emily S. Chambers, Israel Canadas, Tran Thai, Camilla L. Christensen, Chunxiao Xu, Patrick H. Lizotte, Geoffrey R. Oxnard, Hideo Watanabe, Henry W. Long, Prafulla C. Gokhale, Cloud P. Paweletz, Lynette M. Sholl, Matthew G. Oser, David A. Barbie, Michael Y. Tolstorukov, Pasi A. Jänne
Total views: 1780
Abstract
Chronic liver injury results in activation of quiescent hepatic stellate cells (HSCs) into collagen type I–producing activated HSCs that make the liver fibrotic. We identified ETS1 and ETS2 (ETS1/2) as lineage-specific transcription factors regulating HSC phenotypes. Here, we investigated the role of ETS1/2 in HSCs in liver fibrosis using toxic liver injury models and 3D human liver spheroids. Liver fibrosis was induced in WT and HSC-specific Ets1-KO (Ets1ΔHSC) and Ets2-KO (Ets2ΔHSC) mice by administration of CCl4 for 6 weeks, followed by cessation of liver injury for 2 weeks. Liver fibrosis was more severe in Ets1ΔHSC and to a lesser extent Ets2ΔHSC mice compared with WT mice. Regression of liver fibrosis was suppressed only in Ets1ΔHSC mice, indicating Ets1 is the predominant isoform maintaining a quiescent-like phenotype in HSCs. Similar results were obtained in a metabolic dysfunction–associated steatohepatitis (MASH) model using 3D human liver spheroids. Knockdown of ETS1 in human HSCs caused upregulation of fibrogenic genes in MASH human liver spheroids and prevented fibrosis regression. ETS1 regulated the quiescent HSC phenotype via the CREB-regulated transcription coactivator 2 (CRTC2)/PGC1α/PPARγ pathway. Knockdown of CRTC2 abrogated PPARγ responses and facilitated HSC activation. These findings suggest that ETS1 may represent a therapeutic target for antifibrotic therapy.
Authors
Wonseok Lee, Xiao Liu, Sara Brin Rosenthal, Charlene Miciano, Sadatsugu Sakane, Kanani Hokutan, Debanjan Dhar, Hyun Young Kim, David A. Brenner, Tatiana Kisseleva
Total views: 1766
Abstract
Mitochondria-derived acyl-coenzyme A (acyl-CoA) species chemically modify proteins, causing damage when acylation reactions are not adequately detoxified by enzymatic removal or protein turnover. Defects in genes encoding the mitochondrial respiratory complex and TCA cycle enzymes have been shown to increase acyl-CoA levels due to reduced enzymatic flux and result in proteome-wide hyperacylation. How pathologically elevated acyl-CoA levels contribute to bioenergetics failure in mitochondrial diseases is not well understood. Here, we demonstrate that bulk succinylation from succinyl-CoA excess consumes the enzymatic cofactor NAD+ and propagates mitochondrial respiratory defects in a zebrafish model of succinyl-CoA ligase deficiency, a childhood-onset encephalomyopathy. To explore this mechanism as a therapeutic target, we developed a workflow to monitor behavioral defects in sucla2–/– zebrafish and show that hypersuccinylation is associated with reduced locomotor behavior and impaired ability to execute food hunting patterns. Postembryonic NAD+ precursor supplementation restores NAD+ levels and improves locomotion and survival of sucla2–/– zebrafish. Mechanistically, nicotinamide and nicotinamide riboside require the NAD+-dependent desuccinylase Sirt5 to enhance oxidative metabolism and nitrogen elimination through the urea cycle. Collectively, NAD+ supplementation activates Sirt5 to protect against damage to mitochondria and locomotor circuits caused by protein succinylation.
Authors
Joy Richard, Giulia Lizzo, Noélie Rochat, Adrien Jouary, Pedro T.M. Silva, Alice Parisi, Stefan Christen, Sofia Moco, Michael B. Orger, Philipp Gut
Total views: 1765
