bluuebunny/crossref_metadata_2025_split huggingface dataset:
The role of immature myeloid suppressor cells (IMSCs) in transgenic mammary tumor chemoprevention and therapy by Celecoxib (49.21)
Authors: Talmadge James E , Donkor Moses , Scholar Eric , Singh Rakesh , Dafferner Alicia , Hoke Traci , Westphal Sherry , Solheim Joyce 
Published: January 2023

Abstract
Immune manipulation can control tumor initiation and growth while tumor growth may suppress host immunity. In our studies of tumor–host interactions, we observed a tumor associated expansion of IMSCs and suppression of T cell number and tumor infiltration. Further, the cyclooxygenase-2 (COX-2) inhibitor, Celecoxib had chemopreventative and as shown for the first time, therapeutic activity for mammary tumors in HER-2/neu transgenic BALB/c mice. Tumor growth was associated with a significant decrease in T cells and a significant increase in IMSCs (CD11b+Gr1+). In addition type 1 cytokine transcripts were depressed, while transcription levels of COX-2, arginase-1 (ARG1), nitric oxide synthetase-2 (NOS2), granulocyte (G) and G-monocyte colony stimulating factor, and vascular endothelial growth factor-alpha (VEGF-a) were increased in the preneoplastic lesions, tumors, and spleens and to a greater extent tumor infiltrating leukocytes. Celecoxib chemoprevention reduced the changes in IMSC and T cell numbers and cytokine and enzyme transcription levels. We posit that the increase in IMSCs may be due to the increased levels of COX-2, VEGF-a and growth factor(s), while the loss of T cell numbers and function maybe due to the heightened levels of ARG1 and NOS2. Further, as Celecoxib administration does not increase T cell infiltration of tumors or decrease IMSC infiltration, the changes in cytokine and growth factor levels maybe critical to the improved clinical outcomes. Together, these studies suggest an important role for IMSCs and its regulation by Celecoxib in cancer induction, and therapeutic intervention.
Supported in part by funding from NIH grant 5 RO1 AT001739, Eppley Cancer Center and Nebraska DHHS LB506.
CCR9-CCL25 interaction mediates breast cancer cell survival via Akt activation (49.22)
Authors: Johnson-Holiday Crystal , Singh Shailesh , Johnson Erica , Singh Udai , Lillard James W. 
Published: January 2023

Abstract
Breast cancer (BrCa) is one of the most frequently diagnosed cancers and the second leading cause of cancer-related deaths in the U.S. Most cancer-related deaths are due to metastasis. In addition, BrCa cells readily become resistant to a wide variety of chemotherapeutic agents, which is a major obstacle in the treatment of BrCa. Tumor cell migration and metastasis share similarities with leukocyte trafficking, which is regulated, in part, by chemokines and their receptors. We have previously shown that CCR9 is functionally expressed by BrCa cells and its expression is enhanced by the presence of its ligand, CCL25. This study characterizes the role of CCL25-CCR9 cell-signaling cascades involved in BrCa cell resistance to cisplatin. This drug is often ineffective due to cancer cell resistance and the development of anti-apoptotic mechanisms. In this regard, CCR9-CCL25 interaction plays a role in immature T-cell survival through PI3K and G ai protein-dependent activation of Akt/protein kinase B. Activated Akt phosphorylates multiple downstream targets that are involved in cell survival signaling, which include glycogen synthase kinase (GSK-3), forkhead transcriptional factor (FKHR), and caspase-9. We examined the effect of CCR9-CCL25 interactions on BrCa cell lines MDA-MB-231 and MDA-435, with or without cisplatin treatment. CCR9-CCL25 interactions decreased cisplatin-induced apoptosis. These interactions also modulated the activation of cell signaling cascades involved in cell survival. These studies provide important new information regarding the cellular and molecular mechanisms that mediate BrCa cell survival.
Synergistic effect of VR1 agonist Capsaicin and its antagonist IRTX, in tumor cell apoptosis: implication for involvement of VR1 (49.24)
Authors: Ghosh Amiya Kumar , Basu Sreyashi 
Published: January 2023

Abstract
Capsaicin (CP) is the principal pungent ingredient of red peppers. The CP receptor, VR1 has been shown to be highly expressed by nociceptive neurons in dorsal root and trigeminal ganglia. Recently we have demonstrated that intratumoral administration of CP into a preexisting tumor results in retarded progression of the injected tumor. Here we report that tumor cells express VR1 and treatment with CP leads to tumor cell death by apoptosis as evidenced by positive TUNEL staining. Unlike tumor cells normal embryonic fibroblasts (MEFS) do not succumb to apoptosis by this treatment. CP treatment induced up-regulation of reactive oxygen species (ROS) and Caspase-3 activation in a dose-dependent manner. Further, we observed that VR1 antagonist I-RTX has synergistic apoptotic effect with CP like a partial agonist of VR1, indicating the involvement of VR1 in this apoptotic event. We also report that CP treatment leads to degradation of FAF1 (Fas associated factor1) a VR1 associated protein in a dose-dependent manner. In summary, our data suggests that VR1 engagement and subsequent degradation of FAF1 is one of the mechanisms of CP mediated apoptosis in tumor cells.
Failure of vSAg29-responsive CD4+CD25+ Treg cells to inhibit CD4+CD25− T cells resides in their differential regulation of cytokine, chemokine and toll-like receptor family genes (50.1)
Authors: Li Yu , Tsiagbe Vincent K 
Published: January 2023

Abstract
Endogenous mammary tumor virus (Mtv29)-encoded superantigen (vSAg29) mediates “reverse immune surveillance” that characterizes SJL lymphoma (RCS) development. CD4+Vβ16+ vSAg29-responsive T cells provide growth factors (notably IL-5 and IL-4) for RCS growth. The vSAg29-responsive CD4+ T cells belong to both CD4+CD25+ (Treg) and CD4+CD25− (non-Treg) populations. Unlike the known inhibitory ability of Treg cell on non-Treg cell responses to nominal antigens, Treg cells responding to vSAg29 fail to inhibit response of vSAg29-responsive non-Treg cells. This unique behavior of vSAg29-responsive T cells was found to be linked to their differential expression of cytokine, chemokine and toll-like receptor family genes. Treg cells responding to vSAg29 significantly inhibited the production of IL-4, IL-5, IL-10, IFN-γ, CCR4, CCL17, TOLLIP, UBE2N, NFKBIB, by CD4+CD25− cells. On the other hand, the addition of CD4+ Treg cells to non-Treg cells responding to vSAg29, resulted in enhanced production of mRNA for MIF, IL-10R, BCL6, CXCL4 (PF4), MAPK8 (JNK1), UBE2V1.
Research funded by CA10273 from NCI.
Hsp70-containing exosomes - potent stimulators of the innate immune system (50.19)
Authors: Multhoff Gabriele 
Published: January 2023

AbstractDepending on their intra- and/or extracellular localization heat shock proteins (HSP) either mediate protection against stress-induced cell damage or act as danger signals stimulating the adaptive and innate immune system (1–3). However, it remained elusive how cytosolic HSPs become externalized and thus communicate with immunocompetent effector cells. Several groups demonstrated that a variety of different cell types, including tumor cells, have the capacity for an active release of Hsp70 in detergent-soluble vesicles (4,5). Biophysical properties including floating properties (1.17g/ml) correlating with a maximum acetylcholine esterase activity characterized them as exosomes (3–5). Profiling of luminal proteins revealed that tumor-derived exosomes contain cytosolic proteins but lack ER-residing proteins. An exosomal enrichment of the small GTPase Rab-4 documented their intracellular transport route from the early endosomal compartment to the plasma membrane. Exosomes originating from Hsp70 plasma membrane-positive tumors present Hsp70 on their exosomal membrane. In line with these findings only Hsp70 surface-positive exosomes but not their negative counterparts had the capacity to stimulate the innate immune system (3). These data provide an explanation how the innate immune system might become activated by tumor-derived exosomal Hsp70 in vivo.
Multicolor flow cytometric analysis of CD4+ T-cells for CD25 and Foxp3 expression in human Prostate Cancer (50.21)
Authors: Perambakam Supriya , Peace David J 
Published: January 2023

Abstract
CD4+CD25+ T regulatory cells (Treg) are postulated to regulate immune responses against self-antigen, infectious agents, tumor antigens and transplantation antigens. The objective of the study is to examine whether PSA146–154 peptide vaccination impacts the frequency and/or phenotype of Treg in peripheral blood mononuclear cells (PBMC) of patients with prostate cancer (CaP). Frozen PBMC were rapidly thawed, enumerated, checked for viability and directly stained with fluorescent labeled antibodies to CD3, CD4, CD8, CD25 and Foxp3 and analyzed on a flow cytometer. Based on morphology, gates were set to include, (a) whole PBMC population but exclude debris and clumps or, (b) predominantly large lymphocyte population and then back gated on CD3+CD4+ T-cells. Quadrant analysis demonstrated the presence of 1–5% of CD4+CD25+Foxp3−, less than 1% of CD4+CD25−Foxp3+ and CD4+CD25+Foxp3+ cells in the whole PBMC population. While, 10–44% of CD4+CD25−Foxp3+, 1–2% of CD4+CD25+Foxp3−, 1–3% of CD4+CD25+Foxp3+ cells were observed in the large lymphocyte population. However, there was no significant difference between before and post vaccine samples. CD4+CD25−Foxp3+ cells may represent a distinct T-cell subset and warrants further investigation.
Funding: The Illinois Department of Public Health (IDPH# 4328301)
Macrophage functional plasticity: IL-12 rapidly alters the functional profile of tumor associated and tumor infiltrating macrophages in vivo. (50.4)
Authors: Watkins Stephanie Kaye , Egilmez Nejat K. , Suttles Jill , Stout Robert D. 
Published: January 2023

Abstract
Tumor-associated macrophages play a major role in promoting tumor growth and metastasis and in suppressing the anti-tumor immune response. Despite the immunosuppressive environment created by the tumor and enforced by tumor-associated macrophages, treatment of tumor-bearing mice with IL-12 induces tumor regression associated with appearance of activated NK cells and activated tumor-specific cytotoxic T cells. We therefore tested the hypothesis that IL-12 treatment could alter the function of these tumor-associated “suppressor” macrophages. Analysis of tumor infiltrating macrophages (TIMs) and distal tumor associated macrophages (TAMs) revealed that IL-12, both in vivo and in vitro, induced a rapid (&lt; 90 min) reduction of tumor supportive macrophage activities (IL-10, MCP-1, MIF, TGFâ production) and a concomitant increase in pro-inflammatory and pro-immunogenic activities (TNFá, IL-15, IL-18 production). Similar shifts in functional phenotype were induced by IL-12 in TIMs isolated from the primary tumor mass and in TAMs isolated from lung containing metastases, spleen and peritoneal cavity. Therefore, although tumor associated macrophages display a strongly polarized immunosuppressive functional profile, they retain the ability to change their functional profile to pro-inflammatory activities given the appropriate stimulus. The ability of IL-12 to initiate this functional conversion may contribute to early amplification of the subsequent destructive anti-tumor immune response.
This research was supported by the Nat’l Cancer Institute, the KY Lung Cancer Research Fdn, the American Lung Assoc., and the KY Research Challenge Trust Fund.
Proteasome inhibition promotes tumor cell apoptosis by exogenous TRAIL without blocking anti-tumor immune effectors in vivo (50.6)
Authors: Shanker Anil , Brooks Alan D , Tristan Carlos A , Wine John , Sayers Thomas J 
Published: January 2023

Abstract
The resistance of tumors to cell death poses a major clinical problem. Bortezomib (Velcade/PS-341), a specific and reversible proteasome inhibitor, sensitized renal (Renca) and mammary (4T1) mouse carcinomas to apoptosis induced by the TNF family ligand TRAIL or its receptor (DR5) agonist antibody. The molecular basis of the tumoritoxicity of the combination of bortezomib and TRAIL seemingly involved amplification of the extrinsic cell death pathway as increased expression of DR5, activation of caspase-8 and -3, and decreased apoptosis inhibitory proteins cFLIP, cIAP-1 and XIAP were observed in bortezomib-treated tumors. In an established tumor setting, anti-DR5 administration to mice pre-treated with bortezomib not only reduced lung metastases of Renca and 4T1 tumors but also significantly increased long-term survival in mice bearing Renca as compared to either agent alone. Encouragingly, no evidence of any overt tissue damage was noted in the treated mice. This provides the first experimental evidence that proteasome inhibition can be combined with DR5 agonist antibody for successful cancer therapy. Moreover, bortezomib administration 24 hours prior to adoptive transfer of T cells did not block their anti-tumor effector function. This suggests that tumor sensitization with bortezomib may also be combined with tumor-specific T cell immunotherapy of cancer.
Funded in part by NCI contract N01-CO-12400.
CD18 Separates GVHD and GVL effect (50.9)
Authors: Liang Yaming , Yu Xue-Zhong 
Published: January 2023

Abstract
Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality in allogeneic hematopoietic stem cell transplantation. Migration of donor-derived T cells into GVHD target organs plays an essential role in the development of GVHD. β2 integrins, a group of heterodimeric molecules including CD11a/CD18 (LFA-1), CD11b/CD18 (Mac-1), CD11c/CD18 and CD11d/CD18, are of critical importance for leukocyte extravasation through vascular endothelia and for T cell activation. We asked whether CD18-deficient T cells would induce less GVHD while sparing graft-versus-leukemia (GVL) effect. In murine allogeneic BMT models, we found that recipients of CD18−/− donor T cells had significantly less GVHD morbidity and mortality compared with recipients of WT donor T cells. A cell-dose titration experiment indicated that the ability of CD18−/− T cells had more than 4-fold reduction compared to that of WT T cells in the induction of GVHD. Analysis of alloreactive showed that CD18−/− and WT T cells had comparable activation, expansion and cytokine production in vivo. Reduced GVHD was associated with a significant decrease in donor-T cell infiltration of recipient intestine and with an overall decrease in pathologic scores in intestine and liver. Finally, we found that in vivo GVL effect of CD18−/− donor T cells was largely preserved, because mortality of the recipients transplanted with CD18−/− T cells plus tumor cells was greatly delayed or prevented. Our data suggest that strategies to target β2 intergrin have clinical potential to alleviate or prevent GVHD while sparing GVL activity.
Evolution of antibody responses against carbohydrate and protein antigens of Pneumocystis carinii: Implications for antibody-based vaccine protection (51.12)
Authors: Rapaka Rekha R. , Zheng Mingquan , Kolls Jay K. 
Published: January 2023

Abstract
Pneumocystis (PC) pneumonia is a leading opportunistic infection among HIV+ individuals. Mice deficient in CD4+ T cells or B cells are susceptible to PC pneumonia, yet adoptive transfer of serum from PC challenged mice can prevent PC pneumonia. To evaluate factors critical for antibody-based resistance against PC, we assessed antibody responses to intratracheal PC challenge in Balb/c mice. The kinetics of anti-PC Ig induction are prolonged, peaking after the majority of PC is cleared from the lungs. Low anti-PC IgM titers(1:120) exist at baseline and are enhanced by vaccination(1:2600), and the induced anti-PC IgM is strongly cross-reactive with zymosan. Anti-PC IgG is absent at baseline but is rapidly induced through day 36 post-challenge (titer 1:38,000). We assessed the evolution of Igs directed against the PC cellular wall carbohydrates β-glucan and chitosan, which may potentially elicit B cell responses in a CD4+ T cell independent manner. Baseline IgM directed against the PC cellular wall antigen β-glucan is high, rapidly enhances 2 days post challenge (titer 1:5000), and diminishes, suggesting a potential role for B1 cells in this response, while PC induces anti-β-glucan IgG (titer 1:1000) with a significantly delayed timecourse, peaking at day 42 post-challenge; IgM and IgG responses directed against chitosan manifest similar kinetics. Finally, mice exposed to PC and subsequently depleted of CD4+ T cells after the primary response with the antibody GK1.5, mount similar boosting responses to CD4+ T cell intact mice. Our studies suggest that PC elicits antibodies against protein and carbohydrate antigens, implicating B1 and B2 cells in these responses, and suggest that components of anti-PC B cell memory may be maintained under CD4+ T cell deficiency.
The C2 receptor CRIT protects Trypanosoma cruzi against classical and MBL-directed, but not alternative pathway complement activation (51.14)
Authors: Inal Jameel Malhador , Cestari Igor dos Santos , Ingrid Evans-Osses , Juliana Freitas , Ramirez Marcel 
Published: January 2023

Abstract
We show that the sylvatic class I strains of Trypanosoma cruzi resist more effectively the classical (CP) and mannan-binding lectin (LP) mediated complement activation than the domestic class II strains. T. cruzi Colombiana (sylvatic class II) showed under 3% survival compared with 45% for the Y strain (domestic class I). The AP plays a minimal role in lysis mediated in the short-term. The complement C2 receptor CRIT gene is highly similar in T. cruzi class I and class II parasites. It is not expressed in log growth phase epimastigote insect forms of either class and is only expressed in late growth phase epimastigote (infective stage) forms of T. cruzi Y (class I ) but not Colombiana (class II) strains. When the Tc-CRIT gene of T. cruzi Y strain was overexpressed in Y and Colombiana strains, the transgenic parasites (pTEX-Tc-CRIT) showed 86% survival after 5 minutes in normal human serum (NHS) compared to 57.4 % (pTEX) and 53.4% (wild type). Once more in the presence of AP alone there was 80% survival after 5 and 10 minutes. As CRIT is a receptor which principally binds complement C2 it is presumed that overexpressed CRIT in epimastigote forms of T. cruzi Y strain resist CP and LP by depletion of C2 from NHS. Experiments in which an excess of C2 was added to NHS confirmed this mechanism by restoring hemolytic activity.
Diacylglycerol kinase zeta regulates microbial recognition and host resistance to Toxoplasma gondii (51.16)
Authors: Liu Cheng-hu , Machado Fabiana S. , Guo Rishu , Nichols Kim E. , Burks A. Wesley , Aliberti Julio C. , Zhong Xiao-Ping 
Published: January 2023

Abstract
Mammalian Toll-like receptors (TLRs) recognize microbial pathogen-associated molecular patterns and are critical for innate immunity against microbial infection. Diacylglycerol kinases (DGKs) regulate the intracellular levels of two important second messengers involved in signaling from many surface receptors by converting diacylglycerol (DAG) to phosphatidic acid (PA). Here, we demonstrate that the ζ isoform of the DGK family (DGKζ) is expressed in macrophages (Mϕ) and dendritic cells (DC). DGKζ deficiency results in impaired IL-12 and TNFα production following TLR stimulation in vitro and in vivo, increased resistance to endotoxin shock, and enhanced susceptibility to Toxoplasma gondii infection. We further show that DGKζ negatively controls the PI3K-Akt pathway and that inhibition of PI3K activity can restore LPS-induced IL-12 production by DGKζ deficient macrophages. Collectively, our data provide the first genetic evidence that an enzyme involved in DAG/PA metabolism plays an important role in innate immunity and indicate that DGKζ promotes TLR responses via a pathway involving inhibition of PI3K.
Mouse strain affects Stachybotrys chartarum induced alveolar macrophage cytotoxicity (51.9)
Authors: Lichtenstein Jamie H Rosenblum , Donaghey Thomas C , Molina Ramon M , Brain Joseph D. 
Published: January 2023

Abstract
The fungus Stachybotrys chartarum (S. chartarum) releases mycotoxins that can cause lung injury, inflammation, hemorrhage and cytotoxicity. We have shown that when BALB/c mice receive instilled spores, they have greater lung inflammation, hemorrhage, and cytokine production and less efficient spore clearance than C57BL/6J mice.
To investigate these mouse strain differences, we exposed alveolar macrophages (AMs) lavaged from these two strains of mice to spores in vitro. Then the cells were stained with calcein AM (live) and EthD1 (dead), and images were collected on a BD Pathway Bioimager. Both strains exhibited increasing AM death as doses increased from 200 to 5000 spores per 75,000 AMs (p=0.0001) with more C57BL/6J than BALB/c AMs dying (slopes significantly different at p=0.007). After one day, 84 ± 4% of C57BL/6J AMs versus 66 ± 5% of BALB/c AMs died at the 1000:75,000 spores:AMs dose. The spores killed C57BL/6J AMs sooner (p=0.04) than BALB/c AMs. Many of the dead AMs from both strains appear morphologically apoptotic.
In vivo, AM death may diminish cytokine levels and inflammation in C57BL/6J mice because dead cells do not synthesize cytokines. This increased cytotoxicity coupled with improved spore clearance, causing a lower effective spore dose, may reduce inflammation in C57BL/6J mice. Analogous differences may contribute to the range of sensitivity to S. chartarum seen among humans.
γδ T cells characteristic of the gut mucosa are stimulated by oligomeric tannins (52.11)
Authors: Holderness Jeff , Freedman Brett , Kimmel Emily , Jutila Mark A. 
Published: January 2023

Abstract
γδ T cells function, in part, to regulate the innate immune response and maintain tissue homeostasis at mucosal surfaces. Increasing the activity of the γδ T cells may be effective for treating a variety of pathogens that target the gut mucosa including rotavirus and Salmonella. Treatment with the phosphoantigen family of agonists stimulates only the Vδ2 subset of human γδ T cells and does not stimulate Vδ1 T cells, the primary γδ T cell population at the sites of pathogen entry. Here we define the biological activity of an agonist that stimulates both the Vδ2 and importantly, the Vδ1 subsets of human γδ T cell population. Initial examination of the effects in vivo suggests that the agonist may induce expansion of mouse intestinal γδ T cells after oral administration. The agonist is part of an unripe apple peel extract that contains a mixture of phenolics including monomeric and oligomeric tannins. Preliminary characterization of the extract suggests that the γδ T cell stimulation is due to the specific interaction of an oligomeric tannin.