bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibitory Effect of Sargassum muticum (Yendo) Fensholt on Adipogenesis in 3T3-L1 Cells (44.29)
Authors: Ahn Eun-Kyung , Lee Jung A , Baik Seung Ho , Hong Seong Su , Oh Joa Sub 
Published: January 2023

Abstract
In this study, we investigated the ethanol extract of Sargassum muticum (Yendo) Fensholt (ESMF) inhibits adipocyte differentiation and expression of adipogenic marker genes, such as PPARγ (peroxisome proliferator activated receptor γ), C/EBPα (CCAAT-enhancer-binding protein α), GLUT4 (glucose transporter 4), adiponectin, aP2 (adipocyte fatty acid-binding protein 2) and ADD1/SREBP1c (adipocyte determination and differentiation factor 1/sterol regulatory element binding protein 1c) in 3T3-L1 cells. We demonstrated that ESMF induced a significant decrease in lipid accumulation and expression of adipogenic marker genes in a dose-dependent manner. In addition, ESMF reduced the transcripitional activity of PPARγ induced by troglitazone, a potent diabetes agent; it also suppressed expression of PPARγ and C/EBPα protein levels. Our findings provide that ESMF inhibits adipocyte differentiation through downregulation of various adipocytokines by blocking PPARγ and C/EBPα expression.
Generation and characterization of a CXCR3-EGFP bicistronic reporter (CIBER) mouse reveals phenotypically and functionally distinct populations of innate CD8+ T cells (44.9)
Authors: Oghumu Steve , Dong Ran , Shawler Todd , Kampfrath Thomas , Rajagopalan Sanjay , Sharpe Arlene , Satoskar Abhay 
Published: January 2023

Abstract
The chemokine receptor CXCR3 is expressed mainly on activated T cells, NK cells and NKT cells. CXCR3 is implicated in a host of immunological conditions and it contributes either to disease resolution or pathology. Here, we report the generation and characterization of a novel CXCR3 IRES bicistronic EGFP reporter (CIBER) mouse in which EGFP expression correlates with surface levels of CXCR3. Using CIBER mice, we have identified two distinct populations of innate CD8+ T cells, one which constitutively express CXCR3 and the other which does not. We demonstrate that CXCR3+ innate CD8+ T cells preferentially express higher levels of Ly6C and CD122 but lower levels of CCR9 compared to CXCR3- innate CD8+ T cells. Furthermore, we show that CXCR3+ innate CD8+ T cells express high transcript levels of anti-apoptotic and low levels of pro-apoptotic co-stimulatory molecules, respond more robustly to IL-2 and IL-15, and produce significantly more IFN-γ and granzyme B as compared to CXCR3- innate CD8+ T cells. Interestingly, CXCR3+ innate CD8+ T cells do not respond to IL-12 or IL-18 alone, but produce significant amounts of IFN-γ upon stimulation with a combination of these cytokines. Taken together, these findings demonstrate that CXCR3+ and CXCR3- innate CD8+ T cells are phenotypically and functionally distinct. CIBER mice could be a novel tool for studying the role of CXCR3 and CXCR3-expressing cells in vivo during infectious, autoimmune and neoplastic diseases.
Balance of Positive and Negative Roles of Alpha-beta and Gamma-delta CD1d-reactive T Cell Populations in Th1-type Anti-Viral and Anti-Tumor Responses (45.15)
Authors: Exley Mark , Simon Yue , Varghese Bindu , Lynch Lydia , Nowak Michael 
Published: January 2023

Abstract
iNKT can enhance anti-pathogen and anti-tumor immunity via NK and DC, leading to lymphocyte activation. Th1-biased NKT can contribute to protective responses against cancer and viruses. iNKT respond like CD1d+ DC to immunotherapy, but reciprocally to NK and Treg. Patient iNKT defects are reversible in vitro, so we are investigating correcting such defects in models and clinic. NKT are required for optimal resistance to certain viruses. CD1d KO mice are impaired in lymphocyte activation and in picornavirus clearance. Conversely to acute infection, chronic viral stimulation of NKT can lead to immunopathology. CD1d-specific gamma-delta T cells respond to CD1d induced by infection, causing viral myocarditis and potentially contributing to hepatitis C, since human dominant liver gamma-delta T cells Vd3+ T cells were largely CD1d-reactive. We also found CD1d is up-regulated and high levels of hepatic CD1d-reactive NKT in chronic hepatitis C (CHC) produce pro-inflammatory Th1 cytokines and their Type 2 responses (which can suppress anti-tumor responses and promote fibrosis) increase in cirrhosis. NKT in CHC, instead of being protective against virus and hepatocellular carcinoma, may promote inflammation and fibrosis while suppressing anti-tumor responses. Cancer model iNKT have functional defects similar to patients, apparently due to iNKT:CD1d+ tumor interactions, but reversed by alpha-Galcer+IL-12. Models are being utilized to optimize immuno-monitoring of an iNKT clinical trial.
Activation of murine γδ T-cells by mitochondrial damage-associated molecular patterns (DAMPS) (45.4)
Authors: Schwacha Martin , Rani Meenakshi , Zhang Qiong 
Published: January 2023

Abstract
Gamma delta T-cells have been shown to be important in the early immunoinflammatory response to injury, which can be independent of infection. This sterile inflammatory response is in part associated with DAMPs. Mitochondrial DAMPs (MTDs) have been shown to be important in trauma-induced neutrophil activation, but it is unknown whether MTDs activate other innate immune cells, such as γδ T-cells. To study this, splenic CD3+ γδ T-cells were isolated from αβ T-cell deficient C57BL/6 mice and mitochondria isolated from wildtype mouse livers. MTDs were isolated from mitochondria by sonication and centrifugation. Gamma delta T-cells were incubated with various concentrations of MTDs (0-1000 µg/ml) for 24 hr. T-cells were phenotyped for Toll-like receptor (TLR) expression by flow cytometry and the supernatants assayed for cytokine and growth factor content. MTDs caused a dose-dependent increase in TLR-2 and TLR-4 expression by γδ T-cells. Both the percentage of cells positive for TLRs and the degree of expression increased. MTDs also induced the dose-dependent production of the chemokine RANTES and the growth factors FGF and VEGF. These findings support the concept that the MTDs released after tissue/cellular injury are capable of activating γδ T-cells, thus initiating sterile inflammation as well as subsequent healing processes.
Essential roles of heat shock protein gp96 (Hsp90b1, grp94) in melanoma growth and melanosome development (46.1)
Authors: Zhang YONGLIANG , Liu Bei , Sun Shaoli , Li Zihai 
Published: January 2023

Abstract
Heat shock protein gp96(HSP90b1,grp94) is an endoplasmic reticulum chaperone of the HSP90 family. It is a master molecular chaperone for Toll-like receptors and integrins. Accumulating clinical and pathological evidences indicate that enhanced gp96 expression in cancer tissue is a poor prognostic factor. However, the underlying mechanism is unclear. To address this question, we knocked down gp96 from melanoma cell line B16F1 (B16-KD) using lentivirus-mediated shRNA strategy. We found that knockdown of gp96 did not interfere with the in vitro growth of B16F1, but robustly suppressed the growth of orthotopically inoculated tumor in mice. Mechanistic study demonstrates that gp96 deletion compromises VEGF-A expression and inhibited tumor-associated angiogenesis. These results suggest that altered tumor microenvironment upon gp96 knockdown was responsible for the delayed tumor growth in vivo. Unexpectedly, we also observed that melanin production was significantly inhibited in B16-KD, which correlated with the reduced tyrosinase activity but not its expression in B16-KD cells. Thus, our study has uncovered two novel roles of gp96 in regulating tumor angiogenesis and in facilitating melanin synthesis. The molecular mechanisms of these findings are under active investigation.
Is lymphatic pumping safe for breast cancer patients?: The role of lymphatic flow in tumor formation and metastasis (46.19)
Authors: Odeh Adam , McKee Courtney , McCauley Lyndsey , Jones Harlan , Hodge Lisa 
Published: January 2023

Abstract
Lymphedema, a common side effect of breast cancer, can only be treated effectively with techniques such as pneumatic compression, exercise, massage, and osteopathic manipulation. However, the effect of such therapies on tumors and metastases is unknown. We have developed a murine model to test the effect of abdominal lymphatic pump treatment (LPT) on cancer. F344 rats were injected intravenously or subcutaneously with MADB106 mammary carcinoma cells. Rats were then given 4 minutes of LPT under anesthesia, 4 minutes of light touch under anesthesia (sham), or no treatment (control) for 7 days. At day 8, lung tissues were analyzed for metastases, and for leukocyte number/activity. LPT on intravenously-inoculated rats reduced tumor metastases in the lungs by more than 40% compared to sham and control. This corresponded with an increase in IFN-γ, and in CCR9+CD4+, CCR9+CD8+, and CCR9+ NK cells in the lungs, suggesting that these cells were actually gut-derived. Interestingly, in the case of subcutaneous solid tumors, LPT may be detrimental, as tumor size and number of metastases were more than doubled. These data suggest that increasing lymphatic flow may mobilize gut-derived leukocytes, which can traffic to the lungs and confer protection against tumor metastases, possibly through IFN-γ. To our knowledge, this is the first time gut-derived cells have been shown to be protective in the lungs. However, these therapies may cause harm when performed in proximity to solid tumors.
Multiple mechanisms for ATP release from apoptotic tumor cells (46.21)
Authors: Boyd Tressler Andrea , Dubyak George 
Published: January 2023

Abstract
Extracellular ATP released from dying tumor cells treated with pro-apoptotic chemotherapeutic drugs plays a key role in activating anti-tumor immune responses. However, the mechanisms by which ATP is released from such tumor cells remain poorly defined. Physiological apoptosis induced by Fas signaling can elicit ATP release via pannexin 1 (panx1) channels gated by caspase 3/7 (casp3/7)-mediated proteolytic cleavage of the panx1 C-terminus. We used human Jurkat leukemia and murine EG7 lymphoma cells to test whether the pro-apoptotic drugs doxorubicin (Dx) and staurosporine (STS) elicit the same casp3/7&gt; panx1&gt; ATP release pathway. Cells were treated with Dx or STS for 1-18 h in the presence or absence of the pan-caspase inhibitor zVAD and then assayed for accumulation of extracellular adenine nucleotides (ANex) and intracellular active casp3/7. Accumulation of ANex in response to Dx required prolonged (&gt; 8h) treatment in both cell models and was insensitive to zVAD inhibition of casp3/7. Similar results were observed in EG7 cells treated with STS. In contrast, STS-treatment of Jurkat cells induced rapid ANex accumulation within 2-4 h that was markedly suppressed by zVAD. Thus, while ATP release is a common response of tumor cells to chemotherapeutic and other pro-apoptotic stimuli, its mediation via proteolytic gating of panx1 channels requires cell-specific and drug-specific factors that are differentially expressed in tumor cell models.
Progression of acute lymphoblastic leukemia (ALL) results in compartment-restricted T cell expression of PD-1 and T cell dysfunction (46.22)
Authors: Su Paul , Burk Chad , Fix William , Qin Hai-Ying , Fry Terry 
Published: January 2023

Abstract
ALL is the most common cause of cancer related mortality in children. Although immune-based therapies for B cell malignancies have recently demonstrated promising results, the limited efficacy of donor lymphocyte infusions after allogeneic transplantation suggest that ALL may compromise immune responses. Using a murine model of pre-B-cell ALL, we have shown that leukemia progression is associated with PD-1 and TIM3 expression on CD4+ and CD8+ T cells evident at early infiltration of ALL with eventual expression on 80% of T cells with advanced disease. This was apparent in all leukemia-containing compartments including bone marrow, spleen and lymph nodes. PD-1 expressing CD8+ cells in leukemia compartments are predominantly CD44+CD62L- consistent with effector memory phenotype and a subset also express KLRG1 and LAG3. Finally, we assessed functionality of T cells from ALL mice including expression of the degranulation marker CD107a as well as production of TNFα, IFNγ, and IL-2 cytokines. Preliminary data suggests global impairments of functionality in the presence of leukemia. Currently, we are investigating the antigen-specificity of PD-1 acquisition, the translatability of our findings to clinical samples, and the effects of anti-PD-1 blockade on tumor progression. Given the pervasiveness of PD-1 and evidence for T cell dysfunction with ALL progression, elucidating the mechanism by which this process occurs could provide therapeutic targets for advancing ALL immunotherapy.
IL-33 promotes type 1 cell-mediated immunity and has a potent antitumor function (46.25)
Authors: Li Gang , Yang Qianting , Zhu Yibei , Gao Xin , Zhang Xueguang , Finn Olivera J. , Lu Binfeng 
Published: January 2023

Abstract
Interleukin-33 is a member of the IL-1 family of cytokines and is released by stressed cells, necrotic cells or activated innate immune cells such as macrophages during trauma or infection. Thus, IL-33 is thought to serve as an endogenous “danger signal” to trigger inflammation and promote cell-mediated immune responses. Prior studies have supported the role of IL-33 in promoting type 2 immune responses but little was known for its role in type 1 immune responses such as the anti-tumor immune response. We have found that that ST2, a receptor for IL-33, is highly expressed in CD8 T cells cultured in Th1 conditions. We have further revealed that, T-bet, a critical transcriptional factor for Th1 differentiation and effector functions, is required for ST2 expression by CD8 T cells, suggesting that ST2 is an integral part of the Th1 gene network in CD8 T cells. Furthermore, we have demonstrated that IL-33 synergized with TCR or IL-12 in increasing both human and mouse CD8 T cell functions such as IFN-γ production. Thus IL-33 can greatly enhance type 1 cell-mediated immune responses in both human and mice. The in vivo relevance of this pathway is examined in a preclinical model of tumor immunity. Our results support a potent function of IL-33 in inhibiting tumor growth and provide a novel therapeutic approach for tumor immunity.
Dendritic cells transduced with T-bet and IL-12 effectively restrict immunosuppressive activity of myeloid-derived suppressor cells and regulatory T cells in a murine tumor model (46.26)
Authors: Chen Lu , Qu Yanyan , Taylor Jennifer , Storkus Walter 
Published: January 2023

Abstract
Despite recent attempts to take advantage of dendritic cell (DC)-based vaccines for cancer immunotherapy, clinical results for such approaches have been disappointing, partly due to tumor-associated immune suppression in the tumor-bearing host. Successful DC-based cancer vaccines must overcome the immunosuppressive functions of myeloid-derived suppressor cells (MDSC), regulatory T cells (Treg) or inhibitory soluble factors and promote the survival of protective central memory T cells. We have recently shown that DC adenovirally-engineered to express Tbet and IL-12p70 (i.e. DC.Tbet/IL12) mediate superior anti-tumor effects in mice. The dominant mechanism of action associated with the therapeutic efficacy of DC.Tbet/IL12 remains unknown, although preliminary gene array analyses suggest these antigen-presenting cells may be coordinately enriched in NOTCH- and depleted of IL-10/TGF-β-signaling potential. In the current study, an analysis of TIL suggests that DC.Tbet/IL-12-based therapy downregulates MDSC and Treg numbers in tumor microenvironment (TME), and promotes higher levels of central memory T cells (Tcm) that are capable of mediating durable anti-tumor effects. This potential may be all related to a selective silencing of p38 MAPK signaling, and a coordinate reinforcement of ERK-signaling in DC.Tbet/IL12 cells, which has been suggested to dramatically enhance the immunogenicity of DC based vaccines in supporting Type-1 immune responses.
Enhanced levels of endogenous common γ chain receptor cytokines influence CD8 T cell subpopulation numbers and phenotype in cancer patients receiving CD4 T cell immunotherapy: Observations In Four Cases Of Patients With Ovarian Cancer (46.31)
Authors: Dobrzanski Mark , Rewers-Felkins Kathleen , Samad Khaliquzzaman , Quinlin Imelda , Phillips Catherine , Robinson William , Dobrzanski David , Wright Stephen 
Published: January 2023

Abstract
The common γ chain receptor family of cytokines have been associated with T cell homeostasis, development and survival. In this study, we assessed the therapeutic effects of adoptively transferred CD4 T cells and their affects on endogenous expression of such cytokines in patients with ovarian cancer. Using MUC1 peptide and IL-2 for ex vivo CD4 effector cell generation, we show that 3 monthly treatment cycles of autologous T cell restimulation and local intraperitoneal reinfusion resulted in diminished serum CA125 tumor marker levels and enhanced patient survival. One patient remains disease free, another patient experienced prolonged survival for nearly 16 months with recurrent disease and two patients expired within 3-5 months following treatment. Prolonged survivors showed lower levels of systemic memory (CD8+CD45RO+)/naïve (CD8+CD45RA+) CD8 T cell ratios when compared to that of short-term survivors. Such subpopulations among prolonged survivors were predominantly FoxP3-NEG and at relatively greater levels when compared to that of corresponding pre-treatment conditions. Lastly, peptide-restimulated PBMCs from these patients showed variable gene expression levels of pre- and post-treatment IL-15, IL-21 and IL-9 that were further associated with prolonged and/or disease-free survival. This suggests that CD4 cell transfer may induce levels of endogenous cytokines associated with CD8 survival and/or homeostasis that may contribute to enhanced CD4 therapeutic potentials
TLR7 and -9 activation of human plasmacytoid dendritic cells enhance endocytosis and processing of membrane material from a Her2/neu positive breast cancer cells (46.32)
Authors: Pierog Piotr , Singh Sukhwinder , Fitzgerald-Bocarsly Patricia 
Published: January 2023

Abstract
pDC detect viral nucleic acids and mount an immune response by secretion of IFN-α as well as TNF-α and chemokines which results in recruitment and activation of the adaptive immune system. Over-expression of Her2/neu in breast cancer patients results in poor prognosis; however, CTL specific to Her2/neu have been identified in patients indicating an active immune response towards this antigen. Unfortunately, Her2/neu is a self-antigen and therefore has a low immunogenicity. Therefore, we hypothesize that by making tumor cells more immunogenic for human pDC through introduction of HSV-infection, we will be able to efficiently activate Her2/neu specific cytotoxic T lymphocytes (CTL) through the process of antigen cross-presentation. Here we report that pDC take up membrane material from cancerous MCF-7 cells and that viral infection of MCF-7 cells significantly enhances this process. Interestingly, pDC activated with other TLR7 or TLR9 agonists had higher nibbling and endocytic capacity. The membrane nibbled from HSV-infected MCF-7 cells was endocytosed and processed through CD71 and CD107 positive compartments, as assessed by AMNIS Imaging Flow Cytometry. As expected, the nibbling of membrane from HSV-infected MCF-7 cells induced production of IFN-α by pDC as measured by FACS and ELISA. HSV-infected but not uninfected MCF-7 cells induced maturation of pDC as determined by loss of CD62-L and upregulation of CD40 and CD80 co-stimulatory molecules.
Intravenous administration of a novel IL-2 fusion protein, ALT-801, inhibits bladder cancer in mouse models (46.35)
Authors: Wong Hing , Wen Jinghai , You Lijing , Xu Wenxin , Edwards Ana , Rhode Peter 
Published: January 2023

Abstract
ALT-801 is a fusion protein between interleukin-2 and a T cell receptor domain capable of recognizing tumors presenting human p53 peptide (aa264-272)/HLA-A*0201 complexes. Previously, we have reported that ALT-801 exhibits significantly better antitumor activity than IL-2 in various mouse tumor models. Substantial efficacy in human malignancies has been observed. In this study, we found that intravenous administration of ALT-801 significantly prolonged survival of C57BL/6 mice bearing MB49luc orthotopic muscle invasive and superficial bladder cancer when compared with PBS treatment. The ALT-801-treated mice also survived rechallenge with MB49luc tumor cells, indicating long-lasting immune response and long-term memory. Additionally, ALT-801 exhibited potent antitumor activity against human bladder cancer HLA-A*0201+/p53+ UMUC-14 and HLA-A*0201-negative/p53+ KU7 xenografts in nude mice, suggesting its targeting activity is not required for efficacy. ALT-801 combined with gemcitabine showed better antitumor effects and less toxicity than gemcitabine + cisplatin (GC) chemotherapy in the UMUC-14 and KU7 xenograft models, despite the different sensitivity of these tumor cells to GC. We’ll discuss the mechanisms of action of ALT-801 in this report. Based on these preclinical findings, we have already initiated a clinical study of ALT-801 on human metastatic bladder cancer.
A Polymorphism in CD1e is associated with enhanced immune responses in African American Prostate Cancer Patients (46.40)
Authors: Webb Tonya , Dorsey Tiffany , Goloubeva Olga , Klyushnenkova Elena , Alexander Richard , Ambs Stefan , Mann Dean , Strome Scott , Moudgil Kamal , Sun Wenji 
Published: January 2023

Abstract
Prostate cancer is the second leading cause of cancer mortality in men older than 40 years in the United States. African American (AA) men and men with a family history of prostate cancer are at a significantly increased risk for developing prostate cancer. A recent study found highly significant differences in the expression of immune regulatory genes and cytokines between tumors from AA and European-American (EA) patients. Therefore, we tested the hypothesis that genetic variations in immune regulatory genes including the CD1 locus may confer an increased disease risk and a poor outcome prostate cancer phenotype in African-American men. Natural Killer T (NKT) cells produce large amounts of cytokines following activation vis-à-vis recognition of lipid antigen presented in the context of CD1d molecules. Prostate tumors commonly express CD1 family members, thus polymorphisms in CD1 genes may be responsible for differences in tumor biology between AA and EA patients. We report that a polymorphism in CD1e occurs commonly in AA but not EA men. When the distribution of this polymorphism was examined in a large cohort (n=562), we found that it is ethnicity specific and occurs primarily in men of African ancestry (P&lt;0.0001). We also observed that this polymorphism strongly influences IFN-γ production following stimulation. Thus, our data indicate that an ethnicity-related polymorphism affects a key function of NKT cells which in turn may modulate prostate cancer biology.