tbuckley/cabot-search huggingface dataset:
GrB-Fc-KS49, an anti-EMP2 granzyme B fusion protein therapeutic alters immune cell infiltration and suppresses breast cancer growth
Authors: Khalid A Mohamedali, Brian Aguirre, Cheng-Hsiang Lu, Anubhav Chandla, Nidhi Kejriwal, Lucia Liu, Ann M Chan, Lawrence H Cheung, SuYin Kok, Sergio Duarte, Ana Alvarez de Cienfuegos, David Casero, Michael G Rosenblum, Madhuri Wadehra
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Granzyme B (GrB) is a key effector molecule, delivered by cytotoxic T lymphocytes and natural killer cells during immune surveillance to induce cell death. Fusion proteins and immunoconjugates represent an innovative therapeutic approach to specifically deliver a deadly payload to target cells. Epithelial membrane protein-2 (EMP2) is highly expressed in invasive breast cancer (BC), including triple-negative BC (TNBC), and represents an attractive therapeutic target. Methods We designed a novel fusion protein (GrB-Fc-KS49) composed of an active GrB fused to an anti-EMP2 single-chain antibody tethered through the immunoglobulin G heavy chain (Fc) domain. We assessed the construct’s GrB enzymatic activity, anti-EMP2 binding affinity, and cytotoxicity against a panel of BC cells. The construct’s pharmacokinetics (PK), toxicity profile, and in vivo efficacy were also evaluated. Results GrB-Fc-KS49 exhibited comparable GrB enzymatic activity to commercial GrB, as well as high affinity to an EMP2 peptide, with the dissociation constant in the picomolar range. The fusion protein rapidly internalized into EMP2+cancer cells and showed in vitro cytotoxicity to cell lines expressing surface EMP2, with half-maximal cytotoxicity (IC 50 ) values below 100 nM for most positive lines. Ex vivo stability at 37°C indicated a half-life exceeding 96 hours while in vivo PK indicated a biexponential plasma clearance, with a moderate initial clearance (t 1/2 α=18.4 hours) and a much slower terminal clearance rate (t 1/2 β=73.1 hours). No toxicity was measured in a Chem16 panel between the control and the GrB-Fc-KS49. In vivo, the GrB-Fc-KS49 showed efficacy against a TNBC syngeneic (4T1/ FLuc ) mouse model, reducing tumor volume and cell proliferation and increasing cell death compared with controls. Treatment using an EMT6 mouse model confirmed these results. In addition to a significant impact on cell proliferation, GrB-Fc-KS49 treatment also resulted in a dramatic increase of tumor-infiltrating CD45+ cells and redistribution of tumor-associated macrophages. Transcriptomic analysis of tumors post-treatment confirmed the remodeling of the immune tumor microenvironment by the GrB-Fc-KS49 immunotoxin. Conclusions GrB-Fc-KS49 showed high specificity and cytotoxicity towards EMP2-positive cells. In vivo, it reduced tumor burden and increased the recruitment of immune cells into the tumor, suggesting that GrB-Fc-KS49 is a promising therapeutic candidate against BC.
Neuropsychiatric manifestations following chimeric antigen receptor T cell therapy for cancer: a systematic review of clinical outcomes and management strategies
Authors: Anna Fleischer, Sophia Kurth, Johannes Duell, Max Topp, Patrick-Pascal Strunz, Julia Mersi, Leo Rasche, Carmen Sanges, Michael Hudecek, Hermann Einsele, Imad Maatouk
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Chimeric antigen receptor (CAR)-T cell therapy has emerged as a transformative modality in the treatment of patients with cancer. However, it is increasingly evident that this therapeutic approach is not without its challenges. The unique nature of CAR-T cells as living drugs introduces a distinct set of side effects. As the application of CAR-T cell therapy expands to treat a broader range of diseases, it becomes increasingly important to devise effective strategies for handling the associated toxicities. Challenges in treating patients with CAR-T cells include addressing complications such as cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and cytopenias. This comprehensive review seeks to systematically identify, categorize and elucidate all previously described neurological and psychological side effects associated with CAR-T cell therapy, shedding light on the pertinent laboratory findings that underscore these phenomena. Methods PubMed, Springer Link, and ScienceDirect were systematically searched for empirical studies on adult patients with cancer receiving CAR-T cell therapy for hemato-oncological malignancies. Quality assessment was conducted using Version 2 of the Cochrane risk-of-bias tool (RoB 2) for randomized trials and adherence to the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) checklist for observational studies. The synthesis of findings was conducted via a narrative approach, consolidating the diverse array of data into a coherent framework. Results From an initial pool of 2,276 citations, 546 studies met the inclusion criteria, exhibiting a rich tapestry of heterogeneity in terms of study characteristics and patient samples. The incidence of neuropsychological symptoms varied notably across different CAR-T cell products and hematological malignancies. Among the most frequently reported neuropsychological symptoms were aphasia, attention deficits, impaired consciousness, and disorientation, alongside a constellation of other symptoms including confusion, cognitive impairment, memory loss, writing difficulties, fatigue, headache, agitation, tremor, seizures, and psychomotor retardation. Early intervention strategies, including corticosteroids and tocilizumab, have shown the potential to reduce the intensity of neuropsychological symptoms and prevent their progression to critical complications. Conclusion These insights underscore the imperative of extending neuropsychological assessments beyond the conventional Immune Effector Cell-Associated Encephalopathy score framework.
CAR-T cell therapy in developing countries: how long should we wait?
Authors: Sanjivan Gautam, Balram Gautam, Ramila Shilpakar, Sudhamshu K C, Om P Kurmi
Journal: Journal for ImmunoTherapy of Cancer (2024)

Low- and middle-income countries (LMICs) face a significant burden of cancer prevalence and incidence. However, the survival rates for patients with cancer in these regions are notably lower than those in high-income countries, primarily due to late diagnosis and limited access to advanced treatments. Chimeric antigen receptor (CAR) T-cell therapy has demonstrated promising outcomes in certain terminally ill patients with cancer, yet access to this treatment remains limited in LMICs, including Nepal. The Center for Regenerative Medicine in Nepal has initiated efforts to make CAR-T cell therapy accessible to patients with cancer at a substantially reduced cost. This initiative includes successful research to test the feasibility of local laboratory capabilities using reagents sourced locally or from developed countries. Additionally, a Good Manufacturing Practicies (GMP) grade CAR-T cell manufacturing facility is being established to commence clinical manufacturing. This endeavor has encountered several challenges, including technical difficulties, regulatory barriers, and resource limitations, which could provide valuable insights for other developing countries. This experience from Nepal highlights the importance of interdisciplinary collaboration, shared knowledge, funding, and innovative solutions from the global scientific community to achieve equitable access to advanced medical treatments.
Pembrolizumab Retreatment in Patients with Advanced or Metastatic Urothelial Carcinoma Who Responded to First-course Pembrolizumab-based Therapy
Authors: Vadim S Koshkin, Pongwut Danchaivijitr, Woo Kyun Bae, Andrey Semenov, Ozgur Ozyilkan, Yu-Li Su, José A Arranz Arija, Masao Tsujihata, Martin Bögemann, Mathijs P Hendriks, Silvia Neciosup Delgado, Eli Rosenbaum, Karla Alejandra Lopez, Abhishek Bavle, Chih-Chin Liu, Kentaro Imai, Andrea Furka
Journal: European Urology (2024)
Ultrasmall iron-gallic acid coordination polymer nanoparticles for scavenging ROS and suppressing inflammation in tauopathy-induced Alzheimer’s disease
Authors: Jiani Huang, Fei Wu, Wenzhao Cao, Yuhan Chen, Qiong Yao, Peili Cen, Jing Wang, Lu Hong, Xiaohui Zhang, Rui Zhou, Chentao Jin, Mei Tian, Hong Zhang, Yan Zhong
Journal: Biomaterials (2024)
Janus LAAM-loaded electrospun fibrous buccal films for treating opioid use disorder
Authors: Hadi Sudarjat, Chaolong Qin, Diane Ingabire, Aji Alex Moothedathu Raynold, Rudra Pangeni, Adam Pearcy, Tuo Meng, Long Zhao, Michelle Arriaga, Woon N Chow, Jennifer L Puetzer, Xiuling Lu, F Gerard Moeller, Matthew S Halquist, Charles O'Keeffe, Matthew L Banks, Qingguo Xu
Journal: Biomaterials (2024)
Lipid Nanoparticles Encapsulating Both Adjuvant and Antigen mRNA Improve Influenza Immune Cross-protection in Mice
Authors: Lai Wei, Wandi Zhu, Chunhong Dong, Joo Kyung Kim, Yao Ma, Timothy L Denning, Sang-Moo Kang, Bao-Zhong Wang
Journal: Biomaterials (2024)
Dura immunity configures leptomeningeal metastasis immunosuppression for cerebrospinal fluid barrier invasion
Authors: Jiaxu Zhao, Rui Zeng, Xiaohui Li, Ying Lu, Zuoyun Wang, Haibao Peng, Hao Chen, Minjie Fu, Ye Zhang, Yang Huang, Wenhan Chen, Xin Wang, Yun Guan, Wei Han, Ruofan Huang, Chengjun Yao, Zhiyong Qin, Lingchao Chen, Liang Chen, Xue Feng, Hanting Yang, Patrícia M R Pereira, Xuemei Tong, Bin Li, Qiangqiang Zhang, Yudan Chi
Journal: Nature Cancer (2024)
Inflammasomes in neurodegenerative diseases
Authors: Qianchen Wang, Songwei Yang, Xuan Zhang, Shanshan Zhang, Liping Chen, Wanxue Wang, Naihong Chen, Jiaqing Yan
Journal: Translational Neurodegeneration (2024)

Abstract Inflammasomes represent a crucial component of the innate immune system, which respond to threats by recognizing different molecules. These are known as pathogen-associated molecular patterns (PAMPs) or host-derived damage-associated molecular patterns (DAMPs). In neurodegenerative diseases and neuroinflammation, the accumulation of misfolded proteins, such as beta-amyloid and alpha-synuclein, can lead to inflammasome activation, resulting in the release of interleukin (IL)-1β and IL-18. This activation also induces pyroptosis, the release of inflammatory mediators, and exacerbates neuroinflammation. Increasing evidence suggests that inflammasomes play a pivotal role in neurodegenerative diseases. Therefore, elucidating and investigating the activation and regulation of inflammasomes in these diseases is of paramount importance. This review is primarily focused on evidence indicating that inflammasomes are activated through the canonical pathway in these diseases. Inflammasomes as potential targets for treating neurodegenerative diseases are also discussed.
Multifunctional dietary approach reduces intestinal inflammation in relation with changes in gut microbiota composition in subjects at cardiometabolic risk: the SINFONI project
Authors: Hugo Hornero-Ramirez, Arianne Morisette, Bruno Marcotte, Armelle Penhoat, Béryle Lecomte, Baptiste Panthu, Jacob Lessard Lord, Florence Thirion, Laurie Van-Den-Berghe, Emilie Blond, Chantal Simon, Cyrielle Caussy, Nathalie Feugier, Joël Doré, Philippe Sanoner, Alexandra Meynier, Yves Desjardins, Geneviève Pilon, André Marette, Patrice D. Cani, Martine Laville, Sophie Vinoy, Marie-Caroline Michalski, Julie-Anne Nazare
Journal: Gut Microbes (2024)

The development of cardiometabolic (CM) diseases is associated with chronic low-grade inflammation, partly linked to alterations of the gut microbiota (GM) and reduced intestinal integrity. The SINFONI project investigates a multifunctional (MF) nutritional strategy's impact combining different bioactive compounds on inflammation, GM modulation and CM profile. In this randomized crossover-controlled study, 30 subjects at CM-risk consumed MF cereal-products, enriched with polyphenols, fibers, slowly-digestible starch, omega-3 fatty acids or Control cereal-products (without bioactive compounds) for 2 months. Metabolic endotoxemia (lipopolysaccharide (LPS), lipopolysaccharide-binding protein over soluble cluster of differentiation-14 (LBP/sCD14), systemic inflammation and cardiovascular risk markers, intestinal inflammation, CM profile and response to a one-week fructose supplementation, were assessed at fasting and post mixed-meal. GM composition and metabolomic analysis were conducted. Mixed linear models were employed, integrating time (pre/post), treatment (MF/control), and sequence/period. Compared to control, MF intervention reduced intestinal inflammation (fecal calprotectin, p = 0.007) and endotoxemia (fasting LPS, p < 0.05), without alteration of systemic inflammation. MF decreased serum branched-chain amino acids compared to control (p < 0.05) and increased B.ovatus, B.uniformis, A.butyriciproducens and unclassified Christensenellaceae.CAG-74 (p < 0.05). CM markers were unchanged. A 2-month dietary intervention combining multiple bioactive compounds improved intestinal inflammation and induced GM modulation. Such strategy appears as an effective strategy to target low-grade inflammation through multi-target approach.
<i>Fusobacterium nucleatum</i> -driven CX3CR1 <sup>+</sup> PD-L1 <sup>+</sup> phagocytes route to tumor tissues and reshape tumor microenvironment
Authors: Fangfang Chen, Songhe Guo, Yiqiu Li, Yongfan Lu, Le Liu, Shengxin Chen, Jun An, Ge Zhang
Journal: Gut Microbes (2024)

The intracellular bacterium Fusobacterium nucleatum (Fn) mediates tumorigenesis and progression in colorectal cancer (CRC). However, the origin of intratumoral Fn and the role of Fn-infected immunocytes in the tumor microenvironment remain unclear. Here, we observed that Fn-infected neutrophils/macrophages (PMNs/MΦs), especially PMNs, accumulate in tumor tissues and fecal Fn abundance correlates positively with an abundance of blood PD-L1+ PMNs in CRC patients. Moreover, Fn accumulates in tumor tissues of tumor-bearing mice via intragingival infection and intravenous injection. Mechanistically, Fn can survive inside PMNs by reducing intracellular ROS levels and producing H2S. Specifically, the lysozyme inhibitor Fn1792 as a novel virulence factor of Fn suppressed apoptosis of phagocytes by inducing CX3CR1 expression. Furthermore, Fn-driven CX3CR1+PD-L1+ phagocytes transfer intracellular Fn to tumor cells, which recruit PMNs/MΦs through the CXCL2/8-CXCR2 and CCL5/CCR5 axes. Consequently, CX3CR1+PD-L1+ PMNs infiltration promotes CRC metastasis and weakens the efficacy of immunotherapy. Treatment with the doxycycline eradicated intracellular Fn, thereby reducing the CX3CR1+PD-L1+ PMNs populations and slowing Fn-promoted tumor growth and metastasis in mice. These results suggest phagocytes as Fn-presenting cells use mutualistic strategies to home to tumor tissues and induce immunosuppression, and treatment with ROS-enhanced antibiotics can inhibit Fn-positive tumor progression.
Nanomedicines harnessing cGAS-STING pathway: sparking immune revitalization to transform ‘cold’ tumors into ‘hot’ tumors
Authors: Xiaohong Ying, Qiaohui Chen, Yongqi Yang, Ziyu Wu, Wan Zeng, Chenxi Miao, Qiong Huang, Kelong Ai
Journal: Molecular Cancer (2024)
Maternal probiotic exposure enhances CD8 T cell protective neonatal immunity and modulates offspring metabolome to control influenza virus infection
Authors: Clara Valentin, Patricia Brito Rodrigues, Marko Verce, Sandrine Delbauve, Léa La Palombara, Florine Demaret, Justine Allard, Isabelle Salmon, Patrice D. Cani, Arnaud Köhler, Amandine Everard, Véronique Flamand
Journal: Gut Microbes (2024)

Maternal gut microbiota composition contributes to the status of the neonatal immune system and could influence the early life higher susceptibility to viral respiratory infections. Using a novel protocol of murine maternal probiotic supplementation, we report that perinatal exposure to Lacticaseibacillus rhamnosus (L.rh) or Bifidobacterium animalis subsp. lactis (B.lac) increases the influenza A/PR8 virus (IAV) clearance in neonates. Following either supplementation, type 1 conventional dendritic cells (cDC1) were amplified in the lymph nodes leading to an enhanced IAV antigen-experienced IFN-γ producing effector CD8 T cells in neonates and IAV-specific resident memory CD8 T cells in adulthood. This was compatible with a higher protection of the offspring upon a secondary infection. Interestingly, only mice born to L.rh supplemented mothers further displayed an increased activation of IFN-γ producing virtual memory CD8 T cells and a production of IL-10 by CD4 and CD8 T cells that could explain a better control of the lung damages upon infection. In the offspring and the mothers, no disturbance of the gut microbiota was observed but, as analyzed through an untargeted metabolomic approach, both exposures modified neonatal plasma metabolites. Among them, we further demonstrated that genistein and 3-(3-hydroxyphenyl)propionic acid recapitulate viral clearance or cDC1 activation in neonates exposed to IAV. We conclude that maternal L.rh or B.lac supplementation confers the neonates specific metabolomic modulations with a better CD8 T cell-mediated immune protection against IAV infection.
Transient perivascular inflammation of the carotid artery (<scp>TIPIC</scp>) syndrome
Authors: Neeharika Namineni, Sowmya Mahalingam, Abhijeet Danve
Journal: Arthritis & Rheumatology (2024)

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Correction: Circular RNA-encoded oncogenic PIAS1 variant blocks immunogenic ferroptosis by modulating the balance between SUMOylation and phosphorylation of STAT1
Authors: Xin Zang, Xiao‑Yu He, Cheng‑Mei Xiao, Qing Lin, Meng‑Yue Wang, Cheng‑Yan Liu, Ling‑Yi Kong, Zhong Chen, Yuan‑Zheng Xia
Journal: Molecular Cancer (2024)
Metabolic Stress expands Polyfunctional, Proinflammatory Th<sub>17</sub> cells in Psoriatic Arthritis, where there is <scp>IL</scp>‐23‐independent <scp>IL</scp>‐17 production
Authors: Carmel B. Stober, Louise Ellis, Jane C. Goodall, Marc Veldhoen, J.S. Hill Gaston
Journal: Arthritis & Rheumatology (2024)

Objective Genetic associations and blockade of the interleukin‐23/IL‐17 axis with monoclonal antibodies support a role for this pathway in psoriatic arthritis (PsA). This study examines the requirement of IL‐23 for IL‐17 production, and the role of the metabolic microenvironment in the expansion of Th 17 ‐derived cells in PsA. Methods PsA patient synovial fluid or peripheral blood Th 17 cell frequencies were evaluated by flow cytometry using CCR6, CD161 and T‐bet as phenotypic markers, and the cytokines IFN‐γ, GM‐CSF and IL‐17 assessed by flow cytometry and ELISA. The impact of IL‐23 and metabolic stress on T cell differentiation was investigated. Results Polyfunctional IL‐17 pos CD4 (p&lt;0.0001) &amp; CD8 (p&lt;0.0001), and GM‐CSF pos Th 17 ‐derived (p&lt;0.0001) cells were increased in inflamed joints of patients with PsA, with a proportional decrease in patient peripheral blood. We demonstrate IL‐23‐independent IL‐17 release by PsA patient CD4 T cells, where the absence of IL‐23 during Th 17 differentiation reduced IL‐17 by 31±5.8%. Exogenous IL‐23 increased IL‐17, negatively regulated GM‐CSF and co‐operated with TGF‐β to augment IL‐17. Polyfunctional Th 17 and Th 17 ‐derived cells, but not Th 1 cells, were expanded by metabolic stress in patients with PsA. Conclusions We confirmed the abundance of polyfunctional Type 17 CD4 and CD8 cells in PsA inflamed joints. We demonstrate IL‐23‐independent expansion of Th 17 cells, where IL‐23 negatively regulates GM‐CSF. This may account for therapeutic differences in IL‐17 and IL‐23 inhibition in PsA and the Spondyloarthritides. Polyfunctional IL‐17 pos Th 17 , and Th 17 ‐derived but not Th 1 cells, were expanded by metabolic stress, where metabolic stress may itself represent a unique therapeutic target.
Expert Perspective: Management of Relapses in Giant Cell Arteritis
Authors: Marco A Alba, Sebastian Unizony, Kenneth J. Warrington, Giuseppe Murgia, Sergio Prieto‐González, Carlo Salvarani, Eric L. Matteson, Tanaz A Kermani
Journal: Arthritis & Rheumatology (2024)

Giant cell arteritis (GCA) is a relapsing large‐vessel vasculitis with risk of serious ischemic manifestations including vision loss and vascular damage in the form of large‐artery stenosis, aneurysms and dissections. Approximately 50% of patients treated with glucocorticoid (GC) monotherapy and 30% of patients receiving adjunctive therapy with tocilizumab experience disease relapses, often during the first 2 years after diagnosis. Although most relapses in GCA do not involve life‐ or organ‐threatening presentations and can be controlled successfully, frequent relapses may lead to increased use of GC and consequent treatment‐related morbidity, in addition to risk of further vascular damage. Emerging data suggests that persistent disease activity may lead to increased vascular morbidity. Additionally, while tocilizumab decreases the frequency of relapses, more than 50% of patients relapse after discontinuation of therapy. Therefore, while interleukin‐6 blockade suppresses disease activity, it does not restore tolerance. In this article, we discuss the practical diagnosis and management of GCA relapses from an expert perspective. Current treatment options for GCA relapses, including those recommended by international guidelines, and novel potential therapies are reviewed.
MARC1 downregulation reduces hepatocyte lipid content by increasing beta-oxidation
Authors: Ester Ciociola, Tanmoy Dutta, Kavitha Sasidharan, Lohitesh Kovooru, Francesca R. Noto, Grazia Pennisi, Salvatore Petta, Angela Mirarchi, Samantha Maurotti, Bernardette Scopacasa, Luca Tirinato, Patrizio Candeloro, Marcus Henricsson, Daniel Lindén, Oveis Jamialahmadi, Arturo Pujia, Rosellina M. Mancina, Stefano Romeo
Journal: Clinical and Molecular Hepatology (2024)

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global epidemic.MASLD has a strong genetic component, and a common missense variant (rs2642438) in the mitochondrial amidoxime-reducing component 1 (MARC1) gene confers protection against its onset and severity.However, there are contrasting results regarding the mechanisms entangling this protection. Methods:We downregulated MARC1 in primary human hepatocytes (PHH) using short interfering RNA (siRNA).Neutral lipid content was measured by Oil-Red O staining and fatty acid oxidation measured using radiolabeled tracers.RNA-seq and proteomic analysis using LC-MS were also performed.Additionally, we analyzed data from 239,075 participants from the UK Biobank.Results: Downregulation of MARC1 reduced neutral lipid content in PHH homozygous for the wild type (p.A165, risk) but not for the mutant (p.T165, protective) protein.Experimental results demonstrated that this reduction was mediated by an increased fatty acid utilization by beta-oxidation.Consistently, 3-hydroxybutyrate levels, a by-product of β-oxidation, were higher in carriers of the rs2642438 minor allele from the UK Biobank indicating higher βoxidation in these individuals.Moreover, downregulation of MARC1 p.A165 variant resulted in a more favorable phenotype by reducing ferroptosis and reactive oxygen species levels.Conclusions: MARC1 downregulation in carriers of the risk allele results in lower hepatocyte neutral lipids content due to higher β-oxidation, and upregulates beneficial pathways for cell survival.
Comment on: Targeting long non‐coding RNA H19 in Subchondral Bone Osteocytes Alleviates Cartilage Degradation in Osteoarthritis
Authors: An‐Fang Huang, Wang‐Dong Xu
Journal: Arthritis & Rheumatology (2024)

Disclosure Form 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.