tbuckley/cabot-search huggingface dataset:
RICTOR/mTORC2 downregulation in BRAFV600E melanoma cells promotes resistance to BRAF/MEK inhibition
Authors: Luca Ponzone, Valentina Audrito, Claudia Landi, Enrico Moiso, Chiara Levra Levron, Sara Ferrua, Aurora Savino, Nicoletta Vitale, Massimiliano Gasparrini, Lidia Avalle, Lorenza Vantaggiato, Enxhi Shaba, Beatrice Tassone, Stefania Saoncella, Francesca Orso, Daniele Viavattene, Eleonora Marina, Irene Fiorilla, Giulia Burrone, Youssef Abili, Fiorella Altruda, Luca Bini, Silvia Deaglio, Paola Defilippi, Alessio Menga, Valeria Poli, Paolo Ettore Porporato, Paolo Provero, Nadia Raffaelli, Chiara Riganti, Daniela Taverna, Federica Cavallo, Enzo Calautti
Journal: Molecular Cancer (2024)

The main drawback of BRAF/MEK inhibitors (BRAF/MEKi)-based targeted therapy in the management of BRAF-mutated cutaneous metastatic melanoma (MM) is the development of therapeutic resistance. We aimed to assess in this context the role of mTORC2, a signaling complex defined by the presence of the essential RICTOR subunit, regarded as an oncogenic driver in several tumor types, including MM.
DNMT1-targeting remodeling global DNA hypomethylation for enhanced tumor suppression and circumvented toxicity in oral squamous cell carcinoma
Authors: Yangfan Liu, Yu Sun, Jin Yang, Deyang Wu, Shuang Yu, Junjiang Liu, Tao Hu, Jingjing Luo, Hongmei Zhou
Journal: Molecular Cancer (2024)

Abstract Background The faithful maintenance of DNA methylation homeostasis indispensably requires DNA methyltransferase 1 (DNMT1) in cancer progression. We previously identified DNMT1 as a potential candidate target for oral squamous cell carcinoma (OSCC). However, how the DNMT1- associated global DNA methylation is exploited to regulate OSCC remains unclear. Methods The shRNA-specific DNMT1 knockdown was employed to target DNMT1 on oral cancer cells in vitro, as was the use of DNMT1 inhibitors. A xenografted OSCC mouse model was established to determine the effect on tumor suppression. High-throughput microarrays of DNA methylation, bulk and single-cell RNA sequencing analysis, multiplex immunohistochemistry, functional sphere formation and protein immunoblotting were utilized to explore the molecular mechanism involved. Analysis of human samples revealed associations between DNMT1 expression, global DNA methylation and collaborative molecular signaling with oral malignant transformation. Results We investigated DNMT1 expression boosted steadily during oral malignant transformation in human samples, and its inhibition considerably minimized the tumorigenicity in vitro and in a xenografted OSCC model. DNMT1 overexpression was accompanied by the accumulation of cancer-specific DNA hypomethylation during oral carcinogenesis; conversely, DNMT1 knockdown caused atypically extensive genome-wide DNA hypomethylation in cancer cells and xenografted tumors. This novel DNMT1-remodeled DNA hypomethylation pattern hampered the dual activation of PI3K-AKT and CDK2-Rb and inactivated GSK3β collaboratively. When treating OSCC mice, targeting DNMT1 achieved greater anticancer efficacy than the PI3K inhibitor, and reduced the toxicity of blood glucose changes caused by the PI3K inhibitor or combination of PI3K and CDK inhibitors as well as adverse insulin feedback. Conclusions Targeting DNMT1 remodels a novel global DNA hypomethylation pattern to facilitate anticancer efficacy and minimize potential toxic effects via balanced signaling synergia. Our study suggests DNMT1 is a crucial gatekeeper regarding OSCC destiny and treatment outcome.
Allele-Specific Suppression of Variant MHC With High-Precision RNA Nuclease CRISPR-Cas13d Prevents Hypertrophic Cardiomyopathy
Authors: Ping Yang, Yingmei Lou, Zilong Geng, Zhizhao Guo, Shuo Wu, Yige Li, Kaiyuan Song, Ting Shi, Shasha Zhang, Junhao Xiong, Alex F. Chen, Dali Li, William T. Pu, Lintai Da, Yan Zhang, Kun Sun, Bing Zhang
Journal: Circulation (2024)

BACKGROUND: Familial hypertrophic cardiomyopathy has severe clinical complications of heart failure, arrhythmia, and sudden cardiac death. Heterozygous single nucleotide variants (SNVs) of sarcomere genes such as MYH7 are the leading cause of this type of disease. CRISPR-Cas13 (clustered regularly interspaced short palindromic repeats and their associated protein 13) is an emerging gene therapy approach for treating genetic disorders, but its therapeutic potential in genetic cardiomyopathy remains unexplored. METHODS: We developed a sensitive allelic point mutation reporter system to screen the mutagenic variants of Cas13d. On the basis of Cas13d homology structure, we rationally designed a series of Cas13d variants and obtained a high-precision Cas13d variant (hpCas13d) that specifically cleaves the MYH7 variant RNAs containing 1 allelic SNV. We validated the high precision and low collateral cleavage activity of hpCas13d through various in vitro assays. We generated 2 HCM mouse models bearing distinct MYH7 SNVs and used adenovirus-associated virus serotype 9 to deliver hpCas13d specifically to the cardiomyocytes. We performed a large-scale library screening to assess the potency of hpCas13d in resolving 45 human MYH7 allelic pathogenic SNVs. RESULTS: Wild-type Cas13d cannot distinguish and specifically cleave the heterozygous MYH7 allele with SNV. hpCas13d, with 3 amino acid substitutions, had minimized collateral RNase activity and was able to resolve various human MYH7 pathological sequence variations that cause hypertrophic cardiomyopathy. In vivo application of hpCas13d to 2 hypertrophic cardiomyopathy models caused by distinct human MYH7 analogous sequence variations specifically suppressed the altered allele and prevented cardiac hypertrophy. CONCLUSIONS: Our study unveils the great potential of CRISPR-Cas nucleases with high precision in treating inheritable cardiomyopathy and opens a new avenue for therapeutic management of inherited cardiac diseases.
Genome-Wide CRISPR Screen Identifies an NF2-Adherens Junction Mechanistic Dependency for Cardiac Lineage
Authors: Chang Jie Mick Lee, Matias I. Autio, Wenhao Zheng, Yoohyun Song, Shyi Chyi Wang, Darren Chen Pei Wong, Jingwei Xiao, Yike Zhu, Permeen Yusoff, Xi Yei, Wan Kee Chock, Boon Chuan Low, Marius Sudol, Roger S.-Y. Foo
Journal: Circulation (2024)

Cardiomyocyte differentiation involves a stepwise clearance of repressors and fate-restricting regulators through the modulation of BMP (bone morphogenic protein)/Wnt-signaling pathways. However, the mechanisms and how regulatory roadblocks are removed with specific developmental signaling pathways remain unclear.
Aspirin use in essential thrombocythemia: Once‐daily or twice‐daily or not at all?
Authors: Ayalew Tefferi, Tiziano Barbui
Journal: American Journal of Hematology (2024)

Asprin dosing strategy in low risk (young and JAK2 mutated without history of thrombosis) or very low risk (young JAK2 wild-type without history of thrombosis) essential thrombocythemia.
Reply to: The puzzles surrounding the impact of face masks on 6-minute walking distance in pulmonary hypertension
Authors: Max Wissmüller, Veit Wartner, Christopher Hohmann, Joana Adler, Tilmann Kramer, Martin Hellmich, Felix Gerhardt, Stephan Baldus, Stephan Rosenkranz
Journal: European Respiratory Journal (2024)

<h3>Shareable abstract</h3> <b>This study shows that wearing a face mask during the COVID-19 pandemic had significant impact on the 6-min walking distance in patients with pulmonary hypertension (PH), irrespective of the underlying cause of PH</b>https://bit.ly/3JgB0Rn
Repositioning compounds for idiopathic pulmonary fibrosis treatment: seeking the future in the past
Authors: Bruno Crestani
Journal: European Respiratory Journal (2024)

Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease with only two approved treatments, pirfenidone and nintedanib, which have been shown to slow lung function decline and may improve survival by 2 years [1, 2]. Repositioning drugs provides exciting opportunities for rare diseases, including fibrotic interstitial lung diseases <https://bit.ly/44ciXFv>
Prevention of dementia using mobile phone applications (PRODEMOS): a multinational, randomised, controlled effectiveness–implementation trial
Authors: Eric P Moll van Charante, Marieke P Hoevenaar-Blom, Manshu Song, Sandrine Andrieu, Linda Barnes, Cindy Birck, Rachael Brooks, Nicola Coley, Esmé Eggink, Jean Georges, Melanie Hafdi, Willem A van Gool, Ron Handels, Haifeng Hou, Jihui Lyu, Yixuan Niu, Libin Song, Wenzhi Wang, Youxin Wang, Anders Wimo, Yueyi Yu, Jinxia Zhang, Wei Zhang, Carol Brayne, Wei Wang, Edo Richard
Journal: The Lancet Healthy Longevity (2024)
NEMO/NF-κB signaling functions as a double-edged sword in PanIN formation versus progression to pancreatic cancer
Authors: Miltiadis Tsesmelis, Ulrike F G Büttner, Melanie Gerstenlauer, Uta Manfras, Konstantinos Tsesmelis, Ziwei Du, Nadine Sperb, Stephanie Ellen Weissinger, Peter Möller, Thomas F E Barth, Harald J Maier, Lap Kwan Chan, Thomas Wirth
Journal: Molecular Cancer (2024)

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is marked by a dismal survival rate, lacking effective therapeutics due to its aggressive growth, late-stage diagnosis, and chemotherapy resistance. Despite debates on NF-κB targeting for PDAC treatment, no successful approach has emerged. Methods To elucidate the role of NF-κB, we ablated NF-κB essential modulator (NEMO), critical for conventional NF-κB signaling, in the pancreata of mice that develop precancerous lesions (KC mouse model). Secretagogue-induced pancreatitis by cerulein injections was utilized to promote inflammation and accelerate PDAC development. Results NEMO deletion reduced fibrosis and inflammation in young KC mice, resulting in fewer pancreatic intraepithelial neoplasias (PanINs) at later stages. Paradoxically, however, NEMO deletion accelerated the progression of these fewer PanINs to PDAC and reduced median lifespan. Further, analysis of tissue microarrays from human PDAC sections highlighted the correlation between reduced NEMO expression in neoplastic cells and poorer prognosis, supporting our observation in mice. Mechanistically, NEMO deletion impeded oncogene-induced senescence (OIS), which is normally active in low-grade PanINs. This blockage resulted in fewer senescence-associated secretory phenotype (SASP) factors, reducing inflammation. However, blocked OIS fostered replication stress and DNA damage accumulation which accelerated PanIN progression to PDAC. Finally, treatment with the DNA damage-inducing reagent etoposide resulted in elevated cell death in NEMO-ablated PDAC cells compared to their NEMO-competent counterparts, indicative of a synthetic lethality paradigm. Conclusions NEMO exhibited both oncogenic and tumor-suppressive properties during PDAC development. Caution is suggested in therapeutic interventions targeting NF-κB, which may be detrimental during PanIN progression but beneficial post-PDAC development. Graphical Abstract
The puzzles surrounding the impact of face masks on 6-minute walking distance in pulmonary hypertension
Authors: Jie-Ling Ma, An-Yi Wang, Dan Lu, Chun-Yan Cheng, Zhi-Cheng Jing
Journal: European Respiratory Journal (2024)

<h3>Shareable abstract</h3> <b>For the impact of face masks on 6-min walk distance in pulmonary hypertension, pathophysiological heterogeneity in different types of PH and subjective confounding factors when wearing a mask with higher Borg dyspnoea score cannot be ignored</b>https://bit.ly/40v5V3W
T-cells and precision medicine for allergic bronchopulmonary aspergillosis
Authors: Richard B. Moss
Journal: European Respiratory Journal (2024)

The pathogenesis of allergic bronchopulmonary aspergillosis (ABPA) remains poorly understood, despite its widely accepted recognition as a distinct endotype of severe asthmatic disease [1]. Unravelling the central role of T-cell subpopulations in ABPA can lead to personalised targeting of pathogenetic pathways <https://bit.ly/3VQpCmp>
Environmental Factors Associated with Risk of Crohn’s Disease Development in the Crohn’s and Colitis Canada - Genetic, Environmental, Microbial Project
Authors: Mingyue Xue, Haim Leibovitzh, Shao Jingcheng, Anna Neustaeter, Mei Dong, Wei Xu, Osvaldo Espin-Garcia, Anne M. Griffiths, A. Hillary Steinhart, Dan Turner, Hien Q. Huynh, Levinus A. Dieleman, Remo Panaccione, Guy Aumais, Brian Bressler, Alain Bitton, Sanjay Murthy, John K. Marshall, Jeffrey S. Hyams, Anthony Otley, Charles N. Bernstein, Paul Moayyedi, Wael El-Matary, Alexander Fich, Lee A. Denson, Mark J. Ropeleski, Maria T. Abreu, Colette Deslandres, Maria Cino, Irit Avni-Biron, Sun-Ho Lee, Williams Turpin, Maria Abreu, Paul Beck, Charles Bernstein, Kenneth Croitoru, Levinus A. Dieleman, Brian Feagan, Anne Griffiths, David Guttman, Kevan Jacobson, Gilaad Kaplan, Denis O. Krause, Karen Madsen, John Marshall, Paul Moayyedi, Mark Ropeleski, Ernest Seidman, Mark Silverberg, Scott Snapper, Andy Stadnyk, Hillary Steinhart, Michael Surette, Dan Turner, Thomas Walters, Bruce Vallance, Guy Aumais, Alain Bitton, Maria Cino, Jeff Critch, Lee Denson, Colette Deslandres, Wael El-Matary, Hans Herfarth, Peter Higgins, Hien Huynh, Jeffrey S. Hyams, David Mack, Jerry McGrath, Anthony Otley, Remo Panancionne, Kenneth Croitoru
Journal: Clinical Gastroenterology and Hepatology (2024)
CircTRIM1 encodes TRIM1-269aa to promote chemoresistance and metastasis of TNBC via enhancing CaM-dependent MARCKS translocation and PI3K/AKT/mTOR activation
Authors: Yaming Li, Zekun Wang, Jingwen Yang, Yuhan Sun, Yinqiao He, Yuping Wang, Xi Chen, Yiran Liang, Ning Zhang, Xiaolong Wang, Wenjing Zhao, Guohong Hu, Qifeng Yang
Journal: Molecular Cancer (2024)

Peptides and proteins encoded by noncanonical open reading frames (ORFs) of circRNAs have recently been recognized to play important roles in disease progression, but the biological functions and mechanisms of these peptides and proteins are largely unknown. Here, we identified a potential coding circular RNA, circTRIM1, that was upregulated in doxorubicin-resistant TNBC cells by intersecting transcriptome and translatome RNA-seq data, and its expression was correlated with clinicopathological characteristics and poor prognosis in patients with TNBC. CircTRIM1 possesses a functional IRES element along with an 810 nt ORF that can be translated into a novel endogenously expressed protein termed TRIM1-269aa. Functionally, we demonstrated that TRIM1-269aa, which is involved in the biological functions of circTRIM1, promoted chemoresistance and metastasis in TNBC cells both in vitro and in vivo. In addition, we found that TRIM1-269aa can be packaged into exosomes and transmitted between TNBC cells. Mechanistically, TRIM1-269aa enhanced the interaction between MARCKS and calmodulin, thus promoting the calmodulin-dependent translocation of MARCKS, which further initiated the activation of the PI3K/AKT/mTOR pathway. Overall, circTRIM1, which encodes TRIM1-269aa, promoted TNBC chemoresistance and metastasis by enhancing MARCKS translocation and PI3K/AKT/mTOR activation. Our investigation has yielded novel insights into the roles of protein-coding circRNAs and supported circTRIM1/TRIM1-269aa as a novel promising prognostic and therapeutic target for patients with TNBC.
Comprehensive profiling of cancer neoantigens from aberrant RNA splicing
Authors: Daniel P Wickland, Colton McNinch, Erik Jessen, Brian Necela, Barath Shreeder, Yi Lin, Keith L Knutson, Yan W Asmann
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Cancer neoantigens arise from protein-altering somatic mutations in tumor and rank among the most promising next-generation immuno-oncology agents when used in combination with immune checkpoint inhibitors. We previously developed a computational framework, REAL-neo, for identification, quality control, and prioritization of both class-I and class-II human leucocyte antigen (HLA)-presented neoantigens resulting from somatic single-nucleotide mutations, small insertions and deletions, and gene fusions. In this study, we developed a new module, SPLICE-neo, to identify neoantigens from aberrant RNA transcripts from two distinct sources: (1) DNA mutations within splice sites and (2) de novo RNA aberrant splicings. Methods First, SPLICE-neo was used to profile all DNA splice-site mutations in 11,892 tumors from The Cancer Genome Atlas (TCGA) and identified 11 profiles of splicing donor or acceptor site gains or losses. Transcript isoforms resulting from the top seven most frequent profiles were computed using novel logic models. Second, SPLICE-neo identified de novo RNA splicing events using RNA sequencing reads mapped to novel exon junctions from either single, double, or multiple exon-skipping events. The aberrant transcripts from both sources were then ranked based on isoform expression levels and z-scores assuming that individual aberrant splicing events are rare. Finally, top-ranked novel isoforms were translated into protein, and the resulting neoepitopes were evaluated for neoantigen potential using REAL-neo. The top splicing neoantigen candidates binding to HLA-A*02:01 were validated using in vitro T2 binding assays. Results We identified abundant splicing neoantigens in four representative TCGA cancers: BRCA, LUAD, LUSC, and LIHC. In addition to their substantial contribution to neoantigen load, several splicing neoantigens were potent tumor antigens with stronger bindings to HLA compared with the positive control of antigens from influenza virus. Conclusions SPLICE-neo is the first tool to comprehensively identify and prioritize splicing neoantigens from both DNA splice-site mutations and de novo RNA aberrant splicings. There are two major advances of SPLICE-neo. First, we developed novel logic models that assemble and prioritize full-length aberrant transcripts from DNA splice-site mutations. Second, SPLICE-neo can identify exon-skipping events involving more than two exons, which account for a quarter to one-third of all skipping events.
Bivalent and bitopic ligands of the opioid receptors: The prospects of a dual approach
Authors: Marie Emilie Hovah, Ulrike Holzgrabe
Journal: Medicinal Research Reviews (2024)

Abstract Opioid receptors belonging to the class A G‐protein coupled receptors (GPCRs) are the targets of choice in the treatment of acute and chronic pain. However, their on‐target side effects such as respiratory depression, tolerance and addiction have led to the advent of the ‘opioid crisis’. In the search for safer analgesics, bivalent and more recently, bitopic ligands have emerged as valuable tool compounds to probe these receptors. The activity of bivalent and bitopic ligands rely greatly on the allosteric nature of the GPCRs. Bivalent ligands consist of two pharmacophores, each binding to the individual orthosteric binding site (OBS) of the monomers within a dimer. Bitopic or dualsteric ligands bridge the gap between the OBS and the spatially distinct, less conserved allosteric binding site (ABS) through the simultaneous occupation of these two sites. Bivalent and bitopic ligands stabilize distinct conformations of the receptors which ultimately translates into unique signalling and pharmacological profiles. Some of the interesting properties shown by these ligands include improved affinity and/or efficacy, subtype and/or functional selectivity and reduced side effects. This review aims at providing an overview of some of the bivalent and bitopic ligands of the opioid receptors and, their pharmacology in the hope of inspiring the design and discovery of the next generation of opioid analgesics.
Therapeutic Inducers of Natural Killer cell Killing (ThINKK): preclinical assessment of safety and efficacy in allogeneic hematopoietic stem cell transplant settings
Authors: Nicolas Poirier, Valérie Paquin, Séverine Leclerc, Véronique Lisi, Carolina Marmolejo, Hicham Affia, Paulo Cordeiro, Yves Théorêt, Elie Haddad, Gregor Andelfinger, Vincent Philippe Lavallée, Michel Duval, Sabine Herblot
Journal: Journal for ImmunoTherapy of Cancer (2024)

Allogeneic hematopoietic stem cell transplantation (HSCT) remains the standard of care for chemotherapy-refractory leukemia patients, but cure rates are still dismal. To prevent leukemia relapse following HSCT, we aim to improve the early graft-versus-leukemia effect mediated by natural killer (NK) cells. Our approach is based on the adoptive transfer of Therapeutic Inducers of Natural Killer cell Killing (ThINKK). ThINKK are expanded and differentiated from HSC, and exhibit blood plasmacytoid dendritic cell (pDC) features. We previously demonstrated that ThINKK stimulate NK cells and control acute lymphoblastic leukemia (ALL) development in a preclinical mouse model of HSCT for ALL. Here, we assessed the cellular identity of ThINKK and investigated their potential to activate allogeneic T cells. We finally evaluated the effect of immunosuppressive drugs on ThINKK-NK cell interaction. ThINKK cellular identity was explored using single-cell RNA sequencing and flow cytometry. Their T-cell activating potential was investigated by coculture of allogeneic T cells and antigen-presenting cells in the presence or the absence of ThINKK. A preclinical human-to-mouse xenograft model was used to evaluate the impact of ThINKK injections on graft-versus-host disease (GvHD). Finally, the effect of immunosuppressive drugs on ThINKK-induced NK cell cytotoxicity against ALL cells was tested. The large majority of ThINKK shared the key characteristics of canonical blood pDC, including potent type-I interferon (IFN) production following Toll-like receptor stimulation. A minor subset expressed some, although not all, markers of other dendritic cell populations. Importantly, while ThINKK were not killed by allogeneic T or NK cells, they did not increase T cell proliferation induced by antigen-presenting cells nor worsened GvHD in vivo. Finally, tacrolimus, sirolimus or mycophenolate did not decrease ThINKK-induced NK cell activation and cytotoxicity. Our results indicate that ThINKK are type I IFN producing cells with low T cell activation capacity. Therefore, ThINKK adoptive immunotherapy is not expected to increase the risk of GvHD after allogeneic HSCT. Furthermore, our data predict that the use of tacrolimus, sirolimus or mycophenolate as anti-GvHD prophylaxis regimen will not decrease ThINKK therapeutic efficacy. Collectively, these preclinical data support the testing of ThINKK immunotherapy in a phase I clinical trial.