tbuckley/cabot-search huggingface dataset:
Static Magnetic Stimulation and Magnetic Microwires Synergistically Enhance and Guide Neurite Outgrowth
Authors: Katelyn Neuman, Xiaoyu Zhang, Brian. T. Lejeune, Dominic Pizzarella, Manuel Vázquez, Laura H. Lewis, Abigail N. Koppes, Ryan A. Koppes
Journal: Advanced Healthcare Materials (2024)

Abstract Axonal growth is heavily influenced by topography and biophysical stimuli including magnetic and electrical fields. Despite extensive investigation, the degree of influence and the underlying genetic mechanisms remain poorly understood. Here, a novel approach to guide neurite growth is undertaken using an innovative ferromagnetic composite material – glass‐coated magnetic microwire – to furnish a synergistic combination of magnetic and topographical cues. Whole rat dorsal root ganglia (DRG) are cultured under five different conditions: control, static magnetic field, magnetic microwire, static magnetic field + glass fiber, and static magnetic field + magnetic microwire. DRG outgrowth responses under each condition, including total neurite outgrowth and directionality, are compared. The combination of both magnetic stimulation and topography significantly increases total neurite outgrowth compared to the controls. The combination of magnetic stimulation and magnetic microwire lead to a strong directional bias of growth along the microwire, double what is observed with the glass fiber. Next generation RNA sequencing of DRG exposed to static magnetic field + magnetic microwire reveals the downregulation of genes relating to the immune response, interleukin signaling, and signal transduction. These results set the stage for contemplating future biophysical stimulation for axonal guidance and improved understanding of material‐tissue interactions.
Treatment‐Free Remissions in Children With Chronic Myeloid Leukemia (<scp>CML</scp>): A Prospective Study From the Tata Memorial Hospital (<scp>TMH</scp>) Pediatric <scp>CML</scp> (<scp>pCML</scp>) Cohort
Authors: Nirmalya Roy Moulik, Swaminathan Keerthivasagam, Gaurav Chatterjee, Jayesh Agiwale, Pallavi Rane, Chetan Dhamne, Akanksha Chichra, Shyam Srinivasan, Purvi Mohanty, Hemani Jain, Dhanlaxmi Shetty, Sweta Rajpal, Prashant Tembhare, Nikhil Patkar, Gaurav Narula, Papagudi G. Subramanian, Shripad Banavali
Journal: American Journal of Hematology (2024)

ABSTRACT Pediatric chronic myeloid leukemia (pCML) is a rare childhood malignancy, representing 2%–3% of all childhood leukemia. Tyrosine kinase inhibitors (TKIs) have greatly improved survival but pose challenges due to their long‐term effects on growth and bone health in children. We prospectively studied treatment‐free remission (TFR) in 45 children with pCML in chronic phase on imatinib. Eligibility criteria were as per current NCCN guidelines, with a less stringent qPCR monitoring scheduled every 3 months. TFR was successful in 71.1% (32 out of 45) of patients after a median follow‐up of 25 (range: 6–42) months. The TFR rates at 12 and 24 months were 70% and 66%, respectively. Children under 5 years had a TFR rate of 88.9%, compared to 61.8% in those over 5 years ( p = 0.18). Eleven of the 13 patients who lost MMR did so within 6 months of discontinuation. The cumulative incidence of loss in MMR at 6, 12, and 24 months was 26.4%, 27%, and 33%, respectively. Ten out of 13 (76.9%) patients with discontinuation failure (DF) regained MMR within 3 (2–20) months of restarting imatinib. A significant correlation was found between higher T‐regulatory cell levels at baseline and DF ( p = 0.005). More than half patients showed improved bone mineral density after 2 years of TFR. Our findings suggest that high TFR rates can be attained in pCML, with added benefits for bone health. Less frequent molecular monitoring was not associated with adverse outcomes and there seems to be a role of the immune system in sustaining TFR. The study is registered in the Clinical Trials Registry‐India (CTRI/2020/11/029199).
IL-18R supported CAR T cells targeting oncofetal tenascin C for the immunotherapy of pediatric sarcoma and brain tumors
Authors: Elizabeth Wickman, Shannon Lange, Jessica Wagner, Jorge Ibanez, Liqing Tian, Meifen Lu, Heather Sheppard, Jason Chiang, Selene C Koo, Peter Vogel, Deanna Langfitt, S Scott Perry, Raghuvaran Shanmugam, Matthew Bell, Timothy I Shaw, Giedre Krenciute, Jinghui Zhang, Stephen Gottschalk
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Oncofetal splice variants of extracellular matrix (ECM) proteins present a unique group of target antigens for the immunotherapy of pediatric cancers. However, limited data is available if these splice variants can be targeted with T cells expressing chimeric antigen receptors (CARs). Methods To determine the expression of the oncofetal version of tenascin C (TNC) encoding the C domain (C.TNC) in pediatric brain and solid tumors, we used quantitative reverse transcription PCR and immunohistochemistry. Genetically modified T cells were generated from human peripheral blood mononuclear cells and evaluated in vitro and in vivo. Results We demonstrate that C.TNC is expressed on a protein level in pediatric tumors, including diffuse intrinsic pontine glioma, osteosarcoma, rhabdomyosarcoma, and Ewing sarcoma. We generate C.TNC-CAR T cells and establish that these recognize and kill C.TNC-positive tumor cells. However, their antitumor activity in vivo is limited. To improve the effector function of C.TNC-CAR T cells, we design a leucine zipper-based chimeric cytokine receptor that activates interleukin-18 signaling pathways (Zip18R). Expression of Zip18R in C.TNC-CAR T cells improves their ability to secrete cytokines and expand in repeat stimulation assays. C.TNC-CAR.Zip18R T cells also have significantly greater antitumor activity in vivo compared with unmodified C.TNC-CAR T cells. Conclusions Our study identifies the C domain of the ECM protein TNC as a promising CAR T-cell therapy for pediatric solid tumors and brain tumors. While we focus here on pediatric cancer, our work has relevance to a broad range of adult cancers that express C.TNC.
Immune microenvironment of Epstein-Barr virus (EBV)-negative compared to EBV-associated gastric cancers: implications for immunotherapy
Authors: Tracee L McMiller, Sepideh Besharati, Mark Yarchoan, Qingfeng Zhu, Keziban Ünsal-Kaçmaz, Ke Xu, Junghwa Lee, Feriyl Bhaijee, Logan L Engle, Janis M Taube, Alan E Berger, Robert A Anders, Suzanne L Topalian
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Gastric carcinomas (GC) are aggressive malignancies, and only ~15% of patients respond to anti-programmed cell death (ligand) 1 (PD-(L)1) monotherapy. However, Epstein-Barr virus (EBV)-associated GCs (~5–10% of GCs) often harbor PD-L1 and PD-L2 chromosomal amplifications and robust CD8+ T cell infiltrates, and respond at a high rate to anti-PD-1. The current study compares the tumor immune microenvironments (TiMEs) of EBV+ versus EBV(−) GCs. Methods Over 1000 cases of primary invasive GCs were screened to identify 25 treatment-naïve specimens for study (11 EBV+, 14 EBV(−)). Quantitative immunohistochemistry (IHC) was conducted for markers of immune cell subsets and co-regulatory molecules. Gene expression profiling (GEP) was performed on RNAs isolated from macrodissected areas of CD3+ T cell infiltrates abutting PD-L1+ stromal/tumor cells, using multiplex quantitative reverse transcriptase PCR for a panel of 122 candidate immune-related genes. Results IHC revealed that 17/25 GCs contained PD-L1+ stromal cells, with no significant difference between EBV+/- specimens; however, only 3/25 specimens (all EBV+) contained PD-L1+ tumor cells. CD8+ T cell densities were higher in EBV+ versus EBV(−) tumors (p=0.044). With GEP normalized to the pan-leukocyte marker PTPRC/ CD45, EBV+ GCs overexpressed ITGAE (CD103, marking intraepithelial T cells and a dendritic cell subset) and the interferon-inducible genes CXCL9 and IDO1 . In contrast, EBV(−) tumors overexpressed several functionally-related gene groups associated with myeloid cells ( CD163 , IL1A , NOS2, RIGI), immunosuppressive cytokines/chemokines ( CXCL2 , CXCR4 , IL10, IL32), coinhibitory molecules ( HAVCR2/ TIM-3 and VSIR/ VISTA), and adenosine pathway components ( ENTPD1/ CD39 and NT5E/ CD73). Notably, compared with EBV+ GCs, EBV(−) GCs also overexpressed components of the cyclooxygenase 2 (COX-2)/prostaglandin E2 (PGE2) pathway associated with cancer-promoting inflammation, including PTGS2/ COX-2 (most highly upregulated gene, 32-fold, p=0.005); prostaglandin receptors PTGER1 (EP1; up 21-fold, p=0.015) and PTGER4 (EP4; up twofold, p=0.022); and the major COX-2-inducing cytokine IL1B (up 11-fold, p=0.019). Consistent with these findings, COX-2 protein expression trended higher in EBV(−) versus EBV+ GCs (p=0.068). Conclusions While certain markers of immunosuppression are found in the GC TiME regardless of EBV status, EBV(−) GCs, which are much more common than EBV+ GCs, overexpress components of the COX-2/PGE2 pathway. These findings provide novel insights into the immune microenvironments of EBV+ and EBV(−) GC, and offer potential targets to overcome resistance to anti-PD-(L)1 therapies.
Divergent lineage trajectories and genetic landscapes in human gastric intestinal metaplasia organoids associated with early neoplastic progression
Authors: Sarah S K Yue, Yin Tong, Hoi Cheong Siu, Siu Lun Ho, Simon Y K Law, Wai Yin Tsui, Dessy Chan, Yuanhua Huang, Annie S Y Chan, Shui Wa Yun, Ho Sang Hui, Jee-Eun Choi, Matthew S S Hsu, Frank P L Lai, April S Chan, Siu Tsan Yuen, Hans Clevers, Suet Yi Leung, Helen H N Yan
Journal: Gut (2024)

Background Gastric intestinal metaplasia (IM) is a precancerous stage spanning a morphological spectrum that is poorly represented by human cell line models. Objective We aim to establish and characterise human IM cell models to better understand IM progression along the cancer spectrum. Design A large human gastric IM organoid (IMO) cohort (n=28), their clonal derivatives and normal gastric organoids (n=42) for comparison were established. Comprehensive multi-omics profiling and functional characterisation were performed. Results Single-cell transcriptomes revealed IMO cells spanning a spectrum from hybrid gastric/intestinal to advanced intestinal differentiation. Their lineage trajectories connected different cycling and quiescent stem and progenitors, highlighting differences in gastric to IM transition and the potential origin of IM from STMN1 cycling isthmus stem cells. Hybrid IMOs showed impaired differentiation potential, high lineage plasticity beyond gastric or intestinal fates and reactivation of a fetal gene programme. Cell populations in gastric IM and cancer tissues were highly similar to those derived from IMOs and exhibited a fetal signature. Genomically, IMOs showed elevated mutation burden, frequent chromosome 20 gain and epigenetic deregulation of many intestinal and gastric genes. Functionally, IMOs were FGF10 independent and showed downregulated FGFR2. Several IMOs exhibited a cell-matrix adhesion independent subpopulation that displayed chromosome 20 gain but lacked key cancer driver mutations, potentially representing the earliest neoplastic precursor of IM-induced gastric cancer. Conclusions Overall, our IMO biobank captured the heterogeneous nature of IM, revealing mechanistic insights on IM pathogenesis and progression, offering an ideal platform for studying early gastric neoplastic transformation and chemoprevention.
MAGE-A4 pMHC-targeted CAR-T cells exploiting TCR machinery exhibit significantly improved in vivo function while retaining antigen specificity
Authors: Meiou Liu, Yasushi Akahori, Naoko Imai, Linan Wang, Kohei Negishi, Takuma Kato, Hiroshi Fujiwara, Hiroshi Miwa, Hiroshi Shiku, Yoshihiro Miyahara
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background The development of chimeric antigen receptor (CAR)-T cell therapies for solid tumors has attracted considerable attention, yet their clinical efficacy remains limited. Therefore, various efforts have been made to improve the efficacy of CAR-T cell therapy. As one promising strategy, incorporating the T-cell receptor (TCR) machinery into CAR structures has been reported to improve the efficacy of CAR-T cells in studies using conventional CARs targeting such as EGFR. However, in the case of peptide/major histocompatibility complex (pMHC)-targeted CARs, the advantages of exploiting TCR machinery have not been fully elucidated. We recently developed MAGE-A4-derived pMHC (MAGE-A4 pMHC)-targeted CAR-T cells (MA-CAR-T cells) using a highly specific human scFv antibody against MAGE-A4 p230-239 /HLA-A*02:01. We aimed to determine whether MAGE-A4 pMHC-targeted CAR-T cells using the TCR machinery (Hybrid MA-TCR-T cells) exhibit superior functionality without compromising antigen specificity. Methods We constructed a retroviral vector expressing Hybrid MA-TCR where MAGE-A4 pMHC-specific scFv are fused to human TCR constant chains. Results Hybrid MA-TCR-T cells demonstrated superior in vitro functions compared with MA-CAR-T cells, while maintaining strict antigen specificity. In addition, functional superiority of Hybrid MA-TCR-T cells to MA-CAR-T cells became more pronounced on repetitive antigen stimulation. In particular, Hybrid MA-TCR-T cells significantly inhibited tumor growth in an immunodeficient mouse model more effectively than MA-CAR-T cells. Ex vivo analyses indicated that their enhanced therapeutic efficacy might result from higher infiltration of functionally active, less differentiated Hybrid MA-TCR-T cells in tumor tissues. Conclusions These findings suggest that leveraging the TCR machinery is a promising strategy for enhancing pMHC-targeted CAR-T cell therapy for solid tumors, potentially leading to more effective treatments.
TIPS insertion leads to sustained reversal of systemic inflammation in patients with decompensated liver cirrhosis
Authors: Anja Tiede, Lena Stockhoff, Zhaoli Liu, Hannah Rieland, Jim B Mauz, Valerie Ohlendorf, Birgit Bremer, Jennifer Witt, Anke Kraft, Markus Cornberg, Jan B Hinrichs, Bernhard C Meyer, Heiner Wedemeyer, Cheng-Jian Xu, Christine S Falk, Benjamin Maasoumy
Journal: Clinical and Molecular Hepatology (2024)

Systemic Inflammation (SI) is considered a key mechanism in disease progression and development of complications in decompensated liver cirrhosis. SI is mainly driven by portal hypertension and bacterial translocation. Transjugular intrahepatic portosystemic shunt (TIPS)-insertion represents an effective treatment for portal hypertension. This study aims to investigate the impact of TIPS-insertion on SI and bacterial translocation.
Mechanisms of HCC and cirrhosis development in concurrent steatotic liver disease and chronic hepatitis B
Authors: Saisai Zhang, Lung-Yi Mak, Man-Fung Yuen, Wai-Kay Seto
Journal: Clinical and Molecular Hepatology (2024)

Chronic hepatitis B (CHB) poses a major global public health challenge and is a leading cause of cirrhosis and liver cancer. Hepatic steatosis is common in individuals with CHB compared to the non-CHB population and is particularly prevalent in HBV-endemic regions, affecting about one-third of CHB patients. The interaction between hepatic steatosis and CHB-related disease progression is complex and still under debate. Evidence demonstrates that co-existing steatosis may worsen liver fibrosis while paradoxically increasing the likelihood of achieving better HBV control. In particular, despite the association of steatotic liver disease (SLD) with lower HBV viral loads and higher rates of HBsAg seroclearance, the coexistence of CHB and SLD can potentially accelerate liver disease progression. Factors such as fat deposition, lipotoxicity, oxidative stress, and chronic inflammation in SLD may foster a pro-fibrotic and pro-carcinogenic environment, accelerating the disease progression. Additionally, loss of global DNA methylation, changes in the immune microenvironment, and genetic susceptibility further contribute to the development of CHB-related cirrhosis and HCC. This review examines the mechanisms driving liver disease progression and the heightened risk of cirrhosis and HCC in patients with concurrent CHB and steatotic liver disease, underscoring the importance of prioritizing antiviral therapy for CHB in addition to addressing SLD.
Altered IL-6 signalling and risk of tuberculosis: a multi-ancestry mendelian randomisation study
Authors: Fergus Hamilton, Haiko Schurz, Tom A Yates, James J Gilchrist, Marlo Möller, Vivek Naranbhai, Peter Ghazal, Nicholas J Timpson, Tom Parks, Gabriele Pollara
Journal: The Lancet Microbe (2024)
Rotavirus rewires host cell metabolic pathways toward glutamine catabolism for effective virus infection
Authors: Suvrotoa Mitra, Ratul Datta Chaudhuri, Rakesh Sarkar, Shreya Banerjee, Arpita Mukherjee, Ranjana Sharma, Animesh Gope, Kei Kitahara, Shin-Ichi Miyoshi, Mamta Chawla-Sarkar
Journal: Gut Microbes (2024)

Rotavirus (RV) accounts for 19.11% of global diarrheal deaths. Though GAVI assisted vaccine introduction has curtailed RV induced mortality, factors like RV strain diversity, differential infantile gut microbiome, malnutrition, interference from maternal antibodies and other administered vaccines, etc. often compromise vaccine efficacy. Herein emerges the need of antivirals which can be administered adjunct to vaccination to curb the socio-economic burden stemming from frequent RV infection. Cognisance of pathogen-perturbed host cellular physiology has revolutionized translational research and aided precision-based therapy, particularly for viruses, with no metabolic machinery of their own. To date there has been limited exploration of the host cellular metabolome in context of RV infection. In this study, we explored the endometabolomic landscape of human intestinal epithelial cells (HT-29) on RV-SA11 infection. Significant alteration of host cellular metabolic pathways like the nucleotide biosynthesis pathway, alanine, aspartate and glutamate metabolism pathway, the host citric acid cycle was observed in RV-SA11 infection scenario. Detailed study further revealed that RV replication is exclusively dependent on glutamine metabolism for their propagation in host cells. Glutamine metabolism generates glutamate, aspartate, and asparagine which facilitates virus infection. Abrogation of aspartate biogenesis from glutamine by use of Aminooxyacetic acid (AOAA), significantly curbed RV-SA11 infection in-vitro and in-vivo. Overall, the study improves our understanding of host-rotavirus interactome and recognizes host glutamine metabolism pathway as a suitable target for effective therapeutic intervention against RV infection.
More than just a number: the gut microbiota and brain function across the extremes of life
Authors: Nathan D. Nuzum, Clara Deady, Sarah Kittel-Schneider, John F. Cryan, Siobhain M. O'Mahony, Gerard Clarke
Journal: Gut Microbes (2024)

Understanding the interrelationship between the gut microbiota and host physiology, although still in its relative infancy, has taken important steps forward over the past decade. In the context of brain disorders including those characterized by neurodevelopmental and neurodegenerative changes there have been important advances. However, initially research involved correlational analyses, had limited translational scope, and lacked functional assessments. Thus, largescale longitudinal clinical investigations that assess causation and underlying mechanisms via in depth analysis methods are needed. In neurodegeneration research, strong causal evidence now links the gut microbiome to Alzheimer's (AD), and Parkinson's Disease (PD), as supported by human-to-animal transplantation studies. Longitudinal interventions are being conducted in AD, PD, amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis. Neurodevelopmental research has also seen a boon in microbiome-related clinical research including in autism, Attention-deficit/hyperactivity disorder, and schizophrenia, which is confirming prior animal model work regarding the key time-windows in the gut microbiome important for infant cognition. While recent research advances represent important progress, fundamental knowledge gaps and obstacles remain. Knowing how and why the gut microbiome changes at the extremes of life will develop our mechanistic understanding and help build the evidence base as we strive toward counteracting microbial missteps with precision therapeutic interventions.
Synergistic metabolic modulation of fibroblast-like synoviocytes via targeted dual prodrug nanoparticles to mitigate rheumatoid arthritis
Authors: Shaobing Li, Juntao Lin, Chengxinqiao Wang, Junhan Liu, Yupeng Wang, Yan Chen, Dongfang Zhou
Journal: Acta Pharmaceutica Sinica B (2024)

Elevated glucose metabolism is a prominent characteristic of fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA). However, the efficacy of inhibiting a single target of glucose metabolism in FLS using small molecular inhibitors is limited for RA treatment. Herein, the synergistic inhibition of FLS' survival, proliferation, and activation by combining two glucose metabolism inhibitors, diclofenac (DC) and lonidamine (LND) was first verified. Subsequently, DC and LND were individually conjugated to cystamine-modified hyaluronic acid (HA) to prepare two polymer-prodrug conjugates. A HAP-1 peptide-modified dual polymer-prodrug conjugates-assembled nanoparticles system (HAP-1NPDC+LND) was further tailored in the optimal synergistic ratio for targeted and synergistic metabolic modulation of FLS to alleviate RA symptoms. Upon targeted uptake by FLS in inflamed joints, HAP-1NPDC+LND released DC and LND within the intracellular reductive microenvironment, where DC hinders glucose uptake and LND suppresses glycolytic enzymes to eliminate FLS synergistically. Additionally, the secretion of lactic acid and pro-inflammatory factors from FLS were reduced, thereby disrupting the crosstalk between FLS and pro-inflammatory macrophages. Finally, HAP-1NPDC+LND demonstrated promising efficacy in a mouse model of collagen-induced arthritis (CIA). Overall, this research provides valuable insights into novel therapeutic strategies for the safe and effective of treatment RA through targeted and synergistic metabolic modulation of FLS.