Selectively down-regulated PD-L1 by albumin-phenformin nanoparticles mediated mitochondrial dysfunction to stimulate tumor-specific immunological response for enhanced mild-temperature photothermal efficacy

Abstract Background Mild-temperature photothermal therapy (mild-PTT) has emerged as a highly promising antitumor strategy by triggering immunogenic cell death (ICD) to elicit both innate and adaptive immune responses for tumor control. However, mild-PTT still leads to the risk of tumor recurrence or metastasis because it could hardly completely eradicate tumors due to its impaired immunological efficacy owing to the enhanced PD-L1 expression in tumor cells after treatment. Results In this study, we described a hydrogen peroxide (H2O2) responsive manganese dioxide mineralized albumin nanocomposite loading with mitochondria function inhibitor phenformin (PM) and near-infrared photothermal dye indocyanine green (ICG) by modified two-step biomineralization method. In combination with ICG induced mild-PTT and PM mediated mitochondria dysfunction, PD-L1 expression was obviously down-regulated and the generated immunological responses was able to effectively attack the remaining tumor cells. Meanwhile, the risk of tumor metastasis was effectively inhibited by reducing the expression of tumor invasion-related signal molecules (TGF-β and vimentin) after combining treatment. Conclusion Such a strategy offers novel insight into the development of nanomedicine for mild-PTT as well as cancer immunotherapy, which can provide protection against tumor relapse post elimination of their initial and metastatic tumors. Graphical Abstract

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The role of epigenetic modifications for the pathogenesis of Crohn's disease

Clinical Epigenetics ◽

10.1186/s13148-021-01089-3 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

M. Hornschuh ◽

E. Wirthgen ◽

M. Wolfien ◽

K. P. Singh ◽

O. Wolkenhauer ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Adaptive Immune Response ◽

Adaptive Immune ◽

Bowel Diseases ◽

Inflammatory Bowel ◽

New Biomarkers ◽

Insight Into ◽

Specific Evaluation

AbstractEpigenetics has become a promising field for finding new biomarkers and improving diagnosis, prognosis, and drug response in inflammatory bowel disease. The number of people suffering from inflammatory bowel diseases, especially Crohn's disease, has increased remarkably. Crohn's disease is assumed to be the result of a complex interplay between genetic susceptibility, environmental factors, and altered intestinal microbiota, leading to dysregulation of the innate and adaptive immune response. While many genetic variants have been identified to be associated with Crohn's disease, less is known about the influence of epigenetics in the pathogenesis of this disease. In this review, we provide an overview of current epigenetic studies in Crohn's disease. In particular, we enable a deeper insight into applied bioanalytical and computational tools, as well as a comprehensive update toward the cell-specific evaluation of DNA methylation and histone modifications.

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Single-cell evaluation reveals shifts in the tumor-immune niches that shape and maintain aggressive lesions in the breast

Nature Communications ◽

10.1038/s41467-021-25240-z ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Vidya C. Sinha ◽

Amanda L. Rinkenbaugh ◽

Mingchu Xu ◽

Xinhui Zhou ◽

Xiaomei Zhang ◽

...

Keyword(s):

Breast Cancer ◽

T Cells ◽

Mouse Model ◽

Transition State ◽

Tumor Cell ◽

Single Cell ◽

Tumor Cells ◽

Breast Lesions ◽

Aggressive Tumor ◽

Insight Into

AbstractThere is an unmet clinical need for stratification of breast lesions as indolent or aggressive to tailor treatment. Here, single-cell transcriptomics and multiparametric imaging applied to a mouse model of breast cancer reveals that the aggressive tumor niche is characterized by an expanded basal-like population, specialization of tumor subpopulations, and mixed-lineage tumor cells potentially serving as a transition state between luminal and basal phenotypes. Despite vast tumor cell-intrinsic differences, aggressive and indolent tumor cells are functionally indistinguishable once isolated from their local niche, suggesting a role for non-tumor collaborators in determining aggressiveness. Aggressive lesions harbor fewer total but more suppressed-like T cells, and elevated tumor-promoting neutrophils and IL-17 signaling, disruption of which increase tumor latency and reduce the number of aggressive lesions. Our study provides insight into tumor-immune features distinguishing indolent from aggressive lesions, identifies heterogeneous populations comprising these lesions, and supports a role for IL-17 signaling in aggressive progression.

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Assessment of chicken breast shelf life based on bench-top and portable NIR spectroscopy tools coupled with chemometrics

Food Quality and Safety ◽

10.1093/fqsafe/fyaa032 ◽

2020 ◽

Author(s):

Ilaria Lanza ◽

Daniele Conficoni ◽

Stefania Balzan ◽

Marco Cullere ◽

Luca Fasolato ◽

...

Keyword(s):

Discriminant Analysis ◽

Shelf Life ◽

Meat Quality ◽

Near Infrared ◽

Nir Spectroscopy ◽

Life Assessment ◽

Chicken Breast ◽

Portable Devices ◽

Physicochemical Processes ◽

Insight Into

Abstract Near-infrared (NIR) spectroscopy is a rapid technique able to assess meat quality even if its capability to determine the shelf life of chicken fresh cuts is still debated, especially for portable devices. The aim of the study was to compare bench-top and portable NIR instruments in discriminating between four chicken breast refrigeration times (RT), coupled with multivariate classifier models. Ninety-six samples were analysed by both NIR tools at 2, 6, 10 and 14 days post-mortem. NIR data were subsequently submitted to partial least squares discriminant analysis (PLS-DA) and canonical discriminant analysis (CDA). The latter was preceded by double feature selection based on Boruta and Stepwise procedures. PLS-DA sorted moderate separation of RT theses, while shelf life assessment was more accurate on application of Stepwise-CDA. Bench-top tool had better performance than portable one, probably because it captured more informative spectral data as shown by the variable importance in projection (VIP) and restricted pool of Stepwise-CDA predictive scores (SPS). NIR tools coupled with a multivariate model provide deep insight into the physicochemical processes occurring during storage. Spectroscopy showed reliable effectiveness to recognise a 7-day shelf life threshold of breasts, suitable for routine at-line application for screening of meat quality.

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A smart mitochondria-targeting TP-NIR fluorescent probe for selective and sensitive sensing H2S in living cells and mice

New Journal of Chemistry ◽

10.1039/d1nj00840d ◽

2021 ◽

Author(s):

Qiaomei Yang ◽

Liyi Zhou ◽

Longpeng Peng ◽

Gangqiang Yuan ◽

Haiyuan Ding ◽

...

Keyword(s):

Hydrogen Sulfide ◽

Fluorescent Probe ◽

Near Infrared ◽

Living Cells ◽

Signal Molecules ◽

Two Photon ◽

Mitochondria Targeting

Hydrogen sulfide (H2S) is one of the important gaseous signal molecules and plays key roles in various biologically crucial processes. In this work, we report a novel two-photon near-infrared (TP-NIR)...

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Combining PD-L1 Inhibitors with Immunogenic Cell Death Triggered by Chemo-Photothermal therapy via a Thermosensitive Liposome System to Stimulate Tumor-specific Immunological Response

Nanoscale ◽

10.1039/d1nr03288g ◽

2021 ◽

Author(s):

Jie Yu ◽

Xidong He ◽

Zigui Wang ◽

Yu Peng Wang ◽

Sha Liu ◽

...

Keyword(s):

Cell Death ◽

Immune Responses ◽

Photothermal Therapy ◽

Immunological Response ◽

Immune Checkpoint Blockade ◽

Immunogenic Cell Death ◽

Adaptive Immune Responses ◽

Adaptive Immune ◽

Thermosensitive Liposome ◽

Liposome System

Immune checkpoint blockade (ICB) therapy in combination with immunogenic death (ICD) triggered by photothermal therapy (PTT) and oxaliplatin (OXA) treatment was expected to elicit both innate and adaptive immune responses...

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Technical Insights into Highly Sensitive Isolation and Molecular Characterization of Fixed and Live Circulating Tumor Cells for Early Detection of Tumor Invasion

PLoS ONE ◽

10.1371/journal.pone.0169427 ◽

2017 ◽

Vol 12 (1) ◽

pp. e0169427 ◽

Cited By ~ 34

Author(s):

Sophie Laget ◽

Lucile Broncy ◽

Katia Hormigos ◽

Dalia M. Dhingra ◽

Fatima BenMohamed ◽

...

Keyword(s):

Early Detection ◽

Tumor Cells ◽

Molecular Characterization ◽

Circulating Tumor Cells ◽

Tumor Invasion ◽

Highly Sensitive

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Production of matrix metalloproteinases and tissue inhibitor of metalloproteinases-1 by human brain tumors

Journal of Neurosurgery ◽

10.3171/jns.1994.81.1.0069 ◽

1994 ◽

Vol 81 (1) ◽

pp. 69-77 ◽

Cited By ~ 133

Author(s):

Takao Nakagawa ◽

Toshihiko Kubota ◽

Masanori Kabuto ◽

Kazufumi Sato ◽

Hirokazu Kawano ◽

...

Keyword(s):

Brain Tumor ◽

Matrix Metalloproteinases ◽

Brain Tumors ◽

Human Brain ◽

Tumor Cells ◽

Tumor Invasion ◽

Gelatinolytic Activity ◽

Normal Brain ◽

Tissue Inhibitor Of Metalloproteinases ◽

Human Brain Tumor

✓ The role of matrix metalloproteinases (MMP's) and their inhibitor, tissue inhibitor of metalloproteinases-1 (TIMP-1), in human brain tumor invasion was investigated. Gelatinolytic activity was assayed via gelatin zymography, and four MMP's (MMP-1, MMP-2, MMP-3, and MMP-9) and TIMP-1 were immunolocalized in human brain tumors and in normal brain tissues using monoclonal antibodies. The tissue was surgically removed from 44 patients: glioblastoma (five cases), anaplastic astrocytoma (six cases), astrocytoma (four cases), metastatic tumor (six cases), neurinoma (10 cases), meningioma (10 cases), and normal brain tissue (three cases). Glioblastomas, anaplastic astrocytomas, and metastatic tumors showed high gelatinolytic activity and positive immunostaining for MMP's; TIMP-1 was also expressed in these tumors, but some tumor cells were negative for the antibody. Astrocytomas had low gelatinolytic activity and the tumor cells showed no immunoreactivity for MMP's and TIMP-1. Although neurinomas and meningiomas had only moderate proteinase activity and exhibited positive immunoreactivity for MMP-9, intense expression of TIMP-1 was simultaneously observed in these tumor cells. These findings suggest that MMP's play an important role in human brain tumor invasion, probably due to an imbalance between the production of MMP's and TIMP-1 by the tumor cells.

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Prospective observational study of SARS-CoV-2 infection, transmission and immunity in a cohort of households in Liverpool City Region, UK (COVID-LIV): a study protocol

BMJ Open ◽

10.1136/bmjopen-2020-048317 ◽

2021 ◽

Vol 11 (3) ◽

pp. e048317

Author(s):

Wega Setiabudi ◽

Daniel Hungerford ◽

Krishanthi Subramaniam ◽

Natasha Marcella Vaselli ◽

Victoria E Shaw ◽

...

Keyword(s):

Observational Study ◽

Prospective Observational Study ◽

Initial Period ◽

Immunological Response ◽

Nucleic Acid Amplification ◽

Service Research ◽

City Region ◽

Immunological Responses ◽

Household Transmission ◽

Population Spread

IntroductionThe emergence and rapid spread of COVID-19 have caused widespread and catastrophic public health and economic impact, requiring governments to restrict societal activity to reduce the spread of the disease. The role of household transmission in the population spread of SARS-CoV-2, and of host immunity in limiting transmission, is poorly understood. This paper describes a protocol for a prospective observational study of a cohort of households in Liverpool City Region, UK, which addresses the transmission of SARS-CoV-2 between household members and how immunological response to the infection changes over time.Methods and analysisHouseholds in the Liverpool City Region, in which members have not previously tested positive for SARS-CoV-2 with a nucleic acid amplification test, are followed up for an initial period of 12 weeks. Participants are asked to provide weekly self-throat and nasal swabs and record their activity and presence of symptoms. Incidence of infection and household secondary attack rates of COVID-19 are measured. Transmission of SARS-CoV-2 will be investigated against a range of demographic and behavioural variables. Blood and faecal samples are collected at several time points to evaluate immune responses to SARS-CoV-2 infection and prevalence and risk factors for faecal shedding of SARS-CoV-2, respectively.Ethics and disseminationThe study has received approval from the National Health Service Research Ethics Committee; REC Reference: 20/HRA/2297, IRAS Number: 283 464. Results will be disseminated through scientific conferences and peer-reviewed open access publications. A report of the findings will also be shared with participants. The study will quantify the scale and determinants of household transmission of SARS-CoV-2. Additionally, immunological responses before and during the different stages of infection will be analysed, adding to the understanding of the range of immunological response by infection severity.

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A mass-conserved tumor invasion system with quasi-variational degenerate diffusion

Analysis and Applications ◽

10.1142/s0219530521500159 ◽

2021 ◽

pp. 1-66

Author(s):

Akio Ito

Keyword(s):

Hilbert Space ◽

Tumor Cells ◽

Tumor Invasion ◽

Real Hilbert Space ◽

Initial Boundary ◽

Inner Product ◽

Boundary Problems ◽

Theory Of Evolution ◽

Cross Diffusion ◽

Variational Structure

This paper deals with a nonlinear system (S) composed of three PDEs and one ODE below: [Formula: see text] The system (S) was proposed as one of the mathematical models which describe tumor invasion phenomena with chemotaxis effects. The most important and interesting point is that the diffusion coefficient of tumor cells, denoted by [Formula: see text], is influenced by both nonlocal effect of a chemical attractive substance, denoted by [Formula: see text], and the local one of extracellular matrix, denoted by [Formula: see text]. From this point, the first PDE in (S) contains a nonlinear cross diffusion. Actually, this mathematical setting gives an inner product of a suitable real Hilbert space, which governs the dynamics of the density of tumor cells [Formula: see text], a quasi-variational structure. Hence, the first purpose in this paper is to make it clear what this real Hilbert space is. After this, we show the existence of strong time local solutions to the initial-boundary problems associated with (S) when the space dimension is [Formula: see text] by applying the general theory of evolution inclusions on real Hilbert spaces with quasi-variational structures. Moreover, for the case [Formula: see text] we succeed in constructing a strong time global solution.

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IMMU-44. AN IMMUNOTHERAPEUTIC VACCINE COMPOSED OF IRRADIATED WHOLE TUMOR CELLS PULSED WITH MANNAN-BAM, TLR LIGANDS AND ANTI-CD40 ANTIBODY INDUCES POTENT IMMUNE RESPONSE IN PRECLINICAL GBM ANIMAL MODEL

Neuro-Oncology ◽

10.1093/neuonc/noab196.403 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi102-vi102

Author(s):

Herui Wang ◽

Rogelio Medina ◽

Juan Ye ◽

Pashayar Lookian ◽

Ondrej Uher ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

Tumor Cells ◽

T Lymphocyte ◽

Cd8 T Cells ◽

Therapeutic Efficacy ◽

Poly I:C ◽

Control Group ◽

Complete Regression ◽

Adaptive Immune

Abstract Despite numerous therapeutic advances, the treatment of glioblastoma multiforme (GBM) remains a challenge, with current 5-year survival rates estimated at 4%. Multiple characteristic elements of GBM contribute to its treatment-resistance, including its low immunogenicity and its highly immunosuppressive microenvironment that can effectively disarm adaptive immune responses. Hence, therapeutic strategies that aim to boost T-lymphocyte mediated responses against GBM are of great therapeutic value. Herein, we present a therapeutic vaccination strategy that promotes the phagocytosis of tumor cells, enhances tumor antigen presentation, and induces a tumor-specific adaptive immune response. This strategy consists of vaccinations with irradiated whole tumor cells (rWTC) pulsed with phagocytic agonists (Mannan-BAM), TLR ligands [LTA, Poly (I:C), and R-848], and anti-CD40 antibody (collectively abbreviated as rWTC-MBTA). We evaluated the therapeutic efficacy of rWTC-MBTA strategy in a mouse syngeneic GL261 orthotopic GBM tumor model. rWTC-MBTA or vehicle control were administered subcutaneously over the right foreleg three days after intracranial injection of GL261 cells. Complete regression (CR) of intracranial tumors was achieved in 70% (7/10) of rWTC-MBTA treated animals while none survived in the control group. Immunophenotyping analyses of peripheral lymph nodes and brain tumors of rWTC-MBTA treated mice demonstrated: (1) increased mature dendritic cells and MHC II+ monocytes; (2) increased effector (CD62L-CD44+) CD4-T and CD8-T cells; (3) increased cytotoxic IFNγ-, TNFα-, and granzyme B-secreting CD4-T and CD8-T cells. Of note, the therapeutic efficacy of rWTC-MBTA disappeared in CD4-T and/or CD8-T lymphocyte depleted mice. Three mice that achieved CR were rechallenged with 50k GL261 cells intracranially 14 months after the last rWTC-MBTA treatment and all rechallenged animals resisted GL261 tumor development, confirming the establishment of long-term immunological memory against GL261 tumor cells. Collectively, our study demonstrated that rWTC-MBTA strategy can effectively activate antigen presenting cells and induce more favorable T-cell signatures in the GBM tumors.

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