bluuebunny/crossref_metadata_2025_split huggingface dataset:
Distinct immune and clinical responses to alcohol-soluble vs. salt-soluble wheat proteins in mice
Authors: Gangur Venugopal , Jin Yining , Ebaugh Sarah , Martens Anna , Olson Eric , Ng Perry KW 
Published: January 2023

Abstract
Food hypersensitivity is a growing global public health problem. Wheat has been linked to distinct types of human hypersensitivities with incompletely understood mechanisms. Although wheat proteins (WP) differ in solubility, it is unknown whether alcohol-soluble (AS) and salt-soluble (SS) WP differ in their immune and disease activation properties. Here we tested the hypothesis that AS and SSWP extracted from soft-wheat will elicit distinct types of immune and clinical responses in inbred mice. Groups of BALB/cJ mice weaned onto a plant-protein free diet received IP injections with AS and SSWP (0.01 mg/mouse) along with alum. The WP-specific (S) IgE, IgG1, IgG2a, IgA and total (T) IgE responses were analyzed. Systemic anaphylaxis and mucosal mast cell degranulation response (MMCR) upon IP challenge were quantified by hypothermia shock response (HSR) and elevation of plasma mMCP-1, respectively. Mice were monitored for dermatitis and alopecia. Spleen tissue extracts were used in measuring immune-activation biomarkers. Whereas the SSWP elicited higher titers of SIgA, the ASWP elicited higher titers of SIgE, SIgG1, SIgG2a and higher TIgE levels. The ASWP elicited significantly higher HSR and MMCR. Only ASWP but not SSWP elicited dorsal neck dermatitis lesions in 44% of mice. Alopecia lesions, without inflammation, were noted in 22% of ASWP- and 33% of SSWP-injected mice. Furthermore, ASWP and SSWP elicited distinct patterns of activation of acute-phase response proteins, chemokines, cytokines, growth factors, matrix proteins and signaling proteins. These data provide the first direct evidence that WP fractions that differ in solubility elicit qualitatively distinct immune and clinical reactions in genetically identical mice.
Tumor-derived indoleamine 2,3- dioxygenase regulates density of tumor infiltrating CD8+ T cells and myeloid derived suppressor cells in a murine model of ovarian cancer
Authors: Amobi Adaobi , Odunsi Kunle 
Published: January 2023

Abstract
The catabolism of the essential amino-acid tryptophan by indoleamine 2,3-dioxygenase (IDO1) is a central pathway that contributes to an immunosuppressive microenvironment in many types of cancer. Our lab has previously shown that IDO1 expression in human ovarian tumor correlates with poor prognosis and poor tumor infiltration by CD8+ T cells, and that improved survival is associated with increased tumor infiltrating lymphocytes. Thus, IDO1 inhibition represents an attractive target for cancer immunotherapy.
To establish the mechanism by which IDO1 inhibition augments immune responses in a murine model of metastatic ovarian cancer, we generated a stable IDO1-overexpressing cell line (IE9mp1-mIDO1) and confirmed functional IDO1 enzyme activity. C57BL/6 mice were challenged intraperitoneally with IE9mp1-mIDO1 or IE9mp1-Empty Vector as a control. IE9mp1-mIDO1 tumor-bearing mice displayed earlier onset of tumor burden and decreased overall survival.
To delineate the role of host- and tumor-derived IDO1 on immune cell infiltration in the tumor, IDO1 genetic knockout and C57BL/6 mice were challenged with IE9mp1-EV or -mIDO1 tumor cells. All mice challenged with IE9mp1-mIDO1 demonstrate decreased CD8+ T cells in the tumor compared to IDO1KO mice challenged with IE9mp1-EV tumor cells. Moreover, tumor-derived IDO1 mediates increased CD11b+Gr1+ myeloid derived suppressor cells (MDSC) in tumor ascites.
From these data, we conclude that regulation of IDO1 will promote anti-tumor immune responses by permitting increased effector T cells in tumor tissues and decrease MDSCs in ascites. Ongoing experiments will characterize the mechanism by which IDO1 inhibition may augment vaccine-induced immune responses in ovarian cancer.
Microbiota metabolites derived from tryptophan modulate macrophage inflammation and migration in non-alcoholic fatty liver disease
Authors: Ding Yufang , Krishnan Smitha , Lee Kyongbum , Jayaraman Arul 
Published: January 2023

Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease in western countries. While it is established that the gut microbiota plays a role in NAFLD, the identities of microbiota metabolites involved and their target pathways in host cells is poorly understood. Based on prior work showing that the microbiota metabolite indole attenuates indicators of inflammation in intestinal epithelial cells, we hypothesized that microbiota metabolites modulate macrophage inflammation in the liver. Mass spectrometry analysis of microbiota metabolites in serum and liver of mice identified tryptamine (TA) and indole-3-acetate (I3A) as depleted in mice on a high-fat diet compared to low-fat diet. Therefore, we investigated the effect of I3A and TA on macrophage inflammation and migration. RAW 264.7 murine macrophages were treated with different concentrations of I3A and TA for 4 hours, stimulated with palmitate for 18 hours followed by LPS for 6 hours in the presence of metabolites. Our results show that treatment with I3A significantly attenuated the induction of the pro-inflammatory cytokines TNFa, IL-1b and MCP-1 by palmitate and LPS in a dose dependent manner at both mRNA and protein levels. Unlike I3A, TA only decreased the gene expression of IL-1b but significantly decreased TNFa and MCP-1 protein levels. Both I3A and TA significantly decreased bone marrow derived macrophage migration towards MCP-1 in a dose dependent manner. Together, our results suggest that microbiota metabolites can modulate NAFLD by directly acting on macrophages. Ongoing work focuses on investigating the mechanisms underlying the anti-inflammatory activity of I3A and TA, which could provide new strategies to treat NAFLD.
Comparison of cytotoxic dynamics between cytokine-induced killer cells and natural killer cells at the single cell level
Authors: Lee Jae Hee , Kim Ji Sung , Lee Hong Kyung , Kim Ki Hun , Choi Jeong Eun , Ji A Young , Hong Jin Tae , Kim Youngsoo , Han Sang-Bae 
Published: January 2023

Abstract
Although much has been learned about the cytotoxic mechanisms of cytokine-induced killer (CIK) and natural killer (NK) cells, little is known about how they kill cancer cells at the single-cell level. In the present study, we examined the contact dynamics of CIK and NK cells at the single-cell level by using time-lapse imaging. CIK cells killed MHC-I-negative and -positive cancer cells, but NK cells destroyed MHC-I-negative cells only. Moreover, CIK cells moved in all directions and showed longer tracks than did NK cells. CIK cells showed higher displacement and straightness scores than did NK cells, which indicates long-distance random migration of CIK cells. CIK and NK cells moved at 6.7 mm/min and 4.5 mm/min on average, respectively. These data suggest that CIK cells are likely moving more actively than NK cells. The average threshold number of CIK cells required to kill an individual cancer cell was 6.7 for MHC-I-negative cells and 6.9 for MHC-I-positive cells. That of NK cells was 2.4 for MHC-I-negative cells. Likely due to the higher threshold numbers, killing by CIK cells was delayed in comparison with NK cells: 40% of MHC-negative target cells were killed after 5 h when co-cultured with CIK cells and after 2 h with NK cells. Our data have implications for the rational design of CIK or NK cell–based immunotherapy of cancer patients
A murine model of suicide gene therapy in the brainstem demonstrates efficacy without toxic inflammation, suggesting possible use as a treatment for diffuse intrinsic pontine glioma (DIPG)
Authors: Schuelke Matt , Evgin Laura , Thompson Jill , Daniels David , Rao Amulya Nageswara , Bram Richard J , Kasahara Noriyuki , Vile Richard 
Published: January 2023

Abstract
Diffuse intrinsic pontine glioma (DIPG) is a rare pediatric brainstem tumor that is the leading cause of death among pediatric brain malignancies. Despite over 200 clinical trials, no significant progress has been made, leading our lab to consider suicide gene therapy. The brainstem has particularly sensitive anatomy, creating the potential for toxic inflammation. Furthermore, the clinical standard of care for DIPG includes conventional radiation therapy (RT) followed by dexamethasone (DEX), each of which can alter the efficacy of gene therapy. In this study we found that a variety of gliomas, including human DIPG and murine glioma cell lines, are infectable in vitro with a replication-competent Moloney murine leukemia virus (MoMLV) (currently in Phase 2/3 clinical trials) and susceptible to ganciclovir (GCV)-mediated killing via the HSV thymidine kinase (tk) suicide gene. A B16 melanoma cell line expressing HSV tk implanted into the brainstem of mice, extended median survival with GCV therapy from 13 days to 38.5 days (p=.0006) with no signs of toxic inflammation. Pre-treatment with RT and DEX did not affect therapeutic efficacy. We have shown that GCV/TK therapy is mediated by NK and CD8 cells in subcutaneous tumors, and we are investigating whether a similar immunologic mechanism is involved in this brainstem model. These preclinical data will pave the way for novel clinical trials for the treatment of DIPG.
Granzyme B: a biomarker of influenza infection in older adults
Authors: Merani Shahzma , McNeil Shelly , McElhaney Janet E 
Published: January 2023

Abstract
The importance of a T-cell mediated response against influenza infection in older adults has growing support. It has been previously shown that effector cells in older adults challenged with influenza virus produce granzyme B (GrB) in the absence of perforin. This lack of perforin could impair CTL directed killing and result in high extracellular GrB levels.
GrB has been associated with various inflammatory and age related conditions and could also play an important role in influenza infection severity. We postulate that GrzB is a key mediator of inflammatory processes involved in severe influenza illness and could be used as a marker of influenza infection in older adults.
Subjects over the age of 65 admitted to hospital with influenza like symptoms were recruited and grouped into cases of laboratory confirmed influenza illness (LCII) and influenza like illness (ILI). PBMCs were isolated from blood samples collected from participants on hospital admission and one month post-discharge. PBMCs were challenge with live influenza virus. Real-time PCR was used to quantify IFNγ, GrB and IL10 in PBMCs and isolated T-cells.
We found that in vivo GrB levels in T-cells at the time of influenza infection in older adults were significantly higher in the LCII than the ILI group. Furthermore, ex vivo influenza virus challenge resulted in higher IFNγ, GrB and IL10 responses in subjects with LCII than ILI.
Our study supports the association of elevated GrB and influenza infection status as well as the importance of T-cell mediated responses to infection. Future work will characterize GrB levels in older adults with varying severities of influenza illness with the aim to develop a point of care test to identify patients likely to develop serious outcomes.
Combination treatment with erlotinib and ampelopsin overcomes erlotinib resistance in NSCLC cells via the Nox2-ROS-Bim pathway
Authors: Noh Minhye , Hong Seung-Woo , Park Nam-Sook , Shim Ju A , Ahn Byul-Nim , Kim Yeong Seok , Kim Daejin , Lee Hyun-Kyung , Hur Dae Young 
Published: January 2023

Abstract
Erlotinib, a tyrosine kinase inhibitor (TKI) of epidermal growth factor receptor (EGFR), has been shown to have a dramatic effect in non-small cell lung cancer (NSCLC) patients with EGFR mutation. However, the presence of primary resistance or acquired resistance to EGFR-TKI is the most common reason for switching to other anti-cancer agents. Even though there are newer agents that have activity in the presence of the T790M mutation, identification of potential agents that could overcome resistance to EGFR-TKI is still needed for the treatment of NSCLC patients. In this study, we used erlotinib-resistant NSCLC cell lines to investigate the effects of combination treatment with erlotinib and ampelopsin. To determine the effect of Nox2 and Bim on the combined treatment with erlotinib and ampelopsin-induced cell death, we transfected with Nox2 or Bim specific siRNA and performed with western blot assay for evaluation of its expression. Combined treatment with erlotinib and ampelopsin at non-cytotoxic concentrations significantly induced caspase-dependent cell death in erlotinib-resistant NSCLC cells. Furthermore, cell death resulted in the accumulation of reactive oxygen species (ROS) through upregulation of nicotinamide adenine dinucleotide phosphate oxidase 2 (Nox2) expression, a direct source of ROS. The expression level of Bim increased with combination treatment, but not with either treatment alone. Here in this study, we demonstrate that the combination of erlotinib and ampelopsin induces cell death via the Nox2-ROS-Bim pathway, and ampelopsin could be used as a novel anti-cancer agent combined with EGFR-TKI to overcome resistance to erlotinib in EGFR-mutant NSCLC.
Radiation improved IL-21 cancer immunotherapy
Authors: Lee I-Jung , Wu Chia-Jen , Wu Ping-Yi , Tao Mi-Hua 
Published: January 2023

Abstract
Interleukin-21 is a pleiotropic cytokine which has shown promising antitumor activities in several preclinical models but the response rate in phase I–II clinical studies has been disappointing. Therefore, the optimal usage of IL-21 as an effective therapy against cancers remains to be studied. Radiotherapy, a well establish treatment modality for cancers, has shown its potential in immunogenic modulation by stimulating immune cell phagocytosis and inducing local tumor-associated antigens releasing. We hypothesize that a synergistic antitumor effect could be achieved by combining IL-21 with radiation through releasing neoantigens and amplifying adaptive antitumor immune responses against both primary and metastatic tumors. We treated mice bearing large established tumors with radiation, IL-21 or a combination of radiation and IL-21. Mice treated with radiation alone showed delayed tumor growth, while IL-21 treatment had very little effect. In contrast, a synergistic antitumor effect was achieved in the combination group, which not only led to complete tumor regression of primary tumors, but also significantly suppressed the growth of distant, untreated metastatic tumors. Mechanistic analysis revealed that combination therapy increased accumulation of tumor-infiltrating CD8+ T cells which showed enhanced functional activities, marked by increased expression of CD107a, IFN-γ and TNF-α. Moreover, mice that had been cured by the combination therapy developed memory responses against the subsequent tumor re-challenge. Our results demonstrate that combination of IL-21 and radiation has potent antitumor activity against both primary and metastatic tumors and could open a new perspective for cancer therapy.
Generation of

I

mmuno-

M

odulator

R

eceptors (IMR)-transduced human JY cell lines to test combo immuno-therapies.
Authors: Le Saux Sabine , Li Sophie , Shields Robert , Nourzaie Omar , Ugarte Fernando , De Waal Malefyt Rene 
Published: January 2023

Abstract
T cell activation is initiated by signal 1 through an antigen–specific TCR recognition and engagement, then a second co-stimulation signal is needed. This co-stimulation is provided by the interaction of IMR receptors and ligands expressed on the T cells and APC or tumor cells. These receptor-ligand interactions can either stimulate or inhibit T cell activation and they are the main targets for the new therapeutics developed in the oncology field.
The establishment of Ag-specific human T cell clones is essential to study IMR biology and even more to test different biologics targeting those molecules. In our laboratory, we developed primary-cell based assays to test such biologics. In those assays allo-Ag-specific human CD4+ T cell clones are activated by HLA-DR-positive JY cells, a human B cell line, to proliferate and to produce IFNγ. To analyze the efficacy of PD-1/Lag3 and PD-1/TIGIT biologics, we generated by lentivirus transduction, different JY cell line clones expressing PD-L1, CD155 or PD-L1/CD155. The JY clones isolated after infection showed a stable expression of the IMRs and they modulated activation of the CD4+ T cell clones.
Tumor Control Index: a novel tool to assess and compare tumor growth in experimental animals
Authors: Ebrahimi-Nik Hakimeh , Corwin William L. , Floyd Stephanie M. , Tavousi Pouya , Mandoiu Ion I , Srivastava Pramod K 
Published: January 2023

Abstract
Measurement of tumor diameters, tumor volumes, or area under the curve has been traditionally used to quantitate the effects of experimental manipulations in immune competent as well as immune-compromised mice and rats. However, using these parameters to measure the kinetics of tumor growth fail to reveal several complexities of growing tumors. Here, by means of tumor growth data from a large number of mice challenged with live tumor cells, we describe the use of a new composite parameter, Tumor Control Index (TCI) as an alternative method to do the same. This index, comprised of three distinct values, the Tumor Progression Score, Tumor Rejection Score, and Tumor Stability Score, provides a complete picture of nearly every aspect of tumor growth in large numbers of animals, can be deduced automatically from tumor diameter or volume data, and can be used to compare several groups of animals in different experiments. This automatically derivable index also corresponds neatly to the use of complete and partial responses and tumor stability data generated in human tumors, and can be used to assess the efficacy of interventions to be used in clinical studies.
Obesity-induced changes in baseline immune responses to pre-clinical breast cancer
Authors: Gibson Justin Tyler , Nagareddy Prabhakara , Norian Lyse A 
Published: January 2023

Abstract
Obesity is known to increase morbidity and mortality in breast cancer patients; however, the immunological mechanisms behind these changes remain unclear. The long-term goal of our study is to investigate the broad impact of obesity on anti-tumor immunity, with a particular focus on better understanding immune alterations that may influence the use of immunotherapeutics in breast cancer patients. We began by utilizing the leptin-deficient ob/ob mouse model of obesity and non-obese age matched C57BL/6 controls, in combination with the syngeneic E0771 mammary carcinoma cell line. Tumor outgrowth was quantified by means of caliper measurements, endpoint tumor weight, and bioluminescent imaging (BLI) via luciferase-expressing E0771 (E0771-fLUC) cells; immune cell populations were evaluated via multi-parameter flow cytometry. Primary and metastatic tumor growth were not significantly different between lean and ob/ob mice. In primary tumors, we found that obesity caused significant decreases in the frequencies of tumor-infiltrating granulocytic myeloid derived suppressor cells (G-MDSCs) and CD19+ B cells, and trending decreases in the frequencies of T (CD3+, CD4+, and CD8+) cells. In spleens, we found that both obesity and breast cancer induced a significant decrease in the frequency of dendritic and natural killer (NK) cell populations. Additionally, obesity induced a significant increase in the frequency of splenic monocytic myeloid-derived suppressor cells (M-MDSCs). Our findings suggest several cellular candidates for future mechanistic investigations into obesity-induced dysfunctions in breast cancer immunity.
Melittin suppresses tumor progression by regulating tumor-associated macrophages in a Lewis lung carcinoma mouse model
Authors: Lee Chanju , Choi Dabin , Lee Sujin , Bae Sung-joo S. , Joo Hwansoo , Bae Hyunsu 
Published: January 2023

Abstract
Tumor-associated macrophages (TAM) are a major component of tumor stroma. It has been reported that TAMs have M2-like phenotype and facilitate tumor progression by promoting angiogenesis and immunosuppression. Melittin, a major polypeptide of bee venom, has been widely studied as an anti-cancer drug due to its cytotoxicity to malignant cells. However, very little is known regarding the effect of melittin on immune cells in the tumor microenvironment. We demonstrated here that melittin inhibited the rapid tumor growth compared to the control in vivo. Melittin increased the M1/M2 ratio of TAMs by selectively reducing the number of CD206+ M2-like TAMs, while not affecting the number of CD86+ M1-like TAMs. Melittin also preferentially bound to CD11b+ cells and this binding was not associated with phagocytosis. Gene expression of vascular endothelial growth factor (Vegf) and mannose receptor C type 1 (Mrc1/CD206) was reduced in M2-like bone marrow-derived macrophages by melittin treatment, but there was no significant change in the gene level of Vegf and FMS-like tyrosine kinase 1 (Flt1/VEGFR1) in tumor cells. Additionally, the levels of VEGF and CD31, markers of angiogenesis, were significantly decreased by melittin treatment in tumor tissues. This study revealed a novel role for melittin in tumor treatment and suggested that melittin could be a promising therapeutic agent for targeting M2-like TAMs.
Role of macrophages in the therapeutic effect of Regulatory T Cell ablation in breast cancer
Authors: Clark Nicholas M , Martínez Leandro M , Effi Comfort C , Bos Paula D 
Published: January 2023

Abstract
Tumor progression ensues when cancer cells escape the control of immune system. An important tumor immune evasion mechanism is the recruitment of regulatory T (Treg) cells. Treg cells, characterized by the expression of the transcription factor Foxp3, comprise a large proportion of the T lymphocyte population infiltrating mouse and human tumors. Treg cells correlate with poor prognosis in various tumors, such as breast carcinomas. Using the MMTV-PyMT-driven model of murine mammary gland cancer, our lab has demonstrated that short-term Treg cell ablation provides a significant therapeutic effect in vivo. Importantly, this effect does not require cytotoxic CD8+ and NK+ cells, but is dependent on INFg. The goal of this study is to identify the effector cell type responsible for this therapeutic effect, and characterize the mechanisms by which they lead to tumor growth inhibition. We discovered that bone marrow-derived inflammatory monocytes and macrophages play a critical role in the anti-tumorigenic effect observed after Treg cell ablation by adopting a pro-inflammatory phenotype, leading to increased tumor cell killing. Ongoing studies are addressing the role of INFg on this Treg cell induced phenotypic plasticity. Together, these results demonstrate an essential role for myeloid cells in the anti-tumor effect observed upon Treg cell ablation. Our studies have the potential to reveal promising targets for therapeutic intervention.