tbuckley/cabot-search huggingface dataset:
Tuft cell–produced cysteinyl leukotrienes and IL-25 synergistically initiate lung type 2 inflammation
Authors: Saltanat Ualiyeva, Evan Lemire, Evelyn C. Aviles, Caitlin Wong, Amelia A. Boyd, Juying Lai, Tao Liu, Ichiro Matsumoto, Nora A. Barrett, Joshua A. Boyce, Adam L. Haber, Lora G. Bankova
Journal: Science Immunology (2021)

Aeroallergen sensing by airway epithelial cells triggers pathogenic immune responses leading to type 2 inflammation, the hallmark of chronic airway diseases such as asthma. Tuft cells are rare epithelial cells and the dominant source of interleukin-25 (IL-25), an epithelial cytokine, and cysteinyl leukotrienes (CysLTs), lipid mediators of vascular permeability and chemotaxis. How these two mediators derived from the same cell might cooperatively promote type 2 inflammation in the airways has not been clarified. Here, we showed that inhalation of the parent leukotriene C4 (LTC4) in combination with a subthreshold dose of IL-25 led to activation of two innate immune cells: inflammatory type 2 innate lymphoid cell (ILC2) for proliferation and cytokine production, and dendritic cells (DCs). This cooperative effect led to a much greater recruitment of eosinophils and CD4+ T cell expansion indicative of synergy. Whereas lung eosinophilia was dominantly mediated through the classical CysLT receptor CysLT1R, type 2 cytokines and activation of innate immune cells required signaling through CysLT1R and partially CysLT2R. Tuft cell–specific deletion of Ltc4s, the terminal enzyme required for CysLT production, reduced lung inflammation and the systemic immune response after inhalation of the mold aeroallergen Alternaria; this effect was further enhanced by concomitant blockade of IL-25. Our findings identified a potent synergy of CysLTs and IL-25 downstream of aeroallergen-trigged activation of airway tuft cells leading to a highly polarized type 2 immune response and further implicate airway tuft cells as powerful modulators of type 2 immunity in the lungs.
Predicting heterogeneity in clone-specific therapeutic vulnerabilities using single-cell transcriptomic signatures
Authors: Chayaporn Suphavilai, Shumei Chia, Ankur Sharma, Lorna Tu, Rafael Peres Da Silva, Aanchal Mongia, Ramanuj DasGupta, Niranjan Nagarajan
Journal: Genome Medicine (2021)

Abstract While understanding molecular heterogeneity across patients underpins precision oncology, there is increasing appreciation for taking intra-tumor heterogeneity into account. Based on large-scale analysis of cancer omics datasets, we highlight the importance of intra-tumor transcriptomic heterogeneity (ITTH) for predicting clinical outcomes. Leveraging single-cell RNA-seq (scRNA-seq) with a recommender system (CaDRReS-Sc), we show that heterogeneous gene-expression signatures can predict drug response with high accuracy (80%). Using patient-proximal cell lines, we established the validity of CaDRReS-Sc’s monotherapy (Pearson r &gt;0.6) and combinatorial predictions targeting clone-specific vulnerabilities (&gt;10% improvement). Applying CaDRReS-Sc to rapidly expanding scRNA-seq compendiums can serve as in silico screen to accelerate drug-repurposing studies. Availability: https://github.com/CSB5/CaDRReS-Sc .
Abstract P077: Midlife Physical Activity Is Associated With Gut Microbial Species And Metabolic Pathways: Coronary Artery Risk Development In Young Adults Study
Authors: Anju Lulla, Kelley P Gabriel, Eli Puterman, Katherine H Ingram, Joseph Petrosino, James M Shikany, Osorio Meirelles, Lenore J Launer, Katie Meyer
Journal: Circulation (2022)

Background: Behavioral factors for cardiometabolic outcomes have been shown to influence the composition and function of the gut microbiota, which has been associated with cardiometabolic outcomes. Observational studies have documented associations between physical activity and gut microbial composition using 16S rRNA sequencing data, but there is a paucity of data on functional measures, which can be generated from whole-metagenomics sequencing (WMS). Methods: Data are from 480 CARDIA participants who attended the Year 30 follow-up exam (2015-2016, ages 48-60, 47:53 Black:White race, 47:53 male:female gender). Physical activity (exercise units) was estimated from reported frequency and duration of 13 activity types of at least moderate intensity during the previous year. Species, metabolic pathways, and enzyme families were assigned using standard reference databases. Multivariate measures of beta-diversity (between-person) was assessed with principal coordinates analysis (PCoA) and tested with PERMANOVA. Multivariable-adjusted linear regression was used to test associations between distinct microbial features and physical activity, adjusting for false discovery rate (FDR). Results: Sequence data mapped to 105 species 1,307 enzyme families, and 318 metabolic pathways. Beta-diversity of species, but not for enzyme families or metabolic pathways, was significantly differentiated according to physical activity. In analysis of distinct microbial features, 7 species, 15 enzyme families, and 3 metabolic pathways were significantly associated with physical activity at an FDR-adjusted p-value of 0.10 (Table). Conclusion: These findings support associations between gut microbial features and physical activity in a middle-aged, bi-race population-based cohort. Although temporality cannot be established from these cross-sectional analyses, our results are consistent with data suggesting that physical activity may influence composition and function of the gut microbiota.
Next-Generation Sequencing of Minimal Residual Disease for Predicting Relapse after Tisagenlecleucel in Children and Young Adults with Acute Lymphoblastic Leukemia
Authors: Michael A. Pulsipher, Xia Han, Shannon L. Maude, Theodore W. Laetsch, Muna Qayed, Susana Rives, Michael W. Boyer, Hidefumi Hiramatsu, Gregory A. Yanik, Tim Driscoll, G. Doug Myers, Peter Bader, Andre Baruchel, Jochen Buechner, Heather E. Stefanski, Creton Kalfoglou, Kevin Nguyen, Edward R. Waldron, Karen Thudium Mueller, Harald J. Maier, Gabor Kari, Stephan A. Grupp
Journal: Blood Cancer Discovery (2021)

We assessed minimal residual disease (MRD) detection and B-cell aplasia after tisagenlecleucel therapy for acute lymphoblastic leukemia (ALL) to define biomarkers predictive of relapse (N = 143). Next-generation sequencing (NGS) MRD detection >0 in bone marrow (BM) was highly associated with relapse. B-cell recovery [signifying loss of functional chimeric antigen receptor (CAR) T cells] within the first year of treatment was associated with a hazard ratio (HR) for relapse of 4.5 [95% confidence interval (CI), 2.03-9.97; P < 0.001]. Multivariate analysis at day 28 showed independent associations of BMNGS-MRD >0 (HR = 4.87; 95% CI, 2.18-10.8; P < 0.001) and B-cell recovery (HR = 3.33; 95% CI, 1.44-7.69; P = 0.005) with relapse. By 3 months, the BMNGS-MRD HR increased to 12 (95% CI, 2.87-50; P < 0.001), whereas B-cell recovery was not independently predictive (HR = 1.27; 95% CI, 0.33-4.79; P = 0.7). Relapses occurring with persistence of B-cell aplasia were largely CD19- (23/25: 88%). Detectable BMNGS-MRD reliably predicts risk with sufficient time to consider approaches to relapse prevention such as hematopoietic cell transplantation (HCT) or second CAR-T cell infusion. SIGNIFICANCE: Detectable disease by BMNGS-MRD with or without B-cell aplasia is highly predictive of relapse after tisagenlecleucel therapy for ALL. Clonotypic rearrangements used to follow NGS-MRD did not change after loss of CD19 or lineage switch. High-risk patients identified by these biomarkers may benefit from HCT or investigational cell therapies.See related commentary by Ghorashian and Bartram, p. 2.This article is highlighted in the In This Issue feature, p. 1.
Critical role of FPR1 in splenocyte migration into brain to worsen inflammation and ischemic brain injury in mice
Authors: Jun Li, Mahendra D. Chordia, Yi Zhang, Hui Zong, Dongfeng Pan, Zhiyi Zuo
Journal: Theranostics (2022)

Background: Splenocyte contribution to ischemic brain injury has been suggested. It is not known whether this effect is due to systemic action or direct influence in ischemic brain tissues. It is also not known how splenocytes migrate into the brain and worsen neurological outcome after brain ischemia. We determined the role of formyl peptide receptor 1 (FPR1), a receptor expressed in monocytes, in the migration of splenocytes into ischemic brain tissues and the contribution of these splenocytes to ischemic brain injury. Methods: Mice with or without fpr1 knockout were subjected to transient focal brain ischemia. The migration of splenocytes was assessed under in vivo and in vitro conditions. Results: cFLFLF, a FPR1 antagonist, inhibited splenocyte migration into the brain and neuroinflammation after ischemic stroke. cFLFLF improved neurological outcome assessed 24 hours or 28 days after stroke. cFLFLF did not alter blood-brain barrier permeability in the ischemic brain. fpr1-/- mice had an attenuated peripheral monocyte and neutrophil infiltration into the brain, a reduced proinflammatory cytokine level and an improved neurological outcome compared with wild-type mice after brain ischemia. cFLFLF did not affect the proinflammatory cytokine levels in the spleen and brain of fpr1-/- mice after ischemic stroke. Conclusions: These results suggest that FPR1 facilitates splenocyte migration into the brain and proinflammatory cytokine production to worsen neurological outcome after brain ischemia, indicating a direct effect of splenocytes on ischemic brain tissues. Our results support the notion that cFLFLF via blocking FPR1 signaling inhibits those pathological processes and is a potential agent for neuroprotection.
Reinfection with new variants of SARS-CoV-2 after natural infection: a prospective observational cohort in 13 care homes in England
Authors: Anna Jeffery-Smith, Thomas A J Rowland, Monika Patel, Heather Whitaker, Nalini Iyanger, Sarah V Williams, Rebecca Giddings, Leah Thompson, Maria Zavala, Felicity Aiano, Joanna Ellis, Angie Lackenby, Katja Höschler, Kevin Brown, Mary E Ramsay, Robin Gopal, J Yimmy Chow, Shamez N Ladhani, Maria Zambon
Journal: The Lancet Healthy Longevity (2021)

BackgroundUnderstanding the duration of protection and risk of reinfection after natural infection is crucial to planning COVID-19 vaccination for at-risk groups, including care home residents, particularly with the emergence of more transmissible variants. We report on the duration, neutralising activity, and protection against the alpha variant of previous SARS-CoV-2 infection in care home residents and staff infected more than 6 months previously.MethodsWe did this prospective observational cohort surveillance in 13 care homes in Greater London, England. All staff and residents were included. Staff and residents had regular nose and throat screening for SARS-CoV-2 by RT-PCR according to national guidelines, with ad hoc testing of symptomatic individuals. From January, 2021, antigen lateral flow devices were also used, but positive tests still required RT-PCR confirmation. Staff members took the swab samples for themselves and the residents. The primary outcome was SARS-CoV-2 RT-PCR positive primary infection or reinfection in previously infected individuals, as determined by previous serological testing and screening or diagnostic RT-PCR results. Poisson regression and Cox proportional hazards models were used to estimate protective effectiveness of previous exposure. SARS-CoV-2 spike, nucleoprotein, and neutralising antibodies were assessed at multiple timepoints as part of the longitudinal follow-up.FindingsBetween April 10 and Aug 3, 2020, we recruited and tested 1625 individuals (933 staff and 692 residents). 248 participants were lost to follow-up (123 staff and 125 residents) and 1377 participants were included in the follow-up period to Jan 31, 2021 (810 staff and 567 residents). There were 23 reinfections (ten confirmed, eight probable, five possible) in 656 previously infected individuals (366 staff and 290 residents), compared with 165 primary infections in 721 susceptible individuals (444 staff and 277 residents). Those with confirmed reinfections had no or low neutralising antibody concentration before reinfection, with boosting of titres after reinfection. Kinetics of binding and neutralising antibodies were similar in older residents and younger staff.InterpretationSARS-CoV-2 reinfections were rare in older residents and younger staff. Protection from SARS-CoV-2 was sustained for longer than 9 months, including against the alpha variant. Reinfection was associated with no or low neutralising antibody before reinfection, but significant boosting occurred on reinfection.FundingPublic Health England.
The Protein Kinase Activity of NME7 Activates Wnt/β-Catenin Signaling to Promote One-Carbon Metabolism in Hepatocellular Carcinoma
Authors: Xinxin Ren, Zhuoxian Rong, Xiaoyu Liu, Jie Gao, Xu Xu, Yuyuan Zi, Yun Mu, Yidi Guan, Zhen Cao, Yuefang Zhang, Zimei Zeng, Qi Fan, Xitao Wang, Qian Pei, Xiang Wang, Haiguang Xin, Zhi Li, Yingjie Nie, Zilong Qiu, Nan Li, Lunquan Sun, Yuezhen Deng
Journal: Cancer Research (2021)

Abstract Metabolic reprogramming by oncogenic signaling is a hallmark of cancer. Hyperactivation of Wnt/β-catenin signaling has been reported in hepatocellular carcinoma (HCC). However, the mechanisms inducing hyperactivation of Wnt/β-catenin signaling and strategies for targeting this pathway are incompletely understood. In this study, we find nucleoside diphosphate kinase 7 (NME7) to be a positive regulator of Wnt/β-catenin signaling. Upregulation of NME7 positively correlated with the clinical features of HCC. Knockdown of NME7 inhibited HCC growth in vitro and in vivo, whereas overexpression of NME7 cooperated with c-Myc to drive tumorigenesis in a mouse model and to promote the growth of tumor-derived organoids. Mechanistically, NME7 bound and phosphorylated serine 9 of GSK3β to promote β-catenin activation. Furthermore, MTHFD2, the key enzyme in one-carbon metabolism, was a target gene of β-catenin and mediated the effects of NME7. Tumor-derived organoids with NME7 overexpression exhibited increased sensitivity to MTHFD2 inhibition. In addition, expression levels of NME7, β-catenin, and MTHFD2 correlated with each other and with poor prognosis in patients with HCC. Collectively, this study emphasizes the crucial roles of NME7 protein kinase activity in promoting Wnt/β-catenin signaling and one-carbon metabolism, suggesting NME7 and MTHFD2 as potential therapeutic targets for HCC. Significance: The identification of NME7 as an activator of Wnt/β-catenin signaling and MTHFD2 expression in HCC reveals a mechanism regulating one-carbon metabolism and potential therapeutic strategies for treating this disease.
WITHDRAWN: Incidence and affecting factors of pulmonary diffusing capacity impairment with COVID-19 survivors 18 months after discharge in Wuhan, China
Authors: Bo XU, Fu-qiang MA, Cong HE, Zi-qi WU, Cun-yu FAN, He-rong MAO, Ji-xian ZHANG, Min YANG, Zuo-wei HU
Journal: Journal of Infection (2022)
A Review of Techniques for Surface Electromyography Signal Quality Analysis
Authors: Emma Farago, Dawn MacIsaac, Michelle Suk, Adrian D. C. Chan
Journal: IEEE Reviews in Biomedical Engineering (2022)

Electromyography (EMG) signals are instrumental in a variety of applications including prosthetic control, muscle health assessment, rehabilitation, and workplace monitoring. Signal contaminants including noise, interference, and artifacts can degrade the quality of the EMG signal, leading to misinterpretation; therefore it is important to ensure that collected EMG signals are of sufficient quality prior to further analysis. A literature search was conducted to identify current approaches for detecting, identifying, and quantifying contaminants within surface EMG signals. We identified two main strategies: 1) bottom-up approaches for identifying specific and well-characterized contaminants and 2) top-down approaches for detecting anomalous EMG signals or outlier channels in high-density EMG arrays. The best type(s) of approach are dependent on the circumstances of data collection including the environment, the susceptibility of the application to contaminants, and the resilience of the application to contaminants. Further research is needed for assessing EMG with multiple simultaneous contaminants, identifying ground-truths for clean EMG data, and developing user-friendly and autonomous methods for EMG signal quality analysis.
Germline Pathogenic Variants in Cancer Predisposition Genes Among Women With Invasive Lobular Carcinoma of the Breast
Authors: Siddhartha Yadav, Chunling Hu, Katherine L. Nathanson, Jeffrey N. Weitzel, David E. Goldgar, Peter Kraft, Rohan D. Gnanaolivu, Jie Na, Hongyan Huang, Nicholas J. Boddicker, Nicole Larson, Chi Gao, Song Yao, Clarice Weinberg, Celine M. Vachon, Amy Trentham-Dietz, Jack A. Taylor, Dale R. Sandler, Alpa Patel, Julie R. Palmer, Janet E. Olson, Susan Neuhausen, Elena Martinez, Sara Lindstrom, James V. Lacey, Allison W. Kurian, Esther M. John, Christopher Haiman, Leslie Bernstein, Paul W. Auer, Hoda Anton-Culver, Christine B. Ambrosone, Rachid Karam, Elizabeth Chao, Amal Yussuf, Tina Pesaran, Jill S. Dolinsky, Steven N. Hart, Holly LaDuca, Eric C. Polley, Susan M. Domchek, Fergus J. Couch
Journal: Journal of Clinical Oncology (2021)

PURPOSE To determine the contribution of germline pathogenic variants (PVs) in hereditary cancer testing panel genes to invasive lobular carcinoma (ILC) of the breast. MATERIALS AND METHODS The study included 2,999 women with ILC from a population-based cohort and 3,796 women with ILC undergoing clinical multigene panel testing (clinical cohort). Frequencies of germline PVs in breast cancer predisposition genes ( ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, and TP53) were compared between women with ILC and unaffected female controls and between women with ILC and infiltrating ductal carcinoma (IDC). RESULTS The frequency of PVs in breast cancer predisposition genes among women with ILC was 6.5% in the clinical cohort and 5.2% in the population-based cohort. In case-control analysis, CDH1 and BRCA2 PVs were associated with high risks of ILC (odds ratio [OR] &gt; 4) and CHEK2, ATM, and PALB2 PVs were associated with moderate (OR = 2-4) risks. BRCA1 PVs and CHEK2 p.Ile157Thr were not associated with clinically relevant risks (OR &lt; 2) of ILC. Compared with IDC, CDH1 PVs were &gt; 10-fold enriched, whereas PVs in BRCA1 were substantially reduced in ILC. CONCLUSION The study establishes that PVs in ATM, BRCA2, CDH1, CHEK2, and PALB2 are associated with an increased risk of ILC, whereas BRCA1 PVs are not. The similar overall PV frequencies for ILC and IDC suggest that cancer histology should not influence the decision to proceed with genetic testing. Similar to IDC, multigene panel testing may be appropriate for women with ILC, but CDH1 should be specifically discussed because of low prevalence and gastric cancer risk.
92P Exploring immune dysfunction in surgically treated early stage NSCLC
Authors: L. Sellmer, J. Kovács, J. Walter, J. Kumbrink, J. Neumann, D. Kauffmann-Guerrero, R. Kiefl, C. Schneider, A. Jung, J. Behr, A. Tufman
Journal: Annals of Oncology (2022)
Prevalence of sleep-disordered breathing in an African general population: The Benin Society and Sleep (BeSAS) study
Authors: Ablo Prudence Wachinou, Corinne Houehanou, Serge Ade, Terence Totah, Mathieu Berger, Geoffroy Solelhac, Salmane Amidou, Attanon Arnauld Fiogbe, Frederic Alovokpinhou, Philipe Lacroix, Pierre-Marie Preux, Pedro Marques-Vidal, Gildas Agodokpessi, Dismand Houinato, Raphael Heinzer
Journal: The Lancet Respiratory Medicine (2022)
An antibody targeting the N-terminal domain of SARS-CoV-2 disrupts the spike trimer
Authors: Naveenchandra Suryadevara, Andrea R. Shiakolas, Laura A. VanBlargan, Elad Binshtein, Rita E. Chen, James Brett Case, Kevin J. Kramer, Erica C. Armstrong, Luke Myers, Andrew Trivette, Christopher Gainza, Rachel S. Nargi, Christopher N. Selverian, Edgar Davidson, Benjamin J. Doranz, Summer M. Diaz, Laura S. Handal, Robert H. Carnahan, Michael S. Diamond, Ivelin S. Georgiev, James E. Crowe
Journal: Journal of Clinical Investigation (2022)

The protective human antibody response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) focuses on the spike (S) protein, which decorates the virion surface and mediates cell binding and entry. Most SARS-CoV-2 protective antibodies target the receptor-binding domain or a single dominant epitope ("supersite") on the N-terminal domain (NTD). Using the single B cell technology called linking B cell receptor to antigen specificity through sequencing (LIBRA-Seq), we isolated a large panel of NTD-reactive and SARS-CoV-2–neutralizing antibodies from an individual who had recovered from COVID-19. We found that neutralizing antibodies against the NTD supersite were commonly encoded by the IGHV1-24 gene, forming a genetic cluster representing a public B cell clonotype. However, we also discovered a rare human antibody, COV2-3434, that recognizes a site of vulnerability on the SARS-CoV-2 S protein in the trimer interface (TI) and possesses a distinct class of functional activity. COV2-3434 disrupted the integrity of S protein trimers, inhibited the cell-to-cell spread of the virus in culture, and conferred protection in human angiotensin-converting enzyme 2–transgenic (ACE2-transgenic) mice against the SARS-CoV-2 challenge. This study provides insight into antibody targeting of the S protein TI region, suggesting this region may be a site of virus vulnerability.
Therapeutic Potential of Chemically Modified, Synthetic, Triplex Peptide Nucleic Acid–Based Oncomir Inhibitors for Cancer Therapy
Authors: Karishma Dhuri, Ravinder Reddy Gaddam, Ajit Vikram, Frank J. Slack, Raman Bahal
Journal: Cancer Research (2021)

miRNA-155 (miR-155) is overexpressed in various types of lymphomas and leukemias, suggesting that targeting miR-155 could be a potential platform for the development of precision medicine. Here, we tested the anticancer activity of novel, chemically modified, triplex peptide nucleic acid (PNA)-based antimiRs compared with the current state-of-the-art conventional full-length antimiRs. Next-generation modified PNAs that bound miR-155 by Watson-Crick and Hoogsteen domains possessed superior therapeutic efficacy in vivo and ex vivo compared with conventional full-length anti-miR-155. The efficacy of anti-miR-155 targeting in multiple lymphoma cell lines was comprehensively corroborated by gene expression, Western blot analysis, and cell viability-based functional studies. Finally, preclinical testing in vivo in xenograft mouse models containing lymphoma cell lines demonstrated that treatment with the miR-155-targeting next-generation antimiR resulted in a significant decrease in miR-155 expression, followed by reduced tumor growth. These findings support the effective therapeutic application of chemically modified triplex PNAs to target miR-155 to treat lymphoma. Overall, the present proof-of-concept study further implicates the potential for next-generation triplex gamma PNAs to target other miRNAs for treating cancer. SIGNIFICANCE: This study demonstrates the utility of novel oncomiR inhibitors as cancer therapeutics, providing a new approach for targeting miRNAs and other noncoding RNAs.