tbuckley/cabot-search huggingface dataset:
Targeting <scp>IL</scp>‐13 with tralokinumab normalizes type 2 inflammation in atopic dermatitis both early and at 2 years
Authors: Emma Guttman‐Yassky, Kenji Kabashima, Delphine Staumont‐Salle, Walter K. Nahm, Sylvia Pauser, Joel Correa Da Rosa, Britta Cathrina Martel, Daniel Elenius Madsen, Mads Røpke, Petra Arlert, Louise Steffensen, Andrew Blauvelt, Kristian Reich
Journal: Allergy (2024)

Abstract Background Tralokinumab is a monoclonal antibody that specifically neutralizes interleukin (IL)‐13, a key driver of skin inflammation and barrier abnormalities in atopic dermatitis (AD). This study evaluated early and 2‐year impacts of IL‐13 neutralization on skin and serum biomarkers following tralokinumab treatment in adults with moderate‐to‐severe AD. Methods Skin biopsies and blood samples were evaluated from a subset of patients enrolled in the Phase 3 ECZTRA 1 (NCT03131648) and the long‐term extension ECZTEND (NCT03587805) trials. Gene expression was assessed by RNA sequencing; protein expression was assessed by immunohistochemistry and immunoassay. Results Tralokinumab improved the transcriptomic profile of lesional skin by Week 4. Mean improvements in the expression of genes dysregulated in AD were 39% at Week 16 and 85% at 2 years with tralokinumab, with 15% worsening at Week 16 with placebo. At Week 16, tralokinumab significantly decreased type 2 serum biomarkers (CCL17/TARC, periostin, and IgE), reduced epidermal thickness versus placebo, and increased loricrin coverage versus baseline. Two years of tralokinumab treatment significantly reduced expression of genes in the Th2 ( IL4R , IL31 , CCL17 , and CCL26 ), Th1 ( IFNG ), and Th17/Th22 ( IL22 , S100A7 , S100A8 , and S100A9 ) pathways as well as increased expression of epidermal differentiation and barrier genes ( CLDN1 and LOR ). Tralokinumab also shifted atherosclerosis signaling pathway genes ( SELE , IL‐37 , and S100A8 ) toward non‐lesional expression. Conclusion Tralokinumab treatment improved epidermal pathology, reduced systemic markers of type 2 inflammation, and shifted expression of key AD biomarkers in skin towards non‐lesional levels, further highlighting the key role of IL‐13 in the pathogenesis of AD. Clinical Trial Registration NCT03131648, NCT03587805.
Erratum. Individualizing Treatment of Type 2 Diabetes After Metformin: More Insights From GRADE. Diabetes Care 2024;47:556–561
Authors: Matthew C. Riddle
Journal: Diabetes Care (2024)

In the Commentary cited above, the HbA1c value calling for insulin rescue therapy was twice inadvertently given as 7.0%; the correct value of 7.5% is shown in the revised text below.
Proteomic profiles of peritoneal fluid-derived small extracellular vesicles correlate with patient outcome in ovarian cancer
Authors: Miguel Quiralte, Arantzazu Barquín, Mónica Yagüe-Fernández, Paloma Navarro, Tatiana P. Grazioso, Elena Sevillano-Fernández, Juan F. Rodriguez-Moreno, Alejandra Balarezo-Saldivar, Héctor Peinado, Elena Izquierdo, Carlos Millán, Irene López-Carrasco, Mario Prieto, Rodrigo Madurga, Ismael Fernández-Miranda, Sergio Ruiz-Llorente, Jesús García-Donas
Journal: Journal of Clinical Investigation (2024)

Cancer-derived small extracellular vesicles (sEVs) are capable of modifying tumor microenvironment and promoting tumor progression. Ovarian cancer (OvCa) is a lethal malignancy that preferentially spreads through the abdominal cavity. Thus, the secretion of such vesicles into the peritoneal fluid could be a determinant factor in the dissemination and behavior of this disease. We designed a prospective observational study to assess the impact of peritoneal fluid-derived sEVs (PFD-sEVs) in OvCa clinical outcome. For this purpose, two patient cohorts were enrolled, including OvCa cases who underwent a diagnostic or cytoreductive surgery, and non-oncological patients as controls, who underwent abdominal surgery for benign gynecological conditions. PFD-sEVs systematic extraction from surgical samples enabled us to observe significant quantitative and qualitative differences associated with cancer diagnosis, disease stage and platinum chemosensitivity. Proteomic profiling of PFD-sEVs led to the identification of molecular pathways and proteins of interest and to the biological validation of S100A4 and STX5. In addition, unsupervised analysis of PFD-sEVs proteomic profiles in high-grade serous ovarian carcinomas (HGSOC) revealed two clusters with different outcomes in terms of overall survival. In conclusion, comprehensive characterization of the PFD-sEVs content provided a prognostic value with potential implications in HGSOC clinical management.
NFĸB signaling drives myocardial injury via CCR2+ macrophages in a preclinical model of arrhythmogenic cardiomyopathy
Authors: Stephen P. Chelko, Vinay R. Penna, Morgan Engel, Emily A. Shiel, Ann M. Centner, Waleed Farra, Elisa N. Cannon, Maicon Landim-Vieira, Niccole Schaible, Kory Lavine, Jeffrey E. Saffitz
Journal: Journal of Clinical Investigation (2024)

Nuclear factor kappa-B (NFκB) is activated in arrhythmogenic cardiomyopathy (ACM) patient-derived iPSC-cardiac myocytes under basal conditions and inhibition of NFκB signaling prevents disease in Dsg2mut/mut mice, a robust mouse model of ACM. Here, we used genetic approaches and single cell RNA sequencing to define the contributions of immune signaling in cardiac myocytes and macrophages in the natural progression of ACM using Dsg2mut/mut mice. We found that NFκB signaling in cardiac myocytes drives myocardial injury, contractile dysfunction, and arrhythmias in Dsg2mut/mut mice. NFκB signaling in cardiac myocytes mobilizes macrophages expressing C-C motif chemokine receptor-2 (CCR2+ cells) to affected areas within the heart, where they mediate myocardial injury and arrhythmias. Contractile dysfunction in Dsg2mut/mut mice is caused both by loss of heart muscle and negative inotropic effects of inflammation in viable muscle. Single nucleus RNA sequencing and cellular indexing of transcriptomes and epitomes (CITE-seq) studies revealed marked pro-inflammatory changes in gene expression and the cellular landscape in hearts of Dsg2mut/mut mice involving cardiac myocytes, fibroblasts and CCR2+ macrophages. Changes in gene expression in cardiac myocytes and fibroblasts in Dsg2mut/mut mice were dependent on CCR2+ macrophage recruitment to the heart. These results highlight complex mechanisms of immune injury and regulatory crosstalk between cardiac myocytes, inflammatory cells and fibroblasts in the pathogenesis of ACM.
Single-Cell RNA Sequencing Reveals Repair Features of Human Umbilical Cord Mesenchymal Stromal Cells
Authors: Chanèle Cyr-Depauw, David P Cook, Ivana Mižik, Flore Lesage, Arul Vadivel, Laurent Renesme, Yupu Deng, Shumei Zhong, Pauline Bardin, Liqun Xu, Marius A. Möbius, Jenny Marzahn, Daniel Freund, Duncan J. Stewart, Barbara C Vanderhyden, Mario Rüdiger, Bernard Thébaud
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

The chronic lung disease bronchopulmonary dysplasia (BPD) is the most severe complication of extreme prematurity. BPD results in impaired lung alveolar and vascular development and long-term respiratory morbidity, for which only supportive therapies exist. Umbilical cord-derived mesenchymal stromal cells (UC-MSCs) improve lung structure and function in experimental BPD. Results of clinical trials with MSCs for many disorders do not yet match the promising preclinical studies. A lack of specific criteria to define functionally distinct MSCs persists.
Prevalence and Associated Factors of E-Cigarette Use and Susceptibility Among Adolescents in China
Authors: Kaiyuan Min, Mingyao Wang, Chuan Wang, Pascal Geldsetzer, Till Bärnighausen, Chen Wang, Jiangfeng Liu, Simiao Chen, Juntao Yang
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

"Prevalence and Associated Factors of E-Cigarette Use and Susceptibility Among Adolescents in China." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp.
Lung Transplant Outcomes Keep BUGging Us: Acute Cellular Rejection and the Lung Microbiome
Authors: Mark E. Snyder, Georgios D. Kitsios
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

"Lung Transplant Outcomes Keep BUGging Us: Acute Cellular Rejection and the Lung Microbiome." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp.
Positive affect during adolescence and health and well-being in adulthood: An outcome-wide longitudinal approach
Authors: Eric S. Kim, Renae Wilkinson, Sakurako S. Okuzono, Ying Chen, Koichiro Shiba, Richard G. Cowden, Tyler J. VanderWeele
Journal: PLoS Medicine (2024)

Background Several intergovernmental organizations, including the World Health Organization and United Nations, are urging countries to use well-being indicators for policymaking. This trend, coupled with increasing recognition that positive affect is beneficial for health/well-being, opens new avenues for intervening on positive affect to improve outcomes. However, it remains unclear if positive affect in adolescence shapes health/well-being in adulthood. We examined if increases in positive affect during adolescence were associated with better health/well-being in adulthood across 41 outcomes. Methods and findings We conducted a longitudinal cohort study using data from Add Health—a prospective and nationally representative cohort of community-dwelling U.S. adolescents. Using regression models, we evaluated if increases in positive affect over 1 year (between Wave I; 1994 to 1995 and Wave II; 1995 to 1996) were associated with better health/well-being 11.37 years later (in Wave IV; 2008; N = 11,040) or 20.64 years later (in Wave V; 2016 to 2018; N = 9,003). Participants were aged 15.28 years at study onset, and aged 28.17 or 37.20 years—during the final assessment. Participants with the highest (versus lowest) positive affect had better outcomes on 3 (of 13) physical health outcomes (e.g., higher cognition (β = 0·12, 95% CI = 0·05, 0·19, p = 0.002)), 3 (of 9) health behavior outcomes (e.g., lower physical inactivity (RR = 0·80, CI = 0·66, 0·98, p = 0.029)), 6 (of 7) mental health outcomes (e.g., lower anxiety (RR = 0·81, CI = 0·71, 0·93, p = 0.003)), 2 (of 3) psychological well-being (e.g., higher optimism (β = 0·20, 95% CI = 0·12, 0·28, p &lt; 0.001)), 4 (of 7) social outcomes (e.g., lower loneliness (β = −0·09, 95% CI = −0·16, −0·02, p = 0.015)), and 1 (of 2) civic/prosocial outcomes (e.g., more voting (RR = 1·25, 95% CI = 1·16, 1·36, p &lt; 0.001)). Study limitations include potential unmeasured confounding and reverse causality. Conclusions Enhanced positive affect during adolescence is linked with a range of improved health/well-being outcomes in adulthood. These findings suggest the promise of testing scalable positive affect interventions and policies to more definitively assess their impact on outcomes.
National Estimates of the Participation of Patients With Cancer in Clinical Research Studies Based on Commission on Cancer Accreditation Data
Authors: Joseph M. Unger, Lawrence N. Shulman, Matthew A. Facktor, Heidi Nelson, Mark E. Fleury
Journal: Journal of Clinical Oncology (2024)

PURPOSE National estimates of cancer clinical trial participation are nearly two decades old and have focused solely on enrollment to treatment trials, which does not reflect the willingness of patients to contribute to other elements of clinical research. We determined inclusive, contemporary estimates of clinical trial participation for adults with cancer using a national sample of data from the Commission on Cancer (CoC). METHODS The data were obtained from accreditation information submitted by the 1,200 CoC programs, which represent more than 70% of all cancer cases diagnosed in the United States each year. Deidentified, institution-level aggregate counts of annual enrollment to treatment, biorepository, diagnostic, economic, genetic, prevention, quality-of-life (QOL), and registry studies were examined. Overall, study-type estimates for the period 2013-2017 were estimated. Multiple imputation by chained equations was used to account for missing data, with summary estimates calculated separately by type of program (eg, National Cancer Institute [NCI]–designated cancer centers) and pooled. RESULTS The overall estimated patient participation rate to cancer treatment trials was 7.1%. Patients with cancer participated in a wide variety of other studies, including biorepository (12.9%), registry (7.3%), genetic (3.6%), QOL (2.8%), diagnostic (2.5%), and economic (2.4%) studies. Treatment trial enrollment was 21.6% at NCI-designated comprehensive cancer centers, 5.4% at academic (non–NCI-designated) comprehensive cancer programs, 5.7% at integrated network cancer programs, and 4.1% at community programs. One in five patients (21.9%) participated in one or more cancer clinical research studies. CONCLUSION In a first-time use of national accreditation information from the CoC, enrollment to cancer treatment trials was 7.1%, higher than historical estimates of &lt;5%. Patients participated in a diverse set of other study types. Contributions of adult patients with cancer to clinical research is more common than previously understood.
Activating Point Mutations in the <i>MET</i> Kinase Domain Represent a Unique Molecular Subset of Lung Cancer and Other Malignancies Targetable with MET Inhibitors
Authors: Federica Pecci, Seshiru Nakazawa, Biagio Ricciuti, Guilherme Harada, Jessica K. Lee, Joao V. Alessi, Adriana Barrichello, Victor R. Vaz, Giuseppe Lamberti, Alessandro Di Federico, Malini M. Gandhi, Dimitris Gazgalis, William W. Feng, Jie Jiang, Simon Baldacci, Marie-Anaïs Locquet, Felix H. Gottlieb, Monica F. Chen, Elinton Lee, Danielle Haradon, Anna Smokovich, Emma Voligny, Tom Nguyen, Vikas K. Goel, Zachary Zimmerman, Sumandeep Atwal, Xinan Wang, Magda Bahcall, Rebecca S. Heist, Sumaiya Iqbal, Nishant Gandhi, Andrew Elliott, Ari M. Vanderwalde, Patrick C. Ma, Balazs Halmos, Stephen V. Liu, Jianwei Che, Alexa B. Schrock, Alexander Drilon, Pasi A. Jänne, Mark M. Awad
Journal: Cancer Discovery (2024)

Abstract Activating point mutations in the MET tyrosine kinase domain (TKD) are oncogenic in a subset of papillary renal cell carcinomas. Here, using comprehensive genomic profiling among &amp;gt;600,000 patients, we identify activating MET TKD point mutations as putative oncogenic driver across diverse cancers, with a frequency of ∼0.5%. The most common mutations in the MET TKD defined as oncogenic or likely oncogenic according to OncoKB resulted in amino acid substitutions at positions H1094, L1195, F1200, D1228, Y1230, M1250, and others. Preclinical modeling of these alterations confirmed their oncogenic potential and also demonstrated differential patterns of sensitivity to type I and type II MET inhibitors. Two patients with metastatic lung adenocarcinoma harboring MET TKD mutations (H1094Y, F1200I) and no other known oncogenic drivers achieved confirmed partial responses to a type I MET inhibitor. Activating MET TKD mutations occur in multiple malignancies and may confer clinical sensitivity to currently available MET inhibitors. Significance: The identification of targetable genomic subsets of cancer has revolutionized precision oncology and offers patients treatments with more selective and effective agents. Here, we demonstrate that activating, oncogenic MET tyrosine kinase domain mutations are found across a diversity of cancer types and are responsive to MET tyrosine kinase inhibitors.
Leveraging new methods for comprehensive characterization of mitochondrial DNA in esophageal squamous cell carcinoma
Authors: Xuehan Zhuang, Rui Ye, Yong Zhou, Matthew Yibo Cheng, Heyang Cui, Longlong Wang, Shuangping Zhang, Shubin Wang, Yongping Cui, Weimin Zhang
Journal: Genome Medicine (2024)

Abstract Background Mitochondria play essential roles in tumorigenesis; however, little is known about the contribution of mitochondrial DNA (mtDNA) to esophageal squamous cell carcinoma (ESCC). Whole-genome sequencing (WGS) is by far the most efficient technology to fully characterize the molecular features of mtDNA; however, due to the high redundancy and heterogeneity of mtDNA in regular WGS data, methods for mtDNA analysis are far from satisfactory. Methods Here, we developed a likelihood-based method dMTLV to identify low-heteroplasmic mtDNA variants. In addition, we described fNUMT, which can simultaneously detect non-reference nuclear sequences of mitochondrial origin (non-ref NUMTs) and their derived artifacts. Using these new methods, we explored the contribution of mtDNA to ESCC utilizing the multi-omics data of 663 paired tumor-normal samples. Results dMTLV outperformed the existing methods in sensitivity without sacrificing specificity. The verification using Nanopore long-read sequencing data showed that fNUMT has superior specificity and more accurate breakpoint identification than the current methods. Leveraging the new method, we identified a significant association between the ESCC overall survival and the ratio of mtDNA copy number of paired tumor-normal samples, which could be potentially explained by the differential expression of genes enriched in pathways related to metabolism, DNA damage repair, and cell cycle checkpoint. Additionally, we observed that the expression of CBWD1 was downregulated by the non-ref NUMTs inserted into its intron region, which might provide precursor conditions for the tumor cells to adapt to a hypoxic environment. Moreover, we identified a strong positive relationship between the number of mtDNA truncating mutations and the contribution of signatures linked to tumorigenesis and treatment response. Conclusions Our new frameworks promote the characterization of mtDNA features, which enables the elucidation of the landscapes and roles of mtDNA in ESCC essential for extending the current understanding of ESCC etiology. dMTLV and fNUMT are freely available from https://github.com/sunnyzxh/dMTLV and https://github.com/sunnyzxh/fNUMT , respectively.
Incidence of anxiety disorder in adults with hidradenitis suppurativa
Authors: Erica Cohn, Gabriela Palma, Nicole Mastacouris, Andrew Strunk, Amit Garg
Journal: British Journal of Dermatology (2024)

Abstract Background There are limited data on the risk of new-onset anxiety disorders in patients with hidradenitis suppurativa (HS). Objectives To compare the risk of new-onset anxiety disorder in patients with HS and controls, and to describe risk factors for the development of anxiety in patients with HS. Methods We carried out a retrospective cohort analysis of a US electronic health records database between 2011 and 2020. Adults newly diagnosed with HS at a dermatology or primary care visit and control participants were included. The primary outcome was a new diagnosis of generalized anxiety disorder, phobic disorders, panic disorder or unspecified anxiety. Cox proportional hazards regression was used to compare the crude risk of any anxiety disorder between groups and to assess the independent association with HS while controlling for potential demographic, clinical and healthcare-related confounders. Results Among 9597 patients with HS and 959 493 controls, the incidence rate (IR) of anxiety was 5.74 and 3.86 per 100 person-years (PY), respectively. The crude risk among all patients was 48% higher for those with HS vs. controls [hazard ratio (HR) 1.48, 95% confidence interval (CI) 1.40–1.55]. When stratified by index encounter type, patients with HS had 2.43 (95% CI 2.13–2.77) times the risk of anxiety disorder than dermatology controls and 1.46 (95%CI 1.38–1.55) times the risk than primary care controls. The adjusted HR for patients with HS vs. controls was 1.11 (95% CI 1.05–1.17) overall, 1.26 (95% CI 1.07–1.48) in the dermatology subgroup and 1.07 (95% CI 1.01–1.13) in the primary care subgroup. Risk factors for an incident anxiety diagnosis among patients with HS included depression (HR 1.69, 95% CI 1.48–1.93), female sex (HR 1.41, 95% CI 1.23–1.60), younger age (HR 0.87 per 10-year increase, 95% CI 0.84–0.90), White race, in the Medicaid insurance programme (HR 1.22, 95% CI 1.07–1.40), tobacco smoking (HR 1.16, 95% CI 1.03–1.31) and having one or more emergency department visits in the year before a HS diagnosis. Absolute IRs of anxiety disorders were highest among patients with HS who were aged 18–29 years (7.10 per 100 PY), female (6.34 per 100 PY) and White (6.79 per 100 PY). Conclusions HS is independently associated with an increased risk of anxiety disorders. An increased risk remains but is attenuated when confounders are controlled for. The relative risk may be particularly high in patients managed by dermatologists.
Engineering Nanoplatforms for Theranostics of Atherosclerotic Plaques
Authors: Yuying Liu, Zeyu Jiang, Xiao Yang, Yin Wang, Bin Yang, Qinrui Fu
Journal: Advanced Healthcare Materials (2024)

Atherosclerotic plaque formation is considered the primary pathological mechanism underlying atherosclerotic cardiovascular diseases, leading to severe cardiovascular events such as stroke, acute coronary syndromes, and even sudden cardiac death. Early detection and timely intervention of plaques are challenging due to the lack of typical symptoms in the initial stages. Therefore, precise early detection and intervention play a crucial role in risk stratification of atherosclerotic plaques and achieving favorable post-interventional outcomes. The continuously advancing nanoplatforms have demonstrated numerous advantages including high signal-to-noise ratio, enhanced bioavailability, and specific targeting capabilities for imaging agents and therapeutic drugs, enabling effective visualization and management of atherosclerotic plaques. Motivated by these superior properties, various noninvasive imaging modalities for early recognition of plaques in the preliminary stage of atherosclerosis are comprehensively summarized. Additionally, several therapeutic strategies are proposed to enhance the efficacy of treating atherosclerotic plaques. Finally, existing challenges and promising prospects for accelerating clinical translation of nanoplatform-based molecular imaging and therapy for atherosclerotic plaques are discussed. In conclusion, this review provides an insightful perspective on the diagnosis and therapy of atherosclerotic plaques.