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Pediatric lead exposure and risk of influenza and pneumonia in an underrepresented, urban sample

Science of the Total Environment 2025年 969卷 178963页

作者： Feiler, Marina Oktapodas Odiko, Eva Nie, Jing Yucel, Recai Lehman, Heather K. Kulick, Erin R. Spiegel, Nitzana Khan, Adil I. Turella, John Department of Epidemiology and Environmental Health School of Public Health and Health Professions University at Buffalo BuffaloNY United States Department of Epidemiology and Biostatistics College of Public Health Temple University PhiladelphiaPA United States Department of Pediatrics Jacobs School of Medicine and Biomedical Sciences University at Buffalo BuffaloNY United States Department of Pathology and Laboratory Medicine Lewis Katz School of Medicine Temple University PhiladelphiaPA United States Bioinformatics Core Center for Biostatistics and Epidemiology Lewis Katz School of Medicine Temple University PhiladelphiaPA United States

The present objective was to estimate the association between childhood blood lead concentrations (BLC) and clinical diagnoses of influenza or pneumonia among a large, low-income, underrepresented cohort of children using a retrospective design. Medical records were pulled from the Temple University Hospital System (TUHS) located in inner-city Philadelphia, PA from 2010 to 2020. All children ≤14 years of age with an available lead value in their medical records were included in the analysis (N = 14,217). Lead exposure was measured via BLC as reported in the medical records through screening practices. Respiratory outcomes, influenza and pneumonia, were measured from ICD codes. Log-binomial regression models were fit to estimate the prevalence ratios and 95 % confidence intervals for the associations between BLC and influenza or pneumonia. Poisson regression models were fit to estimate the associations between BLC and counts of influenza or pneumonia recurrence. Additional models examined sexually dimorphic associations between BLC and outcomes. Compared to children with a BLC © 2025

关键词： Pb Respiratory Infection Children Healthy inequity BLC

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Phase 1 trial of durvalumab (anti–PD-L1) combined with lenalidomide in relapsed/refractory cutaneous T-cell lymphoma

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Blood Advances 2025年第9期9卷 2247-2260页

作者： Querfeld, Christiane Palmer, Joycelynne Han, Zhen Wu, Xiwei Yuan, Yate-Ching Chen, Min-Hsuan Su, Chingyu Tsai, Ni-Chun Smith, D. Lynne Hammond, Samantha N. Crisan, Liliana Song, Joo Y. Pillai, Raju Rosen, Steven T. Zain, Jasmine Division of Dermatology Center for Informatics City of Hope Duarte CA United States Department of Pathology Center for Informatics City of Hope Duarte CA United States Department of Hematology and Hematopoietic Cell Transplantation Center for Informatics City of Hope Duarte CA United States Beckman Research Institute Center for Informatics City of Hope Duarte CA United States Division of Biostatistics Center for Informatics City of Hope Duarte CA United States Department of Computational and Quantitative Medicine Center for Informatics City of Hope Duarte CA United States Integrative Genomics Core Center for Informatics City of Hope Duarte CA United States Department of Translational Bioinformatics Center for Informatics City of Hope Duarte CA United States

Selective targeting of the functionally exhausted malignant T cells in cutaneous T-cell lymphoma (CTCL) and distinct cells within the tumor microenvironment (TME) via programmed cell death 1/programmed cell death ligand 1 blockade (durvalumab) may restore an antitumor immune response. The oral immunomodulator lenalidomide, which has activity in CTCL, may enhance durvalumab immune checkpoint blockade. Our phase 1/ 2 clinical trial of durvalumab and lenalidomide in patients with refractory/advanced CTCL sought to assess the safety and tolerability and to identify the maximum tolerated dose and recommended phase 2 dose (RP2D) of lenalidomide plus fixed-dose durvalumab. Secondary and tertiary objectives were to investigate the efficacy and effects on the TME. Thirteen patients were evaluable for toxicities and 12 for dose decisions and response. No serious adverse events (AEs) or dose-limiting toxicities (DLTs) were observed during cycles 1 to 3 (DLT evaluation period), and dose level 3 was identified as the RP2D. The most frequent AEs were tumor flare, fatigue, neutropenia, and leukopenia. Three patients developed grade 1 or 2 autoimmune thyroiditis that resolved with treatment. Best overall and skin response rates were 58.3% (95% confidence interval (95% CI), 27.7-84.8%) and 75% (95% CI: 42.8-94.5%), respectively. The median cycles of treatment were 11, and the median duration of response was 25.5 months. The combination showed clinical activity with 7 partial responses and 4 stable disease. Potentially predictive immune signatures were downregulation of -α signaling via NF-κB, interferon gamma, and phosphoinositide 3 kinase-AKT-mammalian target of rapamycin signaling pathways in responders and upregulation of MYC targets and proinflammatory pathways in nonresponders. Profiling of immune cell compositions revealed changes in individual immune cell clusters based on treatment response. © 2025 American Society of Hematology.

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Comparative analysis of continuous similarity measures for compound identification in mass spectrometry-based metabolomics

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Chemometrics and Intelligent Laboratory Systems 2025年 263卷

作者： Dlugas, Hunter Zhang, Xiang Kim, Seongho Biostatistics and Bioinformatics Core Karmanos Cancer Institute Department of Oncology Wayne State University DetroitMI United States Department of Chemistry University of Louisville LouisvilleKY United States

In mass spectrometry (MS)-based metabolomics, the most straightforward and efficient approach for compound identification is the comparison of similarity scores between experimental spectra and reference spectra. Among various single and composite similarity measures, the Cosine Correlation is favored due to its simplicity, efficiency, and effectiveness. Recently, the Shannon Entropy Correlation has shown superior performance over several other measures, including the Cosine Correlation, in LC-MS-based metabolomics, particularly concerning receiver operating characteristic (ROC) curves and false discovery rates. However, previous comparisons did not consider the weight factor transformation, which is critical for achieving higher accuracy with the cosine correlation. This study conducted a comparative analysis of the Cosine Correlation and Shannon Entropy Correlation, incorporating the weight factor transformation during preprocessing. Additionally, we developed a novel entropy correlation measure, the Tsallis Entropy Correlation, which offers greater versatility than the Shannon Entropy Correlation. Our accuracy-based results indicate that the weight factor transformation is essential for achieving higher identification performance in both LC-MS and GC-MS-based compound identification. Although the Tsallis Entropy Correlation outperforms the Shannon Entropy Correlation in terms of accuracy, it comes with higher computational expense. In contrast, the Cosine Correlation, when combined with the weight factor transformation, achieves the highest accuracy and the lowest computational expense, demonstrating both robustness and efficiency in MS-based compound identification. © 2025 Elsevier B.V.

关键词： Cosine transforms

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B-cell infiltration distinguishes mucosal from skin patterns of rejection in facial vascularized composite allografts

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American Journal of Transplantation 2025年第6期25卷 1193-1207页

作者： Kauke-Navarro, Martin Crisler, William J. Younis, Nour Khetani, Radhika S. Sadigh, Sam Teague, Jessica E. Ho Sui, Shannan J. Ko, Christine Zhan, Qian Steuart, Samuel Treister, Nathaniel S. Pober, Jordan Azzi, Jamil Clark, Rachael A. Pomahac, Bohdan Department of Surgery Division of Plastic Surgery Yale School of Medicine New Haven CT United States Department of Dermatology Brigham and Women's Hospital Harvard Medical School Boston MA United States Transplantation Research Cenyounter Renal Division Brigham and Women's Hospital and Children's Hospital Boston MA United States Harvard Chan Bioinformatics Core Department of Biostatistics Harvard T.H. Chan School of Public Health Boston MA United States Department of Pathology Brigham and Women's Hospital Harvard Medical School Boston MA United States Department of Pathology Yale School of Medicine New Haven CT United States Division of Oral Medicine and Dentistry Brigham and Women's Hospital Boston MA United States Department of Immunobiology Yale School of Medicine New Haven CT United States

Rejection monitoring in facial vascularized composite allotransplantation traditionally focuses on skin biopsies. However, mucosal rejection frequently presents with more pronounced signs of immune activity. To explore mechanistic differences between skin and mucosal rejection, rejection and nonrejection biopsies from allograft skin and oral mucosa of 9 facial vascularized composite allotransplantation recipients were retrospectively analyzed using histology, multiplex immunostaining, and gene expression profiling, with peripheral blood mononuclear cells quantified via mass cytometry. Both skin and mucosa exhibited similar patterns of granzyme B expressing (GZMB⁺) T cells, indicating T cell–mediated rejection in both tissues. However, mucosa demonstrated additional CD19⁺ B cell infiltration and occasional plasma cells, which were absent in skin. These intramucosal B cells expressed AHNAK and CD43, suggesting they may be innate-like B cells (Bin cells). CD8⁺/GZMB⁺ cells and B cell populations were enriched in peripheral blood mononuclear cells during combined skin and mucosal rejection but not isolated skin rejection. These findings suggest distinct rejection mechanisms in skin and mucosa, with mucosa uniquely involving B cells. Current skin-focused rejection monitoring may overlook important mucosal rejection events, emphasizing the need to monitor both tissues concurrently. Mucosal biopsies could improve the accuracy in detecting acute rejection. © 2025 American Society of Transplantation & American Society of Transplant Surgeons

关键词： face transplant mucosa rejection skin VCA

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Exploring Pruritus in Bullous Pemphigoid: Analysis of QOL Metrics and Potential Biological Mechanisms

JID Innovations

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JID Innovations 2025年第2期5.0卷 100329-100329页

作者： Osuoji, Olive C. DeGrazia, Taryn Rolader, Robin Cole, Emily F. Lawson, Katy Hilley, Henry Xing, Yanyan Han, Liang Chisolm, Sarah Claussen, Henry Yan, Xiaobo Sun, Yuxian Liu, Yuan Chen, Suephy C. Feldman, Ron J. Department of Dermatology Emory University School of Medicine Atlanta GA United States Department of Dermatology Duke University School of Medicine Durham NC United States Department of Biological Sciences Georgia Institute of Technology Atlanta GA United States Department of Biostatistics and Bioinformatics Emory University Rollins School of Public Health Atlanta GA United States Emory Integrated Computational Core Emory University School of Medicine Atlanta GA United States

Bullous pemphigoid is a devastating autoimmune blistering disease with need for improved therapeutics. Limited data are available on the overall burden of pruritus and alterations over time;however, treatment of itch-specific pathways may provide novel therapeutics. In this paper, we analyzed the QOL impact particularly related to itch and determined corresponding changes in intraepidermal nerve fiber density and gene expression. A total of 43 patients with bullous pemphigoid were followed prospectively on standard-of-care treatment and showed average Bullous Pemphigoid Disease Area Index total activity score decrease from 19.1 ± 19.2 to 8.2 ± 11.3 and improvement in QOL measures Autoimmune Bullous Disease Quality of Life, Treatment of Autoimmune Bullous Disease Quality of Life, and ItchyQoL. At baseline, intraepidermal nerve fiber density in patients with bullous pemphigoid and atopic dermatitis were significantly lower than in healthy controls (7.3 ± 1.5 and 3.2 ± 2.0 vs 9.7 ± 5.4 fibers/mm, P = .031) and increased from baseline to follow-up visit (11.7 ± 0.4 and 5.8 ± 2.7), although only atopic dermatitis reached statistical significance (P = .018). S100A8, S100A9, CCL17, and CCL18 genes were highly upregulated in the skin of patients with bullous pemphigoid compared with those in healthy controls. Our data provide evidence for improvements in itch-related QOL over time on standard-of-care therapies with unique alterations in inflammatory mediators related to early immune cell activation and recruitment. © 2024 The Authors

关键词： Bullous pemphigoid Intraepidermal nerve fiber density Pruritus QOL

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Acute and chronic post-COVID-19 conditions: A study of genetic integrity and clinical markers

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Mutation Research - Genetic Toxicology and Environmental Mutagenesis 2025年 904卷 503870页

作者： Martins, Bruna Alves Alonso Garcia, Ana Leticia Hilario Borges, Malu Siqueira Nobles, Daiane Dias Ribeiro Hansen, Alana Witt Spilki, Fernando Rosado Schuler-Faccini, Lavínia Rampelotto, Pabulo Henrique da Silva, Juliana Graduate Program in Genetics and Molecular Biology Federal University of Rio Grande do Sul (UFRGS) Porto Alegre 91501-970 Brazil Laboratory of Genetic Toxicology La Salle University (UniLaSalle) and Lutheran University of Brazil (ULBRA) Canoas 92010-000 Brazil Bioinformatics and Biostatistics Core Facility Institute of Basic Health Sciences Federal University of Rio Grande do Sul (UFRGS) Porto Alegre 91501-970 Brazil University Feevale Institute Ciencias Saude Molecular Microbiology Lab Novo Hamburgo 93525-075 Brazil

The long-term effects of COVID-19 infection on genomic integrity, along with hematological, biochemical, and inflammatory, remain poorly understood. Viral infections, including SARS-CoV-2, are known to induce genomic instability, potentially contributing to the persistence of post-COVID-19 symptoms. This study aimed to assess genomic instability in individuals with acute and chronic post-COVID-19 conditions, alongside hematological profiles, metabolic parameters, and inflammatory markers, compared to a SARS-CoV-2-negative control group. Participants (n = 231) from southern Brazil were stratified into acute post-COVID (n = 78), chronic post-COVID (n = 79), and control groups (n = 74). DNA damage was assessed using alkaline and enzyme-modified comet assays. Oxidative lesions were detected across all groups, but no significant differences were observed among them. Correlations with biochemical markers suggest inflammation and oxidative stress as central mechanisms in post-COVID-19 pathophysiology. Hematological and biochemical analyses revealed persistent inflammation, lipid metabolism disruptions, and gender-specific alterations, such as higher levels of inflammatory markers (C-reactive protein and ferritin) and lipid abnormalities in men, whereas women exhibited distinct hematological patterns. Age-related influences on metabolic and inflammatory markers further illustrate the systemic complexity of post-COVID-19 effects. The chronic group exhibited ongoing but attenuated markers of inflammation and oxidative stress compared to the acute group. These findings suggest that genetic instability alone may not fully explain the observed clinical manifestations, emphasizing the role of persistent inflammation and metabolic dysregulation. This study provides a comprehensive view of the interplay between genomic instability, inflammation, oxidative damage, and systemic alterations in post-COVID-19 condition. It underscores the importance of a multifaceted approach to underst

关键词： Biochemical analyses DNA damage Long COVID Post-COVID SARS-CoV-2 Symptoms

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Protecting and evaluating genomic privacy in medical tests and personalized medicine

Protecting and evaluating genomic privacy in medical tests a...

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1st ACM Workshop on Language Support for Privacy-Enhancing Technologies, PETShop 2013 - Co-located with the 20th ACM Conference on Computer and Communications Security, CCS 2013

作者： Ayday, Erman Raisaro, Jean Louis Hubaux, Jean-Pierre Rougemont, Jacques Laboratory for Communications and Applications EPFL Lausanne Switzerland Bioinformatics and Biostatistics Core Facility School of Life Sciences EPFL Lausanne Switzerland

ISBN: (纸本)9781450324854

In this paper, we propose privacy-enhancing technologies for medical tests and personalized medicine methods that use patients' genomic data. Focusing on genetic disease-susceptibility tests, we develop a new architecture (between the patient and the medical unit) and propose a "privacy-preserving disease susceptibility test" (PDS) by using homomorphic encryption and proxy re-encryption. Assuming the whole genome sequencing to be done by a certified institution, we propose to store patients' genomic data encrypted by their public keys at a "storage and processing unit" (SPU). Our proposed solution lets the medical unit retrieve the encrypted genomic data from the SPU and process it for medical tests and personalized medicine methods, while preserving the privacy of patients' genomic data. We also quantify the genomic privacy of a patient (from the medical unit's point of view) and show how a patient's genomic privacy decreases with the genetic tests he undergoes due to (i) the nature of the genetic test, and (ii) the characteristics of the genomic data. Furthermore, we show how basic policies and obfuscation methods help to keep the genomic privacy of a patient at a high level. We also implement and show, via a complexity analysis, the practicality of PDS. © 2013 ACM.

关键词： Genome

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Engineering ERα degraders with pleiotropic ubiquitin ligase ligands maximizes therapeutic efficacy by co-opting distinct effector ligases

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Cell Chemical Biology 2025年第5期32卷 694-709.e35页

作者： Shemorry, Anna Besten, Willem den Mulvihill, Melinda M. Essenburg, Curt J. Blaquiere, Nicole Kleinheinz, Tracy Villemure, Elisia Peale, Frank Deshmukh, Gauri Maddalo, Danilo Levy, Elizabeth Yu, Kebing Steensma, Matthew R. Tovar, Elizabeth A. Wolfrum, Emily Nagapudi, Karthik Blake, Robert A. Forrest, William F. Staben, Steven T. Graveel, Carrie R. Fairbrother, Wayne J. Wertz, Ingrid E. Discovery Oncology Genentech South San Francisco 94080 CA United States Early Discovery Biochemistry Genentech South San Francisco 94080 CA United States Biochemical and Cellular Pharmacology Genentech South San Francisco 94080 CA United States Department of Cell Biology Van Andel Research Institute Grand Rapids 49503 MI United States Department of Discovery Chemistry Genentech South San Francisco 94080 CA United States Translational Oncology Genentech South San Francisco 94080 CA United States Department of Research Pathology Genentech South San Francisco CA United States DMPK Genentech South San Francisco 94080 CA United States Department of Small Molecule Pharmaceutical Sciences Genentech South San Francisco 94080 CA United States Microchemistry Proteomics and Lipidomics Genentech South San Francisco 94080 CA United States Bioinformatics and Biostatistics Core Van Andel Research Institute Grand Rapids 49503 MI United States OMNI Bioinformatics Genentech South San Francisco 94080 CA United States

Proximity-inducing compounds that modulate target protein homeostasis represent an emerging therapeutic strategy. While the inherent complexity of these bifunctional compounds presents certain challenges, their unique composition offers opportunities to co-opt specific cellular effectors to enhance therapeutic impact. In this study, we systematically evaluate a series of bifunctional degrader compounds engineered with the estrogen receptor-alpha (ERα) inhibitor endoxifen linked to various bioactive ubiquitin ligase ligands. Notably, ERα degraders containing pan-IAP antagonist ligands significantly reduced the proliferation of ERα-dependent cells compared to clinical-stage ERα degraders. These pan-IAP antagonist-based ERα degraders leverage distinct effector ligases to achieve dual therapeutic effects: They utilize XIAP within tumor cells to promote ERα degradation and activate cIAP1/2 in both tumor and immune cells to induce TNFα, which drives tumor cell death. Our findings illustrate a broader concept that co-opting the discrete functions of selected cellular effectors, while simultaneously modulating therapeutic target protein homeostasis, are dual strategies that can significantly enhance the efficacy of induced proximity therapeutics. © 2025 Elsevier Ltd

关键词： chemical biology cIAP1/2 degrader efficacy ERα degraders induced proximity pleiotropic ligands TNFα tumor cell death XIAP

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A new regularized least squares support vector regression for gene selection

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BMC bioinformatics 2009年第1期10卷 1-11页

作者： Chen, Pei-Chun Huang, Su-Yun Chen, Wei J. Hsiao, Chuhsing K. Bioinformatics and Biostatistics Core Laboratory National Taiwan University Taipei Taiwan Institute of Statistical Science Academia Sinica Taipei Taiwan Department of Public Health National Taiwan University Taipei Taiwan Institute of Epidemiology National Taiwan University Taipei Taiwan

Background: Selection of influential genes with microarray data often faces the difficulties of a large number of genes and a relatively small group of subjects. In addition to the curse of dimensionality, many gene selection methods weight the contribution from each individual subject equally. This equal-contribution assumption cannot account for the possible dependence among subjects who associate similarly to the disease, and may restrict the selection of influential genes. Results: A novel approach to gene selection is proposed based on kernel similarities and kernel weights. We do not assume uniformity for subject contribution. Weights are calculated via regularized least squares support vector regression (RLS-SVR) of class levels on kernel similarities and are used to weight subject contribution. The cumulative sum of weighted expression levels are next ranked to select responsible genes. These procedures also work for multiclass classification. We demonstrate this algorithm on acute leukemia, colon cancer, small, round blue cell tumors of childhood, breast cancer, and lung cancer studies, using kernel Fisher discriminant analysis and support vector machines as classifiers. Other procedures are compared as well. Conclusion: This approach is easy to implement and fast in computation for both binary and multiclass problems. The gene set provided by the RLS-SVR weight-based approach contains a less number of genes, and achieves a higher accuracy than other procedures. © 2009 Chen et al;licensee BioMed Central Ltd.

关键词： Discriminant analysis

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Comparison of inter- and intraobserver agreement between [18F]AlF-NOTA-octreotide and [68Ga]Ga-DOTA-SSA PET/CT

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EJNMMI Reports 2025年第1期9卷 1-15页

作者： Leupe, Hannes Ahmadi Bidakhvidi, Niloefar Goffin, Karolien Van den Broeck, Bliede Jentjens, Sander Laenen, Annouschka Pauwels, Elin Lybaert, Willem Van Cutsem, Eric Bormans, Guy Vandamme, Timon Cleeren, Frederik Dekervel, Jeroen Geboes, Karen Stroobants, Sigrid Verslype, Chris Deroose, Christophe M. Nuclear Medicine University Hospitals Leuven and Nuclear Medicine and Molecular Imaging Department of Imaging and Pathology KU Leuven Herestraat 49 Leuven 3000 Belgium Nuclear Medicine Department of Medical Imaging Ghent University Hospital Ghent Belgium Leuven Biostatistics and Statistical Bioinformatics Center KU Leuven Leuven Belgium Department of Oncology Antwerp University Hospital and NETwerk Antwerpen-Waasland CoE Edegem Belgium Digestive Oncology University Hospitals Leuven Leuven Belgium Radiopharmaceutical Research Department of Pharmacy and Pharmacology KU Leuven Leuven Belgium Center for Oncological Research (CORE) Integrated Personalized and Precision Oncology Network (IPPON) University of Antwerp Antwerp Belgium Digestive Oncology Department of Gastroenterology Ghent University Hospital Ghent Belgium Nuclear Medicine Antwerp University Hospital and Molecular Imaging and Radiology Faculty of Medicine and Health Sciences University of Antwerp Wilrijk Belgium

Purpose: This study compares inter- and intraobserver agreement between [18F]AlF-NOTA-octreotide ([18F]AlF-OC) and [68Ga]Ga-DOTA-somatostatin analogues (SSAs) in PET/CT imaging for neuroendocrine neoplasm (NEN) patients. Materials and methods: This is a secondary endpoint analysis from our multicenter trial (clin *** identifier: NCT04552847) including 75 NEN patients who received both [68Ga]Ga-DOTATATE (n = 56) or [68Ga]Ga-DOTA-NOC (n = 19) and [18F]AlF-OC PET imaging. Five readers assessed lesion detection and characterization across multiple organs, scoring lesions by number and conspicuity using a 5-point Likert scale. Agreement was measured using Gwet’s agreement coefficient. Results: Results demonstrated nearly perfect interobserver agreement for lesion characterization across all organs for both tracers (0.921 for [18F]AlF-OC;0.934 for [68Ga]Ga-DOTA-SSA). Similar agreement was observed for the number of lesions across organs (0.736 for [18F]AlF-OC and 0.749 for [68Ga]Ga-DOTA-SSAs). Organ-specific analysis revealed strong agreement for bone and liver lesions, with slightly lower agreement for lymph nodes. Both tracers also showed excellent agreement in determining Krenning scores (0.925 for [18F]AlF-OC and 0.927 for [68Ga]Ga-DOTA-SSAs). While mean lesion conspicuity was similar between tracers, [18F]AlF-OC had a higher global image quality score (4.22 vs. 3.86, p < 0.0001). Intraobserver agreement was consistent between tracers for lesion characterization (> 0.95 for both readers) and lesion count (> 0.80 for both readers). Conclusion: [18F]AlF-OC and [68Ga]Ga-DOTA-SSAs demonstrate comparable and excellent inter- and intraobserver agreement, reinforcing the clinical interchangeability of [18F]AlF-OC PET/CT with [68Ga]Ga-DOTA-SSAs in routine practice. © The Author(s) 2025.

关键词： Interobserver agreement Neuroendocrine tumor Somatostatin receptor [18F]AlF-NOTA-octreotide [68Ga]Ga-DOTATATE

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