Prognostic significance of tumor-infiltrating immune cells and PD-L1 expression in esophageal squamous cell carcinoma.

PubMed

Jiang, Yubo; Lo, Anthony W I; Wong, Angela; Chen, Wenfeng; Wang, Yan; Lin, Li; Xu, Jianming

2017-05-02

Programmed death-1 receptor (PD-1) and its ligand (PD-L1) play an integral role in regulating the immune response against cancer. This study investigated the prognostic significance of PD-L1 expression on tumor cells and tumor-infiltrating immune cells (TILs) in the tumor microenvironment in Chinese patients with esophageal squamous cell carcinoma (ESCC). Archival formalin-fixed, paraffin-embedded ESCC samples from treatment-naïve patients with ESCC after surgery or by diagnostic endoscopic biopsy were collected between 2004 and 2014. Expression of PD-L1 in ESCC tumor specimens was assessed by immunohistochemistry (IHC), and the degree of TIL infiltration was evaluated by examining hematoxylin and eosin-stained (H&E) specimens. PD-L1+ as defined as ≥1% of tumor cell membranes showing ≥1+ intensity. In 428 patients, specimens from 341 (79.7%) were PD-L1+. In the definitive treatment group (patients who received curative esophagectomy or definitive [chemo-]radiation therapy), PD-L1 positivity was associated with a significantly shorter DFS and OS. In the palliative chemotherapy group exhibited, neither PFS nor OS correlated significantly with PD-L1 expression. PD-L1 expression was positively associated with TIL density. In 17 paired tumor tissues collected before and after treatment, an increase in PD-L1 expression was associated with disease progression, whereas a decrease in PD-L1 expression was associated with response to chemotherapy or disease control. So, PD-L1 expression was associated with a significantly worse prognosis in patients with ESCC. These observations suggest that PD-L1 may play a critical role in ESCC cancer progression and provide a rationale for developing PD-L1 inhibitors for treatment of a subset of ESCC patients.

Armed oncolytic adenovirus expressing PD-L1 mini-body enhances anti-tumor effects of chimeric antigen receptor T-cells in solid tumors

PubMed Central

Tanoue, Kiyonori; Shaw, Amanda Rosewell; Watanabe, Norihiro; Porter, Caroline; Rana, Bhakti; Gottschalk, Stephen; Brenner, Malcolm; Suzuki, Masataka

2017-01-01

Chimeric antigen receptor-modified T cells (CAR T-cells) produce pro-inflammatory cytokines that increase expression of T cell checkpoint signals such as PD-L1, which may inhibit their functionality against solid tumors. In this study, we evaluated in human tumor xenograft models the pro-inflammatory properties of an oncolytic adenovirus (Onc.Ad) with a helper-dependent Ad (HDAd) that expresses a PD-L1 blocking mini-antibody (mini-body) (HDPDL1), as a strategy to enhance CAR T-cell killing. Co-administration of these agents (CAd-VECPDL1) exhibited oncolytic effects with production of PD-L1 mini-body locally at the tumor site. On their own, HDPDL1 exhibited no anti-tumor effect and CAd-VECPDL1 alone reduced tumors only to volumes comparable to Onc.Ad treatment. However, combining CAd-VECPDL1 with HER2.CAR T-cells enhanced anti-tumor activity compared to treatment with either HER2.CAR T-cells alone, or HER2.CAR T-cells plus Onc.Ad. The benefits of locally produced PD-L1 mini-body by CAd-VECPDL1 could not be replicated by infusion of anti-PD-L1 IgG plus HER2.CAR T-cells and co-administration of Onc.Ad in a HER2+ prostate cancer xenograft model. Overall, our data document the superiority of local production of PD-L1 mini-body by CAd-VECPDL1 combined with administration of tumor-directed CAR T-cells to control the growth of solid tumors. PMID:28235763

Evaluation of PD-L1 expression on vortex-isolated circulating tumor cells in metastatic lung cancer.

PubMed

Dhar, Manjima; Wong, Jessica; Che, James; Matsumoto, Melissa; Grogan, Tristan; Elashoff, David; Garon, Edward B; Goldman, Jonathan W; Sollier Christen, Elodie; Di Carlo, Dino; Kulkarni, Rajan P

2018-02-07

Metastatic non-small cell lung cancer (NSCLC) is a highly fatal and immunogenic malignancy. Although the immune system is known to recognize these tumor cells, one mechanism by which NSCLC can evade the immune system is via overexpression of programmed cell death ligand 1 (PD-L1). Recent clinical trials of PD-1 and PD-L1 inhibitors have returned promising clinical responses. Important for personalizing therapy, patients with higher intensity staining for PD-L1 on tumor biopsies responded better. Thus, there has been interest in using PD-L1 tumor expression as a criterion for patient selection. Currently available methods of screening involve invasive tumor biopsy, followed by histological grading of PD-L1 levels. Biopsies have a high risk of complications, and only allow sampling from limited tumor sections, which may not reflect overall tumor heterogeneity. Circulating tumor cell (CTC) PD-L1 levels could aid in screening patients, and could supplement tissue PD-L1 biopsy results by testing PD-L1 expression from disseminated tumor sites. Towards establishing CTCs as a screening tool, we developed a protocol to isolate CTCs at high purity and immunostain for PD-L1. Monitoring of PD-L1 expression on CTCs could be an additional biomarker for precision medicine that may help in determining response to immunotherapies.

Transfer of allogeneic CD4+ T cells rescues CD8+ T cells in anti-PD-L1–resistant tumors leading to tumor eradication

PubMed Central

Arina, Ainhoa; Karrison, Theodore; Galka, Eva; Schreiber, Karin; Weichselbaum, Ralph R.; Schreiber, Hans

2017-01-01

Adoptively transferred CD8+ T cells can stabilize the size of solid tumors over long periods of time by exclusively recognizing antigen cross-presented on tumor stroma. However, these tumors eventually escape T cell–mediated growth control. The aim of this study was to eradicate such persistent cancers. In our model, the SIYRYYGL antigen is expressed by cancer cells that lack the MHC-I molecule Kb needed for direct presentation, but the antigen is picked up and cross-presented by tumor stroma. A single injection of antigen-specific 2C CD8+ T cells caused long-term inhibition of tumor growth, but without further intervention, tumors started to progress after approximately 3 months. Escape was associated with reduced numbers of circulating 2C cells. Tumor-infiltrating 2C cells produced significantly less TNFα and expressed more of the “exhaustion” markers PD-1 and Tim-3 than T cells from lymphoid organs. High-dose local ionizing radiation, depletion of myeloid-derived suppressor cells, infusions of additional 2C cells, and antibodies blocking PD-L1 did not prevent tumor escape. In contrast, adoptive transfer of allogeneic CD4+ T cells restored the numbers of circulating Ag-specific CD8+ T cells and their intratumoral function, resulting in tumor eradication. These CD4+ T cells had no antitumor effects in the absence of CD8+ T cells and recognized the alloantigen cross-presented on tumor stroma. CD4+ T cells might also be effective in cancer patients when PD1/PD-L1 blockade does not rescue intratumoral CD8+ T-cell function and tumors persist. PMID:28077434

O-naphthoquinone isolated from Capraria biflora L. induces selective cytotoxicity in tumor cell lines.

PubMed

de S Wisintainer, G G N; Scola, G; Moura, S; Lemos, T L G; Pessoa, C; de Moraes, M O; Souza, L G S; Roesch-Ely, M; Henriques, J A P

2015-12-21

Biflorin is an o-naphthoquinone isolated from the roots of the plant Capraria biflora L. (Scrophulariaceae). In this study, the cytotoxic effects of biflorin were verified, and late apoptosis was detected in various cancer cell lines by in situ analysis. The cytotoxicity was further evaluated exclusively for 48 h of treatment in different tumor and non-tumor cell lines (Hep-2, HeLa, HT-29, A-375, and A-549, and HEK-293, respectively). The results indicated that biflorin induced selective cytotoxicity in tumor cells. HeLa cells were more susceptible to biflorin, followed by HT-29, A-549, A-375, and Hep-2 at all concentrations (range 5-50 μg/mL), and the highest half-maximal inhibitory concentration IC50 (56.01 ± 1.17 μg/mL) was observed in HEK-293 cells. Late apoptotic/necrotic events, observed by in situ immunostaining with Annexin V, varied with each cell line; an increase in late apoptotic events was observed corresponding to the increase in biflorin dosage. Hep-2 cells showed a greater percentage of late apoptotic events among the tumor cell lines when treated with higher concentrations of biflorin (69.63 ± 2.28%). The non-tumor HEK-293 line showed greater resistance to late apoptotic events, as well as a lower level of cytotoxicity (77.69 ± 6.68%) than the tested tumor lines. The data presented indicate that biflorin showed an important, possibly selective, cytotoxicity against tumor cell lines, thereby revealing a promising novel substance with potential anticancer activity for tumor therapy.

Photoaffinity analogues of methotrexate as folate antagonist binding probes. 2. Transport studies, photoaffinity labeling, and identification of the membrane carrier protein for methotrexate from murine L1210 cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Price, E.M.; Freisheim, J.H.

1987-07-28

A membrane-derived component of the methotrexate/one-carbon-reduced folate transport system in murine L1210 cells has been identified by using a photoaffinity analogue of methotrexate. The compound, a radioiodinated 4-azidosalicylyl derivative of the lysine analogue of methotrexate, is transported into murine L1210 cells in a temperature-dependent, sulfhydryl reagent inhibitable manner with a K/sub t/ of 506 +/- 79 nM and a V/sub max/ of 17.9 +/- 4.2 pmol min/sup -1/ (mg of total cellular protein)/sup -1/. Uptake of the iodinated compound at 200 nM is inhibited by low amounts of methotrexate. The parent compounds of the iodinated photoprobe inhibit (/sup 3/H)methotrexate uptake,more » with the uniodinated 4-azidosalicylyl derivative exhibiting a K/sub i/ of 66 +/- 21 nM. UV irradiation, at 4 /sup 0/C, of a cell suspension that had been incubated with the probe results in the covalent modification of a 46K-48K protein. This can be demonstrated when the plasma membranes from the labeled cells are analyzed via sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography. Labeling of this protein occurs half-maximally at a reagent concentration that correlates with the K/sub t/ for transport of the iodinated compound. Protection against labeling of this protein by increasing amounts of methotrexate parallels the concentration dependence of inhibition of photoprobe uptake by methotrexate. Evidence that, in the absence of irradiation and at 37/sup 0/C, the iodinated probe is actually internalized is demonstrated by the labeling of two soluble proteins (M/sub r/ 38K and 21K) derived from the cell homogenate supernatant.« less

PD-L1 Expression of Tumor Cells, Macrophages, and Immune Cells in Non-Small Cell Lung Cancer Patients with Malignant Pleural Effusion.

PubMed

Tseng, Yen-Han; Ho, Hsiang-Ling; Lai, Chiung-Ru; Luo, Yung-Hung; Tseng, Yen-Chiang; Whang-Peng, Jacqueline; Lin, Yi-Hsuan; Chou, Teh-Ying; Chen, Yuh-Min

2018-03-01

Whether immunohistochemical staining of programmed death ligand 1 (PD-L1) on cells of pleural effusion could be used to predict response to immunotherapy treatment has not been reported. We retrospectively enrolled patients who had undergone malignant pleural effusion drainage and had effusion cell block specimens from 2014 to 2016. Immunohistochemical staining for PD-L1 was performed with tumor cells, immune cells, and macrophages of all cell block specimens. Immunoactivity was scored as 0 for absence of staining and 1+ for faint, 2+ for moderate, and 3+ for intense membranous staining. Patients' clinicopathological characteristics were also collected. PD-L1 expression of pleural effusion tumor cells was associated with the PD-L1 expression of macrophages (p = 0.003) and immune cells (p < 0.001). However, the PD-L1 expression of immune cells was not associated with that of macrophages. The PD-L1 expression of tumor cells was correlated with sex (p = 0.012), smoking status (p = 0.032), and Eastern Cooperative Oncology Group performance status (p = 0.017). The PD-L1 expression of immune cells was associated with the overall survival of patients (p = 0.004). These results suggest that there might be an immune interaction between pleural effusion tumor cells and macrophages. The low intensity of PD-L1 expression in immune cells is associated with the poor survival of patients with lung cancer with malignant pleural effusion. Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Basal cell carcinoma: PD-L1/PD-1 checkpoint expression and tumor regression after PD-1 blockade.

PubMed

Lipson, Evan J; Lilo, Mohammed T; Ogurtsova, Aleksandra; Esandrio, Jessica; Xu, Haiying; Brothers, Patricia; Schollenberger, Megan; Sharfman, William H; Taube, Janis M

2017-01-01

Monoclonal antibodies that block immune regulatory proteins such as programmed death-1 (PD-1) have demonstrated remarkable efficacy in controlling the growth of multiple tumor types. Unresectable or metastatic basal cell carcinoma, however, has largely gone untested. Because PD-Ligand-1 (PD-L1) expression in other tumor types has been associated with response to anti-PD-1, we investigated the expression of PD-L1 and its association with PD-1 expression in the basal cell carcinoma tumor microenvironment. Among 40 basal cell carcinoma specimens, 9/40 (22%) demonstrated PD-L1 expression on tumor cells, and 33/40 (82%) demonstrated PD-L1 expression on tumor-infiltrating lymphocytes and associated macrophages. PD-L1 was observed in close geographic association to PD-1+ tumor infiltrating lymphocytes. Additionally, we present, here, the first report of an objective anti-tumor response to pembrolizumab (anti-PD-1) in a patient with metastatic PD-L1 (+) basal cell carcinoma, whose disease had previously progressed through hedgehog pathway-directed therapy. The patient remains in a partial response 14 months after initiation of therapy. Taken together, our findings provide a rationale for testing anti-PD-1 therapy in patients with advanced basal cell carcinoma, either as initial treatment or after acquired resistance to hedgehog pathway inhibition.

Malignant mesothelioma effusions are infiltrated by CD3+ T cells highly expressing PD-L1 and the PD-L1+ tumor cells within these effusions are susceptible to ADCC by the anti-PD-L1 antibody avelumab

PubMed Central

Khanna, Swati; Thomas, Anish; Abate-Daga, Daniel; Zhang, Jingli; Morrow, Betsy; Steinberg, Seth M.; Orlandi, Augusto; Ferroni, Patrizia; Schlom, Jeffrey; Guadagni, Fiorella; Hassan, Raffit

2016-01-01

INTRODUCTION The functional aspects of programmed death 1 (PD-1) and PD ligand 1 (PD-L1) immune checkpoints in malignant mesothelioma have not been studied. METHODS Tumor samples from 65 patients with mesothelioma were evaluated for PD-L1 expression by immunohistochemistry and its prognostic significance. Malignant effusions from patients with pleural and peritoneal mesothelioma were evaluated for PD-1+ and PD-L1+ infiltrating lymphocytes and their role in inducing tumor cell PD-L1 expression. Antibody dependent cellular cytotoxicity (ADCC) of avelumab, a fully humanized IgG1 anti PD-L1 antibody towards primary mesothelioma cell lines was evaluated in presence of autologous and allogeneic NK cells. RESULTS Of 65 pleural and peritoneal mesothelioma tumors examined, 41 (63%) were PD-L1 positive, which was associated with slightly inferior overall survival compared to patients with PD-L1 negative tumors (median 23.0 vs. 33.3 months; p=0.35). The frequency of PD-L1 expression was similar in pleural and peritoneal mesothelioma patients with 62% and 64% of samples positive, respectively. Of nine mesothelioma effusion samples evaluated, the fraction of cells expressing PD-L1 ranged from 12 to 83%. Of 7 patients with paired malignant effusion and peripheral blood mononuclear cells (PBMC) samples, PD-L1 expression was significantly higher on CD3+ T cells present in malignant effusions as compared with PBMC (p=0.016). In addition, CD14+PD-1+ cells were elevated in malignant effusions compared with PBMC (p=0.031). The lymphocytes present in malignant effusions recognized autologous tumor cells and induced IFN-γ-mediated PD-L1 expression on the tumor cell surface. Of the three primary mesothelioma cell lines tested, two were susceptible to avelumab mediated ADCC in presence of autologous NK cells. CONCLUSION The majority of pleural as well as peritoneal mesothelioma express PD-L1. Malignant effusions in this disease are characterized by presence of tumor cells and CD3+ T

Malignant Mesothelioma Effusions Are Infiltrated by CD3+ T Cells Highly Expressing PD-L1 and the PD-L1+ Tumor Cells within These Effusions Are Susceptible to ADCC by the Anti-PD-L1 Antibody Avelumab.

PubMed

Khanna, Swati; Thomas, Anish; Abate-Daga, Daniel; Zhang, Jingli; Morrow, Betsy; Steinberg, Seth M; Orlandi, Augusto; Ferroni, Patrizia; Schlom, Jeffrey; Guadagni, Fiorella; Hassan, Raffit

2016-11-01

The functional aspects of programmed death 1 (PD-1) and PD ligand 1 (PD-L1) immune checkpoints in malignant mesothelioma have not been studied. Tumor samples from 65 patients with mesothelioma were evaluated for PD-L1 expression by immunohistochemistry, and its prognostic significance was examined. Malignant effusions from patients with pleural and peritoneal mesothelioma were evaluated for PD-1-positive and PD-L1-positive infiltrating lymphocytes and their role in inducing PD-L1 expression in tumor cells. Antibody-dependent cellular cytotoxicity (ADCC) of avelumab, a fully humanized immunoglobulin G1 anti PD-L1 antibody against primary mesothelioma cell lines, was evaluated in presence of autologous and allogeneic natural killer cells. Of 65 pleural and peritoneal mesothelioma tumors examined, 41 (63%) were PD-L1-positive, which was associated with slightly inferior overall survival compared to patients with PD-L1-negative tumors (median 23.0 versus 33.3 months, p = 0.35). The frequency of PD-L1 expression was similar in patients with pleural and peritoneal mesothelioma, with 62% and 64% of samples testing positive, respectively. In nine mesothelioma effusion samples evaluated, the fraction of cells expressing PD-L1 ranged from 12% to 83%. In seven patients with paired malignant effusion and peripheral blood mononuclear cell (PBMC) samples, PD-L1 expression was significantly higher on CD3-positive T cells present in malignant effusions as compared with PBMCs (p = 0.016). In addition, the numbers of CD14-positive PD-1-positive cells were increased in malignant effusions compared with PBMCs (p = 0.031). The lymphocytes present in malignant effusions recognized autologous tumor cells and induced interferon-γ-mediated PD-L1 expression on the tumor cell surface. Of the three primary mesothelioma cell lines tested, two were susceptible to avelumab-mediated ADCC in the presence of autologous natural killer cells. Most pleural as well as peritoneal mesotheliomas

FasL Mediates T-Cell Eradication of Tumor Cells Presenting Low Levels of Antigens | Center for Cancer Research

Cancer.gov

One approach to cancer immunotherapy, as opposed to therapeutic vaccination, is the transfusion of large numbers of tumor-specific killer T cells (cytotoxic T cells or CTLs) into patients. The body’s own defense killer T cells are a subgroup of T lymphocytes (a type of white blood cells) that are capable of inducing death in tumor cells. CTLs can cause the death of target cells either by releasing granules containing toxic molecules including perforin, or by producing a membrane protein called Fas ligand (FasL) which on interaction with the tumor cell results in cell death.

Effects of Mg2+ and adenine nucleotides on thymidylate synthetase from different mouse tumors.

PubMed

Rode, W; Jastreboff, M M

1984-01-01

Magnesium ions variably influenced activity of highly purified thymidylate synthetase preparations from different mouse tumors, activating the enzyme from Ehrlich ascites carcinoma (EAC) cells and inhibiting the enzyme from L1210 and L5178Y cells and from 5-fluorodeoxyuridine (FdUrd)-resistant EAC cells. In the presence of Mg2+ in a concentration resulting in either maximum activation or inhibition (25-30 mM) the enzymes from both the sensitive and FdUrd-resistant EAC lines and L5178Y cells were activated by ATP. Under the same conditions of Mg2+ concentration ADP and AMP inhibited the enzyme from the parental but not from the FdUrd-resistant EAC cells.

Modulation of the Effect of l‐β‐D‐Arabinofuranosylcytosine by 6‐Mercaptopurine in L1210 Cells

PubMed Central

Kawai, Yasukazu; Ueda, Takanori; Nakamura, Toru

1994-01-01

In L1210 cells incubated with l‐β‐D‐arabinofuranosylcytosine (ara‐C), 6‐mercaptopurine (6‐MP) significantly potentiated 1‐β‐D‐arabinofuranosylcytosme 5′‐triphosphate (ara‐CTP) accumulation and ara‐C incorporation into DNA (ara‐C/DNA). The cytotoxicity of these two drugs was assessed to be at least additive by clonogenic assay. l‐β‐D‐Arabinofuranosylnracil (ara‐U) level in a cell suspension was suppressed by 6‐MP in a concentration‐dependent fashion, though intracellular cytidine deaminase (CDD) activity was not affected by 6‐MP. In addition, extracted CDD activity was not directly inhibited by 6‐MP or by its intracellular metabolites in vitro. After preincubation in the presence or absence of 6‐MP, the cell suspension was fractionated to obtain the spent medium and cell pellet. Then, each fraction was incubated with ara‐C. Ara‐U formation in the spent medium was found to increase conspicuously in relation to the time of preincubation in the control and it was suppressed by 6‐MP pretreatment. Ara‐U formation in the cell compartment increased slightly in relation to the time of preincubation in the control and substantially no suppression of ara‐U formation was observed in spite of 6‐MP pretreatment. In conclusion, intracellularly synthesized CDD was thought to be rapidly shed into the medium and the released CDD could play an important role in ara‐C inactivation. 6‐MP interrupted some step between synthesis and shedding of CDD, resulting in a decrease of the ara‐C deamination in the medium and enhancement of its antileukemic effect. PMID:7961129

TCP10L acts as a tumor suppressor by inhibiting cell proliferation in hepatocellular carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zuo, Jie; Cai, Hao; Wu, Yanhua

2014-03-28

Highlights: • TCP10L was down-regulated in clinical hepatocellular carcinoma (HCC). • Expression of TCP10L correlated significantly with tumor size and Milan criteria. • Overexpression of TCP10L attenuated growth of HCC cells both in vitro and in vivo. • Knocking down TCP10L promoted cell proliferation and tumorigenesis of HCC cells. - Abstract: TCP10L (T-complex 10 (mouse)-like) has been identified as a liver and testis-specific gene. Although a potential transcriptional suppression function of TCP10L has been reported previously, biological function of this gene still remains largely elusive. In this study, we reported for the first time that TCP10L was significantly down-regulated inmore » clinical hepatocellular carcinoma (HCC) samples when compared to the corresponding non-tumorous liver tissues. Furthermore, TCP10L expression was highly correlated with advanced cases exceeding the Milan criteria. Overexpression of TCP10L in HCC cells suppressed colony formation, inhibited cell cycle progression through G0/G1 phase, and attenuated cell growth in vivo. Consistently, silencing of TCP10L promoted cell cycle progression and cell growth. Therefore, our study has revealed a novel suppressor role of TCP10L in HCC, by inhibiting proliferation of HCC cells, which may facilitate the diagnosis and molecular therapy in HCC.« less

Characterization of Compounds with Tumor-Cell Proliferation Inhibition Activity from Mushroom (Phellinus baumii) Mycelia Produced by Solid-State Fermentation.

PubMed

Zhang, Henan; Shao, Qian; Wang, Wenhan; Zhang, Jingsong; Zhang, Zhong; Liu, Yanfang; Yang, Yan

2017-04-27

The inhibition of tumor-cell proliferationbyan organicsolvent extract from the solid-state fermentation of Phellinus baumii mycelia inoculated in rice medium was investigated in vitro. The active compounds inhibiting tumor-cell proliferation were characterized. Results revealed that all (petroleum ether, chloroform, ethyl acetate, and butanol) fractions inhibited tumor-cell proliferation in a dose-dependent fashion. The ethyl acetate extract had the highest inhibitory effecton tumor-cell proliferation, and the butanol fraction had the lowest. Six compounds were isolated and purified from the ethyl acetate extract of P. baumii mycelia by the tandem application of silica-gel column chromatography (SGCC), high-speed countercurrent chromatography (HSCCC), and preparative HPLC. These compounds were identified by NMR and electrospray ionization-mass spectrometry (ESI-MS) spectroscopic methods as ergosterol (RF1), ergosta-7,22-dien-3β-yl pentadecanoate (RF3), 3,4-dihydroxy benzaldehyde(RF6), inoscavinA (RF7), baicalein(RF10), and 24-ethylcholesta-5,22-dien-3β-ol (RF13). To further clarify the activity of these compounds, the cell-proliferation-inhibition tests of these compounds on various tumor cells were carried out and evaluatedin vitro. Results suggested that compounds RF6, RF7, and RF10 had potent inhibition effects on the proliferation of a series of tumor cell lines, including K562, L1210, SW620, HepG2, LNCaP, and MCF-7cells. These findings indicated that P. baumii mycelia produced by solid-state fermentation in rice canbe used to obtain active compounds with the ability to inhibittumor-cell proliferation.

Therapeutic efficacy of interleukin-2 activated killer cells against adriamycin resistant mouse B16-BL6 melanoma.

PubMed

Gautam, S C; Chikkala, N F; Lewis, I; Grabowski, D R; Finke, J H; Ganapathi, R

1992-01-01

Development of multidrug-resistance (MDR) remains a major cause of failure in the treatment of cancer with chemotherapeutic agents. In our efforts to explore alternative treatment regimens for multidrug-resistant tumors we have examined the sensitivity of MDR tumor cell lines to lymphokine activated killer (LAK) cells. Adriamycin (ADM) resistant B16-BL6 melanoma, L1210 and P388 leukemic cell lines were tested for sensitivity to lysis by LAK cells in vitro. While ADM-resistant B16-BL6 and L1210 sublines were found to exhibit at least 2-fold greater susceptibility to lysis by LAK cells, sensitivity of ADM-resistant P388 cell was similar to that of parental cells. Since ADM-resistant B16-BL6 cells were efficiently lysed by LAK cells in vitro, the efficacy of therapy with LAK cells against the ADM-resistant B16-BL6 subline in vivo was evaluated. Compared to mice bearing parental B16-BL6 tumor cells, the adoptive transfer of LAK cells and rIL2 significantly reduced formation of experimental metastases (P less than 0.009) and extended median survival time (P less than 0.001) of mice bearing ADM-resistant B16-BL6 tumor cells. Results suggest that immunotherapy with LAK cells and rIL2 may be a useful modality in the treatment of cancers with the MDR phenotype.

COX2/mPGES1/PGE2 pathway regulates PD-L1 expression in tumor-associated macrophages and myeloid-derived suppressor cells

PubMed Central

Prima, Victor; Kaliberova, Lyudmila N.; Kaliberov, Sergey; Curiel, David T.; Kusmartsev, Sergei

2017-01-01

In recent years, it has been established that programmed cell death protein ligand 1 (PD-L1)–mediated inhibition of activated PD-1+ T lymphocytes plays a major role in tumor escape from immune system during cancer progression. Lately, the anti–PD-L1 and –PD-1 immune therapies have become an important tool for treatment of advanced human cancers, including bladder cancer. However, the underlying mechanisms of PD-L1 expression in cancer are not fully understood. We found that coculture of murine bone marrow cells with bladder tumor cells promoted strong expression of PD-L1 in bone marrow–derived myeloid cells. Tumor-induced expression of PD-L1 was limited to F4/80+ macrophages and Ly-6C+ myeloid-derived suppressor cells. These PD-L1–expressing cells were immunosuppressive and were capable of eliminating CD8 T cells in vitro. Tumor-infiltrating PD-L1+ cells isolated from tumor-bearing mice also exerted morphology of tumor-associated macrophages and expressed high levels of prostaglandin E2 (PGE2)-forming enzymes microsomal PGE2 synthase 1 (mPGES1) and COX2. Inhibition of PGE2 formation, using pharmacologic mPGES1 and COX2 inhibitors or genetic overexpression of PGE2-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH), resulted in reduced PD-L1 expression. Together, our study demonstrates that the COX2/mPGES1/PGE2 pathway involved in the regulation of PD-L1 expression in tumor-infiltrating myeloid cells and, therefore, reprogramming of PGE2 metabolism in tumor microenvironment provides an opportunity to reduce immune suppression in tumor host. PMID:28096371

Optimizing the dosing schedule of l-asparaginase improves its anti-tumor activity in breast tumor-bearing mice.

PubMed

Shiromizu, Shoya; Kusunose, Naoki; Matsunaga, Naoya; Koyanagi, Satoru; Ohdo, Shigehiro

2018-04-01

Proliferation of acute lymphoblastic leukemic cells is nutritionally dependent on the external supply of asparagine. l-asparaginase, an enzyme hydrolyzing l-asparagine in blood, is used for treatment of acute lymphoblastic leukemic and other related blood cancers. Although previous studies demonstrated that l-asparaginase suppresses the proliferation of cultured solid tumor cells, it remains unclear whether this enzyme prevents the growth of solid tumors in vivo. In this study, we demonstrated the importance of optimizing dosing schedules for the anti-tumor activity of l-asparaginase in 4T1 breast tumor-bearing mice. Cultures of several types of murine solid tumor cells were dependent on the external supply of asparagine. Among them, we selected murine 4T1 breast cancer cells and implanted them into BALB/c female mice kept under standardized light/dark cycle conditions. The growth of 4T1 tumor cells implanted in mice was significantly suppressed by intravenous administration of l-asparaginase during the light phase, whereas its administration during the dark phase failed to show significant anti-tumor activity. Decreases in plasma asparagine levels due to the administration of l-asparaginase were closely related to the dosing time-dependency of its anti-tumor effects. These results suggest that the anti-tumor efficacy of l-asparaginase in breast tumor-bearing mice is improved by optimizing the dosing schedule. Copyright © 2018 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

Dendritic and tumor cell fusions transduced with adenovirus encoding CD40L eradicate B-cell lymphoma and induce a Th17-type response.

PubMed

Alvarez, E; Moga, E; Barquinero, J; Sierra, J; Briones, J

2010-04-01

Fusion of dendritic cells and tumor cells (FCs) constitutes a promising tool for generating an antitumor response because of their capacity to present tumor antigens and provide appropriate costimulatory signals. CD40-CD40L interaction has an important role in the maturation and survival of dendritic cells and provides critical help for T-cell priming. In this study, we sought to improve the effectiveness of FC vaccines in a murine model of B-cell lymphoma by engineering FCs to express CD40L by means of an adenovirus encoding CD40L (Adv-CD40L). Before transduction with Adv-CD40L, no CD40L expression was detected in FCs, DCs or tumor cells. The surface expression of CD40L in FC transduced with Adv-CD40L (FC-CD40L) ranged between 50 and 60%. FC-CD40L showed an enhanced expression of CD80, CD86, CD54 and MHC class II molecules and elicited a strong in vitro immune response in a syngeneic mixed lymphocyte reaction. Furthermore, FC-CD40L showed enhanced migration to secondary lymphoid organs. Splenocytes from mice treated with FC-CD40L had a dramatic increase in the production of IL-17, IL-6 and IFN-gamma, compared with controls. Treatment with the FC-CD40L vaccine induced regression of established tumors and increased survival. Our data demonstrate that FC transduced with Adv-CD40L enhances the antitumor effect of FC vaccines in a murine lymphoma model and this is associated with an increased Th17-type immune response.

NK Cells, Tumor Cell Transition, and Tumor Progression in Solid Malignancies: New Hints for NK-Based Immunotherapy?

PubMed Central

Huergo-Zapico, Leticia; Parodi, Monica; Pedrazzi, Marco; Mingari, Maria Cristina; Sparatore, Bianca; Gonzalez, Segundo; Olive, Daniel; Bottino, Cristina

2016-01-01

Several evidences suggest that NK cells can patrol the body and eliminate tumors in their initial phases but may hardly control established solid tumors. Multiple factors, including the transition of tumor cells towards a proinvasive/prometastatic phenotype, the immunosuppressive effect of the tumor microenvironment, and the tumor structure complexity, may account for limited NK cell efficacy. Several putative mechanisms of NK cell suppression have been defined in these last years; conversely, the cross talk between NK cells and tumor cells undergoing different transitional phases remains poorly explored. Nevertheless, recent in vitro studies and immunohistochemical analyses on tumor biopsies suggest that NK cells could not only kill tumor cells but also influence their evolution. Indeed, NK cells may induce tumor cells to change the expression of HLA-I, PD-L1, or NKG2D-L and modulate their susceptibility to the immune response. Moreover, NK cells may be preferentially located in the borders of tumor masses, where, indeed, tumor cells can undergo Epithelial-to-Mesenchymal Transition (EMT) acquiring prometastatic phenotype. Finally, the recently highlighted role of HMGB1 both in EMT and in amplifying the recruitment of NK cells provides further hints on a possible effect of NK cells on tumor progression and fosters new studies on this issue. PMID:27294158

Supplementation with L-glutamine prevents tumor growth and cancer-induced cachexia as well as restores cell proliferation of intestinal mucosa of Walker-256 tumor-bearing rats.

PubMed

Martins, Heber Amilcar; Sehaber, Camila Caviquioli; Hermes-Uliana, Catchia; Mariani, Fernando Augusto; Guarnier, Flavia Alessandra; Vicentini, Geraldo Emílio; Bossolani, Gleison Daion Piovezana; Jussani, Laraine Almeida; Lima, Mariana Machado; Bazotte, Roberto Barbosa; Zanoni, Jacqueline Nelisis

2016-12-01

This study aimed to evaluate the intestinal mucosa of the duodenum and jejunum of Walker-256 tumor-bearing rats supplemented with L-glutamine. Thirty-two male 50-day-old Wistar rats (Rattus norvegicus) were randomly divided into four groups: control (C), control supplemented with 2 % L-glutamine (GC), Walker-256 tumor (WT), and Walker-256 tumor supplemented with 2 % L-glutamine (TWG). Walker-256 tumor was induced by inoculation viable tumor cells in the right rear flank. After 10 days, celiotomy was performed and duodenal and jejunal tissues were removed and processed. We evaluated the cachexia index, proliferation index, villus height, crypt depth, total height of the intestinal wall, and number of goblet cells by the technique of periodic acid-Schiff (PAS). Induction of Walker-256 tumor promoted a reduction of metaphase index in the TW group animals, which was accompanied by a reduction in the villous height and crypt depths, resulting in atrophy of the intestinal wall as well as increased PAS-positive goblet cells. Supplementation with L-glutamine reduced the tumor growth and inhibited the development of the cachectic syndrome in animals of the TWG group. Furthermore, amino acid supplementation promoted beneficial effects on the intestinal mucosa in the TWG animals through restoration of the number of PAS-positive goblet cells. Therefore, supplementation with 2 % L-glutamine exhibited a promising role in the prevention of tumor growth and cancer-associated cachexia as well as restoring the intestinal mucosa in the duodenum and jejunum of Walker-256 tumor-bearing rats.

Occurrence of the malate-aspartate shuttle in various tumor types.

PubMed

Greenhouse, W V; Lehninger, A L

1976-04-01

The activity of the malate-aspartate shuttle for the reoxidation of cytoplasmic reduced nicotinamide adenine dinucleotide (NADH) by mitochondria was assessed in six lines of rodent ascites tumor cells (two strains of Ehrlich ascites carcinoma, Krebs II carcinoma, Novikoff hepatoma, AS-30D hepatoma, and L1210 mouse leukemia). All the tumor cells examined showed mitochondrial reoxidation of cytoplasmic NADH, as evidenced by the accumulation of pyruvate when the cells were incubated aerobically with L-lactate. Reoxidation of cytoplasmic NADH thus generated was completely inhibited by the transaminase inhibitor aminooxyacetate. The involvement of the respiratory chain in the reoxidation of cytoplasmic NADH was demonstrated by the action of cyanide, rotenone, and antimycin A, which strongly inhibited the formation of pyruvate from added L-lactate. Compounds that inhibit the carrier-mediated entry of malate into mitochondria, such as butylmalonate, benzenetricarboxylate, and iodobenzylmalonate, also inhibited the accumulation of pyruvate from added L-lactate by the tumor cells. The maximal rate of the malate-aspartate shuttle was established by addtion of arsenite to inhibit the mitochondrial oxidation of the pyruvate formed from added lactate. The capacity of the various tumor lines for the reoxidation of cytoplasmic NADH via the malate-aspartate shuttle approaches 20% of the total respiratory rate of the cells and thus appears to be sufficient to account for the mitochondrial reoxidation of that fraction of glycolytic NADH not reoxidized by pyruvate and lactate dehydrognenase in the cytoplasm.

Classifying Non-Small Cell Lung Cancer by Status of Programmed Cell Death Ligand 1 and Tumor-Infiltrating Lymphocytes on Tumor Cells.

PubMed

Cui, Shaohua; Dong, Lili; Qian, Jialin; Ye, Lin; Jiang, Liyan

2018-01-01

Purpose: To explore the possible correlation between programmed death ligand 1 (PD-L1)/tumor-infiltrating lymphocytes (TIL) status and clinical factors in non-small cell lung (NSCLC). Materials and Methods: A total of 126 surgical NSCLC samples with stage I to IIIA were retrospectively collected and analyzed. Immunohistochemistry (IHC) assays were used to detect PD-L1 protein expression. PD-L1 positivity on tumor cells was defined by positive tumor cell (TC) percentage using 5% cutoff value. Results: Thirty-seven patients (29.4%), thirty patients (23.8%), six patients (4.8%) and fifty-three patients (42%) were classified as type I (PD-L1+, TIL+), type II (PD-L1-, TIL-), type III (PD-L1+, TIL-) and type IV (PD-L1-, TIL+) tumor environments according to PD-L1/TIL status, respectively. Statistical differences could be observed in factors including gender ( P <0.001), smoking status ( P <0.001), age ( P =0.002), histological types ( P <0.001), EGFR mutation ( P =0.008) and KRAS mutation ( P =0.003) across the four type tumors. Type I tumors were associated with ever smoking, non-adenocarcinoma histological types and KRAS mutation. Type II tumors were associated with female gender, never-smoking, adenocarcinoma histological types and EGFR mutation. Type III tumors were associated with ever smoking and type IV tumors were associated with female gender and EGFR mutation. Conclusion: Clinical factors associated with NSCLC microenvironment types based on PD-L1/TIL differed a lot across different types. The findings of this study may help to facilitate the understanding of the relationship between tumor microenvironment and clinical factors, and also the selecting of patients for combination immunotherapies.

Prognostic role of programmed-death ligand 1 (PD-L1) expressing tumor infiltrating lymphocytes in testicular germ cell tumors.

PubMed

Chovanec, Michal; Cierna, Zuzana; Miskovska, Viera; Machalekova, Katarina; Svetlovska, Daniela; Kalavska, Katarina; Rejlekova, Katarina; Spanik, Stanislav; Kajo, Karol; Babal, Pavel; Mardiak, Jozef; Mego, Michal

2017-03-28

Testicular germ cell tumors (TGCTs) are nearly universally curable malignancies. Nevertheless, standard cisplatin-based chemotherapy is not curative in a small subgroup of patients. Previously, we showed that PD-L1 overexpression is associated with worse prognosis in TGCTs, while tumor infiltrating lymphocytes (TILs) are prognostic in different types of cancer. This study aimed to evaluate the prognostic value of PD-1 and PD-L1 expressing TILs in TGCTs. PD-L1 positive TILs were found significantly more often in seminomas (95.9% of patients) and embryonal carcinomas (91.0%) compared to yolk sac tumors (60.0%), choriocarcinomas (54.5%) or teratomas (35.7%) (All p < 0.05). TGCTs patients with high infiltration of PD-L1 positive TILs (HS ≥ 160) had significantly better progression-free survival (HR = 0.17, 95% CI 0.09 - 0.31, p = 0.0006) and overall survival (HR = 0.08, 95% CI 0.04 - 0.16, p = 0.001) opposite to patients with lower expression of PD-L1 (HS < 150). PD-1 expressing TILs were not prognostic in TGCTs. Surgical specimens from 240 patients with primary TGCTs were included into this translational study. The PD-1 and PD-L1 expression on tumor and TILs were detected by immunohistochemistry using anti-PD-1 and anti-PD-L1 monoclonal antibody. Scoring was performed semiquantitatively by weighted histoscore (HS) method. The prognostic value of PD-L1 expressing TILs in TGCTs was demonstrated for the first time.

Antibody-Dependent Cellular Cytotoxicity Activity of a Novel Anti-PD-L1 Antibody Avelumab (MSB0010718C) on Human Tumor Cells.

PubMed

Boyerinas, Benjamin; Jochems, Caroline; Fantini, Massimo; Heery, Christopher R; Gulley, James L; Tsang, Kwong Yok; Schlom, Jeffrey

2015-10-01

Several anti-PD-1/PD-L1 monoclonal antibodies (mAb) are currently providing evidence of clinical benefit in subsets of cancer patients. The mode of action of these mAbs is to inhibit PD-1 on immune cells interacting with PD-L1 on tumor cells. These mAbs are either designed or engineered to eliminate antibody-dependent cell-mediated cytotoxicity (ADCC), which, however, has been implicated as an important mechanism in several highly effective mAb-mediated cancer therapies. A fully human anti-PD-L1 mAb would potentially be able to block PD-1/PD-L1 interactions and also mediate the ADCC lysis of tumor cells. MSB0010718C (designated avelumab) is a fully human IgG1 anti-PD-L1 mAb. The studies reported here demonstrate (i) the ability of avelumab to lyse a range of human tumor cells in the presence of PBMC or NK effectors; (ii) IFNγ can enhance tumor cell PD-L1 expression and, in some cases, enhance ADCC tumor cell lysis; (iii) purified NK cells are potent effectors for avelumab; (iv) similar levels of avelumab-mediated ADCC lysis of tumor cells are seen using purified NK as effectors from either healthy donors or cancer patients; (v) very low levels of avelumab-mediated lysis are seen using whole PBMCs as targets; this finding complements results seen in analyses of PBMC subsets of patients receiving avelumab; and (vi) the addition of IL12 to NK cells greatly enhances avelumab-mediated ADCC. These studies thus provide an additional mode of action for an anti-PD-L1 mAb and support the rationale for further studies to enhance avelumab-mediated ADCC activity. ©2015 American Association for Cancer Research.

Primed tumor-reactive multifunctional CD62L+ human CD8+T-cells for immunotherapy

PubMed Central

Wölfl, Matthias; Merker, Katharina; Morbach, Henner; Van Gool, Stefaan W.; Eyrich, Matthias; Greenberg, Philip D.; Schlegel, Paul G.

2011-01-01

T-cell mediated immunotherapy against malignancies has been shown to be effective for certain types of cancer. However ex vivo expansion of tumor-reactive T-cells has been hindered by the low precursor frequency of such cells, often requiring multiple rounds of stimulation, resulting in full differentiation, loss of homing receptors and potential exhaustion of the expanded T-cells. Here we show that when using highly purified naïve CD8+ T-cells, a single stimulation with peptide pulsed, IFNγ/LPS-matured dendritic cells in combination with the sequential use of IL-21, IL-7 and IL-15 is sufficient for extensive expansion of antigen-specific T-cells. Short-term expanded T-cells were tumor-reactive, multifunctional and retained a central memory-like phenotype (CD62L+, CCR7+, CD28+). The procedure is highly reproducible and robust as demonstrated for different healthy donors and for cancer patients. Such short-term tumor-antigen-primed, multifunctional T-cells may therefore serve as a platform to target different malignancies accessible to immunotherapy. PMID:20972785

Antibody-based delivery of tumor necrosis factor (L19-TNFα) and interleukin-2 (L19-IL2) to tumor-associated blood vessels has potent immunological and anticancer activity in the syngeneic J558L BALB/c myeloma model.

PubMed

Menssen, Hans D; Harnack, Ulf; Erben, Ulrike; Neri, Dario; Hirsch, Burkhard; Dürkop, Horst

2018-03-01

To analyze the impact of TNFα or IL2 on human lymphocytes in vitro and the anti-tumor and immune-modifying effects of L19-IL2 and L19-TNFα on subcutaneously growing J558L myeloma in immunocompetent mice. PBMCs from three healthy volunteers were incubated with IL2, TNFα, or with IL2 plus addition of TNFα (final 20 h). BALB/c J558L mice with subcutaneous tumors were treated with intravenous L19-TNFα plus L19-IL2, or controls. Tumor growth and intra- and peri-tumoral tissues were analyzed for micro-vessel density, necrosis, immune cell composition, and PD1 or PD-L1 expressing cells. Exposure of PBMC in vitro to IL2, TNFα, or to IL2 over 3 and 5 days plus TNFα for the final 20 h resulted in an approximately 50 and 75% reduction of the CD25low effector cell/CD25high Treg cell ratio, respectively, compared to medium control. IL2 or TNFα increased the proportion of CD4- CD25low effector lymphocytes while reducing the proportion of CD4+ CD25low Teff cells. In the J558L myeloma model, tumor eradication was observed in 58, 42, 25, and 0% of mice treated with L19-TNFα plus L19-IL2, L19-TNFα, L19-IL2, and PBS, respectively. L19-TNFα/L19-IL2 combination caused tumor necrosis, capillary density doubling, peri-tumoral T cell and PD1+ T cell reduction (- 50%), and an increase in PD-L1+ myeloma cells. IL2, TNFα, or IL2 plus TNFα (final 20 h) increased the proportion of CD4- CD25low effector lymphocytes possibly indicating immune activation. L19-TNFα/L19-IL2 combination therapy eradicated tumors in J558L myeloma BALB/c mice likely via TNFα-induced tumor necrosis and L19-TNFα/L19-IL2-mediated local cellular immune reactions.

7 CFR 1210.327 - Powers.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 7 Agriculture 10 2011-01-01 2011-01-01 false Powers. 1210.327 Section 1210.327 Agriculture... PLAN Watermelon Research and Promotion Plan National Watermelon Promotion Board § 1210.327 Powers. The Board shall have the following powers subject to § 1210.363: (a) To administer the provisions of this...

Antibody-dependent cellular cytotoxicity (ADCC) activity of a novel anti-PD-L1 antibody avelumab (MSB0010718C) on human tumor cells

PubMed Central

Fantini, Massimo; Heery, Christopher R.; Gulley, James L.; Tsang, Kwong Yok; Schlom, Jeffrey

2015-01-01

Several anti-PD1/PD-L1 monoclonal antibodies (MAb) are currently providing evidence of clinical benefit in subsets of cancer patients. The mode of action of these MAbs is to inhibit PD1 on immune cells interacting with PD-L1 on tumor cells. These MAbs are either designed or engineered to eliminate antibody-dependent cell-mediated cytotoxicity (ADCC), which, however, has been implicated as an important mechanism in several highly effective MAb-mediated cancer therapies. A fully human anti-PD-L1 MAb would potentially be able to block PD-L1/PD1 interactions and also mediate the ADCC lysis of tumor cells. MSB0010718C (designated avelumab) is a fully human IgG1 anti-PD-L1 MAb. The studies reported here demonstrate (a) the ability of avelumab to lyse a range of human tumor cells in the presence of PBMC or NK effectors; (b) IFNγ can enhance tumor cell PD-L1 expression and in some cases enhance ADCC tumor cell lysis; (c) purified NK cells are potent effectors for avelumab; (d) similar levels of avelumab-mediated ADCC lysis of tumor cells are seen using purified NK as effectors from either healthy donors or cancer patients; (e) very low levels of avelumab-mediated lysis are seen using whole PBMCs as targets; this finding complements results seen in analyses of PBMC subsets of patients receiving avelumab; and (f) the addition of IL12 to NK cells greatly enhances avelumab-mediated ADCC. These studies thus provide an additional mode of action for an anti-PD-L1 MAb and support the rationale for further studies to enhance avelumab-mediated ADCC activity. PMID:26014098

21 CFR 1210.18 - Scoring.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Scoring. 1210.18 Section 1210.18 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) REGULATIONS UNDER... MILK ACT Inspection and Testing § 1210.18 Scoring. Scoring of sanitary conditions required by §§ 1210...

21 CFR 1210.18 - Scoring.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Scoring. 1210.18 Section 1210.18 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) REGULATIONS UNDER... MILK ACT Inspection and Testing § 1210.18 Scoring. Scoring of sanitary conditions required by §§ 1210...

CD3+/CD8+ T-cell density and tumoral PD-L1 predict survival irrespective of rituximab treatment in Chinese diffuse large B-cell lymphoma patients.

PubMed

Shi, Yunfei; Deng, Lijuan; Song, Yuqin; Lin, Dongmei; Lai, Yumei; Zhou, LiXin; Yang, Lei; Li, Xianghong

2018-05-10

To investigate the prognostic value of tumor-infiltrating T-cell density and programmed cell death ligand-1 (PD-L1) expression in diffuse large B cell lymphoma (DLBCL). One-hundred-twenty-five Chinese DLBCL patients were enrolled in our study and provided samples; 76 of all cases were treated with rituximab (R). Tumor tissues were immunostained and analyzed for CD3+ and CD8+ tumor-infiltrating T-cell density, tumoral PD-L1, and microenvironmental PD-L1 (mPD-L1). The density of CD3 was rated as high in 33.6% cases, while 64.0% of DLBCLs were classified as high CD8 density. Of all cases, 16.8% were PD-L1+. Of the remaining PD-L1-DLBCLs, 29.8% positively expressed mPD-L1. Both CD3 high density and CD8 high density were associated with mPD-L1 positivity (P = 0.001 and P = 0.0001). In multivariate analysis, independently, high CD3 density predicted better OS (P = 0.023), while CD8 high density and PD-L1 positivity were both associated with prolonged PFS (P = 0.013 and P = 0.036, respectively). Even in the subgroup treated with R, univariate analyses indicated that high CD3 density and PD-L1 positivity were associated with better OS (P = 0.041) and PFS (P = 0.033), respectively. The infiltrating densities of CD3+ T-cells, CD8+ T-cells, and PD-L1 expression are predictive of survival in DLBCLs, irrespective of R usage.

Anti-tumor effect of hot aqueous extracts from Sonchus oleraceus (L.) L. and Juniperus sabina L - Two traditional medicinal plants in China.

PubMed

Huyan, Ting; Li, Qi; Wang, Yi-Lin; Li, Jing; Zhang, Jian-Yang; Liu, Ya-Xiong; Shahid, Muhammad Riaz; Yang, Hui; Li, Huan-Qing

2016-06-05

Sonchus oleraceus (L.) L (SO) and Juniperus sabina L (JS) are traditional medicinal plants in China. And the aqueous extracts of them have been used to treat tumor, inflammatory diseases, infection and so on in Chinese folk culture. However, the underlying mechanisms of their anti-tumor activities have not been illustrated yet. This study aims to evaluate the inhibitory effects of aqueous extracts from SO and JS on tumor cells. The prepared aqueous extracts of SO and JS were used to treat HepG-2 and K562 tumor cells, while the human peripheral blood mononuclear cells (PBMCs) were set as normal control. The viabilities, cell cycle and apoptosis of tumor cells after extracts treatment were assessed, in addition the expression of apoptosis-related genes (FasL, caspase 3, 6, 7, 8, 9, and 10) were analyzed. Meanwhile, the adherence and migration of HepG-2 were tested, and the expression levels of MMPs and ICAM-1 were analyzed. On top of that, the pSTAT in the two cells were also analyzed and suggested the related signaling pathway that the extracts acted on with in these tumor cells. Results showed that aqueous extracts of SO and JS have inhibitory effects on HepG-2 and K562 cells by decreasing cell viability and inducing apoptosis via up-regulation of the expression of the apoptosis-related genes FasL, caspase 3 and caspase 9. The extracts had different IC50 on tumor cells and PBMCs, which could block the tumor cell cycle at the G(0)/G(1) stage and significantly inhibit the adherence of HepG-2 cells. The extracts inhibited migration of these cells by inhibiting the expression of ICAM-1, MMP-2 and MMP-9. Further study indicated that the inhibition of pSTAT1 and 3 might be responsible for the inhibitory effects of the extracts on tumor cells. The results of this study indicated that SO and JS extracts had the anti-tumor effects, which may be developed as novel anti-tumor drugs and used in cancer therapy. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

16 CFR 1210.15 - Specifications.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 16 Commercial Practices 2 2011-01-01 2011-01-01 false Specifications. 1210.15 Section 1210.15 Commercial Practices CONSUMER PRODUCT SAFETY COMMISSION CONSUMER PRODUCT SAFETY ACT REGULATIONS SAFETY STANDARD FOR CIGARETTE LIGHTERS Certification Requirements § 1210.15 Specifications. (a) Requirement...

7 CFR 1210.324 - Vacancies.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 10 2010-01-01 2010-01-01 false Vacancies. 1210.324 Section 1210.324 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS... PLAN Watermelon Research and Promotion Plan National Watermelon Promotion Board § 1210.324 Vacancies...

7 CFR 1210.343 - [Reserved

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 10 2010-01-01 2010-01-01 false [Reserved] 1210.343 Section 1210.343 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS... PLAN Watermelon Research and Promotion Plan Expenses and Assessments § 1210.343 [Reserved] ...

7 CFR 1210.323 - Acceptance.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 10 2010-01-01 2010-01-01 false Acceptance. 1210.323 Section 1210.323 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS... PLAN Watermelon Research and Promotion Plan National Watermelon Promotion Board § 1210.323 Acceptance...

7 CFR 1210.305 - Watermelon.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 10 2010-01-01 2010-01-01 false Watermelon. 1210.305 Section 1210.305 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS... PLAN Watermelon Research and Promotion Plan Definitions § 1210.305 Watermelon. Watermelon means all...

7 CFR 1210.327 - Powers.

Code of Federal Regulations, 2010 CFR

2010-01-01

... AND ORDERS; MISCELLANEOUS COMMODITIES), DEPARTMENT OF AGRICULTURE WATERMELON RESEARCH AND PROMOTION PLAN Watermelon Research and Promotion Plan National Watermelon Promotion Board § 1210.327 Powers. The... 7 Agriculture 10 2010-01-01 2010-01-01 false Powers. 1210.327 Section 1210.327 Agriculture...

7 CFR 1210.312 - Promotion.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 10 2010-01-01 2010-01-01 false Promotion. 1210.312 Section 1210.312 Agriculture... AND ORDERS; MISCELLANEOUS COMMODITIES), DEPARTMENT OF AGRICULTURE WATERMELON RESEARCH AND PROMOTION PLAN Watermelon Research and Promotion Plan Definitions § 1210.312 Promotion. Promotion means any...

7 CFR 1210.313 - Research.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 10 2010-01-01 2010-01-01 false Research. 1210.313 Section 1210.313 Agriculture... AND ORDERS; MISCELLANEOUS COMMODITIES), DEPARTMENT OF AGRICULTURE WATERMELON RESEARCH AND PROMOTION PLAN Watermelon Research and Promotion Plan Definitions § 1210.313 Research. Research means any type of...

7 CFR 1210.313 - Research.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 7 Agriculture 10 2014-01-01 2014-01-01 false Research. 1210.313 Section 1210.313 Agriculture... AND ORDERS; MISCELLANEOUS COMMODITIES), DEPARTMENT OF AGRICULTURE WATERMELON RESEARCH AND PROMOTION PLAN Watermelon Research and Promotion Plan Definitions § 1210.313 Research. Research means any type of...

7 CFR 1210.313 - Research.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 7 Agriculture 10 2012-01-01 2012-01-01 false Research. 1210.313 Section 1210.313 Agriculture... AND ORDERS; MISCELLANEOUS COMMODITIES), DEPARTMENT OF AGRICULTURE WATERMELON RESEARCH AND PROMOTION PLAN Watermelon Research and Promotion Plan Definitions § 1210.313 Research. Research means any type of...

7 CFR 1210.313 - Research.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 7 Agriculture 10 2011-01-01 2011-01-01 false Research. 1210.313 Section 1210.313 Agriculture... AND ORDERS; MISCELLANEOUS COMMODITIES), DEPARTMENT OF AGRICULTURE WATERMELON RESEARCH AND PROMOTION PLAN Watermelon Research and Promotion Plan Definitions § 1210.313 Research. Research means any type of...

7 CFR 1210.313 - Research.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 7 Agriculture 10 2013-01-01 2013-01-01 false Research. 1210.313 Section 1210.313 Agriculture... AND ORDERS; MISCELLANEOUS COMMODITIES), DEPARTMENT OF AGRICULTURE WATERMELON RESEARCH AND PROMOTION PLAN Watermelon Research and Promotion Plan Definitions § 1210.313 Research. Research means any type of...

7 CFR 1210.308 - Handler.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 10 2010-01-01 2010-01-01 false Handler. 1210.308 Section 1210.308 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS... PLAN Watermelon Research and Promotion Plan Definitions § 1210.308 Handler. Handler means any person...

7 CFR 1210.314 - Importer.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 10 2010-01-01 2010-01-01 false Importer. 1210.314 Section 1210.314 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS... PLAN Watermelon Research and Promotion Plan Definitions § 1210.314 Importer. Importer means any person...

7 CFR 1210.306 - Producer.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 10 2010-01-01 2010-01-01 false Producer. 1210.306 Section 1210.306 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS... PLAN Watermelon Research and Promotion Plan Definitions § 1210.306 Producer. Producer means any person...

7 CFR 1210.604 - Subagents.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 10 2010-01-01 2010-01-01 false Subagents. 1210.604 Section 1210.604 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS... PLAN Referendum Procedures § 1210.604 Subagents. The referendum agent may appoint any individual or...

7 CFR 1210.309 - Person.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 10 2010-01-01 2010-01-01 false Person. 1210.309 Section 1210.309 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS... PLAN Watermelon Research and Promotion Plan Definitions § 1210.309 Person. Person means any individual...

7 CFR 1210.302 - Act.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 10 2010-01-01 2010-01-01 false Act. 1210.302 Section 1210.302 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS... PLAN Watermelon Research and Promotion Plan Definitions § 1210.302 Act. Act means the Watermelon...

7 CFR 1210.303 - Plan.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 10 2010-01-01 2010-01-01 false Plan. 1210.303 Section 1210.303 Agriculture... PLAN Watermelon Research and Promotion Plan Definitions § 1210.303 Plan. Plan means this watermelon research and promotion Plan issued by the Secretary pursuant to the Act. ...

7 CFR 1210.304 - Board.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 10 2010-01-01 2010-01-01 false Board. 1210.304 Section 1210.304 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS... PLAN Watermelon Research and Promotion Plan Definitions § 1210.304 Board. Board means the National...

MHC-I modulation due to changes in tumor cell metabolism regulates tumor sensitivity to CTL and NK cells

PubMed Central

Catalán, Elena; Charni, Seyma; Jaime, Paula; Aguiló, Juan Ignacio; Enríquez, José Antonio; Naval, Javier; Pardo, Julián; Villalba, Martín; Anel, Alberto

2015-01-01

Tumor cells have a tendency to use glucose fermentation to obtain energy instead of mitochondrial oxidative phosphorylation (OXPHOS). We demonstrated that this phenotype correlated with loss of ERK5 expression and with reduced MHC class I expression. Consequently, tumor cells could evade cytotoxic T lymphocyte (CTL)-mediated immune surveillance, but also increase their sensitivity to natural killer (NK) cells. These outcomes were evaluated using two cellular models: leukemic EL4 cells and L929 transformed fibroblasts and their derived ρ° cell lines, which lack mitochondrial DNA. We have also used a L929 cell sub-line that spontaneously lost matrix attachment (L929dt), reminiscent of metastasis generation, that also downregulated MHC-I and ERK5 expression. MHC-I expression is lower in ρ° cells than in the parental cell lines, but they were equally sensitive to CTL. On the contrary, ρ° cells were more sensitive to activated NK cells than parental cells. On the other hand, L929dt cells were resistant to CTL and NK cells, showed reduced viability when forced to perform OXPHOS, and surviving cells increased MHC-I expression and became sensitive to CTL. The present results suggest that when the reduction in MHC-I levels in tumor cells due to glycolytic metabolism is partial, the increase in sensitivity to NK cells seems to predominate. However, when tumor cells completely lose MHC-I expression, the combination of treatments that increase OXPHOS with CTL-mediated immunotherapy could be a promising therapeutic approach. PMID:25949869

MHC-I modulation due to changes in tumor cell metabolism regulates tumor sensitivity to CTL and NK cells.

PubMed

Catalán, Elena; Charni, Seyma; Jaime, Paula; Aguiló, Juan Ignacio; Enríquez, José Antonio; Naval, Javier; Pardo, Julián; Villalba, Martín; Anel, Alberto

2015-01-01

Tumor cells have a tendency to use glucose fermentation to obtain energy instead of mitochondrial oxidative phosphorylation (OXPHOS). We demonstrated that this phenotype correlated with loss of ERK5 expression and with reduced MHC class I expression. Consequently, tumor cells could evade cytotoxic T lymphocyte (CTL)-mediated immune surveillance, but also increase their sensitivity to natural killer (NK) cells. These outcomes were evaluated using two cellular models: leukemic EL4 cells and L929 transformed fibroblasts and their derived ρ° cell lines, which lack mitochondrial DNA. We have also used a L929 cell sub-line that spontaneously lost matrix attachment (L929dt), reminiscent of metastasis generation, that also downregulated MHC-I and ERK5 expression. MHC-I expression is lower in ρ° cells than in the parental cell lines, but they were equally sensitive to CTL. On the contrary, ρ° cells were more sensitive to activated NK cells than parental cells. On the other hand, L929dt cells were resistant to CTL and NK cells, showed reduced viability when forced to perform OXPHOS, and surviving cells increased MHC-I expression and became sensitive to CTL. The present results suggest that when the reduction in MHC-I levels in tumor cells due to glycolytic metabolism is partial, the increase in sensitivity to NK cells seems to predominate. However, when tumor cells completely lose MHC-I expression, the combination of treatments that increase OXPHOS with CTL-mediated immunotherapy could be a promising therapeutic approach.

7 CFR 1210.301 - Secretary.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 7 Agriculture 10 2011-01-01 2011-01-01 false Secretary. 1210.301 Section 1210.301 Agriculture... PLAN Watermelon Research and Promotion Plan Definitions § 1210.301 Secretary. Secretary means the Secretary of Agriculture of the United States or any officer or employee of the Department to whom authority...

7 CFR 1210.301 - Secretary.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 7 Agriculture 10 2013-01-01 2013-01-01 false Secretary. 1210.301 Section 1210.301 Agriculture... PLAN Watermelon Research and Promotion Plan Definitions § 1210.301 Secretary. Secretary means the Secretary of Agriculture of the United States or any officer or employee of the Department to whom authority...

7 CFR 1210.301 - Secretary.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 7 Agriculture 10 2014-01-01 2014-01-01 false Secretary. 1210.301 Section 1210.301 Agriculture... PLAN Watermelon Research and Promotion Plan Definitions § 1210.301 Secretary. Secretary means the Secretary of Agriculture of the United States or any officer or employee of the Department to whom authority...

7 CFR 1210.301 - Secretary.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 10 2010-01-01 2010-01-01 false Secretary. 1210.301 Section 1210.301 Agriculture... PLAN Watermelon Research and Promotion Plan Definitions § 1210.301 Secretary. Secretary means the Secretary of Agriculture of the United States or any officer or employee of the Department to whom authority...

7 CFR 1210.301 - Secretary.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 7 Agriculture 10 2012-01-01 2012-01-01 false Secretary. 1210.301 Section 1210.301 Agriculture... PLAN Watermelon Research and Promotion Plan Definitions § 1210.301 Secretary. Secretary means the Secretary of Agriculture of the United States or any officer or employee of the Department to whom authority...

21 CFR 1210.13 - Tuberculin test.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Tuberculin test. 1210.13 Section 1210.13 Food and... IMPORT MILK ACT Inspection and Testing § 1210.13 Tuberculin test. (a) Except as provided in § 1210.27 any... United States shall be free from tuberculosis, as determined by a tuberculin test applied by an official...

PD-L1 Detection in Tumors Using [(64)Cu]Atezolizumab with PET.

PubMed

Lesniak, Wojciech G; Chatterjee, Samit; Gabrielson, Matthew; Lisok, Ala; Wharram, Bryan; Pomper, Martin G; Nimmagadda, Sridhar

2016-09-21

The programmed death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) pair is a major immune checkpoint pathway exploited by cancer cells to develop and maintain immune tolerance. With recent approvals of anti-PD-1 and anti-PD-L1 therapeutic antibodies, there is an urgent need for noninvasive detection methods to quantify dynamic PD-L1 expression in tumors and to evaluate the tumor response to immune modulation therapies. To address this need, we assessed [(64)Cu]atezolizumab for the detection of PD-L1 expression in tumors. Atezolizumab (MPDL3208A) is a humanized, human and mouse cross-reactive, therapeutic PD-L1 antibody that is being investigated in several cancers. Atezolizumab was conjugated with DOTAGA and radiolabeled with copper-64. The resulting [(64)Cu]atezolizumab was assessed for in vitro and in vivo specificity in multiple cell lines and tumors of variable PD-L1 expression. We performed PET-CT imaging, biodistribution, and blocking studies in NSG mice bearing tumors with constitutive PD-L1 expression (CHO-hPD-L1) and in controls (CHO). Specificity of [(64)Cu]atezolizumab was further confirmed in orthotopic tumor models of human breast cancer (MDAMB231 and SUM149) and in a syngeneic mouse mammary carcinoma model (4T1). We observed specific binding of [(64)Cu]atezolizumab to tumor cells in vitro, correlating with PD-L1 expression levels. Specific accumulation of [(64)Cu]atezolizumab was also observed in tumors with high PD-L1 expression (CHO-hPD-L1 and MDAMB231) compared to tumors with low PD-L1 expression (CHO, SUM149). Collectively, these studies demonstrate the feasibility of using [(64)Cu]atezolizumab for the detection of PD-L1 expression in different tumor types.

7 CFR 1210.350 - Reports.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 7 Agriculture 10 2012-01-01 2012-01-01 false Reports. 1210.350 Section 1210.350 Agriculture... PLAN Watermelon Research and Promotion Plan Reports, Books, and Records § 1210.350 Reports. (a) Each... watermelons produced and handled by the handler. Handlers shall report to the Board at such times and in such...

7 CFR 1210.350 - Reports.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 10 2010-01-01 2010-01-01 false Reports. 1210.350 Section 1210.350 Agriculture... PLAN Watermelon Research and Promotion Plan Reports, Books, and Records § 1210.350 Reports. (a) Each... watermelons produced and handled by the handler. Handlers shall report to the Board at such times and in such...

PD-L1 Is Not Constitutively Expressed on Tasmanian Devil Facial Tumor Cells but Is Strongly Upregulated in Response to IFN-γ and Can Be Expressed in the Tumor Microenvironment

PubMed Central

Flies, Andrew S.; Lyons, A. Bruce; Corcoran, Lynn M.; Papenfuss, Anthony T.; Murphy, James M.; Knowles, Graeme W.; Woods, Gregory M.; Hayball, John D.

2016-01-01

The devil facial tumor disease (DFTD) is caused by clonal transmissible cancers that have led to a catastrophic decline in the wild Tasmanian devil (Sarcophilus harrisii) population. The first transmissible tumor, now termed devil facial tumor 1 (DFT1), was first discovered in 1996 and has been continually transmitted to new hosts for at least 20 years. In 2015, a second transmissible cancer [devil facial tumor 2 (DFT2)] was discovered in wild devils, and the DFT2 is genetically distinct and independent from the DFT1. Despite the estimated 136,559 base pair substitutions and 14,647 insertions/deletions in the DFT1 genome as compared to two normal devil reference genomes, the allograft tumors are not rejected by the host immune system. Additionally, genome sequencing of two sub-strains of DFT1 detected greater than 15,000 single-base substitutions that were found in only one of the DFT1 sub-strains, demonstrating the transmissible tumors are evolving and that generation of neoantigens is likely ongoing. Recent evidence in human clinical trials suggests that blocking PD-1:PD-L1 interactions promotes antitumor immune responses and is most effective in cancers with a high number of mutations. We hypothesized that DFTD cells could exploit the PD-1:PD-L1 inhibitory pathway to evade antitumor immune responses. We developed recombinant proteins and monoclonal antibodies (mAbs) to provide the first demonstration that PD-1 binds to both PD-L1 and PD-L2 in a non-placental mammal and show that PD-L1 is upregulated in DFTD cells in response to IFN-γ. Immunohistochemistry showed that PD-L1 is rarely expressed in primary tumor masses, but low numbers of PD-L1+ non-tumor cells were detected in the microenvironment of several metastatic tumors. Importantly, in vitro testing suggests that PD-1 binding to PD-L1 and PD-L2 can be blocked by mAbs, which could be critical to understanding how the DFT allografts evade the immune system. PMID:28018348

PD-1/PD-L1 blockade together with vaccine therapy facilitates effector T cell infiltration into pancreatic tumors

PubMed Central

Soares, Kevin C.; Rucki, Agnieszka A.; Wu, Annie A.; Olino, Kelly; Xiao, Qian; Chai, Yi; Wamwea, Anthony; Bigelow, Elaine; Lutz, Eric; Liu, Linda; Yao, Sheng; Anders, Robert A.; Laheru, Daniel; Wolfgang, Christopher L.; Edil, Barish H.; Schulick, Richard D.; Jaffee, Elizabeth M.; Zheng, Lei

2014-01-01

Pancreatic ductal adenocarcinoma (PDA) has a poor prognosis due to late detection and resistance to conventional therapies. Published studies show that the PDA tumor microenvironment (TME) is predominantly infiltrated with immune suppressive cells and signals that if altered, would allow effective immunotherapy. However, single-agent checkpoint inhibitors including agents that alter immune suppressive signals in other human cancers such as cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed death 1 (PD-1) and its ligand PD-L1, have failed to demonstrate objective responses when given as single agents to PDA patients. We recently reported that inhibition of the CTLA-4 pathway when given together with a T cell inducing vaccine gives objective responses in metastatic PDA patients. In this study, we evaluated blockade of the PD-1/PD-L1 pathway. We found that PD-L1 is weakly expressed at a low frequency in untreated human and murine PDAs but treatment with a GM-CSF secreting PDA vaccine (GVAX) significantly upregulates PD-L1 membranous expression after treatment of tumor bearing mice. In addition, combination therapy with vaccine and PD-1 antibody blockade improved murine survival compared to PD-1 antibody monotherapy or GVAX therapy alone. Furthermore, PD-1 blockade increased effector CD8+ T lymphocytes and tumor-specific interferon-γ production of CD8+ T cells in the TME. Immunosuppressive pathways, including regulatory T cells (Tregs) and CTLA-4 expression on T cells were overcome by the addition of vaccine and low dose cyclophosphamide to PD-1 blockade. Collectively, our study supports combining PD-1 or PD-L1 antibody therapy with a T cell inducing agent for PDA treatment. PMID:25415283

16 CFR 1210.12 - Certificate of compliance.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 1210.12 Commercial Practices CONSUMER PRODUCT SAFETY COMMISSION CONSUMER PRODUCT SAFETY ACT REGULATIONS SAFETY STANDARD FOR CIGARETTE LIGHTERS Certification Requirements § 1210.12 Certificate of compliance. (a..., based on a reasonable testing program or a test of each product, as required by §§ 1210.13-1210.14 and...

16 CFR 1210.14 - Qualification testing.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 16 Commercial Practices 2 2011-01-01 2011-01-01 false Qualification testing. 1210.14 Section 1210.14 Commercial Practices CONSUMER PRODUCT SAFETY COMMISSION CONSUMER PRODUCT SAFETY ACT REGULATIONS SAFETY STANDARD FOR CIGARETTE LIGHTERS Certification Requirements § 1210.14 Qualification testing. (a...

16 CFR 1210.16 - Production testing.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 16 Commercial Practices 2 2011-01-01 2011-01-01 false Production testing. 1210.16 Section 1210.16 Commercial Practices CONSUMER PRODUCT SAFETY COMMISSION CONSUMER PRODUCT SAFETY ACT REGULATIONS SAFETY STANDARD FOR CIGARETTE LIGHTERS Certification Requirements § 1210.16 Production testing. (a) General...

Essential requirement of I-A region-identical host bone marrow or bone marrow-derived cells for tumor neutralization by primed L3T4+ T cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ozawa, H.; Iwaguchi, T.; Kataoka, T.

1987-12-01

The antitumor activity of Meth A-hyperimmunized BALB/c mouse spleen cells (Meth A-Im-SPL) was assayed by the Winn test in H-2 incompatible bone marrow chimeras in closed colony CD-1 (nu/nu), inbred DDD/1(nu/nu) (H-2s), or inbred BALB/c(nu/nu) (H-2d) mice as recipients. We found that Meth A-Im-SPL suppressed Meth A growth in the chimera nude mice which were reconstituted with bone marrow cells of the H-2d haplotype (i.e., BALB/c, DBA/2 and B10.D2), but not in the chimeras which were reconstituted with bone marrow cells of the H-2a, H-2b, or H-2k haplotype (i.e., B10.A, B10, and B10.BR). These results suggested that H-2 restriction occurredmore » between Meth A-Im-SPL and bone marrow or bone marrow-derived cells in tumor neutralization. Furthermore, Meth A-Im-SPL did not suppress Meth 1 tumors (antigenically distinct from Meth A tumors) in the presence or absence of mitomycin C-treated Meth A in a Winn assay. These results suggested that there is tumor specificity in the effector phase as well as in the induction phase. The phenotype of the effectors in the Meth A-Im-SPL was Thy-1.2+ and L3T4+, because Meth A-Im-SPL lost their antitumor activity with pretreatment with anti-Thy-1.2 monoclonal antibody (mAb) and complement or anti-L3T4 mAb and complement, but not with anti-Lyt-2.2 mAb and complement or complement alone. Positively purified L3T4+ T cells from Meth A-Im-SPL (Meth A-Im-L3T4), obtained by the panning method, suppressed the tumor growth in the chimera nude mice which were reconstituted with bone marrow cells of B10.KEA2 mice (that were I-A region-identical with Meth A-Im-L3T4 cells but not others in H-2) as well as B10.D2 cells (that were fully identical with Meth A-Im-L3T4 cells in H-2). We conclude that Meth A-Im-SPL (L3T4+) neutralized the tumors in collaboration with I-A region-identical host bone marrow or bone marrow-derived cells, and the neutralization was not accompanied by the bystander effect.« less

Tumor exosomes block dendritic cells maturation to decrease the T cell immune response.

PubMed

Ning, Yongling; Shen, Kai; Wu, Qiyong; Sun, Xiao; Bai, Yu; Xie, Yewen; Pan, Jie; Qi, Chunjian

2018-07-01

Tumors can induce the generation and accumulation of immunosuppression in a tumor microenvironment, contributing to the tumor's escape from immunological surveillance. Although tumor antigen-pulsed dendritic cell can improve anti-tumor immune responses, tumor associated regulatory dendritic cells are involved in the induction of immune tolerance. The current study sought to investigate whether exosomes produced by tumor cells had any effect on DCs in immune suppression. In this study, we examined the effect of tumor exosomes on DCs and found that exosomes from LLC Lewis lung carcinoma or 4T1 breast cancer cell blocked the differentiation of myeloid precursor cells into CD11c + DCs and induced cell apoptosis. Tumor exosome treatment inhibited the maturation and migration of DCs and promoted the immune suppression of DCs. The treatment of tumor exosomes drastically decreased CD4 + IFN-γ + Th1 differentiation but increased the rates of regulatory T (Treg) cells. The immunosuppressive ability of tumor exosome-treated DCs were partially restored with PD-L1 blockage. These data suggested that PD-L1 played a role in tumor exosome-induced DC-associated immune suppression. Copyright © 2018 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

7 CFR 1210.315 - United States.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 7 Agriculture 10 2013-01-01 2013-01-01 false United States. 1210.315 Section 1210.315 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS... PLAN Watermelon Research and Promotion Plan Definitions § 1210.315 United States. United States means...

7 CFR 1210.315 - United States.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 7 Agriculture 10 2014-01-01 2014-01-01 false United States. 1210.315 Section 1210.315 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS... PLAN Watermelon Research and Promotion Plan Definitions § 1210.315 United States. United States means...

7 CFR 1210.315 - United States.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 7 Agriculture 10 2011-01-01 2011-01-01 false United States. 1210.315 Section 1210.315 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS... PLAN Watermelon Research and Promotion Plan Definitions § 1210.315 United States. United States means...

7 CFR 1210.315 - United States.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 7 Agriculture 10 2012-01-01 2012-01-01 false United States. 1210.315 Section 1210.315 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS... PLAN Watermelon Research and Promotion Plan Definitions § 1210.315 United States. United States means...

16 CFR § 1210.15 - Specifications.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 16 Commercial Practices 2 2013-01-01 2013-01-01 false Specifications. § 1210.15 Section § 1210.15 Commercial Practices CONSUMER PRODUCT SAFETY COMMISSION CONSUMER PRODUCT SAFETY ACT REGULATIONS SAFETY STANDARD FOR CIGARETTE LIGHTERS Certification Requirements § 1210.15 Specifications. (a...

16 CFR 1210.13 - Certification tests.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 16 Commercial Practices 2 2011-01-01 2011-01-01 false Certification tests. 1210.13 Section 1210.13 Commercial Practices CONSUMER PRODUCT SAFETY COMMISSION CONSUMER PRODUCT SAFETY ACT REGULATIONS SAFETY STANDARD FOR CIGARETTE LIGHTERS Certification Requirements § 1210.13 Certification tests. (a) General. As...

7 CFR 1210.344 - Operating reserve.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 10 2010-01-01 2010-01-01 false Operating reserve. 1210.344 Section 1210.344 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING... PROMOTION PLAN Watermelon Research and Promotion Plan Expenses and Assessments § 1210.344 Operating reserve...

16 CFR 1210.13 - Certification tests.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 16 Commercial Practices 2 2010-01-01 2010-01-01 false Certification tests. 1210.13 Section 1210.13 Commercial Practices CONSUMER PRODUCT SAFETY COMMISSION CONSUMER PRODUCT SAFETY ACT REGULATIONS SAFETY STANDARD FOR CIGARETTE LIGHTERS Certification Requirements § 1210.13 Certification tests. (a) General. As...

Radiation-induced equilibrium is a balance between tumor cell proliferation and T cell-mediated killing

PubMed Central

Liang, Hua; Deng, Liufu; Chmura, Steven; Burnette, Byron; Liadis, Nicole; Darga, Thomas; Beckett, Michael A.; Lingen, Mark W.; Witt, MaryEllyn; Weichselbaum, Ralph R.; Fu, Yang-Xin

2013-01-01

Local failures following radiation therapy are multifactorial and the contributions of the tumor and the host are complex. Current models of tumor equilibrium suggest that a balance exists between cell birth and cell death due to insufficient angiogenesis, immune effects, or intrinsic cellular factors. We investigated whether host immune responses contribute to radiation induced tumor equilibrium in animal models. We report an essential role for immune cells and their cytokines in suppressing tumor cell regrowth in two experimental animal model systems. Depletion of T cells or neutralization of interferon-gamma reversed radiation-induced equilibrium leading to tumor regrowth. We also demonstrate that PD-L1 blockade augments T cell responses leading to rejection of tumors in radiation induced equilibrium. We identify an active interplay between tumor cells and immune cells that occurs in radiation-induced tumor equilibrium and suggest a potential role for disruption of the PD-L1/PD-1 axis in increasing local tumor control. PMID:23630355

16 CFR 1210.16 - Production testing.

Code of Federal Regulations, 2010 CFR

2010-01-01

... in the manufacturing process, the assembly process, the equipment used to manufacture the product, or... 16 Commercial Practices 2 2010-01-01 2010-01-01 false Production testing. 1210.16 Section 1210.16... STANDARD FOR CIGARETTE LIGHTERS Certification Requirements § 1210.16 Production testing. (a) General...

16 CFR 1210.13 - Certification tests.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 16 Commercial Practices 2 2012-01-01 2012-01-01 false Certification tests. 1210.13 Section 1210.13... STANDARD FOR CIGARETTE LIGHTERS Certification Requirements § 1210.13 Certification tests. (a) General. As... reasonable testing programs shall include qualification tests, which must be performed on surrogates of each...

Xenograft tumors derived from malignant pleural effusion of the patients with non-small-cell lung cancer as models to explore drug resistance.

PubMed

Xu, Yunhua; Zhang, Feifei; Pan, Xiaoqing; Wang, Guan; Zhu, Lei; Zhang, Jie; Wen, Danyi; Lu, Shun

2018-05-09

Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) fusions show dramatic responses to specific tyrosine kinase inhibitors (TKIs); however, after 10-12 months, secondary mutations arise that confer resistance. We generated a murine xenograft model using patient-derived NSCLC cells isolated from the pleural fluid of two patients with NSCLC to investigate the mechanisms of resistance against the ALK- and EGFR-targeted TKIs crizotinib and osimertinib, respectively. Genotypes of patient biopsies and xenograft tumors were determined by whole exome sequencing (WES), and patients and xenograft-bearing mice received targeted treatment (crizotinib or osimertinib) accordingly. Xenograft mice were also treated for prolonged periods to identify whether the development of drug resistance and/or treatment responses were associated with tumor size. Finally, the pathology of patients biopsies and xenograft tumors were compared histologically. The histological characteristics and chemotherapy responses of xenograft tumors were similar to the actual patients. WES showed that the genotypes of the xenograft and patient tumors were similar (an echinoderm microtubule-associated protein-like 4-ALK (EML4-ALK) gene fusion (patient/xenograft: CTC15035 EML4-ALK ) and EGFR L858R and T790M mutations (patient/xenograft: CTC15063 EGFR L858R, T790M )). After continuous crizotinib or osimertinib treatment, WES data suggested that acquired ALK E1210K mutation conferred crizotinib resistance in the CTC15035 EML4-ALK xenograft, while decreased frequencies of EGFR L858R and T790M mutations plus the appearance of v-RAF murine sarcoma viral oncogene homolog B (BRAF) G7V mutations and phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 alpha (PIK3C2A) A86fs frame shift mutations led to osimertinib resistance in the CTC15063 EGFR L858R, T790M xenografts. We successfully developed a new method of generating

21 CFR 582.1210 - Calcium oxide.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Calcium oxide. 582.1210 Section 582.1210 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS....1210 Calcium oxide. (a) Product. Calcium oxide. (b) Conditions of use. This substance is generally...

21 CFR 582.1210 - Calcium oxide.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Calcium oxide. 582.1210 Section 582.1210 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS....1210 Calcium oxide. (a) Product. Calcium oxide. (b) Conditions of use. This substance is generally...

21 CFR 582.1210 - Calcium oxide.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Calcium oxide. 582.1210 Section 582.1210 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS....1210 Calcium oxide. (a) Product. Calcium oxide. (b) Conditions of use. This substance is generally...

21 CFR 582.1210 - Calcium oxide.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 6 2014-04-01 2014-04-01 false Calcium oxide. 582.1210 Section 582.1210 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS....1210 Calcium oxide. (a) Product. Calcium oxide. (b) Conditions of use. This substance is generally...

21 CFR 582.1210 - Calcium oxide.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Calcium oxide. 582.1210 Section 582.1210 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS....1210 Calcium oxide. (a) Product. Calcium oxide. (b) Conditions of use. This substance is generally...

7 CFR 1210.315 - United States.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 10 2010-01-01 2010-01-01 false United States. 1210.315 Section 1210.315 Agriculture... PLAN Watermelon Research and Promotion Plan Definitions § 1210.315 United States. United States means each of the several States and the District of Columbia. [60 FR 10797, Feb. 28, 1995] National...

21 CFR 1210.21 - Permit number.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Permit number. 1210.21 Section 1210.21 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) REGULATIONS... IMPORT MILK ACT Permit Control § 1210.21 Permit number. Each permit issued under the Federal Import Milk...

21 CFR 1210.21 - Permit number.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Permit number. 1210.21 Section 1210.21 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) REGULATIONS... IMPORT MILK ACT Permit Control § 1210.21 Permit number. Each permit issued under the Federal Import Milk...

16 CFR 1210.4 - Test protocol.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 16 Commercial Practices 2 2012-01-01 2012-01-01 false Test protocol. 1210.4 Section 1210.4... STANDARD FOR CIGARETTE LIGHTERS Requirements for Child Resistance § 1210.4 Test protocol. (a) Child test panel. (1) The test to determine if a lighter is resistant to successful operation by children uses a...

21 CFR 184.1210 - Calcium oxide.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 3 2014-04-01 2014-04-01 false Calcium oxide. 184.1210 Section 184.1210 Food and....1210 Calcium oxide. (a) Calcium oxide (CaO, CAS Reg. No. 1305-78-8) is also known as lime, quick lime, burnt lime, or calx. It is produced from calcium carbonate, limestone, or oyster shells by calcination...

21 CFR 1210.21 - Permit number.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Permit number. 1210.21 Section 1210.21 Food and... IMPORT MILK ACT Permit Control § 1210.21 Permit number. Each permit issued under the Federal Import Milk Act, including each temporary permit, shall bear an individual number. The right to the use of such...

21 CFR 1210.21 - Permit number.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Permit number. 1210.21 Section 1210.21 Food and... IMPORT MILK ACT Permit Control § 1210.21 Permit number. Each permit issued under the Federal Import Milk Act, including each temporary permit, shall bear an individual number. The right to the use of such...

21 CFR 1210.21 - Permit number.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Permit number. 1210.21 Section 1210.21 Food and... IMPORT MILK ACT Permit Control § 1210.21 Permit number. Each permit issued under the Federal Import Milk Act, including each temporary permit, shall bear an individual number. The right to the use of such...

5-(2-18F-fluoroethoxy)-L-tryptophan as a substrate of system L transport for tumor imaging by PET.

PubMed

Krämer, Stefanie D; Mu, Linjing; Müller, Adrienne; Keller, Claudia; Kuznetsova, Olga F; Schweinsberg, Christian; Franck, Dominic; Müller, Cristina; Ross, Tobias L; Schibli, Roger; Ametamey, Simon M

2012-03-01

Large neutral l-amino acids are substrates of system L amino acid transporters. The level of one of these, LAT1, is increased in many tumors. Aromatic l-amino acids may also be substrates of aromatic l-amino acid decarboxylase (AADC), the level of which is enhanced in endocrine tumors. Increased amino acid uptake and subsequent decarboxylation result in the intracellular accumulation of the amino acid and its decarboxylation product. (18)F- and (11)C-labeled neutral aromatic amino acids, such as l-3,4-dihydroxy-6-(18)F-fluorophenylalanine ((18)F-FDOPA) and 5-hydroxy-l-[β-(11)C]tryptophan, are thus successfully used in PET to image endocrine tumors. However, 5-hydroxy-l-[β-(11)C]tryptophan has a relatively short physical half-life (20 min). In this work, we evaluated the in vitro and in vivo characteristics of the (18)F-labeled tryptophan analog 5-(2-(18)F-fluoroethoxy)-l-tryptophan ((18)F-l-FEHTP) as a PET probe for tumor imaging. (18)F-l-FEHTP was synthesized by no-carrier-added (18)F fluorination of 5-hydroxy-l-tryptophan. In vitro cell uptake and efflux of (18)F-l-FEHTP and (18)F-FDOPA were studied with NCI-H69 endocrine small cell lung cancer cells, PC-3 pseudoendocrine prostate cancer cells, and MDA-MB-231 exocrine breast cancer cells. Small-animal PET was performed with the respective xenograft-bearing mice. Tissues were analyzed for potential metabolites. (18)F-l-FEHTP specific activity and radiochemical purity were 50-150 GBq/μmol and greater than 95%, respectively. In vitro cell uptake of (18)F-l-FEHTP was between 48% and 113% of added radioactivity per milligram of protein within 60 min at 37°C and was blocked by greater than 95% in all tested cell lines by the LAT1/2 inhibitor 2-amino-2-norboranecarboxylic acid. (18)F-FDOPA uptake ranged from 26% to 53%/mg. PET studies revealed similar xenograft-to-reference tissue ratios for (18)F-l-FEHTP and (18)F-FDOPA at 30-45 min after injection. In contrast to the (18)F-FDOPA PET results, pretreatment with the

A humanized antibody for imaging immune checkpoint ligand PD-L1 expression in tumors

PubMed Central

Gabrielson, Matthew; Lisok, Ala; Wharram, Bryan; Sysa-Shah, Polina; Azad, Babak Behnam; Pomper, Martin G.; Nimmagadda, Sridhar

2016-01-01

Antibodies targeting the PD-1/PD-L1 immune checkpoint lead to tumor regression and improved survival in several cancers. PD-L1 expression in tumors may be predictive of response to checkpoint blockade therapy. Because tissue samples might not always be available to guide therapy, we developed and evaluated a humanized antibody for non-invasive imaging of PD-L1 expression in tumors. Radiolabeled [111In]PD-L1-mAb and near-infrared dye conjugated NIR-PD-L1-mAb imaging agents were developed using the mouse and human cross-reactive PD-L1 antibody MPDL3280A. We tested specificity of [111In]PD-L1-mAb and NIR-PD-L1-mAb in cell lines and in tumors with varying levels of PD-L1 expression. We performed SPECT/CT imaging, biodistribution and blocking studies in NSG mice bearing tumors with constitutive PD-L1 expression (CHO-PDL1) and in controls (CHO). Results were confirmed in triple negative breast cancer (TNBC) (MDAMB231 and SUM149) and non-small cell lung cancer (NSCLC) (H2444 and H1155) xenografts with varying levels of PD-L1 expression. There was specific binding of [111In]PD-L1-mAb and NIR-PD-L1-mAb to tumor cells in vitro, correlating with PD-L1 expression levels. In mice bearing subcutaneous and orthotopic tumors, there was specific and persistent high accumulation of signal intensity in PD-L1 positive tumors (CHO-PDL1, MDAMB231, H2444) but not in controls. These results demonstrate that [111In]PD-L1-mAb and NIR-PD-L1-mAb can detect graded levels of PD-L1 expression in human tumor xenografts in vivo. As a humanized antibody, these findings suggest clinical translation of radiolabeled versions of MPDL3280A for imaging. Specificity of NIR-PD-L1-mAb indicates the potential for optical imaging of PD-L1 expression in tumors in relevant pre-clinical as well as clinical settings. PMID:26848870

In Vitro Activity of E1210, a Novel Antifungal, against Clinically Important Yeasts and Molds▿

PubMed Central

Miyazaki, Mamiko; Horii, Takaaki; Hata, Katsura; Watanabe, Nao-aki; Nakamoto, Kazutaka; Tanaka, Keigo; Shirotori, Syuji; Murai, Norio; Inoue, Satoshi; Matsukura, Masayuki; Abe, Shinya; Yoshimatsu, Kentaro; Asada, Makoto

2011-01-01

E1210 is a new antifungal compound with a novel mechanism of action and broad spectrum of antifungal activity. We investigated the in vitro antifungal activities of E1210 compared to those of fluconazole, itraconazole, voriconazole, amphotericin B, and micafungin against clinical fungal isolates. E1210 showed potent activities against most Candida spp. (MIC90 of ≤0.008 to 0.06 μg/ml), except for Candida krusei (MICs of 2 to >32 μg/ml). E1210 showed equally potent activities against fluconazole-resistant and fluconazole-susceptible Candida strains. E1210 also had potent activities against various filamentous fungi, including Aspergillus fumigatus (MIC90 of 0.13 μg/ml). E1210 was also active against Fusarium solani and some black molds. Of note, E1210 showed the greatest activities against Pseudallescheria boydii (MICs of 0.03 to 0.13 μg/ml), Scedosporium prolificans (MIC of 0.03 μg/ml), and Paecilomyces lilacinus (MICs of 0.06 μg/ml) among the compounds tested. The antifungal action of E1210 was fungistatic, but E1210 showed no trailing growth of Candida albicans, which has often been observed with fluconazole. In a cytotoxicity assay using human HK-2 cells, E1210 showed toxicity as low as that of fluconazole. Based on these results, E1210 is likely to be a promising antifungal agent for the treatment of invasive fungal infections. PMID:21825291

21 CFR 184.1210 - Calcium oxide.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Calcium oxide. 184.1210 Section 184.1210 Food and... Substances Affirmed as GRAS § 184.1210 Calcium oxide. (a) Calcium oxide (CaO, CAS Reg. No. 1305-78-8) is also known as lime, quick lime, burnt lime, or calx. It is produced from calcium carbonate, limestone, or...

21 CFR 184.1210 - Calcium oxide.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 3 2011-04-01 2011-04-01 false Calcium oxide. 184.1210 Section 184.1210 Food and... Substances Affirmed as GRAS § 184.1210 Calcium oxide. (a) Calcium oxide (CaO, CAS Reg. No. 1305-78-8) is also known as lime, quick lime, burnt lime, or calx. It is produced from calcium carbonate, limestone, or...

N-ω-chloroacetyl-L-ornithine has in-vitro activity against cancer cell lines and in-vivo activity against ascitic and solid tumors.

PubMed

Vargas-Ramírez, Alba L; Medina-Enríquez, Miriam M; Cordero-Rodríguez, Neira I; Ruiz-Cuello, Tatiana; Aguilar-Faisal, Leopoldo; Trujillo-Ferrara, José G; Alcántara-Farfán, Verónica; Rodríguez-Páez, Lorena

2016-07-01

N-ω-chloroacetyl-L-ornithine (NCAO) is an ornithine decarboxylase (ODC) inhibitor that is known to exert cytotoxic and antiproliferative effects on three neoplastic human cancer cell lines (HeLa, MCF-7, and HepG2). Here, we show that NCAO has antiproliferative activity in 13 cancer cell lines, of diverse tissue origin from human and mice, and in a mouse cancer model in vivo. All cell lines were sensitive to NCAO after 72 h of treatment (the EC50 ranged from 1 to 50.6 µmol/l). The Ca Ski cell line was the most sensitive (EC50=1.18±0.07 µmol/l) and MDA-MB-231 was the least sensitive (EC50=50.6±0.3 µmol/l). This ODC inhibitor showed selectivity for cancer cells, exerting almost no cytotoxic effect on the normal Vero cell line (EC50>1000 µmol/l). NCAO induced apoptosis and inhibited tumor cell migration in vitro. Furthermore, in vivo, this compound (at 50 and 100 mg/kg, daily intraperitoneal injection for 7 days) exerted potent antitumor activity against both solid and ascitic tumors in a mouse model using the myeloma (Ag8) cell line. At these same two doses, the toxicological evaluation showed that NCAO has no obvious systemic toxicity. The current results suggest that the antitumor activity is exerted by apoptosis related not only to a local but also a systemic cytotoxic effect exerted by NCAO on tumor cells. The applications for NCAO as an antitumor agent may be extensive; however, further studies are needed to ascertain the antitumor activity on other types of tumor in vivo and to determine the precise molecular mechanism of its activity.

Pharmacology of liposomal vincristine in mice bearing L1210 ascitic and B16/BL6 solid tumours.

PubMed Central

Mayer, L. D.; Masin, D.; Nayar, R.; Boman, N. L.; Bally, M. B.

1995-01-01

Vincristine pharmacokinetic, tumour uptake and therapeutic characteristics were investigated here in order to elucidate the processes underlying the enhanced efficacy observed for vincristine entrapped in small (120 nm) distearoylphosphatidylcholine/cholesterol liposomes. Plasma vincristine levels after intravenous (i.v.) injection are elevated more than 100-fold in the liposomal formulation compared with free drug in tumour-bearing as well as non-tumour-bearing mice over 24 h. Biodistribution studies demonstrate that the extent and duration of tumour exposure to vincristine is dramatically improved when the drug is administered i.v. in liposomal form. Specifically, 72 h trapezoidal area under the curve values for liposomal vincristine in the murine L1210 ascitic and B16/BL6 solid tumours are 12.9- to 4.1-fold larger, respectively, than observed for free drug. Similar to previous results with the L1210 model, increased drug delivery to the B16 tumour results in significant inhibition of tumour growth, whereas no anti-tumour activity is observed with free vincristine. Comparisons of drug and liposomal lipid accumulation in tumour and muscle tissue indicate that the enhanced efficacy of liposomal vincristine is related predominantly to drug delivered by liposomes to the tumour site rather than drug released from liposomes in the circulation. Consequently, improvements in liposomal vincristine formulations must focus on factors that increase uptake of liposomes into tumour sites as well as enhance liposomal drug retention in the circulation. PMID:7880728

Immunohistochemical analysis and prognostic significance of PD-L1, PD-1, and CD8+ tumor-infiltrating lymphocytes in Ewing's sarcoma family of tumors (ESFT).

PubMed

Machado, Isidro; López-Guerrero, Jose Antonio; Scotlandi, Katia; Picci, Piero; Llombart-Bosch, Antonio

2018-05-01

Ewing's sarcoma family of tumors (ESFT) are aggressive neoplasms with scant tumor-infiltrating lymphocytes. We analyzed the immunohistochemical (IHC) expression of PD-L1 and PD-1 and their prognostic significance in clinically localized neoplasms in a cohort of 370 ESFT. Slides prepared from tissue microarrays were stained for PD-L1, PD-1, and CD8. Membranous/cytoplasmic staining over 5% of tumor cells was regarded as positive for PD-L1 and PD-1. Prognostic analysis was done considering only clinically localized tumors (n = 217). PD-L1 expression was present in 19% of ESFT, while PD-1 was expressed in 26%. Forty-eight percent of tumors were negative and 12% were positive for both PD-L1 and PD-1. Metastatic tumors displayed higher expression of PD-L1 (p < 0.0001). Histological subtypes were not correlated with PD-L1 or PD-1 positivity. ESFT with elevated proliferation index (Ki-67) were associated with higher PD-L1 expression (p = 0.049). Regarding prognosis, no significant association was found between PD-L1 expression and progression-free survival (PFS) or overall survival (OS), whereas lack of PD-1 expression in tumor cells was correlated with both poor PFS (p = 0.02) and poor OS (p = 0.004). Tumor-infiltrating CD8(+) T lymphocytes were observed in 15.4% of ESFT with informative results (347 tumors). No correlation was found between tumor-infiltrating CD8(+) T lymphocytes and ESFT histological subtypes, tumor location, or PD-1 and PD-L1 expression, nor with PFS (p = 0.473) or OS (p = 0.087). PD-L1 expression was not significantly related to prognosis. PD-1 was expressed in 26% of ESFT tumor cells and may have prognostic and therapeutic implications. CD8 expression in tumor-infiltrating lymphocytes was not related to prognosis.

16 CFR 1210.18 - Refusal of importation.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 16 Commercial Practices 2 2011-01-01 2011-01-01 false Refusal of importation. 1210.18 Section 1210.18 Commercial Practices CONSUMER PRODUCT SAFETY COMMISSION CONSUMER PRODUCT SAFETY ACT REGULATIONS SAFETY STANDARD FOR CIGARETTE LIGHTERS Certification Requirements § 1210.18 Refusal of importation. (a...

10 CFR 603.1210 - Articles of collaboration.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 10 Energy 4 2013-01-01 2013-01-01 false Articles of collaboration. 603.1210 Section 603.1210 Energy DEPARTMENT OF ENERGY (CONTINUED) ASSISTANCE REGULATIONS TECHNOLOGY INVESTMENT AGREEMENTS Definitions of Terms Used in this Part § 603.1210 Articles of collaboration. An agreement among the...

10 CFR 603.1210 - Articles of collaboration.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 10 Energy 4 2011-01-01 2011-01-01 false Articles of collaboration. 603.1210 Section 603.1210 Energy DEPARTMENT OF ENERGY (CONTINUED) ASSISTANCE REGULATIONS TECHNOLOGY INVESTMENT AGREEMENTS Definitions of Terms Used in this Part § 603.1210 Articles of collaboration. An agreement among the...

10 CFR 603.1210 - Articles of collaboration.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 10 Energy 4 2010-01-01 2010-01-01 false Articles of collaboration. 603.1210 Section 603.1210 Energy DEPARTMENT OF ENERGY (CONTINUED) ASSISTANCE REGULATIONS TECHNOLOGY INVESTMENT AGREEMENTS Definitions of Terms Used in this Part § 603.1210 Articles of collaboration. An agreement among the...

10 CFR 603.1210 - Articles of collaboration.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 10 Energy 4 2014-01-01 2014-01-01 false Articles of collaboration. 603.1210 Section 603.1210 Energy DEPARTMENT OF ENERGY (CONTINUED) ASSISTANCE REGULATIONS TECHNOLOGY INVESTMENT AGREEMENTS Definitions of Terms Used in this Part § 603.1210 Articles of collaboration. An agreement among the...

10 CFR 603.1210 - Articles of collaboration.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 10 Energy 4 2012-01-01 2012-01-01 false Articles of collaboration. 603.1210 Section 603.1210 Energy DEPARTMENT OF ENERGY (CONTINUED) ASSISTANCE REGULATIONS TECHNOLOGY INVESTMENT AGREEMENTS Definitions of Terms Used in this Part § 603.1210 Articles of collaboration. An agreement among the...

7 CFR 1210.321 - Nominations and selection.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 10 2010-01-01 2010-01-01 false Nominations and selection. 1210.321 Section 1210.321 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING... PROMOTION PLAN Watermelon Research and Promotion Plan National Watermelon Promotion Board § 1210.321...

36 CFR 1210.37 - Property trust relationship.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 36 Parks, Forests, and Public Property 3 2011-07-01 2011-07-01 false Property trust relationship. 1210.37 Section 1210.37 Parks, Forests, and Public Property NATIONAL ARCHIVES AND RECORDS... Standards § 1210.37 Property trust relationship. Real property, equipment, intangible property and debt...

16 CFR 1210.15 - Specifications.

Code of Federal Regulations, 2010 CFR

2010-01-01

... Commercial Practices CONSUMER PRODUCT SAFETY COMMISSION CONSUMER PRODUCT SAFETY ACT REGULATIONS SAFETY STANDARD FOR CIGARETTE LIGHTERS Certification Requirements § 1210.15 Specifications. (a) Requirement... described in a written product specification. (Section 1210.4(c) requires that six surrogate lighters be...

Melanoma cell-intrinsic PD-1 receptor functions promote tumor growth

PubMed Central

Kleffel, Sonja; Posch, Christian; Barthel, Steven R.; Mueller, Hansgeorg; Schlapbach, Christoph; Guenova, Emmanuella; Elco, Christopher P.; Lee, Nayoung; Juneja, Vikram R.; Zhan, Qian; Lian, Christine G.; Thomi, Rahel; Hoetzenecker, Wolfram; Cozzio, Antonio; Dummer, Reinhard; Mihm, Martin C.; Flaherty, Keith T.; Frank, Markus H.; Murphy, George F.; Sharpe, Arlene H.; Kupper, Thomas S.; Schatton, Tobias

2015-01-01

SUMMARY Therapeutic antibodies targeting programmed cell death-1 (PD-1) activate tumor-specific immunity and have shown remarkable efficacy in the treatment of melanoma. Yet, little is known about tumor cell-intrinsic PD-1 pathway effects. Here we show that murine and human melanomas contain PD-1-expressing cancer subpopulations and demonstrate that melanoma cell-intrinsic PD-1 promotes tumorigenesis, even in mice lacking adaptive immunity. PD-1 inhibition on melanoma cells by RNA interference, blocking antibodies, or mutagenesis of melanoma-PD-1 signaling motifs suppresses tumor growth in immunocompetent, immunocompromised and PD-1-deficient tumor graft recipient mice. Conversely, melanoma-specific PD-1 overexpression enhances tumorigenicity, as does engagement of melanoma-PD-1 by its ligand, PD-L1, whereas melanoma-PD-L1 inhibition or knockout of host-PD-L1 attenuate growth of PD-1-positive melanomas. Mechanistically, the melanoma-PD-1 receptor modulates downstream effectors of mTOR signaling. Our results identify melanoma cell-intrinsic functions of the PD-1:PD-L1 axis in tumor growth and suggest that blocking melanoma-PD-1 might contribute to the striking clinical efficacy of anti-PD-1 therapy. PMID:26359984

16 CFR § 1210.14 - Qualification testing.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 16 Commercial Practices 2 2013-01-01 2013-01-01 false Qualification testing. § 1210.14 Section § 1210.14 Commercial Practices CONSUMER PRODUCT SAFETY COMMISSION CONSUMER PRODUCT SAFETY ACT REGULATIONS SAFETY STANDARD FOR CIGARETTE LIGHTERS Certification Requirements § 1210.14 Qualification testing. (a...

21 CFR 870.1210 - Continuous flush catheter.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Continuous flush catheter. 870.1210 Section 870.1210 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CARDIOVASCULAR DEVICES Cardiovascular Diagnostic Devices § 870.1210 Continuous flush...

16 CFR § 1210.13 - Certification tests.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 16 Commercial Practices 2 2013-01-01 2013-01-01 false Certification tests. § 1210.13 Section § 1210.13 Commercial Practices CONSUMER PRODUCT SAFETY COMMISSION CONSUMER PRODUCT SAFETY ACT REGULATIONS SAFETY STANDARD FOR CIGARETTE LIGHTERS Certification Requirements § 1210.13 Certification tests. (a...

16 CFR § 1210.16 - Production testing.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 16 Commercial Practices 2 2013-01-01 2013-01-01 false Production testing. § 1210.16 Section § 1210.16 Commercial Practices CONSUMER PRODUCT SAFETY COMMISSION CONSUMER PRODUCT SAFETY ACT REGULATIONS SAFETY STANDARD FOR CIGARETTE LIGHTERS Certification Requirements § 1210.16 Production testing. (a...

7 CFR 1210.322 - Term of office.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 10 2010-01-01 2010-01-01 false Term of office. 1210.322 Section 1210.322 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS... PLAN Watermelon Research and Promotion Plan National Watermelon Promotion Board § 1210.322 Term of...

21 CFR 870.1210 - Continuous flush catheter.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Continuous flush catheter. 870.1210 Section 870.1210 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CARDIOVASCULAR DEVICES Cardiovascular Diagnostic Devices § 870.1210 Continuous flush...

Plasmacytoid dendritic cells induce NK cell-dependent, tumor antigen-specific T cell cross-priming and tumor regression in mice.

PubMed

Liu, Chengwen; Lou, Yanyan; Lizée, Gregory; Qin, Hong; Liu, Shujuan; Rabinovich, Brian; Kim, Grace J; Wang, Yi-Hong; Ye, Yang; Sikora, Andrew G; Overwijk, Willem W; Liu, Yong-Jun; Wang, Gang; Hwu, Patrick

2008-03-01

A prerequisite for strong adaptive antiviral immunity is the robust initial activation of the innate immune system, which is frequently mediated by TLR-activated plasmacytoid DCs (pDCs). Natural antitumor immunity is often comparatively weak, potentially due to the lack of TLR-mediated activation signals within the tumor microenvironment. To assess whether pDCs are capable of directly facilitating effective antitumor immune responses, mice bearing established subcutaneous B16 melanoma tumors were administered TLR9-activated pDCs directly into the tumor. We found that TLR9-activated pDCs induced robust, spontaneous CTL cross-priming against multiple B16 tumor antigens, leading to the regression of both treated tumors and untreated tumors at distant contralateral sites. This T cell cross-priming was mediated by conventional DCs (cDCs) and was completely dependent upon the early recruitment and activation of NK cells at the tumor site. NK cell recruitment was mediated by CCR5 via chemokines secreted by pDCs, and optimal IFN-gamma production by NK cells was mediated by OX40L expressed by pDCs. Our data thus demonstrated that activated pDCs are capable of initiating effective and systemic antitumor immunity through the orchestration of an immune cascade involving the sequential activation of NK cells, cDCs, and CD8(+) T cells.

7 CFR 1210.602 - Voting.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 10 2010-01-01 2010-01-01 false Voting. 1210.602 Section 1210.602 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS... each producer in a landlord-tenant relationship or a divided ownership arrangement involving totally...

7 CFR 1210.340 - Budget and expenses.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 10 2010-01-01 2010-01-01 false Budget and expenses. 1210.340 Section 1210.340... PROMOTION PLAN Watermelon Research and Promotion Plan Expenses and Assessments § 1210.340 Budget and... shall prepare and recommend a budget on a fiscal period basis of its anticipated expenses and...

Immune infiltration and PD-L1 expression in the tumor microenvironment are prognostic in osteosarcoma

PubMed Central

Koirala, Pratistha; Roth, Michael E.; Gill, Jonathan; Piperdi, Sajida; Chinai, Jordan M.; Geller, David S.; Hoang, Bang H.; Park, Amy; Fremed, Michael A.; Zang, Xingxing; Gorlick, Richard

2016-01-01

Osteosarcoma patient survival has remained stagnant for 30 years. Novel therapeutic approaches are needed to improve outcomes. We examined the expression of Programmed Death Ligand 1 (PD-L1) and defined the tumor immune microenvironment to assess the prognostic utility in osteosarcoma. PD-L1 expression in osteosarcoma was examined in two patient cohorts using immunohistochemistry (IHC) (n = 48, n = 59) and expression was validated using quantitative real time PCR (n = 21) and western blotting (n = 9). IHC was used to determine the presence of tumor infiltrating lymphocytes and antigen-presenting cells (APCs) in the tumor. Expression of PD-L1 was correlated with immune cell infiltration and event-free-survival (EFS). The 25% of primary osteosarcoma tumors that express PD-L1 were more likely to contain cells that express PD-1 than PD-L1 negative tumors (91.7% vs 47.2%, p = 0.002). Expression of PD-L1 was significantly associated with the presence of T cells, dendritic cells, and natural killer cells. Although all immune cell types examined were present in osteosarcoma samples, only infiltration by dendritic cells (28.3% vs. 83.9%, p = 0.001) and macrophages (45.5% vs. 84.4%, p = 0.031) were associated with worse five-year-EFS. PD-L1 expression was significantly associated with poorer five-year-EFS (25.0%. vs. 69.4%, p = 0.014). Further studies in osteosarcoma are needed to determine if targeting the PD-L1:PD-1 axis improves survival. PMID:27456063

King cobra (Ophiophagus hannah) venom L-amino acid oxidase induces apoptosis in PC-3 cells and suppresses PC-3 solid tumor growth in a tumor xenograft mouse model.

PubMed

Lee, Mui Li; Fung, Shin Yee; Chung, Ivy; Pailoor, Jayalakshmi; Cheah, Swee Hung; Tan, Nget Hong

2014-01-01

King cobra (Ophiophagus hannah) venom L-amino acid oxidase (OH-LAAO), a heat stable enzyme, has been shown to exhibit very potent anti-proliferative activity against human breast and lung tumorigenic cells but not in their non-tumorigenic counterparts. We further examine its in vitro and in vivo anti-tumor activity in a human prostate adenocarcinoma (PC-3) model. OH-LAAO demonstrated potent cytotoxicity against PC-3 cells with IC50 of 0.05 µg/mL after 72 h incubation in vitro. It induced apoptosis as evidenced with an increase in caspase-3/7 cleavages and an increase in annexin V-stained cells. To examine its in vivo anti-tumor activity, we treated PC-3 tumor xenograft implanted subcutaneously in immunodeficient NU/NU (nude) mice with 1 µg/g OH-LAAO given intraperitoneally (i.p.). After 8 weeks of treatment, OH-LAAO treated PC-3 tumors were markedly inhibited, when compared to the control group (P <0.05). TUNEL staining analysis on the tumor sections showed a significantly increase of apoptotic cells in the LAAO-treated animals. Histological examinations of the vital organs in these two groups showed no significant differences with normal tissues, indicating no obvious tissue damage. The treatment also did not cause any significant changes on the body weight of the mice during the duration of the study. These observations suggest that OH-LAAO cytotoxic effects may be specific to tumor xenografts and less to normal organs. Given its potent anti-tumor activities shown in vitro as well as in vivo, the king cobra venom LAAO can potentially be developed to treat prostate cancer and other solid tumors.

Nucleolin antagonist triggers autophagic cell death in human glioblastoma primary cells and decreased in vivo tumor growth in orthotopic brain tumor model

PubMed Central

d'Angelo, Michele; Cristiano, Loredana; Galzio, Renato; Destouches, Damien; Florio, Tiziana Marilena; Dhez, Anne Chloé; Astarita, Carlo; Cinque, Benedetta; Fidoamore, Alessia; Rosati, Floriana; Cifone, Maria Grazia; Ippoliti, Rodolfo; Giordano, Antonio; Courty, José; Cimini, Annamaria

2015-01-01

Nucleolin (NCL) is highly expressed in several types of cancer and represents an interesting therapeutic target. It is expressed at the plasma membrane of tumor cells, a property which is being used as a marker for several human cancer including glioblastoma. In this study we investigated targeting NCL as a new therapeutic strategy for the treatment of this pathology. To explore this possibility, we studied the effect of an antagonist of NCL, the multivalent pseudopeptide N6L using primary culture of human glioblastoma cells. In this system, N6L inhibits cell growth with different sensitivity depending to NCL localization. Cell cycle analysis indicated that N6L-induced growth reduction was due to a block of the G1/S transition with down-regulation of the expression of cyclin D1 and B2. By monitoring autophagy markers such as p62 and LC3II, we demonstrate that autophagy is enhanced after N6L treatment. In addition, N6L-treatment of mice bearing tumor decreased in vivo tumor growth in orthotopic brain tumor model and increase mice survival. The results obtained indicated an anti-proliferative and pro-autophagic effect of N6L and point towards its possible use as adjuvant agent to the standard therapeutic protocols presently utilized for glioblastoma. PMID:26540346

7 CFR 1210.325 - Procedure.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 7 Agriculture 10 2011-01-01 2011-01-01 false Procedure. 1210.325 Section 1210.325 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS... mail, telegraph, telephone, or by other means of communication; Provided, That each member receives an...

7 CFR 1210.325 - Procedure.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 10 2010-01-01 2010-01-01 false Procedure. 1210.325 Section 1210.325 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS... mail, telegraph, telephone, or by other means of communication; Provided, That each member receives an...

36 CFR 13.1210 - Firearms.

Code of Federal Regulations, 2012 CFR

2012-07-01

....1210 Parks, Forests, and Public Property NATIONAL PARK SERVICE, DEPARTMENT OF THE INTERIOR NATIONAL PARK SYSTEM UNITS IN ALASKA Special Regulations-Katmai National Park and Preserve General Provisions § 13.1210 Firearms. The superintendent may designate areas or routes within Katmai National Park where...

7 CFR 1210.362 - Influencing government action.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 7 Agriculture 10 2011-01-01 2011-01-01 false Influencing government action. 1210.362 Section 1210... RESEARCH AND PROMOTION PLAN Watermelon Research and Promotion Plan Miscellaneous § 1210.362 Influencing government action. No funds received by the Board under this Plan shall in any manner be used for the purpose...

7 CFR 1210.362 - Influencing government action.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 10 2010-01-01 2010-01-01 false Influencing government action. 1210.362 Section 1210... RESEARCH AND PROMOTION PLAN Watermelon Research and Promotion Plan Miscellaneous § 1210.362 Influencing government action. No funds received by the Board under this Plan shall in any manner be used for the purpose...

7 CFR 1210.351 - Books and records.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 7 Agriculture 10 2013-01-01 2013-01-01 false Books and records. 1210.351 Section 1210.351... PROMOTION PLAN Watermelon Research and Promotion Plan Reports, Books, and Records § 1210.351 Books and... make available for inspection by employees of the Board or Secretary, such books and records as are...

7 CFR 1210.351 - Books and records.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 7 Agriculture 10 2011-01-01 2011-01-01 false Books and records. 1210.351 Section 1210.351... PROMOTION PLAN Watermelon Research and Promotion Plan Reports, Books, and Records § 1210.351 Books and... make available for inspection by employees of the Board or Secretary, such books and records as are...

7 CFR 1210.351 - Books and records.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 10 2010-01-01 2010-01-01 false Books and records. 1210.351 Section 1210.351... PROMOTION PLAN Watermelon Research and Promotion Plan Reports, Books, and Records § 1210.351 Books and... make available for inspection by employees of the Board or Secretary, such books and records as are...

7 CFR 1210.351 - Books and records.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 7 Agriculture 10 2012-01-01 2012-01-01 false Books and records. 1210.351 Section 1210.351... PROMOTION PLAN Watermelon Research and Promotion Plan Reports, Books, and Records § 1210.351 Books and... make available for inspection by employees of the Board or Secretary, such books and records as are...

7 CFR 1210.351 - Books and records.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 7 Agriculture 10 2014-01-01 2014-01-01 false Books and records. 1210.351 Section 1210.351... PROMOTION PLAN Watermelon Research and Promotion Plan Reports, Books, and Records § 1210.351 Books and... make available for inspection by employees of the Board or Secretary, such books and records as are...

21 CFR 862.1210 - Creatine test system.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Creatine test system. 862.1210 Section 862.1210....1210 Creatine test system. (a) Identification. A creatine test system is a device intended to measure creatine (a substance synthesized in the liver and pancreas and found in biological fluids) in plasma...

Histone deacetylase inhibitors prevent activation-induced cell death and promote anti-tumor immunity

PubMed Central

Cao, K; Wang, G; Li, W; Zhang, L; Wang, R; Huang, Y; Du, L; Jiang, J; Wu, C; He, X; Roberts, A I; Li, F; Rabson, A B; Wang, Y; Shi, Y

2015-01-01

The poor efficacy of the in vivo anti-tumor immune response has been partially attributed to ineffective T-cell responses mounted against the tumor. Fas-FasL-dependent activation-induced cell death (AICD) of T cells is believed to be a major contributor to compromised anti-tumor immunity. The molecular mechanisms of AICD are well-investigated, yet the possibility of regulating AICD for cancer therapy remains to be explored. In this study, we show that histone deacetylase inhibitors (HDACIs) can inhibit apoptosis of CD4+ T cells within the tumor, thereby enhancing anti-tumor immune responses and suppressing melanoma growth. This inhibitory effect is specific for AICD through suppressing NFAT1-regulated FasL expression on activated CD4+ T cells. In gld/gld mice with mutation in FasL, the beneficial effect of HDACIs on AICD of infiltrating CD4+ T cells is not seen, confirming the critical role of FasL regulation in the anti-tumor effect of HDACIs. Importantly, we found that the co-administration of HDACIs and anti-CTLA4 could further enhance the infiltration of CD4+ T cells and achieve a synergistic therapeutic effect on tumor. Therefore, our study demonstrates that the modulation of AICD of tumor-infiltrating CD4+ T cells using HDACIs can enhance anti-tumor immune responses, uncovering a novel mechanism underlying the anti-tumor effect of HDACIs. PMID:25745993

7 CFR 1210.307 - Handle.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 10 2010-01-01 2010-01-01 false Handle. 1210.307 Section 1210.307 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS..., process, sell, transport, purchase, or in any other way to place or cause watermelons to which one has...

9 CFR 12.10 - Stipulations.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Stipulations. 12.10 Section 12.10 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE ANIMAL WELFARE RULES OF PRACTICE GOVERNING PROCEEDINGS UNDER THE HORSE PROTECTION ACT Supplemental Rules of...

7 CFR 1210.605 - Ballots.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 10 2010-01-01 2010-01-01 false Ballots. 1210.605 Section 1210.605 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS..., the agent or subagent shall endorse above their signature, on the ballot, a statement to the effect...

PD-L1 expression in Xp11.2 translocation renal cell carcinoma: Indicator of tumor aggressiveness.

PubMed

Chang, Kun; Qu, Yuanyuan; Dai, Bo; Zhao, Jian-Yuan; Gan, Hualei; Shi, Guohai; Zhu, Yiping; Shen, Yijun; Zhu, Yao; Zhang, Hailiang; Ye, Dingwei

2017-05-18

Programmed death ligand-1 (PD-L1), a promising antitumor target, has proven clinical value against many malignancies. However, the PD-L1 content of Xp11.2 translocation renal cell carcinoma (Xp11.2 RCC) and its correlation with clinical outcomes remain unclear. This study aimed to investigate PD-L1 expression in Xp11.2 RCC and to assess its prognostic value. Formalin-fixed paraffin-embedded specimens from 36 adult patients that were histologically confirmed (by fluorescence in situ hybridization) were subjected to immunohistochemical analysis. Of the 36 Xp11.2 RCC patients, 9 (25.0%) had tumors with positive PD-L1 expression and 27 (75.0%) had tumors with negative PD-L1 expression. Positive PD-L1 expression correlated with advanced tumor stage (P = 0.001), regional lymph node metastasis (P < 0.001), and distant metastasis (P < 0.001). A multivariate analysis identified positive PD-L1 expression was an independent adverse prognostic factor for both progression free survival (hazard ratio: 3.7, P = 0.018) and overall survival (hazard ratio: 4.5, P = 0.034). The median PFS and OS for the whole cohort were 13.0 months (95% confidence interval [CI], 9.4-16.6 months) and 36.0 months (95% CI, 23.9-48.1 months), respectively. Our findings suggest that positive PD-L1 expression is indicative of worse clinical outcome in Xp11.2 RCC. Further studies are needed to explore the potential efficacy of targeting PD-L1 in Xp11.2 RCC.

16 CFR 1210.2 - Definitions.

Code of Federal Regulations, 2010 CFR

2010-01-01

... STANDARD FOR CIGARETTE LIGHTERS Requirements for Child Resistance § 1210.2 Definitions. As used in this part 1210: (a) Cigarette lighter. See lighter. (b) Disposable lighter—means a lighter that either is..., is $2.25. (c) Lighter, also referred to as cigarette lighter, means a flame-producing product...

21 CFR 1210.1 - Authority.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Authority. 1210.1 Section 1210.1 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) REGULATIONS UNDER CERTAIN OTHER ACTS ADMINISTERED BY THE FOOD AND DRUG ADMINISTRATION REGULATIONS UNDER THE FEDERAL IMPORT...

36 CFR 1210.43 - Competition.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 36 Parks, Forests, and Public Property 3 2010-07-01 2010-07-01 false Competition. 1210.43 Section..., HOSPITALS, AND OTHER NON-PROFIT ORGANIZATIONS Post-Award Requirements Procurement Standards § 1210.43 Competition. All procurement transactions shall be conducted in a manner to provide, to the maximum extent...

21 CFR 1210.2 - Scope of act.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Scope of act. 1210.2 Section 1210.2 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) REGULATIONS UNDER... MILK ACT General Provisions § 1210.2 Scope of act. The provisions of the act apply to all milk and...

21 CFR 1210.2 - Scope of act.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Scope of act. 1210.2 Section 1210.2 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) REGULATIONS UNDER... MILK ACT General Provisions § 1210.2 Scope of act. The provisions of the act apply to all milk and...

A novel MDSC-induced PD-1-PD-L1+ B-cell subset in breast tumor microenvironment possesses immuno-suppressive properties.

PubMed

Shen, Meng; Wang, Jian; Yu, Wenwen; Zhang, Chen; Liu, Min; Wang, Kaiyuan; Yang, Lili; Wei, Feng; Wang, Shizhen Emily; Sun, Qian; Ren, Xiubao

2018-01-01

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of myeloid cells that suppress T-cell activity in a tumor microenvironment. However, the suppressive function of MDSCs on B cells and its underlying mechanism remain unclear. Here, we show that in 4T1 breast cancer mice, a significantly increased number of MDSCs, in parallel with splenic B cells, are accumulated when compared to normal mice. In the presence of MDSCs, the surface molecules of B cells are remolded, with checkpoint-related molecules such as PD-1 and PD-L1 changing prominently. MDSCs also emerge as vital regulators in B-cell immune functions such as proliferation, apoptosis and the abilities to secrete antibodies and cytokines. Our study further identifies that MDSCs can transform normal B cells to a subtype of immuno- regulatory B cells (Bregs) which inhibit T-cell response. Furthermore, we identified a novel kind of Bregs with a specific phenotype PD-1 - PD-L1 + CD19 + , which exert the greatest suppressive effects on T cells in comparison with the previously reported Bregs characterized as CD1d + CD5 + CD19 + , CD5 + CD19 + and Interleukin (IL)-10-secreting B cells. Our results highlight that MDSCs regulate B-cell response and may serve as a therapeutic approach in anti-tumor treatment. Investigation of this new Breg subtype extends our understanding of regulation of T-cell response and sheds new light on anti-tumor immunity and immune therapy.

7 CFR 12.10 - Scheme or device.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 1 2010-01-01 2010-01-01 false Scheme or device. 12.10 Section 12.10 Agriculture... § 12.10 Scheme or device. All or any part of the benefits listed in § 12.4 otherwise due a person from... scheme or device designed to evade, or which has the effect of evading, the provisions of this part. Such...

7 CFR 12.10 - Scheme or device.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 7 Agriculture 1 2014-01-01 2014-01-01 false Scheme or device. 12.10 Section 12.10 Agriculture... § 12.10 Scheme or device. All or any part of the benefits listed in § 12.4 otherwise due a person from... scheme or device designed to evade, or which has the effect of evading, the provisions of this part. Such...

7 CFR 12.10 - Scheme or device.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 7 Agriculture 1 2013-01-01 2013-01-01 false Scheme or device. 12.10 Section 12.10 Agriculture... § 12.10 Scheme or device. All or any part of the benefits listed in § 12.4 otherwise due a person from... scheme or device designed to evade, or which has the effect of evading, the provisions of this part. Such...

7 CFR 12.10 - Scheme or device.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 7 Agriculture 1 2011-01-01 2011-01-01 false Scheme or device. 12.10 Section 12.10 Agriculture... § 12.10 Scheme or device. All or any part of the benefits listed in § 12.4 otherwise due a person from... scheme or device designed to evade, or which has the effect of evading, the provisions of this part. Such...

7 CFR 12.10 - Scheme or device.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 7 Agriculture 1 2012-01-01 2012-01-01 false Scheme or device. 12.10 Section 12.10 Agriculture... § 12.10 Scheme or device. All or any part of the benefits listed in § 12.4 otherwise due a person from... scheme or device designed to evade, or which has the effect of evading, the provisions of this part. Such...

Enhanced tumor control with combination mTOR and PD-L1 inhibition in syngeneic oral cavity cancers

PubMed Central

Moore, Ellen C.; Cash, Harrison A.; Caruso, Andria M.; Uppaluri, Ravindra; Hodge, James W.; Van Waes, Carter; Allen, Clint T.

2016-01-01

Significant subsets of patients with oral cancer fail to respond to single-agent programmed death (PD) blockade. Syngeneic models of oral cancer were used to determine if blocking oncogenic signaling improved in vivo responses to PD-L1 monoclonal antibody (mAb). Anti-PD-L1 enhanced durable primary tumor control and survival when combined with mTOR (rapamycin), but not in combination with MEK inhibition (PD901) in immunogenic MOC1 tumors. Conversely, PD-L1 mAb did not enhance tumor control in poorly immunogenic MOC2 tumors. Rapamycin enhanced expansion of peripheral antigen-specific CD8 T cells and IFNγ production following ex vivo antigen stimulation. More CD8 T cells infiltrated and were activated after PD-L1 mAb treatment in mice with immunogenic MOC1 tumors, which was stable or increased by the addition of rapamycin, but suppressed when PD901 was added. Rapamycin increased IFNγ production capacity in peripheral and tumor-infiltrating CD8 T cells. In vivo antibody depletion revealed a CD8 T cell, and not NK cell, -dependent mechanism of tumor growth inhibition after treatment with rapamycin and PD-L1 mAb, ruling out significant effects from NK cell–mediated antibody-dependent cellular cytotoxicity. Rapamycin also enhanced IFNγ or PD-L1 mAb treatment–associated induction of MHC class I expression on MOC1 tumor cells, an effect abrogated by depleting infiltrating CD8 T cells from the tumor microenvironment. This data conflicts with traditional views of rapamycin as a universal immunosuppressant, and when combined with evidence of enhanced antitumor activity with the combination of rapamycin and PD-L1 mAb, suggests that this treatment combination deserves careful evaluation in the clinical setting. PMID:27076449

NF-κB functions as a molecular link between tumor cells and Th1/Tc1 T cells in the tumor microenvironment to exert radiation-mediated tumor suppression

PubMed Central

Simon, Priscilla S.; Bardhan, Kankana; Chen, May R.; Paschall, Amy V.; Lu, Chunwan; Bollag, Roni J.; Kong, Feng-Chong; Jin, JianYue; Kong, Feng-Ming; Waller, Jennifer L.; Pollock, Raphael E.; Liu, Kebin

2016-01-01

Radiation modulates both tumor cells and immune cells in the tumor microenvironment to exert its anti-tumor activity; however, the molecular connection between tumor cells and immune cells that mediates radiation-exerted tumor suppression activity in the tumor microenvironment is largely unknown. We report here that radiation induces rapid activation of the p65/p50 and p50/p50 NF-κB complexes in human soft tissue sarcoma (STS) cells. Radiation-activated p65/p50 and p50/p50 bind to the TNFα promoter to activate its transcription in STS cells. Radiation-induced TNFα induces tumor cell death in an autocrine manner. A sublethal dose of Smac mimetic BV6 induces cIAP1 and cIAP2 degradation to increase tumor cell sensitivity to radiation-induced cell death in vitro and to enhance radiation-mediated suppression of STS xenografts in vivo. Inhibition of caspases, RIP1, or RIP3 blocks radiation/TNFα-induced cell death, whereas inhibition of RIP1 blocks TNFα-induced caspase activation, suggesting that caspases and RIP1 act sequentially to mediate the non-compensatory cell death pathways. Furthermore, we determined in a syngeneic sarcoma mouse model that radiation up-regulates IRF3, IFNβ, and the T cell chemokines CCL2 and CCL5 in the tumor microenvironment, which are associated with activation and increased infiltration of Th1/Tc1 T cells in the tumor microenvironment. Moreover, tumor-infiltrating T cells are in their active form since both the perforin and FasL pathways are activated in irradiated tumor tissues. Consequently, combined BV6 and radiation completely suppressed tumor growth in vivo. Therefore, radiation-induced NF-κB functions as a molecular link between tumor cells and immune cells in the tumor microenvironment for radiation-mediated tumor suppression. PMID:27014915

7 CFR 1210.360 - Right of the Secretary.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 10 2010-01-01 2010-01-01 false Right of the Secretary. 1210.360 Section 1210.360 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING... PROMOTION PLAN Watermelon Research and Promotion Plan Miscellaneous § 1210.360 Right of the Secretary. All...

Maintenance of tumor initiating cells of defined genetic composition by nucleostemin.

PubMed

Okamoto, Naoko; Yasukawa, Mami; Nguyen, Christine; Kasim, Vivi; Maida, Yoshiko; Possemato, Richard; Shibata, Tatsuhiro; Ligon, Keith L; Fukami, Kiyoko; Hahn, William C; Masutomi, Kenkichi

2011-12-20

Recent work has identified a subset of cells resident in tumors that exhibit properties similar to those found in normal stem cells. Such cells are highly tumorigenic and may be involved in resistance to treatment. However, the genes that regulate the tumor initiating cell (TIC) state are unknown. Here, we show that overexpression of either of the nucleolar GTP-binding proteins nucleostemin (NS) or GNL3L drives the fraction of genetically defined tumor cells that exhibit markers and tumorigenic properties of TICs. Specifically, cells that constitutively express elevated levels of NS or GNL3L exhibit increased TWIST expression, phosphorylation of STAT3, expression of genes that induce pluripotent stem cells, and enhanced radioresistance; in addition, they form tumors even when small numbers of cells are implanted and exhibit an increased propensity to metastasize. GNL3L/NS forms a complex with the telomerase catalytic subunit [human telomerase reverse transcriptase (hTERT)] and the SWItch-Sucrose NonFermentable (SWI-SNF) complex protein brahma-related gene 1 (BRG1), and the expression of each of these components is necessary to facilitate the cancer stem cell state. Together, these observations define a complex composed of TERT, BRG1, and NS/GNL3L that maintains the function of TICs.

16 CFR § 1210.18 - Refusal of importation.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 16 Commercial Practices 2 2013-01-01 2013-01-01 false Refusal of importation. § 1210.18 Section § 1210.18 Commercial Practices CONSUMER PRODUCT SAFETY COMMISSION CONSUMER PRODUCT SAFETY ACT REGULATIONS SAFETY STANDARD FOR CIGARETTE LIGHTERS Certification Requirements § 1210.18 Refusal of importation. (a...

36 CFR 1210.3 - Effect on other issuances.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 36 Parks, Forests, and Public Property 3 2010-07-01 2010-07-01 false Effect on other issuances. 1210.3 Section 1210.3 Parks, Forests, and Public Property NATIONAL ARCHIVES AND RECORDS ADMINISTRATION... EDUCATION, HOSPITALS, AND OTHER NON-PROFIT ORGANIZATIONS General § 1210.3 Effect on other issuances. For...

45 CFR 1210.3-10 - Reinstatement of Volunteer.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 45 Public Welfare 4 2010-10-01 2010-10-01 false Reinstatement of Volunteer. 1210.3-10 Section 1210... COMMUNITY SERVICE VISTA TRAINEE DESELECTION AND VOLUNTEER EARLY TERMINATION PROCEDURES VISTA Volunteer Early Termination § 1210.3-10 Reinstatement of Volunteer. (a) If the Regional Director or Director of VISTA...

45 CFR 1210.3-10 - Reinstatement of Volunteer.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 45 Public Welfare 4 2014-10-01 2014-10-01 false Reinstatement of Volunteer. 1210.3-10 Section 1210... COMMUNITY SERVICE VISTA TRAINEE DESELECTION AND VOLUNTEER EARLY TERMINATION PROCEDURES VISTA Volunteer Early Termination § 1210.3-10 Reinstatement of Volunteer. (a) If the Regional Director or Director of VISTA...

45 CFR 1210.3-10 - Reinstatement of Volunteer.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 45 Public Welfare 4 2013-10-01 2013-10-01 false Reinstatement of Volunteer. 1210.3-10 Section 1210... COMMUNITY SERVICE VISTA TRAINEE DESELECTION AND VOLUNTEER EARLY TERMINATION PROCEDURES VISTA Volunteer Early Termination § 1210.3-10 Reinstatement of Volunteer. (a) If the Regional Director or Director of VISTA...

45 CFR 1210.3-10 - Reinstatement of Volunteer.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 45 Public Welfare 4 2012-10-01 2012-10-01 false Reinstatement of Volunteer. 1210.3-10 Section 1210... COMMUNITY SERVICE VISTA TRAINEE DESELECTION AND VOLUNTEER EARLY TERMINATION PROCEDURES VISTA Volunteer Early Termination § 1210.3-10 Reinstatement of Volunteer. (a) If the Regional Director or Director of VISTA...

45 CFR 1210.3-10 - Reinstatement of Volunteer.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 45 Public Welfare 4 2011-10-01 2011-10-01 false Reinstatement of Volunteer. 1210.3-10 Section 1210... COMMUNITY SERVICE VISTA TRAINEE DESELECTION AND VOLUNTEER EARLY TERMINATION PROCEDURES VISTA Volunteer Early Termination § 1210.3-10 Reinstatement of Volunteer. (a) If the Regional Director or Director of VISTA...

Angiostatic, tumor inflammatory and anti-tumor effects of CXCL4(47-70) and CXCL4L1(47-70) in an EGF-dependent breast cancer model.

PubMed

Van Raemdonck, Katrien; Berghmans, Nele; Vanheule, Vincent; Bugatti, Antonella; Proost, Paul; Opdenakker, Ghislain; Presta, Marco; Van Damme, Jo; Struyf, Sofie

2014-11-15

CXCL4 and CXCL4L1, platelet-derived CXC chemokines, and their carboxy-terminal peptides CXCL4(47-70) and CXCL4L1(47-70) previously displayed angiostatic and anti-tumoral activity in a melanoma model. Here, we found CXCL4(47-70) and CXCL4L1(47-70) to inhibit lymphatic endothelial cell proliferation in vitro. Furthermore, the angiostatic potential of CXCL4(47-70) and CXCL4L1(47-70) was tested against different angiogenic stimuli (FGF1, FGF2, FGF8, EGF and VEGF). Besides reducing FGF2-induced vascular endothelial cell growth, CXCL4(47-70) and CXCL4L1(47-70) efficiently counteracted EGF. Consequently, we considered their anti-tumoral potential in EGF-dependent MDA-MB-231 breast tumors. In tumor-bearing mice, CXCL4(47-70) reduced tumor growth better than CXCL4L1(47-70). In CXCL4(47-70)-treated tumors significantly more intratumoral monocytes/macrophages and dendritic cells were present and higher expression levels of CCL5 and IFN- γ were detected by qPCR on tumor lysates. Because neither peptide was able to specifically bind CXCR3A or CXCR3B, differential glycosaminoglycan binding and direct interaction with cytokines (EGF and CCL5) might explain any differences in anti-tumoral effects. Notably, CCL5-induced monocyte chemotaxis in vitro was increased by addition of CXCL4(47-70) or CXCL4L1(47-70). Finally, CXCL4(47-70) and CXCL4L1(47-70) inhibited proliferation of MDA-MB-231 cells. Our results suggest a tumor type-dependent responsiveness to either CXCL4(47-70) or CXCL4L1(47-70) treatment, defined by anti-proliferative, angiostatic and inflammatory actions, and substantiate their therapeutic potential.

Angiostatic, tumor inflammatory and anti-tumor effects of CXCL447–70 and CXCL4L147–70 in an EGF-dependent breast cancer model

PubMed Central

Van Raemdonck, Katrien; Berghmans, Nele; Vanheule, Vincent; Bugatti, Antonella; Proost, Paul; Opdenakker, Ghislain; Presta, Marco; Van Damme, Jo; Struyf, Sofie

2014-01-01

CXCL4 and CXCL4L1, platelet-derived CXC chemokines, and their carboxy-terminal peptides CXCL447–70 and CXCL4L147–70 previously displayed angiostatic and anti-tumoral activity in a melanoma model. Here, we found CXCL447–70 and CXCL4L147–70 to inhibit lymphatic endothelial cell proliferation in vitro. Furthermore, the angiostatic potential of CXCL447–70 and CXCL4L147–70 was tested against different angiogenic stimuli (FGF1, FGF2, FGF8, EGF and VEGF). Besides reducing FGF2-induced vascular endothelial cell growth, CXCL447–70 and CXCL4L147–70 efficiently counteracted EGF. Consequently, we considered their anti-tumoral potential in EGF-dependent MDA-MB-231 breast tumors. In tumor-bearing mice, CXCL447–70 reduced tumor growth better than CXCL4L147–70. In CXCL447–70-treated tumors significantly more intratumoral monocytes/macrophages and dendritic cells were present and higher expression levels of CCL5 and IFN-γ were detected by qPCR on tumor lysates. Because neither peptide was able to specifically bind CXCR3A or CXCR3B, differential glycosaminoglycan binding and direct interaction with cytokines (EGF and CCL5) might explain any differences in anti-tumoral effects. Notably, CCL5-induced monocyte chemotaxis in vitro was increased by addition of CXCL447–70 or CXCL4L147–70. Finally, CXCL447–70 and CXCL4L147–70 inhibited proliferation of MDA-MB-231 cells. Our results suggest a tumor type-dependent responsiveness to either CXCL447–70 or CXCL4L147–70 treatment, defined by anti-proliferative, angiostatic and inflammatory actions, and substantiate their therapeutic potential. PMID:25373734

16 CFR 1210.3 - Requirements for cigarette lighters.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 16 Commercial Practices 2 2012-01-01 2012-01-01 false Requirements for cigarette lighters. 1210.3... REGULATIONS SAFETY STANDARD FOR CIGARETTE LIGHTERS Requirements for Child Resistance § 1210.3 Requirements for cigarette lighters. (a) A lighter subject to this part 1210 shall be resistant to successful operation by at...

16 CFR 1210.3 - Requirements for cigarette lighters.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 16 Commercial Practices 2 2010-01-01 2010-01-01 false Requirements for cigarette lighters. 1210.3... REGULATIONS SAFETY STANDARD FOR CIGARETTE LIGHTERS Requirements for Child Resistance § 1210.3 Requirements for cigarette lighters. (a) A lighter subject to this part 1210 shall be resistant to successful operation by at...

16 CFR 1210.3 - Requirements for cigarette lighters.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 16 Commercial Practices 2 2011-01-01 2011-01-01 false Requirements for cigarette lighters. 1210.3... REGULATIONS SAFETY STANDARD FOR CIGARETTE LIGHTERS Requirements for Child Resistance § 1210.3 Requirements for cigarette lighters. (a) A lighter subject to this part 1210 shall be resistant to successful operation by at...

16 CFR 1210.3 - Requirements for cigarette lighters.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 16 Commercial Practices 2 2014-01-01 2014-01-01 false Requirements for cigarette lighters. 1210.3... REGULATIONS SAFETY STANDARD FOR CIGARETTE LIGHTERS Requirements for Child Resistance § 1210.3 Requirements for cigarette lighters. (a) A lighter subject to this part 1210 shall be resistant to successful operation by at...

16 CFR 1210.14 - Qualification testing.

Code of Federal Regulations, 2010 CFR

2010-01-01

....14 Commercial Practices CONSUMER PRODUCT SAFETY COMMISSION CONSUMER PRODUCT SAFETY ACT REGULATIONS SAFETY STANDARD FOR CIGARETTE LIGHTERS Certification Requirements § 1210.14 Qualification testing. (a... accordance with § 1210.4. (b) Product modifications. If any changes are made to a product after initial...

Nanoparticle Imaging of Integrins on Tumor Cells1

PubMed Central

Montet, Xavier; Montet-Abou, Karin; Reynolds, Fred; Weissleder, Ralph; Josephson, Lee

2006-01-01

Abstract Nanoparticles 10 to 100 nm in size can deliver large payloads to molecular targets, but undergo slow diffusion and/or slow transport through delivery barriers. To examine the feasibility of nanoparticles targeting a marker expressed in tumor cells, we used the binding of cyclic arginine-glycine-aspartic acid (RGD) nanoparticle targeting integrins on BT-20 tumor as a model system. The goals of this study were: 1) to use nanoparticles to image αvβ3 integrins expressed in BT-20 tumor cells by fluorescence-based imaging and magnetic resonance imaging, and, 2) to identify factors associated with the ability of nanoparticles to target tumor cell integrins. Three factors were identified: 1) tumor cell integrin expression (the αvβ3 integrin was expressed in BT-20 cells, but not in 9L cells); 2) nanoparticle pharmacokinetics (the cyclic RGD peptide cross-linked iron oxide had a blood half-life of 180 minutes and was able to escape from the vasculature over its long circulation time); and 3) tumor vascularization (the tumor had a dense capillary bed, with distances of <100 µm between capillaries). These results suggest that nanoparticles could be targeted to the cell surface markers expressed in tumor cells, at least in the case wherein the nanoparticles and the tumor model have characteristics similar to those of the BT-20 tumor employed here. PMID:16611415

21 CFR 1210.23 - Permits granted on certificates.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Permits granted on certificates. 1210.23 Section 1210.23 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... FEDERAL IMPORT MILK ACT Permit Control § 1210.23 Permits granted on certificates. In the discretion of the...

21 CFR 1210.23 - Permits granted on certificates.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Permits granted on certificates. 1210.23 Section 1210.23 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... FEDERAL IMPORT MILK ACT Permit Control § 1210.23 Permits granted on certificates. In the discretion of the...

Small cell lung cancer: Recruitment of macrophages by circulating tumor cells

PubMed Central

Hamilton, Gerhard; Rath, Barbara; Klameth, Lukas; Hochmair, Maximilan J.

2016-01-01

ABSTRACT Tumor-associated macrophages (TAMs) play an important role in tumor progression, suppression of antitumor immunity and dissemination. Blood monocytes infiltrate the tumor region and are primed by local microenvironmental conditions to promote tumor growth and invasion. Although many of the interacting cytokines and factors are known for the tumor-macrophage interactions, the putative contribution of circulating tumor cells (CTCs) is not known so far. These specialized cells are characterized by increased mobility, ability to degrade the extracellular matrix (ECM) and to enter the blood stream and generate secondary lesions which is a leading cause of death for the majority of tumor patients. The first establishment of two permanent CTC lines, namely BHGc7 and 10, from blood samples of advanced stage small cell lung cancer (SCLC) patients allowed us to investigate the CTC-immune cell interaction. Cocultures of peripheral blood mononuclear cells (PBMNCs) with CTCs or addition of CTC-conditioned medium (CTC-CM) in vitro resulted in monocyte-macrophage differentiation and appearance of CD14+, CD163weak and CD68+ macrophages expressing markers of TAMs. Furthermore, we screened the supernatants of CTC-primed macrophages for presence of approximately 100 cytokines and compared the expression with those induced by the local metastatic SCLC26A cell line. Macrophages recruited by SCLC26A-CM showed expression of osteopontin (OPN), monocyte chemoattractant protein-1 (MCP-1), IL-8, chitinase3-like 1 (CHI3L1), platelet factor (Pf4), IL-1ra and matrix metalloproteinase-9 (MMP-9) among other minor cytokines/chemokines. In contrast, BHGc7-CM induced marked overexpression of complement factor D (CFD)/adipsin and vitamin D-BP (VDBP), as well as increased secretion of OPN, lipocalin-2 (LCN2), CHI3L1, uPAR, MIP-1 and GDF-15/MIC-1. BHGc10, derived independently from relapsed SCLC, revealed an almost identical pattern with added expression of ENA-78/CXCL5. CMs of the non-tumor

Small cell lung cancer: Recruitment of macrophages by circulating tumor cells.

PubMed

Hamilton, Gerhard; Rath, Barbara; Klameth, Lukas; Hochmair, Maximilan J

2016-03-01

Tumor-associated macrophages (TAMs) play an important role in tumor progression, suppression of antitumor immunity and dissemination. Blood monocytes infiltrate the tumor region and are primed by local microenvironmental conditions to promote tumor growth and invasion. Although many of the interacting cytokines and factors are known for the tumor-macrophage interactions, the putative contribution of circulating tumor cells (CTCs) is not known so far. These specialized cells are characterized by increased mobility, ability to degrade the extracellular matrix (ECM) and to enter the blood stream and generate secondary lesions which is a leading cause of death for the majority of tumor patients. The first establishment of two permanent CTC lines, namely BHGc7 and 10, from blood samples of advanced stage small cell lung cancer (SCLC) patients allowed us to investigate the CTC-immune cell interaction. Cocultures of peripheral blood mononuclear cells (PBMNCs) with CTCs or addition of CTC-conditioned medium (CTC-CM) in vitro resulted in monocyte-macrophage differentiation and appearance of CD14 + , CD163 weak and CD68 + macrophages expressing markers of TAMs. Furthermore, we screened the supernatants of CTC-primed macrophages for presence of approximately 100 cytokines and compared the expression with those induced by the local metastatic SCLC26A cell line. Macrophages recruited by SCLC26A-CM showed expression of osteopontin (OPN), monocyte chemoattractant protein-1 (MCP-1), IL-8, chitinase3-like 1 (CHI3L1), platelet factor (Pf4), IL-1ra and matrix metalloproteinase-9 (MMP-9) among other minor cytokines/chemokines. In contrast, BHGc7-CM induced marked overexpression of complement factor D (CFD)/adipsin and vitamin D-BP (VDBP), as well as increased secretion of OPN, lipocalin-2 (LCN2), CHI3L1, uPAR, MIP-1 and GDF-15/MIC-1. BHGc10, derived independently from relapsed SCLC, revealed an almost identical pattern with added expression of ENA-78/CXCL5. CMs of the non-tumor HEK293

7 CFR 1210.607 - Confidential information.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 7 Agriculture 10 2012-01-01 2012-01-01 false Confidential information. 1210.607 Section 1210.607 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING... contents and all other information or reports furnished to, compiled by, or in possession of, the...

7 CFR 1210.607 - Confidential information.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 7 Agriculture 10 2011-01-01 2011-01-01 false Confidential information. 1210.607 Section 1210.607 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING... contents and all other information or reports furnished to, compiled by, or in possession of, the...

7 CFR 1210.607 - Confidential information.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 7 Agriculture 10 2014-01-01 2014-01-01 false Confidential information. 1210.607 Section 1210.607 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING... contents and all other information or reports furnished to, compiled by, or in possession of, the...

7 CFR 1210.607 - Confidential information.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 7 Agriculture 10 2013-01-01 2013-01-01 false Confidential information. 1210.607 Section 1210.607 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING... contents and all other information or reports furnished to, compiled by, or in possession of, the...

7 CFR 1210.607 - Confidential information.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 10 2010-01-01 2010-01-01 false Confidential information. 1210.607 Section 1210.607 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING... contents and all other information or reports furnished to, compiled by, or in possession of, the...

7 CFR 1210.352 - Confidential treatment.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 10 2010-01-01 2010-01-01 false Confidential treatment. 1210.352 Section 1210.352 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING... treatment. (a) All information obtained from the books, records, or reports required to be maintained under...

PD-L1 Promotes Self-Renewal and Tumorigenicity of Malignant Melanoma Initiating Cells

PubMed Central

Dang, Jianzhong; Zha, Hui; Zhang, Bingyu; Lin, Ming

2017-01-01

Recent studies have indicated that therapeutic antibodies targeting PD-L1 show remarkable efficacy in clinical trials in multiple tumors and that a melanoma cell-intrinsic PD-1: PD-L1 axis promotes tumor growth. However, few studies have shown tumor-intrinsic PD-L1 effects in malignant melanoma initiating cells (MMICs). Here, we aim to determine the possible regulatory effects of PD-L1 on MMICs. The ALDEFLUOR kit was used to identify ALDH+ MMICs. Flow cytometry was used to examine the expression of PD-L1 on ALDH+ MMICs. To determine the role of PD-L1 in MMICs self-renewal, we cultured melanoma cells with anti-PD-L1 and measured tumorsphere formation and apoptosis. In addition, the effects of anti-PD-L1 on tumorigenicity and residual ALDH+ MMICs in tumors were evaluated in vivo. We demonstrated that melanoma cell-intrinsic PD-L1 was expressed in ALDH+ MMICs. Blocking PD-L1 in melanoma cell lines impaired tumorsphere formation and induced the apoptosis of sphere cells. In addition, blocking PD-L1 inhibited tumor growth in vivo. We observed residual ALDH+ MMICs within the tumor. The results showed that blocking PD-L1 also significantly decreased the residual ALDH+ MMICs in the tumors. In conclusion, these results suggest a new mechanism underlying melanoma progression and PD-L1-targeted therapy, which is distinct from the immunomodulatory actions of PD-L1. PMID:29250533

21 CFR 1210.12 - Physical examination of cows.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Physical examination of cows. 1210.12 Section 1210... FEDERAL IMPORT MILK ACT Inspection and Testing § 1210.12 Physical examination of cows. (a) Physical.... (b) The result of the physical examination shall be set forth in the form prescribed by the Secretary. ...

21 CFR 1210.12 - Physical examination of cows.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Physical examination of cows. 1210.12 Section 1210... FEDERAL IMPORT MILK ACT Inspection and Testing § 1210.12 Physical examination of cows. (a) Physical.... (b) The result of the physical examination shall be set forth in the form prescribed by the Secretary. ...

21 CFR 1210.12 - Physical examination of cows.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Physical examination of cows. 1210.12 Section 1210... FEDERAL IMPORT MILK ACT Inspection and Testing § 1210.12 Physical examination of cows. (a) Physical.... (b) The result of the physical examination shall be set forth in the form prescribed by the Secretary. ...

21 CFR 1210.12 - Physical examination of cows.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Physical examination of cows. 1210.12 Section 1210... FEDERAL IMPORT MILK ACT Inspection and Testing § 1210.12 Physical examination of cows. (a) Physical.... (b) The result of the physical examination shall be set forth in the form prescribed by the Secretary. ...

PD-L1 expression on malignant cells is no prerequisite for checkpoint therapy.

PubMed

Kleinovink, Jan Willem; Marijt, Koen A; Schoonderwoerd, Mark J A; van Hall, Thorbald; Ossendorp, Ferry; Fransen, Marieke F

2017-01-01

Immunotherapy with PD-1/PD-L1-blocking antibodies is clinically effective for several tumor types, but the mechanism is not fully understood. PD-L1 expression on tumor biopsies is generally regarded as an inclusion criterion for this cancer therapy. Here, we describe the PD-L1-blocking therapeutic responses of preclinical tumors in which PD-L1 expression was removed from cancer cells, but not from immune infiltrate. Lack of PD-L1 expression on malignant cells delayed tumor outgrowth in a CD8 + T cell-mediated fashion, showing the importance of this molecule in immune suppression. PD-L1 expression was evident on myeloid-infiltrating cells in the microenvironment of these tumors and targeting stromal PD-L1 with blocking antibody therapy had additional antitumor effect, demonstrating that PD-L1 on both malignant cells and immune cells is involved in the mechanism of immunotherapeutic antibodies. Importantly, comparable results were obtained with PD-1-blocking therapy. These findings have implications for inclusion of cancer patients in PD-1/PD-L1 blockade immunotherapies.

PD-L1 expression on malignant cells is no prerequisite for checkpoint therapy

PubMed Central

Marijt, Koen A.; Schoonderwoerd, Mark J. A.; Ossendorp, Ferry; Fransen, Marieke F.

2017-01-01

ABSTRACT Immunotherapy with PD-1/PD-L1-blocking antibodies is clinically effective for several tumor types, but the mechanism is not fully understood. PD-L1 expression on tumor biopsies is generally regarded as an inclusion criterion for this cancer therapy. Here, we describe the PD-L1-blocking therapeutic responses of preclinical tumors in which PD-L1 expression was removed from cancer cells, but not from immune infiltrate. Lack of PD-L1 expression on malignant cells delayed tumor outgrowth in a CD8+ T cell-mediated fashion, showing the importance of this molecule in immune suppression. PD-L1 expression was evident on myeloid-infiltrating cells in the microenvironment of these tumors and targeting stromal PD-L1 with blocking antibody therapy had additional antitumor effect, demonstrating that PD-L1 on both malignant cells and immune cells is involved in the mechanism of immunotherapeutic antibodies. Importantly, comparable results were obtained with PD-1-blocking therapy. These findings have implications for inclusion of cancer patients in PD-1/PD-L1 blockade immunotherapies. PMID:28507803

7 CFR 1210.361 - Personal liability.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 10 2010-01-01 2010-01-01 false Personal liability. 1210.361 Section 1210.361 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING... others, in any way whatsoever to any person for errors in judgment, mistakes, or other acts, either of...

7 CFR 1210.401 - District conventions.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 10 2010-01-01 2010-01-01 false District conventions. 1210.401 Section 1210.401 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING... multi-State districts, no one State shall have nominees for more than three of the four district...

Lack of FasL-mediated killing leads to in vivo tumor promotion in mouse Lewis lung cancer.

PubMed

Lee, J-K; Sayers, T J; Back, T C; Wigginton, J M; Wiltrout, R H

2003-03-01

Lewis lung carcinoma (3LL) cells were constitutively resistant to Fas-mediated apoptosis, but overexpression of Fas on 3LL cells allowed Fas-mediated apoptosis after crosslinking with agonist anti-Fas antibody (Jo2) in vitro. Surprisingly, Fas-overexpressing 3LL cells showed enhanced in vivo tumor progression, whereas no promotion of in vivo tumor growth was observed for dominant negative (DN) Fas-overexpressing 3LL transfectants in which the cytoplasmic death domain was deleted. In addition, the promotion of in vivo tumor growth by Fas-overexpression was reduced in gld (FasL-mutation) mice compared to normal mice. These data indicate that intact Fas/FasL cell signaling is required for the promotion of in vivo tumor growth by Fas overexpression in 3LL cells. In contrast to the efficient Fas-mediated killing induced in vitro by crosslinking with anti-Fas antibody, Fas-overexpressing 3LL cells were resistant in vitro to Fas-mediated apoptosis by activated T cells or transient FasL transfection. These data suggest that agonist anti-Fas antibody and natural FasL can transmit qualitatively different signals, and crosslinking of Fas with natural FasL on 3LL cells does not deliver the expected death signal. Thus, our results demonstrate that in some cases overexpression of Fas can result in a survival advantage for tumor cells in vivo.

16 CFR 1210.12 - Certificate of compliance.

Code of Federal Regulations, 2011 CFR

2011-01-01

... SAFETY STANDARD FOR CIGARETTE LIGHTERS Certification Requirements § 1210.12 Certificate of compliance. (a... Product Safety Standard for Cigarette Lighters (16 CFR 1210),” (2) The name and address of the...

21 CFR 1210.12 - Physical examination of cows.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Physical examination of cows. 1210.12 Section 1210... FEDERAL IMPORT MILK ACT Inspection and Testing § 1210.12 Physical examination of cows. (a) Physical examination of any and all cows in herds producing milk or cream which is to be shipped or transported into...

PD-L1 expression in colorectal cancer defines three subsets of tumor immune microenvironments.

PubMed

Valentini, Anna Maria; Di Pinto, Federica; Cariola, Filomena; Guerra, Vito; Giannelli, Gianluigi; Caruso, Maria Lucia; Pirrelli, Michele

2018-02-02

We investigated the PD-L1 expression in colorectal cancer (CRC) and in its microenvironment. PD-L1 was expressed in neoplastic cells (NCs) and tumor-infiltrating immune cells (IICs). All samples PD-L1+ on NCs were also on IICs. Three types of cancers could be grouped: group A(NCs-/ IICs-); group B (NCs-/ IICs+); group C (NCs+/IICs+). To group A belong tumors characterized by poorly immunogenic competence, poor immune response but massive granulocyte infiltrate, justifying the absence of PD-L1 as an immunoinhibitor receptor. To Group B probably belong more immunogenic CRCs, justifying the strong IICs-mediated immune response, and up-regulation of PD-L1 expression only on IICs. To group C belong CRCs probably characterized by a large amount of tumor neoantigens resulting in a marked infiltration of lymphocytes and PD-L1 upregulation also in NCs. Sixty-three colorectal cancer specimens from a cohort of 61 patients were retrospectively reviewed. Thirty-seven MSS and 26 MSI-H CRCs enrolled in this study. Immunohistochemical staining to PD-L1 was performed by using MAb E1L3N. Our study calls attention to the importance to assess PD-L1 expression in tumor microenvironment also evaluating type and density of infiltrating immune cells to better stratify CRCs with different immunological patterns.

PD-L1 expression in colorectal cancer defines three subsets of tumor immune microenvironments

PubMed Central

Valentini, Anna Maria; Di Pinto, Federica; Cariola, Filomena; Guerra, Vito; Giannelli, Gianluigi; Caruso, Maria Lucia; Pirrelli, Michele

2018-01-01

Objectives We investigated the PD-L1 expression in colorectal cancer (CRC) and in its microenvironment. Results PD-L1 was expressed in neoplastic cells (NCs) and tumor-infiltrating immune cells (IICs). All samples PD-L1+ on NCs were also on IICs. Three types of cancers could be grouped: group A(NCs-/ IICs-); group B (NCs-/ IICs+); group C (NCs+/IICs+). To group A belong tumors characterized by poorly immunogenic competence, poor immune response but massive granulocyte infiltrate, justifying the absence of PD-L1 as an immunoinhibitor receptor. To Group B probably belong more immunogenic CRCs, justifying the strong IICs-mediated immune response, and up-regulation of PD-L1 expression only on IICs. To group C belong CRCs probably characterized by a large amount of tumor neoantigens resulting in a marked infiltration of lymphocytes and PD-L1 upregulation also in NCs. Materials and Methods Sixty-three colorectal cancer specimens from a cohort of 61 patients were retrospectively reviewed. Thirty-seven MSS and 26 MSI-H CRCs enrolled in this study. Immunohistochemical staining to PD-L1 was performed by using MAb E1L3N. Conclusions Our study calls attention to the importance to assess PD-L1 expression in tumor microenvironment also evaluating type and density of infiltrating immune cells to better stratify CRCs with different immunological patterns. PMID:29492219

32 CFR 37.1210 - Advanced research.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 32 National Defense 1 2011-07-01 2011-07-01 false Advanced research. 37.1210 Section 37.1210... research. Research that creates new technology or demonstrates the viability of applying existing technology to new products and processes in a general way. Advanced research is most closely analogous to...

32 CFR 37.1210 - Advanced research.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 32 National Defense 1 2013-07-01 2013-07-01 false Advanced research. 37.1210 Section 37.1210... research. Research that creates new technology or demonstrates the viability of applying existing technology to new products and processes in a general way. Advanced research is most closely analogous to...

32 CFR 37.1210 - Advanced research.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 32 National Defense 1 2010-07-01 2010-07-01 false Advanced research. 37.1210 Section 37.1210... research. Research that creates new technology or demonstrates the viability of applying existing technology to new products and processes in a general way. Advanced research is most closely analogous to...

32 CFR 37.1210 - Advanced research.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 32 National Defense 1 2014-07-01 2014-07-01 false Advanced research. 37.1210 Section 37.1210... research. Research that creates new technology or demonstrates the viability of applying existing technology to new products and processes in a general way. Advanced research is most closely analogous to...

32 CFR 37.1210 - Advanced research.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 32 National Defense 1 2012-07-01 2012-07-01 false Advanced research. 37.1210 Section 37.1210... research. Research that creates new technology or demonstrates the viability of applying existing technology to new products and processes in a general way. Advanced research is most closely analogous to...

21 CFR 1210.13 - Tuberculin test.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Tuberculin test. 1210.13 Section 1210.13 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) REGULATIONS UNDER CERTAIN OTHER ACTS ADMINISTERED BY THE FOOD AND DRUG ADMINISTRATION REGULATIONS UNDER THE FEDERAL...

21 CFR 1210.13 - Tuberculin test.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Tuberculin test. 1210.13 Section 1210.13 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) REGULATIONS UNDER CERTAIN OTHER ACTS ADMINISTERED BY THE FOOD AND DRUG ADMINISTRATION REGULATIONS UNDER THE FEDERAL...

21 CFR 1210.13 - Tuberculin test.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Tuberculin test. 1210.13 Section 1210.13 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) REGULATIONS UNDER CERTAIN OTHER ACTS ADMINISTERED BY THE FOOD AND DRUG ADMINISTRATION REGULATIONS UNDER THE FEDERAL...

[Experimental tumors of the central nervous system: standardisation of a model in rats using the 9L glioma cells].

PubMed

Michailowsky, Custódio; Niura, Flavio Key; do Valle, Angela C; Sonohara, Shigueko; Meneguin, Thales D'Alessandro; Tsanaclis, Ana Maria C

2003-06-01

A number of experimental models have been established during the last decades in order to study tumor biology and the effects of treatment or manipulation of the microenvironment of malignant glial tumors. Even though those models have been well characterised and are, to a certain extent, easily reproducible, there are limitations as to their use and to the interpretation of the results. The aim of this study is to standardize a model of a malignant glial tumor and detect possible events able to modify its development. 9L cells were inoculated intracerebrally in 48 Sprague-Dawley rats; from these, 25 animals were also implanted with a device containing electrodes for the registration of the electroencephalogramm. Animals were daily evaluated by neurologic examination. Twenty four animals developed tumor - 10 animals died either in the immediate pos-operatory period or during evolution; 14 animals did not develop tumor. Macroscopically the tumor was well demarcated from the adjacent brain; by light microscopy the tumor exhibited malignant characteristics as well as extensive infiltration of the brain parenchyma. Diagnosis was that of a malignant astrocytoma. The use of the stereotaxic frame and care to infuse a small volume of liquid containing cells during a period of 120 seconds were the most important procedures to obtain sucess in the model. Additional care should be taken in counting cells in the Neubauer camera and in maintaining cells in constant agitation before injecting the tumor-containing solution. The model here developed was efficient besides being of low cost and of relatively easy execution.

36 CFR 1210.48 - Contract provisions.

Code of Federal Regulations, 2010 CFR

2010-07-01

... instances in which a contractor violates or breaches the contract terms, and provide for such remedial... 36 Parks, Forests, and Public Property 3 2010-07-01 2010-07-01 false Contract provisions. 1210.48... § 1210.48 Contract provisions. The recipient shall include, in addition to provisions to define a sound...

16 CFR 1210.1 - Scope, application, and effective date.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 16 Commercial Practices 2 2010-01-01 2010-01-01 false Scope, application, and effective date. 1210.1 Section 1210.1 Commercial Practices CONSUMER PRODUCT SAFETY COMMISSION CONSUMER PRODUCT SAFETY ACT REGULATIONS SAFETY STANDARD FOR CIGARETTE LIGHTERS Requirements for Child Resistance § 1210.1 Scope...

36 CFR 1210.24 - Program income.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 36 Parks, Forests, and Public Property 3 2010-07-01 2010-07-01 false Program income. 1210.24... Management § 1210.24 Program income. (a) The NHPRC applies the standards set forth in this section in requiring recipient organizations to account for program income related to projects financed in whole or in...

Concordance of anaplastic lymphoma kinase (ALK) gene rearrangements between circulating tumor cells and tumor in non-small cell lung cancer

PubMed Central

Lim, Tony KH; Tan, Daniel Shao-Weng; Chua, Yong Wei; Ang, Mei Kim; Pang, Brendan; Lim, Chwee Teck; Takano, Angela; Lim, Alvin Soon-Tiong; Leong, Man Chun; Lim, Wan-Teck

2016-01-01

Anaplastic lymphoma kinase (ALK) gene rearrangement in non-small cell lung cancer (NSCLC) is routinely evaluated by fluorescent in-situ hybridization (FISH) testing on biopsy tissues. Testing can be challenging however, when suitable tissue samples are unavailable. We examined the relevance of circulating tumor cells (CTC) as a surrogate for biopsy-based FISH testing. We assessed paired tumor and CTC samples from patients with ALK rearranged lung cancer (n = 14), ALK-negative lung cancer (n = 12), and healthy controls (n = 5) to derive discriminant CTC counts, and to compare ALK rearrangement patterns. Blood samples were enriched for CTCs to be used for ALK FISH testing. ALK-positive CTCs counts were higher in ALK-positive NSCLC patients (3–15 cells/1.88 mL of blood) compared with ALK-negative NSCLC patients and healthy donors (0–2 cells/1.88 mL of blood). The latter range was validated as the ‘false positive’ cutoff for ALK FISH testing of CTCs. ALK FISH signal patterns observed on tumor biopsies were recapitulated in CTCs in all cases. Sequential CTC counts in an index case of lung cancer with no evaluable tumor tissue treated with crizotinib showed six, three and eleven ALK-positive CTCs per 1.88 mL blood at baseline, partial response and post-progression time points, respectively. Furthermore, ALK FISH rearrangement suggestive of gene copy number increase was observed in CTCs following progression. Recapitulation of ALK rearrangement patterns in the tumor on CTCs, suggested that CTCs might be used to complement tissue-based ALK testing in NSCLC to guide ALK-targeted therapy when suitable tissue biopsy samples are unavailable for testing. PMID:26993609

Concordance of anaplastic lymphoma kinase (ALK) gene rearrangements between circulating tumor cells and tumor in non-small cell lung cancer.

PubMed

Tan, Chye Ling; Lim, Tse Hui; Lim, Tony Kh; Tan, Daniel Shao-Weng; Chua, Yong Wei; Ang, Mei Kim; Pang, Brendan; Lim, Chwee Teck; Takano, Angela; Lim, Alvin Soon-Tiong; Leong, Man Chun; Lim, Wan-Teck

2016-04-26

Anaplastic lymphoma kinase (ALK) gene rearrangement in non-small cell lung cancer (NSCLC) is routinely evaluated by fluorescent in-situ hybridization (FISH) testing on biopsy tissues. Testing can be challenging however, when suitable tissue samples are unavailable. We examined the relevance of circulating tumor cells (CTC) as a surrogate for biopsy-based FISH testing. We assessed paired tumor and CTC samples from patients with ALK rearranged lung cancer (n = 14), ALK-negative lung cancer (n = 12), and healthy controls (n = 5) to derive discriminant CTC counts, and to compare ALK rearrangement patterns. Blood samples were enriched for CTCs to be used for ALK FISH testing. ALK-positive CTCs counts were higher in ALK-positive NSCLC patients (3-15 cells/1.88 mL of blood) compared with ALK-negative NSCLC patients and healthy donors (0-2 cells/1.88 mL of blood). The latter range was validated as the 'false positive' cutoff for ALK FISH testing of CTCs. ALK FISH signal patterns observed on tumor biopsies were recapitulated in CTCs in all cases. Sequential CTC counts in an index case of lung cancer with no evaluable tumor tissue treated with crizotinib showed six, three and eleven ALK-positive CTCs per 1.88 mL blood at baseline, partial response and post-progression time points, respectively. Furthermore, ALK FISH rearrangement suggestive of gene copy number increase was observed in CTCs following progression. Recapitulation of ALK rearrangement patterns in the tumor on CTCs, suggested that CTCs might be used to complement tissue-based ALK testing in NSCLC to guide ALK-targeted therapy when suitable tissue biopsy samples are unavailable for testing.

Ectopic prolactin secretion from a perivascular epithelioid cell tumor (PEComa).

PubMed

Korytnaya, Evgenia; Liu, Jiayan; Camelo-Piragua, Sandra; Sullivan, Stephen; Auchus, Richard J; Barkan, Ariel

2014-11-01

The diagnosis of ectopic pituitary hormone secretion requires abnormally high circulating hormone levels, absence of a pituitary tumor, and localization of the hormone in question to the extrapituitary malignant neoplasm. No case of a malignant solid tumor producing prolactin has been documented thus far. A 47-year-old woman presented with amenorrhea and galactorrhea of 3-year duration. Serum prolactin ranged from 300 to > 900 ng/mL, and other pituitary and thyroid indices were normal, including testing for macroprolactinemia. Pituitary magnetic resonance imaging revealed a partially empty sella but no tumor. Cabergoline 0.5 mg twice weekly did not affect her prolactinemia (1700 to 1900 ng/mL), and the medication was stopped. In the meantime, she developed abdominal pain, and a computed tomography scan showed a 17 × 13 × 8-cm mass abutting the distal stomach, proximal duodenum, and right colon. After the tumor was excised, her galactorrhea resolved, menstrual periodicity resumed within the first month, and serum prolactin fell to 5 ng/mL. Pathological examination of the excised tumor was consistent with perivascular epithelioid cell tumor. Between 5 and 10% of the tumor cells were strongly positive for prolactin on immunohistochemistry. RT-PCR detected prolactin mRNA in the tumor cell extract, confirming the diagnosis of ectopic prolactin synthesis and secretion. We present the first example of massive and symptomatic hyperprolactinemia due to ectopic prolactin production by a solid extrapituitary mesenchymal tumor confirmed with both mRNA analysis and immunohistochemistry. Ectopic prolactin secretion should be suspected in patients with a prolactin >200 ng/mL and negative sellar MRI.

Single-Cell, Multiplexed Protein Detection of Rare Tumor Cells Based on a Beads-on-Barcode Antibody Microarray.

PubMed

Yang, Liu; Wang, Zhihua; Deng, Yuliang; Li, Yan; Wei, Wei; Shi, Qihui

2016-11-15

Circulating tumor cells (CTCs) shed from tumor sites and represent the molecular characteristics of the tumor. Besides genetic and transcriptional characterization, it is important to profile a panel of proteins with single-cell precision for resolving CTCs' phenotype, organ-of-origin, and drug targets. We describe a new technology that enables profiling multiple protein markers of extraordinarily rare tumor cells at the single-cell level. This technology integrates a microchip consisting of 15000 60 pL-sized microwells and a novel beads-on-barcode antibody microarray (BOBarray). The BOBarray allows for multiplexed protein detection by assigning two independent identifiers (bead size and fluorescent color) of the beads to each protein. Four bead sizes (1.75, 3, 4.5, and 6 μm) and three colors (blue, green, and yellow) are utilized to encode up to 12 different proteins. The miniaturized BOBarray can fit an array of 60 pL-sized microwells that isolate single cells for cell lysis and the subsequent detection of protein markers. An enclosed 60 pL-sized microchamber defines a high concentration of proteins released from lysed single cells, leading to single-cell resolution of protein detection. The protein markers assayed in this study include organ-specific markers and drug targets that help to characterize the organ-of-origin and drug targets of isolated rare tumor cells from blood samples. This new approach enables handling a very small number of cells and achieves single-cell, multiplexed protein detection without loss of rare but clinically important tumor cells.

47 CFR 27.1210 - Remote control operation.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 47 Telecommunication 2 2013-10-01 2013-10-01 false Remote control operation. 27.1210 Section 27.1210 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) COMMON CARRIER SERVICES MISCELLANEOUS WIRELESS COMMUNICATIONS SERVICES Broadband Radio Service and Educational Broadband Service § 27...

47 CFR 27.1210 - Remote control operation.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 47 Telecommunication 2 2010-10-01 2010-10-01 false Remote control operation. 27.1210 Section 27.1210 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) COMMON CARRIER SERVICES MISCELLANEOUS WIRELESS COMMUNICATIONS SERVICES Broadband Radio Service and Educational Broadband Service § 27...

47 CFR 27.1210 - Remote control operation.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 47 Telecommunication 2 2012-10-01 2012-10-01 false Remote control operation. 27.1210 Section 27.1210 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) COMMON CARRIER SERVICES MISCELLANEOUS WIRELESS COMMUNICATIONS SERVICES Broadband Radio Service and Educational Broadband Service § 27...

47 CFR 27.1210 - Remote control operation.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 47 Telecommunication 2 2011-10-01 2011-10-01 false Remote control operation. 27.1210 Section 27.1210 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) COMMON CARRIER SERVICES MISCELLANEOUS WIRELESS COMMUNICATIONS SERVICES Broadband Radio Service and Educational Broadband Service § 27...

47 CFR 27.1210 - Remote control operation.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 47 Telecommunication 2 2014-10-01 2014-10-01 false Remote control operation. 27.1210 Section 27.1210 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) COMMON CARRIER SERVICES MISCELLANEOUS WIRELESS COMMUNICATIONS SERVICES Broadband Radio Service and Educational Broadband Service § 27...

Circulating tumor cells in patients with testicular germ cell tumors.

PubMed

Nastały, Paulina; Ruf, Christian; Becker, Pascal; Bednarz-Knoll, Natalia; Stoupiec, Małgorzata; Kavsur, Refik; Isbarn, Hendrik; Matthies, Cord; Wagner, Walter; Höppner, Dirk; Fisch, Margit; Bokemeyer, Carsten; Ahyai, Sascha; Honecker, Friedemann; Riethdorf, Sabine; Pantel, Klaus

2014-07-15

Germ cell tumors (GCTs) represent the most frequent malignancies among young men, but little is known about circulating tumor cells (CTCs) in these tumors. Considering their heterogeneity, CTCs were investigated using two independent assays targeting germ cell tumor and epithelial cell-specific markers, and results were correlated with disease stage, histology, and serum tumor markers. CTCs were enriched from peripheral blood (n = 143 patients) and testicular vein blood (TVB, n = 19 patients) using Ficoll density gradient centrifugation. For CTC detection, a combination of germ cell tumor (anti-SALL4, anti-OCT3/4) and epithelial cell-specific (anti-keratin, anti-EpCAM) antibodies was used. In parallel, 122 corresponding peripheral blood samples were analyzed using the CellSearch system. In total, CTCs were detected in 25 of 143 (17.5%) peripheral blood samples, whereas only 11.5% of patients were CTC-positive when considering exclusively the CellSearch assay. The presence of CTCs in peripheral blood correlated with clinical stage (P < 0.001) with 41% of CTC positivity in patients with metastasized tumors and 100% in patients with relapsed and chemotherapy-refractory disease. Histologically, CTC-positive patients suffered more frequently from nonseminomatous primary tumors (P < 0.001), with higher percentage of yolk sac (P < 0.001) and teratoma (P = 0.004) components. Furthermore, CTC detection was associated with elevated serum levels of α-fetoprotein (AFP; P = 0.025), β-human chorionic gonadotropin (βHCG; P = 0.002), and lactate dehydrogenase (LDH; P = 0.002). Incidence and numbers of CTCs in TVB were much higher than in peripheral blood. The inclusion of germ cell tumor-specific markers improves CTC detection in GCTs. CTCs occur frequently in patients with more aggressive disease, and there is a gradient of CTCs with decreasing numbers from the tumor-draining vein to the periphery. ©2014 American Association for Cancer Research.

16 CFR § 1210.3 - Requirements for cigarette lighters.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 16 Commercial Practices 2 2013-01-01 2013-01-01 false Requirements for cigarette lighters. § 1210... ACT REGULATIONS SAFETY STANDARD FOR CIGARETTE LIGHTERS Requirements for Child Resistance § 1210.3 Requirements for cigarette lighters. (a) A lighter subject to this part 1210 shall be resistant to successful...

23 CFR 1210.4 - Adoption of zero tolerance law.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 23 Highways 1 2011-04-01 2011-04-01 false Adoption of zero tolerance law. 1210.4 Section 1210.4... TRANSPORTATION GUIDELINES OPERATION OF MOTOR VEHICLES BY INTOXICATED MINORS § 1210.4 Adoption of zero tolerance... that license suspensions or revocations are authorized for any violation of the State zero tolerance...

23 CFR 1210.4 - Adoption of zero tolerance law.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 23 Highways 1 2013-04-01 2013-04-01 false Adoption of zero tolerance law. 1210.4 Section 1210.4... TRANSPORTATION GUIDELINES OPERATION OF MOTOR VEHICLES BY INTOXICATED MINORS § 1210.4 Adoption of zero tolerance... that license suspensions or revocations are authorized for any violation of the State zero tolerance...

23 CFR 1210.4 - Adoption of zero tolerance law.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 23 Highways 1 2012-04-01 2012-04-01 false Adoption of zero tolerance law. 1210.4 Section 1210.4... TRANSPORTATION GUIDELINES OPERATION OF MOTOR VEHICLES BY INTOXICATED MINORS § 1210.4 Adoption of zero tolerance... that license suspensions or revocations are authorized for any violation of the State zero tolerance...

23 CFR 1210.4 - Adoption of zero tolerance law.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 23 Highways 1 2014-04-01 2014-04-01 false Adoption of zero tolerance law. 1210.4 Section 1210.4... TRANSPORTATION GUIDELINES OPERATION OF MOTOR VEHICLES BY INTOXICATED MINORS § 1210.4 Adoption of zero tolerance... that license suspensions or revocations are authorized for any violation of the State zero tolerance...

23 CFR 1210.4 - Adoption of zero tolerance law.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 23 Highways 1 2010-04-01 2010-04-01 false Adoption of zero tolerance law. 1210.4 Section 1210.4... TRANSPORTATION GUIDELINES OPERATION OF MOTOR VEHICLES BY INTOXICATED MINORS § 1210.4 Adoption of zero tolerance... that license suspensions or revocations are authorized for any violation of the State zero tolerance...

21 CFR 1210.13 - Tuberculin test.

Code of Federal Regulations, 2013 CFR

2013-04-01

... IMPORT MILK ACT Inspection and Testing § 1210.13 Tuberculin test. (a) Except as provided in § 1210.27 any and all animals in herds producing milk or cream which is to be shipped or transported raw into the... any event, shall have been made within 1 year previous to the time of the importation. All animals...

Correlation between anti-PD-L1 tumor concentrations and tumor-specific and nonspecific biomarkers in a melanoma mouse model

PubMed Central

Contreras, Ana M.; Merino, María; Vasquez, Marcos; Trocóniz, Iñaki F.

2016-01-01

Blockade of PD-L1 with specific monoclonal antibodies (anti-PD-L1) represents a therapeutic strategy to increase the capability of the immune system to modulate the tumor immune-resistance. The relationship between anti-PD-L1 tumor exposition and anti-tumor effect represents a challenge that has been addressed in this work through the identification of certain biomarkers implicated in the antibody's mechanism of action, using a syngeneic melanoma mouse model. The development of an in-vitro/in-vivo platform has allowed us to investigate the PD-L1 behavior after its blockage with anti-PD-L1 at cellular level and in animals. In-vitro studies showed that the complex PD-L1/anti-PD-L1 was retained mainly at the cell surface. The antibody concentration and time exposure affected directly the recycling or ligand turnover. In-vivo studies showed that anti-PD-L1 was therapeutically active at all stage of the disease, with a rapid onset, a low but durable efficacy and non-relevant toxic effect. This efficacy measured as tumor shrinkage correlated with tumor-specific infiltrating lymphocytes (TILs), which increased as antibody tumor concentrations increased. Both, TILS and antibody concentrations followed similar kinetic patterns, justifying the observed anti-PD-L1 rapid onset. Interestingly, peripheral lymphocytes (PBLs) behave as infiltrating lymphocytes, suggesting that these PBLs might be considered as a possible biomarker for antibody activity. PMID:27764774

Lipocalin-type prostaglandin D synthase-derived PGD2 attenuates malignant properties of tumor endothelial cells.

PubMed

Omori, Keisuke; Morikawa, Teppei; Kunita, Akiko; Nakamura, Tatsuro; Aritake, Kosuke; Urade, Yoshihiro; Fukayama, Masashi; Murata, Takahisa

2018-01-01

Endothelial cells (ECs) are a key component of the tumor microenvironment. They have abnormal characteristics compared to the ECs in normal tissues. Here, we found a marked increase in lipocalin-type prostaglandin D synthase (L-PGDS) mRNA (Ptgds) expression in ECs isolated from mouse melanoma. Immunostaining of mouse melanoma revealed expression of L-PGDS protein in the ECs. In situ hybridization also showed L-PGDS (PTGDS) mRNA expression in the ECs of human melanoma and oral squamous cell carcinoma. In vitro experiments showed that stimulation with tumor cell-derived IL-1 and TNF-α increased L-PGDS mRNA expression and its product prostaglandin D 2 (PGD 2 ) in human normal ECs. We also investigated the contribution of L-PGDS-PGD 2 to tumor growth and vascularization. Systemic or EC-specific deficiency of L-PGDS accelerated the growth of melanoma in mice, whereas treatment with an agonist of the PGD 2 receptor, DP1 (BW245C, 0.1 mg/kg, injected intraperitoneally twice daily), attenuated it. Morphological and in vivo studies showed that endothelial L-PGDS deficiency resulted in functional changes of tumor ECs such as accelerated vascular hyperpermeability, angiogenesis, and endothelial-to-mesenchymal transition (EndMT) in tumors, which in turn reduced tumor cell apoptosis. These observations suggest that tumor cell-derived inflammatory cytokines increase L-PGDS expression and subsequent PGD 2 production in the tumor ECs. This PGD 2 acts as a negative regulator of the tumorigenic changes in tumor ECs. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

[Immunogenicity of L5178Y cells modified by different reagents].

PubMed

Gómez-Estrada, H; López-de la Rosa, L M; Becerril-Meza, G; Arellano-Blanco, J; Fernández-Quintero, P

1977-01-01

Lymphoma L5178Y cells were treated with neuraminidase of Vibrio cholerae, potassium iodine, dithiotreitol (DTT), mercaptoethanol, glutaraldehyde, iodoacetamide, merthiolate, sodium periodate, urea, papaine, trypsine and EDTA, to increase immunoreaction in tumor cells. Mice were immunized with modified tumor cells every week for one month. Thereafter non modified tumor cells were transplanted to previously immunized mice. Only the immunization with neuraminidase-treated cells rejected the tumor. Although the immunization with cells treated with potassium iodine, DTT and mercaptoethanol did not reject tumor, prolonged significantly span of life. The other reactives had neither effect on tumor rejection nor on span of life.

Ovarian tumor-initiating cells display a flexible metabolism

DOE Office of Scientific and Technical Information (OSTI.GOV)

Anderson, Angela S.; Roberts, Paul C.; Frisard, Madlyn I.

2014-10-15

An altered metabolism during ovarian cancer progression allows for increased macromolecular synthesis and unrestrained growth. However, the metabolic phenotype of cancer stem or tumor-initiating cells, small tumor cell populations that are able to recapitulate the original tumor, has not been well characterized. In the present study, we compared the metabolic phenotype of the stem cell enriched cell variant, MOSE-L{sub FFLv} (TIC), derived from mouse ovarian surface epithelial (MOSE) cells, to their parental (MOSE-L) and benign precursor (MOSE-E) cells. TICs exhibit a decrease in glucose and fatty acid oxidation with a concomitant increase in lactate secretion. In contrast to MOSE-L cells,more » TICs can increase their rate of glycolysis to overcome the inhibition of ATP synthase by oligomycin and can increase their oxygen consumption rate to maintain proton motive force when uncoupled, similar to the benign MOSE-E cells. TICs have an increased survival rate under limiting conditions as well as an increased survival rate when treated with AICAR, but exhibit a higher sensitivity to metformin than MOSE-E and MOSE-L cells. Together, our data show that TICs have a distinct metabolic profile that may render them flexible to adapt to the specific conditions of their microenvironment. By better understanding their metabolic phenotype and external environmental conditions that support their survival, treatment interventions can be designed to extend current therapy regimens to eradicate TICs. - Highlights: • Ovarian cancer TICs exhibit a decreased glucose and fatty acid oxidation. • TICs are more glycolytic and have highly active mitochondria. • TICs are more resistant to AICAR but not metformin. • A flexible metabolism allows TICs to adapt to their microenvironment. • This flexibility requires development of specific drugs targeting TIC-specific changes to prevent recurrent TIC outgrowth.« less

A steady-state mechanism can account for the properties of inositol 2,4,5-trisphosphate-stimulated Ca2+ release from permeabilized L1210 cells.

PubMed Central

Loomis-Husselbee, J W; Dawson, A P

1993-01-01

We have investigated the effects of sub-maximal Ins(2,4,5)P3 concentrations on the Ca2+ permeability of the residual undischarged Ca2+ stores in electroporated or digitonin-permeabilized L1210 cells by measuring Ca(2+)-efflux rate after addition of the ATPase inhibitor thapsigargin. Low concentrations of Ins(2,4,5)P3, causing rapid discharge of a small proportion of the releasable Ca2+, result in a substantial stimulation of Ca2+ efflux after thapsigargin addition. This indicates firstly that in the absence of thapsigargin there must have been a substantial, counterbalancing, increase in rate of Ca2+ pumping, and secondly that the increased Ca2+ permeability is more consistent with a steady state than with a quantal model of Ca2+ release. Similar increases in passive Ca2+ permeability are produced by addition of concentrations of ionomycin which produce equivalent changes in Ca2+ loading to those produced by Ins(2,4,5)P3, although the time course and initial rate of Ca2+ release are very much slower. In the presence of a Ca(2+)-buffering system, the time course of Ca2+ release by Ins(2,4,5)P3 becomes superimposable on that of ionomycin, indicating that the initial rapid phase of Ins(2,4,5)P3-stimulated Ca2+ is at least partially due to positive feedback from extravesicular Ca2+. PMID:8382056

Modulation of doxorubicin-induced oxidative stress by a grape (Vitis vinifera L.) seed extract in normal and tumor cells.

PubMed

Postescu, Ion Dan; Chereches, Gabriela; Tatomir, Corina; Daicoviciu, Doina; Filip, Gabriela Adriana

2012-07-01

The major limitation of Doxorubicin (Dox) clinical use is the development of chronic and acute toxic side effects induced through the generation of reactive oxygen species. The present work was designated to investigate in vitro effects of a red grape-seed hydroethanolic extract Burgund Mare (BM), in associated administration with Dox (30 min before drug administration) in normal (Hfl-1) and tumor cell lines (HepG2 and Mls). The BM concentrations administered were below the level of the extract cytotoxiciy threshold (40 μg gallic acid [GA] Eq/mL; 37.5, 25.0, and 12.5 μg GA Eq/mL). The antioxidant capacity of the BM extract was assessed by measuring the acute toxicity at 24 h, lipid peroxides (LP), and protein oxidation. In normal cells, the product statistically decreased cytotoxicity and markedly inhibited LP and protein carbonyl (PC) formation, in a dose-dependent relationship. On contrary, in tumor cells, such treatment resulted in a reversed effect, cell death, malondialdehyde, and PC contents increasing with BM dose enhancement. BM extract treatment prior to subsequent administration of Dox afforded a differential protection against Dox-negative toxic side effects in normal cells without weakening (even enhancing) Dox's antitumor activity.

16 CFR § 1210.12 - Certificate of compliance.

Code of Federal Regulations, 2013 CFR

2013-01-01

... REGULATIONS SAFETY STANDARD FOR CIGARETTE LIGHTERS Certification Requirements § 1210.12 Certificate of... Product Safety Standard for Cigarette Lighters (16 CFR 1210),” (2) The name and address of the...

36 CFR 1210.11 - Pre-award policies.

Code of Federal Regulations, 2012 CFR

2012-07-01

... RULES UNIFORM ADMINISTRATIVE REQUIREMENTS FOR GRANTS AND AGREEMENTS WITH INSTITUTIONS OF HIGHER EDUCATION, HOSPITALS, AND OTHER NON-PROFIT ORGANIZATIONS Pre-Award Requirements § 1210.11 Pre-award policies... 36 Parks, Forests, and Public Property 3 2012-07-01 2012-07-01 false Pre-award policies. 1210.11...

Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition

PubMed Central

Cherkassky, Leonid; Morello, Aurore; Villena-Vargas, Jonathan; Feng, Yang; Dimitrov, Dimiter S.; Jones, David R.; Sadelain, Michel; Adusumilli, Prasad S.

2016-01-01

Following immune attack, solid tumors upregulate coinhibitory ligands that bind to inhibitory receptors on T cells. This adaptive resistance compromises the efficacy of chimeric antigen receptor (CAR) T cell therapies, which redirect T cells to solid tumors. Here, we investigated whether programmed death-1–mediated (PD-1–mediated) T cell exhaustion affects mesothelin-targeted CAR T cells and explored cell-intrinsic strategies to overcome inhibition of CAR T cells. Using an orthotopic mouse model of pleural mesothelioma, we determined that relatively high doses of both CD28- and 4-1BB–based second-generation CAR T cells achieved tumor eradication. CAR-mediated CD28 and 4-1BB costimulation resulted in similar levels of T cell persistence in animals treated with low T cell doses; however, PD-1 upregulation within the tumor microenvironment inhibited T cell function. At lower doses, 4-1BB CAR T cells retained their cytotoxic and cytokine secretion functions longer than CD28 CAR T cells. The prolonged function of 4-1BB CAR T cells correlated with improved survival. PD-1/PD-1 ligand [PD-L1] pathway interference, through PD-1 antibody checkpoint blockade, cell-intrinsic PD-1 shRNA blockade, or a PD-1 dominant negative receptor, restored the effector function of CD28 CAR T cells. These findings provide mechanistic insights into human CAR T cell exhaustion in solid tumors and suggest that PD-1/PD-L1 blockade may be an effective strategy for improving the potency of CAR T cell therapies. PMID:27454297

21 CFR 862.1210 - Creatine test system.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Creatine test system. 862.1210 Section 862.1210 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems § 862...

7 CFR 1210.362 - Influencing government action.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 7 Agriculture 10 2013-01-01 2013-01-01 false Influencing government action. 1210.362 Section 1210.362 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING... government action. No funds received by the Board under this Plan shall in any manner be used for the purpose...

21 CFR 862.1210 - Creatine test system.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Creatine test system. 862.1210 Section 862.1210 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems § 862...

21 CFR 862.1210 - Creatine test system.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Creatine test system. 862.1210 Section 862.1210 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems § 862...

21 CFR 862.1210 - Creatine test system.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Creatine test system. 862.1210 Section 862.1210 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems § 862...

7 CFR 1210.540 - OMB assigned numbers.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 10 2010-01-01 2010-01-01 false OMB assigned numbers. 1210.540 Section 1210.540 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING... Management and Budget (OMB) under the provisions of 44 U.S.C. chapter 35 and have been assigned OMB Control...

42 CFR 493.1210 - Condition: Routine chemistry.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 42 Public Health 5 2010-10-01 2010-10-01 false Condition: Routine chemistry. 493.1210 Section 493....1210 Condition: Routine chemistry. If the laboratory provides services in the subspecialty of Routine chemistry, the laboratory must meet the requirements specified in §§ 493.1230 through 493.1256, § 493.1267...

40 CFR 721.1210 - Benzene, (2-chloroethoxy)-.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Benzene, (2-chloroethoxy)-. 721.1210... Substances § 721.1210 Benzene, (2-chloroethoxy)-. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified as benzene, (2-chloroethoxy)- (PMN P-87-1471) is subject to...

40 CFR 721.1210 - Benzene, (2-chloroethoxy)-.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Benzene, (2-chloroethoxy)-. 721.1210... Substances § 721.1210 Benzene, (2-chloroethoxy)-. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified as benzene, (2-chloroethoxy)- (PMN P-87-1471) is subject to...

40 CFR 721.1210 - Benzene, (2-chloroethoxy)-.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Benzene, (2-chloroethoxy)-. 721.1210... Substances § 721.1210 Benzene, (2-chloroethoxy)-. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified as benzene, (2-chloroethoxy)- (PMN P-87-1471) is subject to...

40 CFR 721.1210 - Benzene, (2-chloroethoxy)-.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Benzene, (2-chloroethoxy)-. 721.1210... Substances § 721.1210 Benzene, (2-chloroethoxy)-. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified as benzene, (2-chloroethoxy)- (PMN P-87-1471) is subject to...

40 CFR 721.1210 - Benzene, (2-chloroethoxy)-.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Benzene, (2-chloroethoxy)-. 721.1210... Substances § 721.1210 Benzene, (2-chloroethoxy)-. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified as benzene, (2-chloroethoxy)- (PMN P-87-1471) is subject to...

42 CFR 493.1210 - Condition: Routine chemistry.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 42 Public Health 5 2013-10-01 2013-10-01 false Condition: Routine chemistry. 493.1210 Section 493....1210 Condition: Routine chemistry. If the laboratory provides services in the subspecialty of Routine chemistry, the laboratory must meet the requirements specified in §§ 493.1230 through 493.1256, § 493.1267...

42 CFR 493.1210 - Condition: Routine chemistry.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 42 Public Health 5 2011-10-01 2011-10-01 false Condition: Routine chemistry. 493.1210 Section 493....1210 Condition: Routine chemistry. If the laboratory provides services in the subspecialty of Routine chemistry, the laboratory must meet the requirements specified in §§ 493.1230 through 493.1256, § 493.1267...

42 CFR 493.1210 - Condition: Routine chemistry.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 42 Public Health 5 2012-10-01 2012-10-01 false Condition: Routine chemistry. 493.1210 Section 493....1210 Condition: Routine chemistry. If the laboratory provides services in the subspecialty of Routine chemistry, the laboratory must meet the requirements specified in §§ 493.1230 through 493.1256, § 493.1267...

42 CFR 493.1210 - Condition: Routine chemistry.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 42 Public Health 5 2014-10-01 2014-10-01 false Condition: Routine chemistry. 493.1210 Section 493....1210 Condition: Routine chemistry. If the laboratory provides services in the subspecialty of Routine chemistry, the laboratory must meet the requirements specified in §§ 493.1230 through 493.1256, § 493.1267...

FasL Mediates T-Cell Eradication of Tumor Cells Presenting Low Levels of Antigens | Center for Cancer Research

Cancer.gov

One approach to cancer immunotherapy, as opposed to therapeutic vaccination, is the transfusion of large numbers of tumor-specific killer T cells (cytotoxic T cells or CTLs) into patients. The body’s own defense killer T cells are a subgroup of T lymphocytes (a type of white blood cells) that are capable of inducing death in tumor cells. CTLs can cause the death of target

Differentiated State of Initiating Tumor Cells Is Key to Distinctive Immune Responses Seen in H-RasG12V-Induced Squamous Tumors.

PubMed

Podolsky, Michael A; Bailey, Jacob T; Gunderson, Andrew J; Oakes, Carrie J; Breech, Kyle; Glick, Adam B

2017-03-01

Heterogeneity in tumor immune responses is a poorly understood yet critical parameter for successful immunotherapy. In two doxycycline-inducible models where oncogenic H-Ras G12V is targeted either to the epidermal basal/stem cell layer with a Keratin14-rtTA transgene (K14Ras), or committed progenitor/suprabasal cells with an Involucrin-tTA transgene (InvRas), we observed strikingly distinct tumor immune responses. On threshold doxycycline levels yielding similar Ras expression, tumor latency, and numbers, tumors from K14Ras mice had an immunosuppressed microenvironment, whereas InvRas tumors had a proinflammatory microenvironment. On a Rag1 -/- background, InvRas mice developed fewer and smaller tumors that regressed over time, whereas K14Ras mice developed more tumors with shorter latency than Rag1 +/+ controls. Adoptive transfer and depletion studies revealed that B-cell and CD4 T-cell cooperation was critical for tumor yield, lymphocyte polarization, and tumor immune phenotype in Rag1 +/+ mice of both models. Coculture of tumor-conditioned B cells with CD4 T cells implicated direct contact for Th1 and regulatory T cell (Treg) polarization, and CD40-CD40L for Th1, Th2, and Treg generation, a response not observed from splenic B cells. Anti-CD40L caused regression of InvRas tumors but enhanced growth in K14Ras, whereas a CD40 agonist mAb had opposite effects in each tumor model. These data show that position of tumor-initiating cells within a stratified squamous epithelial tissue provokes distinct B- and CD4 T-cell interactions, which establish unique tumor microenvironments that regulate tumor development and response to immunotherapy. Cancer Immunol Res; 5(3); 198-210. ©2017 AACR . ©2017 American Association for Cancer Research.

36 CFR 1210.20 - Purpose of financial and program management.

Code of Federal Regulations, 2010 CFR

2010-07-01

... Financial and Program Management § 1210.20 Purpose of financial and program management. Sections 1210.21 through 1210.28 prescribe standards for financial management systems, methods for making payments and... 36 Parks, Forests, and Public Property 3 2010-07-01 2010-07-01 false Purpose of financial and...

36 CFR § 1210.24 - Program income.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 36 Parks, Forests, and Public Property 3 2013-07-01 2012-07-01 true Program income. § 1210.24 Section § 1210.24 Parks, Forests, and Public Property NATIONAL ARCHIVES AND RECORDS ADMINISTRATION.... However, Patent and Trademark Amendments (35 U.S.C. 18) apply to inventions made under an experimental...

Synergistic antineoplastic and cytogenetic effects by the combined action of two homo-aza-steroidal esters of nitrogen mustards on P388 and L1210 leukaemias in vivo and in vitro.

PubMed

Nikolaropoulos, S; Tsavdaridis, D; Arsenou, E; Papageorgiou, A; Karaberis, E; Mourelatos, D

2000-01-01

In order to increase the damaging effects on specific DNA sequences and decrease the subsequent toxicity, the use of homo-aza-steroidal esters of nitrogen mustards is already known. Two specific homo-aza-steroidal esters were mixed at different proportions and the resultant final mixtures were tested in vivo and in vitro. The effects of these on P388 and L1210 leukaemias, on SCE rates and on human lymphocyte proliferation kinetics were studied. The results demonstrate that the combined substances enhanced SCE induction (p < 0.05) and antitumour activity (p < 0.02) in a synergistic manner. A correlation was observed (p < 0.001) between the magnitude of the SCE response and the depression of the cell proliferation index.

Combination of lentivector immunization and low-dose chemotherapy or PD-1/PD-L1 blocking primes self-reactive T cells and induces anti-tumor immunity.

PubMed

Sierro, Sophie R; Donda, Alena; Perret, Rachel; Guillaume, Philippe; Yagita, Hideo; Levy, Frédéric; Romero, Pedro

2011-08-01

In the last two decades, anti-cancer vaccines have yielded disappointing clinical results despite the fact that high numbers of self/tumor-specific T cells can be elicited in immunized patients. Understanding the reasons behind this lack of efficacy is critical in order to design better treatment regimes. Recombinant lentivectors (rLVs) have been successfully used to induce antigen-specific T cells to foreign or mutated tumor antigens. Here, we show that rLV expressing a murine nonmutated self/tumor antigen efficiently primes large numbers of self/tumor-specific CD8(+) T cells. In spite of the large number of tumor-specific T cells, however, no anti-tumor activity could be measured in a therapeutic setting, in mice vaccinated with rLV. Accumulating evidence shows that, in the presence of malignancies, inhibition of T-cell activity may predominate overstimulation. Analysis of tumor-infiltrating lymphocytes revealed that specific anti-tumor CD8(+) T cells fail to produce cytokines and express high levels of inhibitory receptors such as programmed death (PD)-1. Association of active immunization with chemotherapy or antibodies that block inhibitory pathways often leads to better anti-tumor effects. We show here that combining rLV vaccination with either cyclophosphamide or PD-1 and PD-L1 blocking antibodies enhances rLV vaccination efficacy and improves anti-tumor immunity. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

In vivo antitumor activity of 4-amino 4-methyl 2-pentyne 1-al, an inhibitor of aldehyde dehydrogenase.

PubMed

Quemener, V; Quash, G; Moulinoux, J P; Penlap, V; Ripoll, H; Havouis, R; Doutheau, A; Goré, J

1989-01-01

4-amino-4-methyl-2-pentyne-1-al (AMPAL), a new irreversible inhibitor of aldehyde dehydrogenase (ALDH) has been assayed for its in vitro and in vivo antitumor activity. In vitro, AMPAL inhibits the proliferation and the ALDH activity of L1210 and RBL5 cell lines. In vivo, AMPAL significantly increases the mean survival time of mice i.p. grafted with leukemia (L1210, P815, MBL2, EL4, RBL5 cell lines) or carcinoma cells (Krebs cell line), without haematopoetic toxicity. No carcinostatic effect was observed against the P388 leukemia and the 3LL Lewis lung carcinoma. A possible relationship between the ALDH isoenzyme activity of the tumor and its sensitivity to AMPAL is discussed in the light of previous reports concerning the role of aldehydes in cell growth control.

21 CFR 1210.25 - Permits for pasteurized milk or cream.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Permits for pasteurized milk or cream. 1210.25 Section 1210.25 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... UNDER THE FEDERAL IMPORT MILK ACT Permit Control § 1210.25 Permits for pasteurized milk or cream...

21 CFR 1210.25 - Permits for pasteurized milk or cream.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Permits for pasteurized milk or cream. 1210.25 Section 1210.25 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... UNDER THE FEDERAL IMPORT MILK ACT Permit Control § 1210.25 Permits for pasteurized milk or cream...

45 CFR 1210.3-8 - Termination file and Examiner's report.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 45 Public Welfare 4 2012-10-01 2012-10-01 false Termination file and Examiner's report. 1210.3-8 Section 1210.3-8 Public Welfare Regulations Relating to Public Welfare (Continued) CORPORATION FOR NATIONAL AND COMMUNITY SERVICE VISTA TRAINEE DESELECTION AND VOLUNTEER EARLY TERMINATION PROCEDURES VISTA Volunteer Early Termination § 1210.3-8...

7 CFR 1210.505 - Department of Agriculture costs.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 7 Agriculture 10 2013-01-01 2013-01-01 false Department of Agriculture costs. 1210.505 Section 1210.505 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS AND ORDERS; MISCELLANEOUS COMMODITIES), DEPARTMENT OF AGRICULTURE WATERMELON...

7 CFR 1210.505 - Department of Agriculture costs.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 7 Agriculture 10 2012-01-01 2012-01-01 false Department of Agriculture costs. 1210.505 Section 1210.505 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS AND ORDERS; MISCELLANEOUS COMMODITIES), DEPARTMENT OF AGRICULTURE WATERMELON...

7 CFR 1210.505 - Department of Agriculture costs.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 7 Agriculture 10 2011-01-01 2011-01-01 false Department of Agriculture costs. 1210.505 Section 1210.505 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS AND ORDERS; MISCELLANEOUS COMMODITIES), DEPARTMENT OF AGRICULTURE WATERMELON...

7 CFR 1210.505 - Department of Agriculture costs.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 10 2010-01-01 2010-01-01 false Department of Agriculture costs. 1210.505 Section 1210.505 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS AND ORDERS; MISCELLANEOUS COMMODITIES), DEPARTMENT OF AGRICULTURE WATERMELON...

7 CFR 1210.505 - Department of Agriculture costs.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 7 Agriculture 10 2014-01-01 2014-01-01 false Department of Agriculture costs. 1210.505 Section 1210.505 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS AND ORDERS; MISCELLANEOUS COMMODITIES), DEPARTMENT OF AGRICULTURE WATERMELON...

5 CFR 890.1210 - Reconsideration and appeal rights.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 5 Administrative Personnel 2 2013-01-01 2013-01-01 false Reconsideration and appeal rights. 890.1210 Section 890.1210 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES HEALTH BENEFITS PROGRAM Benefits for United States Hostages in Iraq...

5 CFR 890.1210 - Reconsideration and appeal rights.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 5 Administrative Personnel 2 2014-01-01 2014-01-01 false Reconsideration and appeal rights. 890.1210 Section 890.1210 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL EMPLOYEES HEALTH BENEFITS PROGRAM Benefits for United States Hostages in Iraq...

Comprehensive immunohistochemical analysis of tumor microenvironment immune status in esophageal squamous cell carcinoma

PubMed Central

Hatogai, Ken; Kitano, Shigehisa; Fujii, Satoshi; Kojima, Takashi; Daiko, Hiroyuki; Nomura, Shogo; Yoshino, Takayuki; Ohtsu, Atsushi; Takiguchi, Yuichi; Doi, Toshihiko; Ochiai, Atsushi

2016-01-01

Immunotherapy with anti-PD-1 antibody preliminarily showed promising efficacy for treating esophageal squamous cell carcinoma (ESCC). Herein, we used tissue microarrays and immunohistochemically analyzed PD-L1 and various tumor infiltrating immune cells (TIICs) in specimens from 196 ESCC patients who had undergone curative resection without preoperative therapy. PD-L1 expressions in tumor cells (TCs) and TIICs, as well as infiltration of lymphocytes (CD4+, CD8+, FOXP3+, and PD- 1+) and macrophages (CD68+ and CD204+), were evaluated. PD-L1 was expressed in TCs of 18.4% and in TIICs of 83.3% of these patients. PD-L1 expressions in TCs and TIICs were associated with significant infiltration of various TIIC types, especially CD8+ cells. PD-L1 expressions in both TCs and TIICs were significantly associated with favorable overall survival, and combining their levels enhanced prognostic accuracy. Prognostic impacts of PD-L1 expressions in TCs and TIICs, abundant PD-1+ cell infiltration, a high CD8+/FOXP3+ ratio, and the CD8+/CD204+ ratio remained significant after adjusting for clinicopathological factors. In conclusion, PD-L1 expression reflects anti-tumor immunity, and PD-1/PD-L1 expression and the ratio of infiltrating effector to immune suppressor cells have prognostic value. Therapeutic strategies inhibiting the PD-1/PD-L1 signal and immune suppressor cells are anticipated in ESCC patients. PMID:27322149

Proteolysis during Tumor Cell Extravasation In Vitro: Metalloproteinase Involvement across Tumor Cell Types

PubMed Central

Voura, Evelyn B.; English, Jane L.; Yu, Hoi-Ying E.; Ho, Andrew T.; Subarsky, Patrick; Hill, Richard P.; Hojilla, Carlo V.; Khokha, Rama

2013-01-01

To test if proteolysis is involved in tumor cell extravasation, we developed an in vitro model where tumor cells cross an endothelial monolayer cultured on a basement membrane. Using this model we classified the ability of the cells to transmigrate through the endothelial cell barrier onto the underlying matrix, and scored this invasion according to the stage of passage through the endothelium. Metalloproteinase inhibitors reduced tumor cell extravasation by at least 35%. Visualization of protease and cell adhesion molecules by confocal microscopy demonstrated the cell surface localization of MMP-2, MMP-9, MT1-MMP, furin, CD44 and αvβ3, during the process of transendothelial migration. By the addition of inhibitors and bio-modulators we assessed the functional requirement of the aforementioned molecules for efficient migration. Proteolytic digestion occurred at the cell-matrix interface and was most evident during the migratory stage. All of the inhibitors and biomodulators affected the transition of the tumor cells into the migratory stage, highlighting the most prevalent use of proteolysis at this particular step of tumor cell extravasation. These data suggest that a proteolytic interface operates at the tumor cell surface within the tumor-endothelial cell microenvironment. PMID:24194929

Chimeric peptide containing both B and T cells epitope of tumor-associated antigen L6 enhances anti-tumor effects in HLA-A2 transgenic mice.

PubMed

Lin, Su-I; Huang, Ming-Hsi; Chang, Yu-Wen; Chen, I-Hua; Roffler, Steve; Chen, Bing-Mae; Sher, Yuh-Pyng; Liu, Shih-Jen

2016-07-28

Synthetic peptides are attractive for cancer immunotherapy because of their safety and flexibility. In this report, we identified a new B cell epitope of tumor-associated antigen L6 (TAL6) that could induce antibody-dependent cellular cytotoxicity (ADCC) in vivo. We incorporated the B cell epitope with a cytotoxic T lymphocyte (CTL) and a helper T (Th) epitope to form a chimeric long peptide. We formulated the chimeric peptide with different adjuvants to immunize HLA-A2 transgenic mice and evaluate their immunogenicity. The chimeric peptide formulated with an emulsion type nanoparticle (PELC) adjuvant and a toll-like receptor 9 agonist (CpG ODN) (PELC/CpG) induced the greatest ADCC and CTL responses. The induced anti-tumor immunity inhibited the growth of TAL6-positive cancer cells. Moreover, we observed that immunization with the chimeric peptide inhibited cancer cell migration in vitro and metastasis in vivo. These data suggest that a chimeric peptide containing both B and T cell epitopes of TAL6 formulated with PELC/CpG adjuvant is feasible for cancer immunotherapy. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Vaccine of engineered tumor cells secreting stromal cell-derived factor-1 induces T-cell dependent antitumor responses.

PubMed

Shi, Meiqing; Hao, Siguo; Su, Liping; Zhang, Xueshu; Yuan, Jinying; Guo, Xuling; Zheng, Changyu; Xiang, Jim

2005-08-01

The CXC chemokine SDF-1 has been characterized as a T-cell chemoattractant both in vitro and in vivo. To determine whether SDF-1 expression within tumors can influence tumor growth, we transfected an expression vector pCI-SDF-1 for SDF-1 into J558 myeloma cells and tested their ability to form tumors in BALB/c. Production of biologically active SDF-1 (1.2 ng/mL) was detected in the culture supernatants of cells transfected with the expression vector pCI-SDF-1. J558 cells gave rise to a 100% tumor incidence, whereas SDF-1-expressing J558/SDF-1 tumors invariably regressed in BALB/c mice and became infiltrated with CD4(+) and CD8(+) T cells. Regression of the J558/SDF-1 tumors was dependent on both CD4(+) and CD8(+) T-cells. Our data also indicate that TIT cells containing both CD4(+) and CD8(+) T-cells within J558/SDF-1 tumors express the SDF-1 receptor CXCR4, and that SDF-1 specifically chemoattracts these cells in vitro. Furthermore, immunization of mice with engineered J558/SDF-1 cells elicited the most potent protective immunity against 0.5 x 10(6) cells J558 tumor challenge in vivo, compared to immunization with the J558 alone, and this antitumor immunity mediated by J558/SDF-1 tumor cell vaccination in vivo appeared to be dependent on CD8(+) CTL. Thus, SDF-1 has natural adjuvant activities that may augment antitumor responses through their effects on T-cells and thereby could be important in gene transfer immunotherapies for some cancers.

Benign notochordal cell tumors.

PubMed

Martínez Gamarra, C; Bernabéu Taboada, D; Pozo Kreilinger, J J; Tapia Viñé, M

Benign notochordal cell tumors (TBCN) are lesions with notochordal differentiation which affect the axial skeleton. They are characterized by asymptomatic or non-specific symptomatology and are radiologically unnoticed because of their small size, or because they are mistaken with other benign bone lesions, such as vertebral hemangiomas. When they are large, or symptomatic, can be differential diagnosis with metastases, primary bone tumors and chordomas. We present a case of a TBCN in a 50-year-old woman, with a sacral lesion seen in MRI. A CT-guided biopsy was scheduled to analyze the lesion, finding that the tumor was not clearly recognizable on CT, so the anatomical references of MRI were used to select the appropriate plane. The planning of the approach and the radio-pathological correlation were determinant to reach the definitive diagnosis. Copyright © 2017 SERAM. Publicado por Elsevier España, S.L.U. All rights reserved.

The effects of 6-mercaptopurine nucleotide derivatives on the growth and survival of 6-mercaptopurine-sensitive and -resistant cell culture lines.

PubMed

Johnston, H P; Hawley, P; White, S E; Gibson, I; Tidd, D M

1985-04-01

6-Mercaptopurine (MP)-sensitive and -resistant cell culture lines were used to further characterize the apparent ability of MP nucleotide derivatives to overcome resistance to the parent drug. 6-Mercaptopurine-9-beta-D-ribofuranoside 5'-monophosphate [MPRP], bis(6-mercaptopurine-9-beta-D-ribofuranoside)-5', 5"'-monophosphate [bis(MPR)P], bis(O2',O3'-dibutyryl-6-mercaptopurine-9-beta-D-ribofuranoside)-5', 5"'-monophosphate [bis(dibut.MPR)P], and O2',O3'-dibutyryl-6-mercaptopurine-9-beta-D-ribofuranoside 5'-monophosphate [dibut.MPRP] were tested for cytotoxic and/or growth inhibitory effects against MP-resistant sublines of V79 Chinese hamster lung fibroblasts (CH/TG) and L1210 mouse leukaemia cells (L1210/MPR) in which deficiencies of hypoxanthine-guanine phosphoribosyltransferase, and hence drug nucleotide forming capacity were the basis of resistance. L1210/MPR cells were totally resistant to 1 mM 6-mercaptopurine-9-beta-D-ribofuranoside [MPR] and 2 mM MPRP, but were inhibited by high concentrations (greater than 0.25 mM) of bis(MPR)P. These results suggested that bis(MPR)P was taken up by cells as the intact molecule since MPR and MPRP were its extracellular breakdown products. L1210/MPR cells were much more sensitive to the lipophilic bis(dibut.MPR)P derivative which had a predominantly cytotoxic action as judged by trypan blue staining and the ability of treated cells to produce macroscopic colonies in soft agar medium. However, cells killed by bis(dibut.MPR)P did not disintegrate appreciably over periods of up to 10 days. The effects of bis(dibut.MPR)P were probably the result of cellular uptake of the intact molecule. Dibut.MPRP showed minimal ability to inhibit L1210/MPR cells although this compound was a possible breakdown product of bis(dibut.MPR)P and a source of the same extracellular degradation products. The median cell size decreased in L1210/MPR cultures during exposure to both bis(MPR)P and bis(dibut.MPR)P. This effect was elicited more rapidly and

The effects of 6-mercaptopurine nucleotide derivatives on the growth and survival of 6-mercaptopurine-sensitive and -resistant cell culture lines.

PubMed Central

Johnston, H. P.; Hawley, P.; White, S. E.; Gibson, I.; Tidd, D. M.

1985-01-01

6-Mercaptopurine (MP)-sensitive and -resistant cell culture lines were used to further characterize the apparent ability of MP nucleotide derivatives to overcome resistance to the parent drug. 6-Mercaptopurine-9-beta-D-ribofuranoside 5'-monophosphate [MPRP], bis(6-mercaptopurine-9-beta-D-ribofuranoside)-5', 5"'-monophosphate [bis(MPR)P], bis(O2',O3'-dibutyryl-6-mercaptopurine-9-beta-D-ribofuranoside)-5', 5"'-monophosphate [bis(dibut.MPR)P], and O2',O3'-dibutyryl-6-mercaptopurine-9-beta-D-ribofuranoside 5'-monophosphate [dibut.MPRP] were tested for cytotoxic and/or growth inhibitory effects against MP-resistant sublines of V79 Chinese hamster lung fibroblasts (CH/TG) and L1210 mouse leukaemia cells (L1210/MPR) in which deficiencies of hypoxanthine-guanine phosphoribosyltransferase, and hence drug nucleotide forming capacity were the basis of resistance. L1210/MPR cells were totally resistant to 1 mM 6-mercaptopurine-9-beta-D-ribofuranoside [MPR] and 2 mM MPRP, but were inhibited by high concentrations (greater than 0.25 mM) of bis(MPR)P. These results suggested that bis(MPR)P was taken up by cells as the intact molecule since MPR and MPRP were its extracellular breakdown products. L1210/MPR cells were much more sensitive to the lipophilic bis(dibut.MPR)P derivative which had a predominantly cytotoxic action as judged by trypan blue staining and the ability of treated cells to produce macroscopic colonies in soft agar medium. However, cells killed by bis(dibut.MPR)P did not disintegrate appreciably over periods of up to 10 days. The effects of bis(dibut.MPR)P were probably the result of cellular uptake of the intact molecule. Dibut.MPRP showed minimal ability to inhibit L1210/MPR cells although this compound was a possible breakdown product of bis(dibut.MPR)P and a source of the same extracellular degradation products. The median cell size decreased in L1210/MPR cultures during exposure to both bis(MPR)P and bis(dibut.MPR)P. This effect was elicited more rapidly and

The transcription factor Wilms tumor 1 confers resistance in myeloid leukemia cells against the proapoptotic therapeutic agent TRAIL (tumor necrosis factor α-related apoptosis-inducing ligand) by regulating the antiapoptotic protein Bcl-xL.

PubMed

Bansal, Hima; Seifert, Theresea; Bachier, Carlos; Rao, Manjeet; Tomlinson, Gail; Iyer, Swaminathan Padmanabhan; Bansal, Sanjay

2012-09-21

Tumor necrosis factor α-related apoptosis-inducing ligand (TRAIL) is considered a promising cancer therapeutic agent due to its ability to induce apoptosis in a variety of cancer cells, while sparing normal cells. However, many human tumors including acute myeloid leukemia (AML) are partially or completely resistant to monotherapy with TRAIL, limiting its therapeutic utility. Therefore, identification of factors that contribute to TRAIL resistance may facilitate future development of more effective TRAIL-based cancer therapies. Here, we report a previously unknown role for WT1 in mediating TRAIL resistance in leukemia. Knockdown of WT1 with shRNA rendered TRAIL-resistant myeloid leukemia cells sensitive to TRAIL-induced cell death, and re-expression of shRNA-resistant WT1 restored TRAIL resistance. Notably, TRAIL-mediated apoptosis in WT1-silenced cells was largely due to down-regulation of the antiapoptotic protein Bcl-xL. Moreover, WT1 expression strongly correlated with overexpression of Bcl-xL in AML cell lines and blasts from AML patients. Furthermore, we found that WT1 transactivates Bcl-xL by directly binding to its promoter. We previously showed that WT1 is a novel client protein of heat shock protein 90 (Hsp90). Consistent with this, pharmacological inhibition of Hsp90 resulted in reduced WT1 and Bcl-xL expression leading to increased sensitivity of leukemia cells to TRAIL-mediated apoptosis. Collectively, our results suggest that WT1-dependent Bcl-xL overexpression contributes to TRAIL resistance in myeloid leukemias.

Enhancing Antitumor Efficacy of Chimeric Antigen Receptor T Cells Through Constitutive CD40L Expression

PubMed Central

Curran, Kevin J; Seinstra, Beatrijs A; Nikhamin, Yan; Yeh, Raymond; Usachenko, Yelena; van Leeuwen, Dayenne G; Purdon, Terence; Pegram, Hollie J; Brentjens, Renier J

2015-01-01

Adoptive cell therapy with genetically modified T cells expressing a chimeric antigen receptor (CAR) is a promising therapy for patients with B-cell acute lymphoblastic leukemia. However, CAR-modified T cells (CAR T cells) have mostly failed in patients with solid tumors or low-grade B-cell malignancies including chronic lymphocytic leukemia with bulky lymph node involvement. Herein, we enhance the antitumor efficacy of CAR T cells through the constitutive expression of CD40 ligand (CD40L, CD154). T cells genetically modified to constitutively express CD40L (CD40L-modified T cells) demonstrated increased proliferation and secretion of proinflammatory TH1 cytokines. Further, CD40L-modified T cells augmented the immunogenicity of CD40+ tumor cells by the upregulated surface expression of costimulatory molecules (CD80 and CD86), adhesion molecules (CD54, CD58, and CD70), human leukocyte antigen (HLA) molecules (Class I and HLA-DR), and the Fas-death receptor (CD95). Additionally, CD40L-modified T cells induced maturation and secretion of the proinflammatory cytokine interleukin-12 by monocyte-derived dendritic cells. Finally, tumor-targeted CD19-specific CAR/CD40L T cells exhibited increased cytotoxicity against CD40+ tumors and extended the survival of tumor-bearing mice in a xenotransplant model of CD19+ systemic lymphoma. This preclinical data supports the clinical application of CAR T cells additionally modified to constitutively express CD40L with anticipated enhanced antitumor efficacy. PMID:25582824

5 CFR 831.1210 - Annuity rights after a disability annuity terminates.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false Annuity rights after a disability annuity terminates. 831.1210 Section 831.1210 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT Disability Retirement § 831.1210 Annuity rights after a...

5 CFR 831.1210 - Annuity rights after a disability annuity terminates.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Annuity rights after a disability annuity terminates. 831.1210 Section 831.1210 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT Disability Retirement § 831.1210 Annuity rights after a...

45 CFR 156.1210 - Confirmation of HHS payment and collections reports.

Code of Federal Regulations, 2014 CFR

2014-10-01

... reports. 156.1210 Section 156.1210 Public Welfare Department of Health and Human Services REQUIREMENTS RELATING TO HEALTH CARE ACCESS HEALTH INSURANCE ISSUER STANDARDS UNDER THE AFFORDABLE CARE ACT, INCLUDING STANDARDS RELATED TO EXCHANGES Qualified Health Plan Issuer Responsibilities § 156.1210 Confirmation of HHS...

21 CFR 1210.26 - Permits for raw milk or cream.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Permits for raw milk or cream. 1210.26 Section... FEDERAL IMPORT MILK ACT Permit Control § 1210.26 Permits for raw milk or cream. Except as provided in § 1210.27, permits to ship or transport raw milk or cream into the United States will be granted only...

21 CFR 1210.26 - Permits for raw milk or cream.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Permits for raw milk or cream. 1210.26 Section... FEDERAL IMPORT MILK ACT Permit Control § 1210.26 Permits for raw milk or cream. Except as provided in § 1210.27, permits to ship or transport raw milk or cream into the United States will be granted only...

Tumor-infiltrating lymphocyte composition, organization and PD-1/ PD-L1 expression are linked in breast cancer

PubMed Central

Garaud, Soizic; de Wind, Alexandre; Van den Eynden, Gert; Boisson, Anais; Gu-Trantien, Chunyan; Naveaux, Céline; Lodewyckx, Jean-Nicolas; Duvillier, Hugues; Craciun, Ligia; Veys, Isabelle; Larsimont, Denis; Piccart-Gebhart, Martine; Stagg, John; Sotiriou, Christos

2017-01-01

ABSTRACT The clinical relevance of tumor-infiltrating lymphocytes (TIL) in breast cancer (BC) has been clearly established by their demonstrated correlation with long-term positive outcomes. Nevertheless, the relationship between protective immunity, observed in some patients, and critical features of the infiltrate remains unresolved. This study examined TIL density, composition and organization together with PD-1 and PD-L1 expression in freshly collected and paraffin-embedded tissues from 125 patients with invasive primary BC. Tumor and normal breast tissues were analyzed using both flow cytometry and immunohistochemistry. TIL density distribution is a continuum with 25% of tumors identified as TIL-negative at a TIL density equivalent to normal breast tissues. TIL-positive tumors (75%) were equally divided into TIL-intermediate and TIL-high. Tumors had higher mean frequencies of CD4+ T cells and CD19+ B cells and a lower mean frequency of CD8+ T cells compare with normal tissues, increasing the CD4+/CD8+ T-cell ratio. Tertiary lymphoid structures (TLS), principally located in the peri-tumoral stroma, were detected in 60% of tumors and correlated with higher TIL infiltration. PD-1 and PD-L1 expression were also associated with higher TIL densities and TLS. TIL density, TLS and PD-L1 expression were correlated with more aggressive tumor characteristics, including higher proliferation and hormone receptor negativity. Our findings reveal an important relationship between PD-1/PD-L1 expression, increased CD4+ T and B-cell infiltration, TIL density and TLS, suggesting that evaluating not only the extent but also the nature and location of the immune infiltrate should be considered when evaluating antitumor immunity and the potential for benefit from immunotherapies. PMID:28197375

36 CFR 1210.45 - Cost and price analysis.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 36 Parks, Forests, and Public Property 3 2010-07-01 2010-07-01 false Cost and price analysis. 1210.45 Section 1210.45 Parks, Forests, and Public Property NATIONAL ARCHIVES AND RECORDS ADMINISTRATION... in various ways, including the comparison of price quotations submitted, market prices and similar...

40 CFR 60.1210 - What pollutants are regulated by this subpart?

Code of Federal Regulations, 2012 CFR

2012-07-01

... subpart? 60.1210 Section 60.1210 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR... Modification or Reconstruction is Commenced After June 6, 2001 Emission Limits § 60.1210 What pollutants are.... (1) Hydrogen chloride. (2) Nitrogen oxides. (3) Sulfur dioxide. (d) Other. (1) Carbon monoxide. (2...

40 CFR 60.1210 - What pollutants are regulated by this subpart?

Code of Federal Regulations, 2011 CFR

2011-07-01

... subpart? 60.1210 Section 60.1210 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR... Modification or Reconstruction is Commenced After June 6, 2001 Emission Limits § 60.1210 What pollutants are.... (1) Hydrogen chloride. (2) Nitrogen oxides. (3) Sulfur dioxide. (d) Other. (1) Carbon monoxide. (2...

7 CFR 1210.516 - Exemption for organic watermelons.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 10 2010-01-01 2010-01-01 false Exemption for organic watermelons. 1210.516 Section... RESEARCH AND PROMOTION PLAN Rules and Regulations Assessments § 1210.516 Exemption for organic watermelons. (a) A producer who produces only products that are eligible to be labeled as 100 percent organic...

30 CFR 1210.352 - Special forms and reports.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 30 Mineral Resources 3 2012-07-01 2012-07-01 false Special forms and reports. 1210.352 Section 1210.352 Mineral Resources OFFICE OF NATURAL RESOURCES REVENUE, DEPARTMENT OF THE INTERIOR NATURAL... the requirements of the Paperwork Reduction Act of 1980 and other applicable laws. [56 FR 57286, Nov...

30 CFR 1210.352 - Special forms and reports.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 30 Mineral Resources 3 2013-07-01 2013-07-01 false Special forms and reports. 1210.352 Section 1210.352 Mineral Resources OFFICE OF NATURAL RESOURCES REVENUE, DEPARTMENT OF THE INTERIOR NATURAL... the requirements of the Paperwork Reduction Act of 1980 and other applicable laws. [56 FR 57286, Nov...

30 CFR 1210.352 - Special forms and reports.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 30 Mineral Resources 3 2014-07-01 2014-07-01 false Special forms and reports. 1210.352 Section 1210.352 Mineral Resources OFFICE OF NATURAL RESOURCES REVENUE, DEPARTMENT OF THE INTERIOR NATURAL... the requirements of the Paperwork Reduction Act of 1980 and other applicable laws. [56 FR 57286, Nov...

21 CFR 1210.15 - Pasteurization; equipment and methods.

Code of Federal Regulations, 2011 CFR

2011-04-01

... Section 1210.15 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... UNDER THE FEDERAL IMPORT MILK ACT Inspection and Testing § 1210.15 Pasteurization; equipment and methods. All dairy farms and plants at which any milk or cream is pasteurized for shipment or transportation...

21 CFR 1210.15 - Pasteurization; equipment and methods.

Code of Federal Regulations, 2010 CFR

2010-04-01

... Section 1210.15 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... UNDER THE FEDERAL IMPORT MILK ACT Inspection and Testing § 1210.15 Pasteurization; equipment and methods. All dairy farms and plants at which any milk or cream is pasteurized for shipment or transportation...

7 CFR 1210.516 - Exemption for organic watermelons.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 7 Agriculture 10 2013-01-01 2013-01-01 false Exemption for organic watermelons. 1210.516 Section... RESEARCH AND PROMOTION PLAN Rules and Regulations Assessments § 1210.516 Exemption for organic watermelons. (a) A producer who produces only products that are eligible to be labeled as 100 percent organic...

7 CFR 1210.516 - Exemption for organic watermelons.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 7 Agriculture 10 2012-01-01 2012-01-01 false Exemption for organic watermelons. 1210.516 Section... RESEARCH AND PROMOTION PLAN Rules and Regulations Assessments § 1210.516 Exemption for organic watermelons. (a) A producer who produces only products that are eligible to be labeled as 100 percent organic...

7 CFR 1210.516 - Exemption for organic watermelons.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 7 Agriculture 10 2014-01-01 2014-01-01 false Exemption for organic watermelons. 1210.516 Section... RESEARCH AND PROMOTION PLAN Rules and Regulations Assessments § 1210.516 Exemption for organic watermelons. (a) A producer who produces only products that are eligible to be labeled as 100 percent organic...

Diverse solid tumors expressing a restricted epitope of L1-CAM can be targeted by chimeric antigen receptor redirected T lymphocytes.

PubMed

Hong, Hao; Stastny, Michael; Brown, Christine; Chang, Wen-Chung; Ostberg, Julie R; Forman, Stephen J; Jensen, Michael C

2014-01-01

Adhesion molecule L1-CAM (CD171) was originally reported to be overexpressed on neuroblastoma and to play an important role during tumor progression. More recently, it has been shown to be overexpressed on many other solid tumors such as melanoma and carcinomas of the cervix, ovary, bladder, and others. Thus, there has been a growing interest in using this cell-surface molecule as a target for both antibody-based and cellular-based therapy-our group has previously examined the clinical utility of chimeric antigen receptor (CAR)-redirected cytolytic T cells that specifically target the CE7 epitope of L1-CAM on neuroblastoma patients. Here, we sought to determine whether this CE7 epitope is present on other recently identified L1-CAM tumors and whether it too can be targeted by CAR T cells. Our studies demonstrate that a diverse array of human tumor cell lines and primary solid tumors (ovarian, lung, and renal carcinoma, glioblastoma and neuroblastoma) do express the CE7 epitope and can efficiently stimulate CE7-specific CAR-redirected (CE7R) T-cell lytic activity and secretion of proinflamatory cytokines. L1-CAM was also detected on a limited number of normal tissues; however, L1-CAM expressed on normal human monocytes was not bound by the CE7 mAb nor was it targeted by CE7R T cells, suggesting that the CE7 epitope is more tumor restricted and not expressed on all L1-CAM tissues. Overall, the CE7 epitope of L1-CAM on a variety of tumors may be amenable to targeting by CE7R T cells, making it a promising target for adoptive immunotherapy.

18 CFR 12.10 - Reporting safety-related incidents.

Code of Federal Regulations, 2011 CFR

2011-04-01

...-related incidents. 12.10 Section 12.10 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY REGULATIONS UNDER THE FEDERAL POWER ACT SAFETY OF WATER POWER PROJECTS AND... providing a copy of a clipping from a newspaper article, if available. (4) For the purposes of this...

36 CFR 1210.23 - Cost sharing or matching.

Code of Federal Regulations, 2010 CFR

2010-07-01

.... 1210.23 Section 1210.23 Parks, Forests, and Public Property NATIONAL ARCHIVES AND RECORDS... records at the time of donation. (2) The current fair market value. However, when there is sufficient justification, the NHPRC may approve the use of the current fair market value of the donated property, even if...

40 CFR 63.1210 - What are the notification requirements?

Code of Federal Regulations, 2011 CFR

2011-07-01

...? 63.1210 Section 63.1210 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) NATIONAL EMISSION STANDARDS FOR HAZARDOUS AIR POLLUTANTS FOR SOURCE CATEGORIES National Emission Standards for Hazardous Air Pollutants from Hazardous Waste Combustors Notification...

40 CFR 63.1210 - What are the notification requirements?

Code of Federal Regulations, 2010 CFR

2010-07-01

...? 63.1210 Section 63.1210 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) NATIONAL EMISSION STANDARDS FOR HAZARDOUS AIR POLLUTANTS FOR SOURCE CATEGORIES National Emission Standards for Hazardous Air Pollutants from Hazardous Waste Combustors Notification...

Sertoli-Leydig cell tumor

MedlinePlus

Sertoli-stromal cell tumor; Arrhenoblastoma; Androblastoma; Ovarian cancer - Sertoli-Leydig cell tumor ... The Sertoli cells are normally located in the male reproductive glands (the testes). They feed sperm cells. The Leydig cells, also ...

A common deletion in two gamma ray induced rat pulmonary tumor cell lines.

PubMed

Van Klaveren, P; De Bruijne, J; Van der Winden, H; Kal, H B; Bentvelzen, P

1994-01-01

Subtraction hybridization was performed on normal WAG/Rij rat DNA with DNA from a syngeneic Ir-192 induced pulmonary tumor cell line L37. The residual DNA was amplified by means of sequence-independent PCR. This procedure yielded a sequence, of which multiple copies are present in normal rat DNA. In the tumor line L37 two restriction fragments hybridizing with this repeat sequence are lacking. In another Ir-192 induced pulmonary tumor line, L33, one of these fragments was also lacking. This indicates a common deletion in the two tumor lines.

OX40 ligand-transduced tumor cell vaccine synergizes with GM-CSF and requires CD40-Apc signaling to boost the host T cell antitumor response.

PubMed

Gri, Giorgia; Gallo, Elena; Di Carlo, Emma; Musiani, Piero; Colombo, Mario P

2003-01-01

Efficient T cell priming by GM-CSF and CD40 ligand double-transduced C26 murine colon carcinoma is not sufficient to cure metastases in a therapeutic setting. To determine whether a cellular vaccine that interacts directly with both APC and T cells in vivo might be superior, we generated C26 carcinoma cells transduced with the T cell costimulatory molecule OX40 ligand (OX40L) either alone (C26/OX40L) or together with GM-CSF (C26/GM/OX40L), which is known to activate APC. Mice injected with C26/OX40L cells displayed only a delay in tumor growth, while the C26/GM/OX40L tumor regressed in 85% of mice. Tumor rejection required granulocytes, CD4+, CD8+ T cells, and APC-mediated CD40-CD40 ligand cosignaling, but not IFN-gamma or IL-12 as shown using subset-depleted and knockout (KO) mice. CD40KO mice primed with C26/GM/OX40L cells failed to mount a CTL response, and T cells infiltrating the C26/GM/OX40L tumor were OX40 negative, suggesting an impairment in APC-T cell cross-talk in CD40KO mice. Indeed, CD4+ T cell-depleted mice failed to mount any CTL activity against the C26 tumor, while treatment with agonistic mAb to CD40, which acts on APC, bypassed the requirement for CD4+ T cells and restored CTL activation. C26/GM/OX40L cells cured 83% of mice bearing lung metastases, whereas C26/OX40L or C26/GM vaccination cured only 28 and 16% of mice, respectively. These results indicate the synergistic activity of OX40L and GM-CSF in a therapeutic setting.

21 CFR 1210.14 - Sanitary inspection of plants.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 1210.14 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... FEDERAL IMPORT MILK ACT Inspection and Testing § 1210.14 Sanitary inspection of plants. The sanitary conditions of any plant handling milk or cream any part of which is to be shipped or transported into the...

The Transcription Factor Wilms Tumor 1 Confers Resistance in Myeloid Leukemia Cells against the Proapoptotic Therapeutic Agent TRAIL (Tumor Necrosis Factor α-related Apoptosis-inducing Ligand) by Regulating the Antiapoptotic Protein Bcl-xL*

PubMed Central

Bansal, Hima; Seifert, Theresea; Bachier, Carlos; Rao, Manjeet; Tomlinson, Gail; Iyer, Swaminathan Padmanabhan; Bansal, Sanjay

2012-01-01

Tumor necrosis factor α-related apoptosis-inducing ligand (TRAIL) is considered a promising cancer therapeutic agent due to its ability to induce apoptosis in a variety of cancer cells, while sparing normal cells. However, many human tumors including acute myeloid leukemia (AML) are partially or completely resistant to monotherapy with TRAIL, limiting its therapeutic utility. Therefore, identification of factors that contribute to TRAIL resistance may facilitate future development of more effective TRAIL-based cancer therapies. Here, we report a previously unknown role for WT1 in mediating TRAIL resistance in leukemia. Knockdown of WT1 with shRNA rendered TRAIL-resistant myeloid leukemia cells sensitive to TRAIL-induced cell death, and re-expression of shRNA-resistant WT1 restored TRAIL resistance. Notably, TRAIL-mediated apoptosis in WT1-silenced cells was largely due to down-regulation of the antiapoptotic protein Bcl-xL. Moreover, WT1 expression strongly correlated with overexpression of Bcl-xL in AML cell lines and blasts from AML patients. Furthermore, we found that WT1 transactivates Bcl-xL by directly binding to its promoter. We previously showed that WT1 is a novel client protein of heat shock protein 90 (Hsp90). Consistent with this, pharmacological inhibition of Hsp90 resulted in reduced WT1 and Bcl-xL expression leading to increased sensitivity of leukemia cells to TRAIL-mediated apoptosis. Collectively, our results suggest that WT1-dependent Bcl-xL overexpression contributes to TRAIL resistance in myeloid leukemias. PMID:22898820

7 CFR 1210.365 - Effect of termination or amendment.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 10 2010-01-01 2010-01-01 false Effect of termination or amendment. 1210.365 Section 1210.365 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS AND ORDERS; MISCELLANEOUS COMMODITIES), DEPARTMENT OF AGRICULTURE WATERMELON...

21 CFR 1210.14 - Sanitary inspection of plants.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Sanitary inspection of plants. 1210.14 Section... FEDERAL IMPORT MILK ACT Inspection and Testing § 1210.14 Sanitary inspection of plants. The sanitary conditions of any plant handling milk or cream any part of which is to be shipped or transported into the...

21 CFR 1210.14 - Sanitary inspection of plants.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Sanitary inspection of plants. 1210.14 Section... FEDERAL IMPORT MILK ACT Inspection and Testing § 1210.14 Sanitary inspection of plants. The sanitary conditions of any plant handling milk or cream any part of which is to be shipped or transported into the...

21 CFR 1210.14 - Sanitary inspection of plants.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Sanitary inspection of plants. 1210.14 Section... FEDERAL IMPORT MILK ACT Inspection and Testing § 1210.14 Sanitary inspection of plants. The sanitary conditions of any plant handling milk or cream any part of which is to be shipped or transported into the...

21 CFR 1210.14 - Sanitary inspection of plants.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Sanitary inspection of plants. 1210.14 Section... FEDERAL IMPORT MILK ACT Inspection and Testing § 1210.14 Sanitary inspection of plants. The sanitary conditions of any plant handling milk or cream any part of which is to be shipped or transported into the...

Tumor relapse prevented by combining adoptive T cell therapy with Salmonella typhimurium

PubMed Central

Binder, David C.; Arina, Ainhoa; Wen, Frank; Tu, Tony; Zhao, Ming; Hoffman, Robert M.; Wainwright, Derek A.; Schreiber, Hans

2016-01-01

ABSTRACT We recently reported that therapeutic vaccination with live tumor antigen-producing Salmonella typhimurium rescues dysfunctional endogenous T cell responses and eradicates long-established tumors refractory to αCTLA-4 and αPD-L1 checkpoint inhibitor blockade. Here, we show that live intravenously injected or heat-killed (HK) intratumorally injected Salmonella typhimurium, even when not producing tumor antigen, synergize with adoptive T cell therapy to eradicate tumors. These data demonstrate that the combination of adoptive T cell transfer with the injection of live or dead Salmonella typhimurium is a promising approach for cancer treatment. PMID:27471609

Bcl-xL mediates therapeutic resistance of a mesenchymal breast cancer cell subpopulation

PubMed Central

Keitel, Ulrike; Scheel, Andreas; Thomale, Jürgen; Halpape, Rovena; Kaulfuß, Silke; Scheel, Christina; Dobbelstein, Matthias

2014-01-01

The transition from an epithelial to a mesenchymal phenotype (EMT) confers increased invasiveness and clonogenic potential to tumor cells. We used a breast epithelium-derived cell culture model to evaluate the impact of EMT on the cellular sensitivity towards chemotherapeutics and apoptotic stimuli. Cells that had passed through an EMT acquired resistance towards chemotherapeutics and death ligands. Mechanistically, we found that the levels of the apoptosis inhibitor Bcl-xL were strongly enhanced in mesenchymal versus epithelial cells, whereas the pro-apoptotic proteins Bim and Puma were diminished. Clinical samples from breast cancer showed enhanced Bcl-xL staining in cells that had dispersed into the desmoplastic stroma, as compared to cells that were part of large tumor cell aggregates, suggesting increased Bcl-xL expression when cells invade the stroma. Bcl-xL was necessary for apoptotic resistance in mesenchymal cells, and its expression was sufficient to confer such resistance to epithelial cells. To antagonize Bcl-xL, BH3-mimetics were used. They successfully interfered with the proliferation and survival of mesenchymal cells, and also inhibited the growth of xenograft tumors raised from the mesenchymal subpopulation. We conclude that enhanced Bcl-xL levels confer resistance to cells upon EMT, and that Bcl-xL represents a promising target for therapy directed against invasive cancer cells. PMID:25473892

Tumor-Infiltrating Immune Cells Promoting Tumor Invasion and Metastasis: Existing Theories

PubMed Central

Man, Yan-gao; Stojadinovic, Alexander; Mason, Jeffrey; Avital, Itzhak; Bilchik, Anton; Bruecher, Bjoern; Protic, Mladjan; Nissan, Aviram; Izadjoo, Mina; Zhang, Xichen; Jewett, Anahid

2013-01-01

It is a commonly held belief that infiltration of immune cells into tumor tissues and direct physical contact between tumor cells and infiltrated immune cells is associated with physical destructions of the tumor cells, reduction of the tumor burden, and improved clinical prognosis. An increasing number of studies, however, have suggested that aberrant infiltration of immune cells into tumor or normal tissues may promote tumor progression, invasion, and metastasis. Neither the primary reason for these contradictory observations, nor the mechanism for the reported diverse impact of tumor-infiltrating immune cells has been elucidated, making it difficult to judge the clinical implications of infiltration of immune cells within tumor tissues. This mini-review presents several existing hypotheses and models that favor the promoting impact of tumor-infiltrating immune cells on tumor invasion and metastasis, and also analyzes their strength and weakness. PMID:23386907

Genetic tagging of tumor cells with retrovirus vectors: Clonal analysis of tumor growth and metastasis in vivo

DOE Office of Scientific and Technical Information (OSTI.GOV)

Korczak; Robson, I.B.; Lamarche, C.

1988-08-01

Retrovirus vector infection was used to introduce large numbers of unique genetic markers into tumor cell populations for the purpose of analyzing comparative changes in the clonal composition of metastatic versus that of nonmetastatic tumors during their progressive growth in vivo. The cell lines were SP1, a nonmetastatic, aneuploid mouse mammary adenocarcinoma, and SP1HU9L, a metastatic variant of SP1. Cells were infected with ..delta..e..delta..rhoMoTn, a replication-defective retrovirus vector which possesses the dominant selectable neo gene and crippled long terminal repeats. G418/sup r/ colonies were obtained at a frequency of 4 x 10/sup -3/. Southern blot analysis of a number ofmore » clones provided evidence of random and heritable integration of one or two copies of the proviral DNA. Clonal equation of primary tumor growth and the nature of lineage relationships among spontaneous metastases and primary tumors were analyzed by subcutaneously injecting 10/sup 5/ cells from a pooled mixture of 3.6 x 10/sup 2/ G418/sup r/ SP1HU9L or 10/sup 4/ G418/sup r/ SP1 colonies into syngeneic CBA/J mice. The most striking finding was the relative clonal homogeneity of advanced primary tumors; they invariably consisted of a small number (less than 10) of distinct clones despite the fact that hundreds of thousands of uniquely marked clones had been injected.« less

Determination of EGFR mutations in single cells microdissected from enriched lung tumor cells in peripheral blood.

PubMed

Ran, Ran; Li, Longyun; Wang, Mengzhao; Wang, Shulan; Zheng, Zhi; Lin, Peter Ping

2013-09-01

A minimally invasive and repeatable approach for real-time epidermal growth factor receptor (EGFR) mutation surveillance would be highly beneficial for individualized therapy of late stage lung cancer patients whose surgical specimens are often not available. We aim to develop a viable method to detect EGFR mutations in single circulating tumor cells (CTCs). Using a model CTC system of spiked tumor cells in whole blood, we evaluated EGFR mutation determination in single tumor cells enriched from blood. We used magnetic beads labeled with antibody against leukocyte surface antigens to deplete leukocytes and enrich native CTCs independent of epithelial marker expression level. We then used laser cell microdissection (LCM) to isolate individual CTCs, followed by whole-genome amplification of the DNA for exon 19 microdeletion, L858R and T790M mutation detection by PCR sequencing. EGFR mutations were successfully measured in individual spiked tumor cells enriched from 7.5 ml whole blood. Whole-genome amplification provided sufficient DNA for mutation determination at multiple sites. Ninety-five percent of the single CTCs microdissected by LCM (19/20) yielded PCR amplicons for at least one of the three mutation sites. The amplification success rates were 55 % (11/20) for exon 19 deletion, 45 % (9/20) for T790M, and 85 % (17/20) for L858R. Sequencing of the amplicons showed allele dropout in the amplification reactions, but mutations were correctly identified in 80 % of the amplicons. EGFR mutation determination from single captured tumor cells from blood is feasible with the approach described here. However, to overcome allele dropout and to obtain reliable information about the tumor's EGFR status, multiple individual tumor cells should be assayed.

Programmed Death Cell Ligand 1 (PD-L1) Is Associated With Survival in Stage I Non-Small Cell Lung Cancer.

PubMed

Sepesi, Boris; Cuentas, Edwin Parra; Canales, Jaime Rodriguez; Behrens, Carmen; Correa, Arlene M; Vaporciyan, Ara; Weissferdt, Annikka; Kalhor, Neda; Moran, Cesar; Swisher, Stephen; Wistuba, Ignacio

2017-01-01

Programmed cell death ligand (PD-L1) has been studied as a predictive immunotherapy biomarker. We investigated PD-L1 expression in the whole tumor and in tumor-infiltrating macrophages (TIMs) as a prognostic biomarker in surgically resected pathologic stage I non-small cell lung cancer. Pathologic specimen from 113 patients with stage I lung cancer (pT1-2a, N0, M0, tumor size 1-5 cm, 79 adenocarcinoma, 34 squamous cell carcinoma) were analyzed for PD-L1 expression in the tumor and in the TIMs using immunohistochemistry and image analysis. Statistics included recursive partitioning, univariable, multivariable, and Kaplan-Meier analyses. Patients whose tumors expressed <4.7% PD-L1 (N = 87) experienced significantly better overall survival (OS) (P = 0.001) than patients with PD-L1 >4.7% (N = 26). Patients with PD-L1 expression in macrophages <6.3% (N = 24) also experienced significantly better (P = 0.005) OS than patients with >6.3% (N = 89). The best outcomes were observed in patients with low PD-L1 expression in both tumor and macrophages with 5-year OS of 94% (N = 17). Contrarily, patients with high PD-L1 expression in both tumor and macrophages experienced 5-year OS of 20% (N = 19). Low PD-L1 expression in the tumor and in the TIMs was independently associated with survival in multivariable analysis (P = 0.000 and P = 0.030, respectively). Lower PD-L1 % expression in the tumor and in the TIMs seems to be associated with significantly better OS in surgically resected stage I lung cancer. Additional studies are needed to validate PD-L1 as a prognostic biomarker in lung cancer and to study the mechanisms of intratumoral immune response. Copyright © 2017 Elsevier Inc. All rights reserved.

30 CFR 1210.40 - Will ONRR keep the information I provide confidential?

Code of Federal Regulations, 2013 CFR

2013-07-01

... confidential? 1210.40 Section 1210.40 Mineral Resources OFFICE OF NATURAL RESOURCES REVENUE, DEPARTMENT OF THE INTERIOR NATURAL RESOURCES REVENUE FORMS AND REPORTS General Provisions § 1210.40 Will ONRR keep the... to the extent permitted by law as specified at 43 CFR part 2. ...

30 CFR 1210.40 - Will ONRR keep the information I provide confidential?

Code of Federal Regulations, 2014 CFR

2014-07-01

... confidential? 1210.40 Section 1210.40 Mineral Resources OFFICE OF NATURAL RESOURCES REVENUE, DEPARTMENT OF THE INTERIOR NATURAL RESOURCES REVENUE FORMS AND REPORTS General Provisions § 1210.40 Will ONRR keep the... to the extent permitted by law as specified at 43 CFR part 2. ...

30 CFR 1210.40 - Will ONRR keep the information I provide confidential?

Code of Federal Regulations, 2012 CFR

2012-07-01

... confidential? 1210.40 Section 1210.40 Mineral Resources OFFICE OF NATURAL RESOURCES REVENUE, DEPARTMENT OF THE INTERIOR NATURAL RESOURCES REVENUE FORMS AND REPORTS General Provisions § 1210.40 Will ONRR keep the... to the extent permitted by law as specified at 43 CFR part 2. ...

Escape From Tumor Cell Dormancy

DTIC Science & Technology

2011-10-01

addressed using a novel organotypic bioreactor in which tumor cells can be followed for weeks to months, the process of seeding, dormancy and...and Kupffer cells (months 7-24) 3. seed bioreactors with cells (months 1-24) 4. label tumor cells for fluorescence (months 1-6) 5. label tumor... cells for mass reporting (months 3-9) Objective 2: 1. generate liver organ bioreactors for tumor cell seeding (months 3-24) 2. seed organotypic

7 CFR 1210.307 - Handle.

Code of Federal Regulations, 2012 CFR

2012-01-01

... AND ORDERS; MISCELLANEOUS COMMODITIES), DEPARTMENT OF AGRICULTURE WATERMELON RESEARCH AND PROMOTION PLAN Watermelon Research and Promotion Plan Definitions § 1210.307 Handle. Handle means to grade, pack...

7 CFR 1210.307 - Handle.

Code of Federal Regulations, 2014 CFR

2014-01-01

... AND ORDERS; MISCELLANEOUS COMMODITIES), DEPARTMENT OF AGRICULTURE WATERMELON RESEARCH AND PROMOTION PLAN Watermelon Research and Promotion Plan Definitions § 1210.307 Handle. Handle means to grade, pack...

7 CFR 1210.307 - Handle.

Code of Federal Regulations, 2011 CFR

2011-01-01

... AND ORDERS; MISCELLANEOUS COMMODITIES), DEPARTMENT OF AGRICULTURE WATERMELON RESEARCH AND PROMOTION PLAN Watermelon Research and Promotion Plan Definitions § 1210.307 Handle. Handle means to grade, pack...

7 CFR 1210.307 - Handle.

Code of Federal Regulations, 2013 CFR

2013-01-01

... AND ORDERS; MISCELLANEOUS COMMODITIES), DEPARTMENT OF AGRICULTURE WATERMELON RESEARCH AND PROMOTION PLAN Watermelon Research and Promotion Plan Definitions § 1210.307 Handle. Handle means to grade, pack...

Mathematical modeling of tumor-induced immunosuppression by myeloid-derived suppressor cells: Implications for therapeutic targeting strategies.

PubMed

Shariatpanahi, Seyed Peyman; Shariatpanahi, Seyed Pooya; Madjidzadeh, Keivan; Hassan, Moustapha; Abedi-Valugerdi, Manuchehr

2018-04-07

Myeloid-derived suppressor cells (MDSCs) belong to immature myeloid cells that are generated and accumulated during the tumor development. MDSCs strongly suppress the anti-tumor immunity and provide conditions for tumor progression and metastasis. In this study, we present a mathematical model based on ordinary differential equations (ODE) to describe tumor-induced immunosuppression caused by MDSCs. The model consists of four equations and incorporates tumor cells, cytotoxic T cells (CTLs), natural killer (NK) cells and MDSCs. We also provide simulation models that evaluate or predict the effects of anti-MDSC drugs (e.g., l-arginine and 5-Fluorouracil (5-FU)) on the tumor growth and the restoration of anti-tumor immunity. The simulated results obtained using our model were in good agreement with the corresponding experimental findings on the expansion of splenic MDSCs, immunosuppressive effects of these cells at the tumor site and effectiveness of l-arginine and 5-FU on the re-establishment of antitumor immunity. Regarding this latter issue, our predictive simulation results demonstrated that intermittent therapy with low-dose 5-FU alone could eradicate the tumors irrespective of their origins and types. Furthermore, at the time of tumor eradication, the number of CTLs prevailed over that of cancer cells and the number of splenic MDSCs returned to the normal levels. Finally, our predictive simulation results also showed that the addition of l-arginine supplementation to the intermittent 5-FU therapy reduced the time of the tumor eradication and the number of iterations for 5-FU treatment. Thus, the present mathematical model provides important implications for designing new therapeutic strategies that aim to restore antitumor immunity by targeting MDSCs. Copyright © 2018 Elsevier Ltd. All rights reserved.

An Atypical Acidophil Cell Line Tumor Showing Focal Differentiation Toward Both Growth Hormone and Prolactin Cells.

PubMed

Naritaka, Heiji; Kameya, Toru; Sato, Yuichi; Furuhata, Shigeru; Okui, Junichi; Kamiguchi, Yuji; Otani, Mitsuhiro; Toya, Shigeo

1995-01-01

We report a case of giant pituitary adenoma in a child. Computerized tomography (CT) scan revealed a suprasellar extension tumor mass with hydrocephalus. There was no clinical evidence of acromegaly, gigantism, and other hormonal symptoms. Endocrinologic studies showed within normal value of serum growth hormone (GH: 4.2 ng/mL) and slightly increased levels of prolactin (PRL: 78 ng/mL) and other pituitary hormone values were within normal range. On suppression test by bromocryptin, both GH and PRL levels were reduced. Histopathological findings revealed that the tumor consisted of predominantly chromophobic and partly eosinophilic adenoma cells. Immunohistochemical staining detected GH and PRL in a small number of distinctly different adenoma cells, respectively. Nonradioactive in situ hybridization (ISH) also showed GH and PRL mRNA expression in identical immunopositive cells. Electron microscopy (EM) demonstrated adenoma cells with moderate or small numbers of two types of dense granules and without fibrous body which are characteristic of sparsely granulated GH-cell adenomas. The adenoma does not fit into any classification but may be an atypical acidophil cell line tumor showing focal differentiation toward both GH and PRL cells.

Apo2L/TRAIL Inhibits Tumor Growth and Bone Destruction in a Murine Model of Multiple Myeloma

PubMed Central

Labrinidis, Agatha; Diamond, Peter; Martin, Sally; Hay, Shelley; Liapis, Vasilios; Zinonos, Irene; Sims, Natalie A.; Atkins, Gerald J.; Vincent, Cristina; Ponomarev, Vladimir; Findlay, David M.; Zannettino, Andrew C.W.; Evdokiou, Andreas

2017-01-01

Purpose Multiple myeloma is an incurable disease, for which the development of new therapeutic approaches is required. Here, we report on the efficacy of recombinant soluble Apo2L/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to inhibit tumor progression and bone destruction in a xenogeneic model of human multiple myeloma. Experimental Design We established a mouse model of myeloma, in which Apo2L/TRAIL-sensitive RPMI-8226 or KMS-11 cells, tagged with a triple reporter gene construct (NES-HSV-TK/GFP/Luc), were transplanted directly into the tibial marrow cavity of nude mice. Tumor burden was monitored progressively by bioluminescence imaging and the development of myeloma-induced osteolysis was measured using high resolution in vivo micro-computed tomography. Results Tumor burden increased progressively in the tibial marrow cavity of mice transplanted with Apo2L/TRAIL-sensitive RPMI-8226 or KMS-11 cells associated with extensive osteolysis directly in the area of cancer cell transplantation. Treatment of mice with recombinant soluble Apo2L/TRAIL reduced myeloma burden in the bone marrow cavity and significantly protected against myeloma-induced osteolysis. The protective effects of Apo2L/TRAIL treatment on bone were mediated by the direct apoptotic actions of Apo2L/TRAIL on myeloma cells within the bone microenvironment. Conclusions This is the first in vivo study that investigates the efficacy of recombinant Apo2L/TRAIL on myeloma burden within the bone microenvironment and associated myeloma-induced bone destruction. Our findings that recombinant soluble Apo2L/TRAIL reduces myeloma burden within the bone microenvironment and protects the bone from myeloma-induced bone destruction argue against an inhibitory role of osteoprotegerin in Apo2L/TRAIL-induced apoptosis in vivo and highlight the need to clinically evaluate Apo2L/TRAIL in patients with multiple myeloma. PMID:19276263

Tumor stem cells: A new approach for tumor therapy (Review)

PubMed Central

MENG, MIN; ZHAO, XIN-HAN; NING, QIAN; HOU, LEI; XIN, GUO-HONG; LIU, LI-FENG

2012-01-01

Recent studies have demonstrated the existence of a minority of tumor cells possessing the stem cell properties of self-renewal and differentiation in leukemia and several solid tumors. However, these cells do not possess the normal regulatory mechanisms of stem cells. Following transplantation, they are capable of initiating tumorigenesis and are therefore known as ‘tumor stem cells’. Cellular origin analysis of tumor stem cells has resulted in three hypotheses: Embryonal rest hypothesis, anaplasia and maturation arrest. Several signaling pathways which are involved in carcinogenesis, including Wnt/β-catenin, Notch and Oct-4 signaling pathways are crucial in normal stem cell self-renewal decisions, suggesting that breakdown in the regulation of self-renewal may be a key event in the development of tumors. Thus, tumors can be regarded as an abnormal organ in which stem cells have escaped from the normal constraints on self-renewal, thus, leading to abnormally differentiated tumor cells that lose the ability to form tumors. This new model for maligancies has significance for clinical research and treatment. PMID:22844351

Detection of circulating tumor cells harboring a unique ALK rearrangement in ALK-positive non-small-cell lung cancer.

PubMed

Pailler, Emma; Adam, Julien; Barthélémy, Amélie; Oulhen, Marianne; Auger, Nathalie; Valent, Alexander; Borget, Isabelle; Planchard, David; Taylor, Melissa; André, Fabrice; Soria, Jean Charles; Vielh, Philippe; Besse, Benjamin; Farace, Françoise

2013-06-20

The diagnostic test for ALK rearrangement in non-small-cell lung cancer (NSCLC) for crizotinib treatment is currently done on tumor biopsies or fine-needle aspirations. We evaluated whether ALK rearrangement diagnosis could be performed by using circulating tumor cells (CTCs). The presence of an ALK rearrangement was examined in CTCs of 18 ALK-positive and 14 ALK-negative patients by using a filtration enrichment technique and filter-adapted fluorescent in situ hybridization (FA-FISH), a FISH method optimized for filters. ALK-rearrangement patterns were determined in CTCs and compared with those present in tumor biopsies. ALK-rearranged CTCs and tumor specimens were characterized for epithelial (cytokeratins, E-cadherin) and mesenchymal (vimentin, N-cadherin) marker expression. ALK-rearranged CTCs were monitored in five patients treated with crizotinib. All ALK-positive patients had four or more ALK-rearranged CTCs per 1 mL of blood (median, nine CTCs per 1 mL; range, four to 34 CTCs per 1 mL). No or only one ALK-rearranged CTC (median, one per 1 mL; range, zero to one per 1 mL) was detected in ALK-negative patients. ALK-rearranged CTCs harbored a unique (3'5') split pattern, and heterogeneous patterns (3'5', only 3') of splits were present in tumors. ALK-rearranged CTCs expressed a mesenchymal phenotype contrasting with heterogeneous epithelial and mesenchymal marker expressions in tumors. Variations in ALK-rearranged CTC levels were detected in patients being treated with crizotinib. ALK rearrangement can be detected in CTCs of patients with ALK-positive NSCLC by using a filtration technique and FA-FISH, enabling both diagnostic testing and monitoring of crizotinib treatment. Our results suggest that CTCs harboring a unique ALK rearrangement and mesenchymal phenotype may arise from clonal selection of tumor cells that have acquired the potential to drive metastatic progression of ALK-positive NSCLC.

Potentiating action of 5-fluorouracil when used in combination with platinium compounds and cyclophosphamide in treatment of advanced L1210 leukemia.

PubMed

Gale, G R; Atkins, L M; Schwartz, P; Meischen, S J

1978-01-01

Nine new organoplatinum (Pt) compounds, cyclophosphamide (CY), and 5-fluorouracil (FU) were used singly and in combination in treatment of advanced L1210 leukemia in C57BL/6 X DBA/2 hybrid mice. In each experiment the Pt + CY dual combination was minimally supra-additive at the doses chosen. However, eight of the nine Pt + CY + FU combination regimens enhanced markedly the increased life span of treated mice as compared with the corresponding dual Pt + CY combination. Collectively, the cure rate (greater than 60-day survival) was less than 6% with the various Pt + CY combinations, and was increased to over 63% upon inclusion of FU in the regimens.

Reversing drug resistance of soft tumor-repopulating cells by tumor cell-derived chemotherapeutic microparticles

PubMed Central

Ma, Jingwei; Zhang, Yi; Tang, Ke; Zhang, Huafeng; Yin, Xiaonan; Li, Yong; Xu, Pingwei; Sun, Yanling; Ma, Ruihua; Ji, Tiantian; Chen, Junwei; Zhang, Shuang; Zhang, Tianzhen; Luo, Shunqun; Jin, Yang; Luo, Xiuli; Li, Chengyin; Gong, Hongwei; Long, Zhixiong; Lu, Jinzhi; Hu, Zhuowei; Cao, Xuetao; Wang, Ning; Yang, Xiangliang; Huang, Bo

2016-01-01

Developing novel approaches to reverse the drug resistance of tumor-repopulating cells (TRCs) or stem cell-like cancer cells is an urgent clinical need to improve outcomes of cancer patients. Here we show an innovative approach that reverses drug resistance of TRCs using tumor cell-derived microparticles (T-MPs) containing anti-tumor drugs. TRCs, by virtue of being more deformable than differentiated cancer cells, preferentially take up T-MPs that release anti-tumor drugs after entering cells, which in turn lead to death of TRCs. The underlying mechanisms include interfering with drug efflux and promoting nuclear entry of the drugs. Our findings demonstrate the importance of tumor cell softness in uptake of T-MPs and effectiveness of a novel approach in reversing drug resistance of TRCs with promising clinical applications. PMID:27167569

30 CFR 1210.51 - Who must submit royalty reports?

Code of Federal Regulations, 2011 CFR

2011-07-01

... 30 Mineral Resources 3 2011-07-01 2011-07-01 false Who must submit royalty reports? 1210.51 Section 1210.51 Mineral Resources OFFICE OF SURFACE MINING RECLAMATION AND ENFORCEMENT, DEPARTMENT OF THE INTERIOR Natural Resources Revenue FORMS AND REPORTS Royalty Reports-Oil, Gas, and Geothermal Resources...

7 CFR 1210.310 - Fiscal period and marketing year.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 10 2010-01-01 2010-01-01 false Fiscal period and marketing year. 1210.310 Section 1210.310 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS AND ORDERS; MISCELLANEOUS COMMODITIES), DEPARTMENT OF AGRICULTURE WATERMELON RESEARCH AND PROMOTION PLAN Watermelon...

7 CFR 1210.532 - Confidential books, records, and reports.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 7 Agriculture 10 2012-01-01 2012-01-01 false Confidential books, records, and reports. 1210.532... WATERMELON RESEARCH AND PROMOTION PLAN Rules and Regulations Records § 1210.532 Confidential books, records, and reports. All information obtained from the books, records, and reports of handlers and importers...

7 CFR 1210.532 - Confidential books, records, and reports.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 7 Agriculture 10 2014-01-01 2014-01-01 false Confidential books, records, and reports. 1210.532... WATERMELON RESEARCH AND PROMOTION PLAN Rules and Regulations Records § 1210.532 Confidential books, records, and reports. All information obtained from the books, records, and reports of handlers and importers...

7 CFR 1210.532 - Confidential books, records, and reports.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 10 2010-01-01 2010-01-01 false Confidential books, records, and reports. 1210.532... WATERMELON RESEARCH AND PROMOTION PLAN Rules and Regulations Records § 1210.532 Confidential books, records, and reports. All information obtained from the books, records, and reports of handlers and importers...

7 CFR 1210.532 - Confidential books, records, and reports.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 7 Agriculture 10 2011-01-01 2011-01-01 false Confidential books, records, and reports. 1210.532... WATERMELON RESEARCH AND PROMOTION PLAN Rules and Regulations Records § 1210.532 Confidential books, records, and reports. All information obtained from the books, records, and reports of handlers and importers...

7 CFR 1210.532 - Confidential books, records, and reports.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 7 Agriculture 10 2013-01-01 2013-01-01 false Confidential books, records, and reports. 1210.532... WATERMELON RESEARCH AND PROMOTION PLAN Rules and Regulations Records § 1210.532 Confidential books, records, and reports. All information obtained from the books, records, and reports of handlers and importers...

Chimeric antigen receptor T cells secreting anti-PD-L1 antibodies more effectively regress renal cell carcinoma in a humanized mouse model.

PubMed

Suarez, Eloah Rabello; Chang, De Kuan; Sun, Jiusong; Sui, Jianhua; Freeman, Gordon J; Signoretti, Sabina; Zhu, Quan; Marasco, Wayne A

2016-06-07

Advances in the treatment of metastatic clear cell renal cell carcinoma (ccRCC) have led to improved progression-free survival of many patients; however the therapies are toxic, rarely achieve durable long-term complete responses and are not curative. Herein we used a single bicistronic lentiviral vector to develop a new combination immunotherapy that consists of human anti-carbonic anhydrase IX (CAIX)-targeted chimeric antigen receptor (CAR) T cells engineered to secrete human anti-programmed death ligand 1 (PD-L1) antibodies at the tumor site. The local antibody delivery led to marked immune checkpoint blockade. Tumor growth diminished 5 times and tumor weight reduced 50-80% when compared with the anti-CAIX CAR T cells alone in a humanized mice model of ccRCC. The expression of PD-L1 and Ki67 in the tumors decreased and an increase in granzyme B levels was found in CAR T cells. The anti-PD-L1 IgG1 isotype, which is capable of mediating ADCC, was also able to recruit human NK cells to the tumor site in vivo. These armed second-generation CAR T cells empowered to secrete human anti-PD-L1 antibodies in the ccRCC milieu to combat T cell exhaustion is an innovation in this field that should provide renewed potential for CAR T cell immunotherapy of solid tumors where limited efficacy is currently seen.

The tumor suppressor cybL, a component of the respiratory chain, mediates apoptosis induction.

PubMed

Albayrak, Timur; Scherhammer, Volker; Schoenfeld, Nicole; Braziulis, Erik; Mund, Thomas; Bauer, Manuel K A; Scheffler, Immo E; Grimm, Stefan

2003-08-01

A genetic screen was established to clone apoptosis-inducing genes in a high-throughput format. It led to the isolation of several proapoptotic genes whose proteins are localized to mitochondria. One of the isolated genes is cytochrome bL (cybL also known as SDHC, CII-3, or QPs-1), a component of the respiratory chain complex II. It was further investigated because both cybL and another component of complex II, cybS, have recently been identified as tumor suppressor proteins, some of which act by controlling apoptosis. Our studies reveal that cell death induction by cybL expression is concomitant with a transient inhibition of complex II and the generation of reactive oxygen species. Importantly, cells that are constitutively deficient in cybL are resistant to a variety of proapoptotic cytostatic drugs and to the effects of the Fas receptor. Our results therefore identify complex II as a sensor for apoptosis induction and could explain the unexpected observation that complex II is inactivated in tumors.

Intraperitoneal Administration of a Tumor-Associated Antigen SART3, CD40L, and GM-CSF Gene-Loaded Polyplex Micelle Elicits a Vaccine Effect in Mouse Tumor Models

PubMed Central

Furugaki, Kouichi; Cui, Lin; Kunisawa, Yumi; Osada, Kensuke; Shinkai, Kentaro; Tanaka, Masao; Kataoka, Kazunori; Nakano, Kenji

2014-01-01

Polyplex micelles have demonstrated biocompatibility and achieve efficient gene transfection in vivo. Here, we investigated a polyplex micelle encapsulating genes encoding the tumor-associated antigen squamous cell carcinoma antigen recognized by T cells-3 (SART3), adjuvant CD40L, and granulocyte macrophage colony-stimulating factor (GM-CSF) as a DNA vaccine platform in mouse tumor models with different types of major histocompatibility antigen complex (MHC). Intraperitoneally administrated polyplex micelles were predominantly found in the lymph nodes, spleen, and liver. Compared with mock controls, the triple gene vaccine significantly prolonged the survival of mice harboring peritoneal dissemination of CT26 colorectal cancer cells, of which long-term surviving mice showed complete rejection when re-challenged with CT26 tumors. Moreover, the DNA vaccine inhibited the growth and metastasis of subcutaneous CT26 and Lewis lung tumors in BALB/c and C57BL/6 mice, respectively, which represent different MHC haplotypes. The DNA vaccine highly stimulated both cytotoxic T lymphocyte and natural killer cell activities, and increased the infiltration of CD11c+ DCs and CD4+/CD8a+ T cells into tumors. Depletion of CD4+ or CD8a+ T cells by neutralizing antibodies deteriorated the anti-tumor efficacy of the DNA vaccine. In conclusion, a SART3/CD40L+GM-CSF gene-loaded polyplex micelle can be applied as a novel vaccine platform to elicit tumor rejection immunity regardless of the recipient MHC haplotype. PMID:25013909

Tumor specific cytotoxicity of arctigenin isolated from herbal plant Arctium lappa L.

PubMed

Susanti, Siti; Iwasaki, Hironori; Itokazu, Yukiyoshi; Nago, Mariko; Taira, Naoyuki; Saitoh, Seikoh; Oku, Hirosuke

2012-10-01

The effectiveness of cancer chemotherapy is often limited by the toxicity to other tissues in the body. Therefore, the identification of non-toxic chemotherapeutics from herbal medicines remains to be an attractive goal to advance cancer treatments. This study evaluated the cytotoxicity profiles of 364 herbal plant extracts, using various cancer and normal cell lines. The screening found occurrence of A549 (human lung adenocarcinoma) specific cytotoxicity in nine species of herbal plants, especially in the extract of Arctium lappa L. Moreover, purification of the selective cytotoxicity in the extract of Arctium lappa L. resulted in the identification of arctigenin as tumor specific agent that showed cytotoxicity to lung cancer (A549), liver cancer (HepG2) and stomach cancer (KATO III) cells, while no cytotoxicity to several normal cell lines. Arctigenin specifically inhibited the proliferation of cancer cells, which might consequently lead to the induction of apoptosis. In conclusion, this study found that arctigenin was one of cancer specific phytochemicals, and in part responsible for the tumor selective cytotoxicity of the herbal medicine.

Agaritine purified from Agaricus blazei Murrill exerts anti-tumor activity against leukemic cells.

PubMed

Endo, Masahiro; Beppu, Hidehiko; Akiyama, Hidehiko; Wakamatsu, Kazumasa; Ito, Shosuke; Kawamoto, Yasuko; Shimpo, Kan; Sumiya, Toshimitu; Koike, Takaaki; Matsui, Taei

2010-07-01

Mushrooms of the genus Agaricus are a common folk remedy against carcinoma. The active ingredients, polysaccharides and protein-polysaccharide complexes containing beta-glucan, have been isolated and shown to have indirect tumor-suppressing activity via an immunological activation. The diffusible fraction of a hot-water extract of Agaricus blazei Murrill (ABM) powder was fractionated by HPLC based on the anti-tumor activity against leukemic cells in vitro. The structure of the anti-tumor substance was determined by NMR and MS analyses. We purified a tumorcidal substance from the diffusible fraction of ABM and identified it as agaritine, beta-N-(gamma-l(+)-glutamyl)-4-(hydroxymethyl) phenylhydrazine, having a molecular mass of 267 Da. This compound inhibited the proliferation of leukemic cell lines such as U937, MOLT4, HL60 and K562 with IC(50) values of 2.7, 9.4, 13.0, and 16.0 microg/mL, respectively, but showed no significant effect on normal lymphatic cells at concentrations up to 40 microg/mL. Although agaritine has been suspected of having genotoxic or carcinogenic properties, agaritine did not activate the umu gene of Salmonella, which reacts to carcinogens. The results indicate that agaritine from ABM has direct anti-tumor activity against leukemic tumor cells in vitro. This is in contrast to the carcinogenic activity previously ascribed to this compound. Our results also show that this activity is distinct from that of beta-glucan, which indirectly suppresses proliferation of tumor cells. Copyright 2010 Elsevier B.V. All rights reserved.

21 CFR 1210.10 - Availability for examination and inspection.

Code of Federal Regulations, 2011 CFR

2011-04-01

....10 Section 1210.10 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... REGULATIONS UNDER THE FEDERAL IMPORT MILK ACT Inspection and Testing § 1210.10 Availability for examination and inspection. Dairy farms and plants from which milk or cream is shipped or transported into the...

21 CFR 1210.10 - Availability for examination and inspection.

Code of Federal Regulations, 2010 CFR

2010-04-01

....10 Section 1210.10 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... REGULATIONS UNDER THE FEDERAL IMPORT MILK ACT Inspection and Testing § 1210.10 Availability for examination and inspection. Dairy farms and plants from which milk or cream is shipped or transported into the...

36 CFR Appendix A to Part 1210 - Contract Provisions

Code of Federal Regulations, 2011 CFR

2011-07-01

... EDUCATION, HOSPITALS, AND OTHER NON-PROFIT ORGANIZATIONS Pt. 1210, App. A Appendix A to Part 1210—Contract Provisions All contracts, awarded by a recipient including small purchases, shall contain the following... not apply to the purchases of supplies or materials or articles ordinarily available on the open...

Round Cell Tumors: Classification and Immunohistochemistry.

PubMed

Sharma, Shweta; Kamala, R; Nair, Divya; Ragavendra, T Raju; Mhatre, Swapnil; Sabharwal, Robin; Choudhury, Basanta Kumar; Rana, Vivek

2017-01-01

Round cell tumors as the name suggest are comprised round cells with increased nuclear-cytoplasmic ratio. This group of tumor includes entities such as peripheral neuroectodermal tumor, rhabdomyosarcoma, synovial sarcoma, non-Hodgkin's lymphoma, neuroblastoma, hepatoblastoma, Wilms' tumor, and desmoplastic small round cell tumor. These round cells tumors are characterized by typical histological pattern, immunohistochemical, and electron microscopic features that can help in differential diagnosis. The present article describes the classification and explains the histopathology and immunohistochemistry of some important round cell tumors.

16 CFR 1210.11 - General.

Code of Federal Regulations, 2011 CFR

2011-01-01

... CIGARETTE LIGHTERS Certification Requirements § 1210.11 General. Section 14(a) of the Consumer Product... certify that their products comply with the Safety Standard for Cigarette Lighters. This subpart B...

Suppression of NF-κB Survival Signaling by Nitrosylcobalamin Sensitizes Neoplasms to the Anti-tumor Effects of Apo2L/TRAIL*

PubMed Central

Chawla-Sarkar, Mamta; Bauer, Joseph A.; Lupica, Joseph A.; Morrison, Bei H.; Tang, Zhuo; Oates, Rhonda K.; Almasan, Alex; DiDonato, Joseph A.; Borden, Ernest C.; Lindner, Daniel J.

2007-01-01

We have previously demonstrated the anti-tumor activity of nitrosylcobalamin (NO-Cbl), an analog of vitamin B12 that delivers nitric oxide (NO) and increases the expression of tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) and its receptors in human tumors. The specific aim of this study was to examine whether NO-Cbl could sensitize drug-resistant melanomas to Apo2L/TRAIL. Antiproliferative effects of NO-Cbl and Apo2L/TRAIL were assessed in malignant melanomas and non-tumorigenic melanocyte and fibro-blast cell lines. Athymic nude mice bearing human melanoma A375 xenografts were treated with NO-Cbl and Apo2L/TRAIL. Apoptosis was measured by TUNEL and confirmed by examining levels and activity of key mediators of apoptosis. The activation status of NF-κB was established by assaying DNA binding, luciferase reporter activity, the phosphorylation status of IκBα, and in vitro IKK activity. NO-Cbl sensitized Apo2L/TRAIL-resistant melanoma cell lines to growth inhibition by Apo2L/TRAIL but had minimal effect on normal cell lines. NO-Cbl and Apo2L/TRAIL exerted synergistic anti-tumor activity against A375 xenografts. Treatment with NO-Cbl followed by Apo2L/TRAIL induced apoptosis in Apo2L/TRAIL-resistant tumor cells, characterized by cleavage of caspase-3, caspase-8, and PARP. NO-Cbl inhibited IKK activation, characterized by decreased phosphorylation of IκBα and inhibition of NF-κB DNA binding activity. NO-Cbl suppressed Apo2L/TRAIL- and TNF-α-mediated activation of a transfected NF-κB-driven luciferase reporter. XIAP, an inhibitor of apoptosis, was inactivated by NO-Cbl. NO-Cbl treatment rendered Apo2L/TRAIL-resistant malignancies sensitive to the anti-tumor effects of Apo2L/TRAIL in vitro and in vivo. The use of NO-Cbl and Apo2L/TRAIL capitalizes on the tumor-specific properties of both agents and represents a promising anti-cancer combination. PMID:12881518

Assessment of programmed death-ligand 1 expression and tumor-associated immune cells in pediatric cancer tissues.

PubMed

Majzner, Robbie G; Simon, Jason S; Grosso, Joseph F; Martinez, Daniel; Pawel, Bruce R; Santi, Mariarita; Merchant, Melinda S; Geoerger, Birgit; Hezam, Imene; Marty, Virginie; Vielh, Phillippe; Daugaard, Mads; Sorensen, Poul H; Mackall, Crystal L; Maris, John M

2017-10-01

Programmed death 1 (PD-1) signaling in the tumor microenvironment dampens immune responses to cancer, and blocking this axis induces antitumor effects in several malignancies. Clinical studies of PD-1 blockade are only now being initiated in pediatric patients, and little is known regarding programmed death-ligand 1 (PD-L1) expression in common childhood cancers. The authors characterized PD-L1 expression and tumor-associated immune cells (TAICs) (lymphocytes and macrophages) in common pediatric cancers. Whole slide sections and tissue microarrays were evaluated by immunohistochemistry for PD-L1 expression and for the presence of TAICs. TAICs were also screened for PD-L1 expression. Thirty-nine of 451 evaluable tumors (9%) expressed PD-L1 in at least 1% of tumor cells. The highest frequency histotypes comprised Burkitt lymphoma (80%; 8 of 10 tumors), glioblastoma multiforme (36%; 5 of 14 tumors), and neuroblastoma (14%; 17 of 118 tumors). PD-L1 staining was associated with inferior survival among patients with neuroblastoma (P = .004). Seventy-four percent of tumors contained lymphocytes and/or macrophages. Macrophages were significantly more likely to be identified in PD-L1-positive versus PD-L1-negative tumors (P < .001). A subset of diagnostic pediatric cancers exhibit PD-L1 expression, whereas a much larger fraction demonstrates infiltration with tumor-associated lymphocytes. PD-L1 expression may be a biomarker for poor outcome in neuroblastoma. Further preclinical and clinical investigation will define the predictive nature of PD-L1 expression in childhood cancers both at diagnosis and after exposure to chemoradiotherapy. Cancer 2017;123:3807-3815. © 2017 American Cancer Society. © 2017 American Cancer Society.

25 CFR 11.1210 - Duration and renewal of a regular protection order.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 25 Indians 1 2010-04-01 2010-04-01 false Duration and renewal of a regular protection order. 11.1210 Section 11.1210 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR LAW AND ORDER COURTS OF INDIAN OFFENSES AND LAW AND ORDER CODE Child Protection and Domestic Violence Procedures § 11.1210...

20 CFR 418.1210 - What is not a major life-changing event?

Code of Federal Regulations, 2010 CFR

2010-04-01

... 20 Employees' Benefits 2 2010-04-01 2010-04-01 false What is not a major life-changing event? 418.1210 Section 418.1210 Employees' Benefits SOCIAL SECURITY ADMINISTRATION MEDICARE SUBSIDIES Medicare... Adjusted Gross Income § 418.1210 What is not a major life-changing event? We will not consider events other...

25 CFR 11.1210 - Duration and renewal of a regular protection order.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 25 Indians 1 2011-04-01 2011-04-01 false Duration and renewal of a regular protection order. 11.1210 Section 11.1210 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR LAW AND ORDER COURTS OF INDIAN OFFENSES AND LAW AND ORDER CODE Child Protection and Domestic Violence Procedures § 11.1210...

20 CFR 418.1210 - What is not a major life-changing event?

Code of Federal Regulations, 2011 CFR

2011-04-01

... 20 Employees' Benefits 2 2011-04-01 2011-04-01 false What is not a major life-changing event? 418.1210 Section 418.1210 Employees' Benefits SOCIAL SECURITY ADMINISTRATION MEDICARE SUBSIDIES Medicare... Adjusted Gross Income § 418.1210 What is not a major life-changing event? We will not consider events other...

Biodisposition and metabolism of [18F]fluorocholine in 9L glioma cells and 9L glioma-bearing Fisher rats

PubMed Central

Bansal, Aditya; Shuyan, Wang; Hara, Toshiko; Harris, Robert A.; DeGrado, Timothy R.

2008-01-01

Purpose [18F]Fluorocholine [18F]FCH) was developed as an analog of [11C]choline for tumor imaging, however, its metabolic handling remains ill-defined. In this study, the metabolism of [18F]FCH is evaluated in cultured 9L glioma cells and Fisher 344 rats bearing 9L glioma tumors. Methods 9L glioma cells were incubated with [18F]FCH and [14C]choline under normoxic and hypoxic (1% O2) conditions and analyzed for metabolic fate. [18F]FCH and [14C]choline kinetics and metabolism were studied in Fisher 344 rats bearing subcutaneous 9L tumors. Results [18F]FCH and [14C]choline were similarly metabolized in 9L cells in both normoxic and hypoxic conditions over a 2 hr incubation period. In normoxia, radioactivity was predominantly in phosphorylated form for both tracers after 5 min incubation. In hypoxia, the tracers remained mainly in nonmetabolized form at early timepoints (< 20 min). Slow dephosphorylation of intracellular [18F]phosphofluorocholine (0.043–0.060 min−1) and [14C]phosphocholine (0.072–0.088 min−1) was evidenced via efflux measurements. In rat, both [18F]FCH and [14C]choline showed high renal and hepatic uptake. Blood clearance of both tracers was rapid with oxidative metabolites, [18F]fluorobetaine and [14C]betaine, representing the majority of radiolabel in plasma after 5 min post-injection. Oxidation (in liver) and lipid incorporation (in lung) were somewhat slower for [18F]FCH relative to [14C]choline. The majority of radiolabel in hypoxic subcutaneous tumor, as in hypoxic cultured 9L cells, was found as nonmetabolized [18F]FCH and [14C]choline. Conclusions [18F]FCH mimics choline uptake and metabolism by 9L glioma cells and tumors. However, subtle changes in biodistribution, oxidative metabolism, dephosphorylation, lipid incorporation and renal excretion show moderate effects of the presence of the radiofluorine atom in [18F]FCH. The decrease in phosphorylation of exogenous choline by cancer cells should be considered in interpretation of PET

21 CFR 1210.11 - Sanitary inspection of dairy farms.

Code of Federal Regulations, 2011 CFR

2011-04-01

... Section 1210.11 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... UNDER THE FEDERAL IMPORT MILK ACT Inspection and Testing § 1210.11 Sanitary inspection of dairy farms. The sanitary conditions of any dairy farm producing milk or cream to be shipped or transported into...

21 CFR 1210.17 - Authority to sample and inspect.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 1210.17 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... FEDERAL IMPORT MILK ACT Inspection and Testing § 1210.17 Authority to sample and inspect. Inspectors engaged in the enforcement of the Federal Import Milk Act are empowered to test for temperature, to take...

21 CFR 1210.11 - Sanitary inspection of dairy farms.

Code of Federal Regulations, 2010 CFR

2010-04-01

... Section 1210.11 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... UNDER THE FEDERAL IMPORT MILK ACT Inspection and Testing § 1210.11 Sanitary inspection of dairy farms. The sanitary conditions of any dairy farm producing milk or cream to be shipped or transported into...

21 CFR 1210.17 - Authority to sample and inspect.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 1210.17 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... FEDERAL IMPORT MILK ACT Inspection and Testing § 1210.17 Authority to sample and inspect. Inspectors engaged in the enforcement of the Federal Import Milk Act are empowered to test for temperature, to take...

16 CFR 1210.20 - Stockpiling.

Code of Federal Regulations, 2011 CFR

2011-01-01

... STANDARD FOR CIGARETTE LIGHTERS Stockpiling § 1210.20 Stockpiling. (a) Definition. Stockpiling means to... cigarette lighters shall not manufacture or import lighters that do not comply with the requirements of this...

16 CFR 1210.20 - Stockpiling.

Code of Federal Regulations, 2010 CFR

2010-01-01

... STANDARD FOR CIGARETTE LIGHTERS Stockpiling § 1210.20 Stockpiling. (a) Definition. Stockpiling means to... cigarette lighters shall not manufacture or import lighters that do not comply with the requirements of this...

General Information about Pancreatic Neuroendocrine Tumors (Islet Cell Tumors)