bluuebunny/crossref_metadata_2025_split huggingface dataset:
Circulating Immature Myeloid Cells (ImC) Levels Correlate with Clinical Cancer Stage and Cyclophosphamide (CTX) Treatment (49.15)
Authors: Montero Alberto J. , Salem Mohamed L. , Al-Khami Amir , Vissage Kristi , Diaz-Montero C. Marcela 
Published: January 2023

Abstract
Tumor-associated immune suppression is known to be an important contributor to cancer progression. One such mechanism is the abnormal accumulation of ImC in the peripheral blood. Although both tumor burden and CTX-induced accumulation of ImC are well described in animal studies, human studies have been limited. Thus, the goal of our study was to determine whether levels of ImC in whole blood correlate with clinical cancer stage in cancer patients (pts). Flow cytometry analyses were performed on whole peripheral blood from newly diagnosed solid tumor pts. ImC population was defined as lineage−CD33+HLA-DR−CD11b+. Peripheral blood specimens from 14 normal healthy controls and 35 cancer pts (stages: I, n=3; II, n=9; III, n=9; IV, n=14), revealed greater ImC in cancer pts vs. normal (3.21% vs. 1.47%; p=.002). Stage IV pts had the highest percentage of ImC (4.39%). Initial results from stage II-III breast cancer pts (n=10) treated with preoperative chemotherapy showed that CTX treatment was associated with significant increases in circulating ImC compared with baseline (2.91% vs. 10.57%; p=0.001), and also when compared to taxane chemotherapy independent of G-CSF (10.57% vs. 3.25%; p=0.00025). In conclusion, overall ImC levels correlate with clinical cancer stage and CTX treatment leads to transient increases in ImC in breast cancer pts.
Macrophages from tumor-bearing mice contribute to tumor immune escape: a novel mechanism (49.16)
Authors: Torroella-Kouri Marta , Harhaj Ed , Alonso-Diaz Luis , Carrio Roberto , Cardentey Yoslayma , Lopez Diana M 
Published: January 2023

Abstract
Tumor progression is associated with the development of a state of immunosuppression in the host. Macrophages from mice bearing advanced mammary tumors are profoundly dysfunctional, exhibiting decreased levels of several pro-inflammatory cytokines and of nitric oxide, which are critical in the anti-tumor immune response. We have found that the impaired function of these macrophages is associated with reduced expression and nuclear translocation of transcription factors NFkB and C/EBP. The diminished expression of these transcription factors is observed both at the protein and mRNA levels, and interestingly, there is evidence that proteasomal degradation might also be involved in their proteolysis. We have shown that several factors produced by the mammary tumor are associated with this phenomenon. Our results provide evidence that NFkB and C/EBP are targets of the tumor evasion mechanisms observed in advanced cancers.
Preferential Migration of T Regulatory Cells Mediated by Glioma-Secreted Chemokines (49.3)
Authors: Sun Wei , Jordan Justin T , Hussain Sakina F , DeAngulo Guillermo , Weinberg Jeffery S , Heimberger Amy B 
Published: January 2023

Abstract
Despite the immunogenicity of glioblastoma multiforme (GBM), the most common primary brain neoplasm, immune clearance of these tumors is still insufficient for tumor eradication and control. Elevated frequency of CD4+ CD25+FoxP3+ T regulatory (Treg) cells in peripheral blood or tumor-infiltrating lymphocytes has been observed in patients with various solid tumors including glioblastoma. This presence of high Treg fraction contributes to the dismal immune responses generated within these patients and prompted us to investigate the possible mechanism of Tregs selective recruitment in GBM patients. We hypothesized that the chemokines produced by gliomas induce this preferentially Treg migration. In the human malignant glioma cell lines D-54, U-87, U-251 and LN229, the chemokines CCL22 and CCL2 were preferentially produced compared to CXCL9, CCL3, and CCL4 by using cytokine flow cytometry and confirmed with ELISA. Additionally, gliomas obtained directly from human patients demonstrated a similar chemokine expression profile. Glioma supernatants, recombinant CCL2 and CCL22 could induce the migration of Tregs, which could be blocked by neutralizing antibodies to these chemokines. Flow cytometric investigation of the expressions of the CCL2 and CCL22 chemokine receptors CCR2 and CCR4 on peripheral T cells indicated that GBM patients have more CD4+CD25+ T cells that express CCR2 (26%) and CCR4 (53%) in contrast to the CD4+CD25+ T subset from normal individuals that express CCR2 (17%) and CCR4 (42%). These data indicate that gliomas modulate immunosuppression by the selective recruitment of Tregs into the tumor microenvironment and those therapies that modulate this interaction may be potentially synergistic with tumor immunotherapies.
Role of hepatocyte growth factor in the thymic involution of tumor-bearing mice. (49.32)
Authors: Carrio Roberto , Torroella-Kouri Marta , Lopez Diana M 
Published: January 2023

Abstract
During mammary tumorigenesis, there is a profound thymus involution associated with a severe depletion of the most abundant subset of thymocytes, CD4+CD8+ immature cells, however, the mechanisms involved in this phenomenon remain to be elucidated. We have previously reported that the thymic involution observed in tumor bearing mice is associated with an early block in T cell maturation. This alteration in thymocyte differentiation might be due to an impaired function of stromal cell microenvironment in this organ. Using the D1-DMBA-3 mammary tumor model we found that IL-7 and IL-15 mRNA, crucial cytokines involved in thymic development and cellular homeostasis respectively, are profoundly down-regulated in the thymuses of tumor hosts. Importantly, the expression of the gene for hepatocyte growth factor (HGF), which has been associated with proliferation, cell survival, angiogenesisand differentiation, is down-regulated in thymuses of tumor bearers. Injection of HGF into mice implanted with the mammary tumor resulted in a partial restoration of the thymus volume and of the levels of IL-7 and IL-15 in this organ. Collectively, our data suggest that HGF may play an important role in the thymic involution in tumor bearing hosts and that the cytokines expressed in the thymus microenvironment may be modulated by this growth factor.
Human dialyzable leukocyte extracts (DLE) have ligands for TLR- 2 but not for TLR-4 (49.34)
Authors: ROBLEDO-AVILA FRANK , WONG-BAEZA ISABEL , SERAFIN-LOPEZ JEANET , ISIBASI-ARAUJO ARMANDO , LOPEZ-MACIAS CONSTANTINO , PEREZ-TAPIA SONIA MAYRA , ESTRADA-GARCIA IRIS CITLALLI , ESTRADA-PARRA SERGIO ANTONIO 
Published: January 2023

Abstract
Human dialyzable leukocyte extracts (DLE) have been used for the last 50 years to successfully treat different diseases. They are obtained by disruption of cells in buffy coats and subsequent dialysis (&lt;12 KDa) of the extracts. They can transfer cellular immune response from an immune donor to a naïve recipient, and despite their immunomodulatory effect, until now little is known about their mechanism of action. One possibility is that they may contain ligands that activate TLRs. In this work using a reporter gene assay and HEK293 cells transfected with either TLR-2 or TLR-4 plasmids, we showed that different concentrations of DLE (100, 10 and 1 microg/mL) resulted in the activation of NF-kappaB (luciferase reporter system) in cells TLR-2 transfected cells with 10 or 1 microg/mL DLE. Interesting none of the DLE concentrations used induced a significant luciferase activity in the TLR-4 transfected cells. Our result can explain in part the immunomodulatory effects produced by DLE both in vivo and in vitro. Work will now focus in the identification of this ligand(s).
This work was supported in part by SIP/IPN. 1Are fellows of COFAA, EDI and SNI.
Use of dialyzable leukocyte extracts (DLE) in patients with severe sepsis (49.35)
Authors: PEREZ-TAPIA SONIA MAYRA , LOPEZ-ISLAS INES , DE LA FUENTE-GRANADA MARISOL , ARRATIA-VALDELAMAR KARINA , JIMENEZ-GALLEGOS NYDIA , RODRIGUEZ-FLORES AZUCENA , ESTRADA-GARCIA IRIS , ESTRADA-PARRA SERGIO ANTONIO 
Published: January 2023

Abstract
Dialyzable leukocyte extracts (DLE) are obtained from freezed-thawed buffy coats and subsequent dialysis ( &lt;12 KDa). They can transfer cellular immune response from an immune donor to a naïve recipient. DLE have been used as immunomodulators for the last 50 years with good results. The sepsis is the main cause of death in the units of noncoronary intensive cares. A controlled clinical study randomized double blind person was made in 24 patients with the diagnosis of severe sepsis and a score of scale of gravity of APACHE II of 20 to 24 points, two groups were created. Group A was administered with one unit of DLE (Transferon) every 24hrs by 7 days, to group Z, was administered with placebo in the same amount and presentation. In both groups the score of APACHE II, IL-1beta, IL-6, IL-8, IL-10, IL-12p70, TNF alpha, PCR, DR/CD14 cells and lymphocyte subpopulations were measured after 1, 2, 3 and 7 days. Results showed that DLE (Transferon) increased DR expression in the CD14+ cells, increased number of Th (CD3+/CD4+) population and decreased the time of stay in UCI
TUMOR-SECRETED VEGF-A DISRUPTS ENDOTHELIAL CELL STIMULATION OF T-CELL, MACROPHAGE AND NK CELL FUNCTIONS (49.5)
Authors: Mulligan Jennifer Konopa , Lathers Deanne M. R. , Young Rita I 
Published: January 2023

Abstract
Our current studies examined tumor-secreted products ability to disrupt endothelial cell stimulation of immune cell functions. Supernatants from EC exposed to tumor-conditioned media (EndoT-sup) contained increased levels of PGE2, IL-6 and VEGF as compared to control supernatants from endothelial cells exposed to media (EndoMedia) or media conditioned by epithelial cells (EndoEpi-sup). Conversely, levels of IL-12 and ET-1 were decreased in EndoT-sup compared to controls. Next we examined NK, T-cell and macrophage functions following exposure to media alone, EndoMedia, EndoEpi-sup or EndoT-sup. NK cell activity measured by TNFα and IFNγ secretion was increased following exposure to EndoMediaand EndoEpi-sup, but reduced following exposure to EndoT-sup. T-cell IFN-γ production was increased following exposure to EndoMedia and EndoEpi-supcompared to media alone. However, T-cell IFNγ and TNFα secretion was reduced following exposure to EndoT-sup. Macrophage function was assessed by microbead uptake showed decreased macrophage phagocytosis following exposure to EndoT-supcompared to controls. Neutralization of tumor secreted VEGF-A restored endothelial cell secretion of IL-12, VEGF and PGE2 to control levels. These studies identify tumor disruption of endothelial cell immune stimulation as a novel mechanism of tumor-induced immune suppression.
Supported by Dept. of Veterans Affairs and NIH.
Reduction of the number and/or suppressive mechanisms of myeloid cells by mammary tumor cells expressing a secreted isoform of MUC1 (50.10)
Authors: Ilkovitch Dan , Herbert Lynn M , Lopez Diana M 
Published: January 2023

Abstract
Expression of the transmembrane isoform of MUC1 (MUC1/TM) in an aggressive murine mammary tumor line, DA-3, results in tumor development leading to metastasis and death of the host, as does the untransfected parental tumor line. However, tumor cells expressing a secreted isoform of MUC1 (MUC1/sec) fail to develop tumors in vivo. The rejection of tumors was found to be immunologically mediated, as initially innate cells and ultimately T cells are required. Previous work to determine which lymphoreticular cells may be involved in the immune rejection revealed that MUC1/sec expressing cells recruited four times the amount of F4/80+ cells, while recruiting significantly lower numbers of GR-1+ cells, relative to MUC1/TM expressing tumor cells. Gr-1+CD11b+ cells known as immature Myeloid Derived Suppressor Cells (MDSC) have been correlated with immune suppression in many models of cancer and chronic infections. MDSC accumulate in response to MUC1/TM expressing tumor cells, but remaine at normal levels in animals exposed to MUC1/sec expressing tumor cells. Futhermore, supernatants from MUC1/sec expressing tumor cells blocked induction of arginase in MDSC, a mechanism of suppression. This block in induction of arginase could also be demonstrated by use of a unique peptide, Immuno Enhancing Peptide, only found in the MUC1/sec protein. NIH, NCI R01CA25583.
LTbR Mediates Cell Contact-Dependent CTL-Directed Anti-Tumor Cytotoxicity (50.11)
Authors: Liu Kebin , Din Najam ud , Browing Darren D , Abrams Scott I , Yang Dafeng 
Published: January 2023

Abstract
Cytotoxic T lymphocytes (CTLs) are thought to use two cell contact-dependent effector mechanisms, perforin- and Fas-mediated cytotoxicity, to suppress tumor growth. Using a CTL adoptive immunotherapy model, we report here that perforin-deficient CTLs (pfp CTLs) exhibited a significant cytotoxicity against Fas-resistant tumors in vivo. We further demonstrated that the anti-tumor activity is directly mediated by the adoptively transferred CTLs. but does not involve CTL-secreted soluble molecules, such as IFNγ and TNFα as lytic agents, since these cytokines exhibited no direct cytotoxicity against these targets. Moreover, it was observed that LTβR, a cell-surface death receptor, is expressed on the tumor cell surface, and LTα, LTβ, and LIGHT, all of which are ligands for LTβR, were either constitutively expressed by or activated in the tumor-specific CTLs and primary CD8+ T cells. Silencing LTβR in these Fas-resistant tumor cells with LTβR-specific shRNA significantly decreased the ability of pfp CTL to mediate tumor rejection in vivo. Taken together, our data suggest that tumor-specific CTL use LTβR-mediated cytotoxicity as a third cell contact-dependent effector mechanism against tumor growth in vivo.
Cooperative downregulation of IFN[gamma]R and Fas is functionally linked to CTL-mediated immunoselection and tumor promotion (50.3)
Authors: Yang Dafeng , Smith Kimberly K , Georgi David , Abrams Scott I , Liu Kebin 
Published: January 2023

Abstract
The host immune system functions as an intrinsic surveillance network in the recognition and destruction of tumor cells. But the immune system, at the same time can “edit” tumor cells and select for tumor variants with reduced immunogenicity through immunoselection. We report here that Fas and IFNγR were coordinately downregulated in the tumor escape variants in vitro. Examination of spontaneously arising mouse primary mammary carcinoma and lung metastases revealed that both Fas and IFNγR protein levels were also dramatically lower in lung metastases than in primary tumors in vivo. Functional disruption of either the Fas-mediated apoptosis pathway, the IFNγ signaling pathway, or both pathways together enhanced the metastatic capability of tumor cells. Gene expression profiling revealed that altered expression of genes involved in immediate IFNγR signaling, the interferon primary response, apoptosis, and tumor colonization are associated with tumor escape. Furthermore, disruption of IFNγR function did not alter tumor cell susceptibility to CTL-mediated cytotoxicity, but is linked to enhanced infiltration of endogenous T cells in the tumor microenvironment and tumor promotion in vivo. These findings suggest that coordinate downregulation of Fas and IFNγR by tumor cells, two key components of cancer immunosurveillance and immunoediting, leads to a more aggressive metastatic phenotype.
The status of IFN-gamma receptor on tumor cells will determine the outcome of tumor relapse or tumor-free survival in FVB mice (50.7)
Authors: Kmieciak Maciej , Kostick Jessica L , Bolesta Elizabeth , Manjili Masoud H 
Published: January 2023

Abstract
We have previously shown that inoculation of the rat neu-overexpressing mouse mammary carcinoma (MMC), derived from FVBN202 mice, into parental FVB mice resulted in the initial tumor rejection and relapse of the neu antigen negative variant (ANV) in a large fraction of FVB mice. Here, we show that status of IFN-gamma receptor alpha in MMC will determine whether this tumor may or may not relapse in FVB mice. We generated MMC transfectants expressing a dominant negative IFN-gamma receptor (dnIFN-gammaRMMC). Animals were then depleted of CD4+ T cells prior to the tumor challenge in order to omit the contribution of the neu-specific antibody and retard the rejection of MMC. Then, we inoculated FVB mice with MMC or dnIFN-gammaRMMC. Interestingly, animals that were depleted of CD4+ T cells at the priming phase of the immune responses failed to reject MMC and showed tumor relapse of the neu negative variant (ANV), but they managed to reject the dnIFN-gammaRMMC with no relapse until 3 months after the challenge. We also showed that status of IFN-gamma receptor alpha in human carcinoma cells SKBR3 will determine IFN-gamma-mediated down-regulation of HER-2/neu in this human carcinoma line. Treatment of tumor cells with IL-6 or TNF-alpha in order to increase IFN-gamma receptor expression rendered tumors more sensitive to IFN-gamma-mediated downregulation of HER-2/neu. Together, our data suggest that determination of the status of IFN-gamma receptor alpha in tumor lesions of HER-2/neu positive breast cancer patients may be a prognostic factor for relapse of their metastatic tumors.
Role of TLR2 and dectin-1 in the host response to Penicillium marneffei (51.10)
Authors: Nakamura Kiwamu , Miyazato Akiko , Saijo Shinobu , Iwakura Yoichiro , Kaku Mitsuo , Kawakami Kazuyoshi 
Published: January 2023

Abstract
Pathogen-associated molecular patterns (PAMP) are recognized by Toll-like receptors (TLR) and C-type lectin receptors including Dectin-1. In the current study, we examined the role of TLR2 and 4 and dectin-1, a β-glucan receptor, in the host response to Penicillium marneffei, an opportunistic fungal pathogen in AIDS patients. IL-12p40 production by bone marrow-derived dendritic cells (BMDCs) stimulated with yeast cells of this fungal pathogens was significantly reduced in TLR2KO and MyD88KO mice, but not in TLR4KO and C3H/HeJ mice, compared to that in control mice. Such production was significantly lower in dectin-1KO mice than wild-type mice. In further experiments, HEK293 cells transfected with TLR2 and/or dectin-1 genes were stimulated with P. marneffei for a NFκB promoter assay. Compared to the cells transfected with control vector, significantly higher activity of NFκB was detected in TLR2-transfectant, but this response was not further enhanced by co-transfection with dectin-1. Taken together, these results demonstrated that TLR2 and dectin-1 played an important role in the recognition of P. marneffei by BMDCs.
Delayed production of TNF-α in neonatal mice in response to Pneumocystis carinii infection corresponds to increased TGF-β levels in the lungs (51.11)
Authors: Rogosky Amy M , Hollifield Melissa , Garvy Beth A 
Published: January 2023

Abstract
Neonatal mice challenged with Pneumocystis carinii (PC) exhibit a three week delay in clearance as compared to adults, corresponding to a delayed CD4+ T cell infiltration into the alveolar spaces. We have published that messenger RNA levels of transforming growth factor (TGF)-β and interleukin (IL)-10 are constitutively expressed in neonatal lungs, suggesting that the lung environment is not adequate to recruit circulating lymphocytes. We have since found that pups have increased TGF-β1 protein levels compared to adults until three weeks of age. The infiltration of CD4+ T cells corresponded to decreasing lung TGF-β levels. Moreover, production of TNF–α by CD4+ T cells was also delayed in pups compared to adults. Ongoing experiments will determine whether TGF-β dampens the proinflammatory response until it is developmentally downregulated or if decreased TGF-β levels follow lung infiltration by activated CD4+ T cells.
This research was supported by PHS grant HL062053.
Heat labile secretory proteins released by Naegleria fowleri induces apoptotic cell death of Jurkat T cells (51.13)
Authors: Shin Myeong Heon , Shin Ho-Joon , Kim Kyeong Ah , Lee Young Ah 
Published: January 2023

Abstract
Naegleria fowleri, a free-living amoeba of soil, ponds, andfresh water, causes primary amoebic meningoencephalitis in humansand other mammals. Upon invasion in vivo, N. fowleri is capable of destructing or killing host cells by cytolysis. However, it is unknown on the mechanism by which N. fowleri induces host cell death. In this study, we investigated the mechanism of host cell death induced by N. fowleri. Incubation of Jurkat T cells with live trophozoites of N. fowleri resulted in cell death, as measured by LDH release assay or propidium iodide staining. In addition, N. fowleri induced DNA fragmentation in Jurkat cells in a time and dose-dependent manner. N. fowleri caused cleavage of calpain, caspase-3, and cytoskeletal proteins such as vinculin and paxillin. Pretreatment of cells with NADPH oxidase inhibitor DPI inhibited N. foweleri-induced apoptosis, whereas calpain inhibitor calpeptin or pan-caspase inhibitor z-VAD-fmk did not. When we incubated Jurkat cells with N. fowleri in a Transwell chamber (pore size 0.4 μm), comparable level of cell death rate was found compared to control without chamber, suggesting an important role of secretory factors in N. foweleri-induced cell death. Moreover, secretroy components released by N. fowleri induced host cell death, and heat treatment abolished host cell death by secretory components. These results suggest that heat labile proteins secreted by N. fowleri induce apoptotic cell death in Jurkat T cells.
Expression of TREM-1 in Macrophages is TLR2 dependent (51.7)
Authors: Choi Esther S , Buckland Karen , Hogaboam Cory 
Published: January 2023

Abstract
Triggering receptors expressed on myeloid cells (TREM) are a group of cell surface proteins that contribute to inflammation, allergy, bone homeostasis, neurological development and coagulation, among other cellular processes. Specifically, activation of TREM-1 on monocytes has been shown to enhance the synthesis of multiple proinflammatory cytokines, chemokines and cell surface molecules in the presence of Toll-like receptor (TLR) specific pathogen associated molecular patterns (PAMPs). Presently, little is known about the regulatory role of TLRs on TREM-1 expression and function in macrophages. Accordingly, we examined the expression and function of TREM-1 in bone marrow derived macrophages (BMMØ) from non-sensitized and Aspergillus fumigatus sensitized wild type C57BL/6 (WT) and TLR2 deficient mice (TLR2−/−). In naïve WT BMMØ, TREM-1 expression was upregulated by IFNγ. BMMØ from naïve TLR2−/− mice did not express TREM-1 transcripts nor was it altered by cytokine or PAMP activation. In the context of sensitization, WT BMMØ expressed greater TREM-1 levels when compared with naive WT BMMØ. TREM-1 was detected in sensitized TLR2 −/− BMMØ but at much lower levels than sensitized WT BMMØ. Finally, both IFNγ and IL-13 increased expression of TREM-1 sensitized WT and TLR2−/− BMMØ. Thus, TLR2 expression was required for TREM-1 expression by BMMØ. Also, TREM-1 expression is markedly increased in BMMØ derived from allergic mice confirming a role for this receptor in allergic responses. Thus, regulation of TREM-1 expression may be a therapeutic target in allergic airway disease.
HL069865