tbuckley/cabot-search huggingface dataset:
Stealth transgenes enable CAR-T cells to evade host immune responses
Authors: Korneel Grauwet, Trisha Berger, Michael C Kann, Harrison Silva, Rebecca Larson, Mark B Leick, Stefanie R Bailey, Amanda A Bouffard, David Millar, Kathleen Gallagher, Cameron J Turtle, Matthew J Frigault, Marcela V Maus
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Adoptive cell therapy, such as chimeric antigen receptor (CAR)-T cell therapy, has improved patient outcomes for hematological malignancies. Currently, four of the six FDA-approved CAR-T cell products use the FMC63-based αCD19 single-chain variable fragment, derived from a murine monoclonal antibody, as the extracellular binding domain. Clinical studies demonstrate that patients develop humoral and cellular immune responses to the non-self CAR components of autologous CAR-T cells or donor-specific antigens of allogeneic CAR-T cells, which is thought to potentially limit CAR-T cell persistence and the success of repeated dosing. Methods In this study, we implemented a one-shot approach to prevent rejection of engineered T cells by simultaneously reducing antigen presentation and the surface expression of both Classes of the major histocompatibility complex (MHC) via expression of the viral inhibitors of transporter associated with antigen processing (TAPi) in combination with a transgene coding for shRNA targeting class II MHC transactivator (CIITA). The optimal combination was screened in vitro by flow cytometric analysis and mixed lymphocyte reaction assays and was validated in vivo in mouse models of leukemia and lymphoma. Functionality was assessed in an autologous setting using patient samples and in an allogeneic setting using an allogeneic mouse model. Results The combination of the Epstein-Barr virus TAPi and an shRNA targeting CIITA was efficient and effective at reducing cell surface MHC classes I and II in αCD19 ‘stealth’ CAR-T cells while retaining in vitro and in vivo antitumor functionality. Mixed lymphocyte reaction assays and IFNγ ELISpot assays performed with T cells from patients previously treated with autologous αCD19 CAR-T cells confirm that CAR T cells expressing the stealth transgenes evade allogeneic and autologous anti-CAR responses, which was further validated in vivo. Importantly, we noted anti-CAR-T cell responses in patients who had received multiple CAR-T cell infusions, and this response was reduced on in vitro restimulation with autologous CARs containing the stealth transgenes. Conclusions Together, these data suggest that the proposed stealth transgenes may reduce the immunogenicity of autologous and allogeneic cellular therapeutics. Moreover, patient data indicate that repeated doses of autologous FMC63-based αCD19 CAR-T cells significantly increased the anti-CAR T cell responses in these patients.
Targeting NKG2D ligands in glioblastoma with a bispecific T-cell engager is augmented with conventional therapy and enhances oncolytic virotherapy of glioma stem-like cells
Authors: Richard Baugh, Hena Khalique, Emma Page, Janet Lei-Rossmann, Peter Kok-Ting Wan, Timothy Johanssen, Daniel Ebner, Olaf Ansorge, Leonard W Seymour
Journal: Journal for ImmunoTherapy of Cancer (2024)

Glioblastoma (GBM) almost invariably becomes resistant towards conventional treatment of radiotherapy and temozolomide (TMZ) chemotherapy, partly due to subpopulations of intrinsically resistant glioma stem-like cells (GSC). The oncolytic herpes simplex virus-1 G207 is a promising approach for GBM virotherapy although its efficacy in patients with GBM is often limited. Natural killer group 2 member D ligands (NKG2DLs) are minimally expressed by healthy cells but are upregulated by the DNA damage response (DDR) and in malignant cells with chronic DDR signaling, resulting in innate immune activation. We have designed a bispecific T-cell engager (BiTE) capable of cross-linking CD3 on T cells with NKG2DL-expressing GBM cells. We then engineered the G207 virus to express the NKG2D BiTE and secrete it from infected cells. The efficacy of the free BiTE and BiTE delivered by G207 was evaluated in combination with conventional therapies in GBM cells and against patient-derived GSCs in the context of T-cell activation and target cell viability. NKG2D BiTE-mediated cross-linking of GBM cells and T cells causes antigen-independent T-cell activation, pro-inflammatory cytokine release, and tumor cell death, thereby combining direct viral oncolysis with BiTE-mediated cytotoxicity. Surface NKG2DL expression was further elevated on GBM cells following pretreatment with sublethal doses of TMZ and radiation to induce the DDR, increasing sensitivity towards G207-NKG2D BiTE and achieving synergistic cytotoxicity. We also demonstrate a novel strategy for targeting GSCs that are non-permissive to G207 infection but remain sensitive to NKG2D BiTE. We propose a potential model for targeting GSCs in heterogeneous tumors, whereby differentiated GBM cells infected with G207-NKG2D BiTE produce NKG2D BiTE locally, directing T-cell cytotoxicity towards the GSC subpopulations in the tumor microenvironment.
Gene network-based and ensemble modeling-based selection of tumor-associated antigens with a predicted low risk of tissue damage for targeted immunotherapy
Authors: Christopher Lischer, Martin Eberhardt, Cindy Flamann, Johannes Berges, Esther Güse, Anja Wessely, Adrian Weich, Jimmy Retzlaff, Jan Dörrie, Niels Schaft, Manuel Wiesinger, Johannes März, Beatrice Schuler-Thurner, Harald Knorr, Shailendra Gupta, Krishna Pal Singh, Gerold Schuler, Markus Vincent Heppt, Elias Andreas Thomas Koch, Nadine D van Kleef, Julian J Freen-van Heeren, Annelies W Turksma, Olaf Wolkenhauer, Bettina Hohberger, Carola Berking, Heiko Bruns, Julio Vera
Journal: Journal for ImmunoTherapy of Cancer (2024)

Tumor-associated antigens and their derived peptides constitute an opportunity to design off-the-shelf mainline or adjuvant anti-cancer immunotherapies for a broad array of patients. A performant and rational antigen selection pipeline would lay the foundation for immunotherapy trials with the potential to enhance treatment, tremendously benefiting patients suffering from rare, understudied cancers. We present an experimentally validated, data-driven computational pipeline that selects and ranks antigens in a multipronged approach. In addition to minimizing the risk of immune-related adverse events by selecting antigens based on their expression profile in tumor biopsies and healthy tissues, we incorporated a network analysis-derived antigen indispensability index based on computational modeling results, and candidate immunogenicity predictions from a machine learning ensemble model relying on peptide physicochemical characteristics. In a model study of uveal melanoma, Human Leukocyte Antigen (HLA) docking simulations and experimental quantification of the peptide-major histocompatibility complex binding affinities confirmed that our approach discriminates between high-binding and low-binding affinity peptides with a performance similar to that of established methodologies. Blinded validation experiments with autologous T-cells yielded peptide stimulation-induced interferon-γ secretion and cytotoxic activity despite high interdonor variability. Dissecting the score contribution of the tested antigens revealed that peptides with the potential to induce cytotoxicity but unsuitable due to potential tissue damage or instability of expression were properly discarded by the computational pipeline. In this study, we demonstrate the feasibility of the de novo computational selection of antigens with the capacity to induce an anti-tumor immune response and a predicted low risk of tissue damage. On translation to the clinic, our pipeline supports fast turn-around validation, for example, for adoptive T-cell transfer preparations, in both generalized and personalized antigen-directed immunotherapy settings.
Osteosarcopenic adiposity (OSA) phenotype and its connection with cardiometabolic disorders: Is there a cause-and-effect?
Authors: Jasminka Z. Ilich, Biljana Pokimica, Danijela Ristić-Medić, Snjezana Petrović, Aleksandra Arsić, Nadja Vasiljević, Vesna Vučić, Owen J. Kelly
Journal: Ageing Research Reviews (2024)
ncRNAs and their impact on dopaminergic neurons: Autophagy pathways in Parkinson's disease
Authors: Riya Thapa, Ehssan Moglad, Muhammad Afzal, Gaurav Gupta, Asif Ahmad Bhat, Waleed Hassan almalki, Imran Kazmi, Sami I. Alzarea, Kumud Pant, Haider Ali, Keshav Raj Paudel, Harish Dureja, Thakur Gurjeet Singh, Sachin Kumar Singh, Kamal Dua
Journal: Ageing Research Reviews (2024)
Labelling with dynamics: A data-efficient learning paradigm for medical image segmentation
Authors: Yuanhan Mo, Fangde Liu, Guang Yang, Shuo Wang, Jianqing Zheng, Fuping Wu, Bartłomiej W. Papież, Douglas McIlwraith, Taigang He, Yike Guo
Journal: Medical Image Analysis (2024)

The success of deep learning on image classification and recognition tasks has led to new applications in diverse contexts, including the field of medical imaging. However, two properties of deep neural networks (DNNs) may limit their future use in medical applications. The first is that DNNs require a large amount of labeled training data, and the second is that the deep learning-based models lack interpretability. In this paper, we propose and investigate a data-efficient framework for the task of general medical image segmentation. We address the two aforementioned challenges by introducing domain knowledge in the form of a strong prior into a deep learning framework. This prior is expressed by a customized dynamical system. We performed experiments on two different datasets, namely JSRT and ISIC2016 (heart and lungs segmentation on chest X-ray images and skin lesion segmentation on dermoscopy images). We have achieved competitive results using the same amount of training data compared to the state-of-the-art methods. More importantly, we demonstrate that our framework is extremely data-efficient, and it can achieve reliable results using extremely limited training data. Furthermore, the proposed method is rotationally invariant and insensitive to initialization.
Interactions of Nutrition and Infection: The Role of Micronutrient Deficiencies in the Immune Response to Pathogens and Implications for Child Health
Authors: Amanda C. Palmer, Jacquelyn R. Bedsaul-Fryer, Charles B. Stephensen
Journal: Annual Review of Nutrition (2024)

Approximately five million children die each year from preventable causes, including respiratory infections, diarrhea, and malaria. Roughly half of those deaths are attributable to undernutrition, including micronutrient deficiencies (MNDs). The influence of infection on micronutrient status is well established: The inflammatory response to pathogens triggers anorexia, while pathogens and the immune response can both alter nutrient absorption and cause nutrient losses. We review the roles of vitamin A, vitamin D, iron, zinc, and selenium in the immune system, which act in the regulation of molecular- or cellular-level host defenses, directly affecting pathogens or protecting against oxidative stress or inflammation. We further summarize high-quality evidence regarding the synergistic or antagonistic interactions between MNDs, pathogens, and morbidity or mortality relevant to child health in low- and middle-income countries. We conclude with a discussion of gaps in the literature and future directions for multidisciplinary research on the interactions of MNDs, infection, and inflammation.
The future of public health doctoral education in Africa: transforming higher education institutions to enhance research and practice
Authors: Justine Bukenya, Derege Kebede, Henry Mwambi, Muhammed Pate, Philip Adongo, Yemane Berhane, Chelsey R Canavan, Tobias Chirwa, Olufunmilayo I Fawole, David Guwatudde, Elizabeth Jackson, Isabel Madzorera, Mosa Moshabela, Ayoade M J Oduola, Bruno Sunguya, Amadou Sall, Tajudeen Raji, Wafaie Fawzi
Journal: The Lancet Public Health (2024)

The African Union and the Africa Centers for Disease Control and Prevention issued a Call to Action in 2022 for Africa's New Public Health Order that underscored the need for increased capacity in the public health workforce. Additional domestic and global investments in public health workforce development are central to achieving the aspirations of Agenda 2063 of the African Union, which aims to build and accelerate the implementation of continental frameworks for equitable, people-centred growth and development. Recognising the crucial role of higher education and research, we assessed the capabilities of public health doctoral training in schools and programmes of public health in Africa across three conceptual components: instructional, institutional, and external. Six inter-related and actionable recommendations were derived to advance doctoral training, research, and practice capacity within and between universities. These can be achieved through equitable partnerships between universities, research centres, and national, regional, and global public health institutions.
Enhanced Mechanical Strength and Sustained Drug Release in Carrier‐Free Silver‐Coordinated Anthraquinone Natural Antibacterial Anti‐Inflammatory Hydrogel for Infectious Wound Healing
Authors: Xiaoliu Liang, Linyu Ding, Jiaxin Ma, Jiwei Li, Lei Cao, Hui Liu, Minglei Teng, Zhenjie Li, Yisheng Peng, Hu Chen, Yali Zheng, Hongwei Cheng, Gang Liu
Journal: Advanced Healthcare Materials (2024)

The persistent challenge of healing infectious wounds and the rise of bacterial resistance represent significant hurdles in contemporary medicine. In this study, based on the natural small molecule drug Rhein self-assembly to form hydrogels and coordinate assembly with silver ions (Ag
Extrahepatic malignancies and antiviral drugs for chronic hepatitis B: A nationwide cohort study
Authors: Moon Haeng Hur, Dong Hyeon Lee, Jeong-Hoon Lee, Mi-Sook Kim, Jeayeon Park, Hyunjae Shin, Sung Won Chung, Hee Jin Cho, Min Kyung Park, Heejoon Jang, Yun Bin Lee, Su Jong Yu, Sang Hyub Lee, Yong Jin Jung, Yoon Jun Kim, Jung-Hwan Yoon
Journal: Clinical and Molecular Hepatology (2024)

Chronic hepatitis B (CHB) is related to an increased risk of extrahepatic malignancy (EHM), and antiviral treatment is associated with an incidence of EHM comparable to controls. We compared the risks of EHM and intrahepatic malignancy (IHM) between entecavir (ETV) and tenofovir disoproxil fumarate (TDF) treatment. Using data from the National Health Insurance Service of Korea, this nationwide cohort study included treatment-naïve CHB patients who initiated ETV (n=24,287) or TDF (n=29,199) therapy between 2012 and 2014. The primary outcome was the development of any primary EHM. Secondary outcomes included overall IHM development. E-value was calculated to assess the robustness of results to unmeasured confounders. The median follow-up duration was 5.9 years, and all baseline characteristics were well balanced after propensity score matching. EHM incidence rate differed significantly between within versus beyond 3 years in both groups (P<0.01, Davies test). During the first 3 years, EHM risk was comparable in the propensity score-matched cohort (5.88 versus 5.84/1,000 person-years; subdistribution hazard ratio [SHR]=1.01, 95% confidence interval [CI]=0.88-1.17, P=0.84). After year 3, however, TDF was associated with a significantly lower EHM incidence compared to ETV (4.92 versus 6.91/1,000 person-years; SHR=0.70, 95% CI=0.60-0.81, P<0.01; E-value for SHR=2.21). Regarding IHM, the superiority of TDF over ETV was maintained both within (17.58 versus 20.19/1,000 person-years; SHR=0.88, 95% CI=0.81-0.95, P<0.01) and after year 3 (11.45 versus 16.20/1,000 person-years; SHR=0.68, 95% CI=0.62-0.75, P<0.01; E-value for SHR=2.30). TDF was associated with approximately 30% lower risks of both EHM and IHM than ETV in CHB patients after 3 years of antiviral therapy.
Macrophage ATG16L1 expression suppresses metabolic dysfunction-associated steatohepatitis progression by promoting lipophagy
Authors: Qi Wang, Qingfa Bu, Zibo Xu, Yuan Liang, Jinren Zhou, Yufeng Pan, Haoming Zhou, Ling Lu
Journal: Clinical and Molecular Hepatology (2024)

Background/Aims: Metabolic dysfunction-associated steatohepatitis (MASH) is an unmet clinical challenge due to the rapid increased occurrence but lacking approved drugs. Autophagy-related protein 16-like 1 (ATG16L1) plays an important role in the process of autophagy, which is indispensable for proper biogenesis of the autophagosome, but its role in modulating macrophage-related inflammation and metabolism during MASH has not been documented. Here, we aimed to elucidate the role of ATG16L1 in the progression of MASH.Methods: Expression analysis was performed with liver samples from human and mice. MASH models were induced in myeloid-specific Atg16l1-deficient and myeloid-specific Atg16l1-overexpressed mice by high-fat and high-cholesterol diet or methionine- and choline-deficient diet to explore the function and mechanism of macrophage ATG16L1 in MASH.Results: Macrophage-specific Atg16l1 knockout exacerbated MASH and inhibited energy expenditure, whereas macrophage-specific Atg16l1 transgenic overexpression attenuated MASH and promotes energy expenditure. Mechanistically, Atg16l1 knockout inhibited macrophage lipophagy, thereby suppressing macrophage β-oxidation and decreasing the production of 4-hydroxynonenal, which further inhibited stimulator of interferon genes(STING) carbonylation. STING palmitoylation was enhanced, STING trafficking from the endoplasmic reticulum to the Golgi was promoted, and downstream STING signaling was activated, promoting proinflammatory and profibrotic cytokines secretion, resulting in hepatic steatosis and hepatic stellate cells activation. Moreover, Atg16l1-deficiency enhanced macrophage phagosome ability but inhibited lysosome formation, engulfing mtDNA released by pyroptotic hepatocytes. Increased mtDNA promoted cGAS/STING signaling activation. Moreover, pharmacological promotion of ATG16L1 substantially blocked MASH progression.Conclusions: ATG16L1 suppresses MASH progression by maintaining macrophage lipophagy, restraining liver inflammation, and may be a promising therapeutic target for MASH management.
Spexin Diminishes Atrial Fibrillation Vulnerability by Acting on Galanin Receptor 2
Authors: Desheng Li, Yang Liu, Changzhu Li, Zhiwen Zhou, Kangyi Gao, Hairong Bao, Jiming Yang, Genlong Xue, Dechun Yin, Xinbo Zhao, Kewei Shen, Lingmin Zhang, Jialiang Li, Chenhong Li, Jiahui Song, Lexin Zhao, Yao Pei, Lina Xuan, Yang Zhang, Yanjie Lu, Zhi-Ren Zhang, Baofeng Yang, Yue Li, Zhenwei Pan
Journal: Circulation (2024)

G protein-coupled receptors play a critical role in atrial fibrillation (AF). Spexin is a novel ligand of galanin receptors (GALRs). In this study, we investigated the regulation of spexin and GALRs on AF and the underlying mechanisms.
Letter to the editor: Critical need for robust surveillance in response to DENV-2 and SARS-CoV-2 cross-reactivity
Authors: Chia Siang Kow, Dinesh Sangarran Ramachandram, Syed Shahzad Hasan, Kaeshaelya Thiruchelvam
Journal: Eurosurveillance (2024)

Preview this article: Letter to the editor: Critical need for robust surveillance in response to DENV-2 and SARS-CoV-2 cross-reactivity, Page 1 of 1 < Previous page | Next page > /docserver/preview/fulltext/eurosurveillance/29/19/eurosurv-29-19_4-1.gif
Anorectal lymphogranuloma venereum among men who have sex with men: a 3-year nationwide survey, France, 2020 to 2022
Authors: Olivia Peuchant, Cécile Laurier-Nadalié, Laura Albucher, Carla Balcon, Amandine Dolzy, Nadège Hénin, Arabella Touati, Cécile Bébéar
Journal: Eurosurveillance (2024)

Background In France, lymphogranuloma venereum (LGV) testing switched from universal to selective testing in 2016. Aim To investigate changes in LGV-affected populations, we performed a nationwide survey based on temporarily reinstated universal LGV testing from 2020 to 2022. Methods Each year, during three consecutive months, laboratories voluntarily sent anorectal Chlamydia trachomatis -positive samples from men and women to the National Reference Centre for bacterial sexually transmitted infections. We collected patients’ demographic, clinical and biological data. Genovars L of C. trachomatis were detected using real-time PCR. In LGV-positive samples, the omp A gene was sequenced. Results In 2020, LGV positivity was 12.7% (146/1,147), 15.2% (138/907) in 2021 and 13.3% (151/1,137) in 2022 (p &gt; 0.05). It occurred predominantly in men who have sex with men (MSM), with rare cases among transgender women. The proportion of HIV-negative individuals was higher than that of those living with HIV. Asymptomatic rectal LGV increased from 36.1% (44/122) in 2020 to 52.4% (66/126) in 2022 (p = 0.03). Among users of pre-exposure prophylaxis (PrEP), LGV positivity was 13.8% (49/354) in 2020, 15.6% (38/244) in 2021 and 10.9% (36/331) in 2022, and up to 50% reported no anorectal symptoms. Diversity of the LGV ompA genotypes in the Paris region increased during the survey period. An unexpectedly high number of ompA genotype L1 variant was reported in 2022. Conclusion In rectal samples from MSM in France, LGV positivity was stable, but the proportion of asymptomatic cases increased in 2022. This underscores the need of universal LGV testing and the importance of continuous surveillance.
Notch‐Targeted Therapeutic in Colorectal Cancer by Notch1 Attenuation Via Tumor Microenvironment‐Responsive Cascade DNA Delivery
Authors: Yan Lu, Yufei Cao, Xiaowen Guo, Yijie Gao, Xue Chen, Zixi Zhang, Zhishen Ge, Dake Chu
Journal: Advanced Healthcare Materials (2024)

The Notch signaling is a key molecular pathway that regulates cell fate and development. Aberrant Notch signaling can lead to carcinogenesis and progression of malignant tumors. However, current therapies targeting Notch pathway lack specificity and induce high toxicity. In this report, a tumor microenvironment-responsive and injectable hydrogel is designed to load plasmid DNA complexes as a cascade gene delivery system to achieve precise Notch-targeted gene therapy of colorectal cancer (CRC). The hydrogels are prepared through cross-linking between phenylboric acid groups containing poly(oligo(ethylene glycol)methacrylate) (POEGMA) and epigallocatechin gallate (EGCG), used to load the complexes between plasmid DNA encoding short hairpin RNAs of Notch1 (shNotch1) and fluorinated polyamidoamine (PAMAM-F) (PAMAM-F/shNotch1). In response to low pH and H
Monocyte bioenergetics: An immunometabolic perspective in metabolic dysfunction-associated steatohepatitis
Authors: Moris Sangineto, Martina Ciarnelli, Tommaso Colangelo, Archana Moola, Vidyasagar Naik Bukke, Loren Duda, Rosanna Villani, Antonino Romano, Stefania Giandomenico, Hina Kanwal, Gaetano Serviddio
Journal: Cell Reports Medicine (2024)

Monocytes (Mos) are crucial in the evolution of metabolic dysfunction-associated steatotic liver disease (MASLD) to metabolic dysfunction-associated steatohepatitis (MASH), and immunometabolism studies have recently suggested targeting leukocyte bioenergetics in inflammatory diseases. Here, we reveal a peculiar bioenergetic phenotype in circulating Mos of patients with MASH, characterized by high levels of glycolysis and mitochondrial (mt) respiration. The enhancement of mt respiratory chain activity, especially complex II (succinate dehydrogenase [SDH]), is unbalanced toward the production of reactive oxygen species (ROS) and is sustained at the transcriptional level with the involvement of the AMPK-mTOR-PGC-1α axis. The modulation of mt activity with dimethyl malonate (DMM), an SDH inhibitor, restores the metabolic profile and almost abrogates cytokine production. Analysis of a public single-cell RNA sequencing (scRNA-seq) dataset confirms that in murine models of MASH, liver Mo-derived macrophages exhibit an upregulation of mt and glycolytic energy pathways. Accordingly, the DMM injection in MASH mice contrasts Mo infiltration and macrophagic enrichment, suggesting immunometabolism as a potential target in MASH.