tbuckley/cabot-search huggingface dataset:
Letter to the editor: Loss of Sam50 in hepatocytes induces cardiolipin‐dependent mitochondrial membrane remodeling to trigger mtDNA release and liver injury
Authors: Zhuqing Rao, Fei Li, Zhu Guan, Haoming Zhou
Journal: Hepatology (2022)

To the editor, We read the recent article by Li Chen et al.,[1] reporting that sorting and assembly machinery 50 (Sam50) depletion or acetaminophen (APAP) treatment caused mitochondrial DNA (mtDNA) release to activate the cyclic GMP‐AMP synthase (cGAS)–stimulator of interferon genes (STING) signaling pathway and liver inflammation in mice. It is really an interesting study which greatly improves our understanding of the pathogenesis of APAP‐induced liver injury. However, there are a few concerns in the current research that require attention. A critical role of mtDNA from hepatocytes in activating macrophage cGAS–STING signaling has been reported.[2] Although increased levels of mtDNA in hepatocyte cytoplasm and mouse serum were observed in the current study, it is necessary to provide more evidence not only for the cytosolic accumulation but, even more importantly, for the extracellular release of mtDNA from hepatocytes. The increased receptor interacting protein 3–mediated necrosis found by the investigators would contribute to the extracellular release of mtDNA. Similarly, in a recent study, we found that X box binding protein 1 (XBP1) depletion in hepatocytes aggravated hepatocellular pyroptosis, facilitating the cytosolic accumulation and extracellular release of mtDNA to enhance macrophage STING activation in thioacetamide (TAA)–induced liver injury.[3] The investigators demonstrated significantly increased protein levels of STING in both hepatocytes and Kupffer cells. In contrast, a previous study showed that STING was not detectable in both human and mouse primary hepatocytes and that in vitro stimulation with DNA failed to activate cGAS–STING signaling in hepatocytes.[4] Therefore, the expression and role of STING in hepatocytes need to be further determined. Loss of Sam50 or APAP treatment was found to increase reactive oxygen species (ROS) production, and the investigators previously reported an important role of Sam50 in regulating phosphatase and tensin homolog–induced kinase 1 (PINK1)–Parkin–mediated mitophagy (29874585). Interplay between ROS and mitophagy has been reported.[5] Thus, it would be interesting to test the alteration and effects of hepatocellular mitophagy. In a TAA‐induced liver injury model, we found that XBP1 deficiency increased mitochondrial ROS production by impairing PINK1‐mediated mitophagy, causing enhanced hepatocyte pyroptosis.[3] In conclusion, we agree with the investigators’ conclusion that Sam50 depletion induces mtDNA release to activate the cGAS–STING signaling and liver inflammatory injury. However, further studies are required to determine the extracellular mtDNA release, the expression and activation of STING in hepatocytes, and the mitophagy alteration in Sam50‐deficient or APAP‐treated hepatocytes. CONFLICT OF INTEREST Nothing to report.
Characterization of Eosinophilic Bronchiectasis: A European Multicohort Study
Authors: Amelia Shoemark, Michal Shteinberg, Anthony De Soyza, Charles S. Haworth, Hollian Richardson, Yonghua Gao, Lidia Perea, Alison J. Dicker, Pieter C. Goeminne, Erin Cant, Eva Polverino, Josje Altenburg, Holly R. Keir, Michael R. Loebinger, Francesco Blasi, Tobias Welte, Oriol Sibila, Stefano Aliberti, James D. Chalmers
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Rationale: Bronchiectasis is classically considered a neutrophilic disorder, but eosinophilic subtypes have recently been described. Objectives: To use multiple datasets available through the European Multicentre Bronchiectasis Audit and Research Collaboration to characterize eosinophilic bronchiectasis as a clinical entity focusing on the impact of eosinophils on bronchiectasis exacerbations. Methods: Patients were included from five countries to examine the relationships between blood eosinophil counts and clinical phenotypes after excluding coexisting asthma. 16S rRNA sequencing was used to examine relationships between eosinophil counts and the sputum microbiome. A post hoc analysis of the PROMIS (Inhaled Promixin in the Treatment of Non-Cystic Fibrosis Bronchiectasis) phase 2 trial was used to examine the impact of blood eosinophil counts on exacerbations in patients with Pseudomonas aeruginosa infection. Measurements and Main Results: A relationship between sputum and blood eosinophil counts was demonstrated in two cohorts. In analysis of 1,007 patients from five countries, 22.6% of patients had blood eosinophil counts of ⩾300 cells/μl. Counts of <100 cells/μl were associated with higher bronchiectasis severity and increased mortality. There was no clear relationship with exacerbations. Blood eosinophil counts of ⩾300 cells/μl were associated with both Streptococcus- and Pseudomonas-dominated microbiome profiles. To investigate the relationship of eosinophil counts with exacerbations after controlling for the confounding effects of infection, 144 patients were studied in a clinical trial after treatment with antipseudomonal antibiotics. Compared with patients with blood eosinophil counts of <100 cells/μl (reference), elevated eosinophil counts of 100-299 cells/μl (hazard ratio, 2.38; 95% confidence interval, 1.33-4.25; P = 0.003) and ⩾300 cells/μl (hazard ratio, 3.99; 95% confidence interval, 2.20-7.85; P < 0.0001) were associated with shorter time to exacerbation. Conclusions: Eosinophilic bronchiectasis affects approximately 20% of patients. After accounting for infection status, raised blood eosinophil counts are associated with shortened time to exacerbation.
Development of a clinical polygenic risk score assay and reporting workflow
Authors: Limin Hao, Peter Kraft, Gabriel F. Berriz, Elizabeth D. Hynes, Christopher Koch, Prathik Korategere V Kumar, Shruti S. Parpattedar, Marcie Steeves, Wanfeng Yu, Ashley A. Antwi, Charles A. Brunette, Morgan Danowski, Manish K. Gala, Robert C. Green, Natalie E. Jones, Anna C. F. Lewis, Steven A. Lubitz, Pradeep Natarajan, Jason L. Vassy, Matthew S. Lebo
Journal: Nature Medicine (2022)

Abstract Implementation of polygenic risk scores (PRS) may improve disease prevention and management but poses several challenges: the construction of clinically valid assays, interpretation for individual patients, and the development of clinical workflows and resources to support their use in patient care. For the ongoing Veterans Affairs Genomic Medicine at Veterans Affairs (GenoVA) Study we developed a clinical genotype array-based assay for six published PRS. We used data from 36,423 Mass General Brigham Biobank participants and adjustment for population structure to replicate known PRS–disease associations and published PRS thresholds for a disease odds ratio (OR) of 2 (ranging from 1.75 (95% CI: 1.57–1.95) for type 2 diabetes to 2.38 (95% CI: 2.07–2.73) for breast cancer). After confirming the high performance and robustness of the pipeline for use as a clinical assay for individual patients, we analyzed the first 227 prospective samples from the GenoVA Study and found that the frequency of PRS corresponding to published OR &gt; 2 ranged from 13/227 (5.7%) for colorectal cancer to 23/150 (15.3%) for prostate cancer. In addition to the PRS laboratory report, we developed physician- and patient-oriented informational materials to support decision-making about PRS results. Our work illustrates the generalizable development of a clinical PRS assay for multiple conditions and the technical, reporting and clinical workflow challenges for implementing PRS information in the clinic.
Four decades of experience of prosthetic valve endocarditis reflect a high variety of diverse pathogens
Authors: Andreas Oberbach, Nadine Schlichting, Christian Hagl, Stefanie Lehmann, Yvonne Kullnick, Maik Friedrich, Ulrike Köhl, Friedemann Horn, Vivek Kumbhari, Bettina Löffler, Frank Schmidt, Dominik Joskowiak, Frank Born, Shekhar Saha, Erik Bagaev
Journal: Cardiovascular Research (2022)

Abstract Prosthetic valve endocarditis (PVE) remains a serious condition with a high mortality rate. Precise identification of the PVE-associated pathogen/s and their virulence is essential for successful therapy and patient survival. The commonly described PVE-associated pathogens are staphylococci, streptococci, and enterococci, with Staphylococcus aureus being the most frequently diagnosed species. Furthermore, multi-drug resistance pathogens are increasing in prevalence and continue to pose new challenges mandating a personalized approach. Blood cultures in combination with echocardiography are the most common methods to diagnose PVE, often being the only indication, it exists. In many cases, the diagnostic strategy recommended in the clinical guidelines does not identify the precise microbial agent, and frequently, false-negative blood cultures are reported. Despite the fact that blood culture findings are not always a good indicator of the actual PVE agent in the valve tissue, only a minority of re-operated prostheses are subjected to microbiological diagnostic evaluation. In this review, we focus on the diversity and the complete spectrum of PVE-associated bacterial, fungal, and viral pathogens in blood and prosthetic heart valve, their possible virulence potential, and their challenges in making a microbial diagnosis. We are curious to understand if the unacceptable high mortality of PVE is associated with the high number of negative microbial findings in connection with a possible PVE. Herein, we discuss the possibilities and limits of the diagnostic methods conventionally used and make recommendations for enhanced pathogen identification. We also show possible virulence factors of the most common PVE-associated pathogens and their clinical effects. Based on blood culture, molecular biological diagnostics, and specific valve examination, better derivations for the antibiotic therapy as well as possible preventive intervention can be established in the future.
Association of Maternal Autoimmune Diseases With Risk of Mental Disorders in Offspring in Denmark
Authors: Hua He, Yongfu Yu, Zeyan Liew, Mika Gissler, Krisztina D. László, Unnur Anna Valdimarsdóttir, Jun Zhang, Fei Li, Jiong Li
Journal: JAMA Network Open (2022)

<h3>Importance</h3> Maternal immune activation during pregnancy is associated with increased risks of several mental disorders in offspring during childhood, but little is known about how maternal autoimmune diseases during pregnancy are associated with mental health in offspring during and after childhood. <h3>Objective</h3> To investigate the association between maternal autoimmune diseases before childbirth and risk of mental disorders among offspring up to early adulthood. <h3>Design, Setting, and Participants</h3> This population-based nationwide cohort study used data from Danish national registers on singletons born in Denmark from 1978 to 2015 with up to 38 years of follow-up. Data analyses were conducted from March 1, 2020, through September 30, 2021. <h3>Exposures</h3> Maternal autoimmune disease diagnosed before or during pregnancy according to the Danish National Patient Register. <h3>Main Outcomes and Measures</h3> The main outcome was mental disorders, defined by hospital diagnoses, in offspring. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% CIs for mental disorders. <h3>Results</h3> Of the 2 254 234 singleton infants included in the study (median age, 16.7 years [IQR, 10.5-21.7 years]; 51.28% male), 2.26% were born to mothers with autoimmune diseases before childbirth. Exposed participants had an increased risk of overall mental disorders compared with their unexposed counterparts (HR, 1.16; 95% CI, 1.13-1.19; incidence, 9.38 vs 7.91 per 1000 person-years). Increased risks of overall mental disorders in offspring were seen in different age groups for type 1 diabetes (1-5 years: HR, 1.35 [95% CI, 1.17-1.57]; 6-18 years: HR, 1.24 [95% CI, 1.15-1.33]; &gt;18 years: HR, 1.19 [95% CI, 1.09-1.30]) and rheumatoid arthritis (1-5 years: HR, 1.42 [95% CI, 1.16-1.74]; 6-18 years: HR, 1.19 [95% CI, 1.05-1.36]; &gt;18 years: HR, 1.28 [95% CI, 1.02-1.60]). Regarding specific mental disorders, increased risk after exposure to any maternal autoimmune disorder was observed for organic disorders (HR, 1.54; 95% CI, 1.21-1.94), schizophrenia (HR, 1.35; 95% CI, 1.21-1.51), obsessive-compulsive disorder (HR, 1.42; 95% CI, 1.24-1.63), mood disorders (HR, 1.12; 95% CI, 1.04-1.21), and a series of neurodevelopmental disorders (eg, childhood autism [HR, 1.21; 95% CI, 1.08-1.36] and attention-deficit/hyperactivity disorder [HR, 1.19; 95% CI, 1.12-1.26]). <h3>Conclusions and Relevance</h3> In this cohort study in Denmark, prenatal exposure to maternal autoimmune diseases was associated with increased risks of overall and type-specific mental disorders in offspring. Maternal type 1 diabetes and rheumatoid arthritis during pregnancy were associated with offspring's mental health up to early adulthood. Individuals prenatally exposed to autoimmune disease may benefit from long-term surveillance for mental disorders.
Combinatorial Inactivation of Tumor Suppressors Efficiently Initiates Lung Adenocarcinoma with Therapeutic Vulnerabilities
Authors: Maryam Yousefi, Gábor Boross, Carly Weiss, Christopher W. Murray, Jess D. Hebert, Hongchen Cai, Emily L. Ashkin, Saswati Karmakar, Laura Andrejka, Leo Chen, Minwei Wang, Min K. Tsai, Wen-Yang Lin, Chuan Li, Pegah Yakhchalian, Caterina I. Colón, Su-Kit Chew, Pauline Chu, Charles Swanton, Christian A. Kunder, Dmitri A. Petrov, Monte M. Winslow
Journal: Cancer Research (2022)

Abstract Lung cancer is the leading cause of cancer death worldwide, with lung adenocarcinoma being the most common subtype. Many oncogenes and tumor suppressor genes are altered in this cancer type, and the discovery of oncogene mutations has led to the development of targeted therapies that have improved clinical outcomes. However, a large fraction of lung adenocarcinomas lacks mutations in known oncogenes, and the genesis and treatment of these oncogene-negative tumors remain enigmatic. Here, we perform iterative in vivo functional screens using quantitative autochthonous mouse model systems to uncover the genetic and biochemical changes that enable efficient lung tumor initiation in the absence of oncogene alterations. Generation of hundreds of diverse combinations of tumor suppressor alterations demonstrates that inactivation of suppressors of the RAS and PI3K pathways drives the development of oncogene-negative lung adenocarcinoma. Human genomic data and histology identified RAS/MAPK and PI3K pathway activation as a common feature of an event in oncogene-negative human lung adenocarcinomas. These Onc-negativeRAS/PI3K tumors and related cell lines are vulnerable to pharmacologic inhibition of these signaling axes. These results transform our understanding of this prevalent yet understudied subtype of lung adenocarcinoma. Significance: To address the large fraction of lung adenocarcinomas lacking mutations in proto-oncogenes for which targeted therapies are unavailable, this work uncovers driver pathways of oncogene-negative lung adenocarcinomas and demonstrates their therapeutic vulnerabilities.
Is Glucagon Administration Compatible With FDG PET/MRI?
Authors: Bruno Maucherat, Roshanack Movassaghi, Vincent Fleury, Maelle Le Thiec, Delphine Geffroy, Catherine Labbe-Devilliers, Caroline Rousseau
Journal: Clinical Nuclear Medicine (2022)

Abstract Digestive peristalsis generates many artifacts that limit the abdominal and pelvic MRI interpretation. Apart from the hypoglycemia treatment in patients with diabetes, glucagon analog is also indicated for the digestive peristalsis reduction to reduce MRI artifacts. However, its use in PET/MRI is not described, given the risk of interaction with the metabolism of FDG. To assess the importance of this interaction on the FDG PET images, we report FDG PET/MRI images obtained with and without glucagon analog injection.
The Developmental Origin of Calcific Aortic Stenosis
Authors: Elena Aikawa, Joshua D. Hutcheson
Journal: New England Journal of Medicine (2022)

How do pathologic stimuli result in fibrosis and the development of calcific nodules, which compromise the biomechanical integrity of the aortic valve and lead to stenosis? A recent study of a mouse model underscores the need to better understand how pathways critical to early developmental stages contribute to stenosis.
Classification of human chronic inflammatory skin disease based on single-cell immune profiling
Authors: Yale Liu, Hao Wang, Mark Taylor, Christopher Cook, Alejandra Martínez-Berdeja, Jeffrey P. North, Paymann Harirchian, Ashley A. Hailer, Zijun Zhao, Ruby Ghadially, Roberto R. Ricardo-Gonzalez, Roy C. Grekin, Theodora M. Mauro, Esther Kim, Jaehyuk Choi, Elizabeth Purdom, Raymond J. Cho, Jeffrey B. Cheng
Journal: Science Immunology (2022)

Inflammatory conditions represent the largest class of chronic skin disease, but the molecular dysregulation underlying many individual cases remains unclear. Single-cell RNA sequencing (scRNA-seq) has increased precision in dissecting the complex mixture of immune and stromal cell perturbations in inflammatory skin disease states. We single-cell–profiled CD45 + immune cell transcriptomes from skin samples of 31 patients (7 atopic dermatitis, 8 psoriasis vulgaris, 2 lichen planus (LP), 1 bullous pemphigoid (BP), 6 clinical/histopathologically indeterminate rashes, and 7 healthy controls). Our data revealed active proliferative expansion of the T reg and Trm components and universal T cell exhaustion in human rashes, with a relative attenuation of antigen-presenting cells. Skin-resident memory T cells showed the greatest transcriptional dysregulation in both atopic dermatitis and psoriasis, whereas atopic dermatitis also demonstrated recurrent abnormalities in ILC and CD8 + cytotoxic lymphocytes. Transcript signatures differentiating these rash types included genes previously implicated in T helper cell (T H 2)/T H 17 diatheses, segregated in unbiased functional networks, and accurately identified disease class in untrained validation data sets. These gene signatures were able to classify clinicopathologically ambiguous rashes with diagnoses consistent with therapeutic response. Thus, we have defined major classes of human inflammatory skin disease at the molecular level and described a quantitative method to classify indeterminate instances of pathologic inflammation. To make this approach accessible to the scientific community, we created a proof-of-principle web interface (RashX), where scientists and clinicians can visualize their patient-level rash scRNA-seq–derived data in the context of our T H 2/T H 17 transcriptional framework.
Tumor-associated macrophages in multiple myeloma: advances in biology and therapy
Authors: Jennifer Sun, Chaelee Park, Nicole Guenthner, Shannon Gurley, Luna Zhang, Berit Lubben, Ola Adebayo, Hannah Bash, Yixuan Chen, Mina Maksimos, Barbara Muz, Abdel Kareem Azab
Journal: Journal for ImmunoTherapy of Cancer (2022)

Multiple myeloma (MM) is a cancer of plasma cells in the bone marrow (BM) and represents the second most common hematological malignancy in the world. The MM tumor microenvironment (TME) within the BM niche consists of a wide range of elements which play important roles in supporting MM disease progression, survival, proliferation, angiogenesis, as well as drug resistance. Together, the TME fosters an immunosuppressive environment in which immune recognition and response are repressed. Macrophages are a central player in the immune system with diverse functions, and it has been long established that macrophages play a critical role in both inducing direct and indirect immune responses in cancer. Tumor-associated macrophages (TAMs) are a major population of cells in the tumor site. Rather than contributing to the immune response against tumor cells, TAMs in many cancers are found to exhibit protumor properties including supporting chemoresistance, tumor proliferation and survival, angiogenesis, immunosuppression, and metastasis. Targeting TAM represents a novel strategy for cancer immunotherapy, which has potential to indirectly stimulate cytotoxic T cell activation and recruitment, and synergize with checkpoint inhibitors and chemotherapies. In this review, we will provide an updated and comprehensive overview into the current knowledge on the roles of TAMs in MM, as well as the therapeutic targets that are being explored as macrophage-targeted immunotherapy, which may hold key to future therapeutics against MM.
Correction: Sphingosine Kinase-1 Enhances Resistance to Apoptosis through Activation of PI3K/Akt/NFκB Pathway in Human Non–small Cell Lung Cancer
Authors: Libing Song, Huaping Xiong, Jun Li, Wenting Liao, Lan Wang, Jueheng Wu, Mengfeng Li
Journal: Clinical Cancer Research (2022)

In the original version of this article (1), Figs. 1C, 4A, and 4B contained multiple duplicated panels. The figures have been corrected with the original data in the latest online HTML and PDF versions of the article. The authors regret the errors.
Aging Microbiota-Gut-Brain Axis in Stroke Risk and Outcome
Authors: Pedram Honarpisheh, Robert M. Bryan, Louise D. McCullough
Journal: Circulation Research (2022)

The microbiota-gut-brain-axis (MGBA) is a bidirectional communication network between gut microbes and their host. Many environmental and host-related factors affect the gut microbiota. Dysbiosis is defined as compositional and functional alterations of the gut microbiota that contribute to the pathogenesis, progression and treatment responses to disease. Dysbiosis occurs when perturbations of microbiota composition and function exceed the ability of microbiota and its host to restore a symbiotic state. Dysbiosis leads to dysfunctional signaling of the MGBA, which regulates the development and the function of the host’s immune, metabolic, and nervous systems. Dysbiosis-induced dysfunction of the MGBA is seen with aging and stroke, and is linked to the development of common stroke risk factors such as obesity, diabetes, and atherosclerosis. Changes in the gut microbiota are also seen in response to stroke, and may impair recovery after injury. This review will begin with an overview of the tools used to study the MGBA with a discussion on limitations and potential experimental confounders. Relevant MGBA components are introduced and summarized for a better understanding of age-related changes in MGBA signaling and its dysfunction after stroke. We will then focus on the relationship between the MGBA and aging, highlighting that all components of the MGBA undergo age-related alterations that can be influenced by or even driven by the gut microbiota. In the final section, the current clinical and preclinical evidence for the role of MGBA signaling in the development of stroke risk factors such as obesity, diabetes, hypertension, and frailty are summarized, as well as microbiota changes with stroke in experimental and clinical populations. We conclude by describing the current understanding of microbiota-based therapies for stroke including the use of pre-/pro-biotics and supplementations with bacterial metabolites. Ongoing progress in this new frontier of biomedical sciences will lead to an improved understanding of the MGBA’s impact on human health and disease.