tbuckley/cabot-search huggingface dataset:
CRISPR-Cas9 library screening combined with an exosome-targeted delivery system addresses tumorigenesis/TMZ resistance in the mesenchymal subtype of glioblastoma
Authors: Jixing Zhao, Xiaoteng Cui, Qi Zhan, Kailiang Zhang, Dongyuan Su, Shixue Yang, Biao Hong, Qixue Wang, Jiasheng Ju, Chunchao Cheng, Chen Li, Chunxiao Wan, Yunfei Wang, Junhu Zhou, Chunsheng Kang
Journal: Theranostics (2024)

Rationale:The large-scale genomic analysis classifies glioblastoma (GBM) into three major subtypes, including classical (CL), proneural (PN), and mesenchymal (MES) subtypes.Each of these subtypes exhibits a varying degree of sensitivity to the temozolomide (TMZ) treatment, while the prognosis corresponds to the molecular and genetic characteristics of the tumor cell type.Tumors with MES features are predominantly characterized by the NF1 deletion/alteration, leading to sustained activation of the RAS and PI3K-AKT signaling pathways in GBM and tend to acquire drug resistance, resulting in the worst prognosis compared to other subtypes (PN and CL).Here, we used the CRISPR/Cas9 library screening technique to detect TMZ-related gene targets that might play roles in acquiring drug resistance, using overexpressed KRAS-G12C mutant GBM cell lines.The study identified a key therapeutic strategy to address the chemoresistance against the MES subtype of GBM.Methods: The CRISPR-Cas9 library screening was used to discover genes associated with TMZ resistance in the U87-KRAS (U87-MG which is overexpressed KRAS-G12C mutant) cells.The patient-derived GBM primary cell line TBD0220 was used for experimental validations in vivo and in vitro.Chromatin isolation by RNA purification (ChIRP) and chromatin immunoprecipitation (ChIP) assays were used to elucidate the silencing mechanism of tumor suppressor genes in the MES-GBM subtype.The small-molecule inhibitor EPIC-0412 was obtained through high-throughput screening.Transmission electron microscopy (TEM) was used to characterize the exosomes (Exos) secreted by GBM cells after TMZ treatment.Blood-derived Exos-based targeted delivery of siRNA, TMZ, and EPIC-0412 was optimized to tailor personalized therapy in vivo.Results: Using the genome-wide CRISPR-Cas9 library screening, we found that the ERBIN gene could be epigenetically regulated in the U87-KRAS cells.ERBIN overexpression inhibited the RAS signaling and downstream proliferation and invasion effects of GBM tumor cells.EPIC-0412 treatment inhibited tumor proliferation and EMT progression by upregulating the ERBIN expression both in vitro and in vivo.Genome-wide CRISPR-Cas9 screening also identified RASGRP1(Ras guanine nucleotide-releasing protein 1) and VPS28(Vacuolar protein sorting-associated protein 28) genes as synthetically lethal in response to TMZ treatment in the U87-KRAS cells.We found that RASGRP1 activated the RAS-mediated DDR pathway by promoting the RAS-GTP transformation.VPS28 promoted the Exos secretion and decreased intracellular TMZ concentration in GBM cells.The targeted Exos delivery system encapsulating drugs and siRNAs together showed a powerful therapeutic effect against GBM in vivo. Ivyspring
Nicotinamide phosphoribosyltransferase prompts bleomycin-induced pulmonary fibrosis by driving macrophage M2 polarization in mice
Authors: Yaling Chen, Tong Wang, Fuxiang Liang, Jia Han, Zhiling Lou, Yifan Yu, Jinsheng Li, Tianwei Zhan, Yuqing Gu, Lingjun Dong, Bo Jiang, Weiping Zhang, Ming Wu, Yunbi Lu
Journal: Theranostics (2024)

Rationale: Idiopathic pulmonary fibrosis (IPF) is an irreversible, fatal interstitial lung disease lacking specific therapeutics.Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the nicotinamide adenine dinucleotide (NAD) salvage biosynthesis pathway and a cytokine, has been previously reported as a biomarker for lung diseases; however, the role of NAMPT in pulmonary fibrosis has not been elucidated.Methods: We identified the NAMPT level changes in pulmonary fibrosis by analyzing public RNA-Seq databases, verified in collected clinical samples and mice pulmonary fibrosis model by Western blotting, qRT-PCR, ELISA and Immunohistochemical staining.We investigated the role and mechanism of NAMPT in lung fibrosis by using pharmacological inhibition on NAMPT and Nampt transgenic mice.In vivo macrophage depletion by clodronate liposomes and reinfusion of IL-4-induced M2 bone marrow-derived macrophages (BMDMs) from wild-type mice, combined with in vitro cell experiments, were performed to further validate the mechanism underlying NAMPT involving lung fibrosis.Results: We found that NAMPT increased in the lungs of patients with IPF and mice with bleomycin (BLM)-induced pulmonary fibrosis.NAMPT inhibitor FK866 alleviated BLM-induced pulmonary fibrosis in mice and significantly reduced NAMPT levels in bronchoalveolar lavage fluid (BALF).The lung single-cell RNA sequencing showed that NAMPT expression in monocytes/macrophages of IPF patients was much higher than in other lung cells.Knocking out NAMPT in mouse monocytes/macrophages (Nampt fl/fl ;Cx3cr1 CreER ) significantly alleviated BLM-induced pulmonary fibrosis in mice, decreased NAMPT levels in BALF, reduced the infiltration of M2 macrophages in the lungs and improved mice survival.Depleting monocytes/macrophages in Nampt fl/fl ;Cx3cr1 CreER mice by clodronate liposomes and subsequent pulmonary reinfusion of IL-4-induced M2 BMDMs from wild-type mice, reversed the protective effect of monocyte/macrophage NAMPT-deletion on lung fibrosis.In vitro experiments confirmed that the mechanism of NAMPT engaged in pulmonary fibrosis is related to the released NAMPT by macrophages promoting M2 polarization in a non-enzyme-dependent manner by activating the STAT6 signal pathway.Conclusions: NAMPT prompts bleomycin-induced pulmonary fibrosis by driving macrophage M2 polarization in mice.Targeting the NAMPT of monocytes/macrophages is a promising strategy for treating pulmonary fibrosis.
Targeting tumor cell-to-macrophage communication by blocking Vtn-C1qbp interaction inhibits tumor progression via enhancing macrophage phagocytosis
Authors: Chen Zhang, Yi Liu, Jiayu Jiang, Chong Chen, Zhaojun Duan, Huifang Su, Shijian Wang, Baorui Tian, Yi Shi, Rong Xiang, Yunping Luo
Journal: Theranostics (2024)

Background: Cancer cells are capable of evading clearance by macrophages through overexpression of anti-phagocytic surface proteins known as "don't eat me" signals.Monoclonal antibodies that antagonize the "don't-eat-me" signaling in macrophages and tumor cells by targeting phagocytic checkpoints have shown therapeutic promises in several cancer types.However, studies on the responses to these drugs have revealed the existence of other unknown "don't eat me" signals.Moreover, identification of key molecules and interactions regulating macrophage phagocytosis is required for tumor therapy.Methods: CRISPR screen was used to identify genes that impede macrophage phagocytosis.To explore the function of Vtn and C1qbp in phagocytosis, knockdown and subsequent functional experiments were conducted.Flow cytometry were performed to explore the phagocytosis rate, polarization of macrophage, and immune microenvironment of mouse tumor.To explore the underlying molecular mechanisms, RNA sequencing, immunoprecipitation, mass spectrometry, and immunofluorescence were conducted.Then, in vivo experiments in mouse models were conducted to explore the probability of Vtn knockdown combined with anti-CD47 therapy in breast cancer.Single-cell sequencing data from the Gene Expression Omnibus from The Cancer Genome Atlas database were analyzed.Results: We performed a genome-wide CRISPR screen to identify genes that impede macrophage phagocytosis, followed by analysis of cell-to-cell interaction databases.We identified a ligand-receptor pair of Vitronectin (Vtn) and complement C1Q binding protein (C1qbp) in tumor cells or macrophages, respectively.We demonstrated tumor cell-secreted Vtn interacts with C1qbp localized on the cell surface of tumor-associated macrophages, inhibiting phagocytosis of tumor cells and shifting macrophages towards the M2-like subtype in the tumor microenvironment.Mechanistically, the Vtn-C1qbp axis facilitated FcγRIIIA/CD16-induced Shp1 recruitment, which reduced the phosphorylation of Syk.Furthermore, the combination of Vtn knockdown and anti-CD47 antibody effectively enhanced phagocytosis and infiltration of macrophages, resulting in a reduction of tumor growth in vivo.Conclusions: This work has revealed that the Vtn-C1qbp axis is a new anti-phagocytic signal in tumors, and targeting Vtn and its interaction with C1qbp may sensitize cancer to immunotherapy, providing a new molecular target for the treatment of triple-negative breast cancer.
Critical roles and clinical perspectives of RNA methylation in cancer
Authors: Ganglei Li, Qinfan Yao, Peixi Liu, Hongfei Zhang, Yingjun Liu, Sichen Li, Yuan Shi, Zongze Li, Wei Zhu
Journal: MedComm (2024)

Abstract RNA modification, especially RNA methylation, is a critical posttranscriptional process influencing cellular functions and disease progression, accounting for over 60% of all RNA modifications. It plays a significant role in RNA metabolism, affecting RNA processing, stability, and translation, thereby modulating gene expression and cell functions essential for proliferation, survival, and metastasis. Increasing studies have revealed the disruption in RNA metabolism mediated by RNA methylation has been implicated in various aspects of cancer progression, particularly in metabolic reprogramming and immunity. This disruption of RNA methylation has profound implications for tumor growth, metastasis, and therapy response. Herein, we elucidate the fundamental characteristics of RNA methylation and their impact on RNA metabolism and gene expression. We highlight the intricate relationship between RNA methylation, cancer metabolic reprogramming, and immunity, using the well‐characterized phenomenon of cancer metabolic reprogramming as a framework to discuss RNA methylation's specific roles and mechanisms in cancer progression. Furthermore, we explore the potential of targeting RNA methylation regulators as a novel approach for cancer therapy. By underscoring the complex mechanisms by which RNA methylation contributes to cancer progression, this review provides a foundation for developing new prognostic markers and therapeutic strategies aimed at modulating RNA methylation in cancer treatment.
KEYNOTE‐811: Potential to revise first‐line therapy for metastatic human epidermal growth factor receptor 2‐positive gastric cancer
Authors: Yuwei Ding, Ying Yuan, Shanshan Weng
Journal: MedComm (2024)

The first-line therapy pattern transition of metastatic HER2-positive gastric cancer is shifting. The KEYNOTE-811 study demonstrated that the addition of immunotherapy to the standard treatment of HER2-targeted therapy and chemotherapy showed good results in terms of PFS, especially in subgroup patients with PD-L1 CPS≥1. In the future, the first-line therapy pattern of metastatic HER2-positive gastric cancer will be radically changed based on ongoing randomized controlled clinical trials.
ESM1 enhances fatty acid synthesis and vascular mimicry in ovarian cancer by utilizing the PKM2-dependent warburg effect within the hypoxic tumor microenvironment
Authors: Juan Zhang, Fan Ouyang, Anbo Gao, Tian Zeng, Ming Li, Hui Li, Wenchao Zhou, Qing Gao, Xing Tang, Qunfeng Zhang, Xiaomin Ran, Gang Tian, Xiyun Quan, Zhenzi Tang, Juan Zou, Yifei Zeng, Yunzhu Long, Yukun Li
Journal: Molecular Cancer (2024)

Abstract Background The hypoxic tumor microenvironment is a key factor that promotes metabolic reprogramming and vascular mimicry (VM) in ovarian cancer (OC) patients. ESM1, a secreted protein, plays an important role in promoting proliferation and angiogenesis in OC. However, the role of ESM1 in metabolic reprogramming and VM in the hypoxic microenvironment in OC patients has not been determined. Methods Liquid chromatography coupled with tandem MS was used to analyze CAOV3 and OV90 cells. Interactions between ESM1, PKM2, UBA2, and SUMO1 were detected by GST pull-down, Co-IP, and molecular docking. The effects of the ESM1-PKM2 axis on cell glucose metabolism were analyzed based on an ECAR experiment. The biological effects of the signaling axis on OC cells were detected by tubule formation, transwell assay, RT‒PCR, Western blot, immunofluorescence, and in vivo xenograft tumor experiments. Results Our findings demonstrated that hypoxia induces the upregulation of ESM1 expression through the transcription of HIF-1α. ESM1 serves as a crucial mediator of the interaction between PKM2 and UBA2, facilitating the SUMOylation of PKM2 and the subsequent formation of PKM2 dimers. This process promotes the Warburg effect and facilitates the nuclear translocation of PKM2, ultimately leading to the phosphorylation of STAT3. These molecular events contribute to the promotion of ovarian cancer glycolysis and vasculogenic mimicry. Furthermore, our study revealed that Shikonin effectively inhibits the molecular interaction between ESM1 and PKM2, consequently preventing the formation of PKM2 dimers and thereby inhibiting ovarian cancer glycolysis, fatty acid synthesis and vasculogenic mimicry. Conclusion Our findings demonstrated that hypoxia increases ESM1 expression through the transcriptional regulation of HIF-1α to induce dimerization via PKM2 SUMOylation, which promotes the OC Warburg effect and VM.
Converting “cold” to “hot”: epigenetics strategies to improve immune therapy effect by regulating tumor‐associated immune suppressive cells
Authors: Yijia Tang, Guangzu Cui, Haicong Liu, Ying Han, Changjing Cai, Ziyang Feng, Hong Shen, Shan Zeng
Journal: Cancer Communications (2024)

Abstract Significant developments in cancer treatment have been made since the advent of immune therapies. However, there are still some patients with malignant tumors who do not benefit from immunotherapy. Tumors without immunogenicity are called “cold” tumors which are unresponsive to immunotherapy, and the opposite are “hot” tumors. Immune suppressive cells (ISCs) refer to cells which can inhibit the immune response such as tumor‐associated macrophages (TAMs), myeloid‐derived suppressor cells (MDSCs), regulatory T (Treg) cells and so on. The more ISCs infiltrated, the weaker the immunogenicity of the tumor, showing the characteristics of “cold” tumor. The dysfunction of ISCs in the tumor microenvironment (TME) may play essential roles in insensitive therapeutic reaction. Previous studies have found that epigenetic mechanisms play an important role in the regulation of ISCs. Regulating ISCs may be a new approach to transforming “cold” tumors into “hot” tumors. Here, we focused on the function of ISCs in the TME and discussed how epigenetics is involved in regulating ISCs. In addition, we summarized the mechanisms by which the epigenetic drugs convert immunotherapy‐insensitive tumors into immunotherapy‐sensitive tumors which would be an innovative tendency for future immunotherapy in “cold” tumor.
Advances in gene therapy approaches targeting neuro-inflammation in neurodegenerative diseases
Authors: Kuldeep Singh, Pranshul Sethi, Samaresh Datta, Jitendra Singh Chaudhary, Sunil Kumar, Divya Jain, Jeetendra Kumar Gupta, Shivendra Kumar, Ajay Guru, Siva Prasad Panda
Journal: Ageing Research Reviews (2024)
Liver Fibrosis Assessed Via Noninvasive Tests is Associated With Incident Heart Failure in a General Population Cohort
Authors: Theresa J Hydes, Oliver J Kennedy, Kate Glyn-Owen, Ryan Buchanan, Julie Parkes, Daniel J Cuthbertson, Paul Roderick, Christopher D Byrne
Journal: Clinical Gastroenterology and Hepatology (2024)

The aim of this study was to determine whether liver fibrosis is associated with heart failure in a general population cohort, and if genetic polymorphisms (PNPLA3 rs738409; TM6SF2 rs58542926), linked to increased risk of liver fibrosis and decreased risk of coronary artery disease, modify this association.
Ozanimod in Patients With Moderate to Severe Ulcerative Colitis Naive to Advanced Therapies
Authors: Bruce E. Sands, Geert D’Haens, Remo Panaccione, Miguel Regueiro, Subrata Ghosh, David Hudesman, Harris A. Ahmad, Dimpy Mehra, Hsiuanlin Wu, Anjali Jain, AnnKatrin Petersen, Mark T. Osterman, Anita Afzali, Silvio Danese
Journal: Clinical Gastroenterology and Hepatology (2024)

The pivotal phase 3 True North (TN) study demonstrated the efficacy and safety of ozanimod in patients with moderately to severely active ulcerative colitis. This analysis assessed ozanimod during TN and the ongoing open-label extension (OLE) in patients with active disease who were naive to advanced therapies (ATs).
Treatment avenues for age-related macular degeneration: Breakthroughs and bottlenecks
Authors: Popat Kumbhar, Kaustubh Kolekar, Sukriti Vishwas, Priya Shetti, Vijay Kumbar, Terezinha de Jesus Andreoli Pinto, Ana Cláudia Paiva-Santos, Francisco Veiga, Guarav Gupta, Sachin Kumar Singh, Kamal Dua, John Disouza, Vandana Patravale
Journal: Ageing Research Reviews (2024)
Effects of a personalized nutrition program on cardiometabolic health: a randomized controlled trial
Authors: Kate M. Bermingham, Inbar Linenberg, Lorenzo Polidori, Francesco Asnicar, Alberto Arrè, Jonathan Wolf, Fatema Badri, Hannah Bernard, Joan Capdevila, William J. Bulsiewicz, Christopher D. Gardner, Jose M. Ordovas, Richard Davies, George Hadjigeorgiou, Wendy L. Hall, Linda M. Delahanty, Ana M. Valdes, Nicola Segata, Tim D. Spector, Sarah E. Berry
Journal: Nature Medicine (2024)

Large variability exists in people's responses to foods. However, the efficacy of personalized dietary advice for health remains understudied. We compared a personalized dietary program (PDP) versus general advice (control) on cardiometabolic health using a randomized clinical trial. The PDP used food characteristics, individual postprandial glucose and triglyceride (TG) responses to foods, microbiomes and health history, to produce personalized food scores in an 18-week app-based program. The control group received standard care dietary advice (US Department of Agriculture Guidelines for Americans, 2020-2025) using online resources, check-ins, video lessons and a leaflet. Primary outcomes were serum low-density lipoprotein cholesterol and TG concentrations at baseline and at 18 weeks. Participants (n = 347), aged 41-70 years and generally representative of the average US population, were randomized to the PDP (n = 177) or control (n = 170). Intention-to-treat analysis (n = 347) between groups showed significant reduction in TGs (mean difference = -0.13 mmol l
Diagnostic leukapheresis reveals distinct phenotypes of NSCLC circulating tumor cells
Authors: Lisa-Marie Rieckmann, Michael Spohn, Lisa Ruff, David Agorku, Lisa Becker, Alina Borchers, Jenny Krause, Roisin O’Reilly, Jurek Hille, Janna-Lisa Velthaus-Rusik, Niklas Beumer, Armin Günther, Lena Willnow, Charles D. Imbusch, Peter Iglauer, Ronald Simon, Sören Franzenburg, Hauke Winter, Michael Thomas, Carsten Bokemeyer, Nicola Gagliani, Christian F. Krebs, Martin Sprick, Olaf Hardt, Sabine Riethdorf, Andreas Trumpp, Nikolas H. Stoecklein, Sven Peine, Philipp Rosenstiel, Klaus Pantel, Sonja Loges, Melanie Janning
Journal: Molecular Cancer (2024)

Circulating tumor cells (CTCs) hold immense promise for unraveling tumor heterogeneity and understanding treatment resistance. However, conventional methods, especially in cancers like non-small cell lung cancer (NSCLC), often yield low CTC numbers, hindering comprehensive analyses. This study addresses this limitation by employing diagnostic leukapheresis (DLA) to cancer patients, enabling the screening of larger blood volumes. To leverage DLA's full potential, this study introduces a novel approach for CTC enrichment from DLAs.
Interleukin-21 receptor signaling promotes metabolic dysfunction-associated steatohepatitis-driven hepatocellular carcinoma by inducing immunosuppressive IgA+ B cells
Authors: Ying Xie, Yu Huang, Zhi-Yong Li, Weihua Jiang, Nan-Xi Shi, Yuanzhi Lu, Guangchao Cao, Zhinan Yin, Xue-Jia Lin
Journal: Molecular Cancer (2024)

Abstract Background Dysregulation of immune surveillance is tightly linked to the development of metabolic dysfunction-associated steatohepatitis (MASH)-driven hepatocellular carcinoma (HCC); however, its underlying mechanisms remain unclear. Herein, we aimed to determine the role of interleukin-21 receptor (IL-21R) in MASH-driven HCC. Methods The clinical significance of IL-21R was assessed in human HCC specimens using immunohistochemistry staining. Furthermore, the expression of IL-21R in mice was assessed in the STAM model. Thereafter, two different MASH-driven HCC mouse models were applied between IL-21R-deficient mice and wild type controls to explore the role of IL-21R in MASH-driven HCC. To further elucidate the potential mechanisms by which IL-21R affected MASH-driven HCC, whole transcriptome sequencing, flow cytometry and adoptive lymphocyte transfer were performed. Finally, flow cytometry, enzyme-linked immunosorbent assay, immunofluorescent staining, chromatin immunoprecipitation assay and western blotting were conducted to explore the mechanism by which IL-21R induced IgA + B cells. Results HCC patients with high IL-21R expression exhibited poor relapse-free survival, advanced TNM stage and severe steatosis. Additionally, IL-21R was demonstrated to be upregulated in mouse liver tumors. Particularly, ablation of IL-21R impeded MASH-driven hepatocarcinogenesis with dramatically reduction of lipid accumulation. Moreover, cytotoxic CD8 + T lymphocyte activation was enhanced in the absence of IL-21R due to the reduction of immunosuppressive IgA + B cells. Mechanistically, the IL-21R-STAT1-c-Jun/c-Fos regulatory axis was activated in MASH-driven HCC and thus promoted the transcription of Igha , resulting in the induction of IgA + B cells. Conclusions IL-21R plays a cancer-promoting role by inducing IgA + B cells in MASH-driven hepatocarcinogenesis. Targeting IL-21R signaling represents a potential therapeutic strategy for cancer therapy.
Pathophysiological significance and modulation of the transient receptor potential canonical 3 ion channel
Authors: Vijay K. Boda, Nelufar Yasmen, Jianxiong Jiang, Wei Li
Journal: Medicinal Research Reviews (2024)

Abstract Transient receptor potential canonical 3 (TRPC3) protein belongs to the TRP family of nonselective cation channels. Its activation occurs by signaling through a G protein‐coupled receptor (GPCR) and a phospholipase C‐dependent (PLC) pathway. Perturbations in the expression of TRPC3 are associated with a plethora of pathophysiological conditions responsible for disorders of the cardiovascular, immune, and central nervous systems. The recently solved cryo‐EM structure of TRPC3 provides detailed inputs about the underlying mechanistic aspects of the channel, which in turn enables more efficient ways of designing small‐molecule modulators. Pharmacologically targeting TRPC3 in animal models has demonstrated great efficacy in treating diseases including cancers, neurological disorders, and cardiovascular diseases. Despite extensive scientific evidence supporting some strong correlations between the expression and activity of TRPC3 and various pathophysiological conditions, therapeutic strategies based on its pharmacological modulations have not led to clinical trials. The development of small‐molecule TRPC3 modulators with high safety, sufficient brain penetration, and acceptable drug‐like profiles remains in progress. Determining the pathological mechanisms for TRPC3 involvement in human diseases and understanding the requirements for a drug‐like TRPC3 modulator will be valuable in advancing small‐molecule therapeutics to future clinical trials. In this review, we provide an overview of the origin and activation mechanism of TRPC3 channels, diseases associated with irregularities in their expression, and new development in small‐molecule modulators as potential therapeutic interventions for treating TRPC3 channelopathies.