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  1. Discovery of ATP-Competitive Inhibitors of tRNAIle Lysidine Synthetase (TilS) by High-Throughput Screening.

    PubMed

    Shapiro, Adam B; Plant, Helen; Walsh, Jarrod; Sylvester, Mark; Hu, Jun; Gao, Ning; Livchak, Stephania; Tentarelli, Sharon; Thresher, Jason

    2014-09-01

    A novel, ultrahigh-throughput, fluorescence anisotropy-based assay was developed and used to screen a 1.4-million-sample library for compounds that compete with adenosine triphosphate (ATP) for binding to Escherichia coli tRNA(Ile) lysidine synthetase (TilS), an essential, conserved, ATP-dependent, tRNA-modifying enzyme of bacterial pathogens. TilS modifies a cytidine base in the anticodon loop of Ile2 tRNA by attaching lysine, thereby altering codon recognition of the CAU anticodon from AUG (methionine) to AUA (isoleucine). A scintillation proximity assay for the incorporation of lysine into Ile2 tRNA was used to eliminate false positives in the initial screen resulting from detection artifacts as well as compounds competitive with the fluorescent label instead of ATP, and to measure inhibitor potencies against E. coli and Pseudomonas aeruginosa TilS isozymes. The tRNA(Ile) substrate for P. aeruginosa TilS was identified for the first time to enable these measurements. ATP-competitive binding of inhibitors was confirmed by one-dimensional ligand-observe nuclear magnetic resonance. A preliminary structure-activity relationship is shown for two inhibitor series.

  2. Evaluation of TILS for use as the orbiter landing NAVAID

    NASA Technical Reports Server (NTRS)

    Tate, J. M.

    1974-01-01

    An evaluation of the tactical instrument landing systems (TILS) for use in the orbiter autoland system was made. It was found that with certain modifications, the TILS can satisfy orbiter autoland requirements. These modifications, include (1) addition of DME equipment, (2) expansion of elevation coverage from 0-10 deg to 0-30 deg, and (3) expansion to redundant systems with associated ground monitors. Additional modifications that are not necessary to meet the orbiter requirements, but that can enhance performance margin are (1) tightening of elevation antenna beam width from 1.3 deg to 0.5 deg and (2) split site configuration to provide azimuth and range coverage through rollout.

  3. Telltale Tumor Infiltrating Lymphocytes (TIL) in Oral, Head & Neck Cancer

    PubMed Central

    Lei, Yu; Xie, Yuying; Tan, Yee Sun; Prince, Mark E.; Moyer, Jeffrey S.; Nör, Jacques; Wolf, Gregory T.

    2017-01-01

    Evidence gleaned from recent studies on the role of tumor-infiltrating lymphocytes (TILs) suggests that cancer is not only a genetic disease but also an immunologic disease. Head and Neck Squamous Cell Carcinoma (HNSCC) has been a significant model to study cancer cell-immune cell interactions. First, immune cell infiltration is an important feature of these tumors. Second, HNSCC frequently develops resistance to immunogenic cytotoxicity, which provides a window to decipher how tumors engage the immune system to establish immune tolerance. Finally, chemoradiation therapy, as a central modality for HNSCC treatment, has been shown to elicit immune activation. The presence of effector immune cells in the tumor microenvironment is often associated with superior clinical response to adjuvant therapy. On the other hand, an activated immune system, in addition to limiting tumor initiation and progression, could also exert selective pressure to promote the growth of less immunogenic tumors, as a pivotal immunoediting process. But it remains unclear how cancer cell signaling regulates tumor immunogenicity and how to mitigate HNSCC-potentiated TIL suppression. In this review, we will revisit the prognostic role of TILs in HNSCC, and collectively discuss how cancer cell machinery impacts upon the plasticity of TILs. PMID:27553942

  4. Expressions of CD8+TILs, PD-L1 and Foxp3+TILs in stage I NSCLC guiding adjuvant chemotherapy decisions

    PubMed Central

    Teng, Feifei; Meng, Xiangjiao; Wang, Xin; Yuan, Jupeng; Liu, Sujing; Mu, Dianbin; Zhu, Hui; Kong, Li; Yu, Jinming

    2016-01-01

    Purpose Currently, adjuvant chemotherapy is recommended for patients with high risk stage I non-small cell lung cancer (NSCLC). However, identifying high risk patients remains a challenge. This study aims to identify the patient cohorts more likely to benefit from adjuvant chemotherapy based on the tumor micro-immune environment. Results CD8+TILs significantly associated with disease-free survival (DFS) and overall survial (OS) (p=0.002; 0.040). Patients with high risk factors may also predict shorter DFS (P=0.056). When compared together, patients with high-CD8+TILs showed better DFS than patients with low-CD8+TILs, no matter their risk factors status. There's no correlation between PD-L1 expressions and survival. PD-L1 was highly expressed in men, squamous and well differentiated carcinoma. In addition, Foxp3+TILs alone didn't show any prognostic effects, but low-Foxp3/high-CD8+TILs were associated with prolonged DFS (p=0.031). Methods A total of 126 patients with surgically resected stage I NSCLC were included to perform immunohistochemistry of CD8+ tumor infiltrating lymphocytes (TILs), programmed death ligand-1(PD-L1) and forkhead box P3 (Foxp3)+TILs. Conclusion CD8+TILs are effective prognostic predictors. Patients with surgically resected stage I NSCLC showing low CD8+TILs could be considered for adjuvant chemotherapy, even if they have no high risk features. PMID:27602763

  5. Hearing in Drosophila Requires TilB, a Conserved Protein Associated With Ciliary Motility

    PubMed Central

    Kavlie, Ryan G.; Kernan, Maurice J.; Eberl, Daniel F.

    2010-01-01

    Cilia were present in the earliest eukaryotic ancestor and underlie many biological processes ranging from cell motility and propulsion of extracellular fluids to sensory physiology. We investigated the contribution of the touch insensitive larva B (tilB) gene to cilia function in Drosophila melanogaster. Mutants of tilB exhibit dysfunction in sperm flagella and ciliated dendrites of chordotonal organs that mediate hearing and larval touch sensitivity. Mutant sperm axonemes as well as sensory neuron dendrites of Johnston's organ, the fly's auditory organ, lack dynein arms. Through deficiency mapping and sequencing candidate genes, we identified tilB mutations in the annotated gene CG14620. A genomic CG14620 transgene rescued deafness and male sterility of tilB mutants. TilB is a 395-amino-acid protein with a conserved N-terminal leucine-rich repeat region at residues 16–164 and a coiled-coil domain at residues 171–191. A tilB-Gal4 transgene driving fluorescently tagged TilB proteins elicits cytoplasmic expression in embryonic chordotonal organs, in Johnston's organ, and in sperm flagella. TilB does not appear to affect tubulin polyglutamylation or polyglycylation. The phenotypes and expression of tilB indicate function in cilia construction or maintenance, but not in intraflagellar transport. This is also consistent with phylogenetic association of tilB homologs with presence of genes encoding axonemal dynein arm components. Further elucidation of tilB functional mechanisms will provide greater understanding of cilia function and will facilitate understanding ciliary diseases. PMID:20215474

  6. The Educational Thought of Cornelius Van Til: Philosophical Foundations of the Contemporary Christian School Movement.

    ERIC Educational Resources Information Center

    Maffet, Gregory J.; Dye, Charles M.

    This paper gives an account of the thoughts of Cornelius Van Til on the contemporary Christian school movement. An account of the historical development of Christian compromise is given, followed by a critique of the compromise among contemporary Christian educators. Van Til claims that any educational position which falls short of being founded…

  7. Adoptive TIL transfer in the adjuvant setting for melanoma: long-term patient survival.

    PubMed

    Khammari, Amir; Knol, Anne-Chantal; Nguyen, Jean-Michel; Bossard, Céline; Denis, Marc-Guillaume; Pandolfino, Marie-Christine; Quéreux, Gaëlle; Bercegeay, Sylvain; Dréno, Brigitte

    2014-01-01

    Two first analyses of our clinical trial on TIL as adjuvant therapy for melanoma were published in 2002 and 2007. We present here an update of the clinical results after a 17-year median followup. In this trial, disease-free patients were randomly assigned to receive either TIL/IL-2 or IL-2. The relapse-free survival (RFS) was the primary objective. Eighty-eight patients were enrolled. A new analysis performed in May 2013 did not show significant changes in RFS or OS duration. However, our first finding on the association between the number of invaded lymph nodes and TIL effectiveness was strengthened. The Cox model adjusted on this interaction showed for the first time a significant treatment effect when considering the overall population, both on the RFS and OS. Patients treated with TIL had a longer RFS (P = 0.023) or OS (P = 0.020). This study being with a very long followup (17 years), confirmed the association between TIL effectiveness and the number of invaded lymph nodes, indicating that a low tumor burden could be a crucial factor enhancing the curative effect of TIL in possible microscopic residual disease. Moreover, we confirmed that a prolonged survival was associated with the presence of specific TIL and a decrease in Foxp3 expression.

  8. Use of Tumor-infiltrating lymphocytes (TILs) to predict the treatment response to eribulin chemotherapy in breast cancer

    PubMed Central

    Kashiwagi, Shinichiro; Goto, Wataru; Takada, Koji; Takahashi, Katsuyuki; Noda, Satoru; Takashima, Tsutomu; Onoda, Naoyoshi; Tomita, Shuhei; Ohsawa, Masahiko; Hirakawa, Kosei

    2017-01-01

    Background Eribulin mesylate (eribulin) is currently indicated for treatment of locally advanced or metastatic breast cancer (MBC). It is a cytotoxic agent with unique mechanisms that suppress epithelial-mesenchymal transition (EMT) of cancer cells. On the other hand, Tumor-infiltrating lymphocytes (TILs), which are considered indicators of immune response monitoring, have been reported as prognostic factors and predictors of therapeutic efficacy. We thought that eribulin, which has an EMT-inhibiting mechanism, may produce an antitumor effect by improving the immune microenvironment, and in this study investigated the effects of breast cancer eribulin chemotherapy on the immune microenvironment with TILs as a marker. Methods TILs was evaluated in 52 patients with MBC who underwent chemotherapy with eribulin. The correlation between TILs evaluated according to the standard method, and prognosis, including the efficacy of eribulin chemotherapy, was investigated retrospectively. Results Of the 52 MBC patients, 29 (55.8%) were in the high TILs group and 23 (44.2%) were in the low TILs group. The high TILs group included significantly more triple-negative breast cancer (TNBC) (p = 0.008) than the low TILs group. In an analysis of outcomes, TNBC patients in the high TILs group had significantly longer disease-free survival than TNBC patients in the low TILs group (p = 0.033, log-rank), but no significant differences were seen in all breast cancer patients (p = 0.489, log-rank) or in non-TNBC patients (p = 0.878, log-rank). In a multivariate analysis of recurrence in TNBC patients, being in the high TILs group was again an independent factor for a good outcome (p = 0.031, HR = 0.063). Conclusion The results of this study suggest that TILs may be useful as a predictive marker of the therapeutic effect of eribulin chemotherapy in TNBC. PMID:28166544

  9. Aircraft borne combined measurements of the Fukushima radionuclide Xe-133 and fossil fuel combustion generated pollutants in the TIL - Implications for Cyclone induced lift and TIL physical-chemical processes

    NASA Astrophysics Data System (ADS)

    Arnold, Frank; Schlager, Hans; Simgen, Hardy; Aufmhoff, Heinfried; Baumann, Robert; Lindemann, Sigfried; Rauch, Ludwig; Kaether, Frank; Pirjolla, Liisa; Schumann, Ulrich

    2013-04-01

    The radionuclide Xe-133, released by the March 2011 nuclear disaster at Fukushima/Daiichi (hereafter FD), represents an ideal tracer for atmospheric transport. We report the, to our best knowledge, only aircraft borne measurements of FD Xe-133 in the Tropopause Inversion Layer (TIL), indicating rapid lift of Xe-133 rich planetary boundary layer air to the TIL. On the same research aircraft (FALCON), we have also conducted on-line measurements of fossil fuel combustion generated pollutant gases (SO2, NOx, HNO3,NOy), which were found to have increased concentrations in the TIL. In addition, we have conducted supporting model simulations of transport, chemical processes, and aerosol processes. Our investigations reveal a potentially important influence of East-Asian cyclone induced pollutants transport to the TIL, particularly influencing aerosol formation in the TIL.

  10. Tumor infiltrating lymphocytes (TILs) improve prognosis in patients with triple negative breast cancer (TNBC).

    PubMed

    Adams, Sylvia; Goldstein, Lori J; Sparano, Joseph A; Demaria, Sandra; Badve, Sunil S

    2015-09-01

    Upon analysis of archived primary tumors of 482 patients with triple negative breast cancer (TNBC) enrolled in two randomized Phase III adjuvant chemotherapy trials, we have found that tumor infiltrating lymphocytes (TILs), as assessed and quantified by hematoxylin and eosin (H&E) staining are a robust and independent predictor of disease-free survival (DFS), distant recurrence-free interval (DRFI) and overall survival (OS).(1) Our findings provide confirmation of results observed in TNBC in a European adjuvant chemotherapy dataset and therefore elevate TILs as prognostic biomarker for operable TNBC to level I evidence.

  11. Evaluation of particulate filtering respirators using inward leakage (IL) or total inward leakage (TIL) testing--Korean experience.

    PubMed

    Han, Don-Hee; Lee, Jinheon

    2005-10-01

    Korean certification regulation for particulate filtering respirators requires inward leakage (IL) or total inward leakage (TIL) testing according to European Standard EN 13274-1, and the standard levels of compliance are similar to those of the European Standard. This study was conducted to evaluate particulate filtering respirators being commercially used in the Korean market using an IL or TIL test and the validity of standard level in Korea. Three half masks and 10 filtering facepieces (two top class, four 1st class and four 2nd class)-a total of 13 brand name respirators-were selected for the test with panels of 10 subjects. Each subject was classified with nine facial dimension grid squares in accordance with face length and lip length. IL or TIL testing was conducted at the laboratory of the 3M Innovation Center in which the experimental instruments and systems were established in compliance with European standards. The testing procedure followed EN 13274-1 (2001). As expected, leakages of half masks were less than those of filtering facepieces and the latter were significantly different among brands. TILs of the 1st class filtering facepieces were found to be much more than those of the 2nd class and the result may cause a wearer to get confused when selecting a mask. The main route leakage for filtering facepieces may not be the filter medium but the face seal. Therefore, it is necessary to develop well-fitting filtering facepieces for Koreans. Because leakages were significantly different for different facial dimensions, a defined test panel for IL or TIL testing according to country or race should be developed. A more precise method to demonstrate fit, for example, fit testing such as in the US regulations, will be needed before IL or TIL testing or when selecting a respirator. Another finding implies that geometric mean of five exercises for IL or TIL may be better than arithmetic mean to establish a standard individual subject mean.

  12. The 1-min Screening Test for Reading Problems in College Students: Psychometric Properties of the 1-min TIL.

    PubMed

    Fernandes, Tânia; Araújo, Susana; Sucena, Ana; Reis, Alexandra; Castro, São Luís

    2017-02-01

    Reading is a central cognitive domain, but little research has been devoted to standardized tests for adults. We, thus, examined the psychometric properties of the 1-min version of Teste de Idade de Leitura (Reading Age Test; 1-min TIL), the Portuguese version of Lobrot L3 test, in three experiments with college students: typical readers in Experiment 1A and B, dyslexic readers and chronological age controls in Experiment 2. In Experiment 1A, test-retest reliability and convergent validity were evaluated in 185 students. Reliability was >.70, and phonological decoding underpinned 1-min TIL. In Experiment 1B, internal consistency was assessed by presenting two 45-s versions of the test to 19 students, and performance in these versions was significantly associated (r = .78). In Experiment 2, construct validity, criterion validity and clinical utility of 1-min TIL were investigated. A multiple regression analysis corroborated construct validity; both phonological decoding and listening comprehension were reliable predictors of 1-min TIL scores. Logistic regression and receiver operating characteristics analyses revealed the high accuracy of this test in distinguishing dyslexic from typical readers. Therefore, the 1-min TIL, which assesses reading comprehension and potential reading difficulties in college students, has the necessary psychometric properties to become a useful screening instrument in neuropsychological assessment and research. Copyright © 2017 John Wiley & Sons, Ltd.

  13. TIL therapy broadens the tumor-reactive CD8(+) T cell compartment in melanoma patients.

    PubMed

    Kvistborg, Pia; Shu, Chengyi Jenny; Heemskerk, Bianca; Fankhauser, Manuel; Thrue, Charlotte Albæk; Toebes, Mireille; van Rooij, Nienke; Linnemann, Carsten; van Buuren, Marit M; Urbanus, Jos H M; Beltman, Joost B; Thor Straten, Per; Li, Yong F; Robbins, Paul F; Besser, Michal J; Schachter, Jacob; Kenter, Gemma G; Dudley, Mark E; Rosenberg, Steven A; Haanen, John B A G; Hadrup, Sine Reker; Schumacher, Ton N M

    2012-07-01

    There is strong evidence that both adoptive T cell transfer and T cell checkpoint blockade can lead to regression of human melanoma. However, little data are available on the effect of these cancer therapies on the tumor-reactive T cell compartment. To address this issue we have profiled therapy-induced T cell reactivity against a panel of 145 melanoma-associated CD8(+) T cell epitopes. Using this approach, we demonstrate that individual tumor-infiltrating lymphocyte cell products from melanoma patients contain unique patterns of reactivity against shared melanoma-associated antigens, and that the combined magnitude of these responses is surprisingly low. Importantly, TIL therapy increases the breadth of the tumor-reactive T cell compartment in vivo, and T cell reactivity observed post-therapy can almost in full be explained by the reactivity observed within the matched cell product. These results establish the value of high-throughput monitoring for the analysis of immuno-active therapeutics and suggest that the clinical efficacy of TIL therapy can be enhanced by the preparation of more defined tumor-reactive T cell products.

  14. TIL therapy broadens the tumor-reactive CD8+ T cell compartment in melanoma patients

    PubMed Central

    Kvistborg, Pia; Shu, Chengyi Jenny; Heemskerk, Bianca; Fankhauser, Manuel; Thrue, Charlotte Albæk; Toebes, Mireille; van Rooij, Nienke; Linnemann, Carsten; van Buuren, Marit M.; Urbanus, Jos H.M.; Beltman, Joost B.; thor Straten, Per; Li, Yong F.; Robbins, Paul F.; Besser, Michal J.; Schachter, Jacob; Kenter, Gemma G.; Dudley, Mark E.; Rosenberg, Steven A.; Haanen, John B.A.G.; Hadrup, Sine Reker; Schumacher, Ton N.M.

    2012-01-01

    There is strong evidence that both adoptive T cell transfer and T cell checkpoint blockade can lead to regression of human melanoma. However, little data are available on the effect of these cancer therapies on the tumor-reactive T cell compartment. To address this issue we have profiled therapy-induced T cell reactivity against a panel of 145 melanoma-associated CD8+ T cell epitopes. Using this approach, we demonstrate that individual tumor-infiltrating lymphocyte cell products from melanoma patients contain unique patterns of reactivity against shared melanoma-associated antigens, and that the combined magnitude of these responses is surprisingly low. Importantly, TIL therapy increases the breadth of the tumor-reactive T cell compartment in vivo, and T cell reactivity observed post-therapy can almost in full be explained by the reactivity observed within the matched cell product. These results establish the value of high-throughput monitoring for the analysis of immuno-active therapeutics and suggest that the clinical efficacy of TIL therapy can be enhanced by the preparation of more defined tumor-reactive T cell products. PMID:22754759

  15. Gene expression analysis of TIL rich HPV-driven head and neck tumors reveals a distinct B-cell signature when compared to HPV independent tumors

    PubMed Central

    Savelyeva, Natalia; McCann, Katy J.; Singh, Divya; Jones, Terry; Peel, Lailah; Breen, Michael S.; Ward, Matthew; Martin, Eva Garrido

    2016-01-01

    Human papilloma virus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) has a better prognosis than it's HPV negative (HPV(−)) counterpart. This may be due to the higher numbers of tumor-infiltrating lymphocytes (TILs) in HPV positive (HPV(+)) tumors. RNA-Sequencing (RNA-Seq) was used to evaluate whether the differences in clinical behaviour simply reflect a numerical difference in TILs or whether there is a fundamental behavioural difference between TILs in these two settings. Thirty-nine HNSCC tumors were scored for TIL density by immunohistochemistry. After the removal of 16 TILlow tumors, RNA-Seq analysis was performed on 23 TILhigh/med tumors (HPV(+) n=10 and HPV(−) n=13). Using EdgeR, differentially expressed genes (DEG) were identified. Immune subset analysis was performed using Functional Analysis of Individual RNA-Seq/ Microarray Expression (FAIME) and immune gene RNA transcript count analysis. In total, 1,634 DEGs were identified, with a dominant immune signature observed in HPV(+) tumors. After normalizing the expression profiles to account for differences in B- and T-cell number, 437 significantly DEGs remained. A B-cell associated signature distinguished HPV(+) from HPV(−) tumors, and included the DEGs CD200, GGA2, ADAM28, STAG3, SPIB, VCAM1, BCL2 and ICOSLG; the immune signal relative to T-cells was qualitatively similar between TILs of both tumor cohorts. Our findings were validated and confirmed in two independent cohorts using TCGA data and tumor-infiltrating B-cells from additional HPV(+) HNSCC patients. A B-cell associated signal segregated tumors relative to HPV status. Our data suggests that the role of B-cells in the adaptive immune response to HPV(+) HNSCC requires re-assessment. PMID:27462861

  16. Gene expression analysis of TIL rich HPV-driven head and neck tumors reveals a distinct B-cell signature when compared to HPV independent tumors.

    PubMed

    Wood, Oliver; Woo, Jeongmin; Seumois, Gregory; Savelyeva, Natalia; McCann, Katy J; Singh, Divya; Jones, Terry; Peel, Lailah; Breen, Michael S; Ward, Matthew; Garrido Martin, Eva; Sanchez-Elsner, Tilman; Thomas, Gareth; Vijayanand, Pandurangan; Woelk, Christopher H; King, Emma; Ottensmeier, Christian

    2016-08-30

    Human papilloma virus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) has a better prognosis than it's HPV negative (HPV(-)) counterpart. This may be due to the higher numbers of tumor-infiltrating lymphocytes (TILs) in HPV positive (HPV(+)) tumors. RNA-Sequencing (RNA-Seq) was used to evaluate whether the differences in clinical behaviour simply reflect a numerical difference in TILs or whether there is a fundamental behavioural difference between TILs in these two settings. Thirty-nine HNSCC tumors were scored for TIL density by immunohistochemistry. After the removal of 16 TILlow tumors, RNA-Seq analysis was performed on 23 TILhigh/med tumors (HPV(+) n=10 and HPV(-) n=13). Using EdgeR, differentially expressed genes (DEG) were identified. Immune subset analysis was performed using Functional Analysis of Individual RNA-Seq/ Microarray Expression (FAIME) and immune gene RNA transcript count analysis. In total, 1,634 DEGs were identified, with a dominant immune signature observed in HPV(+) tumors. After normalizing the expression profiles to account for differences in B- and T-cell number, 437 significantly DEGs remained. A B-cell associated signature distinguished HPV(+) from HPV(-) tumors, and included the DEGs CD200, GGA2, ADAM28, STAG3, SPIB, VCAM1, BCL2 and ICOSLG; the immune signal relative to T-cells was qualitatively similar between TILs of both tumor cohorts. Our findings were validated and confirmed in two independent cohorts using TCGA data and tumor-infiltrating B-cells from additional HPV(+) HNSCC patients. A B-cell associated signal segregated tumors relative to HPV status. Our data suggests that the role of B-cells in the adaptive immune response to HPV(+) HNSCC requires re-assessment.

  17. Deep Sequencing of T-Cell Receptor DNA as a biomarker of clonally expanded TILs in breast cancer after immunotherapy

    PubMed Central

    Page, David B.; Yuan, Jianda; Redmond, David; Wen, Y Hanna; Durack, Jeremy C.; Emerson, Ryan; Solomon, Stephen; Dong, Zhiwan; Wong, Phillip; Comstock, Christopher; Diab, Adi; Sung, Janice; Maybody, Majid; Morris, Elizabeth; Brogi, Edi; Morrow, Monica; Sacchini, Virgilio; Elemento, Olivier; Robins, Harlan; Patil, Sujata; Allison, James P.; Wolchok, Jedd D.; Hudis, Clifford; Norton, Larry; McArthur, Heather

    2016-01-01

    In early stage breast cancer, the degree of tumor-infiltrating lymphocytes (TILs) predicts response to chemotherapy and overall survival. Combination immunotherapy with immune checkpoint antibody plus tumor cryoablation can induce lymphocytic infiltrates and improve survival in mice. We used T-cell receptor (TCR) DNA sequencing to evaluate both the effect of cryo-immunotherapy in humans and the feasibility of TCR sequencing in early-stage breast cancer. In a pilot clinical trial, 18 women with early-stage breast cancer were treated preoperatively with cryoablation, single-dose anti-CTLA-4 (ipilimumab), or cryoablation + ipilimumab. TCRs within serially collected peripheral blood and tumor tissue were sequenced. In baseline tumor tissues, T-cell density as measured by TCR sequencing correlated with TIL scores obtained by hematoxylin and eosin (H&E) staining. However, tumors with little or no lymphocytes by H&E contained up to 3.6 × 106 TCR DNA sequences, highlighting the sensitivity of the ImmunoSEQ platform. In this dataset, ipilimumab increased intratumoral T-cell density over time, whereas cryoablation ± ipilimumab diversified and remodeled the intratumoral T-cell clonal repertoire. Compared to monotherapy, cryoablation plus ipilimumab was associated with numerically greater numbers of peripheral blood and intratumoral T-cell clones expanding robustly following therapy. In conclusion, TCR sequencing correlates with H&E lymphocyte scoring, and provides additional information on clonal diversity. These findings support further study of the use of TCR sequencing as a biomarker for T cell responses to therapy and for the study of cryo-immunotherapy in early-stage breast cancer. PMID:27587469

  18. Deep Sequencing of T-cell Receptor DNA as a Biomarker of Clonally Expanded TILs in Breast Cancer after Immunotherapy.

    PubMed

    Page, David B; Yuan, Jianda; Redmond, David; Wen, Y Hanna; Durack, Jeremy C; Emerson, Ryan; Solomon, Stephen; Dong, Zhiwan; Wong, Phillip; Comstock, Christopher; Diab, Adi; Sung, Janice; Maybody, Majid; Morris, Elizabeth; Brogi, Edi; Morrow, Monica; Sacchini, Virgilio; Elemento, Olivier; Robins, Harlan; Patil, Sujata; Allison, James P; Wolchok, Jedd D; Hudis, Clifford; Norton, Larry; McArthur, Heather L

    2016-10-01

    In early-stage breast cancer, the degree of tumor-infiltrating lymphocytes (TIL) predicts response to chemotherapy and overall survival. Combination immunotherapy with immune checkpoint antibody plus tumor cryoablation can induce lymphocytic infiltrates and improve survival in mice. We used T-cell receptor (TCR) DNA sequencing to evaluate both the effect of cryoimmunotherapy in humans and the feasibility of TCR sequencing in early-stage breast cancer. In a pilot clinical trial, 18 women with early-stage breast cancer were treated preoperatively with cryoablation, single-dose anti-CTLA-4 (ipilimumab), or cryoablation + ipilimumab. TCRs within serially collected peripheral blood and tumor tissue were sequenced. In baseline tumor tissues, T-cell density as measured by TCR sequencing correlated with TIL scores obtained by hematoxylin and eosin (H&E) staining. However, tumors with little or no lymphocytes by H&E contained up to 3.6 × 10(6) TCR DNA sequences, highlighting the sensitivity of the ImmunoSEQ platform. In this dataset, ipilimumab increased intratumoral T-cell density over time, whereas cryoablation ± ipilimumab diversified and remodeled the intratumoral T-cell clonal repertoire. Compared with monotherapy, cryoablation plus ipilimumab was associated with numerically greater numbers of peripheral blood and intratumoral T-cell clones expanding robustly following therapy. In conclusion, TCR sequencing correlates with H&E lymphocyte scoring and provides additional information on clonal diversity. These findings support further study of the use of TCR sequencing as a biomarker for T-cell responses to therapy and for the study of cryoimmunotherapy in early-stage breast cancer. Cancer Immunol Res; 4(10); 835-44. ©2016 AACR.

  19. TIL-type protease inhibitors may be used as targeted resistance factors to enhance silkworm defenses against invasive fungi.

    PubMed

    Li, Youshan; Zhao, Ping; Liu, Huawei; Guo, Xiaomeng; He, Huawei; Zhu, Rui; Xiang, Zhonghuai; Xia, Qingyou

    2015-02-01

    Entomopathogenic fungi penetrate the insect cuticle using their abundant hydrolases. These hydrolases, which include cuticle-degrading proteases and chitinases, are important virulence factors. Our recent findings suggest that many serine protease inhibitors, especially TIL-type protease inhibitors, are involved in insect resistance to pathogenic microorganisms. To clarify the molecular mechanism underlying this resistance to entomopathogenic fungi and identify novel genes to improve the silkworm antifungal capacity, we conducted an in-depth study of serine protease inhibitors. Here, we cloned and expressed a novel silkworm TIL-type protease inhibitor, BmSPI39. In activity assays, BmSPI39 potently inhibited the virulence protease CDEP-1 of Beauveria bassiana, suggesting that it might suppress the fungal penetration of the silkworm integument by inhibiting the cuticle-degrading proteases secreted by the fungus. Phenol oxidase activation studies showed that melanization is involved in the insect immune response to fungal invasion, and that fungus-induced excessive melanization is suppressed by BmSPI39 by inhibiting the fungal cuticle-degrading proteases. To better understand the mechanism involved in the inhibition of fungal virulence by protease inhibitors, their effects on the germination of B. bassiana conidia was examined. BmSPI38 and BmSPI39 significantly inhibited the germination of B. bassiana conidia. Survival assays showed that BmSPI38 and BmSPI39 markedly improved the survival rates of silkworms, and can therefore be used as targeted resistance proteins in the silkworm. These results provided new insight into the molecular mechanisms whereby insect protease inhibitors confer resistance against entomopathogenic fungi, suggesting their potential application in medicinal or agricultural fields.

  20. CD3+, CD4+ & CD8+ tumour infiltrating lymphocytes (TILs) are predictors of favourable survival outcome in infiltrating ductal carcinoma of breast

    PubMed Central

    Rathore, Ankita Singh; Kumar, Sandeep; Konwar, Rituraj; Makker, Annu; Negi, M.P.S.; Goel, Madhu Mati

    2014-01-01

    Background & objectives: Tumour infiltrating lymphocytes (TILs) represent the host immune response against cancer cells associated with good or bad prognosis in different tumour types. This study was undertaken to evaluate the significance of CD3+, CD4+ and CD8+ TILs in breast cancer tissues in relation to clinico-pathological variables and survival outcome. Methods: Immunohistochemistry (IHC) was performed with antibodies against CD3, CD4 and CD8 antigens on formalin-fixed paraffin-embedded tissue sections of 150 breast cancer patients. Intratumoural and stromal TIL counting was performed semiquantitatively. Results: The higher CD3+, CD4+ and CD8+ intratumoural and stromal counts showed independent and direct association with good prognosis. The prognostic predictor value of intratumoural counts was higher than stromal counts. The independent associations of intratumoural and stromal counts became more prominent when adjusted with stage and grade, respectively. Among intratumoural counts, the high (++/+++) CD4+ count (OR=3.85, 95% CI=3.28-16.71, P<0.001) showed the highest survival followed by CD3+ (OR=2.70, 95% CI=1.76-8.30, P=0.001) and CD8+ (OR=2.58, 95% CI=1.55-5.86, P=0.001) the least when compared to respective low (+) counts. In contrast, among stromal counts, the high CD8+ count (OR=3.13, 95% CI=2.20-9.57, P<0.001) showed the highest survival followed by CD4+ (OR=3.02, 95% CI=2.07-8.89, P<0.001) and CD3+ (OR=2.45, 95% CI=1.53-6.73, P=0.002) the least. Interpretation & conclusions: Our results suggest that intratumoural CD4+ and stromal CD8+ counts by immunohistochemistry may serve as an independent prognosticator for favourable outcome in breast cancer. PMID:25366203

  1. 'Til the Needle Breaks

    ERIC Educational Resources Information Center

    Hawkins, B. Denise

    2011-01-01

    After more than half a century, the music of Motown not only thrives, it transcends generations. The iconic sound of Motown has led a handful of scholars to write, teach, lecture and share the music, history and business of Motown on their campuses. In its golden age, from 1959 to 1972, the sound Berry Gordy pioneered at Motown Records in Detroit…

  2. Registration of TIL:383.13, TIL:625 and TIL:634, three long grain tropical Japonica Rice (Oryza sativa L.) germplasm lines containing novel Indica Alleles that increase tiller production and grain yield

    Technology Transfer Automated Retrieval System (TEKTRAN)

    These three breeding lines were from a set of 123 progeny lines that were released by the USDA-ARS in 2012 as a mapping population. Chromosomal regions containing genes for increased tiller number under greenhouse conditions were subsequently identified in this population. We used the molecular an...

  3. The Repeal of Section 28: It Ain't over 'til It's over

    ERIC Educational Resources Information Center

    Greenland, Katy; Nunney, Rosalind

    2008-01-01

    Section 28 (part of the Local Government Act of 1988) was a notorious piece of legislation that sought to prevent local education authorities in the UK from "promoting homosexuality". The effect of Section 28 was to create uncertainty and fear among teachers as to what was (and what was not) permitted in schools. Over time practitioners…

  4. 'Keep complaining til someone listens': Exchanges of tacit healthcare knowledge in online illness communities.

    PubMed

    Foster, Drew

    2016-10-01

    This article examines online exchanges of advice and knowledge among patients. It draws a distinction between explicit healthcare knowledge (i.e., facts about symptoms and treatments) and tacit healthcare knowledge (i.e., know-how about navigating the healthcare system). Based on analysis of message board interactions at a prominent online illness community, I find that patients routinely encourage one another to exercise agency strategically in clinical encounters by honing specific interactional skills. I isolate three major techniques that are advocated within the community (affect regulation, information management, and treatment persistence) and frame them as discrete examples of tacit healthcare knowledge. I argue that tacit healthcare knowledge constitutes a potentially potent source of empowerment for patients that can help them to receive their desired form of care from the health system and to negotiate relationships with medical professionals and institutions. I conclude by discussing how the concept of tacit healthcare knowledge further clarifies the wide variety of lay knowledge exchanged among patients online.

  5. William Van Til and the Nashville Story: Curriculum, Supervision, and Civil Rights

    ERIC Educational Resources Information Center

    Perlstein, Daniel

    2004-01-01

    Massive white resistance to the Supreme Court's 1954 Brown decision encouraged educational administrators and leaders who supported school integration to ally themselves with progressive civic activists. Desegregation thus catalyzed the development of a new, more openly political vision of educational leadership. If schools of education were to…

  6. Clinical relevance of host immunity in breast cancer: from TILs to the clinic.

    PubMed

    Savas, Peter; Salgado, Roberto; Denkert, Carsten; Sotiriou, Christos; Darcy, Phillip K; Smyth, Mark J; Loi, Sherene

    2016-04-01

    The clinical relevance of the host immune system in breast cancer has long been unexplored. Studies developed over the past decade have highlighted the biological heterogeneity of breast cancer, prompting researchers to investigate whether the role of the immune system in this malignancy is similar across different molecular subtypes of the disease. The presence of high levels of lymphocytic infiltration has been consistently associated with a more-favourable prognosis in patients with early stage triple-negative and HER2-positive breast cancer. These infiltrates seem to reflect favourable host antitumour immune responses, suggesting that immune activation is important for improving survival outcomes. In this Review, we discuss the composition of the immune infiltrates observed in breast cancers, as well as data supporting the clinical relevance of host antitumour immunity, as represented by lymphocytic infiltration, and how this biomarker could be used in the clinical setting. We also discuss the rationale for enhancing immunity in breast cancer, including early data on the efficacy of T-cell checkpoint inhibition in this setting.

  7. 'Til death parts us: women’s domestic partnerships in eighteenth-century Brittany.

    PubMed

    Locklin, Nancy

    2011-01-01

    This article investigates the legal provision for two adult, unmarried women to create a “perpetual society” with one another found in the customary code of 1725 for the French province of Brittany. This arrangement allowed women who shared a household to designate one another as primary heir and to protect their community property from the claims of others. Evidence of this arrangement demonstrates that single women in some places had options outside of marriage and the convent. The contracts filed by the women also reveal the extent to which this arrangement went beyond considerations of property to express both affection and loyalty. Available to siblings as well as to pairs of unrelated women, this union is likely not the equivalent of same-sex marriage. It does however broaden our knowledge of the meaning of marriage, partnership, and kin in early modern Europe.

  8. ''Fake It 'Til You Make It'': Why Community College Students' Aspirations ''Hold Steady''

    ERIC Educational Resources Information Center

    Nielsen, Kelly

    2015-01-01

    Sociologists of education have explored the relationship between students' postsecondary aspirations and their propensity to get "cooled out" in community colleges. However, researchers have directed little attention to students whose aspirations remain stable over long periods of time or to the different roles that college degree goals…

  9. Twist `til we tear the house down: How Clifford solved the universe in 1870

    NASA Astrophysics Data System (ADS)

    Beichler, James

    2010-02-01

    It is commonly believed that the first hyperspace theories in physics were developed in the early twentieth century - Kaluza's five-dimensional extension of relativity is the best known, but this is untrue. It is also commonly believed that W.K. Clifford `speculated' on a higher space in 1870, had no followers and never published his theory (if he even had one). Nothing could be further from the historical truth. As early as 1869, Clifford, his followers and students began to develop a physical theory of matter based on a three-dimensional space curved in four dimensions. Clifford began to publish his theory, but modern researchers have failed to recognize his theoretical work because they look for something like Einstein's theory even though Clifford developed an electromagnetic theory. Clifford may not have directly influenced Einstein's relativity, but he made plausible arguments for the reality of space curvature, rendering the rapid acceptance of Einstein's concept of curved space-time more plausible. Clifford's work is either largely ignored by historians, scientists and other scholars or considered irrelevant because the early work on hyperspaces has been associated with ether theories that were abandoned, utilized quaternion algebras that were replaced by vectors and tensors, and was unfortunately associated with spiritualism. )

  10. Fish gotta swim, Birds gotta fly, I gotta do Feynmann Graphs 'til I die: A continuum Theory of Flocking

    NASA Astrophysics Data System (ADS)

    Toner, John; Tu, Yu-Hai

    2002-05-01

    We have developed a new continuum dynamical model for the collective motion of large "flocks" of biological organisms (e.g., flocks of birds, schools of fish, herds of wildebeest, hordes of bacteria, slime molds, etc.) . This model does for flocks what the Navier-Stokes equation does for fluids. The model predicts that, unlike simple fluids, flocks show huge fluctuation effects in spatial dimensions d < 4 that radically change their behavior. In d=2, it is only these effects that make it possible for the flock to move coherently at all. This explains why a million wildebeest can march together across the Serengeti plain, despite the fact that a million physicists gathered on the same plane could NOT all POINT in the same direction. Detailed quantitative predictions of this theory agree beautifully with computer simulations of flock motion.

  11. Breeding Value of the qSB9b and qSB12a QTLs in RiceBreeding Value of the qSB9b and qSB12a QTLs in Rice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Sheath blight (SB) caused by Rhizoctonia solani Kuhn is a serious rice disease worldwide. The results of 123 TeQing-into-Lemont (TILs) showed those with introgressions containing qSB9b and/or qSB12a were among the most SB resistant TILs. TIL:615, TIL:642 and TIL:567 have consistently appeared modera...

  12. 'Faking til you make it': social capital accumulation of individuals on low incomes living in contrasting socio-economic neighbourhoods and its implications for health and wellbeing.

    PubMed

    Browne-Yung, Kathryn; Ziersch, Anna; Baum, Fran

    2013-05-01

    People on low-income living in low socio-economic neighbourhoods have poorer health in comparison with those living in advantaged neighbourhoods. To explore neighbourhood effects on health and social capital creation, the experiences of low-income people living in contrasting socio-economic neighbourhoods were compared, in order to examine how low-income status and differing levels of neighbourhood resources contributed to perceived health and wellbeing. Quantitative and qualitative data were analysed: survey data from 601 individuals living in contrasting socio-economic areas and in-depth interviews with a new sample of 24 individuals on low-incomes. The study was guided by Bourdieu's theory of practice, which examines how social inequalities are created and reproduced through the relationship between individuals' varying resources of economic, social and cultural capital. This included an examination of individual life histories, cultural distinction and how social positions are reproduced. Participants' accounts of their early life experience showed how parental socio-economic position and socially patterned events taking place across the life course, created different opportunities for social network creation, choice of neighbourhood and levels of resources available throughout life, all of which can influence health and wellbeing. A definition of poverty by whether an individual or household has sufficient income at a particular point in time was an inadequate measure of disadvantage. This static measure of 'low income' as a category disguised a number of different ways in which disadvantage was experienced or, conversely, how life course events could mitigate the impact of low-income. This study found that the resources necessary to create social capital such as cultural capital and the ability to socially network, differed according to the socio-economic status of the neighbourhood, and that living in an advantaged area does not automatically guarantee access to potentially beneficial social networks.

  13. Don't Know What You've Got 'Til It's Gone? Skills-Led Qualifications, Secondary School Attainment and Policy Choices

    ERIC Educational Resources Information Center

    Harrison, Neil; James, David; Last, Kathryn

    2015-01-01

    In the name of curriculum breadth and raising standards, recent government policy in England has removed a large number of non-academic qualifications from the list of those that secondary schools can count in league tables, discouraging their use. Most of these were vocational qualifications, but they also include skills-led qualifications. This…

  14. Evaluation of the prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers

    PubMed Central

    Tian, Tian; Ruan, Miao; Yang, Wentao; Shui, Ruohong

    2016-01-01

    Tumor-infiltrating lymphocytes (TILs) may be associated with clinical outcome in triple-negative breast cancers (TNBCs). However, lacking of standardized methodologies in TILs evaluation has hindered its application in clinical practice. To evaluate the prognostic role of TILs scored by methods recommended by International TILs Working Group 2014, we performed a retrospective study of TILs in 425 primary invasive TNBCs in a Chinese population with a median follow-up of 4 years. Intratumoral TILs (iTILs) and stromal TILs (sTILs) were scored respectively. The associations between TILs and disease-free survival (DFS), distant disease-free survival (DDFS) and overall survival (OS) were evaluated with COX models. ITILs were not associated with prognosis. Higher sTILs were associated with better prognosis; for every 10% increase in sTILs, a 5% reduction of risk of recurrence or death (P < 0.001), 5% reduction of risk of distant recurrence (P < 0.001), and 4% reduction of risk of death (P = 0.002) were observed. Multivariate analysis confirmed sTILs to be an independent prognostic marker. 3.5% of TNBCs had more than 50% lymphocytes (lymphocyte-predominant breast cancer, LPBC), and associations between LPBC status and prognosis were observed but did not reach statistical significance. TNBCs with more than 20% sTILs had a significantly better prognosis than the patients with no more than 20% sTILs. In conclusion, our study indicated that sTILs scored by methods recommended by International TILs Working Group 2014 were associated with the prognosis of TNBCs. STILs could be an independent prognostic biomarker in TNBCs, increasing sTILs predicting better prognosis. PMID:27323808

  15. Human gene transfer: Characterization of human tumor-infiltrating lymphocytes as vehicles for retroviral-mediated gene transfer in man

    SciTech Connect

    Kasid, A.; Morecki, S.; Aebersold, P.; Cornetta, K.; Culver, K.; Freeman, S.; Director, E.; Lotze, M.T.; Blaese, R.M.; Anderson, W.F.; Rosenberg, S.A. )

    1990-01-01

    Tumor-infiltrating lymphocytes (TILs) are cells generated from tumor suspensions cultured in interleukin 2 that can mediate cancer regression when adoptively transferred into mice or humans. Since TILs proliferate rapidly in vitro, recirculate, and preferentially localize at the tumor site in vivo, they provide an attractive model for delivery of exogenous genetic material into man. To determine whether efficient gene transfer into TILs is feasible. The authors transduced human TILs with the bacterial gene for neomycin-resistance (Neo{sup R}) using the retroviral vector N2. The transduced TIL populations were stable and polyclonal with respect to the intact Neo{sup R} gene integration and expressed high levels of neomycin phosphotransferase activity. The Neo{sup R} gene insertion did not alter the in vitro growth pattern and interleukin 2 dependence of the transduced TILs. Analyses of T-cell receptor gene rearrangement for {beta}- and {gamma}-chain genes revealed the oligoclonal nature of the TIL populations with no major change in the DNA rearrangement patterns or the levels of mRNA expression of the {beta} and {gamma} chains following transduction and selection of TILs in the neomycin analog G418. Human TILs expressed mRNA for tumor necrosis factors ({alpha} and {beta}) and interleukin 2 receptor P55. This pattern of cytokine-mRNA expression was not significantly altered following the transduction of TILs. The studies demonstrate the feasibility of TILs as suitable cellular vehicles for the introduction of therapeutic genes into patients receiving autologous TILs.

  16. Tumour infiltrating lymphocytes correlate with improved survival in patients with esophageal squamous cell carcinoma

    PubMed Central

    Jiang, Dongxian; Liu, Yalan; Wang, Hao; Wang, Haixing; Song, Qi; Sujie, Akesu; Huang, Jie; Xu, Yifan; Zeng, Haiying; Tan, Lijie; Hou, Yingyong; Xu, Chen

    2017-01-01

    We undertook a study of tumour infiltrating lymphocytes (TILs) in a large and relatively homogeneous group of patients with completely resected esophageal squamous cell carcinoma (ESCC). Hematoxylin and eosin–stained sections of 235 ESCC tumours were evaluated for density of TILs in intratumoural (iTIL) and stromal compartments (sTIL). Foxp3+, CD4+, and CD8+ T cells in tumoural and stromal areas were evaluated by immunohistochemistry. Of the 235 tumours, high sTIL (>10%), and iTIL (>10%) were observed in 101 (43.0%) and 98 (41.7%), respectively. The median follow-up period was 36.0 months (95% CI 29.929–42.071). Univariate analysis revealed that sTIL (>10%), iTIL (>20%), vessels involvement, lymph node metastasis, and clinical stage were significantly associated with postoperative outcome. In multivariate analysis, high sTIL (HR: 0.664, P = 0.019 for Disease free survival; HR: 0.608, P = 0.005 for Overall survival) was identified as independent better prognostic factor. Further analysis, sTIL was identified as independently prognostic factor in Stage III-IVa disease, which was not found in Stage I-II disease. Our study demonstrated that sTIL was associated with better ESCC patients’ survival, especially in Stage III-IVa disease. Assessment of sTIL could be useful to discriminate biological behavior for ESCC patients. PMID:28322245

  17. Tumour infiltrating lymphocytes correlate with improved survival in patients with esophageal squamous cell carcinoma.

    PubMed

    Jiang, Dongxian; Liu, Yalan; Wang, Hao; Wang, Haixing; Song, Qi; Sujie, Akesu; Huang, Jie; Xu, Yifan; Zeng, Haiying; Tan, Lijie; Hou, Yingyong; Xu, Chen

    2017-03-21

    We undertook a study of tumour infiltrating lymphocytes (TILs) in a large and relatively homogeneous group of patients with completely resected esophageal squamous cell carcinoma (ESCC). Hematoxylin and eosin-stained sections of 235 ESCC tumours were evaluated for density of TILs in intratumoural (iTIL) and stromal compartments (sTIL). Foxp3+, CD4+, and CD8+ T cells in tumoural and stromal areas were evaluated by immunohistochemistry. Of the 235 tumours, high sTIL (>10%), and iTIL (>10%) were observed in 101 (43.0%) and 98 (41.7%), respectively. The median follow-up period was 36.0 months (95% CI 29.929-42.071). Univariate analysis revealed that sTIL (>10%), iTIL (>20%), vessels involvement, lymph node metastasis, and clinical stage were significantly associated with postoperative outcome. In multivariate analysis, high sTIL (HR: 0.664, P = 0.019 for Disease free survival; HR: 0.608, P = 0.005 for Overall survival) was identified as independent better prognostic factor. Further analysis, sTIL was identified as independently prognostic factor in Stage III-IVa disease, which was not found in Stage I-II disease. Our study demonstrated that sTIL was associated with better ESCC patients' survival, especially in Stage III-IVa disease. Assessment of sTIL could be useful to discriminate biological behavior for ESCC patients.

  18. Increased CD4 and CD8-positive T cell infiltrate signifies good prognosis in a subset of triple-negative breast cancer.

    PubMed

    Matsumoto, Hirofumi; Thike, Aye Aye; Li, Huihua; Yeong, Joe; Koo, Si-Lin; Dent, Rebecca Alexandra; Tan, Puay Hoon; Iqbal, Jabed

    2016-04-01

    Tumour-infiltrating lymphocytes (TILs) signify immune response to tumour in a variety of cancers including breast cancer. However, earlier studies examining the clinical significance of TILs in breast cancers have generated mixed results. There are only a few that address the relationship between TILs and clinical outcomes in triple-negative breast cancers (TNBC). The aim of this study is to evaluate the clinical significance of TILs that express CD4 + and CD8 + , in TNBC. Immunohistochemical staining of CD4 and CD8 was performed on tissue microarrays of 164 cases of TNBC. TILs were counted separately as intratumoral when within the cancer cell nests (iTILs) and as stromal when within cancer stroma (sTILs). High CD8 + iTILs and sTILs, and CD4 + iTILs correlated with histologic grade. On Kaplan-Meier analysis, a significantly better survival rate was observed in high CD8 + iTIL (disease-free survival, DFS: P = 0.004, overall survival, OS: P = 0.02) and both high CD4 + iTILs (DFS: P = 0.025, OS: P = 0.023) and sTILs (DFS: P = 0.01, OS: P = 0.002). In multivariate analysis, CD8 + iTILs (DFS: P = 0.0095), CD4 + sTILs (DFS: P = 0.0084; OS: P = 0.0118), and CD4 (high) CD8 (high) CD8 iTILs (DFS: P = 0.0121; OS: P = 0.0329) and sTILs (DFS: P = 0.0295) showed significantly better survival outcomes. These results suggest that high levels of both CD8 + iTILs and CD4 + sTILs as well as CD4 (high) CD8 (high) iTILs and sTILs are independent prognostic factors in TNBC.

  19. Prognostic value of tumor-infiltrating lymphocytes on residual disease after primary chemotherapy for triple-negative breast cancer: a retrospective multicenter study

    PubMed Central

    Dieci, M. V.; Criscitiello, C.; Goubar, A.; Viale, G.; Conte, P.; Guarneri, V.; Ficarra, G.; Mathieu, M. C.; Delaloge, S.; Curigliano, G.; Andre, F.

    2014-01-01

    Background There is a need to develop surrogates for treatment efficacy in the neoadjuvant setting to speed-up drug development and stratify patients according to outcome. Preclinical studies showed that chemotherapy induces an antitumor immune response. In order to develop new surrogates for drug efficacy, we assessed the prognostic value of tumor-infiltrating lymphocytes (TIL) on residual disease after neoadjuvant chemotherapy (NACT) in patients with triple-negative breast cancer (TNBC). Patients and methods Three hundred four TNBC patients with residual disease after NACT were retrospectively identified in three different hospitals. Hematoxylin and eosin-stained slides from surgical postchemotherapy specimens were evaluated for intratumoral (It-TIL) and stromal (Str-TIL) TIL. Cases were classified as High-TIL if It-TIL and/or Str-TIL >60%. Results TIL were assessable for 278 cases. Continuous It-TIL and Str-TIL variables were strong prognostic factors in the multivariate model, both for metastasis-free [hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.77–0.96, P = 0.01 and HR 0.85, 95% CI 0.75–0.98, P = 0.02 for Str-TIL and It-TIL, respectively] and overall survival (HR 0.86, 95% CI 0.77–0.97, P = 0.01 and HR 0.86, 95% CI 0.75–0.99, P = 0.03 for Str-TIL and It-TIL, respectively). The 5-year overall survival rate was 91% (95% CI 68% to 97%) for High-TIL patients (n = 27) and 55% (95% CI 48% to 61%) for Low-TIL patients (HR 0.19, 95% CI 0.06–0.61, log-rank P = 0.0017). The major prognostic impact of TIL was seen for patients with large tumor burden following NACT (residual tumor >2 cm and/or node metastasis). In all but one High-TIL case, It-TIL and Str-TIL values were lower on the prechemotherapy sample. Conclusions The presence of TIL in residual disease after NACT is associated with better prognosis in TNBC patients. This parameter may represent a new surrogate of drug efficacy to test investigational agents in the neoadjuvant setting and a new

  20. Tumor-Infiltrating Lymphocyte Grade in Primary Melanomas Is Independently Associated With Melanoma-Specific Survival in the Population-Based Genes, Environment and Melanoma Study

    PubMed Central

    Thomas, Nancy E.; Busam, Klaus J.; From, Lynn; Kricker, Anne; Armstrong, Bruce K.; Anton-Culver, Hoda; Gruber, Stephen B.; Gallagher, Richard P.; Zanetti, Roberto; Rosso, Stefano; Dwyer, Terence; Venn, Alison; Kanetsky, Peter A.; Groben, Pamela A.; Hao, Honglin; Orlow, Irene; Reiner, Anne S.; Luo, Li; Paine, Susan; Ollila, David W.; Wilcox, Homer; Begg, Colin B.; Berwick, Marianne

    2013-01-01

    Purpose Although most hospital-based studies suggest more favorable survival with tumor-infiltrating lymphocytes (TILs) present in primary melanomas, it is uncertain whether TILs provide prognostic information beyond existing melanoma staging definitions. We addressed the issue in an international population-based study of patients with single and multiple primary melanomas. Patients and Methods On the basis of the Genes, Environment and Melanoma (GEM) study, we conducted follow-up of 2,845 patients diagnosed from 1998 to 2003 with 3,330 invasive primary melanomas centrally reviewed for TIL grade (absent, nonbrisk, or brisk). The odds of TIL grades associated with clinicopathologic features and survival by TIL grade were examined. Results Independent predictors (P < .05) for nonbrisk TIL grade were site, histologic subtype, and Breslow thickness, and for brisk TIL grade, they were age, site, Breslow thickness, and radial growth phase. Nonbrisk and brisk TIL grades were each associated with lower American Joint Committee on Cancer (AJCC) tumor stage compared with TIL absence (Ptrend < .001). Death as a result of melanoma was 30% less with nonbrisk TIL grade (hazard ratio [HR], 0.7; 95% CI, 0.5 to 1.0) and 50% less with brisk TIL grade (HR, 0.5; 95% CI, 0.3 to 0.9) relative to TIL absence, adjusted for age, sex, site, and AJCC tumor stage. Conclusion At the population level, higher TIL grade of primary melanoma is associated with a lower risk of death as a result of melanoma independently of tumor characteristics currently used for AJCC tumor stage. We conclude that TIL grade deserves further prospective investigation to determine whether it should be included in future AJCC staging revisions. PMID:24127443

  1. Tumor infiltrating lymphocytes in ovarian cancer.

    PubMed

    Santoiemma, Phillip P; Powell, Daniel J

    2015-01-01

    The accumulation of tumor infiltrating lymphocytes (TILs) in ovarian cancer is prognostic for increased survival while increases in immunosuppressive regulatory T-cells (Tregs) are associated with poor outcomes. Approaches that bolster tumor-reactive TILs may limit tumor progression. However, identifying tumor-reactive TILs in ovarian cancer has been challenging, though adoptive TIL therapy in patients has been encouraging. Other forms of TIL immunomodulation remain under investigation including Treg depletion, antibody-based checkpoint modification, activation and amplification using dendritic cells, antigen presenting cells or IL-2 cytokine culture, adjuvant cytokine injections, and gene-engineered T-cells. Many approaches to TIL manipulation inhibit ovarian cancer progression in preclinical or clinical studies as monotherapy. Here, we review the impact of TILs in ovarian cancer and attempts to mobilize TILs to halt tumor progression. We conclude that effective TIL therapy for ovarian cancer is at the brink of translation and optimal TIL activity may require combined methodologies to deliver clinically-relevant treatment.

  2. The emergence of non-cytolytic NK1.1+ T cells in the long-term culture of murine tumour-infiltrating lymphocytes: a possible role of transforming growth factor-beta.

    PubMed Central

    Tamada, K; Harada, M; Ito, O; Takenoyama, M; Mori, T; Matsuzaki, G; Nomoto, K

    1996-01-01

    The mechanism by which murine tumour-infiltrating lymphocytes (TIL) decreased their anti-tumour activity during an in vitro culture with interleukin-2 (IL-2) was investigated. A phenotype analysis revealed that the TIL cultured for 7 days (TIL-d7) were exclusively NKI.1- CD4- CD8+ CD3+ cells and that this population was replaced by natural killer (NK)1.1+ CD4- CD8 CD3+ cells by day 27 (TIL-d27) during the culture of TIL. The TIL-d7 cells showed a cytolytic activity against B16 melanoma, whereas the TIL-d27 cells had lost this activity, suggesting that the decrease in the anti tumour effect of TIL during the culture with IL-2 was due to their populational change. Analysis on the characteristics of the TIL-d27 cells revealed that they expressed skewed T-cell receptor (TCR) V beta 5 and increased mRNA expression of V alpha 14. In addition, they expressed transforming growth factor beta (TGF-beta) mRNA. Interestingly, TGF-beta augmented the proliferation of TIL-d27 cells under the presence of IL-2, but suppressed that of TIL-d7 cells. Moreover, the proliferation of TIL-d27 cells was suppressed by anti-TGF-beta monoclonal antibody. Collectively, these results suggest that, in contrast to its suppressive effect on anti-tumour effector T cells. TGF-beta could be an autocrine growth factor for NKL1.1+ T cells and thereby induce non-cytolytic NK1.1+ T cells in the long-term culture of TIL. Images Figure 4 Figure 6 PMID:9014832

  3. Similar lymphocytic infiltration pattern in primary breast cancer and their corresponding distant metastases.

    PubMed

    Sobottka, Bettina; Pestalozzi, Bernhard; Fink, Daniel; Moch, Holger; Varga, Zsuzsanna

    2016-06-01

    Tumor infiltrating lymphocytes in primary breast cancer (TIL) are acknowledged measures of disease free survival (DFS) in adjuvant and neoadjuvant settings. Little is known about the biology of metastasis infiltrating lymphocytes (mTIL) although the local immunity of the metastatic site may critically influence the infiltrate composite. To address this question, we compared mTIL with their matched TIL in 87 breast cancer patients and their corresponding distant metastasis at four different anatomical locations. Sections of surgical specimen were immunohistochemically analyzed for CD4(+), CD8(+) and CD20(+) lymphocytes in three different tumor compartments: intratumoral lymphocytes (iTIL) defined as lymphocytes in direct contact with breast cancer cells, stromal lymphocytes (sTIL) located within the intratumoral stromal tissue and invasive-margin lymphocytes (imTIL). Overall, we found fewer (p < 0.001) mTIL than TIL. Within the tumor compartments, imTIL were more frequent than sTIL and iTIL both within metastases and the matched primary tumors (PT) (p < 0.001). CD4(+) T cells were more numerous than CD8(+) T cells and CD20(+) B cells (p < 0.001). There was a similar pattern in PT and their corresponding metastasis. Only patients with brain metastases differed from the others displaying less CD20(+) B cells at the infiltrative margin of the PT (p < 0.05). In summary, mTIL were significantly reduced within metastases but still mirrored the infiltrate pattern of the PT, interestingly regardless of the metastatic anatomical locations investigated. Our results suggest that the PT assigns the infiltrating lymphocyte pattern resumed at the metastatic site.

  4. Similar lymphocytic infiltration pattern in primary breast cancer and their corresponding distant metastases

    PubMed Central

    Sobottka, Bettina; Pestalozzi, Bernhard; Fink, Daniel; Moch, Holger; Varga, Zsuzsanna

    2016-01-01

    ABSTRACT Tumor infiltrating lymphocytes in primary breast cancer (TIL) are acknowledged measures of disease free survival (DFS) in adjuvant and neoadjuvant settings. Little is known about the biology of metastasis infiltrating lymphocytes (mTIL) although the local immunity of the metastatic site may critically influence the infiltrate composite. To address this question, we compared mTIL with their matched TIL in 87 breast cancer patients and their corresponding distant metastasis at four different anatomical locations. Sections of surgical specimen were immunohistochemically analyzed for CD4+, CD8+ and CD20+ lymphocytes in three different tumor compartments: intratumoral lymphocytes (iTIL) defined as lymphocytes in direct contact with breast cancer cells, stromal lymphocytes (sTIL) located within the intratumoral stromal tissue and invasive-margin lymphocytes (imTIL). Overall, we found fewer (p < 0.001) mTIL than TIL. Within the tumor compartments, imTIL were more frequent than sTIL and iTIL both within metastases and the matched primary tumors (PT) (p < 0.001). CD4+ T cells were more numerous than CD8+ T cells and CD20+ B cells (p < 0.001). There was a similar pattern in PT and their corresponding metastasis. Only patients with brain metastases differed from the others displaying less CD20+ B cells at the infiltrative margin of the PT (p < 0.05). In summary, mTIL were significantly reduced within metastases but still mirrored the infiltrate pattern of the PT, interestingly regardless of the metastatic anatomical locations investigated. Our results suggest that the PT assigns the infiltrating lymphocyte pattern resumed at the metastatic site. PMID:27471624

  5. Reliability and Validity of the Therapy Intensity Level Scale: Analysis of Clinimetric Properties of a Novel Approach to Assess Management of Intracranial Pressure in Traumatic Brain Injury.

    PubMed

    Zuercher, Patrick; Groen, Justus L; Aries, Marcel J H; Steyerberg, Ewout W; Maas, Andrew I R; Ercole, Ari; Menon, David K

    2016-10-01

    We aimed to assess the reliability and validity of the Therapy Intensity Level scale (TIL) for intracranial pressure (ICP) management. We reviewed the medical records of 31 patients with traumatic brain injury (TBI) in two European intensive care units (ICUs). The ICP TIL was derived over a 4-day period for 4-h (TIL4) and 24-h epochs (TIL24). TIL scores were compared with historical schemes for TIL measurement, with each other, and with clinical variables. TIL24 scores in ICU patients with TBI were compared with two control groups: patients with extracranial trauma necessitating intensive care (Trauma_ICU; n = 20) and patients with TBI not needing ICU care (TBI_WARD; n = 19), to further determine the discriminative validity of the TIL for ICP-related ICU interventions. Interrater and intraobserver agreement were excellent for TIL4 and TIL24 (Cohen κ: 0.98-0.99; intraclass correlation coefficient: 0.99-1; p < 0.0005). The mean + standard deviation (SD) TIL24 in the ICU TBI cohort was significantly higher than the Trauma_ICU patients and the TBI_WARD patients (8.2 ± 3.2 vs. 2.2 ± 0.9 and 0.1 ± 0.1, respectively; p < 0.005 for both comparisons). Correlations between the TIL scale scores and historical TIL scores, between TIL24 and the Glasgow Coma Scale, and between a range of TIL metrics and summary measures of ICP over the 4-day period, were all highly significant (p < 0.01). The results were consistent with the expected direction. A linear mixed effect analysis, accounting for within-subjects repeated measures, showed strong correlation between TIL4 and 4-h ICP (p < 0.0000005). The TIL scale is a reliable measurement instrument with a high degree of validity for assessing the therapeutic intensity level of ICP management in patients with TBI.

  6. Knowledge generating in expert systems as support of immunological investigations.

    PubMed

    Biljana, M; Jelena, M; Milorad, R; Branislav, J; Nebojsa, A

    1997-01-01

    One of the most important parameters in immunologic investigations linked with the analysis of TIL phenotypic characteristics is the ratio between particular populations and subpopulations of TIL. Values of exact parameter are not obtained with its direct measurement but with indirect measurement of values in its numerator and its denominator that represent mean values of absolute TIL figures. Exactness of estimate of specific parameter is obtained by determining the intervals of values where this parameter should lie. Determination of confidence intervals for relationship between particular populations and subpopulations of TIL was performed using Fieller's theorem which full filled requests from the nature and process of obtaining exact parameter. By analyzing the obtained confidence intervals informations can be obtained regarding TIL phenotypic characteristics of various histologic types of tumors and various types of intervals within, as well as changes in TIL content that are occurring in malignant tumors.

  7. 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

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

    PubMed

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

    2017-01-01

    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.

  9. Prognostic Value of Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancers From Two Phase III Randomized Adjuvant Breast Cancer Trials: ECOG 2197 and ECOG 1199

    PubMed Central

    Adams, Sylvia; Gray, Robert J.; Demaria, Sandra; Goldstein, Lori; Perez, Edith A.; Shulman, Lawrence N.; Martino, Silvana; Wang, Molin; Jones, Vicky E.; Saphner, Thomas J.; Wolff, Antonio C.; Wood, William C.; Davidson, Nancy E.; Sledge, George W.; Sparano, Joseph A.; Badve, Sunil S.

    2014-01-01

    Purpose Recent studies suggest that tumor-infiltrating lymphocytes (TILs) are associated with disease-free (DFS) and overall survival (OS) in operable triple-negative breast cancer (TNBC). We seek to validate the prognostic impact of TILs in primary TNBCs in two adjuvant phase III trials conducted by the Eastern Cooperative Oncology Group (ECOG). Patients and Methods Full-face hematoxylin and eosin–stained sections of 506 tumors from ECOG trials E2197 and E1199 were evaluated for density of TILs in intraepithelial (iTILs) and stromal compartments (sTILs). Patient cases of TNBC from E2197 and E1199 were randomly selected based on availability of sections. For the primary end point of DFS, association with TIL scores was determined by fitting proportional hazards models stratified on study. Secondary end points were OS and distant recurrence–free interval (DRFI). Reporting recommendations for tumor marker prognostic studies criteria were followed, and all analyses were prespecified. Results The majority of 481 evaluable cancers had TILs (sTILs, 80%; iTILs, 15%). With a median follow-up of 10.6 years, higher sTIL scores were associated with better prognosis; for every 10% increase in sTILs, a 14% reduction of risk of recurrence or death (P = .02), 18% reduction of risk of distant recurrence (P = .04), and 19% reduction of risk of death (P = .01) were observed. Multivariable analysis confirmed sTILs to be an independent prognostic marker of DFS, DRFI, and OS. Conclusion In two national randomized clinical trials using contemporary adjuvant chemotherapy, we confirm that stromal lymphocytic infiltration constitutes a robust prognostic factor in TNBCs. Studies assessing outcomes and therapeutic efficacies should consider stratification for this parameter. PMID:25071121

  10. Augmented lymphocyte expansion from solid tumors with engineered cells for costimulatory enhancement

    PubMed Central

    Friedman, Kevin M; DeVillier, Laura E; Feldman, Steven A; Rosenberg, Steven A; Dudley, Mark E

    2011-01-01

    Treatment of patients with adoptive T cell therapy requires expansion of unique tumor-infiltrating lymphocyte (TIL) cultures from single cell suspensions processed from melanoma biopsies. Strategies which increase the expansion and reliability of TIL generation from tumor digests are necessary to improve access to TIL therapy. Prior work evaluated artificial antigen presenting cells (aAPCs) for their antigen-specific and costimulatory properties. We investigated engineered cells for co-stimulatory enhancement (ECCE) consisting of K562 cells which express 4-1BBL in the absence of artificial antigen stimulation. ECCE accelerated TIL expansion and significantly improved TIL numbers (p=0.001) from single cell melanoma suspensions. TIL generated with ECCE contain significantly more CD8+CD62L+ and CD8+CD27+ T cells then comparable IL-2-expanded TIL and maintained anti-tumor reactivity. Moreover, ECCE improved TIL expansion from non-melanoma cell suspensions similar to that seen with melanoma tumors. These data demonstrate that ECCE addition to TIL production will enable treatment of patients ineligible using current methods. PMID:21989413

  11. Augmented lymphocyte expansion from solid tumors with engineered cells for costimulatory enhancement.

    PubMed

    Friedman, Kevin M; Devillier, Laura E; Feldman, Steven A; Rosenberg, Steven A; Dudley, Mark E

    2011-01-01

    Treatment of patients with adoptive T-cell therapy requires expansion of unique tumor-infiltrating lymphocyte (TIL) cultures from single-cell suspensions processed from melanoma biopsies. Strategies which increase the expansion and reliability of TIL generation from tumor digests are necessary to improve access to TIL therapy. Previous studies have evaluated artificial antigen presenting cells for their antigen-specific and costimulatory properties. We investigated engineered cells for costimulatory enhancement (ECCE) consisting of K562 cells that express 4-1BBL in the absence of artificial antigen stimulation. ECCE accelerated TIL expansion and significantly improved TIL numbers (P=0.001) from single-cell melanoma suspensions. TIL generated with ECCE contain significantly more CD8CD62L and CD8CD27 T cells then comparable interleukin-2-expanded TIL and maintained antitumor reactivity. Moreover, ECCE improved TIL expansion from nonmelanoma-cell suspensions similar to that seen with melanoma tumors. These data demonstrate that the addition of ECCE to TIL production will enable the treatment of patients that are ineligible using current methods.

  12. CD8+ enriched “young” tumor infiltrating lymphocytes can mediate regression of metastatic melanoma

    PubMed Central

    Dudley, Mark E.; Gross, Colin A.; Langhan, Michelle M.; Garcia, Marcos R.; Sherry, Richard M.; Yang, James C.; Phan, Giao Q.; Kammula, Udai S.; Hughes, Marybeth S.; Citrin, Deborah E.; Restifo, Nicholas P.; Wunderlich, John; Prieto, Peter A.; Hong, Jenny J.; Langan, Russell C.; Zlott, Daniel A.; Morton, Kathleen E.; White, Donald E.; Laurencot, Carolyn; Rosenberg, Steven A.

    2010-01-01

    Purpose Tumor infiltrating lymphocytes (TIL) and interleukin (IL)-2 administered following lymphodepletion can cause the durable complete regression of bulky metastatic melanoma in patients refractory to approved treatments. However, the generation of a unique tumor-reactive TIL culture for each patient may be prohibitively difficult. We therefore investigated the clinical and immunological impact of unscreened, CD8+ enriched “young” TIL. Experimental Design Methods were developed for generating TIL that minimized the time in culture and eliminated the individualized tumor-reactivity screening step. Thirty-three patients were treated with these CD8+ enriched young TIL and IL-2 following non-myeloablative lymphodepletion (NMA). Twenty-three additional patients were treated with CD8+ enriched young TIL and IL-2 after lymphodepletion with NMA and 6Gy of total body irradiation (TBI). Results Young TIL cultures for therapy were successfully established from 83% of 122 consecutive melanoma patients. Nineteen of 33 patients (58%) treated with CD8+ enriched young TIL and NMA had an objective response (RECIST) including three complete responders. Eleven of 23 patients (48%) treated with TIL and 6Gy TBI had an objective response including two complete responders. At one month after TIL infusion the absolute CD8+ cell numbers in the periphery were highly correlated with response. Conclusion This study shows that a rapid and simplified method can be used to reliably generate CD8+ enriched young TIL for administration as an individualized therapy for advanced melanoma, and may allow this potentially effective treatment to be applied at other institutions and to reach additional patients. PMID:20668005

  13. The combination of PD-L1 expression and decreased tumor-infiltrating lymphocytes is associated with a poor prognosis in triple-negative breast cancer.

    PubMed

    Mori, Hitomi; Kubo, Makoto; Yamaguchi, Rin; Nishimura, Reiki; Osako, Tomofumi; Arima, Nobuyuki; Okumura, Yasuhiro; Okido, Masayuki; Yamada, Mai; Kai, Masaya; Kishimoto, Junji; Oda, Yoshinao; Nakamura, Masafumi

    2017-01-17

    This study included patients with primary triple-negative breast cancer (TNBC) who underwent resection without neoadjuvant chemotherapy between January 2004 and December 2014. Among the 248 TNBCs studied, programmed cell death ligand-1 (PD-L1) expression was detected in 103 (41.5%) tumors, and high levels of tumor-infiltrating lymphocytes (TILs) were present in 118 (47.6%) tumors. PD-L1 expression correlated with high levels of TILs, but was not a prognostic factor. Patients with TILs-high tumors had better overall survival than those with TILs-low tumors (P = 0.016). There was a strong interaction between PD-L1 expression and TILs that was associated with both recurrence-free survival (P = 0.0018) and overall survival (P = 0.015). Multivariate Cox proportional hazards model analysis showed that PD-L1-positive/TILs-low was an independent negative prognostic factor for both recurrence-free survival and overall survival. Our findings suggest that PD-L1-positive/TILs-low tumors are associated with a poor prognosis in patients with TNBC, and that it is important to focus on the combination of PD-L1 expression on tumor cells and TILs present in the tumor microenvironment. These biomarkers may be useful for stratification of TNBCs and for predicting prognosis and developing novel cancer immunotherapies.

  14. Tumor Infiltrating Lymphocytes Affect the Outcome of Patients with Operable Triple-Negative Breast Cancer in Combination with Mutated Amino Acid Classes

    PubMed Central

    Kotoula, Vassiliki; Lakis, Sotiris; Vlachos, Ioannis S.; Giannoulatou, Eleni; Zagouri, Flora; Alexopoulou, Zoi; Gogas, Helen; Pectasides, Dimitrios; Aravantinos, Gerasimos; Efstratiou, Ioannis; Pentheroudakis, George; Papadopoulou, Kyriaki; Chatzopoulos, Kyriakos; Papakostas, Pavlos; Sotiropoulou, Maria; Nicolaou, Irene; Razis, Evangelia; Psyrri, Amanda; Kosmidis, Paris; Papadimitriou, Christos; Fountzilas, George

    2016-01-01

    Background Stromal tumor infiltrating lymphocytes (TILs) density is an outcome predictor in triple-negative breast cancer (TNBC). Herein we asked whether TILs are related to coding mutation load and to the chemical class of the resulting mutated amino acids, i.e., charged, polar, and hydrophobic mutations. Methods We examined paraffin tumors from TNBC patients who had been treated with adjuvant chemotherapy mostly within clinical trials (training cohort, N = 133; validation, N = 190) for phenotype concordance; TILs density; mutation load and types. Results Concordance of TNBC phenotypes was 42.1% upon local / central, and 72% upon central / central pathology assessment. TILs were not associated with mutation load, type and class of mutated amino acids. Polar and charged mutation patterns differed between TP53 and PIK3CA (p<0.001). Hydrophobic mutations predicted for early relapse in patients with high nodal burden and <50% TILs tumors (training: HR 3.03, 95%CI 1.11–8.29, p = 0.031; validation: HR 2.90, 95%CI 0.97–8.70, p = 0.057), especially if compared to patients with >50% TILs tumors (training p = 0.003; validation p = 0.015). Conclusions TILs density is unrelated to mutation load in TNBC, which may be regarded as an unstable phenotype. If further validated, hydrophobic mutations along with TILs density may help identifying TNBC patients in higher risk for relapse. PMID:27685159

  15. A New Approach to the Adoptive Immunotherapy of Cancer with Tumor-Infiltrating Lymphocytes

    NASA Astrophysics Data System (ADS)

    Rosenberg, Steven A.; Spiess, Paul; Lafreniere, Rene

    1986-09-01

    The adoptive transfer of tumor-infiltrating lymphocytes (TIL) expanded in interleukin-2 (IL-2) to mice bearing micrometastases from various types of tumors showed that TIL are 50 to 100 times more effective in their therapeutic potency than are lymphokine-activated killer (LAK) cells. Therefore the use of TIL was explored for the treatment of mice with large pulmonary and hepatic metastatic tumors that do not respond to LAK cell therapy. Although treatment of animals with TIL alone or cyclophosphamide alone had little impact, these two modalities together mediated the elimination of large metastatic cancer deposits in the liver and lung. The combination of TIL and cyclophosphamide was further potentiated by the simultaneous administration of IL-2. With the combination of cyclophosphamide, TIL, and IL-2, 100% of mice (n = 12) bearing the MC-38 colon adenocarcinoma were cured of advanced hepatic metastases, and up to 50% of mice were cured of advanced pulmonary metastases. Techniques have been developed to isolate TIL from human tumors. These experiments provide a rationale for the use of TIL in the treatment of humans with advanced cancer.

  16. A Novel Trypsin Inhibitor-Like Cysteine-Rich Peptide from the Frog Lepidobatrachus laevis Containing Proteinase-Inhibiting Activity.

    PubMed

    Wang, Yu-Wei; Tan, Ji-Min; Du, Can-Wei; Luan, Ning; Yan, Xiu-Wen; Lai, Ren; Lu, Qiu-Min

    2015-08-01

    Various bio-active substances in amphibian skins play important roles in survival of the amphibians. Many protease inhibitor peptides have been identified from amphibian skins, which are supposed to negatively modulate the activity of proteases to avoid premature degradation or release of skin peptides, or to inhibit extracellular proteases produced by invading bacteria. However, there is no information on the proteinase inhibitors from the frog Lepidobatrachus laevis which is unique in South America. In this work, a cDNA encoding a novel trypsin inhibitor-like (TIL) cysteine-rich peptide was identified from the skin cDNA library of L. laevis. The 240-bp coding region encodes an 80-amino acid residue precursor protein containing 10 half-cysteines. By sequence comparison and signal peptide prediction, the precursor was predicted to release a 55-amino acid mature peptide with amino acid sequence, IRCPKDKIYKFCGSPCPPSCKDLTPNCIAVCKKGCFCRDGTVDNNHGKCVKKENC. The mature peptide was named LL-TIL. LL-TIL shares significant domain similarity with the peptides from the TIL supper family. Antimicrobial and trypsin-inhibitory abilities of recombinant LL-TIL were tested. Recombinant LL-TIL showed no antimicrobial activity, while it had trypsin-inhibiting activity with a Ki of 16.5178 μM. These results suggested there was TIL peptide with proteinase-inhibiting activity in the skin of frog L. laevis. To the best of our knowledge, this is the first report of TIL peptide from frog skin.

  17. Baroclinic mixing of potential vorticity as the principal sharpening mechanism for the extratropical Tropopause Inversion Layer

    NASA Astrophysics Data System (ADS)

    Wang, Shu Meir; Geller, Marvin A.

    2016-09-01

    Previous works have shown that a dry, idealized general circulation model could produce many features of the extratropical Tropopause Inversion Layer (TIL). In particular, the following have been shown, but no explanations were given for these results. (1) A sharper extratropical TIL resulted more from increased horizontal resolution than from increased vertical resolution. (2) If the Equator-to-Pole temperature gradient was varied, the annual variation of the extratropical TIL found in observations could be reproduced. (3) The extratropical TIL altitude showed excellent correlation with the upper tropospheric relative vorticity, as had been previously proposed. (4) Increased horizontal model resolutions led to extratropical TILs that were at lower altitudes. We show that these conclusions follow from baroclinic mixing of high stratospheric potential vorticity into the troposphere being the principal sharpening mechanism for the extratropical TIL and the increased baroclinic activity occurring in higher horizontal resolution models. We furthermore suggest that the distance from the jet exerts a greater influence on the height and sharpness of the extratropical TIL than does the upper tropospheric relative vorticity, and this accounts for the annual behavior of the extratropical TIL found in observations and reproduced with a dry, mechanistic, global model.

  18. Regulation of the Prostate Cancer Tumor Microenvironment

    DTIC Science & Technology

    2015-04-01

    are interested in understanding the mechanisms for development of TILs and how they modulate prostate cancer. Our hypothesis is that the innate ...growth can be altered through modulating the composition of TILs through innate immunity. Body Pathogens or cancerous cells alike can produce danger... innate immunity, including Toll-like receptors (TLRs). Thirteen mammalian TLRs have been identified to date with ligands ranging from

  19. Current Issues and Clinical Evidence in Tumor-Infiltrating Lymphocytes in Breast Cancer

    PubMed Central

    Ahn, Sung Gwe; Jeong, Joon; Hong, SoonWon; Jung, Woo Hee

    2015-01-01

    With the advance in personalized therapeutic strategies in patients with breast cancer, there is an increasing need for biomarker-guided therapy. Although the immunogenicity of breast cancer has not been strongly considered in research or practice, tumor-infiltrating lymphocytes (TILs) are emerging as biomarkers mediating tumor response to treatments. Earlier studies have provided evidence that the level of TILs has prognostic value and the potential for predictive value, particularly in triple-negative and human epidermal growth factor receptor 2–positive breast cancer. Moreover, the level of TILs has been associated with treatment outcome in patients undergoing neoadjuvant chemotherapy. To date, no standardized methodology for measuring TILs has been established. In this article, we review current issues and clinical evidence for the use of TILs in breast cancer. PMID:26278518

  20. Verslag Van De 15e Conferentie Over Very Large Data Bases Van 22 t/m 25 Augustus 1989 Te Amsterdam (Report on the 15th Conference on Very Large Data Bases in Amsterdam from August 22 til August 25 1989)

    DTIC Science & Technology

    1989-10-04

    8217Aunt Nellie Heuristic’ of ’Tante Nellie Methode’ (TNM): ’ Neem bet voorbeeld ter band. Ga ervan uit dat je bet voorbeeld over de telefoon moet...Un. Dortmund ’The LSD tree : spatial access to multidimensional point and non-point objects’ A. Henrich, H-W. Six and P. Widmayer; Fern Un., Hagen...USA ’Optimization and dataflow algorithms for nested tree queries’ M. Muralikrishna; DEC, Colorada Springs CO, USA ’Parallel processing of recursive

  1. Engineered artificial antigen presenting cells facilitate direct and efficient expansion of tumor infiltrating lymphocytes

    PubMed Central

    2011-01-01

    Background Development of a standardized platform for the rapid expansion of tumor-infiltrating lymphocytes (TILs) with anti-tumor function from patients with limited TIL numbers or tumor tissues challenges their clinical application. Methods To facilitate adoptive immunotherapy, we applied genetically-engineered K562 cell-based artificial antigen presenting cells (aAPCs) for the direct and rapid expansion of TILs isolated from primary cancer specimens. Results TILs outgrown in IL-2 undergo rapid, CD28-independent expansion in response to aAPC stimulation that requires provision of exogenous IL-2 cytokine support. aAPCs induce numerical expansion of TILs that is statistically similar to an established rapid expansion method at a 100-fold lower feeder cell to TIL ratio, and greater than those achievable using anti-CD3/CD28 activation beads or extended IL-2 culture. aAPC-expanded TILs undergo numerical expansion of tumor antigen-specific cells, remain amenable to secondary aAPC-based expansion, and have low CD4/CD8 ratios and FOXP3+ CD4+ cell frequencies. TILs can also be expanded directly from fresh enzyme-digested tumor specimens when pulsed with aAPCs. These "young" TILs are tumor-reactive, positively skewed in CD8+ lymphocyte composition, CD28 and CD27 expression, and contain fewer FOXP3+ T cells compared to parallel IL-2 cultures. Conclusion Genetically-enhanced aAPCs represent a standardized, "off-the-shelf" platform for the direct ex vivo expansion of TILs of suitable number, phenotype and function for use in adoptive immunotherapy. PMID:21827675

  2. TGF-β1-mediated Smad3 enhances PD-1 expression on antigen-specific T cells in cancer

    PubMed Central

    Park, Benjamin V.; Freeman, Zachary T.; Ghasemzadeh, Ali; Chattergoon, Michael A.; Rutebemberwa, Alleluiah; Steigner, Jordana; Winter, Matthew E.; Huynh, Thanh V.; Sebald, Suzanne M.; Lee, Se-Jin; Pan, Fan; Pardoll, Drew M.; Cox, Andrea L.

    2017-01-01

    Programmed Death-1 (PD-1) is a co-inhibitory receptor that down-regulates the activity of tumor-infiltrating lymphocytes (TIL) in cancer and of virus-specific T cells in chronic infection. The molecular mechanisms driving high PD-1 expression on TIL have not been fully investigated. We demonstrate that transforming growth factor-β1 (TGF-β1) directly enhances antigen-induced PD-1 expression through Smad3-dependent, Smad2-independent transcriptional activation in T cells in vitro and in TIL in vivo. The PD-1hi subset seen in CD8+ TIL is absent in Smad3-deficient tumor-specific CD8+ TIL, resulting in enhanced cytokine production by TIL and in draining lymph nodes and of anti-tumor activity. In addition to TGF-β1’s previously known effects on T cell function, our findings suggest that TGF-β1 mediates T cell suppression via PD-1 upregulation in the TME. They highlight bidirectional crosstalk between effector TIL and TGF-β-producing cells that upregulates multiple components of the PD-1 signaling pathway to inhibit anti-tumor immunity. PMID:27683557

  3. Endoplasmic reticulum stress induces secretion of high-mobility group proteins and is associated with tumor-infiltrating lymphocytes in triple-negative breast cancer

    PubMed Central

    Park, In Ah; Heo, Sun-Hee; Song, In Hye; Kim, Young-Ae; Park, Hye Seon; Bang, Won Seon; Park, Suk Young; Jo, Jeong-Hyon; Lee, Hee Jin; Gong, Gyungyub

    2016-01-01

    Background Although the prognostic and predictive significance of tumor-infiltrating lymphocytes (TILs) in triple-negative breast cancer (TNBC) have been shown, the cause of the TIL influx is unclear. Here, we investigated whether extracellular secretion of HMGN1 is associated with TIL influx, as well as increased endoplasmic reticulum stress (ERS), in human TNBC. Methods We reviewed the slides of 767 patients with TNBC and evaluated the TIL levels. We also assessed the expression of HMGs and several ERS-associated molecules using immunohistochemical staining. Western blot analysis of human TNBC cell lines and pharmacological ERS inducers was used to determine if HMGN1 migrates from the nucleus to the extracellular space in response to ERS. Results On immunohistochemical staining, either higher nuclear or cytoplasmic expression of both HMGB1 and HMGN1 was significantly associated with ERS. TILs showed a positive correlation with the cytoplasmic expression of the HMGs. Western blot analysis of TNBC cell lines showed that ERS induction resulted in the secretion of HMG proteins. Conclusions This is the first study to elucidate the associations among ERS, secretion of HMGs, and degree of TILs in TNBCs. Understanding the mechanisms of TIL influx will help in the development of effective immunotherapeutic agents for TNBC. PMID:27494867

  4. Modulating Effects of Spirulina platensis against Tilmicosin-Induced Cardiotoxicity in Mice

    PubMed Central

    Ibrahim, Abdelaziz E.; Abdel-Daim, Mohamed Mohamed

    2015-01-01

    Objective Tilmicosin (TIL) is a long-acting macrolide antibiotic used to treat cattle for pathogens that cause bovine respiratory disease. However, overdoses of this medication have been reported to induce cardiac damage. Our experimental objective was to evaluate the protective effects of Spirulina platensis (SP) administration against TIL-induced cardiotoxicity in mice. Materials and Methods Our experimental in vivo animal study used 40 male albino mice that were divided into five groups of eight mice per group. The first group served as a control group and was injected with saline. The second group received SP at dose of 1000 mg/kg body weight for five days. The third group received a single dose of TIL (75 mg/kg, subcutaneously). Groups 4 and 5 were given SP at doses of 500 and 1000 mg/kg body weight for five consecutive days just before administration of TIL at the same dose and regimen used for group 3. Results TIL treated animals showed a significant increase in serum cardiac injury biomarkers as well as cardiac lipid peroxidation, however they had evidence of an inhibition in antioxidant biomarkers. SP normalized elevated serum levels of lactate dehydrogenase (LDH), creatine kinase (CK), and CK-MB. Furthermore, SP reduced TIL-induced lipid peroxidation and oxidative stress in a dose-dependent manner. Conclusion Administration of SP minimized the toxic effects of TIL by its free radicalscavenging and potent antioxidant activity. PMID:25870843

  5. Synergistic protective role of mirazid (Commiphora molmol) and ascorbic acid against tilmicosin-induced cardiotoxicity in mice.

    PubMed

    Abdel-Daim, Mohamed M; Ghazy, Emad W; Fayez, Mostafa

    2015-01-01

    Tilmicosin (TIL) is a long-acting macrolide antibiotic approved for the treatment of cattle with Bovine Respiratory Disease. However, overdose of TIL has been reported to induce cardiotoxicity. The purpose of our experiment was to evaluate the protective effects of Commiphora molmol (mirazid (MRZ); myrrh) and (or) ascorbic acid (AA) against TIL-induced cardiotoxicity in mice. MRZ and AA were orally administered using stomach gavage, either alone or in combination for 5 consecutive days, followed with a single TIL overdose. TIL overdose induced a significant increase in serum levels of cardiac damage biomarkers (AST, LDH, CK, CK-MB, and cTnT), as well as cardiac lipid peroxidation, but cardiac levels of antioxidant biomarkers (GSH, SOD, CAT, and TAC) were decreased. Both MRZ and AA tended to normalize the elevated serum levels of cardiac injury biomarkers. Furthermore, MRZ and AA reduced TIL-induced lipid peroxidation and oxidative stress parameters. MRZ and AA combined produced a synergistic cardioprotective effect. We conclude that myrrh and (or) vitamin C administration minimizes the toxic effects of TIL through their free-radical-scavenging and potent antioxidant activities.

  6. Glutaminase expression is a poor prognostic factor in node-positive triple-negative breast cancer patients with a high level of tumor-infiltrating lymphocytes.

    PubMed

    Kim, Joo Young; Heo, Sun-Hee; Choi, Seul Ki; Song, In Hye; Park, In Ah; Kim, Young-Ae; Park, Hye Seon; Park, Suk Young; Bang, Won Seon; Gong, Gyungyub; Lee, Hee Jin

    2017-04-01

    Glutamine metabolism is emerging as one aspect of dysregulated metabolism of tumors. Triple-negative breast cancer (TNBC) cells are glutamine dependent, whereas luminal-type cells tend to be glutamine independent. Therefore, TNBC patients might benefit from therapies targeting glutamine metabolism. To investigate the clinical significance of glutamine metabolism, we examined expression and prognostic significance of glutaminase in tumor cells and tumor-infiltrating lymphocytes (TILs) in TNBC. We retrieved 658 surgically resected TNBCs and analyzed glutaminase expression in tumor cells and TILs by immunohistochemical staining. Glutaminase expression was observed in 237 cases (36.0%) in tumor cells and 104 cases (15.5%) in TILs. Although glutaminase expression in tumor cells was significantly associated with a low level of TILs (p = 0.018), glutaminase expression in TILs was significantly higher in cases with a high level of TILs (p = 0.031). Glutaminase expression in tumor cells was significantly associated with poor disease-free survival in patients with lymph node metastasis and high levels of TILs (p = 0.020). In addition, it was an independent poor prognostic factor (hazard ratio = 10.643, 95% confidence interval = 1.999-56.668; p = 0.006). Glutaminase expression in tumor cells was observed in a subset of TNBC patients. It was significantly associated with a low level of TILs and poor disease-free survival in TNBCs presenting with lymph node metastasis and high levels of TILs.

  7. Phenotype and function of T cells infiltrating visceral metastases from gastrointestinal cancers and melanoma: implications for adoptive cell transfer therapy.

    PubMed

    Turcotte, Simon; Gros, Alena; Hogan, Katherine; Tran, Eric; Hinrichs, Christian S; Wunderlich, John R; Dudley, Mark E; Rosenberg, Steven A

    2013-09-01

    Adoptive cell transfer of tumor-infiltrating lymphocytes (TILs) can mediate cancer regression in patients with metastatic melanoma, but whether this approach can be applied to common epithelial malignancies remains unclear. In this study, we compared the phenotype and function of TILs derived from liver and lung metastases from patients with gastrointestinal (GI) cancers (n = 14) or melanoma (n = 42). Fewer CD3(+) T cells were found to infiltrate GI compared with melanoma metastases, but the proportions of CD8(+) cells, T cell differentiation stage, and expression of costimulatory molecules were similar for both tumor types. Clinical-scale expansion up to ~50 × 10(9) T cells on average was obtained for all patients with GI cancer and melanoma. From GI tumors, however, TIL outgrowth in high-dose IL-2 yielded 22 ± 1.4% CD3(+)CD8(+) cells compared with 63 ± 2.4% from melanoma (p < 0.001). IFN-γ ELISA demonstrated MHC class I-mediated reactivity of TIL against autologous tumor in 5 of 7 GI cancer patients tested (9% of 188 distinct TIL cultures) and in 9 of 10 melanoma patients (43% of 246 distinct TIL cultures). In these assays, MHC class I-mediated up-regulation of CD137 (4-1BB) expression on CD8(+) cells suggested that 0-3% of TILs expanded from GI cancer metastases were tumor-reactive. This study implies that the main challenge to the development of TIL adoptive cell transfer for metastatic GI cancers may not be the in vitro expansion of bulk TILs, but the ability to select and enrich for tumor-reactive T cells.

  8. Tumor-infiltrating lymphocytes in breast cancer predict the response to chemotherapy and survival outcome: A meta-analysis

    PubMed Central

    Wang, Ke; Xu, Jianjun; Zhang, Tao; Xue, Dan

    2016-01-01

    Tumor-infiltrating lymphocytes (TILs) influence tumor prognosis and the chemotherapeutic response. Here, we quantified the clinical relevance of TILs, including the effect of TILs on lymphocyte subpopulations and assessed their consistency in breast cancer. We searched published literature from January 2000 to January 2016. The main parameters analyzed were pathological complete response (pCR) and survival outcome following chemotherapy in patients with breast cancer. Pooled odds ratio (OR) or relative risk (RR) values with 95% confidence intervals (CIs) were computed using random and fixed-effects models. Subgroup and heterogeneity analyses were also conducted. Twenty-three studies, which included 13,100 patients, met the inclusion criteria. The pooled results showed that TILs were associated with clinicopathological parameters of biologically aggressive phenotypes, such as high tumor grade or estrogen/progesterone receptor negativity, but they were not correlated with human epidermal growth factor receptor-2 expression. Moreover, a high TIL level was associated with a significantly improved pCR rate compared with a low TIL level (OR, 2.81; P < 0.001), particularly in the triple-negative breast cancer subtype (OR, 4.67; P < 0.001). An analysis of lymphocyte subpopulations showed that infiltration by CD8 lymphocytes, but not by CD4 lymphocytes and Foxp3 cells, was associated with a high pCR rate. Furthermore, a high TIL level was associated with significantly longer disease-free survival and overall survival. Our present meta-analysis indicates that an increased number of TILs predicted pCR to chemotherapy and improved survival. A high TIL level, characterized mainly by the infiltration of CD8 lymphocytes, is a strong predictive and prognostic factor. PMID:27329588

  9. Antigen(s)-specific tumour-infiltrating lymphocytes from tumour induced by human herpes virus-6 (HHV-6) DNA transfected NIH 3T3 transformants.

    PubMed Central

    Puri, R K; Leland, P; Razzaque, A

    1991-01-01

    Tumour infiltrating lymphocytes (TIL) have recently been shown to mediate potent therapeutic effects in certain malignancies in mice and in humans. To understand the mechanism of TIL immunotherapy it would be advantageous to generate tumour-specific TIL and to study a defined system of TIL and target cells in which the tumour epitope(s) recognized by TIL might be identified. We have established tumourigenic cell lines by transfection of NIH 3T3 cells with the entire genome of human herpesvirus-6 (HHV-6) and its small fragment (about 5% of the viral DNA sequence). Injection of these cells into nude mice produced tumours termed G-2T and 14-2T, respectively. Cell lines derived from these tumours when injected in NIH Swiss mice produced tumours, G-2TS and 14-2TS, respectively. We have generated TIL from G-2TS tumour that can kill G-2TS tumour cells in vitro but not other related tumours (14-2TS or MCA-106). These TIL can be expanded between 2-6.5 every 3-5 days. The TIL proliferated in tissue culture in response to recombinant interleukin-2 and interleukin-4 and maintained their tumor specificity for up to 6 months in vitro. Their phenotype was Thy 1.2+, Lyt-2+ and L3T4-. The availability of such tumour-specific stable TIL lines and specific viral-transformed targets will provide an opportunity to characterize the tumour-associated antigen critical for the specific cytotoxicity in this system and thereby to clarify the mechanism of this promising immunological approach to cancer therapy. Images Fig. 1 PMID:1703057

  10. The effects of granulocyte-macrophage colony-stimulating factor on tumour-infiltrating lymphocytes from renal cell carcinoma.

    PubMed Central

    Steger, G. G.; Kaboo, R.; deKernion, J. B.; Figlin, R.; Belldegrun, A.

    1995-01-01

    It has been shown that granulocyte-macrophage colony-stimulating factor (GM-CSF) can induce specific and non-specific anti-tumour cytotoxicity and also stimulates the proliferation and function of peripheral lymphocytes and thymocytes. GM-CSF and interleukin 2 (IL-2) act synergistically on peripheral lymphocytes for the induction of a highly effective cytotoxic cell population. Thus, the goal of our investigation was to study the effects of GM-CSF upon expansion, proliferation and in vitro killing activity of tumour-infiltrating lymphocytes (TILs) from renal cell carcinoma (RCC). TILs from seven consecutive tumours were cultured with GM-CSF (500 or 1000 nmol ml-1) without IL-2 supplementation, with suboptimal doses of IL-2 (8 and 40 U ml-1) plus GM-CSF (1000 nmol ml-1), and with a dose of IL-2 (400 U ml-1) which sufficed alone to induce TIL development plus GM-CSF (500 or 1000 nmol ml-1). GM-CSF alone or together with suboptimal doses of IL-2 was not able to induce or facilitate TIL development in these cultures. When GM-CSF at both concentrations studied was added to optimal doses of IL-2 the resulting TIL populations proliferated significantly better and faster (+66%), resulting in a higher cell yield (+24%) at the time of maximal expansion of the TIL cultures. The length of the culture periods of TILs was not affected by GM-CSF when compared with the control cultures supplemented with IL-2 alone. In vitro killing activity of TIL populations stimulated with IL-2 and GM-CSF remained unspecific, but lysis of the autologous tumour targets as well as the allogeneic renal tumour targets was significantly enhanced (+138%) as compared with the corresponding control TILs stimulated with IL-2 alone. Lysis of the natural killer (NK)-sensitive control cell line K562 and the NK-resistant Daudi cell line remained unchanged even though FACS analysis of TILs cultured with IL-2 and 1000 nmol of GM-CSF demonstrated a significantly higher proportion of cells expressing the CD56

  11. Holistic Debriefing: A Paradigm Shift in Leadership

    DTIC Science & Technology

    2009-04-01

    Officer Rolf Folland for the RNOAF 330 Squadron on the subject “debriefing”, 8 October 2005. 2 Bjartveit and Kjærstad, Fra kaos til kosmos , 17 3... kosmos , 22 25 Ibid, 23 26 Moxnes, Hverdagens Angst, 194 27 Bjartveit and Kjærstad, Fra kaos til kosmos , 17 28 Useem, The Leadership Moment, 60 29 Ibid...Psychology (9. ed.). Orlando, FL: Harcourt Brace Jovanovich Publishers. 1985. Bjartveit, S. & Kjærstad, T. Fra kaos til kosmos . Oslo: Oslo Kolle Forlag

  12. Stress and Hair Loss: Are They Related?

    MedlinePlus

    ... hair. Trichotillomania. Trichotillomania (trik-o-til-o-MAY-nee-uh) is an irresistible urge to pull out ... Flavin, M.D. References Shapiro J, et al. Evaluation and diagnosis of hair loss. http://www.uptodate. ...

  13. Improved Personalized Cancer Immunotherapy: Rapid Selection of Tumor-Reactive T Cells based on Expression of Specific Cell Surface Markers | NCI Technology Transfer Center | TTC

    Cancer.gov

    The National Cancer Institute’s Surgery Branch seeks partners interested in collaborative research to co-develop adoptive transfer of tumor infiltrating leukocytes (TIL) for cancers other than melanoma.

  14. Tumor infiltrating lymphocytes in triple negative breast cancer receiving neoadjuvant chemotherapy

    PubMed Central

    Castaneda, Carlos A; Mittendorf, Elizabeth; Casavilca, Sandro; Wu, Yun; Castillo, Miluska; Arboleda, Patricia; Nunez, Teresa; Guerra, Henry; Barrionuevo, Carlos; Dolores-Cerna, Ketty; Belmar-Lopez, Carolina; Abugattas, Julio; Calderon, Gabriela; De La Cruz, Miguel; Cotrina, Manuel; Dunstan, Jorge; Gomez, Henry L; Vidaurre, Tatiana

    2016-01-01

    AIM To determine influence of neoadjuvant-chemotherapy (NAC) over tumor-infiltrating-lymphocytes (TIL) in triple-negative-breast-cancer (TNBC). METHODS TILs were evaluated in 98 TNBC cases who came to Instituto Nacional de Enfermedades Neoplasicas from 2005 to 2010. Immunohistochemistry staining for CD3, CD4, CD8 and FOXP3 was performed in tissue microarrays (TMA) sections. Evaluation of H/E in full-face and immunohistochemistry in TMA sections was performed in pre and post-NAC samples. STATA software was used and P value < 0.05 was considered statistically significant. RESULTS Higher TIL evaluated in full-face sections from pre-NAC tumors was associated to pathologic-complete-response (pCR) (P = 0.0251) and outcome (P = 0.0334). TIL evaluated in TMA sections showed low level of agreement with full-face sections (ICC = 0.017-0.20) and was not associated to pCR or outcome. TIL in post-NAC samples were not associated to response or outcome. Post-NAC lesions with pCR had similar TIL levels than those without pCR (P = 0.6331). NAC produced a TIL decrease in full-face sections (P < 0.0001). Percentage of TIL subpopulations was correlated with their absolute counts. Higher counts of CD3, CD4, CD8 and FOXP3 in pre-NAC samples had longer disease-free-survival (DFS). Higher counts of CD3 in pre-NAC samples had longer overall-survival. Higher ratio of CD8/CD4 counts in pre-NAC was associated with pCR. Higher ratio of CD4/FOXP3 counts in pre-NAC was associated with longer DFS. Higher counts of CD4 in post-NAC samples were associated with pCR. CONCLUSION TIL in pre-NAC full-face sections in TNBC are correlated to longer survival. TIL in full-face differ from TMA sections, absolute count and percentage analysis of TIL subpopulation closely related. PMID:27777881

  15. Subverting the adaptive immune resistance mechanism to improve clinical responses to immune checkpoint blockade therapy

    PubMed Central

    Kim, Young J

    2015-01-01

    The correlation between tumor-infiltrating lymphocyte (TIL)-expression of programmed cell death ligand 1 (PD-L1) and clinical responsiveness to the PD-1 blocking antibody nivolumab implicates adaptive immune evasion mechanisms in cancer. We review our findings that tumor cell PD-L1 expression is induced by interferon γ (IFNγ) producing TILs. We provide a mechanistic rationale for combining IFNγ+ T helper type 1 (Th1)-inducing cancer vaccines with PD-1 immune checkpoint blockade. PMID:25964860

  16. Specific lymphocyte subsets predict response to adoptive cell therapy using expanded autologous tumor-infiltrating lymphocytes in metastatic melanoma patients

    PubMed Central

    Radvanyi, Laszlo G.; Bernatchez, Chantale; Zhang, Minying; Fox, Patricia S.; Miller, Priscilla; Chacon, Jessica; Wu, Richard; Lizee, Gregory; Mahoney, Sandy; Alvarado, Gladys; Glass, Michelle; Johnson, Valen E.; McMannis, John D.; Shpall, Elizabeth; Prieto, Victor; Papadopoulos, Nicholas; Kim, Kevin; Homsi, Jade; Bedikian, Agop; Hwu, Wen-Jen; Patel, Sapna; Ross, Merrick I.; Lee, Jeffrey E.; Gershenwald, Jeffrey E.; Lucci, Anthony; Royal, Richard; Cormier, Janice N.; Davies, Michael A.; Mansaray, Rahmatu; Fulbright, Orenthial J.; Toth, Christopher; Ramachandran, Renjith; Wardell, Seth; Gonzalez, Audrey; Hwu, Patrick

    2012-01-01

    Purpose Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) is a promising treatment for metastatic melanoma unresponsive to conventional therapies. We report here on the results of an ongoing Phase II clinical trial testing the efficacy of ACT using TIL in metastatic melanoma patients and the association of specific patient clinical characteristics and the phenotypic attributes of the infused TIL with clinical response. Experimental Design Altogether, 31 transiently lymphodepleted patients were treated with their expanded TIL followed by two cycles of high-dose (HD) IL-2 therapy. The effects of patient clinical features and the phenotypes of the T-cells infused on clinical response were determined. Results Overall, 15/31 (48.4%) patients had an objective clinical response using immune-related response criteria (irRC), with two patients (6.5%) having a complete response. Progression-free survival of >12 months was observed for 9/15 (60%) of the responding patients. Factors significantly associated with objective tumor regression included a higher number of TIL infused, a higher proportion of CD8+ T-cells in the infusion product, a more differentiated effector phenotype of the CD8+ population and a higher frequency of CD8+ T-cells co-expressing the negative costimulation molecule “B- and T-lymphocyte attenuator” (BTLA). No significant difference in telomere lengths of TIL between responders and non-responders was identified. Conclusion These results indicate that immunotherapy with expanded autologous TIL is capable of achieving durable clinical responses in metastatic melanoma patients and that CD8+ T-cells in the infused TIL, particularly differentiated effectors cells and cells expressing BTLA, are associated with tumor regression. PMID:23032743

  17. Co-stimulation through the CD137/4-1BB pathway protects human melanoma tumor-infiltrating lymphocytes from activation-induced cell death and enhances anti-tumor effector function

    PubMed Central

    Hernandez-Chacon, Jessica Ann; Li, Yufeng; Wu, Richard C.; Bernatchez, Chantale; Wang, Yijun; Weber, Jeffrey; Hwu, Patrick; Radvanyi, Laszlo

    2011-01-01

    Adoptive T-cell therapy (ACT) using expanded tumor-infiltrating lymphocytes (TIL) with high-dose IL-2 is a promising form of immunotherapy for Stage IV melanoma having clinical response rates of 50% or more. One of the major problems preventing further success of this therapy is that the current protocols used to highly expand TIL for infusion drive CD8+ T cells to differentiate into effector cells losing key co-stimulatory molecules such as CD28 and CD27. This has been associated with a lack of persistence in vivo for reasons not entirely clear. In this study, we demonstrate that while human melanoma CD8+ TIL lost CD27 and CD28 expression during the rapid expansion for ACT, they gained expression of the alternative co-stimulatory molecule CD137/4-1BB, and to a lesser extent CD134/OX40. Post-REP TIL were found to be highly sensitive to activation-induced cell death (AICD) when re-activated through the TCR with low levels of OKT3 antibody. However, co-ligation of 4-1BB using two different agonistic anti-4-1BB antibodies potently prevented AICD of post-REP CD8+ TIL, including those specific for MART-1, and facilitated even further cell expansion. This was correlated with increased levels of bcl-2 and bcl-xL together with decreased bim expression. 4-1BB-co-stimulated post-REP TIL also expressed increased levels of the cytolytic granule proteins and exhibited enhanced CTL activity against melanoma cells. Lastly, post-REP CD8+ TIL were protected from cell death by anti-4-1BB ligation when exposed to HLA-matched melanoma cells. Our results indicate that 4-1BB co-stimulation may significantly improve TIL survival during melanoma ACT and boost anti-tumor cytolytic activity. PMID:21389874

  18. Adaptive resistance to anti-PD1 therapy by Tim-3 upregulation is mediated by the PI3K-Akt pathway in head and neck cancer.

    PubMed

    Shayan, Gulidanna; Srivastava, Raghvendra; Li, Jing; Schmitt, Nicole; Kane, Lawrence P; Ferris, Robert L

    2017-01-01

    Programmed Death 1 (PD-1) and T cell Ig and mucin domain-3 protein (Tim-3) are immune checkpoint receptors that are expressed on tumor-infiltrating lymphocytes (TIL) in tumor-bearing mice and humans. As anti-PD-1 single agent response rates are only <20% in head and neck squamous cell carcinoma (HNSCC) patients, it is important to understand how multiple inhibitory checkpoint receptors maintain suppressed cellular immunity. One such receptor, Tim-3, activates downstream proliferative pathways through Akt/S6, and is highly expressed in dysfunctional TIL. We observed that PD-1 and Tim-3 co-expression was associated with a more exhausted phenotype, with the highest PD-1 levels on TIL co-expressing Tim-3. Dampened Akt/S6 phosphorylation in these PD-1(+)Tim-3(+) TIL, when the PD-1 pathway was ligated, suggested that signaling cross-talk could lead to escape through Tim-3 expression. Indeed, PD-1 blockade of human HNSCC TIL led to further Tim-3 upregulation, supporting a circuit of compensatory signaling and potentially permitting escape from anti-PD-1 blockade in the tumor microenvironment. Also, in a murine HNC tumor model that is partially responsive to anti-PD-1 therapy, Tim-3 was upregulated in TIL from persistently growing tumors. Significant antitumor activity was observed after sequential addition of anti-Tim-3 mAb to overcome adaptive resistance to anti-PD-1 mAb. This increased Tim-3-mediated escape of exhausted TIL from PD-1 inhibition that was mediated by phospho-inositol-3 kinase (PI3K)/Akt complex downstream of TCR signaling but not cytokine-mediated pathways. Taken together, we conclude that during PD-1 blockade, TIL upregulate Tim-3 in a PI3K/Akt-dependent manner, providing further support for dual targeting of these molecules for more effective cancer immunotherapy.

  19. Identification of Tumor Rejection Antigens for Breast Cancer Using a Mouse Tumor Rejection Model

    DTIC Science & Technology

    2009-05-01

    high throughput antigen discovery tools have been developed that have greatly helped the identification of immunogenic proteins in breast cancer...streptomycin and L-glutamine. T cell enrichment Tumor-infiltrating lymphocytes (TIL) were harvested by mincing the tu- mor and screening. The TIL were...kinase 1. Multiple proteins involved in the Rho/Rho-associated, coiled coil–containing protein kinase (Rock) signal transduction pathway were found to

  20. Up-regulation of cerebral cytochrome-c-oxidase and hemodynamics by transcranial infrared laser stimulation: A broadband near-infrared spectroscopy study.

    PubMed

    Wang, Xinlong; Tian, Fenghua; Reddy, Divya D; Nalawade, Sahil S; Barrett, Douglas W; Gonzalez-Lima, Francisco; Liu, Hanli

    2017-01-01

    Transcranial infrared laser stimulation (TILS) is a noninvasive form of brain photobiomulation. Cytochrome-c-oxidase (CCO), the terminal enzyme in the mitochondrial electron transport chain, is hypothesized to be the primary intracellular photoacceptor. We hypothesized that TILS up-regulates cerebral CCO and causes hemodynamic changes. We delivered 1064-nm laser stimulation to the forehead of healthy participants ( n = 11), while broadband near-infrared spectroscopy was utilized to acquire light reflectance from the TILS-treated cortical region before, during, and after TILS. Placebo experiments were also performed for accurate comparison. Time course of spectroscopic readings were analyzed and fitted to the modified Beer-Lambert law. With respect to the placebo readings, we observed (1) significant increases in cerebral concentrations of oxidized CCO (Δ[CCO]; >0.08 µM; p < 0.01), oxygenated hemoglobin (Δ[HbO]; >0.8 µM; p < 0.01), and total hemoglobin (Δ[HbT]; >0.5 µM; p < 0.01) during and after TILS, and (2) linear interplays between Δ[CCO] versus Δ[HbO] and between Δ[CCO] versus Δ[HbT]. Ratios of Δ[CCO]/Δ[HbO] and Δ[CCO]/Δ[HbT] were introduced as TILS-induced metabolic-hemodynamic coupling indices to quantify the coupling strength between TILS-enhanced cerebral metabolism and blood oxygen supply. This study provides the first demonstration that TILS causes up-regulation of oxidized CCO in the human brain, and contributes important insight into the physiological mechanisms.

  1. Development of tunable high pressure CO2 laser for lidar measurements of pollutants and wind velocities

    NASA Technical Reports Server (NTRS)

    Levine, J. S.; Guerra, M.; Javan, A.

    1980-01-01

    The problem of laser energy extraction at a tunable monochromatic frequency from an energetic high pressure CO2 pulsed laser plasma, for application to remote sensing of atmospheric pollutants by Differential Absorption Lidar (DIAL) and of wind velocities by Doppler Lidar, was investigated. The energy extraction principle analyzed is based on transient injection locking (TIL) at a tunable frequency. Several critical experiments for high gain power amplification by TIL are presented.

  2. Prognostic value, localization and correlation of PD-1/PD-L1, CD8 and FOXP3 with the desmoplastic stroma in pancreatic ductal adenocarcinoma

    PubMed Central

    Diana, Angela; Wang, Lai Mun; D'Costa, Zenobia; Allen, Paul; Azad, Abul; Silva, Michael A.; Soonawalla, Zahir; Liu, Stanley; McKenna, W. Gillies; Muschel, Ruth J.; Fokas, Emmanouil

    2016-01-01

    We examined the prognostic value of programmed cell death-1 (PD-1) and its ligand (PD-L1) together with CD8+ tumor-infiltrating lymphocytes (TILs) and FOXP3+ Tregs in resectable pancreatic ductal adenocarcinoma (PDAC) samples treated with adjuvant chemotherapy. Whole-mount FFPE tissue sections from 145 pancreatectomies were immunohistochemically stained for PD-1, PD-L1, CD8 and FOXP3. Their expression was correlated with clinicopathological characteristics, and overall survival (OS), progression-free survival (PFS), local progression-free survival (LPFS) and distant metastases free-survival (DMFS), in the context of stroma density (haematoxylin-eosin) and activity (alpha-smooth muscle actin) and in regard to intratumoral lymphoid aggregates. The median OS was 21 months after a mean follow-up of 20 months (range, 2-69 months). In multivariate analysis, high PD-1+ TILs expression was associated with better OS (p = 0.049), LPFS (p = 0.017) and DMFS (p = 0.021). Similar findings were observed for CD8+ TILs, whereas FOXP3 and PD-L1 lacked prognostic significance. Although TIL distribution was heterogeneous, tumors of high stroma density had higher infiltration of CD8+ TILs than loose density stroma and vice versa (p < 0.001), whereas no correlation was found with stromal activity. Sixty (41.4%) tumors contained lymphoid aggregates and the presence of PD-1+ TILs was associated with better OS (p = 0.030), LPFS (p = 0.025) and DMFS (p = 0.033), whereas CD8+ TILs only correlated with superior LPFS (p = 0.039). PD-1+ and CD8+ TILs constitute independent prognostic markers in patients with PDAC treated with adjuvant chemotherapy. Our study provides important insight on the role of PD-1/PD-L1 in the context of desmoplastic stroma and could help guide future immunotherapies in PDAC. PMID:27329602

  3. Identification by digital immunohistochemistry of intratumoral changes of immune infiltrates after vaccine in the absence of modifications of PBMC immune cell subsets.

    PubMed

    Farsaci, Benedetto; Jochems, Caroline; Grenga, Italia; Donahue, Renee N; Tucker, Jo A; Pinto, Peter A; Merino, Maria J; Heery, Christopher R; Madan, Ravi A; Gulley, James L; Schlom, Jeffrey

    2014-08-15

    Preclinical studies have demonstrated that the combination of systemic subcutaneous (s.c.) vaccination with intratumoral (i.t.) vaccination was superior in the induction of antitumor activity vs. vaccination with either route alone. A subsequent phase I study employing i.t.-s.c. vaccination was carried out in men with locally recurrent or progressive prostate cancer. rF-PSA-TRICOM (PROSTVAC) vaccine was administered intraprostatically and rV-PSA-TRICOM followed by rF-PSA-TRICOM vaccine was administered systemically. In that study no dose limiting toxicities were observed, 19/21 patients had stable or improved prostate-specific antigen (PSA) values and tumor-infiltrating lymphocytes (TILs) increased in post- vs. pre-treatment tumor biopsies, analyzed employing conventional immunohistochemistry (IHC). In the studies reported here, 31 phenotypes of peripheral blood mononuclear cells (PBMCs) were analyzed prevaccination and postvaccination as well as the functions of PBMC regulatory T cells (Tregs) and natural killer cells. A trend was observed in decreases in serum PSA with the reduction of circulating Tregs postvaccination. Digital IHC was employed prevaccination and postvaccination to measure CD4 and CD8 TILs, as well as Treg TILs by conventional IHC. Few correlations were observed with CD4, CD8 or Treg in TILs vs. PBMCs. However, patients with lower levels of CD4 TILs prevaccination showed the greatest increases in CD4 TILs postvaccine, while Treg TILs decreased postvaccine. There was also a strong correlation between decreases in serum PSA and increases in CD8 TILs postvaccine. These studies provide additional rationale for the use of i.t.-s.c. vaccinations and demonstrate a noncoordinate expression of specific immune subsets in PBMCs vs. tumor.

  4. Evaluation of the Toxicokinetic Study of 1,2-Propanediol Dinitrate (PGDN) in the Dog.

    DTIC Science & Technology

    1982-05-01

    JAFAMRL-TR-82-27 EVALUATION OF THE TOXICOKINETIC STUDY OF 1,2- PROPANEDIOL DINMITATE (PGDN) IN THE DOG P. K NEWTON J. A. MA CE WAN p- HV.R NOTm...Rltoo COVERED EVALUATION OF TIlE TOXICOKIXETIC STUDY OF 1,2- PROPANEDIOL DINITRATE (PGDN) IN TIlE Technical Report DOG 1 PERFORMNG OIG REPORT NUMAER...l,2- Propanediol Dinitrate ilypotension PGDN Tachycardia Toxicokinetics Dog *.ilethemoglobin Bolus injections of PGDN, an organic dinitrate, were made

  5. Targeting programmed cell death ligand 1 in osteosarcoma: an auto-commentary on therapeutic potential.

    PubMed

    Shen, Jacson K; Cote, Gregory M; Choy, Edwin; Hornicek, Francis J; Duan, Zhenfeng

    Programmed cell death ligand 1 (PDL1) expression was recently shown to correlate with tumor-infiltrating lymphocytes (TILs) in a subset of osteosarcoma patients. Among clinical factors evaluated across human osteosarcoma samples, a pulmonary origin of metastases correlated with high PDL1 expression and prominent TILs. Considering that multiple agents targeting PD-1/PDL1 are under development, targeting this immune checkpoint may be a novel immunotherapeutic route for osteosarcoma in future clinical trials.

  6. Tumor-infiltrating lymphocyte activity is enhanced in tumors with low IL-10 production in HBV-induced hepatocellular carcinoma

    SciTech Connect

    Shi, Yang Song, Qingwei; Hu, Dianhe; Zhuang, Xiaohu; Yu, Shengcai

    2015-05-22

    Hepatocellular carcinoma (HCC) is one of the most common cancers and can be induced by chronic HBV infection. The role of HBV-specific immune responses in mediating tumorigenesis and HCC prognosis is debated. The effect of intratumoral microenvironment on tumor-infiltrating lymphocytes (TILs) is also unclear. Here, we examined resected tumor tissue from 36 patients with HBV-induced HCC. We categorized study cohort based on ex vivo IL-10 secretion by tumor cells into high IL-10-secreting (Hi10) and low IL-10-secreting (Lo10) groups, and found that the Lo10 group was less sensitive to TLR ligand stimulation. TILs from the Lo10 group contained higher frequencies of HBV-specific IFN-g-producing cells and total IFN-g-producing cells, and possessed higher proliferative capacity. Moreover, the proliferative capacity of TILs from the Hi10 group was negatively correlated with IL-10 secretion from tumor cells. Together, our data demonstrated that low IL-10-producing capacity in HBV-induced HCC tumors is associated with enhanced TIL activity. - Highlights: • We examined intratumoral IL-10 production in HBV-induced HCC. • We grouped HCC tumors into Hi10 and Lo10 groups based on their IL-10 production. • Lo10 groups had better IFN-g response by TILs. • Lo10 groups had better TIL proliferative capacity. • Lo10 group tumor cells were refractory to TLR ligand stimulation.

  7. BTLA marks a less-differentiated tumor-infiltrating lymphocyte subset in melanoma with enhanced survival properties

    PubMed Central

    Haymaker, Cara L; Wu, Richard C; Ritthipichai, Krit; Bernatchez, Chantale; Forget, Marie-Andrée; Chen, Jie Qing; Liu, Hui; Wang, Ena; Marincola, Francesco; Hwu, Patrick; Radvanyi, Laszlo G

    2015-01-01

    In a recent adoptive cell therapy (ACT) clinical trial using autologous tumor-infiltrating lymphocytes (TILs) in patients with metastatic melanoma, we found an association between CD8+ T cells expressing the inhibitory receptor B- and T-lymphocyte attenuator (BTLA) and clinical response. Here, we further characterized this CD8+BTLA+ TIL subset and their CD8+BTLA− counterparts. We found that the CD8+ BTLA+ TILs had an increased response to IL-2, were less-differentiated effector-memory (TEM) cells, and persisted longer in vivo after infusion. In contrast, CD8+BTLA− TILs failed to proliferate and expressed genes associated with T-cell deletion/tolerance. Paradoxically, activation of BTLA signaling by its ligand, herpes virus entry mediator (HVEM), inhibited T-cell division and cytokine production, but also activated the Akt/PKB pathway thus protecting CD8+BTLA+ TILs from apoptosis. Our results point to a new role of BTLA as a useful T-cell differentiation marker in ACT and a dual signaling molecule that curtails T-cell activation while also conferring a survival advantage for CD8+ T cells. These attributes may explain our previous observation that BTLA expression on CD8+ TILs correlates with clinical response to adoptive T-cell therapy in metastatic melanoma. PMID:26405566

  8. Reprogramming of Melanoma Tumor-Infiltrating Lymphocytes to Induced Pluripotent Stem Cells

    PubMed Central

    Saito, Hidehito; Okita, Keisuke; Fusaki, Noemi; Sabel, Michael S.; Chang, Alfred E.; Ito, Fumito

    2016-01-01

    Induced pluripotent stem cells (iPSCs) derived from somatic cells of patients hold great promise for autologous cell therapies. One of the possible applications of iPSCs is to use them as a cell source for producing autologous lymphocytes for cell-based therapy against cancer. Tumor-infiltrating lymphocytes (TILs) that express programmed cell death protein-1 (PD-1) are tumor-reactive T cells, and adoptive cell therapy with autologous TILs has been found to achieve durable complete response in selected patients with metastatic melanoma. Here, we describe the derivation of human iPSCs from melanoma TILs expressing high level of PD-1 by Sendai virus-mediated transduction of the four transcription factors, OCT3/4, SOX2, KLF4, and c-MYC. TIL-derived iPSCs display embryonic stem cell-like morphology, have normal karyotype, express stem cell-specific surface antigens and pluripotency-associated transcription factors, and have the capacity to differentiate in vitro and in vivo. A wide variety of T cell receptor gene rearrangement patterns in TIL-derived iPSCs confirmed the heterogeneity of T cells infiltrating melanomas. The ability to reprogram TILs containing patient-specific tumor-reactive repertoire might allow the generation of patient- and tumor-specific polyclonal T cells for cancer immunotherapy. PMID:27057178

  9. Clinical Scale Zinc Finger Nuclease-mediated Gene Editing of PD-1 in Tumor Infiltrating Lymphocytes for the Treatment of Metastatic Melanoma

    PubMed Central

    Beane, Joal D; Lee, Gary; Zheng, Zhili; Mendel, Matthew; Abate-Daga, Daniel; Bharathan, Mini; Black, Mary; Gandhi, Nimisha; Yu, Zhiya; Chandran, Smita; Giedlin, Martin; Ando, Dale; Miller, Jeff; Paschon, David; Guschin, Dmitry; Rebar, Edward J; Reik, Andreas; Holmes, Michael C; Gregory, Philip D; Restifo, Nicholas P; Rosenberg, Steven A; Morgan, Richard A; Feldman, Steven A

    2015-01-01

    Programmed cell death-1 (PD-1) is expressed on activated T cells and represents an attractive target for gene-editing of tumor targeted T cells prior to adoptive cell transfer (ACT). We used zinc finger nucleases (ZFNs) directed against the gene encoding human PD-1 (PDCD-1) to gene-edit melanoma tumor infiltrating lymphocytes (TIL). We show that our clinical scale TIL production process yielded efficient modification of the PD-1 gene locus, with an average modification frequency of 74.8% (n = 3, range 69.9–84.1%) of the alleles in a bulk TIL population, which resulted in a 76% reduction in PD-1 surface-expression. Forty to 48% of PD-1 gene-edited cells had biallelic PD-1 modification. Importantly, the PD-1 gene-edited TIL product showed improved in vitro effector function and a significantly increased polyfunctional cytokine profile (TNFα, GM-CSF, and IFNγ) compared to unmodified TIL in two of the three donors tested. In addition, all donor cells displayed an effector memory phenotype and expanded approximately 500–2,000-fold in vitro. Thus, further study to determine the efficiency and safety of adoptive cell transfer using PD-1 gene-edited TIL for the treatment of metastatic melanoma is warranted. PMID:25939491

  10. Early T cell signalling is reversibly altered in PD-1+ T lymphocytes infiltrating human tumors.

    PubMed

    Wang, Shu-Fang; Fouquet, Stéphane; Chapon, Maxime; Salmon, Hélène; Regnier, Fabienne; Labroquère, Karine; Badoual, Cécile; Damotte, Diane; Validire, Pierre; Maubec, Eve; Delongchamps, Nicolas B; Cazes, Aurélie; Gibault, Laure; Garcette, Marylène; Dieu-Nosjean, Marie-Caroline; Zerbib, Marc; Avril, Marie-Françoise; Prévost-Blondel, Armelle; Randriamampita, Clotilde; Trautmann, Alain; Bercovici, Nadège

    2011-03-07

    To improve cancer immunotherapy, a better understanding of the weak efficiency of tumor-infiltrating T lymphocytes (TIL) is necessary. We have analyzed the functional state of human TIL immediately after resection of three types of tumors (NSCLC, melanoma and RCC). Several signalling pathways (calcium, phosphorylation of ERK and Akt) and cytokine secretion are affected to different extents in TIL, and show a partial spontaneous recovery within a few hours in culture. The global result is an anergy that is quite distinct from clonal anergy induced in vitro, and closer to adaptive tolerance in mice. PD-1 (programmed death -1) is systematically expressed by TIL and may contribute to their anergy by its mere expression, and not only when it interacts with its ligands PD-L1 or PD-L2, which are not expressed by every tumor. Indeed, the TCR-induced calcium and ERK responses were reduced in peripheral blood T cells transfected with PD-1. Inhibition by sodium stibogluconate of the SHP-1 and SHP-2 phosphatases that associate with several inhibitory receptors including PD-1, relieves part of the anergy apparent in TIL or in PD-1-transfected T cells. This work highlights some of the molecular modifications contributing to functional defects of human TIL.

  11. Clinical Scale Zinc Finger Nuclease-mediated Gene Editing of PD-1 in Tumor Infiltrating Lymphocytes for the Treatment of Metastatic Melanoma.

    PubMed

    Beane, Joal D; Lee, Gary; Zheng, Zhili; Mendel, Matthew; Abate-Daga, Daniel; Bharathan, Mini; Black, Mary; Gandhi, Nimisha; Yu, Zhiya; Chandran, Smita; Giedlin, Martin; Ando, Dale; Miller, Jeff; Paschon, David; Guschin, Dmitry; Rebar, Edward J; Reik, Andreas; Holmes, Michael C; Gregory, Philip D; Restifo, Nicholas P; Rosenberg, Steven A; Morgan, Richard A; Feldman, Steven A

    2015-08-01

    Programmed cell death-1 (PD-1) is expressed on activated T cells and represents an attractive target for gene-editing of tumor targeted T cells prior to adoptive cell transfer (ACT). We used zinc finger nucleases (ZFNs) directed against the gene encoding human PD-1 (PDCD-1) to gene-edit melanoma tumor infiltrating lymphocytes (TIL). We show that our clinical scale TIL production process yielded efficient modification of the PD-1 gene locus, with an average modification frequency of 74.8% (n = 3, range 69.9-84.1%) of the alleles in a bulk TIL population, which resulted in a 76% reduction in PD-1 surface-expression. Forty to 48% of PD-1 gene-edited cells had biallelic PD-1 modification. Importantly, the PD-1 gene-edited TIL product showed improved in vitro effector function and a significantly increased polyfunctional cytokine profile (TNFα, GM-CSF, and IFNγ) compared to unmodified TIL in two of the three donors tested. In addition, all donor cells displayed an effector memory phenotype and expanded approximately 500-2,000-fold in vitro. Thus, further study to determine the efficiency and safety of adoptive cell transfer using PD-1 gene-edited TIL for the treatment of metastatic melanoma is warranted.

  12. Sunitinib pretreatment improves tumor-infiltrating lymphocyte expansion by reduction in intratumoral content of myeloid-derived suppressor cells in human renal cell carcinoma.

    PubMed

    Guislain, Aurelie; Gadiot, Jules; Kaiser, Andrew; Jordanova, Ekaterina S; Broeks, Annegien; Sanders, Joyce; van Boven, Hester; de Gruijl, Tanja D; Haanen, John B A G; Bex, Axel; Blank, Christian U

    2015-10-01

    Targeted therapy with sunitinib, pazopanib or everolimus has improved treatment outcome for patients with metastatic renal cell carcinoma patients (RCC). However, despite considerable efforts in sequential or combined modalities, durable remissions are rare. Immunotherapy like cytokine therapy with interleukin-2, T cell checkpoint blockade or adoptive T cell therapies can achieve long-term benefit and even cure. This raises the question of whether combining targeted therapy with immunotherapy could also be an effective treatment option for RCC patients. Sunitinib, one of the most frequently administered therapeutics in RCC patients has been implicated in impairing T cell activation and proliferation in vitro. In this work, we addressed whether this notion holds true for expansion of tumor-infiltrating lymphocytes (TILs) in sunitinib-treated patients. We compared resected primary RCC tumor material of patients pretreated with sunitinib with resection specimen from sunitinib-naïve patients. We found improved TIL expansion from sunitinib-pretreated tumor digests. These TIL products contained more PD-1 expressing TIL, while the regulatory T cell infiltration was not altered. The improved TIL expansion was associated with reduced intratumoral myeloid-derived suppressor cell (MDSC) content. Depletion of MDSCs from sunitinib-naïve RCC tissue-digest improved TIL expansion, proving the functional relevance of the MDSC alteration by sunitinib. Our in vivo results do not support previous in vitro observations of sunitinib inhibiting T cell function, but do provide a possible rationale for the combination of sunitinib with immunotherapy.

  13. Surface Proteome Analysis of a Natural Isolate of Lactococcus lactis Reveals the Presence of Pili Able to Bind Human Intestinal Epithelial Cells*

    PubMed Central

    Meyrand, Mickael; Guillot, Alain; Goin, Mélodie; Furlan, Sylviane; Armalyte, Julija; Kulakauskas, Saulius; Cortes-Perez, Naima G.; Thomas, Ginette; Chat, Sophie; Péchoux, Christine; Dupres, Vincent; Hols, Pascal; Dufrêne, Yves F.; Trugnan, Germain; Chapot-Chartier, Marie-Pierre

    2013-01-01

    Surface proteins of Gram-positive bacteria play crucial roles in bacterial adhesion to host tissues. Regarding commensal or probiotic bacteria, adhesion to intestinal mucosa may promote their persistence in the gastro-intestinal tract and their beneficial effects to the host. In this study, seven Lactococcus lactis strains exhibiting variable surface physico-chemical properties were compared for their adhesion to Caco-2 intestinal epithelial cells. In this test, only one vegetal isolate TIL448 expressed a high-adhesion phenotype. A nonadhesive derivative was obtained by plasmid curing from TIL448, indicating that the adhesion determinants were plasmid-encoded. Surface-exposed proteins in TIL448 were analyzed by a proteomic approach consisting in shaving of the bacterial surface with trypsin and analysis of the released peptides by LC-MS/MS. As the TIL448 complete genome sequence was not available, the tryptic peptides were identified by a mass matching approach against a database including all Lactococcus protein sequences and the sequences deduced from partial DNA sequences of the TIL448 plasmids. Two surface proteins, encoded by plasmids in TIL448, were identified as candidate adhesins, the first one displaying pilin characteristics and the second one containing two mucus-binding domains. Inactivation of the pilin gene abolished adhesion to Caco-2 cells whereas inactivation of the mucus-binding protein gene had no effect on adhesion. The pilin gene is located inside a cluster of four genes encoding two other pilin-like proteins and one class-C sortase. Synthesis of pili was confirmed by immunoblotting detection of high molecular weight forms of pilins associated to the cell wall as well as by electron and atomic force microscopy observations. As a conclusion, surface proteome analysis allowed us to detect pilins at the surface of L. lactis TIL448. Moreover we showed that pili appendages are formed and involved in adhesion to Caco-2 intestinal epithelial cells

  14. Tumour-infiltrating lymphocytes and the emerging role of immunotherapy in breast cancer.

    PubMed

    Luen, Stephen J; Savas, Peter; Fox, Stephen B; Salgado, Roberto; Loi, Sherene

    2017-02-01

    Breast cancer has not previously been considered a highly immunogenic cancer. Observations of tumour-infiltrating lymphocytes (TILs) in and around neoplastic cells in tumour samples, and associations with improved pathological complete response and clinical survival end points have changed our perspective on this. Lymphocytic infiltrates have long been observed in breast cancer; however, more recently, retrospective analysis of prospectively collected tissue samples from clinical trials has demonstrated the potential role of host immunosurveillance in influencing the biology of breast cancer. This association appears to be strongest in triple negative and HER2 positive breast cancer subtypes. Contrastingly, the association in luminal tumours is less clear, and is potentially limited by substantial tumoural heterogeneity. Several methodologies have been employed to quantify, and describe the composition of TILs, each with its own advantages and disadvantages. The results of these analyses have been generally consistent, and valuable efforts are currently underway to standardise the evaluation of TILs toward a universal approach. More technical methods of TIL characterisation remain important in the research setting. The evaluation of TILs becomes increasingly relevant with the emerging role of immunotherapy in breast cancer. Early phase trials of checkpoint blockade show promising results; however, it is likely that some patients will require combination treatments to maximise therapeutic benefits. Equally, some patients may not derive any benefit from immunotherapies. This underscores the importance of the development of relevant predictive biomarkers. As a key representative of the immune interaction between host and tumour, lymphocytic infiltrates are ideally placed for continued research into the determinants of immunogenicity, and response to immunotherapeutic approaches. In this review, we will discuss the current methodologies of evaluation, and the clinical

  15. Correlation between class I antigen expression and the ability to generate tumour infiltrating lymphocytes from bladder tumour biopsies.

    PubMed Central

    Nouri, A. M.; dos Santos, A. V.; Crosby, D.; Oliver, R. T.

    1991-01-01

    Analysis of tissue sections from transurethrally resected bladder tumours using anti-CD3 antibody showed the presence of T lymphocytes in intra-epithelial layers in eight of 12 cases investigated. In a larger group of patients, Tumour Infiltrating Lymphocyte (TIL) growth was established from six of 19 cases using Interleukin-2 (IL-2) and conditioned medium (CM) and resulted in the expansion of TILs up to 100-fold. TILs from these individuals were phenotyped with W6/32 (anti-HLA-A,B,C), HB55 (anti-DR) and anti-CD3 antibodies using FAC sorter. The mean +/- s.d. frequency of positive staining with these antibodies were 96.7 +/- 4.0%, 87.5 +/- 10.0% and 82.5 +/- 7.8% respectively, indicating the activated nature of these T cells. The cytotoxic activity of these TILs against Daudi (ie, LAK activity) cell line at 25/1 E/T ratios varied from 26.3 +/- 3.2 to 62.8 +/- 5.2%. In one case where TILs and autologous tumour cell line were established, cytotoxicity studies showed low level of cytotoxicity against the autologous tumour cells (15.8 +/- 1.6%) compared with 62.8 +/- 5.2% against Daudi. Staining of tumour sections from these 19 individuals with W6/32 and BBM.1 revealed positive staining in six of six that developed TILs but only six of 13 (46%) cases, whose tumour failed to grow TILs (P less than 0.02, Fisher exact test). These results are indicative of the presence of IL-2 passageable T cells in bladder cancer biopsy and demonstrate that the successful expansion of these cells correlates with the normal expression of class I antigens on the tumour cells. Images Figure 5 PMID:1764393

  16. Neoadjuvant Chemotherapy of Ovarian Cancer Results in Three Patterns of Tumor-Infiltrating Lymphocyte Response with Distinct Implications for Immunotherapy.

    PubMed

    Lo, Charlotte S; Sanii, Sanaz; Kroeger, David R; Milne, Katy; Talhouk, Aline; Chiu, Derek S; Rahimi, Kurosh; Shaw, Patricia A; Clarke, Blaise A; Nelson, Brad H

    2017-02-15

    Purpose: Some forms of chemotherapy can enhance antitumor immunity through immunogenic cell death, resulting in increased T-cell activation and tumor infiltration. Such effects could potentially sensitize tumors to immunotherapies, including checkpoint blockade. We investigated whether platinum- and taxane-based chemotherapy for ovarian cancer induces immunologic changes consistent with this possibility.Experimental Design: Matched pre- and post-neoadjuvant chemotherapy tumor samples from 26 high-grade serous carcinoma (HGSC) patients were analyzed by immunohistochemistry (IHC) for a large panel of immune cells and associated factors. The prognostic significance of post-chemotherapy TIL patterns was assessed in an expanded cohort (n = 90).Results: Neoadjuvant chemotherapy was associated with increased densities of CD3(+), CD8(+), CD8(+) TIA-1(+), PD-1(+) and CD20(+) TIL. Other immune subsets and factors were unchanged, including CD79a(+) CD138(+) plasma cells, CD68(+) macrophages, and MHC class I on tumor cells. Immunosuppressive cell types were also unchanged, including FoxP3(+) PD-1(+) cells (putative regulatory T cells), IDO-1(+) cells, and PD-L1(+) cells (both macrophages and tumor cells). Hierarchical clustering revealed three response patterns: (i) TIL(high) tumors showed increases in multiple immune markers after chemotherapy; (ii) TIL(low) tumors underwent similar increases, achieving patterns indistinguishable from the first group; and (iii) TIL(negative) cases generally remained negative. Despite the dramatic increases seen in the first two patterns, post-chemotherapy TIL showed limited prognostic significance.Conclusions: Chemotherapy augments pre-existing TIL responses but fails to relieve major immune-suppressive mechanisms or confer significant prognostic benefit. Our findings provide rationale for multipronged approaches to immunotherapy tailored to the baseline features of the tumor microenvironment. Clin Cancer Res; 23(4); 925-34. ©2016 AACR.

  17. Numerical studies on the performance of an aerosol respirator with faceseal leakage

    NASA Astrophysics Data System (ADS)

    Zaripov, S. K.; Mukhametzanov, I. T.; Grinshpun, S. A.

    2016-11-01

    We studied the efficiency of a facepiece filtering respirator (FFR) in presence of a measurable faceseal leakage using the previously developed model of a spherical sampler with porous layer. In our earlier study, the model was validated for a specific filter permeability value. In this follow-up study, we investigated the effect of permeability on the overall respirator performance accounting for the faceseal leakage. The Total Inward Leakage (TIL) was calculated as a function of the leakage-to-filter surface ratio and the particle diameter. A good correlation was found between the theoretical and experimental TIL values. The TIL value was shown to increase and the effect of particle size on TIL to decrease as the leakage-to- filter surface ratio grows. The model confirmed that within the most penetrating particle size range (∼50 nm) and at relatively low leakage-to-filter surface ratios, an FFR performs better (TIL is lower) when the filter has a lower permeability which should be anticipated as long as the flow through the filter represents the dominant particle penetration pathway. An increase in leak size causes the TIL to rise; furthermore, under certain leakage-to-filter surface ratios, TIL for ultrafine particles becomes essentially independent on the filter properties due to a greater contribution of the aerosol flow through the faceseal leakage. In contrast to the ultrafine fraction, the larger particles (e.g., 800 nm) entering a typical high- or medium-quality respirator filter are almost fully collected by the filter medium regardless of its permeability; at the same time, the fraction penetrated through the leakage appears to be permeability- dependent: higher permeability generally results in a lower pressure drop through the filter which increases the air flow through the filter at the expense of the leakage flow. The latter reduces the leakage effect thus improving the overall respiratory protection level. The findings of this study provide

  18. Tumor infiltrating T lymphocytes expressing FoxP3, CCR7 or PD-1 predict the outcome of prostate cancer patients subjected to salvage radiotherapy after biochemical relapse.

    PubMed

    Nardone, Valerio; Botta, Cirino; Caraglia, Michele; Martino, Elodia Claudia; Ambrosio, Maria Raffaella; Carfagno, Tommaso; Tini, Paolo; Semeraro, Leonardo; Misso, Gabriella; Grimaldi, Anna; Boccellino, Mariarosaria; Facchini, Gaetano; Berretta, Massimiliano; Vischi, Gianluca; Rocca, Bruno Jim; Barone, Aurora; Tassone, Pierfrancesco; Tagliaferri, Pierosandro; Del Vecchio, Maria Teresa; Pirtoli, Luigi; Correale, Pierpaolo

    2016-11-01

    Tumor immunologic microenvironment is strongly involved in tumor progression and the presence of tumor infiltrating lymphocytes (TIL) with different phenotypes has been demonstrated to be of prognostic relevance in different malignancies. We investigated whether TIL infiltration of tumor tissues could also predict the outcome of prostate cancer patients. To this end, we carried out a retrospective analysis correlating the outcome of locally advanced prostate cancer patients undergone salvage radiotherapy upon relapse after radical surgery with the infiltration by different TIL populations. Twenty-two patients with resectable prostate cancer, with a mean age of 67 (+/-3.93) years, who received salvage radiotherapy with a mean of 69.66 (+/- 3.178) Gy in 8 weeks, between June 1999 and January 2009 and with a median follow up of 123 (+/- 55.82) months, were enrolled in this study. We evaluated, by immunohistochemistry, the intratumoral ((t)) and peripheral stroma ((p)) infiltration by CD45, CD3, CD4, CD8, CCR7, FoxP3 or PD-1-positive cells on tumor samples taken at the diagnosis ((d)) and relapse times ((R)). We correlated these variables with patients' biochemical progression free survival (bPFS), post-radiotherapy progression free survival (PFS), and overall survival (OS). Substantial changes in the rate of TIL subsets were found between the first and the second biopsy with progressive increase in CD4, CCR7, FoxP3, PD-1(+) cells. Our analysis revealed that higher CD8(p,R+) and lower PD-1(R+) TIL scores correlated to a longer bPFS. Higher CD8(p,R+) and CCR7(t,R+) TIL scores and lower CD45(p,R+) and FoxP3(p,R+) TIL scores correlated to a prolonged PFS and OS. These results suggest that the immunological microenvironment of primary tumor is strictly correlated with patient outcome and provide the rationale for immunological treatment of prostate cancer.

  19. Prognostic and predictive value of tumor-infiltrating lymphocytes for clinical therapeutic research in patients with non-small cell lung cancer

    PubMed Central

    Zeng, Dong-Qiang; Yu, Yun-Fang; Ou, Qi-Yun; Li, Xiao-Yin; Zhong, Ru-Zhi; Xie, Chuan-Miao; Hu, Qiu-Gen

    2016-01-01

    Background Previous preclinical and clinical studies have shown that levels of tumor-infiltrating lymphocytes (TILs) significantly correlated with prognosis in non-small cell lung cancer (NSCLC), and survival after therapy; however, this finding remains controversial. We performed a meta-analysis, to evaluate, systematically, the clinical utilization of TIL subtypes in patients with NSCLC. Methods The PubMed, ISI Web of Science, EMBASE, and Cochrane Library databases were searched to identify relevant studies. We pooled estimates of treatment effects, and hazards were summarized using random or fixed effects models to evaluate survival outcomes. Results A total of 24 relevant studies involving 7,006 patients were eligible. The median percentage of lymph node positivity was 45.7% (95% confidence interval [CI], 37.1–56.4%). Pooled analysis shows that high levels of CD8+ TILs had a good prognostic effect on survival with a hazard ratio (HR) of 0.91 (P = 0.013) for death and 0.74 (P = 0.001) for recurrence, as did high levels of CD3+ and CD4+ TILs, with HRs of 0.77 (P = 0.009) and 0.78 (P = 0.005) for death, respectively. By contrast, high levels of FoxP3+ regulatory TILs had a worse prognostic effect for overall and recurrence-free survival, with HRs of 1.69 (P = 0.042) and 1.79 (P = 0.001), respectively. No individual study affected the results, and no publication bias was found. Conclusions Our findings support the hypothesis that TILs could be a prognostic marker in NSCLC. High-quality randomized studies are needed to verify statistically the effect of TILs on prognosis in future research. PMID:26871598

  20. Identification and Functional Analysis of Interleukin-1β in the Chinese Soft-Shelled Turtle Pelodiscus sinensis

    PubMed Central

    Liang, Quan; Li, Weifen; Guo, Ningning; Tong, Chao; Zhou, Yingshan; Fang, Weihuan; Li, Xiaoliang

    2016-01-01

    Chinese soft-shelled turtle (Pelodiscus sinensis) is commercially cultured in East and Southeast Asia for its nutritional and medicinal values. In this study, we identified interleukin-1β (IL-1β) from Chinese soft-shelled turtle. The full-length cDNA of Pelodiscus sinensis IL-1β (tIL-1β) consists of 1529 base pairs with an 831-base-pair open reading frame, encoding 277 amino acids. The guanine-cytosine (GC) content in the coding sequence and 3’ untranslated region of tIL-1β is considerably higher than that of other vertebrates. Its mRNA expression level increased significantly during Aeromonas hydrophila infection. The tIL-1β lacks the typical IL-1β-converting enzyme (ICE) cut site found in mammalian IL-1β, but still could be cleaved by turtle caspase-1. By mutating the potential cleavage sites, we identified aspartic acid (Asp/D) 130 as the ICE cut site in tIL-1β. The peptide truncated at D130 was expressed using the baculovirus expression system; its bioactivity is confirmed by the ability to induce cyclooxygenase-2 (COX-2) and tIL-1β itself in peripheral blood monocytes. In conclusion, we characterized IL-1β from Chinese soft-shelled turtle and identified its D130 as a non-typical ICE cut size. PMID:27153094

  1. CD8+ tumor-infiltrating lymphocytes predict favorable prognosis in malignant pleural mesothelioma after resection.

    PubMed

    Yamada, Noriyuki; Oizumi, Satoshi; Kikuchi, Eiki; Shinagawa, Naofumi; Konishi-Sakakibara, Jun; Ishimine, Atsushi; Aoe, Keisuke; Gemba, Kenichi; Kishimoto, Takumi; Torigoe, Toshihiko; Nishimura, Masaharu

    2010-10-01

    Defects in human leukocyte antigen (HLA) class I expression may allow tumor cells to escape immune recognition. T cell infiltration is associated with a good prognosis in many cancers. However, the role of HLA class I expression and tumor-infiltrating lymphocytes (TILs) in malignant pleural mesothelioma (MPM) has not been fully analyzed. In the present study, we investigated the immune profiles and conducted outcome analyses of MPM patients. HLA class I expression and TILs (CD4(+), CD8(+), and NK cells) were detected by immunohistochemistry in a series of 44 MPM cases. To detect HLA class I expression, specimens were stained with the anti-pan HLA class I monoclonal antibody EMR8-5. The expression of HLA class I was positive in all patients. There was no case that showed negative HLA class I expression. The density of CD4(+) and CD8(+) TILs were strongly correlated (R = 0.76, p < 0.001). A high density of CD8(+) TILs was a significantly better prognostic factor for the survival of patients with extrapleural pneumonectomy (p < 0.05). Multivariate analysis revealed that a high density of CD8(+) TILs is an independent prognostic factor for patients who underwent extrapleural pneumonectomy. The presence of intratumoral CD8(+) T cells was correlated with an improved clinical outcome, raising the possibility that CD8(+) T cells might play a pivotal role in the antitumor immune response against MPMs. Thus, the stimulation of CD8(+) lymphocytes might be an efficacious immunotherapy for MPM patients.

  2. Tumor-Infiltrating Lymphocytes in Triple Negative Breast Cancer: The Future of Immune Targeting.

    PubMed

    García-Teijido, Paula; Cabal, María Luque; Fernández, Ignacio Peláez; Pérez, Yolanda Fernández

    2016-01-01

    Triple negative breast cancer (TNBC) is a highly heterogeneous tumor. There is increasing evidence of the role of tumor lymphocytic immune infiltrates in this subtype of breast cancer. Robust levels of tumor infiltrating lymphocytes (TILs) have been associated with improved disease-free and overall survival rates in TNBC patients with and without any treatment. Recent efforts have been made to develop a standardized methodology for evaluating TILs. The presence of TILs in the breast tumor microenvironment can also predict responses not only to neoadjuvant but also to adjuvant chemotherapy treatments. High numbers of TILs correlate with increased pathological complete responses (pCR) in TNBC. TILs are prognostic and predictive of response to standard therapies; thus, the immune system appears to play an active role in a subgroup of breast cancer. There is an increasing interest in directly targeting the immune system as part of breast cancer therapy, mainly in patients with TNBC. New immune modulatory agents, including immune checkpoints inhibitors, have shown promising activity in a subgroup of metastatic TNBC. Increased programmed cell death protein 1 ligand (PD-L1) expression on the surface of TNBC provides the rationale for implementing therapeutic strategies targeting the PD-1/PD-L1 axis in TNBC. The programmed cell death protein 1 (PD-1) inhibitor pembrolizumab, and the PD-L1 inhibitor atezolizumab have shown promising results in clinical trials.

  3. A major secretory defect of tumour-infiltrating T lymphocytes due to galectin impairing LFA-1-mediated synapse completion

    PubMed Central

    Petit, Anne-Elisabeth; Demotte, Nathalie; Scheid, Benoît; Wildmann, Claude; Bigirimana, René; Gordon-Alonso, Monica; Carrasco, Javier; Valitutti, Salvatore; Godelaine, Danièle; van der Bruggen, Pierre

    2016-01-01

    Surface galectin has been shown to contribute to dysfunctions of human tumour-infiltrating lymphocytes (TILs). We show here that galectin-covered CD8 TILs produce normal amounts of intracellular cytokines, but fail to secrete them because of defective actin rearrangements at the synapse. The non-secreting TILs also display reduced adhesion to their targets, together with defective LFA-1 recruitment and activation at the synapse. These defects are relieved by releasing surface galectin. As mild LFA-1 blockade on normal blood T cells emulate the defects of galectin-covered TILs, we conclude that galectin prevents the formation of a functional secretory synapse by preventing optimal LFA-1 triggering. Our results highlight a major secretory defect of TILs that is not revealed by widely used intracellular cytokine immunomonitoring assays. They also provide additional insights into the T-cell response, by showing that different thresholds of LFA-1 triggering are required to promote the intracellular production of cytokines and their secretion. PMID:27447355

  4. CD103+ intraepithelial T cells in high-grade serous ovarian cancer are phenotypically diverse TCRαβ+ CD8αβ+ T cells that can be targeted for cancer immunotherapy

    PubMed Central

    Workel, Hagma H.; Tijans, Aline M.; Terwindt, Anouk L.J.; Brunekreeft, Kim L.; Plat, Annechien; Klip, Harry G.; Eggink, Florine A.; Leffers, Ninke; Helfrich, Wijnand; Samplonius, Douwe F.; Bremer, Edwin; Wisman, G. Bea A.; Daemen, Toos; Duiker, Evelien W.; Hollema, Harry; Nijman, Hans W.; de Bruyn, Marco

    2016-01-01

    CD103+ tumor-infiltrating lymphocytes (TIL) have been linked to specific epithelial infiltration and a prolonged survival in high-grade serous epithelial ovarian cancer (HGSC). However, whether these cells are induced as part of an ongoing anti-HGSC immune response or represent non-specifically expanded resident or mucosal lymphocytes remains largely unknown. In this study, we first confirmed that CD103+ TIL from HGSC were predominantly localized in the cancer epithelium and were strongly correlated with an improved prognosis. We further demonstrate that CD103+ TIL were almost exclusively CD3+ TCRαβ+ CD8αβ+ CD4- T cells, but heterogeneously expressed T cell memory and differentiation markers. Activation of peripheral T cells in the presence of HGSC was sufficient to trigger induction of CD103 in over 90% of all CD8+ cells in a T cell receptor (TCR)- and TGFβR1-dependent manner. Finally, CD103+ TIL isolated from primary HGSC showed signs of recent activation and dominantly co-expressed key immunotherapeutic targets PD-1 and CD27. Taken together, our data indicate CD103+ TIL in HGSC are formed as the result of an adaptive anti-tumor immune response that might be reactivated by (dual) checkpoint inhibition. PMID:27650547

  5. Ex-vivo analysis of CD8+ T cells infiltrating colorectal tumors identifies a major effector-memory subset with low perforin content.

    PubMed

    Ye, Sheng-Wei; Wang, Yu; Valmori, Danila; Ayyoub, Maha; Han, Yan; Xu, Xiao-Lan; Zhao, Ai-Lian; Qu, Li; Gnjatic, Sacha; Ritter, Gerd; Old, Lloyd J; Gu, Jin

    2006-09-01

    Previous studies have indicated that the infiltration of CD8+ T cells in colorectal cancer is an independent predictor of increased survival but clinical observations have suggested that the cytotoxic function of CD8+ T cells infiltrating colorectal cancer may often be limited. In this study, we have assessed the phenotype of colorectal cancer CD8+ tumor-infiltrating lymphocytes (TILs) isolated ex vivo from tumor tissue, and assessed the perforin content of TIL with respect to their location using immunohistochemistry. We found that CD8+ T cells TILs isolated from colorectal cancer are mainly composed of antigen-experienced cells of effector memory type (TEM, CD45RA-CCR7-, and CD27+/CD28- or CD27-/CD28-), and contain only minor proportions of terminally differentiated CD8+ T cells (TEMRA, CD45RA+CCR7-). The perforin content of these TILs, however, is significantly lower than that of antigen-experienced T cells in PBMCs due to the much lower levels of perforin found in the CD27-CD28- subset in TILs compared with CD8+ T cells of similar phenotype in PBMCs.

  6. Boosting antitumor responses of T lymphocytes infiltrating human prostate cancers.

    PubMed

    Bronte, Vincenzo; Kasic, Tihana; Gri, Giorgia; Gallana, Keti; Borsellino, Giovanna; Marigo, Ilaria; Battistini, Luca; Iafrate, Massimo; Prayer-Galetti, Tommaso; Pagano, Francesco; Viola, Antonella

    2005-04-18

    Immunotherapy may provide valid alternative therapy for patients with hormone-refractory metastatic prostate cancer. However, if the tumor environment exerts a suppressive action on antigen-specific tumor-infiltrating lymphocytes (TIL), immunotherapy will achieve little, if any, success. In this study, we analyzed the modulation of TIL responses by the tumor environment using collagen gel matrix-supported organ cultures of human prostate carcinomas. Our results indicate that human prostatic adenocarcinomas are infiltrated by terminally differentiated cytotoxic T lymphocytes that are, however, in an unresponsive status. We demonstrate the presence of high levels of nitrotyrosines in prostatic TIL, suggesting a local production of peroxynitrites. By inhibiting the activity of arginase and nitric oxide synthase, key enzymes of L-arginine metabolism that are highly expressed in malignant but not in normal prostates, reduced tyrosine nitration and restoration of TIL responsiveness to tumor were achieved. The metabolic control exerted by the tumor on TIL function was confirmed in a transgenic mouse prostate model, which exhibits similarities with human prostate cancer. These results identify a novel and dominant mechanism by which cancers induce immunosuppression in situ and suggest novel strategies for tumor immunotherapy.

  7. Tumor-Infiltrating Lymphocytes in Triple Negative Breast Cancer: The Future of Immune Targeting

    PubMed Central

    García-Teijido, Paula; Cabal, María Luque; Fernández, Ignacio Peláez; Pérez, Yolanda Fernández

    2016-01-01

    Triple negative breast cancer (TNBC) is a highly heterogeneous tumor. There is increasing evidence of the role of tumor lymphocytic immune infiltrates in this subtype of breast cancer. Robust levels of tumor infiltrating lymphocytes (TILs) have been associated with improved disease-free and overall survival rates in TNBC patients with and without any treatment. Recent efforts have been made to develop a standardized methodology for evaluating TILs. The presence of TILs in the breast tumor microenvironment can also predict responses not only to neoadjuvant but also to adjuvant chemotherapy treatments. High numbers of TILs correlate with increased pathological complete responses (pCR) in TNBC. TILs are prognostic and predictive of response to standard therapies; thus, the immune system appears to play an active role in a subgroup of breast cancer. There is an increasing interest in directly targeting the immune system as part of breast cancer therapy, mainly in patients with TNBC. New immune modulatory agents, including immune checkpoints inhibitors, have shown promising activity in a subgroup of metastatic TNBC. Increased programmed cell death protein 1 ligand (PD-L1) expression on the surface of TNBC provides the rationale for implementing therapeutic strategies targeting the PD-1/PD-L1 axis in TNBC. The programmed cell death protein 1 (PD-1) inhibitor pembrolizumab, and the PD-L1 inhibitor atezolizumab have shown promising results in clinical trials. PMID:27081325

  8. Human spontaneous labor without histologic chorioamnionitis is characterized by an acute inflammation gene expression signature

    PubMed Central

    Haddad, Ramsi; Tromp, Gerard; Kuivaniemi, Helena; Chaiworapongsa, Tinnakorn; Kim, Yeon Mee; Mazor, Moshe; Romero, Roberto

    2006-01-01

    OBJECTIVE The purpose of this study was to identify which biological processes may be involved in normal labor. STUDY DESIGN Transcriptional profiles for chorioamniotic membranes (n=24) and blood (n=20) were generated from patients at term with no labor (TNL) and in labor (TIL). RESULTS Expression of 197 transcripts (P≤0.02) differentiated TIL and TNL chorioamniotic membrane samples. Gene Ontology analysis indicated that TIL samples had increased expression of multiple chemokines and transcripts associated with neutrophil and monocyte recruitment. Microarray results were verified using quantitative real-time RT-PCR with independent samples. Transcriptional profiles from blood RNA revealed no Gene Ontology category enrichment of discriminant probe sets. CONCLUSION Labor induces gene expression changes consistent with localized inflammation, despite the absence of histologically detectable inflammation. PMID:16890549

  9. Production in vitro of thyroglobulin autoantibody by obese strain (OS) chickens.

    PubMed Central

    Tempelis, C H; Schauenstein, K; Wick, G

    1987-01-01

    Thyroglobulin autoantibody (Tg-AAb) can be spontaneously produced in vitro with thyroid infiltrating lymphocytes (TIL) collected from Obese strain chickens 3.5 and 4 weeks old. Attempts to enhance Tg-AAb synthesis with two known polyclonal stimulators of immunoglobulin synthesis in chickens, Staphylococcus aureus Cowan strain 1 and dextran sulphate, failed to increase Tg-AAb production in vitro. Spleen cells and peripheral blood lymphocytes obtained from the same chickens as the TIL and older chickens known to produce moderate to high levels of Tg-AAb in vivo did not produce autoantibody either spontaneously or in the presence of polyclonal Ig stimulators with one exception. With this single, exceptional chicken we obtained a small amount of Tg-AAb produced in vitro with spleen cells. This suggests that in the OS chicken TIL, and to a much lesser extent, the spleen, contribute to the total Tg-AAb produced in this model of autoimmune thyroiditis. PMID:2440629

  10. A novel human truncated IL12rβ1-Fc fusion protein ameliorates experimental autoimmune encephalomyelitis via specific binding of p40 to inhibit Th1 and Th17 cell differentiation

    PubMed Central

    Wang, Xin; Luo, Cheng; Yu, Dongmei; Wang, Yuheng; Chen, Yucong; Lei, Wen; Gao, Xiangdong; Yao, Wenbing

    2015-01-01

    Interleukin (IL)-12 and IL-23 respectively driving polarization of T helper (Th) 1 and Th17 cells has been strongly implicated in the pathogenesis of both multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). In this study, we first constructed, expressed and purified a novel human truncated IL12rβ1-Fc fusion protein (tIL12rβ1/Fc) binding multiple forms of the p40 subunit of human IL-12 and IL-23. tIL12rβ1/Fc was found to effectively ameliorate MOG35–55-induced EAE through reducing the production of Th1- and Th17-polarized pro-inflammatory cytokines and suppressing inflammation and demyelination in the focused parts. Moreover, tIL12rβ1/Fc suppressed Th1 (IFN-γ+ alone) and IFN-γ+ IL-17+ as well as the population of classic Th17 (IL-17+ alone) cells in vivo. Furthermore, tIL12rβ1/Fc ameliorated EAE at the peak of disease via the inhibition of STAT pathway, thereby causing a prominent reduction of RORγt (Th17) and T-bet (Th1) expression. Notably, tIL12rβ1/Fc could increase the relative number of CD4+ Foxp3+ regulatory T cells. These findings indicates that tIL12rβ1/Fc is a novel fusion protein for specific binding multiple forms of p40 subunit to exert potent anti-inflammatory effects and provides a valuable approach for the treatment of MS and other autoimmune diseases. PMID:26384304

  11. How does breathing frequency affect the performance of an N95 filtering facepiece respirator and a surgical mask against surrogates of viral particles?

    PubMed

    He, Xinjian; Reponen, Tiina; McKay, Roy; Grinshpun, Sergey A

    2014-01-01

    Breathing frequency (breaths/min) differs among individuals and levels of physical activity. Particles enter respirators through two principle penetration pathways: faceseal leakage and filter penetration. However, it is unknown how breathing frequency affects the overall performance of N95 filtering facepiece respirators (FFRs) and surgical masks (SMs) against viral particles, as well as other health-relevant submicrometer particles. A FFR and SM were tested on a breathing manikin at four mean inspiratory flows (MIFs) (15, 30, 55, and 85 L/min) and five breathing frequencies (10, 15, 20, 25, and 30 breaths/min). Filter penetration (Pfilter) and total inward leakage (TIL) were determined for the tested respiratory protection devices against sodium chloride (NaCl) aerosol particles in the size range of 20 to 500 nm. "Faceseal leakage-to-filter" (FLTF) penetration ratios were calculated. Both MIF and breathing frequency showed significant effects (p < 0.05) on Pfilter and TIL. Increasing breathing frequency increased TIL for the N95 FFR whereas no clear trends were observed for the SM. Increasing MIF increased Pfilter and decreased TIL resulting in decreasing FLTF ratio. Most of FLTF ratios were >1, suggesting that the faceseal leakage was the primary particle penetration pathway at various breathing frequencies. Breathing frequency is another factor (besides MIF) that can significantly affect the performance of N95 FFRs, with higher breathing frequencies increasing TIL. No consistent trend of increase or decrease of TIL with either MIF or breathing frequency was observed for the tested SM. To potentially extend these findings beyond the manikin/breathing system used, future studies are needed to fully understand the mechanism causing the breathing frequency effect on the performance of respiratory protection devices on human subjects.

  12. Immunomodulation by MYB is associated with tumor relapse in patients with early stage colorectal cancer

    PubMed Central

    Millen, Rosemary; Malaterre, Jordane; Cross, Ryan S.; Carpinteri, Sandra; Desai, Jayesh; Tran, Ben; Darcy, Phillip; Gibbs, Peter; Sieber, Oliver; Zeps, Nikolajs; Waring, Paul; Fox, Stephen; Pereira, Lloyd; Ramsay, Robert G.

    2016-01-01

    ABSTRACT The presence of tumor immune infiltrating cells (TILs), particularly CD8+ T-cells, is a robust predictor of outcome in patients with colorectal cancer (CRC). We revisited TIL abundance specifically in patients with microsatellite stable (MSS) CRC without evidence of lymph node or metastatic spread. Examination of the density of CD8+ T-cells in primary tumors in the context of other pro-oncogenic markers was performed to investigate potential regulators of TILs. Two independent cohorts of patients with MSS T2-4N0M0 CRC, enriched for cases with atypical relapse, were investigated. We quantified CD8+ and CD45RO+ -TILs, inflammatory markers, NFkBp65, pStat3, Cyclo-oxygenase-2 (COX2) and GRP78 as well as transcription factors (TF), β-catenin and MYB. High CD8+ TILs correlated with a better relapse-free survival in both cohorts (p = 0.002) with MYB and its target gene, GRP78 being higher in the relapse group (p = 0.001); no difference in pSTAT3 and p65 was observed. A mouse CRC (CT26) model was employed to evaluate the effect of MYB on GRP78 expression as well as T-cell infiltration. MYB over-expressing in CT26 cells increased GRP78 expression and the analysis of tumor-draining lymph nodes adjacent to tumors showed reduced T-cell activation. Furthermore, MYB over-expression reduced the efficacy of anti-PD-1 to modulate CT26 tumor growth. This high MYB and GRP78 show a reciprocal relationship with CD8+ TILs which may be useful refining the prediction of patient outcome. These data reveal a new immunomodulatory function for MYB suggesting a basis for further development of anti-GRP78 and/or anti-MYB therapies. PMID:27622014

  13. Enthalpic and entropic contributions mediate the role of disulfide bonds on the conformational stability of Interleukin-4

    PubMed Central

    Vaz, Daniela C.; Rodrigues, J. Rui; Sebald, Walter; Dobson, Christopher M.; Brito, Rui M.M.

    2006-01-01

    The role of disulfide bridges in the structure, stability, and folding pathways of proteins has been the subject of wide interest in the fields of protein design and engineering. However, the relative importance of entropic and enthalpic contributions for the stabilization of proteins provided by disulfides is not always clear. Here, we perform a detailed analysis of the role of disulfides in the conformational stability of human Interleukin-4 (IL4), a four-helix bundle protein. In order to evaluate the contribution of two out of the three disulfides to the structure and stability of IL4, two IL4 mutants, C3T-IL4 and C24T-IL4, were used. NMR and ANS binding experiments were compatible with altered dynamics and an increase of the nonpolar solvent-accessible surface area of the folded state of the mutant proteins. Chemical and thermal unfolding experiments followed by fluorescence and circular dichroism revealed that both mutant proteins have lower conformational stability than the wild-type protein. Transition temperatures of unfolding decreased 14°C for C3T-IL4 and 10°C for C24T-IL4, when compared to WT-IL4, and the conformational stability, at 25°C, decreased 4.9 kcal/mol for C3T-IL4 and 3.2 kcal/mol for C24T-IL4. Interestingly, both the enthalpy and the entropy of unfolding, at the transition temperature, decreased in the mutant proteins. Moreover, a smaller change in heat capacity of unfolding was also observed for the mutants. Thus, disulfide bridges in IL4 play a critical role in maintaining the thermodynamic stability and core packing of the helix bundle. PMID:16373475

  14. The expressions of MIF and CXCR4 protein in tumor microenvironment are adverse prognostic factors in patients with esophageal squamous cell carcinoma

    PubMed Central

    2013-01-01

    Background Tumor-derived cytokines and their receptors usually take important roles in the disease progression and prognosis of cancer patients. In this survey, we aimed to detect the expression levels of MIF and CXCR4 in different cell populations of tumor microenvironments and their association with survivals of patients with esophageal squamous cell carcinoma (ESCC). Methods MIF and CXCR4 levels were measured by immunochemistry in tumor specimens from 136 resected ESCC. Correlation analyses and independent prognostic outcomes were determined using Pearson’s chi-square test and Cox regression analysis. Results The expression of CXCR4 in tumor cells was positively associated with tumor status (P = 0.045) and clinical stage (P = 0.044); whereas the expression of CXCR4 in tumor-infiltrating lymphocytes (TILs) and the expression of MIF in tumor cells and in TILs were not associated with clinical parameters of ESCC patients. High MIF expression in tumor cells or in TILs or high CXCR4 expression in tumor cells was significantly related to poor survival of ESCC patients (P < 0.05). Multivariate analysis showed that the expression of MIF or CXCR4 in tumor cells and the expression of MIF in TILs were adverse independent factors for disease-free survival (DFS) and overall survival (OS) in the whole cohort of patients (P < 0.05). Furthermore, the expression of MIF and CXCR4 in tumor cells were independent factors for reduced DFS and OS in metastatic/recurrent ESCC patients (P < 0.05). Interestingly, the expressions of MIF and CXCR4 in tumor cells and in TILs were significantly positively correlated (P < 0.05), and the combined MIF and CXCR4 expression in tumor cells was an independent adverse predictive factor for DFS and OS (P < 0.05). Conclusion The expressions of MIF and CXCR4 proteins in tumor cells and TILs have different clinically predictive values in ESCC. PMID:23497377

  15. PD-1 identifies the patient-specific CD8⁺ tumor-reactive repertoire infiltrating human tumors.

    PubMed

    Gros, Alena; Robbins, Paul F; Yao, Xin; Li, Yong F; Turcotte, Simon; Tran, Eric; Wunderlich, John R; Mixon, Arnold; Farid, Shawn; Dudley, Mark E; Hanada, Ken-Ichi; Almeida, Jorge R; Darko, Sam; Douek, Daniel C; Yang, James C; Rosenberg, Steven A

    2014-05-01

    Adoptive transfer of tumor-infiltrating lymphocytes (TILs) can mediate regression of metastatic melanoma; however, TILs are a heterogeneous population, and there are no effective markers to specifically identify and select the repertoire of tumor-reactive and mutation-specific CD8⁺ lymphocytes. The lack of biomarkers limits the ability to study these cells and develop strategies to enhance clinical efficacy and extend this therapy to other malignancies. Here, we evaluated unique phenotypic traits of CD8⁺ TILs and TCR β chain (TCRβ) clonotypic frequency in melanoma tumors to identify patient-specific repertoires of tumor-reactive CD8⁺ lymphocytes. In all 6 tumors studied, expression of the inhibitory receptors programmed cell death 1 (PD-1; also known as CD279), lymphocyte-activation gene 3 (LAG-3; also known as CD223), and T cell immunoglobulin and mucin domain 3 (TIM-3) on CD8⁺ TILs identified the autologous tumor-reactive repertoire, including mutated neoantigen-specific CD8⁺ lymphocytes, whereas only a fraction of the tumor-reactive population expressed the costimulatory receptor 4-1BB (also known as CD137). TCRβ deep sequencing revealed oligoclonal expansion of specific TCRβ clonotypes in CD8⁺PD-1⁺ compared with CD8⁺PD-1- TIL populations. Furthermore, the most highly expanded TCRβ clonotypes in the CD8⁺ and the CD8⁺PD-1⁺ populations recognized the autologous tumor and included clonotypes targeting mutated antigens. Thus, in addition to the well-documented negative regulatory role of PD-1 in T cells, our findings demonstrate that PD-1 expression on CD8⁺ TILs also accurately identifies the repertoire of clonally expanded tumor-reactive cells and reveal a dual importance of PD-1 expression in the tumor microenvironment.

  16. Guidelines and Data to Support Plans for Reallocating Food during Crisis Relocation. Regional Appendix. FEMA Region IV,

    DTIC Science & Technology

    1982-09-01

    distri- butors serving the region, arid a list of counties served by each distributor is included for reference. U TOP TEN FOOD DISTRIBUTORSco D SERVING...SUPER VALU STORES INC XENIA Oil 122,750 28 4,:84 HOPKINS MN 10,000 1 10,000 SUPER VALU STORES HOPKINS MN 5,000 1 5,000 r p p C-3 LIST OF COUNTIES SERVED...BY EACH DISTRIBUTOR IN FEMA REGION IV 𔃻. 9 COUNTY SUPPLIERS TOTAL 500K- 1-2 2-4 4-8 6+ EST ACV STORES I MIL tIL MIL MIL tIL ($1000) REGION 041! STATE

  17. PD-1, PD-L1 Protein Expression in Non-Small Cell Lung Cancer and Their Relationship with Tumor-Infiltrating Lymphocytes

    PubMed Central

    He, Yayi; Rozeboom, Leslie; Rivard, Christopher J.; Ellison, Kim; Dziadziuszko, Rafał; Yu, Hui; Zhou, Caicun; Hirsch, Fred R.

    2017-01-01

    Background Immunotherapy targeting the programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) checkpoint has shown the good outcomes in non-small cell lung cancer (NSCLC). We investigated PD-1 and PD-L1 protein expression and their correlation with tumor-infiltrating lymphocytes (TILs), and association with survival in NSCLC. Material/Methods The expression of PD-1 (NAT105, Cell Marque) and PD-L1 (28-8, Dako) protein was assessed in 55 NSCLC cell lines by immunohistochemistry (IHC). PD-1 (NAT105, Cell Marque) and PD-L1 (22C3, Dako) protein expression was evaluated by IHC, and TIL percentage was scored, in 139 surgically resected specimens from patients with NSCLC. Results PD-1 was not expressed on NSCLC cell lines. PD-L1 was expressed on 20 NSCLC cell lines (36.4%). A total of 60 patient samples (43.2%) were positive for PD-1 on the TILs, and 25 (18.0%) were positive for PD-L1 on tumor cells. High expression of PD-1 on tumor cells was significantly correlated with higher expression of PD-L1 (P=0.026) and a higher percentage of TILs (P<0.001). In the Cox regression model, the odds ratio for PD-1 was 2.828 (95% CI: 1.325–11.165; P=0.013) and 8.579 (95% CI: 4.148–22.676; P<0.001) when PD-L1 and TILs were positive. Patients whose tumor cells were PD-L1 negative had a tendency for longer relapse-free survival (RFS) than patients who were PD-L1 positive (1.85 years, 95% CI: 0.77–2.93 vs. 0.97 years, 95% CI: 0.71–1.23; P=0.054). Conclusions PD-1 was expressed on TILs in tumor tissues in NSCLC patients. PD-L1 was expressed on both TILs and tumor tissues. PD-1 expression was correlated with PD-L1 on tumor cells and TILs. Patients who were PD-L1 positive tended to experience progression after surgery. PMID:28275222

  18. Phenotypic and functional analysis of tumor-infiltrating lymphocytes compared with tumor-associated lymphocytes from ascitic fluid and peripheral blood lymphocytes in patients with advanced ovarian cancer.

    PubMed

    Santin, A D; Hermonat, P L; Ravaggi, A; Bellone, S; Roman, J J; Smith, C V; Pecorelli, S; Radominska-Pandya, A; Cannon, M J; Parham, G P

    2001-01-01

    To investigate and compare the phenotype and function of lymphocytes collected from patients harboring advanced ovarian cancer, leukocytes from peripheral blood (n = 18), ascitic fluid (n = 13) and tumor tissues (n = 13) were evaluated for the relative proportions of lymphocyte subsets, including CD3+, CD4+, CD8+, CD19+, CD56 and the early (CD25) and late (HLA-DR) activation markers on CD3+ T cells. The ability to synthesize type 1 cytokines (IFN-gamma and IL-2) and a type 2 cytokine (IL-4) was assessed by flow cytometry. In all patients, T cells (CD3+) were the major leukocyte population detected in each tissue, with CD4+ T cells being dominant in peripheral blood lymphocytes (PBL) and tumor-associated lymphocytes (TAL) but not in tumor-infiltrating lymphocytes (TIL) (CD4:CD8 ratios: 3.0 vs. 2.0 vs. 1.0, respectively). CD19+ lymphocytes (B cells) and CD56+ lymphocytes (NK cells) were significantly higher in PBL compared to TAL and TIL (p < 0.05). TAL and TIL had a higher proportion of T cells expressing the late activation marker HLA-DR compared to PBL. In contrast, no significant differences were detected in PBL, TAL and TIL in the expression of the early activation marker CD25. Type 1 cytokines were the dominant type produced by in vitro stimulated T cells for each population, with a greater proportion of IFN-gamma+ T cells in TAL and TIL compared to PBL (p < 0.01), and a higher proportion of IL-2+ T cells in PBL compared with TAL and TIL (p < 0.05). Low percentages of IL-4+ T cells (i.e. Th2) were detected in each tissue. Taken together, these data demonstrate the recruitment and accumulation of high concentrations of antigen-experienced T lymphocytes in TAL and TIL compared to PBL. However, low surface expression of IL-2 receptor (i.e. CD25), as well as depressed intracellular IL-2 production in chronically stimulated TAL and TIL suggests that the impaired antitumor function commonly detected in these lymphocyte populations may be secondary to an acquired

  19. 78 FR 35290 - Government-Owned Inventions; Availability for Licensing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-06-12

    ... attacking TIL from a patient's tumor based on these markers prior to re-infusion, in vitro culture time is... specific cell surface markers will reduce the culture time for these T cells before re-infusion into the... for autologous tumor recognition before re- infusion into the patient Development Stage:...

  20. Estimating soil organic carbon using aerial imagery and soil surveys

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Widespread implementation of precision agriculture practices requires low-cost, high-quality, georeferenced soil organic carbon (SOC) maps, but currently these maps require expensive sample collection and analysis. Widely available aerial imagery is a low-cost source of georeferenced data. After til...

  1. Hydrogeological analysis of the upper Dupi Tila Aquifer, towards the implementation of a managed aquifer-recharge project in Dhaka City, Bangladesh

    NASA Astrophysics Data System (ADS)

    Rahman, Mohammad Azizur; Wiegand, Bettina A.; Badruzzaman, A. B. M.; Ptak, Thomas

    2013-08-01

    A preliminary feasibility assessment of managed aquifer-recharge (MAR) techniques was undertaken for Dhaka City, Bangladesh. Considering the top impermeable-layer (TIL) thickness and the land-use classification, four primary MAR techniques have been suggested: (1) soil-aquifer treatment (SAT) for TIL thickness 0-8 m, (2) cascade-type recharge trenches/pits for TIL thickness 9-30 m, (3) aquifer storage, transfer and recovery (ASR/ASTR) for TIL thickness 31-52 m, and (4) use of natural wetlands to recharge water collected from open spaces. The study suggests that recharge trenches and pits will be the most appropriate MAR techniques, which can be implemented in most parts of the recharge area (ca. 277 km2). In case of a recharge trench, the lower parts (15-20 m) that are in direct contact with the aquifer can be backfilled with biosand filters with a reactive layer containing metallic iron (Fe0) to offer pre-treatment of the infiltrated water. In addition to the suggested four techniques, the regional groundwater flow direction, from the northwest and northeast towards Dhaka City, may allow use of the aquifer as a natural treatment and transport medium for groundwater, if spreading basins are installed in the greater Dhaka area.

  2. US EPA, Pesticide Product Label, , 01/14/1994

    EPA Pesticide Factsheets

    2011-04-21

    ... t. (.-}iP ' . 1 , " . " . _1. :.!J::·'lt }'.'f· (r)) Cd[)ic's uf your final l:rinl,·,l }'Ji'clin" : efl 1" '.'-0 t· 1.~~JS;· t}lf:~ pr'Jducl for shipmet"!t. :·'f~l.~r to til('~ l\\-· ...

  3. Throw the Book at 'Em

    NASA Astrophysics Data System (ADS)

    Statler, Thomas S.

    1997-09-01

    Buchangst pervades college astronomy. Instructors fret that no textbook is quite right, authors and publishers get shot down when they try to innovate, students count the days 'til they can sell back their unfriendly tomes. But none of this is going to change unless we make it happen.

  4. Channel Protein Engineering: A Novel Approach towards the Molecular Dissection Determinants in Ligand-Regulated Channels

    DTIC Science & Technology

    1990-02-15

    Biochemical and Biophysical Research Communications 162...Soc. Neurosci. 15 (1):970a. (1989) Vol. 162, No. 1, 1989 BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS July 14, 1989 Pages 352-356 TIlE M25...Press. hic. All rights of reproduction in any form reserved. 352 Vol. 162, No. 1, 1989 BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS pli

  5. ASCD in Retrospect. Contributions to the History of the Association for Supervision and Curriculum Development.

    ERIC Educational Resources Information Center

    Van Til, William, Ed.

    Nine past presidents, the current president, and the executive director of the Association for Supervision and Curriculum Development (ASCD) contributed a chapter each to this history of ASCD and the fields it has represented since its founding in 1943. The book's editor, William Van Til, provides an introductory overview of the organization's…

  6. Remote sensing of soil tilage intensity in central Iowa

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Crop residues on the soil surface decrease soil erosion, increase soil organic matter, improve soil quality, and reduce the amount of nutrients and pesticides that reaches stream and rivers. Crop residue cover is often used to classify soil tillage intensity and assess the extent of conservation til...

  7. Closing the Student Achievement Gap in California's Elementary Schools: A Lead Teachers' Perspective on Transformational Instructional Leadership

    ERIC Educational Resources Information Center

    Hays, Kelli

    2010-01-01

    This study has tackled the thorny problem of closing the Student Achievement Gap (SAG) in California's elementary schools. To address that problem, an "Integrated" form of educational leadership called Transformational Instructional Leadership (TIL), a form grounded in "best practices" of Transformational and Instructional…

  8. Manipulations of soil microbiota for C sequestration and mitigation of greenhouse gas emissions in managed systems

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Soil microbes dominate processes that regulate soil trace gas emissions and soil C and N dynamics. Intensive management in agroecosystems provides unique opportunities to assess the effectiveness of microbial manipulations to enhance soil C retention and reduce trace gas emissions. While reduced til...

  9. US EPA, Pesticide Product Label, , 01/29/1996

    EPA Pesticide Factsheets

    2011-04-21

    ... tbt 11 Ut 1 :-, !lilt d i(aL~(;n " [lot con.'--) L<-;~l'Il·._ \\,1 til tit.' t f'l11l-i I)f f~ ~~ It let' (,- , md .j) Ill; ; ~:, J 1. tillS \\',n.itH t_ rll\\" III' j)-~ In vjrddtl"r1 . ...

  10. US EPA, Pesticide Product Label, FERTI-LOME TOMATO ...

    EPA Pesticide Factsheets

    2011-04-14

    ... {i{'Hii,=-~~ til :Y4 ~! t :fff":> (i1"ffi ~ rro:JT~ • ~ ill 111' foi ' I .' ' .. J' I'L"I"~ln,!J' \\ .f ."l.:JIl":U ~.H: ~wr) ::J;I:i~1 ;1if:i,;\\l)iJlmJ1!}.I~:\\ij1(ih~' 1 , + J II , . ...

  11. US EPA, Pesticide Product Label, METHYL BROMIDE 99.75% ...

    EPA Pesticide Factsheets

    2011-04-21

    ... ",alt.. Ind .. "t'l l.balaM., with ,robabla r.COyary .ft.r • parlod of na •• ,.,vr.. Ilood lIrO-l4. 1 • .".ls ... l~ ·Do "ot r ..... Ie .... _til ttl. -art.. T ••• t .... , MI'It".ra ... a1 ...

  12. US EPA, Pesticide Product Label, , 12/10/1986

    EPA Pesticide Factsheets

    2011-04-14

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  13. RAS/MAPK activation is associated with reduced tumor-infiltrating lymphocytes in triple-negative breast cancer: therapeutic cooperation between MEK and PD-1/PD-L1 immune checkpoint inhibitors

    PubMed Central

    Loi, Sherene; Dushyanthen, Sathana; Beavis, Paul A; Salgado, Roberto; Denkert, Carsten; Savas, Peter; Combs, Susan; Rimm, David L.; Giltnane, Jennifer M.; Estrada, Monica V.; Sánchez, Violeta; Sanders, Melinda E.; Cook, Rebecca S.; Pilkinton, Mark A.; Mallal, Simon A.; Wang, Kai; Miller, Vincent A.; Stephens, Phil J.; Yelensky, Roman; Doimi, Franco D.; Gómez, Henry; Ryzhov, Sergey V.; Darcy, Phillip K.; Arteaga, Carlos L.; Balko, Justin M.

    2015-01-01

    Purpose Tumor-infiltrating lymphocytes (TILs) in the residual disease (RD) of triple-negative breast cancers (TNBCs) after neoadjuvant chemotherapy (NAC) are associated with improved survival, but insight into tumor cell-autonomous molecular pathways affecting these features are lacking. Experimental Design We analyzed TILs in the RD of clinically and molecularly characterized TNBCs after NAC and explored therapeutic strategies targeting combinations of MEK inhibitors with PD-1/PD-L1-targeted immunotherapy in mouse models of breast cancer. Results Presence of TILs in the RD was significantly associated with improved prognosis. Genetic or transcriptomic alterations in Ras/MAPK signaling were significantly correlated with lower TILs. MEK inhibition up-regulated cell-surface major histocompatibility complex (MHC) expression and PD-L1 in TNBC cells both in vivo and in vitro. Moreover, combined MEK and PDL-1/PD-1 inhibition enhanced anti-tumor immune responses in mouse models of breast cancer. Conclusions These data suggest the possibility that Ras/MAPK pathway activation promotes immune-evasion in TNBC, and support clinical trials combining MEK- and PD-L1-targeted therapies. Furthermore, Ras/MAPK activation and MHC expression may be predictive biomarkers of response to immune checkpoint inhibitors. PMID:26515496

  14. Interlesional diversity of T cell receptors in melanoma with immune checkpoints enriched in tissue-resident memory T cells

    PubMed Central

    Boddupalli, Chandra Sekhar; Bar, Noffar; Kadaveru, Krishna; Krauthammer, Michael; Pornputtapong, Natopol; Ariyan, Stephan; Narayan, Deepak; Kluger, Harriet; Deng, Yanhong; Verma, Rakesh; Das, Rituparna; Bacchiocchi, Antonella; Halaban, Ruth; Sznol, Mario; Dhodapkar, Madhav V.; Dhodapkar, Kavita M.

    2016-01-01

    Heterogeneity of tumor cells and their microenvironment can affect outcome in cancer. Blockade of immune checkpoints (ICPs) expressed only on a subset of immune cells leads to durable responses in advanced melanoma. Tissue-resident memory T (TRM) cells have recently emerged as a distinct subset of memory T cells in nonlymphoid tissues. Here, we show that functional properties and expression of ICPs within tumor-infiltrating lymphocytes (TILs) differ from those of blood T cells. TILs secrete less IL-2, IFN-γ, and TNF-α compared with circulating counterparts, and expression of VEGF correlated with reduced TIL infiltration. Within tumors, ICPs are particularly enriched within T cells with phenotype and genomic features of TRM cells and the CD16+ subset of myeloid cells. Concurrent T cell receptor (TCR) and tumor exome sequencing of individual metastases in the same patient revealed that interlesional diversity of TCRs exceeded differences in mutation/neoantigen load in tumor cells. These findings suggest that the TRM subset of TILs may be the major target of ICP blockade and illustrate interlesional diversity of tissue-resident TCRs within individual metastases, which did not equilibrate between metastases and may differentially affect the outcome of immune therapy at each site. PMID:28018970

  15. US EPA, Pesticide Product Label, BIOBAN-C, 01/18/1971

    EPA Pesticide Factsheets

    2011-04-13

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  16. The Desire to Learn as a Kind of Love: Gardening, Cooking, and Passion in Outdoor Education

    ERIC Educational Resources Information Center

    Wistoft, Karen

    2013-01-01

    "Gardens for Bellies" ["Haver til Maver"] is an organic school gardens project at Krogerup farm in Northern Sealand, Denmark, which provides children with first-hand experiences in a natural, outdoor environment. The general intention of the project is to expand children's competences and their knowledge of nature, farming and…

  17. Algunos Resumenes

    NASA Astrophysics Data System (ADS)

    1980-12-01

    EI "Palomar Observatory Sky Survey" es un medio auxiliar bien conocido y ütil para los astronomos. Todo el cielo dei hemisferio Norte esta captado en lotografias, cuyas reproducciones se encuentran archivadas en las bibliotecas de casi todos los observatorios importantes dei mundo.

  18. US EPA, Pesticide Product Label, METHYL BROMIDE 99.5% ...

    EPA Pesticide Factsheets

    2011-04-21

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  19. Phenotypic gain from introgression of two QTLs, qSB9-2 and qSB12-1, for rice sheath blight resistance

    Technology Transfer Automated Retrieval System (TEKTRAN)

    F2:3 families from crosses between three indica introgression lines and their common japonica recurrent parent were used to evaluate two quantitative trait loci (QTLs) for sheath blight (SB) resistance. Three selected ‘TeQing’-into-‘Lemont’ backcross introgression lines (TILs) were more resistant th...

  20. Results of the Second U.S. Manned Suborbital Space Flight, July 21, 1961

    DTIC Science & Technology

    1961-07-21

    SPACECRAFT AND FLIGHT PLAN FOR THE MERCURY -REDSTONE 4 FLIGHT .............................................................. 3 By Jercme B. Haammack... Mercury -Redstone Project Engineer, NASA Manned Spacecraft Center. 3. RESULTS OF TIlE MR-4 PREFLIGHT AND POSTFLIGHT MEDICAL EXAMI- NATION CONDUCTED ON... MERCURY -REDSTONF MISSIONS 3 AND 4 ................................................................... 23 By William K. Douglas, M.D., Astronaut Fi

  1. Programming for Adolescents with Behavioral Disorders.

    ERIC Educational Resources Information Center

    Braaten, Sheldon, Ed.; And Others

    This book presents 17 papers from a 1982 national multidisciplinary conference on services for behaviorally disordered adolescents. The following papers are included: "Programming for Youth in Secondary Schools and the Community," (W. Van Til); "Who's Crazy? II" (C. Michael Nelson); "Correlates of Successful Adaptive Behavior: Comparative Studies…

  2. Predictive and Prognostic Role of Tumor-Infiltrating Lymphocytes for Early Breast Cancer According to Disease Subtypes: Sensitivity Analysis of Randomized Trials in Adjuvant and Neoadjuvant Setting

    PubMed Central

    Carbognin, Luisa; Pilotto, Sara; Nortilli, Rolando; Brunelli, Matteo; Nottegar, Alessia; Sperduti, Isabella; Giannarelli, Diana; Tortora, Giampaolo

    2016-01-01

    Background. The role of tumor-infiltrating lymphocytes (TILs) in breast cancer (BC) is still an issue for clinical research. Toward this end, a sensitivity analysis of neoadjuvant and adjuvant randomized clinical trials was performed according to disease subtypes. Methods. Pathological complete responses (pCRs) after neoadjuvant treatment according to the presence or absence of lymphocyte-predominant BC (LPBC) were extracted and cumulated as odds ratios (ORs) by adopting a random-effects model by subtype. Overall survival hazard ratios as a function of 10% incremental values of stromal TILs (sTILs) in adjuvant trials were extracted. The interaction test was adopted to determine the differential effect according to the subtype. Results. Eight trials (5,514 patients) were identified. With regard to neoadjuvant setting (4 studies), a significant interaction (p < .0001) according to LPBC was found. The presence of LPBC was associated with a 29.5% increase in pCR rate compared with non-LPBC (p < .0001). The pCR rate was significantly higher in patients with LPBC in triple-negative BC (TNBC) and HER2-positive BC settings, with an absolute difference of 15.7% (95% confidence interval [CI], 4.9%–26.2%) and 33.3% (95% CI, 23.6%–42.7%), respectively. With respect to the adjuvant setting (4 studies), a significant interaction (p < .0001) according to sTILs was found. A survival benefit was more likely to be determined for HER2-positive BC (p = .025) and TNBC (p < .0001), with no statistically significant difference for estrogen receptor-positive/HER2-negative disease. Conclusion. Despite the retrospective nature of this analysis, the presence of TILs may represent a robust predictive and prognostic marker for BC, particularly for TNBC and HER2-positive disease. Implications for Practice: This sensitivity analysis of neoadjuvant and adjuvant randomized clinical trials in breast cancer explores the potential predictive and prognostic role of tumor-infiltrating lymphocytes

  3. Effects of TP53 and PIK3CA mutations in early breast cancer: a matter of co-mutation and tumor-infiltrating lymphocytes.

    PubMed

    Kotoula, Vassiliki; Karavasilis, Vasilios; Zagouri, Flora; Kouvatseas, George; Giannoulatou, Eleni; Gogas, Helen; Lakis, Sotiris; Pentheroudakis, George; Bobos, Mattheos; Papadopoulou, Kyriaki; Tsolaki, Eleftheria; Pectasides, Dimitrios; Lazaridis, Georgios; Koutras, Angelos; Aravantinos, Gerasimos; Christodoulou, Christos; Papakostas, Pavlos; Markopoulos, Christos; Zografos, George; Papandreou, Christos; Fountzilas, George

    2016-07-01

    The purpose of this study is to investigate whether the outcome of breast cancer (BC) patients treated with adjuvant chemotherapy is affected by co-mutated TP53 and PIK3CA according to stromal tumor-infiltrating lymphocytes (TILs). Paraffin tumors of all clinical subtypes from 1661 patients with operable breast cancer who were treated within 4 adjuvant trials with anthracycline-taxanes chemotherapy were informative for TP53 and PIK3CA mutation status (semiconductor sequencing genotyping) and for stromal TILs density. Disease-free survival (DFS) was examined. TP53 mutations were associated with higher (p < 0.001) and PIK3CA with lower (p = 0.004) TILs in an ER /PgR-specific manner (p < 0.001). Mutations did not affect the favorable DFS of patients with lymphocyte-predominant (LP) BC. Within non-LPBC, PIK3CA-only mutations conferred best, while TP53-PIK3CA co-mutations (6 % of all tumors) conferred worst DFS (HR 0.59; 95 % CI 0.44-0.79; p = 0.001 for PIK3CA-only). TP53-only mutations were unfavorable in patients with lower TILs, while patients with lower TILs performed worse if their tumors carried TP53-only mutations (interaction p = 0.046). Multivariate analysis revealed favorable PIK3CA-only mutations in non-LPBC (HR 0.64; 95 % CI 0.47-0.88; p = 0.007), and unfavorable TP53 mutations in ER/PgRpos/HER2neg (HR 1.55; 95 % CI 1.07-2.24; p = 0.021). Mutations did not interact with TILs in non-LP triple-negative and HER2-positive patients. TP53 and PIK3CA mutations appear to have diverse effects on the outcome of early BC patients, according to whether these genes are co-mutated or not, and for TP53 according to TILs density and ER/PgR-status. These findings need to be considered when evaluating the effect of these two most frequently mutated genes in the context of large clinical trials.

  4. Association between Chemotherapy-Response Assays and Subsets of Tumor-Infiltrating Lymphocytes in Gastric Cancer: A Pilot Study

    PubMed Central

    Lee, Jee Youn; Son, Taeil; Cheong, Jae-Ho; Hyung, Woo Jin; Noh, Sung Hoon; Kim, Choong-Bai; Park, Chung-Gyu

    2015-01-01

    Purpose The purpose of this pilot study was to evaluate the association between adenosine triphosphate-based chemotherapy response assays (ATP-CRAs) and subsets of tumor infiltrating lymphocytes (TILs) in gastric cancer. Materials and Methods In total, 15 gastric cancer tissue samples were obtained from gastrectomies performed between February 2007 and January 2011. Chemotherapy response assays were performed on tumor cells from these samples using 11 chemotherapeutic agents, including etoposide, doxorubicin, epirubicin, mitomycin, 5-fluorouracil (5-FU), oxaliplatin, irinotecan, docetaxel, paclitaxel, methotrexate, and cisplatin. TILs in the tissue samples were evaluated using antibodies specific for CD3, CD4, CD8, Foxp3, and Granzyme B. Results The highest cancer cell death rates were induced by etoposide (44.8%), 5-FU (43.1%), and mitomycin (39.9%). Samples from 10 patients who were treated with 5-FU were divided into 5-FU-sensitive and -insensitive groups according to median cell death rate. No difference was observed in survival between the two groups (P=0.216). Only two patients were treated with a chemotherapeutic agent determined by an ATP-CRA and there was no significant difference in overall survival compared with that of patients treated with their physician's choice of chemotherapeutic agent (P=0.105). However, a high number of CD3 TILs was a favorable prognostic factor (P=0.008). Pearson's correlation analyses showed no association between cancer cell death rates in response to chemotherapeutic agents and subsets of TILs. Conclusions Cancer cell death rates in response to specific chemotherapeutic agents were not significantly associated with the distribution of TIL subsets. PMID:26819801

  5. OX40, PD-1 and CTLA-4 are selectively expressed on tumor-infiltrating T cells in head and neck cancer

    PubMed Central

    Montler, Ryan; Bell, R Bryan; Thalhofer, Colin; Leidner, Rom; Feng, Zipei; Fox, Bernard A; Cheng, Allen C; Bui, Tuan G; Tucker, Christopher; Hoen, Helena; Weinberg, Andrew

    2016-01-01

    The tumor microenvironment of squamous cell carcinoma of the head and neck (SCCHN) has been shown to be immune suppressive. Therefore, strategies aimed at overcoming this issue could have a positive therapeutic impact. Hence, we investigated the expression of the known immune-modulatory proteins OX40, programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) in SCCHN on different T-cell subsets of tumor-infiltrating lymphocytes (TIL) to ascertain whether these proteins could potentially be targeted alone or in combination for future clinical trials. T cells from peripheral blood (PBL) and tumor were analyzed for the expression of OX40, PD-1 and CTLA-4 in 29 patients undergoing surgery. These proteins were all expressed significantly higher in T-cell subsets isolated from tumors compared with PBL of the same patient. OX40 expression was significantly greater in the TIL regulatory T-cell (Treg) population relative to conventional CD4 and CD8 TIL or the Treg isolated from PBL. PD-1 expression was increased in all T-cell subsets relative to PBL. CTLA-4 was also increased in all TIL subsets relative to blood, and similar to OX40, its highest level of expression was observed in the Treg TIL. The highest frequency of PD-1, CTLA-4 and OX40 triple-positive cells were found in the Treg population isolated from the tumor. We analyzed both human papilloma virus-positive and -negative patients and found similar levels and expression patterns of these two patient populations for all three proteins. These data suggest that there may be therapeutic advantages of targeting these pathways independently or in combination for patients with this disease. PMID:27195113

  6. TIGIT and PD-1 impair tumor antigen–specific CD8+ T cells in melanoma patients

    PubMed Central

    Chauvin, Joe-Marc; Pagliano, Ornella; Fourcade, Julien; Sun, Zhaojun; Wang, Hong; Sander, Cindy; Kirkwood, John M.; Chen, Tseng-hui Timothy; Maurer, Mark; Korman, Alan J.; Zarour, Hassane M.

    2015-01-01

    T cell Ig and ITIM domain (TIGIT) is an inhibitory receptor expressed by activated T cells, Tregs, and NK cells. Here, we determined that TIGIT is upregulated on tumor antigen–specific (TA-specific) CD8+ T cells and CD8+ tumor-infiltrating lymphocytes (TILs) from patients with melanoma, and these TIGIT-expressing CD8+ T cells often coexpress the inhibitory receptor PD-1. Moreover, CD8+ TILs from patients exhibited downregulation of the costimulatory molecule CD226, which competes with TIGIT for the same ligand, supporting a TIGIT/CD226 imbalance in metastatic melanoma. TIGIT marked early T cell activation and was further upregulated by T cells upon PD-1 blockade and in dysfunctional PD-1+TIM-3+ TA-specific CD8+ T cells. PD-1+TIGIT+, PD-1–TIGIT+, and PD-1+TIGIT– CD8+ TILs had similar functional capacities ex vivo, suggesting that TIGIT alone, or together with PD-1, is not indicative of T cell dysfunction. However, in the presence of TIGIT ligand–expressing cells, TIGIT and PD-1 blockade additively increased proliferation, cytokine production, and degranulation of both TA-specific CD8+ T cells and CD8+ TILs. Collectively, our results show that TIGIT and PD-1 regulate the expansion and function of TA-specific CD8+ T cells and CD8+ TILs in melanoma patients and suggest that dual TIGIT and PD-1 blockade should be further explored to elicit potent antitumor CD8+ T cell responses in patients with advanced melanoma. PMID:25866972

  7. Programmed death-1 ligand 1 and 2 are highly expressed in pleomorphic carcinomas of the lung: Comparison of sarcomatous and carcinomatous areas.

    PubMed

    Kim, Sehui; Kim, Moon-Young; Koh, Jaemoon; Go, Heounjeong; Lee, Dong Soo; Jeon, Yoon Kyung; Chung, Doo Hyun

    2015-11-01

    Pleomorphic carcinoma (PC) of the lung is a rare type of poorly differentiated non-small cell lung carcinoma (NSCLC) that belongs to sarcomatoid carcinoma (SC). It exhibits aggressive behaviour and resistance to chemotherapy and radiotherapy. Recently, immunotherapy targeting the programmed death-1 (PD-1)/PD ligand 1 (PD-L1) pathway has demonstrated favourable clinical outcomes in NSCLC. However, the expression patterns of PD-1-related molecules in pulmonary PC remain elusive. PD-L1 and PD-L2 expression was estimated in 41 cases of PC using immunohistochemistry. CD8(+) and PD-1(+) tumour-infiltrating lymphocytes (TILs) were also evaluated. PD-L1 and PD-L2 were highly expressed in pulmonary PCs (90.2% [37/41)]; 87.8% [36/41]). The amount of CD8(+) or PD-1(+) TILs and the ratio of PD-1(+)/CD8(+) TILs in PC were higher in males, smokers and older patients. PD-L1-positive PCs were infiltrated by higher numbers of CD8(+) TILs compared to PD-L1-negative cases (P=0.006). Of note, PD-L1 expression in pulmonary PCs was significantly higher in sarcomatous areas than in the carcinomatous portion (P=0.006). PC patients with a high ratio of PD-1(+)/CD8(+) TILs showed a shorter progression-free survival (P=0.036), whereas PD-L1 and PD-L2 expression had no prognostic implications. Our study demonstrates that pulmonary PCs very frequently express PD-L1 and PD-L2. Moreover, their expression is higher in sarcomatous cells than in carcinomatous areas. Thus, targeting the PD-1/PD-L1 pathway may represent a potential therapeutic candidate for this aggressive tumour.

  8. Impact of chemokine receptor CXCR3 on tumor-infiltrating lymphocyte recruitment associated with favorable prognosis in advanced gastric cancer.

    PubMed

    Li, Kai; Zhu, Zhengpeng; Luo, Jin; Fang, Jingyi; Zhou, Huanhuan; Hu, Min; Maskey, Ninu; Yang, Guifang

    2015-01-01

    Chemokine receptor CXCR3 has been proved to play an important role in tumorigenesis and tumor progression in many malignancies, but its precise efficacy on gastric cancer (GC) has not been evaluated yet. The present study was aimed to explore the correlation of chemokine receptor CXCR3 with tumor-infiltrating lymphocytes (TILs) and prognosis in advanced gastric cancer (GC). Expression of CXCR3 and CD4+, CD8+ TILs was conducted in 192 advanced GC specimens and 48 corresponding paracancerous tissues by immunohistochemical (IHC) analysis. CXCR3 expression in GC tissues was significantly higher than that in paracancerous tissues (P<0.001) and CD8+, CD4+ TILs infiltration increased with high CXCR3 expression (P=0.032 and P<0.001, respectively). Our study showed significantly lower CXCR3 expression in patients with greater tumor invasion depth and lymph node metastasis compared with patients with lesser tumor invasion depth and without lymph node metastasis (P=0.002 and P=0.001, respectively). Univariate analysis indicated that patients with high CXCR3 expression and high CD8+ TILs infiltration had longer overall survival (OS) (log-rank test, P<0.001 and P=0.002, respectively). Univariate and multivariate analyses indicated that CXCR3 expression was an independent prognostic factor for OS (P=0.002). The present study suggested that CXCR3 expression was upregulated in advanced GC and was associated with increased CD4+, CD8+ TILs infiltration and improved OS. Therefore, CXCR3 overexpression is implicated as a favorable prognostic biomarker in human advanced GC.

  9. Identification of a human melanoma antigen recognized by tumor-infiltrating lymphocytes associated with in vivo tumor rejection.

    PubMed Central

    Kawakami, Y; Eliyahu, S; Delgado, C H; Robbins, P F; Sakaguchi, K; Appella, E; Yannelli, J R; Adema, G J; Miki, T; Rosenberg, S A

    1994-01-01

    The cultured T-cell line TIL1200, established from the tumor-infiltrating lymphocytes (TILs) of a patient with advanced metastatic melanoma, recognized an antigen on most HLA-A2+ melanomas and on all HLA-A2+ cultured neonatal melanocytes in an HLA-A2 restricted manner but not on other types of tissues or cell lines tested. A cDNA encoding an antigen recognized by TIL1200 was isolated by screening an HLA-A2+ breast cancer cell line transfected with an expression cDNA library prepared from an HLA-A2+ melanoma cell line. The nucleotide and amino acid sequences of this cDNA were almost identical to the genes encoding glycoprotein gp100 or Pmel17 previously registered in the GenBank. Expression of this gene was restricted to melanoma and melanocyte cell lines and retina but was not expressed on other fresh or cultured normal tissues or other types of tumor tested. The cell line transfected with this cDNA also expressed antigen recognized by the melanoma-specific antibody HMB45 that bound to gp100. A synthetic 10-amino acid peptide derived from gp100 was recognized by TIL1200 in the context of HLA-A2.1. Since the administration of TIL1200 plus interleukin 2 resulted in regression of metastatic cancer in the autologous patient, gp100 is a possible tumor rejection antigen and may be useful for the development of immunotherapies for patients with melanoma. Images PMID:8022805

  10. A mechanism to explain the variations of tropopause and tropopause inversion layer in the Arctic region during a sudden stratospheric warming in 2009

    NASA Astrophysics Data System (ADS)

    Wang, Rui; Tomikawa, Yoshihiro; Nakamura, Takuji; Huang, Kaiming; Zhang, Shaodong; Zhang, Yehui; Yang, Huigen; Hu, Hongqiao

    2016-10-01

    The mechanism to explain the variations of tropopause and tropopause inversion layer (TIL) in the Arctic region during a sudden stratospheric warming (SSW) in 2009 was studied with the Modern-Era Retrospective analysis for Research and Applications reanalysis data and GPS/Constellation Observing system for Meteorology, Ionosphere, and Climate (COSMIC) temperature data. During the prominent SSW in 2009, the cyclonic system changed to the anticyclonic system due to the planetary wave with wave number 2 (wave2). The GPS/COSMIC temperature data showed that during the SSW in 2009, the tropopause height in the Arctic decreased accompanied with the tropopause temperature increase and the TIL enhancement. The variations of the tropopause and TIL were larger in higher latitudes. A static stability analysis showed that the variations of the tropopause and TIL were associated with the variations of the residual circulation and the static stability due to the SSW. Larger static stability appeared in the upper stratosphere and moved downward to the narrow region just above the tropopause. The descent of strong downward flow was faster in higher latitudes. The static stability tendency analysis showed that the strong downward residual flow induced the static stability change in the stratosphere and around the tropopause. The strong downwelling in the stratosphere was mainly induced by wave2, which led to the tropopause height and temperature changes due to the adiabatic heating. Around the tropopause, a pair of downwelling above the tropopause and upwelling below the tropopause due to wave2 contributed to the enhancement of static stability in the TIL immediately after the SSW.

  11. High numbers of granzyme B/CD8-positive tumour-infiltrating lymphocytes in nasopharyngeal carcinoma biopsies predict rapid fatal outcome in patients treated with curative intent.

    PubMed

    Oudejans, Joost J; Harijadi, Hari; Kummer, J Alain; Tan, I Bing; Bloemena, Elizabeth; Middeldorp, Jaap M; Bladergroen, Belinda; Dukers, Danny F; Vos, Wim; Meijer, Chris J L M

    2002-12-01

    This study determined whether tumour-infiltrating lymphocytes (TILs) in nasopharyngeal carcinomas (NPCs) include activated cytotoxic T lymphocytes (CTLs) and whether the numbers of activated CTLs in these biopsies are related to clinical outcome. Moreover, the study investigated whether the numbers of activated CTLs are associated with the expression of MHC class I proteins and the granzyme B antagonist PI-9 in the tumour cells. Forty-three Indonesian NPC patients (T(1-3), N(1-3), M(0)), who were treated with curative intent by radiotherapy only, were studied. Tumour-infiltrating activated CTLs were detected using antibodies against granzyme B, CD8, and CD56. Expression of MHC class I proteins and PI-9 was also determined by immunohistochemistry. Granzyme B-positive TILs were detected in all NPC biopsies. The presence of a high percentage (>25%) of granzyme B-positive TILs appeared to be a very strong predictor of a rapid fatal clinical outcome, independent of stage. Complete absence of MHC class I heavy chain expression in tumour cells was observed in 11 of 31 evaluable cases and low levels were observed in seven additional cases. No association between MHC class I expression and the numbers of granzyme B-positive TILs was observed. Expression of the granzyme B antagonist PI-9 in tumour cells was detected in three cases. It is concluded that the presence of many granzyme B-positive TILs in a selected group of Indonesian NPC patients is a strong and stage-independent marker for a rapid fatal clinical outcome.

  12. CD45RO+ Memory T Lymphocytes — a Candidate Marker for TNM-Immunoscore in Squamous Non–Small Cell Lung Cancer1

    PubMed Central

    Paulsen, Erna-Elise; Kilvaer, Thomas; Khanehkenari, Mehrdad Rakaee; Maurseth, Ramona Johansen; Al-Saad, Samer; Hald, Sigurd M.; Al-Shibli, Khalid; Andersen, Sigve; Richardsen, Elin; Busund, Lill-Tove; Bremnes, Roy; Donnem, Tom

    2015-01-01

    Tumor-infiltrating lymphocytes (TILs) are vital in limiting cancer progression and may supplement the TNM classification. CD45RO+ memory TILs show major prognostic impact in various malignancies but have not been extensively explored in non–small cell lung cancer (NSCLC). In this study, we aimed to evaluate their potential in a NSCLC TNM-Immunoscore. Tissue microarrays were constructed from tumor tissue samples from two cohorts including in total 536 patients (University Hospital of North Norway, n = 285; Nordland Hospital, n = 251) with primary resected stage I to IIIA NSCLC. The density of CD45RO+ and CD8+ TILs in tumor epithelial and stromal compartments of the tumors was evaluated by immunohistochemistry. In univariate analyses, intraepithelial CD45RO+ TIL density (T-CD45RO) was a significant prognostic factor for disease-specific survival (P = .007), limited to the squamous cell carcinoma (SCC) histology subgroup (P < .001), where it was significant in both cohorts (University Hospital of North Norway, P = .003; Nordland Hospital, P = .022). Combining T-CD45RO and stromal CD8+ TIL density (S-CD8) increased the prognostic impact in SCC (P < .001) and showed a significant impact within all pathological stages (I, P = .025; II, P < .001; III, P = .001). In the multivariate analysis, T-CD45RO was an independent positive prognostic factor for SCC (hazard ratio 2.65, 95% confidence interval 1.64-4.28, P < .001), and in combination with S-CD8, the prognostic impact increased vastly (high + high versus low + low: hazard ratio 6.50, 95% confidence interval 3.54-11.91, P < .001). In conclusion, T-CD45RO was an independent prognostic factor for SCC NSCLC. When combined with S-CD8, the prognostic impact increased and was significant within each pathological stage. We propose CD45RO as a candidate marker for TNM-Immunoscore in SCC NSCLC. PMID:26678911

  13. Prognostic impact of programmed cell death-1 (PD-1) and PD-ligand 1 (PD-L1) expression in cancer cells and tumor-infiltrating lymphocytes in ovarian high grade serous carcinoma

    PubMed Central

    Kulbe, Hagen; Sehouli, Jalid; Wienert, Stephan; Lindner, Judith; Budczies, Jan; Bockmayr, Michael; Dietel, Manfred; Denkert, Carsten; Braicu, Ioana; Jöhrens, Korinna

    2016-01-01

    Aims Antibodies targeting the checkpoint molecules programmed cell death 1 (PD-1) and its ligand PD-L1 are emerging cancer therapeutics. We systematically investigated PD-1 and PD-L1 expression patterns in the poor-prognosis tumor entity high-grade serous ovarian carcinoma. Methods PD-1 and PD-L1 protein expression was determined by immunohistochemistry on tissue microarrays from 215 primary cancers both in cancer cells and in tumor-infiltrating lymphocytes (TILs). mRNA expression was measured by quantitative reverse transcription PCR. An in silico validation of mRNA data was performed in The Cancer Genome Atlas (TCGA) dataset. Results PD-1 and PD-L1 expression in cancer cells, CD3+, PD-1+, and PD-L1+ TILs densities as well as PD-1 and PD-L1 mRNA levels were positive prognostic factors for progression-free (PFS) and overall survival (OS), with all factors being significant for PFS (p < 0.035 each), and most being significant for OS. Most factors also had prognostic value that was independent from age, stage, and residual tumor. Moreover, high PD-1+ TILs as well as PD-L1+ TILs densities added prognostic value to CD3+TILs (PD-1+: p = 0.002,; PD-L1+: p = 0.002). The significant positive prognostic impact of PD-1 and PD-L1 mRNA expression could be reproduced in the TCGA gene expression datasets (p = 0.02 and p < 0.0001, respectively). Conclusions Despite their reported immune-modulatory function, high PD-1 and PD-L1 levels are indicators of a favorable prognosis in ovarian cancer. Our data indicate that PD-1 and PD-L1 molecules are biologically relevant regulators of the immune response in high-grade serous ovarian carcinoma, which is an argument for the evaluation of immune checkpoint inhibiting drugs in this tumor entity. PMID:26625204

  14. The microenvironment in primary cutaneous melanoma with associated spontaneous tumor regression: evaluation for T-regulatory cells and the presence of an immunosuppressive microenvironment.

    PubMed

    Gray, Arielle; Grushchak, Solomiya; Mudaliar, Kumaran; Kliethermes, Stephanie; Carey, Kyle; Hutchens, Kelli A

    2017-04-01

    Spontaneous tumor regression, regression in the absence of therapeutic intervention, can be identified histologically in over 25% of primary cutaneous melanomas at initial diagnosis. A unique subset of T lymphocytes found in areas of regression can be histologically distinguished from tumor-infiltrating T lymphocytes (TIL) found in areas of tumor progression. We call this unique subset of T lymphocytes regression-associated T lymphocytes (RATs). The aim of this study is to determine the phenotype of lymphocytes and the density of specific cell types linked to immunosuppression in areas of tumor progression compared with areas of tumor regression. These specific cell types include T-regulatory cells (Tregs) and S100A9 cells. A total of 14 primary cutaneous melanomas with areas of progression and regression were used. Immunohistochemistry staining was used to identify CD4 cells, CD8 cells, Tregs, and S100A9 cells. Two independent observers manually counted three high-powered ×40 fields. There was no predominance of CD4 or CD8 T lymphocytes in either RATs or TIL. We identified a lower density of Tregs in RATs compared with TIL when using the FOXP3/CD4 Treg marker (P=0.04) and a marginal difference when using our second, confirmatory Treg marker, FOXP3/CD25 (P=0.11). We observed a lower density of S100A9 cells in RATs compared with TIL (P=0.002). There was an observable difference in the tumor microenvironments of RATs and TIL, with RATs having a significantly lower density of Tregs and S100A9 cells. We deduce that the absence of immunosuppression in areas of regression allows for a more robust immune response and thus effective eradication of tumor cells.

  15. TIGIT and PD-1 impair tumor antigen-specific CD8⁺ T cells in melanoma patients.

    PubMed

    Chauvin, Joe-Marc; Pagliano, Ornella; Fourcade, Julien; Sun, Zhaojun; Wang, Hong; Sander, Cindy; Kirkwood, John M; Chen, Tseng-hui Timothy; Maurer, Mark; Korman, Alan J; Zarour, Hassane M

    2015-05-01

    T cell Ig and ITIM domain (TIGIT) is an inhibitory receptor expressed by activated T cells, Tregs, and NK cells. Here, we determined that TIGIT is upregulated on tumor antigen-specific (TA-specific) CD8⁺ T cells and CD8⁺ tumor-infiltrating lymphocytes (TILs) from patients with melanoma, and these TIGIT-expressing CD8⁺ T cells often coexpress the inhibitory receptor PD-1. Moreover, CD8⁺ TILs from patients exhibited downregulation of the costimulatory molecule CD226, which competes with TIGIT for the same ligand, supporting a TIGIT/CD226 imbalance in metastatic melanoma. TIGIT marked early T cell activation and was further upregulated by T cells upon PD-1 blockade and in dysfunctional PD-1⁺TIM-3⁺ TA-specific CD8⁺ T cells. PD-1⁺TIGIT⁺, PD-1⁻TIGIT⁺, and PD-1⁺TIGIT⁻ CD8⁺ TILs had similar functional capacities ex vivo, suggesting that TIGIT alone, or together with PD-1, is not indicative of T cell dysfunction. However, in the presence of TIGIT ligand-expressing cells, TIGIT and PD-1 blockade additively increased proliferation, cytokine production, and degranulation of both TA-specific CD8⁺ T cells and CD8⁺ TILs. Collectively, our results show that TIGIT and PD-1 regulate the expansion and function of TA-specific CD8⁺ T cells and CD8⁺ TILs in melanoma patients and suggest that dual TIGIT and PD-1 blockade should be further explored to elicit potent antitumor CD8⁺ T cell responses in patients with advanced melanoma.

  16. Experimental demonstration of coherent beam combining over a 7 km propagation path.

    PubMed

    Weyrauch, Thomas; Vorontsov, Mikhail A; Carhart, Gary W; Beresnev, Leonid A; Rostov, Andrey P; Polnau, Ernst E; Liu, Jony Jiang

    2011-11-15

    We demonstrate coherent combining (phase locking) of seven laser beams emerging from an adaptive fiber-collimator array over a 7 km atmospheric propagation path using a target-in-the-loop (TIL) setting. Adaptive control of the piston and the tip and tilt wavefront phase at each fiber-collimator subaperture resulted in automatic focusing of the combined beam onto an unresolved retroreflector target (corner cube) with precompensation of quasi-static and atmospheric turbulence-induced phase aberrations. Both phase locking (piston) and tip-tilt control were performed by maximizing the target-return optical power using iterative stochastic parallel gradient descent (SPGD) techniques. The performance of TIL coherent beam combining and atmospheric mitigation was significantly increased by using an SPGD control variation that accounts for the round-trip propagation delay (delayed SPGD).

  17. Target-in-the-loop remote sensing of laser beam and atmospheric turbulence characteristics.

    PubMed

    Vorontsov, Mikhail A; Lachinova, Svetlana L; Majumdar, Arun K

    2016-07-01

    A new target-in-the-loop (TIL) atmospheric sensing concept for in situ remote measurements of major laser beam characteristics and atmospheric turbulence parameters is proposed and analyzed numerically. The technique is based on utilization of an integral relationship between complex amplitudes of the counterpropagating optical waves known as overlapping integral or interference metric, whose value is preserved along the propagation path. It is shown that the interference metric can be directly measured using the proposed TIL sensing system composed of a single-mode fiber-based optical transceiver and a remotely located retro-target. The measured signal allows retrieval of key beam and atmospheric turbulence characteristics including scintillation index and the path-integrated refractive index structure parameter.

  18. Expression of immune checkpoints in T cells of esophageal cancer patients

    PubMed Central

    Xie, Jinhua; Wang, Ji; Cheng, Shouliang; Zheng, Liangfeng; Ji, Feiyue; Yang, Lin; Zhang, Yan; Ji, Haoming

    2016-01-01

    Inhibition of immune checkpoint proteins (checkpoints) has become a promising anti-esophageal cancer strategy. We here tested expressions of immune checkpoints in human esophageal cancers. Our results showed the expressions of many immune checkpoints, including CD28, CD27, CD137L, programmed death 1 (PD-1), T cell immunoglobulin mucin-3 (TIM-3), T cell Ig and ITIM domain (TIGIT), CD160, cytotoxic T lymphocyte antigen 4 (CTLA-4), CD200, CD137 and CD158, were dysregulated in peripheral T cells of esophageal cancer patients. Further, the expressions of PD-1, TIM-3 and TIGIT were upregulated in tumor infiltrating lymphocytes (TILs), which might be associated with TILs exhaustion. Meanwhile, the expressions of PD-1 and TIM-3 on CD4+ T cells were closely associated with clinic pathological features of esophageal cancer patients. These results indicate that co-inhibitory receptors PD-1, TIM-3 and TIGIT may be potential therapeutic oncotargets for esophageal cancer. PMID:27577071

  19. Habitat fragmentation influences gene structure and gene differentiation among the Loxoblemmus aomoriensis populations in the Thousand Island Lake.

    PubMed

    Lv, Kun; Zhou, Jing; Gu, Jian-Qiang; Zhou, Guo-Xing; Wang, Wei; Xu, Zhi-Hong

    2017-02-16

    Thousand Island Lake (TIL) is a fragmented landscape consisting of more than 1000 land-bridge islands isolated during reservoir formation. To evaluate the effects of fragmentation and island attributes on insect populations, we examined the genetic structure of Loxoblemmus aomoriensis, a species of cricket widely distributed in TIL, and compared genetic diversity between islands samples. Population genetic analyses was conducted based on mitochondrial DNA haplotype frequencies of 10 sample islands. By comparing three island attributes with population genetic diversity reveals that island area influenced population genetic diversity (r(2 )=( )0.5094, p = 0.00204). Using Pairwise Fst values, we also found that long-distance isolation increased the genetic differentiation, while short-distance isolation can be offset by dispersal. These results indicate that fragmentation can impact populations on a genetic level.

  20. Exploiting natural anti-tumor immunity for metastatic renal cell carcinoma

    PubMed Central

    Murphy, Katherine A; James, Britnie R; Guan, Yue; Torry, Donald S; Wilber, Andrew; Griffith, Thomas S

    2015-01-01

    Clinical observations of spontaneous disease regression in some renal cell carcinoma (RCC) patients implicate a role for tumor immunity in controlling this disease. Puzzling, however, are findings that high levels of tumor infiltrating lymphocytes (TIL) are common to RCC. Despite expression of activation markers by TILs, functional impairment of innate and adaptive immune cells has been consistently demonstrated contributing to the failure of the immune system to control RCC. Immunotherapy can overcome the immunosuppressive effects of the tumor and provide an opportunity for long-term disease free survival. Unfortunately, complete response rates remain sub-optimal indicating the effectiveness of immunotherapy remains limited by tumor-specific factors and/or cell types that inhibit antitumor immune responses. Here we discuss immunotherapies and the function of multiple immune system components to achieve an effective response. Understanding these complex interactions is essential to rationally develop novel therapies capable of renewing the immune system's ability to respond to these tumors. PMID:25996049

  1. No Further Action Decision Under CERCLA, Fort Devens Study Area 28 Waste Explosives Detonation Range (Training Area 14)

    DTIC Science & Technology

    1994-01-01

    Environmental Response, Compensation and Lability Act ( CERCLA ) as amended by the Superfund Amendments and Reauthorization Act. An Enhanced Preliminary...til3i NO FURT ACTION DECISION UNDER CERCLA FORT DEVENS STUDY AREA 28 WASTE EXPLOSIVES DETONATION RANGE (TRAINING AREA 14) DATA ITEM A009...UNDER CERCLA STUDY AREA 28 WASTE EXPLOSIVES DETONATION RANGE (TRAINING AREA 14) FORT DEVENS, MASSACHUSETTS Prepared for: U.S. Army Environmental

  2. Detection and Characterization of a Novel Subset of CD8+CD57+ T-cells in Metastatic Melanoma with an Incompletely-Differentiated Phenotype

    PubMed Central

    Wu, Richard C.; Liu, Shujuan; Chacon, Jessica A.; Wu, Sheng; Li, Yufeng; Sukhumalchandra, Pariya; Murray, James L.; Molldrem, Jeffrey J.; Hwu, Patrick; Pircher, Hanspeter; Lizée, Gregory; Radvanyi, Laszlo G.

    2012-01-01

    PURPOSE Tumor-specific T-cells are frequently induced naturally in melanoma patients and infiltrate tumors. It is enigmatic why these patients fail to experience tumor regression. Given that CD8+ T cells mediate antigen-specific killing of tumor cells, the focus of this study was to identify alterations in the differentiation of CD8+ residing at the tumor site, with emphasis on a population expressing CD57, a marker for terminal differentiation. EXPERIMENTAL DESIGN We performed flow cytometric analysis of CD8+ tumor-infiltrating lymphocytes (TIL) isolated from 44 resected melanoma metastases using known T-cell differentiation markers. For comparison, PBMC were isolated from matched melanoma patients. We sorted different CD8+ subsets found in TIL and determined their effector functions. In addition, we performed Vβ spectratyping of T-cell receptors to determine lineage relationship between the CD8+ TIL subsets. RESULTS The majority of CD8+ TIL were in the early effector-memory stage of differentiation. A significant population consisted of an oligoclonal subset of cells co-expressing early effector-memory markers and end-stage CTL marker, CD57, yet having low to absent perforin expression. These cells could be induced to proliferate, produce a high level of IFN-γ, and differentiate into CD27−CD57+, perforinhigh mature CTL in vitro. Addition of TGF-β1 prevented this further differentiation. CONCLUSIONS Our studies identified a novel subset of incompletely differentiated CD8+ CTL co-expressing early effector-memory and late CTL markers. This population resembles that found by in patients with uncontrolled chronic viral infections. TGF-β1, frequently produced by melanoma tumors, may be a key cytokine inhibiting the further maturation of this subset. PMID:22307139

  3. Targeting PD-1 and Tim-3 Pathways to Reverse CD8 T-Cell Exhaustion and Enhance Ex Vivo T-Cell Responses to Autologous Dendritic/Tumor Vaccines.

    PubMed

    Liu, Jingwei; Zhang, Shurong; Hu, Yuefeng; Yang, Zhaomin; Li, Jingpo; Liu, Xuesong; Deng, Lijuan; Wang, Yue; Zhang, Xiaoyan; Jiang, Ting; Lu, Xu

    2016-05-01

    The paradoxical coexistence of spontaneous tumor antigen-specific immune response with progressive disease in cancer patients need to dissect the molecular pathways involved in tumor-induced T-cell dysfunction or exhaustion. Programmed cell death 1 (PD-1) has been identified as a marker of exhausted T cells in chronic disease states, and blockade of PD-1-PD-L1 interactions has been shown to partially restore T-cell function. We have found that T-cell immunoglobulin mucin (Tim) 3 is expressed on CD8+ tumor-infiltrating lymphocytes (TILs) isolated from patients with colorectal cancer. All T-cell immunoglobulin mucin 3 (Tim-3+) TILs coexpress PD-1, and Tim-3+ PD-1+ CD8+ TILs represent the predominant fraction of Tcells infiltrating tumors. Tim-3+PD-1+ CD8+ TILs exhibit the most severe exhausted phenotype as defined by failure to produce cytokines, such as interferon-γ, tumor necrosis factor-α, and interleukin-2. We further find that combined targeting of the Tim-3 and PD-1 pathways increased the frequencies of not only interferon-γ and tumor necrosis factor-α but also frequencies of proliferating tumor antigen-specific CD8+ T cells than targeting either pathway alone. A concomitant decrease in regulatory T cells and enhanced killing in a cytotoxicity assay was observed. Collectively, our findings support the use of Tim-3-Tim-3L blockade together with PD-1-PD-L1 blockade to reverse tumor-induced T-cell exhaustion/dysfunction in patients with colorectal cancer.

  4. United States Air Force Statistical Digest 1948, Third Annual Edition, Volume 1

    DTIC Science & Technology

    1948-12-31

    The attached material, described below, is forwarded for security and policy review in accordance with AFI 35-101, Chapter 15: TITLE: USAF Summaries...21 jail 2011 Office of the Secretary MEMORANDUM fOR AFIHO FROM: SAFIPA (Security and Policy Review) SUBJECT: Public Release Coordination (PAIRS...SAFJPA (Security and Policy Review) to objection _No objection, subject to recommendation DEV ALEE PRlDGEN-GA TIlSON Security Review Specialist

  5. Multiple-Input Transfer Function Model of Heat Transfer from Square Slab Floors

    DTIC Science & Technology

    1990-01-01

    this study. Further work to develop a definition of the network parameters based on characteristic length could expand the use of the model to non...Validation 57 6 NETWORK PARAMETERS BASED ON CHARACTERISTIC LENGTH .... 78 7 UTILIZATION OF TIlE GTF MODEL FOR ENERGY ANALYSIS ....... 87 8 CONCLUSIONS...BASIC PROGRAM GTF 96 APPENDIX C: TRUBASIC PROGRAM QCALC 108 DISTRIBUTION vi LIST OF FIGURES Figure Number Page 1 7-Node Network Model

  6. Analysis of the hippo transducers TAZ and YAP in cervical cancer and its microenvironment

    PubMed Central

    Buglioni, Simonetta; Vici, Patrizia; Sergi, Domenico; Pizzuti, Laura; Di Lauro, Luigi; Antoniani, Barbara; Sperati, Francesca; Terrenato, Irene; Carosi, Mariantonia; Gamucci, Teresa; Vincenzoni, Cristina; Mariani, Luciano; Vizza, Enrico; Venuti, Aldo; Sanguineti, Giuseppe; Gadducci, Angiolo; Barba, Maddalena; Natoli, Clara; Vitale, Ilio; Mottolese, Marcella; De Maria, Ruggero; Maugeri-Saccà, Marcello

    2016-01-01

    ABSTRACT Hippo is a tumor-suppressor pathway that negatively regulates the oncoproteins TAZ and YAP. Moreover, Hippo affects the biology of a variety of non-neoplastic cells in the tumor microenvironment, even including immune cells. We herein assessed the predictive role of TAZ and YAP, assessed by immunohistochemistry, in 50 cervical cancer patients prevalently treated with neoadjuvant chemotherapy. Tumors were classified as positive or negative according to the percentage of tumor-expressing cells and cellular localization. TAZ/YAP were also evaluated in non-neoplastic cells, namely endothelial cells, non-lymphocytic stromal cells and tumor-infiltrating lymphocytes (TILs). TAZ expression in cancer cells (TAZpos) was associated with a reduced pathological complete response (pCR) rate (p = 0.041). Conversely, the expression of TAZ and YAP in TILs (TAZTIL+ and YAPTIL+) seemed to be associated with increased pCRs (p = 0.083 and p = 0.018, respectively). When testing the predictive significance of the concomitant expression of TAZ in cancer cells and its absence in TILs (TAZpos/TAZTIL-), patients with TAZpos/TAZTIL- showed lower pCR rate (p = 0.001), as confirmed in multivariate analysis (TAZpos/TAZTIL-: OR 8.67, 95% CI: 2.31–32.52, p = 0.001). Sensitivity analysis carried out in the 41 patients treated with neoadjuvant chemotherapy yielded comparable results (TAZpos/TAZTIL-: OR 11.0, 95% CI: 2.42–49.91, p = 0.002). Internal validation carried out with two different procedures confirmed the robustness of this model. Overall, we found evidence on the association between TAZ expression in cervical cancer cells and reduced pCR rate. Conversely, the expression of the Hippo transducers in TILs may predict increased treatment efficacy, possibly mirroring the activation of a non-canonical Hippo/MST pathway necessary for T-cells activation and survival. PMID:27471633

  7. The prognostic value of systemic and local inflammation in patients with laryngeal squamous cell carcinoma

    PubMed Central

    Wang, Jie; Wang, Shengzi; Song, Xinmao; Zeng, Wenjiao; Wang, Shuyi; Chen, Fu; Ding, Hao

    2016-01-01

    Background Cancer-related systemic inflammation has been demonstrated to be associated with poor outcome in multiple types of cancers. Meanwhile, the local inflammation, which is characterized by dense intratumoral immune infiltrate, is a favorable predictor of survival outcome. Purpose To evaluate the role of systemic and local inflammation in predicting outcome in patients with laryngeal squamous cell carcinoma. Patients and methods In this retrospective study, 120 patients who had undergone postoperative radiotherapy were enrolled. Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), as calculated from pretreatment whole blood counts, were used to indicate systemic inflammation. The optimal cutoff values of NLR and PLR were determined using receiver operating characteristic curve analysis. Tumor infiltrating lymphocytes (TILs) density, as assessed by pathologist review of hematoxylin and eosin-stained slides, was used to represent local inflammation. Overall survival (OS) and recurrence-free survival (RFS) were assessed using the Kaplan–Meier method and multivariate Cox regression analysis. Results The best cutoff was 2.79 for NLR and 112 for PLR. Kaplan–Meier analysis revealed that high NLR, high PLR, and low TILs density were significantly correlated with inferior OS and RFS, respectively (all P<0.05). The Cox proportional multivariate hazard model showed that a high pretreatment PLR and a low TILs density were both independently correlated with poor OS and RFS, respectively (all P<0.05). Conclusion Markers of systemic and local inflammation, especially PLR and TILs density, are reliable prognostic factors in patients with laryngeal squamous cell carcinoma. PMID:27920556

  8. OPSATCOM Field Measurements. Volume 1

    DTIC Science & Technology

    1976-06-01

    1-2 S2 FORMULATION OF TIlE EXPERIMENTAL MODEL ........ 2-i 3 EXPERIMENTAL METHODS AND APPARATUS ........... 3-I 3.1 Methods Utilized...lfactors for investigating the optical clharactcr ol’ the seab, For the earliest work, which dates back to 1885, only photographic methods were...I 2-3/2-4 blank I I SECTION 3 I EXPERIMENTAL METHODS AND APPARATUS 3.1 METHODS UTILIZED In general, the atmospheric radiance pattern of’ an underwater

  9. Spacecraft Charging Standard Report.

    DTIC Science & Technology

    1980-09-30

    30.1.3 Backscattering. The deflection of particles by scattering processes in matter such that particles emerge through the same planar surface as they...with filters to provide protection against high frequency (up to 100 MHz), large | amplitude (TBD amperes), fast rise time (< 10 nanoseconds ) pulses of...A discharne con- ment is comprehensive, le vacuum - 100 nsec to I lisec pulse cepts acceptable, tIL -STD-I541, 461. edlations width fiber optics

  10. Net Shape Technology in Aerospace Structures. Volume 1.

    DTIC Science & Technology

    1986-11-01

    maintained at operating temperature b\\ induct ion, rc,,istancc, or gas-fired infrared heating . Induction heating is most Colmon for t it:1 i tIl forgings and...forging titanium at higher than .1750 0 F. 8. Research and dcclopment on die heating systems employing combinations of induction , resistance, and gas...methods being c aluated includc usc of graphite reinforc:ement for resistance hcating a portable induction heating unit dec loped at N -\\SA-Langle

  11. An Analysis of Transmittances Measured through Battlefield Dust Clouds

    DTIC Science & Technology

    1980-02-01

    110 ’N I-000000000 ~~c 0 00 00 Best Available Copy .99 .99 Ř. U ""•i~ lt)Il*) • , -4 I * I 49 9,.99 ,*.t~*Il . .99. . , ,.,’, ., . . * ,t • , , ,j It...599,August 1978. 36.Ducan Lui D. "trtosheicWind Shear Coptdfrom Satellite Thermal SouderMeaureent,"ECOM .8800. September 1978. 37. Tayor F. P.MoanP

  12. The Coast Artillery Journal. Volume 64, Number 6, June 1926

    DTIC Science & Technology

    1926-06-01

    continue its mission of covering the left flank. The 69th Reserve Division was directed upon Solre -Ie-Chateau, with a ,-iew to moving toward Beaumont or...CTURED BY BARTO~ l\\lAl\\’UF ACTURING CO;\\IPANY TilE AWE PAIn. A ~hort time a~o the aide to onc of onT g(’lwral OffiCf’TlS, driving at night, was

  13. Dielectric Constant and Loss Data, Part 3

    DTIC Science & Technology

    1977-05-01

    to the general public, including foreign nations. This technical report has been reviewed and is approved. JOHN C. OLSON Project Engineer FOR TIlE...PERFORIIINO ORGANIZATION NA E AND ADDRESS 10. ROORAM ELEMENT PROJECT , TASKC It. CONTROLLING OFFICE NAME AND ADDRESS Laboratory for Insulation Research...Massachusetts, by W. B. Westphal. This work was performed between I July 1974 and 31 December 1976 under Contract F33615-75-C-5020, Project No. 7371, Task No

  14. US EPA, Pesticide Product Label, , 03/23/1983

    EPA Pesticide Factsheets

    2011-04-14

    ... flor/eflll9 tn·fH., 1 dnd (>'."I'!'(J~f'L'''<' f(lund ~o be inf(,~t."d ,·:ith 1,(,,·t5 1i"t(·rj iii til" fr-ll',;Il'l t,Ll". lJi lute DIJRSEf,ti ~'):: Ii th I".! ((r dl'.wni Il'J to di fee. ...

  15. Task Force Delay Study, Miami International Airport.

    DTIC Science & Technology

    1981-07-01

    13 . .Pe of Pepo., ond P.,iod Co-e,ed 12. Spo’s-: Agency No-.. and Ad. ness U.S. Department of Transportation Fejr ! Aviation Administration...W, 66 U : ~ Ssz tz - c~7j ~~nz Ll ss til-= - -j E E~ -- n -3 .)- m -Q - v c. ~c E c- ’Z -. E- --. It C. ,: -E mo ;. .- - -VC c-&-,J.tv --- -t -. be

  16. Thermal Conductivity of Soils

    DTIC Science & Technology

    1977-07-01

    Rapport sendt til NTNF. Geologisk Institutt, NTH, Trondheim 1961, p. 29 f.f.. R. Selmer-Olsen: IngeniOrgeologi. Del 1. Generell geologi. Tapir forlag...Ingeniorgeologi, Del 1, Generell geologi, Tapir forlag, Troniheim 1971, p. 175. 5. H. Sveian2 Norske jordarters kvartsinnhold. Hoveioppgave i Ingeni~orgeologi...I 16. R. Selmer-Olsen: Ingeni~rgeologi. Del I. Generell geologi. Tapir forlag. Tronheim 1971, p. 8. 17. R. Selmer-Olsen: Ingeni~rgeologi. Del I

  17. Surface Observation Climatic Summaries (SOCS) for Hanau AAF, Germany

    DTIC Science & Technology

    1992-03-01

    oI L ...............- A V EtTIONH NAI6s mADAM AAF DL FIELD ELI’Y: 363 Fr LATITIUDE/LECSITUDEs 50 10 N 008 58 E STATIOC N C: 106420...r AVAILAULE FOR WMER REPO~nTil SITES. AIRIIEAR SEITIG. 3INCER OF CURY (80), TABLES GIVE Hk, W!nffARDA DEVIATIONS, AND SINTON VIOUM.YN IF INESS( MN CW

  18. Serum ferritin level changes in children with sickle cell disease on chronic blood transfusion are nonlinear and are associated with iron load and liver injury

    PubMed Central

    Abboud, Miguel R.; Paley, Carole; Olivieri, Nancy; Kirby-Allen, Melanie; Vichinsky, Elliott; Casella, James F.; Alvarez, Ofelia A.; Barredo, Julio C.; Lee, Margaret T.; Iyer, Rathi V.; Kutlar, Abdullah; McKie, Kathleen M.; McKie, Virgil; Odo, Nadine; Gee, Beatrice; Kwiatkowski, Janet L.; Woods, Gerald M.; Coates, Thomas; Wang, Winfred; Adams, Robert J.

    2009-01-01

    Chronic blood transfusion is increasingly indicated in patients with sickle cell disease. Measuring resulting iron overload remains a challenge. Children without viral hepatitis enrolled in 2 trials for stroke prevention were examined for iron overload (STOP and STOP2; n = 271). Most received desferrioxamine chelation. Serum ferritin (SF) changes appeared nonlinear compared with prechelation estimated transfusion iron load (TIL) or with liver iron concentrations (LICs). Averaged correlation coefficient between SF and TIL (patients/observations, 26 of 164) was r = 0.70; between SF and LIC (patients/observations, 33 of 47) was r = 0.55. In mixed models, SF was associated with LIC (P = .006), alanine transaminase (P = .025), and weight (P = .026). Most patients with SF between 750 and 1500 ng/mL had a TIL between 25 and 100 mg/kg (72.8% ± 5.9%; patients/observations, 24 of 50) or an LIC between 2.5 and 10 mg/g dry liver weight (75% ± 0%; patients/observations, 8 of 9). Most patients with SF of 3000 ng/mL or greater had a TIL of 100 mg/kg or greater (95.3% ± 6.7%; patients/observations, 7 of 16) or an LIC of 10 mg/g dry liver weight or greater (87.7% ± 4.3%; patients/observations, 11 of 18). Although SF changes are nonlinear, levels less than 1500 ng/mL indicated mostly acceptable iron overload; levels of 3000 ng/mL or greater were specific for significant iron overload and were associated with liver injury. However, to determine accurately iron overload in patients with intermediately elevated SF levels, other methods are required. These trials are registered at www.clinicaltrials.gov as #NCT00000592 and #NCT00006182. PMID:19721013

  19. US EPA, Pesticide Product Label, NOVA CONTACT SPRAY ...

    EPA Pesticide Factsheets

    2011-04-21

    I , I " ! '.'f '( i .' l' \\. : ' t ' ~. :' I .1: t . ( . \\ J r )I i It, () I H'! J Il {f ve n t II d t (} f (, ''/ tIl! (l. S l' i! "I; t q ~ p r ; V"I)t" C(),'PI ,.Ii f(lt)d ild!llllll;tj :;\\11 1(1':"', diHi l'(),·1 ...

  20. Potential Prognostic Markers for Human Prostate Cancer

    DTIC Science & Technology

    2001-03-01

    such as proliferation, differentiation and assay [15]. TGF[3 may be produced by metastatic motility. Upregulation of growth factor synthesis or prostate...via mod- ronment include neuroendocrine cells. These cells ulation of tumor cell receptor expression. Control of can secrete bombesin, a gastrin ...controls, indicating that addition ofT015 accelerates tumor expansion. TIl15 synthesis triggered a dramatic increase in cell motility, boosting serum

  1. Immunophenotyping of patients with oral squamous cell carcinoma in peripheral blood and associated tumor tissue.

    PubMed

    Grimm, Martin; Feyen, Oliver; Hofmann, Heiko; Teriete, Peter; Biegner, Thorsten; Munz, Adelheid; Reinert, Siegmar

    2016-03-01

    The immune system is important for elimination of cancer cells. Tumors including oral squamous cell carcinoma (OSCC) are capable of escaping detection by host immune cells through apoptotic depletion of tumor-infiltrating lymphocytes (TILs). Circulating peripheral blood lymphocytes (PBLs) and corresponding TILs of tumor specimen were evaluated before and after curative tumor resection (n = 30) compared with PBLs of controls (n = 87). PBLs were characterized for the total number of T cells (CD3(+)), T helper cells (Th, CD3(+)/CD4(+)), regulatory T cells (Treg, CD4(+)/CD25(+)/CD127(low)), cytotoxic T cells (Tc, CD3(+)/CD8(+)), activated T cells (CD3(+)/HLA-DR(+)), and natural killer (NK) cells (CD3(-)/CD16(+)/CD56(+)). In tumor tissue, the prevalence of CD3(+), CD4(+), and CD8(+) TILs was assessed using immunohistochemistry, whereas the incidence of apoptosis was assessed using terminal deoxynucleotidyl transferase deoxyuridinetriphosphate nick-end labeling (TUNEL) assay. In PBLs of pretreated OSCC patients, a highly significant decrease in total number of T cells (p = 0.0001), Th cells (p < 0.0001), Treg cells (p < 0.0001), Tc cells (p < 0.0001), and NK cells (p = 0.0037) were found compared with controls. Decreased PBLs of OSCC patients were correlated with decreased numbers of corresponding TILs, which were associated with increased detection of apoptosis in the tumor tissue. Compared with the controls, the total number of T cells remained unchanged after surgery but the total number of NK cells significantly increased. Standardized immunophenotyping of OSCC may help to identify patients likely to benefit from cancer immunotherapy strategies and/or chemoradiation. Finally, future attempts to enhance an effective tumor-reactive immune response by immunotherapy or vaccination should be made by promoting tumor-specific Th and/or Tc cell/NK cell responses.

  2. Regulation of the Prostate Cancer Tumor Microenvironment

    DTIC Science & Technology

    2012-04-01

    infiltrating macrophage lineage in the absence of MyD88. We are in the process of understanding the activation of signaling pathways , local and...development, growth, and metastasis is unclear. We are interested in understanding the mechanisms for development of TILs and how they modulate prostate...chromatin component HMG-B1. Activation of these receptors leads to induction of multiple inflammatory pathways , including nuclear factor-kappa B (NF

  3. US EPA, Pesticide Product Label, EMULSAMINE BK WOODY ...

    EPA Pesticide Factsheets

    2011-04-13

    ... T ".., 11I1'Ih,l' ('I" tit' u'>f'd til a", I,""'f' 01 )"'d' lIt .. t fl'lp t">dSP vI d,' "It'",," Un!lI s,"a, Pdddlt"~ '" ,t1(olit>Cla l.j'l(l~"f'f;·"""dfit·Q'(·LJ·'~ 'It' li< .• , I .. ", ...

  4. AGARD/SMP Review Damage Tolerance for Engine Structures. 2. Defects and Quantitative Materials Behaviour

    DTIC Science & Technology

    1988-10-01

    temperature range, moderate strength - two broad lines of developments have been conducted : . alloys with high specific strength for medium... temperatures applications (^♦00 to ^500C) : Ti 6.2.4.6. , Til? , IMI 550 , ... . alloys for high temperature applications : Ti 6.2.4.2.3. , IMI 685 , IMI 829...cation of Titanium alloys established upon the relative stability of the low temperature (hep) and high temperature (bec) phase : this classifi- cation

  5. Tumor-infiltrating Tim-3(+) T cells proliferate avidly except when PD-1 is co-expressed: Evidence for intracellular cross talk.

    PubMed

    Li, Jing; Shayan, Gulidanna; Avery, Lyndsay; Jie, Hyun-Bae; Gildener-Leapman, Neil; Schmitt, Nicole; Lu, Bin Feng; Kane, Lawrence P; Ferris, Robert L

    2016-01-01

    Programmed Death 1 (PD-1) and T cell Ig and mucin domain-3 protein (Tim-3) are immune checkpoint receptors highly expressed on tumor infiltrating T lymphocytes (TIL). PD-1 inhibits T cell activation and type-1 T cell responses, while Tim-3 is proposed to mark more extensively exhausted cells, although the mechanisms underlying Tim-3 function are not clear. Trials of anti-PD-1 therapy have identified a large subset of non-responder patients, likely due to expression of alternative checkpoint molecules like Tim-3. We investigated the phenotypic and functional characteristics of T cells with differential expression of PD-1 (high/low) and Tim-3 (positive/negative), using TIL directly isolated from head and neck squamous cell carcinomas (HNSCC). Unexpectedly, we found that expression of Tim-3 alone does not necessarily mark TIL as dysfunctional/exhausted. In Tim-3-TIL, PD-1 levels correlate with T cell dysfunction, with a PD-1(low/intermed) phenotype identifying recently activated and still functional cells, whereas PD-1(hi)Tim-3(-) T cells are actually exhausted. Nonetheless, PD-1(intermed) cells are still potently suppressed by PD-L1. PD-1 expression was associated with reduced phosphorylation of ribosomal protein S6 (pS6), whereas Tim-3 expression was associated with increased pS6. Using a novel mouse model for inducible Tim-3 expression, we confirmed that expression of Tim-3 does not necessarily render T cells refractory to further activation. These results suggest the existence of PD-1 and Tim-3 crosstalk in regulating antitumor T cell responses, with important implications for anti-PD-1 immunotherapy.

  6. Concordance of immune checkpoints within tumor immune contexture and their prognostic significance in gastric cancer.

    PubMed

    Dai, Congqi; Geng, Ruixuan; Wang, Chenchen; Wong, Angela; Qing, Min; Hu, Jianjun; Sun, Yu; Lo, A W I; Li, Jin

    2016-12-01

    Checkpoint blockade therapy has emerged as a novel approach for cancer immunotherapy in several malignancies. However, patient prognosis and disease progression relevant to immune checkpoints in gastric tumor microenvironment are not defined. This study aims to investigate the expression and prognostic significance of immune checkpoints within gastric cancer. In the study, a cohort of 398 cancer tissues from stage I to IV gastric cancer patients were assessed for programmed cell death 1 ligand 1 (PD-L1) expression and tumor-infiltrating lymphocyte (TIL) infiltration using immunohistochemistry to ascertain their survival correlation. The data revealed that higher TIL density correlated with less risk of disease progression, and exhibited survival benefits in gastric cancer patients, and PD-L1 positivity showed a significant association with the presence of high TIL infiltration. Furthermore, real-time quantitative polymerase chain reaction was performed to detect expression of multiple immune checkpoints with the relation to clinical outcome in 139 samples randomly selected from the same cohort, and higher messenger RNA levels of most immune checkpoints were associated with favorable outcome, while consistently showing a positive correlation with interferon gamma levels. In situ hybridization was used to determine the localization of Epstein-Barr virus (EBV) in 97 specimens, and showed EBV-positive gastric cancer samples correlated with PD-L1 expression and increased TIL density. These results suggest that induction of immune checkpoint within gastric cancer patients reflects a high immune infiltration density, especially in those with EBV-associated gastric cancer, which may direct patient selection for checkpoint blockade therapy.

  7. A nonimmunogenic sarcoma transduced with the cDNA for interferon gamma elicits CD8+ T cells against the wild-type tumor: correlation with antigen presentation capability

    PubMed Central

    1992-01-01

    To be recognized by CD8+ T lymphocytes, target cells must process and present peptide antigens in the context of major histocompatibility complex (MHC) class I molecules. The nonimmunogenic, low class I- expressing, methylcholanthrene (MCA)-induced murine sarcoma cell line, MCA 101, is a poor presenter of endogenously generated viral antigens to specific CD8+ T lymphocytes and cannot be used to generate tumor infiltrating lymphocytes (TIL). Since interferon gamma (IFN-gamma) has been shown to upregulate three sets of molecules important for antigen processing and presentation, we retrovirally transduced wild-type MCA 101 (101.WT) tumor with the mIFN-gamma cDNA to create the 101.NAT cell line. Unlike 101.WT, some clones of retrovirally transduced 101.NAT tumor expressed high levels of class I, and could be used to generate CD8+ TIL. More importantly, these TIL were therapeutic in vivo against established pulmonary metastases from the wild-type tumor. Although not uniformly cytotoxic amongst several separate cultures, these TIL did specifically release cytokines (IFN-gamma and tumor necrosis factor- alpha) in response to 101.WT targets. 101.WT's antigen presentation deficit was also reversed by gene modification with mIFN-gamma cDNA. 101.NAT had a greatly improved capacity to present viral antigens to CD8+ cytotoxic T lymphocytes. These findings show that a nonimmunogenic tumor, incapable of generating a CD8+ T cell immune response, could be gene-modified to generate a therapeutically useful immune response against the wild-type tumor. This strategy may be useful in developing treatments for tumor histologies not thought to be susceptible to T cell-based immunotherapy. PMID:1588273

  8. PD1 and PDL1 expression in primary central nervous system diffuse large B-cell lymphoma are frequent and expression of PD1 predicts poor survival.

    PubMed

    Four, Marion; Cacheux, Valère; Tempier, Ariane; Platero, Dolorès; Fabbro, Michel; Marin, Grégory; Leventoux, Nicolas; Rigau, Valérie; Costes-Martineau, Valérie; Szablewski, Vanessa

    2016-12-13

    Primary central nervous system diffuse large B-cell lymphoma (PCNS-DLBCL) is a rare and aggressive type of diffuse large B-cell lymphoma (DLBCL) whit poorly understood pathogenesis. Finding biomarkers associated with patient survival may be important for understanding its physiopathology and to develop new therapeutic approaches. We investigated 32 PCNS-DLBCL from immunocompetent patients for BCL2, CMYC, LMO2, and P53 expression and for cytogenetic aberrations of BCL2, BCL6, and MYC genes, all known for their prognostic value in systemic DLBCL (s-DLBCL). We analyzed PD1 and PDL1 protein expression in both tumor infiltrating lymphocytes (TILs) and tumor cells. Finally, we searched for correlation between biological data and clinical course. The PCNS-DLBCL expressed BCL2, CMYC, LMO2, and P53 at similar frequency than s-DLBCL but without significant prognostic on survival. None cases harbored aberrations involving BCL2 and MYC gene whereas BCL6 abnormalities were present in 20.7% of cases but without value on survival. Expression of PD1 in TILs and PDL1 in tumor cells was observed at higher rates than in s-DLBCL (58% and 37%, respectively). The PD1 expression in TILs correlated with PDL1 expression in tumor cells (P = .001). Presence of PD1 positive TILs was associated with poorer overall survival (P = .011). Patients with PDL1 overexpression tended to better response to chemotherapy (P = .23). In conclusion PCNS-DLBCL pathogenesis differs from s-DLBCL without prognostic value of the phenotypic and cytogenetic parameters known for their pejorative impact in the latter. The PD1/PDL1 pathway plays a strong role in PCNS-DLBCL and represents an attractive target for this aggressive lymphoma.

  9. Programmed cell death ligand 1 expression in osteosarcoma.

    PubMed

    Shen, Jacson K; Cote, Gregory M; Choy, Edwin; Yang, Pei; Harmon, David; Schwab, Joseph; Nielsen, G Petur; Chebib, Ivan; Ferrone, Soldano; Wang, Xinhui; Wang, Yangyang; Mankin, Henry; Hornicek, Francis J; Duan, Zhenfeng

    2014-07-01

    Programmed cell death ligand 1 (PDL1, also known as B7H1) is a cell-surface protein that suppresses the cytotoxic CD8(+) T-cell-mediated immune response. PDL1 expression and its clinical relevance in sarcomas are not well understood. Therefore, we sought to measure RNA expression levels for PDL1 in 38 clinically annotated osteosarcoma tumor samples and aimed to determine if PDL1 expression correlates with clinical features and tumor-infiltrating lymphocytes (TIL). Quantitative real-time RT-PCR for PDL1 was optimized in 18 cell lines, of which 5 were osteosarcoma derived. qRT-PCR results were validated via flow cytometry and immunohistochemistry (IHC) in select cell lines. Total RNA was isolated from 38 human osteosarcoma samples for qRT-PCR analysis. Clinical data were sorted, and significance was determined by the Student t test. TILs were examined in patient samples by tissue microarray hematoxylin-eosin staining. We confirmed the constitutive PDL1 mRNA expression in cell lines by qRT-PCR, flow cytometry, and IHC. Across human osteosarcoma samples, PDL1 mRNA gene expression ranged over 4 log (>5,000-fold difference). Relative expression levels were evaluated against clinical factors such as age/gender, metastasis, recurrence, chemotherapy, percentage of necrosis, and survival; no significant associations were identified. The presence of TILs was associated with high PDL1 expression (R(2) = 0.37; P = 0.01). In summary, we developed an RNA-based assay to determine PDL1 expression levels, and we show, for the first time, that high levels of PDL1 are expressed in a subset of osteosarcoma, and PDL1 expression is positively correlated with TILs. Multiple agents targeting PD1/PDL1 are in clinical development, and this may be a novel immunotherapeutic strategy for osteosarcoma clinical trials.

  10. Expression of inhibitory receptors on intratumoral T cells modulates the activity of a T cell-bispecific antibody targeting folate receptor.

    PubMed

    Schreiner, Jens; Thommen, Daniela S; Herzig, Petra; Bacac, Marina; Klein, Christian; Roller, Andreas; Belousov, Anton; Levitsky, Victor; Savic, Spasenija; Moersig, Wolfgang; Uhlenbrock, Franziska; Heinzelmann-Schwarz, Viola A; Umana, Pablo; Pisa, Pavel; von Bergwelt-Baildon, M; Lardinois, Didier; Müller, Philipp; Karanikas, Vaios; Zippelius, Alfred

    2016-02-01

    T-cell bispecific antibodies (TCBs) are a novel therapeutic tool designed to selectively recruit T-cells to tumor cells and simultaneously activate them. However, it is currently unknown whether the dysfunctional state of T-cells, embedded into the tumor microenvironment, imprints on the therapeutic activity of TCBs. We performed a comprehensive analysis of activation and effector functions of tumor-infiltrating T-cells (TILs) in different tumor types, upon stimulation by a TCB targeting folate receptor 1 and CD3 (FolR1-TCB). We observed a considerable heterogeneity in T-cell activation, cytokine production and tumor cell killing upon exposure to FolR1-TCB among different FolR1-expressing tumors. Of note, tumors presenting with a high frequency of PD-1(hi) TILs displayed significantly impaired tumor cell killing and T-cell function. Further characterization of additional T-cell inhibitory receptors revealed that PD-1(hi) TILs defined a T-cell subset with particularly high levels of multiple inhibitory receptors compared with PD-1(int) and PD-1(neg) T-cells. PD-1 blockade could restore cytokine secretion but not cytotoxicity of TILs in a subset of patients with scarce PD-1(hi) expressing cells; in contrast, patients with abundance of PD-1(hi) expressing T-cells did not benefit from PD-1 blockade. Our data highlight that FolR1-TCB is a promising novel immunotherapeutic treatment option which is capable of activating intratumoral T-cells in different carcinomas. However, its therapeutic efficacy may be substantially hampered by a pre-existing dysfunctional state of T-cells, reflected by abundance of intratumoral PD-1(hi) T-cells. These findings present a rationale for combinatorial approaches of TCBs with other therapeutic strategies targeting T-cell dysfunction.

  11. Sustainable Contingency Base Camp Operations

    DTIC Science & Technology

    2010-06-17

    L , IJU;TAL 6:1 6>::’JI&O.’ID’ C unums - IVA’TU.Al.V.$ - -~ D Tli,Oil!’tJ Mi’(’(n ~p t::il A•ilt’UJI -~· G_jJ "’"n - AJO ?Solti’U.E - AtT""llq

  12. Physiochemical/Rheological Control of Nonmetallic Materials.

    DTIC Science & Technology

    1982-08-01

    Temperature Tge Temperature at Gel T Glass Transition Temperature rl Viscosity t gel Time to Gel G’ Storage Modulus G" Loss Modulus til Enthalpy...standards were obtained and the amounts of the volatiles were determined by gas chromotography . Where applicable, the thermal and rheological properties...aluminum powder and the fillers. The filtrate , which contained th two epoxies and DICY, cured without any foaming. Attempts to separate the exact blowing

  13. Lymphocyte imprinting with melanoma antigens acquired by trogocytosis facilitates identification of tumor-reactive T cells

    PubMed Central

    Eisenberg, Galit; Uzana, Ronny; Pato, Aviad; Frankenburg, Shoshana; Merims, Sharon; Yefenof, Eitan; Ferrone, Soldano; Peretz, Tamar; Machlenkin, Arthur; Lotem, Michal

    2013-01-01

    Trogocytosis is a contact-dependent inter-cellular transfer of membrane fragments and associated molecules from antigen presenting cells to effector lymphocytes. We previously demonstrated that trogocytosis also occurs between tumor target and cognate melanoma antigen-specific cytotoxic T cells (CTL). Here we show that, following trogocytosis, immune effector cells acquire molecular components of the tumor, including surface antigens, which are detectable by specific monoclonal antibodies. We demonstrate that CD8+ and CD4+ T cells from melanoma patients’ PBMC and tumor infiltrating lymphocytes (TIL) capture melanoma antigens, enabling identification of trogocytosing lymphocytes by staining with antigen-specific antibodies. This finding circumvents the necessity of tumor pre-labeling, which in the past was mandatory to detect membrane-capturing T cells. Through the detection of melanoma antigens on TIL, we sorted trogocytosing T cells and verified their preferential reactivity and cytotoxicity. Furthermore, tumor-antigen imprinted T cells were detected at low frequency in fresh TIL cultures shortly after extraction from the tumor. Thus, T cell imprinting by tumor antigens may allow the enrichment of melanoma antigen-specific T cells for research and potentially even for the adoptive immunotherapy of patients with cancer. PMID:23626012

  14. PD-L1 expression on immune cells, but not on tumor cells, is a favorable prognostic factor for head and neck cancer patients

    PubMed Central

    Kim, Hye Ryun; Ha, Sang-Jun; Hong, Min Hee; Heo, Su Jin; Koh, Yoon Woo; Choi, Eun Chang; Kim, Eun Kyung; Pyo, Kyoung Ho; Jung, Inkyung; Seo, Daekwan; Choi, Jaewoo; Cho, Byoung Chul; Yoon, Sun Och

    2016-01-01

    To investigate the expression of programmed death-ligand 1 (PD-L1) and immune checkpoints and their prognostic value for resected head and neck squamous cell cancer (HNSCC). PD-L1 expression on tumor cells (TC) and tumor-infiltrating immune cells (IC), abundance of tumor-infiltrating lymphocytes (TILs), and expression of the immune checkpoints were investigated in 402 HNSCC patients. PD-L1 expression on TC and IC was categorized into four groups according to the percentage of PD-L1-positive cells. PD-L1 positivity was defined as ≥5% of cells based on immunohistochemistry. High PD-L1 expression on IC, but not TC, was an independent favorable prognostic factor for RFS and OS adjusted for age, gender, smoking, stage, and HPV. High frequencies of CD3+ or CD8+ TILs, Foxp3+ Tregs, and PD-1+ TILs were strongly associated with favorable prognosis. PD-L1 was exclusively expressed on either TC or IC. Transcriptome analysis demonstrated that IC3 expressed higher levels of the effector T cell markers than TC3, suggesting that PD-L1 expression is regulated via an adaptive IFNγ-mediated mechanism. High PD-L1 expression on IC, but not TC, and high abundance of PD-1+ T cells and Foxp3+ Tregs are favorable prognostic factors for resected HNSCC. This study highlights the importance of comprehensive assessment of both TC and IC. PMID:27841362

  15. Diversity and divergence of the glioma-infiltrating T-cell receptor repertoire

    PubMed Central

    Sims, Jennifer S.; Grinshpun, Boris; Feng, Yaping; Ung, Timothy H.; Neira, Justin A.; Samanamud, Jorge L.; Canoll, Peter; Shen, Yufeng; Sims, Peter A.; Bruce, Jeffrey N.

    2016-01-01

    Although immune signaling has emerged as a defining feature of the glioma microenvironment, how the underlying structure of the glioma-infiltrating T-cell population differs from that of the blood from which it originates has been difficult to measure directly in patients. High-throughput sequencing of T-cell receptor (TCR) repertoires (TCRseq) provides a population-wide statistical description of how T cells respond to disease. We have defined immunophenotypes of whole repertoires based on TCRseq of the α- and β-chains from glioma tissue, nonneoplastic brain tissue, and peripheral blood from patients. Using information theory, we partitioned the diversity of these TCR repertoires into that from the distribution of VJ cassette combinations and diversity due to VJ-independent factors, such as selection due to antigen binding. Tumor-infiltrating lymphocytes (TILs) possessed higher VJ-independent diversity than nonneoplastic tissue, stratifying patients according to tumor grade. We found that the VJ-independent components of tumor-associated repertoires diverge more from their corresponding peripheral repertoires than T-cell populations in nonneoplastic brain tissue, particularly for low-grade gliomas. Finally, we identified a “signature” set of TCRs whose use in peripheral blood is associated with patients exhibiting low TIL divergence and is depleted in patients with highly divergent TIL repertoires. This signature is detectable in peripheral blood, and therefore accessible noninvasively. We anticipate that these immunophenotypes will be foundational to monitoring and predicting response to antiglioma vaccines and immunotherapy. PMID:27261081

  16. Feature-based registration of historical aerial images by Area Minimization

    NASA Astrophysics Data System (ADS)

    Nagarajan, Sudhagar; Schenk, Toni

    2016-06-01

    The registration of historical images plays a significant role in assessing changes in land topography over time. By comparing historical aerial images with recent data, geometric changes that have taken place over the years can be quantified. However, the lack of ground control information and precise camera parameters has limited scientists' ability to reliably incorporate historical images into change detection studies. Other limitations include the methods of determining identical points between recent and historical images, which has proven to be a cumbersome task due to continuous land cover changes. Our research demonstrates a method of registering historical images using Time Invariant Line (TIL) features. TIL features are different representations of the same line features in multi-temporal data without explicit point-to-point or straight line-to-straight line correspondence. We successfully determined the exterior orientation of historical images by minimizing the area formed between corresponding TIL features in recent and historical images. We then tested the feasibility of the approach with synthetic and real data and analyzed the results. Based on our analysis, this method shows promise for long-term 3D change detection studies.

  17. Very Late Antigen-1 Marks Functional Tumor-Resident CD8 T Cells and Correlates with Survival of Melanoma Patients

    PubMed Central

    Murray, Timothy; Fuertes Marraco, Silvia A.; Baumgaertner, Petra; Bordry, Natacha; Cagnon, Laurène; Donda, Alena; Romero, Pedro; Verdeil, Grégory; Speiser, Daniel E.

    2016-01-01

    A major limiting factor in the success of immunotherapy is tumor infiltration by CD8+ T cells, a process that remains poorly understood. In the present study, we characterized homing receptors expressed by human melanoma-specific CD8+ T cells. Our data reveal that P-selectin binding and expression of the retention integrin, very late antigen (VLA)-1, by vaccine-induced T cells correlate with longer patient survival. Furthermore, we demonstrate that CD8+VLA-1+ tumor-infiltrating lymphocytes (TILs) are highly enriched in melanoma metastases in diverse tissues. VLA-1-expressing TIL frequently co-express CD69 and CD103, indicating tissue-resident memory T cells (TRM) differentiation. We employed a mouse model of melanoma to further characterize VLA-1-expressing TIL. Our data show that VLA-1+ TRM develop in murine tumors within 2 weeks, where they exhibit increased activation status, as well as superior effector functions. In addition, in vivo blockade of either VLA-1 or CD103 significantly impaired control of subcutaneous tumors. Together, our data indicate that VLA-1+ TRM develop in tumors and play an important role in tumor immunity, presenting novel targets for the optimization of cancer immunotherapy. PMID:28018343

  18. Transport Mechanism of Nicotine in Primary Cultured Alveolar Epithelial Cells.

    PubMed

    Takano, Mikihisa; Nagahiro, Machi; Yumoto, Ryoko

    2016-02-01

    Nicotine is absorbed from the lungs into the systemic circulation during cigarette smoking. However, there is little information concerning the transport mechanism of nicotine in alveolar epithelial cells. In this study, we characterized the uptake of nicotine in rat primary cultured type II (TII) and transdifferentiated type I-like (TIL) epithelial cells. In both TIL and TII cells, [(3)H]nicotine uptake was time and temperature-dependent, and showed saturation kinetics. [(3)H]Nicotine uptake in these cells was not affected by Na(+), but was sensitive to extracellular and intracellular pH, suggesting the involvement of a nicotine/proton antiport system. The uptake of [(3)H]nicotine in these cells was potently inhibited by organic cations such as clonidine, diphenhydramine, and pyrilamine, but was not affected by substrates and/or inhibitors of known organic cation transporters such as carnitine, 1-methyl-4-phenylpyridinium, and tetraethylammonium. In addition, the uptake of [(3)H]nicotine in TIL cells was stimulated by preloading the cells with unlabeled nicotine, pyrilamine, and diphenhydramine, but not with tetraethylammonium. These results suggest that a novel proton-coupled antiporter is involved in the uptake of nicotine in alveolar epithelial cells and its absorption from the lungs into the systemic circulation.

  19. High incidence of interleukin 10 mRNA but not interleukin 2 mRNA detected in human breast tumours.

    PubMed Central

    Venetsanakos, E.; Beckman, I.; Bradley, J.; Skinner, J. M.

    1997-01-01

    Despite the presence of a lymphocytic infiltrate in solid cancers, the failure for tumour growth to be contained suggests an inadequate immune response to the tumour. Poor cytotoxicity exerted by tumour-infiltrating lymphocytes (TILs) against tumour cells in vitro, combined with continued tumour growth in vivo, suggests deficiencies in TIL function or numbers. Various theories have been postulated to explain how tumour cells may escape immunosurveillance and control. One of the many hypotheses is the failure of production of cytokines, which are necessary for T cells to mediate their function. Thus, the expression of cytokine mRNA in human breast tumour sections was investigated by reverse transcriptase polymerase chain reaction (RT-PCR) with cytokine-specific primers. A relatively consistent finding was detection of interleukin (IL) 10 mRNA among the tumours. No IL-2 and little IL-4 mRNA was detected in the tumours. IL-6 and IL-10 mRNA was detected in only one and two of the normal breast tissues respectively. IL-2, IL-4 and tumour necrosis factor (TNF)-alpha mRNA was not detected in any of the normal breast tissues. The reduced function of TILs may be related to IL-10, which has known inhibitory effects on T-cell activation. Images Figure 1 PMID:9192989

  20. Kupffer cells of cirrhotic rat livers sensitize colon cancer cells to Fas-mediated apoptosis.

    PubMed

    Song, E; Chen, J; Ouyang, N; Wang, M; Exton, M S; Heemann, U

    2001-05-04

    Metastasis of colorectal carcinomas rarely occurs in cirrhotic livers. Our study investigated the influence of activated Kupffer cells from cirrhotic rat livers on hepatic colonization and FasR-mediated apoptosis of colon cancer cells. A rat colon cancer cell line, RCN-9, was used to inoculate rat livers. Treatment with conditioned media of Kupffer cells isolated from CCl(4)-induced cirrhotic rat livers (cirrhotic KCM) significantly reduced the incidence of hepatic colonization of RCN-9 cells. In vitro cytotoxicity of Kupffer cells and tumour infiltrating lymphocytes (TILs) on RCN-9 cells was evaluated using [(3)H]-release assay. RCN-9 cells were resistant to cytotoxicity mediated by cirrhotic Kupffer cells, but were sensitized to TIL-mediated killing after treatment with cirrhotic KCM. The specific killing induced by TILs was FasR-mediated, as it was inhibited by ZB4, an antagonistic anti-FasR antibody. In agreement, cirrhotic KCM increased recombinant Fas ligand-induced apoptosis of RCN-9 cells, and up-regulated FasR expression on RCN-9 cells as evaluated by RT-PCR and flow cytometry. These findings suggest that Kupffer cells in cirrhotic livers sensitize metastatic colon cancer cells to FasR-mediated apoptosis by up-regulating the receptors, which thus prepare them to be eliminated by infiltrating lymphocytes.

  1. Tumor infiltrating lymphocyte therapy for ovarian cancer and renal cell carcinoma

    PubMed Central

    Andersen, Rikke; Donia, Marco; Westergaard, Marie Christine Wulff; Pedersen, Magnus; Hansen, Morten; Svane, Inge Marie

    2015-01-01

    Personalized cancer immunotherapy based on infusion of T cells holds the promise to specifically target a patient’s individual tumor. Accumulating evidence indicates that the T cells mediating these tumor regressions after cancer immunotherapies may primarily target patient-specific mutations expressed by the patients’ tumors and that the presence of these “neo-antigen” specific T-cells may be related to a high number of mutations in the tumor. In melanoma, treatment with autologous tumor-infiltrating lymphocytes (TILs) can mediate durable complete responses. Previous trials investigating TIL therapy in solid tumors other than melanoma have shown limited success, however none of these early trials used current preparative chemotherapy regimens, and the methods for in vitro lymphocyte expansion have changed considerably. New advances and understandings in T cell based immunotherapies have stimulated the interest in developing this approach for other indications. Here, we summarize the early clinical data in the field of adoptive cell transfer therapy (ACT) using tumor-infiltrating lymphocytes for patients with renal cell carcinoma (RCC) and ovarian cancer (OC). In addition we describe the major advances in the characterization and application of TIL therapy for patients with RCC and OC. PMID:26308285

  2. Lymphocyte-to-monocyte ratio is associated with prognosis of diffuse large B-cell lymphoma: correlation with CD163 positive M2 type tumor-associated macrophages, not PD-1 positive tumor-infiltrating lymphocytes.

    PubMed

    Wang, Jingxuan; Gao, Kun; Lei, Wanting; Dong, Lina; Xuan, Qijia; Feng, Meiyan; Wang, Jinlu; Ye, Xiangnan; Jin, Tuan; Zhang, Zhongbai; Zhang, Qingyuan

    2017-01-17

    The research aims to examine the prognostic value of the lymphocyte-to-monocyte ratio (LMR), neutrophil-to- lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in diffuse large B-cell lymphoma (DLBCL). The relation of these hematologic indicators to poor antitumor immunity and prognosis must be investigated. Clinicopathologic data and survival information of 355 patients with DLBCL was retrospectively analyzed. Univariate analysis revealed that lower LMR (<2.71), higher NLR (≥2.81), CD163+ M2 tumor-associated macrophages (TAM) content ≥9.5% and programmed cell death 1 (PD-1)+ tumor-infiltrating lymphocytes (TILs) content < 4.5 cells per high power field(HPF) were significantly related to unfavorable overall survival (OS) and progression free survival (PFS). When considering the prognostic indexes of IPI, multivariate analysis confirmed that LMR of <2.71 and CD163+ M2 TAM content ≥9.5% significantly affected the prognosis of DLBCL. Spearman correlation test showed LMR was negatively correlated with CD163+ M2 TAM content. However, there were no correlation was found between LMR and PD-1+ TIL as well as between NLR and PD-1+ TIL content. These results indicated that decreased LMR lead to a weak anti-tumor immunity and could be used as a bad prognosis biomarker of DLBCL.

  3. Quantification of image quality using information theory.

    PubMed

    Niimi, Takanaga; Maeda, Hisatoshi; Ikeda, Mitsuru; Imai, Kuniharu

    2011-12-01

    Aims of present study were to examine usefulness of information theory in visual assessment of image quality. We applied first order approximation of the Shannon's information theory to compute information losses (IL). Images of a contrast-detail mammography (CDMAM) phantom were acquired with computed radiographies for various radiation doses. Information content was defined as the entropy Σp( i )log(1/p ( i )), in which detection probabilities p ( i ) were calculated from distribution of detection rate of the CDMAM. IL was defined as the difference between information content and information obtained. IL decreased with increases in the disk diameters (P < 0.0001, ANOVA) and in the radiation doses (P < 0.002, F-test). Sums of IL, which we call total information losses (TIL), were closely correlated with the image quality figures (r = 0.985). TIL was dependent on the distribution of image reading ability of each examinee, even when average reading ratio was the same in the group. TIL was shown to be sensitive to the observers' distribution of image readings and was expected to improve the evaluation of image quality.

  4. Immune-mediated antitumor effect by type 2 diabetes drug, metformin

    PubMed Central

    Eikawa, Shingo; Nishida, Mikako; Mizukami, Shusaku; Yamazaki, Chihiro; Nakayama, Eiichi; Udono, Heiichiro

    2015-01-01

    Metformin, a prescribed drug for type 2 diabetes, has been reported to have anti-cancer effects; however, the underlying mechanism is poorly understood. Here we show that this mechanism may be immune-mediated. Metformin enabled normal but not T-cell–deficient SCID mice to reject solid tumors. In addition, it increased the number of CD8+ tumor-infiltrating lymphocytes (TILs) and protected them from apoptosis and exhaustion characterized by decreased production of IL-2, TNFα, and IFNγ. CD8+ TILs capable of producing multiple cytokines were mainly PD-1−Tim-3+, an effector memory subset responsible for tumor rejection. Combined use of metformin and cancer vaccine improved CD8+ TIL multifunctionality. The adoptive transfer of antigen-specific CD8+ T cells treated with metformin concentrations as low as 10 μM showed efficient migration into tumors while maintaining multifunctionality in a manner sensitive to the AMP-activated protein kinase (AMPK) inhibitor compound C. Therefore, a direct effect of metformin on CD8+ T cells is critical for protection against the inevitable functional exhaustion in the tumor microenvironment. PMID:25624476

  5. Tumor-infiltrating lymphocytes are dynamically desensitized to antigen but are maintained by homeostatic cytokine

    PubMed Central

    Boldajipour, Bijan; Nelson, Amanda; Krummel, Matthew F.

    2016-01-01

    T cells that enter tumors are largely tolerized, but how that process is choreographed and how the ensuing “dysfunctional” tumor-infiltrating lymphocytes (TILs) are maintained are poorly understood and are difficult to assess in spontaneous disease. We exploited an autochthonous model of breast cancer for high-resolution imaging of the early and later stages of tumor residence to understand the relationships between cellular behaviors and cellular phenotypes. “Dysfunctional” differentiation began within the first days of tumor residence with an initial phase in which T cells arrest, largely on tumor-associated macrophages. Within 10 days, cellular motility increased and resembled a random walk, suggesting a relative absence of TCR signaling. We then studied the concurrent and apparently contradictory phenomenon that many of these cells express molecular markers of activation and were visualized undergoing active cell division. We found that whereas proliferation did not require ongoing TCR/ZAP70 signaling, instead this is driven in part by intratumoral IL-15 cytokine. Thus, TILs undergo sequential reprogramming by the tumor microenvironment and are actively retained, even while being antigen insensitive. We conclude that this program effectively fills the niche with ineffective yet cytokine-dependent TILs, and we propose that these might compete with new clones, when they arise. PMID:27942588

  6. CD74 and intratumoral immune response in breast cancer.

    PubMed

    Wang, Zhi-Qiang; Milne, Katy; Webb, John R; Watson, Peter H

    2016-04-06

    CD74 (invariant chain) plays a role in MHC class II antigen presentation. We assessed CD74 and MHCII expression in tumor cells, as well as CD8, CD4, and CD68 tumor infiltrating leucocyte (TIL) density by immunohistochemistry in a cohort of 492 breast cancer patients. CD74 expression was associated with poor prognostic markers including patient age, tumor grade, ER status, non-Luminal A subtypes, and with MHCII expression and higher TIL densities, particularly in the Basal-like subgroup. Univariate analysis showed a favorable prognostic effect of CD74 (Hazard ratio = 0.46, 95% CI = 0.26-0.89, p = 0.022) and for combined CD74/MHCII (Hazard ratio = 0.26, 95% CI = 0.17-0.81, p = 0.014) positive status for overall survival that was only manifested in the Basal-like subgroup. CD74 and MHCII expression is associated with patient survival in Basal-like breast cancer, and the association with TIL may reflect an effective intratumoral immune response.

  7. Identification of genes and pathways associated with cytotoxic T lymphocyte infiltration of serous ovarian cancer

    PubMed Central

    Leffers, N; Fehrmann, R S N; Gooden, M J M; Schulze, U R J; ten Hoor, K A; Hollema, H; Boezen, H M; Daemen, T; de Jong, S; Nijman, H W; van der Zee, A G J

    2010-01-01

    Background: Tumour-infiltrating lymphocytes (TILs) are predictors of disease-specific survival (DSS) in ovarian cancer. It is largely unknown what factors contribute to lymphocyte recruitment. Our aim was to evaluate genes and pathways contributing to infiltration of cytotoxic T lymphocytes (CTLs) in advanced-stage serous ovarian cancer. Methods: For this study global gene expression was compared between low TIL (n=25) and high TIL tumours (n=24). The differences in gene expression were evaluated using parametric T-testing. Selectively enriched biological pathways were identified with gene set enrichment analysis. Prognostic influence was validated in 157 late-stage serous ovarian cancer patients. Using immunohistochemistry, association of selected genes from identified pathways with CTL was validated. Results: The presence of CTL was associated with 320 genes and 23 pathways (P<0.05). In addition, 54 genes and 8 pathways were also associated with DSS in our validation cohort. Immunohistochemical evaluation showed strong correlations between MHC class I and II membrane expression, parts of the antigen processing and presentation pathway, and CTL recruitment. Conclusion: Gene expression profiling and pathway analyses are valuable tools to obtain more understanding of tumour characteristics influencing lymphocyte recruitment in advanced-stage serous ovarian cancer. Identified genes and pathways need to be further investigated for suitability as therapeutic targets. PMID:20664601

  8. Th17-type cytokines, IL-6 and TNF-α synergistically activate STAT3 and NF-kB to promote colorectal cancer cell growth.

    PubMed

    De Simone, V; Franzè, E; Ronchetti, G; Colantoni, A; Fantini, M C; Di Fusco, D; Sica, G S; Sileri, P; MacDonald, T T; Pallone, F; Monteleone, G; Stolfi, C

    2015-07-01

    Colorectal cancers (CRCs) often show a dense infiltrate of cytokine-producing immune/inflammatory cells. The exact contribution of each immune cell subset and cytokine in the activation of the intracellular pathways sustaining CRC cell growth is not understood. Herein, we isolate tumor-infiltrating leukocytes (TILs) and lamina propria mononuclear cells (LPMCs) from the tumor area and the macroscopically unaffected, adjacent, colonic mucosa of patients who underwent resection for sporadic CRC and show that the culture supernatants of TILs, but not of LPMCs, potently enhance the growth of human CRC cell lines through the activation of the oncogenic transcription factors signal transducer and activator of transcription 3 (STAT3) and nuclear factor-kappa B (NF-kB). Characterization of immune cell complexity of TILs and LPMCs reveals no differences in the percentages of T cells, natural killer T cells, natural killer (NK) cells, macrophages and B cells. However, T cells from TILs show a functional switch compared with those from LPMCs to produce large amounts of T helper type 17 (Th17)-related cytokines (that is, interleukin-17A (IL-17A), IL-17F, IL-21 and IL-22), tumor necrosis factor-α (TNF-α) and IL-6. Individual neutralization of IL-17A, IL-17F, IL-21, IL-22, TNF-α or IL-6 does not change TIL-derived supernatant-driven STAT3 and NF-kB activation, as well as their proproliferative effect in CRC cells. In contrast, simultaneous neutralization of both IL-17A and TNF-α, which abrogates NF-kB signaling, and IL-22 and IL-6, which abrogates STAT3 signaling, reduces the mitogenic effect of supernatants in CRC cells. IL-17A, IL-21, IL-22, TNF-α and IL-6 are also produced in excess in the early colonic lesions in a mouse model of sporadic CRC, associated with enhanced STAT3/NF-kB activation. Mice therapeutically given BP-1-102, an orally bioavailable compound targeting STAT3/NF-kB activation and cross-talk, exhibit reduced colon tumorigenesis and diminished expression of

  9. Tumor-associated immune factors are associated with recurrence and metastasis in non-small cell lung cancer

    PubMed Central

    Yan, X; Jiao, S-C; Zhang, G-Q; Guan, Y; Wang, J-L

    2017-01-01

    Dynamic interaction between tumor cells and the microenvironment is critical for tumorigenesis, and cancer immunosurveillance plays an important role in the tumor evolution. In some tumors (such as esophageal cancer, pancreatic cancer and colorectal cancer), studies have shown that the number of tumor-infiltrating lymphocytes (TILs) has a significant relationship with the prognosis, but there is little research on the prognosis of TILs and non-small cell lung cancer (NSCLC) has been performed. Therefore, it is necessary to discover the relationship between the TILs and cytokines with NSCLC prognosis and metastasis in patients. Tumor samples were carefully examined for tissue preservation and complete follow-up. A total of 107 tumor samples from NSCLC patients with radical surgical resection were enrolled for the analysis. All samples were subjected to immunohistochemistry for detection of CD3, CD4, CD8, CD28, forkhead box protein P3 (Foxp3), cytotoxic T lymphocyte-associated protein-4, cyclooxygenase2 (COX-2), transforming growth factor β 1, interleukin-2 (IL-2), interleukin-6, interleukin-10, interleukin-12 receptor and hypoxia inducible factor 1a (HIF-1a). The number, function and location of the targets were analyzed to determine their correlation with disease-free survival (DFS) and overall survival (OS). Immunhistochemical results from 107 samples indicated that the FoxP3+ regulatory TIL (HR=1.336, P=0.031), IL-2 (HR=0.595, P=0.007) and HIF-1a (HR=1.510, P=0.002) levels in tumor cells closely correlated with DFS in a COX analysis model. FoxP3+ regulatory TILs (HR=1.566, P=0.002) significantly correlated with OS and tumor node metastasis staging. The patients were divided into two groups due to the coexpression pattern of the IL-2, FoxP3+ and HIF-1a. The high-risk group had an overall worse survival than those at low risk. We confirmed that Foxp3 expression in lymphocyte and IL-2 expression in tumor cells were associated with recurrence or transfer

  10. Squamous cell carcinomas escape immune surveillance via inducing chronic activation and exhaustion of CD8+ T Cells co-expressing PD-1 and LAG-3 inhibitory receptors

    PubMed Central

    Mishra, Ameet K.; Kadoishi, Tanya; Wang, Xiaoguang; Driver, Emily; Chen, Zhangguo; Wang, Xiao-Jing; Wang, Jing H.

    2016-01-01

    Squamous cell carcinoma (SCC) is the second commonest type of skin cancer. Moreover, about 90% of head and neck cancers are SCCs. SCCs develop at a significantly higher rate under chronic immunosuppressive conditions, implicating a role of immune surveillance in controlling SCCs. It remains largely unknown how SCCs evade immune recognition. Here, we established a mouse model by injecting tumor cells derived from primary SCCs harboring KrasG12D mutation and Smad4 deletion into wild-type (wt) or CD8−/− recipients. We found comparable tumor growth between wt and CD8−/− recipients, indicating a complete escape of CD8+ T cell-mediated anti-tumor responses by these SCCs. Mechanistically, CD8+ T cells apparently were not defective in infiltrating tumors given their relatively increased percentage among tumor infiltrating lymphocytes (TILs). CD8+ TILs exhibited phenotypes of chronic activation and exhaustion, including overexpression of activation markers, co-expression of programmed cell death 1 (PD-1) and lymphocyte activation gene-3 (LAG-3), as well as TCRβ downregulation. Among CD4+ TILs, T regulatory cells (Tregs) were preferentially expanded. Contradictory to prior findings in melanoma, Treg expansion was independent of CD8+ T cells in our SCC model. Unexpectedly, CD8+ T cells were required for promoting NK cell infiltration within SCCs. Furthermore, we uncovered AKT-dependent lymphocyte-induced PD-L1 upregulation on SCCs, which was contributed greatly by combinatorial effects of CD8+ T and NK cells. Lastly, dual blockade of PD-1 and LAG-3 inhibited the tumor growth of SCCs. Thus, our findings identify novel immune evasion mechanisms of SCCs and suggest that immunosuppressive mechanisms operate in a cancer-type specific and context-dependent manner. PMID:27835902

  11. PD-1/SHP-2 inhibits Tc1/Th1 phenotypic responses and the activation of T cells in the tumor microenvironment.

    PubMed

    Li, Jing; Jie, Hyun-Bae; Lei, Yu; Gildener-Leapman, Neil; Trivedi, Sumita; Green, Tony; Kane, Lawrence P; Ferris, Robert L

    2015-02-01

    Immune rejection of tumors is mediated by IFNγ production and T-cell cytolytic activity. These processes are impeded by PD-1, a coinhibitory molecule expressed on T cells that is elevated in tumor-infiltrating lymphocytes (TIL). PD-1 elevation may reflect T-cell exhaustion marked by decreased proliferation, production of type I cytokines, and poor cytolytic activity. Although anti-PD-1 antibodies enhance IFNγ secretion after stimulation of the T-cell receptor (TCR), the mechanistic link between PD-1 and its effects on T-cell help (Tc1/Th1 skewing) remains unclear. In prospectively collected cancer tissues, we found that TIL exhibited dampened Tc1/Th1 skewing and activation compared with peripheral blood lymphocytes (PBL). When PD-1 bound its ligand PD-L1, we observed a marked suppression of critical TCR target genes and Th1 cytokines. Conversely, PD-1 blockade reversed these suppressive effects of PD-1:PD-L1 ligation. We also found that the TCR-regulated phosphatase SHP-2 was expressed higher in TIL than in PBL, tightly correlating with PD-1 expression and negative regulation of TCR target genes. Overall, these results defined a PD-1/SHP-2/STAT1/T-bet signaling axis mediating the suppressive effects of PD-1 on Th1 immunity at tumor sites. Our findings argue that PD-1 or SHP-2 blockade will be sufficient to restore robust Th1 immunity and T-cell activation and thereby reverse immunosuppression in the tumor microenvironment.

  12. Fast SiPM Readout of the PANDA TOF Detector

    NASA Astrophysics Data System (ADS)

    Böhm, M.; Lehmann, A.; Motz, S.; Uhlig, F.

    2016-05-01

    For the identification of low momentum charged particles and for event timing purposes a barrel Time-of-Flight (TOF) detector surrounding the interaction point is planned for the PANDA experiment at FAIR . Since the boundary conditions in terms of available radial space and radiation length are quite strict the favored layout is a hodoscope composed of several thousand small scintillating tiles (SciTils) read out by silicon photomultipliers (SiPMs). A time resolution of well below 100 ps is aimed for. With the originally proposed 30 × 30 × 5 mm3 SciTils read out by two single 3 × 3 mm2 SiPMs at the rims of the scintillator the targeted time resolution can be just reached, but with a considerable position dependence across the scintillator surface. In this paper we discuss other design options to further improve the time resolution and its homogeneity. It will be shown that wide scintillating rods (SciRods) with a size of, e.g., 50 × 30 × 5 mm3 or longer and read out at opposite sides by a chain of four serially connected SiPMs a time resolution down to 50 ps can be reached without problems. In addition, the position dependence of the time resolution is negligible. These SciRods were tested in the laboratory with electrons of a 90Sr source and under real experimental conditions in a particle beam at CERN. The measured time resolutions using fast BC418 or BC420 plastic scintillators wrapped in aluminum foil were consistently between 45 and 75 ps dependent on the SciRod design. This is a significant improvement compared to the original SciTil layout.

  13. Immunoscore encompassing CD3+ and CD8+ T cell densities in distant metastasis is a robust prognostic marker for advanced colorectal cancer

    PubMed Central

    Kwak, Yoonjin; Koh, Jiwon; Kim, Duck-Woo; Kang, Sung-Bum; Kim, Woo Ho; Lee, Hye Seung

    2016-01-01

    Background The immunoscore (IS), an index based on the density of CD3+ and CD8+ tumor-infiltrating lymphocytes (TILs) in the tumor center (CT) and invasive margin (IM), has gained considerable attention as a prognostic marker. Tumor-associated macrophages (TAMs) have also been reported to have prognostic value. However, its clinical significance has not been fully clarified in patients with advanced CRC who present with distant metastases. Methods The density of CD3+, CD4+, CD8+, FOXP3+, CD68+, and CD163+ immune cells within CRC tissue procured from three sites–the primary CT, IM, and distant metastasis (DM)–was determined using immunohistochemistry and digital image analyzer (n=196). The IS was obtained by quantifying the densities of CD3+ and CD8+ TILs in the CT and IM. IS-metastatic and IS-macrophage–additional IS models designed in this study–were obtained by adding the score of CD3 and CD8 in DM and the score of CD163 in primary tumors (CT and IM), respectively, to the IS. Result Higher IS, IS-metastatic, and IS-macrophage values were significantly correlated with better prognosis (p=0.020, p≤0.001, and p=0.005, respectively). Multivariate analysis revealed that only IS-metastatic was an independent prognostic marker (p=0.012). No significant correlation was observed between KRAS mutation and three IS models. However, in the subgroup analysis, IS-metastatic showed a prognostic association regardless of the KRAS mutational status. Conclusion IS is a reproducible method for predicting the survival of patients with advanced CRC. Additionally, an IS including the CD3+ and CD8+ TIL densities at DM could be a strong prognostic marker for advanced CRC. PMID:27835889

  14. T cell receptor transgenic lymphocytes infiltrating murine tumors are not induced to express foxp3

    PubMed Central

    2011-01-01

    Regulatory T cells (Treg) that express the transcription factor Foxp3 are enriched within a broad range of murine and human solid tumors. The ontogeny of these Foxp3 Tregs - selective accumulation or proliferation of natural thymus-derived Treg (nTreg) or induced Treg (iTreg) converted in the periphery from naïve T cells - is not known. We used several strains of mice in which Foxp3 and EGFP are coordinately expressed to address this issue. We confirmed that Foxp3-positive CD4 T cells are enriched among tumor-infiltrating lymphocytes (TIL) and splenocytes (SPL) in B16 murine melanoma-bearing C57BL/6 Foxp3EGFP mice. OT-II Foxp3EGFP mice are essentially devoid of nTreg, having transgenic CD4 T cells that recognize a class II-restricted epitope derived from ovalbumin; Foxp3 expression could not be detected in TIL or SPL in these mice when implanted with ovalbumin-transfected B16 tumor (B16-OVA). Likewise, TIL isolated from B16 tumors implanted in Pmel-1 Foxp3EGFP mice, whose CD8 T cells recognize a class I-restricted gp100 epitope, were not induced to express Foxp3. All of these T cell populations - wild-type CD4, pmel CD8 and OTII CD4 - could be induced in vitro to express Foxp3 by engagement of their T cell receptor (TCR) and exposure to transforming growth factor β (TGFβ). B16 melanoma produces TGFβ and both pmel CD8 and OTII CD4 express TCR that should be engaged within B16 and B16-OVA respectively. Thus, CD8 and CD4 transgenic T cells in these animal models failed to undergo peripheral induction of Foxp3 in a tumor microenvironment. PMID:22112546

  15. Evaluation of γ-retroviral vectors that mediate the inducible expression of IL-12 for clinical application.

    PubMed

    Zhang, Ling; Feldman, Steven A; Zheng, Zhili; Chinnasamy, Nachimuthu; Xu, Hui; Nahvi, Azam V; Dudley, Mark E; Rosenberg, Steven A; Morgan, Richard A

    2012-06-01

    The clinical application of interleukin-12 (IL-12) has been hindered by the toxicity associated with its systemic administration. To potentially overcome this problem, we developed a promoter designed to direct IL-12 expression within the tumor environment using an inducible composite promoter containing binding motifs for the nuclear factor of activated T cells (NFAT) linked to a minimal IL-2 promoter. In this study, the NFAT promoter was coupled to a single-chain human IL-12 gene and inserted into 2 γ-retroviral self-inactivating vectors (SERS.NFAT.hIL12 and SERS.NFAT.hIL12.PA2) and 1 γ-retroviral vector (MSGV1.NFAT.hIL.12 PA2). Peripheral blood lymphocytes (PBLs) were double transduced with an antigen-specific T-cell receptor and the 3 NFAT.hIL12 vectors. Evaluation of inducible IL-12 expression, transduction efficiency, and vector production considerations led to the choice of the MSGV1.NFAT.hIL12.PA2 vector for clinical application. MSGV1.NFAT.hIL12.PA2 PG13 retroviral vector producer cell clones were screened by transduction of tumor antigen-specific PBLs. On the basis of expression studies in PBL, clone D3 was chosen to produce clinical-grade viral vector supernatant and was demonstrated to efficiently transduce young tumor-infiltrating lymphocytes (TIL). The vector-transduced young TIL with known tumor recognition demonstrated specific inducible IL-12 production after coculture with HLA-matched tumor targets and had augmented effector function as demonstrated by increased IFN-γ secretion. These results support the clinical application of adoptive transfer of young TIL engineered with the NFAT.hIL12 vector as a new approach for cancer immunotherapy.

  16. Squamous cell carcinomas escape immune surveillance via inducing chronic activation and exhaustion of CD8+ T Cells co-expressing PD-1 and LAG-3 inhibitory receptors.

    PubMed

    Mishra, Ameet K; Kadoishi, Tanya; Wang, Xiaoguang; Driver, Emily; Chen, Zhangguo; Wang, Xiao-Jing; Wang, Jing H

    2016-12-06

    Squamous cell carcinoma (SCC) is the second commonest type of skin cancer. Moreover, about 90% of head and neck cancers are SCCs. SCCs develop at a significantly higher rate under chronic immunosuppressive conditions, implicating a role of immune surveillance in controlling SCCs. It remains largely unknown how SCCs evade immune recognition. Here, we established a mouse model by injecting tumor cells derived from primary SCCs harboring KrasG12D mutation and Smad4 deletion into wild-type (wt) or CD8-/- recipients. We found comparable tumor growth between wt and CD8-/- recipients, indicating a complete escape of CD8+ T cell-mediated anti-tumor responses by these SCCs. Mechanistically, CD8+ T cells apparently were not defective in infiltrating tumors given their relatively increased percentage among tumor infiltrating lymphocytes (TILs). CD8+ TILs exhibited phenotypes of chronic activation and exhaustion, including overexpression of activation markers, co-expression of programmed cell death 1 (PD-1) and lymphocyte activation gene-3 (LAG-3), as well as TCRβ downregulation. Among CD4+ TILs, T regulatory cells (Tregs) were preferentially expanded. Contradictory to prior findings in melanoma, Treg expansion was independent of CD8+ T cells in our SCC model. Unexpectedly, CD8+ T cells were required for promoting NK cell infiltration within SCCs. Furthermore, we uncovered AKT-dependent lymphocyte-induced PD-L1 upregulation on SCCs, which was contributed greatly by combinatorial effects of CD8+ T and NK cells. Lastly, dual blockade of PD-1 and LAG-3 inhibited the tumor growth of SCCs. Thus, our findings identify novel immune evasion mechanisms of SCCs and suggest that immunosuppressive mechanisms operate in a cancer-type specific and context-dependent manner.

  17. Groundwater Productivity and Quality of The Quartzite Ridge of RÓdA~o and Their Vicinities (center of Portugal)

    NASA Astrophysics Data System (ADS)

    Duque, J.; Chambel, A.

    When the ESA Huygens Probe arrives at Titan in 2005, measurements taken during and after the descent through the atmosphere are likely to revolutionise our under- standing of SaturnSs most enigmatic moon. The accurate atmospheric profiling of Titan from these measurements will require knowledge of the probe descent trajectory and in some cases attitude history, whilst certain atmospheric information (e.g. wind speeds) may be inferred directly from the probe dynamics during descent. Two of the instruments identified as contributing valuable information for the reconstruction of the probeSs parachute descent dynamics are the Surface Science Package Tilt sensor (SSP-TIL) and the Huygens Atmospheric Structure Instrument servo accelerometer (HASI-ACC). This presentation provides an overview of these sensors and their static calibration before describing an investigation into their real-life dynamic performance under simulated Titan-gravity conditions via a low-cost parabolic flight opportunity. The combined use of SSP-TIL and HASI-ACC in characterising the aircraft dynam- ics is also demonstrated and some important challenges are highlighted. Results from some simple spin tests are also presented. Finally, having validated the performance of the sensors under simulated Titan conditions, estimates are made as to the output of SSP-TIL and HASI-ACC under a variety of probe dynamics, ranging from verti- cal descent with spin to a simple 3 degree-of-freedom parachute descent model with horizontal gusting. It is shown how careful consideration must be given to the instru- mentsS principles of operation in each case, and also the impact of the sampling rates and resolutions as selected for the Huygens mission. The presentation concludes with a discussion of ongoing work on more advanced descent modelling and surface dy- namics modelling, and also of a proposal for the testing of the sensors on a sea-surface.

  18. Reduced-gravity Testing of The Huygens Probe Ssp Tiltmeter and Hasi Accelerometer Sensors and Their Role In Reconstruction of The Probe Descent Dynamics

    NASA Astrophysics Data System (ADS)

    Ghafoor, N.; Zarnecki, J.

    When the ESA Huygens Probe arrives at Titan in 2005, measurements taken during and after the descent through the atmosphere are likely to revolutionise our under- standing of SaturnSs most enigmatic moon. The accurate atmospheric profiling of Titan from these measurements will require knowledge of the probe descent trajectory and in some cases attitude history, whilst certain atmospheric information (e.g. wind speeds) may be inferred directly from the probe dynamics during descent. Two of the instruments identified as contributing valuable information for the reconstruction of the probeSs parachute descent dynamics are the Surface Science Package Tilt sensor (SSP-TIL) and the Huygens Atmospheric Structure Instrument servo accelerometer (HASI-ACC). This presentation provides an overview of these sensors and their static calibration before describing an investigation into their real-life dynamic performance under simulated Titan-gravity conditions via a low-cost parabolic flight opportunity. The combined use of SSP-TIL and HASI-ACC in characterising the aircraft dynam- ics is also demonstrated and some important challenges are highlighted. Results from some simple spin tests are also presented. Finally, having validated the performance of the sensors under simulated Titan conditions, estimates are made as to the output of SSP-TIL and HASI-ACC under a variety of probe dynamics, ranging from verti- cal descent with spin to a simple 3 degree-of-freedom parachute descent model with horizontal gusting. It is shown how careful consideration must be given to the instru- mentsS principles of operation in each case, and also the impact of the sampling rates and resolutions as selected for the Huygens mission. The presentation concludes with a discussion of ongoing work on more advanced descent modelling and surface dy- namics modelling, and also of a proposal for the testing of the sensors on a sea-surface.

  19. Temporal and spatial discordance of programmed cell death-ligand 1 expression and lymphocyte tumor infiltration between paired primary lesions and brain metastases in lung cancer

    PubMed Central

    Mansfield, A. S.; Aubry, M. C.; Moser, J. C.; Harrington, S. M.; Dronca, R. S.; Park, S. S.; Dong, H.

    2016-01-01

    Background The dynamics of PD-L1 expression may limit its use as a tissue-based predictive biomarker. We sought to expand our understanding of the dynamics of PD-L1 expression and tumor-infiltrating lymphocytes (TILs) in patients with lung cancer-related brain metastases. Experimental design Paired primary lung cancers and brain metastases were identified and assessed for PD-L1 and CD3 expression by immunohistochemistry. Lesions with 5% or greater PD-L1 expression were considered positive. Agreement statistics and the χ2 or Fisher's exact test were used for analysis. Results We analyzed 146 paired lesions from 73 cases. There was disagreement of tumor cell PD-L1 expression in 10 cases (14%, κ = 0.71), and disagreement of TIL PD-L1 expression in 19 cases (26%, κ = 0.38). Most paired lesions with discordant tumor cell expression of PD-L1 were obtained 6 or more months apart. When specimens were categorized using a proposed tumor microenvironment categorization scheme based on PD-L1 expression and TILs, there were significant changes in the classifications because many of the brain metastases lacked either PD-L1 expression, tumor lymphocyte infiltration or both even when they were present in the primary lung cancer specimens (P = 0.009). Conclusions We identified that there are significant differences between the tumor microenvironment of paired primary lung cancers and brain metastases. When physicians decide to treat patients with lung cancer with a PD-1 or PD-L1 inhibitor, they must do so in the context of the spatial and temporal heterogeneity of the tumor microenvironment. PMID:27502709

  20. Ada Compiler Validation Summary Report: Certificate Number: 940325S1. 11344 DDC-I, DACS Sun SPARC/Solaris to 80186 Bare Ada Cross Compiler System with Rate Monotonic Scheduling, Version 4.6.4 Sun SPARCclassic => Intel iSBC 186/100 (Bare Machine)

    DTIC Science & Technology

    1994-03-25

    5*n" "i~m~ &4" W4000 Vmh~ . a=. 1=3-EOTTP AND KIE 4. TIL5N . FUNDING 940325SI.11344, AMF 94ddc500_iC DDC-I, DACS Sun SPARC/Solaris to 80186 Bare Ada...DISTRIBUTION Approved for Public Release; .. distribution unlimited 13. (Maxinxm 200 Host: Sun SPARCclassic (under Sokaris, Release 2.1) Target: Intel...COMPILER VALIDATION SUMMARY REPORT: Certificate Number: 940325S1.11344 DDC-I DACS Sun SPARC/Solaris to 80186 Bare Ada Cross Compiler System with Rate

  1. 1. Innovative Relaxor-Based PiezoCrystals: Phase Diagrams, Crystal Growth, Domain Structures and Electric Properties. 2. Piezo- and Ferroelectric Materials Based on Morphotropic Phase Boundary Synthesis, Characterization and Structure - Property Relations

    DTIC Science & Technology

    2006-03-31

    Aug. 2-8, 2003. [48] Z.-G. Ye, A. Bokov and M . Maglione , "Dielectric and Structural Properties of Relaxor Ferroelectrics", 55 Years of Ferroelectrics...Pacific Center for Advanced Materials and Microstructure (PCAMM), NRC / UBC, Dec. 4, 2004. [64] A. A. Bokov, M . Maglione and Z.-G. Ye, "Low-Frequency...Argentina, Sept. 5 - 9, 2005. [78] A. A. Bokov, M . Maglione and Z.-G. Ye, "Critical Dielectric Behaviour in Ba(Til-,Zr,)0 3 Solid Solution" (0), 1 1 1h

  2. Air Force Human Resources Laboratory Annual Report - Fiscal Year 1981.

    DTIC Science & Technology

    1982-06-01

    with its application of fiber-optics. technical reviews was based on a week-long meeting with helmet- mounted display. advanced (IG. and division...optics. training and combat conditions. The thrust consists of helmet- mounted display. advanced computer image four subthtrusts: (a) Air Combat ,’aining...formais of Mntissiort T rainier . N\\e% efforts inivolvi ig t[lie use of T \\C expjetiritenrtalI cotoli are- di fficulIt a ti(l % here resources toi BR A L

  3. Producibility and Serviceability of Kevlar-49 Structures Made on Hot Layup Tools

    DTIC Science & Technology

    1975-05-01

    34 roducibility rviceability evlar-4 ructures de t yup ols. " e poses s gram re: • • aluate duc bility licopter ctural ponent de m evlar-4...ore tensiv e pera ture urvey ver e LT urface rea . ut or is ro gram airings e r e bjected ur e e f pr oximate l y inutes nsur e at cured rea s...9 la inates 2 1 Go od Fairly clean edges c: ɘ Fu ller ton Fib e rg las s ::T ~ outer B it til :I: N outi ng Techno log y As ooc. 9 l aminate s

  4. Investigation and Assessment of Hardware for Guidance of Gliding Airdrop Systems

    DTIC Science & Technology

    1979-02-28

    i r- i" r- 1 u VI ?x U 41 IS u u ai 2 *J 41 u m " > 4i i— ** 4i a 4 til a i- c E «<— a. x U 41 lii u 41 ’F— ftoC IS 5N *« £5 V...and these range measurements are translated through tri-lateration into a position fix. The family trees of this configuration ai -e shown in...Configuration description Estimated cost System cost 4 airborne + 1 ground Ai rborne Ground I II III IV V _______ DME/Airborne DF DME/Ground ADF Mini

  5. Refractive Index of Silicon and Germanium and Its Wavelength and Temperature Derivatives.

    DTIC Science & Technology

    1979-03-01

    59. Tauc , J., Abraham, A., Pajasova, L., Grigorovici, R., and Vancu, A., "Optical Properties of Non-Crystalline Semiconductors," in Physics of Non...259 onm 1 84 9!. vojn: .p r us TlI II io L, rinc 11 1US I11L ni . 3 1.98’ ,iii til n i,:n ;Ivvi i Li o i Ili LtI loi ,I ,.kii d.i / T ’I 2 .1) 11 L...index measured using interference method. 40 (T-298 K) Amorphous germanium thin film prepared Tauc , J., Abraham, A., 159) 0.695 4.742 by evaporation

  6. Exploration and Production of Hydrocarbon Resources in Coastal Alabama and Mississippi. Executive Summary.

    DTIC Science & Technology

    1984-11-01

    service industry Increases at meeting more than l /2 Iold workecs; most coald maintenance. sioon In Tanlrs 2-, i region, so increases points. Potential...hydrocarbon Industry is developing In the study area. included in this minor impacts category are: 13-3 r I ct, c 1 til b l tv; rom .a A 11 u I and p...537-2o58 iv HAER 4 - MITIGATING MEASURES4- I NTdO DUCT ION 4-1 REGUL.AT RY RFUIREHENTrs 4-1 INDUSTRY PRACrIC] ci4-1 5V’[lcR P~OTENTIAL, MITIGATING

  7. Seal Technology in Gas Turbine Engines

    DTIC Science & Technology

    1978-08-01

    B) Specialists’ Meeting In London, United Klngdozn 6-7 April 1978. TIlE MISSION OF AGARD The mission of AGARD is to bring together the leading...consisting of officially appointed senior representatives from each member nation. The mi •ion of AGARD Is carried out through the Panels which are...teclanologio des Joints de turbines A giz. L 𔄀tude flat llmitde aux cia oil intervient un mouvement relatif entre let divergse partle des Joints, et couvrit i Ia

  8. National Hydroelectric Power Resources Study: Regional Assessment: Volume XXII: Western Systems Coordinating Council, (WSCC). Volume 22

    DTIC Science & Technology

    1981-09-01

    I 5 _ BINGHAM -* - -• I05NPWOOgS * HAKER CREEK - I 5 _ BLAINE * * -• _ 43 24.0 - SNAKE RIVER _ 112 Q.o_ • • - - - NW . - Til _ * * EASLEY HUT...0 * 7~S. o. NNYUVUN * • I 5 • HAKER BURNT RIVER * 117 39.9 * IS • 8100 * 7bO • 303b. 245.33 • • * NW • • b50 * 100.0. 80:9. 7&0 * 303b...IS • 403500 * 7811 * 2585 * 1805.3 * * * NW * * 1021 * 180.0* 339.0 * 7811 * 2585 * * UYVUNNNUN * * * HAKER 11250000

  9. Synthesis, Spectroscopic and Toxicity Studies of Titanocene Chelates of Isatin-3-Thiosemicarbazones

    PubMed Central

    Vatsa, Garima; Pandey, O. P.; Sengupta, S. K.

    2005-01-01

    The reactions of bis(cyclopentadienyl)titanium(IV) dichloride with a new class of thiosemicarbazone (LH2), derived by condensing isatin with different N(4)-substituted thiosemicarbazides, have been studied and products of type [Cp2Ti(L)] have been isolated. On the basis of various physico-chemical and spectral studies, five coordinate structures have been assigned to these derivatives. Toxicity studies of titanocene complexes at tbur different concentrations have been carried out against snail Lymnaea acuminata. The effect of most potent compounds on the activity of acetylcholinesterase enzyme, which inhibits the activity of enzyme, possibly by the formation of enzyme-inhibitor complex, was also studied. PMID:18365096

  10. Military Health Service System Ambulatory Work Unit (AWU).

    DTIC Science & Technology

    1988-04-01

    probability of a value outside 2.0 standard deviations ranges from .0456 for A-3 -Al" 122 NILITRY HEALTH SERVICE SYSTEM AMULRTORY MORKe UurNT CANdU )(U) ARMY...00 2 w w >4 &4~ ~z til 0n0 rz~ co00 P - xU) I : 0 ) ) %z E-4 z U) HHw H~~ ~ ~ 0 olf4 E1E- 004 H U) UDm 0 4 E- H wE- ~ H E-4 H 04 H Z U H Q z HO H % x z

  11. Military Schools for Prospective Officers of the Soviet Armed Forces

    DTIC Science & Technology

    1975-03-31

    SCHOOLS4FOR IROSPECTIVE O’FICERS, OF TilE SOVIET MED FORCES DDC(, 1. ie i E II n - CAPTAIN JA MES- - G RU S ID501UDUTION s81.’ . Approved jot l Divtiumion...Ma~or 2 Gonoral WK ’Kre 01amalycsakia komandirikie -navyki, Voonnyl etlk o (1973), Pp. 57-58. 4 14400 orel N. Ar4litov and~ Captain Y., Ptamolo0...cosmopolitan mision (frequent ’foreign contacts), also are doing well In this field. eCf., Naval Captain L. Ufimtsev and Commander A.- I)t~Aktual’nyt zaclach

  12. The Turbulent Boundary Layer: An Experimental Study of the Transport of Momentum and Heat with the Effect of Roughness

    DTIC Science & Technology

    1975-05-01

    COMMERCE TIlE TURBULENT BOUNDARY LAYER: AN EXPERIMENTAL STUDY OF THE TRANSPORT OF 1 M(IMENTUM AND HEAT W\\ ITHl THE EFFECT OF ROUGIINESS I • • 11. . 1 ...1975 NATIONAL TECHNICAL INFORMATION SERVICE US D.l’. 2 C....51.3’ tt.VA. 22t51 II Unclassified - SECURTY CLAISSIFICATION OF TUIS PAGE 1 --. 0- 1 ...EoI1*’*dl REPORT DOCUMENTATION4 PAGE BEOECMLEIGFR REPO T N] 1 :ER:.10VT ACCESSION NO. 3 RsECIPIENT Sl CATALOG NUMBER 4 TITLE (sI4S.btIIII.) 5. TYPE OF

  13. SANs and Large Scale Data Migration at the NASA Center for Computational Sciences

    NASA Technical Reports Server (NTRS)

    Salmon, Ellen M.

    2004-01-01

    Evolution and migration are a way of life for provisioners of high-performance mass storage systems that serve high-end computers used by climate and Earth and space science researchers: the compute engines come and go, but the data remains. At the NASA Center for Computational Sciences (NCCS), disk and tape SANs are deployed to provide high-speed I/O for the compute engines and the hierarchical storage management systems. Along with gigabit Ethernet, they also enable the NCCS's latest significant migration: the transparent transfer of 300 Til3 of legacy HSM data into the new Sun SAM-QFS cluster.

  14. Development of a Decompression Algorithm for Constant 0.7 ATA Oxygen Partial Pressure in Helium Diving.

    DTIC Science & Technology

    1985-04-01

    HVAL02 140/15 ( 1 ) Hips, costo -vertebral Joints, costo -chondral junctions. 4 Bin Hip pain gone by 5 min at 60 FSW. All other Symptoms gone upon...AD-A158 142 UNCLASSIFIED DEVELOPMENT OF A DECOMPRESSION ALGORITHM FOR CONSTANT 1 /Jt 97 ATA OXVGEN PARTI.. <U> NAVY EXPERIMENTAL DIVING UNIT...PANAMA CITV FL E D THALMANN APR 85 NEDU- 1 -85 F/G 6/19 NL T i i •• » 1.1.1« j*. .*••’ ’*• J ’ ’*"’" -f" ll til5 |M 2-5 •• 2

  15. The Influence of a Lower Heated Tube on Nucleate Pool Boiling from a Horizontal Tube

    DTIC Science & Technology

    1992-06-01

    AD-A256 833 NAVAL POSTGRADUATE SCHOOL Monterey, California (,-A So Ic THESIS TIlE INFLUENCE OF A LOWER IIEATED TUBE ON NUCLEATE POOL BOILING FROM A...HORIZONTAL TUBE by Lannic R. Lake June 1992 Thesis Advisor Paul J. Marto Co-Advisor Stephen B. Memory Approved for public rclcase; distribution is...day) 15 Page • nt Master’s Thesis From . To June 1992 16 Supplementary Notation The views expressed in this thesis are those of the author and do

  16. Classification Management. Journal. Volume X - 1974. Papers from the National Seminar (10th), 16-17-18 July 1974

    DTIC Science & Technology

    1974-01-01

    Contract. Even at the end of the three year period, if a continued need to 1 : - I dl i~ t Ivtop nttaa go sil tlisa Itraltec il~ t onf In ti-l 142. Fiartlivi...This is one of the problems dares, standards and criteria necessary to meet we are continuing to address. In this connection, changing conditions...inforhiation. Tlhe major problems arise diem satlaries. *and so, forth. It doesn ’ t matter when and It peoplIr feel a c tasuif icat ion is made

  17. Erratum to "Predicting sulphur and nitrogen deposition using a simple statistical method" [Atmos. Environ. 140 (2016) 456-468

    NASA Astrophysics Data System (ADS)

    Oulehle, Filip; Kopáček, Jiří; Chuman, Tomáš; Černohous, Vladimír; Hůnová, Iva; Hruška, Jakub; Krám, Pavel; Lachmanová, Zora; Navrátil, Tomáš; Štěpánek, Petr; Tesař, Miroslav; Evans, Christopher D.

    2016-10-01

    The Journal regrets that the author's names were tagged incorrectly resulting in author forenames appearing as surnames. The correct author names are: Filip Oulehle, Jiří Kopáček, Tomáš Chuman, Vladimír Černohous, Iva Hůnová, Jakub Hruška, Pavel Krám, Zora Lachmanová, Tomáš Navrátil, Petr Štěpánek, Miroslav Tesař, Christopher D. Evans. The Journal would like to apologise for any inconvenience caused.

  18. Association Between NRAS and BRAF Mutational Status and Melanoma-Specific Survival Among Patients With Higher Risk Primary Melanoma

    PubMed Central

    Thomas, Nancy E.; Edmiston, Sharon N.; Alexander, Audrey; Groben, Pamela A.; Parrish, Eloise; Kricker, Anne; Armstrong, Bruce K.; Anton-Culver, Hoda; Gruber, Stephen B.; From, Lynn; Busam, Klaus J.; Hao, Honglin; Orlow, Irene; Kanetsky, Peter A.; Luo, Li; Reiner, Anne S.; Paine, Susan; Frank, Jill S.; Bramson, Jennifer I.; Marrett, Lorraine D.; Gallagher, Richard P.; Zanetti, Roberto; Rosso, Stefano; Dwyer, Terence; Cust, Anne E.; Ollila, David W.; Begg, Colin B.; Berwick, Marianne; Conway, Kathleen

    2015-01-01

    Importance NRAS and BRAF mutations in melanoma inform current treatment paradigms but their role in survival from primary melanoma has not been established. Identification of patients at high risk of melanoma-related death based on their primary melanoma characteristics before evidence of recurrence could inform recommendations for patient follow-up and eligibility for adjuvant trials. Objective To determine tumor characteristics and survival from primary melanoma by somatic NRAS and BRAF status. Design, Setting, and Participants A population-based study with median follow-up of 7.6 years for 912 patients with first primary cutaneous melanoma analyzed for NRAS and BRAF mutations diagnosed in the year 2000 from the United States and Australia in the Genes, Environment and Melanoma Study and followed through 2007. Main Outcomes and Measures Tumor characteristics and melanoma-specific survival of primary melanoma by NRAS and BRAF mutational status. Results The melanomas were 13% NRAS+, 30% BRAF+, and 57% with neither NRAS nor BRAF mutation (wildtype). In a multivariable model including clinicopathologic characteristics, NRAS+ melanoma was associated (P<.05) with mitoses, lower tumor infiltrating lymphocyte (TIL) grade, and anatomic site other than scalp/neck and BRAF+ melanoma was associated with younger age, superficial spreading subtype, and mitoses, relative to wildtype melanoma. There was no significant difference in melanoma-specific survival for melanoma harboring mutations in NRAS (HR 1.7, 95% CI, 0.8–3.4) or BRAF (HR, 1.5, 95% CI, 0.8–2.9) compared to wildtype melanoma adjusted for age, sex, site, AJCC tumor stage, TIL grade, and study center. However, melanoma-specific survival was significantly poorer for higher risk (T2b or higher stage) tumors with NRAS (HR 2.9; 95% CI 1.1–7.7) or BRAF (HR 3.1; 95% CI 1.2–8.5) mutations but not for lower risk (T2a or lower) tumors (P=.65) adjusted for age, sex, site, AJCC tumor stage, TIL grade, and study center

  19. Highlights of the society for immunotherapy of cancer (SITC) 27th annual meeting

    PubMed Central

    2013-01-01

    The 27th annual meeting of the Society for Immunotherapy of Cancer (SITC) was held on October 26–28, 2012 in North Bethesda, Maryland and the highlights of the meeting are summarized. The topics covered at this meeting included advances in cancer treatment using adoptive cell therapy (ACT), oncolytic viruses, dendritic cells (DCs), immune check point modulators and combination therapies. Advances in immune editing of cancer, immune modulation by cancer and the tumor microenvironment were also discussed as were advances in single cell analysis and the manufacture and potency testing of tumor infiltrating lymphocytes (TIL).

  20. Cell Transfer Therapy for Cancer: Past, Present, and Future

    PubMed Central

    Qian, Xiaoling; Wang, Xian; Jin, Hongchuan

    2014-01-01

    Cell transfer therapy for cancer has made a rapid progress recently and the immunotherapy has been recognized as the fourth anticancer modality after operation, chemotherapy, and radiotherapy. Lymphocytes used for cell transfer therapy include dendritic cells, natural killer (NK) cells, and T lymphocytes such as tumor-infiltrating lymphocytes (TILs) and cytotoxic T lymphocytes (CTLs). In vitro activated or engineered immune cells can traffic to cancer tissues to elicit persistent antitumor immune response which is very important especially after immunosuppressive treatments such as chemotherapy. In this review, we overviewed recent advances in the exploration of dendritic cells, NK cells, and T cells for the treatment of human cancer cells. PMID:24741604

  1. Optimal Stationary Linear Control of the Wiener Process.

    DTIC Science & Technology

    1980-02-29

    OPTIMAL STATIONARY LINEAR CONTROL OF THE WIENER PROCESS. (U) FES 80 V E BENES. I KARATZAS AFOSR-76-3063 UNCLASSIFIED AFOSR -TR-8O-0338 NL...mElllllllllll mhmmmmmmmmm mmmmmmmr( EFOSR-TR- 2 0-0S8 0 3 OPTIMAL STATIONARY LINEAR CONTROL OF THE WIENER PROCESS by LEVEL CVACLAV E. BENES Bell Telephone...or " DIst. special D U L I. F UNCLASSIFIED _ _ _ , ,_I_ _ _ _ _ _. OPTIMAL STATIONARY LINEAR CONTROL OF TIlE WIENER PROCESS V’aclav E. Benes and

  2. How Quickly Can Attention Affect Form Perception?

    DTIC Science & Technology

    1987-11-01

    of targetA in1c’ntxi i,’jtio iretLrairilg triails giveni pri or to Th is exicr inmen t 4) run ii iei ia to lyj after Fxperim int I, uslnj t;]il same...cue would still require the retrieval of the to-be-attended location from memory . fut there is no longer jiuch reason to suspect that the time...dttention. The Journal of Neuroscience, 4, 1863-1874. Reeves, A., & Sperling, G. (in press). Attentiori rjati, it, sh1 r t term visual memory

  3. 3W Analysis of FY 78 Army Aircraft Accidents.

    DTIC Science & Technology

    1979-05-01

    Callen, J. R., "Pilot Error Accidents Aren’t All Pilot," United States Army Agency for Aviation Safety, May 1975. 25 ~ ~ - APPENDICES 27 til - -1P I If 2...LJSASC-TR-79- ML DIS RII3UMUN STATZLIA USASC TECHNICAL REPORT Approved fox public releaqw TR 79.3 Ana Iyss Of FY78 704Acidents. A.L:fM ;what happened...construed as an official Department of the Army position, policy , or decision, unless so designated by other official authority. The findings of this

  4. The Shock and Vibration Bulletin. Part 2. Ship Shock, Shock and Blast and Ground Shock

    DTIC Science & Technology

    1984-06-01

    1 ~S*ISie spoloo-s TSwSo SWot P1. * Iseel PS.... 0 A*6I 6 r.S 0 " .- 3 *(O f~*,,* m a se aa’atevw b te rd 2Plto oltv ~pems tu tu toe po00til...4--------4 are shown with the arrows indicating Icame go. WIII~jI I4I1~a (ACC) maxis : the direction of decreasing (y’)m x.. In I. Is .0 Its...corresponds to the maxi - is simply repeated using the other input in mum displacement response was also determined. place of Equation 4-1. The damping

  5. Protein Kinase C is a Mediator of Lipopolysaccharide-Induced Vascular Suppression in the Rat Aorta

    DTIC Science & Technology

    1994-01-01

    28). A possible require- 0 ,] ment for multiple LPS-stimulated mediators to full\\ induce300o •"NOS activity in VSM can explain the apparent paradox...A D - A 286 074 )AGE 0704-0pprove IIIo- 1 DC 199 AGENC U EPORT TYPE AND DATES COVERED 1994L N S-TIL Journal article 4. ITE ND UBITES. Fý;.:DlNG...ADDRESS(ES) 110. SAPOENSCOYRINEGO/RMONNITNOR~ING Naval Medical Research and Development Command AEC EOTNME National Naval Medical Center Building 1 , Towver

  6. Staffing Cyber Operations (Briefing Charts)

    DTIC Science & Technology

    2015-05-01

    w hi ch p os iti on s co ns tit ut e D ire ct P ar tic ip at io n in C yb er sp ac e H os til iti es (D P H ) = C yb er sp ac e C om ba ta...un ity  ID A a lte rn at iv e la rg el y su bs tit ut es c iv ili an s fo r e nl is te d pe rs on ne l a nd co nt ra ct or s  M ili ta ry a

  7. Investigations at Site 32 (41EP325), Keystone Dam Project. A Multicomponent Archeological Site in Western El Paso County, Texas.

    DTIC Science & Technology

    1983-03-01

    In studying thoc surface dlstrLft 151c, of Ire-crack’s( rocks, platn maps shoiwiii surf ici features and dispersed ruock densi I (is (by iwelo’.t ,ind...noteI i r tt til 1 -s:uI roucuiJT I I, t fc-. rocks, hut pi t 7, 1 1n:1 Cul no h,1r*1 e dfc lir it A, wi1thI Feat ure t, Feat ure( 14 is ltterjret’l...clear that all vessels represented in the collection are tempered with sand (each specimen was examined using a variable power binocular micro- scope

  8. Atmospheric Transmittance/Radiance: Computer Code LOWTRAN 6. Supplement: Program Listings

    DTIC Science & Technology

    1983-08-01

    Program Listings F. X. KNEIZYS E. P . SHETTLE W. 0. GALLERY J. HK CHETWYND, Jr. <L. W. ABRFU J,. E, A. SELBY Z S. A. CLOUGH R. W. FENN DTIC ELECT 1...Kneizys J. H. Chetwynd, Jr. E. P . Shettle L. W. Abreu , S. A. Clough W.O0. Galler JI.A Selby* R. W. Fenni S. P ;,.IkPORUING ORGANIZATO N;. r AN. ARES...PATH TO TIlE EXTIRATEFUIWSTRIAL SOURCE. 73 EXA B IN LOADIS A ROS I, EXt’IACTION AND P AlW SO •1 TION COEPFFICIFNTS I.FOR THE APPROPU SATE MODEIL AND

  9. Multiaperture Optics.

    DTIC Science & Technology

    1986-03-01

    is collected and gives rise to one point only. The con- sequence is that the location of the image point is determined by the - eye architecture and is...encountered con- sists only of a sequence of rectangles. The picture language used has only one word "rectangle." The information describing the...l i tt i t l 1t 11111 VI11 21 1 illill t 111111t ... . Ill tt Ill ttttttt Ill ii it itlilt I til liii 1 1111 111111 1 t 11111111illl its1 II till Iti

  10. Experiment in Water Dowsing

    DTIC Science & Technology

    1994-09-01

    0)0 "• •,• • -• )• .EEP C .7 7:i EXPERIMENT IN WATER DOWSING Til I"SIS EEDavid 1. (Gaisford. 1). E. AFIT/GEE/F.NS/94S-O I ~~m - DEPARTMENT... WATER DOWSING THESIS David I. Gaisford, P. E. AFIT/GEE/ENS/94S-01 Approved for Public Release; distribution unlimited =TC QUALITY pSP-ECTED 3 S0694-30622...Specils THESIS APPROVAL Student: David I. Gaisford Class: GEE 94S Thesis Title: Experiment in Water Dowsing Defense Date: 11 Aug 94 Committee Name

  11. Department of Defense, Office of Inspector General Semiannual Report to the Congress, 1 April - 30 September 1984.

    DTIC Science & Technology

    1984-11-29

    2i. • .2•.A . ’~ o ****~ " ’ *~~ " .... ............... -77 -7 - 71𔄁" 7.. ..7.. ......-. . x ’ - INTERNAL AUDIT FOLLOWUP ACCOMPUSHMENTS...rcl ioinit’ ti s il th i specifieatitoits and si atidards, interpret itng ti-st resulIts and - ti~l’ts: 40 involved proiilts with i litlenttig i- X ...Rooms in * steadl of* the 14-passe-nger aircraft being sotlicitecl. lu r- Hawaii. Thel( Nav- x rented hotel acc(Inm mdat ions for * hasing three leased

  12. Foulois and the U.S. Army Air Corps 1931-1935,

    DTIC Science & Technology

    1983-01-01

    anl inhibiting agent . "Fhe War 1)1,1111 heri 111 iiii19~ sI󈧞 JIknossledi!d at mutltitude ot’ tasks that military .1 ou ildl pciioini sonie tar...leasin tilIle post \\ iaatit usiti ! tile 1\\Il ii ecuses of ecotiotlnv and War lDepartnm t conisoiidationi. II oosci &J ot na me a ep cnntdmuine tile remli...briefly considered the wartime strength and composition of the GHQ Air Force. The War Plans Division was reconsidering the RED and ORANGE %sar plans

  13. Development and Evaluation of Reproductive and Developmental Toxicity Tests for Assessing the Hazards of Environmental Contaminants

    DTIC Science & Technology

    1997-08-01

    the report. D. METHODLOGY VI length data were colleced and analyzed E*e°*U^ Eglin AFB soil in sealed jars, exposure in Petn dishes q to...ft 0! as Ta- hn a in m *c O u u rn n. -M 43 u m s. n> ft O n o <u l-i U O r3 -M c U a> ’Si s T3 (0 til 43 « o ffl t^ u 01 ca ’’ ’! -M

  14. E15, Cost Analysis and Funding. User’s Manual Version 1.0

    DTIC Science & Technology

    1991-04-01

    C es Ava il amd/o - Dist special CONTRACT DAAA2I-86-D-0025 Ds PC~ for HO US AMCCOM INTEGRATED LOGISTIC SUPPORT OFFICE AMSMC-LSP ROCK ISLAND, IL by...provided by Barbara Boren and Denise Montanez . We gratefully acknowledge the significant contributions made to the quality of this product by Messrs. T...ILS ELEMENT E15COST ANALYSIS AND FUNDING DATA FLOW DIAGRAMS C .. i I, .. - I 4, - ., t .. •-! Ŗ 4 4 i -4- \\ o a _ __/ / ," I •i.\\ , Az!• "!-. * >Us

  15. High-Resolution Autoradiography

    DTIC Science & Technology

    1955-01-01

    Laboratory, Cleveland, Ohio WALTER C. WILLIAMS, B. S., Chief, High-Speed Flight Station, Edwards, Calif. HIItIU-ItE•,OL.I’TION Al’TIlT.AI) iIO (ltAIIII 3 Of )4r...comparison was made betw,,ia wvet-prociss autoraffio- eraluate this autoradiographic technique, several types of radio - graphs and autoradiographs...apart. heterogeneous system. The radiation emitted by the radio - Wet-process autoradiography, as developed in 1949 by Dr. active elements acts on a

  16. Application and Comparison of Stable Periodic Orbits in the Vicinity of Lagrangian Points L4 and L5 to a Four-Body Truth Model.

    DTIC Science & Technology

    1979-12-01

    IT/ /A/A79D-2 APPLICATION A-ND COMPARISON OF STABLE PERIODIC ORBITS IN THE VICXNyTy OF LAGRANGIAN POINTS L4 AND L5 TO A FOUR -BODY TRUTH MODEL THESISE...COMPARISON OF STABLE PERIODIC ORBITS IN TIlE ICINITY OF LAGRJ.NGIAN POINTS L4 AND LS TO A FOUR -BODY TRUTH MODEL. 11 ~ ’ THESIS PRESENTED TO THE FACULTY OF...15 Restricted Four -Body Equations of Motion .............. 18 III. Wheeler’s Orbit ......................................... 23 overview of Wheeler’s

  17. The PD1/PDL1 axis, a promising therapeutic target in aggressive breast cancers.

    PubMed

    Bertucci, François; Finetti, Pascal; Birnbaum, Daniel; Mamessier, Emilie

    2016-03-01

    Analysis of PDL1 mRNA expression in ∼5,500 breast cancers showed PDL1 upregulation in 38% of basal tumors and 38% of inflammatory breast cancers (IBC). Upregulation, associated with signs of strong cytotoxic local immune response, was associated with a better survival in the basal or triple-negative subtypes, and with a better pathological response to chemotherapy in these subtypes and IBC. Reactivation of dormant tumor-infiltrating lymphocytes (TILs) by PD1/PDL1-inhibitors represents a promising strategy in these aggressive tumors.

  18. Atomic and Molecular Physics Program

    DTIC Science & Technology

    2012-03-07

    i i å Sz i +1 -hzSz i -hxSx i hx =0: classical first order phase transition Finite hx: quantum phase transition, second order 13...transition H = J i å Sz iSz i +1 - (1- D) Sz i - 23/2 t Sx i D = E-U E: energy difference per lattice site, or lattice tilt U: onsite interaction...distribution is unlimited. Laser cooling Dysprosium \\.J ••• • ·=--·-Rtnes • Ce ., Til Periodic Table of the Elements [iO " I

  19. The PD1/PDL1 axis, a promising therapeutic target in aggressive breast cancers

    PubMed Central

    Bertucci, François; Finetti, Pascal; Birnbaum, Daniel; Mamessier, Emilie

    2016-01-01

    ABSTRACT Analysis of PDL1 mRNA expression in ∼5,500 breast cancers showed PDL1 upregulation in 38% of basal tumors and 38% of inflammatory breast cancers (IBC). Upregulation, associated with signs of strong cytotoxic local immune response, was associated with a better survival in the basal or triple-negative subtypes, and with a better pathological response to chemotherapy in these subtypes and IBC. Reactivation of dormant tumor-infiltrating lymphocytes (TILs) by PD1/PDL1-inhibitors represents a promising strategy in these aggressive tumors. PMID:27141340

  20. Manufacturing Methods and Technology for Digital Fault Isolation of Hybrid Microelectronic Assemblies.

    DTIC Science & Technology

    1982-03-01

    8217I I’ U F ~roef is 24 1lines by MI ) columns with video and inverse, vidleo d ispl ay mfodus. F~or the 111:1 protrun, 1(ijr ’-leirints of’ lIP) systemis...expansion, 2-15 ,%~~................. ............. . . . -. %% ." - .- Sect ion 2 - W ork< Aeooijshed Stibseet ionl I) - til *\\1t01 rohe Sy’.tomi...operating mode to automatic. • MI - Set AP operating mode to manual. * M2 - Set AP operating mode to test. • UP - Raise probe. e DN - Lower probe

  1. National Dam Safety Program. Watchung Lake Dam (NJ00767), Raritan River Basin, Stony Brook, Somerset County, New Jersey Phase I Inspection Report.

    DTIC Science & Technology

    1981-07-01

    ACCESSION NO. 3. RECIPIENT’S CATALOG NUMBER IDAEN/NAPi-53842/NJ00767-81/07 ~J.. ______________ 4. TIL E W-d ubtile)5. TYPE OF REPORT & PERIOD COVERED Phase...develop written operating procedures and a periodic maintenance plan to ensure the safety of Lhe dam within one year from the date of approval of this...written operating procedures and a periodic maintenance plan to ensure the safety of the dam within one year from the date of approval of this report

  2. Characterization of Anaerobic Chemical Processes in Reservoirs: Problem Description and Conceptual Model Formulation.

    DTIC Science & Technology

    1981-04-01

    CHARACTERIZATION OF ANAEROBIC CHEMICAL PROCESSES IN RESERVOIRS...ETC(U) APR al D GUNNISON, J M BRANNON UNCLASSIFIED WES/TR/E-8i-6 L 1111 1.01115 32...INISTRUCTIONS REPORT DOCUMENTATION PAGE RECINT. COMSPLETIG FORM 4. TIL adSb~)S. TYPE Of REPORT G PERIOD COySRED OIARACTERIZATION OFAAEROBIC QEMICAL...Engineers, U. S. Army Ap(J%8 Washington, D . C. 2031480r J 14. MONITORING AGENCY NAME & ADORESS(f different bass Conti.IIing Office) 1S. SECURITY CLASS

  3. Prognostic impact of the tumor-infiltrating regulatory T-cell (Foxp3+)/activated cytotoxic T lymphocyte (granzyme B+) ratio on resected left-sided pancreatic cancer

    PubMed Central

    Hwang, Ho Kyoung; Kim, Hyoung-Il; Kim, Se Hoon; Choi, Junjeong; Kang, Chang Moo; Kim, Kyung Sik; Lee, Woo Jung

    2016-01-01

    Among the subsets of tumor-infiltrating lymphocytes (TILs), activated cytotoxic T lymphocytes (granzyme B+) have an antitumor effect, while regulatory T lymphocytes [forkhead box P3 (Foxp3)+] suppress the antitumor immune response. The aim of the present study was to investigate the possible associations between TIL subsets and survival outcomes in patients with left-sided pancreatic ductal adenocarcinoma (PDAC). From January 2000 to December 2008, 30 patients who underwent curative distal pancreatectomy without neoadjuvant chemoradiotherapy due to left-sided PDAC were enrolled in the present study. TIL subsets were enumerated by immunohistochemical staining for cluster of differentiation (CD)3, CD4, CD8, Foxp3 and granzyme B in the intra-tumoral areas of tissue blocks. Patients were divided into two groups according to the median value of the absolute counts and relative ratios of TIL subsets. In the univariate analysis, age, gender, tumor size, nodal stage, tumor differentiation and lymphovascular/perineural invasion were not significantly associated with survival outcome. However, low levels of preoperative cancer antigen (CA) 19–9 were associated with a longer overall survival (OS), although the association was not significant (37 vs. 18 months; P=0.061). A high level of granzyme B+ was associated with enhanced disease-free survival (DFS) (25 vs. 10 months; P=0.023), and a low Foxp3+/granzyme B+ ratio was associated with a favorable prognosis in terms of DFS (25 vs. 8 months; P=0.008) and OS (47 vs. 17 months; P=0.003). In the multivariate analysis, the ratio of Foxp3+/granzyme B+ was an independent prognostic factor for determining DFS [Exp(B), 3.060; 95% confidence interval (CI), 1.259–47.436; P=0.014] and OS [Exp(B), 3.580; 95% CI, 1.460–8.780; P=0.005]. Among the clinicopathological factors, low levels of CA 19–9 were significantly associated with a low Foxp3+/granzyme B+ ratio (P=0.016). The results of the present study suggested that a low Foxp3

  4. On-the-Disk Development of the Halo Coronal Mass Ejection on 1998 May 2

    NASA Astrophysics Data System (ADS)

    Pohjolainen, S.; Maia, D.; Pick, M.; Vilmer, N.; Khan, J. I.; Otruba, W.; Warmuth, A.; Benz, A.; Alissandrakis, C.; Thompson, B. J.

    2001-07-01

    A halo coronal mass ejection (CME) was observed at 15:03 UT on 1998 May 2 by the Solar and Heliospheric Observatory Large-Angle Spectrometric Coronagraph. The observation of the CME was preceded by a major soft X-ray flare in NOAA Active Region 8210, characterized by a delta spot magnetic configuration and some activity in region 8214. A large transequatorial interconnecting loop (TIL) seen in the soft X-rays connected AR 8210 to a faint magnetic field region in the periphery of region 8214. Smaller loop systems were also connecting AR 8210 to other fainter bipolar magnetic structures, the interconnecting loop (IL) east of AR 8210 being one of the most visible. We present here a multiwavelength analysis of the large- and small-scale coronal structures associated with the development of the flare and of the CME, with emphasis placed on radio-imaging data. In the early phases of the flare, the radio emission sources traced the propagation paths of electrons along the TIL and the IL, which are accelerated in the vicinity of AR 8210. Furthermore, jetlike flows were observed in soft X-rays and in Hα in these directions. Significantly, the TIL and IL loop systems disappeared at least partially after the CME. An EUV Imaging Telescope (EIT) dimming region of similar size and shape to the soft X-ray TIL, but noticeably offset from it, was also observed. During the ``flash'' phase of the flare, new radio sources appeared, presenting signatures of destabilization and reconnection at discrete locations of the connecting loops. We interpret these as possible signatures of the CME liftoff on the disk. An Hα Moreton wave (blast wave) and an ``EIT wave'' were also observed, originating from the flaring AR 8210. The signatures in radio, after the wave propagated high into the corona, include type II-like emissions in the spectra. The radio images link these emissions to fast-moving sources, presumably formed at locations where the blast wave encounters magnetic structures. The

  5. First results of a search for double beta decay of {sup 100}Mo with the NEMO 2 detector

    SciTech Connect

    NEMO Collaboration

    1993-06-15

    Double beta decay of {sup 100}Mo (172g) is studied with the NEMO 2 detector in the Frejus Underground Laboratory. The experiment has now accumulated 2485 hours of data taking. A clear signal of 380 events for 2{beta}2{nu} decay has been obtained corresponding to a half-life of T{sub {1/2}} = 1.0 {plus_minus} 0.08 (syst.) 10{sup 19} y. Limits are presented for 2{beta}(0{nu}, {chi}), 2{beta}0{nu} (ground state and excited states 2{sub 1}{sup +} and 0{sub 1}{sup +}). The experiment will run til October 1993.

  6. Expansion of activated lymphocytes obtained from renal cell carcinoma in an automated hollow fiber bioreactor.

    PubMed

    Hillman, G G; Wolf, M L; Montecillo, E; Younes, E; Ali, E; Pontes, J E; Haas, G P

    1994-01-01

    Immunotherapy using IL-2 alone or combined with activated lymphocytes has been promising for metastatic renal cell carcinoma. Cytotoxic lymphocytes can be isolated from tumors, expanded in vitro with IL-2, and adoptively transferred back into the tumor-bearing host. These cells can also be transduced with the genes coding for cytokines for local delivery to tumor sites. A major drawback in adoptive immunotherapy is the cumbersome and expensive culture technology associated with the growth of large numbers of cells required for their therapeutic effect. To reduce the cost, resources, and manpower, we have developed the methodology for lymphocyte activation and expansion in the automated hollow fiber bioreactor IMMUNO*STAR Cell Expander (ACT BIOMEDICAL, INC). Tumor Infiltrating Lymphocytes (TIL) isolated from human renal cell carcinoma tumor specimens were inoculated at a number of 10(8) cells in a small bioreactor of 30 ml extracapillary space volume. We have determined the medium flow rates and culture conditions to obtain a significant and repeated expansion of TIL at weekly intervals. The lymphocytes cultured in the bioreactor demonstrated the same phenotype and cytotoxic activity as those expanded in parallel in tissue culture plates. Lymphocyte expansion in the hollow fiber bioreactor required lower volumes of medium, human serum, IL-2 and minimal labor. This technology may facilitate the use of adoptive immunotherapy for the treatment of refractory malignancies.

  7. Co-expression of TIM-3 and CEACAM1 promotes T cell exhaustion in colorectal cancer patients.

    PubMed

    Zhang, Yang; Cai, Pengcheng; Li, Lei; Shi, Liang; Chang, Panpan; Liang, Tao; Yang, Qianqian; Liu, Yang; Wang, Lin; Hu, Lihua

    2017-02-01

    T-cell immunoglobulin domain and mucin domain-3(TIM-3) is an activation induced inhibitory molecule involved in immune tolerance and is recently reported to induce T cell exhaustion which is mediated by carcinoembryonic antigen cell adhesion molecule 1(CEACAM1), another well-known molecule expressed on activated T cells and involved in T cell inhibition. To investigate the expression of TIM-3 and CEACAM1 on circulating CD8(+) T cells and tumor infiltrating lymphocytes (TILs), 65 diagnosed colorectal cancer (CRC) patients and 38 healthy controls were enrolled in this study and the results showed that TIM-3 and CEACAM1 were both highly expressed on circulating CD8(+) T cells in CRC patients and elevated on TILs compared with paraneoplastic T cells. Furthermore, TIM-3(+)CEACAM1(+) CD8(+) T cells represented the most dysfunctional population with the least IFN-γ production. In addition, the expressions of TIM-3 and CEACAM1 were correlated with advanced stage and could be independent risk factors for CRC. We for the first time to our knowledge suggested that co-expression of TIM-3 and CEACAM1 can mediate T cell exhaustion and may be potential biomarkers for CRC prediction, highlighting the possibility of being immunotherapy targets.

  8. Use of HLA peptidomics and whole exome sequencing to identify human immunogenic neo-antigens

    PubMed Central

    Kalaora, Shelly; Qutob, Nouar; Teer, Jamie K.; Shimony, Nilly; Schachter, Jacob; Rosenberg, Steven A.; Samuels, Yardena

    2016-01-01

    The antigenicity of cells is demarcated by the peptides bound by their Human Leucocyte Antigen (HLA) molecules. Through this antigen presentation, T cell specificity response is controlled. As a fraction of the expressed mutated peptides is presented on the HLA, these neo-epitopes could be immunogenic. Such neoantigens have recently been identified through screening for predicted mutated peptides, using synthetic peptides or ones expressed from minigenes, combined with screening of patient tumor-infiltrating lymphocytes (TILs). Here we present a time and cost-effective method that combines whole-exome sequencing analysis with HLA peptidome mass spectrometry, to identify neo-antigens in a melanoma patient. Of the 1,019 amino acid changes identified through exome sequencing, two were confirmed by mass spectrometry to be presented by the cells. We then synthesized peptides and evaluated the two mutated neo-antigens for reactivity with autologous bulk TILs, and found that one yielded mutant-specific T-cell response. Our results demonstrate that this method can be used for immune response prediction and promise to provide an alternative approach for identifying immunogenic neo-epitopes in cancer. PMID:26819371

  9. Isolation of neoantigen-specific T cells from tumor and peripheral lymphocytes

    PubMed Central

    Cohen, Cyrille J.; Gartner, Jared J.; Horovitz-Fried, Miryam; Shamalov, Katerina; Trebska-McGowan, Kasia; Bliskovsky, Valery V.; Parkhurst, Maria R.; Ankri, Chen; Prickett, Todd. D.; Crystal, Jessica S.; Li, Yong F.; El-Gamil, Mona; Rosenberg, Steven A.; Robbins, Paul F.

    2015-01-01

    Adoptively transferred tumor-infiltrating T lymphocytes (TILs) that mediate complete regression of metastatic melanoma have been shown to recognize mutated epitopes expressed by autologous tumors. Here, in an attempt to develop a strategy for facilitating the isolation, expansion, and study of mutated antigen–specific T cells, we performed whole-exome sequencing on matched tumor and normal DNA isolated from 8 patients with metastatic melanoma. Candidate mutated epitopes were identified using a peptide-MHC–binding algorithm, and these epitopes were synthesized and used to generate panels of MHC tetramers that were evaluated for binding to tumor digests and cultured TILs used for the treatment of patients. This strategy resulted in the identification of 9 mutated epitopes from 5 of the 8 patients tested. Cells reactive with 8 of the 9 epitopes could be isolated from autologous peripheral blood, where they were detected at frequencies that were estimated to range between 0.4% and 0.002%. To the best of our knowledge, this represents the first demonstration of the successful isolation of mutation-reactive T cells from patients’ peripheral blood prior to immune therapy, potentially providing the basis for designing personalized immunotherapies to treat patients with advanced cancer. PMID:26389673

  10. Long-term prospects for the environmental profile of advanced sugar cane ethanol.

    PubMed

    da Silva, Cinthia R U; Franco, Henrique Coutinho Junqueira; Junqueira, Tassia Lopes; van Oers, Lauran; van der Voet, Ester; Seabra, Joaquim E A

    2014-10-21

    This work assessed the environmental impacts of the production and use of 1 MJ of hydrous ethanol (E100) in Brazil in prospective scenarios (2020-2030), considering the deployment of technologies currently under development and better agricultural practices. The life cycle assessment technique was employed using the CML method for the life cycle impact assessment and the Monte Carlo method for the uncertainty analysis. Abiotic depletion, global warming, human toxicity, ecotoxicity, photochemical oxidation, acidification, and eutrophication were the environmental impacts categories analyzed. Results indicate that the proposed improvements (especially no-til farming-scenarios s2 and s4) would lead to environmental benefits in prospective scenarios compared to the current ethanol production (scenario s0). Combined first and second generation ethanol production (scenarios s3 and s4) would require less agricultural land but would not perform better than the projected first generation ethanol, although the uncertainties are relatively high. The best use of 1 ha of sugar cane was also assessed, considering the displacement of the conventional products by ethanol and electricity. No-til practices combined with the production of first generation ethanol and electricity (scenario s2) would lead to the largest mitigation effects for global warming and abiotic depletion. For the remaining categories, emissions would not be mitigated with the utilization of the sugar cane products. However, this conclusion is sensitive to the displaced electricity sources.

  11. A Chimeric Switch-Receptor Targeting PD1 Augments the Efficacy of Second-Generation CAR T Cells in Advanced Solid Tumors.

    PubMed

    Liu, Xiaojun; Ranganathan, Raghuveer; Jiang, Shuguang; Fang, Chongyun; Sun, Jing; Kim, Soyeon; Newick, Kheng; Lo, Albert; June, Carl H; Zhao, Yangbing; Moon, Edmund K

    2016-03-15

    Chimeric antigen receptor (CAR)-modified adoptive T-cell therapy has been successfully applied to the treatment of hematologic malignancies, but faces many challenges in solid tumors. One major obstacle is the immune-suppressive effects induced in both naturally occurring and genetically modified tumor-infiltrating lymphocytes (TIL) by inhibitory receptors (IR), namely PD1. We hypothesized that interfering with PD1 signaling would augment CAR T-cell activity against solid tumors. To address this possibility, we introduced a genetically engineered switch receptor construct, comprising the truncated extracellular domain of PD1 and the transmembrane and cytoplasmic signaling domains of CD28, into CAR T cells. We tested the effect of this supplement, "PD1CD28," on human CAR T cells targeting aggressive models of human solid tumors expressing relevant tumor antigens. Treatment of mice bearing large, established solid tumors with PD1CD28 CAR T cells led to significant regression in tumor volume due to enhanced CAR TIL infiltrate, decreased susceptibility to tumor-induced hypofunction, and attenuation of IR expression compared with treatments with CAR T cells alone or PD1 antibodies. Taken together, our findings suggest that the application of PD1CD28 to boost CAR T-cell activity is efficacious against solid tumors via a variety of mechanisms, prompting clinical investigation of this potentially promising treatment modality.

  12. HAGE (DDX43) is a biomarker for poor prognosis and a predictor of chemotherapy response in breast cancer

    PubMed Central

    Abdel-Fatah, T M A; McArdle, S E B; Johnson, C; Moseley, P M; Ball, G R; Pockley, A G; Ellis, I O; Rees, R C; Chan, S Y T

    2014-01-01

    Background: HAGE protein is a known immunogenic cancer-specific antigen. Methods: The biological, prognostic and predictive values of HAGE expression was studied using immunohistochemistry in three cohorts of patients with BC (n=2147): early primary (EP-BC; n=1676); primary oestrogen receptor-negative (PER-BC; n=275) treated with adjuvant anthracycline-combination therapies (Adjuvant-ACT); and primary locally advanced disease (PLA-BC) who received neo-adjuvant anthracycline-combination therapies (Neo-adjuvant-ACT; n=196). The relationship between HAGE expression and the tumour-infiltrating lymphocytes (TILs) in matched prechemotherapy and postchemotherapy samples were investigated. Results: Eight percent of patients with EP-BC exhibited high HAGE expression (HAGE+) and was associated with aggressive clinico-pathological features (Ps<0.01). Furthermore, HAGE+expression was associated with poor prognosis in both univariate and multivariate analysis (Ps<0.001). Patients with HAGE+did not benefit from hormonal therapy in high-risk ER-positive disease. HAGE+and TILs were found to be independent predictors for pathological complete response to neoadjuvant-ACT; P<0.001. A statistically significant loss of HAGE expression following neoadjuvant-ACT was found (P=0.000001), and progression-free survival was worse in those patients who had HAGE+residual disease (P=0.0003). Conclusions: This is the first report to show HAGE to be a potential prognostic marker and a predictor of response to ACT in patients with BC. PMID:24755885

  13. Temperature-controlled ionic liquid-based ultrasound-assisted microextraction for preconcentration of trace quantity of cadmium and nickel by using organic ligand in artificial saliva extract of smokeless tobacco products

    NASA Astrophysics Data System (ADS)

    Arain, Sadaf Sadia; Kazi, Tasneem Gul; Arain, Asma Jabeen; Afridi, Hassan Imran; Baig, Jameel Ahmed; Brahman, Kapil Dev; Naeemullah; Arain, Salma Aslam

    2015-03-01

    A new approach was developed for the preconcentration of cadmium (Cd) and nickel (Ni) in artificial saliva extract of dry snuff (brown and black) products using temperature-controlled ionic liquid-based ultrasound-assisted dispersive liquid-liquid microextraction (TIL-UDLLμE) followed by electrothermal atomic absorption spectrometry (ETAAS). The Cd and Ni were complexed with ammonium pyrrolidinedithiocarbamate (APDC), extracted in ionic liquid drops, 1-butyl-3-methylimidazolium hexafluorophosphate [C4MIM][PF6]. The multivariate strategy was applied to estimate the optimum values of experimental variables influence the % recovery of analytes by TIL-UDLLμE method. At optimum experimental conditions, the limit of detection (3s) were 0.05 and 0.14 μg L-1 while relative standard deviations (% RSD) were 3.97 and 3.55 for Cd and Ni respectively. After extraction, the enhancement factors (EF) were 87 and 79 for Cd and Ni, respectively. The RSD for six replicates of 10 μg L-1 Cd and Ni were 3.97% and 3.55% respectively. To validate the proposed method, certified reference material (CRM) of Virginia tobacco leaves was analyzed, and the determined values of Cd and Ni were in good agreement with the certified values. The concentration of Cd and Ni in artificial saliva extracts corresponds to 39-52% and 21-32%, respectively, of the total contents of both elements in dry brown and black snuff products.

  14. Anatomical study of the posterior cruciate ligament with the knee flexed at 90°☆☆☆

    PubMed Central

    Cho, Daniel Kyubin; Rosa, Sthéphano Pellizzaro; Prestes, Guilherme Bello; da Cunha, Luiz Antônio Munhoz; de Moura, Márcio Fernando Aparecido; Stieven Filho, Edmar

    2014-01-01

    Objective To study the anatomy of the posterior cruciate ligament (PCL) and define anatomical parameters with the knee flexed at 90°. Methods Eight knees from cadavers were dissected in order to make measurements from the center of the anterolateral band to the roof (AL1), from the center of the anterolateral band to the anterior cartilage (AL2), from the center of the posteromedial band to the roof (PM1), from the center of the posteromedial band to the anterior cartilage (PM2), from the center of the tibial insertion to the medial region of the tibia (TIM), from the center of the tibial insertion to the lateral region of the tibia (TIL), from the center of the medial insertion to the medial meniscus (IMM) and the width of the origin of the PCL (WO). To obtain the results from each anatomical structure, the means and standard deviations of the measurements were calculated. Results The measurements in millimeters that were found were AL1, 6.2; AL2, 4.9; PM1, 11.7; PM2, 5.5; TIM, 32.5; TIL, 40.6; IMM, 9.4; and WO, 32.5. Conclusions The PCL has an extensive origin. The center of the anterolateral band is 6 mm from the roof and 5 mm from the anterior cartilage of the knee. The tibial insertion is slightly medial and 10 mm distal to the posterior cornu of the medial meniscus. PMID:26229851

  15. T-cell subsets in peripheral blood and tumors of patients treated with oncolytic adenoviruses.

    PubMed

    Kristian, Taipale; Ilkka, Liikanen; Juuso, Juhila; Aila, Karioja-Kallio; Minna, Oksanen; Riku, Turkki; Nina, Linder; Johan, Lundin; Ari, Ristimäki; Anna, Kanerva; Anniina, Koski; Timo, Joensuu; Markus, Vähä-Koskela; Akseli, Hemminki

    2015-05-01

    The quality of the antitumor immune response is decisive when developing new immunotherapies for cancer. Oncolytic adenoviruses cause a potent immunogenic stimulus and arming them with costimulatory molecules reshapes the immune response further. We evaluated peripheral blood T-cell subsets of 50 patients with refractory solid tumors undergoing treatment with oncolytic adenovirus. These data were compared to changes in antiviral and antitumor T cells, treatment efficacy, overall survival, and T-cell subsets in pre- and post-treatment tumor biopsies. Treatment caused a significant (P < 0.0001) shift in T-cell subsets in blood, characterized by a proportional increase of CD8(+) cells, and decrease of CD4(+) cells. Concomitant treatment with cyclophosphamide and temozolomide resulted in less CD4(+) decrease (P = 0.041) than cyclophosphamide only. Interestingly, we saw a correlation between T-cell changes in peripheral blood and the tumor site. This correlation was positive for CD8(+) and inverse for CD4(+) cells. These findings give insight to the interconnections between peripheral blood and tumor-infiltrating lymphocyte (TIL) populations regarding oncolytic virotherapy. In particular, our data suggest that induction of T-cell response is not sufficient for clinical response in the context of immunosuppressive tumors, and that peripheral blood T cells have a complicated and potentially misleading relationship with TILs.

  16. BmSI-7, a novel subtilisin inhibitor from Boophilus microplus, with activity toward Pr1 proteases from the fungus Metarhizium anisopliae.

    PubMed

    Sasaki, Sergio D; de Lima, Cássia A; Lovato, Diogo V; Juliano, Maria A; Torquato, Ricardo J S; Tanaka, Aparecida S

    2008-02-01

    BmSI-7 and BmSI-6, two Boophilus microplus subtilisin inhibitors (BmSI) were purified and characterized from eggs. The inhibitors isolated by classical purification methods presented molecular masses of 7408 and 7271Da, respectively, by MALDI-TOF-MS. Both BmSI-7 and BmSI-6 inhibited neutrophil elastase (K(i) 0.4 and 0.3nM) and subtilisin A (K(i) 1.4nM for both inhibitors). They also strongly inhibited Pr1 proteases from the fungus Metarhizium anisopliae; BmSI-7 (K(i) 50nM) and BmSI-6 (K(i) 2.2nM). The BmSI-7 full length cDNA was obtained using amino acid sequence information of BmSI-7 peptides generated by proteolytic digestion. BmSI-7 belongs to trypsin inhibitor like cysteine rich domain family (TIL), and it is transcribed in ovary, fat body, gut, salivary gland and haemocytes. BmSI-7 is the first TIL inhibitor described with inhibitory activity toward subtilisin A and Pr1 proteases of entomopathogenic fungi.

  17. Characteristics of nanocomposite ZrO2/Al2O3 films deposited by plasma-enhanced atomic layer deposition.

    PubMed

    Yun, Sun Jin; Lim, Jung Wook; Kim, Hyun-Tak

    2007-11-01

    Nanocomposite ZrO2/Al2O3 (ZAO) films were deposited on Si by plasma-enhanced atomic layer deposition and the film characteristics including interfacial oxide formation, dielectric constant (k), and electrical breakdown strength were investigated without post-annealing process. In both the mixed and nano-laminated ZAO films, the thickness of the interfacial oxide layer (T(IL)) was considerably reduced compared to ZrO2 and Al2O3 films. The T(IL) was 0.8 nm in nano-composite films prepared at a mixing ratio (ZrO2:Al2O3) of 1:1. The breakdown strength and the leakage current level were greatly improved by adding Al2O3 as little as 7.9% compared to that of ZrO2 and were enhanced more with increasing content of Al2O3. The k of ZrO2 and mixed ZAO (Al2O3 7.9%) films were 20.0 and 16.5, respectively. These results indicate that the addition of Al2O3 to ZrO2 greatly improves the electrical properties with less cost of k compared to the addition of SiO2.

  18. The effect of preoperative local interleukin-2 (IL-2) injections in patients with head and neck squamous cell carcinoma. An immunological study.

    PubMed

    Cortesina, G; De Stefani, A; Galeazzi, E; Bussi, M; Giordano, C; Cavallo, G P; Jemma, C; Vai, S; Forni, G; Valente, G

    1991-01-01

    Clinical, immunological, immunophenotypical, pathological and molecular biological studies were performed on tumor infiltrating lymphocytes (TIL) and lymph node lymphocytes (LN-ly) of 8 patients with squamous cell carcinoma of the oral cavity and oropharynx treated with 10 daily locoregional injections of low doses of IL-2 before surgery. No complications were seen during or after surgery. In 3 cases the LN-ly showed a moderate LAK activity, higher in the LN-ly omolateral to the tumor and near the IL-2 injection site; in 2 of these 3 patients a good LAK activity was induced after 6-day culture with IL-2. The LN-ly derived from nodes next to the tumor showed a decreased NK activity and proliferative ability both in basal conditions and after in vitro lymphokine challenging. LN-ly of 2 IL-2 treated patients showed high levels of mRNA encoding for IL-2-R, while it was absent in 2 untreated cases. Immunophenotypical studies on TIL showed statistically improved levels of CD25+ and LAK1+ cells in treated cases. Clusters of CD11c+ (macrophages) cells were seen close to the neoplastic sheets.

  19. Comparison of circulating and intratumoral regulatory T cells in patients with renal cell carcinoma.

    PubMed

    Asma, Gati; Amal, Gorrab; Raja, Marrakchi; Amine, Derouiche; Mohammed, Chebil; Amel, Ben Ammar Elgaaied

    2015-05-01

    The clear evidence that tumor-infiltrating lymphocytes (TIL) exists in the tumor microenvironment raises the question why renal cell carcinoma (RCC) progresses. Numerous studies support the implication of CD4(+)CD25(high) regulatory T (Treg) cells in RCC development. We aimed in this study to characterize the phenotype and function of circulating and intratumoral Treg cells of RCC patient in order to evaluate their implication in the inhibition of the local antitumor immune response. Our results demonstrate that the proportion of Treg in TIL was, in average, similar to that found in circulating CD4(+) T cells of patients or healthy donors. However, intratumoral Treg exhibit a marked different phenotype when compared with the autologous circulating Treg. A higher CD25 mean level, HLA-DR, Fas, and GITR, and a lower CD45RA expression were observed in intratumoral Treg, suggesting therefore that these cells are effector in the tumor microenvironment. Additionally, intratumoral Treg showed a higher inhibitory function on autologous CD4(+)CD25(-) T cells when compared with circulating Treg that may be explained by an overexpression of FoxP3 transcription factor. These findings suggest that intratumoral Treg could be major actors in the impairment of local antitumor immune response for RCC patients.

  20. DPP4 truncated GM-CSF & IL-3 manifest distinct receptor binding & regulatory functions compared to their full length forms.

    PubMed

    O'Leary, H A; Capitano, M; Cooper, S; Mantel, C; Boswell, H S; Kapur, R; Ramdas, B; Chan, R; Deng, L; Qu, C-K; Broxmeyer, H E

    2017-03-27

    Dipeptidylpeptidase 4 (DPP4/CD26) enzymatically cleaves select penultimate amino acids of proteins, including colony stimulating factors (CSFs), and has been implicated in cellular regulation. To better understand the role of DPP4 regulation of hematopoiesis, we analyzed the activity of DPP4 on the surface of immature blood cells and then comparatively assessed the interactions and functional effects of full-length (FL) and DPP4 truncated factors [(T)-GM-CSF and- IL-3] on both in vitro and in vivo models of normal and leukemic cells. T-GM-CSF and T-IL-3 had enhanced receptor binding, but decreased CSF activity, compared to their FL forms. Importantly, T-GM-CSF and T-IL-3 significantly, and reciprocally, blunted receptor binding and myeloid progenitor cell proliferation activity of both FL-GM-CSF and FL-IL-3 in vitro and in vivo. Similar effects were apparent in vitro using cluster forming cells from patients with Acute Myeloid Leukemia (AML) regardless of cytogenetic or molecular alterations and in vivo utilizing animal models of leukemia. This suggests that DPP4 T-molecules have modified binding and functions compared to their FL counterparts and may serve regulatory roles in normal and malignant hematopoiesis.Leukemia accepted article preview online, 27 March 2017. doi:10.1038/leu.2017.98.

  1. 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

  2. Barrel time-of-flight detector for the PANDA experiment at FAIR

    NASA Astrophysics Data System (ADS)

    Gruber, L.; Brunner, S. E.; Marton, J.; Orth, H.; Suzuki, K.

    2016-07-01

    The barrel time-of-flight detector for the PANDA experiment at FAIR is foreseen as a Scintillator Tile (SciTil) Hodoscope based on several thousand small plastic scintillator tiles read-out with directly attached Silicon Photomultipliers (SiPMs). The main tasks of the system are an accurate determination of the time origin of particle tracks to avoid event mixing at high collision rates, relative time-of-flight measurements as well as particle identification in the low momentum regime. The main requirements are the use of a minimum material amount and a time resolution of σ < 100 ps. We have performed extensive optimization studies and prototype tests to prove the feasibility of the SciTil design and finalize the R&D phase. In a 2.7 GeV/c proton beam at Forschungszentrum Jülich a time resolution of about 80 ps has been achieved using SiPMs from KETEK and Hamamatsu with an active area of 3 × 3mm2. Employing the Digital Photon Counter from Philips a time resolution of about 30 ps has been reached.

  3. Optimization of Stability, Encapsulation, Release, and Cross-Priming of Tumor Antigen-Containing PLGA Nanoparticles

    PubMed Central

    Prasad, Shashi; Cody, Virginia; Saucier-Sawyer, Jennifer K.; Fadel, Tarek R.; Edelson, Richard L.; Birchall, Martin A.

    2014-01-01

    Purpose In order to investigate Poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NP) as potential vehicles for efficient tumor antigen (TA) delivery to dendritic cells (DC), this study aimed to optimize encapsulation/release kinetics before determining immunogenicity of antigen-containing NP. Methods Various techniques were used to liberate TA from cell lines. Single (gp100) and multiple (B16-tumor lysate containing gp100) antigens were encapsulated within differing molecular weight PLGA co-polymers. Differences in morphology, encapsulation/release and biologic potency were studied. Findings were adopted to encapsulate fresh tumor lysate from patients with advanced tumors and compare stimulation of tumor infiltrating lymphocytes (TIL) against that achieved by soluble lysate. Results Four cycles of freeze-thaw + 15 s sonication resulted in antigen-rich lysates without the need for toxic detergents or protease inhibitors. The 80KDa polymer resulted in maximal release of payload and favorable production of immunostimulatory IL-2 and IFN-γ. NP-mediated antigen delivery led to increased IFN-γ and decreased immunoinhibitory IL-10 synthesis when compared to soluble lysate. Conclusions Four cycles of freeze-thaw followed by 15 s sonication is the ideal technique to obtain complex TA for encapsulation. The 80KDa polymer has the most promising combination of release kinetics and biologic potency. Encapsulated antigens are immunogenic and evoke favorable TIL-mediated anti-tumor responses. PMID:22798259

  4. A comparative study on genetic effects of artificial and natural habitat fragmentation on Loropetalum chinense (Hamamelidaceae) in Southeast China

    PubMed Central

    Yuan, N; Comes, H P; Cao, Y N; Guo, R; Zhang, Y H; Qiu, Y X

    2015-01-01

    Elucidating the demographic and landscape features that determine the genetic effects of habitat fragmentation has become fundamental to research in conservation and evolutionary biology. Land-bridge islands provide ideal study areas for investigating the genetic effects of habitat fragmentation at different temporal and spatial scales. In this context, we compared patterns of nuclear microsatellite variation between insular populations of a shrub of evergreen broad-leaved forest, Loropetalum chinense, from the artificially created Thousand-Island Lake (TIL) and the Holocene-dated Zhoushan Archipelago of Southeast China. Populations from the TIL region harboured higher levels of genetic diversity than those from the Zhoushan Archipelago, but these differences were not significant. There was no correlation between genetic diversity and most island features, excepting a negative effect of mainland–island distance on allelic richness and expected heterozygosity in the Zhoushan Archipelago. In general, levels of gene flow among island populations were moderate to high, and tests of alternative models of population history strongly favoured a gene flow-drift model over a pure drift model in each region. In sum, our results showed no obvious genetic effects of habitat fragmentation due to recent (artificial) or past (natural) island formation. Rather, they highlight the importance of gene flow (most likely via seed) in maintaining genetic variation and preventing inter-population differentiation in the face of habitat ‘insularization' at different temporal and spatial scales. PMID:25515015

  5. Thermal safety characterization and explosion violence of energetic materials

    NASA Astrophysics Data System (ADS)

    Hsu, Peter; Hust, Gary; Pagoria, Philip; Fried, Larry

    2015-06-01

    Some energetic materials could thermally explode at fairly low temperatures (<100 C) and the violence from thermal explosion may cause a significant damage. Thus understanding the response of energetic material to thermal events is very important for the storage and handling of energetic materials. Over the last few decades, there has been considerable research effort on the thermal decomposition and thermal explosion violence of energetic materials at elevated temperatures in different sample geometries and confinements. Among them, the ODTX system is an interesting option due to its sample requirement and easiness for data modeling. It has been used since 1970s for cook-off study at LLNL. It generates 3 technical data: (1) lowest temperature at which thermal explosion would occur (threshold temperature, Til) , (2) times to thermal explosion at temperature above Til, for the calculation of activation energy and frequency factor; and (3) thermal explosion violence. In this paper, we will present some recent ODTX experimental data of several new energetic materials as well as gas pressure data at elevated temperature.

  6. A comparative study on genetic effects of artificial and natural habitat fragmentation on Loropetalum chinense (Hamamelidaceae) in Southeast China.

    PubMed

    Yuan, N; Comes, H P; Cao, Y N; Guo, R; Zhang, Y H; Qiu, Y X

    2015-06-01

    Elucidating the demographic and landscape features that determine the genetic effects of habitat fragmentation has become fundamental to research in conservation and evolutionary biology. Land-bridge islands provide ideal study areas for investigating the genetic effects of habitat fragmentation at different temporal and spatial scales. In this context, we compared patterns of nuclear microsatellite variation between insular populations of a shrub of evergreen broad-leaved forest, Loropetalum chinense, from the artificially created Thousand-Island Lake (TIL) and the Holocene-dated Zhoushan Archipelago of Southeast China. Populations from the TIL region harboured higher levels of genetic diversity than those from the Zhoushan Archipelago, but these differences were not significant. There was no correlation between genetic diversity and most island features, excepting a negative effect of mainland-island distance on allelic richness and expected heterozygosity in the Zhoushan Archipelago. In general, levels of gene flow among island populations were moderate to high, and tests of alternative models of population history strongly favoured a gene flow-drift model over a pure drift model in each region. In sum, our results showed no obvious genetic effects of habitat fragmentation due to recent (artificial) or past (natural) island formation. Rather, they highlight the importance of gene flow (most likely via seed) in maintaining genetic variation and preventing inter-population differentiation in the face of habitat 'insularization' at different temporal and spatial scales.

  7. Metastasis is regulated via microRNA-200/ZEB1 axis control of tumor cell PD-L1 expression and intratumoral immunosuppression

    PubMed Central

    Goswami, Sangeeta; Cortez, Maria Angelica; Ahn, Young-Ho; Byers, Lauren A.; Zhang, Xuejun; Yi, Xiaohui; Dwyer, David; Lin, Wei; Diao, Lixia; Wang, Jing; Roybal, Jonathon; Patel, Mayuri; Ungewiss, Christin; Peng, David; Antonia, Scott; Mediavilla-Varela, Melanie; Robertson, Gordon; Suraokar, Milind; Welsh, James W.; Erez, Baruch; Wistuba, Ignacio I.; Chen, Lieping; Peng, Di; Wang, Shanshan; Ullrich, Stephen E.; Heymach, John V.; Kurie, Jonathan M.; Qin, F. Xiao-Feng

    2014-01-01

    Immunosuppression of tumor-infiltrating lymphocytes (TIL) is a common feature of advanced cancer, but its biological basis has remained obscure. We demonstrate here a molecular link between epithelial-to-mesenchymal transition (EMT) and CD8+ TIL immunosuppression, two key drivers of cancer progression. We show that microRNA-200 (miR-200), a cell-autonomous suppressor of EMT and metastasis, targets PD-L1. Moreover, ZEB1, an EMT activator and transcriptional repressor of miR-200, relieves miR-200 repression of PD-L1 on tumor cells, leading to CD8+ T cell immunosuppression and metastasis. These findings are supported by robust correlations between the EMT score, miR-200 levels and PD-L1 expression in multiple human lung cancer datasets. In addition to revealing a link between EMT and T cell dysfunction, these findings also show that ZEB1 promotes metastasis through a heretofore unappreciated cell non-autonomous mechanism, and suggest that subgroups of patients in whom malignant progression is driven by EMT activators may respond to treatment with PD-L1 antagonists. PMID:25348003

  8. HHLA2, a member of the B7 family, is expressed in human osteosarcoma and is associated with metastases and worse survival

    PubMed Central

    Koirala, Pratistha; Roth, Michael E.; Gill, Jonathan; Chinai, Jordan M.; Ewart, Michelle R.; Piperdi, Sajida; Geller, David S.; Hoang, Bang H.; Fatakhova, Yekaterina V.; Ghorpade, Maya; Zang, Xingxing; Gorlick, Richard

    2016-01-01

    Over the past four decades there have been minimal improvements in outcomes for patients with osteosarcoma. New targets and novel therapies are needed to improve outcomes for these patients. We sought to evaluate the prevalence and clinical significance of the newest immune checkpoint, HHLA2, in osteosarcoma. HHLA2 protein expression was evaluated in primary tumor specimens and metastatic disease using an osteosarcoma tumor microarray (TMA) (n = 62). The association of HHLA2 with the presence of tumor infiltrating lymphocytes (TILs) and five-year-event-free-survival were examined. HHLA2 was expressed in 68% of osteosarcoma tumors. HHLA2 was expressed in almost all metastatic disease specimens and was more prevalent than in primary specimens without known metastases (93% vs 53%, p = 0.02). TILs were present in 75% of all osteosarcoma specimens. Patients whose tumors were ≥25% or ≥50% HHLA2 positive had significantly worse five-year event-free-survival (33% vs 64%, p = 0.03 and 14% vs 59%, p = 0.02). Overall, we have shown that HHLA2 is expressed in the majority of osteosarcoma tumors and its expression is associated with metastatic disease and poorer survival. Along with previously reported findings that HHLA2 is a T cell co-inhibitor, these results suggest that HHLA2 may be a novel immunosuppressive mechanism within the osteosarcoma tumor microenvironment. PMID:27531281

  9. Stereospecificity of isotopic exchange of C-α-protons of glycine catalyzed by three PLP-dependent lyases: the unusual case of tyrosine phenol-lyase.

    PubMed

    Koulikova, Vitalia V; Zakomirdina, Lyudmila N; Gogoleva, Olga I; Tsvetikova, Marina A; Morozova, Elena A; Komissarov, Vsevolod V; Tkachev, Yaroslav V; Timofeev, Vladimir P; Demidkina, Tatyana V; Faleev, Nicolai G

    2011-11-01

    A comparative study of the kinetics and stereospecificity of isotopic exchange of the pro-2R- and pro-2S protons of glycine in (2)H(2)O under the action of tyrosine phenol-lyase (TPL), tryptophan indole-lyase (TIL) and methionine γ-lyase (MGL) was undertaken. The kinetics of exchange was monitored using both (1)H- and (13)C-NMR. In the three compared lyases the stereospecificities of the main reactions with natural substrates dictate orthogonal orientation of the pro-2R proton of glycine with respect to the cofactor pyridoxal 5'-phosphate (PLP) plane. Consequently, according to Dunathan's postulate with all the three enzymes pro-2R proton should exchange faster than does the pro-2S one. In fact the found ratios of 2R:2S reactivities are 1:20 for TPL, 108:1 for TIL, and 1,440:1 for MGL. Thus, TPL displays an unprecedented inversion of stereospecificity. A probable mechanism of the observed phenomenon is suggested, which is based on the X-ray data for the quinonoid intermediate, formed in the reaction of TPL with L-alanine. The mechanism implies different conformational changes in the active site upon binding of glycine and alanine. These changes can lead to relative stabilization of either the neutral amino group, accepting the α-proton, or the respective ammonium group, which is formed after the proton abstraction.

  10. Regulatory T cells, especially ICOS+ FOXP3+ regulatory T cells, are increased in the hepatocellular carcinoma microenvironment and predict reduced survival

    PubMed Central

    Tu, Jian-Fei; Ding, Ya-Hui; Ying, Xi-Hui; Wu, Fa-Zong; Zhou, Xin-Mu; Zhang, Deng-Ke; Zou, Hai; Ji, Jian-Song

    2016-01-01

    Hepatocellular carcinoma (HCC) is a common malignant tumour, especially in Asia. Its prognosis is poor, and there are limited methods for predicting patient survival. This study was carried out to analyse the prognostic value of tumour-infiltrating lymphocytes (TILs), especially regulatory T cells (Tregs), in HCC patients. TILs were analysed in 57 randomly selected HCC patients. The prognostic effects of groups with high and low numbers were evaluated by the Kaplan-Meier and Cox model analyses. Although higher densities of CD3+, CD4+, and CD8+ cytotoxic lymphocytes (CTLs) as well as CD56+ NK cells and CD68+ macrophages were observed in peritumoural tissue, increased numbers of forkhead/winged helix transcription factor P3+ (FOXP3+) Tregs were found in intratumoural tissue. Additionally, regarding ICOS+ FOXP3+ Tregs, an increased prevalence in carcinoma was not only associated with the absolute number but also with the percentage of FOXP3+ cells. Higher Treg levels in tumour tissues indicated a worse prognosis, and the FOXP3+ Tregs/CD4+ T cells ratio was an independent prognostic factor for OS. Therefore, FOXP3+ Tregs, especially ICOS+ FOXP3+ Tregs, contribute to the immunosuppressive HCC microenvironment. High tumour-infiltrating Tregs are thought to be an unfavourable prognostic indicator of HCC. PMID:27725696

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

    PubMed

    Contreras-Sandoval, Ana M; Merino, María; Vasquez, Marcos; Trocóniz, Iñaki F; Berraondo, Pedro; Garrido, María J

    2016-11-22

    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.

  12. Crucial Contributions by T Lymphocytes (Effector, Regulatory, and Checkpoint Inhibitor) and Cytokines (TH1, TH2, and TH17) to a Pathological Complete Response Induced by Neoadjuvant Chemotherapy in Women with Breast Cancer

    PubMed Central

    Verma, Chandan; Eremin, Jennifer M.; Cowley, Gerard; Ilyas, Mohammed; Eremin, Oleg

    2016-01-01

    The tumour microenvironment consists of malignant cells, stroma, and immune cells. Prominent tumour-infiltrating lymphocytes (TILs) in breast cancer are associated with a good prognosis and are predictors of a pathological complete response (pCR) with neoadjuvant chemotherapy (NAC). The contribution of different T effector/regulatory cells and cytokines to tumour cell death with NAC requires further characterisation and was investigated in this study. Breast tumours from 33 women with large and locally advanced breast cancers undergoing NAC were immunohistochemically (intratumoural, stromal) assessed for T cell subsets and cytokine expression using labelled antibodies, employing established semiquantitative methods. Prominent levels of TILs and CD4+, CD8+, and CTLA-4+ (stromal) T cells and CD8+ : FOXP3+ ratios were associated with a significant pCR; no association was seen with FOXP3+, CTLA-4+ (intratumoural), and PD-1+ T cells. NAC significantly reduced CD4+, FOXP3+, CTLA-4+ (stromal) (concurrently blood FOXP3+, CTLA-4+ Tregs), and PD-1+ T cells; no reduction was seen with CD8+ and CTLA-4+ (intratumoural) T cells. High post-NAC tumour levels of FOXP3+ T cells, IL-10, and IL-17 were associated with a failed pCR. Our study has characterised further the contribution of T effector/regulatory cells and cytokines to tumour cell death with NAC. PMID:27777963

  13. Temperature-controlled ionic liquid-based ultrasound-assisted microextraction for preconcentration of trace quantity of cadmium and nickel by using organic ligand in artificial saliva extract of smokeless tobacco products.

    PubMed

    Arain, Sadaf Sadia; Kazi, Tasneem Gul; Arain, Asma Jabeen; Afridi, Hassan Imran; Baig, Jameel Ahmed; Brahman, Kapil Dev; Naeemullah; Arain, Salma Aslam

    2015-03-05

    A new approach was developed for the preconcentration of cadmium (Cd) and nickel (Ni) in artificial saliva extract of dry snuff (brown and black) products using temperature-controlled ionic liquid-based ultrasound-assisted dispersive liquid-liquid microextraction (TIL-UDLLμE) followed by electrothermal atomic absorption spectrometry (ETAAS). The Cd and Ni were complexed with ammonium pyrrolidinedithiocarbamate (APDC), extracted in ionic liquid drops, 1-butyl-3-methylimidazolium hexafluorophosphate [C4MIM][PF6]. The multivariate strategy was applied to estimate the optimum values of experimental variables influence the % recovery of analytes by TIL-UDLLμE method. At optimum experimental conditions, the limit of detection (3s) were 0.05 and 0.14μgL(-1) while relative standard deviations (% RSD) were 3.97 and 3.55 for Cd and Ni respectively. After extraction, the enhancement factors (EF) were 87 and 79 for Cd and Ni, respectively. The RSD for six replicates of 10μgL(-1) Cd and Ni were 3.97% and 3.55% respectively. To validate the proposed method, certified reference material (CRM) of Virginia tobacco leaves was analyzed, and the determined values of Cd and Ni were in good agreement with the certified values. The concentration of Cd and Ni in artificial saliva extracts corresponds to 39-52% and 21-32%, respectively, of the total contents of both elements in dry brown and black snuff products.

  14. Effects of Urechis unicinctus juveniles on chemical characteristics of organically contaminated coastal sediment

    NASA Astrophysics Data System (ADS)

    Kang, Kyoung Ho; Zhang, Zhifeng; Kim, Jae Min; Seon, Seung Chun; Shao, Mingyu

    2010-03-01

    Biological activities of marine benthos such as burrowing and feeding may change sediment characteristics. We conducted three experiments to examine the potential of using juveniles of a spoon worm Urechis unicinctus to improve the quality of organically contaminated coastal sediment. Sediment samples were collected from a site that was heavily contaminated with organic matter (Seonso) and two sites that were clean (Myo-do, Dolsan-do). Urechis juveniles, obtained by artificial fertilization and cultured in the laboratory, were introduced to the sediment (weight 3 kg, depth 10 cm) at a density of 500 individuals per aquarium (length 50 cm, width 35 cm, height 30 cm) (Experiment 1), or at densities ranging from 100 to 900 individuals per beaker (Experiment 2). To examine how sediment contamination can be modified by the effects of Urechis, 500 individuals (per aquarium) were exposed to the Seonso contaminated sediment that had been mixed with 0-100% clean sand (Experiment 3). Each experiment lasted two months and sediment samples were collected every 15 d to determine the several indexes of sediment quality, which included acid volatile sulfide (AVS), chemical oxygen demand (COD) and total ignition loss (TIL). In Experiment 1, the existence of Urechis did not result in significant changes in quality indexes in the sediments collected from Myo-do, Dolsan-do. However, AVS, COD and TIL of the Seonso sediment all decreased significantly after co-incubation with Urechis juveniles for 30 to 45 d. Experiment 2 showed that a density of at least 300 juveniles per beaker was necessary to significantly reduce all three quality indexes, and the magnitude of reduction was positively correlated with juvenile density. Experiment 3 revealed that Urechis juveniles were effective in reducing the AVS, COD and TIL of the Seonso sediment that had been mixed with 60%, 80%, and 80% of clean sand, respectively. The results of the present study therefore indicated that juveniles of this

  15. Distribution of immune cells in head and neck cancer: CD8+ T-cells and CD20+ B-cells in metastatic lymph nodes are associated with favourable outcome in patients with oro- and hypopharyngeal carcinoma

    PubMed Central

    2009-01-01

    Background Tumour infiltrating lymphocytes (TIL) are generally considered to represent a host immune response directed against tumour antigens. TIL are also increasingly recognised as possible prognostic parameters. However, the effects observed are variable indicating that results cannot be extrapolated from type of tumour to another. Moreover, it has been suggested that primary solid tumours may be ignored by the immune system and that a meaningful immune response is only mounted in regional lymph nodes. Methods We have examined the local distribution of immune cells in tumour-related compartments in head and neck squamous cell carcinomas (HNSCC). In a second step, the prognostic impact of these cells on disease-free survival (DFS) was analysed. A total of 198 tissue cores from 33 patients were evaluated using tissue mircroarray technique and immunohistochemistry. Tumour-infiltrating immune cells were identified using antibodies specific for CD3, CD8, GranzymeB, FoxP3, CD20 and CD68 and quantified using an image analysis system. Results We demonstrate a relative expansion of FoxP3+ regulatory T-cells (Treg) and of cytotoxic T-cells among tumour infitrating T-cells. We also show that intratumoural CD20+ B-cells are significantly more frequent in metastatic deposits than in primary tumours. Furthermore, we observed a reduced number of peritumoural CD8+ T-cells in metastatic lymph nodes as compared to univolved regional nodes suggesting a local down-modulation of cellular immunity. All other immune cells did not show significant alterations in distribution. We did not observe an association of tumour infiltrating immune cells at the primary site with outcome. However, increased numbers of intraepithelial CD8+ TIL in metastatic tumours as well as large numbers of peritumoural B-cells in lymph node metastases were associated with favourable outcome. Unexpectedly, no effect on patient outcome was observed for Treg in any compartment. Conclusion Our results suggest that

  16. Variants in autophagy-related genes and clinical characteristics in melanoma: a population-based study.

    PubMed

    White, Kirsten A M; Luo, Li; Thompson, Todd A; Torres, Salina; Hu, Chien-An Andy; Thomas, Nancy E; Lilyquist, Jenna; Anton-Culver, Hoda; Gruber, Stephen B; From, Lynn; Busam, Klaus J; Orlow, Irene; Kanetsky, Peter A; Marrett, Loraine D; Gallagher, Richard P; Sacchetto, Lidia; Rosso, Stefano; Dwyer, Terence; Cust, Anne E; Begg, Colin B; Berwick, Marianne

    2016-11-01

    Autophagy has been linked with melanoma risk and survival, but no polymorphisms in autophagy-related (ATG) genes have been investigated in relation to melanoma progression. We examined five single-nucleotide polymorphisms (SNPs) in three ATG genes (ATG5; ATG10; and ATG16L) with known or suspected impact on autophagic flux in an international population-based case-control study of melanoma. DNA from 911 melanoma patients was genotyped. An association was identified between (GG) (rs2241880) and earlier stage at diagnosis (OR 0.47; 95% Confidence Intervals (CI) = 0.27-0.81, P = 0.02) and a decrease in Breslow thickness (P = 0.03). The ATG16L heterozygous genotype (AG) (rs2241880) was associated with younger age at diagnosis (P = 0.02). Two SNPs in ATG5 were found to be associated with increased stage (rs2245214 CG, OR 1.47; 95% CI = 1.11-1.94, P = 0.03; rs510432 CC, OR 1.84; 95% CI = 1.12-3.02, P = 0.05). Finally, we identified inverse associations between ATG5 (GG rs2245214) and melanomas on the scalp or neck (OR 0.20, 95% CI = 0.05-0.86, P = 0.03); ATG10 (CC) (rs1864182) and brisk tumor infiltrating lymphocytes (TILs) (OR 0.42; 95% CI = 0.21-0.88, P = 0.02), and ATG5 (CC) (rs510432) with nonbrisk TILs (OR 0.55; 95% CI = 0.34-0.87, P = 0.01). Our data suggest that ATG SNPs might be differentially associated with specific host and tumor characteristics including age at diagnosis, TILs, and stage. These associations may be critical to understanding the role of autophagy in cancer, and further investigation will help characterize the contribution of these variants to melanoma progression.

  17. OSRD Reports: Bibliography and Index of Declassified Reports Having OSRD Numbers

    DTIC Science & Technology

    1947-06-01

    lillti. tD HI ,’.00 Ph ".00. OSRD 116 ’BL QI)f (I-SO. toftlllt. J. L, WId OIadoel1, "arrl. M. 11 .ortUl. phllta for til. ,roduetlOft of liquid 0...1071) H .... leo. Jr. ..,de.ta for , .. lIted Uk_ff of ,1,,1 ., • .; t"’l r: u .. .,d th. ,rtYllltion 0’ ,I .. t Injury tD the ,1,,1.,.. ’ro...34lty. I".Utul, of OpUc. ’ Ald. tD "IIIIIt vl.ton: EJt.ft.𔃺II of the _topic yl.lblllt1. ClInt to atSQA and to IOODA. Ita, 1M!. ’SO dr ... I

  18. NERF - A Computer Program for the Numerical Evaluation of Reliability Functions - Reliability Modelling, Numerical Methods and Program Documentation,

    DTIC Science & Technology

    1983-09-01

    no.t, tl J)’HS( ( (%-no)t/tl j +nO-,d )tij/ Ais (nO+(,&-no)tij/t). ...... (2.52) For given no, all structures with _no1-(td-no)t/til have been removed by...the reliability functions is that the inverse crack growth function is available, i.e., t - a’ 1 (a) (3.21) for at, a&af, where ai -a(Ti) and afb- a( t...r I ( t)ZI I P no¢ ni)P.C€ .in/f (noft)lRRn/#f(nott) nOet, not t) .,R -t I(R3 ~oet 3T3 mi n X ai ny"( Zt) ( .T 3 which leads to the expression for

  19. Word Frequency Analysis MOS: 71M. Skill Levels 1 & 2.

    DTIC Science & Technology

    1981-05-01

    2016 P»3E P> 9 O e D C o •j o 2 a^c ">n t ut-.li ro I Ul -A l...S032S 2016 *HGE cruNT« vc»a^ 3 EXTENSION 2 f’XTPC": 4 FACCS I* F..C1LITY 9 F,.IK 1 fCB 16 FICLJ • til il 1 • it Flies 1... 2016 PAGE CCJN*4 WCRD* I l«T’EP.SP 1 I’ll" ? I ’VIT1NG 1 UMK V IIW MS •) ll’rmr, 4 ItWGKH « IF’TNG JuV’iJ Hi i ill i I I • ’ •

  20. Storm Induced Changes of the Topside Ionosphere as Deduced from Incoherent Scatter Radars

    DTIC Science & Technology

    1990-01-01

    11484 Sep 18 05 16 to 1q84 Sep1, 9 05.16 UT Millstone Hill Ion teOMPO’dture (Til (K 2 4 6 8 10 12 14 16 18 20 22 24 LT 600 550 (b) j 500 450 350 b B 10 2...l 350 320 L/ 2 4 6 8 10 12 Id 16. )s 20 22 24 -1 1q84 Oct 17 00 08 o 19)84 Oct 18 00 08 UT Arecibo 22 24 2 4 6 8 0 12 14 16 8 20L 600 I (b) 450 400Y...22 24 UT 19B4 Sep iq 00.08 to 1q84 Sop 20 eZ.OB UT Arecibo Ion, tomp.o-atw-. IT1 K 1 22 24 2 4 6 8 10 12 14 16 18 20 LT 550 500J.50 (b) 45 400 350

  1. Mapping titanium and tin oxide phases using EELS: an application of independent component analysis.

    PubMed

    de la Peña, F; Berger, M-H; Hochepied, J-F; Dynys, F; Stephan, O; Walls, M

    2011-01-01

    We study materials that present challenges for conventional elemental mapping techniques and can in some cases be treated successfully using independent component analysis (ICA). In this case the material in question is obtained from a TiO₂-SiO₂ solid solution that is spinodally decomposed into TiO₂ rich-SnO₂ rich multilayers. Conventional elemental mapping is difficult because the edges most easily mapped for these elements (Ti-L, Sn-M and O-K) all have onsets within the same 80 eV range. ICA is used to separate entire spectral signals corresponding to particular material phases or molecular units rather than particular elements and is thus able to distinguish between TiO₂ and SnO₂. We show that quantification of oxide species can be performed by different methods that require extra assumptions, but nevertheless should be feasible in many cases.

  2. Intravital imaging of multicolor-labeled tumor immune microenvironment through skin-fold window chamber

    NASA Astrophysics Data System (ADS)

    Qi, Shuhong; Zhang, Zhihong

    2015-03-01

    Tumor immune microenvironment became very important for the tumor immunotherapy. There were several kinds of immune cells in tumor stromal, and they played very different roles in tumor growth. In order to observe the behaviors of multiple immune cells in tumor microenvironment and the interaction between immune cells and tumor cells at the same time, we generated a multicolor-labeled tumor immune microenvironment model. The tumor cells and immune cells were labeled by different fluorescent proteins. By using of skin-fold window chamber implanted into mice and intravital imaging technology, we could dynamically observe the different immune cells in tumor microenvironment. After data analysis from the video, we could know the behavior of TILs, DCs and Tregs in tumor immune microenvironment; furthermore, we could know these immune cells play different roles in the tumor microenvironment.

  3. Modeling of Shadows in Radar Clutter.

    DTIC Science & Technology

    1980-07-01

    0005 wAITE 46.20001 TITLE 060 WRITE 46.21331 N!.4V.NC.NTIN.N4TOUT.M4TIRL.1PAUtF.NETNGO 0007 N1.1 0006 4 2WNI*NCONV 0000 N43 .42 * PIC 0010 NA-43#HE 0011...PARTMtON PARAM7!E C EPpTI. SEP.) PCtNTS ARE %fLPCTEfW FQROS THE 0ATA UNITS. c PEA) TM" SEOU.INCF NUftERS POrN TeE CHOSEN 0A74 cjo ItSOPOPM A"OfS so2 IN...34 MCM WASIARLE FOR Iwo, CLU6Tal 00*?0 00 M.0TMI 006444 gu. 910V 006? so sOMITIN C TilPt PIC W e"RijiUO 0011 CPIOTRJI TOTALIJI 1/00141014JI 60S4Go o ca its

  4. Tall oil as additive in gas drive hydrocarbon oil recovery

    SciTech Connect

    Djabbarah, N.F.

    1988-04-12

    A miscible displacement process for recovering oil from a subterranean, oil-containing formation penetrated by at least one injection well and at least one spaced-apart production well and having fluid communication between the injection and the production wells is described comprising: (a) injecting a slug of til oil into the formation through the injection well; (b) injecting a slug of a displacing fluid into the formation through the injection well, the displacing fluid being selected from the group consisting of carbon monoxide, carbon dioxide, methane, nitrogen, air, flue gas, combustion gas and mixtures thereof, the injection of the tall oil lowering the minimum miscibility pressure of the displacing fluid in the formation oil; and (c) recovering the oil through the production well.

  5. [Genetic information from tumor-infiltrating B lymphocytes as a driver tool ("GPS") for anti-tumor T cell CARs].

    PubMed

    Kotlan, Beatrix; Csuka, Orsolya; Tóth, László; Farkas, Emil; Plótár, Vanda; Horváth, Szabolcs; Éles, Klára; Olasz, Judit; Tóth, József; Kásler, Miklós; Liszkay, Gabriella

    2016-03-02

    The rapidly growing field of gene therapy techniques to modify T cells with chimeric antigen receptors (CARs) for cancer care solutions, reached considerable achievements. However, there is an urgent need of reliable, well tolerable tumor-associated antigen specific antibodies. Tumor-infiltrating B (TIL-B) cell originated single chain Fv (scFv) gene regions could be selected with tumor specificity. DNA sequences of these antibody variable regions were subjects to get engineered into new CAR constructs. Our novel strategy harnesses tumor-infiltrating B cells' unique capacity to reveal highly tumor-associated disialylated glycosphingolipids (GD3 gangliosides). We used these human antibody fragments for generating GD3 ganglioside specific CAR gene constructs for potential usage in solid tumors.

  6. U.S. Atlantic Command Exercise Cooperative Safeguard 1997 (CS-97) After Action Report

    DTIC Science & Technology

    1997-10-01

    m t^ t^ CO CO CO a o O o o s in m (O r~ i~- CM CM CM CM CM 01 X <o m E3ro 1A-: til:: lO- H ifl> Lfl:- H tn: WMwWwM i in IO m in in fi.i\\ tu...tn ct in tn :° |^ = H :0 |cn io :*H : 1 iO ■o ■o Ct o m in in ._ o CD in •-4 m •-I v4 i c ■ « ■ fc JCQ i c ■•H...Thomas Hall Dir. Naval Reserve Association Ms Nan Borton Dir. Office of Foreign Disaster Assistance Dr. Clair Blong Dir. Of International Programs

  7. Ammonium Perchlorate Transportation Hazards Testing

    DTIC Science & Technology

    1989-04-01

    n1 t- TI T1W- r- T’ T II 0 0L 10 T. J II )0 In L11 n n i) ) C, (71 T-. d n 𔃺 ’ O 4j ’G134j L) ) 0 4j .1-10. 0 Il I-I 60 In 0 InI ni ni nini r , - r...n Q TIT a tf M L) QtQ0 O 4 4 0.14 3 41,31)-1 17 �’tIl 014 l’ 01 i. 0 - a. OC t. L 0I n nI nini n0ni nu n- n-r- rd Ifl 0n - 44 4 0o 3-00- 300- -TI

  8. Computer Graphics Research Laboratory Quarterly Progress Report Number 49, July-September 1993

    DTIC Science & Technology

    1993-11-22

    foj’ e f ",0, " Wl oIMOn of 6flnOmatl.0. q~ mttmatel(a tO fa d 1q no 0.* -Ae i.o’ ncluding thN t.me w NYll.1O’ Wae.ctuni e .4.inq "ato ’.Okdt" qaute...Ad na n* nt.flq I-P Gala -"eede and co4Iwelatqn ade r@...*nq thpoec.ti~lon of ,MOUtft.Ofl %end tooWnkM’ti tidatnq in"i awler",f P"t’~. e a’ 4ny...other aWed of tk.n coiloct Onal o1nlfl,.nat,0P fl..(o.afq ’.uqqe..on’. to, eaucintq til’. Guidoe- to *44.n qton .oeaom.alite.%’ . e Dfeedle. for IntOIAt’O

  9. Word Criticality Analysis MOS: 13F. Skill Level 1 and 2.

    DTIC Science & Technology

    1981-09-01

    W.’ s PP060. 12’?p PFGE 3 13#AMSW41SSY(Rs 7~ ,F 2-182.1I 2- 1241*I TSKIKY- P1231/6 -2-131I v &tC. 2-309,2 2-308,1 2-107,1 2-222.2 2-14.9,1 2- 11.5 2...0000 0 ON IfCFILE COPY HEADQUARTERS DATA CONTflL 11 UNITED STATES ARMY TRAINING AND DOCTRINE COMMAND FORT MONROE, VIRGINIA 23651 " S \\, / UA 4 E.U,~ I...I 77 = FTM-,~ ’T M777 i_ - ’. UM9CLW~IFIED SECUMTT CLASSIFICATION OF THIS PACE (1W.. 001. Bntwnq REPORT DOCUMENTATION PAGE 83I OM~m 4TIL(adA~daa S

  10. New Insights into the Role of the Immune Microenvironment in Breast Carcinoma

    PubMed Central

    de la Cruz-Merino, Luis; Barco-Sánchez, Antonio; Henao Carrasco, Fernando; Nogales Fernández, Esteban; Vallejo Benítez, Ana; Brugal Molina, Javier; Martínez Peinado, Antonio; Grueso López, Ana; Ruiz Borrego, Manuel; Codes Manuel de Villena, Manuel; Sánchez-Margalet, Víctor; Nieto-García, Adoración; Alba Conejo, Emilio; Casares Lagar, Noelia; Ibáñez Martínez, José

    2013-01-01

    Recently, immune edition has been recognized as a new hallmark of cancer. In this respect, some clinical trials in breast cancer have reported imppressive outcomes related to laboratory immune findings, especially in the neoadjuvant and metastatic setting. Infiltration by tumor infiltrating lymphocytes (TIL) and their subtypes, tumor-associated macrophages (TAM) and myeloid-derived suppressive cells (MDSC) seem bona fide prognostic and even predictive biomarkers, that will eventually be incorporated into diagnostic and therapeutic algorithms of breast cancer. In addition, the complex interaction of costimulatory and coinhibitory molecules on the immune synapse and the different signals that they may exert represent another exciting field to explore. In this review we try to summarize and elucidate these new concepts and knowledge from a translational perspective focusing on breast cancer, paying special attention to those aspects that might have more significance in clinical practice and could be useful to design successful therapeutic strategies in the future. PMID:23861693

  11. Liquid Nitrogen (Oxygen Simulant) Thermodynamic Vent System Test Data Analysis

    NASA Technical Reports Server (NTRS)

    Hedayat, A.; Nelson, S. L.; Hastings, L. J.; Flachbart, R. H.; Tucker, S. P.

    2005-01-01

    In designing systems for the long-term storage of cryogens in low-gravity (space) environments, one must consider the effects of thermal stratification on tank pressure that will occur due to environmental heat leaks. During low-gravity operations, a Thermodynamic Vent System (TVS) concept is expected to maintain tank pressure without propellant resettling. A series of TVS tests was conducted at NASA Marshall Space Flight Center (MSFC) using liquid nitrogen (LN2) as a liquid oxygen (LO2) simulant. The tests were performed at tank til1 levels of 90%, 50%, and 25%, and with a specified tank pressure control band. A transient one-dimensional TVS performance program is used to analyze and correlate the test data for all three fill levels. Predictions and comparisons of ullage pressure and temperature and bulk liquid saturation pressure and temperature with test data are presented.

  12. Integrated Data Analysis (IDCA) Program - PETN Class 4 Standard

    SciTech Connect

    Sandstrom, Mary M.; Brown, Geoffrey W.; Preston, Daniel N.; Pollard, Colin J.; Warner, Kirstin F.; Sorensen, Daniel N.; Remmers, Daniel L.; Shelley, Timothy J.; Reyes, Jose A.; Phillips, Jason J.; Hsu, Peter C.; Reynolds, John G.

    2012-08-01

    The Integrated Data Collection Analysis (IDCA) program is conducting a proficiency study for Small- Scale Safety and Thermal (SSST) testing of homemade explosives (HMEs). Described here are the results for impact, friction, electrostatic discharge, and differential scanning calorimetry analysis of PETN Class 4. The PETN was found to have: 1) an impact sensitivity (DH50) range of 6 to 12 cm, 2) a BAM friction sensitivity (F50) range 7 to 11 kg, TIL (0/10) of 3.7 to 7.2 kg, 3) a ABL friction sensitivity threshold of 5 or less psig at 8 fps, 4) an ABL ESD sensitivity threshold of 0.031 to 0.326 j/g, and 5) a thermal sensitivity of an endothermic feature with Tmin = ~ 141 °C, and a exothermic feature with a Tmax = ~205°C.

  13. Fasting-Mimicking Diet Reduces HO-1 to Promote T Cell-Mediated Tumor Cytotoxicity.

    PubMed

    Di Biase, Stefano; Lee, Changhan; Brandhorst, Sebastian; Manes, Brianna; Buono, Roberta; Cheng, Chia-Wei; Cacciottolo, Mafalda; Martin-Montalvo, Alejandro; de Cabo, Rafael; Wei, Min; Morgan, Todd E; Longo, Valter D

    2016-07-11

    Immune-based interventions are promising strategies to achieve long-term cancer-free survival. Fasting was previously shown to differentially sensitize tumors to chemotherapy while protecting normal cells, including hematopoietic stem and immune cells, from its toxic side effects. Here, we show that the combination of chemotherapy and a fasting-mimicking diet (FMD) increases the levels of bone marrow common lymphoid progenitor cells and cytotoxic CD8(+) tumor-infiltrating lymphocytes (TILs), leading to a major delay in breast cancer and melanoma progression. In breast tumors, this effect is partially mediated by the downregulation of the stress-responsive enzyme heme oxygenase-1 (HO-1). These data indicate that FMD cycles combined with chemotherapy can enhance T cell-dependent targeted killing of cancer cells both by stimulating the hematopoietic system and by enhancing CD8(+)-dependent tumor cytotoxicity.

  14. PREFACE: XXII International Conference on Integrable Systems and Quantum Symmetries (ISQS-22)

    NASA Astrophysics Data System (ADS)

    2014-11-01

    The XXII International Conference on Integrable Systems and Quantum symmetries (ISQS-22), organized by the Department of Mathematics, Faculty of Nuclear Sciences and Physical Engineering, Czech Technical University Prague and the Bogoliubov Laboratory of Theoretical Physics of the Joint Institute for Nuclear Research, belongs to the successful series of conferences held at the Czech Technical University which began in 1992 and is devoted to problems of mathematical physics related to the theory of integrable systems, quantum groups and quantum symmetries. During the last 20 years, each of the conferences gathered around 60 scientists from all over the world. 33 papers of plenary lectures and contributions presented at ISQS-22 are published in the present issue of Journal of Physics: Conference Series. Čestmír Burdík, Ondřej Navrátil, Severin Pošta Editors

  15. FOREWORD: XXth International Conference on Integrable Systems and Quantum Symmetries (ISQS-20)

    NASA Astrophysics Data System (ADS)

    Burdík, Čestmír; Navrátil, Ondřej; Pošta, Severin

    2013-01-01

    The XXth International Conference on Integrable Systems and Quantum Symmetries (ISQS-20), organized by the Department of Mathematics, Faculty of Nuclear Sciences and Physical Engineering, Czech Technical University, Prague, and the Bogoliubov Laboratory of Theoretical Physics of the Joint Institute for Nuclear Research, is part of the successful series of conferences held at the Czech Technical University which began in 1992, and is devoted to problems of mathematical physics related to the theory of integrable systems, quantum groups and quantum symmetries. During the last 20 years each of these conferences has gathered around 60 scientists from all over the world. 31 plenary lectures and contributions presented at ISQS-20 are published in this volume of Journal of Physics: Conference Series. Guest Editors Čestmír Burdík, Ondřej Navrátil and Severin Pošta

  16. US Army Human Engineering Laboratory Communications Survey-A Pilot Study (HELCOMS-PS).

    DTIC Science & Technology

    1984-11-01

    AD-Ai5i 434 US ARMY HUMAN ENGINEERING LABORATORY COMMUNICATIONS i/I. SURVEY-A PILOT STUDY (HELCOMS- PS )(U) RRMAMENT SYSTEMS INC ABERDEEN ND R M PHELPS...P gITT)Y ( HIE1JY)i1- PS S VtW A 1 ,’ ii ’ M TT))’ jn kj I DTI itprov, f or ’ , 1 19𔃿 , ’t r ih),I t ni-til re m l " U. S. ARMY HUMAN ENGINEERING...Final % VE-A P {1,0T STUDY (HEI :OMS- PS ) Y PERFORMING ORG. REPORT N, MREIR 7 A 8 CONTRACT OR GRANT NUMHLFP-,|j1 ,I (ell 𔃻. Phelps ( eorfi- A. Kupets, Sr

  17. USAF/SCEEE Graduate Student Summer Support Program (1982). Management and Technical Report.

    DTIC Science & Technology

    1982-10-01

    and testing of a nitric oxide Raman cell wavelength shifter is described. This device is used in conjunction with a Q-switched Nd:Glass laser system, to...ignment~ , i-l r-tit’? -t a nvtric oxid ,- Rami-n 1. -.,.%o-t-,lth l -i ft er ; 4o r;c iI4. m qv!;*, t t l, ai vt 1, ;gb n e ak no’.or qI r irl pmht pTIL... odifiCations can be easily made since the model has captured the essence of the problem. With the val id~ited rl.,del thle sinalybt can Lreate enough

  18. Evaluation of Alumina Ceramic Housings for Deep Submergence Service. Fifth Generation Housings. Part 1

    DTIC Science & Technology

    1994-03-01

    consolida- assembly. Similarly, eight hemispheres were iso - tion process results in net shrinkage of the ceramic statically pressed to yield the two...I Cr)- * .5 ! C * 0 Cic I " 45I (ID II C . LC m Ir o 0 0 0 , Ire, II -j ILJ z . U I - 4 46 I IM I CA * 09 .4 m Iso Po I I C -~LL iii II w, HLn0 00...013369 0 1X1279 0 19-1,. 0 ( 13333 0.Ŕ:38 0119I5 W 11(61527 0 (IM-19 0 (100899 (OX)40, It19(9tI-l, 11 I4561o - - )1110N4115 - - 111)(2710 - - I 11 L3

  19. Strategies to modulate the immune system in breast cancer: checkpoint inhibitors and beyond

    PubMed Central

    Migali, Cristina; Milano, Monica; Trapani, Dario; Criscitiello, Carmen; Esposito, Angela; Locatelli, Marzia; Minchella, Ida; Curigliano, Giuseppe

    2016-01-01

    Is breast cancer (BC) immunogenic? Many data suggest that it is. Many observations demonstrated the prognostic role of tumor-infiltrating lymphocytes (TILs) in triple negative (TN) and human epidermal growth factor receptor 2 (HER-2)-positive BC. TNBCs are poorly differentiated tumors with high genetic instability and very high heterogeneity. This heterogeneity enhances the ‘danger signals’ and select clone variants that could be more antigenic or, in other words, that could more strongly stimulate a host immune antitumor response. The response to chemotherapy is at least partly dependent on an immunological reaction against those tumor cells that are dying during the chemotherapy. One of the mechanisms whereby chemotherapy can stimulate the immune system to recognize and destroy malignant cells is commonly known as immunogenic cell death (ICD). ICD elicits an adaptive immune response. Which are the clinical implications of all ‘immunome’ data produced in the last years? First, validate prognostic or predictive role of TILs. Second, validate immune genomic signatures that may be predictive and prognostic in patients with TN disease. Third, incorporate an ‘immunoscore’ into traditional classification of BC, thus providing an essential prognostic and potentially predictive tool in the pathology report. Fourth, implement clinical trials for BC in the metastatic setting with drugs that target immune-cell–intrinsic checkpoints. Blockade of one of these checkpoints, cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) or the programmed cell death 1 (PD-1) receptor may provide proof of concepts for the activity of an immune-modulation approach in the treatment of a BC. PMID:27583028

  20. The Identification of Congeners and Aliens by Drosophila Larvae.

    PubMed

    Del Pino, Francisco; Jara, Claudia; Pino, Luis; Medina-Muñoz, María Cristina; Alvarez, Eduardo; Godoy-Herrera, Raúl

    2015-01-01

    We investigated the role of Drosophila larva olfactory system in identification of congeners and aliens. We discuss the importance of these activities in larva navigation across substrates, and the implications for allocation of space and food among species of similar ecologies. Wild type larvae of cosmopolitan D. melanogaster and endemic D. pavani, which cohabit the same breeding sites, used species-specific volatiles to identify conspecifics and aliens moving toward larvae of their species. D. gaucha larvae, a sibling species of D. pavani that is ecologically isolated from D. melanogaster, did not respond to melanogaster odor cues. Similar to D. pavani larvae, the navigation of pavani female x gaucha male hybrids was influenced by conspecific and alien odors, whereas gaucha female x pavani male hybrid larvae exhibited behavior similar to the D. gaucha parent. The two sibling species exhibited substantial evolutionary divergence in processing the odor inputs necessary to identify conspecifics. Orco (Or83b) mutant larvae of D. melanogaster, which exhibit a loss of sense of smell, did not distinguish conspecific from alien larvae, instead moving across the substrate. Syn97CS and rut larvae of D. melanogaster, which are unable to learn but can smell, moved across the substrate as well. The Orco (Or83b), Syn97CS and rut loci are necessary to orient navigation by D. melanogaster larvae. Individuals of the Trana strain of D. melanogaster did not respond to conspecific and alien larval volatiles and therefore navigated randomly across the substrate. By contrast, larvae of the Til-Til strain used larval volatiles to orient their movement. Natural populations of D. melanogaster may exhibit differences in identification of conspecific and alien larvae. Larval locomotion was not affected by the volatiles.

  1. Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer.

    PubMed

    Matsuzaki, Junko; Gnjatic, Sacha; Mhawech-Fauceglia, Paulette; Beck, Amy; Miller, Austin; Tsuji, Takemasa; Eppolito, Cheryl; Qian, Feng; Lele, Shashikant; Shrikant, Protul; Old, Lloyd J; Odunsi, Kunle

    2010-04-27

    NY-ESO-1 is a "cancer-testis" antigen frequently expressed in epithelial ovarian cancer (EOC) and is among the most immunogenic tumor antigens defined to date. In an effort to understand in vivo tolerance mechanisms, we assessed the phenotype and function of NY-ESO-1-specific CD8(+) T cells derived from peripheral blood lymphocytes (PBLs), tumor-infiltrating lymphocytes (TILs), and tumor-associated lymphocytes (TALs) of EOC patients with NY-ESO-1-expressing tumors, with or without humoral immunity to NY-ESO-1. Whereas NY-ESO-1-specific CD8(+) T cells were readily detectable ex vivo with tetramers in TILs and TALs of seropositive patients, they were only detectable in PBLs following in vitro stimulation. Compared with PBLs, tumor-derived NY-ESO-1-specific CD8(+) T cells demonstrated impaired effector function, preferential usage of dominant T-cell receptor, and enriched coexpression of inhibitory molecules LAG-3 and PD-1. Expression of LAG-3 and PD-1 on CD8(+) T cells was up-regulated by IL-10, IL-6 (cytokines found in tumor ascites), and tumor-derived antigen-presenting cells. Functionally, CD8(+)LAG-3(+)PD-1(+) T cells were more impaired in IFN-gamma/TNF-alpha production compared with LAG-3(+)PD-1(-) or LAG-3(-)PD-1(-) subsets. Dual blockade of LAG-3 and PD-1 during T-cell priming efficiently augmented proliferation and cytokine production by NY-ESO-1-specific CD8(+) T cells, indicating that antitumor function of NY-ESO-1-specific CD8(+) T cells could potentially be improved by therapeutic targeting of these inhibitory receptors.

  2. Plastid Proteomic Analysis in Tomato Fruit Development

    PubMed Central

    Kondo, Takanori; Dohra, Hideo; Ito, Yumihiko; Kiriiwa, Yoshikazu; Hayashi, Marina; Kamiya, Shiori; Kato, Masaya; Fujiwara, Masayuki; Fukao, Yoichiro; Kobayashi, Megumi; Nagata, Noriko; Motohashi, Reiko

    2015-01-01

    To better understand the mechanism of plastid differentiation from chloroplast to chromoplast, we examined proteome and plastid changes over four distinct developmental stages of ‘Micro-Tom’ fruit. Additionally, to discover more about the relationship between fruit color and plastid differentiation, we also analyzed and compared ‘Micro-Tom’ results with those from two other varieties, ‘Black’ and ‘White Beauty’. We confirmed that proteins related to photosynthesis remain through the orange maturity stage of ‘Micro-Tom’, and also learned that thylakoids no longer exist at this stage. These results suggest that at a minimum there are changes in plastid morphology occurring before all related proteins change. We also compared ‘Micro-Tom’ fruits with ‘Black’ and ‘White Beauty’ using two-dimensional gel electrophoresis. We found a decrease of CHRC (plastid-lipid-associated protein) and HrBP1 (harpin binding protein-1) in the ‘Black’ and ‘White Beauty’ varieties. CHRC is involved in carotenoid accumulation and stabilization. HrBP1 in Arabidopsis has a sequence similar to proteins in the PAP/fibrillin family. These proteins have characteristics and functions similar to lipocalin, an example of which is the transport of hydrophobic molecules. We detected spots of TIL (temperature-induced lipocalin) in 2D-PAGE results, however the number of spots and their isoelectric points differed between ‘Micro-Tom’ and ‘Black’/‘White Beauty’. Lipocalin has various functions including those related to environmental stress response, apoptosis induction, membrane formation and fixation, regulation of immune response, cell growth, and metabolism adjustment. Lipocalin related proteins such as TIL and HrBP1 could be related to the accumulation of carotenoids, fruit color and the differentiation of chromoplast. PMID:26371478

  3. Generation of autologous tumor-specific T cells for adoptive transfer based on vaccination, in vitro restimulation and CD3/CD28 dynabead-induced T cell expansion.

    PubMed

    Brimnes, Marie Klinge; Gang, Anne Ortved; Donia, Marco; Thor Straten, Per; Svane, Inge Marie; Hadrup, Sine Reker

    2012-08-01

    Adoptive cell transfer (ACT) of in vitro expanded autologous tumor-infiltrating lymphocytes (TIL) has been shown to exert therapeutic efficacy in melanoma patients. We aimed to develop an ACT protocol based on tumor-specific T cells isolated from peripheral blood and in vitro expanded by Dynabeads® ClinExVivo™CD3/CD28. We show here that the addition of an in vitro restimulation step with relevant peptides prior to bead expansion dramatically increased the proportion of tumor-specific T cells in PBMC-cultures. Importantly, peptide-pulsed dendritic cells (DCs) as well as allogeneic tumor lysate-pulsed DCs from the DC vaccine preparation could be used with comparable efficiency to peptides for in vitro restimulation, to increase the tumor-specific T-cell response. Furthermore, we tested the use of different ratios and different types of Dynabeads® CD3/CD28 and CD3/CD28/CD137 T-cell expander, for optimized expansion of tumor-specific T cells. A ratio of 1:3 of Dynabeads® CD3/CD28 T-cell expander to T cells resulted in the maximum number of tumor-specific T cells. The addition of CD137 did not improve functionality or fold expansion. Both T-cell expansion systems could generate tumor-specific T cells that were both cytotoxic and effective cytokine producers upon antigen recognition. Dynabeads®-expanded T-cell cultures shows phenotypical characteristics of memory T cells with potential to migrate and expand in vivo. In addition, they possess longer telomeres compared to TIL cultures. Taken together, we demonstrate that in vitro restimulation of tumor-specific T cells prior to bead expansion is necessary to achieve high numbers of tumor-specific T cells. This is effective and easily applicable in combination with DC vaccination, by use of vaccine-generated DCs, either pulsed with peptide or tumor-lysate.

  4. Temperature controlled ionic liquid-based dispersive micro-extraction using two ligands, for determination of aluminium in scalp hair samples of Alzheimer's patients: A multivariate study

    NASA Astrophysics Data System (ADS)

    Arain, Mariam S.; Arain, Salma A.; Kazi, Tasneem G.; Afridi, Hassan I.; Ali, Jamshaid; Naeemulllah; Arain, Sadaf S.; Brahman, Kapil Dev; Mughal, Moina Akhtar

    2015-02-01

    A green and sensitive temperature controlled dispersive liquid-liquid microextraction (TIL-DLLME) methodology based on the application of ionic liquid 1-butyl-3-methylimidazolium hexafluorophosphate, [C4mim][PF6], as an extractant solvent was proposed for the preconcentration of trace levels of aluminium (Al3+) in scalp hair samples of Alzheimer's (AD) patients, prior to analyzing by flame atomic absorption spectrometry (FAAS). The Al3+ was complexed with 8-hydrooxyquinoline (oxine) (L1) and 3,5,7,2‧-4‧ pentahydroxy flavone (morin) (L2) separately and then extracted by IL at temperature (50 ± 2.0 °C). Some effective factors that influence the TIL-DLLME efficiency such as pH, ligands concentrations, volume of IL, ionic strength, and incubation time were investigated and optimized by multivariate analysis. In the optimum experimental conditions, the limit of detection (3 s) and enhancement factor were 0.56 μg L-1, 0.64 μg L-1 and 85, 73 for both ligands, respectively. The relative standard deviation (RSD) for six replicate determinations of 100 μg L-1 Al3+ complexed with oxine and morin were found to be 3.88% and 4.74%, respectively. The developed method was validated by the analysis of certified reference material of human hair (NCSZC81002).and applied satisfactorily to the determination of Al3+ in acid digested scalp hair samples of AD patients and healthy controls. The resulted data shows significant higher level in scalp hair samples of AD male patients with related to referents of same age and socioeconomic status.

  5. The sialotranscriptome of Antricola delacruzi female ticks is compatible with non-hematophagous behavior and an alternative source of food

    PubMed Central

    Ribeiro, José Marcos C.; Labruna, Marcelo B.; Mans, Ben J.; Maruyama, Sandra Regina; Francischetti, Ivo M. B.; Barizon, Gustavo Canavaci; de Miranda Santos, Isabel K. F.

    2012-01-01

    The hosts for Antricola delacruzi ticks are insectivorous, cave-dwelling bats on which only larvae are found. The mouthparts of nymphal and adult A. delacruzi are compatible with scavenging feeding because the hypostome is small and toothless. How a single blood meal of a larva provides energy for several molts as well as for oviposition by females is not known. Adults of A. delacruzi possibly feed upon an unknown food source in bat guano, a substrate on which nymphal and adult stages are always found. Guano produced by insectivorous bats contains twice the amount of protein and 60 times the amount of iron as beef. In addition, bacteria and chitin-rich fungi proliferate on guano. Comparative data on the transcriptome of the salivary glands of A. delacruzi is nonexistent and would help to understand the physiological adaptations of salivary glands that accompany different sources of food as well as the steps taken by the Acari towards haematophagy, believed to have evolved from scavenging dead animals. Annotation of the transcriptome of salivary glands from female instars of A. delacruzi collected on guano categorized 5.7% of the clusters of expressed genes as putative secreted proteins. They included abundantly expressed TIL domain-containing proteins (possible anti-microbials), an abundantly expressed protein similar to a serum amyloid found in the sialotranscriptomes of Ornithodoros spp., a savignygrin, a family of mucin/peritrophin/cuticle-like proteins, antimicrobials and an HIV envelope-like glycoprotein also found in soft ticks. When comparing the transcriptome of A. delacruzi with those of blood-feeding female soft and hard ticks some notable differences were observed; they consisted of the following transcripts over- or under-represented or absent in the sialotranscriptome of A. delacuzi that may reflect its source of food: ferritin, mucins with chitin-binding domains and TIL domain-containing proteins versus lipocalins, basic tail proteins

  6. Induced Pluripotent Stem Cells: Challenges and Opportunities for Cancer Immunotherapy

    PubMed Central

    Sachamitr, Patty; Hackett, Simon; Fairchild, Paul Jonathan

    2014-01-01

    Despite recent advances in cancer treatment over the past 30 years, therapeutic options remain limited and do not always offer a cure for malignancy. Given that tumor-associated antigens (TAA) are, by definition, self-proteins, the need to productively engage autoreactive T cells remains at the heart of strategies for cancer immunotherapy. These have traditionally focused on the administration of autologous monocyte-derived dendritic cells (moDC) pulsed with TAA, or the ex vivo expansion and adoptive transfer of tumor-infiltrating lymphocytes (TIL) as a source of TAA-specific cytotoxic T cells (CTL). Although such approaches have shown some efficacy, success has been limited by the poor capacity of moDC to cross present exogenous TAA to the CD8+ T-cell repertoire and the potential for exhaustion of CTL expanded ex vivo. Recent advances in induced pluripotency offer opportunities to generate patient-specific stem cell lines with the potential to differentiate in vitro into cell types whose properties may help address these issues. Here, we review recent success in the differentiation of NK cells from human induced pluripotent stem (iPS) cells as well as minor subsets of dendritic cells (DCs) with therapeutic potential, including CD141+XCR1+ DC, capable of cross presenting TAA to naïve CD8+ T cells. Furthermore, we review recent progress in the use of TIL as the starting material for the derivation of iPSC lines, thereby capturing their antigen specificity in a self-renewing stem cell line, from which potentially unlimited numbers of naïve TAA-specific T cells may be differentiated, free of the risks of exhaustion. PMID:24860566

  7. Characterizing the immune microenvironment of malignant peripheral nerve sheath tumor by PD-L1 expression and presence of CD8+ tumor infiltrating lymphocytes

    PubMed Central

    Shurell, Elizabeth; Singh, Arun S.; Crompton, Joseph G.; Jensen, Sarah; Li, Yunfeng; Dry, Sarah; Nelson, Scott; Chmielowski, Bartosz; Bernthal, Nicholas; Federman, Noah; Tumeh, Paul; Eilber, Fritz C.

    2016-01-01

    Background Malignant peripheral nerve sheath tumor (MPNST) is an aggressive sarcoma with few treatment options. Tumor immune state has not been characterized in MPNST, and is important in determining response to immune checkpoint blockade. Our aim was to evaluate the expression of programmed death-ligand 1 (PD-L1), programmed cell death protein 1 (PD-1), and presence of CD8+ tumor infiltrating lymphocytes (TILs) in MPNST, and correlate these findings with clinical behavior and outcome. Results PD-L1 staining of at least 1% was seen in 0/20 nerves, 2/68 benign lesions and 9/53 MPNST. Two of 68 benign lesions and 7/53 (13%) MPNST had at least 5% PD-L1 staining. CD8 staining of at least 5% was seen in 1/20 (5%) nerves, 45/68 (66%) benign lesions and 30/53 (57%) MPNST. PD-L1 was statistically more prevalent in MPNST than both nerves and benign lesions (p=0.049 and p=0.008, respectively). Expression of PD-1 was absent in all tissue specimens. There was no correlation of PD-L1 or CD8 expression with disease state (primary versus metastatic) or patient survival. Methods A comprehensive PNST tissue microarray was created from 141 surgical specimens including primary, recurrent, and metastatic MPNST (n=53), neurofibromas (n=57), schwannoma (n=11), and normal nerve (n=20). Cores were stained in triplicate for PD-L1, PD-1, and CD8, and expression compared between tumor types. These data were then examined for survival correlates in 35 patients with primary MPNST. Conclusions MPNST is characterized by low PD-L1 and absent PD-1 expression with significant CD8+ TIL presence. MPNST immune microenvironment does not correlate with patient outcome. PMID:27588404

  8. PD-1 expression conditions T cell avidity within an antigen-specific repertoire

    PubMed Central

    Simon, Sylvain; Vignard, Virginie; Florenceau, Laetitia; Dreno, B.; Khammari, A.; Lang, F.; Labarriere, N.

    2016-01-01

    ABSTRACT Despite its negative regulatory role on tumor-specific T cells, Programmed cell death 1 (PD-1) is also a marker of activated tumor-infiltrating T cells. In cancer, PD-1 blockade partially reverses T cell dysfunction allowing the amplification of tumor reactive T cells. Here, we investigated the role of PD-1 signaling on effector/memory human T cells specific for shared melanoma antigens, derived from blood. We documented for the first time the existence of melanoma-specific T cell clones unable to express PD-1. This stable feature was due to the persistent methylation of the PDCD1 promoter. These PD-1neg clones were of lower avidity than their PD-1pos counterparts, suggesting that high-affinity-specific T cell clones unable to express PD-1 are not or rarely present in peripheral blood, as they are probably eliminated by negative selection, due to their high reactivity. We also documented the existence of such PD-1neg T cell clones in melanoma tumor-infiltrating lymphocytes (TIL), which also exhibited a lower functional avidity than PD-1pos TIL clones. This clearly shows that PD-1 expression identifies antigen-specific T cell clonotypes of high functional avidity. Finally, we demonstrated that PD-1 blockade during the in vitro selection process of Melan-A-specific T cells favored the amplification of higher avidity T cell clonotypes. This preferential amplification of high-avidity memory T cells upon PD-1 blockade resonates with the expansion of reactive T cells, including neo-antigen-specific T cells observed in anti-PD-1-treated patients. This feature should also be a useful biomarker of clinical efficiency, while providing new insights for adoptive transfer treatments. PMID:26942093

  9. Importance of CD200 expression by tumor or host cells to regulation of immunotherapy in a mouse breast cancer model.

    PubMed

    Curry, Anna; Khatri, Ismat; Kos, Olha; Zhu, Fang; Gorczynski, Reginald

    2017-01-01

    Cell-surface CD200 expression by mouse EMT6 breast tumor cells increased primary tumor growth and metastasis to the draining lymph nodes (DLN) in normal (WT) BALB/c female recipients, while lack of CD200R1 expression in a CD200R1-/- host negated this effect. Silencing CD200 expression in EMT6siCD200 tumor cells also reduced their ability to grow and metastasize in WT animals. The cellular mechanisms responsible for these effects have not been studied in detail. We report characterization of tumor infiltrating (TILs) and draining lymph node (DLN) cells in WT and CD200-/- BALB/c mice, receiving WT tumor cells, or EMT6 lacking CD200 expression (EMT6siCD200 cells). Our data show an important correlation with augmented CD8+ cytotoxic T cells and resistance to tumor growth in mice lacking exposure (on either host cells or tumor) to the immunoregulatory molecule CD200. Confirmation of the importance of such CD8+ cells came from monitoring tumor growth and characterization of the TILs and DLN cells in WT mice challenged with EMT6 and EMT6siCD200 tumors and treated with CD8 and CD4 depleting antibodies. Finally, we have assessed the mechanisms(s) whereby addition of metformin as an augmenting chemotherapeutic agent in CD200-/- animals given EMT6 tumors and treated with a previously established immunotherapy regime can increase host resistance. Our data support the hypothesis that increased autophagy in the presence of metformin increases CD8+ responses and tumor resistance, an effect attenuated by the autophagy inhibitor verteporfin.

  10. Clonal expansion of antitumor T cells in breast cancer correlates with response to neoadjuvant chemotherapy

    PubMed Central

    Park, Jae-Hyun; Jang, Miran; Tarhan, Yunus Emre; Katagiri, Toyomasa; Sasa, Mitsunori; Miyoshi, Yasuo; Kalari, Krishna R.; Suman, Vera J.; Weinshilboum, Richard; Wang, Liewei; Boughey, Judy C.; Goetz, Matthew P.; Nakamura, Yusuke

    2016-01-01

    The immune microenvironment of tumor plays a critical role in therapeutic responses to chemotherapy. Cancer tissues are composed of a complex network between anti-tumor and pro-tumor immune cells and molecules; therefore a comprehensive analysis of the tumor immune condition is imperative for better understanding of the roles of the immune microenvironment in anticancer treatment response. In this study, we performed T cell receptor (TCR) repertoire analysis of tumor infiltrating T cells (TILs) in cancer tissues of pre- and post-neoadjuvant chemotherapy (NAC) from 19 breast cancer patients; five cases showed CR (complete response), ten showed PR (partial response), and four showed SD/PD (stable disease/progressive disease) to the treatment. From the TCR sequencing results, we calculated the diversity index of the TCRβ chain and found that clonal expansion of TILs could be detected in patients who showed CR or PR to NAC. Noteworthy, the diversity of TCR was further reduced in the post-NAC tumors of CR patients. Our quantitative RT-PCR also showed that expression ratio of CD8/Foxp3 was significantly elevated in the post-NAC tumors of CR cases (p=0.0032), indicating that antitumor T cells were activated and enriched in these tumors. Collectively, our findings suggest that the clonal expansion of antitumor T cells may be a critical factor associated with response to chemotherapy and that their TCR sequences might be applicable for the development of TCR-engineered T cells treatment for individual breast cancer patients when their tumors relapse. PMID:27278091

  11. Genome-wide identification and immune response analysis of serine protease inhibitor genes in the silkworm, Bombyx mori.

    PubMed

    Zhao, Ping; Dong, Zhaoming; Duan, Jun; Wang, Genhong; Wang, Lingyan; Li, Youshan; Xiang, Zhonghuai; Xia, Qingyou

    2012-01-01

    In most insect species, a variety of serine protease inhibitors (SPIs) have been found in multiple tissues, including integument, gonad, salivary gland, and hemolymph, and are required for preventing unwanted proteolysis. These SPIs belong to different families and have distinct inhibitory mechanisms. Herein, we predicted and characterized potential SPI genes based on the genome sequences of silkworm, Bombyx mori. As a result, a total of eighty SPI genes were identified in B. mori. These SPI genes contain 10 kinds of SPI domains, including serpin, Kunitz_BPTI, Kazal, TIL, amfpi, Bowman-Birk, Antistasin, WAP, Pacifastin, and alpha-macroglobulin. Sixty-three SPIs contain single SPI domain while the others have at least two inhibitor units. Some SPIs also contain non-inhibitor domains for protein-protein interactions, including EGF, ADAM_spacer, spondin_N, reeler, TSP_1 and other modules. Microarray analysis showed that fourteen SPI genes from lineage-specific TIL family and Group F of serpin family had enriched expression in the silk gland. The roles of SPIs in resisting pathogens were investigated in silkworms when they were infected by four pathogens. Microarray and qRT-PCR experiments revealed obvious up-regulation of 8, 4, 3 and 3 SPI genes after infection with Escherichia coli, Bacillus bombysepticus, Beauveria bassiana or B. mori nuclear polyhedrosis virus (BmNPV), respectively. On the contrary, 4, 11, 7 and 9 SPI genes were down-regulated after infection with E. coli, B. bombysepticus, B. bassiana or BmNPV, respectively. These results suggested that these SPI genes may be involved in resistance to pathogenic microorganisms. These findings may provide valuable information for further clarifying the roles of SPIs in the development, immune defence, and efficient synthesis of silk gland protein.

  12. Compensatory upregulation of PD-1, LAG-3, and CTLA-4 limits the efficacy of single-agent checkpoint blockade in metastatic ovarian cancer.

    PubMed

    Huang, Ruea-Yea; Francois, Ariel; McGray, Aj Robert; Miliotto, Anthony; Odunsi, Kunle

    2017-01-01

    Tumor-associated or -infiltrating lymphocytes (TALs or TILs) co-express multiple immune inhibitory receptors that contribute to immune suppression in the ovarian tumor microenvironment (TME). Dual blockade of PD-1 along with LAG-3 or CTLA-4 has been shown to synergistically enhance T-cell effector function, resulting in a delay in murine ovarian tumor growth. However, the mechanisms underlying this synergy and the relative contribution of other inhibitory receptors to immune suppression in the ovarian TME are unknown. Here, we report that multiple immune checkpoints are expressed in TALs and TILs isolated from ovarian tumor-bearing mice. Importantly, blockade of PD-1, LAG-3, or CTLA-4 alone using genetic ablation or blocking antibodies conferred a compensatory upregulation of the other checkpoint pathways, potentiating their capacity for local T-cell suppression that, in turn, could be overcome through combinatorial blockade strategies. Whereas single-agent blockade led to tumor outgrowth in all animals, dual antibody blockade against PD-1/CTLA-4 or triple blockade against PD-1/LAG-3/CTLA-4 resulted in tumor-free survival in 20% of treated mice. In contrast, dual blockade of LAG-3 and CTLA-4 pathways using PD-1 knockout mice led to tumor-free survival in 40% of treated mice, suggesting a hierarchical ordering of checkpoint function. Durable antitumor immunity was most strongly associated with increased numbers of CD8(+) T cells, the frequency of cytokine-producing effector T cells, reduced frequency of Tregs and arginine-expressing monocytic myeloid-derived suppressor cells in the peritoneal TME. These data provide a basis for combinatorial checkpoint blockade in clinical intervention for ovarian cancer.

  13. Cytokine profiling of tumor interstitial fluid of the breast and its relationship with lymphocyte infiltration and clinicopathological characteristics.

    PubMed

    Espinoza, Jaime A; Jabeen, Shakila; Batra, Richa; Papaleo, Elena; Haakensen, Vilde; Timmermans Wielenga, Vera; Møller Talman, Maj-Lis; Brunner, Nils; Børresen-Dale, Anne-Lise; Gromov, Pavel; Helland, Åslaug; Kristensen, Vessela N; Gromova, Irina

    2016-01-01

    The tumor microenvironment is composed of many immune cell subpopulations and is an important factor in the malignant progression of neoplasms, particularly breast cancer (BC). However, the cytokine networks that coordinate various regulatory events within the BC interstitium remain largely uncharacterized. Moreover, the data obtained regarding the origin of cytokine secretions, the levels of secretion associated with tumor development, and the possible clinical relevance of cytokines remain controversial. Therefore, we profiled 27 cytokines in 78 breast tumor interstitial fluid (TIF) samples, 43 normal interstitial fluid (NIF) samples, and 25 matched serum samples obtained from BC patients with Luminex xMAP multiplex technology. Eleven cytokines exhibited significantly higher levels in the TIF samples compared with the NIF samples: interleukin (IL)-7, IL-10, fibroblast growth factor-2, IL-13, interferon (IFN)γ-inducible protein (IP-10), IL-1 receptor antagonist (IL-1RA), platelet-derived growth factor (PDGF)-β, IL-1β, chemokine ligand 5 (RANTES), vascular endothelial growth factor, and IL-12. An immunohistochemical analysis further demonstrated that IL-1RA, IP-10, IL-10, PDGF-β, RANTES, and VEGF are widely expressed by both cancer cells and tumor-infiltrating lymphocytes (TILs), whereas IP-10 and RANTES were preferentially abundant in triple-negative breast cancers (TNBCs) compared to Luminal A subtype cancers. The latter observation corresponds with the high level of TILs in the TNBC samples. IL-1β, IL-7, IL-10, and PDGFβ also exhibited a correlation between the TIF samples and matched sera. In a survival analysis, high levels of IL-5, a hallmark TH2 cytokine, in the TIF samples were associated with a worse prognosis. These findings have important implications for BC immunotherapy research.

  14. The Identification of Congeners and Aliens by Drosophila Larvae

    PubMed Central

    Del Pino, Francisco; Jara, Claudia; Pino, Luis; Medina-Muñoz, María Cristina; Alvarez, Eduardo; Godoy-Herrera, Raúl

    2015-01-01

    We investigated the role of Drosophila larva olfactory system in identification of congeners and aliens. We discuss the importance of these activities in larva navigation across substrates, and the implications for allocation of space and food among species of similar ecologies. Wild type larvae of cosmopolitan D. melanogaster and endemic D. pavani, which cohabit the same breeding sites, used species-specific volatiles to identify conspecifics and aliens moving toward larvae of their species. D. gaucha larvae, a sibling species of D. pavani that is ecologically isolated from D. melanogaster, did not respond to melanogaster odor cues. Similar to D. pavani larvae, the navigation of pavani female x gaucha male hybrids was influenced by conspecific and alien odors, whereas gaucha female x pavani male hybrid larvae exhibited behavior similar to the D. gaucha parent. The two sibling species exhibited substantial evolutionary divergence in processing the odor inputs necessary to identify conspecifics. Orco (Or83b) mutant larvae of D. melanogaster, which exhibit a loss of sense of smell, did not distinguish conspecific from alien larvae, instead moving across the substrate. Syn97CS and rut larvae of D. melanogaster, which are unable to learn but can smell, moved across the substrate as well. The Orco (Or83b), Syn97CS and rut loci are necessary to orient navigation by D. melanogaster larvae. Individuals of the Trana strain of D. melanogaster did not respond to conspecific and alien larval volatiles and therefore navigated randomly across the substrate. By contrast, larvae of the Til-Til strain used larval volatiles to orient their movement. Natural populations of D. melanogaster may exhibit differences in identification of conspecific and alien larvae. Larval locomotion was not affected by the volatiles. PMID:26313007

  15. Unraveling the Role of Surface Mucus-Binding Protein and Pili in Muco-Adhesion of Lactococcus lactis

    PubMed Central

    Duviau, Marie-Pierre; Meyrand, Mickael; Guérardel, Yann; Castelain, Mickaël; Loubière, Pascal; Chapot-Chartier, Marie-Pierre; Dague, Etienne; Mercier-Bonin, Muriel

    2013-01-01

    Adhesion of bacteria to mucus may favor their persistence within the gut and their beneficial effects to the host. Interactions between pig gastric mucin (PGM) and a natural isolate of Lactococcus lactis (TIL448) were measured at the single-cell scale and under static conditions, using atomic force microscopy (AFM). In parallel, these interactions were monitored at the bacterial population level and under shear flow. AFM experiments with a L. lactis cell-probe and a PGM-coated surface revealed a high proportion of specific adhesive events (60%) and a low level of non-adhesive ones (2%). The strain muco-adhesive properties were confirmed by the weak detachment of bacteria from the PGM-coated surface under shear flow. In AFM, rupture events were detected at short (100−200 nm) and long distances (up to 600−800 nm). AFM measurements on pili and mucus-binding protein defective mutants demonstrated the comparable role played by these two surface proteinaceous components in adhesion to PGM under static conditions. Under shear flow, a more important contribution of the mucus-binding protein than the pili one was observed. Both methods differ by the way of probing the adhesion force, i.e. negative force contact vs. sedimentation and normal-to-substratum retraction vs. tangential detachment conditions, using AFM and flow chamber, respectively. AFM blocking assays with free PGM or O-glycan fractions purified from PGM demonstrated that neutral oligosaccharides played a major role in adhesion of L. lactis TIL448 to PGM. This study dissects L. lactis muco-adhesive phenotype, in relation with the nature of the bacterial surface determinants. PMID:24260308

  16. Anti-PD-L1 treatment enhances antitumor effect of everolimus in a mouse model of renal cell carcinoma.

    PubMed

    Hirayama, Yukiyoshi; Gi, Min; Yamano, Shotaro; Tachibana, Hirokazu; Okuno, Takahiro; Tamada, Satoshi; Nakatani, Tatsuya; Wanibuchi, Hideki

    2016-12-01

    Immunotherapy based on blockade of the programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis has shown promising clinical activity for renal cell carcinoma (RCC) patients; however, the most effective use of these agents in combination with conventional targeted therapy remains to be resolved. Here we evaluated the therapeutic efficacy of the combination of the mTOR inhibitor everolimus (EVE) and anti-PD-L1 using an immunocompetent mouse model of RCC. We first assessed the in vitro effect of EVE on PD-L1 expression in the human 786-O and mouse RENCA RCC cell lines and found that EVE upregulated PD-L1 expression in these RCC cell lines. We then treated RENCA tumor-bearing mice with EVE and found that PD-L1 expression was also increased in tumor cells after EVE treatment. To determine the antitumor effects of EVE alone, anti-PD-L1 alone, and EVE in combination with anti-PD-L1, we evaluated their antitumor effects on RENCA tumor-bearing mice. A significant decrease in the tumor burden was observed in the EVE alone but not in the anti-PD-L1 alone treatment group compared with the control group. Importantly, the combination of EVE with anti-PD-L1 significantly reduced tumor burden compared with the EVE alone treatment, increasing tumor infiltrating lymphocytes (TILs) and the ratio of cytotoxic CD8(+) T cells to TILs. The results of the present study demonstrated that anti-PD-L1 treatment enhanced the antitumor effect of EVE in a mouse model, supporting a direct translation of this combination strategy to the clinic for the treatment of RCC.

  17. Compensatory upregulation of PD-1, LAG-3, and CTLA-4 limits the efficacy of single-agent checkpoint blockade in metastatic ovarian cancer

    PubMed Central

    Francois, Ariel; McGray, AJ Robert; Miliotto, Anthony; Odunsi, Kunle

    2017-01-01

    ABSTRACT Tumor-associated or -infiltrating lymphocytes (TALs or TILs) co-express multiple immune inhibitory receptors that contribute to immune suppression in the ovarian tumor microenvironment (TME). Dual blockade of PD-1 along with LAG-3 or CTLA-4 has been shown to synergistically enhance T-cell effector function, resulting in a delay in murine ovarian tumor growth. However, the mechanisms underlying this synergy and the relative contribution of other inhibitory receptors to immune suppression in the ovarian TME are unknown. Here, we report that multiple immune checkpoints are expressed in TALs and TILs isolated from ovarian tumor-bearing mice. Importantly, blockade of PD-1, LAG-3, or CTLA-4 alone using genetic ablation or blocking antibodies conferred a compensatory upregulation of the other checkpoint pathways, potentiating their capacity for local T-cell suppression that, in turn, could be overcome through combinatorial blockade strategies. Whereas single-agent blockade led to tumor outgrowth in all animals, dual antibody blockade against PD-1/CTLA-4 or triple blockade against PD-1/LAG-3/CTLA-4 resulted in tumor-free survival in 20% of treated mice. In contrast, dual blockade of LAG-3 and CTLA-4 pathways using PD-1 knockout mice led to tumor-free survival in 40% of treated mice, suggesting a hierarchical ordering of checkpoint function. Durable antitumor immunity was most strongly associated with increased numbers of CD8+ T cells, the frequency of cytokine-producing effector T cells, reduced frequency of Tregs and arginine-expressing monocytic myeloid-derived suppressor cells in the peritoneal TME. These data provide a basis for combinatorial checkpoint blockade in clinical intervention for ovarian cancer. PMID:28197366

  18. Temperature controlled ionic liquid-based dispersive micro-extraction using two ligands, for determination of aluminium in scalp hair samples of Alzheimer's patients: a multivariate study.

    PubMed

    Arain, Mariam S; Arain, Salma A; Kazi, Tasneem G; Afridi, Hassan I; Ali, Jamshaid; Naeemulllah; Arain, Sadaf S; Brahman, Kapil Dev; Mughal, Moina Akhtar

    2015-02-25

    A green and sensitive temperature controlled dispersive liquid-liquid microextraction (TIL-DLLME) methodology based on the application of ionic liquid 1-butyl-3-methylimidazolium hexafluorophosphate, [C4mim][PF6], as an extractant solvent was proposed for the preconcentration of trace levels of aluminium (Al(3+)) in scalp hair samples of Alzheimer's (AD) patients, prior to analyzing by flame atomic absorption spectrometry (FAAS). The Al(3+) was complexed with 8-hydrooxyquinoline (oxine) (L1) and 3,5,7,2'-4' pentahydroxy flavone (morin) (L2) separately and then extracted by IL at temperature (50±2.0°C). Some effective factors that influence the TIL-DLLME efficiency such as pH, ligands concentrations, volume of IL, ionic strength, and incubation time were investigated and optimized by multivariate analysis. In the optimum experimental conditions, the limit of detection (3s) and enhancement factor were 0.56 μg L(-1), 0.64 μg L(-1) and 85, 73 for both ligands, respectively. The relative standard deviation (RSD) for six replicate determinations of 100 μg L(-1) Al(3+) complexed with oxine and morin were found to be 3.88% and 4.74%, respectively. The developed method was validated by the analysis of certified reference material of human hair (NCSZC81002).and applied satisfactorily to the determination of Al(3+) in acid digested scalp hair samples of AD patients and healthy controls. The resulted data shows significant higher level in scalp hair samples of AD male patients with related to referents of same age and socioeconomic status.

  19. T-lymphocyte homing: an underappreciated yet critical hurdle for successful cancer immunotherapy.

    PubMed

    Sackstein, Robert; Schatton, Tobias; Barthel, Steven R

    2017-03-27

    Advances in cancer immunotherapy have offered new hope for patients with metastatic disease. This unfolding success story has been exemplified by a growing arsenal of novel immunotherapeutics, including blocking antibodies targeting immune checkpoint pathways, cancer vaccines, and adoptive cell therapy (ACT). Nonetheless, clinical benefit remains highly variable and patient-specific, in part, because all immunotherapeutic regimens vitally hinge on the capacity of endogenous and/or adoptively transferred T-effector (Teff) cells, including chimeric antigen receptor (CAR) T cells, to home efficiently into tumor target tissue. Thus, defects intrinsic to the multi-step T-cell homing cascade have become an obvious, though significantly underappreciated contributor to immunotherapy resistance. Conspicuous have been low intralesional frequencies of tumor-infiltrating T-lymphocytes (TILs) below clinically beneficial threshold levels, and peripheral rather than deep lesional TIL infiltration. Therefore, a Teff cell 'homing deficit' may arguably represent a dominant factor responsible for ineffective immunotherapeutic outcomes, as tumors resistant to immune-targeted killing thrive in such permissive, immune-vacuous microenvironments. Fortunately, emerging data is shedding light into the diverse mechanisms of immune escape by which tumors restrict Teff cell trafficking and lesional penetrance. In this review, we scrutinize evolving knowledge on the molecular determinants of Teff cell navigation into tumors. By integrating recently described, though sporadic information of pivotal adhesive and chemokine homing signatures within the tumor microenvironment with better established paradigms of T-cell trafficking under homeostatic or infectious disease scenarios, we seek to refine currently incomplete models of Teff cell entry into tumor tissue. We further summarize how cancers thwart homing to escape immune-mediated destruction and raise awareness of the potential impact of immune

  20. Activation of aryl hydrocarbon receptor promotes invasion of clear cell renal cell carcinoma and is associated with poor prognosis and cigarette smoke.

    PubMed

    Ishida, Masaru; Mikami, Shuji; Shinojima, Toshiaki; Kosaka, Takeo; Mizuno, Ryuichi; Kikuchi, Eiji; Miyajima, Akira; Okada, Yasunori; Oya, Mototsugu

    2015-07-15

    Although exposure to environmental pollutants is one of the risk factors for renal cell carcinoma (RCC), its relationship with carcinogenesis and the progression of RCC remains unknown. The present study was designed to elucidate the role of the aryl hydrocarbon receptor (AhR), a major mediator of carcinogenesis caused by environmental pollutants, in the progression of RCC. The expression of AhR was investigated in 120 patients with RCC using immunohistochemistry, and its relationship with clinicopathological parameters and prognoses was statistically analyzed. RCC cell lines were exposed to indirubin or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), AhR ligands, to activate the AhR pathway, or were transfected with small interfering RNA (siRNA) for AhR. The expression of the AhR target genes CYP1A1 and CYP1B1, matrix metalloproteinases (MMPs), and invasion through Matrigel(TM) were then examined. AhR was predominantly expressed in the nuclei of high-grade clear cell RCC (ccRCC) and tumor-infiltrating lymphocytes (TILs), and its expression levels in cancer cells and TILs correlated with the pathological tumor stage and histological grade. A multivariate Cox analysis revealed that the strong expression of AhR in cancer cells was a significant and independent predictor of disease-specific survival. AhR ligands up-regulated the expression of AhR and CYPs and promoted invasion by up-regulating MMPs. Furthermore, siRNA for AhR down-regulated CYPs, and inhibited cancer cell invasion together with the down-regulation of MMPs. These results suggest that AhR regulates the invasion of ccRCC and may be involved in tumor immunity. Therefore, inhibiting the activation of AhR may represent a potentially attractive therapeutic target for ccRCC patients.

  1. Importance of CD200 expression by tumor or host cells to regulation of immunotherapy in a mouse breast cancer model

    PubMed Central

    Curry, Anna; Khatri, Ismat; Kos, Olha; Zhu, Fang; Gorczynski, Reginald

    2017-01-01

    Cell-surface CD200 expression by mouse EMT6 breast tumor cells increased primary tumor growth and metastasis to the draining lymph nodes (DLN) in normal (WT) BALB/c female recipients, while lack of CD200R1 expression in a CD200R1-/- host negated this effect. Silencing CD200 expression in EMT6siCD200 tumor cells also reduced their ability to grow and metastasize in WT animals. The cellular mechanisms responsible for these effects have not been studied in detail. We report characterization of tumor infiltrating (TILs) and draining lymph node (DLN) cells in WT and CD200-/- BALB/c mice, receiving WT tumor cells, or EMT6 lacking CD200 expression (EMT6siCD200 cells). Our data show an important correlation with augmented CD8+ cytotoxic T cells and resistance to tumor growth in mice lacking exposure (on either host cells or tumor) to the immunoregulatory molecule CD200. Confirmation of the importance of such CD8+ cells came from monitoring tumor growth and characterization of the TILs and DLN cells in WT mice challenged with EMT6 and EMT6siCD200 tumors and treated with CD8 and CD4 depleting antibodies. Finally, we have assessed the mechanisms(s) whereby addition of metformin as an augmenting chemotherapeutic agent in CD200-/- animals given EMT6 tumors and treated with a previously established immunotherapy regime can increase host resistance. Our data support the hypothesis that increased autophagy in the presence of metformin increases CD8+ responses and tumor resistance, an effect attenuated by the autophagy inhibitor verteporfin. PMID:28234914

  2. Local morphologic scale: application to segmenting tumor infiltrating lymphocytes in ovarian cancer TMAs

    NASA Astrophysics Data System (ADS)

    Janowczyk, Andrew; Chandran, Sharat; Feldman, Michael; Madabhushi, Anant

    2011-03-01

    classes based on local structural properties. In this paper, we apply LMS to the specific problem of classifying regions of interest in Ovarian Cancer (OCa) histology images as either tumor or stroma. This approach is used to classify lymphocytes as either tumor infiltrating lymphocytes (TILs) or non-TILs; the presence of TILs having been identified as an important prognostic indicator for disease outcome in patients with OCa. We present preliminary results on the tumor/stroma classification of 11,000 randomly selected locations of interest, across 11 images obtained from 6 patient studies. Using a Probabilistic Boosting Tree (PBT), our supervised classifier yielded an area under the receiver operation characteristic curve (AUC) of 0.8341 +/-0.0059 over 5 runs of randomized cross validation. The average LMS computation time at every spatial location for an image patch comprising 2000 pixels with 24 particles at every location was only 18s.

  3. The sialotranscriptome of Antricola delacruzi female ticks is compatible with non-hematophagous behavior and an alternative source of food.

    PubMed

    Ribeiro, José Marcos C; Labruna, Marcelo B; Mans, Ben J; Maruyama, Sandra Regina; Francischetti, Ivo M B; Barizon, Gustavo Canavaci; de Miranda Santos, Isabel K F

    2012-05-01

    The hosts for Antricola delacruzi ticks are insectivorous, cave-dwelling bats on which only larvae are found. The mouthparts of nymphal and adult A. delacruzi are compatible with scavenging feeding because the hypostome is small and toothless. How a single blood meal of a larva provides energy for several molts as well as for oviposition by females is not known. Adults of A. delacruzi possibly feed upon an unknown food source in bat guano, a substrate on which nymphal and adult stages are always found. Guano produced by insectivorous bats contains twice the amount of protein and 60 times the amount of iron as beef. In addition, bacteria and chitin-rich fungi proliferate on guano. Comparative data on the transcriptome of the salivary glands of A. delacruzi is nonexistent and would help to understand the physiological adaptations of salivary glands that accompany different sources of food as well as the steps taken by the Acari toward haematophagy, believed to have evolved from scavenging dead animals. Annotation of the transcriptome of salivary glands from female instars of A. delacruzi collected on guano categorized 5.7% of the clusters of expressed genes as putative secreted proteins. They included abundantly expressed TIL-domain-containing proteins (possible anti-microbials), an abundantly expressed protein similar to a serum amyloid found in the sialotranscriptomes of Ornithodoros spp., a savignygrin, a family of mucin/peritrophin/cuticle-like proteins, anti-microbials and an HIV envelope-like glycoprotein also found in soft ticks. When comparing the transcriptome of A. delacruzi with those of blood-feeding female soft and hard ticks some notable differences were observed; they consisted of the following transcripts over- or under-represented or absent in the sialotranscriptome of A. delacruzi that may reflect its source of food: ferritin, mucins with chitin-binding domains and TIL-domain-containing proteins versus lipocalins, basic tail proteins

  4. Timescales of transport from the troposphere into the lowermost stratosphere

    NASA Astrophysics Data System (ADS)

    Boenisch, Harald; Hoor, Peter; Wernli, Heini

    2010-05-01

    The lowermost stratosphere (LMS) as part of the extratropical UTLS can be divided into dynamically and chemically distinct regions. A layer of mixed tropospheric and stratospheric tracer characteristics in the proximity of the extratropical tropopause: the extratropical tropopause transition layer (ExTL). This chemically distinct layer roughly coincides with a layer of strongly enhanced thermal stratification: the tropopause inversion layer (TIL) (Birner, 2006). The LMS above the ExTL, also named the free LMS (Bönisch et al., 2009), is less coupled to the local extratropical troposphere. Simultaneous in-situ measurements of CO2 and SF6 have been used to calculate mean transport time from the troposphere to the measurement location in the free LMS (Bönisch et al., 2009) which is on the order of months. In this study, we will use backward trajectories driven by operational ECMWF analyses wind fields to investigate the TST timescales into the LMS using the LAGRANTO scheme (Wernli and Davies, 1997). We applied a statistical data set of trajectories, which were initialized on isentropes above the 2 PVU surface up to 450K and calculated backward over 270 days (9 month) for our analysis. The results will be compared with the results from mass balance studies based on in-situ observations (Hoor et al., 2005; Bönisch et al., 2009). Furthermore, a focus is on the role of timescales of TIL formation in the LMS. Birner, T.: Fine-scale structure of the extratropical tropopause region, Journal of Geophysical Research-Atmospheres, 111, Doi 10.1029/2005jd006301, 2006. Bönisch, H., Engel, A., Curtius, J., Birner, T., and Hoor, P.: Quantifying transport into the lowermost stratosphere using simultaneous in-situ measurements of sf6 and co2, Atmospheric Chemistry and Physics, 9, 5905-5919, 2009. Hoor, P., Gurk, C., Brunner, D., Hegglin, M. I., Wernli, H., and Fischer, H.: Seasonality and extent of extratropical tst derived from in-situ co measurements during spurt, Atmospheric

  5. Successful application of spatial difference technique to electron energy-loss spectroscopy studies of Mo/SrTiO3 interfaces.

    PubMed

    Gao, M; Scheu, C; Tchernychova, E; Rühle, M

    2003-04-01

    The electron energy-loss near-edge structure (ELNES) of Mo/SrTiO3 interfaces has been studied using high spatial resolution electron energy-loss spectroscopy (EELS) in a dedicated scanning transmission electron microscope. Thin films of Mo with a thickness of 50 nm were grown on (001)-orientated SrTiO3 surfaces by molecular beam epitaxy at 600 degrees C. High-resolution transmission electron microscopy revealed that the interfaces were atomically abrupt with the (110)Mo plane parallel to the substrate surface. Ti-L2,3 ( approximately 460 eV), O-K ( approximately 530 eV), Sr-L2,3 ( approximately 1950 eV) and Mo-L2,3 ( approximately 2500 eV) absorption edges were acquired by using the Gatan Enfina parallel EELS system with a CCD detector. The interface-specific components of the ELNES were extracted by employing the spatial difference method. The interfacial Ti-L2,3 edge shifted to lower energy values and the splitting due to crystal field became less pronounced compared to bulk SrTiO3, which indicated that the Ti atoms at the interface were in a reduced oxidation state and that the symmetry of the TiO6 octahedra was disturbed. No interfacial Sr-L2,3 edge was observed, which may demonstrate that Sr atoms do not participate in the interfacial bonding. An evident interface-specific O-K edge was found, which differs from that of the bulk in both position (0.8 +/- 0.2 eV positive shift) and shape. In addition, a positive shift (0.9 +/- 0.3 eV) occurred for the interfacial Mo-L2,3, revealing an oxidized state of Mo at the interface. Our results indicated that at the interface SrTiO3 was terminated with TiO2. The validity of the spatial difference technique is discussed and examined by introducing subchannel drift intentionally.

  6. Recombinant Salmonella-based CEACAM6 and 4-1BBL vaccine enhances T-cell immunity and inhibits the development of colorectal cancer in rats: In vivo effects of vaccine containing 4-1BBL and CEACAM6.

    PubMed

    Jin, Chunhui; Liu, Yingying; Zhu, Jianhong; Xia, Tingting; Zhang, Baonan; Fei, Yajun; Ma, Bo; Ye, Jianxin; Chen, Weichang

    2015-06-01

    The present study aimed to determine the effect of recombinant Salmonella (SL3261)-based CEACAM6 and 4-1BB ligand (4-1BBL) vaccine on the development of colorectal cancer in rats and the potential immune mechanisms involved. Attenuated Salmonella typhimurium (vaccine strain)‑carrying plasmids pIRES-CEACAM6, pIRES‑4‑1BBL and pIRES-CEACAM6-4-1BBL were constructed. The rats were administered subcutaneous injections of 1,2-dimethyl-hydrazine (DMH) once a week for 18 weeks. Eight weeks after the first injection, the rats were divided into the pIRES/SL3261, pIRES-4-1BBL/SL3261, pIRES-CEACAM6/SL3261 and pIRES-CEACAM6-4-1BBL/SL3261 groups, and fed with corresponding vaccine strains. The rats were then sacrificed, the number of colon tumors were recorded, and the Dukes' stage were evaluated. CD3, CD4, CD8, CD56, FOXP3 and CEACAM6 expression in tumor tissues was determined by immunohistochemical staining. Compared with the expression levels in the pIRES/SL3261 group, similar levels of CD3+, CD8+ and CD56+ expression were identified for the pIRES-CEACAM6/SL3261 group of rats. Additionally, a comparable number of tumors was detected in the pIRES-4-1BBL/SL3261 and pIRES-CEACAM6/SL3261 groups. By contrast, a significantly fewer number of tumors, albeit with a higher density of CD3+CD8+, CD56+ and a lower density of Foxp3+ tumor-infiltrating lymphocyte (TIL) cells was detected in the pIRES-CEACAM6-4-1BBL/SL3261 group of rats. The results indicated that vaccination with recombinant attenuated Salmonella harboring the CEACAM6 and 4-1BBL gene efficiently increased the number of CD3+CD8+ TIL and NK cells, decreased the number of FOXP3 cells and inhibited the development of DMH-induced colorectal cancer in rats.

  7. Expression of programmed cell death ligand 1 is associated with poor overall survival in patients with diffuse large B-cell lymphoma

    PubMed Central

    Kiyasu, Junichi; Miyoshi, Hiroaki; Hirata, Akie; Arakawa, Fumiko; Ichikawa, Ayako; Niino, Daisuke; Sugita, Yasuo; Yufu, Yuji; Choi, Ilseung; Abe, Yasunobu; Uike, Naokuni; Nagafuji, Koji; Okamura, Takashi; Akashi, Koichi; Takayanagi, Ryoichi; Shiratsuchi, Motoaki

    2015-01-01

    Programmed cell death ligand 1 (PD-L1) is expressed on both select diffuse large B-cell lymphoma (DLBCL) tumor cells and on tumor-infiltrating nonmalignant cells. The programmed cell death 1 (PD-1)/PD-L1 pathway inhibits host antitumor responses; however, little is known about how this pathway functions in the tumor microenvironment. The aim of this study was to determine the clinicopathological impact of PD-L1+ DLBCL. We performed PD-L1/PAX5 double immunostaining in 1253 DLBCL biopsy samples and established a new definition of PD-L1+ DLBCL. We also defined the criteria for microenvironmental PD-L1+ (mPD-L1+) DLBCL (ie, PD-L1– DLBCL in which PD-L1+ nonmalignant cells are abundant in the tumor microenvironment). Of the 273 patients whose clinical information was available, quantitative analysis of PD-1+ tumor-infiltrating lymphocytes (TILs) was performed. The prevalence rates of PD-L1+ and mPD-L1+ DLBCL were 11% and 15.3%, respectively. Both PD-L1+ and mPD-L1+ DLBCL were significantly associated with non–germinal center B-cell (GCB) type and Epstein-Barr virus positivity. The number of PD-1+ TILs was significantly higher in GCB-type tumors and lower in mPD-L1– and PD-L1+ DLBCL. Patients with PD-L1+ DLBCL had inferior overall survival (OS) compared with that in patients with PD-L1– DLBCL (P = .0009). In contrast, there was no significant difference in OS between mPD-L1+ and mPD-L1– DLBCL (P = .31). The expression of PD-L1 maintained prognostic value for OS in multivariate analysis (P = .0323). This is the first report describing the clinicopathological features and outcomes of PD-L1+ DLBCL. Immunotherapy targeting the PD-1/PD-L1 pathway should be considered in this distinct DLBCL subgroup. PMID:26239088

  8. Synthesis, characterization, and reactivity of Ti(IV)-monosubstituted Keggin polyoxometalates.

    PubMed

    Kholdeeva, Oxana A; Trubitsina, Tatiana A; Maksimov, Gennadii M; Golovin, Anatolii V; Maksimovskaya, Raisa I

    2005-03-07

    Ti(IV)-monosubstituted Keggin-type polyoxometalates (Ti-POMs), mu-oxo dimer [Bu4N]8[(PTiW11O39)2O] (1), and three monomers [Bu4N]4[PTi(L)W11O39], where L = OH (2), OMe (3), and OAr (4, ArOH = 2,3,6-trimethylphenol (TMP)), have been prepared starting from mu-hydroxo dimer [Bu4N]7[(PTiW11O39)2OH] (5) or heteropolyacid H5PW11TiO40 or both. The compounds have been characterized by elemental analysis, IR, UV-vis, and multinuclear (31P, 1H, 183W) NMR. The interaction of 1 and 3-5 with H2O in MeCN produces 2. The hydrolysis constants, estimated from 31P and 1H NMR data, are 0.006 and 0.04 for 1 and 3, respectively. Studies by 31P NMR, IR, potentiometric titration, and cyclic voltammetry revealed that 1-3 and 5 afford the same protonated titanium peroxo complex [Bu4N]4[HPTi(O2)W11O39] (I) upon interaction with aqueous H2O2 in MeCN. The rates of formation of I correlate with the rates of hydrolysis of the Ti-POMs and follow the order of 5 > 1 > 3. A two-step mechanism of the reaction of Ti-POMs with H2O2, which involves hydrolysis of the Ti-L bonds to yield 2 followed by fast interaction of 2 with hydrogen peroxide producing I, is suggested. The equilibrium constant for the reaction of 2 with H2O2 to yield I and H2O, estimated using 31P NMR, is 10. The interaction of the Ti-POMs with TMP follows the trends similar to their interaction with H2O) and requires preliminary hydrolysis of the Ti-L bonds. All of the Ti-POMs catalyze the oxidation of TMP with H2O2 in MeCN to give 2,3,5-trimethyl-p-benzoquinone and 2,2',3,3',5,5'-hexamethyl-4,4'-biphenol. The product distribution is similar for all of the Ti-POMs. The catalytic activities of the Ti-POMs correlate with the rates of formation of I and follow the order of 2 > 5 > 1 > 3. The findings lay a basis for a better understanding of the nature of the reactivity of titanium in Ti-catalyzed oxidations.

  9. The promise of PD-1 inhibitors in gastro-esophageal cancers: microsatellite instability vs. PD-L1

    PubMed Central

    Jin, Zhaohui

    2016-01-01

    Preliminary clinical studies of anti-programmed cell death-1 (anti-PD-1) therapy in gastro-esophageal cancers have suggested promising single-agent activity. In patients who received prior treatment for advanced disease, pembrolizumab has been associated with a response rate of 20% in programmed cell death-1 ligand 1 (PD-L1)-positive tumors, and nivolumab with a response rate of 12% in unselected tumors. Both agents yielded a median duration of response lasting ~6–7 months. PD-L1 expression and microsatellite instability (MSI) have emerged as potential predictive markers for PD-1/PD-L1 blockade. PD-L1 expression in tumor cells and in immune cells within the tumor microenvironment has been detected in 14–24% and ~35% of patients with gastro-esophageal cancer, respectively. PD-L1 tumor cell expression appears to be more common in Epstein-Barr virus (EBV)-positive gastric cancers (GCs) and has been associated with an increased density of tumor-infiltrating lymphocytes (TIL). To date, data are too sparse to determine whether PD-L1 expression predicts efficacy of anti-PD-1 therapy in gastro-esophageal cancer, but data from other tumor types have not been consistent regarding its predictive value. MSI occurs in 10–20% of gastro-esophageal cancers and arises from deficient mismatch repair (MMR). MSI is highly correlated with non-synonymous mutation burden, as well as a dense accumulation of TILs. MSI has been associated with improved response to anti-PD-1 therapy in gastrointestinal cancers. Multiple studies are ongoing which examine therapeutic blockade of the PD-1/PD-L1 axis in unselected patients with gastro-esophageal cancer, as well as patients whose tumors express PD-L1 or exhibit MSI. These studies will clarify their activity in this disease and potentially can determine whether identify a strong predictive biomarker can be identified. Checkpoint inhibition is also being studied in combination with curative-intent chemo (radio) therapy and surgery. PMID

  10. [Implications of TCGA Network Data on 2nd Generation Immunotherapy Concepts Based on PD-L1 and PD-1 Target Structures].

    PubMed

    Peters, I; Tezval, H; Kramer, M W; Wolters, M; Grünwald, V; Kuczyk, M A; Serth, J

    2015-11-01

    The era of cytokines, given to patients with metastatic renal cell carcinoma (mRCC) as part of an unspecific immunomodulatory treatment concept, seems to have ended with the introduction of targeted therapies. However, preliminary data from studies on treatment with checkpoint inhibitors (e. g. anti-PD-1 and anti-PD-L1) may point the way to second-generation immunotherapy. The rationale of such immunomodulatory treatment is to stop or interrupt the tumour from "escaping" the body's immune defence. Thompson et al. report that increased protein expression of PD-L1 (CD274/ B7-H1) in tumour cells and tumour-infiltrating immune cells (TILs; lymphocytes and histiocytes) is associated with unfavourable clinical pathological parameters as well as poor survival. In small pilot groups of mRCC patients it was found that increased PD-L1 protein expression in tumours and TILs may be correlated with the objective response to anti-PD-1 treatment. Sometimes, however, a very wide variety of response rates was observed, which raises the question if this can be explained by individual expression levels of PD-L1 (CD 274) or PD-1 (PDCD1).Recently published data from the Cancer Genome Atlas (TCGA) Kidney Renal Clear Cell Carcinoma (KIRC) Network now provide a genome-wide data base that allows us to review or validate the molecular results obtained in clear cell renal cell carcinomas (ccRCC) to date.In this study, we analysed the TCGA KIRC mRNA expression data for PD-L1 and PD-1 for a possible association with clinical pathological parameters and the survival of 417 ccRCC patients.The mRNA expression of PD-L1 in primary nephrectomy specimens revealed no significant association with unfavourable clinical parameters. Interestingly, though, a positive correlation with patient survival was found (HR=0,59, p=0,006).These results, which partly contradict the concept applied to date, point out the necessity to ascertain the characteristics of PD-L1 and PD-1 expression at mRNA and protein

  11. The promise of PD-1 inhibitors in gastro-esophageal cancers: microsatellite instability vs. PD-L1.

    PubMed

    Jin, Zhaohui; Yoon, Harry H

    2016-10-01

    Preliminary clinical studies of anti-programmed cell death-1 (anti-PD-1) therapy in gastro-esophageal cancers have suggested promising single-agent activity. In patients who received prior treatment for advanced disease, pembrolizumab has been associated with a response rate of 20% in programmed cell death-1 ligand 1 (PD-L1)-positive tumors, and nivolumab with a response rate of 12% in unselected tumors. Both agents yielded a median duration of response lasting ~6-7 months. PD-L1 expression and microsatellite instability (MSI) have emerged as potential predictive markers for PD-1/PD-L1 blockade. PD-L1 expression in tumor cells and in immune cells within the tumor microenvironment has been detected in 14-24% and ~35% of patients with gastro-esophageal cancer, respectively. PD-L1 tumor cell expression appears to be more common in Epstein-Barr virus (EBV)-positive gastric cancers (GCs) and has been associated with an increased density of tumor-infiltrating lymphocytes (TIL). To date, data are too sparse to determine whether PD-L1 expression predicts efficacy of anti-PD-1 therapy in gastro-esophageal cancer, but data from other tumor types have not been consistent regarding its predictive value. MSI occurs in 10-20% of gastro-esophageal cancers and arises from deficient mismatch repair (MMR). MSI is highly correlated with non-synonymous mutation burden, as well as a dense accumulation of TILs. MSI has been associated with improved response to anti-PD-1 therapy in gastrointestinal cancers. Multiple studies are ongoing which examine therapeutic blockade of the PD-1/PD-L1 axis in unselected patients with gastro-esophageal cancer, as well as patients whose tumors express PD-L1 or exhibit MSI. These studies will clarify their activity in this disease and potentially can determine whether identify a strong predictive biomarker can be identified. Checkpoint inhibition is also being studied in combination with curative-intent chemo (radio) therapy and surgery.

  12. Genetic Mapping Reveals Broader Role of Vrn-H3 Gene in Root and Shoot Development beyond Heading in Barley

    PubMed Central

    Bungartz, Annemarie; Muzammil, Shumaila; P. Afsharyan, Nazanin; Léon, Jens; Naz, Ali Ahmad

    2016-01-01

    The aim of the present study was to dissect the genetic inheritance and interplay of root, shoot and heading attributes for a better understanding of these traits in crop production. For this, we utilized quantitative trait loci (QTL) and candidate gene analysis approach using a second filial (F2) population originated from a cross between spring cultivar Cheri and wild barley accession ICB181160. The F2 population comprising 182 plants was phenotyped for root dry weight (RDW), root volume (RV), root length (RL) and shoot dry weight (SDW), tiller number per plant (TIL) and days to heading (HEA). In parallel, this population was genotyped using polymerase chain reaction (PCR) based cleaved amplified polymorphic sequence (CAPS) markers distributed across the whole genome. Marker by trait analysis revealed 16 QTL for root and shoot traits localized on chromosomes 1H, 3H, 4H, 5H and 7H. The strongest and a common QTL effect for root, shoot and heading traits was identified on chromosome 7H at the putative region of Vrn-H3 gene. Later, we have established PCR based gene specific marker HvVrnH3 revealing polymorphism for early heading Vrn-H3 allele in Cheri and late heading allele vrn-H3 in ICB181160. Genotyping of these alleles revealed a clear co-segregation of early heading Vrn-H3 allele with lower root and shoot attributes, while late heading vrn-H3 allele with more TIL and higher root biomass suggesting a primary insight on the function of Vrn-H3 gene beyond flowering. Genetic interactions of vernalization genes Vrn-H3 with Vrn-H2 and Vrn-H1 also suggested the major role of Vrn-H3 alleles in determining root and shoot trait variations in barley. We believe, these data provide an opportunity for further research to test a precise significance of early heading on yield components and root associated sustainability in crops like barley and wheat. PMID:27442506

  13. Dollar Summary of Federal Supply Classification and Service Category by Company. Part 7. (1005-2845)

    DTIC Science & Technology

    1989-01-01

    0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 wi 0000 000000000000000001 - U In ti-I Ut IA U tilE Ut Ut tD Ut Ut Ut U Ut Ut Ut Qt ut IA Q z )- l 1 .,4 -4 .. 4...O O O-4 4)ou o L L.0h.4 - 4 -44 𔃾 - 4 - -4 -P4 -4 -4 L. td -4 t4 -4 -4 -4 -4 L. 1 Ix 1tt 0 0 0 0 0 0 0 0 0 ’D 0 E o 0 o 0 0 0m 0 W 4 0 (0 I I 4- %- 4...m )0 z 0 0 I 1 I ) 4- 4- I.- %- 0 D C %- =---4 L1 I ZI C 4 0 >, . 4 N 0 ., 4 0 0 1 H - I =)I C 44 L - -- 4- M 4 0 4-L - 4 3 ex I o 0 4 0 td . go m0 4

  14. In vitro stimulation of stage-specific deoxyribonucleic acid synthesis in rat seminiferous tubule segments by interleukin-1. alpha

    SciTech Connect

    Parvinen, M.; Soeder, O.M.; Mali, P.; Froeysa, B.R.; Ritzen, E.M. )

    1991-09-01

    Levels of rat testicular interleukin-1-like factor (tIL-1) have been shown to correlate with DNA synthetic activity during the cycle of the rat seminiferous epithelium, suggesting its role as a spermatogonial or meiotic growth factor. To explore this further, a new in vitro model system was developed. Rat seminiferous tubule segments from stages I, V, VIIa, and VIII-IX of the cycle were isolated by transillumination-assisted microdissection, cultured in chemically defined serum-free medium supplemented with human recombinant IL-1 {alpha}, and labeled with (3H)thymidine. During incubation, spontaneous progression of spermatogenesis was noted. Inactive stage VIIa tubule segments differentiated to stage VIII and initiated DNA synthesis, and concomitantly started to secrete IL-1-like factor. DNA synthesis of stages VIII-IX ceased through differentiation of spermatocytes to leptotene-zygotene (stages XII-XIII of the cycle). IL-1 {alpha} stimulated DNA synthesis significantly in spermatogonia of stage I. Meiotic DNA synthesis at stage VIIa was stimulated (48 h/34 C) and maintained at stages VIII-IX (48 h/34 C). IL-1 {alpha} seems to act as a regulator of spermatogenic DNA synthesis in both mitotic and meiotic phases. It has mainly stimulating and maintaining effects, but it may also be inhibitory under certain conditions.

  15. Reasoning about real-time systems with temporal interval logic constraints on multi-state automata

    NASA Technical Reports Server (NTRS)

    Gabrielian, Armen

    1991-01-01

    Models of real-time systems using a single paradigm often turn out to be inadequate, whether the paradigm is based on states, rules, event sequences, or logic. A model-based approach to reasoning about real-time systems is presented in which a temporal interval logic called TIL is employed to define constraints on a new type of high level automata. The combination, called hierarchical multi-state (HMS) machines, can be used to model formally a real-time system, a dynamic set of requirements, the environment, heuristic knowledge about planning-related problem solving, and the computational states of the reasoning mechanism. In this framework, mathematical techniques were developed for: (1) proving the correctness of a representation; (2) planning of concurrent tasks to achieve goals; and (3) scheduling of plans to satisfy complex temporal constraints. HMS machines allow reasoning about a real-time system from a model of how truth arises instead of merely depending of what is true in a system.

  16. [Treatment of renal anemia in hemodialysis patients in General Hospital Bjelovar from 2007 to 2010].

    PubMed

    Lovcić, Vesna; Vujić, Jovana; Basić-Jukić, Nikolina; Kurtović, Ivana; Janković, Renata Ivanac; Lovcić, Petra; Dzapo, Marko

    2011-10-01

    Renal anemia is complication of chronic kidney disease. It is caused by crythropoietin deficency and is associated with adverse outcomes in CKD patients. Renal anemia should be treated with erythropoesis-stimulating agents (ESAs), supplementary iron, adequate dialysis, and if necessary with red blood cells transfusions. The main problem of treatment is how to determine target hemoglobin value and keep it within the constant range. Current guidelines recommend target hemoglobin level 110 - 120 g/l, but optimal value need to be adjusted for every patient individualy keeping in mind primary kidney disease, age, gender and comorbidities. In Department of Dialysis of General Hospital Bjelovar we carried out a retrospective study about treating renal anemia in 67 patients on chronic hemodialysis program during 36 months in a period from 2007. til 2010. We monitored hemoglobin, feritin, saturation of transferin (TSAT), dose of LSE, number of change in dosage and number of transfusion. Mean hemoglobin level was 107.8 g/l, feritin level 196.8 mcg/l, TSAT 24.16%, weekly dose of ESAs 5951.9 IU. in 53.7% patiens dose was changed 11 - 20 times during that period, and 34% of patiens was treated with at least 1 dose of transfusion of red blood cells. We conclude that better iron supplementation and moderately higher doses of FSAs correlate with higher hemoglobin value, and hemoglobin variations is still big problem in renal anemia treatment.

  17. Whole-Transcriptome Selection and Evaluation of Internal Reference Genes for Expression Analysis in Protocorm Development of Dendrobium officinale Kimura et Migo

    PubMed Central

    An, Hongqiang; Zhu, Qiankun; Pei, Wei; Fan, Jing; Liang, Yi; Cui, Yihui; Lv, Nan; Wang, Wanjun

    2016-01-01

    Dendrobium officinale Kimu et Migo has increased many researchers’ interest for its high medical and horticultural values and the molecular mechanism of its protocorm development remains unclear. In this study, 19 genes from 26 most stably expressed genes in whole transcriptome of protocorms and 5 housekeeping genes were used as candidate reference genes and screened with 4 application softwares (geNorm, NormFinder, BestKeeper and RefFinder). The results showed that a few reference genes could effectively normalize expression level of specific genes in protocorm development and the optimal top 2 reference genes were ASS and APH1L. Meanwhile, validation of GNOM, AP2 and temperature induced gene (TIL) for normalization demonstrates the usefulness of the validated candidate reference genes. The expression profiles of these genes varied under protocorms and temperature stress according to the stablest and unstablest reference genes, which proved the importance of the choice of appropriate reference genes. The first systematic evaluation of stably expressed genes will be very useful in the future analysis of specific genes expression in D. officinale. PMID:27814359

  18. Primitive robotic procedures: automotions for medical liquids in 12th century Asia minor.

    PubMed

    Penbegul, Necmettin; Atar, Murat; Kendirci, Muammer; Bozkurt, Yasar; Hatipoglu, Namık Kemal; Verit, Ayhan; Kadıoglu, Ates

    2014-12-30

    In recent years, day by day, robotic surgery applications have increase their role in our medical life. In this article, we reported the discovery of the first primitive robotic applications as automatic machines for the sensitive calculation of liquids such as blood in the literature. Al-Jazari who wrote the book "Elcâmi 'Beyne'l - 'ilm ve'l - 'amel en-nâfi 'fi es-sınaâ 'ti'l - hiyel", lived in Anatolian territory between 1136 and 1206. In this book that was written in the twelfth century, Al-Jazari described nearly fifty graphics of robotic machines and six of them that were designed for medical purposes. We found that some of the robots mentioned in this book are related to medical applications. This book reviews approximately 50 devices, including water clocks, candle clocks, ewers, various automata used for amusement in drink assemblies, automata used for ablution, blood collection tanks, fountains, music devices, devices for water lifting, locks, a protractor, a boat-shaped water clock, and the gate of Diyarbakir City in south-east of Turkey, actually in northern Mesopotamia. We found that automata used for ablution and blood collection tanks were related with medical applications; therefore, we will describe these robots.

  19. Evolution and classification of acapulcoites and lodranites from a chemical point of view

    NASA Astrophysics Data System (ADS)

    Patzer, Andrea; Hill, Dolores H.; Boynton, William V.

    2004-01-01

    We examined 15 bulk samples of the acapulcoite-lodranite clan for their major, minor, and trace element concentrations using INAA techniques. Among the analyzed meteorites are 2 new acapulcoites (Dhofar [Dho] 290, Thiel Mountains [TIL] 99002) as well as an additional acapulcoite that has been described previously only in very brief form (Graves Nunataks [GRA] 98028). The petrographic attributes of these 3 samples are addressed thoroughly. We also include petrographic information on 2 acapulcoites from Africa: Northwest Africa (NWA) 725 and NWA 1058. In general, our study strongly supports the widely accepted idea that acapulcoites and lodranites evolved through partial melting and melt migration of metal/sulfide phases and plagioclase. Furthermore, we concur with previous researchers that the original bimodal classification scheme for acapulcoites and lodranites proves to be too simple. Based on our data set, we introduce an alternative, extended scheme. With respect to their elemental distribution patterns, we distinguish 5 subtypes comprising primitive, typical, transitional, and enriched acapulcoites on one hand and lodranites on the other. The chemical distinction between the primitive, typical, and transitional acapulcoites is rather subtle and gradual. It stands in contrast to the clear modifications observed for the signatures of the enriched acapulcoites and the lodranites. The definition of subcategories basically reflects the concentrations of 2 key elements: K and Se. We note, however, that the assignment of subgroups may not be exclusively inferred from elemental abundances but should also consider additional petrographic information.

  20. Multispectral imaging and image processing

    NASA Astrophysics Data System (ADS)

    Klein, Julie

    2014-02-01

    The color accuracy of conventional RGB cameras is not sufficient for many color-critical applications. One of these applications, namely the measurement of color defects in yarns, is why Prof. Til Aach and the Institute of Image Processing and Computer Vision (RWTH Aachen University, Germany) started off with multispectral imaging. The first acquisition device was a camera using a monochrome sensor and seven bandpass color filters positioned sequentially in front of it. The camera allowed sampling the visible wavelength range more accurately and reconstructing the spectra for each acquired image position. An overview will be given over several optical and imaging aspects of the multispectral camera that have been investigated. For instance, optical aberrations caused by filters and camera lens deteriorate the quality of captured multispectral images. The different aberrations were analyzed thoroughly and compensated based on models for the optical elements and the imaging chain by utilizing image processing. With this compensation, geometrical distortions disappear and sharpness is enhanced, without reducing the color accuracy of multispectral images. Strong foundations in multispectral imaging were laid and a fruitful cooperation was initiated with Prof. Bernhard Hill. Current research topics like stereo multispectral imaging and goniometric multispectral measure- ments that are further explored with his expertise will also be presented in this work.

  1. Bone formation in vivo induced by Cbfa1-carrying adenoviral vectors released from a biodegradable porous β-tricalcium phosphate (β-TCP) material

    NASA Astrophysics Data System (ADS)

    Uemura, Toshimasa; Kojima, Hiroko

    2011-06-01

    Overexpression of Cbfa1 (a transcription factor indispensable for osteoblastic differentiation) is expected to induce the formation of bone directly and indirectly in vivo by accelerating osteoblastic differentiation. Adenoviral vectors carrying the cDNA of Cbfa1/til-1(Adv-Cbf1) were allowed to be adsorbed onto porous blocks of β-tricalcium phosphate (β-TCP), a biodegradable ceramic, which were then implanted subcutaneously and orthotopically into bone defects. The adenoviral vectors were released sustainingly by biodegradation, providing long-term expression of the genes. Results of the subcutaneous implantation of Adv-Cbfa1-adsorbed β-TCP/osteoprogenitor cells suggest that a larger amount of bone formed in the pores of the implant than in the control material. Regarding orthotopic implantation into bone defects, the released Adv-Cbfa1 accelerated regeneration in the cortical bone, whereas it induced bone resorption in the marrow cavity. A safer gene transfer using a smaller amount of the vector was achieved using biodegradable porous β-TCP as a carrier.

  2. An insight into the salivary transcriptome and proteome of the soft tick and vector of epizootic bovine abortion, Ornithodoros coriaceus

    PubMed Central

    Francischetti, Ivo M. B.; Meng, Zhaojing; Mans, Ben J.; Gudderra, Nanda; Hall, Mark; Veenstra, Timothy D.; Pham, Van M.; Kotsyfakis, Michail; Ribeiro, José M. C.

    2008-01-01

    The salivary glands of blood sucking arthropods contain a redundant ‘magic potion’ that counteracts their vertebrate host’s hemostasis, inflammation, and immunity. We here describe the salivary transcriptome and proteomics (sialome) of the soft tick Ornithodoros coriaceus. The resulting analysis helps to consolidate the classification of common proteins found in both soft and hard ticks, such as the lipocalins, Kunitz, cystatin, basic tail, hebraein, defensin, TIL domain, metalloprotease, 5′-nucleotidase/apyrase, and phospholipase families, and also to identify protein families uniquely found in the Argasidae, such as the adrenomedullin/CGRP peptides, 7DB, 7 kDa, and the RGD containing single Kunitz proteins. Additionally, we found a protein belonging to the cytotoxin protein family that has so far only been identified in hard ticks. Three other unique families common only to the Ornithodoros genus were discovered. Edman degradation, 2D and 1D PAGE of salivary gland homogenates followed by tryptic digestion and HPLC MS/MS of results confirms the presence of several proteins. These results indicate that each genus of hematophagous arthropods studied to date evolved unique protein families that assist blood feeding, thus characterizing potentially new pharmacologically active components or antimicrobial agents. PMID:18725333

  3. Size scales over which ordinary chondrites and their parent asteroids are homogeneous in oxidation state and oxygen-isotopic composition

    NASA Astrophysics Data System (ADS)

    Rubin, Alan E.; Ziegler, Karen; Young, Edward D.

    2008-02-01

    Literature data demonstrate that on a global, asteroid-wide scale (plausibly on the order of 100 km), ordinary chondrites (OC) have heterogeneous oxidation states and O-isotopic compositions (represented, respectively, by the mean olivine Fa and bulk Δ 17O compositions of equilibrated samples). Samples analyzed here include: (a) two H5 chondrite Antarctic finds (ALHA79046 and TIL 82415) that have the same cosmic-ray exposure age (7.6 Ma) and were probably within ˜1 km of each other when they were excavated from the H-chondrite parent body, (b) different individual stones from the Holbrook L/LL6 fall that were probably within ˜1 m of each other when their parent meteoroid penetrated the Earth's atmosphere, and (c) drill cores from a large slab of the Estacado H6 find located within a few tens of centimeters of each other. Our results indicate that OC are heterogeneous in their bulk oxidation state and O-isotopic composition on 100-km-size scales, but homogeneous on meter-, decimeter- and centimeter-size scales. (On kilometer size scales, oxidation state is heterogeneous, but O isotopes appear to be homogeneous.) The asteroid-wide heterogeneity in oxidation state and O-isotopic composition was inherited from the solar nebula. The homogeneity on small size scales was probably caused in part by fluid-assisted metamorphism and mainly by impact-gardening processes (which are most effective at mixing target materials on scales of ⩽1 m).

  4. Targeting solid tumors via T cell receptor complementarity-determining region 3delta in an engineered antibody.

    PubMed

    Wang, Zhun; Zhang, Tie; Hu, Hongbo; Zhang, Huiyuan; Yang, Zhi; Cui, Lianxian; He, Wei

    2008-12-18

    Human Vdelta2 gammadelta T lymphocytes killed multiple solid tumors, even displaying comparable therapeutic efficacy with anti-tumor chemical-cis-platinum in an adoptive experiment in both nude and SCID murine model shown in present study. We previously found that T cell receptor (TCR) gammadelta recognize tumors via complementarity-determining region 3 (CDR3), briefly named as CDR3delta. Based on characteristics of specific binding of CDR3delta to tumor targets, we developed a novel tumor-targeting antibody, whose CDR3 in heavy chain is replaced by CDR3delta sequence derived from human ovarian carcinoma (OEC) infiltrating gammadelta T cells (gammadeltaTILs). This CDR3delta-grafted antibody OT3 exhibited specific binding activities to OEC line SKOV3 both in vitro and in vivo, which included specific binding to several tumor cell lines, interacting with heat shock protein (HSP) 60 and triggering ADCC against tumors in vitro, as well as displaying tumor imaging by radioisotope 99mTc-labeled antibody OT3 in vivo. Moreover, immunotoxin OT3-DT, CDR3delta-grafted antibody OT3 chemically conjugated with diphtheria toxin (DT) showed the anti-tumor effect on the growth of several solid tumors including OEC, cervix adenocarcinoma, hepatocellular carcinoma, and rectum adenocarcinoma to various extents in nude mice. Therefore, we have found and confirmed a novel therapeutic strategy for targeting solid tumors, making use of immune recognition characteristics of gammadelta T cells.

  5. [Edge effect of the plant community structure on land-bridge islands in the Thousand Island Lake].

    PubMed

    Su, Xiao-Fei; Yuan, Jin-Feng; Hu, Guang; Xu, Gao-Fu; Yu, Ming-Jian

    2014-01-01

    The research was conducted on 29 land-bridge islands in the Thousand Island Lake (TIL), where long-term monitoring plots were set up during 2009-2010. The community attributes including species richness, Shannon index, plant mean height, plant mean diameter at breast height (DBH) and plant density along the edge-interior gradient from edge to interior forest were calculated to investigate the edge effect. The results showed that the species richness and Shannon index were affected through the whole gradient (larger than 50 m), while the range of edge effect was 20-30 m on mean plant height, and 10 m on plant density and mean DBH. Community attributes differed significantly among the edge gradients. The species richness and Shannon index peaked at the intermediate edge gradient. Plant density decreased and plant mean height increased along the edge to interior gradient. All five community attributes were significantly associated with the edge gradient, also different functional groups, evergreen or deciduous species, trees or shrubs, shade tolerant or shade intolerant species, were differentially influenced by the edge effect. It was demonstrated the influence of edge effect on the fragmented forest community varied with community attributes and functional groups.

  6. Adoptive immunotherapy for hematological malignancies using T cells gene-modified to express tumor antigen-specific receptors.

    PubMed

    Fujiwara, Hiroshi

    2014-12-15

    Accumulating clinical evidence suggests that adoptive T-cell immunotherapy could be a promising option for control of cancer; evident examples include the graft-vs-leukemia effect mediated by donor lymphocyte infusion (DLI) and therapeutic infusion of ex vivo-expanded tumor-infiltrating lymphocytes (TIL) for melanoma. Currently, along with advances in synthetic immunology, gene-modified T cells retargeted to defined tumor antigens have been introduced as "cellular drugs". As the functional properties of the adoptive immune response mediated by T lymphocytes are decisively regulated by their T-cell receptors (TCRs), transfer of genes encoding target antigen-specific receptors should enable polyclonal T cells to be uniformly redirected toward cancer cells. Clinically, anticancer adoptive immunotherapy using genetically engineered T cells has an impressive track record. Notable examples include the dramatic benefit of chimeric antigen receptor (CAR) gene-modified T cells redirected towards CD19 in patients with B-cell malignancy, and the encouraging results obtained with TCR gene-modified T cells redirected towards NY-ESO-1, a cancer-testis antigen, in patients with advanced melanoma and synovial cell sarcoma. This article overviews the current status of this treatment option, and discusses challenging issues that still restrain the full effectiveness of this strategy, especially in the context of hematological malignancy.

  7. Organization of cytoskeletal elements and organelles preceding growth cone emergence from an identified neuron in situ

    PubMed Central

    1989-01-01

    The purpose of this study was to investigate the arrangement of cytoskeletal elements and organelles in an identified neuron in situ at the site of emergence of its growth cone just before and concurrent with the onset of axonogenesis. The Ti1 pioneer neurons are the first pair of afferent neurons to differentiate in embryonic grasshopper limbs. They arise at the distal tip of the limb bud epithelium, the daughter cells of a single precursor cell, the Pioneer Mother Cell (PMC). Using immunohistochemical markers, we characterized the organization of microtubules, centrosomes, Golgi apparatus, midbody, actin filaments, and chromatin from mitosis in the PMC through axonogenesis in the Tils. Just before and concurrent with the onset of axonogenesis, a characteristic arrangement of tubulin, actin filaments, and Golgi apparatus is localized at the proximal pole of the proximal pioneer neuron. The growth cone of the proximal cell stereotypically arises from this site. Although the distal cell's axon generally grows proximally, occasionally it arises from its distal pole; in such limbs, the axons from the sister cells extend from mirror symmetric locations on their somata. In the presence of cytochalasin D, the PMC undergoes nuclear division but not cytokinesis and although other neuronal phenotypes are expressed, axongenesis is inhibited. Our data suggest that intrinsic information determines the site of growth cone emergence of an identified neuron in situ. PMID:2654140

  8. The “Vampirome”: Transcriptome and proteome analysis of the principal and accessory submaxillary glands of the vampire bat Desmodus rotundus, a vector of human rabies

    PubMed Central

    Francischetti, Ivo M. B.; Assumpção, Teresa C. F.; Ma, Dongying; Li, Yuan; Vicente, Eliane C.; Uieda, Wilson; Ribeiro, José M.C.

    2013-01-01

    Vampire bats are notorious for being the sole mammals that strictly feed on fresh blood for their survival. While their saliva has been historically associated with anticoagulants, only one antihemostatic (plasminogen activator) has been molecularly and functionally characterized. Here, RNAs from both principal submandibular and accessory glands of Desmodus rotundus were extracted, and ~ 200 million reads were sequenced by Illumina. The principal gland was enriched with plasminogen activators with fibrinolytic properties, members of lipocalin and secretoglobin families, which bind prohemostatic prostaglandins, and endonucleases, which cleave neutrophil-derived procoagulant NETs. Anticoagulant (tissue factor pathway inhibitor, TFPI), vasodilators (PACAP and C-natriuretic peptide), and metalloproteases (ADAMTS-1) were also abundantly expressed. Members of the TSG-6 (anti-inflammatory), antigen 5/CRISP, and CCL28-like (antimicrobial) protein families were also sequenced. Apyrases (which remove platelet agonist ADP), phosphatases (which degrade procoagulant polyphosphates), and sphingomyelinase were found at lower transcriptional levels. Accessory glands were enriched with antimicrobials (lysozyme, defensin, lactotransferrin) and protease inhibitors (TIL-domain, cystatin, Kazal). Mucins, heme-oxygenase, and IgG chains were present in both glands. Proteome analysis by nano LC-MS/MS confirmed that several transcripts are expressed in the glands. The database presented herein is accessible online at http://exon.niaid.nih.gov/transcriptome/D_rotundus/Supplemental-web.xlsx. These results reveal that bat saliva emerges as a novel source of modulators of vascular biology. PMID:23411029

  9. Micromechanics of Drosophila Audition

    NASA Astrophysics Data System (ADS)

    Göpfert, M. C.; Robert, D.

    2003-02-01

    An analysis is presented of the auditory micromechanics of the fruit fly Drosophila melanogaster. In this animal, the distal part of the antenna constitutes a resonantly tuned sound receiver, the vibrations of which are transduced by a chordotonal sense organ in the antenna's base. Analyzing the mechanical behavior of the antennal receiver by means of microscanning laser Doppler vibrometry, we show that the auditory system of wild-type flies exhibits a hardening stiffness nonlinearity and spontaneously generates oscillations in the absence of external stimuli. According to the deprivation of these mechanical properties in mechanosensory mutants, the receiver's nonlinearity and oscillation activity are introduced by chordotonal auditory neurons. Requiring the mechanoreceptor-specific extracellular linker protein No-mechanoreceptor-potential-A (NompA), NompC mechanosensory transduction channels, Beethoven (Btv), and Touch-insensitive-larva-B (TilB), nonlinearity and oscillation activity of the fly's antennal receiver depend on prominent components of the auditory transduction machinery and seem to originate from motility of auditory receptor cilia.

  10. Yakir Aharonov: From A to B

    NASA Astrophysics Data System (ADS)

    Pines, A.

    Twenty years ago, I was accorded the privilege and pleasure of presenting the after banquet speech—reprinted below—at a conference celebrating the sixtieth year of my dear friend Yakir Aharonov. Does what I said then still hold today? You bet it does …the now adult Yakir has maintained the same burning curiosity, fiery enthusiasm and explosive genius for physics that characterized the life of the adolescent sixty year old. There may be no free lunch, but Yakir is living proof that there is free will, and he has exercised his free will to make ever more creative contributions to quantum physics, future and present. My admiration of Yakir as a scientist and mensch has only grown over the years. Sorry I can't be with you all at Chapman to participate in this marvelous eightieth year celebration. Dear Yakir, Ditsa and I wish you, Nilli and your family many more joyous years of health, science and friendship…' til 120.

  11. Location and Density of Immune Cells in Precursor Lesions and Cervical Cancer.

    PubMed

    Bedoya, Astrid M; Jaramillo, Roberto; Baena, Armando; Castaño, Jorge; Olaya, Natalia; Zea, Arnold H; Herrero, Rolando; Sanchez, Gloria I

    2013-04-01

    Only a small proportion of women infected with Human Papillomavirus (HPV) develop cervical cancer. Host immune response seems to play a role eliminating the viral infection and preventing progression to cancer. Characterization of tumor infiltrating lymphocytes (TILs) in cervical pre-neoplastic lesions and cervical cancer may be helpful to understand the mechanisms that mediate this protection. The aim of this study was to determine if there are differences in the localization and density (cells/mm(2)) of CD8+ T-cells, CD4+ T-cells and Tregs (CD25 + Foxp3+) in cervical pre-neoplastic lesions and cervical cancer. Immunohistochemical analysis of sections of 96 (26 CIN1, 21 CIN2, 25 CIN3, and 24 SCC) samples revealed that regardless of CIN grades, CD8+ T-cells are more abundant than CD4+, CD25+ and Foxp3+ cells in both the stroma and epithelium. There was a higher density of CD8+ cells in the stroma of cervical cancer compared to CIN3 (OR = 4.20, 95% CI 1.2-15), CIN2 (OR = 7.86, 95% CI 1.7-36.4) and CIN1 (OR = 4.25, 95% CI 1.1-17). Studies evaluating whether these cells are recruited before or after cancer progression will be helpful to understand the role of these cells in the natural history of HPV-induced lesions.

  12. Popocatepetl Erupts

    NASA Technical Reports Server (NTRS)

    2002-01-01

    The Popocatepetl Volcano, almost 30 miles south of Mexico City, erupted yesterday (December 18, 2000) in what authorities are calling its most spectacular eruption since 800 A.D. This morning, Popocatepetl (pronounced poh-poh-kah-TEH-peh-til) continued spewing red-hot rocks as well as a column of smoke and ash about 2.5 miles high into the atmosphere. This true-color image of the volcano was acquired today by the Sea-viewing Wide Field-of-view Sensor (SeaWiFS) flying aboard the OrbView-2 satellite. In this image, Popocatepetl's plume (greyish pixels) can be seen blowing southward, away from Mexico City. There is a large cloud bank (bright white pixels) just to the east of the volcanic plume. Although Popocatepetl has been active since 1994-when it awoke from a 70-year slumber-this most recent eruption is most concerning to the greater Mexico City region's 20 million residents. The volcano demonstrated what it can do in 800 A.D. when it belched forth enough lava to fill many of the valleys in the surrounding region. Earlier, scientists warned the citizens of Mexico that there is a dome of lava at the base of the volcano that is causing pressure to build inside. They are concerned that, if it continues to build unabated, this pressure could cause even larger eruptions in the future. Image provided by the SeaWiFS Project, NASA/Goddard Space Flight Center, and ORBIMAGE

  13. PD-1 and its ligands are important immune checkpoints in cancer.

    PubMed

    Dong, Yinan; Sun, Qian; Zhang, Xinwei

    2017-01-10

    Checkpoint programmed death-1 (PD-1)/programmed cell death ligands (PD-Ls) have been identified as negative immunoregulatory molecules that promote immune evasion of tumor cells. The interaction of PD-1 and PD-Ls inhibits the function of T cells and tumor-infiltrating lymphocytes (TIL) while increasing the function of immunosuppressive regulatory T cells (Tregs). This condition causes the tumor cells to evade immune response. Thus, the blockade of PD-1/PD-L1 enhances anti-tumor immunity by reducing the number and/or the suppressive activity of Tregs and by restoring the activity of effector T cells. Furthermore, some monoclonal antibodies blockading PD-1/PD-Ls axis have achieved good effect and received Food and Drug Administration approval. The role of PD-1/PD-Ls in tumors has been well studied, but little is known on the mechanism by which PD-1 blocks T-cell activation. In this study, we provide a brief overview on the discovery and regulatory mechanism of PD-1 and PD-L1 dysregulation in tumors, as well as the function and signaling pathway of PD-1 and its ligands; their roles in tumor evasion and clinical treatment were also studied.

  14. Tumor-Induced CD8+ T-Cell Dysfunction in Lung Cancer Patients

    PubMed Central

    Prado-Garcia, Heriberto; Romero-Garcia, Susana; Aguilar-Cazares, Dolores; Meneses-Flores, Manuel; Lopez-Gonzalez, Jose Sullivan

    2012-01-01

    Lung cancer is the leading cause of cancer deaths worldwide and one of the most common types of cancers. The limited success of chemotherapy and radiotherapy regimes have highlighted the need to develop new therapies like antitumor immunotherapy. CD8+ T-cells represent a major arm of the cell-mediated anti-tumor response and a promising target for developing T-cell-based immunotherapies against lung cancer. Lung tumors, however, have been considered to possess poor immunogenicity; even so, lung tumor-specific CD8+ T-cell clones can be established that possess cytotoxicity against autologous tumor cells. This paper will focus on the alterations induced in CD8+ T-cells by lung cancer. Although memory CD8+ T-cells infiltrate lung tumors, in both tumor-infiltrating lymphocytes (TILs) and malignant pleural effusions, these cells are dysfunctional and the effector subset is reduced. We propose that chronic presence of lung tumors induces dysfunctions in CD8+ T-cells and sensitizes them to activation-induced cell death, which may be associated with the poor clinical responses observed in immunotherapeutic trials. Getting a deeper knowledge of the evasion mechanisms lung cancer induce in CD8+ T-cells should lead to further understanding of lung cancer biology, overcome tumor evasion mechanisms, and design improved immunotherapeutic treatments for lung cancer. PMID:23118782

  15. A pictorial presentation of 3.0 Chicago Classification for esophageal motility disorders.

    PubMed

    Herbella, Fernando Augusto; Armijo, Priscila Rodrigues; Patti, Marco Giuseppe

    2016-01-01

    High resolution manometry changed several esophageal motility paradigms. The 3.0 Chicago Classification defined manometric criteria for named esophageal motility disorders. We present a pictorial atlas of motility disorders. Achalasia types, esophagogastric junction obstruction, absent contractility, distal esophageal spasm, hypercontractile esophagus (jackhammer), ineffective esophageal motility, and fragmented peristalsis are depicted with high-resolution manometry plots. RESUMO A manometria de alta resolução mudou vários paradigmas da motilidade digestiva. A Classificação de Chicago, na versão 3.0, definiu critérios manométricos para as doenças da motilidade esofagiana. O presente artigo é um atlas das dismotilidades descritas. Tipos de acalásia, obstrução ao nível da junção esofagogástrica, contrações ausentes, espasmo esofagiano distal, esôfago hipercontrátil, motilidade esofagiana ineficaz e peristalse fragmentada são mostradas em traçados de manometria de alta resolução.

  16. Nanoparticle size and combined toxicity of TiO2 and DSLS (surfactant) contribute to lysosomal responses in digestive cells of mussels exposed to TiO2 nanoparticles.

    PubMed

    Jimeno-Romero, A; Oron, M; Cajaraville, M P; Soto, M; Marigómez, I

    2016-10-01

    The aim of this investigation was to understand the bioaccumulation, cell and tissue distribution and biological effects of disodium laureth sulfosuccinate (DSLS)-stabilised TiO2 nanoparticles (NPs) in marine mussels, Mytilus galloprovincialis. Mussels were exposed in vivo to 0.1, 1 and 10 mg Ti/L either as TiO2 NPs (60 and 180 nm) or bulk TiO2, as well as to DSLS alone. A significant Ti accumulation was observed in mussels exposed to TiO2 NPs, which were localised in endosomes, lysosomes and residual bodies of digestive cells, and in the lumen of digestive tubules, as demonstrated by ultrastructural observations and electron probe X-ray microanalysis. TiO2 NPs of 60 nm were internalised within digestive cell lysosomes to a higher extent than TiO2 NPs of 180 nm, as confirmed by the quantification of black silver deposits after autometallography. The latter were localised mainly forming large aggregates in the lumen of the gut. Consequently, lysosomal membrane stability (LMS) was significantly reduced upon exposure to both TiO2 NPs although more markedly after exposure to TiO2-60 NPs. Exposure to bulk TiO2 and to DSLS also affected the stability of the lysosomal membrane. Thus, effects on the lysosomal membrane depended on the nanoparticle size and on the combined biological effects of TiO2 and DSLS.

  17. Engineering design of the Regolith X-ray Imaging Spectrometer (REXIS) instrument: an OSIRIS-REx student collaboration

    NASA Astrophysics Data System (ADS)

    Jones, Michael; Chodas, Mark; Smith, Matthew J.; Masterson, Rebecca A.

    2014-07-01

    OSIRIS-REx is a NASA New Frontiers mission scheduled for launch in 2016 that will travel to the asteroid Bennu and return a pristine sample of the asteroid to Earth. The REgolith X-ray Imaging Spectrometer (REXIS) is a student collaboration instrument on-board the OSIRIS-REx spacecraft. REXIS is a NASA risk Class D instrument, and its design and development is largely student led. The engineering team consists of MIT graduate and undergraduate students and staff at the MIT Space Systems Laboratory. The primary goal of REXIS is the education of science and engineering students through participation in the development of light hardware. In light, REXIS will contribute to the mission by providing an elemental abundance map of the asteroid and by characterizing Bennu among the known meteorite groups. REXIS is sensitive to X-rays between 0.5 and 7 keV, and uses coded aperture imaging to map the distribution of iron with 50 m spatial resolution. This paper describes the science goals, concept of operations, and overall engineering design of the REXIS instrument. Each subsystem of the instrument is addressed with a high-level description of the design. Critical design elements such as the Thermal Isolation Layer (TIL), radiation cover, coded-aperture mask, and Detector Assembly Mount (DAM) are discussed in further detail.

  18. Tumor-induced CD8+ T-cell dysfunction in lung cancer patients.

    PubMed

    Prado-Garcia, Heriberto; Romero-Garcia, Susana; Aguilar-Cazares, Dolores; Meneses-Flores, Manuel; Lopez-Gonzalez, Jose Sullivan

    2012-01-01

    Lung cancer is the leading cause of cancer deaths worldwide and one of the most common types of cancers. The limited success of chemotherapy and radiotherapy regimes have highlighted the need to develop new therapies like antitumor immunotherapy. CD8+ T-cells represent a major arm of the cell-mediated anti-tumor response and a promising target for developing T-cell-based immunotherapies against lung cancer. Lung tumors, however, have been considered to possess poor immunogenicity; even so, lung tumor-specific CD8+ T-cell clones can be established that possess cytotoxicity against autologous tumor cells. This paper will focus on the alterations induced in CD8+ T-cells by lung cancer. Although memory CD8+ T-cells infiltrate lung tumors, in both tumor-infiltrating lymphocytes (TILs) and malignant pleural effusions, these cells are dysfunctional and the effector subset is reduced. We propose that chronic presence of lung tumors induces dysfunctions in CD8+ T-cells and sensitizes them to activation-induced cell death, which may be associated with the poor clinical responses observed in immunotherapeutic trials. Getting a deeper knowledge of the evasion mechanisms lung cancer induce in CD8+ T-cells should lead to further understanding of lung cancer biology, overcome tumor evasion mechanisms, and design improved immunotherapeutic treatments for lung cancer.

  19. Evidence for a role of the PD-1:PD-L1 pathway in immune resistance of HPV-associated head and neck squamous cell carcinoma

    PubMed Central

    Lyford-Pike, Sofia; Peng, Shiwen; Young, Geoffrey D.; Taube, Janis M.; Westra, William H.; Akpeng, Belinda; Bruno, Tullia C.; Richmon, Jeremy D.; Wang, Hao; Bishop, Justin A.; Chen, Lieping; Drake, Charles G.; Topalian, Suzanne L.; Pardoll, Drew M.; Pai, Sara I.

    2013-01-01

    Human papillomavirus-associated head and neck squamous cell carcinomas (HPV-HNSCC) originate in the tonsils, the major lymphoid organ that orchestrates immunity to oral infections. Despite its location, the virus escapes immune elimination during malignant transformation and progression. Here, we provide evidence for the role of the PD-1:PD-L1 pathway in HPV-HNSCC immune resistance. We demonstrate membranous expression of PD-L1 in the tonsillar crypts, the site of initial HPV infection. In HPV-HNSCCs that are highly infiltrated with lymphocytes, PD-L1 expression on both tumor cells and CD68+ tumor associated macrophages (TAMs) is geographically localized to sites of lymphocyte fronts, while the majority of CD8+ tumor infiltrating lymphocytes (TILs) express high levels of PD-1, the inhibitory PD-L1 receptor. Significant levels of mRNA for interferon-γ (IFN-γ), a major cytokine inducer of PD-L1 expression, were found in HPV+ PD-L1(+) tumors. Our findings support the role of the PD-1:PD-L1 interaction in creating an “immune-privileged” site for initial viral infection and subsequent adaptive immune resistance once tumors are established and suggest a rationale for therapeutic blockade of this pathway in patients with HPV-HNSCC. PMID:23288508

  20. Propagation of gravity waves across the tropopause

    NASA Astrophysics Data System (ADS)

    Bense, Vera; Spichtinger, Peter

    2015-04-01

    The tropopause region is characterised by strong gradients in various atmospheric quantities that exhibit different properties in the troposphere compared to the stratosphere. The temperature lapse rate typically changes from negative to near-zero values resulting in a strong increase in stability. Accordingly, the buoyancy frequency often undergoes a jump at the tropopause. Analysis of radiosounding data also shows the existence of a strong inversion layer (tropopause inversion layer, TIL) characterised by a strong maximum in buoyancy frequency just above the tropopause, see e.g. Birner et al. (2002). Additionally, the magnitude of the vertical wind shear of the horizontal wind maximizes at the tropopause and the region also exhibits characteristical gradients of trace gases. Vertically propagating gravity waves can be excited in the troposphere by several mechanisms, e.g. by flow over topography (e.g. Durran, 1990), by jets and fronts (for a recent review: Plougonven and Zhang, 1990) or by convection (e.g. Clark et al., 1986). When these waves enter the tropopause region, their properties can be changed drastically by the changing stratification and strong wind shear. Within this work, the EULAG (Eulerian/semi-Lagrangian fluid solver, see e.g. Smolarkiewicz and Margolin, 1997) model is used to investigate the impact of the tropopause on vertically propagating gravity waves excited by flows over topography. The choice of topography (sine-shaped mountains, bell-shaped mountain) along with horizontal wind speed and tropospheric value of buoyancy frequency determine the spectrum of waves (horizontal and vertical wavelengths) that is excited in the tropsphere. In order to analyse how these spectra change for several topographies when a tropopause is present, we investigate different idealized cases in a two-dimensional domain. By varying the vertical profiles of buoyancy frequency (step-wise vs. continuos change, including TIL) and wind shear, the tropopause

  1. Subpicosecond Carrier Dynamics in Semiconductor Lasers and Lasers Based on Intersubband Transition.

    NASA Astrophysics Data System (ADS)

    Sung, Chun-Yung

    Recently, research for semiconductor lasers has proceeded in two directions. One direction is towards faster modulation speed for greater optical communication capacity. The second direction is towards long wavelength (10-100 mun) coherent radiation from the novel quantum well laser structures. In both cases, a fundamental understanding of carrier dynamics in the subpicosecond time scale is extremely important. This thesis explores the ultrafast carrier relaxation dynamics in several important optoelectronic semiconductor structures, with an emphasis on intersubband relaxation dynamics. Amplified femtosecond pulses are used for the generation of a femtosecond white light continuum, which has been used for the femtosecond differential transmission spectroscopy. We extensively studied the carrier relaxation for both low and high density excitation. The carrier capture, which is the intrinsic limit to the highest modulation bandwidth for SCH quantum well semiconductor lasers, has been time-resolved via femtosecond differential transmission spectroscopy. Strong capture resonances have been observed. Since the capture experiments reported to date do not directly measure the capture under conditions of laser operation, we have extended a three-pulse technique to remove carriers from the gain region of an inverted quantum well and monitor the gain recovery. This yields capture and relaxation times more appropriate for comparison with modulated laser operation. The gain recovery in a separate-confinement quantum-well structure limited by the carrier capture is directly time-resolved as well as spectral hole burning. Long carrier capture times are observed in the case of high density excitation due to Pauli-exclusion principle. The carrier tunneling dynamics in the new developed high speed tunneling injection laser (TIL) are also spectrally and temporally resolved. The measured ultrafast tunneling times confirm the TIL's potential for high speed applications. Ultrafast

  2. Halo-independent direct detection analyses without mass assumptions

    SciTech Connect

    Anderson, Adam J.; Fox, Patrick J.; Kahn, Yonatan; McCullough, Matthew

    2015-10-06

    Results from direct detection experiments are typically interpreted by employing an assumption about the dark matter velocity distribution, with results presented in the m{sub χ}−σ{sub n} plane. Recently methods which are independent of the DM halo velocity distribution have been developed which present results in the v{sub min}−g-tilde plane, but these in turn require an assumption on the dark matter mass. Here we present an extension of these halo-independent methods for dark matter direct detection which does not require a fiducial choice of the dark matter mass. With a change of variables from v{sub min} to nuclear recoil momentum (p{sub R}), the full halo-independent content of an experimental result for any dark matter mass can be condensed into a single plot as a function of a new halo integral variable, which we call h-til-tilde(p{sub R}). The entire family of conventional halo-independent g-tilde(v{sub min}) plots for all DM masses are directly found from the single h-tilde(p{sub R}) plot through a simple rescaling of axes. By considering results in h-tilde(p{sub R}) space, one can determine if two experiments are inconsistent for all masses and all physically possible halos, or for what range of dark matter masses the results are inconsistent for all halos, without the necessity of multiple g-tilde(v{sub min}) plots for different DM masses. We conduct a sample analysis comparing the CDMS II Si events to the null results from LUX, XENON10, and SuperCDMS using our method and discuss how the results can be strengthened by imposing the physically reasonable requirement of a finite halo escape velocity.

  3. [Immunotherapy of tumors of the central nervous system].

    PubMed

    Monod, L; Sawamura, Y; De Tribolet, N

    1992-01-01

    Malignant brain tumors are rapidly fatal and adjunction of chemo- and radio-therapy to surgical treatment has little changed their poor prognosis. The development of basic and clinical research in immunology of brain tumors has lead to new therapeutic strategies: 1) Humoral factors: Monoclonal antibodies (MAbs): alone or conjugated (to toxins, radionucleides or chemotherapeutic agents), MAbs can theoretically recognize antigens expressed by tumor cells and reach this target with high specificity. Large amounts of tumoricidal agents could be given to the tumor with low toxic effects to normal tissues. 2) Cellular factors: LAK cells: (lymphokine-activated-killer-cells) and activated TILs (tumor-infiltrating-lymphocytes) are autologous cytotoxic cells which can be produced by ex-vivo culture techniques and infused to the patient. These are very potent tumor-killer cells in vitro, however their in vivo effect is far less dramatic at the moment. 3) Cytokines: interferons, interleukins and other biological modifiers can act either directly on the tumor cells (cytotoxic effect) or indirectly through the modulation of the host-to-tumor response. 4) Combination of humoral and cellular factors: bispecific monoclonal antibodies are hybrid-molecules built from two different MAbs which can recognize two different targets, usually a tumor antigen on one hand and the T-cell-receptor (T 3) on the other hand. This combination of humoral and cellular effectors can theoretically lead to a preferential binding of effector cells to the tumor. All these new techniques are extensively studied in research laboratories and clinical trials without clear therapeutical benefit for the moment.

  4. Molecular cloning, tissue expression of gene Muc2 in blunt snout bream Megalobrama amblycephala and regulation after re-feeding

    NASA Astrophysics Data System (ADS)

    Xue, Chunyu; Xi, Bingwen; Ren, Mingchun; Dong, Jingjing; Xie, Jun; Xu, Pao

    2015-03-01

    Mucins are important components of mucus, which form a natural, physical, biochemical and semipermeable mucosal layer on the epidermis of fish gills, skin, and the gastrointestinal tract. As the first step towards characterizing the function of Muc2, we cloned a partial Megalobrama amblycephala Muc2 cDNA of 2 175 bp, and analyzed its tissue-specific expression pattern by quantitative real-time PCR (qPCR). The obtained sequence comprised 41 bp 5'-untranslated region (5'-UTR), 2 134 bp open reading frame encoding a protein of 711 amino acids. BLAST searching and phylogenetic analysis showed that the predicted protein contained several common secreted mucin-module domains (VWD-C8-TIL-VWD-C8) and had high homology with mucins from other vertebrates. Among four candidate reference genes ( β- Actin, RPI13α, RPII, 18S) for the qPCR, RPII was chosen as an appropriate reference gene because of its lowest variation in different tissues. M. amblycephala Muc2 was mainly expressed in the intestine, in the order (highest to lowest) middle-intestine > fore-intestine > hind-intestine. Muc2 was expressed relatively poorly in other organs (brain, liver, kidney, spleen, skin and gill). Furthermore, after 20-days of starvation, M. amblycephala Muc2 expressions after refeeding for 0 h, 3 h, 16 h, 3 d, and 10 d were significantly decreased in the three intestinal segments ( P<0.05) at 16 h, and were then upregulated to near the initial level at 10 d.

  5. Differential expression of immune-regulatory genes associated with PD-L1 display in melanoma: implications for PD-1 pathway blockade

    PubMed Central

    Taube, Janis M.; Young, Geoffrey D.; McMiller, Tracee L.; Chen, Shuming; Salas, January T.; Pritchard, Theresa S.; Xu, Haiying; Meeker, Alan K.; Fan, Jinshui; Cheadle, Chris; Berger, Alan E.; Pardoll, Drew M.; Topalian, Suzanne L.

    2015-01-01

    Purpose Blocking the immunosuppressive PD-1/PD-L1 pathway has anti-tumor activity in multiple cancer types, and PD-L1 expression on tumor cells and infiltrating myeloid cells correlates with the likelihood of response. We previously found that IFNG (interferon-gamma) was over-expressed by TILs in PD-L1+ vs. PD-L1(−) melanomas, creating adaptive immune resistance by promoting PD-L1 display. The current study was undertaken to identify additional factors in the PD-L1+ melanoma microenvironment coordinately contributing to immunosuppression. Experimental design Archived, formalin-fixed paraffin-embedded melanoma specimens were assessed for PD-L1 protein expression at the tumor cell surface with immunohistochemistry (IHC). Whole genome expression analysis, quantitative (q)RT-PCR, immunohistochemistry, and functional in vitro validation studies were employed to assess factors differentially expressed in PD-L1+ versus PD-L1(−) melanomas. Results Functional annotation clustering based on whole genome expression profiling revealed pathways up-regulated in PD-L1+ melanomas, involving immune cell activation, inflammation, and antigen processing and presentation. Analysis by qRT-PCR demonstrated over-expression of functionally related genes in PD-L1+ melanomas, involved in CD8+ T cell activation (CD8A, IFNG, PRF1, CCL5), antigen presentation (CD163, TLR3, CXCL1, LYZ), and immunosuppression [PDCD1 (PD-1), CD274(PD-L1), LAG3, IL10]. Functional studies demonstrated that some factors, including IL-10 and IL-32-gamma, induced PD-L1 expression on monocytes but not tumor cells. Conclusions These studies elucidate the complexity of immune checkpoint regulation in the tumor microenvironment, identifying multiple factors likely contributing to coordinated immunosuppression. These factors may provide tumor escape mechanisms from anti-PD-1/PD-L1 therapy, and should be considered for co-targeting in combinatorial immunomodulation treatment strategies. PMID:25944800

  6. Combined treatment with dabrafenib and trametinib with immune-stimulating antibodies for BRAF mutant melanoma

    PubMed Central

    Homet Moreno, Blanca; Mok, Stephen; Comin-Anduix, Begonya; Hu-Lieskovan, Siwen; Ribas, Antoni

    2016-01-01

    The combination of targeted therapy with BRAF and MEK inhibitors has become the standard of care in patients with BRAFV600E mutant melanoma, but responses are not durable. In addition, the impressive clinical benefits with anti-PD-1 and anti-PD-L1 antibodies (Ab) in patients with heavily pretreated metastatic melanoma and the synergistic effect of dabrafenib, trametinib and anti-PD-1 compared with single therapy alone groups support the idea that combining dabrafenib, trametinib and immunotherapy based on PD-1 blockade could be an interesting approach in the treatment of metastatic melanoma. With our mouse model of syngeneic BRAFV600E driven melanoma (SM1), we tested whether the addition of an immunostimulatory Ab targeting CD137 (4-1BB) and/or CD134 (OX40) would enhance the antitumor effect of dabrafenib, trametinib and anti-PD-1 or anti-PD-L1 therapy. In vitro studies showed that the combination group of dabrafenib, trametinib and anti-PD-1 increases CD8+ tumor infiltrating lymphocytes (TILs), as well as CD4+ T cells and tumor-associated macrophages (TAMs). An upregulation of PD-L1 was observed in the combination of dabrafenib, trametinib and anti-PD-1 therapy. Combination of dabrafenib, trametinib and anti-PD-1, with either anti-CD137 or anti-CD134, showed a superior antitumor effect, but the five-agent combination was not superior to the four-agent combinations. In conclusion, the combination of dabrafenib, trametinib, anti-PD1 or anti-PD-L1 therapy results in robust antitumor activity, which is further improved by adding the immune-stimulating Ab anti-CD137 or anti-CD134. Our findings support the testing of these combinations in patients with BRAFV600E mutant metastatic melanoma. PMID:27622011

  7. The classification and complex thermal history of the enstatite chondrites

    NASA Technical Reports Server (NTRS)

    Zhang, Yanhong; Benoit, Paul H.; Sears, Derek W. G.

    1995-01-01

    We have carried out instrumental neutron activation analysis of 11 enstatite chondrites and electron microprobe analyses of 17 enstatite chondrites, most of which were previously little described. We report here the third known EH5 chondrite (LEW 88180) and an unusual EL6 chondrite (LEW 87119), new data on four EL3 chondrites (ALH 85119, EET 90299, PCA 91020, and MAC 88136, which is paired with MAC 88180 and MAC 88184), the second EL5 chondrite (TIL 91714), and an unusual metal-rich and sulfide-poor EL3 chondrite (LEW 87223). The often discussed differences in mineral composition displayed by the EH and EL chondrites are not as marked after the inclusion of the new samples in the database, and the two classes apparently experienced a similar range of equilibrium temperatures. However, texturally the EL chondrites appear to have experienced much higher levels of metamorphic alteration than EH chondrites of similar equilibration temperatures. Most of the petrologic type criteria are not applicable to enstatite chondrites and, unlike the ordinary chondrites, texture and mineralogy reflect different aspects of the meteorite history. We therefore propose that the existing petrologic type scheme not be used for enstatite chondrites. We suggest that while 'textural type' reflects peak metamorphic temperatures, the 'mineralogical type' reflects equilibration during postmetamorphic (probably regolith) processes. Unlike the ordinary chondrites and EH chondrites, EL chondrites experienced an extensive low-temperature metamorphic episode. There are now a large number of enstatite meteorite breccias and impact melts, and apparently surface processes were important in determining the present nature of the enstatite chondrites.

  8. Patterns of bird functional diversity on land-bridge island fragments.

    PubMed

    Ding, Zhifeng; Feeley, Kenneth J; Wang, Yanping; Pakeman, Robin J; Ding, Ping

    2013-07-01

    The loss of species diversity due to habitat fragmentation has been extensively studied. In contrast, the impacts of habitat fragmentation on functional diversity remains relatively poorly understood. We conducted bird functional diversity studies on a set of 41 recently isolated land-bridge islands in the Thousand Island Lake, China. We analysed differences in bird species richness and a recently developed suite of complementary functional diversity indices (FRic, volume of functional space occupied; FEve, evenness of abundance distribution in the functional trait space; FDiv, divergence in the distribution of abundance in the trait volume) across different gradients (island area and isolation). We found no correlations between FRic and FEve or FEve and FDiv, but negative correlations between FRic and FDiv. As predicted, island area accounted for most of the variation in bird species richness, whereas isolation explained most of the variation in species evenness (decreasing species evenness with increasing isolation). Functional diversity appears to be more strongly influenced by habitat filtering as opposed to limiting similarity. More specifically, across all islands, both FRic and FEve were significantly lower than expected for randomly assembled communities, but FDiv showed no clear patterns. FRic increased with island area, FEve decreased with island area and FDiv showed no clear patterns. Our finding that FEve decreases with island area at TIL may indicate low functional stability on such islands, and as such large islands and habitat patches may deserve extra attention and/or protection. These results help to demonstrate the importance of considering the effects of fragmentation on functional diversity in habitat management and reserve design plans.

  9. Recombinant erythropoietin in humans has a prolonged effect on circulating erythropoietin isoform distribution.

    PubMed

    Aachmann-Andersen, Niels Jacob; Just Christensen, Søren; Lisbjerg, Kristian; Oturai, Peter; Meinild-Lundby, Anne-Kristine; Holstein-Rathlou, Niels-Henrik; Lundby, Carsten; Vidiendal Olsen, Niels

    2014-01-01

    The membrane-assisted isoform immunoassay (MAIIA) quantitates erythropoietin (EPO) isoforms as percentages of migrated isoforms (PMI). We evaluated the effect of recombinant human EPO (rhEPO) on the distribution of EPO isoforms in plasma in a randomized, placebo-controlled, double-blinded, cross-over study. 16 healthy subjects received either low-dose Epoetin beta (5000 IU on days 1, 3, 5, 7, 9, 11 and 13); high-dose Epoetin beta (30.000 IU on days 1, 2 and 3 and placebo on days 5, 7, 9, 11 and 13); or placebo on all days. PMI on days 4, 11 and 25 was determined by interaction of N-acetyl glucosamine with the glycosylation dependent desorption of EPO isoforms. At day 25, plasma-EPO in both rhEPO groups had returned to values not different from the placebo group. PMI with placebo, reflecting the endogenous EPO isoforms, averaged 82.5 (10.3) % (mean (SD)). High-dose Epoetin beta decreased PMI on days 4 and 11 to 31.0 (4.2)% (p<0.00001) and 45.2 (7.3)% (p<0.00001). Low-dose Epoetin beta decreased PMI on days 4 and 11 to 46.0 (12.8)% (p<0.00001) and 46.1 (10.4)% (p<0.00001). In both rhEPO groups, PMI on day 25 was still decreased (high-dose Epoetin beta: 72.9 (19.4)% (p=0.029); low-dose Epoetin beta: 73.1 (17.8)% (p=0.039)). In conclusion, Epoetin beta leaves a footprint in the plasma-EPO isoform pattern. MAIIA can detect changes in EPO isoform distribution up til at least three weeks after administration of Epoetin beta even though the total EPO concentration has returned to normal.

  10. New insights into the chemical structure of Y2Ti2O7-δ nanoparticles in oxide dispersion-strengthened steels designed for sodium fast reactors by electron energy-loss spectroscopy

    NASA Astrophysics Data System (ADS)

    Badjeck, V.; Walls, M. G.; Chaffron, L.; Malaplate, J.; March, K.

    2015-01-01

    In this paper we study by high resolution scanning transmission electron microscopy coupled with electron energy-loss spectroscopy (STEM-EELS) an oxide dispersion-strengthened (ODS) steel with the nominal composition Fe-14Cr-1W-0.3TiH2-0.3Y2O3 (wt.%) designed to withstand the extreme conditions met in Gen. IV nuclear reactors. After denoising via principal component analysis (PCA) the data are analyzed using independent component analysis (ICA) which is useful in the investigation of the physical properties and chemical structure of the material by separating the individual spectral responses. The Y-Ti-O nanoparticles are found to be homogeneously distributed in the ferritic matrix, sized from 1 to 20 nm and match a non-stoichiometric pyrochlore-Y2Ti2O7-δ structure for sizes greater than 5 nm. We show that they adopt a (Y-Ti-O)-Cr core-shell structure and that Cr also segregates at the matrix grain boundaries, which may slightly modify the corrosion properties of the steel. Using Ti-L2,3 and O-K fine structure (ELNES) the Ti oxidation state is shown to vary from the center of the nanoparticles to their periphery, from Ti4+ in distorted Oh symmetry to a valency often lower than 3+. The sensitivity of the Ti "white lines" ELNES to local symmetry distortions is also shown to be useful when investigating the strain induced in the nanoparticles by the surrounding matrix. The Cr-shell and the variation of the Ti valence state highlight a complex nanoparticle-matrix interface.

  11. Targeting metastatic cancer from the inside: a new generation of targeted gene delivery vectors enables personalized cancer vaccination in situ.

    PubMed

    Gordon, Erlinda M; Levy, John P; Reed, Rebecca A; Petchpud, W Nina; Liu, Liqiong; Wendler, Carlan B; Hall, Frederick L

    2008-10-01

    The advent of pathotropic (disease-seeking) targeting technologies, combined with advanced gene delivery vectors, provides a unique opportunity for the systemic delivery of immunomodulatory cytokine genes to remote sites of cancer metastasis. When injected intravenously, such pathotropic nanoparticles seek out and accumulate selectively at sites of tumor invasion and neo-angiogenesis, resulting in enhanced gene delivery, and thus cytokine production, within the tumor nodules. Used in conjunction with a primary tumoricidal agent (e.g., Rexin-G) that exposes tumor neoantigens, the tumor-targeted immunotherapy vector is intended to promote the recruitment and activation of host immune cells into the metastastic site(s), thereby initiating cancer immunization in situ. In this study, we examine the feasibility of cytokine gene delivery to cancerous lesions in vivo using intravenously administered pathotropically targeted nanoparticles bearing the gene encoding granulocyte/macrophage colony-stimulating factor (GM-CSF; i.e., Reximmune-C). In vitro, transduction of target cancer cells with Reximmune-C resulted in the quantitative production of bioactive and immunoreactive GM-CSF protein. In tumor-bearing nude mice, intravenous infusions of Reximmune-C-induced GM-CSF production by transduced cancer cells and paracrine secretion of the cytokine within the tumor nodules, which promoted the recruitment of host mononuclear cells, including CD40+ B cells and CD86+ dendritic cells, into the tumors. With the first proofs of principle established in preclinical studies, we generated an optimized vector configuration for use in advanced clinical trial designs, and extended the feasibility studies to the clinic. Targeted delivery and localized expression of the GM-CSF transgene was confirmed in a patient with metastatic cancer, as was the recruitment of significant tumor-infiltrating lymphocytes (TILs). Taken together, these studies provide the first demonstrations of cytokine gene

  12. Comparative toxicity of metal oxide nanoparticles (CuO, ZnO and TiO2) to developing zebrafish embryos

    NASA Astrophysics Data System (ADS)

    Vicario-Parés, Unai; Castañaga, Luis; Lacave, Jose Maria; Oron, Miriam; Reip, Paul; Berhanu, Deborah; Valsami-Jones, Eugenia; Cajaraville, Miren P.; Orbea, Amaia

    2014-08-01

    Increasing use of nanomaterials is resulting in their release into the environment, making necessary to determine the toxicity of these materials. With this aim, the effects of CuO, ZnO and TiO2 nanoparticles (NPs) on zebrafish development were assessed in comparison with the effects caused by the ionic forms (for copper and zinc), bulk counterparts and the stabilizer used for rutile TiO2 NPs. None of the NPs caused significant embryo mortality. CuO NPs were the most toxic affecting hatching and increasing malformation prevalence (≥1 mg Cu/L), followed by ZnO NPs that affected hatching at ≥5 mg Zn/L and stabilized TiO2 NPs that caused mortality and decreased hatching at 100 mg Ti/L. Exposure to the stabilizer alone provoked the same effect. Thus, toxicity of the TiO2 NP suspension can be linked to the surfactant. For all the endpoints, the greatest effects were exerted by the ionic forms, followed by the NPs and finally by the bulk compounds. By autometallography, metal-bearing deposits were observed in embryos exposed to CuO and ZnO NPs, being more abundant in the case of embryos exposed to CuO NPs. The largest and most abundant metal-bearing deposits were detected in embryos exposed to ionic copper. In conclusion, metal oxide NPs affected zebrafish development altering hatching and increasing the prevalence of malformations. Thus, the use and release of metal oxide NPs to the environment may pose a risk to aquatic organisms as a result of the toxicity caused by NPs themselves or by the additives used in their production.

  13. PREFACE: XXXIV Symposium on Nuclear Physics

    NASA Astrophysics Data System (ADS)

    Barrón-Palos, Libertad; Bijker, Roelof

    2011-10-01

    In the present volume of the Journal of Physics: Conference Series we publish the proceedings of the 'XXXIV Symposium on Nuclear Physics', which was held from 4-7 January 2011 at the Hacienda Cocoyoc, Morelos, Mexico. The proceedings consist of 19 contributions that were presented as invited talks at the meeting. The abstracts of all contributions, plenary talks and posters were published in the Conference Handbook. The Symposium on Nuclear Physics has a long and distinguished history. From the beginning it was intended to be a relatively small meeting designed to bring together some of the leading nuclear scientists in the field. Its most distinctive feature is to provide a forum for specialists in different areas of nuclear physics, both theorists and experimentalists, students, postdocs and senior scientists, in a relaxed and informal environment providing them with a unique opportunity to exchange ideas. From the first meeting in Oaxtepec in 1978, the Symposium has been organized every year without interruption, which makes the present Symposium the 34th in a row. The scientific program consisted of 27 invited talks and 17 posters on a wide variety of hot topics in contemporary nuclear physics, ranging from the traditional fields of nuclear structure (Draayer, Pittel, Van Isacker, Fraser, Lerma, Cejnar, Hirsch, Stránský and Rath) and nuclear reactions (Aguilera, Gómez-Camacho, Scheid, Navrátil and Yennello) to radioactive beams (Padilla-Rodal and Galindo-Uribarri), nuclear astrophysics (Aprahamian, Civitarese and Escher), hadronic physics (Bijker, Valcarce and Hess), fundamental symmetries (Liu, Barrón-Palos and Baessler) and LHC physics (Menchaca-Rocha and Paic). The high quality of the talks, the prestige of the speakers and the broad spectrum of subjects covered in the meeting, shows that nuclear physics is a very active area at the frontier of scientific research which establishes bridges between many different disciplines. Libertad Barr

  14. Programmed Death Ligand 1 (PD-L1) Tumor Expression Is Associated with a Better Prognosis and Diabetic Disease in Triple Negative Breast Cancer Patients.

    PubMed

    Botti, Gerardo; Collina, Francesca; Scognamiglio, Giosuè; Rao, Federica; Peluso, Valentina; De Cecio, Rossella; Piezzo, Michela; Landi, Gabriella; De Laurentiis, Michelino; Cantile, Monica; Di Bonito, Maurizio

    2017-02-21

    Triple Negative Breast Cancers (TNBC) subtype is an aggressive disease with poor clinical outcome. The only treatment available is surgery followed by chemotherapy or radiotherapy. Programmed death-ligand 1 (PD-L1) is a trans-membrane protein expressed on a wide variety of cells including immune cells, epithelial and vascular endothelial cells. Recently, PD-1/PD-L1 pathway signaling was described as an adaptive immune resistance mechanism enacted by the tumor cells to evade the immune response. Its presence on tumor cell membranes, acquired for this reason, through time, is an important prognostic value. However, data available in the literature about PD-L1 immunohistochemical expression in breast cancer are often discordant and not uniform, probably for the use of different antibodies clones and the high molecular heterogeneity of the different tumor types. The absence of target therapies, in particular for TNBC, has shifted the clinical attention mainly on the role of PD-L1 in this subtype of breast cancer. In this study, we evaluated tumor and TIL (tumor infiltrating lymphocytes) PDL-1 expression in a series of TNBC, included in Tissue Micro Arrays (TMAs), to define its real prognostic value, optimizing immunohistochemistry method with an "approved for diagnostic assay" antibody. PD-L1 expression directly correlated with proliferation index (Ki-67), glycemia, the presence of diabetes and indirectly with menopausal status, presence of lymph node metastasis and relapse. The analysis of Kaplan-Meier showed that an increased PD-L1 expression was strongly associated with better disease-free survival (DFS) but not correlated with overall survival (OS). Our data confirmed that PD-L1 could be an important marker for prognostic stratification and for planning immune checkpoint inhibitors therapies in patients with TNBC.

  15. [Current events in immunotherapy for upper aerodigestive tract cancer].

    PubMed

    Outh-Gauer, Sophie; Le Tourneau, Christophe; Broudin, Chloé; Scotte, Florian; Roussel, Hélène; Hans, Stéphane; Mandavit, Marion; Tartour, Eric; Badoual, Cécile

    2017-02-01

    Head and neck (HN) carcinomas (mostly represented by squamous cell carcinomas [SCC]) still have a poor prognosis, which could be dramatically improved with immunotherapy. Tumor's microenvironment changes, caused by many endogenous or exogenous events, can correlate with prognosis and therapeutic response. Here, we review recent data regarding HNSCC, nasopharyngeal carcinomas (NPC) and salivary gland malignant tumors, all three being potential target of immunotherapies. About half of HNSCC exhibit PD-L1 expression, this expression being upregulated in HPV-positive tumors. In recent clinical trials, a better therapeutic response to anti-PD-1 has been obtained in patients with higher PD-L1 expression. Food and Drug Administration (FDA) approved the use of these therapeutics without the screening of patients regarding PD-L1 status. Activation status, density and localisation of TIL as well as PD-L2, γ-interferon, inflammatory cytokines, epithelial-mesenchymal transition phenotype and mutational burden may all be potential therapeutic response markers. In Epstein-Barr Virus (EBV)-induced nasopharyngeal non-keratinizing cancer, PD-L1 is over-expressed compared to EBV negative-tumors. A 22 % response rate has been observed under anti-PD-1 treatment, among PD-L1-positive HNSCC patients. There is little data regarding microenvironment of salivary gland cancer. PD-L1 shows great heterogeneity in localisation, when expressed. A 11 % response rate has been obtained under anti-PD-1 treatment among PD-L1-positive NPC patients. A better understanding of immune checkpoint regulation processes needs to be achieved to allow patients with HN carcinomas to benefit from these promising immunotherapies.

  16. Preparation, characterization, and insecticidal activity evaluation of three different formulations of Beauveria bassiana against Musca domestica.

    PubMed

    Mishra, Sapna; Kumar, Peeyush; Malik, Anushree

    2013-10-01

    Three formulations; bait, encapsulation, and emulsion of Beauveria bassiana were prepared and evaluated for their insecticidal activity in simulated field settings. Tea waste-based bait formulation of B. bassiana showed 100% mortality (within 72 h) in lab assay against adult houseflies. In field assay using traps, 65% relative entrapment and 100 % mortality (within 60 h) of entrapped flies was observed. Although the bait formulation was low cost and easy to prepare and transport, its storage ability was limited. Hence, more advanced formulations in form of encapsulation and emulsion was attempted. Encapsulated B. bassiana conidia (using skimmed milk powder, polyvinyl pyrrolidone K-90 and glucose as additives) showed 100% conidial germination and retained 78% conidial viability, even after storage for 12 months at 30 °C. Encapsulated product showed 54.8% (freshly prepared) and 30.6 % (after 12-months storage) mortality of housefly larvae in a simulated field condition. Emulsion formulation was prepared by using Tween 20 as surfactant with seven vegetable oils: soybean, rapeseed, sunflower, olive, castor, til, and linseed. Emulsion with linseed oil showing maximum conidial germination (94%) was evaluated for shelf life and pathogenecity against housefly larvae. Shelf life analysis of emulsion revealed 28% conidial germination and 19.9% housefly larval mortality after 12 months of storage as opposed to 94% conidial germination and 51.7% of larval mortality with fresh product. Significant increase in shelf × targeted application of formulation is expected to increase its mass applicability for housefly control. Also, the variability among products presents diverse opportunities for commercialization.

  17. Science of Opportunity: Heliophysics on the FASTSAT Mission and STP-S26

    NASA Technical Reports Server (NTRS)

    Rowland, Douglas E.; Collier, Michael R.; Sigwarth, John B.; Jones, Sarah L.; Hill, Joanne K.; Benson, Robert; Choi, Michael; Chornay, Dennis; Cooper, John; Feng, Steven; Gill, Nathaniel; Goodloe, Colby; Han, Lawrence; Hancock, Holly; Hunsaker, Floyd; Jones, Noble; Keller, John W.; Klenzing, Jeffrey; Kleyner, Igor; Moore, Tom; Ogilvie, Keith; Boudreaux, Mark; Casas, Joseph; Myre, David; Smith, Billy

    2011-01-01

    The FASTSAT spacecraft, which was launched on November 19, 2010 on the DoD STP-S26 mission, carries three instruments developed in joint collaboration by NASA GSFC and the US Naval Academy: PISA, TTl, and MINI_ME.I,1 As part of a rapid-development, low-cost instrument design and fabrication program, these instruments were a perfect match for FASTSAT, which was designed and built in less than one year. These instruments, while independently developed, provide a collaborative view of important processes in the upper atmosphere relating to solar and energetic particle input, atmospheric response, and ion outflow. PISA measures in-situ irregularities in electron number density, TIl provides limb measurements of the atomic oxygen temperature profile with altitude, and MINI-ME provides a unique look at ion populations by a remote sen sing technique involving neutral atom imaging. Together with other instruments and payloads on STP-S26 such as the NSF RAX mission, FalconSat-5, and NanoSail-D (launched as a tertiary payload from FASTSAT), these instruments provide a valuable "constellation of opportunity" for following the now of energy and charged and neutral particles through the upper atmosphere. Together, and for a small fraction of the price of a major mission, these spacecraft will measure the energetic electrons impacting the upper atmosphere, the ions leaving it, and the large-scale plasma and neutral response to these energy inputs. The result will be a new model for maximizing scientific return from multiple small, distributed payloads as secondary payloads on a larger launch vehicle.

  18. Gene expression profile correlates with T cell infiltration and relative survival in glioblastoma patients vaccinated with dendritic cell immunotherapy

    PubMed Central

    Prins, Robert M.; Soto, Horacio; Konkankit, Vera; Odesa, Sylvia K.; Eskin, Ascia; Yong, William H.; Nelson, Stanley F.; Liau, Linda M.

    2010-01-01

    Purpose To assess the feasibility, safety, and toxicity of autologous tumor lysate-pulsed dendritic cell (DC) vaccination and toll-like receptor (TLR) agonists in patients with newly diagnosed and recurrent glioblastoma. Clinical and immune responses were monitored and correlated with tumor gene expression profiles. Experimental Design Twenty-three patients with glioblastoma (WHO grade IV) were enrolled in this dose-escalation study and received three biweekly injections of glioma lysate-pulsed DCs followed by booster vaccinations with either imiquimod or poly-ICLC adjuvant every three months until tumor progression. Gene expression profiling, IHC, FACS, and cytokine bead arrays were performed on patient tumors and PBMC. Results DC vaccinations are safe and not associated with any dose-limiting toxicity. The median overall survival from the time of initial surgical diagnosis of glioblastoma was 31.4 months, with a one-, two-, and three-year survival rate of 91%, 55% and 47%, respectively. Patients whose tumors had mesenchymal gene expression signatures exhibited increased survival following DC vaccination compared to historical controls of the same genetic subtype. Tumor samples with a mesenchymal gene expression signature had a higher number of CD3+ and CD8+ tumor infiltrating lymphocytes (TILs) compared with glioblastomas of other gene expression signatures (p = 0.006). Conclusion Autologous tumor lysate-pulsed DC vaccination in conjunction with TLR agonists is safe as adjuvant therapy in newly diagnosed and recurrent glioblastoma patients. Our results suggest that the mesenchymal gene expression profile may identify an immunogenic subgroup of glioblastoma that may be more responsive to immune-based therapies. PMID:21135147

  19. Integrating the genetic and physical maps of Arabidopsis thaliana: identification of mapped alleles of cloned essential (EMB) genes.

    PubMed

    Meinke, David; Sweeney, Colleen; Muralla, Rosanna

    2009-10-08

    The classical genetic map of Arabidopsis includes more than 130 genes with an embryo-defective (emb) mutant phenotype. Many of these essential genes remain to be cloned. Hundreds of additional EMB genes have been cloned and catalogued (www.seedgenes.org) but not mapped. To facilitate EMB gene identification and assess the current level of saturation, we updated the classical map, compared the physical and genetic locations of mapped loci, and performed allelism tests between mapped (but not cloned) and cloned (but not mapped) emb mutants with similar chromosome locations. Two hundred pairwise combinations of genes located on chromosomes 1 and 5 were tested and more than 1100 total crosses were screened. Sixteen of 51 mapped emb mutants examined were found to be disrupted in a known EMB gene. Alleles of a wide range of published EMB genes (YDA, GLA1, TIL1, AtASP38, AtDEK1, EMB506, DG1, OEP80) were discovered. Two EMS mutants isolated 30 years ago, T-DNA mutants with complex insertion sites, and a mutant with an atypical, embryo-specific phenotype were resolved. The frequency of allelism encountered was consistent with past estimates of 500 to 1000 EMB loci. New EMB genes identified among mapped T-DNA insertion mutants included CHC1, which is required for chromatin remodeling, and SHS1/AtBT1, which encodes a plastidial nucleotide transporter similar to the maize Brittle1 protein required for normal endosperm development. Two classical genetic markers (PY, ALB1) were identified based on similar map locations of known genes required for thiamine (THIC) and chlorophyll (PDE166) biosynthesis. The alignment of genetic and physical maps presented here should facilitate the continued analysis of essential genes in Arabidopsis and further characterization of a broad spectrum of mutant phenotypes in a model plant.

  20. Programmed Death Ligand 1 (PD-L1) Tumor Expression Is Associated with a Better Prognosis and Diabetic Disease in Triple Negative Breast Cancer Patients

    PubMed Central

    Botti, Gerardo; Collina, Francesca; Scognamiglio, Giosuè; Rao, Federica; Peluso, Valentina; De Cecio, Rossella; Piezzo, Michela; Landi, Gabriella; De Laurentiis, Michelino; Cantile, Monica; Di Bonito, Maurizio

    2017-01-01

    Triple Negative Breast Cancers (TNBC) subtype is an aggressive disease with poor clinical outcome. The only treatment available is surgery followed by chemotherapy or radiotherapy. Programmed death-ligand 1 (PD-L1) is a trans-membrane protein expressed on a wide variety of cells including immune cells, epithelial and vascular endothelial cells. Recently, PD-1/PD-L1 pathway signaling was described as an adaptive immune resistance mechanism enacted by the tumor cells to evade the immune response. Its presence on tumor cell membranes, acquired for this reason, through time, is an important prognostic value. However, data available in the literature about PD-L1 immunohistochemical expression in breast cancer are often discordant and not uniform, probably for the use of different antibodies clones and the high molecular heterogeneity of the different tumor types. The absence of target therapies, in particular for TNBC, has shifted the clinical attention mainly on the role of PD-L1 in this subtype of breast cancer. In this study, we evaluated tumor and TIL (tumor infiltrating lymphocytes) PDL-1 expression in a series of TNBC, included in Tissue Micro Arrays (TMAs), to define its real prognostic value, optimizing immunohistochemistry method with an “approved for diagnostic assay” antibody. PD-L1 expression directly correlated with proliferation index (Ki-67), glycemia, the presence of diabetes and indirectly with menopausal status, presence of lymph node metastasis and relapse. The analysis of Kaplan–Meier showed that an increased PD-L1 expression was strongly associated with better disease-free survival (DFS) but not correlated with overall survival (OS). Our data confirmed that PD-L1 could be an important marker for prognostic stratification and for planning immune checkpoint inhibitors therapies in patients with TNBC. PMID:28230773

  1. A Stromal Immune Module Correlated with the Response to Neoadjuvant Chemotherapy, Prognosis and Lymphocyte Infiltration in HER2-Positive Breast Carcinoma Is Inversely Correlated with Hormonal Pathways

    PubMed Central

    Lae, Marick; Moarii, Matahi; Sadacca, Benjamin; Pinheiro, Alice; Galliot, Marion; Abecassis, Judith; Laurent, Cecile; Reyal, Fabien

    2016-01-01

    Introduction HER2-positive breast cancer (BC) is a heterogeneous group of aggressive breast cancers, the prognosis of which has greatly improved since the introduction of treatments targeting HER2. However, these tumors may display intrinsic or acquired resistance to treatment, and classifiers of HER2-positive tumors are required to improve the prediction of prognosis and to develop novel therapeutic interventions. Methods We analyzed 2893 primary human breast cancer samples from 21 publicly available datasets and developed a six-metagene signature on a training set of 448 HER2-positive BC. We then used external public datasets to assess the ability of these metagenes to predict the response to chemotherapy (Ignatiadis dataset), and prognosis (METABRIC dataset). Results We identified a six-metagene signature (138 genes) containing metagenes enriched in different gene ontologies. The gene clusters were named as follows: Immunity, Tumor suppressors/proliferation, Interferon, Signal transduction, Hormone/survival and Matrix clusters. In all datasets, the Immunity metagene was less strongly expressed in ER-positive than in ER-negative tumors, and was inversely correlated with the Hormonal/survival metagene. Within the signature, multivariate analyses showed that strong expression of the “Immunity” metagene was associated with higher pCR rates after NAC (OR = 3.71[1.28–11.91], p = 0.019) than weak expression, and with a better prognosis in HER2-positive/ER-negative breast cancers (HR = 0.58 [0.36–0.94], p = 0.026). Immunity metagene expression was associated with the presence of tumor-infiltrating lymphocytes (TILs). Conclusion The identification of a predictive and prognostic immune module in HER2-positive BC confirms the need for clinical testing for immune checkpoint modulators and vaccines for this specific subtype. The inverse correlation between Immunity and hormone pathways opens research perspectives and deserves further investigation. PMID:28005906

  2. Relationship between expression of PD-L1 and PD-L2 on esophageal squamous cell carcinoma and the antitumor effects of CD8⁺ T cells.

    PubMed

    Leng, Changsen; Li, Yin; Qin, Jianjun; Ma, Jun; Liu, Xianben; Cui, Yingying; Sun, Haibo; Wang, Zongfei; Hua, Xionghuai; Yu, Yongkui; Li, Haomiao; Zhang, Jun; Zheng, Yan; Wang, Wei; Zhu, Junwei; Wang, Qiuming

    2016-02-01

    The programmed death-1 (PD-1)/programmed death-ligands (PD-Ls) signal pathway has been implicated as a potential immune escape mechanism in several human cancers. However, the studies of PD‑1/PD‑Ls pathway in esophageal squamous cell carcinoma (ECSS) are not yet sufficient. The current study investigated the expression of PD‑L1, PD‑L2 and PD‑1 in ESCC tissues. The correlations between the expression of these proteins and clinical histopathological parameters were analyzed. Then the stable transfected Ec109 cell lines overexpressing PD‑L1/PD‑L2 were established by plasmid transfection successfully. Ec109 and CD8+ T cells were co‑cultured to analyze the effects of PD‑1/PD‑Ls signal pathway on the function of CD8+ T cells including proliferation, apoptosis and interferon‑γ production. We found that PD‑L1-positive patients had significantly poorer prognosis than the negative patients, while their prognosis was not related to PD‑L2 expression. The count of PD‑1+ TILs (tumor‑infiltrating lymphocytes) was negatively correlated with both PD‑L1 and PD‑L2 expression. In functional studies, we found that PD‑1/PD‑Ls signal pathway was able to downregulate the function of CD8+ T lymphocyte and its function could be restored by blocking the signal pathway. This indicates that PD‑1/PD‑Ls may prevent effective antitumor immunity, which provides important evidence to delineate the cellular immune deficiency mechanism in ESCC. Therefore, PD-1/PD-Ls are predicted to become novel targets for ESCC immunotherapy.

  3. A straightforward kinetic evidence for coexistence of "induced fit" and "selected fit" in the reaction mechanism of a mutant tryptophan indole lyase Y72F from Proteus vulgaris.

    PubMed

    Faleev, Nicolai G; Zakomirdina, Lyudmila N; Vorob'ev, Mikhail M; Tsvetikova, Marina A; Gogoleva, Olga I; Demidkina, Tatyana V; Phillips, Robert S

    2014-10-01

    The interaction of the mutant tryptophan indole-lyase (TIL) from Proteus vulgaris Y72F with the transition state analogue, oxindolyl-l-alanine (OIA), with the natural substrate, l-tryptophan, and with a substrate S-ethyl-l-cysteine was examined. In the case of wild-type enzyme these reactions are described by the same kinetic scheme where binding of holoenzyme with an amino acid, leading to reversible formation of an external aldimine, proceeds very fast, while following transformations, leading finally to reversible formation of a quinonoid intermediate proceed with measureable rates. Principally the same scheme ("induced fit") is realized in the case of mutant Y72F enzyme reaction with OIA. For the reaction of mutant enzyme with l-Trp at lower concentrations of the latter a principally different kinetic scheme is observed. This scheme suggests that binding of the substrate and formation of the quinonoid intermediate are at fast equilibrium, while preceding conformational changes of the holoenzyme proceed with measureable rates ("selected fit"). For the reaction with S-ethyl-l-cysteine the observed concentration dependence of kobs agrees with the realization of both kinetic schemes, the "selected fit" becoming predominant at lower concentrations of substrate, the "induced fit"- at higher ones. In the reaction with S-ethyl-l-cysteine the formation of the quinonoid intermediate proceeds slower than does catalytic α,β-elimination of ethylthiol from S-ethyl-l-cysteine, and consequently does not play a considerable role in the catalysis, which may be effected by a concerted E2 mechanism.

  4. Comprehensive profiling of metaplastic breast carcinomas reveals frequent overexpression of programmed death-ligand 1

    PubMed Central

    Joneja, Upasana; Vranic, Semir; Swensen, Jeffrey; Feldman, Rebecca; Chen, Wangjuh; Kimbrough, Jeffrey; Xiao, Nianqing; Reddy, Sandeep; Palazzo, Juan; Gatalica, Zoran

    2017-01-01

    Aims Metaplastic breast carcinoma (MBC) is a rare subtype of breast carcinoma less responsive to conventional chemotherapy than ductal carcinoma. In molecular terms, MBCs usually cluster with triple-negative breast cancers (TNBCs), but have a worse prognosis than TNBCs. Studies investigating MBCs for specific biomarkers of therapy response are rare and limited by the methodological approaches. The aim of the present study was to characterise MBCs on a molecular level and test programmed death-ligand 1 (PD-L1) biomarker expression in MBCs for future therapeutic interventions. Methods We profiled 297 samples (MBC (n=75), TNBC (n=106), human epidermal growth factor receptor 2 (HER2)-positive breast cancers (n=32) and hormone-positive breast cancers (n=84)) by next-generation sequencing. Immunohistochemistry for PD-L1 and programmed cell death 1 (PD-1) expression was performed using automated procedures. Results The most commonly mutated genes in MBCs included TP53 (56%) and PIK3CA (23%). Pathogenic mutations in other genes, including HRAS, FBXW7, PTEN, AKT1 and SMAD4, were rare. PD-L1 expression was detected in a significantly higher proportion of MBCs (46%) than in other subtypes (6% each in hormone-positive and HER2-positive breast cancers, and 9% in TNBC, not otherwise specified, p<0.001). PD-1-positive tumour infiltrating lymphocytes (TILs) varied greatly in MBCs. Conclusions Comprehensive profiling of a large cohort of this rare subtype of breast carcinoma highlighted the predominance of TP53 mutation and increased PD-L1 expression in carcinoma cells. These results can be exploited in clinical trials using immune checkpoint inhibitors. PMID:27531819

  5. Technical Considerations for the Generation of Adoptively Transferred T Cells in Cancer Immunotherapy

    PubMed Central

    Visioni, Anthony; Skitzki, Joseph

    2016-01-01

    A significant function of the immune system is the surveillance and elimination of aberrant cells that give rise to cancer. Even when tumors are well established and metastatic, immune-mediated spontaneous regressions have been documented. While there are have been various forms of immunotherapy, one of the most widely studied for almost 40 years is adoptive cellular immunotherapy, but its success has yet to be fully realized. Adoptive cell transfer (ACT) is a therapeutic modality that has intrigued physicians and researchers for its many theoretical benefits. Preclinical investigations and human trials have utilized natural killer (NK) cells, dendritic cells (DC), macrophages, T-cells or B-cells for ACT with the most intense research focused on T-cell ACT. T-cells are exquisitely specific to the target of its T-cell receptor (TCR), thus potentially reducing the amount of collateral damage and off-target effects from treatment. T-cells also possess a memory subset that may reduce the risk of recurrence of a cancer after the successful treatment of the primary disease. There are several options for the source of T-cells used in the generation of cells for ACT. Perhaps the most widely known source is T-cells generated from tumor-infiltrating lymphocytes (TILs). However, studies have also employed peripheral blood mononuclear cells (PBMCs), lymph nodes, and even induced pluripotent stem cells (IPSCs) as a source of T-cells. Several important technical considerations exist regarding benefits and limitations of each source of T-cells. Unique aspects of T-cells factor into their ability to be efficacious in ACT including the total number of cells available for ACT, the anti-tumor efficacy on a per cell basis, the repertoire of TCRs specific to tumor cells, and their ability to traffic to various organs that harbor tumor. Current research is attempting to unlock the full potential of these cells to effectively and safely treat cancer. PMID:27657129

  6. Therapeutic PD-1 pathway blockade augments with other modalities of immunotherapy T-cell function to prevent immune decline in ovarian cancer.

    PubMed

    Duraiswamy, Jaikumar; Freeman, Gordon J; Coukos, George

    2013-12-01

    The tumor microenvironment mediates induction of the immunosuppressive programmed cell death-1 (PD-1) pathway, and targeted interventions against this pathway can help restore antitumor immunity. To gain insight into these responses, we studied the interaction between PD-1 expressed on T cells and its ligands (PD-1:PD-L1, PD-1:PD-L2, and PD-L1:B7.1), expressed on other cells in the tumor microenvironment, using a syngeneic orthotopic mouse model of epithelial ovarian cancer (ID8). Exhaustion of tumor-infiltrating lymphocytes (TIL) correlated with expression of PD-1 ligands by tumor cells and tumor-derived myeloid cells, including tumor-associated macrophages (TAM), dendritic cells, and myeloid-derived suppressor cells (MDSC). When combined with GVAX or FVAX vaccination (consisting of irradiated ID8 cells expressing granulocyte macrophage colony-stimulating factor or FLT3 ligand) and costimulation by agonistic α-4-1BB or TLR 9 ligand, antibody-mediated blockade of PD-1 or PD-L1 triggered rejection of ID8 tumors in 75% of tumor-bearing mice. This therapeutic effect was associated with increased proliferation and function of tumor antigen-specific effector CD8(+) T cells, inhibition of suppressive regulatory T cells (Treg) and MDSC, upregulation of effector T-cell signaling molecules, and generation of T memory precursor cells. Overall, PD-1/PD-L1 blockade enhanced the amplitude of tumor immunity by reprogramming suppressive and stimulatory signals that yielded more powerful cancer control.

  7. Tumor infiltrating CD8(+) T lymphocyte count is independent of tumor TLR9 status in treatment naïve triple negative breast cancer and renal cell carcinoma.

    PubMed

    Mella, Mikko; Kauppila, Joonas H; Karihtala, Peeter; Lehenkari, Petri; Jukkola-Vuorinen, Arja; Soini, Ylermi; Auvinen, Päivi; Vaarala, Markku H; Ronkainen, Hanna; Kauppila, Saila; Haapasaari, Kirsi-Maria; Vuopala, Katri S; Selander, Katri S

    2015-06-01

    Toll-like receptor 9 (TLR9) is a cellular DNA-receptor of the innate immune system that is widely expressed in cancers. We demonstrated that low tumor TLR9 expression predicts poor disease-specific survival in triple negative breast cancer (TNBC) and renal cell carcinoma (RCC). We hypothesized that this is because TLR9 expression affects tumor immunophenotype. To begin to test this, we compared the number of tumor infiltrating CD8(+) T lymphocytes with TLR9 expression in treatment naïve breast cancer (n = 197) and RCC (n = 94) cohorts with known TLR9 expression status. CD8(+) T lymphocyte counts were assayed with image analysis after immunohistochemistry (IHC). Tumor TLR9 expression was not correlated with CD8(+) T cell counts in breast cancer or RCC. CD8(+) T cell counts were significantly associated with tumor proliferation index in TNBC, but not in non-TNBC. CD8(+) T cell counts were also significantly associated with tumor grade in non-TNBC, but not in TNBC. In RCC, CD8(+) T cell counts were significantly associated with tumor stage. CD8(+) T cell counts were significantly associated with prognosis in TNBC and RCC, but the presence of CD8(+) T cells in these tumors had opposite effects on disease-specific survival: High CD8(+) counts were associated with better prognosis in TNBC and worse prognosis in RCC. Among TNBC patients, those with low tumor TLR9 and low CD8(+) T cell counts had the poorest prognosis (log-rank p = 0.0002 vs. high tumor TLR9 and high CD8(+) T cell count). In conclusion, pre-treatment tumor TLR9 status is not associated with tumor infiltrating CD8(+) T lymphocytes in TNBC or RCC. The combination of TLR9 and CD8(+) TIL count might be a novel composite prognostic marker in TNBC.

  8. Spontaneous Raman Scattering Diagnostics: Applications in Practical Combustion Systems. Chapter 5

    NASA Technical Reports Server (NTRS)

    Kojima, Jun; Viet-Nguyen, Quang; Lackner, Maximilian (Editor); Winter, Franz (Editor); Agarwal, Avinash (Editor)

    2010-01-01

    In this chapter, the recent advancements and practical aspects of laser SRS diagnostics have been reviewed wi til regards to applications in practical combustion systems. Clearly, SRS represents a theoretically and experimentally mature diagnostic technology that has become an essential tool for multiscalar measurements in turbulent combustion at elevated pressures. Today, time-, space-, spectrally, and even polarization-resolved S RS diagnostics is at hand, with aid from recent innovations in theoretical and technological developments on electro-optical or electromechanical devices. Whilst a linear increase in SRS signals can be expected in high-pressure systems (this is perhaps one of the most important advantages for using SRS in high-pressure systems), there are practical (often severe) restrictions associated with pressurized vessels, due mainly to the limited degree of optical access. This narrows ti,e available choice of diagnostics that can be employed at any given time. Point-wise SRS diagnostics provides the highest accuracy on the chemical species and temperature measurements, and will continue to remain a vital approach for the study in such harsh environments. The practical design considerations and hands-on set-up guide for SRS diagnostics provided in this chapter are rarely presented elsewhere. Although the second-harmonic Nd:YAG pulsed laser (532 nm), combined with pulse-stretching optics or the recently introduced White Cell-based laser, seems to be the most favored excitation source of choice by the research community, UV excitation will undoubtedly continue to be used on many occasions, and especially in sooting flames. Detection methods may be divided into ICCD-based nanosecond-gate detection or a rotary-chopper electromechanical shutter-based CCD array detection, and the levels of background flame emission in individual cases would determine this critical design choice. Here, a process of Raman signal calibration based on ti,e crosstalk matrix

  9. Warthin-like papillary renal cell carcinoma: Clinicopathologic, morphologic, immunohistochemical and molecular genetic analysis of 11 cases.

    PubMed

    Skenderi, Faruk; Ulamec, Monika; Vanecek, Tomas; Martinek, Petr; Alaghehbandan, Reza; Foix, Maria Pane; Babankova, Iva; Montiel, Delia Perez; Alvarado-Cabrero, Isabel; Svajdler, Marian; Dubinský, Pavol; Cempirkova, Dana; Pavlovsky, Michal; Vranic, Semir; Daum, Ondrej; Ondic, Ondrej; Pivovarcikova, Kristyna; Michalova, Kvetoslava; Hora, Milan; Rotterova, Pavla; Stehlikova, Adela; Dusek, Martin; Michal, Michal; Hes, Ondrej

    2017-04-01

    Oncocytic papillary renal cell carcinoma (PRCC) is a distinct subtype of PRCC, listed as a possible new variant of PRCC in the 2016 WHO classification. It is composed of papillae aligned by large single-layered eosinophilic cells showing linearly arranged oncocytoma-like nuclei. We analyzed clinicopathologic, morphologic, immunohistochemical and molecular-genetic characteristics of 11 oncocytic PRCCs with prominent tumor lymphocytic infiltrate, morphologically resembling Warthin's tumor. The patients were predominantly males (8/11, 73%), with an average age of 59years (range 14-76), and a mean tumor size of 7cm (range 1-22cm). Tumors had the features of oncocytic PRCCs with focal pseudostratification in 8/11 cases and showed dense stromal inflammatory infiltration in all cases. Papillary growth pattern was predominant, comprising more than 60% of tumor volume. Tubular and solid components were present in 5 and 3 cases, respectively. Uniform immunohistochemical positivity was found for AMACR, PAX-8, MIA, vimentin, and OSCAR. Tumors were mostly negative for carboanhydrase 9, CD117, CK20, and TTF-1. Immunohistochemical stains for DNA mismatch repair proteins MLH1 and PMS2 were retained in all cases, while MSH2 and MSH6 were negative in 1 case. Tumor infiltrating lymphocytes (TILs) consisted of both B and T cells. Chromosomal copy number variation analysis showed great variability in 5 cases, ranging from a loss of one single chromosome to complex genome rearrangements. Only one case showed gains of chromosomes 7 and 17, among other aberrations. In 4 cases no numerical imbalance was found. Follow up data was available for 9 patients (median 47.6months, range 1-132). In 6 patients no lethal progression was noted, while 3 died of disease. In conclusion, Warthin-like PRCC is morphologically very close to oncocytic PRCC, from which it differs by the presence of dense lymphoid stroma. Chromosomal numerical aberration pattern of these tumors is variable; only one case showed

  10. Multilaboratory evaluation of 15 bioassays for (eco)toxicity screening and hazard ranking of engineered nanomaterials: FP7 project NANOVALID

    PubMed Central

    Bondarenko, Olesja M.; Heinlaan, Margit; Sihtmäe, Mariliis; Ivask, Angela; Kurvet, Imbi; Joonas, Elise; Jemec, Anita; Mannerström, Marika; Heinonen, Tuula; Rekulapelly, Rohit; Singh, Shashi; Zou, Jing; Pyykkö, Ilmari; Drobne, Damjana; Kahru, Anne

    2016-01-01

    Abstract Within EU FP7 project NANOVALID, the (eco)toxicity of 7 well-characterized engineered nanomaterials (NMs) was evaluated by 15 bioassays in 4 laboratories. The highest tested nominal concentration of NMs was 100 mg/l. The panel of the bioassays yielded the following toxicity order: Ag > ZnO > CuO > TiO2 > MWCNTs > SiO2 > Au. Ag, ZnO and CuO proved very toxic in the majority of assays, assumingly due to dissolution. The latter was supported by the parallel analysis of the toxicity of respective soluble metal salts. The most sensitive tests/species were Daphnia magna (towards Ag NMs, 24-h EC50 = 0.003 mg Ag/l), algae Raphidocelis subcapitata (ZnO and CuO, 72-h EC50 = 0.14 mg Zn/l and 0.7 mg Cu/l, respectively) and murine fibroblasts BALB/3T3 (CuO, 48-h EC50 = 0.7 mg Cu/l). MWCNTs showed toxicity only towards rat alveolar macrophages (EC50 = 15.3 mg/l) assumingly due to high aspect ratio and TiO2 towards R. subcapitata (EC50 = 6.8 mg Ti/l) due to agglomeration of TiO2 and entrapment of algal cells. Finally, we constructed a decision tree to select the bioassays for hazard ranking of NMs. For NM testing, we recommend a multitrophic suite of 4 in vitro (eco)toxicity assays: 48-h D. magna immobilization (OECD202), 72-h R. subcapitata growth inhibition (OECD201), 30-min Vibrio fischeri bioluminescence inhibition (ISO2010) and 48-h murine fibroblast BALB/3T3 neutral red uptake in vitro (OECD129) representing crustaceans, algae, bacteria and mammalian cells, respectively. Notably, our results showed that these assays, standardized for toxicity evaluation of “regular” chemicals, proved efficient also for shortlisting of hazardous NMs. Additional assays are recommended for immunotoxicity evaluation of high aspect ratio NMs (such as MWCNTs). PMID:27259032

  11. Transmission electron microscopy of carbon-coated and iron-doped titania nanoparticles

    NASA Astrophysics Data System (ADS)

    Anjum, Dalaver H.; Memon, Nasir K.; Ismail, Mohamed; Hedhili, Mohamed N.; Sharif, Usman; Chung, Suk Ho

    2016-09-01

    We present a study on the properties of iron (Fe)-doped and carbon (C)-coated titania (TiO2) nanoparticles (NPs) which has been compiled by using x-ray diffraction (XRD), transmission electron microscopy (TEM), and x-ray photoelectron spectroscopy (XPS). These TiO2 NPs were prepared by using the flame synthesis method. This method allows the simultaneous C coating and Fe doping of TiO2 NPs. XRD investigations revealed that the phase of the prepared NPs was anatase TiO2. Conventional TEM analysis showed that the average size of the TiO2 NPs was about 65 nm and that the NPs were uniformly coated with the element C. Furthermore, from the x-ray energy dispersive spectrometry analysis, it was found that about 8 at.% Fe was present in the synthesized samples. High-resolution TEM (HRTEM) revealed the graphitized carbon structure of the layer surrounding the prepared TiO2 NPs. HRTEM analysis further revealed that the NPs possessed the crystalline structure of anatase titania. Energy-filtered TEM (EFTEM) analysis showed the C coating and Fe doping of the NPs. The ratio of L3 and L2 peaks for the Ti-L23 and Fe-L23 edges present in the core loss electron energy loss spectroscopy (EELS) revealed a +4 oxidation state for the Ti and a +3 oxidation state for the Fe. These EELS results were further confirmed with XPS analysis. The electronic properties of the samples were investigated by applying Kramers-Kronig analysis to the low-loss EELS spectra acquired from the prepared NPs. The presented results showed that the band gap energy of the TiO2 NPs decreased from an original value of 3.2 eV to about 2.2 eV, which is quite close to the ideal band gap energy of 1.65 eV for photocatalysis semiconductors. The observed decrease in band gap energy of the TiO2 NPs was attributed to the presence of Fe atoms at the lattice sites of the anatase TiO2 lattice. In short, C-coated and Fe-doped TiO2 NPs were synthesized with a rather cost-effective and comparatively easily scalable method. The

  12. Experience of study of the incidence of malignant neoplasms population in small areas of Ukraine, which suffered contamination with radionuclides due to the Chornobyl accident.

    PubMed

    Prysyazhnyuk, A Ye; Fuzik, M M; Gudzenko, N A; Bazyka, D A; Fedorenko, Z P; Ryzhov, A Yu; Sumkina, O V; Trotsyuk, N K; Khukhrianska, O M

    2015-12-01

    Ukrainoiu ta Zhytomyrs'koiu oblastiu. Razom z tym, tempy ii zrostannia na tsii terytorii ie naivyshchymy. Vysnovky. Otrymani rezul'taty svidchat' pro neobkhidnist' podal'shogo monitoryngu vynyknennia vypadkiv onkologichnykh zakhvoriuvan' sered naselennia ne til'ky Ukrainy v tsilomu, abo ii krupnykh administratyvnykh odynyts', ale i sered naselennia malykh terytorii, vrakhovuiuchy imovirnist' realizatsii ryzykiv vynyknennia vypadkiv radiatsiino-asotsiiovanykh zakhvoriuvan' vidpovidno do lokal'nykh ekologichnykh umov.

  13. Activation or suppression of the immune response mediators in biliary tract cancer (BTC) patients: a systematic review and meta-analysis

    PubMed Central

    Wang, Ying; Ding, Min; Zhang, Qian; Wang, Jinghan; Yang, Xijing; Zhou, Fuping; Li, Linfang; Yuan, Zhengang; Jin, Huajun; Qian, Qijun

    2017-01-01

    Background: Infiltration of immune cells and immune microenvironment determine the proliferative activity of the tumor and metastasis. The aim of this study was to analyze the influence of activation or suppression of the immune response mediators on the prognosis of biliary tract cancer (BTC). Methods: We searched Pubmed, Web of Science, Embase and The Cochrane Library for relevant literatures until June 2016. The quality of studies was assessed by QUADAS-2 and NOS tools. Forest and funnel plots and all statistical analyses were generated by using Review Manager 5.3. The bias of included studies was estimated by Egger's test using Meta R package. Results: A total of 2339 patients from 12 studies were finally enrolled in this meta-analysis. Patients with high expression of immune active factors, intraepithelial tumor-infiltrating CD4+ , CD8+, and Foxp3+ T lymphocytes, MHC I, NKG2D, showed a better overall survival (OS) than those with low expression (HR=0.52, 95% CI=0.41-0.67, P<0.00001). On the contrary, the high expression of immune suppressive factors (CD66b+ neutrophils, Neutrophil-lymphocyte ratio, Intratumoral IL-17+ cells and PD-1+/CD8+ TILs) was significantly associated with poor OS (HR=1.79, 95% CI=1.44-2.22, P<0.00001). A further analysis of therapies targeting tumor microenvironment modulation showed that the median progression free survival (PFS) for BTC patients who received adjuvant immunotherapy was longer than those who received surgery or chemotherapy alone, and the estimated pooled mean difference demonstrated a highly significant improvement (MD =2.33; 95% CI: 0.63-4.02, P=0.007). The total effect of PFS and OS was statistically longer in experimental group, compared to patients in control groups, respectively (PFS: RR=1.25; 95% CI: 1.08-1.46, P=0.004; OS: RR=1.16; 95% CI: 1.07-1.27, P=0.0006). In subgroup meta-analysis of studies on 6-, 12- and 18-month PFS and OS, it showed that adjuvant immunotherapy could improve the 6-month PFS (RR=1.23; 95

  14. Vertical Distribution of Heterotrophic Bacteria and Their Culturability In The Northeastern Atlantic (pomme 0 Cruise)

    NASA Astrophysics Data System (ADS)

    Denis, M.; Moumas, M.; Bianchi, M.

    In the frame of POMME (Programme Océanographie Multidisciplinaire Méso- Echelle) a French oceanographic programme in the Northeastern Atlantic (39-45N and 15-21W), the vertical distribution of heterotrophic bacteria and their culturability were investigated by combining different independent approaches during the POMME 0 cruise in fall 2000. Bacterial abundances and biomasses were determined by flow cytometric analysis of seawater samples, fixed, frozen and stored in liquid nitrogen un- til their analysis in the laboratory. Cells were stained with the green fluorescent probe SYBR Green IIZ´ (Molecular Probes), a specific probe for nucleic acids. The enumer- ated bacteria were pooled into two fractions according to their DNA content. Bacteria with the higher DNA content (HDNA) are considered as the fraction potentially able of undergoing division, whereas cells with the lower DNA content (LDNA) constitute an inactive fraction (Gasol et al., 1999). The viability of the collected bacteria was determined by using the method of Bianchi &Giuliano (1996) based on the formation of micro-colonies. The percentages of dividing bacteria were calculated with respect to the numbers of HDNA bacteria instead of the total counts which contained the irrel- evant LDNA cells. The percentage of dividing bacteria was larger when the bacteria population was dominated by HDNA bacteria. This result suggests that a bacterial population composed mainly of HDNA cells will have a larger capacity to divide than otherwise. The distribution of the bacterial activity at the sampled stations showed that conditions for the heterotrophic bacteria development were more favorable in the south western zone of the study area. The observed bacterial abundances were in the range 3.7 104 - 5.3 105 cells cm-3. The percentages of the LDNA fractions were in the range 40 - 90%, suggesting the occurrence of a declining ecosystem. The installa- tion of an oligotrophic system was supported by the observation of

  15. Integration & Co-development of a Geophysical CO2 Monitoring Suite

    SciTech Connect

    Friedmann, S J

    2007-07-24

    Carbon capture and sequestration (CCS) has emerged as a key technology for dramatic short-term reduction in greenhouse gas emissions in particular from large stationary. A key challenge in this arena is the monitoring and verification (M&V) of CO2 plumes in the deep subsurface. Towards that end, we have developed a tool that can simultaneously invert multiple sub-surface data sets to constrain the location, geometry, and saturation of subsurface CO2 plumes. We have focused on a suite of unconventional geophysical approaches that measure changes in electrical properties (electrical resistance tomography, electromagnetic induction tomography) and bulk crustal deformation (til-meters). We had also used constraints of the geology as rendered in a shared earth model (ShEM) and of the injection (e.g., total injected CO{sub 2}). We describe a stochastic inversion method for mapping subsurface regions where CO{sub 2} saturation is changing. The technique combines prior information with measurements of injected CO{sub 2} volume, reservoir deformation and electrical resistivity. Bayesian inference and a Metropolis simulation algorithm form the basis for this approach. The method can (a) jointly reconstruct disparate data types such as surface or subsurface tilt, electrical resistivity, and injected CO{sub 2} volume measurements, (b) provide quantitative measures of the result uncertainty, (c) identify competing models when the available data are insufficient to definitively identify a single optimal model and (d) rank the alternative models based on how well they fit available data. We present results from general simulations of a hypothetical case derived from a real site. We also apply the technique to a field in Wyoming, where measurements collected during CO{sub 2} injection for enhanced oil recovery serve to illustrate the method's performance. The stochastic inversions provide estimates of the most probable location, shape, volume of the plume and most likely CO{sub 2

  16. Micro-X-ray diffraction assessment of shock stage in enstatite chondrites

    NASA Astrophysics Data System (ADS)

    Izawa, Matthew R. M.; Flemming, Roberta L.; Banerjee, Neil R.; McCausland, Philip J. A.

    2011-05-01

    A new method for assessing the shock stage of enstatite chondrites has been developed, using in situ micro-X-ray diffraction (μXRD) to measure the full width at half maximum (FWHMχ) of peak intensity distributed along the direction of the Debye rings, or chi angle (χ), corresponding to individual lattice reflections in two-dimensional XRD patterns. This μXRD technique differs from previous XRD shock characterization methods: it does not require single crystals or powders. In situ μXRD has been applied to polished thin sections and whole-rock meteorite samples. Three frequently observed orthoenstatite reflections were measured: (020), (610), and (131); these were selected as they did not overlap with diffraction lines from other phases. Enstatite chondrites are commonly fine grained, stained or darkened by weathering, shock-induced oxidation, and metal/sulfide inclusions; furthermore, most E chondrites have little olivine or plagioclase. These characteristics inhibit transmitted-light petrography, nevertheless, shock stages have been assigned MacAlpine Hills (MAC) 02837 (EL3) S3, Pecora Escarpment (PCA) 91020 (EL3) S5, MAC 02747 (EL4) S4, Thiel Mountains (TIL) 91714 (EL5) S2, Allan Hills (ALHA) 81021 (EL6) S2, Elephant Moraine (EET) 87746 (EH3) S3, Meteorite Hills (MET) 00783 (EH4) S4, EET 96135 (EH4-5) S2, Lewis Cliff (LEW) 88180 (EH5) S2, Queen Alexandra Range (QUE) 94204 (EH7) S2, LaPaz Icefield (LAP) 02225 (EH impact melt) S1; for the six with published shock stages, there is agreement with the published classification. FWHMχ plotted against petrographic shock stage demonstrates positive linear correlation. FWHMχ ranges corresponding to shock stages were assigned as follows: S1 < 0.7°, S2 = 0.7-1.2°, S3 = 1.2-2.3°, S4 = 2.3-3.5°, S5 > 3.5°, S6—not measured. Slabs of Abee (EH impact-melt breccia), and Northwest Africa (NWA) 2212 (EL6) were examined using μXRD alone; FWHMχ values place both in the S2 range, consistent with literature values. Micro

  17. Bond energies of ThO(+) and ThC(+): A guided ion beam and quantum chemical investigation of the reactions of thorium cation with O2 and CO.

    PubMed

    Cox, Richard M; Citir, Murat; Armentrout, P B; Battey, Samuel R; Peterson, Kirk A

    2016-05-14

    Kinetic energy dependent reactions of Th(+) with O2 and CO are studied using a guided ion beam tandem mass spectrometer. The formation of ThO(+) in the reaction of Th(+) with O2 is observed to be exothermic and barrierless with a reaction efficiency at low energies of k/kLGS = 1.21 ± 0.24 similar to the efficiency observed in ion cyclotron resonance experiments. Formation of ThO(+) and ThC(+) in the reaction of Th(+) with CO is endothermic in both cases. The kinetic energy dependent cross sections for formation of these product ions were evaluated to determine 0 K bond dissociation energies (BDEs) of D0(Th(+)-O) = 8.57 ± 0.14 eV and D0(Th(+)-C) = 4.82 ± 0.29 eV. The present value of D0 (Th(+)-O) is within experimental uncertainty of previously reported experimental values, whereas this is the first report of D0 (Th(+)-C). Both BDEs are observed to be larger than those of their transition metal congeners, TiL(+), ZrL(+), and HfL(+) (L = O and C), believed to be a result of lanthanide contraction. Additionally, the reactions were explored by quantum chemical calculations, including a full Feller-Peterson-Dixon composite approach with correlation contributions up to coupled-cluster singles and doubles with iterative triples and quadruples (CCSDTQ) for ThC, ThC(+), ThO, and ThO(+), as well as more approximate CCSD with perturbative (triples) [CCSD(T)] calculations where a semi-empirical model was used to estimate spin-orbit energy contributions. Finally, the ThO(+) BDE is compared to other actinide (An) oxide cation BDEs and a simple model utilizing An(+) promotion energies to the reactive state is used to estimate AnO(+) and AnC(+) BDEs. For AnO(+), this model yields predictions that are typically within experimental uncertainty and performs better than density functional theory calculations presented previously.

  18. Thermal history of type 3 chondrites from the Antarctic meteorite collection determined by Raman spectroscopy of their polyaromatic carbonaceous matter

    NASA Astrophysics Data System (ADS)

    Bonal, Lydie; Quirico, Eric; Flandinet, Laurène; Montagnac, Gilles

    2016-09-01

    This paper is focused on the characterization of the thermal history of 151 CV, CO and unequilibrated ordinary chondrites (UOCs) from the NASA Antarctic meteorite collection, using an approach based on the structure of the included polyaromatic carbonaceous matter determined by Raman spectroscopy. 114 out of these 151 chondrites provided Raman spectra of carbonaceous matter and allowing to assign a petrologic type, which mostly reflects the peak temperature experienced by the rock on the parent body. A thorough review of literature shows however that it is not possible to deduce a peak temperature because accurate calibration is not available. Twenty-three new weakly metamorphosed chondrites have been identified: MIL 07671 (CV3.1); DOM 08006 (CO3.0); DOM 03238, MIL 05024, MIL 05104, MIL 07193 (CO3.1); TIL 82408, LAR 06279 (LL3.05-3.1); EET 90628 (L3.0); GRO 06054, QUE 97008 (L3.05), ALHA 77176, EET 90066, LAR 04380, MET 96515, MIL 05050 (L3.1); ALHA 78133, EET 87735, EET 90909, LEW 87208, PRE 95401 (L3.05-3.1); MCY 05218 (H3.05-3.1) and MET 00506 (H3.1). This study confirms that the width of the D band (FWHMD) and the ratio of the peak intensity of the D and G bands (ID/IG) are the most adapted tracers of the extent of thermal metamorphism in type 3 chondrites. It also unambiguously shows, thanks to the large number of samples, that the width of the G band (FWHMG) does not correlate with the maturity of polyaromatic carbonaceous matter. This parameter is nevertheless very valuable because it shows that Raman spectra of CV chondrites preserve memory of either the metamorphic conditions (possibly oxidation controlled by aqueous alteration) or the nature of the organic precursor. Oxidation memory is our preferred interpretation, however an extensive petrologic characterization of this CV series is required to get firm conclusions. Pre-graphitic carbonaceous matter is reported in seven chondrites and is even the only carbonaceous material detected in the chondrites

  19. Sexual selection on multivariate phenotypes in Anastrepha Fraterculus (Diptera: Tephritidae) from Argentina

    SciTech Connect

    Sciurano, R.; Rodriguero, M.; Gomez Cendra, P.; Vilardi, J.; Segura, D.; Cladera, J.L.; Allinghi, Armando

    2007-03-15

    Despite the interest in applying environmentally friendly control methods such as sterile insect technique (SIT) against Anastrepha fraterculus (Wiedemann) (Diptera: Tephritidae), information about its biology, taxonomy, and behavior is still insufficient. To increase this information, the present study aims to evaluate the performance of wild flies under field cage conditions through the study of sexual competitiveness among males (sexual selection). A wild population from Horco Molle, Tucuman, Argentina was sampled. Mature virgin males and females were released into outdoor field cages to compete for mating. Morphometric analyses were applied to determine the relationship between the multivariate phenotype and copulatory success. Successful and unsuccessful males were measured for 8 traits: head width (HW), face width (FW), eye length (EL), thorax length (THL), wing length (WL), wing width (WW), femur length (FL), and tibia length (TIL). Combinations of different multivariate statistical methods and graphical analyses were used to evaluate sexual selection on male phenotype. The results indicated that wing width and thorax length would be the most probable targets of sexual selection. They describe a non-linear association between expected fitness and each of these 2 traits. This non-linear relation suggests that observed selection could maintain the diversity related to body size. (author) [Spanish] A pesar del interes por la aplicacion de metodos de control de bajo impacto ambiental sobre Anastrepha fraterculus (Diptera: Tephritidae), como la Tecnica del Insecto Esteril (TIE), no existe aun informacion suficiente sobre su biologia, taxonomia y comportamiento. Este trabajo tiene como objetivo evaluar el desempeno de moscas en jaulas de campo a traves del estudio de la competitividad sexual entre machos salvajes (seleccion sexual). Para ello, se muestreo una poblacion de Horco Molle, Tucuman (Argentina). En jaulas de campo se liberaron machos y hembras adultos

  20. Light Pollution Awareness through Globe at Night & IYL2015

    NASA Astrophysics Data System (ADS)

    Walker, Constance E.

    2015-01-01

    The International Astronomical Union (IAU) will be coordinating extensive activities to raise awareness of light pollution through running the Cosmic Light theme of the International Year of Light (IYL2015) and by partnering in particular with the popular Globe at Night program.Globe at Night (www.globeatnight.org) is an international campaign to raise public awareness of the impact of light pollution by having people measure night-sky brightness and submit observations in real-time with smart phone or later with a computer. In 2015, Globe at Night will run for 10-nights each month, an hour after sunset til before the Moon rises. Students can use the data to monitor levels of light pollution around the world, as well as understand light pollution's effects on energy consumption, plants, wildlife, human health and our ability to enjoy a starry night sky.Since its inception in 2006, more than 115,000 measurements from 115 countries have been reported. The last 9 years of data can be explored with Globe at Night's interactive world map or with the 'map app' to view a particular area. A spreadsheet of the data is downloadable from any year. One can compare Globe at Night data with a variety of other databases to see, for example, how light pollution affects the foraging habits of bats.To encourage public participation in Globe at Night during IYL2015, each month will target an area of the world that habitually contributes during that time. Special concerns for how light pollution affects that area and solutions will be featured on the Globe at Night website (www.globeatnight.org), through its Facebook page, in its newsletter or in the 365DaysofAstronomy.org podcasts.Twice during IYL there will be a global Flash Mob event, one on Super Pi Day (March 14, 2015) and a second in mid-September, where the public will be invited to take night-sky brightness measurements en masse. In April, the International Dark-Sky Week hosted by the International Dark-Sky Association will be

  1. Intraoperative near-infrared fluorescent imaging during robotic operations.

    PubMed

    Macedo, Antonio Luiz de Vasconcellos; Schraibman, Vladimir

    2016-01-01

    The intraoperative identification of certain anatomical structures because they are small or visually occult may be challenging. The development of minimally invasive surgery brought additional difficulties to identify these structures due to the lack of complete tactile sensitivity. A number of different forms of intraoperative mapping have been tried. Recently, the near-infrared fluorescence imaging technology with indocyanine green has been added to robotic platforms. In addition, this technology has been tested in several types of operations, and has advantages such as safety, low cost and good results. Disadvantages are linked to contrast distribution in certain clinical scenarios. The intraoperative near-infrared fluorescent imaging is new and promising addition to robotic surgery. Several reports show the utility of this technology in several different procedures. The ideal dose, time and site for dye injection are not well defined. No high quality evidence-based comparative studies and long-term follow-up outcomes have been published so far. Initial results, however, are good and safe. RESUMO A identificação intraoperatória de certas estruturas anatômicas, por seu tamanho ou por elas serem ocultas à visão, pode ser desafiadora. O desenvolvimento da cirurgia minimamente invasiva trouxe dificuldades adicionais, pela falta da sensibilidade tátil completa. Diversas formas de detecção intraoperatória destas estruturas têm sido tentadas. Recentemente, a tecnologia de fluorescência infravermelha com verde de indocianina foi associada às plataformas robóticas. Além disso, essa tecnologia tem sido testada em uma variedade de cirurgias, e suas vantagens parecem estar ligadas a baixo custo, segurança e bons resultados. As desvantagens estão associadas à má distribuição do contraste em determinados cenários. A imagem intraoperatória por fluorescência infravermelha é uma nova e promissora adição à cirurgia robótica. Diversas séries mostram

  2. Impact of ionizing radiation exposure on in vitro differentiation of preosteoblastic cell lines

    NASA Astrophysics Data System (ADS)

    Hu, Yueyuan; Lau, Patrick; Hellweg, Christine; Baumstark-Khan, Christa; Reitz, Guenther

    Bone demineralization of astronauts during residence in microgravity is a well known phe-nomenon during space travel. Besides altered gravity conditions, radiation risk is considered to be one of the major health hazards for astronauts in both orbital and interplanetary space. Un-til know, little is known about the effects of space radiation on the skeletal system especially on the bone forming osteoblasts. Accelerator facilities are used to simulate parts of the radiation environment in space. We examined the effects of heavy ion exposure on osteoblastic differ-entiation of murine preosteoblastic cell lines to gain insight into potential cellular mechanisms involved in bone cellular response after exposure to heavy ions. Therefore, we examined gene expression modulation of bone specific transcription factors, osteoblast specific marker genes as well as genes function as coupling factors that link bone resorption to bone formation. mRNA levels were determined using quantitative real time reverse transcriptase PCR (qRT-PCR). Expression of a target gene was standardized to unregulated reference genes. We investigated the transcriptional regulation of Osteocalcin (OCN) as well as TGF-β1, p21(CDKN1A) and the bone specific transcription factor Runx2 (cbfa1). We investigated gene expression modula-tions after exposure to energetic carbon ions (35 MeV/u, 73 keV/µm), iron ions (1000 MeV/u, 150 keV/µm) and lead ions (29 MeV/u, 9600 keV/µm) versus low LET X-rays. X-irradiation dose-dependently increased the mRNA levels of p21(CDKN1A) and Runx2 (cbfa1) whereas expression of OCN and TGF-β1 were elevated at later time points. Exposure to heavy ions provoked a more pronounced effect on osteoblastic specific gene expression within the dif-ferentiation process. Collectively, our results indicate that heavy ions facilitate osteoblastic differentiation more effectively than X-ray. Using the proposed in vitro model we confirmed that exposure to ionizing radiation significantly

  3. Bond energies of ThO+ and ThC+: A guided ion beam and quantum chemical investigation of the reactions of thorium cation with O2 and CO

    NASA Astrophysics Data System (ADS)

    Cox, Richard M.; Citir, Murat; Armentrout, P. B.; Battey, Samuel R.; Peterson, Kirk A.

    2016-05-01

    Kinetic energy dependent reactions of Th+ with O2 and CO are studied using a guided ion beam tandem mass spectrometer. The formation of ThO+ in the reaction of Th+ with O2 is observed to be exothermic and barrierless with a reaction efficiency at low energies of k/kLGS = 1.21 ± 0.24 similar to the efficiency observed in ion cyclotron resonance experiments. Formation of ThO+ and ThC+ in the reaction of Th+ with CO is endothermic in both cases. The kinetic energy dependent cross sections for formation of these product ions were evaluated to determine 0 K bond dissociation energies (BDEs) of D0(Th+-O) = 8.57 ± 0.14 eV and D0(Th+-C) = 4.82 ± 0.29 eV. The present value of D0 (Th+-O) is within experimental uncertainty of previously reported experimental values, whereas this is the first report of D0 (Th+-C). Both BDEs are observed to be larger than those of their transition metal congeners, TiL+, ZrL+, and HfL+ (L = O and C), believed to be a result of lanthanide contraction. Additionally, the reactions were explored by quantum chemical calculations, including a full Feller-Peterson-Dixon composite approach with correlation contributions up to coupled-cluster singles and doubles with iterative triples and quadruples (CCSDTQ) for ThC, ThC+, ThO, and ThO+, as well as more approximate CCSD with perturbative (triples) [CCSD(T)] calculations where a semi-empirical model was used to estimate spin-orbit energy contributions. Finally, the ThO+ BDE is compared to other actinide (An) oxide cation BDEs and a simple model utilizing An+ promotion energies to the reactive state is used to estimate AnO+ and AnC+ BDEs. For AnO+, this model yields predictions that are typically within experimental uncertainty and performs better than density functional theory calculations presented previously.

  4. Cellular immune responses towards regulatory cells.

    PubMed

    Larsen, Stine Kiær

    2016-01-01

    This thesis describes the results from two published papers identifying spontaneous cellular immune responses against the transcription factors Foxp3 and Foxo3. The tumor microenvironment is infiltrated by cells that hinder effective tumor immunity from developing. Two of these cell types, which have been linked to a bad prognosis for patients, are regulatory T cells (Treg) and tolerogenic dendritic cells (DC). Tregs inhibit effector T cells from attacking the tumor through various mechanisms, including secreted factors and cell-to-cell contact. Tregs express the transcription factor Foxp3, which is necessary for their development and suppressive activities. Tolerogenic DCs participate in creating an environment in the tumor where effector T cells become tolerant towards the tumor instead of attacking it. The transcription factor Foxo3 was recently described to be highly expressed by tolerogenic DCs and to programme their tolerogenic influence. This thesis describes for the first time the existence of spontaneous cellular immune responses against peptides derived from Foxp3 and Foxo3. We have detected the presence of cytotoxic T cells that recognise these peptides in an HLA-A2 restricted manner in cancer patients and for Foxp3 in healthy donors as well. In addition, we have demonstrated that the Foxp3- and Foxo3-specific CTLs recognize Foxp3- and Foxo3-expressing cancer cell lines and importantly, suppressive immune cells, namely Tregs and in vitro generated DCs. Cancer immunotherapy is recently emerging as an important treatment modality improving the survival of selected patients. The current progress is largely owing to targeting of the immune suppressive milieu that is dominating the tumor microenvironment. This is being done through immune checkpoint blockade with CTLA-4 and PD-1/PD-L1 antibodies and through lymphodepleting conditioning of patients and ex vivo activation of TILs in adoptive cell transfer. Several strategies are being explored for depletion of

  5. Comparison of tulathromycin and tilmicosin on the prevalence and severity of bovine respiratory disease in feedlot cattle in association with feedlot performance, carcass characteristics, and economic factors.

    PubMed

    Tennant, T C; Ives, S E; Harper, L B; Renter, D G; Lawrence, T E

    2014-11-01

    The objectives of this study were to 1) quantify effects of metaphylactic treatment for bovine respiratory disease (BRD) on growth performance, carcass characteristics, and lung lesion prevalence and severity; 2) evaluate the association of lung lesion prevalence and severity with carcass characteristics; and 3) evaluate effects of therapeutic treatment on carcass characteristics and lung lesion prevalence and severity. The study was conducted at a commercial feedlot in the Texas Panhandle in which steers (n = 2,336) initially weighing 312.1 ± 9.6 kg were sourced from auction markets and allocated in a randomized complete block design to 1 of 3 treatments (no metaphylactic [no antimicrobial drug {ND}] treatment, tilmicosin at 10 mg/kg BW [TIL], and tulathromycin at 2.5 mg/kg BW [TUL]). Lungs of all steers were evaluated during harvest to assess presence and severity of pneumonic lesions in the anteroventral lobes and the presence and severity of pleural adherences. Compared to the ND treatment, steers treated via metaphylactic therapy had greater (P < 0.05) metaphylactic cost, ADG, shrunk final BW, dressed carcass yield, HCW, 12th rib fat, calculated empty body fat (EBF), and gross revenue, concurrent with reduced (P < 0.05) BRD treatment costs and financial losses from BRD death and railed cattle, cumulatively resulting in greater financial returns. Lung lesions were present in 64.3% of lungs and were distributed similarly between metaphylactic treatments (63.9%) and ND (65.1%) cattle. Steers with advanced lung lesions present at harvest were associated with reduced (P < 0.05) HCW, KPH, 12th rib fat, calculated yield grades, marbling scores, and calculated EBF as compared to steers without lung lesions. Steers pulled for BRD had increased (P < 0.01) incidence of advanced lung lesions, mortality, and railers with decreased (P < 0.05) HCW, 12th rib fat, KPH, marbling score, calculated EBF, and percentage choice carcasses when compared to non-BRD event steers. From

  6. Optimization of an antibiotic sensitivity assay for Mycoplasma hyosynoviae and susceptibility profiles of field isolates from 1997 to 2011.

    PubMed

    Schultz, K K; Strait, E L; Erickson, B Z; Levy, N

    2012-07-06

    Mycoplasma hyosynoviae is a common agent responsible for polyarthritis leading to decreased production in swine herds worldwide. Antimicrobial agents are used to combat infections; however breakpoints for M. hyosynoviae have not yet been established. A number of methods have previously been utilized to analyze minimum inhibitory concentrations (MICs) for antibiotics against M. hyosynoviae; however these techniques as currently described are not easily standardized between laboratories. A dry microbroth dilution method was conducted to compare the minimum inhibitory concentrations (MICs) for 18 antibiotics, representative of different classes, against 24 recent isolates (23 field isolates and the type strain) of M. hyosynoviae. The MICs were determined using standard, commercially available 96-well Sensititre(®) plates containing various freeze-dried antibiotics at a range of concentrations appropriate to their potency. Clindamycin (CLI), a lincosamide antibiotic, showed the highest activity and most consistent inhibition for all isolates with an MIC(50) of ≤ 0.12 μg/ml. Tiamulin (TIA), a pleuromutilin derivative, exhibited an MIC(50) of ≤ 0.25 μg/ml. The isolates had similar levels of susceptibility to the quinolones, enrofloxacin (ENRO) and danofloxacin (DANO), exhibiting an MIC(50) of 0.25 μg/ml and 0.5 μg/ml, respectively. For the macrolides, the MIC(50) for tylosin (TYLT) and tilmicosin (TIL) was ≤ 0.25 μg/ml and ≤ 2 μg/ml respectively, but was ≤ 16 μg/ml for tulathromycin (TUL). For the aminoglycosides, the MIC(50) for gentamicin (GEN) was ≤ 0.5 μg/ml, while spectinomycin (SPE) and neomycin (NEO) had an MIC(50) of ≤ 4 μg/ml. The tetracyclines, oxytetracycline (OXY) and chlortetracycline (CTET) both had an MIC(50) of ≤ 2 μg/ml. Florfenicol (FFN) exhibited a MIC(50) of ≤ 1 μg/ml. All isolates were resistant to penicillin (PEN), ampicillin (AMP), ceftiofur (TIO), trimethoprim/sulfamethoxazole (SXT), and sulphadimethoxine (SDM) at all

  7. Human intestinal Vdelta1+ lymphocytes recognize tumor cells of epithelial origin

    PubMed Central

    1996-01-01

    gammadelta T cells can be grouped into discrete subsets based upon their expression of T cell receptor (TCR) variable (V) region families, their tissue distribution, and their specificity. Vdelta2+ T cells constitute the majority of gammadelta T cells in peripheral blood whereas Vdelta1+T cells reside preferentially in skin epithelium and in the intestine. gammadelta T cells are envisioned as first line host defense mechanisms capable of providing a source of immune effector T cells and immunomodulating cytokines such as interleukin (IL) 4 or interferon (IFN) gamma. We describe here the fine specificity of three distinct gammadelta+ tumor-infiltrating lymphocytes (TIL) obtained from patients with primary or metastatic colorectal cancer, that could be readily expanded in vitro in the presence of IL-1beta and IL-7. Irrespective of donor, these individual gammadelta T cells exhibited a similar pattern of reactivity defined by recognition of autologous and allogeneic colorectal cancer cells, renal cell cancer, pancreatic cancer, and a freshly isolated explant from human intestine as measured by cytolytic T cell responses and by IFN-gamma release. In contrast, tumors of alternate histologies were not lysed, including lung cancer, squamous cell cancer, as well as the natural/lymphocyte-activated killer cell-sensitive hematopoietic cell lines T2, C1R, or Daudi. The cell line K562 was only poorly lysed when compared with colorectal cancer targets. Target cell reactivity mediated by Vdelta1+ T cells was partially blocked with Abs directed against the TCR, the beta2 or beta7 integrin chains, or fibronectin receptor. Marker analysis using flow cytometry revealed that all three gammadelta T cell lines exhibit a similar phenotype. Analysis of the gammadelta TCR junctional suggested exclusive usage of the Vdelta1/Ddelta3/Jdelta1 TCR segments with extensive (< or = 29 bp) N/P region diversity. T cell recognition of target cells did not appear to be a major histocompatibility

  8. Activation or suppression of the immune response mediators in biliary tract cancer (BTC) patients: a systematic review and meta-analysis.

    PubMed

    Wang, Ying; Ding, Min; Zhang, Qian; Wang, Jinghan; Yang, Xijing; Zhou, Fuping; Li, Linfang; Yuan, Zhengang; Jin, Huajun; Qian, Qijun

    2017-01-01

    Background: Infiltration of immune cells and immune microenvironment determine the proliferative activity of the tumor and metastasis. The aim of this study was to analyze the influence of activation or suppression of the immune response mediators on the prognosis of biliary tract cancer (BTC). Methods: We searched Pubmed, Web of Science, Embase and The Cochrane Library for relevant literatures until June 2016. The quality of studies was assessed by QUADAS-2 and NOS tools. Forest and funnel plots and all statistical analyses were generated by using Review Manager 5.3. The bias of included studies was estimated by Egger's test using Meta R package. Results: A total of 2339 patients from 12 studies were finally enrolled in this meta-analysis. Patients with high expression of immune active factors, intraepithelial tumor-infiltrating CD4+ , CD8+, and Foxp3+ T lymphocytes, MHC I, NKG2D, showed a better overall survival (OS) than those with low expression (HR=0.52, 95% CI=0.41-0.67, P<0.00001). On the contrary, the high expression of immune suppressive factors (CD66b+ neutrophils, Neutrophil-lymphocyte ratio, Intratumoral IL-17+ cells and PD-1+/CD8+ TILs) was significantly associated with poor OS (HR=1.79, 95% CI=1.44-2.22, P<0.00001). A further analysis of therapies targeting tumor microenvironment modulation showed that the median progression free survival (PFS) for BTC patients who received adjuvant immunotherapy was longer than those who received surgery or chemotherapy alone, and the estimated pooled mean difference demonstrated a highly significant improvement (MD =2.33; 95% CI: 0.63-4.02, P=0.007). The total effect of PFS and OS was statistically longer in experimental group, compared to patients in control groups, respectively (PFS: RR=1.25; 95% CI: 1.08-1.46, P=0.004; OS: RR=1.16; 95% CI: 1.07-1.27, P=0.0006). In subgroup meta-analysis of studies on 6-, 12- and 18-month PFS and OS, it showed that adjuvant immunotherapy could improve the 6-month PFS (RR=1.23; 95

  9. Targetless T cells in cancer immunotherapy.

    PubMed

    Thor Straten, Per; Garrido, Federico

    2016-01-01

    Attention has recently focused on new cancer immunotherapy protocols aiming to activate T cell mediated anti-tumor responses. To this end, administration of antibodies that target inhibitory molecules regulating T-cell cytotoxicity has achieved impressive clinical responses, as has adoptive cell transfer (ACT) using expanded tumor infiltrating lymphocytes (TIL) or genetically modified cytotoxic T cells. However, despite clear clinical responses, only a fraction of patients respond to treatment and there is an urgent call for characterization of predictive biomarkers. CD8 positive T cells can infiltrate tumor tissues and destroy HLA class I positive tumor cells expressing the specific antigen. In fact, current progress in the field of cancer immune therapy is based on the capacity of T cells to kill cancer cells that present tumor antigen in the context on an HLA class I molecule. However, it is also well established that cancer cells are often characterized by loss or down regulation of HLA class I molecules, documented in a variety of human tumors. Consequently, immune therapy building on CD8 T cells will be futile in patients harboring HLA class-I negative or deficient cancer cells. It is therefore mandatory to explore if these important molecules for T cell cytotoxicity are expressed by cancer target cells. We have indications that different types of immunotherapy can modify the tumor microenvironment and up-regulate reduced HLA class I expression in cancer cells but only if the associated molecular mechanisms is reversible (soft). However, in case of structural (hard) aberrations causing HLA class I loss, tumor cells will not be able to recover HLA class I expression and as a consequence will escape T-cell lysis and continue to growth. Characterization of the molecular mechanism underlying the lack or downregulation of HLA class I expression, seems to be a crucial step predicting clinical responses to T cell mediated immunotherapy, and possibly aid the

  10. Cytotoxicity of TiO2 nanoparticles to mussel hemocytes and gill cells in vitro: Influence of synthesis method, crystalline structure, size and additive.

    PubMed

    Katsumiti, Alberto; Berhanu, Deborah; Howard, Kieren T; Arostegui, Inmaculada; Oron, Miriam; Reip, Paul; Valsami-Jones, Eugenia; Cajaraville, Miren P

    2015-01-01

    Increasing the production and applications of TiO2 nanoparticles (NPs) has led to grow concerns about the consequences for the environment. In this study, we investigated the effects of a set of TiO2 NPs on the viability of mussel hemocytes and gill cells using neutral red and thiazolyl tetrazolium bromide assays. For this, we compared the cytotoxicity of TiO2 NPs (0.1-100 mg Ti/L) produced by different techniques: rutile NPs (60 nm) produced by milling and containing disodium laureth sulfosuccinate (DSLS), rutile NPs (10, 40 and 60 nm) produced by wet chemistry and anatase/rutile NPs (∼100 nm) produced by plasma synthesis. The commercially available P25 anatase/rutile NPs (10-20 nm) were also tested. Exposures were performed in parallel with their respective bulk forms and the cytotoxicity of the additive DSLS was also tested. Z potential values in distilled water indicated different stabilities depending on the NP type and all NPs tested formed agglomerates/aggregates in cell culture media. In general, TiO2 NPs showed a relatively low and dose-dependent toxicity for both cell models with the two assays tested. NPs produced by milling showed the highest effects, probably due to the toxicity of DSLS. Size-dependent toxicity was found for NPs produced by wet chemistry (10 nm > 40 nm and 60 nm). All TiO2 NPs tested were more toxic than bulk forms excepting for plasma produced ones, which were the least toxic TiO2 tested. The mixture bulk anatase/rutile TiO2 was more toxic than bulk rutile TiO2. In conclusion, the toxicity of TiO2 NPs varied with the mode of synthesis, crystalline structure and size of NPs and can also be influenced by the presence of additives in the suspensions.

  11. Focused Cardiac Ultrasound Using a Pocket-Size Device in the Emergency Room.

    PubMed

    Mancuso, Frederico José Neves; Siqueira, Vicente Nicoliello; Moisés, Valdir Ambrósio; Gois, Aécio Flavio Teixeira; Paola, Angelo Amato Vincenzo de; Carvalho, Antonio Carlos Camargo; Campos, Orlando

    2014-10-28

    direcionada como complemento diagnóstico ao exame físico em um serviço terciário de emergências clínicas. Métodos: Foram incluídos cem pacientes adultos sem doenças cardíacas ou pulmonares conhecidas que procuraram atendimento de urgência com queixas cardiológicas. Foram excluídos pacientes com alterações isquêmicas no eletrocardiograma ou febre. A ecocardiografia direcionada foi realizada logo após a avaliação inicial do paciente na sala de emergência, com aparelho ultraportátil GE Vscan, avaliando subjetivamente: dimensões das cavidades, função sistólica ventricular, fluxos intracardíacos pelo mapeamento de fluxo em cores, pericárdio e aorta. Resultados: A idade média dos pacientes foi 61 ± 17 anos. O quadro clínico inicial foi dor torácica (52 pacientes), dispneia (32 pacientes), arritmia/avaliação da função ventricular (dez pacientes), hipotensão/tontura (cinco pacientes) e edema periférico (um paciente). Em 28 pacientes a ecocardiografia direcionada confirmou a hipótese diagnóstica inicial: 19 pacientes com insuficiência cardíaca, cinco com síndrome coronariana aguda, dois com tromboembolismo pulmonar e dois com tamponamento cardíaco. Em 17 pacientes, a ecocardiografia direcionada alterou o diagnóstico, afastando a hipótese clínica inicial em dez casos com suspeita de insuficiência cardíaca, dois com suspeita de tromboembolismo pulmonar, dois com hipotensão a esclarecer, e em cada um dos três restantes com suspeitas de síndrome coronariana aguda, tamponamento cardíaco e dissecção de aorta. Conclusão: A ecocardiografia direcionada ultraportátil em serviço de emergências clínicas pode definir rapidamente o diagnóstico e, com isso, é possível iniciar mais precocemente o tratamento adequado.

  12. [Software for performing a global phenotypic and genotypic nutritional assessment].

    PubMed

    García de Diego, L; Cuervo, M; Martínez, J A

    2013-01-01

    áficos. Está formado por cinco bloques categorizados en diez módulos denominados: Pacientes, Antropometría, Historia clínica, Bioquímica, Historia dietética, Diagnóstico (incluyendo genética), Calidad de vida, Actividad física, Gasto energético y Dietas. Cada módulo tiene una funcionalidad específica que permite valorar un aspecto diferente del estado nutricional del paciente. Conclusiones: UNyDIET es un programa integral, personalizado y actualizable, fácil de usar y versátil, orientado para especialistas de la salud como personal sanitario, dietistas, nutricionistas, científicos y educadores. Esta herramienta se puede utilizar como instrumento de trabajo en programas de promoción de la salud, en valoraciones clínicas y nutricionales, en la evaluación de la calidad asistencial, en estudios epidemiológicos, en programas de intervención nutricional y en docencia.

  13. Complications métaboliques après transplantation rénale à partir du donneur vivant: expérience du CHU Ibn Sina de Rabat

    PubMed Central

    Mouram, Hala; Benamar, Loubna; Ouzeddoune, Naima; Bayahia, Rabia; Ezaitouni, Fatima

    2014-01-01

    La transplantation rénale (TR) constitue le traitement de choix de l'insuffisance rénale chronique terminale. Les complications métaboliques après TR (diabète, dyslipidémie, hyperuricémie, obésité), en grande partie liées au traitement immunosuppresseur, deviennent une préoccupation car elles constituent un facteur de risque de morbimortalité et de perte fonctionnelle du greffon. Le but de notre étude est d’évaluer la fréquence de ces anomalies après TR. Il s'agit d'une étude rétrospective incluant tous les patients ayant bénéficié d'une première TR par donneur vivant (DV) de Juin 1998 à Décembre 2010. Nous avons recensé les données démographiques propres au receveur, le traitement immunosuppresseur après TR. Les paramètres clinico-biologiques recueillis sont (index de masse corporel (IMC), glycémie à jeun, hémoglobine glyquée, CT, C-HDL, C-LDL, TG, acide urique). Soixante dix patients ont été colligés, l’âge moyen est de 36.3 + /-9.6 ans (21 à 62) avec un sex ratio de 0.5. Quinze patients (21.4%) étaient hypertendus avant la TR et 2.9% avaient une néphropathie diabétiques. L’âge moyen du donneur est de 47.5 + /-10.2 ans (20-65). Le traitement immunosuppresseur pendant la phase d'induction était une trithérapie associant corticostéroïdes, anticalcineurines chez tous les patients et mycophénolate mofétil chez 68.6% et azathioprine dans 31.4% des cas. L'IMC moyen était de 24.1 + /-4.0 (16.9 à 37), 33% des patients étaient considérés en surpoids dont 21.8% en obésité. L'hypercholestérolémie, a été retrouvée chez 25 patients soit 36%. Presque la moitié des patients (48.5%) avaient une hyperuricémie. Quatre patients ont développé un diabète après TR soit 6% des cas. La perte du greffon a été notée chez 12 patients et 2 patients sont décédés dont un avec un greffon fonctionnel. En analyse univariée, l'hyperuricémie et la dyslipidémie ont été considérées comme facteur de risque de perte

  14. Age of granites of Wrangel Island metamorphic complex

    NASA Astrophysics Data System (ADS)

    Luchitskaya, Marina; Sergeev, Sergey; Sokolov, Sergey; Tuchkova, Marianna

    2014-05-01

    Within huge arctic shelf of Eastern-Siberian and Chukchi seas the metamorphic basement (Wrangel complex, Berri Formation) is exposed only on the Wrangel Island. There are different points of views on the age of metamorphic rocks of Wrangel complex (Berri Formation): (1) Neoproterozoic (Kameneva, 1970; Ageev, 1979; Kos'ko et al., 1993, 2003), (2) Devonian (Til'man et al., 1964, 1970; Ganelin, 1989). Metamorphic basement is represented by stratified complex, composed of dislocated metavolcanic, metavolcaniclastic and metasedimentary rocks (schists, metasandstones, metaconglomerated) with single lenses and layers of carbonate rocks (Wrangel Island…, 2003). Among basement rocks in the central part of Wrangel Island there are felsic intrusive bodies. They form small tabular bodies from tens centimeters to 70-80 meters in thickness, rarely dikes and small stocks (up to 20 x 30 m) and are composed of granite-porphyres, rarely muscovite porphyr-like granites and granosyenites (Wrangel Island…, 2003). The age of intrusions allow to determine the age of basement formation. Earlier the age of intrusions was determined by different methods and correlated to the boundary between Neoproterozoic and Paleozoic: K-Ar 570-603 Ma, Pb-Pb 590±50 Ma (S.M. Pavlov, Institute of Precambrian Geology and Geochronology, USSR Academy of Sciences), Rb-Sr 475±31 Ma (I.M.Vasil'eva, Institute of Precambrian Geology and Geochronology, USSR Academy of Sciences), U-Pb 609, 633, 677 Ma (Geological Survey of Canada) (Wrangel Island…, 2003; Kos'ko et al., 1993; Cecile et al., 1991). In the lower part of metamorphic rocks of Wrangel complex there are conformable tabular bodies of gneissosed and foliated granitoides. The latter are meramorphosed and transformed in biotite-muscovite-feldspar-quartz-sericite and muscovite-feldspar-quartz-sericite gneisses and schists, where relics of primary minerals (quartz, plagioclase, potassium feldspar, rarely biotite and muscovite) and equigranular granitic

  15. Cancer incidence and novel therapies developed in Japan.

    PubMed

    Iwasaki, M

    2012-01-01

    -injected into the body to exert their action against the cancer. There are different kinds of Immuno-cell therapies being practised in more than 25 private and public institutions in Japan using Natural Killer (NK) cells, Cytotoxic T lymphocytes (CTLs), Tumour Infiltrating Lymphocytes (TIL), Lymphokine activated Killer (LAK) cells, Dendritic cells and Gamma Delta T (γδ T) cells.([7]) Importantly most of the innovations in cell based therapies in the world have been made in Japan because immunotherapy is a part of the Japanese Health care system and routine therapies for cancer in Japan. There have been randomized clinical trials on Immuno-cell therapy for liver cancer, lung cancer, gastric cancer, ovarian cancer with the results suggesting statistically significant increase in survival rate and increase in disease free survival rate. ([8, 9, 10, 11]) There are more than 25 institutions in Japan performing such cell based immunotherapies. A comprehensive review by Egawa et al on 1401 patients showed that when Immuno-cell therapy was combined with the conventional therapies, the efficacy increased upto 20-30%. ([7]) Immuno-cell is the least toxic of all therapies and can be administered even to terminally ill cancer patients. ([12]) Contrast to drugs, as autologous cell based Immuno-therapies are from the patient's own blood and as they are custom tailored to each patient, though expensive, the adverse effects are minimal. To conclude, cancer-Immunocell therapies are the future of cancer therapies and further research is needed to enhance its efficacy and validate the results.

  16. Chronic Stress Improves NO- and Ca2+ Flux-Dependent Vascular Function: A Pharmacological Study.

    PubMed

    Bruder-Nascimento, Thiago; Campos, Dijon Henrique Salome

    2015-01-23

    avaliada em anéis aórticos. Curvas de concentração-efeito foram realizadas para noradrenalina, na presença de L-NAME ou prazosina, cloreto de potássio (KCl), acetilcolina e nitroprussiato de sódio. Também foi efetuado um estudo para avaliação para fluxo de Ca2+. Resultados: Estresse crônico induziu hipertensão e resposta vascular diminuída para noradrenalina e KCl e aumentada para acetilcolina. A pré-incubação com L-NAME eliminou a diferença para noradrenalina. A resposta contrátil vascular para Ca2+ foi reduzida em animais estressados. Conclusão: Nossos dados sugerem que a resposta vascular ao estresse crônico seria uma adaptação aos efeitos deletérios do estresse, incluindo a hipertensão. Além disso, esses mecanismos adaptativos dependem de liberação de NO e fluxo de Ca2+. Esses resultados ajudam a esclarecer os mecanismos envolvidos nas alterações cardiovasculares associadas ao estresse. Entretanto, mais estudos são necessários para a melhor compreensão desses mecanismos.

  17. Comparison of Hydrologic Data from Monroe County, Michigan, 1991-2001

    USGS Publications Warehouse

    Nicholas, J.R.; Blumer, Stephen P.; McGowan, Rose M.

    2001-01-01

    are reported by the USGS in the report by Nicholas and others (1996). Later data come from a variety of sources including USGS, MDEQ, Monroe County, National Oceanic and Atmospheric Administration, U.S. Army Corps of Engineers, and ground-water users. All non-USGS data in this report are given as reported; data verification was not a part of this initial phase. The types of data chosen for comparison in this report include water levels of Lake Erie, precipitation at Monroe, streamflow in the River Raisin at Manchester, ground-water use, ground-water levels, and ground-water quality. The authors acknowledge the cooperation and provision of data and information by several agencies. Ground-water use for irrigation was provided by Ron Van Til of MDEQ. Quarry discharges were provided by Jennifer Rogers of MDEQ. Ground-water-level data for 1993 to 2001 were provided by the Monroe County Health Department. The authors also acknowledge Carlos Hernandez, Chris Hoard, Tom Morgan, Tom Sabin, and Dave Westjohn for collecting streamflow, ground-water, and ground-water-quality data in autumn, 2001. Sharon Baltusis and Jaye Lunsford assisted in the compilation and presentation of hydrologic data in this report.

  18. BN-350 unattended safeguards system current status and initial fuel movement data

    SciTech Connect

    Williams, Richard Brady; Browne, Michael C; Parker, Robert F; Ingegneri, Maurizio

    2009-01-01

    The Unattended and Remote Monitoring (UNARM) system at the BN-350 fast breeder reactor facility in Aktau, Kazakhstan continues to provide safeguards monitoring data as the spent fuel disposition project transitions from wet fuel storage to dry storage casks. Qualitative data from the initial cask loading procedures has been released by the International Atomic Energy Agency (IAEA) and is presented here for the first time. The BN-350 fast breeder reactor in Aktau, Kazakhstan, operated as a plutonium-producing facility from 1973 W1til 1999. Kazakhstan signed the Nonproliferation Treaty (NPT) in February 1994, and shortly afterwards the IAEA began safeguarding the reactor facility and its nuclear material. Slnce the cessation of reactor operations ten years ago, the chief proliferation concern has been the spent fuel assemblies stored in the pond on-site. By 2002, all fuel assemblies in wet storage had been repackaged into proliferation-resistant canisters. From the beginning, the IAEA's safeguards campaign at the BN-350 included a constant unattended sensor presence in the form of UNARM which monitors nuclear material activities at the facility in the absence of inspector presence. The UNARM equipment at the BN-350 was designed to be modular and extensible, allowing the system to adapt as the safeguards requirements change. This has been particularly important at the BN-350 due to the prolonged wet storage phase of the project. The primary function of the BN-350 UNARM system is to provide the IAEA with an independent, radiation-centric Containment and Surveillance (C&S) layer in addition to the standard seals and video systems. The UNARM system has provided continuous Continuity of Knowledge (COK) data for the BN-350's nuclear material storage areas in order to ensure the validity of the attended measurements during the lifetime of the project. The first of these attended measurements was characterization of the spent fuel assemblies. This characterization utilized

  19. [Fractional exhaled nitric oxide in monitoring and therapeutic management of asthma].

    PubMed

    Melo, Bruno; Costa, Patrício; Afonso, Ariana; Machado, Vânia; Moreira, Carla; Gonçalves, Augusta; Gonçalves, Jean-Pierre

    2014-01-01

    Introdução: A asma é uma doença respiratória crónica caracterizada pela hiper-reactividade e inflamação brônquica. A inflamação brônquica destes doentes pode ser monitorizada através da medição da fração exalada de óxido nítrico. Este estudo tem por objetivo determinar a associação do valor da fração exalada de óxido nítrico com o débito expiratório máximo instantâneo e com o controlo da asma determinado pela Classificação da Iniciativa Global para a Asma.Material e Métodos: Estudo observacional, analítico e transversal de crianças com asma, 6-12 anos, seguidas na Consulta Externa de Patologia Respiratória do Hospital de Braga. Informação sociodemográfica e clínica colhida através de um questionário. Determinado o valor da fração exalada de óxido nítrico, através do analisador portátil Niox Mino®, e do débito expiratório máximo instantâneo,através do debitómetro.Resultados: A amostra é constituída por 101 crianças asmáticas, 63 (62,4%) do sexo masculino e 38 (37,6%) do sexo feminino. A idade média dos participantes na amostra é de 9,18 (1,99) anos. A regressão logística, realizada com o valor de cutoff obtido pela curva de ROC, revelou que a fração exalada de óxido nítrico tem um efeito estatisticamente significativo (bNíveis do FENO = 0,85; χ2Wald (1) = 8,71; OR = 2,33; p = 0,003) sobre a probabilidade de mudar de nível de controlo da asma. Por cada nível de fração exalada de óxido nítrico incrementado o odds de passar a não controlada é 2,33 vezes superior.Discussão e Conclusão: A probabilidade de uma criança asmática mudar o seu nível de controlo da asma, de ‘controlada’ para ‘parcialmente controlada/não controlada’, tendo em consideração uma alteração no seu nível da fração exalada de óxido nítrico, aumenta 133%.

  20. Langston University - High Energy Physics (LU-HEP)

    SciTech Connect

    Snow, Dr., Joel

    2012-08-13

    for the experiment. Eventually this included the FNAL SAM data grid system, the SAMGrid (SG) infrastructure, and the Open Science Grid software stacks for computing and storage elements. At the end of 2003 Snow took on the role of global Monte Carlo production coordinator for the DØ experiment. A role which continues til this day. In January of 2004 Snow started working with the SAMGrid development team to help debug, deploy, and integrate SAMGrid with DØ Monte Carlo production. Snow installed and configured SG execution and client sites at LUHEP and OUHEP, and a SG scheduler site at LUHEP. The PI developed a python based GUI (DAJ) that acts as a front end for job submission to SAMGrid. The GUI interfaces to the DZero Mone Carlo (MC) request system that uses SAM to manage MC requests by the physics analysis groups. DAJ significantly simplified SG job submission and was deployed in DZero in an effort to increase the user base of SG. The following year was the advent of SAMGrid job submission to the Open Science Grid (OSG) and LHC Computing Grid (LCG) through a forwarding mechanism. The PI oversaw the integration of these grids into the existing production infrastructure. The PI developed an automatic MC (Automc) request processing system capable of operating without user intervention (other than getting grid credentials), and able to submit to any number of sites on various grids. The system manages production at all but 2 sites. The system was deployed at Fermilab and remains operating there today. The PI's work in distributed computing resulted in several talks at international conferences. UTA, OU, and LU were chosen as the collaborating institutions that form the Southwest Tier 2 Center (SWT2) for ATLAS. During the project period the PI contributed to the online and offline software infrastructure through his work with the Run 2 online group, and played a major role in Monte Carlo production for DZero. During the part of the project period in which the PI served

  1. Age, geochemical affinity and geodynamic setting of granitoids and felsic volcanics in the basement of Wrangel Island

    NASA Astrophysics Data System (ADS)

    Luchitskaya, Marina; Moiseev, Artem; Sokolov, Sergey; Tuchkova, Marianna; Sergeev, Sergey

    2016-04-01

    Granitoids and basic rocks of Wrangel Island are the components of Precambrian metamorphic basement, exposed in the anticlinorium in the central part of the island and named as Wrangel complex (Kameneva, 1970; Ageev, 1979; Til'man et al., 1964, 1970; Ganelin, 1989; Kos'ko et al., 1993, 2003). The latter is composed of volcanic, volcaniclastic and clastic rocks metamorphosed in greenshist to locally lower amphibolite facies (Kos'ko et al., 2003; Cecile et al., 1991). Obtained earlier datings of granitoids and basic rocks from Wrangel complex display a wide scatter: 609-700 Ma, U-Pb zircon (Cecile et al., 1991; Kos'ko et al., 1993); 590 Ma, Pb-Pb zircon; 574, 575 Ma, K-Ar whole rock; 475 Ma, Rb-Sr muscovite (Kos'ko et al., 2003). Our previous U-Pb SHRIMP datings indicate the episode of granitoid activity in 681-707 Ma (Luchitskaya et al., 2014). Here we present new results from zircon SIMS and LA-ICP-MS U-Pb dating and geochemical data for granites and felsic volcanics of Wrangel complex. Granites of Wrangel complex in the area of Khishchnikov River form small tabular bodies less than 30 meters in thickness. They range from slightly recrystallized muscovite granites to gneissic and mylonitic ones. Felsic and basic volcanics are exposed in the central part of Wrangel Island (rivers Neizvestnaya and Krasnyy Flag). Their interrelations are unknown and earlier they were considered as single bymodal assemblage of C1 sequence (Kos'ko et. al., 1993, 2003). Samples were collected in the area of Pervaya Mountain, visible thickness of volcanics ~100 meters. Basalts are overlain by conglomerates with detrite zircons no younger than 550 Ma (Moiseev et al., 2009, 2015). Wheited mean ages of zircons from muscovite granites and mylonitic ones are 592.9±6.7 Ma (n=10) and 692.9±5.0 Ma (n=30); in two samples we suppose the age of crystallization ~700 Ma. Wheited mean ages of zircons from felsic volcanics are 594.4±7.1 Ma (n=10) and 598.6±7.5 Ma (n=10). Granites and felsic

  2. PREFACE: Proceedings of the 7th Liquid Matter Conference (Lund, Sweden, 27 June 1 July 2008)

    NASA Astrophysics Data System (ADS)

    Kahl, Gerhard; Sciortino, Francesco; Ullner, Magnus

    2008-12-01

    , No, you won't be lonely - So, if you feel lonely, you should try! A tough guy tells you: Freeze! This is something that you have to test, 'Cause when you freeze you'll be super-cool, Or else you'll be under arrest. But you won't be lonely, baby, No, you won't be lonely, baby - So, if you feel lonely, you should try! I learn that the slightest nano-rod, That wouldn't seem very large; It still can fill up a lot of space As soon as you give it some charge! So, if you feel lonely, baby, Yes, if you feel lonely, baby - If you feel lonely, you should try! Well, when the party's over, What memories will time erase? Well, the chemistry may be lost on me, But I never forget a phase! And I won't be lonely, No, I won't be lonely - I won't be lonely 'til I die!

  3. PFI-ZEKE (Pulsed Field Ionization-Zero Electron Kinetic Energy) para el estudio de iones

    NASA Astrophysics Data System (ADS)

    Castaño, F.; Fernández, J. A.; Basterretxea, A. Longarte. F.; Sánchez Rayo, M. N.; Martínez, R.

    descubierta, que va en contra de lo esperado en otros sistemas físicos y que consiste en que los altos estados Rydberg de átomos, moléculas y sus complejos de van der Waals (o de los iones) tienen tiempos de vida de centenas de μ s. En resumen, el experimento y la espectroscopía ZEKE consiste en excitar un átomo, molécula o cluster sucesivamente a dos estados excitados selectivos de manera que el final sea un estado Rydberg. A continuación se aplica un campo eléctrico variable que lo ioniza y después de un cierto retraso se aplica un campo eléctrico de extracción, tanto para el electrón como para el ión. El espectro de los iones, es un espectro ZEKE. Hay varias alternativas para hacer este último proceso. El estudio de la espectroscopía y propiedades de iones y sus clusters requiere el conocimiento detallado de la espectroscopía de la molécula neutra, los estados Rydberg, de los confórmeros y sus complejos. Todo ello implica el haber estudiado los sistemas por LIF, REMPI y doble resonancia (hole burning IR-UV, UV-UV). Además solo es posible interpretar los resultados y obtener la información contenida en los espectros con ayuda de cálculos cuánticos ab initio. Hasta el momento hemos aplicado tanto el ZEKE como el conjunto de técnicas mencionadas anteriormente, a varias molécula de interés químico general como anilina y sus derivados, así como sus complejos con agua y amoniaco. Sin embargo, el método es muy versátil y puede aplicarse a iones de átomos, iones múltiples, moléculas sencillas y sus clusters así como a sus semi-reacciones. Como ejemplo de uno de estos espectros PFI-ZEKE se presenta aquí el caso del amonibenzonitrilo, ABN y solamente en su estado fundamental. En la conferencia se presentarán espectros ZEKE del ABN y moléculas similares en estados vibracionales intermedios (islas de estabilidad), así como la determinación de potenciales de ionización precisos, energías de enlace de compuestos del ión con varios disolventes y

  4. Future perspectives in melanoma research : Meeting report from the "Melanoma Bridge". Napoli, December 1st-4th 2015.

    PubMed

    Ascierto, Paolo A; Agarwala, Sanjiv; Botti, Gerardo; Cesano, Alessandra; Ciliberto, Gennaro; Davies, Michael A; Demaria, Sandra; Dummer, Reinhard; Eggermont, Alexander M; Ferrone, Soldano; Fu, Yang Xin; Gajewski, Thomas F; Garbe, Claus; Huber, Veronica; Khleif, Samir; Krauthammer, Michael; Lo, Roger S; Masucci, Giuseppe; Palmieri, Giuseppe; Postow, Michael; Puzanov, Igor; Silk, Ann; Spranger, Stefani; Stroncek, David F; Tarhini, Ahmad; Taube, Janis M; Testori, Alessandro; Wang, Ena; Wargo, Jennifer A; Yee, Cassian; Zarour, Hassane; Zitvogel, Laurence; Fox, Bernard A; Mozzillo, Nicola; Marincola, Francesco M; Thurin, Magdalena

    2016-11-15

    The sixth "Melanoma Bridge Meeting" took place in Naples, Italy, December 1st-4th, 2015. The four sessions at this meeting were focused on: (1) molecular and immune advances; (2) combination therapies; (3) news in immunotherapy; and 4) tumor microenvironment and biomarkers. Recent advances in tumor biology and immunology has led to the development of new targeted and immunotherapeutic agents that prolong progression-free survival (PFS) and overall survival (OS) of cancer patients. Immunotherapies in particular have emerged as highly successful approaches to treat patients with cancer including melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), bladder cancer, and Hodgkin's disease. Specifically, many clinical successes have been using checkpoint receptor blockade, including T cell inhibitory receptors such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death-1 (PD-1) and its ligand PD-L1. Despite demonstrated successes, responses to immunotherapy interventions occur only in a minority of patients. Attempts are being made to improve responses to immunotherapy by developing biomarkers. Optimizing biomarkers for immunotherapy could help properly select patients for treatment and help to monitor response, progression and resistance that are critical challenges for the immuno-oncology (IO) field. Importantly, biomarkers could help to design rational combination therapies. In addition, biomarkers may help to define mechanism of action of different agents, dose selection and to sequence drug combinations. However, biomarkers and assays development to guide cancer immunotherapy is highly challenging for several reasons: (i) multiplicity of immunotherapy agents with different mechanisms of action including immunotherapies that target activating and inhibitory T cell receptors (e.g., CTLA-4, PD-1, etc.); adoptive T cell therapies that include tissue infiltrating lymphocytes (TILs), chimeric antigen receptors (CARs), and

  5. The most important single factor influencing learning is what the learner already knows - What do the learner know about clouds, precipitation, wind and greenhouse effect; a short review of research from 1883 to 2009

    NASA Astrophysics Data System (ADS)

    Hansen, P. J. K.

    2009-09-01

    English environmental educators Edward Boyes and Martin Stanisstreet, staring up in 1992 and writing more than a dozen articles and book chapters - often together with researchers from other countries. Common features of Hansen, Boyes and Stanisstreet and many other researchers' discoveries up to present, are that students on all levels still exchange or confuse the greenhouse effect with the effects of the ozone layer, and many thinks that the greenhouse effect is not necessary for life on the Erath. The greenhouse effect and related topics came into secondary curriculum during the 1990-ies in many countries. The presentation will discuss some ideas of how to teach him accordingly at secondary education. Ausubel, D. P. 1968: Educational Psychology: A Cognitive View. Holt, Rinehart and Winston Inc. New York. Ausubel, D. P., J. D. Novak og H. Hanesian 1978: Educational Psychology. A Cognitive View. Second Edition. Holt, Rinehart and Winston, New York, Chicago, San Francisco, Dallas, Montreal, Toronto, London, Sydney. Hall, G. S. 1883: The Contents of Children's Minds. Princeton Review. Vol.XI, 1883, s.249-272. Piaget, J. 1930: The Child's Conception of Physical Causality. Kegan Paul, Trench, Trubner & Co.LTD, London. New York: Harcourt Brace & Company. Oversettelse av La causalité physique chez l'enfant fra 1927. Piaget, J. 1977: The Child's Conception of the World. 2. Edition. Paladin, London. Oversettelse av La représentation du monde chez l'enfant fra 1926. Boyes, E. og M. Stanisstreet 1992: Students' Perceptions of Global Warming. International Journal of Environmental Studies. 1992, Vol.42, s.287-300. Hansen, P. J. K. 1989: Spørsmål om vær og meteorologi til elever i 9.klasse i Oslo-området i 1989. Oslo lærerhøgskoles skriftserie. Hefte nr.2/92, Oslo (Nå Høgskolen i Oslo, Avdeling for lærerutdanning). 1.opplag 1989, Oslo lærerhøgskole, Oslo. Hansen, P. J. K. 2009: Knowledge about the greenhouse effect and the effects of the ozone layer among Norwegian

  6. Granitoid magmatism of Alarmaut granite-metamorphic dome, West Chukotka, NE Russia

    NASA Astrophysics Data System (ADS)

    Luchitskaya, M. V.; Sokolov, S. D.; Bondarenko, G. E.; Katkov, S. M.

    2009-04-01

    financial support of RFBR (projects № 07-05-00255, 08-05-00547), leading scientific school NSh-3172.2008.5, Programs of basic researches ONZ RAS 6. References 1. Parfenov L.M. Continental margins and island arcs of Mesozoides of North-East Asia. Novosibirsk, 1984. 192 p. (in Russian) 2. Zonenshain L.P., Kuz'min M.I., Natapov L.M. Tectonics of lithospheric plates of USSR territory // М.: Nauka, 1990. V. 2. 327 p. (in Russian) 3. Sokolov S.D. Classification and hierarchy of fold constructions. М. GEOS. 2008. P.71-100. (in Russian) 4. Seslavinsky K.B. South-Anyui suture zone (West Chukotka) // Dokl. AN USSR. 1979. V. 249. P. 1181-1185 (in Russian) 5. Natal'in B.A. Early Mesozoic eugeosynclinal systems in the northern part of Circum-Pacifica. М.: Nauka. 1984. 136 p. (in Russian) 6. Sokolov S.D., Bondarenko G.Ye., Morozov O.L.,. Shekhovtsov V.A., Glotov S.P.,. Ganelin A.V., Kravchenko-Berezhnoy I.R. The South Anyui Suture, NE Arctic Russia: facts and problems to solve. Tectonic Evolution of the Bering Shelf-Chukchi Sea-Arctic Margin and Adjacent Landmasses. Geol. Soc. Amer. Spec. Paper, 2002, 360. P. 209-224 7. Sokolov S.D., Bondarenko G.E., Morozov O.L., Luchitskaya M.V. Tectonics of junction zone between Verkhoyan-Chukotka and Koryak-Kamchatka fold // Byul. MOIP. Otd. Geol. 2001. V. 76. Is.6. P.24-37. (in Russian) 8. Bondarenko G.E. Tectonics and geodynamic evolution of Mesozoides of north framework of Pacific Ocean. М.: MGU, 2004. 46 p. (in Russian) 9. Til'man S.M. Comparative tectonics of Mesozoides of northern part of Pacific rim. Novosibirsk: Nauka. 1973. 325 p. (in Russian) 10. Grantz A., Moore T. E., Roeske S.M. Gulf of Alaska to Arctic Ocean: Geological Society of America Continental-Ocean Transect A-3, scale 1:500,000. Menlo Park, California, 1991, 72 р. 11. Sadovsky A.I. Geologic map of USSR, scale 1:200000. Anyui-Chauna series. Paper R-58-XXVII, XXVIII. (Ed: Gel'man M.L.) Explanatory report. Leningrad: VSEGEI, 1970, 84 p. (in Russian) 12. Gel'man M