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This is a book about the research process that led scientists to the discovery of a group of molecules that act as carriers of information among the cells of our body, which the book refers to collectively as \"body messages.\" Among the thousands of body messages, the author selected those that are part of her own research, the cytokines, adipokines, and other proteins that regulate inflammation and metabolism. She also interviewed twenty researchers who contributed significantly to the field, asking details about their discoveries while also inquiring about their life and education. Along with scientists' personal recollections, the book reconstructs the discovery process based on published reports of the original experimental findings. Though the book's main theme is the process of discovery, it devotes considerable space to the biology of body messages and the consequence of their identification for medical practice.-- Provided by publisher

Geobarrettin D (1), a new bromoindole alkaloid, was isolated from the marine sponge Geodia barretti collected from Icelandic waters. Its structure was elucidated by 1D, and 2D NMR (including [sup.1]H-[sup.15]N HSQC, [sup.1]H-[sup.15]N HMBC spectra), as well as HRESIMS data. Geobarrettin D (1) is a new 6-bromoindole featuring an unusual purinium herbipoline moiety. Geobarrettin D (1) decreased secretion of the pro-inflammatory cytokine IL-12p40 by human monocyte derived dendritic cells, without affecting secretion of the anti-inflammatory cytokine IL-10. Thus, compound 1 shows anti-inflammatory activity.

BackgroundCD19-targeted chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). Despite these advances, up to 60% of patients fail to achieve a complete response. To investigate factors underlying therapeutic response, we conducted single-cell transcriptomic profiling of infusion products from r/r DLBCL patients treated with axicabtagene ciloleucel.MethodsInfusion products from eight r/r DLBCL patients with varying clinical outcomes were analyzed using single-cell RNA sequencing. Differential transcriptional signatures between complete responders and patients with progressive disease were examined. Insights from these analyses informed the development of an ex vivo CAR T-cell manufacturing strategy involving type I interferon (IFN-I) stimulation. To prevent potential in vivo adverse effects, IFN-I was withdrawn prior to infusion. Both CD28- and 4-1BB-based CAR constructs were incorporated in the study. Functional performance of CAR T cells was assessed through in vitro assays and in vivo xenograft tumor models.ResultsComplete responders exhibited elevated IFN-I-associated transcriptional signatures compared to patients with progressive disease. The impact of IFN-I priming on CAR T-cell function was dose-dependent. Low-dose IFN-I enhanced cytotoxic activity in vitro without affecting transduction efficiency. In contrast, high-dose IFN-I triggered apoptosis and reduced cell viability. Low-strength IFN-I did not impair cell expansion and maintained viability. Additionally, CAR T cells primed with low-dose IFN-I demonstrated superior antitumor activity in vivo across both CD28- and 4-1BB-costimulated constructs. These enhancements were consistent across multiple donors.ConclusionsLow-dose IFN-I priming represents a costimulation-independent strategy to augment CAR T-cell function. This approach leverages an FDA-approved cytokine, avoids in vivo toxicity through cytokine removal prior to infusion, and integrates seamlessly with existing CAR platforms. The results support the clinical potential of IFN-I-enhanced CAR T-cell therapies for patients with r/r DLBCL.Ethics ApprovalDeidentified patient biospecimens were collected under Institutional Review Board (IRB)-approved protocols at the University of Chicago Medicine (IRB #18-0025), with informed consent obtained from all patients or their legal guardians in accordance with institutional and federal guidelines. PBMCs from healthy donors were collected under IRB #15-0102 with informed consent. All animal experiments were approved by the Institutional Animal Care and Use Committee (IACUC) at the University of Chicago (ACUP #72707) and conducted in compliance with institutional guidelines.

BackgroundT-cell engager (TCE) is a potent antibody-based molecule that induced T cell-mediated killing by bridging CD3 and tumor-associated antigen(TAA). However, therapeutic potential has been significantly limited due to its poor pharmacokinetic, cytokine release syndrome (CRS), and immune effector cell-associated neurotoxicity syndrome (ICANS).MethodsTo improve the developability of TCEs, a proprietary TCE prodrug platform was established to achieve its overarching objective of modulating immune reactions at a disease site in a selective and controlled manner. Several prodrug-TCE molecules were designed and tested, including binding, cytotoxicity, and cytokine release assays in vitro, as well as safety and efficacy studies in vivo.ResultsHere, we reported ASKG193, a next generation CD19-CD3 TCE, with a masking strategy to attenuate off-target toxicity, extend half-life and improve systemic exposure. The non-activated ASKG193 showed no activity, while the activated form demonstrated >100 folds attenuation in vitro compared to a CD19 Bi-specific T-cell engager (BiTE). In ex vivo B-cell depletion assay, ASKG193 retained potent cytolytic activity comparable to the CD19 BiTE molecule. In addition, ASKG193 was well tolerated in vivo.ConclusionsIn summary, the masked CD19 TCE, ASKG193, exhibited superior anti-tumor efficacy, prolonged half-life, and a significantly improved safety profile. Our data demonstrated that the ASKG193 has the potential to substantially broaden the therapeutic window for CD19-targeted immunotherapies.

BackgroundMacrophages modulate immune activity through cytokine and chemokine release in response to stimuli. These cytokines signal tissue and immune cells to elicit a pro- or anti-inflammatory response. iCell® Macrophages 2.0, which are derived from human induced pluripotent stem cells (iPSC), are functionally naïve and offer an effective, dynamic response to stimulation for a biologically relevant model of human macrophage function.MethodsiCell Macrophages 2.0 can be used directly out of thaw or plated and maintained for up to 14 days in culture. To measure cytokine release, cells were plated and stimulated with pro-inflammatory (LPS, IFNγ) or anti-inflammatory (IL-4, IL-13) stimuli across multiple doses and at different timepoints. Supernatants were collected and cytokines quantified by different immunoassay technologies, including Luminex, ELISA, Lumit, or HTRF. For phagocytosis, iCell Macrophages 2.0 were plated for 3 days, then incubated with pHrodo-labeled bioparticles and monitored for uptake. Antibody-dependent cellular phagocytosis (ADCP) assays were run with stimulated macrophages to measure the potency of Rituximab for CD20+ Raji target cells. iCell Macrophages 2.0 were cultured with isogenic iCell Hepatocytes 2.0, iCell Sensory Neurons, or iCell Cardiomyocytes2 to evaluate the functional effects of macrophage stimulation on complex culture systems.ResultsiCell Macrophages 2.0 express macrophage surface markers such as CD68, CD11c, and CD11b. These full function macrophages can be polarized toward a pro- or anti-inflammatory state, with cytokine release comparable to human primary macrophages for IL-6, TNFα, IL-10, and CCL18. This response can be measured within hours in both mRNA and secreted protein and can be detected at stimulant concentrations below 100pg/ml. Phagocytosis is readily measurable in both short- and long-term culture. iCell Macrophages 2.0 have a functional ADCP response to antibody-labeled target cells with a larger dynamic range than primary monocyte-derived macrophages. Proinflammatory iCell Macrophages 2.0 are able to sensitize hepatocytes to immune-mediated hepatotoxic compounds, while sensory neurons and cardiomyocytes have altered functional outputs to polarized macrophages.ConclusionsHuman iPSC-derived macrophages provide a constant, reproducible source of biologically relevant material. iCell Macrophages 2.0 are in a naïve functional state, able to respond to pro- or anti-inflammatory stimuli. Functionally, cytokine release and phagocytosis assays can be performed anytime from thaw up to 14 days in culture with consistent, reliable lot-to-lot performance. These cells are compatible with complex culture conditions across numerous tissue types. The functional profile of iCell Macrophages 2.0 demonstrates their suitability as a continuing source of human macrophages.

Cytokine storm, a life-threatening disorder involving cytokine elevations and immune-cell hyperactivation, has various causes and is characterized by constitutional symptoms, systemic inflammation, and multiorgan dysfunction. Selective interventions can ameliorate the illness.

The scientific community faces an unexpected and urgent challenge related to the SARS-CoV-2 pandemic and is investigating the role of receptors involved in entry of this virus into cells as well as pathomechanisms leading to a cytokine “storm,” which in many cases ends in severe acute respiratory syndrome, fulminant myocarditis and kidney injury. An important question is if it may also damage hematopoietic stem progenitor cells?