tbuckley/cabot-search huggingface dataset:
Genetic-by-age interaction analyses on complex traits in UK Biobank and their potential to identify effects on longitudinal trait change
Authors: Thomas W. Winkler, Simon Wiegrebe, Janina M. Herold, Klaus J. Stark, Helmut Küchenhoff, Iris M. Heid
Journal: Genome biology (2024)

Genome-wide association studies (GWAS) have identified thousands of loci for disease-related human traits in cross-sectional data. However, the impact of age on genetic effects is underacknowledged. Also, identifying genetic effects on longitudinal trait change has been hampered by small sample sizes for longitudinal data. Such effects on deteriorating trait levels over time or disease progression can be clinically relevant. Under certain assumptions, we demonstrate analytically that genetic-by-age interaction observed in cross-sectional data can be indicative of genetic association on longitudinal trait change. We propose a 2-stage approach with genome-wide pre-screening for genetic-by-age interaction in cross-sectional data and testing identified variants for longitudinal change in independent longitudinal data. Within UK Biobank cross-sectional data, we analyze 8 complex traits (up to 370,000 individuals). We identify 44 genetic-by-age interactions (7 loci for obesity traits, 26 for pulse pressure, few to none for lipids). Our cross-trait view reveals trait-specificity regarding the proportion of loci with age-modulated effects, which is particularly high for pulse pressure. Testing the 44 variants in longitudinal data (up to 50,000 individuals), we observe significant effects on change for obesity traits (near APOE, TMEM18, TFAP2B) and pulse pressure (near FBN1, IGFBP3; known for implication in arterial stiffness processes). We provide analytical and empirical evidence that cross-sectional genetic-by-age interaction can help pinpoint longitudinal-change effects, when cross-sectional data surpasses longitudinal sample size. Our findings shed light on the distinction between traits that are impacted by age-dependent genetic effects and those that are not.
Corrigendum to “Electrically-driven drug delivery into deep cutaneous tissue by conductive microneedles for fungal infection eradication and protective immunity” [Biomaterials 314 (2025) 122908]
Authors: Sumanta Ghosh, Mengjia Zheng, Jiahui He, Yefeng Wu, Yaming Zhang, Weiping Wang, Jie Shen, Kelvin W K Yeung, Prasanna Neelakantan, Chenjie Xu, Wei Qiao
Journal: Biomaterials (2024)
NOTCH2NLC GGC intermediate repeat with serine induces hypermyelination and early Parkinson’s disease-like phenotypes in mice
Authors: Haitao Tu, Xin Yi Yeo, Zhi-Wei Zhang, Wei Zhou, Jayne Yi Tan, Li Chi, Sook-Yoong Chia, Zhihong Li, Aik Yong Sim, Brijesh Kumar Singh, Dongrui Ma, Zhidong Zhou, Isabelle Bonne, Shuo-Chien Ling, Adeline S.L. Ng, Sangyong Jung, Eng-King Tan, Li Zeng
Journal: Molecular Neurodegeneration (2024)

Abstract Background The expansion of GGC repeats (typically exceeding 60 repeats) in the 5’ untranslated region (UTR) of the NOTCH2NLC gene (N2C) is linked to N2C-related repeat expansion disorders (NREDs), such as neuronal intranuclear inclusion disease (NIID), frontotemporal dementia (FTD), essential tremor (ET), and Parkinson’s disease (PD). These disorders share common clinical manifestations, including parkinsonism, dementia, seizures, and muscle weakness. Intermediate repeat sizes ranging from 40 to 60 GGC repeats, particularly those with AGC-encoded serine insertions, have been reported to be associated with PD; however, the functional implications of these intermediate repeats with serine insertion remain unexplored. Methods Here, we utilized cellular models harbouring different sizes of N2C variant 2 (N2C2) GGC repeat expansion and CRISPR-Cas9 engineered transgenic mouse models carrying N2C2 GGC intermediate repeats with and without serine insertion to elucidate the underlying pathophysiology associated with N2C intermediate repeat with serine insertion in NREDs. Results Our findings revealed that the N2C2 GGC intermediate repeat with serine insertion (32G13S) led to mitochondrial dysfunction and cell death in vitro. The neurotoxicity was influenced by the length of the repeat and was exacerbated by the presence of the serine insertion. In 12-month-old transgenic mice, 32G13S intensified intranuclear aggregation and exhibited early PD-like characteristics, including the formation of α-synuclein fibers in the midbrain and the loss of tyrosine hydroxylase (TH)-positive neurons in both the cortex and striatum. Additionally, 32G13S induced neuronal hyperexcitability and caused locomotor behavioural impairments. Transcriptomic analysis of the mouse cortex indicated dysregulation in calcium signaling and MAPK signaling pathways, both of which are critical for mitochondrial function. Notably, genes associated with myelin sheath components, including MBP and MOG , were dysregulated in the 32G13S mouse. Further investigations using immunostaining and transmission electron microscopy revealed that the N2C intermediate repeat with serine induced mitochondrial dysfunction-related hypermyelination in the cortex. Conclusions Our in vitro and in vivo investigations provide the first evidence that the N2C-GGC intermediate repeat with serine promotes intranuclear aggregation of N2C, leading to mitochondrial dysfunction-associated hypermyelination and neuronal hyperexcitability. These changes contribute to motor deficits in early PD-like neurodegeneration in NREDs.
Diagnosis of early-stage bladder cancer via unprocessed urine samples at the point of care
Authors: Changjoon Keum, Haejin Yeom, Tae Il Noh, Seung Yong Yi, Soyeong Jin, Chaekyu Kim, Ji Sung Shim, Sung Goo Yoon, Hojun Kim, Kwan Hyi Lee, Seok Ho Kang, Youngdo Jeong
Journal: Nature Biomedical Engineering (2024)
Antibiotic-mediated selection of randomly mutagenized and cytokine-expressing oncolytic viruses
Authors: Reza Rezaei, Stephen Boulton, Mahsa Ahmadi, Julia Petryk, Miles Da Silva, Nika Kooshki Zamani, Ragunath Singaravelu, Gabriel St-Laurent, Lauren Daniel, Arezoo Sadeghipour, Adrian Pelin, Joanna Poutou, Abril Ixchel Munoz Zuniga, Clarence Choy, Victoria H. Gilchrist, Zumama Khalid, Bradley Austin, Kemal Alper Onsu, Ricardo Marius, Zahra Ameli, Fazel Mohammadi, Valeria Mancinelli, Emily Wang, Abolfazl Nik-Akhtar, Akram Alwithenani, Fatemeh Panahi Arasi, Stephen S. G. Ferguson, Tom C. Hobman, Tommy Alain, Lee-Hwa Tai, Carolina S. Ilkow, Jean-Simon Diallo, John C. Bell, Taha Azad
Journal: Nature Biomedical Engineering (2024)
Circulating tumor-reactive KIR+CD8+ T cells suppress anti-tumor immunity in patients with melanoma
Authors: Benjamin Y. Lu, Liliana E. Lucca, Wesley Lewis, Jiping Wang, Catarina V. Nogueira, Sebastian Heer, Violeta Rayon-Estrada, Pierre-Paul Axisa, Sarah M. Reeves, Nicholas C. Buitrago-Pocasangre, Giang H. Pham, Mina L. Kojima, Wei Wei, Lilach Aizenbud, Antonietta Bacchiocchi, Lin Zhang, Joseph J. Walewski, Veronica Chiang, Kelly Olino, James Clune, Ruth Halaban, Yuval Kluger, Anthony J. Coyle, Jan Kisielow, Franz-Josef Obermair, Harriet M. Kluger, David A. Hafler
Journal: Nature Immunology (2024)
A clinical study of autologous chimeric antigen receptor macrophage targeting mesothelin shows safety in ovarian cancer therapy
Authors: Xiumin Li, Xudong Wang, Hao Wang, Donghua Zuo, Jianpo Xu, Yixuan Feng, Dixuan Xue, Li Zhang, Lin Lin, Jin Zhang
Journal: Journal of Hematology & Oncology (2024)

CAR-macrophage has promising prospect in treating solid tumors, due to its high infiltration into tumors, and its dual roles in phagocytosis and immune modulation. Here we show the clinical results of CAR-macrophage treatment of two ovarian cancer patients. The CAR-macrophages were produced by introducing a mesothelin targeting CAR to patients' primary peripheral blood mononuclear cell-derived macrophages, and the products were infused to patients intravenously. Our data show good safety of the infusion product, and the efficacy can be further improved. Intraperitoneal infusion of CAR-macrophages has proven effective in treating intraperitoneal tumors in a preclinical model, paving the way for demonstrating proof-of-concept clinical efficacy of CAR-macrophages in the treatment of intraperitoneal tumors.
Antitumour vaccination via the targeted proteolysis of antigens isolated from tumour lysates
Authors: Yu Zhao, Donghui Song, Zeyu Wang, Qingqing Huang, Fan Huang, Zhongfeng Ye, Douglas Wich, Mengting Chen, Jennifer Khirallah, Shuliang Gao, Yang Liu, Qiaobing Xu
Journal: Nature Biomedical Engineering (2024)
Safer and efficient base editing and prime editing via ribonucleoproteins delivered through optimized lipid-nanoparticle formulations
Authors: Rafał Hołubowicz, Samuel W. Du, Jiin Felgner, Roman Smidak, Elliot H. Choi, Grazyna Palczewska, Carolline Rodrigues Menezes, Zhiqian Dong, Fangyuan Gao, Omar Medani, Alexander L. Yan, Maria W. Hołubowicz, Paul Z. Chen, Marco Bassetto, Eleonora Risaliti, David Salom, J. Noah Workman, Philip D. Kiser, Andrzej T. Foik, David C. Lyon, Gregory A. Newby, David R. Liu, Philip L. Felgner, Krzysztof Palczewski
Journal: Nature Biomedical Engineering (2024)

Abstract Delivering ribonucleoproteins (RNPs) for in vivo genome editing is safer than using viruses encoding for Cas9 and its respective guide RNA. However, transient RNP activity does not typically lead to optimal editing outcomes. Here we show that the efficiency of delivering RNPs can be enhanced by cell-penetrating peptides (covalently fused to the protein or as excipients) and that lipid nanoparticles (LNPs) encapsulating RNPs can be optimized for enhanced RNP stability, delivery efficiency and editing potency. Specifically, after screening for suitable ionizable cationic lipids and by optimizing the concentration of the synthetic lipid DMG-PEG 2000, we show that the encapsulation, via microfluidic mixing, of adenine base editor and prime editor RNPs within LNPs using the ionizable lipid SM102 can result in in vivo editing-efficiency enhancements larger than 300-fold (with respect to the delivery of the naked RNP) without detectable off-target edits. We believe that chemically defined LNP formulations optimized for RNP-encapsulation stability and delivery efficiency will lead to safer genome editing.
Personalized nanovaccines for treating solid cancer metastases
Authors: Tang Feng, Jia Hu, Jirui Wen, Zhiyong Qian, Guowei Che, Qinghua Zhou, Lingling Zhu
Journal: Journal of Hematology & Oncology (2024)

Cancer vaccines have garnered attention as a potential treatment for cancer metastases. Nevertheless, the clinical response rate to vaccines remains < 30%. Nanoparticles stabilize vaccines and improve antigen recognition and presentation, resulting in high tumor penetration or accumulation, effective co-distribution of drugs to the secondary lymphatic system, and adaptable antigen or adjuvant administration. Such vaccine-like nanomedicines have the ability to eradicate the primary tumors as well as to prevent or eliminate metastases. This review examines state-of-the-art nanocarriers developed to deliver tumor vaccines to metastases, including synthetic, semi-biogenic, and biogenic nanosystems. Moreover, it highlights the physical and pharmacological properties that enhance their anti-metastasis efficiency. This review also addresses the combination of nanovaccines with cancer immunotherapy to target various steps in the metastatic cascade, drawing insights from preclinical and clinical studies. The review concludes with a critical analysis of the challenges and frameworks linked to the clinical translation of cancer nanovaccines.
Clec12b Alleviates Mite‐Induced Dermatitis by Regulating <scp>P2RX7</scp>‐Mediated Mast Cell Activation in Mice
Authors: Ayana Iijima, Kenshiro Matsuda, Sho Yamasaki, Kazuko Shibuya, Akira Shibuya
Journal: Allergy (2024)
High level of circulating cell-free tumor DNA at diagnosis correlates with disease spreading and defines multiple myeloma patients with poor prognosis
Authors: Marina Martello, Vincenza Solli, Gaia Mazzocchetti, Antonio Giovanni Solimando, Davide Bezzi, Barbara Taurisano, Ajsi Kanapari, Andrea Poletti, Enrica Borsi, Silvia Armuzzi, Ilaria Vigliotta, Ignazia Pistis, Vanessa Desantis, Giulia Marzocchi, Ilaria Rizzello, Lucia Pantani, Katia Mancuso, Paola Tacchetti, Nicoletta Testoni, Cristina Nanni, Elena Zamagni, Michele Cavo, Carolina Terragna
Journal: Blood Cancer Journal (2024)

Abstract Multiple myeloma (MM) is a plasma cell (PC) disorder characterized by skeletal involvement at the time of diagnosis. Recently, cell-free DNA (cfDNA) has been proven to recapitulate the heterogeneity of bone marrow (BM) disease. Our aim was to evaluate the prognostic role of cfDNA at diagnosis according to disease distribution, and to investigate the role of the MM microenvironment inflammatory state in supplying the release of cfDNA. A total of 162 newly diagnosed MM patients were screened using 18F-FDG PET/CT and assessed by ultra low-pass whole genome sequencing (ULP-WGS). High cfDNA tumor fraction (ctDNA) levels were correlated with different tumor mass markers, and patients with high ctDNA levels at diagnosis were more likely to present with metabolically active paraskeletal (PS) and extramedullary (EM) lesions. Moreover, we demonstrated that microenvironment cancer-associated fibroblast (CAFs)-mediated inflammation might correlate with high ctDNA levels. Indeed, a high cfDNA TF level at diagnosis predicted a poorer prognosis, independent of R-ISS III and 1q amplification; the inclusion of &gt;12% ctDNA in the current R-ISS risk score enables a better identification of high-risk patients. ctDNA can be a reliable and less invasive marker for disease characterization, and can refine patient risk.
Outcomes with loncastuximab tesirine following CAR T-cell therapy in patients with relapsed or refractory diffuse large B-cell lymphoma
Authors: Narendranath Epperla, Melanie Lucero, Tom Bailey, Laura Mirams, Jolenta Cheung, Mona Amet, Gary Milligan, Lei Chen
Journal: Blood Cancer Journal (2024)

Abstract The efficacy of loncastuximab tesirine (lonca) following chimeric antigen receptor T-cell therapy (CAR-T) progression/failure is unknown. Hence, we sought to examine real-world use and outcomes of lonca following CAR-T in patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) in the USA. In this retrospective study, we included adults (age ≥ 18 years) with R/R DLBCL who received lonca monotherapy as third- (3 L) or fourth line (4 L) treatment after progressing on second line (2 L) or 3 L CAR-T, respectively. Post-CAR-T lonca outcomes included response rates (overall response rate [ORR] and complete response [CR] rate), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). A total of 118 patients were included in the analysis with 95 receiving lonca following 2 L CAR-T (median age:66 years; 61% male) and 23 following 3 L CAR-T (median age:57 years; 43% male). Patients with 2 L CAR-T/3 L lonca had an ORR of 73% (CR rate of 34%). With a median follow-up of 8.5 months following lonca initiation, median DOR, PFS, and OS were not reached. The DOR, PFS, and OS at 12 months were 68%, 77%, and 84%, respectively. Patients with 3 L CAR-T/4 L lonca had an ORR of 78% (CR rate of 17%). With a median follow-up of 13 months following lonca initiation, the median DOR and PFS were 7.6 and 12.0 months, while median OS was not reached. OS at 12 months was 95%. In this study, we found that lonca monotherapy was an effective treatment option in R/R DLBCL in 3 L and 4 L settings including those who were resistant to or progressed after CAR-T.
The Severity of Allergic Reactions in a Real‐World Environment Is Independent of the Eliciting Amounts of Foods
Authors: Alexandre Piletta‐Zanin, Alexander Scherl, Avigael Benhamou, Gabriel Braendle, Jean‐Christoph Caubet, François Graham, Olivier Grosgurin, Thomas Harr, Sergio Manzano, Haig Nigolian, Didier Ortelli, Jean‐Pierre Pahud, Aude Tonson la Tour, Hervé Spechbach, Patrick Edder, Philippe A. Eigenmann
Journal: Allergy (2024)

ABSTRACT Introduction Patients with food allergies need personalized information on their risk of reaction in “real‐life” situations. This multicentric study aimed to investigate the link during accidental reactions between the nature and amount of food allergens consumed in “real‐life situation” and the severity of the symptoms. Methods Patients were prospectively recruited from December 1, 2020, to December 31, 2021, at the emergency departments in the Geneva University Hospitals and local pediatric emergency facilities, through an allergy outpatient clinic, at school and daycare facilities and trough their primary care physicians. Medical history of patients presenting reactions suggestive with immediate food allergy and suspected food samples were collected. Allergy diagnostic tests were retrospectively and prospectively collected. The samples were analyzed for their allergen content. Results We recruited 147 subjects with an accidental immediate‐type allergic reaction to a food. We were able to collect 115 reaction‐eliciting food samples allowing to quantify the allergen amount causing the reaction, as well as correlating this amount to the severity of the reaction. Children represented a large part of the reactors, and most reactions were to common food allergens such as tree nuts, cow's milk as well as peanuts and hen's egg. Reactions were mostly to prepackaged foods and seven reactions were to products with precautionary allergy labeling, or without labelling to the eliciting allergen. Reactions were of various degrees of severity, and independent to the amount of allergen ingested. Discussion The severity of reactions did not show a direct correlation with allergen quantity, emphasizing individual sensitivity. Some reactions occurred with allergen amounts significantly below the legal limit for mandatory labelling of 1 g/kg (1000 ppm) in Switzerland. The study also highlighted considerable variability in allergen concentrations in foods labeled with possible “contaminations” or “traces”. These findings raise questions about the accuracy of allergen labeling and regulations in Switzerland.
B cell c-Maf signaling promotes tumor progression in animal models of pancreatic cancer and melanoma
Authors: Qian Zhong, Hongying Hao, Shu Li, Yongling Ning, Hong Li, Xiaoling Hu, Kelly M McMasters, Jun Yan, Chuanlin Ding
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background The role of B cells in antitumor immunity remains controversial, with studies suggesting the protumor and antitumor activity. This controversy may be due to the heterogeneity in B cell populations, as the balance among the subtypes may impact tumor progression. The immunosuppressive regulatory B cells (Breg) release interleukin 10 (IL-10) but only represent a minor population. Additionally, tumor-specific antibodies (Abs) also exhibit antitumor and protumor functions dependent on the Ab isotype. Transcription factor c-Maf has been suggested to contribute to the regulation of IL-10 in Breg, but the role of B cell c-Maf signaling in antitumor immunity and regulating Ab responses remains unknown. Methods Conditional B cell c-Maf knockout (KO) and control mice were used to establish a KPC pancreatic cancer model and B16.F10 melanoma model. Tumor progression was evaluated. B cell and T cell phenotypes were determined by flow cytometry, mass cytometry, and cytokine/chemokine profiling. Differentially expressed genes in B cells were examined by using RNA sequencing (RNA-seq). Peripheral blood samples were collected from healthy donors and patients with melanoma for B cell phenotyping. Results Compared with B cells from the spleen and lymph nodes (LN), B cells in the pancreas exhibited significantly less follicular phenotype and higher IL-10 production in naïve mice. c-Maf deficiency resulted in a significant reduction of CD9 + IL-10-producing Breg in the pancreas. Pancreatic ductal adenocarcinoma (PDAC) progression resulted in the accumulation of circulating B cells with the follicular phenotype and less IL-10 production in the pancreas. Notably, B cell c-Maf deficiency delayed PDAC tumor progression and resulted in proinflammatory B cells. Further, tumor volume reduction and increased effective T cells in the tumor-draining LN were observed in B cell c-Maf KO mice in the B16.F10 melanoma model. RNA-seq analysis of isolated B cells revealed that B cell c-Maf signaling modulates immunoglobulin-associated genes and tumor-specific Ab production. We furthermore demonstrated c-Maf-positive B cell subsets and an increase of IL-10-producing B cells after incubation with IL-4 and CD40L in the peripheral blood of patients with melanoma. Conclusion Our study highlights that B cell c-Maf signaling drives tumor progression through the modulation of Breg, inflammatory responses, and tumor-specific Ab responses.
Genetic and therapeutic heterogeneity shape the baseline and longitudinal immune ecosystem of ovarian clear cell carcinoma
Authors: Siyu Xia, Lihua Chen, Min Yu, Jiana Li, Jiaxin Chen, Fei Xu, Mengdong Ni, Chaohua Liu, Xiaohua Wu, Xiaojun Chen, Jiajia Li
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Ovarian clear cell carcinoma (OCCC) is a rare and chemo-resistant subtype of ovarian cancer. While immunotherapy has demonstrated effectiveness in some OCCC cases, the mechanisms for heterogeneous immunoreactivity and potential combinatory strategies remain unclear. Methods Tumor samples from 13 patients with OCCC underwent single-cell mRNA-seq and TCR-seq to generate 1 40 683 cells transcriptome, while additionally 31 formalin-fixed paraffin-embedded samples were used for immunohistochemistry. Spatial transcriptomics of two OCCC samples and bulk RNA-seq of 58 patients were incorporated for spatial and interpatient level explorations. Serum tumor markers and radiologic images of three patients with OCCC who received combinatory VEGF and PD-1 inhibition were retrospectively analyzed. Results OCCC exhibited a dynamic immune architecture shaped by genetic and therapeutic pressure. ARID1A mutation linked to baseline immune activation, correlated with an enrichment of neoantigen-reactive CXCL13 + CTLA4 + CD8 + T cells (p&lt;0.001) and enhanced FASLG–FAS interactions. Recurrent OCCC was fibrotic, angiogenic, and immunosuppressive, exhibiting metabolic reprogramming towards activated activity in fatty acid metabolism. High CD36 (log-rank p=0.012, HR: 4.515) and CD47 expression (log-rank p=0.037, HR: 3.246) indicated worse progression-free survival. Treatment with bevacizumab increased intratumoral T cell infiltration and activated T cell interferon-γ signaling. Retrospective analysis of clinical cases revealed that combination therapy with anti-VEGF (vascular endothelial growth factor) and anti-PD-1 agents exerted clinical benefits in patients with OCCC with persistent, recurrent, and metastatic disease. Conclusions ARID1A mutation correlated with OCCC baseline immune activation. Stromal reconstruction and tumor metabolic reprogramming functioned as key processes of OCCC dynamic progression. VEGF inhibition remodeled OCCC stroma, restored T cell function and potentiated immunotherapy. CD36 and CD47 might be potential therapeutic targets for recurrent OCCC.