tbuckley/cabot-search huggingface dataset:
Mosaic chromosomal alterations (mCAs) in individuals with monoclonal B-cell lymphocytosis (MBL)
Authors: Aswin Sekar, Rosalie Griffin, Sameer A. Parikh, Giulio Genovese, Dennis P. Robinson, Aaron D. Norman, Janet E. Olson, Kari G. Rabe, Mingma S. Hoel, Nicholas J. Boddicker, Paul J. Hampel, Neil E. Kay, James R. Cerhan, Esteban Braggio, Curtis A. Hanson, Celine M. Vachon, Tait D. Shanafelt, Benjamin L. Ebert, Susan L. Slager
Journal: Blood Cancer Journal (2024)

Abstract MBL is a precursor condition to chronic lymphocytic leukemia (CLL), characterized by monoclonal B-cells in blood. Mosaic chromosomal alterations (mCAs) are a form of clonal hematopoiesis that include gains, losses, and copy-neutral loss-of-heterozygosity of large DNA segments. Both MBL and mCAs have been found to increase the risk of CLL and lymphoid malignancies, and the aim of our study was to investigate how mCAs relate to MBL, which is currently unknown. We analyzed genetic, flow cytometric, and hematologic data from 4632 individuals from the Mayo Clinic Biobank and CLL Database. MBL was detected using flow cytometry and classified as high-count (HC) or low-count (LC) MBL based on clone size. mCAs were detected primarily from whole blood DNA using sensitive SNP-array-based analyses. mCAs commonly altered in CLL (deletion of 6q, 11q, 13q, 17p, and trisomy 12) were specific (&gt;99%) to individuals with MBL and CLL. HC-MBL and LC-MBL individuals were 881-fold and 8-fold, respectively, more likely to harbor CLL-associated mCAs than those without MBL. The cell fraction bearing these mCAs typically exceeded the B-cell fraction, suggesting their origin prior to the B-cell lineage. Integrating genetic and blood count data enabled detecting HC-MBL with high specificity in a biobank sample. These results quantify the contribution of mCAs to MBL and could enable large studies of HC-MBL without the need for flow cytometric screening.
Multi-omics reveal immune microenvironment alterations in multiple myeloma and its precursor stages
Authors: Yan Cheng, Fumou Sun, Daisy V. Alapat, Visanu Wanchai, David Mery, Eric R. Siegel, Hongwei Xu, Sarah Johnson, Wancheng Guo, Clyde Bailey, Cody Ashby, Michael Anton Bauer, Samer Al Hadidi, Carolina Schinke, Sharmilan Thanendrarajan, Maurizio Zangari, Frits van Rhee, Guido Tricot, John D. Shaughnessy, Fenghuang Zhan
Journal: Blood Cancer Journal (2024)

Abstract Tumor immune microenvironmental alterations occur early in multiple myeloma (MM) development. In this study, we aim to systematically characterize the tumor immune microenvironment (TME) and the tumor-immune interactions from precursor stages, i.e., monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM), to newly diagnosed MM, comparing these to healthy donors. Using CIBERSORT, mass cytometry (CyTOF), and single-cell RNA sequencing (scRNA-Seq), we examined innate and adaptive immune changes across these stages. We found a decrease in granulocytes in the TME predicts MM outcomes. HLA-DR is reduced in CD16 + monocytes and plasmacytoid dendritic cells, while myeloid dendritic cells show decreased expression of stress and immune-response genes. NK cells and CD8 + T cells shift from a GZMK + to a GZMB + cytotoxic phenotype in the TME, with increased inhibitory markers TIM3 and TIGIT. In paired samples, the proportion and gene expression pattern in patient-specific GZMB + CD8 + T cells remain largely unchanged despite MM progression. Our findings provide a comprehensive immune landscape of MM and its precursors, offering insights into therapeutic strategies. Enhancing neutrophil and NK cell cytotoxicity, tumor antigen presentation, and CD8 + T cell versatility in precursor stages may prevent MM progression.
Neutrophil-to-lymphocyte ratio as a prognostic indicator of mortality in Polycythemia Vera: insights from a prospective cohort analysis
Authors: Tiziano Barbui, Alessandra Carobbio, Arianna Ghirardi, Francesca Fenili, Maria Chiara Finazzi, Marta Castelli, Alessandro M. Vannucchi, Paola Guglielmelli, Alessandro Rambaldi, Naseema Gangat, Ayalew Tefferi
Journal: Blood Cancer Journal (2024)

We analyzed the neutrophil-to-lymphocyte ratio (NLR) in 1508 patients with PV and found that those with an NLR ≥ 5 were generally older, had a longer disease history, and had higher cardiovascular risk factors, more arterial thrombosis, and more aggressive blood counts, indicating a more proliferative disease. NLR was an accurate predictor of mortality, with patients with NLR ≥ 5 having significantly worse overall survival and more than twice the mortality rate compared to those with NLR < 5. Multivariable models confirmed that increasing age, previous venous thrombosis and NLR ≥ 5 were strong predictors of death, further influenced by cardiovascular risk factors. We examined the interaction between NLR and the number of cardiovascular risk factors and found a progressive trend of increased mortality risk for NLR values ≥ 5 in addition to the presence of more than one risk factor. In conclusion, patients with NLR ≥ 5 require careful monitoring and management of cardiovascular risk factors because they increase mortality when associated with progressive levels of NLR.
The third generation AKR1C3-activated prodrug, ACHM-025, eradicates disease in preclinical models of aggressive T-cell acute lymphoblastic leukemia
Authors: Cara E. Toscan, Hannah McCalmont, Amir Ashoorzadeh, Xiaojing Lin, Zhe Fu, Louise Doculara, Hansen J. Kosasih, Roxanne Cadiz, Anthony Zhou, Sarah Williams, Kathryn Evans, Faezeh Khalili, Ruilin Cai, Kristy L. Yeats, Andrew J. Gifford, Russell Pickford, Chelsea Mayoh, Jinhan Xie, Michelle J. Henderson, Toby N. Trahair, Adam V. Patterson, Jeff B. Smaill, Charles E. de Bock, Richard B. Lock
Journal: Blood Cancer Journal (2024)

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy that expresses high levels of the enzyme aldo-keto reductase family 1 member C3 (AKR1C3). To exploit this finding, we developed a novel prodrug, ACHM-025, which is selectively activated by AKR1C3 to a nitrogen mustard DNA alkylating agent. We show that ACHM-025 has potent in vivo efficacy against T-ALL patient-derived xenografts (PDXs) and eradicated the disease in 7 PDXs. ACHM-025 was significantly more effective than cyclophosphamide both as a single agent and when used in combination with cytarabine/6-mercaptopurine. Notably, ACHM-025 in combination with nelarabine was curative when used to treat a chemoresistant T-ALL PDX in vivo. The in vivo efficacy of ACHM-025 directly correlated with AKR1C3 expression levels, providing a predictive biomarker for response. Together, our work provides strong preclinical evidence highlighting the potential of ACHM-025 as a targeted and effective therapy for aggressive forms of T-ALL.
CCR8/CCL1 and CXCR3/CXCL10 axis mediated memory T cell activations in recalcitrant drug-induced hypersensitivity patients
Authors: Tsu-Man Chiu, Chun-Bing Chen, Chun-Wei Lu, Rosaline Chung-Yee Hui, Min-Hui Chi, Ya-Ching Chang, Jennifer Wu, Kuan-Yu Chen, Yang Yu-Wei Lin, Pei-Chi Lo, Tsai-Ching Hsu, Chuang-Wei Wang, Wen-Hung Chung
Journal: British Journal of Dermatology (2024)

Abstract Background As a drug-induced hypersensitivity syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS) is potentially fatal. Most patients with DRESS recover within a few weeks; however, some patients may suffer from a prolonged disease course and develop autoimmune sequelae. Objectives To investigate the immune mechanism and therapeutic targets of patients with recalcitrant DRESS with a prolonged disease course. Methods Thirty-two patients with recalcitrant DRESS with a prolonged treatment course (≥ 8 weeks; ‘prolonged DRESS’), 28 patients with DRESS with a short treatment course (&amp;lt; 2 weeks; ‘short-duration DRESS’) and 26 healthy donors (HDs) were enrolled. Results Bulk transcriptome results showed that the mRNA expression levels of CCR8 and CXCR3 were significantly increased in blood samples from patients in the acute stage of prolonged DRESS [Padj = 1.50 × 10–9 (CCR8) and Padj = 2.60 × 10–4 (CXCR3), patients with prolonged DRESS compared with the HD group]. Serum and skin lesion concentrations of CCL1 and CXCL10 (ligands of CCR8 and CXCR3, respectively) were significantly increased in patients with prolonged DRESS compared with patients with short-duration DRESS. The results from high-parameter flow cytometry and autoantibody screening also identified significant increases in CD8+ GNLY+ CXCR3+ effector memory T cells, CD8+ central memory T cells, CD4+ CCR8+ T helper 2 cells and IgG anti-HES-6 autoantibodies in patients with prolonged DRESS. Furthermore, in vitro blocking assays revealed that Janus kinase inhibitors (JAKi; mainly tofacitinib and upadacitinib) significantly decreased the release of CCL1 and CXCL10. Some patients with prolonged DRESS were successfully treated with JAKi. Conclusions JAKi (tofacitinib and upadacitinib) were associated with decreased concentrations of CCL1 and CXCL10, suggesting that they may attenuate CCR8/CCL1 and CXCR3/CXCL10 axis-mediated memory T-cell activation, which contributes to disease pathogenesis in patients with recalcitrant DRESS and a long-term treatment course.
Immunometabolic Effect of Nitric Oxide on Human Macrophages Challenged With the SARS‐CoV2‐Induced Cytokine Storm. A Fluxomic Approach
Authors: Sergio Sánchez‐García, Adrián Povo‐Retana, Silvia Marin, Sergio Madurga, Marco Fariñas, Nuria Aleixandre, Antonio Castrillo, Juan V. de la Rosa, Carlota Alvarez‐Lucena, Rodrigo Landauro‐Vera, Patricia Prieto, Marta Cascante, Lisardo Boscá
Journal: Advanced Healthcare Materials (2024)

Abstract The cytokine storm associated with SARS‐CoV‐2 infection is one of the most distinctive pathological signatures in COVID‐19 patients. Macrophages respond to this pro‐inflammatory challenge by reprogramming their functional and metabolic phenotypes. Interestingly, human macrophages fail to express the inducible form of the NO synthase (NOS2) in response to pro‐inflammatory activation and, therefore, NO is not synthesized by these cells. The contribution of exogenously added NO, via a chemical NO‐donor, on the immunometabolic changes associated with the cytokine storm is investigated. By using metabolic, transcriptomic, and functional assays the effect of NO in human macrophages is evaluated and found specific responses. Moreover, through integrative fluxomic analysis, pathways modified by NO that contribute to the expression of a particular phenotype in human macrophages are identified, which includes a decrease in mitochondrial respiration and TCA with a slight increase in the glycolytic flux. A significant ROS increase and preserved cell viability are observed in the presence of NO, which may ease the inflammatory response and host defense. Also, NO reverses the cytokine storm‐induced itaconate accumulation. These changes offer additional clues to understanding the potential crosstalk between NO and the COVID‐19 cytokine storm‐dependent signaling pathways.
Advanced Nanomaterials for Cancer Therapy: Gold, Silver, and Iron Oxide Nanoparticles in Oncological Applications
Authors: Priyanka Singh, Santosh Pandit, Sri Renukadevi Balusamy, Mukil Madhusudanan, Hina Singh, H. Mohamed Amsath Haseef, Ivan Mijakovic
Journal: Advanced Healthcare Materials (2024)

Cancer remains one of the most challenging health issues globally, demanding innovative therapeutic approaches for effective treatment. Nanoparticles, particularly those composed of gold, silver, and iron oxide, have emerged as promising candidates for changing cancer therapy. This comprehensive review demonstrates the landscape of nanoparticle-based oncological interventions, focusing on the remarkable advancements and therapeutic potentials of gold, silver, and iron oxide nanoparticles. Gold nanoparticles have garnered significant attention for their exceptional biocompatibility, tunable surface chemistry, and distinctive optical properties, rendering them ideal candidates for various cancer diagnostic and therapeutic strategies. Silver nanoparticles, renowned for their antimicrobial properties, exhibit remarkable potential in cancer therapy through multiple mechanisms, including apoptosis induction, angiogenesis inhibition, and drug delivery enhancement. With their magnetic properties and biocompatibility, iron oxide nanoparticles offer unique cancer diagnosis and targeted therapy opportunities. This review critically examines the recent advancements in the synthesis, functionalization, and biomedical applications of these nanoparticles in cancer therapy. Moreover, the challenges are discussed, including toxicity concerns, immunogenicity, and translational barriers, and ongoing efforts to overcome these hurdles are highlighted. Finally, insights into the future directions of nanoparticle-based cancer therapy and regulatory considerations, are provided aiming to accelerate the translation of these promising technologies from bench to bedside.
Novel Less Toxic, Lymphoid Tissue‐Targeted Lipid Nanoparticles Containing a Vitamin B5‐Derived Ionizable Lipid for mRNA Vaccine Delivery
Authors: Soyeon Yoo, Muhammad Faisal, Seo‐Hyeon Bae, Kounghwa Youn, Hyo‐Jung Park, Sung Pil Kwon, Il Kwon Hwang, Jisun Lee, Hyeong Jun Kim, Jae‐Hwan Nam, Gyochang Keum, Eun‐Kyoung Bang
Journal: Advanced Healthcare Materials (2024)

Following their approval by the Food and Drug Administration, lipid nanoparticles (LNPs) have emerged as promising tools for delivering mRNA vaccines and therapeutics. Ionizable lipids are among the essential components of LNPs, as they play crucial roles in encapsulating mRNA and facilitating its release into the cytosol. In this study, 17 innovative ionizable lipids using vitamin B5 are designed as the core structure, aiming to reduce toxicity, to maintain vaccine efficiency, and to ensure synthetic feasibility. The top-performing LNP in terms of mRNA vaccine delivery in the mouse model is LNP 5097, which is generated by incorporating ionizable lipid I97. mRNA⊂LNP 5097 demonstrates favorable structural and physicochemical properties, high mRNA transfection efficiency, and long-term stability. Moreover, mRNA⊂LNP 5097 specifically delivers the mRNA to the spleen and lymph nodes in model mice, induces balanced Th1/Th2 immune responses, and elicits the production of high levels of neutralizing antibodies with low toxicity. The findings here suggest the high utility of LNP 5097, which includes novel vitamin B5-derived ionizable lipids with reduced toxicity, in mRNA vaccine research for both infectious diseases and cancer.
Composite Scaffold Materials of Nanocerium Oxide Doped with Allograft Bone: Dual Optimization Based on Anti‐Inflammatory Properties and Promotion of Osteogenic Mineralization
Authors: Yuqiao Li, Yongkang Huang, Houzhi Yang, Yuxin Li, Gan Luo, Yuan Ma, Haiyang Cheng, Yubin Long, Weiwei Xia, Haiying Liu, Huayi Fang, Yaping Du, Tianwei Sun, Kaifeng Wang, Xinyun Zhai
Journal: Advanced Healthcare Materials (2024)

Abstract Spinal fusion technique is widely used in the treatment of lumbar degeneration, cervical instability, disc injury, and spinal deformity. However, it is usually accompanied by a high incidence of fusion failure and pseudoarthrosis, placing higher demands on bone implants. Therefore, materials with good biocompatibility, osteoconductivity, and even induce bone ingrowth, which can be used to improve spinal fusion rate and bone regeneration, have become a hot research topic. Here, ultra‐small cerium oxide nanoparticles (CeO 2 NPs) are prepared and loaded onto the surface of the homograft bone surface to prepare a composite scaffold AB@PLGA/CeO 2 . The composite scaffold shows the competitive ability to promote osteoblast differentiation in vitro. In vivo experiments show that AB@PLGA/CeO 2 has a good bone enhancement effect. In particular, good biological effects of collagen fiber formation, osteogenic mineralization, and tissue repair are shown in intervertebral implant fusion. Further, transcriptome sequencing confirms that CeO 2 NPs promote osteogenic differentiation and mineralization by regulating extracellular matrix (ECM) and collagen formation. Meanwhile, CeO 2 NPs can regulate the function of the PI3K‐Akt signaling pathway to exert its ability to promote osteogenic differentiation and mineralization and affect p53 and cell cycle signaling pathway to regulate osteogenic differentiation and mineralization. Hence, the proposed scaffold is a promising strategy for intervertebral fusion in the clinic.
Boosting mRNA‐Engineered Monocytes via Prodrug‐Like Microspheres for Bone Microenvironment Multi‐Phase Remodeling
Authors: Yuansheng Wu, Yingjie Zhu, Jie Chen, Lili Song, Chunping Wang, Yanglin Wu, Yanyang Chen, Jiancheng Zheng, Yuankun Zhai, Xiang Zhou, Youwen Liu, Yawei Du, Wenguo Cui
Journal: Advanced Healthcare Materials (2024)

Abstract Monocytes, as progenitors of macrophages and osteoclasts, play critical roles in various stages of bone repair, necessitating phase‐specific regulatory mechanisms. Here, icariin (ICA) prodrug‐like microspheres (ICA@GM) are developed, as lipid nanoparticle (LNP) transfection boosters, to construct mRNA‐engineered monocytes for remodeling the bone microenvironment across multiple stages, including the acute inflammatory and repair phases. Initially, ICA@GM is prepared from ICA‐conjugated gelatin methacryloyl via a microfluidics system. Then, monocyte‐targeting IL‐4 mRNA‐LNPs are then prepared and integrated into injectable microspheres (mRNA‐ICA@GM) via electrostatic and hydrogen bond interactions. After bone‐defect injection, LNPs are controlled released from mRNA‐ICA@GM within 3 days, rapidly transfecting monocytes for monocyte IL‐4 mRNA‐engineering, which effectively suppressed acute inflammatory responses via polarization programming and paracrine signaling. Afterwards, ICA is sustainably released as well via cleavable boronate esters across multiple stages, cooperatively boosting the mRNA‐engineered monocytes to inhibit coenocytic fusion and osteoclastic function. Both in vitro and in vivo data indicated that mRNA‐ICA@GM can not only reverse the inflammatory environment but also suppress monocyte‐derived osteoclast formation to accelerate bone repair. In summary, mRNA‐engineered monocytes and ICA prodrug‐like microspheres are combined to achieve long‐lasting multi‐stage bone microenvironment regulation, offering a promising repair strategy.
Hyaluronic Acid‐Based 3D Bioprinted Hydrogel Structure for Directed Axonal Guidance and Modeling Innervation In Vitro
Authors: Laura Honkamäki, Oskari Kulta, Paula Puistola, Karoliina Hopia, Promise Emeh, Lotta Isosaari, Anni Mörö, Susanna Narkilahti
Journal: Advanced Healthcare Materials (2024)

Abstract Neurons form predefined connections and innervate target tissues through elongating axons, which are crucial for the development, maturation, and function of these tissues. However, innervation is often overlooked in tissue engineering (TE) applications. Here, multimaterial 3D bioprinting is used to develop a novel 3D axonal guidance structure in vitro. The approach uses the stiffness difference of acellular hyaluronic acid‐based bioink printed as two alternating, parallel‐aligned filaments. The structure has soft passages incorporated with guidance cues for axonal elongation while the stiff bioink acts as a structural support and contact guidance. The mechanical properties and viscosity differences of the bioinks are confirmed. Additionally, human pluripotent stem cell (hPSC) ‐derived neurons form a 3D neuronal network in the softer bioink supplemented with guidance cues whereas the stiffer restricts the network formation. Successful 3D multimaterial bioprinting of the axonal structure enables complete innervation by peripheral neurons via soft passages within 14 days of culture. This model provides a novel, stable, and long‐term platform for studies of 3D innervation and axonal dynamics in health and disease.
The effects of gut microbiota on appetite regulation and the underlying mechanisms
Authors: Miao Yu, Bing Yu, Daiwen Chen
Journal: Gut Microbes (2024)

Appetite, a crucial aspect regulated by both the central nervous system and peripheral hormones, is influenced by the composition and dynamics of the intestinal microbiota, as evidenced by recent research. This review highlights the role of intestinal microbiota in appetite regulation, elucidating the involvement of various pathways. Notably, the metabolites generated by intestinal microorganisms, including short-chain fatty acids, bile acids, and amino acid derivatives, play a pivotal role in this intricate process. Furthermore, intestinal microorganisms contribute to appetite regulation by modulating nutritional perception, neural signal transmission, and hormone secretion within the digestive system. Consequently, manipulating and modulating the intestinal microbiota represent innovative strategies for ameliorating appetite-related disorders. This paper provides a comprehensive review of the effects of gut microbes and their metabolites on the central nervous system and host appetite. By exploring their potential regulatory pathways and mechanisms, this study aims to enhance our understanding of how gut microbes influence appetite regulation in the host.
Ethical implications of artificial intelligence in skin cancer diagnostics: use-case analyses
Authors: Syed F H Shah, Daniel Arecco, Heather Draper, Simona Tiribelli, Eli Harriss, Rubeta N Matin
Journal: British Journal of Dermatology (2024)

Abstract Background Skin cancer is the most common cancer worldwide. Early diagnosis is crucial for improving patient survival and morbidity. Artificial intelligence (AI)-assisted smartphone applications (apps) for skin cancer potentially offer accessible, early risk assessment of suspicious skin lesions. However, the integration of novel technologies into dermatology pathways raises ethical concerns. Although ethical principles for AI governance are well known, how these principles should be applied to real-life AI apps readily available for public use is less well understood. Objectives We conducted an ethical use-case analysis of commercially available skin cancer apps to better understand the ethical issues arising from their development and use in a real-world context. Methods Established methods for ethical analysis of clinical AI applications were applied to two popular skin cancer apps in the UK: SkinVision and Scanoma. Systematic searches of published literature, regulatory documents, and websites were conducted to review the evidence regarding app development, effectiveness, and use. Screening for inclusion was undertaken by two researchers independently. Ethical concerns were identified with reference to previously described ethical concerns and principles for AI-assisted healthcare. Results By conceptualising ethical principles within the use-context of skin cancer apps, we identified specific ethical issues arising throughout the AI lifecycle of both apps. One company provided extensive detail regarding algorithm development and decision-making, this information was insufficiently reported for the other app. Other concerns identified related to number, quality, and consistency of studies assessing algorithm efficacy. Limited efforts to address potential skin tone biases and exclusion of individuals with darker skin tones as target users by one app risks perpetuating existing inequalities. Inadequate regulatory oversight was identified. Conclusions Findings from our ethical use-case analysis of two patient-facing AI-assisted skin cancer apps suggest inadequate incorporation of bioethical norms such as justice, responsibility and transparency into the development and deployment of both apps. Improved regulation should increase accountability. Ensuring ethics by design through integration between technology developers, dermatologists, ethicists, and the public is urgently needed to prevent the potential benefits of AI-assisted skin cancer apps being overshadowed by potential ethical harms.