Pavel Ryzhov, PhD’s Post

[PUBLICATION] The role of Notch signaling in macrophage-driven inflammation in metabolic dysfunction-associated steatotic liver disease (MASLD/MASH) is now clearer! 🔍 In MASLD, liver macrophages—resident Kupffer cells and monocyte-derived macrophages—display diverse inflammatory effects that shape disease severity and progression. 🔍 Using single-cell RNA sequencing (scRNA-seq) and fate mapping, Wei Guo et al. reveal how the Notch-RBPJ signaling pathway regulates the monocyte-to-macrophage transition. 🔍 RBPJ deficiency reduces pro-inflammatory macrophage activity and promotes lipid uptake through elevated CD36 expression in Ly6Clo monocytes, enhancing their protective interactions with endothelial cells. 💡 These findings mark a key step toward understanding macrophage differentiation and offer new therapeutic strategies for MASH treatment. 🤝 This work was made possible through a remarkable collaboration across leading institutions in immunology, oncology and metabolic sciences in Europe and Asia, with contributions from INEM’s Nicolas Venteclef and Camille Blériot. 🔗 For more insights, explore the full study in Immunity: https://lnkd.in/d3JzRk3e Université Paris Cité INSERM Inserm : Paris & Île-de-France CNRS CNRS Délégation Île-de-France Villejuif Gustave Roussy Shanghai Jiao Tong University School of Medicine A*STAR - Agency for Science, Technology and Research University of Surrey Tsinghua University

#Immunotherapy | Targeting of #Tumor-associated #Macrophages: Can we be more clever than #Cancer Cells 🤔 | Time to TAMe #TAMs 👍 | Breaking OPEN ACCESS Review Online Now at Cellular & Molecular #Immunology 👏 | With increasing incidence and geography, cancer is one of the leading causes of death, reduced quality of life and disability worldwide. Principal progress in the development of new anticancer therapies, in improving the efficiency of immunotherapeutic tools, and in the personification of conventional therapies needs to consider cancer-specific and patient-specific programming of innate immunity. Intratumoral TAMs and their precursors, resident macrophages and monocytes, are principal regulators of tumor progression and therapy resistance. This review* summarises the accumulated evidence for the subpopulations of TAMs and their increasing number of biomarkers, indicating their predictive value for the clinical parameters of carcinogenesis and therapy resistance, with a focus on solid cancers of non-infectious etiology. It presents the state-of-the-art knowledge about the tumor-supporting functions of TAMs at all stages of tumor progression and highlight biomarkers, recently identified by single-cell and spatial analytical methods, that discriminate between tumor-promoting and tumor-inhibiting TAMs, where both subtypes express a combination of prototype M1 and M2 genes. The review focuses on novel mechanisms involved in the crosstalk among epigenetic, signaling, transcriptional and metabolic pathways in TAMs. Particular attention has been given to the recently identified link between cancer cell metabolism and the epigenetic programming of TAMs by histone lactylation, which can be responsible for the unlimited protumoral programming of TAMs. Finally, it explains how TAMs interfere with currently used anticancer therapeutics and summarise the most advanced data from clinical trials, which it divides into four categories: inhibition of TAM survival and differentiation, inhibition of monocyte/TAM recruitment into tumors, functional reprogramming of TAMs, and genetic enhancement of macrophages. *https://lnkd.in/en8mCybn Celentyx Ltd #immunooncology www.celentyx.com Professor Nicholas Barnes PhD, FBPhS Omar Qureshi Catherine Brady FIGURE | Functions and mediators of TAMs in tumor progression |

In the pursuit of medical breakthroughs, the latest multiomics analysis has shed new light on Multiple Myeloma (MM), a formidable adversary in the realm of plasma cell malignancies. 🧬 By integrating deep tandem mass tag-based quantitative global (phospho)proteomics, RNA sequencing, and nanopore DNA sequencing, the scientists analyzed 138 primary patient-derived samples. Their findings? A highly deregulated (phospho)proteome in malignant plasma cells, distinct from their healthy counterparts, and influenced by both chromosomal alterations and posttranscriptional regulation. 📊 This comprehensive study has not only identified a prognostic protein signature linked to aggressive MM but also unveiled potential targets for innovative (immuno)therapies. It's a giant leap towards understanding MM's complexity and a beacon of hope for developing new therapeutic strategies 💡p/b Max Delbrück Center, DKFZ German Cancer Research Center, Universitätsklinikum Ulm (University Hospital Ulm), Heidelberg University, Berlin Institute of Health, University Hospital Muenster, Technical University of Munich, Albert-Ludwigs-Universität Freiburg im Breisgau, München Klinik gGmbH, Evelyn Ramberger, Valeria Sapozhnikova, Yuen Lam Dora Ng, Matthias Ziehm, Oliver P., Florian Grünschläger, Dr. Arunima Murgai, Dr. med. Jan Braune, Prof. Dr. med. Cyrus Khandanpour MD, MBA, Christian Straka, Dieter Beule, Hermann Einsele, Lars Bullinger, Stefan Knop, Philipp Mertins, Jan Krönke #MultipleMyeloma #Proteogenomics #Innovation https://lnkd.in/gQcAsmit

#openposition #admin #NIH #USA #research #cancer The Cancer Immunology, Hematology, and Etiology Branch in the Division of Cancer Biology, NCI has an open position for Health Science Administrator to direct a program in the scientific area described below:   Bacterial Carcinogenesis and the Role of the Microbiome Increasing evidence indicates that the human microbiome, particularly bacteria in the gut, plays an important role in the initiation and progression of cancer. Research funded in this area seeks to determine the role and mechanism of bacterial carcinogens in cancer and their interactions with other etiologic agents. Key research areas include: The etiological role that changes in host-microbiome interactions have on tumor epithelial cells and the immune system during carcinogenesis Isolation and characterization of microbial agents that may cause or promote tumorigenesis Identification of carcinogenic molecular interactions between host cells and microbiota Oncogenic host responses to microbial agents and their secreted products  Development of tools and preclinical models to determine molecular mechanisms of microbial carcinogenesis Emerging areas relevant to this research include linking dietary intake to microbiome metabolic output and cancer and targeting these links for clinical translation (e.g., prevention, early detection, therapy), understanding how the microbiome regulates host cell epigenetics during carcinogenesis, using systems biology to understand the role of the microbiome in cancer, and understanding how glycan-mediated interactions between host and microbes influence cancer initiation, progression, and treatment.    Interested candidates can contact or send resumes to:   T. Kevin Howcroft, Ph.D. Branch Chief, CIHEB Division of Cancer Biology

#Cancer | Genetically Engineering #Bcells for #AdoptiveCellTherapy | Single-hit Genome Editing optimised for maturation in B cells redirects their specificity towards #Tumor Antigens | Breaking Study from Michel Cogné & Friends 👏 | T-cell-based adoptive immunotherapy is a new pillar of cancer care. Tumor-redirected B cells could also contribute to therapy if their manipulation to rewire immunoglobulin (Ig) genes is mastered. Here*, Marine Cahen, Natsuko Ueda, et al designed a single-chain Ig-encoding cassette (“scFull-Ig”) that redirects antigen specificity when inserted at a single position of the IgH locus. This design, which places combined IgH and IgL variable genes downstream of a pVH promoter, nevertheless preserves all Ig functional domains and the intrinsic mechanisms that regulate expression from the IgM B cell receptor (BCR) expression to Ig secretion, somatic hypermutation and class switching. This single-locus editing provides an efficient and safe strategy to both disrupt endogenous Ig expression and encode a new Ig paratope. As a proof of concept, the functionality of scFull BCR and/or secreted Ig was validated against two different classical human tumor antigens, HER2 and hCD20. Once validated in cell lines, the strategy was extended to primary B cells, confirming the successful engineering of BCR and Ig expression and the ability of scFull-Ig to undergo further class switching. These results further pave the way for future B cell-based adoptive immunotherapy and strategies to express a therapeutic mAb with a variety of switched H-chains that provide complementary functions. *https://lnkd.in/evJmpW6Z Celentyx Ltd #immunooncology www.celentyx.com Professor Nicholas Barnes PhD, FBPhS Omar Qureshi Catherine Brady

𝐂𝐥𝐞𝐯𝐞𝐫 𝐧𝐞𝐮𝐫𝐨𝐧𝐬 𝐒𝐮𝐛𝐭𝐢𝐭𝐥𝐞: 𝐍𝐞𝐮𝐫𝐨𝐧𝐚𝐥 𝐫𝐞𝐩𝐮𝐫𝐩𝐨𝐬𝐢𝐧𝐠 𝐨𝐟 𝐭𝐡𝐞 𝐓𝐋𝐑𝟗 𝐩𝐚𝐭𝐡𝐰𝐚𝐲 🌍 Those familiar with immunology will surely recognise the TLR (Toll-Like Receptor) and STING (STImulator of INterferon Gene) signalling pathways. Professionals in the field of oncology may be aware of how manipulating these pathways can facilitate the infiltration of immune cells into otherwise immune-deserted tumours (turning cold tumours hot 🔥!), to build an immune response against cancer. 👉 As a genuine (endosomal) DNA sensor, TLR9 detects small fragments of pathogen DNA , specifically unmethylated CpG-containing motifs of bacterial and viral origin, activating immune responses to these pathogens. It is well expressed by dendritic cells, macrophages, NK cells and other antigen presenting cells. 👉 Interestingly, TLR9 is also expressed by neurons. A recent research study published in Nature (Jovasevic V et al., 2024) describes how TLR9 plays a crucial role in the formation and retention of context memories. In certain CA1 hippocampal neurons, a learning stimulus (contextual fear conditioning) causes sustained DNA damage and triggers a DNA repair response in those neurons, which seems required to build stable memory. Pretty interesting. 👉 Now comes the totally unexpected bit. It turns out that TLR9 in those same hipocampal neurons is activated by endogenously generated small non-coding dsDNA fragments (sustained DNA damage, remember?). The results obtained suggest that neurons have repurposed TLR9's original pro-inflammatory role and redirected it to suit their needs. Activated neuronal TLR9 is essential to trigger a DNA repair response around the centrosome and the organisation of individual hippocampal neurons into memory clusters. 👉 Direct consequences of these findings: CNS anti-inflammatory treatment strategies, although beneficial for restricting astrocytic and microglial activation, may prove detrimental for preserving neurocognitive health. I rarely post on topics outside of antibody-based therapies. But this paper struck me so much that I had to share it. Have a nice day of worker! #immunooncology, #inflammation, #memory, #hipocampus, #TLRpathway

🌟 Exciting Breakthrough inGlioblastoma Research!🌟 I'm thrilled to share a groundbreaking study that sheds new light on the complex interactions within the glioblastoma (GBM) microenvironment. Researchers have discovered that tumor cell-derived spermidine (SPD) plays a crucial role in promoting a pro-tumorigenic immune environment by inhibiting CD8+ T cells. This finding is a significant step forward in understanding how GBM tumors evade the immune system. 🔬 Key Highlights: Spermidine's Role: Elevated levels of spermidine in the GBM microenvironment contribute to tumor aggressiveness by reducing the frequency and cytotoxic function of CD8+ T cells. Immune Suppression: The GBM microenvironment is rich in immunosuppressive factors, making it challenging for cytotoxic T lymphocytes to function effectively. Therapeutic Potential: Knocking down ornithine decarboxylase, the enzyme responsible for spermidine synthesis, can reduce tumor aggressiveness, suggesting a potential therapeutic target for GBM treatment. 💡 Why This Matters: This discovery opens new avenues for developing targeted therapies that could improve the prognosis for GBM patients. By focusing on the metabolic pathways that cancer cells exploit, we can design more effective treatments that enhance the immune system's ability to fight cancer. 🔗 Read More: For those interested in the detailed findings, I highly recommend diving into the full study to explore the intricate mechanisms at play. Let's continue to support and celebrate the incredible advancements in cancer research. Together, we can make a difference! #CancerResearch #Glioblastoma #Immunotherapy #MedicalBreakthrough #StemCellTherapy #Oncology #HealthcareInnovation #MedicalLaboratoryTechnology #Microbiology #Phlebotomy #LaboratoryTesting #DiagnosticTesting #HealthcareProfessional #MedicalTesting #ClinicalLaboratory #BiomedicalScience #HealthcareIndustry #MedicalScience #LaboratoryMedicine #ClinicalMicrobiology #InfectionControl #PhlebotomyTechnician #MedicalLabTechnician #MicrobiologyLab #ClinicalLab #HealthcareCareer #MedicalCareer #ScienceCareer #COVID19Testing #Virology #Bacteriology #Parasitology #MolecularDiagnosis #GeneticTesting #Cytology #Histopathology #Immunology #Serology

DOI:https://lnkd.in/gR6bSHmT Last September, at the Immunology Conference in Songdo, there was an impressive talk on mechanism of LAG3 by Dario Vignali. Last week, his group published an intriguing paper, which also includes John Wherry who gave an outstanding plenary lecture on the final Saturday in Songdo. This study investigates the synergistic effects of dual inhibition of LAG3 and PD-1 in tumor therapy, using a mouse model to explore the underlying mechanisms. While the model employed is somewhat artificial due to experimental constraints, the study presents an interesting finding: the enhanced T cell activity observed with concurrent inhibition of LAG3 and PD-1 is not primarily due to IFN-γ expression itself, but rather to the expression of an IFN-γ-stimulated gene set(Indeed, the role of IFN-γ within the tumor microenvironment has been reported to be dual-faceted). The key point of the study is that transcriptional changes induced by the simultaneous blockade of LAG3 and PD-1 are crucial. Given recent challenges in the field, such as the suspension of clinical trials related to TIGIT, studies on ICIs beyond PD-1 have not been straightforward. The approach of merely inhibiting immune checkpoints to enhance T cell activity involves many uncertainties. Recent studies have increasingly focused on the gene signature changes induced by immune checkpoint inhibition. One implication of these focuses is that there exist environmental differences in the signals that can boost or induce transcriptional changes between responders and non-responders. If research continues to concentrate on identifying these 'signals' that can transform the immune environment of non-responders to 'responder-like', it could significantly enhance the efficacy of existing ICIs, generating substantial synergy.

🚀 Revolutionizing Glioblastoma Treatment: Insights from HSV-G47Δ Oncolytic Virus Research 🚀 Volume 24, Issue 12, 2024 Published: 13 February 2024 Our latest research article explores the groundbreaking effects of the HSV-G47Δ oncolytic virus on glioblastoma multiforme (GBM) cancer stem cells, specifically focusing on telomerase activity and telomere length under varying oxygen conditions. 🔬 Key Findings: •Impact on Telomeres: HSV-G47Δ induced significant changes in telomere length, showing longer telomeres in normoxic and shorter telomeres in hypoxic conditions. •Gene Regulation: The virus influenced crucial telomerase subunits and genes like hTERC, DKC1, and TEP1, with notable changes in RAD50 and TERF2 across different oxygen environments. •Targeted Therapy Potential: The research suggests that HSV-G47Δ could effectively target the telomeric repair complex in GBM stem cells, offering new avenues for treatment strategies. 🔍 Dive Deeper: Explore how these findings could pave the way for novel therapeutic approaches in glioblastoma treatment. 🔗 Read the Full Study: https://bit.ly/3MvYl2S 📢 Join the Discussion: How do you think HSV-G47Δ could impact future glioblastoma therapies? Share your insights and connect with peers in the field! #Glioblastoma #OncolyticVirus #HSV-G47Δ #CancerResearch #Telomerase #TelomereLength #CancerStemCells #PrecisionMedicine

In collaboration with researchers at the Fred Hutchinson Cancer Center, we developed a 50-color #spectral flow cytometry panel on the BD FACSDiscover™ S8 Cell Sorter for the in-depth analysis of the immune compartment in human blood and tissues. The panel evaluates all the major immune cell subsets with a specific emphasis on phenotyping markers focused on the activation and differentiation status of the T cell and dendritic cell (DC) compartment.   This is one of the first flow cytometry panels reported that describes the parallel use of 50 different fluorochromes in a single experiment. To accomplish this, we utilized existing panel design guidelines, and we also developed new metrics to systematically identify the optimal combination of 50 fluorochromes. Learn more https://lnkd.in/gJ85FJnr   Authors. Andrew Konecny,1 Peter Mage,2 Aaron J. Tyznik, Ph.D.,3 Martin Prlic1,4 and Florian Mair1,5   Affiliations.   1Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle WA, 98107, USA  2Advanced Technology Group, BD Biosciences, San Jose, CA 93105, USA   3Applied Research & Technology, Medical and Scientific Affair, BD Biosciences, San Diego, CA 92037, USA  4Department of Global Health and Department of Immunology, University of Washington, Seattle, WA 98195, USA  5Flow Cytometry Core Facility, Institute of Molecular Health Sciences, ETH Zurich, 8093 Zurich, Switzerland   BD flow cytometers are Class 1 Laser Products. For Research Use Only. Not for use in diagnostic or therapeutic procedures.   #BDBiosciences #flowcytometry #Cellsorting #FACSDiscoverS8 #CellView #Spectralfx #RTISFC #RealBlue #BDHorizon