tbuckley/cabot-search huggingface dataset:
The remission status of AML patients after allo-HCT is associated with a distinct single-cell bone marrow T-cell signature
Authors: Anna Mathioudaki, Xizhe Wang, David Sedloev, Richard Huth, Aryan Kamal, Michael Hundemer, Yi Liu, Spyridoula Vasileiou, Premal Lulla, Carsten Müller-Tidow, Peter Dreger, Thomas Luft, Tim Sauer, Michael Schmitt, Judith B. Zaugg, Caroline Pabst
Journal: Blood (2024)

Acute myeloid leukemia (AML) is a hematologic malignancy for which allogeneic hematopoietic cell transplantation (allo-HCT) often remains the only curative therapeutic approach. However, incapability of T cells to recognize and eliminate residual leukemia stem cells might lead to an insufficient graft-versus-leukemia (GVL) effect and relapse. Here, we performed single-cell RNA-sequencing (scRNA-seq) on bone marrow (BM) T lymphocytes and CD34+ cells of 6 patients with AML 100 days after allo-HCT to identify T-cell signatures associated with either imminent relapse (REL) or durable complete remission (CR). We observed a higher frequency of cytotoxic CD8+ effector and gamma delta (γδ) T cells in CR vs REL samples. Pseudotime and gene regulatory network analyses revealed that CR CD8+ T cells were more advanced in maturation and had a stronger cytotoxicity signature, whereas REL samples were characterized by inflammatory tumor necrosis factor/NF-κB signaling and an immunosuppressive milieu. We identified ADGRG1/GPR56 as a surface marker enriched in CR CD8+ T cells and confirmed in a CD33-directed chimeric antigen receptor T cell/AML coculture model that GPR56 becomes upregulated on T cells upon antigen encounter and elimination of AML cells. We show that GPR56 continuously increases at the protein level on CD8+ T cells after allo-HCT and confirm faster interferon gamma (IFN-γ) secretion upon re-exposure to matched, but not unmatched, recipient AML cells in the GPR56+ vs GPR56- CD8+ T-cell fraction. Together, our data provide a single-cell reference map of BM-derived T cells after allo-HCT and propose GPR56 expression dynamics as a surrogate for antigen encounter after allo-HCT.
The sialic acid–Siglec immune checkpoint: an opportunity to enhance immune responses and therapy effectiveness in melanoma
Authors: Magali Coccimiglio, Fabrizio Chiodo, Yvette van Kooyk
Journal: British Journal of Dermatology (2024)

Modulation of immune responses through immune checkpoint blockade has revolutionized cutaneous melanoma treatment. However, it is still the case that not all patients respond successfully to these therapies, indicating the presence of as yet unknown resistance mechanisms. Hence, it is crucial to find novel targets to improve therapy efficacy. One of the described resistance mechanisms is regulated by immune inhibitory Siglec receptors, which are engaged by the carbohydrates sialic acids expressed on tumour cells, contributing to programmed cell death protein-1 (PD1)-like immune suppression mechanisms. In this review, we provide an overview on the regulation of sialic acid synthesis, its expression in melanoma, and the contribution of the sialic acid-Siglec axis to tumour development and immune suppressive mechanisms in the tumour microenvironment. Finally, we highlight potential sialic acid-Siglec axis-related therapeutics to improve the treatment of melanoma.
Sirpα on tumor-associated myeloid cells restrains antitumor immunity in colorectal cancer independent of its interaction with CD47
Authors: Chunliu Huang, Xuefei Wang, Yingzhao Wang, Yongyi Feng, Xiumei Wang, Shan Chen, Peidong Yan, Jing Liao, Qi Zhang, Chengzhou Mao, Yang Li, Lixiang Wang, Xinyu Wang, Wei Yi, Weibin Cai, Shoudeng Chen, Ni Hong, Weiling He, Jun Chen, Wenfei Jin
Journal: Nature Cancer (2024)
TIME-seq reduces time and cost of DNA methylation measurement for epigenetic clock construction
Authors: Patrick T. Griffin, Alice E. Kane, Alexandre Trapp, Jien Li, Matthew Arnold, Jesse R. Poganik, Ryan J. Conway, Maeve S. McNamara, Margarita V. Meer, Noah Hoffman, João A. Amorim, Xiao Tian, Michael R. MacArthur, Sarah J. Mitchell, Amber L. Mueller, Colleen Carmody, Daniel L. Vera, Csaba Kerepesi, Kejun Ying, Nicole Noren Hooten, James R. Mitchell, Michele K. Evans, Vadim N. Gladyshev, David A. Sinclair
Journal: Nature Aging (2024)
Sputum cytokines associated with raised FeNO after anti‐IL5 biologic therapy in severe asthma
Authors: Pieter‐Paul Hekking, Kayla Zhang, Carmen Paz Venegas Garrido, Raquel Lopez‐Rodriguez, Melanie Kjarsgaard, Manali Mukherjee, Parameswaran Nair
Journal: Allergy (2024)

The data that support the findings of this study are available from the corresponding author upon reasonable request. Data S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Orthogonally Sequential Activation of Self‐Powered DNAzymes Cascade for Reliable Monitoring of mRNA in Living Cells
Authors: Fuqiang Zhang, Nan Yang, Fu Zhou, Ruonan Qiao, Yifei Wan, Rong Liu, Suwan Yang, Mingzheng Gu, Huae Xu, Xiaochen Dong, Guangfeng Wang
Journal: Advanced Healthcare Materials (2024)

Ratiometric imaging of tumor-related mRNA is significant, yet spatiotemporally resolved regulation on the ratiometric signals to avoid non-specific activation in the living cells remains challenging. Herein, orthogonally sequential activation of concatenated DNAzyme circuits is, first, developed for Spatio Temporally regulated Amplified and Ratiometric (STAR) imaging of TK1 mRNA inside living cells with enhanced reliability and accuracy. By virtue of the synthesized CuO/MnO
Integrative functional genomic analyses identify genetic variants influencing skin pigmentation in Africans
Authors: Yuanqing Feng, Ning Xie, Fumitaka Inoue, Shaohua Fan, Joshua Saskin, Chao Zhang, Fang Zhang, Matthew E. B. Hansen, Thomas Nyambo, Sununguko Wata Mpoloka, Gaonyadiwe George Mokone, Charles Fokunang, Gurja Belay, Alfred K. Njamnshi, Michael S. Marks, Elena Oancea, Nadav Ahituv, Sarah A. Tishkoff
Journal: Nature Genetics (2024)
Comprehensive genetic study of the insulin resistance marker TG:HDL-C in the UK Biobank
Authors: Antonino Oliveri, Ryan J Rebernick, Annapurna Kuppa, Asmita Pant, Yanhua Chen, Xiaomeng Du, Kelly C. Cushing, Hannah N Bell, Chinmay Raut, Ponnandy Prabhu, Vincent L. Chen, Brian D. Halligan, Elizabeth K. Speliotes
Journal: Nature Genetics (2024)
Gut microbiome-derived butyrate inhibits the immunosuppressive factors PD-L1 and IL-10 in tumor-associated macrophages in gastric cancer
Authors: Seung Yoon Lee, JooYeon Jhun, Jin Seok Woo, Kun Hee Lee, Sun-Hee Hwang, Jeonghyeon Moon, Goeun Park, Sun Shim Choi, So Jung Kim, Yoon Ju Jung, Kyo Young Song, Mi-La Cho
Journal: Gut Microbes (2024)

Early detection and surgical treatment are essential to achieve a good outcome in gastric cancer (GC). Stage IV and recurrent GC have a poor prognosis. Therefore, new treatments for GC are needed. We investigated the intestinal microbiome of GC patients and attempted to reverse the immunosuppression of the immune and cancer cells of GC patients through the modulation of microbiome metabolites. We evaluated the levels of programmed death-ligand 1 (PD-L1) and interleukin (IL)-10 in the peripheral blood immunocytes of GC patients. Cancer tissues were obtained from patients who underwent surgical resection of GC, and stained sections of cancer tissues were visualized via confocal microscopy. The intestinal microbiome was analyzed using stool samples of healthy individuals and GC patients. Patient-derived avatar model was developed by injecting peripheral blood mononuclear cells (PBMCs) from advanced GC (AGC) patients into NSG mice, followed by injection of AGS cells. PD-L1 and IL-10 had higher expression levels in immune cells of GC patients than in those of healthy controls. The levels of immunosuppressive factors were increased in the immune and tumor cells of tumor tissues of GC patients. The abundances of Faecalibacterium and Bifidobacterium in the intestinal flora were lower in GC patients than in healthy individuals. Butyrate, a representative microbiome metabolite, suppressed the expression levels of PD-L1 and IL-10 in immune cells. In addition, the PBMCs of AGC patients showed increased levels of immunosuppressive factors in the avatar mouse model. Butyrate inhibited tumor growth in mice. Restoration of the intestinal microbiome and its metabolic functions inhibit tumor growth and reverse the immunosuppression due to increased PD-L1 and IL-10 levels in PBMCs and tumor cells of GC patients.
Daily skin-to-skin contact alters microbiota development in healthy full-term infants
Authors: Henrik Andreas Eckermann, Jennifer Meijer, Kelly Cooijmans, Leo Lahti, Carolina de Weerth
Journal: Gut Microbes (2024)

The gut microbiota is vital for human body development and function. Its development in early life is influenced by various environmental factors. In this randomized controlled trial, the gut microbiota was obtained as a secondary outcome measure in a study on the effects of one hour of daily skin-to-skin contact (SSC) for five weeks in healthy full-term infants. Specifically, we studied the effects on alpha/beta diversity, volatility, microbiota maturation, and bacterial and gut-brain-axis-related functional abundances in microbiota assessed thrice in the first year. Pregnant Dutch women (n = 116) were randomly assigned to the SSC or care-as-usual groups. The SSC group participants engaged in one hour of daily SSC from birth to five weeks of age. Stool samples were collected at two, five, and 52 weeks and the V4 region was sequenced. We observed significant differences in the microbiota composition, bacterial abundances, and predicted functional pathways between the groups. The SSC group exhibited lower microbiota volatility during early infancy. Microbiota maturation was slower in the SSC group during the first year and our results suggested that breastfeeding duration may have partially mediated this relation. Our findings provide evidence that postpartum SSC may influence microbiota development. Replication is necessary to validate and generalize these results. Future studies should include direct stress measurements and extend microbiota sampling beyond the first year to investigate stress as a mechanism and research SSC's impact on long-term microbiota maturation trajectories.
Deficiency of Transcription Factor Sp1 Contributes to Hypertrophic Cardiomyopathy
Authors: Fulei Zhang, Huixing Zhou, Jinfeng Xue, Yuemei Zhang, Liping Zhou, Junwei Leng, Guojian Fang, Yuanyuan Liu, Yan Wang, Hongyu Liu, Yahan Wu, Lingbin Qi, Ran Duan, Xiaoyu He, Yan Wang, Yi Liu, Li Li, Jian Yang, Dandan Liang, Yi-Han Chen
Journal: Circulation Research (2024)

Hypertrophic cardiomyopathy (HCM) is the most prevalent monogenic heart disorder. However, the pathogenesis of HCM, especially its nongenetic mechanisms, remains largely unclear. Transcription factors are known to be involved in various biological processes including cell growth. We hypothesized that SP1 (specificity protein 1), the first purified TF in mammals, plays a role in the cardiomyocyte growth and cardiac hypertrophy of HCM.
Cell membrane-anchored and tumor-targeted IL-12 T-cell therapy destroys cancer-associated fibroblasts and disrupts extracellular matrix in heterogenous osteosarcoma xenograft models
Authors: Jiemiao Hu, Alexander J Lazar, Davis Ingram, Wei-Lien Wang, Wendong Zhang, Zhiliang Jia, Dristhi Ragoonanan, Jian Wang, Xueqing Xia, Kris Mahadeo, Richard Gorlick, Shulin Li
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background The extracellular matrix (ECM) and cancer-associated fibroblasts (CAFs) play major roles in tumor progression, metastasis, and the poor response of many solid tumors to immunotherapy. CAF-targeted chimeric antigen receptor-T cell therapy cannot infiltrate ECM-rich tumors such as osteosarcoma. Method In this study, we used RNA sequencing to assess whether the recently invented membrane-anchored and tumor-targeted IL-12-armed (attIL12) T cells, which bind cell-surface vimentin (CSV) on tumor cells, could destroy CAFs to disrupt the ECM. We established an in vitro model of the interaction between osteosarcoma CAFs and attIL12-T cells to uncover the underlying mechanism by which attIL12-T cells penetrate stroma-enriched osteosarcoma tumors. Results RNA sequencing demonstrated that attIL12-T cell treatment altered ECM-related gene expression. Immunohistochemistry staining revealed disruption or elimination of high-density CAFs and ECM in osteosarcoma xenograft tumors following attIL12-T cell treatment, and CAF/ECM density was inversely correlated with T-cell infiltration. Other IL12-armed T cells, such as wild-type IL-12-targeted or tumor-targeted IL-12-T cells, did not disrupt the ECM because this effect depended on the engagement between CSV on the tumor cell and its ligand on the attIL12-T cells. Mechanistic studies found that attIL12-T cell treatment elevated IFNγ production on interacting with CSV + tumor cells, suppressing transforming growth factor beta secretion and in turn upregulating FAS-mediated CAF apoptosis. CAF destruction reshaped the tumor stroma to favor T-cell infiltration and tumor inhibition. Conclusions This study unveiled a novel therapy—attIL12-T cells—for targeting CAFs/ECM. These findings are highly relevant to humans because CAFs are abundant in human osteosarcoma.
Aberrant R-loop–mediated immune evasion, cellular communication, and metabolic reprogramming affect cancer progression: a single-cell analysis
Authors: Shichao Zhang, Yang Liu, Yichi Sun, Qin Liu, Yan Gu, Ya Huang, Zhu Zeng, Fuzhou Tang, Yan Ouyang
Journal: Molecular Cancer (2024)

Abstract Dysregulation of R-loop homeostasis is closely related to various human diseases, including cancer. However, the causality of aberrant R-loops in tumor progression remains unclear. In this study, using single-cell RNA-sequencing datasets from lung adenocarcinoma (LUAD), we constructed an R-loop scoring model to characterize the R-loop state according to the identified R-loop regulators related to EGFR mutations, tissue origins, and TNM stage. We then evaluated the relationships of the R-loop score with the tumor microenvironment (TME) and treatment response. Furthermore, the potential roles of FANCI-mediated R-loops in LUAD were explored using a series of in vitro experiments. Results showed that malignant cells with low R-loop scores displayed glycolysis and epithelial–mesenchymal transition pathway activation and immune escape promotion, thereby hampering the antitumor therapeutic effects. Cell communication analysis suggested that low R-loop scores contributed to T cell exhaustion. We subsequently validated the prognostic value of R-loop scores by using bulk transcriptome datasets across 33 tumor types. The R-loop scoring model well predicted patients’ therapeutic response to targeted therapy, chemotherapy, or immunotherapy in 32 independent cohorts. Remarkably, changes in R-loop distribution mediated by FANCI deficiency blocked the activity of Ras signaling pathway, suppressing tumor-cell proliferation and dissemination. In conclusion, this study reveals the underlying molecular mechanism of metabolic reprogramming and T cell exhaustion under R-loop score patterns, and the changes in R-loops mediated by R-loop regulators resulting in tumor progression. Therefore, incorporating anticancer methods based on R-loop or R-loop regulators into the treatment schemes of precision medicine may be beneficial.
Application of improved GalNAc conjugation in development of cost-effective siRNA therapies targeting cardiovascular diseases
Authors: Qian Li, Ke Yin, Hai-Ping Ma, Hui-Hui Liu, Sha Li, Xiao Luo, Rong Hu, Wei-Wei Zhang, Zheng-Sheng Lv, Xiao-Lei Niu, Mei-Hua Gu, Cheng-Lu Li, Yong-Shuang Liu, Yi-Jiang Liu, Hai-Bo Li, Nancy Li, Chong Li, Wendy Wei Gu, Jian-Jun Li
Journal: Molecular Therapy (2024)
Quantitative visualization of myocardial ischemia-reperfusion-induced cardiac lesions via ferroptosis magnetic particle imaging
Authors: Wenwen Yang, Yueqi Wang, Changgeng Fu, Changjian Li, Feng Feng, Hongzheng Li, Ling Tan, Hua Qu, Hui Hui, Jingjing Wang, Jie Tian, Linzi Long
Journal: Theranostics (2024)

Myocardial ischemia-reperfusion (MI/R) injury is a complication in vascular reperfusion therapy for MI, occurring in approximately 60% of patients.Ferroptosis is an important process in the development of MI/R cardiac lesions.Transferrin receptor 1 (TfR1), a marker of ferroptosis, corresponds to the changes in MI/R cardiac lesions and is expected to be a biomarker for detecting MI/R-induced ferroptosis.However, the noninvasive in vivo visualization of ferroptosis in MI/R is a big challenge.Thus, this study aimed to develop a novel multimodal imaging platform to identify markers of MI/R cardiac lesions in vivo through targeting TfR1.Methods: Magnetic particle imaging (MPI) modality for ferroptosis based on superparamagnetic cubic-iron oxide nanoparticles (SCIO NPs), named feMPI, has been developed.FeMPI used TfR1 as a typical biomarker.The feMPI probe (SCIO-ICG-CRT-CPPs NPs, CCI NPs) consists of SCIO NPs, TfR1-targeting peptides (CRT), cell-penetrating peptides (CPPs), and indocyanine green (ICG).The specificity and sensitivity of CCI NPs in the MI/R mouse model were evaluated by MPI, magnetic resonance imaging (MRI), and near-infrared (NIR) fluorescent imaging.Results: The intensity of the MPI signal correlates linearly with the percentage of infarct area in MI/R stained by TTC, enabling a quantitative assessment of the extent of cardiac lesions.Notably, these findings are consistent with the standard clinical biochemical indicators in MI/R within the first 24 h.FeMPI detects cardiac injury approximately 48 h prior to the current clinical imaging detection methods of MI/R. Conclusion:The feMPI strategy can be a powerful tool for studying the process of MI/R-induced ferroptosis in vivo, providing clues for molecular imaging and drug development of ferroptosis-related treatments.
Non-canonical signaling pathway of SNAI2 induces EMT in ovarian cancer cells by suppressing miR-222-3p transcription and upregulating PDCD10: Erratum
Authors: Lili Fan, Han Lei, Sai Zhang, Yulong Peng, Chunyan Fu, Guang Shu, Gang Yin
Journal: Theranostics (2024)

[This corrects the article DOI: 10.7150/thno.43198.].
Stratifying esophago-gastric cancer treatment using a patient-derived organoid-based threshold
Authors: Tim Schmäche, Juliane Fohgrub, Anna Klimova, Karin Laaber, Stephan Drukewitz, Felix Merboth, Alexander Hennig, Therese Seidlitz, Friederike Herbst, Franziska Baenke, Anne-Marlen Ada, Thomas Groß, Carina Wenzel, Claudia R. Ball, Christian Praetorius, Thomas Schmidt, Barbara Ringelband-Schilling, Ronald Koschny, Albrecht Stenzinger, Ingo Roeder, Dirk Jaeger, Sebastian Zeissig, Thilo Welsch, Daniela Aust, Hanno Glimm, Gunnar Folprecht, Jürgen Weitz, Georg M. Haag, Daniel E. Stange
Journal: Molecular Cancer (2024)

Abstract Background and aims This study sought to determine the value of patient-derived organoids (PDOs) from esophago-gastric adenocarcinoma (EGC) for response prediction to neoadjuvant chemotherapy (neoCTx). Methods Endoscopic biopsies of patients with locally advanced EGC ( n = 120) were taken into culture and PDOs expanded. PDOs' response towards the single substances of the FLOT regimen and the combination treatment were correlated to patients' pathological response using tumor regression grading. A classifier based on FLOT response of PDOs was established in an exploratory cohort ( n = 13) and subsequently confirmed in an independent validation cohort ( n = 13). Results EGC PDOs reflected patients' diverse responses to single chemotherapeutics and the combination regimen FLOT. In the exploratory cohort, PDOs response to single 5-FU and FLOT combination treatment correlated with the patients' pathological response (5-FU: Kendall's τ = 0.411, P = 0.001; FLOT: Kendall's τ = 0.694, P = 2.541e-08). For FLOT testing, a high diagnostic precision in receiver operating characteristic (ROC) analysis was reached with an AUC ROC of 0.994 (CI 0.980 to 1.000). The discriminative ability of PDO-based FLOT testing allowed the definition of a threshold, which classified in an independent validation cohort FLOT responders from non-responders with high sensitivity (90%), specificity (100%) and accuracy (92%). Conclusion In vitro drug testing of EGC PDOs has a high predictive accuracy in classifying patients' histological response to neoadjuvant FLOT treatment. Taking into account the high rate of successful PDO expansion from biopsies, the definition of a threshold that allows treatment stratification paves the way for an interventional trial exploring PDO-guided treatment of EGC patients.
Clinically relevant orthotopic pancreatic cancer models for adoptive T cell transfer therapy
Authors: Natalie K. Horvat, Isaac Karpovsky, Maggie Phillips, Megan M. Wyatt, Margaret A. Hall, Cameron J. Herting, Jacklyn Hammons, Zaid Mahdi, Richard A. Moffitt, Chrystal M. Paulos, Gregory B. Lesinski
Journal: Journal for ImmunoTherapy of Cancer (2024)

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive tumor. Prognosis is poor and survival is low in patients diagnosed with this disease, with a survival rate of ~12% at 5 years. Immunotherapy, including adoptive T cell transfer therapy, has not impacted the outcomes in patients with PDAC, due in part to the hostile tumor microenvironment (TME) which limits T cell trafficking and persistence. We posit that murine models serve as useful tools to study the fate of T cell therapy. Currently, genetically engineered mouse models (GEMMs) for PDAC are considered a "gold-standard" as they recapitulate many aspects of human disease. However, these models have limitations, including marked tumor variability across individual mice and the cost of colony maintenance.
Type-2 inflammation and lung function decline in chronic airway disease in the general population
Authors: Yunus Çolak, Shoaib Afzal, Jacob Louis Marott, Jørgen Vestbo, Børge Grønne Nordestgaard, Peter Lange
Journal: Thorax (2024)

Background It is unclear if type-2 inflammation is associated with accelerated lung function decline in individuals with asthma and chronic obstructive pulmonary disease (COPD). We tested the hypothesis that type-2 inflammation indicated by elevated blood eosinophils (BE) and fraction of exhaled nitric oxide (FeNO) is associated with accelerated lung function decline in the general population. Methods We included adults from the Copenhagen General Population Study with measurements of BE (N=15 605) and FeNO (N=2583) from a follow-up examination and assessed forced expiratory volume in 1 s (FEV 1 ) decline in the preceding 10 years. Based on pre- and post-bronchodilator lung function, smoking history and asthma at follow-up examination, participants were assigned as not having airway disease, asthma with full reversibility (AR), asthma with persistent obstruction (APO), COPD, and not classifiable airflow limitation (NAL). Results FEV 1 decline in mL/year increased with 1.0 (95% CI 0.6 to 1.4, p&lt;0.0001) per 100 cells/µL higher BE and with 3.2 (95% CI 2.0 to 4.5, p&lt;0.0001) per 10 ppb higher FeNO. Adjusted FEV 1 decline in mL/year was 18 (95% CI 17 to 20) in those with BE&lt;300 cells/µL and FeNO&lt;20 ppb, 22 (19–25) in BE≥300 cells/µL or FeNO≥20 ppb, and 27 (21–33) in those with BE≥300 cells/µL and FeNO≥20 ppb (p for trend&lt;0.0001). Corresponding FEV 1 declines were 24 (19–29), 33 (25–40) and 44 (31–56) in AR (0.002), 26 (14–37), 36 (12–60) and 56 (24–89) in APO (0.07), 32 (27–36), 31 (24–38) and 44 (24–65) in COPD (0.46), and 27 (21–33), 35 (26–45), and 37 (25–49) in NAL (0.10), respectively. Conclusions Type-2 inflammation indicated by elevated BE and FeNO is associated with accelerated FEV 1 decline in individuals with chronic airway disease in the general population, and this association was most pronounced in an asthma-like phenotype.