-
International Immunopharmacology Jun 2024The mechanism of early tumor recurrence after incomplete microwave ablation (iMWA) is poorly understood. The anti-programmed cell death protein 1 (anti-PD-1) monotherapy...
The mechanism of early tumor recurrence after incomplete microwave ablation (iMWA) is poorly understood. The anti-programmed cell death protein 1 (anti-PD-1) monotherapy is reported to be ineffective to prevent the progression of residual tumor resulted from iMWA. Transforming growth factor-β (TGFβ) signaling pathway plays an important role in tumorigenesis and development. We assume blocking transforming growth factor-β receptor (TGFβR) after incomplete iMWA may synergistically enhance the effect of anti-PD-1 antibody to prevent the progression of residual tumor. We construct an iMWA model with mice harboring Hepa1-6 derived xenograft. The Tgfb1 expression and phosphorylated-Smad3 protein expression is upregulated in the residual tumor after iMWA. With the application of TGFβR inhibitor SB431542, the cell proliferation potential, the tumor growth, the mRNA expression of epithelial mesenchymal transition (EMT) markers including Cdh2, and Vim, and cancer stem cell marker Epcam, and the infiltrating Treg cells are reduced in the residual tumor tissue. In addition, iMWA combined with TGFβR blocker and anti-PD-1 antibody further decreases the cell proliferation, tumor growth, expression of EMT markers and cancer stem cell marker, and the infiltrating Treg cells in the residual tumor tissue. Blocking TGFβR may alleviate the pro-tumoral effect of tumor microenvironment thereby significantly prevents the progression of residual tumor tissue. Our study indicates that blocking TGFβR may be a novel therapeutic strategy to enhance the effect of anti-PD-1 antibody to prevent residual hepatocellular carcinoma (HCC) progression after iMWA.
PubMed: 38950456
DOI: 10.1016/j.intimp.2024.112585 -
Proceedings of the National Academy of... Jul 2024While the intracellular-extracellular distribution of lactate has been suggested to play a critical role in the healthy and diseased brain, tools are lacking to...
While the intracellular-extracellular distribution of lactate has been suggested to play a critical role in the healthy and diseased brain, tools are lacking to noninvasively probe lactate in intracellular and extracellular spaces. Here, we show that, by measuring the diffusion of lactate with diffusion-weighted magnetic resonance (MR) spectroscopy in vivo and comparing it to the diffusion of purely intracellular metabolites, noninvasive quantification of extracellular and intracellular lactate fractions becomes possible. More specifically, we detect alterations of lactate diffusion in the APP/PS1 mouse model of Alzheimer's disease. Data modeling allows quantifying decreased extracellular lactate fraction in APP/PS1 mice as compared to controls, which is quantitatively confirmed with implanted enzyme-microelectrodes. The capability of diffusion-weighted MR spectroscopy to quantify extracellular-intracellular lactate fractions opens a window into brain metabolism, including in Alzheimer's disease.
Topics: Animals; Lactic Acid; Alzheimer Disease; Brain; Mice; Mice, Transgenic; Diffusion Magnetic Resonance Imaging; Extracellular Space; Disease Models, Animal; Magnetic Resonance Spectroscopy; Male; Amyloid beta-Protein Precursor
PubMed: 38950371
DOI: 10.1073/pnas.2403635121 -
ACS Applied Materials & Interfaces Jul 2024The development of efficient theranostic nanoagents for the precise diagnosis and targeted therapy of glioblastoma (GBM) remains a big challenge. Herein, we designed and...
The development of efficient theranostic nanoagents for the precise diagnosis and targeted therapy of glioblastoma (GBM) remains a big challenge. Herein, we designed and developed porphyrin-based organic nanoparticles (PNP NPs) with strong emission in the near-infrared IIa window (NIR-IIa) for orthotopic GBM theranostics. PNP NPs possess favorable photoacoustic and photothermal properties, high photostability, and low toxicity. After modification with the RGD peptide, the obtained PNPD NPs exhibited enhanced blood-brain barrier (BBB) penetration capability and GBM targeting ability. NIR-IIa imaging was employed to monitor the biodistribution and accumulation of the nanoparticles, revealing a significant enhancement in penetration depth and signal-to-noise ratio. Both and results demonstrated that PNPD NPs effectively inhibited the proliferation of tumor cells and induced negligible side effects in normal brain tissues. In general, the work presented a kind of brain-targeted porphyrin-based NPs with NIR-IIa fluorescence for orthotopic glioblastoma theranostics, showing promising prospects for clinical translation.
PubMed: 38950334
DOI: 10.1021/acsami.4c03012 -
ACS Nano Jul 2024Raman spectroscopy has made significant progress in biosensing and clinical research. Here, we describe how surface-enhanced Raman spectroscopy (SERS) assisted with... (Review)
Review
Raman spectroscopy has made significant progress in biosensing and clinical research. Here, we describe how surface-enhanced Raman spectroscopy (SERS) assisted with machine learning (ML) can expand its capabilities to enable interpretable insights into the transcriptome, proteome, and metabolome at the single-cell level. We first review how advances in nanophotonics-including plasmonics, metamaterials, and metasurfaces-enhance Raman scattering for rapid, strong label-free spectroscopy. We then discuss ML approaches for precise and interpretable spectral analysis, including neural networks, perturbation and gradient algorithms, and transfer learning. We provide illustrative examples of single-cell Raman phenotyping using nanophotonics and ML, including bacterial antibiotic susceptibility predictions, stem cell expression profiles, cancer diagnostics, and immunotherapy efficacy and toxicity predictions. Lastly, we discuss exciting prospects for the future of single-cell Raman spectroscopy, including Raman instrumentation, self-driving laboratories, Raman data banks, and machine learning for uncovering biological insights.
PubMed: 38950145
DOI: 10.1021/acsnano.4c04282 -
PLoS Pathogens Jul 2024The regulation of inflammatory responses and pulmonary disease during SARS-CoV-2 infection is incompletely understood. Here we examine the roles of the prototypic pro-...
The regulation of inflammatory responses and pulmonary disease during SARS-CoV-2 infection is incompletely understood. Here we examine the roles of the prototypic pro- and anti-inflammatory cytokines IFNγ and IL-10 using the rhesus macaque model of mild COVID-19. We find that IFNγ drives the development of 18fluorodeoxyglucose (FDG)-avid lesions in the lungs as measured by PET/CT imaging but is not required for suppression of viral replication. In contrast, IL-10 limits the duration of acute pulmonary lesions, serum markers of inflammation and the magnitude of virus-specific T cell expansion but does not impair viral clearance. We also show that IL-10 induces the subsequent differentiation of virus-specific effector T cells into CD69+CD103+ tissue resident memory cells (Trm) in the airways and maintains Trm cells in nasal mucosal surfaces, highlighting an unexpected role for IL-10 in promoting airway memory T cells during SARS-CoV-2 infection of macaques.
PubMed: 38950078
DOI: 10.1371/journal.ppat.1012339 -
PloS One 2024The objective of this study was to retrospectively assess the effect of Radiofrequency Volumetric Tissue Reduction (RFVTR) on hypertrophic turbinates and clinical...
OBJECTIVE
The objective of this study was to retrospectively assess the effect of Radiofrequency Volumetric Tissue Reduction (RFVTR) on hypertrophic turbinates and clinical outcome in brachycephalic dogs when included in multi-level surgery (MLS).
STUDY DESIGN
Clinical retrospective multicenter study.
ANIMALS
132 client-owned brachycephalic dogs.
METHODS
132 brachycephalic dogs with high-grade Brachycephalic Obstructive Airway Ayndrome (BOAS) and hypertrophic turbinates were treated with RFVTR as part of MLS of the upper airways. Intranasal obstruction was evaluated by computer tomography (CT) and antero-/retrograde rhinoscopy before and 6 months after RFVTR. The clinical records, the CT images and the rhinoscopy videos were reviewed and clinical evolution was evaluated using a standardized questionnaire. The data was scored semi-quantitatively.
RESULTS
In this study, 132 patients were included for a follow-up period of 120 weeks. RFVTR resulted in minor complications, including serous nasal discharge within the first postoperative week in all dogs, and intermittent nasal congestion between 3-8 weeks after treatment in 24.3% of the patients. Rhinoscopy and CT follow-ups were available for 33 patients. Six months after treatment intranasal airspace was increased (p = 0.002) and the presence and overall amount of mucosal contact points was reduced (p = 0.039).
CONCLUSION
MLS with RFVTR led to a significant reduction in turbinate volume at the 6-month follow-up examination and significant clinical improvement over a long-term period of 120 weeks. This suggests the viability of RFVTR as a turbinate-preserving treatment for intranasal obstruction in dogs with BOAS.
CLINICAL SIGNIFICANCE
RFVTR is a minimally invasive turbinoplasty technique for intranasal obstruction in dogs with BOAS and can be included in MLS without increasing complication rates.
Topics: Animals; Dogs; Turbinates; Retrospective Studies; Dog Diseases; Male; Female; Nasal Obstruction; Hypertrophy; Tomography, X-Ray Computed; Treatment Outcome; Airway Obstruction
PubMed: 38950052
DOI: 10.1371/journal.pone.0306391 -
Clinical Cancer Research : An Official... Jul 2024Classic Hodgkin lymphoma (cHL) is a B cell lymphoma that occurs primarily in young adults and, less frequently, in elderly individuals. A hallmark of cHL is the...
PURPOSE
Classic Hodgkin lymphoma (cHL) is a B cell lymphoma that occurs primarily in young adults and, less frequently, in elderly individuals. A hallmark of cHL is the exceptional scarcity (1-5%) of the malignant Hodgkin Reed-Sternberg (HRS) cells within a network of non-malignant immune cells. Molecular determinants governing the relationship between HRS cells and their proximal microenvironment remain largely unknown.
EXPERIMENTAL DESIGN
We performed spatially resolved multiplexed protein imaging and transcriptomic sequencing to characterize HRS cell states, cellular neighborhoods, and gene expression signatures of 23.6 million cells from 36 newly diagnosed Epstein-Barr virus (EBV) positive and EBV-negative cHL tumors.
RESULTS
We show that MHC-I expression on HRS cells is associated with immune inflamed neighborhoods containing CD8+ T cells, MHC-II+ macrophages, and immune checkpoint expression (i.e., PD-1 and VISTA). We identified spatial clustering of HRS cells, consistent with the syncytial variant of cHL, and its association with T cell excluded neighborhoods in a subset of EBV-negative tumors. Finally, a subset of both EBV-positive and EBV-negative tumors contained regulatory T cells high neighborhoods harboring HRS cells with augmented proliferative capacity.
CONCLUSIONS
Our study links HRS cell properties with distinct immunophenotypes and potential immune escape mechanisms in cHL.
PubMed: 38949890
DOI: 10.1158/1078-0432.CCR-24-0942 -
International Journal of Cancer Jul 2024Gliomas are primary brain tumors and are among the most malignant types. Adult-type diffuse gliomas can be classified based on their histological and molecular...
Gliomas are primary brain tumors and are among the most malignant types. Adult-type diffuse gliomas can be classified based on their histological and molecular signatures as IDH-wildtype glioblastoma, IDH-mutant astrocytoma, and IDH-mutant and 1p/19q-codeleted oligodendroglioma. Recent studies have shown that each subtype of glioma has its own specific distribution pattern. However, the mechanisms underlying the specific distributions of glioma subtypes are not entirely clear despite partial explanations such as cell origin. To investigate the impact of multi-scale brain attributes on glioma distribution, we constructed cumulative frequency maps for diffuse glioma subtypes based on T1w structural images and evaluated the spatial correlation between tumor frequency and diverse brain attributes, including postmortem gene expression, functional connectivity metrics, cerebral perfusion, glucose metabolism, and neurotransmitter signaling. Regression models were constructed to evaluate the contribution of these factors to the anatomic distribution of different glioma subtypes. Our findings revealed that the three different subtypes of gliomas had distinct distribution patterns, showing spatial preferences toward different brain environmental attributes. Glioblastomas were especially likely to occur in regions enriched with synapse-related pathways and diverse neurotransmitter receptors. Astrocytomas and oligodendrogliomas preferentially occurred in areas enriched with genes associated with neutrophil-mediated immune responses. The functional network characteristics and neurotransmitter distribution also contributed to oligodendroglioma distribution. Our results suggest that different brain transcriptomic, neurotransmitter, and connectomic attributes are the factors that determine the specific distributions of glioma subtypes. These findings highlight the importance of bridging diverse scales of biological organization when studying neurological dysfunction.
PubMed: 38949756
DOI: 10.1002/ijc.35068 -
The Journal of Cell Biology Sep 2024Contact sites between lipid droplets and other organelles are essential for cellular lipid and energy homeostasis upon metabolic demands. Detection of these contact...
Contact sites between lipid droplets and other organelles are essential for cellular lipid and energy homeostasis upon metabolic demands. Detection of these contact sites at the nanometer scale over time in living cells is challenging. We developed a tool kit for detecting contact sites based on fluorogen-activated bimolecular complementation at CONtact sites, FABCON, using a reversible, low-affinity split fluorescent protein, splitFAST. FABCON labels contact sites with minimal perturbation to organelle interaction. Via FABCON, we quantitatively demonstrated that endoplasmic reticulum (ER)- and mitochondria (mito)-lipid droplet contact sites are dynamic foci in distinct metabolic conditions, such as during lipid droplet biogenesis and consumption. An automated analysis pipeline further classified individual contact sites into distinct subgroups based on size, likely reflecting differential regulation and function. Moreover, FABCON is generalizable to visualize a repertoire of organelle contact sites including ER-mito. Altogether, FABCON reveals insights into the dynamic regulation of lipid droplet-organelle contact sites and generates new hypotheses for further mechanistical interrogation during metabolic regulation.
Topics: Lipid Droplets; Humans; Endoplasmic Reticulum; Mitochondria; Fluorescent Dyes; Lipid Metabolism; HeLa Cells; HEK293 Cells; Luminescent Proteins
PubMed: 38949658
DOI: 10.1083/jcb.202311126 -
Inorganic Chemistry Jul 2024In recent years, the coordination chemistry of high-spin Fe(III) complexes has increasingly attracted interest due to their potential as effective alternatives to...
In recent years, the coordination chemistry of high-spin Fe(III) complexes has increasingly attracted interest due to their potential as effective alternatives to Gd(III)-based MRI contrast agents. This paper discusses the results from our study on Fe(III) complexes with two EDTA derivatives, each modified with either one (EDTA-BOM) or two (EDTA-BOM) benzyloxymethylene (BOM) groups on the acetic arm(s). These pendant hydrophobic groups enable the complexes to form noncovalent adducts with human serum albumin (HSA), leading to an observed increase in relaxivity due to the reduction in molecular tumbling. Our research involved detailed relaxometric measurements and analyses of both H and O NMR data at varying temperatures and magnetic field strengths, which is conducted with and without the presence of a protein. A significant finding of this study is the effect of electronic relaxation time on the effectiveness of [Fe(EDTA-BOM)(HO)] and [Fe(EDTA-BOM)(HO)] as diagnostic MRI probes. By integrating these relaxometric results with comprehensive thermodynamic, kinetic, and electrochemical data, we have thoroughly characterized how structural modifications to the EDTA base ligand influence the properties of the complexes.
PubMed: 38949627
DOI: 10.1021/acs.inorgchem.4c01715