Sample records for uddannelse til socialt

  1. The TIL commissioning and performance

    NASA Astrophysics Data System (ADS)

    Zhang, X.; Zheng, W.; Wei, X.; Jing, F.; Sui, Z.; Zheng, K.; Xu, Q.; Yuan, X.; Jiang, X.; Yang, L.; Ma, P.; Li, M.; Wang, J.; Hu, D.; He, S.; Li, F.; Peng, Z.; Feng, B.; Zhou, H.; Guo, L.; Li, X.; Zhang, X.; Su, J.; Zhu, Q.; Yu, H.; Zhao, R.; Ma, C.; He, H.; Fan, D.; Zhang, W.

    2008-05-01

    The TIL serves for both technological platforms for SG-III construction and physical experiments to study and understand target physics toward ignition and plasma burning [2]. The TIL has been designed to produce 10kJ blue light. Its eight-beam are stacked 4 high by 2 wide, The clear optical aperture is 30cm×30cm The cavity and booster amplifiers have 9 and 6 glass slabs respectively, with thickness of 3.8cm. The cavity is a four-pass amplification stage with the seed pulse injected through its cavity spatial filter, while the booster a single pass amplification stage. The commissioning experiments have successfully been conducted to test the output and control abilities of the system. A single beam line of TIL produced 3-ns pulse of 1645 Joule blue light at the target, which demonstrated that the TIL can deliver ten-thousand-joule blue light to the target. Beam qualities have been investigated jointly with the laser chain simulations using the SG-99 code. The wavefront distortions of the beams will be improved by deformable mirrors.

  2. TIL system with nonlinear phase conjugation

    NASA Astrophysics Data System (ADS)

    Khizhnyak, Anatoliy; Markov, Vladimir

    2007-09-01

    Efficient laser beam delivery on a distant target remains a key problem for practical implementation of tactical laser systems. Since the conventional target-in-the-loop (TIL) concept is generally not effective in such operational environments, new solutions are needed. In this report we discuss an innovative approach for effective compensation of laser beam aberrations in TIL systems. It is based on a recently devised technique that combines optical phase conjugation (OPC) with a TIL system for effective hot-spot formation. The proposed method should enable delivery of enhanced density laser energy to a target within a finite number of iteration cycles. Using the model based on an analogy between the TIL system and laser resonator, pointing of the laser beam on the target is performed at the image plane, resulting in reduced hot-spot formation time.

  3. A Conversation with William Van Til.

    ERIC Educational Resources Information Center

    Beineke, John A.

    1989-01-01

    Reports an interview with William Van Til, Coffman Distinguished Professor Emeritus of Education at Indiana State University (Terre Haute). Van Til reviews his career as a social studies teacher and his writings on curriculum and social foundations. Presents his opinions on progressive education, famous educators, educational history and reform,…

  4. Expansion of tumor-infiltrating lymphocytes (TIL) from human pancreatic tumors.

    PubMed

    Hall, MacLean; Liu, Hao; Malafa, Mokenge; Centeno, Barbara; Hodul, Pamela J; Pimiento, José; Pilon-Thomas, Shari; Sarnaik, Amod A

    2016-01-01

    We evaluated whether tumor infiltrating lymphocytes (TIL) could be expanded from surgically resected tumors from pancreatic cancer patients. Tumors were resected from pancreatic cancer patients. Tumors were minced into fragments and cultured in media containing high dose interleukin-2 (IL-2) for up to 6 weeks. T cell phenotype, activation markers, and reactivity were measured. TIL expansion was measured in 19 patient samples. The majority of these TIL were CD4 + T cells and were highly activated. Purified CD8 + T cells produced IFN-γ in response to HLA-matched pancreatic tumor targets. PD-1 blockade and 4-1BB stimulation were demonstrated as effective strategies to improve effective TIL yield, including the production of tumor-reactive pancreatic TIL. TIL expanded from pancreatic tumors are functional and able to respond to pancreatic tumor associated antigens. PD-1 blockade, 41BB stimulation, and CD8 + T cell enrichment are effective strategies to improve TIL yield and tumor reactivity. These results support the development of adoptive cell therapy strategies using TIL for the treatment of pancreatic cancer.

  5. Tumor infiltrating lymphocyte therapy for metastatic melanoma: analysis of tumors resected for TIL.

    PubMed

    Goff, Stephanie L; Smith, Franz O; Klapper, Jacob A; Sherry, Richard; Wunderlich, John R; Steinberg, Seth M; White, Donald; Rosenberg, Steven A; Dudley, Mark E; Yang, James C

    2010-10-01

    Adoptive cell transfer of tumor-infiltrating lymphocytes (TILs) can mediate objective tumor regression in 49% to 72% of patients with many long-term durable responses. To undergo treatment a patient must have (1) a resectable tumor from which (2) TIL can be generated that (3) exhibit tumor-specific reactivity. From July 2002 to July 2007, 787 tumors from 402 patients were processed for possible use in the generation of TIL, leading to the eventual treatment of 107 patients (27%). Viable TILs were generated in 376 patients (94%), and active, specific TILs were identified in 269 patients (67%). Patient demographics and tumor characteristics were analyzed for possible prognostic factors for growth and activity. Gastrointestinal-derived TIL grew less frequently, whereas lymph node and lung-derived TIL exhibited specific activity more often. TIL that grew and exhibited specific reactivity were from tumors that were larger in diameter and digests that had a higher percentage of lymphocytes. Despite these considerations, active, specific TIL could be generated from almost any site of metastasis. As more centers begin exploring the use of adoptive transfer with TIL, this compendium may provide a framework for therapeutic decision making and future investigation.

  6. Therapeutic efficacy of melanoma-reactive TIL injected in stage III melanoma patients.

    PubMed

    Labarrière, Nathalie; Pandolfino, Marie-Christine; Gervois, Nadine; Khammari, Amir; Tessier, Marie-Hélène; Dréno, Brigitte; Jotereau, Francine

    2002-11-01

    Adoptive therapy for cancer using tumor-infiltrating lymphocytes (TIL) has mainly been investigated in cancer patients with advanced stage disease. The limited clinical success has not been encouraging, although this might be explained by poor TIL specificity and/or high tumor burden. To re-evaluate the effectiveness of adoptive therapy, we analyzed the capacity of tumor-reactive TIL injection in preventing the further development of disease in stage III melanoma patients after complete tumor resection. A phase II/III randomized trial was performed on 88 melanoma patients, who received autologous TIL plus interleukin-2 (IL-2) or IL-2 only. The duration of relapse-free survival was analyzed, taking into account the immunological specificity of injected TIL and the number of metastatic lymph nodes removed before treatment. Kaplan-Meyer analysis revealed that the injection of tumor-reactive TIL was statistically correlated with prolonged relapse-free survival in patients with only one metastatic lymph node. Therefore, improved clinical outcome could be obtained after adoptive therapy by selecting appropriate groups of patients and monitoring the specificity of the injected TIL populations.

  7. [In vitro hepatic targeting tendency of galactosyl-anti CD3 McAb-TILS].

    PubMed

    Jiang, P; He, S; Zhang, C

    1999-03-01

    This study was undertaken to enhance the hepatic targeting tendency of tumor infiltrating lymphocytes (TILs) and hence to lower the recurrence rate of primary liver cancer after hepatectomy. Galactosyl-anti CD3McAb-TILs were prepared and then were incubated together with hepatocytes. Their interaction through asialoglycoprotein receptor-mediated mechanism was observed under the inverted phase contrast microscope. The carbohydrate density of galactosyl-anti CD3McAb and the combining rate of galactosyl-anti CD3McAb with TILs were measured. The results revealed that galactosyl-anti CD3 McAb-TIL obviously were adhered to hepatocytes. The carbohydrate density of galactosyl-anti CD3McAb was 62.18, and the combining rate of galactosyl-anti CD3McAb with TILs was 97.9%. The results suggested that in vitro hepatic targeting tendency of galactosyl-anti CD3McAb-TILs was satisfactory, and that the carbohydrate density of 62.18 and the combining rate of 97.9% ensured the effective use of TILs.

  8. 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.

  9. Antigen-Presenting Intratumoral B Cells Affect CD4+ TIL Phenotypes in Non-Small Cell Lung Cancer Patients.

    PubMed

    Bruno, Tullia C; Ebner, Peggy J; Moore, Brandon L; Squalls, Olivia G; Waugh, Katherine A; Eruslanov, Evgeniy B; Singhal, Sunil; Mitchell, John D; Franklin, Wilbur A; Merrick, Daniel T; McCarter, Martin D; Palmer, Brent E; Kern, Jeffrey A; Slansky, Jill E

    2017-10-01

    Effective immunotherapy options for patients with non-small cell lung cancer (NSCLC) are becoming increasingly available. The immunotherapy focus has been on tumor-infiltrating T cells (TILs); however, tumor-infiltrating B cells (TIL-Bs) have also been reported to correlate with NSCLC patient survival. The function of TIL-Bs in human cancer has been understudied, with little focus on their role as antigen-presenting cells and their influence on CD4 + TILs. Compared with other immune subsets detected in freshly isolated primary tumors from NSCLC patients, we observed increased numbers of intratumoral B cells relative to B cells from tumor-adjacent tissues. Furthermore, we demonstrated that TIL-Bs can efficiently present antigen to CD4 + TILs and alter the CD4 + TIL phenotype using an in vitro antigen-presentation assay. Specifically, we identified three CD4 + TIL responses to TIL-Bs, which we categorized as activated, antigen-associated, and nonresponsive. Within the activated and antigen-associated CD4 + TIL population, activated TIL-Bs (CD19 + CD20 + CD69 + CD27 + CD21 + ) were associated with an effector T-cell response (IFNγ + CD4 + TILs). Alternatively, exhausted TIL-Bs (CD19 + CD20 + CD69 + CD27 - CD21 - ) were associated with a regulatory T-cell phenotype (FoxP3 + CD4 + TILs). Our results demonstrate a new role for TIL-Bs in NSCLC tumors in their interplay with CD4 + TILs in the tumor microenvironment, establishing them as a potential therapeutic target in NSCLC immunotherapy. Cancer Immunol Res; 5(10); 898-907. ©2017 AACR . ©2017 American Association for Cancer Research.

  10. Tissue Biomarkers in Melanoma Patients Treated with TIL

    PubMed Central

    Knol, Anne-Chantal; Nguyen, Jean-Michel; Pandolfino, Marie-Christine; Quéreux, Gaëlle; Brocard, Anabelle; Peuvrel, Lucie; Saint-Jean, Mélanie; Saiagh, Soraya; Khammari, Amir; Dréno, Brigitte

    2012-01-01

    While treating stage III melanoma patients with autologous therapeutic TIL in an adjuvant setting, we previously reported a significant benefit of treatment on both progression-free survival and overall survival in patients with only one invaded lymph node (early stage III) compared to patients with more than one invaded lymph nodes (advanced stage III). In this context, in order to understand the difference of activity of TIL therapy according to the progression of the illness at stage III, the first objective of the present study was to determine potential differences in the characteristics of TIL populations obtained from an early stage III and a more advanced stage III when tumor burden is more important. The second objective was to determine possible differences in tissue expression level of several molecules involved in interactions between tumor cells and T cells between early and advanced stage III considering that the tumor microenvironment of invaded lymph nodes could become more tolerant with the progression of the disease. A total of 47 samples of melanoma invaded LN from stage IIIb (AJCC 2007) melanoma patients treated with TIL plus IL-2 were included in this study. We confirmed that both PFS and OS were significantly associated to the presence of tumor-reactive T-cells among TIL injected to the patients and that these tumor reactive T cells were more frequently observed at the early stage III. Moreover, while analyzing the expression of 17 markers on 34/47 tumor specimens using immunohistochemistry, we identified that 3 tissue markers involved in interactions between melanoma cells and T cells have a significant difference of expression between early and advanced stage III: MHC class I, adhesion molecule ICAM-1 and the co-stimulation molecule LFA-3 had a significantly weaker expression in melanoma tissue specimens from advanced stage III. In addition, the expression of the alpha chain of the IL-2 receptor (CD25) and the nuclear transcription factor

  11. Tissue biomarkers in melanoma patients treated with TIL.

    PubMed

    Knol, Anne-Chantal; Nguyen, Jean-Michel; Pandolfino, Marie-Christine; Quéreux, Gaëlle; Brocard, Anabelle; Peuvrel, Lucie; Saint-Jean, Mélanie; Saiagh, Soraya; Khammari, Amir; Dréno, Brigitte

    2012-01-01

    While treating stage III melanoma patients with autologous therapeutic TIL in an adjuvant setting, we previously reported a significant benefit of treatment on both progression-free survival and overall survival in patients with only one invaded lymph node (early stage III) compared to patients with more than one invaded lymph nodes (advanced stage III). In this context, in order to understand the difference of activity of TIL therapy according to the progression of the illness at stage III, the first objective of the present study was to determine potential differences in the characteristics of TIL populations obtained from an early stage III and a more advanced stage III when tumor burden is more important. The second objective was to determine possible differences in tissue expression level of several molecules involved in interactions between tumor cells and T cells between early and advanced stage III considering that the tumor microenvironment of invaded lymph nodes could become more tolerant with the progression of the disease. A total of 47 samples of melanoma invaded LN from stage IIIb (AJCC 2007) melanoma patients treated with TIL plus IL-2 were included in this study. We confirmed that both PFS and OS were significantly associated to the presence of tumor-reactive T-cells among TIL injected to the patients and that these tumor reactive T cells were more frequently observed at the early stage III. Moreover, while analyzing the expression of 17 markers on 34/47 tumor specimens using immunohistochemistry, we identified that 3 tissue markers involved in interactions between melanoma cells and T cells have a significant difference of expression between early and advanced stage III: MHC class I, adhesion molecule ICAM-1 and the co-stimulation molecule LFA-3 had a significantly weaker expression in melanoma tissue specimens from advanced stage III. In addition, the expression of the alpha chain of the IL-2 receptor (CD25) and the nuclear transcription factor

  12. Adoptive TIL Transfer in the Adjuvant Setting for Melanoma: Long-Term Patient Survival

    PubMed Central

    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. PMID:24741578

  13. 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.

  14. Comparative study on the larvicidal activity of drimane sesquiterpenes and nordrimane compounds against Drosophila melanogaster til-til.

    PubMed

    Montenegro, Ivan; Pino, Luis; Werner, Enrique; Madrid, Alejandro; Espinoza, Luis; Moreno, Luis; Villena, Joan; Cuellar, Mauricio

    2013-04-10

    Natural compounds from Drimys winteri Forst and derivatives exhibited larvicidal effects against Drosophila melanogaster til-til. The most active compound was isodrimenin (4). The highest lethal concentration to the larvae of D. melanogaster was 4.5 ± 0.8 mg/L. At very low concentrations drimenol (1), confertifolin (3), and drimanol (5) displayed antifeedant and larvae growth regulatory activity. The antifeedant results of nordrimanic and drimanic compounds were better in first instar larvae. The EC₅₀ value of polygodial (2) was 60.0 ± 4.2 mg/L; of diol 15 45.0 ± 2.8 mg/L, and of diol 17 36.9 ± 3.7 mg/L, while the new nordrimane compound 12 presented a value of 83.2 ± 3.5 mg/L.

  15. [Evaluation of inflammatory cells (tumor infiltrating lymphocytes - TIL) in malignant melanoma].

    PubMed

    Dundr, Pavel; Němejcová, Kristýna; Bártů, Michaela; Tichá, Ivana; Jakša, Radek

    2018-01-01

    The evaluation of inflammatory infiltrate (tumor infiltrating lymphocytes - TIL) should be a standard part of biopsy examination for malignant melanoma. Currently, the most commonly used assessment method according to Clark is not optimal and there have been attempts to find an alternative system. Here we present an overview of possible approaches involving five different evaluation methods based on hematoxylin-eosin staining, including the recent suggestion of unified TIL evaluation method for all solid tumors. The issue of methodology, prognostic and predictive significance of TIL determination as well as the importance of immunohistochemical subtyping of inflammatory infiltrate is discussed.

  16. Early Therapy Intensity Level (TIL) Predicts Mortality in Spontaneous Intracerebral Hemorrhage.

    PubMed

    Ziai, Wendy C; Siddiqui, Aazim A; Ullman, Natalie; Herrick, Daniel B; Yenokyan, Gayane; McBee, Nichol; Lane, Karen; Hanley, Daniel F

    2015-10-01

    Outcome from spontaneous intracerebral hemorrhage (sICH) may depend on patient-care variability. We developed as ICH-specific therapy intensity level (TIL) metric using evidence-based elements in a high severity sICH cohort. This is a cohort study of 170 patients with sICH and any intraventricular hemorrhage treated in 2 academic neuroICUs. Pre-defined quality indicators were identified based on current guidelines, scientific evidence, and likelihood of care documentation in first 72 h of hospital admission. We assessed performance on each indicator and association with discharge mortality. Significant indicators were aggregated to develop a TIL score. The predictive validity of the best fit TIL score was tested with threefold cross-validation of multivariate logistic regression models of in-hospital survival and good outcome (modified Rankin score 0-3). Median ICH score was 3; discharge mortality was 51.2%. Five/19 tested variables were significantly associated with lower discharge mortality: no DNR/withdrawal of treatment within 24 h of admission, target glucose within 4 h of high glucose, no recurrent hyperpyrexia, clinical reversal of herniation/intracranial pressure >20 mmHg within 60 min of detection, and reversal of INR (<1.4) within 2 h of first elevation. One point was given for each or if not applicable. Median TIL score was significantly higher in survivors versus non-survivors (5[1] vs. 3[1]; P < 0.001). A 4-point aggregated TIL score was most predictive of discharge survival (area under receiving operating characteristic curve 0.85, 95% CI 0.80-0.90) and good outcome (AUC 0.84) and was an independent predictor of both (survival: OR 7.10; 95% CI 3.57-14.11; P < 0.001; good outcome: OR 3.10; 95% CI 1.06-8.79; P < 0.001). A simplified TIL score using evidenced-based patient-care parameters within first 3 days of admission after sICH was significantly associated with early mortality and good outcome. The next step is prospective validation of the

  17. High-scale expansion of melanoma-reactive TIL by a polyclonal stimulus: predictability and relation with disease advancement.

    PubMed

    Pandolfino, M C; Labarrière, N; Tessier, M H; Cassidanius, A; Bercegeay, S; Lemarre, P; Dehaut, F; Dréno, B; Jotereau, F

    2001-05-01

    The rationale of treating melanoma patients by infusion with tumor-infiltrating leukocytes (TIL) is to perform an adoptive therapy through injection of tumor-specific T cells. Nonetheless, methods currently used for ex vivo TIL expansion have not been evaluated for their efficacy to expand TAA-specific T cells. We have addressed this question here, using a culture method in which high TIL growth was induced by a polyclonal T cell stimulus. Intracellular cytokine assays were performed to measure the proportion of T cells responding to autologous tumor cells among the lymphocytes from lymph node biopsies (TIL) of 26 patients with stage III melanoma. The data show that TIL from 18 of these patients contained detectable amounts of tumor-specific T cells before expansion. Although they decreased somewhat in percent abundance during expansion, they were still present afterwards, ranging from 0.3 to 13.8%. Since a median number of 1.7 x 10(10) TIL was obtained from these patients (starting from 3.6 x 10(6) TIL), a total amount of tumor-reactive cytokine-secreting TIL of between 2.8 x 10(6) and 1.12 x 10(9) was obtained in each case from 18 patients. The TIL populations from 8 patients did not contain tumor-reactive T cells: neither before expansion, nor after expansion. Lack of tumor-reactive TIL only occurs for patients bearing several tumor-invaded lymph nodes (40%), but not for those having a single invaded lymph node. Therefore, high numbers of tumor-reactive T cells can be produced, through a polyclonal TIL stimulation, from most early stage III melanoma patients but from only about half of the patients with a more disseminated disease. For this last group, the possibility of getting tumor-reactive TIL can be predicted by checking the presence of these cells before expansion.

  18. Telltale tumor infiltrating lymphocytes (TIL) in oral, head & neck cancer.

    PubMed

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

    2016-10-01

    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. Copyright © 2016 Elsevier Ltd. All rights reserved.

  19. PD-L1 expression and presence of TILs in small intestinal neuroendocrine tumours

    PubMed Central

    Lamarca, Angela; Nonaka, Daisuke; Breitwieser, Wolfgang; Ashton, Garry; Barriuso, Jorge; McNamara, Mairéad G.; Moghadam, Sharzad; Rogan, Jane; Mansoor, Wasat; Hubner, Richard A.; Clark, Christopher; Chakrabarty, Bipasha; Valle, Juan W.

    2018-01-01

    Background The extent of resistance to immune surveillance in patients with well-differentiated (Wd) (grade 1/2) small-intestinal neuroendocrine tumours (Si-NETs) is unknown. Methods Patients diagnosed with Wd Si-NETs (excluding appendix, which are considered to have a different biology to other midgut NETs) were eligible. Tumoural programmed death (PD)-ligand(L) 1 (PD-L1)/PD-L2/PD-1 and tumour infiltrating lymphocytes (TILs) [presence and phenotype] were analysed in archival tissue by immunohistochemistry (IHC); reverse transcription quantitative polymerase chain reaction (RT-qPCR) was used for confirmation of IHC results. Results Of 109 patients screened, 62 were eligible: 54.8% were male; median age was 63.7 years (95%-CI 59.7-67.2); disease stage II: 4.8%, III: 40.3% and IV: 54.8%; 41.9% were functional. Analysed samples (67.1% from primary tumours, 32.9% from metastases) were of grade 1 (67.1%) or 2 (32.86%) with a median Ki-67 of 2%. From the total of 62 eligible patients, 70 and 63 samples were suitable for IHC and RT-qPCR analysis, respectively. PD-L1 expression within tumour cells and TILs were identified in 12.8% and 24.3% of samples respectively; 30% of samples showed PD-L1 expression within tumour cells and/or TILs. PD-1 was present in TILs in 22.8% of samples. Majority of samples showed significant presence of CD4+ (focal 42.86%; moderate 2.86%) and CD8+ (focal 92.86%; moderate 4.29%) TILs. IHC findings were confirmed with RT-qPCR; which showed higher expression levels of PD-L1 (p-value 0.007) and PD-1 (p-value 0.001) in samples positive for IHC compared to negative-IHC. Conclusions Thirty-percent of patients express PD-L1 within tumour cells and/or TILs. Identification of presence of TILs was also significant and warrant the investigation of immunotherapy in this setting. PMID:29599916

  20. TIL 2.0: More effective and predictive T-cell products by enrichment for defined antigen specificities.

    PubMed

    Schober, Kilian; Busch, Dirk H

    2016-06-01

    Adoptive transfer of in vitro-expanded T cells derived from tumor-infiltrating lymphocytes (TILs) in melanoma patients started the era of tumor immunotherapy three decades ago. The approach has demonstrated remarkable clinical responses in several studies since. Reinfusion of TIL-derived T cells represents a highly personalized form of immunotherapy, taking into account the enormous interindividual tumor heterogeneity. However, despite its successes, TIL therapy does not lead to objective clinical responses in all cases. It is thus crucial to find out which tumor antigens are particularly valuable targets and to develop strategies to enhance the reactivity of T-cell products toward them. In this issue of the European Journal of Immunology, Kelderman et al. [Eur. J. Immunol. 2016. 46: 1351-1360] present a platform for the generation of antigen-specific TIL therapy. Combining recently developed technologies for clinical identification and enrichment of antigen-specific CD8(+) T cells, such as MHC Streptamers and UV-mediated peptide exchange, the authors could enrich T-cell populations with defined antigen specificities from melanoma-derived TILs. This T-cell product showed higher reactivity against autologous tumor cell lines than bulk TIL-derived T cells. The novel platform might enable the generation of more effective and predictable TIL-derived T-cell products for future clinical applications. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  1. Importance of choice of materials and methods in PD-L1 and TIL assessment in oropharyngeal squamous cell carcinoma.

    PubMed

    De Meulenaere, Astrid; Vermassen, Tijl; Creytens, David; Aspeslagh, Sandrine; Deron, Philippe; Duprez, Frederic; Rottey, Sylvie; Van Dorpe, Jo; Ferdinande, Liesbeth

    2018-05-16

    A great deal of research is being conducted into PD-L1 immunohistochemistry (IHC) and tumor infiltrating lymphocytes (TILs) as predictive or prognostic biomarkers for immunotherapy, although several practical issues exist concerning their assessment. The aim of this research was therefore to assess the importance of choice of materials and methods in PD-L1 and TILs scoring in oropharyngeal squamous cell carcinoma (OSCC). IHC for PD-L1 (SP142 and 22C3 clone) and TILs subtyping was performed on formalin-fixed paraffin-embedded tissue slides (biopsy, resection and/or lymph nodes specimens) of 99 patients with OSCC. A comparative analysis of PD-L1 and TILs scoring was made between different types of tissue specimens, between different PD-L1 clones, between TILs and different subsets of TILs, and between the quantitative and semi-quantitative assessment. PD-L1 scoring resulted in fair to moderate agreement for 22C3 and SP142 between various tissue specimens, with higher agreement at higher cut-off values, and in moderate agreement for 22C3 versus SP142. Evaluation by four independent observers proved substantial inter-rater agreement for both clones with high consistency in their ratings. Moderate agreement was observed for TILs and TILs subsets for the comparison between biopsy and resection. Lastly, strong correlations were found between quantitative and semi-quantitative assessment for all PD-L1 and TILs scores. Our results highlight the challenges associated with the evaluation of PD-L1 and TILs in OSCC. Further research is warranted to evaluate the use of these biomarkers in order to allow implementation of PD-L1 and TILs infiltrate as biomarkers in daily clinical practice. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  2. Better Clinical Efficiency of TILs for Malignant Pleural Effusion and Ascites than Cisplatin Through Intrapleural and Intraperitoneal Infusion.

    PubMed

    Chu, Hongjin; Du, Fengcai; Gong, Zhaohua; Lian, Peiwen; Wang, Zhixin; Li, Peng; Hu, Baohong; Chi, Cheng; Chen, Jian

    2017-08-01

    To evaluate the clinical efficiency of tumor-infiltrating lymphocytes (TILs) compared to cisplatin for malignant pleural effusion and ascites through intrapleural and intraperitoneal infusion. Thirteen patients with malignant pleural effusion and ascites were divided into a TIL-treated group and a cisplatin-treated group. Patients were given TILs or cisplatin, through intrapleural and intraperitoneal infusion respectively, after drainage of the malignant serous effusion by thoracentesis or abdominocentesis. The overall response rate and disease control rate of the TIL-treated group (33.33% and 83.33%) were higher than that of the cisplatin-treated group (28.57% and 71.43%). The progression-free survival for the TIL-treated group was significantly longer (p=0.002) and better than that of the cisplatin-treated group (66.67% vs. 28.57%). Quality of life apparently improved in the TIL-treated group and was clearly higher than that in the cisplatin-treated group. The use of TILs has a better clinical efficiency for malignant pleural effusion and ascites than cisplatin through intrapleural and intraperitoneal infusion without severe adverse effects. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  3. Tumor associated antigen specific T-cell populations identified in ex vivo expanded TIL cultures.

    PubMed

    Junker, Niels; Kvistborg, Pia; Køllgaard, Tania; Straten, Per thor; Andersen, Mads Hald; Svane, Inge Marie

    2012-01-01

    Ex vivo expanded tumor infiltrating lymphocytes (TILs) from malignant melanoma (MM) and head & neck squamous cell carcinoma (HNSCC) share a similar oligoclonal composition of T effector memory cells, with HLA class I restricted lysis of tumor cell lines. In this study we show that ex vivo expanded TILs from MM and HNSCC demonstrate a heterogeneous composition in frequency and magnitude of tumor associated antigen specific populations by Elispot IFNγ quantitation. TILs from MM and HNSCC shared reactivity towards NY ESO-1, cyclin B1 and Bcl-x derived peptides. Additionally we show that dominating T-cell clones and functionality persists through out expansion among an oligoclonal composition of T-cells. Our findings mirror prior results on the oligoclonal composition of TIL cultures, further indicating a potential for a broader repertoire of specific effector cells recognizing the heterogeneous tumors upon adoptive transfer; increasing the probability of tumor control by minimizing immune evasion by tumor cell escape variants. Copyright © 2011 Elsevier Inc. All rights reserved.

  4. Simplified Method of the Growth of Human Tumor Infiltrating Lymphocytes (TIL) in Gas-Permeable Flasks to Numbers Needed for Patient Treatment

    PubMed Central

    Jin, Jianjian; Sabatino, Marianna; Somerville, Robert; Wilson, John R.; Dudley, Mark E.; Stroncek, David F.; Rosenberg, Steven A.

    2012-01-01

    Adoptive cell therapy (ACT) of metastatic melanoma with autologous tumor infiltrating lymphocytes (TIL) is clinically effective, but TIL production can be challenging. Here we describe a simplified method for initial TIL culture and rapid expansion in gas-permeable flasks. TIL were initially cultured from tumor digests and fragments in 40 mL capacity flasks with a 10 cm2 gas-permeable silicone bottom, G-Rex10. A TIL rapid expansion protocol (REP) was developed using 500 mL capacity flasks with a 100 cm2 gas-permeable silicone bottom, G-Rex100. TIL growth was successfully initiated in G-Rex10 flasks from tumor digests from 13 of 14 patients and from tumor fragments in all 11 tumor samples tested. TIL could then be expanded to 8–10×109 cells in a two-step REP which began by seeding 5 × 106 TIL into a G-Rex100 flask, followed by expansion at day 7 into 3 G-Rex100 flasks. To obtain the 30 to 60 × 109 cells used for patient treatment we seeded 6 G-Rex100 flasks with 5×106 cells and expanded into 18 G-Rex100 flasks. Large scale TIL REP in gas-permeable flasks requires approximately 9 to 10 liters of media, about 3 to 4 times less than other methods. In conclusion, TIL initiation and REP in gas-permeable G-Rex flasks require fewer total vessels, less media, less incubator space and less labor than initiation and REP in 24-well plates, tissue culture flasks and bags. TIL culture in G-Rex flasks will facilitate the production of TIL at the numbers required for patient treatment at most cell processing laboratories. PMID:22421946

  5. Foxp3 and IL17 expression in tumor infiltrating lymphocytes (TIL) and tumor cells - correlated or independent factors?

    PubMed

    Vasilescu, Florina; Arsene, D; Cionca, Florina; Comănescu, Maria; Enache, V; Iosif, Cristina; Alexandru, D O; Georgescu, D; Dobrea, Camelia; Bălan, Adina; Ardeleanu, Carmen

    2013-01-01

    Tumor infiltrating lymphocytes (TIL), as a microenvironment component were studied in various epithelial tumors, with contradictory results. Recent data about regulatory T-cells (Treg) revealed new explanations for pro- and anti-tumor implications of TIL. Tregs immunoprofile was recently completed with Foxp3 expression. A T-cell fraction (Th) is producing cytokine IL17 and is now considered acting in tumor progression. Our study aimed to analyze immunohistochemically (IHC) Foxp3+ and IL17 expression in resected lung adenocarcinomas, since they could become possible targets in the antitumor immunotherapy. The studied material was represented by paraffin-embedded tumor fragments from 59 patients with TIL identified on HE staining. The antibodies used were Foxp3 and IL17. The statistical analysis used logistical regression on SPSS19 software (Chicago, IL, USA). TIL was usually mild or scarce. A positive statistic correlation resulted between the amounts of TIL in peritumoral and intratumoral location but without correlation to histopathological grading. Foxp3 and IL17 were present in TIL lymphocytes, tumor cells and fibroblasts; IL17 was expressed also in periendothelial cells (PEC). Foxp3 positivity was significantly correlated for lymphocytes÷tumor cells, lymphocytes÷fibroblasts and tumor cells÷fibroblasts, suggesting their concerted action. Tumor cells and lymphocytes Foxp3 expression was inversely correlated with the amount of TIL. Between lymphocytic Foxp3 and PEC IL17, we found a weak negative correlation. The TIL had a quite positive correlation with PEC IL17. In these conditions, Foxp3 could be a mediator of the tumor cells inhibitory aggression upon the immune system and could be used as a molecular target for biological antitumor therapy.

  6. Detection and functional analysis of tumor infiltrating T-lymphocytes (TIL) in liver metastases from colorectal cancer.

    PubMed

    Wagner, Philipp; Koch, Moritz; Nummer, Daniel; Palm, Sylvia; Galindo, Luis; Autenrieth, Daniel; Rahbari, Nuh; Schmitz-Winnenthal, Friedrich H; Schirrmacher, Volker; Büchler, Markus W; Beckhove, Philipp; Weitz, Jürgen

    2008-08-01

    Tumor-infiltrating T lymphocytes (TIL) play an important role in primary colorectal cancer, but their activity in liver metastases has not yet been investigated. The aim of this study was to examine whether tumor-selective infiltration, activation, and cytotoxic activity of TIL can be demonstrated in situ in colorectal liver metastases. TIL were obtained from liver metastases and corresponding normal liver tissue of 16 patients with colorectal liver metastases. Characterization of TIL in situ was performed by multicolor flowcytometric analysis. Presence of tumor antigen-reactive T cells was evaluated by interferon gamma Elispot analysis. TIL in colorectal liver metastases responding against tumor antigens were present in most patients. Although the proportions of CD3(+) T cells were comparable in liver metastasis and normal liver tissue, metastases contained significantly enhanced proportions of CD4(+) cells (49% vs. 22%, P < .001). Among all CD4(+) T helper cells, the proportion of activated (CD4(+)CD25(+)) effector cells was significantly increased in liver metastases (15.0% vs. 7.8%, P = .003). Metastases showed significantly higher proportions of activated (CD69(+) [70.1% vs. 49.8%, P = .02] and CD25(+) [4.1% vs. .6%, P = .06]) and cytotoxically active (CD107a(+)) CD8(+) TIL (3.2% vs. 1.3%, P = .03). Importantly, the presence of activated T helper cells correlated with the frequencies of cytotoxic T lymphocytes that exerted cytotoxic activity in situ (P = .02). CD4(+) and CD8(+) TIL are selectively activated in liver metastases, and cytotoxic T lymphocytes exert tumor-selective cytotoxic activity in situ in the presence of activated T helper cells, suggesting the requirement of in-situ-activated T helper cells for efficient cytotoxic T lymphocytes effector function.

  7. Checkpoint Antibodies but not T Cell-Recruiting Diabodies Effectively Synergize with TIL-Inducing γ-Irradiation.

    PubMed

    Hettich, Michael; Lahoti, Jayashree; Prasad, Shruthi; Niedermann, Gabriele

    2016-08-15

    T cell-recruiting bispecific antibodies (bsAb) show promise in hematologic malignancies and are also being evaluated in solid tumors. In this study, we investigated whether T cell-recruiting bsAbs synergize with hypofractionated tumor radiotherapy (hRT) and/or blockade of the programmed death-1 (PD-1) immune checkpoint, both of which can increase tumor-infiltrating lymphocyte (TIL) numbers. Unexpectedly, large melanomas treated with hRT plus bsAb (AC133×CD3) relapsed faster than those treated with hRT alone, accompanied by massive TIL apoptosis. This fast relapse was delayed by the further addition of anti-PD-1. Mechanistic investigations revealed restimulation-induced cell death mediated by BIM and FAS as an additional cause of bsAb-mediated TIL depletion. In contrast, the double combination of hRT and anti-PD-1 strongly increased TIL numbers, and even very large tumors were completely eradicated. Our study reveals the risk that CD3-engaging bsAbs can induce apoptotic TIL depletion followed by rapid tumor regrowth, reminiscent of tolerance induction by CD3 mAb-mediated T-cell depletion, warranting caution in their use for the treatment of solid tumors. Our findings also argue that combining radiotherapy and anti-PD-1 can be quite potent, including against very large tumors. Cancer Res; 76(16); 4673-83. ©2016 AACR. ©2016 American Association for Cancer Research.

  8. 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…

  9. Temperature-induced lipocalin (TIL) is translocated under salt stress and protects chloroplasts from ion toxicity.

    PubMed

    Abo-Ogiala, Atef; Carsjens, Caroline; Diekmann, Heike; Fayyaz, Payam; Herrfurth, Cornelia; Feussner, Ivo; Polle, Andrea

    2014-02-15

    Temperature-induced lipocalins (TIL) have been invoked in the defense from heat, cold and oxidative stress. Here we document a function of TIL for basal protection from salinity stress. Heterologous expression of TIL from the salt resistant poplar Populus euphratica did not rescue growth but prevented chlorophyll b destruction in salt-exposed Arabidopsis thaliana. The protein was localized to the plasma membrane but was re-translocated to the symplast under salt stress. The A. thaliana knock out and knock down lines Attil1-1 and Attil1-2 showed stronger stress symptoms and stronger chlorophyll b degradation than the wildtype (WT) under excess salinity. They accumulated more chloride and sodium in chloroplasts than the WT. Chloroplast chloride accumulation was found even in the absence of salt stress. Since lipocalins are known to bind regulatory fatty acids of channel proteins as well as iron, we suggest that the salt-induced trafficking of TIL may be required for protection of chloroplasts by affecting ion homeostasis. Copyright © 2013 Elsevier GmbH. All rights reserved.

  10. Strong and rapid induction of osteoblast differentiation by Cbfa1/Til-1 overexpression for bone regeneration.

    PubMed

    Kojima, Hiroko; Uemura, Toshimasa

    2005-01-28

    Core binding factor alpha-1 (Cbfa1), known as an essential transcription factor for osteogenic lineage, has two major N-terminal isoforms: Pebp2alphaA and Til-1. To study the roles of these isoforms in bone regeneration, we applied an adenoviral vector carrying their genes to transduce primary osteoprogenitor cells in vitro and in vivo. Overexpression of the two isoforms induced rapid and marked osteoblast differentiation, with Til-1 being more effective in vitro, by examination of the alkaline phosphatase activity, calcium content, and Alizarin red staining. Til-1 overexpressing cells/porous ceramic composites were transplanted into subcutaneous and bone defect sites in Fischer rats (cultured bone transplantation model) and markedly affected in vivo bone formation and osteoblast markers. The results demonstrated that the reconstitution of bone tissues, such as cortical bone and trabecular bone was accelerated by implantation of Til-1 overexpressing cells/porous ceramic composites. Moreover, the new bone formation by Til-1 overexpression appeared to reflect replacement of new bone within the implant boundaries. To ascertain whether implanted Cbfa1 overexpressing cells could differentiate into osteogenic cells to create bone or whether it stimulated the surrounding recipient tissue to regenerate bone, implanted male donor cells were visualized by fluorescent in situ hybridization analysis. The proportion of implanted cells in the presumptive bone forming region was over 80% and did not change throughout from 3 days to 8 weeks after implantation. These findings suggested that the newly formed bone in the porous area of the scaffold is mostly produced by the implanted donor cells or their derived cells, effectively by Til-1 overexpression.

  11. Compact plasma Pockels cell for TIL of SGIII laser facility

    NASA Astrophysics Data System (ADS)

    Zhang, Xiongjun; Wu, Dengsheng; Lin, Doughui; Yu, Haiwu; Zhang, Jun

    2008-01-01

    Compact plasma Pockel's cells (PPC) with 70mm aperture driven by one-pulse process have been constructed for technical integration line (TIL) of SGIII laser facility. The experimental results indicate that the working range of gas pressure is wide, and the delay of gas breakdown is steady. Measurements of the optical performance show static transmittance of 93.1%, static extinction ratio of 3900, and average switching efficiency of 99.7%. Eight compact PPCs are used for the second-stage integrating experiments of TIL. By using of parallel driving technology, one driver can work for four PPCs. An analyzer of optical switch is replaced with Brewster-angle Nd-glass slabs in amplifier. Two years application results show that the PPCs can effectively minimize the growth of parasitic-oscillation, and have a high reliability.

  12. Effects of Glycogen Synthase Kinase-3β Inhibitor TWS119 on Proliferation and Cytokine Production of TILs From Human Lung Cancer.

    PubMed

    Tang, Ying Ying; Sheng, Si Yuan; Lu, Chuan Gang; Zhang, Yu Qing; Zou, Jian Yong; Lei, Yi Yan; Gu, Yong; Hong, Hai

    2018-06-05

    The canonical Wnt-β-catenin signaling pathway arrests the differentiation of T cells and plays an important role in phenotypic maintenance of naive T cells and stem cell-like memory T cells in human peripheral blood, but its effect on tumor-infiltrating lymphocytes (TILs) from non-small cell lung cancer is little known. In this study, we showed that glycogen synthase kinase-3β inhibitor TWS119 has different effects on CD4 and CD8 T cells in TILs. TWS119 preserved the expansion of naive T cell and CD8 stem cell-like memory T cells, and induced CD8 effector T-cell proliferation in TILs. To further determine whether TWS119 impaired the effector function of TILs, TILs were stimulated with polyclonal stimulation, IL-2 and IFN-γ production were detected. Our data showed that TWS119 does not affect the production of IFN-γ in TILs compared with the control group; whereas TWS119 inhibited IFN-γ secretion of T cells from healthy donor. IL-2 production in CD4 central memory T cells and CD4 effector memory T cells from TILs was significantly increased with the TWS119 treatment; TWS119 also promoted the secretion of IL-2 in all cell subsets of CD8 TILs. These findings reveal that TWS119 has a distinct effect on the proliferation and cytokine production of TILs, and provide new insights into the clinical application of TILs with TWS119 treatment for the adoptive immunotherapy.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/.

  13. [Experimental study on the activity of Staphyloccocal enterotoxin A liposome for inducing cytotoxicity of TIL from human hepatocellular carcinoma against tumor cells].

    PubMed

    Li, Mao-de; Li, Zhi-yu; He, Sheng; Xue, Hua

    2004-01-01

    To investigate the activity of Staphyloccocal enterotoxin A liposome (L-SEA) for inducing cytotoxicity of tumor infiltrating lymphocytes (TIL) against tumor cells. TIL were isolated from the tumor tissues of five hepatocellular carcinoma patients. L-SEA, SEA and IL-2 were tested in vitro for their activity levels in stimulating TIL proliferation. The TNF-alpha and IFN-gamma secretion and cytotoxicity of TIL against HepG-2 liver cancer cells were estimated by ELISA and MTT, respectively. Both L-SEA and SEA significantly stimulated the proliferation of TIL. The cytokine secretion of L-SEA group was significantly higher than that of IL-2 group (P < 0.05). There was no significantly statistical difference in cytokine secretion between L-SEA group and SEA group (P > 0.05) except that IFN-gamma secretion of L-SEA group was lower than that of SEA group at day 4 (P < 0.05). Both L-SEA and SEA had potent ability to induce TIL cytotoxicity against HepG-2 cells. And no significant difference was observed between these two groups (P > 0.05). These results suggest that L-SEA is as efficient as SEA in activating TIL.

  14. 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.

  15. Prospective analysis of adoptive TIL therapy in patients with metastatic melanoma: response, impact of anti-CTLA4, and biomarkers to predict clinical outcome.

    PubMed

    Forget, Marie-Andrée; Haymaker, Cara; Hess, Kenneth R; Meng, Yuzhong Jeff; Creasy, Caitlin; Karpinets, Tatiana V; Fulbright, Orenthial J; Roszik, Jason; Woodman, Scott E; Kim, Young Uk; Sakellariou-Thompson, Donastas; Bhatta, Ankit; Wahl, Arely; Flores, Esteban; Thorsen, Shawne T; Tavera, Rene J; Ramachandran, Renjith; Gonzalez, Audrey M; Toth, Christopher; Wardell, Seth; Mansaray, Rahmatu; Patel, Vruti; Carpio, Destiny Joy; Vaughn, Carol S; Farinas, Chantell M; Velasquez, Portia G; Hwu, Wen-Jen; Patel, Sapna P; Davies, Michael A; Diab, Adi; Glitza, Isabella C; Tawbi, Hussein; Wong, Michael K K; Cain, Suzanne; Ross, Merrick I; Lee, Jeffrey E; Gershenwald, Jeffrey E; Lucci, Anthony; Royal, Richard; Cormier, J N; Wargo, Jennifer A; Radvanyi, Laszlo G; Torres Cabala, Carlos A; Beroukhim, Rameen; Hwu, Patrick; Amaria, Rodabe N; Bernatchez, Chantale

    2018-05-30

    Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) has consistently demonstrated clinical efficacy in metastatic melanoma. Recent widespread use of checkpoint blockade has shifted the treatment landscape, raising questions regarding impact of these therapies on response to TIL and appropriate immunotherapy sequence. Seventy-four metastatic melanoma patients were treated with autologous TIL and evaluated for clinical response according to irRC, overall survival and progression free survival. Immunologic factors associated with response were also evaluated. Best overall response for the entire cohort was 42%; 47% in 43 checkpoint naïve patients, 38% when patients were exposed to anti-CTLA4 alone (21 patients) and 33% if also exposed to anti-PD1 (9 patients) prior to TIL ACT. Median overall survival was 17.3 months; 24.6 months in CTLA4 naïve patients and 8.6 months in patients with prior CTLA4 blockade. The latter patients were infused with fewer TIL and experienced a shorter duration of response. Infusion of higher numbers of TIL with CD8 predominance and expression of BTLA correlated with improved response in anti-CTLA-4 naive patients, but not in anti-CTLA-4 refractory patients. Baseline serum levels of IL-9 predicted response to TIL ACT, while TIL persistence, tumor recognition and mutation burden did not correlate with outcome. This study demonstrates the deleterious effects of prior exposure to anti-CTLA4 on TIL ACT response and shows that baseline IL-9 levels can potentially serve as a predictive tool to appropriately select sequence for immunotherapies. Copyright ©2018, American Association for Cancer Research.

  16. 4-1BB-Enhanced Expansion of CD8+ TIL from Triple-Negative Breast Cancer Unveils Mutation-Specific CD8+ T Cells.

    PubMed

    Harao, Michiko; Forget, Marie-Andrée; Roszik, Jason; Gao, Hui; Babiera, Gildy V; Krishnamurthy, Savitri; Chacon, Jessica A; Li, Shumin; Mittendorf, Elizabeth A; DeSnyder, Sarah M; Rockwood, Korrene F; Bernatchez, Chantale; Ueno, Naoto T; Radvanyi, Laszlo G; Vence, Luis; Haymaker, Cara; Reuben, James M

    2017-06-01

    Triple-negative breast cancer (TNBC) highly infiltrated with CD8 + tumor-infiltrating lymphocytes (TIL) has been associated with improved prognosis. This observation led us to hypothesize that CD8 + TIL could be utilized in autologous adoptive cell therapy for TNBC, although this concept has proven to be challenging, given the difficulty in expanding CD8 + TILs in solid cancers other than in melanoma. To overcome this obstacle, we used an agonistic antibody (urelumab) to a TNFR family member, 4-1BB/CD137, which is expressed by recently activated CD8 + T cells. This approach was first utilized in melanoma and, in this study, led to advantageous growth of TILs for the majority of TNBC tumors tested. The agonistic antibody was only added in the initial setting of the culture and yet favored the propagation of CD8 + TILs from TNBC tumors. These expanded CD8 + TILs were capable of cytotoxic functions and were successfully utilized to demonstrate the presence of immunogenic mutations in autologous TNBC tumor tissue without recognition of the wild-type counterpart. Our findings open the way for a successful adoptive immunotherapy for TNBC. Cancer Immunol Res; 5(6); 439-45. ©2017 AACR . ©2017 American Association for Cancer Research.

  17. 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. Copyright © 2017 John Wiley & Sons, Ltd.

  18. Increased PD-1+ and TIM-3+ TILs during cetuximab therapy inversely correlates with response in head and neck cancer patients

    PubMed Central

    Jie, Hyun-Bae; Srivastava, Raghvendra M.; Argiris, Athanassios; Bauman, Julie E.; Kane, Lawrence P.; Ferris, Robert L.

    2017-01-01

    Despite emerging appreciation for the important role of immune checkpoint receptors in regulating the effector functions of T cells, it is unknown whether their expression is involved in determining the clinical outcome in response to cetuximab therapy. We examined the expression patterns of immune checkpoint receptors (including PD-1, CTLA-4, and TIM-3) and cytolytic molecules (including granzyme B and perforin) of CD8+ tumor-infiltrating lymphocytes (TILs) and compared them to those of peripheral blood T lymphocytes (PBLs) in patients with head and neck cancer (HNSCC) during cetuximab therapy. The frequency of PD-1 and TIM-3 expression was significantly increased in CD8+ TILs compared to CD8+ PBLs (P = 0.008 and P = 0.02, respectively). This increased CD8+ TIL population co-expressed granzyme B/perforin and PD-1/TIM-3, which suggests a regulatory role for these immune checkpoint receptors in cetuximab-promoting cytolytic activities of CD8+ TIL. Indeed, the increased frequency of PD-1+ and TIM-3+ CD8+ TILs was inversely correlated with clinical outcome of cetuximab therapy. These findings support the use of PD-1 and TIM-3 as biomarkers to reflect immune status of CD8+ T cells in the tumor microenvironment during cetuximab therapy. Blockade of these immune checkpoint receptors might enhance cetuximab-based cancer immunotherapy to reverse CD8+ TIL dysfunction, thus potentially improving clinical outcomes of HNSCC patients. PMID:28408386

  19. Tumor infiltrating lymphocytes (TIL) and prognosis in oral cavity squamous carcinoma: a preliminary study.

    PubMed

    Wolf, Gregory T; Chepeha, Douglas B; Bellile, Emily; Nguyen, Ariane; Thomas, Daffyd; McHugh, Jonathan

    2015-01-01

    Tumor infiltrating lymphocytes (TILs) in the microenvironment reflect may tumor biology and predict outcome. We previously demonstrated that infiltrates of CD4, CD8, and FoxP3 positive lymphocytes were associated with HPV-status and survival in oropharyngeal cancers. To determine if TILs were of prognostic importance in oral cancer, TIL levels were evaluated retrospectively in 52 oral cancer patients treated with surgery and correlations with outcome determined. Complete TIL and clinical data were available for 39 patients. Levels of CD4, CD8, FoxP3 (Treg), CD68 and NK cells were assessed by immunohistochemistry in tumor cores on a tissue microarray. Associations with clinical variables, tobacco and alcohol use and histologic features were assessed using Spearman correlation coefficient and the non-parametric Kruskal-Wallis testing. Time-to-event outcomes were determined using univariate and multivariate Cox models. Median follow up was 60 months. The ratio of CD4/CD8 (p=.01) and CD8 infiltrates (p=.05) were associated with tumor recurrence but not overall survival. Lower CD4 infiltrates were associated with alcohol use (p=.005) and poor tumor differentiation (p=.02). Interestingly, higher levels of CD68+ macrophages were found associated with positive nodes (p=.06) and poorer overall survival (p=.07). Overall and DSS survival were significantly shorter for patients with positive nodes, extracapsular spread, or perineural invasion. Infiltrating immune cell levels in oral cavity cancer appear influenced by health behaviors and tumor characteristics. In contrast to oropharynx cancer, infiltrates of CD68 positive tumor associated macrophages may contribute to metastatic behavior and outcome in advanced oral cavity carcinoma. Copyright © 2014 Elsevier Ltd. All rights reserved.

  20. Tumor Infiltrating Lymphocytes (TIL) and Prognosis in Oral Cavity Squamous Carcinoma: A Preliminary Study

    PubMed Central

    Wolf, Gregory T.; Chepeha, Douglas B.; Bellile, Emily; Nguyen, Ariane; Thomas, Daffyd; McHugh, Jonathan

    2014-01-01

    Objectives Tumor infiltrating lymphocytes (TILs) in the microenvironment reflect may tumor biology and predict outcome. We previously demonstrated that infiltrates of CD4, CD8, and FoxP3 positive lymphocytes were associated with HPV-status and survival in oropharyngeal cancers. To determine if TILs were of prognostic importance in oral cancer, TIL levels were evaluated retrospectively in 52 oral cancer patients treated with surgery and correlations with outcome determined. Methods Complete TIL and clinical data were available for 39 patients. Levels of CD4, CD8, FoxP3 (Treg), CD68 and NK cells were assessed by immunohistochemistry in tumor cores on a tissue microarray. Associations with clinical variables, tobacco and alcohol use and histologic features were assessed using Spearman correlation coefficient and the non-parametric Kruskal-Wallis testing. Timeto-event outcomes were determined using univariate and multivariate Cox models. Median follow up was 60 months. Results The ratio of CD4/CD8 (p=.01) and CD8 infiltrates (p=.05) were associated with tumor recurrence but not overall survival. Lower CD4 infiltrates were associated with alcohol use (p=.005) and poor tumor differentiation (p=.02). Interestingly, there higher levels of CD68+ macrophages were found associated with positive nodes (p=.06) and poorer overall survival (p=.07). Overall and DSS survival were significantly shorter for patients with positive nodes, extracapsular spread , or perineural invasion. Conclusions Infiltrating immune cell levels in oral cavity cancer appear influenced by health behaviors and tumor characteristics. In contrast to oropharynx cancer, infiltrates of CD68 positive tumor associated macrophages may contribute to metastatic behavior and outcome in advanced oral cavity carcinoma. PMID:25283344

  1. Utilizing T-cell Activation Signals 1, 2, and 3 for Tumor-infiltrating Lymphocytes (TIL) Expansion: The Advantage Over the Sole Use of Interleukin-2 in Cutaneous and Uveal Melanoma.

    PubMed

    Tavera, René J; Forget, Marie-Andrée; Kim, Young Uk; Sakellariou-Thompson, Donastas; Creasy, Caitlin A; Bhatta, Ankit; Fulbright, Orenthial J; Ramachandran, Renjith; Thorsen, Shawne T; Flores, Esteban; Wahl, Arely; Gonzalez, Audrey M; Toth, Christopher; Wardell, Seth; Mansaray, Rahmatu; Radvanyi, Laszlo G; Gombos, Dan S; Patel, Sapna P; Hwu, Patrick; Amaria, Rodabe N; Bernatchez, Chantale; Haymaker, Cara

    2018-05-11

    In this study, we address one of the major critiques for tumor-infiltrating lymphocyte (TIL) therapy-the time needed for proper expansion of a suitable product. We postulated that T-cell receptor activation in the first phase of expansion combined with an agonistic stimulation of CD137/4-1BB and interleukin-2 would favor preferential expansion of CD8 TIL. Indeed, this novel 3-signal approach for optimal T-cell activation resulted in faster and more consistent expansion of CD8CD3 TIL. This new method allowed for successful expansion of TIL from cutaneous and uveal melanoma tumors in 100% of the cultures in <3 weeks. Finally, providing the 3 signals attributed to optimal T-cell activation led to expansion of TIL capable of recognizing their tumor counterpart in cutaneous and uveal melanoma. This new methodology for the initial phase of TIL expansion brings a new opportunity for translation of TIL therapy in challenging malignancies such as uveal melanoma.

  2. Antigen-specific TIL therapy for melanoma: A flexible platform for personalized cancer immunotherapy.

    PubMed

    Kelderman, Sander; Heemskerk, Bianca; Fanchi, Lorenzo; Philips, Daisy; Toebes, Mireille; Kvistborg, Pia; van Buuren, Marit M; van Rooij, Nienke; Michels, Samira; Germeroth, Lothar; Haanen, John B A G; Schumacher, N M

    2016-06-01

    Tumor infiltrating lymphocyte (TIL) therapy has shown objective clinical response rates of 50% in stage IV melanoma patients in a number of clinical trials. Nevertheless, the majority of patients progress either directly upon therapy or after an initial period of tumor control. Recent data have shown that most TIL products that are used for therapy contain only low frequencies of T cells reactive against known melanoma-associated epitopes. Because of this, the development of a technology to create T-cell products that are enriched for reactivity against defined melanoma-associated antigens would seem valuable, both to evaluate the tumoricidal potential of T cells directed against different antigen classes and to potentially increase response rates. Here, we developed and validated a conditional MHC streptamer-based platform for the creation of TIL products with defined antigen reactivities. We have used this platform to successfully enrich both high-frequency (≥1%) and low-frequency (<1%) tumor-specific CD8(+) T-cell populations, and thereby created T-cell products with enhanced tumor recognition potential. Collectively, these data demonstrate that selection of antigen-specific T-cell populations can be used to create defined T-cell products for clinical use. This strategy thus forms a highly flexible platform for the development of antigen-specific cell products for personalized cancer immunotherapy. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  3. PD-1 Expression in Head and Neck Squamous Cell Carcinomas Derives Primarily from Functionally Anergic CD4+ TILs in the Presence of PD-L1+ TAMs.

    PubMed

    Mattox, Austin K; Lee, Jina; Westra, William H; Pierce, Robert H; Ghossein, Ronald; Faquin, William C; Diefenbach, Thomas J; Morris, Luc G; Lin, Derrick T; Wirth, Lori J; Lefranc-Torres, Armida; Ishida, Eiichi; Chakravarty, Patrick D; Johnson, Lauren; Zeng, Yang C; Chen, Huabiao; Poznansky, Mark C; Iyengar, Neil M; Pai, Sara I

    2017-11-15

    Oral tongue squamous cell carcinoma (OTSCC) is the most common oral cavity tumor. In this study, we examined the basis for the activity of programmed cell death protein (PD-1)-based immune checkpoint therapy that is being explored widely in head and neck cancers. Using multispectral imaging, we systematically investigated the OTSCC tumor microenvironment (TME) by evaluating the frequency of PD-1 expression in CD8 + , CD4 + , and FoxP3 + tumor-infiltrating lymphocytes (TIL). We also defined the cellular sources of PD-1 ligand (PD-L1) to evaluate the utility of PD-1:PD-L1 blocking antibody therapy in this patient population. PD-L1 was expressed in 79% of the OTSCC specimens examined within the TME. Expression of PD-L1 was associated with moderate to high levels of CD4 + and CD8 + TILs. We found that CD4 + TILs were present in equal or greater frequencies than CD8 + TILs in 94% of OTSCC and that CD4 + FOXP3neg TILs were colocalized with PD-1/PD-L1/CD68 more frequently than CD8 + TILs. Both CD4 + PD1 + and CD8 + PD1 + TILs were anergic in the setting of PD-L1 expression. Overall, our results highlight the importance of CD4 + TILs as pivotal regulators of PD-L1 levels and in determining the responsiveness of OTSCC to PD1-based immune checkpoint therapy. Cancer Res; 77(22); 6365-74. ©2017 AACR . ©2017 American Association for Cancer Research.

  4. Temperature-induced lipocalin (TIL): a shield against stress-inducing environmental shocks in Saccharomyces cerevisiae.

    PubMed

    Berterame, Nadia Maria; Bertagnoli, Stefano; Codazzi, Vera; Porro, Danilo; Branduardi, Paola

    2017-09-01

    The yeast Saccharomyces cerevisiae is a well-established workhorse, either for recombinant or natural products, thanks to its natural traits and easily editable metabolism. However, during a bio-based industrial process it meets multiple stresses generated by operative conditions such as non-optimal temperature, pH, oxygenation and product accumulation. The development of tolerant strains is therefore indispensable for the improvement of production, yield and productivity of fermentative processes. In this regard, plants as resilient organisms are a generous source for fishing genes and/or metabolites that can help the cell factory to counteract environmental constraints. Plants possess proteins named temperature-induced lipocalins, TIL, whose levels in the cells correlates with the tolerance to sudden temperature changes and with the scavenging of reactive oxygen species. In this work, the gene encoding for the Arabidopsis thaliana TIL protein was for the first time expressed in S. cerevisiae. The recombinant strain was compared and analysed against the parental counterpart under heat shock, freezing, exposure to organic acid and oxidative agents. In all the tested conditions, TIL expression conferred a higher tolerance to the stress imposed, making this strain a promising candidate for the development of robust cell factories able to overtake the major impairments of industrial processes. © FEMS 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  5. CD25 identifies a subset of CD4⁺FoxP3⁻ TIL that are exhausted yet prognostically favorable in human ovarian cancer.

    PubMed

    deLeeuw, Ronald J; Kroeger, David R; Kost, Sara E; Chang, Pheh-Ping; Webb, John R; Nelson, Brad H

    2015-03-01

    CD25, the alpha subunit of the IL2 receptor, is a canonical marker of regulatory T cells (Treg) and hence has been implicated in immune suppression in cancer. However, CD25 is also required for optimal expansion and activity of effector T cells in peripheral tissues. Thus, we hypothesized that CD25, in addition to demarcating Tregs, might identify effector T cells in cancer. To investigate this possibility, we used multiparameter flow cytometry and IHC to analyze tumor-infiltrating lymphocytes (TIL) in primary high-grade serous carcinomas, the most common and fatal subtype of ovarian cancer. CD25 was expressed primarily by CD4⁺ TIL, with negligible expression by CD8⁺ TIL. In addition to conventional CD25⁺FoxP3⁺ Tregs, we identified a subset of CD25⁺FoxP3⁻ T cells that comprised up to 13% of CD4⁺ TIL. In tumors with CD8⁺ TIL, CD25⁺FoxP3⁻ T cells showed a strong positive association with patient survival (HR, 0.56; P = 0.02), which exceeded the negative effect of Tregs (HR, 1.55; P = 0.09). Among CD4⁺ TIL subsets, CD25⁺FoxP3⁻ cells expressed the highest levels of PD-1. Moreover, after in vitro stimulation, they failed to produce common T-helper cytokines (IFNγ, TNFα, IL2, IL4, IL10, or IL17A), suggesting that they were functionally exhausted. In contrast, the more abundant CD25⁻FoxP3⁻ subset of CD4⁺ TIL expressed low levels of PD-1 and produced T-helper 1 cytokines, yet conferred no prognostic benefit. Thus, CD25 identifies a subset of CD4⁺FoxP3⁻ TIL that, despite being exhausted at diagnosis, have a strong, positive association with patient survival and warrant consideration as effector T cells for immunotherapy. ©2014 American Association for Cancer Research.

  6. 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

  7. 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.

  8. 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.

  9. New anatase-type Til-2xNbxAlxO2 solid solution nanoparticles: direct formation, phase stability, and photocatalytic performance.

    PubMed

    Hirano, Masanori; Ito, Takaharu

    2006-12-01

    New anatase-type titania solid solutions co-doped with niobium and aluminum (Til-2xNbxAIlxO2 (X = 0 -0.20)) were synthesized as nanoparticles from precursor solutions of TiOSO4, NbCl5, and Al(NO3)3 under mild hydrothermal conditions at 180 degrees C for 5 h using the hydrolysis of urea. The lattice parameters a0 and c0 of anatase slightly and gradually increased, when the content of niobium and aluminum increased from X = 0 to 0.20. The crystallite size of anatase increased from 12 to 28 nm with increasing the value of X from 0 to 0.20. Their photocatalytic activity and adsorptivity were evaluated separately by the measurement of the concentration of methylene blue (MB) remained in the solution in the dark or under UV-light irradiation. The adsorptivity of TiO2 was improved by the formation of anatase-type Til-2xNbxAlxO2 solid solutions. The photocatalytic activity of anatase-type Til-2xNbxAlxO2 solid solutions was superior to that of commercially available anatase-type pure TiO2 (ST-01) and anatase-type pure TiO2 hydrothermally prepared. The new anatase phase of Til-2xNbxAlxO2 (X = 0-0.20) solid solutions existed stably up to 850 0C during heat treatment in air. In comparison with hydrothermal pure TiO2, the starting temperature of anatase-to-rutile phase transformation was delayed by the formation of Ti1-2xNbxAlxO, (X = 0-0.20) solid solutions, although its completing temperature was accelerated.

  10. 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

  11. Predictive relevance of PD-L1 expression combined with CD8+ TIL density in stage III non-small cell lung cancer patients receiving concurrent chemoradiotherapy.

    PubMed

    Tokito, Takaaki; Azuma, Koichi; Kawahara, Akihiko; Ishii, Hidenobu; Yamada, Kazuhiko; Matsuo, Norikazu; Kinoshita, Takashi; Mizukami, Naohisa; Ono, Hirofumi; Kage, Masayoshi; Hoshino, Tomoaki

    2016-03-01

    Expression of programmed cell death-ligand 1 (PD-L1) is known to be a mechanism whereby cancer can escape immune surveillance, but little is known about factors predictive of efficacy in patients with locally advanced non-small cell lung cancer (NSCLC). We investigated the predictive relevance of PD-L1 expression and CD8+ tumour-infiltrating lymphocytes (TILs) density in patients with locally advanced NSCLC receiving concurrent chemoradiotherapy (CCRT). We retrospectively reviewed 74 consecutive patients with stage III NSCLC who had received CCRT. PD-L1 expression and CD8+ TIL density were evaluated by immunohistochemical analysis. Univariate and multivariate analyses demonstrated that CD8+ TIL density was an independent and significant predictive factor for progression-free survival (PFS) and OS, whereas PD-L1 expression was not correlated with PFS and OS. Sub-analysis revealed that the PD-L1+/CD8 low group had the shortest PFS (8.6 months, p = 0.02) and OS (13.9 months, p = 0.11), and that the PD-L1-/CD8 high group had the longest prognosis (median PFS and OS were not reached) by Kaplan-Meier curves of the four sub-groups. Among stage III NSCLC patients who received CCRT, there was a trend for poor survival in those who expressed PD-L1. Our analysis indicated that a combination of lack of PD-L1 expression and CD8+ TIL density was significantly associated with favourable survival in these patients. It is proposed that PD-L1 expression in combination with CD8+ TIL density could be a useful predictive biomarker in patients with stage III NSCLC. Copyright © 2015 Elsevier Ltd. All rights reserved.

  12. PBMC are as good a source of tumor-reactive T lymphocytes as TIL after selection by Melan-A/A2 multimer immunomagnetic sorting.

    PubMed

    Labarrière, Nathalie; Gervois, Nadine; Bonnin, Annabelle; Bouquié, Régis; Jotereau, Francine; Lang, François

    2008-02-01

    Choosing a reliable source of tumor-specific T lymphocytes and an efficient method to isolate these cells still remains a critical issue in adoptive cellular therapy (ACT). In this study, we assessed the capacity of MHC/peptide based immunomagnetic sorting followed by polyclonal T cell expansion to derive pure polyclonal and tumor-reactive Melan-A specific T cell populations from melanoma patient's PBMC and TIL. We first demonstrated that this approach was extremely efficient and reproducible. We then used this procedure to compare PBMC and TIL-derived cells from three melanoma patients in terms of avidity for Melan-A A27L analog, Melan-A(26-35)and Melan-A(27-35), tumor reactivity (lysis and cytokine production) and repertoire. Regardless of their origin, i.e., fresh PBMC, peptide stimulated PBMC or TIL, all sorted populations (from the three patients) were cytotoxic against HLA-A2+ melanoma cell lines expressing Melan-A. Although some variability in peptide avidity, lytic activity and cytokine production was observed between populations of different origins in a given patient, it differed from one patient to another and thus no correlation could be drawn between T cell source and reactivity. Analysis of Vbeta usage within the sorted populations showed the recurrence of Vbeta3 and Vbeta14 subfamilies in the three patients but differences in the rest of the Melan-A repertoire. In addition, in two patients, we observed major repertoire differences between populations sorted from the three sources. We especially documented that in vitro peptide stimulation of PBMC, used to facilitate the sort by enriching in specific T lymphocytes, could significantly alter their repertoire and reactivity towards tumor cells. We conclude that PBMC which are easily obtained from all melanoma patients, can be as good a source as TIL to derive high amounts of tumor-reactive Melan-A specific T cells, with this selection/amplification procedure. However, the conditions of peptide

  13. Detection of novel cancer-testis antigen-specific T-cell responses in TIL, regional lymph nodes, and PBL in patients with esophageal squamous cell carcinoma.

    PubMed

    Mizukami, Yoshiki; Kono, Koji; Daigo, Yataro; Takano, Atsushi; Tsunoda, Takuya; Kawaguchi, Yoshihiko; Nakamura, Yusuke; Fujii, Hideki

    2008-07-01

    We recently identified three HLA-A2402-restricted epitope peptides derived from cancer-testis antigens (CTA), TTK protein kinase (TTK), lymphocyte antigen 6 complex locus K (LY6K), and insulin-like growth factor (IGF)-II mRNA binding protein 3 (IMP-3) for the development of immunotherapies against esophageal squamous cell carcinoma (ESCC). In order to evaluate their immunotherapeutic potential in ESCC patients, we estimated by ELISPOT assay the TTK-, LY6K-, or IMP-3-specific T-cell immune responses in tumor-infiltrating lymphocytes (TIL), regional lymph node lymphocytes (RLNL), and peripheral blood lymphocytes (PBL) expanded from 20HLA-A2402 (+) ESCC patients, and correlated their immune activity with the expression levels of TTK, LY6K, and IMP-3, and MHC class I in the tumors. Induction of TTK-antigen specific T-cell response in TIL to the peptide-pulsed target cells was detected in 14 out of 20 (70%) cases, while LY6K or IMP-3 specific T-cell activity was observed in 11 of 20 (55%) or in eight of 20 (40%) cases, respectively. Furthermore, T-cell activity in RLNL and PBL was detectable in the similar proportion of the 20 ESCC patients. Interestingly, CTA-specific T-cell immune response was found in 13 of 14 (93%) TIL obtained from ESCC tumors with strong MHC class I expression, while it could be observed only in two of six (33%) TIL from ESCC tumors with weak MHC class I expression. These results strongly suggest the pre-existence of specific T-cell responses to HLA-A24-restricted epitope peptides from TTK, LY6K, and IMP-3 in ESCC patients. Monitoring antigen-specific T-cell responses, as well as the expression levels of MHC class I and epitope CTA in tumors, should be a selection index for application of cancer vaccine therapies to the patients who are likely to show good immune response.

  14. Ubiquitous Exsolution of Pentlandite and Troilite in Pyrrhotite from the TIL 91722 CM2 Carbonaceous Chondrite: A Record of Low Temperature Solid State Processes

    NASA Astrophysics Data System (ADS)

    Brearley, A. J.; Martinez, C.

    2010-03-01

    SEM and TEM studies show that submicron exsolution of pentlandite and troilite occurred at very low temperatures in pyrrhotite in the TIL 91722 CM2 chondrite. The exsolution occurred below 373K on the CM chondrite parent body.

  15. CD8+ TIL recruitment may revert the association of MAGE A3 with aggressive features in thyroid tumors.

    PubMed

    Martins, Mariana Bonjiorno; Marcello, Marjory Alana; Batista, Fernando de Assis; Cunha, Lucas Leite; Morari, Elaine Cristina; Soares, Fernando Augusto; Vassallo, José; Ward, Laura Sterian

    2014-01-01

    We aimed to investigate a possible role of MAGE A3 and its associations with infiltrated immune cells in thyroid malignancy, analyzing their utility as a diagnostic and prognostic marker. We studied 195 malignant tissues: 154 PTCs and 41 FTCs; 102 benign tissues: 51 follicular adenomas and 51 goiter and 17 normal thyroid tissues. MAGE A3 and immune cell markers (CD4 and CD8) were evaluated using immunohistochemistry and compared with clinical pathological features. The semiquantitative analysis and ACIS III analysis showed similar results. MAGE A3 was expressed in more malignant than in benign lesions (P < 0.0001), also helping to discriminate follicular-patterned lesions. It was also higher in tumors in which there was extrathyroidal invasion (P = 0.0206) and in patients with stage II disease (P = 0.0107). MAGE A3+ tumors were more likely to present CD8+ TIL (P = 0.0346), and these tumors were associated with less aggressive features, that is, extrathyroidal invasion and small size. There was a trend of MAGE A3+ CD8+ tumors to evolve free of disease. We demonstrated that MAGE A3 and CD8+ TIL infiltration may play an important role in malignant thyroid nodules, presenting an interesting perspective for new researches on DTC immunotherapy.

  16. Assessing Tumor-infiltrating Lymphocytes in Solid Tumors: A Practical Review for Pathologists and Proposal for a Standardized Method From the International Immunooncology Biomarkers Working Group: Part 1: Assessing the Host Immune Response, TILs in Invasive Breast Carcinoma and Ductal Carcinoma In Situ, Metastatic Tumor Deposits and Areas for Further Research.

    PubMed

    Hendry, Shona; Salgado, Roberto; Gevaert, Thomas; Russell, Prudence A; John, Tom; Thapa, Bibhusal; Christie, Michael; van de Vijver, Koen; Estrada, M V; Gonzalez-Ericsson, Paula I; Sanders, Melinda; Solomon, Benjamin; Solinas, Cinzia; Van den Eynden, Gert G G M; Allory, Yves; Preusser, Matthias; Hainfellner, Johannes; Pruneri, Giancarlo; Vingiani, Andrea; Demaria, Sandra; Symmans, Fraser; Nuciforo, Paolo; Comerma, Laura; Thompson, E A; Lakhani, Sunil; Kim, Seong-Rim; Schnitt, Stuart; Colpaert, Cecile; Sotiriou, Christos; Scherer, Stefan J; Ignatiadis, Michail; Badve, Sunil; Pierce, Robert H; Viale, Giuseppe; Sirtaine, Nicolas; Penault-Llorca, Frederique; Sugie, Tomohagu; Fineberg, Susan; Paik, Soonmyung; Srinivasan, Ashok; Richardson, Andrea; Wang, Yihong; Chmielik, Ewa; Brock, Jane; Johnson, Douglas B; Balko, Justin; Wienert, Stephan; Bossuyt, Veerle; Michiels, Stefan; Ternes, Nils; Burchardi, Nicole; Luen, Stephen J; Savas, Peter; Klauschen, Frederick; Watson, Peter H; Nelson, Brad H; Criscitiello, Carmen; O'Toole, Sandra; Larsimont, Denis; de Wind, Roland; Curigliano, Giuseppe; André, Fabrice; Lacroix-Triki, Magali; van de Vijver, Mark; Rojo, Federico; Floris, Giuseppe; Bedri, Shahinaz; Sparano, Joseph; Rimm, David; Nielsen, Torsten; Kos, Zuzana; Hewitt, Stephen; Singh, Baljit; Farshid, Gelareh; Loibl, Sibylle; Allison, Kimberly H; Tung, Nadine; Adams, Sylvia; Willard-Gallo, Karen; Horlings, Hugo M; Gandhi, Leena; Moreira, Andre; Hirsch, Fred; Dieci, Maria V; Urbanowicz, Maria; Brcic, Iva; Korski, Konstanty; Gaire, Fabien; Koeppen, Hartmut; Lo, Amy; Giltnane, Jennifer; Rebelatto, Marlon C; Steele, Keith E; Zha, Jiping; Emancipator, Kenneth; Juco, Jonathan W; Denkert, Carsten; Reis-Filho, Jorge; Loi, Sherene; Fox, Stephen B

    2017-09-01

    Assessment of tumor-infiltrating lymphocytes (TILs) in histopathologic specimens can provide important prognostic information in diverse solid tumor types, and may also be of value in predicting response to treatments. However, implementation as a routine clinical biomarker has not yet been achieved. As successful use of immune checkpoint inhibitors and other forms of immunotherapy become a clinical reality, the need for widely applicable, accessible, and reliable immunooncology biomarkers is clear. In part 1 of this review we briefly discuss the host immune response to tumors and different approaches to TIL assessment. We propose a standardized methodology to assess TILs in solid tumors on hematoxylin and eosin sections, in both primary and metastatic settings, based on the International Immuno-Oncology Biomarker Working Group guidelines for TIL assessment in invasive breast carcinoma. A review of the literature regarding the value of TIL assessment in different solid tumor types follows in part 2. The method we propose is reproducible, affordable, easily applied, and has demonstrated prognostic and predictive significance in invasive breast carcinoma. This standardized methodology may be used as a reference against which other methods are compared, and should be evaluated for clinical validity and utility. Standardization of TIL assessment will help to improve consistency and reproducibility in this field, enrich both the quality and quantity of comparable evidence, and help to thoroughly evaluate the utility of TILs assessment in this era of immunotherapy.

  17. More Evidence of the Importance of Amorphous Silicates in CM Carbonaceous Chondrites: New Observations from a Fine-Grained Rim in the CM2 Chondrite, TIL 91722

    NASA Astrophysics Data System (ADS)

    Brearley, A. J.; Le Guillou, C.

    2015-07-01

    A fine-grained rim in TIL 91722 contains abundant amorphous silicate material containing nanophase sulfides. Phyllosilicates are rare. The amorphous material has a high ferric iron content indicative of oxidation coupled with hydration.

  18. IL-17A is produced by breast cancer TILs and promotes chemoresistance and proliferation through ERK1/2

    PubMed Central

    Cochaud, Stéphanie; Giustiniani, Jérôme; Thomas, Clémence; Laprevotte, Emilie; Garbar, Christian; Savoye, Aude-Marie; Curé, Hervé; Mascaux, Corinne; Alberici, Gilles; Bonnefoy, Nathalie; Eliaou, Jean-François; Bensussan, Armand; Bastid, Jeremy

    2013-01-01

    The proinflammatory cytokine Interleukin 17A (hereafter named IL–17A) or IL-17A producing cells are elevated in breast tumors environment and correlate with poor prognosis. Increased IL-17A is associated with ER(−) or triple negative tumors and reduced Disease Free Survival. However, the pathophysiological role of IL-17A in breast cancer remains unclear although several studies suggested its involvement in cancer cell dissemination. Here we demonstrated that a subset of breast tumors is infiltrated with IL-17A-producing cells. Increased IL-17A seems mainly associated to ER(−) and triple negative/basal-like tumors. Isolation of tumor infiltrating T lymphocytes (TILs) from breast cancer biopsies revealed that these cells secreted significant amounts of IL-17A. We further established that recombinant IL-17A recruits the MAPK pathway by upregulating phosphorylated ERK1/2 in human breast cancer cell lines thereby promoting proliferation and resistance to conventional chemotherapeutic agents such as docetaxel. We also confirmed here that recombinant IL-17A stimulates migration and invasion of breast cancer cells as previously reported. Importantly, TILs also induced tumor cell proliferation, chemoresistance and migration and treatment with IL-17A-neutralizing antibodies abrogated these effects. Altogether these results demonstrated the pathophysiological role of IL-17A-producing cell infiltrate in a subset of breast cancers. Therefore, IL-17A appears as potential therapeutic target for breast cancer. PMID:24316750

  19. Increase in activated Treg in TIL in lung cancer and in vitro depletion of Treg by ADCC using an antihuman CCR4 mAb (KM2760).

    PubMed

    Kurose, Koji; Ohue, Yoshihiro; Sato, Eiichi; Yamauchi, Akira; Eikawa, Shingo; Isobe, Midori; Nishio, Yumi; Uenaka, Akiko; Oka, Mikio; Nakayama, Eiichi

    2015-01-01

    Tregs infiltrate tumors and inhibit immune responses against them. We investigated subpopulations of Foxp3 CD4 T cells previously defined by Miyara et al. (Immunity 30, 899-911, 2009) in peripheral blood mononuclear cells (PBMCs) and tumor infiltrating lymphocytes (TILs) in lung cancer. We also showed that Tregs in healthy donors that express CCR4 could be efficiently eliminated in vitro by cotreatment with antihuman (h) CCR4 mAb (KM2760) and NK cells. In lung cancer, the number of activated/effector Tregs and non-Tregs, but not resting/naive Tregs, was increased in TILs compared with the number of those cells in PBMCs. The non-Treg population contained Th2 and Th17. CCR4 expression on activated/effector Tregs and non-Tregs in TILs was down-regulated compared with that on those cells in PBMCs. Chemokinetic migration of CD25 CD4 T cells containing the Treg population sorted from the PBMCs of healthy donors to CCL22/MDC was abrogated by pretreatment with anti-hCCR4 mAb (KM2760). The inhibitory activity of CD25 CD127 CD4 Tregs on the proliferative response of CD4 and CD8 T cells stimulated with anti-CD3/CD28 coated beads was abrogated by adding an anti-hCCR4 mAb (KM2760) and CD56 NK cells to the culture. The findings suggested the CCR4 on activated/effector Tregs and non-Tregs was functionally involved in the chemokinetic migration and accumulation of those cells to the tumor site. In vitro findings of efficient elimination of Tregs may give the basis for implementation of a clinical trial to investigate Treg depletion by administration of an anti-hCCR4 mAb to solid cancer patients.

  20. 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. Copyright © 2014 Elsevier Ltd. All rights reserved.

  1. 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. ©2016 American Association for Cancer Research.

  2. Assessing Tumor-Infiltrating Lymphocytes in Solid Tumors: A Practical Review for Pathologists and Proposal for a Standardized Method from the International Immuno-Oncology Biomarkers Working Group: Part 2: TILs in Melanoma, Gastrointestinal Tract Carcinomas, Non-Small Cell Lung Carcinoma and Mesothelioma, Endometrial and Ovarian Carcinomas, Squamous Cell Carcinoma of the Head and Neck, Genitourinary Carcinomas, and Primary Brain Tumors.

    PubMed

    Hendry, Shona; Salgado, Roberto; Gevaert, Thomas; Russell, Prudence A; John, Tom; Thapa, Bibhusal; Christie, Michael; van de Vijver, Koen; Estrada, M V; Gonzalez-Ericsson, Paula I; Sanders, Melinda; Solomon, Benjamin; Solinas, Cinzia; Van den Eynden, Gert G G M; Allory, Yves; Preusser, Matthias; Hainfellner, Johannes; Pruneri, Giancarlo; Vingiani, Andrea; Demaria, Sandra; Symmans, Fraser; Nuciforo, Paolo; Comerma, Laura; Thompson, E A; Lakhani, Sunil; Kim, Seong-Rim; Schnitt, Stuart; Colpaert, Cecile; Sotiriou, Christos; Scherer, Stefan J; Ignatiadis, Michail; Badve, Sunil; Pierce, Robert H; Viale, Giuseppe; Sirtaine, Nicolas; Penault-Llorca, Frederique; Sugie, Tomohagu; Fineberg, Susan; Paik, Soonmyung; Srinivasan, Ashok; Richardson, Andrea; Wang, Yihong; Chmielik, Ewa; Brock, Jane; Johnson, Douglas B; Balko, Justin; Wienert, Stephan; Bossuyt, Veerle; Michiels, Stefan; Ternes, Nils; Burchardi, Nicole; Luen, Stephen J; Savas, Peter; Klauschen, Frederick; Watson, Peter H; Nelson, Brad H; Criscitiello, Carmen; O'Toole, Sandra; Larsimont, Denis; de Wind, Roland; Curigliano, Giuseppe; André, Fabrice; Lacroix-Triki, Magali; van de Vijver, Mark; Rojo, Federico; Floris, Giuseppe; Bedri, Shahinaz; Sparano, Joseph; Rimm, David; Nielsen, Torsten; Kos, Zuzana; Hewitt, Stephen; Singh, Baljit; Farshid, Gelareh; Loibl, Sibylle; Allison, Kimberly H; Tung, Nadine; Adams, Sylvia; Willard-Gallo, Karen; Horlings, Hugo M; Gandhi, Leena; Moreira, Andre; Hirsch, Fred; Dieci, Maria V; Urbanowicz, Maria; Brcic, Iva; Korski, Konstanty; Gaire, Fabien; Koeppen, Hartmut; Lo, Amy; Giltnane, Jennifer; Rebelatto, Marlon C; Steele, Keith E; Zha, Jiping; Emancipator, Kenneth; Juco, Jonathan W; Denkert, Carsten; Reis-Filho, Jorge; Loi, Sherene; Fox, Stephen B

    2017-11-01

    Assessment of the immune response to tumors is growing in importance as the prognostic implications of this response are increasingly recognized, and as immunotherapies are evaluated and implemented in different tumor types. However, many different approaches can be used to assess and describe the immune response, which limits efforts at implementation as a routine clinical biomarker. In part 1 of this review, we have proposed a standardized methodology to assess tumor-infiltrating lymphocytes (TILs) in solid tumors, based on the International Immuno-Oncology Biomarkers Working Group guidelines for invasive breast carcinoma. In part 2 of this review, we discuss the available evidence for the prognostic and predictive value of TILs in common solid tumors, including carcinomas of the lung, gastrointestinal tract, genitourinary system, gynecologic system, and head and neck, as well as primary brain tumors, mesothelioma and melanoma. The particularities and different emphases in TIL assessment in different tumor types are discussed. The standardized methodology we propose can be adapted to different tumor types and may be used as a standard against which other approaches can be compared. Standardization of TIL assessment will help clinicians, researchers and pathologists to conclusively evaluate the utility of this simple biomarker in the current era of immunotherapy.

  3. University Administrators as Forced Language Policy Agents. An Institutional Ethnography of Parallel Language Strategy and Practices at the University of Copenhagen

    ERIC Educational Resources Information Center

    Siiner, Maarja

    2016-01-01

    Nation states increasingly assign the responsibility for meeting the global competitiveness agenda to the universities themselves [Cirius, 2009, "Mobilitetsstatistik for de videregaaende uddannelser 2007/08" [Mobility statistics for higher education 2007/08

  4. Utilization of autoclaved and fermented sesame (Sesamum indicum L.) seed meal in diets for Til-aqua natural male tilapia.

    PubMed

    Olude, Oluwagbenga; George, Francisca; Alegbeleye, Wilfred

    2016-12-01

    Current research emphasis has been on the reduction of feed cost by incorporating processed sesame seed meal in the diet of tilapia. Raw sesame ( Sesamum indicum ) seed was soaked and subjected to either autoclaving or fermentation, after which their oil contents were mechanically extracted. Graded levels of autoclaved (71.2, 165.5 and 296.3 g/kg designated as diets 1, 2 and 3, respectively) and fermented (71.0, 164.3 and 292.2 g/kg designated as diets 4, 5 and 6, respectively) sesame seed meal were included into fishmeal based diets for Til-aqua natural male tilapia (NMT) fry (initial weight, 1.69 ± 0.02 g). A diet without sesame seed meal served as the control. Diets were approximately iso-nitrogenous (35% crude protein). Fish were fed 5 times their maintenance requirement, which was 3.2 × 5 × [fish weight (g)/1,000] 0.8 daily for 56 days. Processing improved the nutritional profile of raw sesame seed meal in terms of its crude protein and antinutrient compositions. Growth performance of fish was similar ( P  > 0.05) in the control and dietary treatments. The group fed diet 3 exhibited significantly poorer feed conversion ratio (1.14), protein efficiency ratio (2.77) and economic conversion ratio (US$1.38/kg) relative to the group that received diet 5. Apparent digestibility coefficients for protein, lipid and energy in diet 3 were similar ( P  > 0.05) to those in diet 6 but significantly lower ( P  < 0.05) than those of the control and other dietary groups. The sesame seed meals processed with different methods did not significantly affect crude protein, crude lipid and gross energy compositions in the fish carcass. The study demonstrated that 71.2 g/kg of autoclaved and 164.3 g/kg of fermented sesame seed meal could be incorporated in the diet of Til-aqua NMT with cost benefit.

  5. Cytosolic high-mobility group box protein 1 (HMGB1) and/or PD-1+ TILs in the tumor microenvironment may be contributing prognostic biomarkers for patients with locally advanced rectal cancer who have undergone neoadjuvant chemoradiotherapy.

    PubMed

    Huang, Chih-Yang; Chiang, Shu-Fen; Ke, Tao-Wei; Chen, Tsung-Wei; Lan, Yu-Ching; You, Ying-Shu; Shiau, An-Cheng; Chen, William Tzu-Liang; Chao, K S Clifford

    2018-04-01

    Rectal cancer, which comprises 30% of all colorectal cancer cases, is one of the most common forms of cancer in the world. Patients with locally advanced rectal cancer (LARC) are often treated with neoadjuvant chemoradiotherapy (neoCRT) followed by surgery. However, after neoCRT treatment, approximately one-third of the patients progress to local recurrence or distant metastasis. In these studies, we found that patients with tumors that exhibited cytosolic HMGB1(Cyto-HMGB1) translocation and/or the presence of PD-1+ tumor-infiltrating lymphocytes (TILs) before treatment had a better clinical outcome. The better outcome is likely due to the release of HMGB1, which triggers the maturation of dendritic cells (DCs) via TLR4 activation, and the subsequent recruitment of PD-1+ tumor-infiltrating lymphocytes to the tumor site, where they participate in immune-scavenging. In conclusion, our results provide evidence that cyto-HMGB1 and/or PD-1+TIL are not only predictive biomarkers before treatment, but they can also potentially designate patients for personalized oncological management including immunotherapy.

  6. Randomized Selection Design Trial Evaluating CD8+-Enriched Versus Unselected Tumor-Infiltrating Lymphocytes for Adoptive Cell Therapy for Patients With Melanoma

    PubMed Central

    Dudley, Mark E.; Gross, Colin A.; Somerville, Robert P.T.; Hong, Young; Schaub, Nicholas P.; Rosati, Shannon F.; White, Donald E.; Nathan, Debbie; Restifo, Nicholas P.; Steinberg, Seth M.; Wunderlich, John R.; Kammula, Udai S.; Sherry, Richard M.; Yang, James C.; Phan, Giao Q.; Hughes, Marybeth S.; Laurencot, Carolyn M.; Rosenberg, Steven A.

    2013-01-01

    Purpose Adoptive cell therapy (ACT) with autologous tumor-infiltrating lymphocytes (TILs) and high-dose interleukin-2 (IL-2) administered to lymphodepleted patients with melanoma can cause durable tumor regressions. The optimal TIL product for ACT is unknown. Patients and Methods Patients with metastatic melanoma were prospectively assigned to receive unselected young TILs versus CD8+-enriched TILs. All patients received lymphodepleting chemotherapy and high-dose IL-2 therapy and were assessed for response, toxicity, survival, and immunologic end points. Results Thirty-four patients received unselected young TILs with a median of 8.0% CD4+ lymphocytes, and 35 patients received CD8+-enriched TILs with a median of 0.3% CD4+ lymphocytes. One month after TIL infusion, patients who received CD8+-enriched TILs had significantly fewer CD4+ peripheral blood lymphocytes (P = .01). Twelve patients responded to therapy with unselected young TILs (according to Response Evaluation Criteria in Solid Tumors [RECIST]), and seven patients responded to CD8+-enriched TILs (35% v 20%; not significant). Retrospective studies showed a significant association between response to treatment and interferon gamma secretion by the infused TILs in response to autologous tumor (P = .04), and in the subgroup of patients who received TILs from subcutaneous tumors, eight of 15 patients receiving unselected young TILs responded but none of eight patients receiving CD8+-enriched TILs responded. Conclusion A randomized selection design trial was feasible for improving individualized TIL therapy. Since the evidence indicates that CD8+-enriched TILs are not more potent therapeutically and they are more laborious to prepare, future studies should focus on unselected young TILs. PMID:23650429

  7. 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

  8. Comparisons of tumor-infiltrating lymphocyte levels and the 21-gene recurrence score in ER-positive/HER2-negative breast cancer.

    PubMed

    Ahn, Sung Gwe; Cha, Yoon Jin; Bae, Soon June; Yoon, Chanik; Lee, Hak Woo; Jeong, Joon

    2018-03-24

    Recent studies have shown that tumors with extensive tumor-infiltrating lymphocytes (TILs) have a higher probability of pathologic complete response, even in luminal/human epidermal growth factor 2 (HER2)-negative breast cancer. We compared TIL levels and the 21-gene recurrence score (RS) in estrogen receptor (ER)-positive/HER2-negative breast cancer. We evaluated the percentage of stromal TILs in 198 ER-positive/HER2-negative patients in whom RS was obtained by examining slides of surgical specimens by standardized methodology proposed by the international TIL Working Group. TIL levels were categorized as high (≥ 60%), intermediate (11-59%), or low (≤ 10%). All tumors were treatment-naïve. Ninety-seven (49.0%), 88 (44.4%), and 13 patients (6.6%) had low, intermediate, and high TIL levels, respectively. There was a significant but weak correlation between continuous RS and continuous TIL levels (Pearson's R = 0.201, p = 0.004). The mean RS was significantly highest in high TIL tumors (17.8 ± 10.7 in low TIL tumors, 19.4 ± 8.7 in intermediate TIL tumors, and 26.2 ± 8.2 in high TIL tumors; p = 0.014). However, when we compared categorized RS and TIL levels, we found that tumors with high TIL levels tended to have higher RS (≥ 26) but it was not significant (p = 0.155). Furthermore, multivariate analysis revealed that high RS was not an independent factor associated with high TIL levels. Chemo-endocrine therapy was more frequently performed among patients with high TILs and less frequently among those with low or intermediate TILs (p <  0.001). Despite of a weak correlation between continuous TIL levels and RS, we found that tumors with high TIL levels tended to have a higher RS in ER-positive/HER2-negative breast cancer. Further study is warranted considering the clinical outcomes.

  9. Tumor infiltrating lymphocytes in ovarian cancer

    PubMed Central

    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. PMID:25894333

  10. Prognostic and predictive value of tumor-infiltrating lymphocytes in two phase III randomized adjuvant breast cancer trials

    PubMed Central

    Dieci, M. V.; Mathieu, M. C.; Guarneri, V.; Conte, P.; Delaloge, S.; Andre, F.; Goubar, A.

    2015-01-01

    Background Tumor-infiltrating lymphocytes (TILs) are emerging as strong prognostic factor for early breast cancer patients, especially in the triple-negative subtype. Here, we aim to validate previous findings on the prognostic role of TIL in the context of two randomized adjuvant trials and to investigate whether lymphocyte infiltrates can predict benefit from adjuvant anthracyclines. Patients and methods A total of 816 patients enrolled and treated at the Gustave Roussy in the context of two multicentric randomized trials comparing adjuvant anthracyclines versus no chemotherapy were included in the present analysis. Primary end point was overall survival (OS). Hematoxilin and eosin slides of primary tumors were retrieved and evaluated for the percentage of intratumoral (It) and stromal (Str) TIL. Each case was also defined as high-TIL or low-TIL breast cancer adopting previously validated cutoffs. Results TIL were assessable for 781 of 816 cases. High-TIL cases were more likely grade 3 and estrogen receptor (ER)-negative (P < 0.001). In multivariate analysis, both continuous It-TIL and Str-TIL were strong prognostic factors for OS [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77–0.95 P = 0.003; HR 0.89, 95% CI 0.81–0.96, P = 0.005 for It-TIL and Str-TIL, respectively]. The prognostic effect of continuous TIL was limited to triple-negative and HER2-positive patients. Ten-year OS rates were: 89% and 68% for triple-negative high-TIL and low-TIL, respectively (HR 0.44, 95% CI 0.18–1.10, P = 0.07) and 78% and 57% for HER2-positive high-TIL versus low-TIL, respectively (HR 0.46, 95% CI 0.20–1.11, P = 0.08). Either continuous or binary TIL variables did not predict for the efficacy of anthracyclines. Test for interaction P value was not significant in the whole study population and in subgroups (ER+/HER2−, HER2+, ER−/HER2−). Conclusions We confirmed the prognostic role of TIL in triple-negative early breast cancer and suggested a prognostic

  11. 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.

  12. Analysis of tumour-infiltrating lymphocytes reveals two new biologically different subgroups of breast ductal carcinoma in situ.

    PubMed

    Beguinot, Marie; Dauplat, Marie-Melanie; Kwiatkowski, Fabrice; Lebouedec, Guillaume; Tixier, Lucie; Pomel, Christophe; Penault-Llorca, Frederique; Radosevic-Robin, Nina

    2018-02-03

    Tumour-infiltrating lymphocytes (TILs) have been demonstrated to significantly influence prognosis and response to therapy of invasive breast cancer (IBC). Thus, it has been suggested that TIL density or/and immunophenotype could serve as biomarkers for selection of IBC patients for immunotherapy. However, much less is known about significance of TILs in breast ductal carcinoma in situ (DCIS). We retrospectively investigated TIL density and immunophenotype in 96 pure DCIS and 35 microinvasive carcinomas (miCa). TIL density was assessed on H&E-stained breast biopsy sections as the percentage of tumour stromal area occupied by TILs, and classified into 4 grades: 0 (0%-9%), 1 (10-29%), 2 (30-49%) and 3 (50%-100%). TIL immunophenotype was assessed by immunohistochemistry for CD8, CD4, FoxP3, CD38 or CD20. Compared to pure DCIS, miCa contained significantly more cases with TIL density grade 3 (p = 0.028). Concordantly, CD8+, CD4+ and CD38+ cells were more numerous in miCa than in pure DCIS. In the pure DCIS subgroup with TIL density grades 2 and 3, all TIL subpopulations were more numerous than in the pure DCIS with TIL density grades 0 and 1, however the ratio between T-lymphocytes (CD8+ and CD4+) and B-lymphocytes (CD20+) was significantly lower (p = 0.029). On the other side, this ratio was significantly higher in miCa, in comparison with pure DCIS having TIL density grades 2 and 3 (p = 0.017). By cluster analysis of tumour cell pathobiological features we demonstrated similarity between miCa and the pure DCIS with TIL density grades 2 and 3. The only significant difference between those two categories was in the ratio of T- to B-TILs, higher in miCa. Results indicate that TIL density level can distinguish 2 biologically different DCIS subgroups, one of which (DCIS with ≥30% TILs, the TIL-rich DCIS) is like miCa. Similarity of TIL-rich pure DCIS and miCa as well as the role of B-lymphocytes in DCIS invasiveness are worth further investigating with

  13. Lymphocytic response to tumour and deficient DNA mismatch repair identify subtypes of stage II/III colorectal cancer associated with patient outcomes.

    PubMed

    Williams, David S; Mouradov, Dmitri; Jorissen, Robert N; Newman, Marsali R; Amini, Elham; Nickless, David K; Teague, Julie A; Fang, Catherine G; Palmieri, Michelle; Parsons, Marie J; Sakthianandeswaren, Anuratha; Li, Shan; Ward, Robyn L; Hawkins, Nicholas J; Faragher, Ian; Jones, Ian T; Gibbs, Peter; Sieber, Oliver M

    2018-01-30

    Tumour-infiltrating lymphocyte (TIL) response and deficient DNA mismatch repair (dMMR) are determinants of prognosis in colorectal cancer. Although highly correlated, evidence suggests that these are independent predictors of outcome. However, the prognostic significance of combined TIL/MMR classification and how this compares to the major genomic and transcriptomic subtypes remain unclear. A prospective cohort of 1265 patients with stage II/III cancer was examined for TIL/MMR status and BRAF / KRAS mutations. Consensus molecular subtype (CMS) status was determined for 142 cases. Associations with 5-year disease-free survival (DFS) were evaluated and validated in an independent cohort of 602 patients. Tumours were categorised into four subtypes based on TIL and MMR status: TIL-low/proficient-MMR (pMMR) (61.3% of cases), TIL-high/pMMR (14.8%), TIL-low/dMMR (8.6%) and TIL-high/dMMR (15.2%). Compared with TIL-high/dMMR tumours with the most favourable prognosis, both TIL-low/dMMR (HR=3.53; 95% CI=1.88 to 6.64; P multivariate <0.001) and TIL-low/pMMR tumours (HR=2.67; 95% CI=1.47 to 4.84; P multivariate =0.001) showed poor DFS. Outcomes of patients with TIL-low/dMMR and TIL-low/pMMR tumours were similar. TIL-high/pMMR tumours showed intermediate survival rates. These findings were validated in an independent cohort. TIL/MMR status was a more significant predictor of prognosis than National Comprehensive Cancer Network high-risk features and was a superior predictor of prognosis compared with genomic (dMMR, pMMR/ BRAF wt / KRAS wt , pMMR/ BRAF mut / KRAS wt , pMMR/ BRAF wt / KRAS mut ) and transcriptomic (CMS 1-4) subtypes. TIL/MMR classification identified subtypes of stage II/III colorectal cancer associated with different outcomes. Although dMMR status is generally considered a marker of good prognosis, we found this to be dependent on the presence of TILs. Prognostication based on TIL/MMR subtypes was superior compared with histopathological, genomic and

  14. Observational Characteristics of the Tropopause Inversion Layer derived from CHAMP/GRACE Radio Occultations and MOZAIC Aircraft Data

    NASA Astrophysics Data System (ADS)

    Schmidt, T.; Cammas, J.; Heise, S.; Wickert, J.; Haser, A.

    2010-12-01

    In this study we discuss characteristics of the northern hemisphere (NH) midlatitude (40°N-60°N) tropopause inversion layer (TIL) based on two datasets. First, temperature measurements from GPS radio occultation data (CHAMP and GRACE) for the time interval 2001-2009 are used to exhibit seasonal properties of the TIL bottom height defined here as the height of the squared buoyancy frequency minimum N2 below the thermal tropopause, the TIL maximum height as the height of the N2 maximum above the tropopause and the TIL top height as the height of the temperature maximum above the tropopause. Mean values of the TIL bottom, TIL maximum and TIL top heights relative to the thermal tropopause for the NH midlatitudes are (-2.08±0.35) km, (0.52±0.10) km and (2.10±0.23) km, respectively. A seasonal cycle of the TIL bottom and TIL top height is observed with values closer to the thermal tropopause during summer. Secondly, high-resolution temperature and trace gas profile measurements onboard commercial aircrafts (MOZAIC program) from 2001-2008 for the NH midlatitude (40°N-60°N) region are used to characterize the TIL as a mixing layer around the tropopause. Mean TIL bottom, TIL maximum and TIL top heights based on the MOZAIC temperature (N2) measurements confirm the results from the GPS data, even though most of the MOZAIC profiles used here are available under cyclonic situations. Further, we demonstrate that the mixing ratio gradients of ozone (O3) and carbon monoxide (CO) are suitable parameters for characterizing the TIL structure. Using O3-CO correlations we also show that on average the highest mixing occurs in a layer less than 1 km above the thermal tropopause, i.e., within the TIL.

  15. Tumor-infiltrating lymphocyte grade in primary melanomas is independently associated with melanoma-specific survival in the population-based genes, environment and melanoma study.

    PubMed

    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

    2013-11-20

    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. 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. 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 (P(trend) < .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. 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.

  16. 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

  17. A Novel Method to Generate and Expand Clinical-Grade, Genetically Modified, Tumor-Infiltrating Lymphocytes

    PubMed Central

    Forget, Marie-Andrée; Tavera, René J.; Haymaker, Cara; Ramachandran, Renjith; Malu, Shuti; Zhang, Minying; Wardell, Seth; Fulbright, Orenthial J.; Toth, Chistopher Leroy; Gonzalez, Audrey M.; Thorsen, Shawne T.; Flores, Esteban; Wahl, Arely; Peng, Weiyi; Amaria, Rodabe N.; Hwu, Patrick; Bernatchez, Chantale

    2017-01-01

    Following the clinical success achieved with the first generation of adoptive cell therapy (ACT) utilizing in vitro expanded tumor-infiltrating lymphocytes (TILs), the second and third generations of TIL ACT are evolving toward the use of genetically modified TIL. TIL therapy generally involves the transfer of a high number of TIL, ranging from 109 to 1011 cells. One of the technical difficulties in genetically modifying TIL, using a retroviral vector, is the ability to achieve large expansion of transduced TIL, while keeping the technique suitable to a Good Manufacturing Practices (GMP) environment. Consequently, we developed and optimized a novel method for the efficient production of large numbers of GMP-grade, gene-modified TIL for the treatment of patients with ACT. The chemokine receptor CXCR2 was used as the gene of interest for methodology development. The optimized procedure is currently used in the production of gene-modified TIL for two clinical trials for the treatment of metastatic melanoma at MD Anderson Cancer Center. PMID:28824634

  18. Structural diagnostics of the tropopause inversion layer and its evolution

    NASA Astrophysics Data System (ADS)

    Gettelman, A.; Wang, T.

    2015-01-01

    The Tropopause Inversion Layer (TIL) is marked by a peak in static stability directly above the tropopause. The TIL is quantitatively defined with new diagnostics using Global Positioning System Radio Occultation temperature soundings and reanalysis data. A climatology of the TIL is developed from reanalysis data (1980-2011) using diagnostics for the position, depth, and strength of the TIL based on the TIL peak in static stability. TIL diagnostics have defined relationships to the synoptic situation in the Upper Troposphere and Lower Stratosphere. The TIL is present nearly all the time. The TIL becomes hard to define in the subtropics where tropical air overlies midlatitude air, in a region of complex static stability profiles. The mean position of the subtropical TIL gradient is sharp and is co-located with the subtropical tropopause break. Over the period 1980-2011 the TIL depth below the tropopause has decreased by 5% per decade and increased above the tropical tropopause by a similar percentage. Furthermore, the latitude of the abrupt change in the TIL from tropical to extratropical in the lower stratosphere appears to have shifted poleward in each hemisphere by ˜1° latitude per decade, depending on the diagnostic examined. Reanalysis trends should be treated with caution.

  19. 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

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

    1996-12-01

    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.

  20. Observational characteristics of the tropopause inversion layer derived from CHAMP/GRACE radio occultations and MOZAIC aircraft data

    NASA Astrophysics Data System (ADS)

    Schmidt, T.; Cammas, J.-P.; Smit, H. G. J.; Heise, S.; Wickert, J.; Haser, A.

    2010-12-01

    In this study we discuss characteristics of the Northern Hemisphere (NH) midlatitude (40°N-60°N) tropopause inversion layer (TIL) based on two data sets. First, temperature measurements from GPS radio occultation data (CHAMP and GRACE) for the time interval 2001-2009 are used to exhibit seasonal properties of the TIL bottom height defined here as the height of the squared buoyancy frequency minimum N2 below the thermal tropopause, the TIL maximum height as the height of the N2 maximum above the tropopause, and the TIL top height as the height of the temperature maximum above the tropopause. Mean values of the TIL bottom, TIL maximum, and TIL top heights relative to the thermal tropopause for the NH midlatitudes are (-2.08 ± 0.35) km, (0.52 ± 0.10) km and (2.10 ± 0.23) km, respectively. A seasonal cycle of the TIL bottom and TIL top height is observed with values closer to the thermal tropopause during summer. Secondly, high-resolution temperature and trace gas profile measurements on board commercial aircrafts (Measurement of Ozone and Water Vapor by Airbus In-Service Aircraft (MOZAIC) program) from 2001-2008 for the NH midlatitude (40°N-60°N) region are used to characterize the TIL as a mixing layer around the tropopause. Mean TIL bottom, TIL maximum, and TIL top heights based on the MOZAIC temperature (N2) measurements confirm the results from the GPS data, even though most of the MOZAIC profiles used here are available under cyclonic situations. Further, we demonstrate that the mixing ratio gradients of ozone (O3) and carbon monoxide (CO) are suitable parameters for characterizing the TIL structure.

  1. Expansion of tumor-infiltrating lymphocytes and their potential for application as adoptive cell transfer therapy in human breast cancer.

    PubMed

    Lee, Hee Jin; Kim, Young-Ae; Sim, Chan Kyu; Heo, Sun-Hee; Song, In Hye; Park, Hye Seon; Park, Suk Young; Bang, Won Seon; Park, In Ah; Lee, Miseon; Lee, Jung Hoon; Cho, Yeon Sook; Chang, Suhwan; Jung, Jaeyun; Kim, Jisun; Lee, Sae Byul; Kim, Sung Youl; Lee, Myeong Sup; Gong, Gyungyub

    2017-12-26

    Adoptive cell transfer (ACT) of ex vivo expanded tumor-infiltrating lymphocytes (TILs) has been successful in treating a considerable proportion of patients with metastatic melanoma. In addition, some patients with several other solid tumors were recently reported to have benefited clinically from such ACT. However, it remains unclear whether ACT using TILs is broadly applicable in breast cancer, the most common cancer in women. In this study, the utility of TILs as an ACT source in breast cancers was explored by deriving TILs from a large number of breast cancer samples and assessing their biological potentials. We successfully expanded TILs ex vivo under a standard TIL culture condition from over 100 breast cancer samples, including all breast cancer subtypes. We also found that the information about the percentage of TIL and presence of tertiary lymphoid structure in the tumor tissues could be useful for estimating the number of obtainable TILs after ex vivo culture. The ex vivo expanded TILs contained a considerable level of central memory phenotype T cells (about 20%), and a large proportion of TIL samples were reactive to autologous tumor cells in vitro . Furthermore, the in vitro tumor-reactive autologous TILs could also function in vivo in a xenograft mouse model implanted with the primary tumor tissue. Collectively, these results strongly indicate that ACT using ex vivo expanded autologous TILs is a feasible option in treating patients with breast cancer.

  2. Expansion of tumor-infiltrating lymphocytes and their potential for application as adoptive cell transfer therapy in human breast cancer

    PubMed Central

    Lee, Hee Jin; Kim, Young-Ae; Sim, Chan Kyu; Heo, Sun-Hee; Song, In Hye; Park, Hye Seon; Park, Suk Young; Bang, Won Seon; Park, In Ah; Lee, Miseon; Lee, Jung Hoon; Cho, Yeon Sook; Chang, Suhwan; Jung, Jaeyun; Kim, Jisun; Lee, Sae Byul; Kim, Sung Youl; Lee, Myeong Sup; Gong, Gyungyub

    2017-01-01

    Adoptive cell transfer (ACT) of ex vivo expanded tumor-infiltrating lymphocytes (TILs) has been successful in treating a considerable proportion of patients with metastatic melanoma. In addition, some patients with several other solid tumors were recently reported to have benefited clinically from such ACT. However, it remains unclear whether ACT using TILs is broadly applicable in breast cancer, the most common cancer in women. In this study, the utility of TILs as an ACT source in breast cancers was explored by deriving TILs from a large number of breast cancer samples and assessing their biological potentials. We successfully expanded TILs ex vivo under a standard TIL culture condition from over 100 breast cancer samples, including all breast cancer subtypes. We also found that the information about the percentage of TIL and presence of tertiary lymphoid structure in the tumor tissues could be useful for estimating the number of obtainable TILs after ex vivo culture. The ex vivo expanded TILs contained a considerable level of central memory phenotype T cells (about 20%), and a large proportion of TIL samples were reactive to autologous tumor cells in vitro. Furthermore, the in vitro tumor-reactive autologous TILs could also function in vivo in a xenograft mouse model implanted with the primary tumor tissue. Collectively, these results strongly indicate that ACT using ex vivo expanded autologous TILs is a feasible option in treating patients with breast cancer. PMID:29371915

  3. T-cell Responses in the Microenvironment of Primary Renal Cell Carcinoma-Implications for Adoptive Cell Therapy.

    PubMed

    Andersen, Rikke; Westergaard, Marie Christine Wulff; Kjeldsen, Julie Westerlin; Müller, Anja; Pedersen, Natasja Wulff; Hadrup, Sine Reker; Met, Özcan; Seliger, Barbara; Kromann-Andersen, Bjarne; Hasselager, Thomas; Donia, Marco; Svane, Inge Marie

    2018-02-01

    In vitro expansion of large numbers of highly potent tumor-reactive T cells appears a prerequisite for effective adoptive cell therapy (ACT) with autologous tumor-infiltrating lymphocytes (TIL) as shown in metastatic melanoma (MM). We therefore sought to determine whether renal cell carcinomas (RCC) are infiltrated with tumor-reactive T cells that could be efficiently employed for adoptive transfer immunotherapy. TILs and autologous tumor cell lines (TCL) were successfully generated from 22 (92%) and 17 (77%) of 24 consecutive primary RCC specimens and compared with those generated from metastatic melanoma. Immune recognition of autologous TCLs or fresh tumor digests was observed in CD8 + TILs from 82% of patients (18/22). Cytotoxicity assays confirmed the tumoricidal capacity of RCC-TILs. The overall expansion capacity of RCC-TILs was similar to MM-TILs. However, the magnitude, polyfunctionality, and ability to expand in classical expansion protocols of CD8 + T-cell responses was lower compared with MM-TILs. The RCC-TILs that did react to the tumor were functional, and antigen presentation and processing of RCC tumors was similar to MM-TILs. Direct recognition of tumors with cytokine-induced overexpression of human leukocyte antigen class II was observed from CD4 + T cells (6/12; 50%). Thus, TILs from primary RCC specimens could be isolated, expanded, and could recognize tumors. However, immune responses of expanded CD8 + RCC-TILs were typically weaker than MM-TILs and displayed a mono-/oligofunctional pattern. The ability to select, enrich, and expand tumor-reactive polyfunctional T cells may be critical in developing effective ACT with TILs for RCC. In summary, TILs isolated from primary RCC specimens could recognize tumors. However, their immune responses were weaker than MM-TILs and displayed a mono-/oligofunctional pattern. The ability to select and expand polyfunctional T cells may improve cell therapy for RCC. Cancer Immunol Res; 6(2); 222-35. ©2018 AACR

  4. Comparison of tumor-infiltrating lymphocytes of breast cancer in core needle biopsies and resected specimens: a retrospective analysis.

    PubMed

    Cha, Yoon Jin; Ahn, Sung Gwe; Bae, Soong June; Yoon, Chang Ik; Seo, Jayeong; Jung, Woo Hee; Son, Eun Ju; Jeong, Joon

    2018-06-05

    Neoadjuvant chemotherapy (NAC) is being increasingly used to treat locally advanced breast cancer and to conserve the breast. In triple-negative breast cancer and HER2-positive breast cancer, a high density of tumor-infiltrating lymphocytes (TILs) is an important predictor of NAC response. Thus far, it remains unclear whether the TIL scores in core needle biopsies (CNBs) are closely representative of those in the whole tumor section in resected specimens. This study aimed to evaluate the concordance between the TIL scores of CNBs and resected specimens of breast cancer. A total of 220 matched pairs of CNBs and resected specimens of breast cancer were included. Stromal TILs were scored on slides stained with hematoxylin and eosin. Clinicopathologic parameters and the agreement of the TIL scores between CNBs and resected specimens were statistically analyzed. The average TIL score was approximately 4.4% higher for the resected specimens than for the CNBs. When the tumors were divided into two groups according to a 60% TIL score cut-off (low and intermediate TIL vs. high TIL), 8.2% showed discordance between the CNB and resected specimen. The overall intraclass correlation coefficient (ICC) value of the TIL score was 0.895 (95% confidence interval, 0.864-0.920, P < 0.001), and all molecular subtypes showed ICC values over 0.8 (P < 0.001). The ICC values were > 0.9 when ≥ 5 cores were included in the CNBs. Tumors with discordant TILs were characterized by histologic grade III, ER negativity, high proliferative index, and HER2 and triple-negative subtypes. A high proliferative index was an independent risk factor for TIL discordance. The TIL score in CNB specimens is a reliable value that reflects the TIL status of the entire tumor in resected specimens of breast cancer. More than five CNB cores may accurately predict the TIL score of the entire tumor.

  5. 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

  6. 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

  7. Minimally cultured or selected autologous tumor-infiltrating lymphocytes after a lympho-depleting chemotherapy regimen in metastatic melanoma patients.

    PubMed

    Besser, Michal J; Shapira-Frommer, Ronnie; Treves, Avraham J; Zippel, Dov; Itzhaki, Orit; Schallmach, Ester; Kubi, Adva; Shalmon, Bruria; Hardan, Izhar; Catane, Raphael; Segal, Eran; Markel, Gal; Apter, Sara; Nun, Alon Ben; Kuchuk, Iryna; Shimoni, Avichai; Nagler, Arnon; Schachter, Jacob

    2009-05-01

    Adoptive cell therapy with autologous tumor-infiltrating lymphocytes (TIL) and high-dose interleukin-2 (IL-2), after nonmyeloablative chemotherapy, has been shown to result in tumor regression in half of refractory metastatic melanoma patients. In the present study, we describe 2 separate clinical protocols. Twelve patients were treated with "Selected"-TIL, as previously reported and 8 patients with the modified version of "Young"-TIL. Selected-TIL protocol required the establishment of multiple T-cell cultures from 1 patient and in vitro selection of cultures secreting interferon-gamma upon antigenic stimulation. In contrast, Young-TIL are minimally cultured T cells with superior in vitro features that do not require further selection. Two of 12 Selected-TIL patients experienced objective clinical responses (1 complete response, 1 partial response). Out of 8 treated Young-TIL patients, 1 experienced complete response, 2 partial response, and 4 patients had disease stabilization. Twenty-one of 33 enrolled Selected-TIL patients were excluded from the protocol, mainly as cultures failed the interferon-gamma selection criteria or due to clinical deterioration, compared with only 3 Young-TIL patients. Expected bone marrow suppression and high-dose IL-2 toxicity were transient. There was no treatment-related mortality. This study vindicates the feasibility and effectiveness of TIL technology and calls for further efforts to implement and enhance this modality. The use of minimally cultured, unselected Young-TIL enables the treatment of most enrolled patients. Although the cohort of Young-TIL patients treated so far is rather small and the follow-up short, the response rate is encouraging.

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

    Kasid, A.; Morecki, S.; Aebersold, P.

    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 andmore » 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.« less

  9. Density of CD8+ lymphocytes in biopsy samples combined with the circulating lymphocyte ratio predicts pathologic complete response to chemoradiotherapy for rectal cancer.

    PubMed

    Xiao, Binyi; Peng, Jianhong; Zhang, Rongxin; Xu, Jing; Wang, Yongchun; Fang, Yujing; Lin, Junzhong; Pan, Zhizhong; Wu, Xiaojun

    2017-01-01

    The systemic status and local immune status, as determined by the neutrophil-lymphocyte ratio (NLR) or the lymphocyte ratio (LYMR) and tumor-infiltrating lymphocyte (TIL) count, respectively, have been suggested as predictors of the tumor response to neoadjuvant chemoradiotherapy (nCRT) in rectal cancer, although the utility of these measures remains controversial. We aimed to investigate the values of the LYMR, NLR and TIL count and their combinations (TIL-LYMR/TIL-NLR) in predicting pathologic complete response (pCR) after nCRT. Pretreatment biopsy samples and data from the blood tests of 92 patients with rectal cancer who underwent curative resection after nCRT were retrospectively obtained. CD8+ TILs were immunostained using an antibody against CD8. The density of CD8+ TILs was recorded as the number of CD8+ T cells per square millimeter, and the results were classified as either "high" or "low". The LYMR and NLR were calculated using pretreatment blood test data and categorized into either "high" or "low" groups. TIL-LYMR was graded as "low," "mid" or "high" when neither, one or both the CD8+ TIL count and LYMR were "high," respectively. TIL-NLR was graded similarly. The associations between TILs and LYMR, NLR and their combinations (TIL-LYMR/TIL-NLR) were evaluated. pCR was significantly associated with a high LYMR, a low NLR and increased chemotherapy cycles ( P =0.039, P =0.043 and P =0.015, respectively), but not with the CD8+ TIL count or carcinoembryonic antigen (CEA) level ( P =0.100 and P =0.590, respectively). Additionally, 40% of patients with high LYMR and 40.7% with low NLR achieved pCR, whereas only 19.7% with low LYMR and 20.3% with high NLR did so. When the combinations were assessed, TIL-LYMR showed a positive correlation with pCR ( P =0.038), while no association between TIL-NLR and pCR was found ( P =0.916). In multivariate analysis, TIL-LYMR remained an independent predictor of pCR (odds ratio [OR]=1.833, 95% confidence interval [CI]=1

  10. Standardized assessment of tumor-infiltrating lymphocytes in breast cancer: an evaluation of inter-observer agreement between pathologists.

    PubMed

    Tramm, Trine; Di Caterino, Tina; Jylling, Anne-Marie B; Lelkaitis, Giedrius; Lænkholm, Anne-Vibeke; Ragó, Péter; Tabor, Tomasz P; Talman, Maj-Lis M; Vouza, Emmanouela

    2018-01-01

    In breast cancer, there is a growing body of evidence that tumor-infiltrating lymphocytes (TILs) may have clinical utility and may be able to direct clinical decisions for subgroups of patients. Clinical utility is, however, not sufficient for warranting the implementation of a new biomarker in the routine practice, and evaluation of the analytical validity is needed, including testing the reproducibility of decentralized assessment of TILs. The aim of this study was to evaluate the inter-observer agreement of TILs assessment using a standardized method, as proposed by the International TILs Working Group 2014, applied to a cohort of breast cancers reflecting an average breast cancer population. Stromal TILs were assessed using full slide sections from 124 breast cancers with varying histology, malignancy grade and ER- and HER2 status. TILs were estimated by nine dedicated breast pathologists using scanned hematoxylin-eosin stainings. TILs results were categorized using various cutoffs, and the inter-observer agreement was evaluated using the intraclass coefficient (ICC), Kappa statistics as well as individual overall agreements with the median value of TILs. Evaluation of TILs led to an ICC of 0.71 (95% CI: 0.65-0.77) corresponding to an acceptable agreement. Kappa values were in the range of 0.38-0.46 corresponding to a fair to moderate agreement. The individual agreements increased, when using only two categories ('high' vs. 'low' TILs) and a cutoff of 50-60%. The results of the present study are in accordance with previous studies, and shows that the proposed methodology for standardized evaluation of TILs renders an acceptable inter-observer agreement. The findings, however, indicate that assessment of TILs needs further refinement, and is in support of the latest St. Gallen Consensus, that routine reporting of TILs for early breast cancer is not ready for implementation in a clinical setting.

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

    Griffith, K.D.; Read, E.J.; Carrasquillo, J.A.

    Patients with metastatic melanoma undergoing therapy with cyclophosphamide (CPM), tumor-infiltrating lymphocytes (TIL), and interleukin-2 (IL-2) were studied for the ability of their 111In-labeled TIL or peripheral blood lymphocytes (PBL) to localize in sites of tumor using gamma camera imaging and biopsies. Nineteen infusions of radiolabeled TIL were given to 18 patients, while five patients received radiolabeled autologous PBL during TIL therapy. Clear tumor localization was seen on 13 of 18 nuclear scan series performed on 111In-TIL recipients, while tumor was imaged in only one of four scan sequences on patients given 111In-PBL. Nineteen paired biopsies of tumor and normal skinmore » were completed on 10 patients receiving 111In-TIL, while eight biopsies were done on three PBL patients receiving 111In-PBL. The mean percentage of total injectate activity localizing per gram of tumor tissue was 0.0049% in the TIL group and 0.0010% in the PBL group (P2 = .0004). The mean of the tumor to normal skin ratios of the 111In-TIL group was three times that for 111In-PBL (P2 = .0072). One patient was studied by nuclear scanning on three consecutive treatment courses of CPM, TIL, and IL-2. He initially demonstrated clear tumor localization by 111In-TIL at several sites, then faint localization with 111In-PBL at a single site, and subsequently positive tumor imaging on repeat 111In-TIL infusion at multiple sites. These results confirm and expand our initial data demonstrating that human TIL transferred with CPM pretreatment and followed by IL-2 preferentially localize to tumor sites and indicate that this localization is greater for TIL than PBL.« less

  12. Prognostic Value of Tumor-Infiltrating Lymphocyte Density Assessed Using a Standardized Method Based on Molecular Subtypes and Adjuvant Chemotherapy in Invasive Breast Cancer.

    PubMed

    Jang, Nuri; Kwon, Hee Jung; Park, Min Hui; Kang, Su Hwan; Bae, Young Kyung

    2018-04-01

    This study investigated the prognostic value of tumor-infiltrating lymphocyte (TIL) density as determined by molecular subtype and receipt of adjuvant chemotherapy in invasive breast cancer (IBC). Stromal TIL densities were evaluated in 1489 IBC samples using recommendations proposed by the International TILs Working Group. Cases were allocated to high- and low-TIL density groups using a cutoff of 10%. Of the 1489 IBC patients, 427 (28.7%) were assigned to the high-TIL group and 1062 (71.3%) to the low-TIL group. High TIL density was found to be significantly associated with large tumor size (p = 0.001), high histologic grade (p < 0.001), and high Ki-67 labeling index (p < 0.001). Triple-negative and human epidermal growth factor receptor 2 (HER2)-positive subtypes had significantly higher TIL densities than luminal A or B (HER2-negative) subtypes (p < 0.001). High TIL density was significantly associated with prolonged disease-free survival (DFS) by univariate (p < 0.001) and multivariate (p < 0.001) analyses. In the low-TIL-density group, the patients who did not receive adjuvant chemotherapy showed better DFS (p < 0.001), but no such survival difference was observed in the high-TIL group (p = 0.222). For the patients who received adjuvant anthracycline, high-TIL density was found to be an independent prognostic factor of favorable DFS in the luminal B (HER2-negative; p = 0.003), HER2-positive (p = 0.019), and triple-negative (p = 0.017) subtypes. Measurements of TIL density in routine clinical practice could give useful prognostic information for the triple-negative, HER2-positive, and luminal B (HER2-negative) IBC subtypes, especially for patients administered adjuvant anthracycline.

  13. Prognostic value of CD8CD45RO tumor infiltrating lymphocytes in patients with extrahepatic cholangiocarcinoma

    PubMed Central

    Kim, Richard; Coppola, Domenico; Wang, Emilie; Chang, Young Doo; Kim, Yuhree; Anaya, Daniel; Kim, Dae Won

    2018-01-01

    Cholangiocarcinoma is a malignancy arising from the biliary tract epithelial cells with poor prognosis. Tumor infiltrating lymphocytes (TIL)s and programmed cell death receptor ligand 1 (PD-L1) have a prognostic impact in various solid tumors. We aimed to investigate TILs and PD-L1 expression and their clinical relevance in cholangiocarcinoma. Tumor samples from 44 patients with resected and histologically verified extrahepatic cholangiocarcinoma were evaluated for CD8, CD45RO and PD-L1 expression, and their correlations with clinicopathological data and survival data were analyzed. Total 44 extrahepatic cholangiocarcinoma tissues were evaluated. CD8+ tumor infiltrating lymphocytes (TIL)s were observed in 30 (68%) tumors. Among them, 14 had CD8+CD45RO+ TILs. PD-L1 was expressed on cancer cells in 10 (22.7%) tumors in 34 evaluable extrahepatic cholangiocarciniomas. The presence of CD8+ TILs or CD8+CD45RO+ TILs was not associated with clinical staging or tumor differentiation. Extrahepatic cholangiocarcinoma with CD8+CD45RO+ TILs had longer overall survival (OS) on univariate (P = 0.013) and multivariate (P = 0.012) analysis. Neither CD8+TIL nor PD-L1 expression on cancer cells correlated significantly with OS. These results add to the understanding of the clinical features associated with CD8 TILs and PD-L1 expression in extrahepatic cholangiocarcinoma, and they support the potential rationale of using PD-1 blockade immunotherapy in cholangiocarcinoma.

  14. The crosstalk: Tumor-infiltrating lymphocytes rich in regulatory T cells suppressed cancer-associated fibroblasts

    PubMed Central

    2013-01-01

    Background. The interactions between cancer-associated fibroblasts (CAFs) and cancer cells or tumor-infiltrating lymphocytes (TILs) and cancer cells play important roles in cancer progression and metastasis. However, studies related to the crosstalk between CAFs and TILs in tumor microenvironment (TME) are still lacking. In this study, we mainly investigated the interactions between CAFs and TILs. Material and methods. The distribution of TILs rich in regulatory T cells (Tregs) in breast cancer tissues was evaluated using hematoxylin-eosin staining and immunohistochemistry with anti-CD3, anti-Foxp3, and anti-α-smooth muscle actin antibodies. Homologous CAFs/normal fibroblasts (NFs) and TILs cultured in vitro were identified and detected using immunocytochemistry and flow cytometry (FCM). The direct interaction among these cell types was studied via a factorial design in a co-cultured system. Their indirect interaction was assayed using Transwell plates. The cell cycle and apoptosis of CAFs/NFs co-cultured with TILs was analyzed using propidium iodide staining. Results. Histochemistry demonstrated most of the TILs including Tregs, were distributed in the cancer stroma, adjoining to CAFs. This finding implies that both cell types interact closely in the TME. Identification of the cultured cells showed that CAFs maintained their activated phenotype within limited passages in vitro, and that the TILs population contained a high percentage of Tregs. Data analysis of the factorial design suggests significant interactions among CAFs, NFs, and TILs in both direct and indirect contact ways. The CAFs and NFs were suppressed signally by TILs, which are probably induced by the secretory cytokines derived from TILs or Tregs. Although apoptosis was not detected in CAFs/NFs, the cell cycle assay suggested that the CAFs/NFs were arrested in the G2/M phase by the TILs and their secretory cytokines. Conclusion. CAFs and NFs were dramatically suppressed by Tregs-rich TILs. This

  15. 76 FR 41795 - Granting of Request for Early Termination of the Waiting Period Under the Premerger Notification...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-07-15

    ...; Robert M. Chipman. 20110936 G 2003 TIL Settlement; LPF Atlanta LLC; 2003 TIL Settlement. 20110937 G.../2011 20110867 G Ebro Food S.A.; SOS Corporacion Alementaria, S.A.; Ebro Food S.A. 20110918 G 2003 TIL Settlement; Thoma Cressey Fund VIII, L.P.; 2003 TIL Settlement. 20110942 G Wells Fargo & Company; Castle...

  16. 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

  17. Context recognition for a hyperintensional inference machine

    NASA Astrophysics Data System (ADS)

    Duží, Marie; Fait, Michal; Menšík, Marek

    2017-07-01

    The goal of this paper is to introduce the algorithm of context recognition in the functional programming language TIL-Script, which is a necessary condition for the implementation of the TIL-Script inference machine. The TIL-Script language is an operationally isomorphic syntactic variant of Tichý's Transparent Intensional Logic (TIL). From the formal point of view, TIL is a hyperintensional, partial, typed λ-calculus with procedural semantics. Hyperintensional, because TIL λ-terms denote procedures (defined as TIL constructions) producing set-theoretic functions rather than the functions themselves; partial, because TIL is a logic of partial functions; and typed, because all the entities of TIL ontology, including constructions, receive a type within a ramified hierarchy of types. These features make it possible to distinguish three levels of abstraction at which TIL constructions operate. At the highest hyperintensional level the object to operate on is a construction (though a higher-order construction is needed to present this lower-order construction as an object of predication). At the middle intensional level the object to operate on is the function presented, or constructed, by a construction, while at the lowest extensional level the object to operate on is the value (if any) of the presented function. Thus a necessary condition for the development of an inference machine for the TIL-Script language is recognizing a context in which a construction occurs, namely extensional, intensional and hyperintensional context, in order to determine the type of an argument at which a given inference rule can be properly applied. As a result, our logic does not flout logical rules of extensional logic, which makes it possible to develop a hyperintensional inference machine for the TIL-Script language.

  18. Tumor-Infiltrating Lymphocytes and PD-L1 Expression in Pre- and Posttreatment Breast Cancers in the SWOG S0800 Phase II Neoadjuvant Chemotherapy Trial.

    PubMed

    Pelekanou, Vasiliki; Barlow, William E; Nahleh, Zeina A; Wasserman, Brad; Lo, Ying-Chun; von Wahlde, Marie-Kristin; Hayes, Daniel; Hortobagyi, Gabriel N; Gralow, Julie; Tripathy, Debu; Porter, Peggy; Szekely, Borbala; Hatzis, Christos; Rimm, David L; Pusztai, Lajos

    2018-06-01

    Our aim was to examine the association of pretreatment tumor-infiltrating lymphocyte (TIL) count and PD-L1 levels with pathologic complete response (pCR) and assess immune marker changes following treatment in tumor specimens from the S0800 clinical trial, which randomized patients to bevacizumab + nab-paclitaxel, followed by doxorubicin/cyclophosphamide (AC) versus two control arms without bevacizumab (varying sequence of AC and nab-paclitaxel). TILs were assessed in 124 pre- and 62 posttreatment tissues (including 59 pairs). PD-L1 was assessed in 120 pre- and 43 posttreatment tissues (including 39 pairs) using the 22C3 antibody. Baseline and treatment-induced immune changes were correlated with pCR and survival using estrogen receptor (ER) and treatment-adjusted logistic and Cox regressions, respectively. At baseline, the mean TIL count was 17.4% (17% had zero TILs, 9% had ≥50% TILs). Posttreatment, mean TIL count decreased to 11% (5% had no TILs, 2% had >50% TILs). In paired samples, the mean TIL change was 15% decrease. Baseline PD-L1 was detected in 43% of cases ( n = 5 in tumor cells, n = 29 stroma, n = 18 tumor + stroma). Posttreatment, PD-L1 expression was not significantly lower (33%). Higher baseline TIL count and PD-L1 positivity rate were associated with higher pCR rate even after adjustment for treatment and ER status ( P = 0.018). There was no association between TIL counts, PD-L1 expression, and survival due to few events. In conclusion, TIL counts, but not PD-L1 expression, decreased significantly after treatment. Continued PD-L1 expression in some residual cancers raises the possibility that adjuvant immune checkpoint inhibitor therapy could improve survival in this patient population. Mol Cancer Ther; 17(6); 1324-31. ©2018 AACR . ©2018 American Association for Cancer Research.

  19. The Tropopause Inversion Layer: New Observations, New Theories

    NASA Astrophysics Data System (ADS)

    Tandon, N.; Randel, W. J.; Pan, L.; Son, S.; Polvani, L. M.

    2009-12-01

    There is now great interest in the tropopause inversion inversion layer (TIL), a 1-2 km region just above the tropopause where there is a spike in static stability. Radio occultation data from the COSMIC GPS mission are providing an unprecedented level of spatial and temporal resolution with which to analyze the TIL. We start by showing the agreement between GPS data and radiosondes. We then examine the causes and consequences of the TIL. Observations from the ACE satellite and fixed dynamical heating calculations suggest strong roles for water vapor and ozone in the formation and modulation of the TIL. This agrees with observations showing a large TIL in the polar winter, where water vapor levels are persistently high. It is also clear that TIL strength is related to vorticity, but observations and models have important differences that need to be reconciled. These dynamical considerations dovetail with observations showing high TIL variability in the storm-track regions. Finally there is evidence from ozonesonde data that the TIL may be coupled to transport across the tropopause.

  20. The Tropopause Inversion Layer in Baroclinic Life Cycle Experiments

    NASA Astrophysics Data System (ADS)

    Wirth, Volkmar; Erler, Andre

    2010-05-01

    The Tropopause Inversion Layer (TIL) is a region of enhanced static stability just above the thermal tropopause. It is a ubiquitous feature in midlatitudes and is well characterized by observations; however, it still lacks a full theoretical explanation. The current study uses adiabatic baroclinic life-cycle experiments in order to investigate dynamical mechanisms that lead to the formation of a TIL. Consistent with earlier results, no TIL is found above cyclonic anomalies, while a pronounced TIL is found above anticyclonic anomalies early during the life cycle. Interestingly, regarding tropopause based global mean profiles, a TIL can be seen only much later during the life cycle, at a time when wave breaking starts to occur. There is a significant rise of the thermal tropopause, which is spatially and temporally correlated with TIL formation. In contrast, the dynamical tropopause does not rise significantly and does not exhibit a TIL in the global mean. The results of these experiments are interpreted using earlier results about the nonlinear dependence of the TIL amplitude on the scale of the tropopause anomaly. The analysis suggests that the TIL (as a global mean feature) is linked to a strongly asymmetric distribution of cyclonic and anticyclonic anomalies, which occurs after the wave breaking event.

  1. Association between tumour infiltrating lymphocytes, histotype and clinical outcome in epithelial ovarian cancer.

    PubMed

    James, Fiona R; Jiminez-Linan, Mercedes; Alsop, Jennifer; Mack, Marie; Song, Honglin; Brenton, James D; Pharoah, Paul D P; Ali, H Raza

    2017-09-20

    There is evidence that some ovarian tumours evoke an immune response, which can be assessed by tumour infiltrating lymphocytes (TILs). To facilitate adoption of TILs as a clinical biomarker, a standardised method for their H&E visual evaluation has been validated in breast cancer. We sought to investigate the prognostic significance of TILs in a study of 953 invasive epithelial ovarian cancer tumour samples, both primary and metastatic, from 707 patients from the prospective population-based SEARCH study. TILs were analysed using a standardised method based on H&E staining producing a percentage score for stromal and intratumoral compartments. We used Cox regression to estimate hazard ratios of the association between TILs and survival. The extent of stromal and intra-tumoral TILs were correlated in the primary tumours (n = 679, Spearman's rank correlation = 0.60, P < 0.001) with a similar correlation in secondary tumours (n = 224, Spearman's rank correlation = 0.62, P < 0.001). There was a weak correlation between stromal TIL levels in primary and secondary tumour samples (Spearman's rank correlation = 0.29, P < 0.001) and intra-tumoral TIL levels in primary and secondary tumour samples (Spearman's rank correlation = 0.19, P = 0.0094). The extent of stromal TILs differed between histotypes (Pearson chi2 (12d.f.) 54.1, P < 0.0001) with higher levels of stromal infiltration in the high-grade serous and endometriod cases. A significant association was observed for higher intratumoral TIL levels and a favourable prognosis (HR 0.74 95% CI 0.55-1.00 p = 0.047). This study is the largest collection of epithelial ovarian tumour samples evaluated for TILs. We have shown that stromal and intratumoral TIL levels are correlated and that their levels correlate with clinical variables such as tumour histological subtype. We have also shown that increased levels of both intratumoral and stromal TILs are associated with a better prognosis; however, this is

  2. Synoptic-scale behavior of the extratropical tropopause inversion layer

    NASA Astrophysics Data System (ADS)

    Pilch Kedzierski, Robin; Matthes, Katja; Bumke, Karl

    2015-11-01

    High-resolution GPS radio occultation temperature profiles from the COSMIC satellite mission (2007-2013) are used to obtain daily snapshots of the strength of the extratropical tropopause inversion layer (TIL). Its horizontal structure and day-to-day variability are linked to the synoptic situation at near-tropopause level. The strength of the TIL in cyclonic as well as anticyclonic conditions is investigated by separating relative vorticity into curl and shear terms. The analysis shows that the TIL has high zonal variability, and its strength is instantaneously adjusted to the synoptic situation at near-tropopause level. Our key finding is that the TIL within midlatitude ridges in winter is as strong as or stronger than the TIL in polar summer. The strongest TIL in anticyclonic conditions is related to the shear term, while the weaker TIL in cyclonic conditions is enhanced by the curl term.

  3. Tropopause inversion layer and water vapour

    NASA Astrophysics Data System (ADS)

    Peinke, Isabel; Reutter, Philipp; Hoor, Peter; Spichtinger, Peter

    2013-04-01

    The tropopause inversion layer (TIL) is a phenomenon located close to the tropopause, characterized by an enhanced static stability (N2) right above the temperature inversion of the tropopause and by its adjacent minima. There is low understanding of formation and maintenance of the TIL, but different hypotheses exist. On one hand, the balanced dynamic in this region has an important impact on the evolution and sustainment of the TIL. On the other hand, the radiative effects of ozone and water vapor near the tropopause might play an important role for the formation and maintenance of the TIL. We use high resolution radiosonde data over the Meteorological Observatory Lindenberg, Germany for the period February 2000 to April 2001 to investigate the impact of water vapor on the TIL. Starting from the mean profiles, we analyze the main features of the tropopause and the TIL. As it is known from the literature, we find a stronger TIL in summer compared to winter. However, our results show a complementary behavior in the seasonal cycle of the tropopause height and the TIL strength. The influence of the relative humidity over ice (RHi) on the TIL was also investigated. We show that high values of RHi lead to a cooler tropopause temperature and an enhanced strength of the TIL. This means that the maximum of the static stability is higher for high values of RHi and the adjacent minima are smaller than for low values of RHi.

  4. Virus-specific CD8+ T cells infiltrate melanoma lesions and retain function independent of PD-1 expression

    PubMed Central

    Erkes, Dan A.; Smith, Corinne J.; Wilski, Nicole A.; Caldeira-Dantas, Sofia; Mohgbeli, Toktam; Snyder, Christopher M.

    2017-01-01

    It is well known that CD8+ tumor infiltrating lymphocytes (TIL) are correlated with positive prognoses in cancer patients and used to determine efficacy of immune therapies. While it is generally assumed that CD8+ TIL will be tumor associated antigen (TAA)-specific, it is unknown whether CD8+ T cells with specificity for common pathogens also infiltrate tumors. If so, the presence of these T cells could alter the interpretation of prognostic and diagnostic TIL assays. We compared TAA-specific and virus-specific CD8+ T cells in the same tumors using murine cytomegalovirus (MCMV), a herpesvirus that causes a persistent/latent infection, and Vaccinia virus (VacV), a poxvirus that is cleared by the host. Virus-specific CD8+ TIL migrated into cutaneous melanoma lesions during acute infection with either virus, as well as after a cleared VacV infection, and during a persistent/latent MCMV infection. Virus-specific TILs developed independent of viral antigen in the tumor and interestingly, expressed low or intermediate levels of full-length PD-1 in the tumor environment. Importantly, PD-1 expression could be markedly induced by antigen, but did not correlate with dysfunction for virus-specific TIL, in sharp contrast to TAA-specific TIL in the same tumors. These data suggest that CD8+ TIL can reflect an individual's immune status, rather than exclusively representing TAA-specific T cells, and that PD-1 expression on CD8+ TIL is not always associated with repeated antigen encounter or dysfunction. Thus, functional virus-specific CD8+ TIL could skew the results of prognostic or diagnostic TIL assays. PMID:28202614

  5. 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.

  6. CD103+CD8+ T lymphocytes in non-small cell lung cancer are phenotypically and functionally primed to respond to PD-1 blockade.

    PubMed

    Wang, Peiliang; Huang, Bing; Gao, Yi; Yang, Jianjian; Liang, Zhihui; Zhang, Ni; Fu, Xiangning; Li, Lequn

    2018-03-01

    CD103 + CD8 + tumor infiltrating lymphocytes (TILs) have been linked to prolonged survival in various types of cancer including non-small cell lung cancer (NSCLC). However, the factors associated with the retention of CD103 + CD8 + TILs in lung cancer tissues remain largely unknown. Additionally, the contribution of CD103 + CD8 + TILs to effective PD-1 based immunotherapy has not been fully elucidated. In this study, we identified that the expression levels of E-cadherin and TGF-β were significantly correlated with the distribution and the density of CD103 + TILs in lung cancer tumor tissues. Unexpectedly, we observed that CD103 + CD8 + TILs that expressed higher levels of PD-1 co-express Ki-67. Moreover, CD103 + CD8 + TILs expressed an increased level of T-bet compared to their counterparts, indicating these cells may be better armed for immunotherapy. Lastly, PD-1 pathway blockade led to a significantly increased production of IFN-γ by CD103 + CD8 + TILs, suggesting CD103 + CD8 + TILs could serve as a predictive biomarker for PD-1 based immunotherapy. Copyright © 2018 Elsevier Inc. All rights reserved.

  7. Metastatic Lung Lesions as a Preferred Resection Site for Immunotherapy With Tumor Infiltrating Lymphocytes.

    PubMed

    Ben-Avi, Ronny; Itzhaki, Orit; Simansky, David; Zippel, Dov; Markel, Gal; Ben Nun, Alon; Schachter, Jacob; Besser, Michal J

    2016-06-01

    Adoptive cell therapy with tumor infiltrating lymphocytes (TIL) yields 50% response rates in metastatic melanoma and shows promising clinical results in other solid tumors. Autologous TIL cultures are isolated from resected tumor tissue, expanded ex vivo to large numbers and reinfused to the preconditioned patient. In this prospective study, we validate the origin of the tumor biopsy and its effect on T-cell function and clinical response. One hundred forty-four patients underwent surgery and 79 patients were treated with TIL adoptive cell therapy. Cultures from lung tissue were compared with other origins. The success rate of establishing TIL culture from lung tissue was significantly higher compared with nonlung tissue (94% vs. 72%, respectively, P≤0.003). Lung-derived TIL cultures gave rise to higher cell numbers (P≤0.011) and exhibited increased in vitro antitumor reactivity. The average fold expansion for lung-derived TIL during a rapid expansion procedure was 1349±557 compared with 1061±473 for nonlung TIL (P≤0.038). Patients treated with TIL cultures of lung origin (compared with nonlung) had prolonged median overall survival (29 vs. 9.5 mo; P≤0.065). Given the remarkable advancement in minimally invasive thoracic surgery and the results of this study, we suggest efforts should be taken to resect lung metastasis rather than other sites to generate TIL cultures for clinical use.

  8. Establishment of adoptive cell therapy with tumor infiltrating lymphocytes for non-small cell lung cancer patients.

    PubMed

    Ben-Avi, Ronny; Farhi, Ronit; Ben-Nun, Alon; Gorodner, Marina; Greenberg, Eyal; Markel, Gal; Schachter, Jacob; Itzhaki, Orit; Besser, Michal J

    2018-05-29

    Adoptive cell therapy (ACT) of tumor infiltration lymphocytes (TIL) yields promising clinical results in metastatic melanoma patients, who failed standard treatments. Due to the fact that metastatic lung cancer has proven to be susceptible to immunotherapy and possesses a high mutation burden, which makes it responsive to T cell attack, we explored the feasibility of TIL ACT in non-small cell lung cancer (NSCLC) patients. Multiple TIL cultures were isolated from tumor specimens of five NSCLC patients undergoing thoracic surgery. We were able to successfully establish TIL cultures by various methods from all patients within an average of 14 days. Fifteen lung TIL cultures were further expanded to treatment levels under good manufacturing practice conditions and functionally and phenotypically characterized. Lung TIL expanded equally well as 103 melanoma TIL obtained from melanoma patients previously treated at our center, and had a similar phenotype regarding PD1, CD28, and 4-1BB expressions, but contained a higher percent of CD4 T cells. Lung carcinoma cell lines were established from three patients of which two possessed TIL cultures with specific in vitro anti-tumor reactivity. Here, we report the successful pre-clinical production of TIL for immunotherapy in the lung cancer setting, which may provide a new treatment modality for patients with metastatic NSCLC. The initiation of a clinical trial is planned for the near future.

  9. Differences in TCR-Vβ Repertoire and Effector Phenotype between Tumor Infiltrating Lymphocytes and Peripheral Blood Lymphocytes Increase with Age

    PubMed Central

    Wang, Teng; Shen, Han; Wu, Fenglin; Zhang, Wenfeng; Tao, Changli; Yuan, Yin; Bo, Huaben; Wang, Hui; Huang, Shulin

    2014-01-01

    Tumor infiltrating lymphocytes (TIL) reflect the host's anti-tumor immune response, and can be a valuable predictor of prognosis. However, many properties of TIL are not fully understood. In the present study, TCR-Vβ repertoires of cancer patients were primarily analyzed by flow cytometry. Abnormally expressed TCR-Vβ subfamilies were generally found in both TIL and peripheral blood lymphocytes (PBL) of each patient. Of note, increased patient age was associated with increasingly biased TCR-Vβ repertoire in TIL but not in PBL, and the dispersion degree of the differences of TCR-Vβ subfamilies between TIL and PBL correlated positively with age (P = 0.007). Utilizing immunoscope analysis, we identified the age-related reduction in TCR-Vβ diversity, but polyclonal pattern was predominant in significantly expanded TCR-Vβ subfamilies. In addition, we found that older patients possessed a decreased ratio of CD8+CD62L+ non-effector cells in TIL compared to PBL, implying age-related increase of CD8+CD62L− effector cells in TIL. The colocalization analysis of CD8 and CD3, however, suggested the suppressed activity of these effector cells in tumor microenvironment. These findings further elucidate the properties of TIL, showing an increasing difference between TIL and PBL with age, which may provide insight for the development of effective immunotherapies for cancer patients of different ages. PMID:25019226

  10. 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

  11. Syngeneic syrian hamster tumors feature tumor-infiltrating lymphocytes allowing adoptive cell therapy enhanced by oncolytic adenovirus in a replication permissive setting.

    PubMed

    Siurala, Mikko; Vähä-Koskela, Markus; Havunen, Riikka; Tähtinen, Siri; Bramante, Simona; Parviainen, Suvi; Mathis, J Michael; Kanerva, Anna; Hemminki, Akseli

    2016-05-01

    Adoptive transfer of tumor-infiltrating lymphocytes (TIL) has shown promising yet sometimes suboptimal results in clinical trials for advanced cancer, underscoring the need for approaches improving efficacy and safety. Six implantable syngeneic tumor cell lines of the Syrian hamster were used to initiate TIL cultures. TIL generated from tumor fragments cultured in human interleukin-2 (IL-2) for 10 d were adoptively transferred into tumor-bearing hamsters with concomitant intratumoral injections of oncolytic adenovirus (Ad5-D24) for the assessment of antitumor efficacy. Pancreatic cancer (HapT1) and melanoma (RPMI 1846) TIL exhibited potent and tumor-specific cytotoxicity in effector-to-target (E/T) assays. MHC Class I blocking abrogated the cell killing of RPMI 1846 TIL, indicating cytotoxic CD8(+) T-cell activity. When TIL were combined with Ad5-D24 in vitro, HapT1 tumor cell killing was significantly enhanced over single agents. In vivo, the intratumoral administration of HapT1 TIL and Ad5-D24 resulted in improved tumor growth control compared with either treatment alone. Additionally, splenocytes derived from animals treated with the combination of Ad5-D24 and TIL killed autologous tumor cells more efficiently than monotherapy-derived splenocytes, suggesting that systemic antitumor immunity was induced. For the first time, TIL of the Syrian hamster have been cultured, characterized and used therapeutically together with oncolytic adenovirus for enhancing the efficacy of TIL therapy. Our results support human translation of oncolytic adenovirus as an enabling technology for adoptive T-cell therapy of solid tumors.

  12. Syngeneic syrian hamster tumors feature tumor-infiltrating lymphocytes allowing adoptive cell therapy enhanced by oncolytic adenovirus in a replication permissive setting

    PubMed Central

    Siurala, Mikko; Vähä-Koskela, Markus; Havunen, Riikka; Tähtinen, Siri; Bramante, Simona; Parviainen, Suvi; Mathis, J. Michael; Kanerva, Anna; Hemminki, Akseli

    2016-01-01

    ABSTRACT Adoptive transfer of tumor-infiltrating lymphocytes (TIL) has shown promising yet sometimes suboptimal results in clinical trials for advanced cancer, underscoring the need for approaches improving efficacy and safety. Six implantable syngeneic tumor cell lines of the Syrian hamster were used to initiate TIL cultures. TIL generated from tumor fragments cultured in human interleukin-2 (IL-2) for 10 d were adoptively transferred into tumor-bearing hamsters with concomitant intratumoral injections of oncolytic adenovirus (Ad5-D24) for the assessment of antitumor efficacy. Pancreatic cancer (HapT1) and melanoma (RPMI 1846) TIL exhibited potent and tumor-specific cytotoxicity in effector-to-target (E/T) assays. MHC Class I blocking abrogated the cell killing of RPMI 1846 TIL, indicating cytotoxic CD8+ T-cell activity. When TIL were combined with Ad5-D24 in vitro, HapT1 tumor cell killing was significantly enhanced over single agents. In vivo, the intratumoral administration of HapT1 TIL and Ad5-D24 resulted in improved tumor growth control compared with either treatment alone. Additionally, splenocytes derived from animals treated with the combination of Ad5-D24 and TIL killed autologous tumor cells more efficiently than monotherapy-derived splenocytes, suggesting that systemic antitumor immunity was induced. For the first time, TIL of the Syrian hamster have been cultured, characterized and used therapeutically together with oncolytic adenovirus for enhancing the efficacy of TIL therapy. Our results support human translation of oncolytic adenovirus as an enabling technology for adoptive T-cell therapy of solid tumors. PMID:27467954

  13. Impact of clinical and pathologic features on tumor-infiltrating lymphocyte expansion from surgically excised melanoma metastases for adoptive T-cell therapy

    PubMed Central

    Joseph, Richard W.; Peddareddigari, Vijay R.; Liu, Ping; Miller, Priscilla W.; Overwijk, Willem W.; Bekele, Nebiyou B.; Ross, Merrick I.; Lee, Jeffrey E.; Gershenwald, Jeffrey E.; Lucci, Anthony; Prieto, Victor G.; McMannis, John D.; Papadopoulos, Nicholas; Kim, Kevin; Homsi, Jade; Bedikian, Agop; Hwu, Wen-Jen; Hwu, Patrick; Radvanyi, Laszlo G.

    2011-01-01

    Purpose Clinical trials on adoptive T-cell therapy (ACT) using expanded tumor-infiltrating lymphocytes (TIL) have shown response rates of over 50% in refractory melanoma. However, little is known how clinical and pathologic features impact TIL outgrowth isolated from metastatic melanoma tumors. Experimental Design We analyzed the impact of clinical and pathologic features on initial TIL outgrowth in 226 consecutive patients undergoing tumor resection. Successful initial TIL outgrowth was defined as ≥40 million viable lymphocytes harvested from all tumor fragments in a 5-week culture. To normalize for the different size of resected tumors and thus available tumor fragments, we divided the number of expanded TIL by the starting number of tumor fragments (TIL/fragment). Results Overall, initial TIL outgrowth was successful in 62% of patients, with patients ≤30 years of age (94%; p=0.01) and female patients (71% vs. 57% for males; p=0.04) having the highest rate of success. Systemic therapy 30 days prior to tumor harvest negatively impacted initial TIL outgrowth compared to patients who never received systemic therapy (47% versus 71%, p=0.02). Biochemotherapy within 0–60 days of tumor harvest negatively impacted the initial TIL outgrowth with a success rate of only 16% (p<0.0001). Conclusion Parameters such as age, sex, and the type and timing of prior systemic therapy significantly affect the success rate of the initial TIL outgrowth from tumor fragments for ACT; these parameters may be helpful in selecting patients for melanoma ACT. PMID:21632855

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

    Robbins, P.F.; El-Gamil, M.; Li, Y.F.

    The role of tumor-specific T cells in mediating the regression of metastatic melanoma has been suggested by the clinical response of patients to treatment with tumor-infiltrating lymphocytes (TIL). A number of Ags recognized by class I-restricted melanoma-specific T cells have recently been isolated, raising the hope that this will lead to the development of improved therapies. In this study, we report the cloning of a tumor Ag recognized by T cells from melanoma patient 888. Previously, we reported that TIL 888, grown from the tumor of this patient, recognized tyrosinase in an HLA-A24 -restricted fashion. This line, when infused intomore » the autologous patient, resulted in complete regression of multiple metastases. Three years later, a second TIL line, TIL 1290, was isolated from a recurrent pelvic tumor. Infusion of a mixture of TIL 888 and TIL 1290 cell lines into the patient resulted in complete regression of a residual abdominal mass and the patient remains disease-free 2 yr later. The TIL 1290 cell line, which recognized melanoma in an HLAA-A24-restricted manner, failed to recognize tyrosinase. TIL 1290 was then used to screen an 888 melanoma cDNA library, and an Ag was isolated that did not correspond to any found in sequence databases. This gene, termed p15, was found to be expressed in a variety of normal tissues, and a peptide epitope recognized by TIL 1290 was found to represent the product of an nonmutated gene. Screening of additional cDNA pools resulted in the isolation of a second clone which stimulated TIL 1290. This clone also appeared to represent a transcript of the p15 gene, indicating that this gene may encode the predominant Ag recognized by TIL 1290. 27 refs., 4 figs., 5 tabs.« less

  15. Density of tumor-infiltrating lymphocytes correlates with extent of brain edema and overall survival time in patients with brain metastases

    PubMed Central

    Berghoff, Anna S; Fuchs, Elisabeth; Ricken, Gerda; Mlecnik, Bernhard; Bindea, Gabriela; Spanberger, Thomas; Hackl, Monika; Widhalm, Georg; Dieckmann, Karin; Prayer, Daniela; Bilocq, Amelie; Heinzl, Harald; Zielinski, Christoph; Bartsch, Rupert; Birner, Peter; Galon, Jerome; Preusser, Matthias

    2016-01-01

    The immune microenvironment of the brain differs from that of other organs and the role of tumor-infiltrating lymphocytes (TILs) in brain metastases (BM), one of the most common and devastating complication of cancer, is unclear. We investigated TIL subsets and their prognostic impact in 116 BM specimens using immunohistochemistry for CD3, CD8, CD45RO, FOXP3, PD1 and PD-L1. The Immunoscore was calculated as published previously. Overall, we found TIL infiltration in 115/116 (99.1%) BM specimens. PD-L1 expression was evident in 19/67 (28.4%) BM specimens and showed no correlation with TIL density (p > 0.05). TIL density was not associated with corticosteroid administration (p > 0.05). A significant difference in infiltration density according to TIL subtype was present (p < 0.001; Chi Square); high infiltration was most frequently observed for CD3+ TILs (95/116; 81.9%) and least frequently for PD1+ TILs (18/116; 15.5%; p < 0.001). Highest TIL density was observed in melanoma, followed by renal cell cancer and lung cancer BM (p < 0.001). The density of CD8+ TILs correlated positively with the extent of peritumoral edema seen on pre-operative magnetic resonance imaging (p = 0.031). The density of CD3+ (15 vs. 6 mo; p = 0.015), CD8+ (15 vs. 11 mo; p = 0.030) and CD45RO+ TILs (18 vs. 8 mo; p = 0.006) showed a positive correlation with favorable median OS times. Immunoscore showed significant correlation with survival prognosis (27 vs. 10 mo; p < 0.001). The prognostic impact of Immunoscore was independent from established prognostic parameters at multivariable analysis (HR 0.612, p < 0.001). In conclusion, our data indicate that dense TILs infiltrates are common in BM and correlate with the amount of peritumoral brain edema and survival prognosis, thus identifying the immune system as potential biomarker for cancer patients with CNS affection. Further studies are needed to substantiate our findings. PMID:26942067

  16. Wave modulation of the extratropical tropopause inversion layer

    NASA Astrophysics Data System (ADS)

    Pilch Kedzierski, Robin; Matthes, Katja; Bumke, Karl

    2017-03-01

    This study aims to quantify how much of the observed strength and variability in the zonal-mean extratropical tropopause inversion layer (TIL) comes from the modulation of the temperature field and its gradients around the tropopause by planetary- and synoptic-scale waves. By analyzing high-resolution observations, it also puts other TIL enhancing mechanisms into context.Using gridded Global Positioning System radio occultation (GPS-RO) temperature profiles from the COSMIC mission (2007-2013), we are able to extract the extratropical wave signal by a simplified wavenumber-frequency domain filtering method and quantify the resulting TIL enhancement. By subtracting the extratropical wave signal, we show how much of the TIL is associated with other processes, at mid- and high latitudes, for both hemispheres and all seasons.The transient and reversible modulation by planetary- and synoptic-scale waves is almost entirely responsible for the TIL in midlatitudes. This means that wave-mean flow interactions, inertia-gravity waves and the residual circulation are of minor importance for the strength and variability in the midlatitude TIL.At polar regions, the extratropical wave modulation is dominant for the TIL strength as well, but there is also a clear fingerprint from sudden stratospheric warmings (SSWs) and final warmings in both hemispheres. Therefore, polar vortex breakups are partially responsible for the observed polar TIL strength in winter (if SSWs occur) and spring. Also, part of the polar summer TIL strength cannot be explained by extratropical wave modulation.We suggest that our wave modulation mechanism integrates several TIL enhancing mechanisms proposed in previous literature while robustly disclosing the overall outcome of the different processes involved. By analyzing observations only, our study identifies which mechanisms dominate the extratropical TIL strength and their relative contribution. It remains to be determined, however, which roles the

  17. Blocking Tim-3 or/and PD-1 reverses dysfunction of tumor-infiltrating lymphocytes in HBV-related hepatocellular carcinoma.

    PubMed

    Liu, Furong; Zeng, Gucheng; Zhou, Shaotang; He, Xiaoshun; Sun, Nianfeng; Zhu, Xiaofeng; Hu, Anbin

    2018-05-01

    The immunosuppression of tumor-infiltrating lymphocytes (TILs) is associated with rapid progression of hepatitis B virus-related hepatocellular carcinoma (HBV-HCC). T cell Ig- and mucin-domain-containing molecule-3 (Tim-3) and programmed cell death 1 (PD-1) are important inhibitory molecules expressed on the surface of T cells, but their roles in the function of TILs in HBV-HCC are poorly understood. We aimed to study the roles of these two markers in HBV-HCC. Ninety patients with pathologically confirmed HBV-associated HCC were enrolled in our study. Blood samples, paired fresh tumor tissues and adjacent tissues were collected, and isolating peripheral blood mononuclear cells, TILs and adjacent-infiltrating lymphocytes were isolated from these samples. The patients were followed-up to allow survival analysis. Tim-3 or/and PD-1 was up-regulated expressed on CD4 + and CD8 + TILs in HBV-HCC patients and a higher proportion of TILs expressed PD-1 alone. Tim-3 + and PD-1 + TILs greatly decreased secretion of IFN-? and TNF-a. Expression of Tim-3 and PD-1 on TILs negatively correlated with disease-free survival of HCC patients. Direct blockade of Tim-3 and PD-1 in vitro significantly enhanced TILs proliferation and secretion of IFN-? and TNF-a. Expression of Tim-3 and/or PD-1 on TILs impairs their function and correlates negatively with disease-free survival in HBV-HCC. Direct blockade of Tim-3 and PD-1 restores anti-tumor effects of TILs, which suggests a potential target for novel immunotherapy in HBV-HCC. Copyright © 2018 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

  18. Genome-wide search and comparative genomic analysis of the trypsin inhibitor-like cysteine-rich domain-containing peptides.

    PubMed

    Zeng, Xian-Chun; Liu, Yichen; Shi, Wanxia; Zhang, Lei; Luo, Xuesong; Nie, Yao; Yang, Ye

    2014-03-01

    It was shown that peptides containing trypsin inhibitor-like cysteine-rich (TIL) domain are able to inhibit proteinase activities, and thus play important roles in various biological processes, such as immune response and anticoagulation. However, only a limited number of the TIL peptides have been identified and characterized so far; and little has been known about the evolutionary relationships of the genes encoding the TIL peptides. BmKAPi is a TIL domain-containing peptide that was identified from Mesobuthus martensii Karsch. Here, we conducted genome-wide searches for new peptides that are homologous to BmKAPi or possess a cysteine pattern similar to that of BmKAPi. As a result, we identified a total of 80 different TIL peptides from 34 species of arthropods. We found that these peptides can be classified into seven evolutionarily distinct groups. Furthermore, we cloned the genomic sequence of BmKAPi; the genomic sequences of the majority of other TIL peptides were also identified from the GenBank database using bioinformatical approaches. Through phylogenetic and comparative genomic analysis, we found 26 cases of intron gain events occurred in the genes of the TIL peptides; however, no instances of intron loss were observed. Moreover, we found that alternative splicing contributes to the diversification of the TIL peptides. It is interesting to see that four genes of the TIL domain-containing peptides overlap in a DNA region located on the chromosome LG B15 of Bombus terretris. These data suggest that the evolution of the TIL peptide genes are dynamic, which was dominated by intron gain. Copyright © 2013 Elsevier Inc. All rights reserved.

  19. Molecular profile of tumor-specific CD8+ T cell hypofunction in a transplantable murine cancer model1

    PubMed Central

    Waugh, Katherine A.; Leach, Sonia M.; Moore, Brandon L.; Bruno, Tullia C.; Buhrman, Jonathan D.; Slansky, Jill E.

    2016-01-01

    Mechanisms of self-tolerance often result in CD8+ tumor-infiltrating lymphocytes (TIL) with a hypofunctional phenotype incapable of tumor clearance. Using a transplantable colon carcinoma model, we found that CD8+ T cells became tolerized in less than 24 hours in an established tumor environment. To define the collective impact of pathways suppressing TIL function, we compared genome-wide mRNA expression of tumor-specific CD8+ T cells from the tumor and periphery. Notably, gene expression induced during TIL hypofunction more closely resembled self-tolerance than viral-exhaustion. Differential gene expression was refined to identify a core set of genes that defined hypofunctional TIL; these data comprise the first “molecular profile” of tumor-specific TIL that are naturally responding and represent a polyclonal repertoire. The molecular profile of TIL was further dissected to determine the extent of overlap and distinction between pathways that collectively restrict T cell functions. As suggested by the molecular profile of TIL, protein expression of inhibitory receptor LAG-3 was differentially regulated throughout prolonged late-G1/early-S phase of the cell cycle. Our data may accelerate efficient identification of combination therapies to boost anti-tumor function of TIL specifically against tumor cells. PMID:27371726

  20. 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.

  1. Dose-Response Relationship of CD8+ Tumor Infiltrating Lymphocytes and Survival Time in High-Grade Serous Ovarian Cancer

    PubMed Central

    Goode, Ellen L; Block, Matthew S; Kalli, Kimberly R; Vierkant, Robert A; Chen, Wenqian; Fogarty, Zachary C; Gentry-Maharaj, Aleksandra; Tołoczko, Aleksandra; Hein, Alexander; Bouligny, Aliecia L; Jensen, Allan; Osorio, Ana; Hartkopf, Andreas D; Ryan, Andy; Chudecka-Głaz, Anita; Magliocco, Anthony M; Hartmann, Arndt; Jung, Audrey Y; Gao, Bo; Hernandez, Brenda Y; Fridley, Brooke L; McCauley, Bryan M; Kennedy, Catherine J; Wang, Chen; Karpinskyj, Chloe; de Sousa, Christiani B; Tiezzi, Daniel G; Wachter, David L; Herpel, Esther; Taran, Florin Andrei; Modugno, Francesmary; Nelson, Gregg; Lubiński, Jan; Menkiszak, Janusz; Alsop, Jennifer; Lester, Jenny; García-Donas, Jesús; Nation, Jill; Hung, Jillian; Palacios, José; Rothstein, Joseph H; Kelley, Joseph L; de Andrade, Jurandyr M; Robles-Díaz, Luis; Intermaggio, Maria P; Widschwendter, Martin; Beckmann, Matthias W; Ruebner, Matthias; Jimenez-Linan, Mercedes; Singh, Naveena; Oszurek, Oleg; Harnett, Paul R; Rambau, Peter F; Sinn, Peter; Wagner, Philipp; Ghatage, Prafull; Sharma, Raghwa; Edwards, Robert P; Ness, Roberta B; Orsulic, Sandra; Brucker, Sara Y; Johnatty, Sharon E; Longacre, Teri A; Eilber, Ursula; McGuire, Valerie; Sieh, Weiva; Natanzon, Yanina; Li, Zheng; Whittemore, Alice S; deFazio, Anna; Staebler, Annette; Karlan, Beth Y; Gilks, Blake; Bowtell, David D; Høgdall, Estrid; Candido dos Reis, Francisco J; Steed, Helen; Campbell, Ian G; Gronwald, Jacek; Benítez, Javier; Koziak, Jennifer M; Chang-Claude, Jenny; Moysich, Kirsten B; Kelemen, Linda E; Cook, Linda S; Goodman, Marc T; García, María José; Fasching, Peter A; Kommoss, Stefan; Deen, Suha; Kjaer, Susanne K; Menon, Usha; Brenton, James D; Pharoah, Paul DP; Chenevix-Trench, Georgia; Huntsman, David G; Winham, Stacey J; Köbel, Martin; Ramus, Susan J

    2017-01-01

    Importance Cytotoxic CD8+ T lymphocytes (TILs) participate in immune control of ovarian cancer; however, little is known about prognostic patterns of CD8+ TILs by histotype and in relation to other clinical factors. Objective To define the prognostic role of CD8+ TILs in epithelial ovarian cancer. Design Prospective survival cohort. Setting Multi-center observational. Participants Over 5,500 patients, including 3,196 high-grade serous ovarian carcinomas (HGSOCs), followed prospectively for over 24,650 person-years. Exposure(s) Following immunohistochemistry, CD8+ TILs were identified within the epithelial components of tumor islets. Patients were grouped based on the estimated number of CD8+ TILs per high-powered field: negative (none), low (1–2), moderate (3–19), and high (≥20). CD8+ TILs in a subset of patients were also assessed in a quantitative, uncategorized manner, and the functional form of associations with survival was assessed using penalized B-splines. Main Outcome Measure(s) Overall survival time. Results Among the five major invasive histotypes, HGSOCs showed the most infiltration. CD8+ TILs in HGSOCs were significantly associated with longer overall survival; median survival was 2.8 years for patients with no CD8+ TILs and 3.0 years, 3.8 years, and 5.1 years for patients with low, moderate, or high levels of CD8+ TILs, respectively (p-trend=4.2 × 10−16). A survival benefit was also observed among women with endometrioid and mucinous carcinomas, but not the other histotypes. Among HGSOCs, CD8+ TILs were favorable regardless of extent of residual disease following cytoreduction, known standard treatment, and germline BRCA1 pathogenic mutation, but were not prognostic for BRCA2 mutation carriers. Evaluation of uncategorized CD8+ TIL counts showed a near linear functional form. Conclusions and Relevance This study demonstrates the histotype-specific nature of immune infiltration and provides definitive evidence for a dose-response relationship

  2. Characteristic cytokine generation patterns in cancer cells and infiltrating lymphocytes in oral squamous cell carcinomas and the influence of chemoradiation combined with immunotherapy on these patterns.

    PubMed

    Yamamoto, Tetsuya; Kimura, Tsuyoshi; Ueta, Eisaku; Tatemoto, Yukihiro; Osaki, Tokio

    2003-01-01

    Cytokines produced by tumor cells and tumor-infiltrating lymphocytes (TIL) appear to regulate tumor cell growth and the cytotoxic activity of TIL. The objectives of the present study were to investigate cytokine generation patterns in tumor cells and TIL and to examine the influence of cancer therapy on this cytokine production and the cytotoxic activity of TIL. We determined the levels of cytokines produced by tumor cells and TIL in vitro and measured the cytotoxic activity of TIL against Daudi cells in patients with oral squamous cell carcinoma (OSC) before and 1 week after the start of concomitant chemo-radio-immunotherapy. Before the therapy, OSC cells generated higher levels of granulocyte-macrophage colony-stimulating factor, tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta (TGF-beta) than did oral keratinocytes isolated from the noninflamed gingivae of healthy individuals, but both kinds of cells generated similar levels of interleukin (IL)-1beta and IL-6. Compared with peripheral blood mononuclear cells (PBMC) of the patients, TIL produced higher levels of IL-1beta, IL-6, IL-10, TNF-alpha and TGF-beta, whereas their production of IL-12 and interferon-gamma (IFN-gamma) was only slightly higher than that in PBMC. After 1 week of therapy, the cytokine production by OSC cells had largely decreased, while the production of TNF-alpha, IFN-gamma, TGF-beta and IL-12 by TIL had increased greatly, although other cytokine levels were almost constant during the investigations. The cytotoxic activity of TIL was higher than that of PBMC before the therapy, and this activity was strongly increased by 1 week of therapy. These results suggest that the cytokine productivities of TIL and tumor cells differ from those of PBMC and normal keratinocytes, respectively, and that chemo-radio-immunotherapy modulates in situ cytokine generation, which is advantageous for inhibition of tumor cell growth and activation of TIL. Copyright 2003 S. Karger AG

  3. 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

  4. Functional Proteomics to Identify Moderators of CD8+ T Cell Function in Melanoma

    DTIC Science & Technology

    2015-05-01

    identified 17 phage that selectively bind TIL rather than effector cells. However, none of these phage influenced CD8+ TIL expansion or function in vitro...Using a novel NextGeneration sequencing approach, we have further defined another 1,000,000 phage that selectively bind TIL , of which 100,000 are unique...Using the original approach outlined in the application, we identified a total of 17 unique phage that selectively bind CD8+ TIL but not effector or

  5. Reproducibility and predictive value of scoring stromal tumour infiltrating lymphocytes in triple-negative breast cancer: a multi-institutional study.

    PubMed

    O'Loughlin, Mark; Andreu, Xavier; Bianchi, Simonetta; Chemielik, Ewa; Cordoba, Alicia; Cserni, Gábor; Figueiredo, Paulo; Floris, Giuseppe; Foschini, Maria P; Heikkilä, Päivi; Kulka, Janina; Liepniece-Karele, Inta; Regitnig, Peter; Reiner, Angelika; Ryska, Ales; Sapino, Anna; Shalaby, Aliaa; Stovgaard, Elisabeth Specht; Quinn, Cecily; Walsh, Elaine M; Zolota, Vicky; Glynn, Sharon A; Callagy, Grace

    2018-05-17

    Several studies have demonstrated a prognostic role for stromal tumour infiltrating lymphocytes (sTILs) in triple-negative breast cancer (TNBC). The reproducibility of scoring sTILs is variable with potentially excellent concordance being achievable using a software tool. We examined agreement between breast pathologists across Europe scoring sTILs on H&E-stained sections without software, an approach that is easily applied in clinical practice. The association between sTILs and response to anthracycline-taxane NACT was also examined. Pathologists from the European Working Group for Breast Screening Pathology scored sTILs in 84 slides from 75 TNBCs using the immune-oncology biomarker working group guidance in two circulations. There were 16 participants in the first and 19 in the second circulation. Moderate agreement was achieved for absolute sTILs scores (intraclass correlation coefficient (ICC) = 0.683, 95% CI 0.601-0.767, p-value < 0.001). Agreement was less when a 25% threshold was used (ICC 0.509, 95% CI 0.416-0.614, p-value < 0.001) and for lymphocyte predominant breast cancer (LPBC) (ICC 0.504, 95% CI 0.412-0.610, p-value < 0.001). Intra-observer agreement was strong for absolute sTIL values (Spearman ρ = 0.727); fair for sTILs ≥ 25% (κ = 0.53) and for LPBC (κ = 0.49), but poor for sTILs as 10% increments (κ = 0.24). Increasing sTILs was significantly associated with an increased likelihood of a pathological complete response (pCR) on multivariable analysis. Increasing sTILs in TNBCs improves the likelihood of a pCR. However, inter-observer agreement is such that H&E-based assessment is not sufficiently reproducible for clinical application. Other methodologies should be explored, but may be at the cost of ease of application.

  6. Bimodal ex vivo expansion of T cells from patients with head and neck squamous cell carcinoma: a prerequisite for adoptive cell transfer.

    PubMed

    Junker, Niels; Andersen, Mads Hald; Wenandy, Lynn; Dombernowsky, Sarah Louise; Kiss, Katalin; Sørensen, Christian Hjort; Therkildsen, Marianne Hamilton; Von Buchwald, Christian; Andersen, Elo; Straten, Per Thor; Svane, Inge Marie

    2011-08-01

    Adoptive transfer of tumor-infiltrating lymphocytes (TIL) has proven effective in metastatic melanoma and should therefore be explored in other types of cancer. The aim of this study was to examine the feasibility of potentially expanding clinically relevant quantities of tumor-specific T-cell cultures from TIL from patients with head and neck squamous cell carcinoma (HNSCC) using a more rapid expansion procedure compared with previous HNSCC studies. In a two-step expansion process, initially TIL bulk cultures were established from primary and recurrent HNSCC tumors in high-dose interleukin (IL)-2. Secondly, selected bulk cultures were rapidly expanded using anti-CD3 antibody, feeder cells and high-dose IL-2. T-cell subsets were phenotypically characterized using flow cytometry. T-cell receptor (TCR) clonotype mapping was applied to examine clonotype dynamics during culture. Interferon (INF)-γ detection by Elispot and Cr(51) release assay determined the specificity and functional capacity of selected TIL pre- and post-rapid expansion. TIL bulk cultures were expanded in 80% of the patients included, showing tumor specificity in 60% of the patients. Rapid expansions generated up to 3500-fold expansion of selected TIL cultures within 17 days. The cultures mainly consisted of T-effector memory cells, with varying distributions of CD8(+) and CD4(+) subtypes both among cultures and patients. TCR clonotype mapping demonstrated oligoclonal expanded cultures, ranging from approximately 10 to 30 T-cell clonotypes. TIL from large-scale rapid expansions maintained functional capacity, and contained tumor-specific T cells. The procedure is feasible for expansion of TIL from HNSCC, ensuring clinically relevant expansion folds within 7 weeks. The cell culture kinetics and phenotypes of the TIL resemble previously published results on TIL from melanoma, setting the stage for clinical testing of this promising treatment strategy for patients with HNSCC.

  7. Novel effector phenotype of Tim-3+ regulatory T cells leads to enhanced suppressive function in head and neck cancer patients.

    PubMed

    Liu, Zhuqing; McMichael, Elizabeth L; Shayan, Gulidanna; Li, Jing; Chen, Kevin; Srivastava, Raghvendra M; Kane, Lawrence P; Lu, Binfeng; Ferris, Robert L

    2018-04-30

    Regulatory T (Treg) cells are important suppressive cells among tumor infiltrating lymphocytes (TIL). Treg express the well-known immune checkpoint receptor PD-1, which is reported to mark "exhausted" Treg with lower suppressive function. T cell immunoglobulin mucin (Tim)-3, a negative regulator of Th1 immunity, is expressed by a sizeable fraction of TIL Tregs, but the functional status of Tim-3+ Tregs remains unclear. CD4+CTLA-4+CD25high Treg were sorted from freshly excised head and neck squamous cell carcinoma (HNSCC) TIL based on Tim-3 expression. Functional and phenotypic features of these Tim-3+ and Tim-3- TIL Tregs were tested by in vitro suppression assays and multi-color flow cytometry. Gene expression profiling and NanoString analysis of Tim-3+ TIL Treg were performed. A murine HNSCC tumor model was used to test the effect of anti-PD-1 immunotherapy on Tim-3+ Treg.  Results: Despite high PD-1 expression, Tim-3+ TIL Treg displayed a greater capacity to inhibit naïve T cell proliferation than Tim-3- Treg. Tim-3+ Treg from human HNSCC TIL also displayed an effector-like phenotype, with more robust expression of CTLA-4, PD-1, CD39 and IFN-γ receptor. Exogenous IFN-γ treatment could partially reverse the suppressive function of Tim-3+ TIL Treg. Anti-PD-1 immunotherapy downregulated Tim-3 expression on Tregs isolated from murine HNSCC tumors, and this treatment reversed the suppressive function of HNSCC TIL Tregs. Tim-3+ Treg are functionally and phenotypically distinct in HNSCC TIL, and are highly effective at inhibiting T cell proliferation despite high PD-1 expression.  IFN-γ induced by anti-PD-1 immunotherapy may be beneficial by reversing Tim-3+ Treg suppression. Copyright ©2018, American Association for Cancer Research.

  8. Mapping of electrophysiological response to transcranial infrared laser stimulation on the human brain in vivo measured by electroencephalography (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Wang, Xinlong; Reddy, Divya Dhandapani; Gonzalez-Lima, F.; Liu, Hanli

    2017-02-01

    Transcranial infrared laser stimulation (TILS) is a non-destructive and non-thermal photobiomodulation therapy or process on the human brain; TILS uses infrared light from lasers or LEDs and has gained increased recognition for its beneficial effects on a variety of neurological and psychological conditions. While the mechanism of TILS has been assumed to stem from cytochrome-c-oxidase (CCO), which is the last enzyme in the electron transportation chain and is the primary photoacceptor, no literature is found to report electrophysiological response to TILS. In this study, a 64-channel electroencephalography (EEG) system was employed to monitor electrophysiological activities from 15 healthy human participants before, during and after TILS. A placebo experimental protocol was also applied for rigorous comparison. After recording a 3-minute baseline, we applied a 1064-nm laser with a power of 3.5W on the right forehead of each human participant for 8 minutes, followed by a 5-minute recovery period. In 64-channel EEG data analysis, we utilized several methods (root mean square, principal component analysis followed by independent component analysis, permutation conditional mutual information, and time-frequency wavelet analysis) to reveal differences in electrophysiological response to TILS between the stimulated versus placebo group. The analyzed results were further investigated using general linear model and paired t-test to reveal statistically meaningful responses induced by TILS. Moreover, this study will provide spatial mapping of human electrophysiological and possibly neural network responses to TILS for first time, indicating the potential of EEG to be an effective method for monitoring neurological improvement induced by TILS.

  9. The interaction between the tropopause inversion layer and the inertial gravity wave activities revealed by radiosonde observations at a midlatitude station

    NASA Astrophysics Data System (ADS)

    Zhang, Yehui; Zhang, Shaodong; Huang, Chunming; Huang, Kaiming; Gong, Yun; Gan, Quan

    2015-08-01

    The interaction between the tropopause inversion layer (TIL) and the inertial gravity wave (IGW) activities is first presented by using a high vertical resolution radiosonde data set at a midlatitude station, Boise, Idaho (43.57°N, 116.22°W), for the period 1998-2008. The tropopause-based vertical coordinate is used for the TIL detection, and for meticulously studying the IGW variation around the TIL, the broad spectral method is used for the IGW extraction. Generally, the TIL at the midlatitude station is stronger and thicker in winter and spring, which is consistent with previous studies. Our study confirmed the intense interaction between the TIL and IGW. It is found that the TIL not only could inhibit the upward propagation of IGWs from below but also imply the possible excitation links between the TIL and IGW. The results also indicate that the enhanced wind shear layer just 1 km above the tropopause may result in instability and finally leads to the IGW breaking and intensive turbulence. Subsequently, the IGW-induced intensive turbulence leads to strong wave energy dissipation and a downward heat flux. This downward heat transportation could significantly cool the tropopause, while it has only negligible thermal effect on the atmosphere above the tropopause. Then, the IGW-induced cooling at the tropopause makes the tropopause colder and sharper and finally forms the TIL. These suggest besides previously proposed mechanisms that IGWs also contribute greatly to the formation of TIL, which is consistent with a recent related simulation study.

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

    PubMed Central

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

    2017-01-01

    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. PMID:28107186

  11. Adoptive Cell Therapy for Patients with Melanoma, Using Tumor-Infiltrating Lymphocytes Genetically Engineered to Secrete Interleukin-2

    PubMed Central

    HEEMSKERK, BIANCA; LIU, KE; DUDLEY, MARK. E.; JOHNSON, LAURA A.; KAISER, ANDREW; DOWNEY, STEPHANIE; ZHENG, ZHILI; SHELTON, THOMAS E.; MATSUDA, KANT; ROBBINS, PAUL F.; MORGAN, RICHARD A.; ROSENBERG, STEVEN A.

    2008-01-01

    Adoptive cell transfer of tumor-infiltrating lymphocytes (TILs) after lymphodepletion mediates regression in 50% of patients with metastatic melanoma. In vivo persistence and telomere length of the transferred cells correlate with antitumor response. In an attempt to prolong the in vivo survival of the transferred cells, TILs were genetically engineered to produce interleukin (IL)-2. In vitro, these transduced TILs secreted IL-2 while retaining tumor specificity and exhibited prolonged survival after IL-2 withdrawal. In a phase I/II clinical trial, seven evaluable patients received transduced TILs and one patient experienced a partial response associated with in vivo persistence of IL-2-transduced TILs in circulating lymphocytes. An additional five patients received transduced TILs in conjunction with IL-2 administration. Persistence of IL-2-transduced TILs was observed in three patients, including one partial responder. The transgene DNA as well as vector-derived IL-2 mRNA could be detected for 4 months in responding patients. The low response rate in this trial was possibly due to a reduction in telomere length in cells as a result of prolonged in vitro culture. In this study, insertion of the IL-2 gene into antitumor TILs increased their ability to survive after IL-2 withdrawal in vitro but did not increase their in vivo persistence or clinical effectiveness. PMID:18444786

  12. 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.

  13. Autocrine Complement Inhibits IL10-Dependent T-Cell Mediated Antitumor Immunity to Promote Tumor Progression

    PubMed Central

    Wang, Yu; Sun, Sheng-Nan; Liu, Qing; Yu, Yang-Yang; Guo, Jian; Wang, Kun; Xing, Bao-Cai; Zheng, Qing-Feng; Campa, Michael J.; Patz, Edward F.; Li, Shi-You; He, You-Wen

    2016-01-01

    In contrast to its inhibitory effects on many cells, IL-10 activates CD8+ tumor infiltrating lymphocytes (TILs) and enhances their antitumor activity. However, CD8+ TILs do not routinely express IL-10 as autocrine complement C3 inhibits IL-10 production through complement receptors C3aR and C5aR. CD8+ TILs from C3-deficient mice, however, express IL-10 and exhibit enhanced effector function. C3-deficient mice are resistant to tumor development in a T cell- and IL-10-dependent manner; human TILs expanded with IL-2 plus IL-10 increase the killing of primary tumors in vitro compared to IL-2 treated TILs. Complement-mediated inhibition of antitumor immunity is independent of the PD-1/PD-L1 immune checkpoint pathway. Our findings suggest that complement receptors C3aR and C5aR expressed on CD8+ TILs represent a novel class of immune checkpoints that could be targeted for tumor immunotherapy. Moreover, incorporation of IL-10 in the expansion of TILs and in gene-engineered T cells for adoptive cell therapy enhances their antitumor efficacy. PMID:27297552

  14. U.S. EPA, Pesticide Product Label, PCNB SOIL & TURF LIQUID DRENCH, 06/02/1986

    EPA Pesticide Factsheets

    2011-04-14

    ... 1"., t. III ., •• Ieal , ... rI,u .... , II ruso"'1J fit' fir til. ,"', 1111. II til. ... III llllluilJ f.fIo 11l1li1110 1101 allllflClIllf lid/if 1lIIar, "' 'Iller .IIU." til rlllt fll 81 allCll .... '

  15. Tropopause sharpening by data assimilation

    NASA Astrophysics Data System (ADS)

    Pilch Kedzierski, R.; Neef, L.; Matthes, K.

    2016-08-01

    Data assimilation was recently suggested to smooth out the sharp gradients that characterize the tropopause inversion layer (TIL) in systems that did not assimilate TIL-resolving observations. We investigate whether this effect is present in the ERA-Interim reanalysis and the European Centre for Medium-Range Weather Forecasts (ECMWF) operational forecast system (which assimilate high-resolution observations) by analyzing the 4D-Var increments and how the TIL is represented in their data assimilation systems. For comparison, we also diagnose the TIL from high-resolution GPS radio occultation temperature profiles from the COSMIC satellite mission, degraded to the same vertical resolution as ERA-Interim and ECMWF operational analyses. Our results show that more recent reanalysis and forecast systems improve the representation of the TIL, updating the earlier hypothesis. However, the TIL in ERA-Interim and ECMWF operational analyses is still weaker and farther away from the tropopause than GPS radio occultation observations of the same vertical resolution.

  16. Preparation, characterization, and pharmacokinetics of tilmicosin- and florfenicol-loaded hydrogenated castor oil-solid lipid nanoparticles.

    PubMed

    Ling, Z; Yonghong, L; Changqing, S; Junfeng, L; Li, Z; Chunyu, J; Xianqiang, L

    2017-06-01

    To effectively control bovine mastitis, tilmicosin (TIL)- and florfenicol (FF)-loaded solid lipid nanoparticles (SLN) with hydrogenated castor oil (HCO) were prepared by a hot homogenization and ultrasonication method. In vitro antibacterial activity, properties, and pharmacokinetics of the TIL-FF-SLN were studied. The results demonstrated that TIL and FF had a synergistic or additive antibacterial activity against Streptococcus dysgalactiae, Streptococcus uberis, and Streptococcus agalactiae. The size, polydispersity index, and zeta potential of nanoparticles were 289.1 ± 13.7 nm, 0.31 ± 0.05, and -26.7 ± 1.3 mV, respectively. The encapsulation efficiencies for TIL and FF were 62.3 ± 5.9% and 85.1 ± 5.2%, and the loading capacities for TIL and FF were 8.2 ± 0.6% and 3.3 ± 0.2%, respectively. The TIL-FF-SLN showed no irritation in the injection site and sustained release in vitro. After medication, TIL and FF could maintain about 0.1 μg/mL for 122 and 6 h. Compared to the control solution, the SLN increased the area under the concentration-time curve (AUC 0-t ), elimination half-life (T ½ke ), and mean residence time (MRT) of TIL by 33.09-, 23.29-, and 37.53-fold, and 1.69-, 5.00-, and 3.83-fold for FF, respectively. These results of this exploratory study suggest that the HCO-SLN could be a useful system for the delivery of TIL and FF for bovine mastitis therapy. © 2016 John Wiley & Sons Ltd.

  17. Prognostic role of tumor-infiltrating lymphocytes in gastric cancer: a meta-analysis

    PubMed Central

    Shao, Yingjie; Xu, Bin; Chen, Lujun; Zhou, Qi; Hu, Wenwei; Zhang, Dachuan; Wu, Changping; Tao, Min; Zhu, Yibei; Jiang, Jingting

    2017-01-01

    Background In patients with gastric cancer, the prognostic value of tumor-infiltrating lymphocytes (TILs) is still controversial. A meta-analysis was performed to evaluate the prognostic value of TILs in gastric cancer. Materials and methods We identify studies from PubMed, Embase and the Cochrane Library to assess the prognostic effect of TILs in patients with gastric cancer. Fixed-effects models or random-effects models were used estimate the pooled hazard ratios (HRs) for overall survival (OS) and disease-free survival (DFS), which depend on the heterogeneity. Results A total of 31 observational studies including 4,185 patients were enrolled. For TILs subsets, the amount of CD8+, FOXP3+, CD3+, CD57+, CD20+, CD45RO+, Granzyme B+ and T-bet+ lymphocytes was significantly associated with improved survival (P < 0.05); moreover, the amount of CD3+ TILs in intra-tumoral compartment (IT) was the most significant prognostic marker (pooled HR = 0.52; 95% CI = 0.43–0.63; P < 0.001). However, CD4+ TILs was not statistically associated with patients’ survival. FOXP3+ TILs showed bidirectional prognostic roles which had positive effect in IT (pooled HR = 1.57; 95% CI = 1.04–2.37; P = 0.033) and negative effect in extra-tumoral compartment (ET) (pooled HR = 0.76; 95% CI = 0.60–0.96; P = 0.022). Conclusions This meta-analysis suggests that some TIL subsets could serve as prognostic biomarkers in gastric cancer. High-quality randomized controlled trials are needed to decide if these TILs could serve as targets for immunotherapy in gastric cancer. PMID:28915679

  18. 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.

  19. Phenotype and Function of T Cells Infiltrating Visceral Metastases from Gastrointestinal Cancers and Melanoma: Implications for Adoptive Cell Transfer Therapy

    PubMed Central

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

    2013-01-01

    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 × 109 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. PMID:23904171

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

    Fisher, B.; Packard, B.S.; Read, E.J.

    Lymphoid cells infiltrating into human tumors can be expanded in vitro in medium containing interleukin-2 (IL-2). Adoptive transfer of these tumor-infiltrating lymphocytes (TIL) mediates potent antitumor effects in murine tumor models. Clinical trials to evaluate the efficacy of these cells in patients with advanced cancer are underway. We have investigated whether infused TIL labeled with indium 111 (111In) oxine can traffic and localize to metastatic deposits of tumor. Six patients with metastatic malignant melanoma who had multiple sites of subcutaneous, nodal, and/or visceral disease were the subjects of the study. The patients received cyclophosphamide 36 hours before receiving the intravenousmore » (IV) infusion of TIL followed by IL-2 IV every eight hours. The distribution and localization of the TIL were evaluated using serial whole body gamma camera imaging, serial blood and urine samplings, and serial biopsies of tumor and normal tissue. 111In-labeled TIL localized to lung, liver, and spleen within two hours after the infusion of activity. Activity in the lung diminished within 24 hours. As early as 24 hours after injection of 111In-labeled TIL, localization of TIL to sites of metastatic deposits was demonstrated in all six patients using either imaging studies or biopsy specimens or both. 111In activity in tumor tissue biopsies ranged from three to 40 times greater than activity in normal tissue. A progressive increase in the radioactive counts at sites of tumor deposit was seen. This study shows that labeled TIL can localize preferentially to tumor, and provides information concerning the possible mechanism of the therapeutic effects of TIL.« less

  1. A numerical experiment on the formation of the tropopause inversion layer associated with an explosive cyclogenesis: possible role of gravity waves

    NASA Astrophysics Data System (ADS)

    Otsuka, Shigenori; Takeshita, Megumi; Yoden, Shigeo

    2014-12-01

    The tropopause inversion layer (TIL) is a persistent layer with high static stability. Although some mechanisms for the formation of the TIL have been proposed, the time evolution of the TIL under realistic conditions especially when factoring in the contribution of small-scale processes such as gravity waves is not well understood. To gain an understanding of this factor, we conducted a numerical experiment on an explosive cyclogenesis in mid-latitudes using a nonhydrostatic regional atmospheric model. Although the TIL in the model is consistent with previous observations in the sense that it is stronger in the negative vorticity areas, the relationship is clear only in the development and mature stages of a cyclone, suggesting that the evolution of the cyclone plays an important role in the formation of the TIL. To ascertain the effects of gravity waves on the TIL, vertical convergence at the tropopause is analyzed. Histograms of maximum buoyancy frequency squared within the TIL show that regions of vertical convergence have higher , in addition to regions with high ∂ 2 w/ ∂ z 2, implying that waves having downward phase propagation also play an important role in the dynamical formation of the TIL. This tendency is clearer in regions of negative relative vorticity at the tropopause. By taking account of the fact that the gravity wave activities associated with the cyclone and the jet streak are enhanced during the development and mature stages of the cyclone, vertical convergence due to gravity waves associated with synoptic weather systems can be seen to be a key process in the formation of the negative correlation between the strength of the TIL and the local relative vorticity at the tropopause.

  2. Dose-Response Association of CD8+ Tumor-Infiltrating Lymphocytes and Survival Time in High-Grade Serous Ovarian Cancer.

    PubMed

    Goode, Ellen L; Block, Matthew S; Kalli, Kimberly R; Vierkant, Robert A; Chen, Wenqian; Fogarty, Zachary C; Gentry-Maharaj, Aleksandra; Tołoczko, Aleksandra; Hein, Alexander; Bouligny, Aliecia L; Jensen, Allan; Osorio, Ana; Hartkopf, Andreas; Ryan, Andy; Chudecka-Głaz, Anita; Magliocco, Anthony M; Hartmann, Arndt; Jung, Audrey Y; Gao, Bo; Hernandez, Brenda Y; Fridley, Brooke L; McCauley, Bryan M; Kennedy, Catherine J; Wang, Chen; Karpinskyj, Chloe; de Sousa, Christiani B; Tiezzi, Daniel G; Wachter, David L; Herpel, Esther; Taran, Florin Andrei; Modugno, Francesmary; Nelson, Gregg; Lubiński, Jan; Menkiszak, Janusz; Alsop, Jennifer; Lester, Jenny; García-Donas, Jesús; Nation, Jill; Hung, Jillian; Palacios, José; Rothstein, Joseph H; Kelley, Joseph L; de Andrade, Jurandyr M; Robles-Díaz, Luis; Intermaggio, Maria P; Widschwendter, Martin; Beckmann, Matthias W; Ruebner, Matthias; Jimenez-Linan, Mercedes; Singh, Naveena; Oszurek, Oleg; Harnett, Paul R; Rambau, Peter F; Sinn, Peter; Wagner, Philipp; Ghatage, Prafull; Sharma, Raghwa; Edwards, Robert P; Ness, Roberta B; Orsulic, Sandra; Brucker, Sara Y; Johnatty, Sharon E; Longacre, Teri A; Ursula, Eilber; McGuire, Valerie; Sieh, Weiva; Natanzon, Yanina; Li, Zheng; Whittemore, Alice S; Anna, deFazio; Staebler, Annette; Karlan, Beth Y; Gilks, Blake; Bowtell, David D; Høgdall, Estrid; Candido dos Reis, Francisco J; Steed, Helen; Campbell, Ian G; Gronwald, Jacek; Benítez, Javier; Koziak, Jennifer M; Chang-Claude, Jenny; Moysich, Kirsten B; Kelemen, Linda E; Cook, Linda S; Goodman, Marc T; García, María José; Fasching, Peter A; Kommoss, Stefan; Deen, Suha; Kjaer, Susanne K; Menon, Usha; Brenton, James D; Pharoah, Paul DP; Chenevix-Trench, Georgia; Huntsman, David G; Winham, Stacey J; Köbel, Martin; Ramus, Susan J

    2017-12-01

    Cytotoxic CD8+ tumor-infiltrating lymphocytes (TILs) participate in immune control of epithelial ovarian cancer; however, little is known about prognostic patterns of CD8+ TILs by histotype and in relation to other clinical factors. To define the prognostic role of CD8+ TILs in epithelial ovarian cancer. This was a multicenter observational, prospective survival cohort study of the Ovarian Tumor Tissue Analysis Consortium. More than 5500 patients, including 3196 with high-grade serous ovarian carcinomas (HGSOCs), were followed prospectively for over 24 650 person-years. Following immunohistochemical analysis, CD8+ TILs were identified within the epithelial components of tumor islets. Patients were grouped based on the estimated number of CD8+ TILs per high-powered field: negative (none), low (1-2), moderate (3-19), and high (≥20). CD8+ TILs in a subset of patients were also assessed in a quantitative, uncategorized manner, and the functional form of associations with survival was assessed using penalized B-splines. Overall survival time. The final sample included 5577 women; mean age at diagnosis was 58.4 years (median, 58.2 years). Among the 5 major invasive histotypes, HGSOCs showed the most infiltration. CD8+ TILs in HGSOCs were significantly associated with longer overall survival; median survival was 2.8 years for patients with no CD8+ TILs and 3.0 years, 3.8 years, and 5.1 years for patients with low, moderate, or high levels of CD8+ TILs, respectively (P value for trend = 4.2 × 10−16). A survival benefit was also observed among women with endometrioid and mucinous carcinomas, but not for those with the other histotypes. Among HGSOCs, CD8+ TILs were favorable regardless of extent of residual disease following cytoreduction, known standard treatment, and germline BRCA1 pathogenic mutation, but were not prognostic for BRCA2 mutation carriers. Evaluation of uncategorized CD8+ TIL counts showed a near-log-linear functional form. This study

  3. Characterization of the CD4+ and CD8+ tumor infiltrating lymphocytes propagated with bispecific monoclonal antibodies.

    PubMed

    Wong, J T; Pinto, C E; Gifford, J D; Kurnick, J T; Kradin, R L

    1989-11-15

    To study the CD4+ and CD8+ tumor infiltrating lymphocytes (TIL) in the antitumor response, we propagated these subsets directly from tumor tissues with anti-CD3:anti-CD8 (CD3,8) and anti-CD3:anti-CD4 (CD3,4) bispecific mAb (BSMAB). CD3,8 BSMAB cause selective cytolysis of CD8+ lymphocytes by bridging the CD8 molecules of target lymphocytes to the CD3 molecular complex of cytolytic T lymphocytes with concurrent activation and proliferation of residual CD3+CD4+ T lymphocytes. Similarly, CD3,4 BSMAB cause selective lysis of CD4+ lymphocytes whereas concurrently activating the residual CD3+CD8+ T cells. Small tumor fragments from four malignant melanoma and three renal cell carcinoma patients were cultured in medium containing CD3,8 + IL-2, CD3,4 + IL-2, or IL-2 alone. CD3,8 led to selective propagation of the CD4+ TIL whereas CD3,4 led to selective propagation of the CD8+ TIL from each of the tumors. The phenotypes of the TIL subset cultures were generally stable when assayed over a 1 to 3 months period and after further expansion with anti-CD3 mAb or lectins. Specific 51Cr release of labeled target cells that were bridged to the CD3 molecular complexes of TIL suggested that both CD4+ and CD8+ TIL cultures have the capacity of mediating cytolysis via their Ti/CD3 TCR complexes. In addition, both CD4+ and CD8+ TIL cultures from most patients caused substantial (greater than 20%) lysis of the NK-sensitive K562 cell line. The majority of CD4+ but not CD8+ TIL cultures also produced substantial lysis of the NK-resistant Daudi cell line. Lysis of the autologous tumor by the TIL subsets was assessed in two patients with malignant melanoma. The CD8+ TIL from one tumor demonstrated cytotoxic activity against the autologous tumor but negligible lysis of allogeneic melanoma targets. In conclusion, immunocompetent CD4+ and CD8+ TIL subsets can be isolated and expanded directly from small tumor fragments of malignant melanoma and renal cell carcinoma using BSMAB. The resultant

  4. 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

    2017-12-01

    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.

  5. 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

  6. Is Progressive Education Obsolete: A Reconsideration.

    ERIC Educational Resources Information Center

    Beineke, John A.

    1993-01-01

    Van Til's 1962 article on whether or not progressive education is obsolete was a response to charges that the new education as espoused by Dewey was outmoded. This paper reexamines Van Til's article and suggests a prognostication similar to Van Til's could be ventured today that another period of progressivism is inevitable. (SM)

  7. Postsecondary Education Employment and Independent Living Outcomes of Persons with Autism and Intellectual Disability

    ERIC Educational Resources Information Center

    Ross, Jeffrey; Marcell, Jamia; Williams, Paula; Carlson, Dawn

    2013-01-01

    The aim of this study is to report employment and independent living outcomes of 125 graduates from the Taft College Transition to Independent Living (TIL) program. The TIL program has served students with intellectual and developmental disabilities, including autism spectrum disorder, since 1995. The TIL program follows graduates from the time of…

  8. Autocrine Complement Inhibits IL10-Dependent T-cell-Mediated Antitumor Immunity to Promote Tumor Progression.

    PubMed

    Wang, Yu; Sun, Sheng-Nan; Liu, Qing; Yu, Yang-Yang; Guo, Jian; Wang, Kun; Xing, Bao-Cai; Zheng, Qing-Feng; Campa, Michael J; Patz, Edward F; Li, Shi-You; He, You-Wen

    2016-09-01

    In contrast to its inhibitory effects on many cells, IL10 activates CD8(+) tumor-infiltrating lymphocytes (TIL) and enhances their antitumor activity. However, CD8(+) TILs do not routinely express IL10, as autocrine complement C3 inhibits IL10 production through complement receptors C3aR and C5aR. CD8(+) TILs from C3-deficient mice, however, express IL10 and exhibit enhanced effector function. C3-deficient mice are resistant to tumor development in a T-cell- and IL10-dependent manner; human TILs expanded with IL2 plus IL10 increase the killing of primary tumors in vitro compared with IL2-treated TILs. Complement-mediated inhibition of antitumor immunity is independent of the programmed death 1/programmed death ligand 1 (PD-1/PD-L1) immune checkpoint pathway. Our findings suggest that complement receptors C3aR and C5aR expressed on CD8(+) TILs represent a novel class of immune checkpoints that could be targeted for tumor immunotherapy. Moreover, incorporation of IL10 in the expansion of TILs and in gene-engineered T cells for adoptive cell therapy enhances their antitumor efficacy. Our data suggest novel strategies to enhance immunotherapies: a combined blockade of complement signaling by antagonists to C3aR, C5aR, and anti-PD-1 to enhance anti-PD-1 efficacy; a targeted IL10 delivery to CD8(+) TILs using anti-PD-1-IL10 or anti-CTLA4-IL10 fusion proteins; and the addition of IL10 in TIL expansion for adoptive cellular therapy. Cancer Discov; 6(9); 1022-35. ©2016 AACR.See related commentary by Peng et al., p. 953This article is highlighted in the In This Issue feature, p. 932. ©2016 American Association for Cancer Research.

  9. Minimally invasive liver resection to obtain tumor-infiltrating lymphocytes for adoptive cell therapy in patients with metastatic melanoma

    PubMed Central

    2012-01-01

    Background Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TIL) in patients with metastatic melanoma has been reported to have a 56% overall response rate with 20% complete responders. To increase the availability of this promising therapy in patients with advanced melanoma, a minimally invasive approach to procure tumor for TIL generation is warranted. Methods A feasibility study was performed to determine the safety and efficacy of laparoscopic liver resection to generate TIL for ACT. Retrospective review of a prospectively maintained database identified 22 patients with advanced melanoma and visceral metastasis (AJCC Stage M1c) who underwent laparoscopic liver resection between 1 October 2005 and 31 July 2011. The indication for resection in all patients was to receive postoperative ACT with TIL. Results Twenty patients (91%) underwent resection utilizing a closed laparoscopic technique, one required hand-assistance and another required conversion to open resection. Median intraoperative blood loss was 100 mL with most cases performed without a Pringle maneuver. Median hospital stay was 3 days. Three (14%) patients experienced a complication from resection with no mortality. TIL were generated from 18 of 22 (82%) patients. Twelve of 15 (80%) TIL tested were found to have in vitro tumor reactivity. Eleven patients (50%) received the intended ACT. Two patients were rendered no evidence of disease after surgical resection, with one undergoing delayed ACT with generated TIL after relapse. Objective tumor response was seen in 5 of 11 patients (45%) who received TIL, with one patient experiencing an ongoing complete response (32+ months). Conclusions Laparoscopic liver resection can be performed with minimal morbidity and serve as an effective means to procure tumor to generate therapeutic TIL for ACT to patients with metastatic melanoma. PMID:22726267

  10. The Extratropical Tropopause Inversion Layer

    NASA Astrophysics Data System (ADS)

    Ming, Alison; Haynes, Peter

    2013-04-01

    The extratropical tropopause inversion layer (TIL) is studied by analyzing numerical simulations with a dry idealized global circulation model. The model temperature field is relaxed towards different restoration profiles. We demonstrate that in simulations with the Held and Suarez restoration profile, a TIL is present in the steady state, whereas for a different restoration profile no TIL arises. Neither restoration profile includes a TIL-like structure and if an enhancement in the static stability occurs, it is a result of the model dynamics. We consider the mechanisms by which the TIL forms following previous work in attributing the formation to the structure of the residual circulation, but by further examining the relation of the residual circulation to the structure of the Eliassen-Palm flux convergence using the downward control principle. The presence of two separate regions of convergence of the Eliassen-Palm flux, one in the troposphere and the other in the stratosphere, is found to be necessary to the formation of the TIL. We also discuss the relations to other theories that emphasize the role of vertical gradients in radiatively active species.

  11. Tilmicosin- and florfenicol-loaded hydrogenated castor oil-solid lipid nanoparticles to pigs: Combined antibacterial activities and pharmacokinetics.

    PubMed

    Ling, Z; Yonghong, L; Junfeng, L; Li, Z; Xianqiang, L

    2018-04-01

    The combined antibacterial effects of tilmicosin (TIL) and florfenicol (FF) against Actinobacillus pleuropneumoniae (APP) (n = 2), Streptococcus suis (S. suis) (n = 2), and Haemophilus parasuis (HPS) (n = 2) were evaluated by chekerboard test and time-kill assays. The pharmacokinetics (PKs) of TIL- and FF-loaded hydrogenated castor oil (HCO)-solid lipid nanoparticles (SLN) were performed in healthy pigs. The results indicated that TIL and FF showed synergistic or additive antibacterial activities against APP, S. suis and HPS with the fractional inhibitory concentration (FIC) ranging from 0.375 to 0.75. The time-kill assays showed that 1/2 minimum inhibitory concentration (MIC) TIL combined with 1/2 MIC FF had a stronger ability to inhibit the growth of APP, S. suis, and HPS than 1 MIC TIL or 1 MIC FF, respectively. After oral administration, plasma TIL and FF concentrations could maintain about 0.1 μg/ml for 192 and 176 hr. The SLN prolonged the last time point with detectable concentrations (T last ), area under the concentration-time curve (AUC 0-t ), elimination half-life (T ½ke ), and mean residence time (MRT) by 3.1, 5.6, 12.7, 3.4-fold of the active pharmaceutical ingredient (API) of TIL and 11.8, 16.5, 18.1, 12.1-fold of the API of FF, respectively. This study suggests that the TIL-FF-SLN could be a useful oral formulation for the treatment of APP, S. suis, and HPS infection in pigs. © 2017 John Wiley & Sons Ltd.

  12. A Pilot Trial of the Combination of Vemurafenib with Adoptive Cell Therapy in Patients with Metastatic Melanoma

    PubMed Central

    Deniger, Drew C.; Kwong, Mei Li M.; Pasetto, Anna; Dudley, Mark E.; Wunderlich, John R.; Langhan, Michelle M.; Lee, Chyi-Chia Richard; Rosenberg, Steven A.

    2016-01-01

    Purpose This pilot feasibility clinical trial evaluated the co-administration of vemurafenib, a small molecule antagonist of BRAFV600 mutations, and tumor infiltrating lymphocytes (TIL) for the treatment of metastatic melanoma. Experimental Design A metastatic tumor was resected for growth of TIL and patients were treated with vemurafenib for 2 weeks followed by resection of a second lesion. Patients then received a non-myeloablative pre-conditioning regimen, infusion of autologous TIL and high-dose interleukin-2 administration. Vemurafenib was restarted at the time of TIL infusion and was continued for 2 years or until disease progression. Clinical responses were evaluated by RECIST 1.0. Metastases resected prior to and after two weeks of vemurafenib were compared using TCRB deep sequencing, immunohistochemistry, proliferation and recognition of autologous tumor. Results The treatment was well tolerated and had a safety profile similar to that of TIL or vemurafenib alone. Seven of 11 patients (64%) experienced an objective clinical response and 2 patients (18%) had a complete response for 3 years (one response is ongoing at 46 months). Proliferation and viability of infusion bag TIL and peripheral blood T cells were inhibited in vitro by vemurafenib (PLX4032) when approaching the maximum serum concentration of vemurafenib. TCRB repertoire (clonotypes numbers, clonality and frequency) did not significantly change between pre- and post-vemurafenib lesions. Recognition of autologous tumor by T cells was similar between TIL grown from pre- and post-vemurafenib metastases. Conclusions Co-administration of vemurafenib and TIL was safe, feasible and generated objective clinical responses in this small pilot clinical trial. PMID:28093487

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

    PubMed

    Ibrahim, Abdelaziz E; Abdel-Daim, Mohamed Mohamed

    2015-01-01

    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. 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. 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. Administration of SP minimized the toxic effects of TIL by its free radicalscavenging and potent antioxidant activity.

  14. Statistics of the tropopause inversion layer over Beijing

    NASA Astrophysics Data System (ADS)

    Bian, Jianchun; Chen, Hongbin

    2008-05-01

    High resolution radiosonde data from Beijing, China in 2002 are used to study the strong tropopause inversion layer (TIL) in the extratropical regions in eastern Asia. The analysis, based on the tropopause-based mean (TB-mean) method, shows that the TIL over Beijing has similar features as over other sites in the same latitude in Northern America. The reduced values of buoyancy frequency in 13 17 km altitude in winter-spring are attributed to the higher occurrence frequency of the secondary tropopause in this season. In the monthly mean temperature profile relative to the secondary tropopause, there also exists a TIL with somewhat enhanced static stability directly over the secondary sharp thermal tropopause, and a 4 km thickness layer with reduced values of buoyancy frequency just below the tropopause, which corresponds to the 13 17 km layer in the first TB-mean thermal profile. In the monthly mean temperature profile relative to the secondary tropopause, a TIL also exists but it is not as strong. For individual cases, a modified definition of the TIL, focusing on the super stability and the small distance from the tropopause, is introduced. The analysis shows that the lower boundary of the newly defined TIL is about 0.42 km above the tropopause, and that it is higher in winter and lower in summer; the thickness of the TIL is larger in winter-spring.

  15. The tropical tropopause inversion layer: variability and modulation by equatorial waves

    NASA Astrophysics Data System (ADS)

    Pilch Kedzierski, Robin; Matthes, Katja; Bumke, Karl

    2016-09-01

    The tropical tropopause layer (TTL) acts as a transition layer between the troposphere and the stratosphere over several kilometers, where air has both tropospheric and stratospheric properties. Within this region, a fine-scale feature is located: the tropopause inversion layer (TIL), which consists of a sharp temperature inversion at the tropopause and the corresponding high static stability values right above, which theoretically affect the dispersion relations of atmospheric waves like Rossby or inertia-gravity waves and hamper stratosphere-troposphere exchange (STE). Therefore, the TIL receives increasing attention from the scientific community, mainly in the extratropics so far. Our goal is to give a detailed picture of the properties, variability and forcings of the tropical TIL, with special emphasis on small-scale equatorial waves and the quasi-biennial oscillation (QBO).We use high-resolution temperature profiles from the COSMIC satellite mission, i.e., ˜ 2000 measurements per day globally, between 2007 and 2013, to derive TIL properties and to study the fine-scale structures of static stability in the tropics. The situation at near tropopause level is described by the 100 hPa horizontal wind divergence fields, and the vertical structure of the QBO is provided by the equatorial winds at all levels, both from the ERA-Interim reanalysis.We describe a new feature of the equatorial static stability profile: a secondary stability maximum below the zero wind line within the easterly QBO wind regime at about 20-25 km altitude, which is forced by the descending westerly QBO phase and gives a double-TIL-like structure. In the lowermost stratosphere, the TIL is stronger with westerly winds. We provide the first evidence of a relationship between the tropical TIL strength and near-tropopause divergence, with stronger (weaker) TIL with near-tropopause divergent (convergent) flow, a relationship analogous to that of TIL strength with relative vorticity in the

  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. Synoptic-Scale Behavior of the Extratropical Tropopause Inversion Layer

    NASA Astrophysics Data System (ADS)

    Pilch Kedzierski, Robin; Matthes, Katja; Bumke, Karl

    2015-04-01

    The Tropopause Inversion Layer (TIL) is a climatological feature of the tropopause region, characterized by enhanced static stability and strong temperature inversion in a thin layer (about 1km deep) right above the tropopause. It was discovered recently via tropopause-based averaging [Birner 2002]. The sharp static stability, temperature and wind shear gradients of the TIL theoretically shall inhibit stratosphere-troposphere exchange and influence the vertical propagation of planetary scale Rossby and small-scale gravity waves. High vertically resolved radiosonde and GPS radio occultation measurements show that the strength of the TIL is positively correlated with the tropopause height and anticyclonic conditions, and that it reaches its maximum strength in polar regions during summer [Birner 2006] [Randel and Wu, 2007 and 2010]. Our study takes advantage of the high density of vertical profiles (~2000 measurements per day, globally) measured by the COSMIC satellites (2007-present), in order to describe the synoptic-scale structures of the TIL and the differences between the seasonal climatologies from earlier studies and the real-time TIL. Also, using ERA-Interim reanalysis wind fields, we split relative vorticity into shear and curl terms and study separately their relation to TIL strength in cyclonic-anticyclonic conditions. We find that the TIL has a rich zonal structure, especially in midlatitude winter, and that its strength is instantly adjusted to the synoptic situation at near-tropopause level. The peaks of strongest TIL at midlatitude ridges in winter are stronger and much more frequent than any peaks found in polar summer. The roles of shear and curl vorticity differ substantially towards higher values of relative vorticity (both cyclonic and anticyclonic).

  18. Hot Spot and Whole-Tumor Enumeration of CD8+ Tumor-Infiltrating Lymphocytes Utilizing Digital Image Analysis Is Prognostic in Triple-Negative Breast Cancer.

    PubMed

    McIntire, Patrick J; Irshaid, Lina; Liu, Yifang; Chen, Zhengming; Menken, Faith; Nowak, Eugene; Shin, Sandra J; Ginter, Paula S

    2018-05-07

    CD8 + tumor-infiltrating lymphocytes (TILs) have emerged as a prognostic indicator in triple-negative breast cancer (TNBC). There is debate surrounding the prognostic value of hot spots for CD8 + TIL enumeration. We compared hot spot versus whole-tumor CD8 + TIL enumeration in prognosticating TNBC using immunohistochemistry on whole tissue sections and quantification by digital image analysis (Halo imaging analysis software; Indica Labs, Corrales, NM). A wide range of clinically relevant hot spot sizes was evaluated. CD8 + TIL enumeration was independently statistically significant for all hot spot sizes and whole-tumor annotations for disease-free survival by multivariate analysis. A 10× objective (2.2 mm diameter) hot spot was found to correlate significantly with overall survival (P = .04), while the remaining hot spots and whole-tumor CD8 + TIL enumeration did not (P > .05). Statistical significance was not demonstrated when comparing between hot spots and whole-tumor annotations, as the groups had overlapping confidence intervals. CD8 + TIL hot spot enumeration is equivalent to whole-tumor enumeration for prognostication in TNBC and may serve as a good alternative methodology in future studies and clinical practice. Copyright © 2018 Elsevier Inc. All rights reserved.

  19. Uncooperative target-in-the-loop performance with backscattered speckle-field effects

    NASA Astrophysics Data System (ADS)

    Kansky, Jan E.; Murphy, Daniel V.

    2007-09-01

    Systems utilizing target-in-the-loop (TIL) techniques for adaptive optics phase compensation rely on a metric sensor to perform a hill climbing algorithm that maximizes the far-field Strehl ratio. In uncooperative TIL, the metric signal is derived from the light backscattered from a target. In cases where the target is illuminated with a laser with suffciently long coherence length, the potential exists for the validity of the metric sensor to be compromised by speckle-field effects. We report experimental results from a scaled laboratory designed to evaluate TIL performance in atmospheric turbulence and thermal blooming conditions where the metric sensors are influenced by varying degrees of backscatter speckle. We compare performance of several TIL configurations and metrics for cases with static speckle, and for cases with speckle fluctuations within the frequency range that the TIL system operates. The roles of metric sensor filtering and system bandwidth are discussed.

  20. The tropopause inversion layer in models and analyses

    NASA Astrophysics Data System (ADS)

    Birner, T.; Sankey, D.; Shepherd, T. G.

    2006-07-01

    Recent high-resolution radiosonde climatologies have revealed a tropopause inversion layer (TIL) in the extratropics: temperature strongly increases just above a sharp local cold point tropopause. Here, it is asked to what extent a TIL exists in current general circulation models (GCMs) and meteorological analyses. Only a weak hint of a TIL exists in NCEP/NCAR reanalysis data. In contrast, the Canadian Middle Atmosphere Model (CMAM), a comprehensive GCM, exhibits a TIL of realistic strength. However, in data assimilation mode CMAM exhibits a much weaker TIL, especially in the Southern Hemisphere where only coarse satellite data are available. The discrepancy between the analyses and the GCM is thus hypothesized to be mainly due to data assimilation acting to smooth the observed strong curvature in temperature around the tropopause. This is confirmed in the reanalysis where the stratification around the tropopause exhibits a strong discontinuity at the start of the satellite era.

  1. 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

  2. High static stability in the mixing layer above the extratropical tropopause

    NASA Astrophysics Data System (ADS)

    Kunz, A.; Konopka, P.; Müller, R.; Pan, L. L.; Schiller, C.; Rohrer, F.

    2009-08-01

    The relationship between the static stability N2 and the mixing in the tropopause inversion layer (TIL) is investigated using in situ aircraft observations during SPURT (trace gas transport in the tropopause region). With a new simple measure of mixing degree based on O3-CO tracer correlations, high N2 related to an enhanced mixing in the extratropical mixing layer is found. This relation becomes even more pronounced if fresh mixing events are excluded, indicating that mixing within the TIL occurs on a larger than synoptic timescale. A temporal variance analysis of N2 suggests that processes responsible for the composition of the TIL take place on seasonal timescales. Using radiative transfer calculations, we simulate the influence of a change in O3 and H2O vertical gradients on the temperature gradient and thus on the static stability above the tropopause, which are contrasted in an idealized nonmixed atmosphere and in a reference mixed atmosphere. The results show that N2 increases with enhanced mixing degree near the tropopause. At the same time, the temperature above the tropopause decreases together with the development of an inversion and the TIL. In the idealized case of nonmixed profiles the TIL vanishes. Furthermore, the results suggest that H2O plays a major role in maintaining the temperature inversion and the TIL structure compared to O3. The results substantiate the link between the extratropical mixing layer and the TIL.

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

    PubMed

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

    2017-03-28

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

  4. CpG Oligodeoxynucleotides Enhance the Efficacy of Adoptive Cell Transfer Using Tumor Infiltrating Lymphocytes by Modifying the Th1 Polarization and Local Infiltration of Th17 Cells

    PubMed Central

    Xu, Lin; Wang, Chunhong; Wen, Zhenke; Zhou, Ya; Liu, Zhongmin; Liang, Yongjie; Xu, Zengguang; Ren, Tao

    2010-01-01

    Adoptive cell transfer immunotherapy using tumor infiltrating lymphocytes (TILs) was an important therapeutic strategy against tumors. But the efficacy remains limited and development of new strategies is urgent. Recent evidence suggested that CpG-ODNs might be a potent candidate for tumor immunotherapy. Here we firstly reported that CpG-ODNs could significantly enhance the antitumor efficacy of adoptively transferred TILs in vivo accompanied by enhanced activity capacity and proliferation of CD8+ T cells and CD8+ T cells, as well as a Th1 polarization immune response. Most importantly, we found that CpG-ODNs could significantly elevate the infiltration of Th17 cells in tumor mass, which contributed to anti-tumor efficacy of TILs in vivo. Our findings suggested that CpG ODNs could enhance the anti-tumor efficacy of adoptively transferred TILs through modifying Th1 polarization and local infiltration of Th17 cells, which might provide a clue for developing a new strategy for ACT based on TILs. PMID:20981279

  5. Costimulation through the CD137/4-1BB pathway protects human melanoma tumor-infiltrating lymphocytes from activation-induced cell death and enhances antitumor effector function.

    PubMed

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

    2011-04-01

    Adoptive T-cell therapy (ACT) using expanded tumor-infiltrating lymphocytes (TIL) with high-dose interleukin-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 costimulatory 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 costimulatory molecule CD137/4-1BB, and to a lesser extent CD134/OX40. Postrapid expansion protocol (REP) TIL were found to be highly sensitive to activation-induced cell death when reactivated through the T-cell receptor with low levels of OKT3 antibody. However, coligation of 4-1BB using 2 different agonistic anti-4-1BB antibodies potently prevented activation-induced cell death of post-REP CD8(+) TIL, including those specific for melanoma antigen recognized by T cells, 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 costimulated post-REP TIL also expressed increased levels of the cytolytic granule proteins and exhibited enhanced cytotoxic T-cell activity against melanoma cells. Lastly, post-REP CD8(+) TIL were protected from cell death by anti-4-1BB ligation when exposed to human leukocyte antigen-matched melanoma cells. Our results indicate that 4-1BB costimulation may significantly improve TIL survival during melanoma ACT and boost antitumor cytolytic activity.

  6. 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

  7. The tropopause inversion layer in baroclinic life-cycle experiments: the role of diabatic processes

    NASA Astrophysics Data System (ADS)

    Kunkel, D.; Hoor, P.; Wirth, V.

    2016-01-01

    Recent studies on the formation of a quasi-permanent layer of enhanced static stability above the thermal tropopause revealed the contributions of dynamical and radiative processes. Dry dynamics leads to the evolution of a tropopause inversion layer (TIL), which is, however, too weak compared to observations and thus diabatic contributions are required. In this study we aim to assess the importance of diabatic processes in the understanding of TIL formation at midlatitudes. The non-hydrostatic model COSMO (COnsortium for Small-scale MOdelling) is applied in an idealized midlatitude channel configuration to simulate baroclinic life cycles. The effect of individual diabatic processes related to humidity, radiation, and turbulence is studied first to estimate the contribution of each of these processes to the TIL formation in addition to dry dynamics. In a second step these processes are stepwise included in the model to increase the complexity and finally estimate the relative importance of each process. The results suggest that including turbulence leads to a weaker TIL than in a dry reference simulation. In contrast, the TIL evolves stronger when radiation is included but the temporal evolution is still comparable to the reference. Using various cloud schemes in the model shows that latent heat release and consecutive increased vertical motions foster an earlier and stronger appearance of the TIL than in all other life cycles. Furthermore, updrafts moisten the upper troposphere and as such increase the radiative effect from water vapor. Particularly, this process becomes more relevant for maintaining the TIL during later stages of the life cycles. Increased convergence of the vertical wind induced by updrafts and by propagating inertia-gravity waves, which potentially dissipate, further contributes to the enhanced stability of the lower stratosphere. Finally, radiative feedback of ice clouds reaching up to the tropopause is identified to potentially further affect

  8. Combination of Ipilimumab and Adoptive Cell Therapy with Tumor-Infiltrating Lymphocytes for Patients with Metastatic Melanoma.

    PubMed

    Mullinax, John E; Hall, MacLean; Prabhakaran, Sangeetha; Weber, Jeffrey; Khushalani, Nikhil; Eroglu, Zeynep; Brohl, Andrew S; Markowitz, Joseph; Royster, Erica; Richards, Allison; Stark, Valerie; Zager, Jonathan S; Kelley, Linda; Cox, Cheryl; Sondak, Vernon K; Mulé, James J; Pilon-Thomas, Shari; Sarnaik, Amod A

    2018-01-01

    Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) for metastatic melanoma can be highly effective, but attrition due to progression before TIL administration (32% in prior institutional experience) remains a limitation. We hypothesized that combining ACT with cytotoxic T lymphocyte-associated antigen 4 blockade would decrease attrition and allow more patients to receive TIL. Thirteen patients with metastatic melanoma were enrolled. Patients received four doses of ipilimumab (3 mg/kg) beginning 2 weeks prior to tumor resection for TIL generation, then 1 week after resection, and 2 and 5 weeks after preconditioning chemotherapy and TIL infusion followed by interleukin-2. The primary endpoint was safety and feasibility. Secondary endpoints included of clinical response at 12 weeks and at 1 year after TIL transfer, progression free survival (PFS), and overall survival (OS). All patients received at least two doses of ipilimumab, and 12 of the 13 (92%) received TIL. A median of 6.5 × 10 10 (2.3 × 10 10 to 1.0 × 10 11 ) TIL were infused. At 12 weeks following infusion, there were five patients who experienced objective response (38.5%), four of whom continued in objective response at 1 year and one of which became a complete response at 52 months. Median progression-free survival was 7.3 months (95% CI 6.1-29.9 months). Grade ≥ 3 immune-related adverse events included hypothyroidism (3), hepatitis (2), uveitis (1), and colitis (1). Ipilimumab plus ACT for metastatic melanoma is feasible, well tolerated, and associated with a low rate of attrition due to progression during cell expansion. This combination approach serves as a model for future efforts to improve the efficacy of ACT.

  9. A Pilot Trial of the Combination of Vemurafenib with Adoptive Cell Therapy in Patients with Metastatic Melanoma.

    PubMed

    Deniger, Drew C; Kwong, Mei Li M; Pasetto, Anna; Dudley, Mark E; Wunderlich, John R; Langhan, Michelle M; Lee, Chyi-Chia Richard; Rosenberg, Steven A

    2017-01-15

    This pilot feasibility clinical trial evaluated the coadministration of vemurafenib, a small-molecule antagonist of BRAF V600 mutations, and tumor-infiltrating lymphocytes (TIL) for the treatment of metastatic melanoma. A metastatic tumor was resected for growth of TILs, and patients were treated with vemurafenib for 2 weeks, followed by resection of a second lesion. Patients then received a nonmyeloablative preconditioning regimen, infusion of autologous TILs, and high-dose interleukin-2 administration. Vemurafenib was restarted at the time of TIL infusion and was continued for 2 years or until disease progression. Clinical responses were evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0. Metastases resected prior to and after 2 weeks of vemurafenib were compared using TCRB deep sequencing, immunohistochemistry, proliferation, and recognition of autologous tumor. The treatment was well tolerated and had a safety profile similar to that of TIL or vemurafenib alone. Seven of 11 patients (64%) experienced an objective clinical response, and 2 patients (18%) had a complete response for 3 years (one response is ongoing at 46 months). Proliferation and viability of infusion bag TILs and peripheral blood T cells were inhibited in vitro by research-grade vemurafenib (PLX4032) when approaching the maximum serum concentration of vemurafenib. TCRB repertoire (clonotypes numbers, clonality, and frequency) did not significantly change between pre- and post-vemurafenib lesions. Recognition of autologous tumor by T cells was similar between TILs grown from pre- and post-vemurafenib metastases. Coadministration of vemurafenib and TILs was safe and feasible and generated objective clinical responses in this small pilot clinical trial. Clin Cancer Res; 23(2); 351-62. ©2016 AACRSee related commentary by Cogdill et al., p. 327. ©2016 American Association for Cancer Research.

  10. Novel approach for beacon formation through simulated turbulence: initial lab-test results

    NASA Astrophysics Data System (ADS)

    Khizhnyak, A.; Markov, V.; Tomov, I.; Wu, F.

    2010-02-01

    In this paper we report the results of the analysis and experimental modeling of the target-in-the-loop (TIL) approach that is used to form a localized beacon for a laser beam propagating through turbulent atmosphere. The analogy between the TIL system and the laser cavity has been used here to simulate the process shaping the laser beacon on a remote image-resolved target with rough surface. The TIL breadboard was integrated and used for laboratory modeling of the proposed approach. This breadboard allowed to simulate the TIL arrangement with a rough-surface target and laser beam propagation through the turbulent atmospheric layer. Here we present the initial results of the performed studies.

  11. 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

  12. Early T Cell Signalling Is Reversibly Altered in PD-1+ T Lymphocytes Infiltrating Human Tumors

    PubMed Central

    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

    2011-01-01

    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. PMID:21408177

  13. 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

  14. 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

  15. The tropopause inversion layer in baroclinic life cycles over the North Atlantic: a pre-WISE case study and climatology

    NASA Astrophysics Data System (ADS)

    Kaluza, Thorsten; Hoor, Peter; Kunkel, Daniel

    2017-04-01

    Studies of baroclinic life cycles recently revelead that the tropopause inversion layer (TIL) in the extratropics is significantly strengthened by diabatic processes related to moist tropospheric dynamics as well as by breaking of the baroclinic wave itself. However, these findings summarize the results from idealized model simulations and the contribution from processes related to baroclinic life cycles relative to other processes enhancing the lower stratospheric static stability (stratospheric dynamics, seasonal variation of radiative feedbacks) to the observed TIL at midlatitudes has yet to be assessed. Further the role of the TIL for stratosphere-troposphere exchange (STE) is currently still under debate. In preparation of the up-coming field campaign WISE (Wave driven isentropic exchange) we explore the state and variability of the TIL over the North Atlantic between August and October in analysis model data. We use high resolution operational analysis from the European Center for Medium Range Weather Forecast to study the mesoscale structure of the TIL. The main focus is on case studies of the TIL in real baroclinic life cycles, in particular on small scale enhancements within the baroclinic disturbances and the relation to STE. Moreover, a summary is presented about the quasi climatological state of the tropopause location and sharpness over the North Atlantic over recent years.

  16. Adoptive Cell Therapy with Tumor-Infiltrating Lymphocytes in Advanced Melanoma Patients

    PubMed Central

    Saint-Jean, Mélanie; Volteau, Christelle; Quéreux, Gaëlle; Peuvrel, Lucie; Brocard, Anabelle; Saiagh, Soraya; Nguyen, Jean-Michel; Bedane, Christophe; Basset-Seguin, Nicole

    2018-01-01

    Immunotherapy for melanoma includes adoptive cell therapy with autologous tumor-infiltrating lymphocytes (TILs). This monocenter retrospective study was undertaken to evaluate the efficacy and safety of this treatment of patients with advanced melanoma. All advanced melanoma patients treated with TILs using the same TIL expansion methodology and same treatment interleukin-2 (IL-2) regimen between 2009 and 2012 were included. After sterile intralesional excision of a cutaneous or subcutaneous metastasis, TILs were produced according to a previously described method and then infused into the patient who also received a complementary subcutaneous IL-2 regimen. Nine women and 1 man were treated for unresectable stage IIIC (n = 4) or IV (n = 6) melanoma. All but 1 patient with unresectable stage III melanoma (1st line) had received at least 2 previous treatments, including anti-CTLA-4 antibody for 4. The number of TILs infused ranged from 0.23 × 109 to 22.9 × 109. Regarding safety, no serious adverse effect was reported. Therapeutic responses included a complete remission, a partial remission, 2 stabilizations, and 6 progressions. Among these 4 patients with clinical benefit, 1 is still alive with 9 years of follow-up and 1 died from another cause after 8 years of follow-up. Notably, patients treated with high percentages of CD4 + CD25 + CD127lowFoxp3+ T cells among their TILs had significantly shorter OS. The therapeutic effect of combining TILs with new immunotherapies needs further investigation. PMID:29750176

  17. Adoptive cell therapy with autologous tumor-infiltrating lymphocytes and high-dose interleukin-2 for metastatic melanoma: The surgeon’s perspective

    PubMed Central

    ZIPPEL, DOUGLAS B.; BESSER, MICHAL; SHAPIRA, RONI; BEN-NUN, ALON; GOITEIN, DAVID; DAVIDSON, TIMA; TREVES, ABRAHAM J.; MARKEL, GAL; SCHACHTER, JACOB; PAPA, MOSHE Z.

    2012-01-01

    Tumor-infiltrating lymphocytes (TILs) are produced by resecting tumor tissue and growing and expanding ex vivo large quantities of autologous T cells. Once the TILs are ready for infusion, the patient undergoes a non-myeloablative lympho-depleting course of chemotherapy and subsequent TIL infusion with high-dose bolus IL-2. This study reviews the surgical experience of the TIL program at the Chaim Sheba Cancer Research Center in Israel. Eligible patients underwent surgical consultation to determine what tumorectomy would be beneficial for harvesting appropriate tissue. Factors involved in the decision included tumor mass size, location and morbidity of the procedure. Between January 2006 and May 2010, 44 patients underwent 47 procedures of adoptive transfer of TILs. Three patients underwent the procedure twice for recurrence after initial good responses, including an additional surgical procedure to produce fresh tumor. Thirty-seven excisions were with general anesthesia and 10 were with local anesthesia. Of the 37 general anesthesia procedures, 27 were open procedures involving a thoracotomy, a laparotomy or dissection of a major lymph node basin. Ten used minimally invasive techniques such as thorascopy or laparoscopy. Tumorectomy sites included 18 lymph node metastasis, 13 subcutaneous nodules, 11 lung specimens and 5 abdominal visceral metastasis including 2 liver lesions. Surgical mortality and major morbidity was 0%. Minor morbidity included only wound complications. Maximal number of TILs were derived from lymph node specimens, while liver metastasis procured the fewest TILs. Adoptive cell transfer technology affords a maximal tumor response with minimal surgical morbidity in metastatic patients. PMID:22969990

  18. A comparison of total inward leakage measured using sodium chloride (NaCl) and corn oil aerosol methods for air-purifying respirators.

    PubMed

    Rengasamy, Samy; Zhuang, Ziqing; Niezgoda, George; Walbert, Gary; Lawrence, Robert; Boutin, Brenda; Hudnall, Judith; Monaghan, William P; Bergman, Michael; Miller, Colleen; Harris, James; Coffey, Christopher

    2018-05-21

    The International Organization for Standardization (ISO) standard 16900-1:2014 specifies the use of sodium chloride (NaCl) and corn oil aerosols, and sulfur hexafluoride gas for measuring total inward leakage (TIL). However, a comparison of TIL between different agents is lacking. The objective of this study was to measure and compare TIL for respirators using corn oil and NaCl aerosols. TIL was measured with 10 subjects donning two models of filtering facepiece respirators (FFRs) including FFP1, N95, P100, and elastomeric half-mask respirators (ERs) in NaCl and corn oil aerosol test chambers, using continuous sampling methods. After fit testing with a PortaCount (TSI, St. Paul, MN) using the Occupational Safety and Health Administration (OSHA) protocol, five subjects were tested in the NaCl chamber first and then in the corn oil chamber, while other subjects tested in the reverse order. TIL was measured as a ratio of mass-based aerosol concentrations in-mask to the test chamber, while the subjects performed ISO 16900-1-defined exercises. The concentration of NaCl aerosol was measured using two flame photometers, and corn oil aerosol was measured with one light scattering photometer. The same instruments were used to measure filter penetration in both chambers using a Plexiglas® setup. The size distribution of aerosols was determined using a scanning mobility particle sizer and charge was measured with an electrometer. Filter efficiency was measured using an 8130 Automated Filter Tester (TSI). Results showed the geometric mean TIL for corn oil aerosol for one model each of all respirator categories, except P100, were significantly (p<0.05) greater than for NaCl aerosol. Filter penetration in the two test chambers showed a trend similar to TIL. The count median diameter was ∼82 nm for NaCl and ∼200 nm for corn oil aerosols. The net positive charge for NaCl aerosol was relatively larger. Both fit factor and filter efficiency influence TIL measurement. Overall

  19. Loss of second and sixth conserved cysteine residues from trypsin inhibitor-like cysteine-rich domain-type protease inhibitors in Bombyx mori may induce activity against microbial proteases.

    PubMed

    Li, Youshan; Liu, Huawei; Zhu, Rui; Xia, Qingyou; Zhao, Ping

    2016-12-01

    Previous studies have indicated that most trypsin inhibitor-like cysteine-rich domain (TIL)-type protease inhibitors, which contain a single TIL domain with ten conserved cysteines, inhibit cathepsin, trypsin, chymotrypsin, or elastase. Our recent findings suggest that Cys 2nd and Cys 6th were lost from the TIL domain of the fungal-resistance factors in Bombyx mori, BmSPI38 and BmSPI39, which inhibit microbial proteases and the germination of Beauveria bassiana conidia. To reveal the significance of these two missing cysteines in relation to the structure and function of TIL-type protease inhibitors in B. mori, cysteines were introduced at these two positions (D36 and L56 in BmSPI38, D38 and L58 in BmSPI39) by site-directed mutagenesis. The homology structure model of TIL domain of the wild-type and mutated form of BmSPI39 showed that two cysteine mutations may cause incorrect disulfide bond formation of B. mori TIL-type protease inhibitors. The results of Far-UV circular dichroism (CD) spectra indicated that both the wild-type and mutated form of BmSPI39 harbored predominantly random coil structures, and had slightly different secondary structure compositions. SDS-PAGE and Western blotting analysis showed that cysteine mutations affected the multimerization states and electrophoretic mobility of BmSPI38 and BmSPI39. Activity staining and protease inhibition assays showed that the introduction of cysteine mutations dramaticly reduced the activity of inhibitors against microbial proteases, such as subtilisin A from Bacillus licheniformis, protease K from Engyodontium album, protease from Aspergillus melleus. We also systematically analyzed the key residue sites, which may greatly influence the specificity and potency of TIL-type protease inhibitors. We found that the two missing cysteines in B. mori TIL-type protease inhibitors might be crucial for their inhibitory activities against microbial proteases. The genetic engineering of TIL-type protease inhibitors may be

  20. Distinct Tertiary Lymphoid Structure Associations and Their Prognostic Relevance in HER2 Positive and Negative Breast Cancers.

    PubMed

    Liu, Xia; Tsang, Julia Y S; Hlaing, Thazin; Hu, Jintao; Ni, Yun-Bi; Chan, Siu Ki; Cheung, Sai Yin; Tse, Gary M

    2017-11-01

    The presence of tumor infiltrating lymphocytes (TIL) is associated with favorable prognosis. Recent evidence suggested that not only their density, but also the spatial organization as tertiary lymphoid structures (TLS), play a key role in determining patient survival. In a cohort of 248 breast cancers, the clinicopathologic association and prognostic role of TLS was examined. Tertiary lymphoid structures were associated with higher tumor grade, apocrine phenotype, necrosis, extensive in situ component, lymphovascular invasion (LVI), and high TIL. For biomarkers, TLS were associated with hormone receptors negativity, HER2 positivity, and c-kit expression. Tertiary lymphoid structures were significantly related to better disease-free survival (DFS) in HER2 positive (HER2+) breast cancers (log-rank = 4.054), which was not dependent on high TIL status. The combined TLS and TIL status was an independent favorable factor associated with DFS in those cases. Interestingly, tumor cell infiltration into the TLS was found in 41.9% of TLS positive cases. It was associated with LVI in HER2 negative (HER2-) TLS positive (particularly estrogen receptor positive [ER+] HER2-) cases. In the ER+ HER2- cases, tumor cell infiltration into TLS was also associated with increased pathologic nodal stage (pN) stage and nodal involvement. Tertiary lymphoid structures showed a similar relationship with clinicopathologic features and biomarkers as TIL. The presence of TLS, irrespective of TIL level, could be an important favorable prognostic indicator in HER2+ breast cancer patients. Given the significance of TLS in promoting effective antitumor immunity, further understanding of its organization and induction may provide new opportunities to improve the current immunotherapy strategies. Despite recent interest on the clinical value of tumor infiltrating lymphocyte (TIL), little was known on the clinical significance on their spatial organization as tertiary lymphoid structures (TLS

  1. Adoptive T-cell Therapy Using Autologous Tumor-infiltrating Lymphocytes for Metastatic Melanoma: Current Status and Future Outlook

    PubMed Central

    Wu, Richard; Forget, Marie-Andree; Chacon, Jessica; Bernatchez, Chantale; Haymaker, Cara; Chen, Jie Qing; Hwu, Patrick; Radvanyi, Laszlo

    2012-01-01

    Immunotherapy using autologous T-cells has emerged to be a powerful treatment option for patients with metastatic melanoma. These include the adoptive transfer of autologous tumor-infiltrating lymphocytes (TIL), T-cells transduced with high-affinity T-cell receptors (TCR) against major melanosomal tumor antigens, and T cells transduced with chimeric antigen receptors (CAR) composed of hybrid immunoglobulin light chains with endo-domains of T-cell signaling molecules. Among these and other options for T-cell therapy, TIL together with high-dose IL-2 has had the longest clinical history with multiple clinical trials in centers across the world consistently demonstrating durable clinical response rates near 50% or more. A distinct advantage of TIL therapy making it still the T-cell therapy of choice is the broad nature of the T-cell recognition against both defined as well as un-defined tumors antigens against all possible MHC, rather than the single specificity and limited MHC coverage of the newer TCR and CAR transduction technologies. In the past decade, significant inroads have been made in defining the phenotypes of T cells in TIL mediating tumor regression. CD8+ T cells are emerging to be critical, although the exact subset of CD8+ T cells exhibiting the highest clinical activity in terms of memory and effector markers is still controversial. We present a model in which both effector-memory and more differentiated effector T cells ultimately may need to cooperate to mediate long-term tumor control in responding patients. Although TIL therapy has shown great potential to treat metastatic melanoma, a number of issues have emerged that need to be addressed to bring it more into the mainstream of melanoma care. First, we have a reached the point where a pivotal phase II or phase III trials are needed in an attempt to gain regulatory approval of TIL as standard-of-care. Second, improvements in how we expand TIL for therapy are needed, that minimize the time the T

  2. Tumor-infiltrating lymphocytes predict response to chemotherapy in patients with advance non-small cell lung cancer.

    PubMed

    Liu, Hui; Zhang, Tiantuo; Ye, Jin; Li, Hongtao; Huang, Jing; Li, Xiaodong; Wu, Benquan; Huang, Xubing; Hou, Jinghui

    2012-10-01

    Accumulating preclinical evidence suggests that anticancer immune responses contribute to the success of chemotherapy. The predictive significance of tumor-infiltrating lymphocytes (TILs) for response to neoadjuvant chemotherapy in non-small cell lung cancer (NSCLC) remains unknown. The aim of this study was to investigate the prognostic and predictive value of TIL subtypes in patients with advanced NSCLC treated with platinum-based chemotherapy. In total, 159 patients with stage III and IV NSCLC were retrospectively enrolled. The prevalence of CD3(+), CD4(+), CD8(+) and Foxp3(+) TILs was assessed by immunohistochemistry in tumor tissue obtained before chemotherapy. The density of TILs subgroups was treated as dichotomous variables using the median values as cutoff. Survival curves were estimated by the Kaplan-Meier method, and differences in overall survival between groups were determined using the Log-rank test. Prognostic effects of TIL subsets density were evaluated by Cox regression analysis. The presence of CD3(+), CD4(+), CD8(+), and FOXP3(+) TILs was not correlated with any clinicopathological features. Neither the prevalence of TILs nor combined analysis displayed obvious prognostic performances for overall survival in Cox regression model. Instead, higher FOXP3(+)/CD8(+) ratio in tumor sites was an independent factor for poor response to platinum-based chemotherapy in overall cohort. These findings suggest that immunological CD8(+) and FOXP3(+)Tregs cell infiltrate within tumor environment is predictive of response to platinum-based neoadjuvant chemotherapy in advanced NSCLC patients. The understanding of the clinical relevance of the microenvironmental immunological milieu might provide an important clue for the design of novel strategies in cancer immunotherapy.

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

    PubMed

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

    2018-01-01

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

  4. Effects of breathing frequency and flow rate on the total inward leakage of an elastomeric half-mask donned on an advanced manikin headform.

    PubMed

    He, Xinjian; Grinshpun, Sergey A; Reponen, Tiina; McKay, Roy; Bergman, Michael S; Zhuang, Ziqing

    2014-03-01

    The objective of this study was to investigate the effects of breathing frequency and flow rate on the total inward leakage (TIL) of an elastomeric half-mask donned on an advanced manikin headform and challenged with combustion aerosols. An elastomeric half-mask respirator equipped with P100 filters was donned on an advanced manikin headform covered with life-like soft skin and challenged with aerosols originated by burning three materials: wood, paper, and plastic (polyethylene). TIL was determined as the ratio of aerosol concentrations inside (C in) and outside (C out) of the respirator (C in/C out) measured with a nanoparticle spectrometer operating in the particle size range of 20-200nm. The testing was performed under three cyclic breathing flows [mean inspiratory flow (MIF) of 30, 55, and 85 l/min] and five breathing frequencies (10, 15, 20, 25, and 30 breaths/min). A completely randomized factorial study design was chosen with four replicates for each combination of breathing flow rate and frequency. Particle size, MIF, and combustion material had significant (P < 0.001) effects on TIL regardless of breathing frequency. Increasing breathing flow decreased TIL. Testing with plastic aerosol produced higher mean TIL values than wood and paper aerosols. The effect of the breathing frequency was complex. When analyzed using all combustion aerosols and MIFs (pooled data), breathing frequency did not significantly (P = 0.08) affect TIL. However, once the data were stratified according to combustion aerosol and MIF, the effect of breathing frequency became significant (P < 0.05) for all MIFs challenged with wood and paper combustion aerosols, and for MIF = 30 l/min only when challenged with plastic combustion aerosol. The effect of breathing frequency on TIL is less significant than the effects of combustion aerosol and breathing flow rate for the tested elastomeric half-mask respirator. The greatest TIL occurred when challenged with plastic aerosol at 30 l/min and

  5. MHC class II expression in lung cancer.

    PubMed

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

    2017-10-01

    Immunotherapy is an exciting development in lung cancer research. In this study we described major histocompatibility complex (MHC) Class II protein expression in lung cancer cell lines and patient tissues. We studied MHC Class II (DP, DQ, DR) (CR3/43, Abcam) protein expression in 55 non-small cell lung cancer (NSCLC) cell lines, 42 small cell lung cancer (SCLC) cell lines and 278 lung cancer patient tissues by immunohistochemistry (IHC). Seven (12.7%) NSCLC cell lines were positive for MHC Class II. No SCLC cell lines were found to be MHC Class II positive. We assessed 139 lung cancer samples available in the Hirsch Lab for MHC Class II. There was no positive MHC Class II staining on SCLC tumor cells. MHC Class II expression on TILs in SCLC was significantly lower than that on TILs in NSCLC (P<0.001). MHC Class II was also assessed in an additional 139 NSCLC tumor tissues from Medical University of Gdansk, Poland. Patients with positive staining of MHC Class II on TILs had longer regression-free survival (RFS) and overall survival (OS) than those whose TILs were MHC Class II negative (2.980 years, 95% CI 1.628-4.332 vs. 1.050 years, 95% CI 0.556-1.554, P=0.028) (3.230 years, 95% CI 2.617-3.843 vs. 1.390 years, 95% CI 0.629-2.151, P=0.014). MHC Class II was expressed both in NSCLC cell lines and tissues. However, MHC Class II was not detected in SCLC cell lines or tissue tumor cells. MHC Class II expression was lower on SCLC TILs than on NSCLC TILs. Loss of expression of MHC Class II on SCLC tumor cells and reduced expression on SCLC TILs may be a means of escaping anti-cancer immunity. Higher MHC Class II expression on TILs was correlated with better prognosis in patients with NSCLC. Copyright © 2017. Published by Elsevier B.V.

  6. Targeting Transcriptional Regulators of CD8+ T Cell Dysfunction to Boost Anti-Tumor Immunity

    PubMed Central

    Waugh, Katherine A.; Leach, Sonia M.; Slansky, Jill E.

    2015-01-01

    Transcription is a dynamic process influenced by the cellular environment: healthy, transformed, and otherwise. Genome-wide mRNA expression profiles reflect the collective impact of pathways modulating cell function under different conditions. In this review we focus on the transcriptional pathways that control tumor infiltrating CD8+ T cell (TIL) function. Simultaneous restraint of overlapping inhibitory pathways may confer TIL resistance to multiple mechanisms of suppression traditionally referred to as exhaustion, tolerance, or anergy. Although decades of work have laid a solid foundation of altered transcriptional networks underlying various subsets of hypofunctional or “dysfunctional” CD8+ T cells, an understanding of the relevance in TIL has just begun. With recent technological advances, it is now feasible to further elucidate and utilize these pathways in immunotherapy platforms that seek to increase TIL function. PMID:26393659

  7. Can inertia-gravity waves persistently alter the tropopause inversion layer?

    NASA Astrophysics Data System (ADS)

    Kunkel, Daniel; Hoor, Peter; Wirth, Volkmar

    2014-11-01

    Previous simulations of baroclinic life cycles have shown, among many other features, the evolution of a tropopause inversion layer (TIL) as well as the spontaneous emission of inertia-gravity waves (IGWs). This study suggests that the latter two are related to each other, i.e., that IGWs may affect the TIL in a persistent manner. The IGWs are emitted along the jet and grow to large amplitudes, leading to the appearance of low-gradient Richardson numbers that indicate Kelvin-Helmholtz instability. Ensuing energy dissipation, local heating, and turbulence may persistently alter the thermodynamical structure of the tropopause region and, therefore, contribute to TIL formation or alter an existing TIL. Moreover, the flow in the region of the IGW favors the occurrence of wave capture, which may enhance the effect of wave breaking.

  8. 78 FR 70388 - Self-Regulatory Organizations; The NASDAQ Stock Market LLC; Notice of Filing and Immediate...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-11-25

    ...-Only Orders may not have a time-in-force designation of Good Til Cancelled or Immediate or Cancel. (f... designation of Good Til Cancelled or Immediate or Cancel.\\8\\ Post-Only Orders received prior to the opening...

  9. 77 FR 39277 - Self-Regulatory Organizations; NASDAQ OMX BX, Inc.; Order Granting Approval of a Proposed Rule...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-07-02

    ... with a time-in- force designation of Good Til canceled (``GTC'') are treated as having a time-in-force... designation of Good Til Cancelled or Immediate or Cancel. See proposed BX Options Rules, Chapter VI, Section 1...

  10. Stromal and intraepithelial tumor-infiltrating lymphocytes in colorectal carcinoma

    PubMed Central

    Jakubowska, Katarzyna; Kisielewski, Wojciech; Kańczuga-Koda, Luiza; Koda, Mariusz; Famulski, Waldemar

    2017-01-01

    The local mechanisms of antitumor immune defense determine the development and organization of the tumor microenvironment, and the composition and relative proportions of the inflammatory cell population affect the quality and characteristics of the immune response. The aim of the present study was to conduct a quantitative morphological evaluation of two types of tumor-infiltrating lymphocyte (TILs) populations, including those located in the stroma and intraepithelial cancer structures, in the invasive front and the center of the tumor in patients with colorectal cancer (CRC). The study included 160 patients with CRC who had undergone surgery. The tissue material was stained with hematoxylin and eosin, as used in routine histopathological diagnosis, and the two TIL populations were observed and counted with light microscopy. The relative extent of infiltration of stromal and intraepithelial TILs into the front and center of the primary tumors was similar. The extent of infiltration by stromal TILs was negatively correlated with the morphological features of tumor progression including the cancer infiltration of blood vessels (P=0.016), the invasion of lymph vessels (P=0.007), perineural invasion (P=0.036), lymph node involvement (P=0.047) and distant metastases (P=0.032). The infiltration by intraepithelial TILs was positively correlated with a desmoplastic reaction (P=0.002). Disease-free survival time was statistically shorter in patients without intraepithelial TILs in the center of the primary tumor mass (P=0.049; hazard ratio = 1.45). These results confirm that the infiltration of TILs into the invasive front and center of the tumor in patients with CRC serves an important role in the invasion and progression of the disease, and should be considered in routine histopathological examinations. PMID:29151905

  11. 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 . ©2016

  12. Selection of Shared and Neoantigen-Reactive T Cells for Adoptive Cell Therapy Based on CD137 Separation.

    PubMed

    Seliktar-Ofir, Sivan; Merhavi-Shoham, Efrat; Itzhaki, Orit; Yunger, Sharon; Markel, Gal; Schachter, Jacob; Besser, Michal J

    2017-01-01

    Adoptive cell therapy (ACT) of autologous tumor infiltrating lymphocytes (TIL) is an effective immunotherapy for patients with solid tumors, yielding objective response rates of around 40% in refractory patients with metastatic melanoma. Most clinical centers utilize bulk, randomly isolated TIL from the tumor tissue for ex vivo expansion and infusion. Only a minor fraction of the administered T cells recognizes tumor antigens, such as shared and mutation-derived neoantigens, and consequently eliminates the tumor. Thus, there are many ongoing effects to identify and select tumor-specific TIL for therapy; however, those approaches are very costly and require months, which is unreasonable for most metastatic patients. CD137 (4-1BB) has been identified as a co-stimulatory marker, which is induced upon the specific interaction of T cells with their target cell. Therefore, CD137 can be a useful biomarker and an important tool for the selection of tumor-reactive T cells. Here, we developed and validated a simple and time efficient method for the selection of CD137-expressing T cells for therapy based on magnetic bead separation. CD137 selection was performed with clinical grade compliant reagents, and TIL were expanded in a large-scale manner to meet cell numbers required for the patient setting in a GMP facility. For the first time, the methodology was designed to comply with both clinical needs and limitations, and its feasibility was assessed. CD137-selected TIL demonstrated significantly increased antitumor reactivity and were enriched for T cells recognizing neoantigens as well as shared tumor antigens. CD137-based selection enabled the enrichment of tumor-reactive T cells without the necessity of knowing the epitope specificity or the antigen type. The direct implementation of the CD137 separation method to the cell production of TIL may provide a simple way to improve the clinical efficiency of TIL ACT.

  13. The tropopause inversion layer in baroclinic life cycles experiments: the role of diabatic and mixing processes

    NASA Astrophysics Data System (ADS)

    Kunkel, D.; Hoor, P.; Wirth, V.

    2015-08-01

    Recent studies on the formation of a quasi-permanent layer of enhanced static stability above the thermal tropopause revealed the contributions of dynamical and radiative processes. Dry dynamics lead to the evolution of a tropopause inversion layer (TIL) which is, however, too weak compared to observations and thus diabatic contributions are required. In this study we aim to assess the importance of diabatic as well as mixing processes in the understanding of TIL formation at midlatitudes. The non-hydrostatic model COSMO is applied in an idealized mid-latitude channel configuration to simulate baroclinic life cycles. The effect of individual diabatic, i.e. related to humidity and radiation, and turbulent processes is studied first to estimate the additional contribution of these processes to dry dynamics. In a second step these processes are stepwise included in the model to increase the complexity and finally estimate the relative importance of each process. The results suggest that including turbulence leads to a weaker TIL than in a dry reference simulation. In contrast, the TIL evolves stronger when radiation is included but the temporal occurrence is still comparable to the reference. Using various cloud schemes in the model shows that latent heat release and consecutive increased vertical motions foster an earlier and stronger appearance of the TIL than in all other life cycles. Furthermore, updrafts moisten the upper troposphere and as such increase the radiative effect from water vapor. Particularly, this process becomes more relevant for maintaining the TIL during later stages of the life cycles. Increased convergence of the vertical wind induced by updrafts and by propagating and potentially dissipating inertia-gravity waves further contributes to the enhanced stability of the lower stratosphere. Furthermore, radiative feedback of ice clouds reaching up to the tropopause is identified to potentially further affect the strength of the TIL in the region of

  14. Activation and propagation of tumor infiltrating lymphocytes on clinical-grade designer artificial antigen presenting cells for adoptive immunotherapy of melanoma

    PubMed Central

    Forget, Marie-Andrée; Malu, Shruti; Liu, Hui; Toth, Christopher; Maiti, Sourindra; Kale, Charuta; Haymaker, Cara; Bernatchez, Chantale; Huls, Helen; Wang, Ena; Marincola, Francesco M.; Hwu, Patrick; Cooper, Laurence J. N.; Radvanyi, Laszlo G.

    2014-01-01

    PURPOSE Adoptive cell therapy (ACT) with autologous tumor infiltrating lymphocytes (TIL) is a therapy for metastatic melanoma with response rates up to 50%. However, the generation of the TIL transfer product is challenging, requiring pooled allogeneic normal donor peripheral blood mononuclear cells (PBMC) used in vitro as “feeders” to support a rapid expansion protocol (REP). Here, we optimized a platform to propagate TIL to a clinical scale using K562-cells genetically modified to express costimulatory molecules such as CD86, CD137-ligand and membrane-bound IL-15 to function as artificial antigen-presenting cell (aAPC) as an alternative to using PBMC feeders. EXPERIMENTAL DESIGN We used aAPC or γ-irradiated PBMC feeders to propagate TIL and measured rates of expansion. The activation and differentiation state was evaluated by flow cytometry and differential gene expression analyses. Clonal diversity was assessed based on pattern of T-cell receptor (TCR) usage. T-cell effector function was measured by evaluation of cytotoxic granule content and killing of target cells. RESULTS The aAPC propagated TIL at numbers equivalent to that found with PBMC feeders, while increasing the frequency of CD8+ T-cell expansion with a comparable effector-memory phenotype. mRNA profiling revealed an up-regulation of genes in the Wnt and stem-cell pathways with the aAPC. The aAPC platform did not skew clonal diversity and CD8+ T cells showed comparable anti-tumor function as those expanded with PBMC feeders. CONCLUSIONS TIL can be rapidly expanded with aAPC to clinical scale generating T cells with similar phenotypic and effector profiles as with PBMC feeders. These data support the clinical-application of aAPC to manufacture TIL for the treatment of melanoma. PMID:25304728

  15. Co-Stimulation through 4-1BB/CD137 Improves the Expansion and Function of CD8+ Melanoma Tumor-Infiltrating Lymphocytes for Adoptive T-Cell Therapy

    PubMed Central

    Chacon, Jessica Ann; Wu, Richard C.; Sukhumalchandra, Pariya; Molldrem, Jeffrey J.; Sarnaik, Amod; Pilon-Thomas, Shari; Weber, Jeffrey; Hwu, Patrick; Radvanyi, Laszlo

    2013-01-01

    Adoptive T-cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) can induce tumor regression in up to 50% or more of patients with unresectable metastatic melanoma. However, current methods to expand melanoma TIL, especially the “rapid expansion protocol” (REP) were not designed to enhance the generation of optimal effector-memory CD8+ T cells for infusion. One approach to this problem is to manipulate specific co-stimulatory signaling pathways to enhance CD8+ effector-memory T-cell expansion. In this study, we determined the effects of activating the TNF-R family member 4-1BB/CD137, specifically induced in activated CD8+ T cells, on the yield, phenotype, and functional activity of expanded CD8+ T cells during the REP. We found that CD8+ TIL up-regulate 4-1BB expression early during the REP after initial TCR stimulation, but neither the PBMC feeder cells in the REP or the activated TIL expressed 4-1BB ligand. However, addition of an exogenous agonistic anti-4-1BB IgG4 (BMS 663513) to the REP significantly enhanced the frequency and total yield of CD8+ T cells as well as their maintenance of CD28 and increased their anti-tumor CTL activity. Gene expression analysis found an increase in bcl-2 and survivin expression induced by 4-1BB that was associated with an enhanced survival capability of CD8+ post-REP TIL when re-cultured in the absence or presence of cytokines. Our findings suggest that adding an agonistic anti-4-1BB antibody during the time of TIL REP initiation produces a CD8+ T cell population capable of improved effector function and survival. This may greatly improve TIL persistence and anti-tumor activity in vivo after adoptive transfer into patients. PMID:23560068

  16. Selection of Shared and Neoantigen-Reactive T Cells for Adoptive Cell Therapy Based on CD137 Separation

    PubMed Central

    Seliktar-Ofir, Sivan; Merhavi-Shoham, Efrat; Itzhaki, Orit; Yunger, Sharon; Markel, Gal; Schachter, Jacob; Besser, Michal J.

    2017-01-01

    Adoptive cell therapy (ACT) of autologous tumor infiltrating lymphocytes (TIL) is an effective immunotherapy for patients with solid tumors, yielding objective response rates of around 40% in refractory patients with metastatic melanoma. Most clinical centers utilize bulk, randomly isolated TIL from the tumor tissue for ex vivo expansion and infusion. Only a minor fraction of the administered T cells recognizes tumor antigens, such as shared and mutation-derived neoantigens, and consequently eliminates the tumor. Thus, there are many ongoing effects to identify and select tumor-specific TIL for therapy; however, those approaches are very costly and require months, which is unreasonable for most metastatic patients. CD137 (4-1BB) has been identified as a co-stimulatory marker, which is induced upon the specific interaction of T cells with their target cell. Therefore, CD137 can be a useful biomarker and an important tool for the selection of tumor-reactive T cells. Here, we developed and validated a simple and time efficient method for the selection of CD137-expressing T cells for therapy based on magnetic bead separation. CD137 selection was performed with clinical grade compliant reagents, and TIL were expanded in a large-scale manner to meet cell numbers required for the patient setting in a GMP facility. For the first time, the methodology was designed to comply with both clinical needs and limitations, and its feasibility was assessed. CD137-selected TIL demonstrated significantly increased antitumor reactivity and were enriched for T cells recognizing neoantigens as well as shared tumor antigens. CD137-based selection enabled the enrichment of tumor-reactive T cells without the necessity of knowing the epitope specificity or the antigen type. The direct implementation of the CD137 separation method to the cell production of TIL may provide a simple way to improve the clinical efficiency of TIL ACT. PMID:29067023

  17. Tumor lymphocyte immune response to preoperative radiotherapy in locally advanced rectal cancer: The LYMPHOREC study.

    PubMed

    Mirjolet, C; Charon-Barra, C; Ladoire, S; Arbez-Gindre, F; Bertaut, A; Ghiringhelli, F; Leroux, A; Peiffert, D; Borg, C; Bosset, J F; Créhange, G

    2018-01-01

    Introduction : Some studies have suggested that baseline tumor-infiltrating-lymphocytes (TILs), such as CD8+ and FoxP3+ T-cells, may be associated with a better prognosis in colorectal cancer. We sought to investigate modulation of the immune response by preoperative radiotherapy (preopRT) and its impact on survival in locally advanced rectal cancer (LARC). Materials & Methods : We analyzed data for 237 patients with LARC who received RT. Density of TILS (CD8+ and FoxP3+) in intraepithelial (iTILs) and stromal compartments (sTILs) were evaluated from surgery pathological specimens and biopsies performed at baseline. The primary endpoint was to assess the impact of infiltration of the tumor or tumor site after preopRT on progression-free survival (PFS) and overall survival (OS). Secondary endpoints were the impact of dose fractionation scheme on TILs. Results : In univariate analysis, several factors significantly correlated (p<0.05) with PFS and/or OS (T-stage, M-stage, the delay between RT and surgery). A high level of post-treatment FoxP3+ TIL density correlated significantly with a better PFS (p = 0.007). In multivariate analysis, a decrease in the CD8+/FoxP3+ iTILs ratio after preopRT correlated with better PFS and OS (p = 0.049 and p = 0.024, respectively). More particularly, patients with a delta CD8+/FoxP3+ <-3.8 had better PFS and OS. Interestingly, the dose fractionation scheme significantly influenced the CD8 + /FoxP3 + ratio after treatment (p = 0.027) with a lower ratio with hypofractionated RT (≥2 Gy). Conclusion : Patients with LARC who had a significant decrease in the CD8+/FoxP3+ ratio after preopRT were more likely to live longer. This ratio needs to be validated prospectively to guide physicians in adjuvant treatment decision-making.

  18. Trans-cranial infrared laser stimulation induces hemodynamic and metabolic response measured by broadband near infrared spectroscopy in vivo on human forehead (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Wang, Xinlong; Nalawade, Sahil Sunil; Reddy, Divya Dhandapani; Tian, Fenghua; Gonzalez-Lima, F.; Liu, Hanli

    2017-02-01

    Transcranial infrared laser stimulation (TILS) uses infrared light (lasers or LEDs) for nondestructive and non-thermal photobiomodulation on the human brain. Although TILS has shown its beneficial effects to a variety of neurological and psychological conditions, its physiological mechanism remains unknown. Cytochrome-c-oxidase (CCO), the last enzyme in the electron transportation chain, is proposed to be the primary photoacceptor of this infrared laser. In this study, we wish to validate this proposed mechanism. We applied 8 minutes in vivo TILS on the right forehead of 11 human participants with a 1064-nm laser. Broad-band near infrared spectroscopy (bb-NIRS) from 740-900nm was also employed near the TILS site to monitor hemodynamic and metabolic responses during the stimulation and 5-minute recovery period. For rigorous comparison, we also performed similar 8-min bb-NIR measurements under placebo conditions. A multi-linear regression analysis based on the modified Beer-Lambert law was performed to estimate concentration changes of oxy-hemoglobin (Δ[HbO]), deoxy-hemoglobin (Δ[Hb]), and cytochrome-c-oxidase (Δ[CCO]). We found that TILS induced significant increases of [CCO], [HbO] and a decrease of [Hb] with dose-dependent manner as compared with placebo treatments. Furthermore, strong linear relationships or interplays between [CCO] versus [HbO] and [CCO] versus [Hb] induced by TILS were observed in vivo for the first time. These relationships have clearly revealed close coupling/relationship between the hemodynamic oxygen supply and blood volume versus up-regulation of CCO induced by photobiomodulation. Our results demonstrate the tremendous potential of bb-NIRS as a non-invasive in vivo means to study photobiomodulation mechanisms and perform treatment evaluations of TILS.

  19. LAG-3 in Non-Small-cell Lung Cancer: Expression in Primary Tumors and Metastatic Lymph Nodes Is Associated With Improved Survival.

    PubMed

    Hald, Sigurd M; Rakaee, Mehrdad; Martinez, Inigo; Richardsen, Elin; Al-Saad, Samer; Paulsen, Erna-Elise; Blix, Egil Støre; Kilvaer, Thomas; Andersen, Sigve; Busund, Lill-Tove; Bremnes, Roy M; Donnem, Tom

    2018-05-01

    Lymphocyte activation gene-3 (LAG-3) is an immune checkpoint receptor and a putative therapeutic target in non-small-cell lung cancer (NSCLC). We explored the prognostic effect of LAG-3 + tumor-infiltrating lymphocytes (TILs) in primary tumors and metastatic lymph nodes in NSCLC and its potential for inclusion in an immunoscore, supplementing the TNM classification. Primary tumor tissue from 553 stage I-IIIB NSCLC patients and 143 corresponding metastatic lymph nodes were collected. The expression of LAG-3 was evaluated by immunohistochemistry on tissue microarrays. On univariate analysis, LAG-3 + TILs in the intraepithelial and stromal compartments of primary tumors and in the intraepithelial and extraepithelial compartments of metastatic lymph nodes were associated with improved disease-specific survival (DSS). On multivariate analysis, stromal LAG-3 + TILs were a significant independent predictor of improved DSS (hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.43-0.82; P = .002). Stromal LAG-3 + TILs did not have prognostic impact across all pathologic stages. In the metastatic lymph nodes, intraepithelial (HR, 0.61; 95% CI, 0.38-0.99; P = .049) and extraepithelial (HR, 0.54; 95% CI, 0.29-0.70; P < .001) LAG-3 + TILs were independently associated with favorable DSS. LAG-3 + TILs are an independent positive prognostic factor in stage I-IIIB NSCLC. LAG-3 in metastatic lymph nodes is a candidate marker for an immunoscore in NSCLC. Copyright © 2017 Elsevier Inc. All rights reserved.

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

    Shi, Yang, E-mail: yangshi_xz@126.com; Song, Qingwei; Hu, Dianhe

    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-specificmore » 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.« less

  1. High Static Stability in the Mixed Layer Above the Extratropical Tropopause

    NASA Astrophysics Data System (ADS)

    Kunz, A.; Konopka, P.; Müller, R.; Pan, L. L.; Schiller, C.

    2009-04-01

    A strong relationship between the static stability N2 in the tropopause inversion layer (TIL) and the intensity of mixing is evident from in-situ observations during SPURT. With a new simple measure of mixing intensity based on O3/CO tracer correlations, a very high mixing intensity connected to a high N2 is found in the extratropical mixing layer. Using radiative transfer calculations we simulate the influence of trace gases such as O3 and H2O on the temperature gradient and thus on the static stability above the tropopause in an idealized (L-shaped) non-mixed and reference mixed atmosphere. N2 enhances due to an intensifying mixing in the LS. At the same time the temperature decreases together with a development of an inversion and the TIL. Hereby H2O plays the dominant role in maintenance the temperature inversion and the TIL structure. In case of non mixed profiles the TIL vanishes. The results motivate a link between the mixing layer and the TIL. The mixing layer contains on the one hand older air masses, with high values of N2 due to radiative adjustment. This part of the mixing layer is spatial identically to the TIL. On the other hand, there are younger air masses with somehow lower N2 values within the mixing layer, because of fast intrusion processes from the troposphere due to the permeability or so-called mid-latitude-breaks associated with the jet.

  2. 76 FR 16844 - Self-Regulatory Organizations; NASDAQ OMX BX, Inc.; Notice of Filing and Immediate Effectiveness...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-03-25

    ...)(4). ix. Exchange Rule 4751(h)(8) to reflect that ``good-til-market close'' \\6\\ orders must be available for entry and potential execution from 7 a.m. ET instead of 8 ET. \\6\\ ``Good-til-market close...

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

    PubMed Central

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

    2005-01-01

    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. PMID:15824085

  4. 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.

  5. Target-in-the-loop high-power adaptive phase-locked fiber laser array using single-frequency dithering technique

    NASA Astrophysics Data System (ADS)

    Tao, R.; Ma, Y.; Si, L.; Dong, X.; Zhou, P.; Liu, Z.

    2011-11-01

    We present a theoretical and experimental study of a target-in-the-loop (TIL) high-power adaptive phase-locked fiber laser array. The system configuration of the TIL adaptive phase-locked fiber laser array is introduced, and the fundamental theory for TIL based on the single-dithering technique is deduced for the first time. Two 10-W-level high-power fiber amplifiers are set up and adaptive phase locking of the two fiber amplifiers is accomplished successfully by implementing a single-dithering algorithm on a signal processor. The experimental results demonstrate that the optical phase noise for each beam channel can be effectively compensated by the TIL adaptive optics system under high-power applications and the fringe contrast on a remotely located extended target is advanced from 12% to 74% for the two 10-W-level fiber amplifiers.

  6. Simplified Screening Approach Identifies Mutated Proteins Expressed in Patient Tumors | Center for Cancer Research

    Cancer.gov

    Adoptive cell therapy using tumor-infiltrating lymphocytes (TILs) is a very effective treatment for patients with metastatic melanoma. In phase 2 clinical trials, up to 70 percent of patients with melanoma who received autologous TILs had considerable regressions of metastatic lesions. Recently, in another trial, 40 percent of patients treated had complete regressions of all measurable lesions lasting more than five years after treatment. Identifying antigens associated with TIL-mediated tumor regression has been a difficult task due to the diversity of these large lymphocyte populations and the complexity of current screening approaches.

  7. Computer-assisted stereology and automated image analysis for quantification of tumor infiltrating lymphocytes in colon cancer.

    PubMed

    Eriksen, Ann C; Andersen, Johnnie B; Kristensson, Martin; dePont Christensen, René; Hansen, Torben F; Kjær-Frifeldt, Sanne; Sørensen, Flemming B

    2017-08-29

    Precise prognostic and predictive variables allowing improved post-operative treatment stratification are missing in patients treated for stage II colon cancer (CC). Investigation of tumor infiltrating lymphocytes (TILs) may be rewarding, but the lack of a standardized analytic technique is a major concern. Manual stereological counting is considered the gold standard, but digital pathology with image analysis is preferred due to time efficiency. The purpose of this study was to compare manual stereological estimates of TILs with automatic counts obtained by image analysis, and at the same time investigate the heterogeneity of TILs. From 43 patients treated for stage II CC in 2002 three paraffin embedded, tumor containing tissue blocks were selected one of them representing the deepest invasive tumor front. Serial sections from each of the 129 blocks were immunohistochemically stained for CD3 and CD8, and the slides were scanned. Stereological estimates of the numerical density and area fraction of TILs were obtained using the computer-assisted newCAST stereology system. For the image analysis approach an app-based algorithm was developed using Visiopharm Integrator System software. For both methods the tumor areas of interest (invasive front and central area) were manually delineated by the observer. Based on all sections, the Spearman's correlation coefficients for density estimates varied from 0.9457 to 0.9638 (p < 0.0001), whereas the coefficients for area fraction estimates ranged from 0.9400 to 0.9603 (P < 0.0001). Regarding heterogeneity, intra-class correlation coefficients (ICC) for CD3+ TILs varied from 0.615 to 0.746 in the central area, and from 0.686 to 0.746 in the invasive area. ICC for CD8+ TILs varied from 0.724 to 0.775 in the central area, and from 0.746 to 0.765 in the invasive area. Exact objective and time efficient estimates of numerical densities and area fractions of CD3+ and CD8+ TILs in stage II colon cancer can be obtained by image

  8. 75 FR 78296 - Self-Regulatory Organizations; Notice of Filing and Immediate Effectiveness of Proposed Rule...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-12-15

    .... See PSX Rule 3301(h)(4). vi. PSX Rule 3301(h)(8) to reflect that ``good-til-market close'' \\6\\ orders must be available for entry and potential execution from 8 a.m. ET instead of 9 a.m. ET. \\6\\ ``Good-til...

  9. The prognostic values of tumor-infiltrating neutrophils, lymphocytes and neutrophil/lymphocyte rates in bladder urothelial cancer.

    PubMed

    Liu, Kangkang; Zhao, Kun; Wang, Lining; Sun, Erlin

    2018-05-20

    Tumor-infiltrating neutrophils (TINs) and lymphocytes (TILs) are found to play essential roles in many tumors and associate with the prognosis of patients. But, the prognostic values of TINs, TILs and NLR (neutrophils-lymphocytes ratio) in bladder cancer (BC) are still undefined. The object of our study was to systematically interrogate the associations of these immune cells with clinical outcomes of BC patients. In our study, a total of 102 patients pathologically diagnosed with BC were included. CD66b + and CD8 + antibodies were used to mark neutrophils and CD8 + lymphocytes by immunohistochemistry. The results found that TINs and NLR were significantly associated with pathological T-stages of tumors (P < 0.01), but TILs were not. And TINs were also related to pathological tumor grades (P = 0.012). Regarding the prognostic values, TINs was related to the high risk of recurrence in non-muscle invasive BC (NMIBC) patients. Elevated TINs and NLR were associated with poor overall survivals of BC patients, whereas higher TILs were related to longer survivals (P < 0.01). Multivariate analysis showed that both of TINs (HR 2.427, 1.024-5.752, P = 0.044) and NLR (HR 3.529, 1.147-10.864, P = 0.028) were independent unfavorable prognosis markers. In conclusion, Tumor infiltrating immune cells, including TINs, TILs and NLR were important markers in predicting the prognosis of bladder cancer patients. TINs and NLR were more likely to be negative predictors, but TILs were favorable in patients with BC. Copyright © 2018 Elsevier GmbH. All rights reserved.

  10. Outcomes of Adoptive Cell Transfer With Tumor-infiltrating Lymphocytes for Metastatic Melanoma Patients With and Without Brain Metastases.

    PubMed

    Mehta, Gautam U; Malekzadeh, Parisa; Shelton, Thomas; White, Donald E; Butman, John A; Yang, James C; Kammula, Udai S; Goff, Stephanie L; Rosenberg, Steven A; Sherry, Richard M

    2018-06-01

    Brain metastases cause significant morbidity and mortality in patients with metastatic melanoma. Although adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TIL) can achieve complete and durable remission of advanced cutaneous melanoma, the efficacy of this therapy for brain metastases is unclear. Records of patients with M1c melanoma treated with ACT using TIL, including patients with treated and untreated brain metastases, were analyzed. Treatment consisted of preparative chemotherapy, autologous TIL infusion, and high-dose interleukin-2. Treatment outcomes, sites of initial tumor progression, and overall survival were analyzed. Among 144 total patients, 15 patients with treated and 18 patients with untreated brain metastases were identified. Intracranial objective responses (OR) occurred in 28% patients with untreated brain metastases. The systemic OR rates for patients with M1c disease without identified brain disease, treated brain disease, and untreated brain disease, and were 49%, 33% and 33%, respectively, of which 59%, 20% and 16% were durable at last follow-up. The site of untreated brain disease was the most likely site of initial tumor progression (61%) in patients with untreated brain metastases. Overall, we found that ACT with TIL can eliminate small melanoma brain metastases. However, following TIL therapy these patients frequently progress in the brain at a site of untreated brain disease. Patients with treated or untreated brain disease are less likely to achieve durable systemic ORs following TIL therapy compared with M1c disease and no history of brain disease. Melanoma brain metastases likely require local therapy despite the systemic effect of ACT.

  11. The importance of the tropopause inversion layer in double tropopause formation, an observational analysis

    NASA Astrophysics Data System (ADS)

    Peevey, T. R.; Gille, J. C.

    2012-12-01

    Over the past decade the tropopause inversion layer (TIL), a layer of enhanced stability above the thermal tropopause, has been studied in earnest. This atmospheric feature is located within the upper troposphere lower stratosphere (UTLS) region of the atmosphere, a region of key importance for the Earth's radiative budget and hence the climate system. Another atmospheric feature of similar interest to the UTLS community is the double tropopause (DT). A recent modeling studied looked at the development of the DT during the LC1 and LC2 lifecycles and found that the DT would not form without the presence of the TIL and that as the TIL increased in strength so did the DT frequency. This study builds on that recent work by analyzing this relationship using observations to first see if the relationship exists and then to understand why it does exist. For this study HIRDLS temperature data is primarily used and shows that as the strength/stability of the TIL increases in the extratropics so does the frequency of DTs. Other datasets, such as COSMIC and WACCM, are also used in this work to verify these results since HIRDLS could miss shallow (<1 km) TIL layers. The relationship between the TIL and the DT is analyzed further by examining vertical profiles within specified latitude regions and by examining events that specifically highlight their relationship. Further research is already planned which will expand upon this study using model simulations to track air movement within these UTLS structures.

  12. Quantifying expert diagnosis variability when grading tumor-infiltrating lymphocytes

    NASA Astrophysics Data System (ADS)

    Toro, Paula; Corredor, Germán.; Wang, Xiangxue; Arias, Viviana; Velcheti, Vamsidhar; Madabhushi, Anant; Romero, Eduardo

    2017-11-01

    Tumor-infiltrating lymphocytes (TILs) have proved to play an important role in predicting prognosis, survival, and response to treatment in patients with a variety of solid tumors. Unfortunately, currently, there are not a standardized methodology to quantify the infiltration grade. The aim of this work is to evaluate variability among the reports of TILs given by a group of pathologists who examined a set of digitized Non-Small Cell Lung Cancer samples (n=60). 28 pathologists answered a different number of histopathological images. The agreement among pathologists was evaluated by computing the Kappa index coefficient and the standard deviation of their estimations. Furthermore, TILs reports were correlated with patient's prognosis and survival using the Pearson's correlation coefficient. General results show that the agreement among experts grading TILs in the dataset is low since Kappa values remain below 0.4 and the standard deviation values demonstrate that in none of the images there was a full consensus. Finally, the correlation coefficient for each pathologist also reveals a low association between the pathologists' predictions and the prognosis/survival data. Results suggest the need of defining standardized, objective, and effective strategies to evaluate TILs, so they could be used as a biomarker in the daily routine.

  13. 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

  14. Status of prototype of SG-III high-power solid-state laser

    NASA Astrophysics Data System (ADS)

    Yu, Haiwu; Jing, Feng; Wei, Xiaofeng; Zheng, Wanguo; Zhang, Xiaomin; Sui, Zhan; Li, Mingzhong; Hu, Dongxia; He, Shaobo; Peng, Zhitao; Feng, Bin; Zhou, Hai; Guo, Liangfu; Li, Xiaoqun; Su, Jingqin; Zhao, Runchang; Yang, Dong; Zheng, Kuixing; Yuan, Xiaodong

    2008-10-01

    We are currently developing a large aperture neodymium-glass based high-power solid state laser, Shenguang-III (SG-III), which will be used to provide extreme conditions for high-energy-density physical experiments in China. As a baseline design, SG-III will be composed of 48 beams arranged in 6 bundles with each beam aperture of 40cm×40cm. A prototype of SG-III (TIL-Technical Integration experimental Line) was developed from 2000, and completed in 2007. TIL is composed of 8 beams (four in vertical and two in horizontal), with each square aperture of 30cm×30cm. After frequency tripling, TIL has delivered about 10kJ in 0.351 μm at 1 ns pulsewidth. As an operational laser facility, TIL has a beam divergence of 70 μrad (focus length of 2.2m, i.e., 30DL) and pointing accuracy of 30 μm (RMS), and meets the requirements of physical experiments.

  15. Coherent beam combining of collimated fiber array based on target-in-the-loop technique

    NASA Astrophysics Data System (ADS)

    Li, Xinyang; Geng, Chao; Zhang, Xiaojun; Rao, Changhui

    2011-11-01

    Coherent beam combining (CBC) of fiber array is a promising way to generate high power and high quality laser beams. Target-in-the-loop (TIL) technique might be an effective way to ensure atmosphere propagation compensation without wavefront sensors. In this paper, we present very recent research work about CBC of collimated fiber array using TIL technique at the Key Lab on Adaptive Optics (KLAO), CAS. A novel Adaptive Fiber Optics Collimator (AFOC) composed of phase-locking module and tip/tilt control module was developed. CBC experimental setup of three-element fiber array was established. Feedback control is realized using stochastic parallel gradient descent (SPGD) algorithm. The CBC based on TIL with piston and tip/tilt correction simultaneously is demonstrated. And the beam pointing to locate or sweep position of combined spot on target was achieved through TIL technique too. The goal of our work is achieve multi-element CBC for long-distance transmission in atmosphere.

  16. 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

  17. Long-Lasting Complete Responses in Patients with Metastatic Melanoma after Adoptive Cell Therapy with Tumor-Infiltrating Lymphocytes and an Attenuated IL2 Regimen.

    PubMed

    Andersen, Rikke; Donia, Marco; Ellebaek, Eva; Borch, Troels Holz; Kongsted, Per; Iversen, Trine Zeeberg; Hölmich, Lisbet Rosenkrantz; Hendel, Helle Westergren; Met, Özcan; Andersen, Mads Hald; Thor Straten, Per; Svane, Inge Marie

    2016-08-01

    Adoptive cell transfer therapy (ACT) based on autologous tumor-infiltrating lymphocytes (TIL) has achieved impressive clinical results in several phase I and II trials performed outside of Europe. Although transient, the toxicities associated with high-dose (HD) bolus IL2 classically administered together with TILs are severe. To further scrutinize whether similar results can be achieved with lower doses of IL2, we have carried out a phase I/II trial of TIL transfer after classical lymphodepleting chemotherapy followed by an attenuated IL2 regimen. Twenty-five patients with progressive treatment-refractory metastatic melanoma, good clinical performance, age < 70 years, and at least one resectable metastasis were eligible. TIL infusion was preceded by standard lymphodepleting chemotherapy and followed by attenuated doses of IL2 administered in an intravenous, continuous decrescendo regimen (ClinicalTrials.gov Identifier: NCT00937625). Classical IL2-related toxicities were observed but patients were manageable in a general oncology ward without the need for intervention from the intensive care unit. RECIST 1.0 evaluation displayed three complete responses and seven partial responses (ORR 42%). Median overall survival was 21.8 months. Tumor regression was associated with a higher absolute number of infused tumor-reactive T cells. Moreover, induction and persistence of antimelanoma T-cell responses in the peripheral blood was strongly correlated to clinical response to treatment. TIL-ACT with a reduced IL2 decrescendo regimen results in long-lasting complete responses in patients with treatment-refractory melanoma. Larger randomized trials are needed to elucidate whether clinical efficacy is comparable with TIL-ACT followed by HD bolus IL2. Clin Cancer Res; 22(15); 3734-45. ©2016 AACR. ©2016 American Association for Cancer Research.

  18. Impact of Diclofenac Sodium on Tilmicosin-Induced Acute Cardiotoxicity in Rats (Tilmicosin and Diclofenac Cardiotoxicity).

    PubMed

    Oda, Samah S; Derbalah, Amira E

    2018-02-01

    To assess the influence of diclofenac sodium (DIC) treatment on tilmicosin (TIL) prompted cardiotoxicity, forty albino rats were randomly divided into four equal groups: control, TIL group (single subcutaneous injection of 75 mg/kg BW tilmicosin phosphate 30%), TIL + DIC group (single subcutaneous injection of tilmicosin phosphate 30% and then injection intramuscularly of 13.5 mg/kg BW/day for 6 days diclofenac sodium) and DIC group (intramuscular injection of 13.5 mg/kg BW/day diclofenac sodium for 6 days). Creatine kinase-MB, lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, urea and creatinine significantly elevated in all treated groups, but markedly in TIL + DIC group serum. Lipid peroxidation significantly increased, and reduced glutathione significantly decreased in tissues of all groups. Several histopathological alterations were noticed in heart, liver, kidneys and lungs of all treated groups, particularly TIL + DIC group. Ultrastructurally, myocardium of TIL and TIL + DIC groups showed characteristic changes for myocardial apoptosis and degeneration. Significant differences were detected in area percentage of caspase-3 protein expression and bcl-2 immunoreactivity in cardiomyocytes, particularly in TIL + DIC group. This study is the first to indicate that one of the possible mechanisms of TIL cardiotoxicity is myocardial apoptosis. DIC amplifies TIL-induced cardiotoxicity besides its hepato-nephrotoxicity.

  19. Pharmacokinetics of tilmicosin in healthy pigs and in pigs experimentally infected with Haemophilus parasuis

    PubMed Central

    Zhang, Ling; Zhao, Li; Liu, Yonghong; Liu, Junfeng

    2017-01-01

    A comparative in vivo pharmacokinetic (PK) study of tilmicosin (TIL) was conducted in 6 crossbred healthy pigs and 6 crossbred pigs infected with Haemophilus (H.) parasuis following oral administration of a single 40 mg/kg dose. The infected model was established by intranasal inoculation and confirmed by clinical signs, blood biochemistry, and microscopic examinations. Plasma TIL concentrations were determined by a validated high-performance liquid chromatography method with ultraviolet detection at 285 nm. PK parameters were calculated by using WinNonlin software. After TIL administration, the main PK parameters of TIL in healthy and H. parasuis-infected pigs were as follows: Area under the concentration-time curve, maximal drug concentration, half-life of the absorption phase, half-life of the distribution phase, and half-life of the elimination phase were 34.86 ± 9.69 vs. 28.73 ± 6.18 µg · h/mL, 1.77 ± 0.33 vs. 1.67 ± 0.28 µg/mL, 2.27 ± 0.45 vs. 2.24 ± 0.44 h, 5.35 ± 1.40 vs. 4.61 ± 0.35 h, and 43.53 ± 8.17 vs. 42.05 ± 9.36 h, respectively. These results of this exploratory study suggest that there were no significant differences between the PK profiles of TIL in the healthy and H. parasuis-infected pigs. PMID:28385011

  20. Pharmacokinetics of tilmicosin in healthy pigs and in pigs experimentally infected with Haemophilus parasuis.

    PubMed

    Zhang, Ling; Zhao, Li; Liu, Yonghong; Liu, Junfeng; Li, Xianqiang

    2017-12-31

    A comparative in vivo pharmacokinetic (PK) study of tilmicosin (TIL) was conducted in 6 crossbred healthy pigs and 6 crossbred pigs infected with Haemophilus ( H .) parasuis following oral administration of a single 40 mg/kg dose. The infected model was established by intranasal inoculation and confirmed by clinical signs, blood biochemistry, and microscopic examinations. Plasma TIL concentrations were determined by a validated high-performance liquid chromatography method with ultraviolet detection at 285 nm. PK parameters were calculated by using WinNonlin software. After TIL administration, the main PK parameters of TIL in healthy and H. parasuis -infected pigs were as follows: Area under the concentration-time curve, maximal drug concentration, half-life of the absorption phase, half-life of the distribution phase, and half-life of the elimination phase were 34.86 ± 9.69 vs. 28.73 ± 6.18 μgㆍh/mL, 1.77 ± 0.33 vs. 1.67 ± 0.28 μg/mL, 2.27 ± 0.45 vs. 2.24 ± 0.44 h, 5.35 ± 1.40 vs. 4.61 ± 0.35 h, and 43.53 ± 8.17 vs. 42.05 ± 9.36 h, respectively. These results of this exploratory study suggest that there were no significant differences between the PK profiles of TIL in the healthy and H. parasuis -infected pigs.

  1. U.S. EPA, Pesticide Product Label, , 07/24/1990

    EPA Pesticide Factsheets

    2011-04-21

    ... PII'IIlta _ CIIIlta 1Il8I: In. 1I1I1l11eICEIJ: III.' Inl Milia.. II lim .1811 •. ... Ell. • DI ..... 1111 lII.e II Fla. ... aD II-.t fOIn. FII CIIu.:L _let til iECl ... file( IF til EIIII 11M. ...

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

    PubMed Central

    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.

    2014-01-01

    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. PMID:24667641

  3. Tropopause Inversion Layer and Stratosphere-Troposphere Exchange in Baroclinic Life Cycles: The Role of Diabatic Processes

    NASA Astrophysics Data System (ADS)

    Kunkel, D.; Hoor, P. M.; Wirth, V.

    2014-12-01

    Observations and model simulations of temperature and tracer profiles in the extratropical upper troposphere/lower stratosphere (UTLS) show the presence of an inversion layer just above the thermal tropopause, i.e., the tropopause inversion layer (TIL), which is situated in a region affected by stratosphere-troposphere exchange (STE). Moreover, from a dynamical perspective the extratropical UTLS is highly affected by baroclinic life cycles. Since both the TIL and STE emerge, amongst many other features, during simulated baroclinic life cycles, we study whether there is a relationship between the TIL and STE. We use the non-hydrostatic model COSMO in an idealized mid-latitude channel configuration to simulate baroclinic life cycles. In a first step contributions of individual diabatic processes from turbulence, radiation, and cloud microphysics to the formation of the TIL are analyzed. These results are compared to those from adiabatic simulations in which the TIL forms during the life cycles with the limitation of being less sharp than in observations. Furthermore, passive tropospheric and stratospheric tracers are used to identify STE. Regions of STE are then analyzed with respect to the temporal evolution of the static stability above the tropopause. The results suggest that radiative effects, especially from water vapor, have the largest additional contribution to the TIL formation, while additional individual effects of cloud microphysics are almost negligible. STE occurs in all diabatic simulations but its strength depends highly on how the underlying diabatic process can affect the thermal and dynamical structure in the tropopause region. Weak STE is found when considering cloud microphysics, while STE is stronger in case of using turbulence and radiation. Tropopause-based vertical profiles of the tropospheric tracers show in some cases similarities with observed tracer profiles of CO.

  4. Local CD34-positive capillaries decrease in mouse models of kidney disease associating with the severity of glomerular and tubulointerstitial lesions.

    PubMed

    Masum, Md Abdul; Ichii, Osamu; Elewa, Yaser Hosny Ali; Nakamura, Teppei; Kon, Yasuhiro

    2017-09-04

    The renal vasculature plays important roles in both homeostasis and pathology. In this study, we examined pathological changes in the renal microvascular in mouse models of kidney diseases. Glomerular lesions (GLs) in autoimmune disease-prone male BXSB/MpJ-Yaa (Yaa) mice and tubulointerstitial lesions (TILs) in male C57BL/6 mice subjected to unilateral ureteral obstruction (UUO) for 7 days were studied. Collected kidneys were examined using histopathological techniques. A nonparametric Mann-Whitney U test (P < 0.05) was performed to compare healthy controls and the experimental mice. The Kruskal-Wallis test was used to compare three or more groups, and multiple comparisons were performed using Scheffe's method when significant differences were observed (P < 0.05). Yaa mice developed severe autoimmune glomerulonephritis, and the number of CD34 + glomerular capillaries decreased significantly in GLs compared to that in control mice. However, UUO-treated mice showed severe TILs only, and CD34 + tubulointerstitial capillaries were decreased significantly in TILs with the progression of tubulointerstitial fibrosis compared to those in untreated control kidneys. Infiltrations of B-cells, T-cells, and macrophages increased significantly in the respective lesions of both disease models (P < 0.05). In observations of vascular corrosion casts by scanning electron microscopy and of microfil rubber-perfused thick kidney sections by fluorescence microscopy, segmental absences of capillaries were observed in the GLs and TILs of Yaa and UUO-treated mice, respectively. Further, transmission electron microscopy revealed capillary endothelial injury in the respective lesions of both models. The numbers of CD34 + glomerular and tubulointerstitial capillaries were negatively correlated with all examined parameters in GLs (P < 0.05) and TILs (P < 0.01), respectively. From the analysis of mouse models, we identified inverse pathological correlations between the number of

  5. Characterization of tumor-associated T-lymphocyte subsets and immune checkpoint molecules in head and neck squamous cell carcinoma

    PubMed Central

    Thelen, Martin; Reuter, Sabrina; Zentis, Peter; Shimabukuro-Vornhagen, Alexander; Theurich, Sebastian; Wennhold, Kerstin; Garcia-Marquez, Maria; Tharun, Lars; Quaas, Alexander; Schauss, Astrid; Isensee, Jörg; Hucho, Tim; Huebbers, Christian

    2017-01-01

    The composition of tumor-infiltrating lymphocytes (TIL) reflects biology and immunogenicity of cancer. Here, we characterize T-cell subsets and expression of immune checkpoint molecules in head and neck squamous cell carcinoma (HNSCC). We analyzed TIL subsets in primary tumors (n = 34), blood (peripheral blood mononuclear cells (PBMC); n = 34) and non-cancerous mucosa (n = 7) of 34 treatment-naïve HNSCC patients and PBMC of 15 healthy controls. Flow cytometry analyses revealed a highly variable T-cell infiltration mainly of an effector memory phenotype (CD45RA−/CCR7−). Naïve T cells (CD45RA+/CCR7+) were decreased in the microenvironment compared to PBMC of patients, while regulatory T cells (CD4+/CD25+/CD127low and CD4+/CD39+) were elevated. Furthermore, we performed digital image analyses of entire cross sections of HNSCC to define the ‘Immunoscore’ (CD3+ and CD8+ cell infiltration in tumor core and invasive margin) and quantified MHC class I expression on tumor cells by immunohistochemistry. Immune checkpoint molecules cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death 1 (PD-1) and programmed cell death 1 ligand 1 (PD-L1) were increased in TILs compared to peripheral T cells in flow-cytometric analysis. Human papillomavirus (HPV) positive tumors showed higher numbers of TILs, but a similar composition of T-cell subsets and checkpoint molecule expression compared to HPV negative tumors. Taken together, the tumor microenvironment of HNSCC is characterized by a strong infiltration of regulatory T cells and high checkpoint molecule expression on T-cell subsets. In view of increasingly used immunotherapies, a detailed knowledge of TILs and checkpoint molecule expression on TILs is of high translational relevance. PMID:28574843

  6. Simplified Screening Approach Identifies Mutated Proteins Expressed in Patient Tumors | Center for Cancer Research

    Cancer.gov

    Adoptive cell therapy using tumor-infiltrating lymphocytes (TILs) is a very effective treatment for patients with metastatic melanoma. In phase 2 clinical trials, up to 70 percent of patients with melanoma who received autologous TILs had considerable regressions of metastatic lesions. Recently, in another trial, 40 percent of patients treated had complete regressions of all

  7. Mutated PPP1R3B is recognized by T cells used to treat a melanoma patient who experienced a durable complete tumor regression

    PubMed Central

    Lu, Yong-Chen; Yao, Xin; Li, Yong F.; El-Gamil, Mona; Dudley, Mark E.; Yang, James C.; Almeida, Jorge R.; Douek, Daniel C.; Samuels, Yardena; Rosenberg, Steven A.; Robbins, Paul F.

    2013-01-01

    Adoptive cell therapy with tumor infiltrating lymphocytes (TILs) represents an effective treatment for patients with metastatic melanoma. However, most of the antigen targets recognized by effective melanoma reactive TILs remain elusive. In this study, patient 2369 experienced a complete response, including regressions of bulky liver tumor masses ongoing beyond seven years following adoptive TILs transfer. The screening of a cDNA library generated from the autologous melanoma cell line resulted in the isolation of a mutated PPP1R3B (protein phosphatase 1, regulatory (inhibitor) subunit 3B) gene product. The mutated PPP1R3B peptide represents the immunodominant epitope recognized by tumor reactive T cells in TIL 2369. Five years following adoptive transfer, peripheral blood T lymphocytes obtained from patient 2369 recognized the mutated PPP1R3B epitope. These results demonstrate that adoptive T cell therapy targeting a tumor-specific antigen can mediate long-term survival for a patient with metastatic melanoma. This study also provides an impetus to develop personalized immunotherapy targeting tumor-specific, mutated antigens. PMID:23690473

  8. Triggering co-stimulation directly in melanoma tumor fragments drives CD8+ tumor-infiltrating lymphocyte expansion with improved effector-memory properties.

    PubMed

    Chacon, Jessica Ann; Sarnaik, Amod A; Pilon-Thomas, Shari; Radvanyi, Laszlo

    2015-12-01

    TIL from solid tumors can express activation/co-stimulatory molecules like 4-1BB/CD137, a sign of recent antigenic stimulation in the tumor microenvironment (TME). This activated state can be exploited ex vivo to enhance the expansion of tumor-reactive CD8 + TIL for adoptive cell therapy through direct addition of immunomodulators to tumor fragments in culture.

  9. Impact of diabatic processes on the tropopause inversion layer formation in baroclinic life cycles

    NASA Astrophysics Data System (ADS)

    Kunkel, Daniel; Hoor, Peter; Wirth, Volkmar

    2015-04-01

    Observations of temperature profiles in the extratropical upper troposphere/lower stratosphere (UTLS) show the presence of an inversion layer just above the thermal tropopause, i.e., the tropopause inversion layer (TIL). In recent studies both diabatic and adiabatic processes have been identified to contribute to the formation of this layer. In particular, adiabatic simulations indicate a TIL formation without the explicit simulation of diabatic, i.e. radiative or humidity related, processes after wave breaking during baroclinic life cycles. One goal of this study is to assess the additional contribution of diabatic processes to the formation and strength of the TIL in such life cycles. Moreover, since irreversible stratosphere-troposphere exchange (STE) is another inherent feature of baroclinic life cycles and a consequence of diabatic processes, we study whether there is a relationship between STE and TIL. We use the non-hydrostatic model COSMO in an idealized mid-latitude channel configuration to simulate baroclinic life cycles. In a first step contributions of individual diabatic processes from turbulence, radiation, and cloud microphysics to the formation of the TIL are analyzed. These results are compared to those from adiabatic simulations of baroclinic life cycles in which the TIL forms during the life cycle with the limitation of being less sharp than in observations. In a second step the combined effects of several diabatic processes are studied to further include interactions between these processes as well as to advance towards a more realistic model setup. The results suggest a much more vigorous development of the TIL due to microphysics and the release of latent heat. Moreover, radiative effects can foster an increase in static stability above the thermal tropopause when large gradients of either water vapor or cloud ice are present at the level of the tropopause. By additionally adding sub-grid scale turbulence, a co-location of high static

  10. Evaluation of T-lymphocyte subpopulations in actinic keratosis, in situ and invasive squamous cell carcinoma of the skin.

    PubMed

    Stravodimou, Aristea; Tzelepi, Vassiliki; Papadaki, Helen; Mouzaki, Athanasia; Georgiou, Sophia; Melachrinou, Maria; Kourea, Eleni P

    2018-05-01

    Tumor infiltrating lymphocytes (TILs) represent important regulators of carcinogenesis. Cutaneous invasive squamous cell carcinoma (inSCC) develops through precursor lesions, namely in situ squamous cell carcinoma (isSCC) and actinic keratosis (AK), representing a natural model of carcinogenesis. The study evaluates TIL subpopulations in inSCC and its precursors by comparing 2 semiquantitative scoring systems, and assesses the presence of regulatory T-cells (Tregs) in these lesions. Paraffin sections from 33 cases of AK, 19 isSCCs and 34 inSCCs with adjacent precursor lesions or normal skin (NS) were immunostained for CD3, CD4, CD8 and Foxp3. TIL subgroups were evaluated by the semiquantitative Klintrup-Mäkinen (K-M) score, and by a more detailed modification of this system. Treg counts were assessed by image analysis quantification. An increase of all TIL subpolulations from precursor lesions toward inSCC was shown by both scoring systems. Treg counts progressively increased from NS to AK and isSCC, but decreased in inSCC. Tregs were more numerous in pT2 and around indolent inSCCs compared to T1 and aggressive subtypes. T-cells and cytotoxic T-cells progressively increase in cutaneous squamous cell carcinogenesis, while Treg counts diminish in inSCC. The K-M score is an appropriate, easily applicable TIL scoring system in cutaneous inSCC. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  11. Adoptive cell transfer using autologous tumor infiltrating lymphocytes in gynecologic malignancies.

    PubMed

    Mayor, Paul; Starbuck, Kristen; Zsiros, Emese

    2018-05-23

    During the last decade, the field of cancer immunotherapy has been entirely transformed by the development of new and more effective treatment modalities with impressive response rates and the prospect of long survival. One of the major breakthroughs is adoptive cell transfer (ACT) based on autologous T cells derived from tumor-infiltrating lymphocytes (TILs). TIL-based ACT is a highly personalized cancer treatment. T cells are harvested from autologous fresh tumor tissues, and after ex vivo activation and extensive expansion, are reinfused to patients. TIL-based therapies have only been offered in small phase I/II studies in a few centers given the highly specialized care required, the complexity of TIL production and the very intensive nature of the three-step treatment protocol. The treatment includes high-dose lymphodepleting chemotherapy, the infusion of the expanded and activated T cells and interleukin-2 (IL-2) injections to increase survival of the T cells. Despite the limited data on ACT, the small published studies consistently confirm an impressive clinical response rate of up to 50% in metastatic melanoma patients, including a significant proportion of patients with durable complete response. These remarkable results justify the need for larger clinical trials in other solid tumors, including gynecologic malignancies. In this review we provide an overview of the current clinical results, future applications of TIL-based ACT in gynecologic malignancies, and on risks and challenges associated with modern T cell therapy. Copyright © 2018. Published by Elsevier Inc.

  12. Programmed death ligand 1 expression and CD8+ tumor-infiltrating lymphocyte density differences between paired primary and brain metastatic lesions in non-small cell lung cancer.

    PubMed

    Zhou, Jie; Gong, Zhihua; Jia, Qingzhu; Wu, Yan; Yang, Zhen-Zhou; Zhu, Bo

    2018-04-15

    Immunotherapy targeting the programmed cell death-1/programmed death ligand 1(PD-L1) pathway has shown promising antitumor activity in brain metastases (BMs) of non-small cell lung cancer (NSCLC) patients with an acceptable safety profile; however, the response rates often differ between primary lesions and intracranial lesions. Studies are necessary to identify detailed characterizations of the response biomarkers. In this study, we aimed to compare the differences of PD-L1 expression and CD8 + tumor-infiltrating lymphocyte (TIL) density, two major response biomarkers of PD-1/PD-L1 blockade, between paired primary and brain metastatic lesions in advanced NSCLC. We observed that among primary lesions or BMs, only a small number of patients harbored common PD-L1 expression on both tumor cells and tumor-infiltrating immune cells. Additionally, we found that the numbers of CD8 + TILs were significantly fewer in BMs than in primary lung cancers. Low stromal CD8 + TIL numbers in BMs were associated with significantly shorter overall survival compared to high stromal CD8 + TIL counts. Notably, we demonstrated a discrepancy in PD-L1 expression and CD8 + TIL density between primary lung cancers and their corresponding BMs. Such heterogeneities are significantly associated with the time at which BMs occurred. Our study emphasizes the spatial and temporal heterogeneity of biomarkers for anti-PD-1/PD-L1 therapy, which should be concerned in clinical practice. Copyright © 2018 Elsevier Inc. All rights reserved.

  13. '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…

  14. Triggering co-stimulation directly in melanoma tumor fragments drives CD8+ tumor-infiltrating lymphocyte expansion with improved effector-memory properties

    PubMed Central

    Chacon, Jessica Ann; Sarnaik, Amod A; Pilon-Thomas, Shari; Radvanyi, Laszlo

    2015-01-01

    TIL from solid tumors can express activation/co-stimulatory molecules like 4–1BB/CD137, a sign of recent antigenic stimulation in the tumor microenvironment (TME). This activated state can be exploited ex vivo to enhance the expansion of tumor-reactive CD8+ TIL for adoptive cell therapy through direct addition of immunomodulators to tumor fragments in culture. PMID:26587314

  15. Evaluation of the Immunologic Impact of RAF Inhibitors to Guide Optimal Combination of RAF Inhibitors and Immunotherapy for the Treatment of Advanced Melanoma

    DTIC Science & Technology

    2016-03-01

    TILS (Vehicle) Fr eq o f P ar en t CD4+ T cells CD4+CD25+Foxp3+ CD8+ CD8+PD1+ CD8+GrzB...PDL1+ CD 4+ T ce lls CD 4+ CD 25 +F ox p3 + CD 8+ CD 8+ PD 1+ CD 8+ Gr zB + CD 8+ Ki6 7+ 0 10 20 30 40 Day 5 - TILS (BRAFi) Fr eq o f P ar en t...ce lls CD 4+ CD 25 +F ox p3 + CD 8+ CD 8+ PD 1+ CD 8+ Gr zB + CD 8+ Ki6 7+ 0 10 20 30 40 Day 2 - TILS (Vehicle) Fr eq o f P ar en t CD4+ T cells

  16. Treating Cancer with Genetically Engineered T Cells

    PubMed Central

    Park, Tristen S.; Rosenberg, Steven A.; Morgan, Richard A.

    2011-01-01

    Administration of ex-vivo cultured, naturally occurring tumor-infiltrating lymphocytes (TILs) have been shown to mediate durable regression of melanoma tumors. However, the generation of TIL is not possible in all patients and there has been limited success in generating TIL in other cancers. Advances in genetic engineering have overcome these limitations by introducing tumor-antigen-targeting receptors into human T lymphocytes. Physicians can now genetically engineer lymphocytes to express highly active T-cell receptors (TCRs) or chimeric antigen receptors (CARs) targeting a variety of tumor antigens expressed in cancer patients. In this review we discuss the development of TCR and CAR gene transfer technology and the expansion of these therapies into different cancers with the recent demonstration of the clinical efficacy of these treatments. PMID:21663987

  17. Phase I trial of adoptively transferred tumor-infiltrating lymphocyte immunotherapy following concurrent chemoradiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma

    PubMed Central

    Li, Jiang; Chen, Qiu-Yan; He, Jia; Li, Ze-Lei; Tang, Xiao-Feng; Chen, Shi-Ping; Xie, Chuan-Miao; Li, Yong-Qiang; Huang, Li-Xi; Ye, Shu-bio; Ke, Miao-La; Tang, Lin-Quan; Liu, Huai; Zhang, Lu; Guo, Shan-Shan; Xia, Jian-Chuan; Zhang, Xiao-Shi; Zheng, Li-Min; Guo, Xiang; Qian, Chao-Nan; Mai, Hai-Qiang; Zeng, Yi-Xin

    2015-01-01

    Adoptive cell therapy (ACT) for cancers using autologous tumor-infiltrating lymphocytes (TILs) can induce immune responses and antitumor activity in metastatic melanoma patients. Here, we aimed to assess the safety and antitumor activity of ACT using expanded TILs following concurrent chemoradiotherapy (CCRT) in patients with locoregionally advanced nasopharyngeal carcinoma (NPC). Twenty-three newly diagnosed, locoregionally advanced NPC patients were enrolled, of whom 20 received a single-dose of TIL infusion following CCRT. All treated patients were assessed for toxicity, survival and clinical and immunologic responses. Correlations between immunological responses and treatment effectiveness were further studied. Only mild adverse events (AEs), including Grade 3 neutropenia (1/23, 5%) consistent with immune-related causes, were observed. Nineteen of 20 patients exhibited an objective antitumor response, and 18 patients displayed disease-free survival longer than 12 mo after ACT. A measurable plasma Epstein–Barr virus (EBV) load was detected in 14 patients at diagnosis, but a measurable EBV load was not found in patients after one week of ACT, and the plasma EBV load remained undetectable in 17 patients at 6 mo after ACT. Expansion and persistence of T cells specific for EBV antigens in peripheral blood following TIL therapy were observed in 13 patients. The apparent positive correlation between tumor regression and the expansion of T cells specific for EBV was further investigated in four patients. This study shows that NPC patients can tolerate ACT with TILs following CCRT and that this treatment results in sustained antitumor activity and anti-EBV immune responses. A larger phase II trial is in progress. PMID:25949875

  18. The double tropopause and its dynamical relationship to the tropopause inversion layer in storm track regions

    NASA Astrophysics Data System (ADS)

    Peevey, T. R.; Gille, J. C.; Homeyer, C. R.; Manney, G. L.

    2014-09-01

    Using High Resolution Dynamic Limb Sounder observations and ERA-Interim reanalysis this study demonstrates that the warm conveyor belt (WCB) is a mechanism responsible for the relationship between the double tropopause (DT) and the tropopause inversion layer (TIL), a relationship recently suggested in the literature based on idealized model simulations of baroclinic disturbances. Using these data sets, spatial and temporal characteristics of the DT-TIL relationship are examined over a 3 year period, 2005-2008. In the extratropics, results from satellite data show that as the TIL increases in strength, so does the frequency of the DT, regardless of season or hemisphere. The inverse relationship is found in the tropics. Using only DT profiles, zonal composites of wind, relative vorticity, and temperature from reanalysis data show that as the TIL increases in strength, the upper tropospheric circulation switches from cyclonic to anticyclonic, and the upward vertical motion increases. This result suggests the WCB as a mechanism since it is on the anticyclonic side of the jet and is characterized by the movement of tropical air poleward and upward from the surface. To verify this relationship, the vertical and horizontal development of a synoptic-scale baroclinic system is analyzed over a 4 day period. Results show the equatorward extension of the polar tropopause, and thus the formation of the DT, due to the strengthening of the TIL in the region of vertical motion associated with the WCB. Moreover, this result suggests that air movement within the DT could originate from high latitudes when associated with a baroclinic disturbance.

  19. 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.

  20. Four distinct immune microenvironment subtypes in gastric adenocarcinoma with special reference to microsatellite instability.

    PubMed

    Cho, Junhun; Chang, Young Hwan; Heo, You Jeong; Kim, Seungtae; Kim, Nayoung Kd; Park, Joon Oh; Kang, Won Ki; Lee, Jeeyun; Kim, Kyoung-Mee

    2018-01-01

    Programmed death-ligand 1 (PD-L1) can be overexpressed in tumours other than Epstein-Barr virus (EBV)-positive (EBV + ) or microsatellite instability-high (MSI-H) gastric cancer (GC) subtypes. We aimed to determine the tumour immune microenvironment (TME) classification of GC to better understand tumour-immune interactions and help patient selection for future immunotherapy with special reference to MSI-H. Immunohistochemistry (IHC) for PD-L1 and CD8 + T cells in three distinct subtypes of GC (43 EBV + , 79 MSI-H and 125 EBV - /MSS) were performed and analysed. In 66 MSI-H GC, mutation counts were compared with PD-L1 expression and survival of the patients. GC TME divided by PD-L1 IHC and tumour-infiltrating lymphocytes (TIL) measured by intratumoural CD8 density showed: (1) about 40% of GC are type I (PD-L1 + /TIL + ) consisting ~70% of MSI-H or EBV + GC, and ~15% of EBV - /microsatellite stable (MSS) GC patients show the best survival in both disease-free (HR 2.044) and overall survival (HR 1.993); this type would respond to a checkpoint blockade therapy; (2) almost 30% of GC are type II (PD-L1 - /TIL - ) with the worst survival; (3) approximately 10% of GC are type III (PD-L1 + /TIL - ); and (4) up to 20% are type IV (PD-L1 - /TIL + ) and, unexpectedly, ~25% of EBV + or MSI-H GC are within this subtype. In MSI-H GC, frequent frameshift mutations were observed in ARID1A , RNF43 , NF1 , MSH6 , BRD3 , NCOA3 , BCORL1 , TNKS2 and NPM1 and the numbers of frameshift mutation correlated significantly with PD-L1 expression (P<0.05). GC can be classified into four TME types based on PD-L1 and TIL, and numbers of frameshift mutation correlate well with PD-L1 expression in MSI-H GC.

  1. Small Bowel Carcinomas in Coeliac or Crohn's Disease: Clinico-pathological, Molecular, and Prognostic Features. A Study From the Small Bowel Cancer Italian Consortium.

    PubMed

    Vanoli, Alessandro; Di Sabatino, Antonio; Furlan, Daniela; Klersy, Catherine; Grillo, Federica; Fiocca, Roberto; Mescoli, Claudia; Rugge, Massimo; Nesi, Gabriella; Fociani, Paolo; Sampietro, Gianluca; Ardizzone, Sandro; Luinetti, Ombretta; Calabrò, Antonio; Tonelli, Francesco; Volta, Umberto; Santini, Donatella; Caio, Giacomo; Giuffrida, Paolo; Elli, Luca; Ferrero, Stefano; Latella, Giovanni; Ciardi, Antonio; Caronna, Roberto; Solina, Gaspare; Rizzo, Aroldo; Ciacci, Carolina; D'Armiento, Francesco P; Salemme, Marianna; Villanacci, Vincenzo; Cannizzaro, Renato; Canzonieri, Vincenzo; Reggiani Bonetti, Luca; Biancone, Livia; Monteleone, Giovanni; Orlandi, Augusto; Santeusanio, Giuseppe; Macciomei, Maria C; D'Incà, Renata; Perfetti, Vittorio; Sandri, Giancarlo; Silano, Marco; Florena, Ada M; Giannone, Antonino G; Papi, Claudio; Coppola, Luigi; Usai, Paolo; Maccioni, Antonio; Astegiano, Marco; Migliora, Paola; Manca, Rachele; Martino, Michele; Trapani, Davide; Cerutti, Roberta; Alberizzi, Paola; Riboni, Roberta; Sessa, Fausto; Paulli, Marco; Solcia, Enrico; Corazza, Gino R

    2017-08-01

    An increased risk of small bowel carcinoma [SBC] has been reported in coeliac disease [CD] and Crohn's disease [CrD]. We explored clinico-pathological, molecular, and prognostic features of CD-associated SBC [CD-SBC] and CrD-associated SBC [CrD-SBC] in comparison with sporadic SBC [spo-SBC]. A total of 76 patients undergoing surgical resection for non-familial SBC [26 CD-SBC, 25 CrD-SBC, 25 spo-SBC] were retrospectively enrolled to investigate patients' survival and histological and molecular features including microsatellite instability [MSI] and KRAS/NRAS, BRAF, PIK3CA, TP53, HER2 gene alterations. CD-SBC showed a significantly better sex-, age-, and stage-adjusted overall and cancer-specific survival than CrD-SBC, whereas no significant difference was found between spo-SBC and either CD-SBC or CrD-SBC. CD-SBC exhibited a significantly higher rate of MSI and median tumour-infiltrating lymphocytes [TIL] than CrD-SBC and spo-SBC. Among the whole SBC series, both MSI─which was the result of MLH1 promoter methylation in all but one cases─and high TIL density were associated with improved survival at univariable and stage-inclusive multivariable analysis. However, only TILs retained prognostic power when clinical subgroups were added to the multivariable model. KRAS mutation and HER2 amplification were detected in 30% and 7% of cases, respectively, without prognostic implications. In comparison with CrD-SBC, CD-SBC patients harbour MSI and high TILs more frequently and show better outcome. This seems mainly due to their higher TIL density, which at multivariable analysis showed an independent prognostic value. MSI/TIL status, KRAS mutations and HER2 amplification might help in stratifying patients for targeted anti-cancer therapy. Copyright © 2017 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com

  2. Clinicopathological predictors of long-term benefit in breast cancer treated with neoadjuvant chemotherapy

    PubMed Central

    Galvez, Marco; Castaneda, Carlos A; Sanchez, Joselyn; Castillo, Miluska; Rebaza, Lia Pamela; Calderon, Gabriela; Cruz, Miguel De La; Cotrina, Jose Manuel; Abugattas, Julio; Dunstan, Jorge; Guerra, Henry; Mejia, Omar; Gomez, Henry L

    2018-01-01

    AIM To investigate the survival impact of clinicopathological factors, including pathological complete response (pCR) and tumor-infiltrating lymphocytes (sTIL) levels according to subtypes, in breast cancer (BC) patients who received neo-adjuvant chemotherapy (NAC). METHODS We evaluated 435 BC patients who presented and received NAC at the Instituto Nacional de Enfermedades Neoplasicas from 2003 to 2014. sTIL was analyzed as the proportion of tumor stroma occupied by lymphocytes, and was prospectively evaluated on hematoxylin and eosin-stained sections of the preNAC core biopsy. pCR was considered in the absence of infiltrating cancer cells in primary tumor and axillary lymph nodes. Analysis of statistical association between clinical pathological features, sTIL, pCR and survival were carried out using SPSSvs19. RESULTS Median age was 49 years (range 24-84 years) and the most frequent clinical stage was IIIB (58.3%). Luminal A, Luminal B, HER2-enriched and (triple-negative) TN phenotype was found in 24.6%, 37.9%, 17.7% and 19.8%, respectively. pCR was observed in 11% and median percentage of sTIL was 40% (2%-95%) in the whole population. pCR was associated to Ct1-2 (P = 0.045) and to high sTIL (P = 0.029) in the whole population. There was a slight trend towards significance for sTIL (P = 0.054) in Luminal A. sTIL was associated with grade III (P < 0.001), no-Luminal A subtype (P < 0.001), RE-negative (P < 0.001), PgR-negative (P < 0.001), HER2-positive (P = 0.002) and pCR (P = 0.029) in the whole population. Longer disease-free survival was associated with grade I-II (P = 0.006), cN0 (P < 0.001), clinical stage II (P = 0.004), ER-positive (P < 0.001), PgR-positive (P < 0.001), luminal A (P < 0.001) and pCR (P = 0.002). Longer disease-free survival was associated with grade I-II in Luminal A (P < 0.001), N0-1 in Luminal A (P = 0.045) and TNBC (P = 0.01), clinical stage II in Luminal A (P = 0.003) and TNBC (P = 0.038), and pCR in TNBC (P < 0.001). Longer overall

  3. 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.

  4. A meridional structure of static stability and ozone vertical gradient around the tropopause in the Southern Hemisphere extratropics

    NASA Astrophysics Data System (ADS)

    Tomikawa, Y.; Yamanouchi, T.

    2010-08-01

    An analysis of the static stability and ozone vertical gradient in the ozone tropopause based (OTB) coordinate is applied to the ozonesonde data at 10 stations in the Southern Hemisphere (SH) extratropics. The tropopause inversion layer (TIL) with a static stability maximum just above the tropopause shows similar seasonal variations at two Antarctic stations, which are latitudinally far from each other. Since the sunshine hour varies with time in a quite different way between these two stations, it implies that the radiative heating due to solar ultraviolet absorption of ozone does not contribute to the seasonal variation of the TIL. A meridional section of the static stability in the OTB coordinate shows that the static stability just above the tropopause has a large latitudinal gradient between 60° S and 70° S in austral winter because of the absence of the TIL over the Antarctic. It is accompanied by an increase of westerly shear with height above the tropopause, so that the polar-night jet is formed above this latitude region. This result suggests a close relationship between the absence of the TIL and the stratospheric polar vortex in the Antarctic winter. A vertical gradient of ozone mixing ratio, referred to as ozone vertical gradient, around the tropopause shows similar latitudinal and seasonal variations with the static stability in the SH extratropics. In a height region above the TIL, a small ozone vertical gradient in the midlatitudes associated with the Antarctic ozone hole is observed in a height region of the subvortex but not around the polar vortex. This is a clear evidence of active latitudinal mixing between the midlatitudes and subvortex.

  5. Evaluation of programmed cell death protein 1 (PD-1) expression as a prognostic biomarker in patients with clear cell renal cell carcinoma.

    PubMed

    Kim, Kyu Seo; Sekar, Rishi R; Patil, Dattatraya; Dimarco, Michelle A; Kissick, Haydn T; Bilen, Mehmet A; Osunkoya, Adeboye O; Master, Viraj A

    2018-01-01

    Programmed cell death protein 1 (PD-1) immune checkpoint inhibitors have shown activity in patients with advanced renal cell carcinoma (RCC). However, the role of PD-1 expression in tumor-infiltrating lymphocytes (TILs) as a biomarker for poor outcome is not clear. In this study, we evaluated the prognostic value of TIL PD-1 expression in patients with clear cell RCC (ccRCC). 82 patients who underwent nephrectomy for localized or metastatic ccRCC and followed up for at least four years were searched from our database and retrospectively enrolled. Their fixed primary tumor specimens were stained with anti-PD-1 (NAT105). The specimens were classified as negative or positive for PD-1 expression, and the positive specimens were further scored in 10% increments. 37 (45.12%) patients were negative (<1% stained), 26 (31.71%) patients were low (<10 and 10%), and 19 (23.17%) patients were high (20-50%) for PD-1 expression. The prognostic value of TIL PD-1 expression was evaluated by univariate Cox proportional hazards regression on overall and recurrence-free survivals. Higher TIL PD-1 expression was not associated with increased risk of death (P = 0.336) or with increased risk of recurrence (P = 0.572). Higher primary tumor stage was associated with increased risk of recurrence (P = 0.003), and higher Fuhrman nuclear grade was associated with increased risk of death (P <0.001) and with increased risk of recurrence (P <0.001). Our study shows that TIL PD-1 expression by immunohistochemistry (IHC) does not correlate with poor clinical outcome in patients with ccRCC and is inferior to established prognosticating tools.

  6. 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

  7. 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.

  8. Adaptive focusing of laser radiation onto a rough reflecting surface through the turbulent and nonlinear atmosphere

    NASA Astrophysics Data System (ADS)

    Vorontsov, Mikhail A.; Kolosov, Valeriy V.

    2004-12-01

    Target-in-the-loop (TIL) wave propagation geometry represents perhaps the most challenging case for adaptive optics applications that are related with maximization of irradiance power density on extended remotely located surfaces in the presence of dynamically changing refractive index inhomogeneities in the propagation medium. We introduce a TIL propagation model that uses a combination of the parabolic equation describing outgoing wave propagation, and the equation describing evolution of the mutual coherence function (MCF) for the backscattered (returned) wave. The resulting evolution equation for the MCF is further simplified by the use of the smooth refractive index approximation. This approximation enables derivation of the transport equation for the returned wave brightness function, analyzed here using method characteristics (brightness function trajectories). The equations for the brightness function trajectories (ray equations) can be efficiently integrated numerically. We also consider wavefront sensors that perform sensing of speckle-averaged characteristics of the wavefront phase (TIL sensors). Analysis of the wavefront phase reconstructed from Shack-Hartmann TIL sensor measurements shows that an extended target introduces a phase modulation (target-induced phase) that cannot be easily separated from the atmospheric turbulence-related phase aberrations. We also show that wavefront sensing results depend on the extended target shape, surface roughness, and the outgoing beam intensity distribution on the target surface.

  9. Analysis of wave propagation and wavefront sensing in target-in-the-loop beam control systems

    NASA Astrophysics Data System (ADS)

    Vorontsov, Mikhail A.; Kolosov, Valeri V.

    2004-10-01

    Target-in-the-loop (TIL) wave propagation geometry represents perhaps the most challenging case for adaptive optics applications that are related with maximization of irradiance power density on extended remotely located surfaces in the presence of dynamically changing refractive index inhomogeneities in the propagation medium. We introduce a TIL propagation model that uses a combination of the parabolic equation describing outgoing wave propagation, and the equation describing evolution of the mutual intensity function (MIF) for the backscattered (returned) wave. The resulting evolution equation for the MIF is further simplified by the use of the smooth refractive index approximation. This approximation enables derivation of the transport equation for the returned wave brightness function, analyzed here using method characteristics (brightness function trajectories). The equations for the brightness function trajectories (ray equations) can be efficiently integrated numerically. We also consider wavefront sensors that perform sensing of speckle-averaged characteristics of the wavefront phase (TIL sensors). Analysis of the wavefront phase reconstructed from Shack-Hartmann TIL sensor measurements shows that an extended target introduces a phase modulation (target-induced phase) that cannot be easily separated from the atmospheric turbulence-related phase aberrations. We also show that wavefront sensing results depend on the extended target shape, surface roughness, and the outgoing beam intensity distribution on the target surface.

  10. Simulation of an Air Cushion Vehicle

    DTIC Science & Technology

    1977-03-01

    Massachusetts 02139 ! DDC Niov 219T March 1977 Final Report for Period January 1975 - December 1976 DOD DISTRIBUTION STATEMENT Approved for public...or in ,art is permitted for any purpose of the United States Government. II II JI UNCLASSI FIED SECURITY CLASSIFICATiON OF TIlS PAGE flWhen Dato...overflow Floating point fault Decimal arithmetic fault Watch Dog timer runout 186 NAVTRAEQUIPCEN 75-C-0057- 1 PROGRAM ENi\\TRY Initial Program - LOAD Inhibit

  11. The Role and Values of Combat Leadership in Modern Warfare: Can Combat Leadership and Personal Leadership Skills be Replaced by Modern Technology?

    DTIC Science & Technology

    2011-04-29

    lett for en kompanisjef a m ~tte forholde seg til s ~ mye at kjernefunksjonen hans scm era lede kompaniet forsvinner eller blir sekundcert. Operasjoner p...the personal relationship that existed between the officers within the Annored brigade (Appendix A ~ S ). 13 Mission command is based upon personal...A208 Norway Colonel CO Telemark Muligheten til a snake med underlagte s ]efer. Man ma ha Push to talk samband Norwegian Battalion sam gj(llr det

  12. Air Force Academy Aeronautics Digest.

    DTIC Science & Technology

    1984-03-01

    Farren, Glauert, R. H. Fowler , George Thomson, E . D. Adrian and Melvill Jones were certainly "Chudleighites." When I arrived at Farnborough I was put to... E . McCann, Lt. Colonel, USAF Director of Research, Studies, and Analysis UNCLASSIFIED SECURITY CLASSIFICATION OF TIlS PAGE REPORT DOCUMENTATION PAGE...NOS P ROGRAM PROJECT TASK WORK UNIT E LE MENT NO. NO. NO. NO * 11 TITLE fInclude Secuity Clawiaiciceton) Air Force Academy Aeronautics Digest

  13. T cell receptor (TCR) structure of autologous melanoma-reactive cytotoxic T lymphocyte (CTL) clones: tumor-infiltrating lymphocytes overexpress in vivo the TCR beta chain sequence used by an HLA-A2- restricted and melanocyte-lineage-specific CTL clone

    PubMed Central

    1993-01-01

    HLA-A2+ melanomas express common melanoma-associated antigens (Ags) recognized in vitro by autologous cytotoxic T lymphocytes (CTL). However, it is not known whether tumor Ags can drive in vivo a selective accumulation/expansion of Ag-specific, tumor-infiltrating T lymphocytes (TIL). Therefore, to evaluate this possibility, 39 CTL clones isolated from several independent mixed lymphocyte tumor cultures (MLTC) of TIL and peripheral blood lymphocytes (PBL) of an HLA- A2+ melanoma patient and selected for T cell receptor (TCR)-dependent, HLA-restricted tumor lysis, were used for analysis of TCR alpha and beta chain structure by the cDNA polymerase chain reaction (PCR) technique with variable gene-specific primers followed by sequencing. Despite absence of oligoclonality in fresh TIL and PBL, as well as in T cells of day 28 MLTC (day of cloning), sequence analysis of TCR alpha and beta chains of TIL clones revealed a dominance of a major category of melanoma-specific, HLA-A2-restricted T cells expressing a V alpha 8.2/J alpha AP511/C alpha and V beta 2.1/D beta 1/J beta 1.1/C beta 1 TCR. The same TCR was also found in 2 out of 14 PBL clones. The other PBL clones employed a V alpha 2.1 gene segment associated with either V beta 13.2, 14, or w22. Clones A81 (V alpha 2.1/J alpha IGRJ alpha 04/C alpha and V beta 14/D beta 1/J beta 1.2/C beta 1) and A21 (V alpha 8.2/J alpha AP511/C alpha and V beta 2.1/D beta 1/J beta 1.1/C beta 1), representative of the two most frequent TCR of PBL and TIL, respectively, expressed different lytic patterns, but both were HLA-A2 restricted and lysed only HLA-A2+ melanomas and normal melanocytes, thus indicating recognition of two distinct HLA-A2-associated and tissue-related Ags. Finally, by the inverse PCR technique, the specific TCR beta chain (V beta 2.1/D beta 1/J beta 1.1/C beta 1) expressed by the dominant TIL clone was found to represent 19 and 18.4% of all V beta 2 sequences expressed in the fresh tumor sample and in the purified TIL

  14. Microencapsulation of Drugs in the Microgravity Environment of the United States Space Shuttle

    DTIC Science & Technology

    1994-10-03

    Fort Detrick, Frederick, MD 21701-5012. AUTHORITY USAMRMC ltr., 21 Apr 97 THIS PAGE IS UNCLASSIFIED AD-B 192 333 Project 7654-X 0 MICROENCAPSULATION OF...X) Ninth Avenue South Birmingham, Alabama 35205 94 l1 t• 7 4 M_ T ’ INI 3 Oct 94 Midterm •.Jý92 - 1,O]J94 % ’ Microencapsulation of Drugs in dte...2-3 ViI. REFERENCES............................................... 24 MICROENCAPSULATION OF DRUGS IN TIlE MICROGRAVIrY ENVIRONMENT OF TilE

  15. Range Reference Atmosphere 0-70 Km Altitude. Kwajalein Missile Range, Kwajalein, Marshall Islands

    DTIC Science & Technology

    1982-01-01

    DOCUMENT 360-82 KWAJALEIN MISSILE RANGE KWAJALEIN, MARSHALL ISLANDS RANGE REFERENCE ATMOSPHERE 0-70 KM ALTITUDE, C00 L’’I METEOROLOGY GROUP .RANGE...34Reference Atmosphere (Part 1), Kwajale 4n Missile Range, Kwajalein, Marshall Islands ," ADA002664. * 19. KEY WORDS (Continue on revorsae d. If necoeewy...CLASSIFICATION OF TIlS PAGE (Whe~n Data EnterecD -v DOCUMENT 360-82 Vo- KWAJALEIN MISSILE RANGE KWAJALEIN, MARSHALL ISLANDS RANGE REFERENCE ATMOSPHERE 0-70 km

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

    Taguchi, Takahiro; Testa, J.R.; Mitcham, J.L.

    This report describes the localization of the the TIL gene to human chromosome 4p14 using fluorescence in situ hybridization. This gene encodes a protein which is related to the Drosophila transmembrane receptor Toll and the mammalian interleukin-1 receptor, which share similarities in structure and function. The Drosophila gene is also important during embryonic development, which makes TIL a candidate locus for human congenital malformations that are genetically linked to human chromosome 4. 17 refs., 1 fig.

  17. Target-in-the-loop phasing of a fiber laser array fed by a linewidth-broadened master oscillator

    NASA Astrophysics Data System (ADS)

    Hyde, Milo W.; Tyler, Glenn A.; Rosado Garcia, Carlos

    2017-05-01

    In a recent paper [J. Opt. Soc. Am. A 33, 1931-1937 (2016)], the target-in-the-loop (TIL) phasing of an RF-modulated or multi-phase-dithered fiber laser array, fed by a linewidth-broadened master oscillator (MO) source, was investigated. It was found that TIL phasing was possible even on a target with scattering features separated by more than the MO's coherence length as long as the received, backscattered irradiance changed with the array's modulation or phase dither. To simplify the problem and gain insight into how temporal coherence affects TIL phasing, speckle and atmospheric turbulence were omitted from the analysis. Here, the scenario analyzed in the prior work is generalized by including speckle and turbulence. First, the key analytical result from the prior paper is reviewed. Simulations, including speckle and turbulence, are then performed to test whether the conclusions derived from that result hold under more realistic conditions.

  18. CXCR3/CCR5 pathways in metastatic melanoma patients treated with adoptive therapy and interleukin-2

    PubMed Central

    Bedognetti, D; Spivey, T L; Zhao, Y; Uccellini, L; Tomei, S; Dudley, M E; Ascierto, M L; De Giorgi, V; Liu, Q; Delogu, L G; Sommariva, M; Sertoli, M R; Simon, R; Wang, E; Rosenberg, S A; Marincola, F M

    2013-01-01

    Background: Adoptive therapy with tumour-infiltrating lymphocytes (TILs) induces durable complete responses (CR) in ∼20% of patients with metastatic melanoma. The recruitment of T cells through CXCR3/CCR5 chemokine ligands is critical for immune-mediated rejection. We postulated that polymorphisms and/or expression of CXCR3/CCR5 in TILs and the expression of their ligands in tumour influence the migration of TILs to tumours and tumour regression. Methods: Tumour-infiltrating lymphocytes from 142 metastatic melanoma patients enrolled in adoptive therapy trials were genotyped for CXCR3 rs2280964 and CCR5-Δ32 deletion, which encodes a protein not expressed on the cell surface. Expression of CXCR3/CCR5 in TILs and CXCR3/CCR5 and ligand genes in 113 available parental tumours was also assessed. Tumour-infiltrating lymphocyte data were validated by flow cytometry (N=50). Results: The full gene expression/polymorphism model, which includes CXCR3 and CCR5 expression data, CCR5-Δ32 polymorphism data and their interaction, was significantly associated with both CR and overall response (OR; P=0.0009, and P=0.007, respectively). More in detail, the predicted underexpression of both CXCR3 and CCR5 according to gene expression and polymorphism data (protein prediction model, PPM) was associated with response to therapy (odds ratio=6.16 and 2.32, for CR and OR, respectively). Flow cytometric analysis confirmed the PPM. Coordinate upregulation of CXCL9, CXCL10, CXCL11, and CCL5 in pretreatment tumour biopsies was associated with OR. Conclusion: Coordinate overexpression of CXCL9, CXCL10, CXCL11, and CCL5 in pretreatment tumours was associated with responsiveness to treatment. Conversely, CCR5-Δ32 polymorphism and CXCR3/CCR5 underexpression influence downregulation of the corresponding receptors in TILs and were associated with likelihood and degree of response. PMID:24129241

  19. Manipulating the tumor microenvironment ex vivo for enhanced expansion of tumor-infiltrating lymphocytes for adoptive cell therapy

    PubMed Central

    Chacon, Jessica Ann; Sarnaik, Amod A; Chen, Jie Qing; Creasy, Caitlin; Kale, Charuta; Robinson, John; Weber, Jeffrey; Hwu, Patrick; Pilon-Thomas, Shari; Radvanyi, Laszlo

    2014-01-01

    Purpose Cultured tumor fragments from melanoma metastases have been used for years as a source of tumor-infiltrating lymphocytes (TIL) for adoptive cell therapy. The expansion of tumor-reactive CD8+ T cells with IL-2 in these early cultures is critical in generating clinically active TIL infusion products, with a population of activated 4-1BB CD8+ T cells recently found to constitute the majority of tumor-specific T cells. Experimental Design We used an agonistic anti-4-1BB antibody added during the initial tumor fragment cultures to provide in situ 4-1BB co-stimulation. Results We found that addition of an agonistic anti-4-1BB antibody could activate 4-1BB signaling within early cultured tumor fragments and accelerated the rate of memory CD8+ TIL outgrowth that were highly enriched for melanoma antigen specificity. This was associated with NFκB activation and the induction of T-cell survival and memory genes, as well as enhanced IL-2 responsiveness, in the CD8+ T cells in the fragments and emerging from the fragments. Early provision of 4-1BB co-stimulation also affected the dendritic cells (DC) by activating NFκB in DC and promoting their maturation inside the tumor fragments. Blocking HLA class I prevented the enhanced outgrowth of CD8+ T cells with anti-4-1BB, suggesting that an ongoing HLA class I-mediated antigen presentation in early tumor fragment cultures plays a role in mediating tumor-specific CD8+ TIL outgrowth. Conclusions Our results highlight a previously unrecognized concept in TIL adoptive cell therapy that the tumor microenvironment can be dynamically regulated in the initial tumor fragment cultures to regulate the types of T cells expanded and their functional characteristics. PMID:25472998

  20. Manipulating the tumor microenvironment ex vivo for enhanced expansion of tumor-infiltrating lymphocytes for adoptive cell therapy.

    PubMed

    Chacon, Jessica Ann; Sarnaik, Amod A; Chen, Jie Qing; Creasy, Caitlin; Kale, Charuta; Robinson, John; Weber, Jeffrey; Hwu, Patrick; Pilon-Thomas, Shari; Radvanyi, Laszlo

    2015-02-01

    Cultured tumor fragments from melanoma metastases have been used for years as a source of tumor-infiltrating lymphocytes (TIL) for adoptive cell therapy (ACT). The expansion of tumor-reactive CD8(+) T cells with interleukin-2 (IL2) in these early cultures is critical in generating clinically active TIL infusion products, with a population of activated 4-1BB CD8(+) T cells recently found to constitute the majority of tumor-specific T cells. We used an agonistic anti-4-1BB antibody added during the initial tumor fragment cultures to provide in situ 4-1BB costimulation. We found that addition of an agonistic anti-4-1BB antibody could activate 4-1BB signaling within early cultured tumor fragments and accelerated the rate of memory CD8(+) TIL outgrowth that were highly enriched for melanoma antigen specificity. This was associated with NFκB activation and the induction of T-cell survival and memory genes, as well as enhanced IL2 responsiveness, in the CD8(+) T cells in the fragments and emerging from the fragments. Early provision of 4-1BB costimulation also affected the dendritic cells (DC) by activating NFκB in DC and promoting their maturation inside the tumor fragments. Blocking HLA class I prevented the enhanced outgrowth of CD8(+) T cells with anti-4-1BB, suggesting that an ongoing HLA class I-mediated antigen presentation in early tumor fragment cultures plays a role in mediating tumor-specific CD8(+) TIL outgrowth. Our results highlight a previously unrecognized concept in TIL ACT that the tumor microenvironment can be dynamically regulated in the initial tumor fragment cultures to regulate the types of T cells expanded and their functional characteristics. ©2014 American Association for Cancer Research.

  1. Predictive Value of Tertiary Lymphoid Structures Assessed by High Endothelial Venule Counts in the Neoadjuvant Setting of Triple-Negative Breast Cancer

    PubMed Central

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

    2017-01-01

    Purpose The tertiary lymphoid structure (TLS) is an important source of tumor-infiltrating lymphocytes (TILs), which have a strong prognostic and predictive value in triple-negative breast cancer (TNBC). A previous study reported that the levels of CXCL13 mRNA expression were associated with TLSs, but measuring the gene expression is challenging in routine practice. Therefore, this study evaluated the MECA79-positive high endothelial venule (HEV) densities and their association with the histopathologically assessed TLSs in biopsy samples. In addition, the relationship of TLSs with the CXCL13 transcript levels and clinical outcomes were examined. Materials and Methods A total of 108 TNBC patients treated with neoadjuvant chemotherapy (NAC) were studied. The amounts of TILs and TLSs were measured histopathologically using hematoxylin and eosin–stained slides. The HEV densities and TIL subpopulations were measured by immunohistochemistry for MECA79, CD3, CD8, and CD20. CXCL13mRNA expression levels using a NanoString assay (NanoString Technologies). Results The mean number of HEVs in pre-NAC biopsies was 12 (range, 0 to 72). The amounts of TILs and TLSs, HEV density, and CXCL13 expression showed robust correlations with each other. A lower pre-NAC clinical T stage, higher TIL and TLS levels, a higher HEV density, CD20-positive cell density, and CXCL13 expression were significant predictors of a pathologic complete response (pCR). Higher CD8-positive cell density and levels of CXCL13 expression were significantly associated with a better disease-free survival rate. Conclusion MECA79-positive HEV density in pre-NAC biopsies is an objective and quantitative surrogate marker of TLS and might be a valuable tool for predicting pCR of TNBC in routine pathology practice. PMID:27488875

  2. Circulating Cell-free DNA for Metastatic Cervical Cancer Detection, Genotyping, and Monitoring.

    PubMed

    Kang, Zhigang; Stevanović, Sanja; Hinrichs, Christian S; Cao, Liang

    2017-11-15

    Purpose: Circulating cell-free (ccf) human papillomavirus (HPV) DNA may serve as a unique tumor marker for HPV-associated malignancies, including cervical cancer. We developed a method to genotype and quantify circulating HPV DNA in patients with HPV16- or HPV18-positive metastatic cervical cancer for potential disease monitoring and treatment-related decision making. Experimental Design: In this retrospective study, HPV ccfDNA was measured in serum samples from 19 metastatic cervical cancer patients by duplex digital droplet PCR (ddPCR). Nine patients had received tumor-infiltrating lymphocyte (TIL) immunotherapy. ccfDNA data were aligned with the tumor HPV genotype, drug treatment, and clinical outcome. Results: In blinded tests, HPV ccfDNA was detected in 19 of 19 (100%) patients with HPV-positive metastatic cervical cancer but not in any of the 45 healthy blood donors. The HPV genotype harbored in the patients' tumors was correctly identified in 87 of 87 (100%) sequential patient serum samples from 9 patients who received TIL immunotherapy. In three patients who experienced objective cancer regression after TIL treatment, a transient HPV ccfDNA peak was detected 2-3 days after TIL infusion. Furthermore, persistent clearance of HPV ccfDNA was only observed in two patients who experienced complete response (CR) after TIL immunotherapy. Conclusions: HPV ccfDNA represents a promising tumor marker for noninvasive HPV genotyping and may be used in selecting patients for HPV type-specific T-cell-based immunotherapies. It may also have value in detecting antitumor activity of therapeutic agents and in the long-term follow-up of cervical cancer patients in remission. Clin Cancer Res; 23(22); 6856-62. ©2017 AACR . ©2017 American Association for Cancer Research.

  3. A potential relation between stratosphere-troposphere exchange and the tropopause inversion layer in idealized baroclinic life cycle experiments

    NASA Astrophysics Data System (ADS)

    Kunkel, Daniel; Kaluza, Thorsten; Wirth, Volkmar; Hoor, Peter

    2017-04-01

    The tropopause inversion layer (TIL) as a well known feature of the lower stratosphere in the extratropics has often been suspected of impeding the exchange between stratospheric and tropospheric air masses (STE). However, it is still an open question whether a physical relation between STE and the TIL exists. We use a non-hydrostatic limited area model to simulate idealized baroclinic life cycles along with different diagnostics for STE such as Eulerian passive tracers and Lagrangian trajectories. Recent findings suggest a strenghtening of the TIL during such life cycles due to diabatic tropospheric processes as well as wave breaking. Moreover, STE also occurs frequently during such baroclinic life cycles, e.g., in the vicinity of tropopause folds, cut-off lows, or stratospheric streamers. Contradicting to current knowledge the analysis of static stability above the thermal tropopause and the identification of regions of STE show that a temporal and spatial co-location of a strong TIL and regions of transport from the troposphere into the stratosphere is possible. Evidence is further presented that such a co-location is related to tropospheric updrafts and small scale waves in the lower stratosphere. These findings are also supported by an analysis of baroclinic life cycles in high resolution operational analysis data from the European Center for Medium-Range Weather Forecasts (ECMWF).

  4. The tropopause inversion layer at midlatitudes: Formation processes and relation to stratosphere-troposphere exchange

    NASA Astrophysics Data System (ADS)

    Kunkel, D.; Hoor, P. M.; Wirth, V.

    2016-12-01

    Recent studies revealed the existence of a quasi-permanent layer of enhanced static stability above the thermal tropopause. This so-called tropopause inversion layer (TIL) is evident in adiabatic baroclinic life cycles suggesting that dry dynamics contribute to its formation. However, compared to observations the TIL in these life cycles is too weak, indicating that other contributions from diabatic processes are relevant. Such processes could be related to moisture or radiation, or other non-linear, subgrid-scale processes such as gravity wave breaking. Moreover, whether there is a causal relation between the occurrence of the TIL and stratosphere-troposphere exchange (STE) is still under debate. In this study various types of baroclinic life cycles are simulated using a non-hydrostatic model in an idealized mid-latitude channel configuration. A simulation using only the dynamical core of the model serves as base simulation, which is modified subsequently by adding different processes. First, these processes such as vertical turbulence, cloud microphysics, radiation as well as surface fluxes for heat and momentum are added individually. In a second set of simulations combinations of these processes are studied to assess the relative importance of the individual processes in the formation of the TIL. Finally, the static stability is analyzed in regions of STE. These regions are identified with the help of passive tracer as well as a Lagrangian trajectory analysis.

  5. Observational characteristics of the tropopause inversion layer derived from CHAMP/GRACE radio occultations and MOZAIC aircraft data

    NASA Astrophysics Data System (ADS)

    Schmidt, Torsten; Heise, Stefan; Wickert, Jens; Haser, Antonia; Cammas, Jean-Pierre; Smit, Herman G. J.

    In this study we discuss characteristics of the tropopause inversion layer (TIL) based on two datasets. Temperature measurements from GPS radio occultation (RO) data (CHAMP and GRACE) for the time interval 2001-2009 are used to exhibit seasonal properties of the TIL on a global scale. In agreement with previous studies the vertical structure of the TIL is investigated using the square of the buoyancy frequency N. For the extratropics on both hemispheres N2 has an universal distribution independent from season: a local minimum about 2 km below the lapse rate tropopause height (LRTH), an absolute maximum about 1 km above the LRTH, and a local minimum about 4 km above the LRTH. In the tropics (15° N-15° S) the N2 maximum above the tropopause is 200-300 m higher compared with the extratropics and the local minimum of N2 below the tropopause appears about 4 km below the LRTH. Trace gas measurements onboard commercial aircrafts from 2001-2008 are used as a complementary dataset (MOZAIC program). We demonstrate that the mixing ratio gradients of ozone, carbon monoxide and water vapor are suitable parameters for characterizing the TIL reproducing most of the vertical structure of N2 . We also show that the LRTH is strongly correlated with the absolute maxima of ozone and carbon monoxide mixing ratio gradients.

  6. Outcomes following neonatal cardiopulmonary resuscitation.

    PubMed

    Boldingh, Anne Marthe; Solevåg, Anne Lee; Nakstad, Britt

    2018-05-29

    Hjerte-lunge-redning av et kritisk sykt barn ved fødsel kan føre til overlevelse eller død. De som overlever kan utvikle komplikasjoner direkte etter fødsel eller senere i småbarns- og skolealder. Hypoksisk iskemisk encefalopati er en tilstand med nevrologiske symptomer hos den nyfødte etter hypoksi ved fødsel. Tilstanden klassifiseres som mild, moderat eller alvorlig. Vi ønsket å gi en oversikt over kort- og langtidsutfall etter hjerte-lunge-redning ved fødsel. Vi søkte i databasen Medline for utfall etter hjerte-lunge-redning ved fødsel. Vi identifiserte 15 indekserte, fagfellevurderte originalartikler og to metaanalyser om utfall etter hjerte-lunge-redning ved fødsel eller fødselsasfyksi. Hypoksisk iskemisk encefalopati rammer generelt 38 % av pasientene i mild til moderat grad og 23 % i alvorlig grad. Dødeligheten varierte fra 10 % i høy- til 28 % i lavinntektsland. Overlevende utvikler ofte motoriske, kognitive og sensoriske utviklingshemninger. I noen tilfeller blir det først avdekket ved skolestart når mer komplekse ferdigheter kreves. Funksjonshemning ved skolealder er sterkt korrelert til tilstanden i småbarnsalder. Endringer i algoritmene ved hjerte-lunge-redning og rutinebehandling med hypotermi har redusert risikoen for alvorlige følgetilstander etter hypoksisk iskemisk encefalopati.

  7. Adoptive Cell Therapy for Metastatic Melanoma.

    PubMed

    Merhavi-Shoham, Efrat; Itzhaki, Orit; Markel, Gal; Schachter, Jacob; Besser, Michal J

    Adoptive cell therapy (ACT) of tumor-infiltrating lymphocytes (TILs) is a powerful form of immunotherapy by inducing durable complete responses that significantly extend the survival of melanoma patients. Mutation-derived neoantigens were recently identified as key factors for tumor recognition and rejection by TILs. The isolation of T-cell receptor (TCR) genes directed against neoantigens and their retransduction into peripheral T cells may provide a new form of ACT.Genetic modifications of T cells with chimeric antigen receptors (CARs) have demonstrated remarkable clinical results in hematologic malignancies, but are so far less effective in solid tumors. Only very limited reports exist in melanoma. Progress in CAR T-cell engineering, including neutralization of inhibitory signals or additional safety switches, may open opportunities also in melanoma.We review clinical results and latest developments of adoptive therapies with TILs, T-cell receptor, and CAR-modified T cells and discuss future directions for the treatment of melanoma.

  8. Observation of laser formation inside a laser cavity containing a phase conjugate mirror

    NASA Astrophysics Data System (ADS)

    Wu, Frank F.

    2012-03-01

    Adaptive optics (AO) systems are used to compensate atmospheric perturbations on a propagating laser beam. However, AO needs a beacon to obtain the phase information. This paper presents a possible formation of beacon in target-in-theloop (TIL) geometry which is analog to a laser cavity. The TIL laser cavity is formed with a high reflectivity mirror on one end and an optical phase conjugate mirror as the second mirror. The TIL laser is initialized by a single frequency 10 ns Q-switched laser pulse. This is very similar to how an injection seeding or regenerative amplifier scheme starts a laser oscillation. With a cavity length of around 11 meters and an initial laser pulse of 10 ns, we have been able to isolate laser field images related to each round-trip pulse. Furthermore, by replacing the first mirror with a rough-surface target to simulate an uncooperative target and adding phase distortion elements to simulate atmospheric effects, we can observe the image status under such conditions.

  9. VLSI Design Tools, Reference Manual, Release 2.0.

    DTIC Science & Technology

    1984-08-01

    eder. 2.3 ITACV: Libary ofC readne. far oesumdg a layoit 1-,, tiling. V ~2.4 "QUILT: CeinS"Wbesa-i-M-8euar ray f atwok til 2.5 "TIL: Tockmeleff...8217patterns package was added so that complex and repetitive digital waveforms could be generated far more easily. The recently written program MTP (Multiple...circuit model to estimate timing delays through digital circuits. It also has a mode that allows it to be used as a switch (gate) level simulator

  10. Self-Delivering RNAi Targeting PD-1 Improves Tumor-Specific T Cell Functionality for Adoptive Cell Therapy of Malignant Melanoma.

    PubMed

    Ligtenberg, Maarten A; Pico de Coaña, Yago; Shmushkovich, Taisia; Yoshimoto, Yuya; Truxova, Iva; Yang, Yuan; Betancur-Boissel, Monica; Eliseev, Alexey V; Wolfson, Alexey D; Kiessling, Rolf

    2018-06-06

    Adoptive cell therapy (ACT) is becoming a prominent alternative therapeutic treatment for cancer patients relapsing on traditional therapies. In parallel, antibodies targeting immune checkpoint molecules, such as cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) and cell death protein 1 pathway (PD-1), are rapidly being approved for multiple cancer types, including as first line therapy for PD-L1-expressing non-small-cell lung cancer. The combination of ACT and checkpoint blockade could substantially boost the efficacy of ACT. In this study, we generated a novel self-delivering small interfering RNA (siRNA) (sdRNA) that knocked down PD-1 expression on healthy donor T cells as well as patient-derived tumor-infiltrating lymphocytes (TIL). We have developed an alternative chemical modification of RNA backbone for improved stability and increased efficacy. Our results show that T cells treated with sdRNA specific for PD-1 had increased interferon γ (IFN-γ) secreting capacity and that this modality of gene expression interference could be utilized in our rapid expansion protocol for production of TIL for therapy. TIL expanded in the presence of PD-1-specific sdRNA performed with increased functionality against autologous tumor as compared to control TIL. This method of introducing RNAi into T cells to modify the expression of proteins could easily be adopted into any ACT protocol and will lead to the exploration of new combination therapies. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

  11. CXCR1 as a novel target for directing reactive T cells toward melanoma: implications for adoptive cell transfer immunotherapy.

    PubMed

    Sapoznik, Sivan; Ortenberg, Rona; Galore-Haskel, Gilli; Kozlovski, Stav; Levy, Daphna; Avivi, Camila; Barshack, Iris; Cohen, Cyrille J; Besser, Michal J; Schachter, Jacob; Markel, Gal

    2012-10-01

    Adoptive cell transfer therapy with reactive T cells is one of the most promising immunotherapeutic modalities for metastatic melanoma patients. Homing of the transferred T cells to all tumor sites in sufficient numbers is of great importance. Here, we seek to exploit endogenous chemotactic signals in order to manipulate and enhance the directional trafficking of transferred T cells toward melanoma. Chemokine profiling of 15 melanoma cultures shows that CXCL1 and CXCL8 are abundantly expressed and secreted from melanoma cultures. However, the complimentary analysis on 40 melanoma patient-derived tumor-infiltrating lymphocytes (TIL) proves that the corresponding chemokine receptors are either not expressed (CXCR2) or expressed at low levels (CXCR1). Using the in vitro transwell system, we demonstrate that TIL cells preferentially migrate toward melanoma and that endogenously expressing CXCR1 TIL cells are significantly enriched among the migrating lymphocytes. The role of the chemokines CXCL1 and CXCL8 is demonstrated by partial abrogation of this enrichment with anti-CXCL1 and anti-CXCL8 neutralizing antibodies. The role of the chemokine receptor CXCR1 is validated by the enhanced migration of CXCR1-engineered TIL cells toward melanoma or recombinant CXCL8. Cytotoxicity and IFNγ secretion activity are unaltered by CXCR1 expression profile. Taken together, these results mark CXCR1 as a candidate for genetic manipulations to enhance trafficking of adoptively transferred T cells. This approach is complimentary and potentially synergistic with other genetic strategies designed to enhance anti-tumor potency.

  12. IL17A Regulates Tumor Latency and Metastasis in Lung Adeno and Squamous SQ.2b and AD.1 Cancer.

    PubMed

    You, Ran; DeMayo, Francesco J; Liu, Jian; Cho, Sung-Nam; Burt, Bryan M; Creighton, Chad J; Casal, Roberto F; Lazarus, Donald R; Lu, Wen; Tung, Hui-Ying; Yuan, Xiaoyi; Hill-McALester, Andrea; Kim, Myunghoo; Perusich, Sarah; Cornwell, Loraine; Rosen, Daniel; Song, Li-Zhen; Paust, Silke; Diehl, Gretchen; Corry, David; Kheradmand, Farrah

    2018-04-13

    Somatic mutations can promote malignant transformation of airway epithelial cells and induce inflammatory responses directed against resultant tumors. Tumor-infiltrating T lymphocytes (TIL) in early-stage non-small cell lung cancer (NSCLC) secrete distinct proinflammatory cytokines, but the contribution of these TILs to tumor development and metastasis remains unknown. We show here that TILs in early-stage NSCLC are biased toward IL17A expression (Th17) when compared with adjacent tumor-free tissue, whereas Th17 cells are decreased in tumor infiltrating locoregional lymph nodes in advanced NSCLC. Mice in which Pten and Smad4 ( Pts4 d/d ) are deleted from airway epithelial cells develop spontaneous tumors, that share genetic signatures with squamous- (SQ.2b), and adeno- (AD.1) subtypes of human NSCLC. Pts4 d/d mice globally lacking in IL17a ( Pts4 d/d Il17a -/- ) showed decreased tumor latency and increased metastasis. Th17 cells were required for recruitment of CD103 + dendritic cells, and adoptive transfer of IL17a -sufficient CD4 + T cells reversed early tumor development and metastasis in Pts4 d/d Il17a -/- mice. Together, these findings support a key role for Th17 cells in TILs associated with the Pts4 d/d model of NSCLC and suggest therapeutic and biomarker strategies for human SQ2b and AD1 lung cancer. Cancer Immunol Res; 1-13. ©2018 AACR. ©2018 American Association for Cancer Research.

  13. Speckle-field propagation in 'frozen' turbulence: brightness function approach

    NASA Astrophysics Data System (ADS)

    Dudorov, Vadim V.; Vorontsov, Mikhail A.; Kolosov, Valeriy V.

    2006-08-01

    Speckle-field long- and short-exposure spatial correlation characteristics for target-in-the-loop (TIL) laser beam propagation and scattering in atmospheric turbulence are analyzed through the use of two different approaches: the conventional Monte Carlo (MC) technique and the recently developed brightness function (BF) method. Both the MC and the BF methods are applied to analysis of speckle-field characteristics averaged over target surface roughness realizations under conditions of 'frozen' turbulence. This corresponds to TIL applications where speckle-field fluctuations associated with target surface roughness realization updates occur within a time scale that can be significantly shorter than the characteristic atmospheric turbulence time. Computational efficiency and accuracy of both methods are compared on the basis of a known analytical solution for the long-exposure mutual correlation function. It is shown that in the TIL propagation scenarios considered the BF method provides improved accuracy and requires significantly less computational time than the conventional MC technique. For TIL geometry with a Gaussian outgoing beam and Lambertian target surface, both analytical and numerical estimations for the speckle-field long-exposure correlation length are obtained. Short-exposure speckle-field correlation characteristics corresponding to propagation in 'frozen' turbulence are estimated using the BF method. It is shown that atmospheric turbulence-induced static refractive index inhomogeneities do not significantly affect the characteristic correlation length of the speckle field, whereas long-exposure spatial correlation characteristics are strongly dependent on turbulence strength.

  14. Tropopause inversion layer: Seasonal and latitudinal variations and representation in standard radiosonde data and global models

    NASA Astrophysics Data System (ADS)

    Bell, Shaun W.; Geller, Marvin A.

    2008-03-01

    Previous publications have given information on the seasonal and latitudinal variations of the tropopause inversion layer (TIL), as seen in high-resolution radiosonde data sets, when soundings are averaged using the tropopause as a reference level. This paper presents a more quantitative analysis of the latitudinal and seasonal structure of the TIL than has been given previously. To do this, we define the region over which the static stability relaxes from its overshoot value at the tropopause to its local minimum in the stratosphere. This region is seen to increase monotonically in thickness from about 1 km at low latitudes to about 4 to 5 km at high latitudes. When the seasons are defined as winter (DJF), spring (MAM), summer (JJA), and fall (SON), the transition from tropical behavior occurs a little poleward of 20°N in both DJF and MAM and moves to a little poleward of 30°N in JJA and SON. Somewhat surprisingly, it is also shown that almost identical information about the TIL can be derived from standard radiosonde data for our period of analysis because of their reporting of the tropopause and other "significant levels," but caution needs to be used in doing this since the number of reported significant levels has varied significantly over the long term and with some distinct discontinuities. Finally, we discuss what sort of information on the TIL can be obtained from global models given their relatively coarse vertical resolution.

  15. Speckle-field propagation in 'frozen' turbulence: brightness function approach.

    PubMed

    Dudorov, Vadim V; Vorontsov, Mikhail A; Kolosov, Valeriy V

    2006-08-01

    Speckle-field long- and short-exposure spatial correlation characteristics for target-in-the-loop (TIL) laser beam propagation and scattering in atmospheric turbulence are analyzed through the use of two different approaches: the conventional Monte Carlo (MC) technique and the recently developed brightness function (BF) method. Both the MC and the BF methods are applied to analysis of speckle-field characteristics averaged over target surface roughness realizations under conditions of 'frozen' turbulence. This corresponds to TIL applications where speckle-field fluctuations associated with target surface roughness realization updates occur within a time scale that can be significantly shorter than the characteristic atmospheric turbulence time. Computational efficiency and accuracy of both methods are compared on the basis of a known analytical solution for the long-exposure mutual correlation function. It is shown that in the TIL propagation scenarios considered the BF method provides improved accuracy and requires significantly less computational time than the conventional MC technique. For TIL geometry with a Gaussian outgoing beam and Lambertian target surface, both analytical and numerical estimations for the speckle-field long-exposure correlation length are obtained. Short-exposure speckle-field correlation characteristics corresponding to propagation in 'frozen' turbulence are estimated using the BF method. It is shown that atmospheric turbulence-induced static refractive index inhomogeneities do not significantly affect the characteristic correlation length of the speckle field, whereas long-exposure spatial correlation characteristics are strongly dependent on turbulence strength.

  16. Medical abortions performed by specialists in private practice.

    PubMed

    Pay, Aase Serine Devold; Aabø, Runa Sigrid; Økland, Inger; Janbu, Torunn; Iversen, Ole-Erik; Løkeland, Mette

    2018-05-29

    I Norge utføres abort kun i offentlige sykehus. I 2010 besluttet Helse- og omsorgsdepartementet å iverksette et toårig prøveprosjekt som ga avtalespesialister i fødselshjelp og kvinnesykdommer adgang til å tilby medikamentell abort før utgangen av 9. svangerskapsuke. Prøveprosjektet ble igangsatt 1.3.2015 og varte til 31.3.2017. I denne artikkelen presenterer vi de første erfaringene, herunder hvordan behandlingstilbudet ble mottatt av kvinnene. Gravide med en svangerskapsvarighet < 63 dager ultrasonografisk vurdert, som oppsøkte avtalespesialist for medikamentell abort, ble fortløpende inkludert i prosjektet (n = 476). Kvinnene inntok 200 mg mifepriston peroralt på legekontoret, 36-48 timer senere satte de selv 800 µg misoprostol vaginalt hjemme. Informasjon ble innhentet ved spørreskjema på den første konsultasjonen, under aborten og ved etterkontrollen 2-4 uker etter aborten. Under aborten rapporterte 66 % (296/450) moderat eller sterk smerte og 79 % (358/451) moderat eller sterk blødning. De fleste opplevde det som trygt å være hjemme. 96 % (390/406) ville valgt medikamentell abort hos avtalespesialist ved en eventuell senere abort, og 97 % (392/405) ville anbefalt behandlingstilbudet til andre i samme situasjon. Kvinnene i studien opplevde abortbehandling hos avtalespesialist som trygt. Tilbudet gir større valgfrihet til gravide som ønsker abort, og pasientene er tilfredse.

  17. Beam wavefront and farfield control for ICF laser driver

    NASA Astrophysics Data System (ADS)

    Dai, Wanjun; Deng, Wu; Zhang, Xin; Jiang, Xuejun; Zhang, Kun; Zhou, Wei; Zhao, Junpu; Hu, Dongxia

    2010-10-01

    Five main problems of beam wavefront and farfield control in ICF laser driver are synthetically discussed, including control requirements, beam propagation principle, distortions source control, system design and adjustment optimization, active wavefront correction technology. We demonstrate that beam can be propagated well and the divergence angle of the TIL pulses can be improved to less than 60μrad with solving these problems, which meets the requirements of TIL. The results can provide theoretical and experimental support for wavefront and farfield control designing requirements of the next large scale ICF driver.

  18. A multiplexed microfluidic system for evaluation of dynamics of immune-tumor interactions.

    PubMed

    Moore, N; Doty, D; Zielstorff, M; Kariv, I; Moy, L Y; Gimbel, A; Chevillet, J R; Lowry, N; Santos, J; Mott, V; Kratchman, L; Lau, T; Addona, G; Chen, H; Borenstein, J T

    2018-05-25

    Recapitulation of the tumor microenvironment is critical for probing mechanisms involved in cancer, and for evaluating the tumor-killing potential of chemotherapeutic agents, targeted therapies and immunotherapies. Microfluidic devices have emerged as valuable tools for both mechanistic studies and for preclinical evaluation of therapeutic agents, due to their ability to precisely control drug concentrations and gradients of oxygen and other species in a scalable and potentially high throughput manner. Most existing in vitro microfluidic cancer models are comprised of cultured cancer cells embedded in a physiologically relevant matrix, collocated with vascular-like structures. However, the recent emergence of immune checkpoint inhibitors (ICI) as a powerful therapeutic modality against many cancers has created a need for preclinical in vitro models that accommodate interactions between tumors and immune cells, particularly for assessment of unprocessed tumor fragments harvested directly from patient biopsies. Here we report on a microfluidic model, termed EVIDENT (ex vivo immuno-oncology dynamic environment for tumor biopsies), that accommodates up to 12 separate tumor biopsy fragments interacting with flowing tumor-infiltrating lymphocytes (TILs) in a dynamic microenvironment. Flow control is achieved with a single pump in a simple and scalable configuration, and the entire system is constructed using low-sorption materials, addressing two principal concerns with existing microfluidic cancer models. The system sustains tumor fragments for multiple days, and permits real-time, high-resolution imaging of the interaction between autologous TILs and tumor fragments, enabling mapping of TIL-mediated tumor killing and testing of various ICI treatments versus tumor response. Custom image analytic algorithms based on machine learning reported here provide automated and quantitative assessment of experimental results. Initial studies indicate that the system is capable of

  19. PD-L1 expression in perihilar and intrahepatic cholangiocarcinoma.

    PubMed

    Fontugne, Jacqueline; Augustin, Jérémy; Pujals, Anaïs; Compagnon, Philippe; Rousseau, Benoit; Luciani, Alain; Tournigand, Christophe; Cherqui, Daniel; Azoulay, Daniel; Pawlotsky, Jean-Michel; Calderaro, Julien

    2017-04-11

    Cholangiocarcinoma is an aggressive biliary neoplasm lacking effective therapeutic agents. Immunotherapies targeting the PD-L1/PD-1 immune checkpoint have shown encouraging results in solid and hematologic cancers in clinical trials. Response to these immunomodulators is correlated with PD-L1 expression. Our goal was to characterize PD-L1 expression in intra-hepatic (iCCA) and perihilar (pCCA) cholangiocarcinomas, and to correlate our results with clinicopathological features, density of tumor-infiltrating lymphocytes (TILs) and PD-1 expression.A series of 58 iCCAs and 41 pCCAs was included in the study. PD-L1, PD-1 and CD3 expression was investigated using immunohistochemistry. Density of TILs was evaluated by immunohistochemistry using a quantitative score of CD3-stained intratumoral lymphocytes.PD-L1 expression by neoplastic cells was observed in 9 cases (9%, 5 iCCAs and 4 pCCAs). PD-L1 positive inflammatory cell aggregates were identified in 46% (n = 46) of the cases (31 iCCAs and 15 pCCAs). PD-L1 expression by either neoplastic or inflammatory cells was associated to high density of CD3-positive TILs (p = 0.01 and p = 0.005, respectively). The number of PD-L1 positive inflammatory cell aggregates was higher in tumors with high PD-1 expression (p < 0.0001).Altogether, PD-L1 in iCCA and pCCA is mainly expressed in tumors with high density of TILs. Our results suggest that CCAs with dense intratumoral lymphocytic infiltration might represent good candidates for PD-L1/PD-1 blocking agents.

  20. Combined evaluation of the FAS cell surface death receptor and CD8+ tumor infiltrating lymphocytes as a prognostic biomarker in breast cancer

    PubMed Central

    Blok, Erik J.; van den Bulk, Jitske; Dekker-Ensink, N. Geeske; Derr, Remco; Kanters, Corné; Bastiaannet, Esther; Kroep, Judith R.; van de Velde, Cornelis J.H.; Kuppen, Peter J.K.

    2017-01-01

    Multiple studies showed the prognostic capacities of tumor-infiltrating lymphocytes (TILs) in triple-negative breast cancer (TNBC), but not in other subtypes. We evaluated tumor expression of FAS, a key receptor in T-cell mediated apoptosis, as possible explanation for this differential prognostic value of TILs. Furthermore, we evaluated the prognostic relevance of FAS, both as an independent biomarker and in relation to CD8-positive T-cell presence. The study cohort consisted of 667 breast cancer patients treated in the LUMC between 1997 and 2009. FAS expression was determined using immunohistochemistry and the percentage of FAS-positive tumor cells was quantified. Furthermore, the number of CD8-positive infiltrating cells was determined, and its prognostic relevance was associated to FAS-expression using stratified survival analysis. In TNBC, FAS was averagely expressed in 49% of tumor cells, whereas ER-positive subtypes showed an average Fas expression of 16-20%. In the entire cohort, FAS was identified as significant prognostic marker for recurrence (adjusted HR 0.53, 95% CI 0.36-0.77) and borderline significant marker for overall survival (adjusted HR 0.72, 95% CI 0.52-1.01). Upon stratification for FAS-expression, CD8+ TILs were only prognostic at high levels (above median) of FAS expression in ER-negative disease. In summary, FAS was identified as an independent prognostic marker for recurrence free survival in breast cancer, with large variation in expression by receptor subtypes. Interestingly, the prognostic effect of CD8+ TILs in ER-negative disease was only valid for tumors with a high FAS expression. PMID:28121628

  1. Combined evaluation of the FAS cell surface death receptor and CD8+ tumor infiltrating lymphocytes as a prognostic biomarker in breast cancer.

    PubMed

    Blok, Erik J; van den Bulk, Jitske; Dekker-Ensink, N Geeske; Derr, Remco; Kanters, Corné; Bastiaannet, Esther; Kroep, Judith R; van de Velde, Cornelis J H; Kuppen, Peter J K

    2017-02-28

    Multiple studies showed the prognostic capacities of tumor-infiltrating lymphocytes (TILs) in triple-negative breast cancer (TNBC), but not in other subtypes. We evaluated tumor expression of FAS, a key receptor in T-cell mediated apoptosis, as possible explanation for this differential prognostic value of TILs. Furthermore, we evaluated the prognostic relevance of FAS, both as an independent biomarker and in relation to CD8-positive T-cell presence. The study cohort consisted of 667 breast cancer patients treated in the LUMC between 1997 and 2009. FAS expression was determined using immunohistochemistry and the percentage of FAS-positive tumor cells was quantified. Furthermore, the number of CD8-positive infiltrating cells was determined, and its prognostic relevance was associated to FAS-expression using stratified survival analysis. In TNBC, FAS was averagely expressed in 49% of tumor cells, whereas ER-positive subtypes showed an average Fas expression of 16-20%. In the entire cohort, FAS was identified as significant prognostic marker for recurrence (adjusted HR 0.53, 95% CI 0.36-0.77) and borderline significant marker for overall survival (adjusted HR 0.72, 95% CI 0.52-1.01). Upon stratification for FAS-expression, CD8+ TILs were only prognostic at high levels (above median) of FAS expression in ER-negative disease. In summary, FAS was identified as an independent prognostic marker for recurrence free survival in breast cancer, with large variation in expression by receptor subtypes. Interestingly, the prognostic effect of CD8+ TILs in ER-negative disease was only valid for tumors with a high FAS expression.

  2. Aircraft observations of East-Asian cyclone induced uplift and long-range transport of polluted boundary layer air to the lowermost stratosphere

    NASA Astrophysics Data System (ADS)

    Schlager, Hans; Arnold, Frank; Aufmhoff, Heinrich; Baumann, Robert; Priola, Lisa; Roiger, Anke; Sailer, Tomas; Wirth, Martin; Schumann, Ulrich

    2013-04-01

    We report on the airborne detection of a large-scale stratified pollution layer in the lowermost stratosphere which contained increased concentrations of sulfur dioxide, reactive nitrogen, water vapour and sulfate aerosols. The measurements were performed over Central Europe with a chemical ionization mass spectrometer and a high spectral resolution Lidar on board the new German research aircraft HALO. Transport model simulations indicate the East-Asian planetary boundary layer (PBL) as the source region of this layer. The PBL air was uplifted by an East Asian warm conveyor belt (WCB) and thereafter experienced mostly horizontal transport and dispersion covering significant part of the northern hemisphere. The pollution layer extent up to 2 km above the thermal tropopause and appears to be trapped in the upper part of the tropopause inversion layer (TIL). Accompanying chemistry and aerosol model simulations indicate efficient SO2 conversion to sulfuric acid during the horizontal transport in the TIL, accelerated by increased OH resulting from the increased water vapour. Low temperature and increased water vapour led to efficient binary H2SO4/H2O nucleation. The uplifted anthropogenic nitrogen oxides experienced OH and particle mediated conversion to HNO3. The layer of sulfate particles formed in the upper part of the TIL was observed in the Lidar backscatter signal. Since mid-latitude East Asia is a region with very large SO2 emissions and a very high frequency of WCBs, SO2 uplift into the lowermost stratosphere from this region may occur frequently, eventually leading very often to corresponding pollution layers in the northern-hemisphere TIL.

  3. Observational characteristics of the tropopause inversion layer derived from CHAMP/GRACE radio occultations and MOZAIC aircraft data

    NASA Astrophysics Data System (ADS)

    Schmidt, Torsten; Cammas, Jean-Pierre; Heise, Stefan; Wickert, Jens; Haser, Antonia

    2010-05-01

    In this study we discuss characteristics of the tropopause inversion layer (TIL) based on two datasets. Temperature measurements from GPS radio occultation (RO) data (CHAMP and GRACE) for the time interval 2001-2009 are used to exhibit seasonal properties of the TIL on a global scale. In agreement with previous studies the vertical structure of the TIL is investigated using the square of the buoyancy frequency N. For the extratropics on both hemispheres N2 has an universal distribution independent from season: a local minimum about 2 km below the lapse rate tropopause height (LRTH), an absolute maximum about 1 km above the LRTH, and a local minimum about 4 km above the LRTH. In the tropics (15°N-15°S) the N2 maximum above the tropopause is 200-300 m higher compared with the extratropics and the local minimum of N2 below the tropopause appears about 4 km below the LRTH. Trace gas measurements onboard commercial aircrafts from 2001-2007 are used as a complementary dataset (MOZAIC program). We demonstrate that the mixing ratio gradients of ozone, carbon monoxide and water vapor are suitable parameters for characterizing the TIL reproducing most of the vertical structure of N2. We also show that the LRTH is strongly correlated with the absolute maxima of ozone and carbon monoxide mixing ratio gradients. Mean deviations of the heights of the absolute maxima of mixing ratio gradients from O3 and CO to the LRTH are (-0.02±1.51) km and (-0.35±1.28) km, respectively.

  4. Target-in-the-loop beam control: basic considerations for analysis and wave-front sensing

    NASA Astrophysics Data System (ADS)

    Vorontsov, Mikhail A.; Kolosov, Valeriy

    2005-01-01

    Target-in-the-loop (TIL) wave propagation geometry represents perhaps the most challenging case for adaptive optics applications that are related to maximization of irradiance power density on extended remotely located surfaces in the presence of dynamically changing refractive-index inhomogeneities in the propagation medium. We introduce a TIL propagation model that uses a combination of the parabolic equation describing coherent outgoing-wave propagation, and the equation describing evolution of the mutual correlation function (MCF) for the backscattered wave (return wave). The resulting evolution equation for the MCF is further simplified by use of the smooth-refractive-index approximation. This approximation permits derivation of the transport equation for the return-wave brightness function, analyzed here by the method of characteristics (brightness function trajectories). The equations for the brightness function trajectories (ray equations) can be efficiently integrated numerically. We also consider wave-front sensors that perform sensing of speckle-averaged characteristics of the wave-front phase (TIL sensors). Analysis of the wave-front phase reconstructed from Shack-Hartmann TIL sensor measurements shows that an extended target introduces a phase modulation (target-induced phase) that cannot be easily separated from the atmospheric-turbulence-related phase aberrations. We also show that wave-front sensing results depend on the extended target shape, surface roughness, and outgoing-beam intensity distribution on the target surface. For targets with smooth surfaces and nonflat shapes, the target-induced phase can contain aberrations. The presence of target-induced aberrations in the conjugated phase may result in a deterioration of adaptive system performance.

  5. Target-in-the-loop beam control: basic considerations for analysis and wave-front sensing.

    PubMed

    Vorontsov, Mikhail A; Kolosov, Valeriy

    2005-01-01

    Target-in-the-loop (TIL) wave propagation geometry represents perhaps the most challenging case for adaptive optics applications that are related to maximization of irradiance power density on extended remotely located surfaces in the presence of dynamically changing refractive-index inhomogeneities in the propagation medium. We introduce a TIL propagation model that uses a combination of the parabolic equation describing coherent outgoing-wave propagation, and the equation describing evolution of the mutual correlation function (MCF) for the backscattered wave (return wave). The resulting evolution equation for the MCF is further simplified by use of the smooth-refractive-index approximation. This approximation permits derivation of the transport equation for the return-wave brightness function, analyzed here by the method of characteristics (brightness function trajectories). The equations for the brightness function trajectories (ray equations) can be efficiently integrated numerically. We also consider wave-front sensors that perform sensing of speckle-averaged characteristics of the wave-front phase (TIL sensors). Analysis of the wave-front phase reconstructed from Shack-Hartmann TIL sensor measurements shows that an extended target introduces a phase modulation (target-induced phase) that cannot be easily separated from the atmospheric-turbulence-related phase aberrations. We also show that wave-front sensing results depend on the extended target shape, surface roughness, and outgoing-beam intensity distribution on the target surface. For targets with smooth surfaces and nonflat shapes, the target-induced phase can contain aberrations. The presence of target-induced aberrations in the conjugated phase may result in a deterioration of adaptive system performance.

  6. Cytotoxic T cell clones isolated from ovarian tumor-infiltrating lymphocytes recognize multiple antigenic epitopes on autologous tumor cells.

    PubMed

    Ioannides, C G; Freedman, R S; Platsoucas, C D; Rashed, S; Kim, Y P

    1991-03-01

    CTL clones were developed from tumor infiltrating lymphocytes (TIL) from the ascites of a patient with ovarian carcinoma by coculture of TIL with autologous tumor cells and subsequent cloning in the presence of autologous tumor cells. These CTL clones expressed preferential cytolytic activity against autologous tumor cells but not against allogeneic ovarian tumor cells and the NK-sensitive cell line K562. The cytolytic activity of these CTL against autologous tumors was inhibited by anti-TCR (WT31 mAb), anti-HLA class I, and anti-CD3 mAb but not by the NK function antibody Leu 11b. Cloning of the autologous tumor cells in vitro revealed that the CTL clones of the ovarian TIL expressed differential abilities to lyse autologous tumor cell clones. The specificity analysis of these autologous tumor specific CTL suggested that they recognize several antigenic determinants present on the ovarian tumor cells. Our results indicate the presence of at least three antigenic epitopes on the tumor cells (designated OVA-1A, OVA-1B, and OVA-1C), one of which (OVA-1C) is unstable. These determinants are present either simultaneously or separately, and six types of ovarian clones can be distinguished on the basis of their expression. These results indicate that CTL of the TIL detect intratumor antigenic heterogeneity. The novel heterogeneity identified within the ovarian tumor cells in this report may be of significance for understanding cellular immunity in ovarian cancer and developing adoptive specific immunotherapeutic approaches in ovarian cancer.

  7. The prognostic advantage of preoperative intratumoral injection of OK-432 for gastric cancer patients

    PubMed Central

    Gochi, A; Orita, K; Fuchimoto, S; Tanaka, N; Ogawa, N

    2001-01-01

    To investigate, by a multi-institutional randomized trial, the prognostic significance of the augmentation of tumour-infiltrating lymphocytes (TILs) by preoperative intratumoral injection of OK-432 (OK-432 it), a bacterial biological response modifier, in patients with gastric cancer. The 10-year survival and disease-free survival were examined and analysis of the factors showing survival benefit was performed. 370 patients who had undergone curative resection of gastric cancer were enrolled in this study and followed up for 10 years postoperatively. Patients were randomized into either an OK-432 it group or a control group. Ten Klinishe Einheit (KE) of OK-432 was endoscopically injected at 1 to 2 weeks before the operation in the OK-432 it group. Both groups received the same adjuvant chemoimmunotherapy consisting of a bolus injection of mitomycin C (0.4 mg kg−1i.v.) and administration of tegafur and OK-432 from postoperative day 14 up to 1 year later. Tegafur (600 mg day−1) was given orally and OK-432 (5 KE/2 weeks) was injected intradermally for a maintenance therapy. The TILs grades in resected tumour specimens and presence of metastasis and metastatic pattern in dissected lymph nodes were examined. Multivariate analysis was performed to determine the efficacy of OK-432 it on prognostic factors. All patients were followed up for 10 years. The overall 5- and 10-year survival rates and disease-free survival rates of the OK-432 it group were not significantly higher than those of the control group. However, OK-432 it significantly increased the 5- and 10-year survival rates of patients with stage IIIA + IIIB, moderate lymph node metastasis (pN2), and positive TILs. OK-432 it was most effective at prolonging the survival of patients who had both positive TILs and lymph node metastasis. The OK-432 it group with positive TILs showed a significant decrease in metastatic lymph node frequency and in the number of lymph node micro- metastatic foci when compared to

  8. William Van Til: The Last Progressive?

    ERIC Educational Resources Information Center

    Beineke, John A.

    2010-01-01

    In 1999, the changing goals of American schools were explored in "Education Week" through the events, achievements, and personalities that had formed United States education in the 20th century. First a series of articles, the collection was later published in book form as "Lessons of a Century: A Nation's Schools Come of Age."…

  9. Acute toxicity study of tilmicosin-loaded hydrogenated castor oil-solid lipid nanoparticles.

    PubMed

    Xie, Shuyu; Wang, Fenghua; Wang, Yan; Zhu, Luyan; Dong, Zhao; Wang, Xiaofang; Li, Xihe; Zhou, Wenzhong

    2011-11-20

    Our previous studies demonstrated that tilmicosin-loaded hydrogenated castor oil solid lipid nanoparticles (Til-HCO-SLN) are a promising formulation for enhanced pharmacological activity and therapeutic efficacy in veterinary use. The purpose of this work was to evaluate the acute toxicity of Til-HCO-SLN. Two nanoparticle doses were used for the study in ICR mice. The low dose (766 mg/kg.bw) with tilmicosin 7.5 times of the clinic dosage and below the median lethal dose (LD(50)) was subcutaneously administered twice on the first and 7th day. The single high dose (5 g/kg.bw) was the practical upper limit in an acute toxicity study and was administered subcutaneously on the first day. Blank HCO-SLN, native tilmicosin, and saline solution were included as controls. After medication, animals were monitored over 14 days, and then necropsied. Signs of toxicity were evaluated via mortality, symptoms of treatment effect, gross and microscopic pathology, and hematologic and biochemical parameters. After administration of native tilmicosin, all mice died within 2 h in the high dose group, in the low dose group 3 died after the first and 2 died after the second injections. The surviving mice in the tilmicosin low dose group showed hypoactivity, accelerated breath, gloomy spirit and lethargy. In contrast, all mice in Til-HCO-SLN and blank HCO-SLN groups survived at both low and high doses. The high nanoparticle dose induced transient clinical symptoms of treatment effect such as transient reversible action retardation, anorexy and gloomy spirit, increased spleen and liver coefficients and decreased heart coefficients, microscopic pathological changes of liver, spleen and heart, and minor changes in hematologic and biochemical parameters, but no adverse effects were observed in the nanoparticle low dose group. The results revealed that the LD50 of Til-HCO-SLN and blank HCO-SLN exceeded 5 g/kg.bw and thus the nanoparticles are considered low toxic according to the toxicity

  10. Acute toxicity study of tilmicosin-loaded hydrogenated castor oil-solid lipid nanoparticles

    PubMed Central

    2011-01-01

    Background Our previous studies demonstrated that tilmicosin-loaded hydrogenated castor oil solid lipid nanoparticles (Til-HCO-SLN) are a promising formulation for enhanced pharmacological activity and therapeutic efficacy in veterinary use. The purpose of this work was to evaluate the acute toxicity of Til-HCO-SLN. Methods Two nanoparticle doses were used for the study in ICR mice. The low dose (766 mg/kg.bw) with tilmicosin 7.5 times of the clinic dosage and below the median lethal dose (LD50) was subcutaneously administered twice on the first and 7th day. The single high dose (5 g/kg.bw) was the practical upper limit in an acute toxicity study and was administered subcutaneously on the first day. Blank HCO-SLN, native tilmicosin, and saline solution were included as controls. After medication, animals were monitored over 14 days, and then necropsied. Signs of toxicity were evaluated via mortality, symptoms of treatment effect, gross and microscopic pathology, and hematologic and biochemical parameters. Results After administration of native tilmicosin, all mice died within 2 h in the high dose group, in the low dose group 3 died after the first and 2 died after the second injections. The surviving mice in the tilmicosin low dose group showed hypoactivity, accelerated breath, gloomy spirit and lethargy. In contrast, all mice in Til-HCO-SLN and blank HCO-SLN groups survived at both low and high doses. The high nanoparticle dose induced transient clinical symptoms of treatment effect such as transient reversible action retardation, anorexy and gloomy spirit, increased spleen and liver coefficients and decreased heart coefficients, microscopic pathological changes of liver, spleen and heart, and minor changes in hematologic and biochemical parameters, but no adverse effects were observed in the nanoparticle low dose group. Conclusions The results revealed that the LD50 of Til-HCO-SLN and blank HCO-SLN exceeded 5 g/kg.bw and thus the nanoparticles are considered low

  11. Observations of the UTLS: An analysis of the double tropopause and its relationship to Rossby waves and the tropopause inversion layer

    NASA Astrophysics Data System (ADS)

    Peevey, Tanya

    The upper troposphere lower stratosphere (UTLS) is a region of minimum temperatures that contains the tropopause. As a transition region between the troposphere and the stratosphere, the UTLS contains various processes that facilitate stratosphere-troposphere exchange (STE) which can redistribute radiatively important species such as water vapor or ozone. One potential marker for STE is the double tropopause (DT). Therefore this study seeks to further understand how DTs form and how they could enhance the current understanding of some STE processes in the UTLS. Using data from the High Resolution Dynamic Limb Sounder (HIRDLS), a data set with high vertical and horizontal resolution, newly discovered DT structures are found over the Pacific and Atlantic oceans that suggest a relationship between the DT and both storm tracks and Rossby waves. The association between DTs and storm tracks is examined by further analyzing the recently discovered and unexpected relationship between the DT and the tropopause inversion layer (TIL) in a developing baroclinic disturbance. Results show an increase in the number of DTs when the lapse rate of the extratropical TIL is less than -2°C/km, i.e. when the TIL is stronger and the local stability is higher. Composites of ERA-Interim DT profiles for three different TIL strengths shows that the vertical motion and relative vorticity both decrease as the TIL increases, which suggests the warm conveyor belt as a mechanism. This is investigated further with a case study analysis of a developing extratropical cyclone in the Pacific Ocean. Additionally, an analysis of DTs in relation to the large scale flow responsible for storm development shows a strong correlation between monthly Rossby wave activity, ozone laminae and DT variability. Further examination shows that if these waves break a DT will be found with a wave breaking event about 30% of the time in the eastern Pacific and eastern Atlantic oceans, both regions of poleward wave

  12. A High RORγT/CD3 Ratio is a Strong Prognostic Factor for Postoperative Survival in Advanced Colorectal Cancer: Analysis of Helper T Cell Lymphocytes (Th1, Th2, Th17 and Regulatory T Cells).

    PubMed

    Yoshida, Naohiro; Kinugasa, Tetsushi; Miyoshi, Hiroaki; Sato, Kensaku; Yuge, Kotaro; Ohchi, Takafumi; Fujino, Shinya; Shiraiwa, Sachiko; Katagiri, Mitsuhiro; Akagi, Yoshito; Ohshima, Koichi

    2016-03-01

    Tumor-infiltrating lymphocytes (TILs), part of the host immune response, have been widely reported as influential factors in the tumor microenvironment for the clinical outcome of colorectal cancer (CRC). However, the network of helper T cells is very complex, and which T-cell subtypes affect the progression of CRC and postoperative prognosis remains unclear. This study investigated the expression of several subtypes of TILs including T helper type 1 (Th1), Th2, Th17, and regulatory T (Treg) cells to determine their correlation with clinicopathologic features and postoperative prognosis. The study investigated the expression of TILs using immunohistochemistry of tissue microarray samples for 199 CRC patients. The number of each T-cell subtype infiltrating tumors was counted using ImageJ software. The relationship between TIL marker expression, clinicopathologic features, and prognosis was analyzed. A high RORγT/CD3 ratio (Th17 ratio) was significantly correlated with lymph node metastasis (p = 0.002), and a high of Foxp3/CD3 ratio (Treg ratio) was correlated with tumor location in the colon (p = 0.04), as shown by the Chi square test. In multivariate analysis, a high RORγT/CD3 ratio was the only independent prognostic factor for overall survival (p = 0.04; hazard ratio [HR], 1.84; 95% confidence interval [CI] 1.02-3.45). This study confirmed a high RORγT/CD3 ratio as a strong prognostic marker for postoperative survival. The immunohistochemistry results suggest that Th17 may affect lymph node metastasis in CRC. If new immunotherapies reducing Th17 expression are established, they may improve the efficiency of cancer treatment and prolong the survival of patients with CRC.

  13. Type, Frequency, and Spatial Distribution of Immune Cell Infiltrates in CNS Germinomas: Evidence for Inflammatory and Immunosuppressive Mechanisms.

    PubMed

    Zapka, Pia; Dörner, Evelyn; Dreschmann, Verena; Sakamato, Noriaki; Kristiansen, Glen; Calaminus, Gabriele; Vokuhl, Christian; Leuschner, Ivo; Pietsch, Torsten

    2018-02-01

    Central nervous system germinomas are characterized by a massive immune cell infiltrate. We systematically characterized these immune cells in 28 germinomas by immunophenotyping and image analysis. mRNA expression was analyzed by Nanostring technology and in situ RNA hybridization. Tumor infiltrating lymphocytes (TILs) were composed of 61.8% ± 3.1% (mean ± SE) CD3-positive T cells, including 45.2% ± 3.5% of CD4-positive T-helper cells, 23.4% ± 1.5% of CD8-positive cytotoxic T cells, 5.5% ± 0.9% of FoxP3-positive regulatory T cells, and 11.9% ±1.3% PD-1-positive TILs. B cells accounted for 35.8% ± 2.9% of TILs and plasma cells for 9.3% ± 1.6%. Tumor-associated macrophages consisted of clusters of activated PD-L1-positive macrophages and interspersed anti-inflammatory macrophages expressing CD163. Germinoma cells did not express PD-L1. Expression of genes encoding immune cell markers and cytokines was high and comparable to mRNA levels in lymph node tissue. IFNG and IL10 mRNA was detected in subfractions of TILs and in PD-L1-positive macrophages. Taken together, the strong immune reaction observed in germinomas involves inflammatory as well as various suppressive mechanisms. Expression of PD-1 and PD-L1 and infiltration of cytotoxic T cells are biomarkers predictive of response to anti-PD-1/PD-L1 therapies, constituting a rationale for possible novel treatment approaches. © 2017 American Association of Neuropathologists, Inc. All rights reserved.

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

    PubMed Central

    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

    ABSTRACT 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-1low/intermed phenotype identifying recently activated and still functional cells, whereas PD-1hiTim-3− T cells are actually exhausted. Nonetheless, PD-1intermed 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. PMID:27853635

  15. 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. Copyright © 2016 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  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. Effects of habitat fragmentation on the genetic diversity and differentiation of Dendrolimus punctatus (Lepidoptera: Lasiocampidae) in Thousand Island Lake, China, based on mitochondrial COI gene sequences.

    PubMed

    Lv, K; Wang, J-R; Li, T-Q; Zhou, J; Gu, J-Q; Zhou, G-X; Xu, Z-H

    2018-05-10

    Thousand Island Lake (TIL) is a typical fragmented landscape and an ideal model to study ecological effects of fragmentation. Partial fragments of the mitochondrial cytochrome oxidase subunit I gene of 23 island populations of Dendrolimus punctatus in TIL were sequenced, 141 haplotypes being identified. The number of haplotypes increased significantly with the increase in island area and shape index, whereas no significant correlation was detected between three island attributes (area, shape and isolation) and haplotype diversity. However, the correlation with number of haplotypes was no longer significant when the 'outlier' island JSD (the largest island) was not included. Additionally, we found no significant relationship between geographic distance and genetic distance. Geographic isolation did not obstruct the gene flow among D. punctatus populations, which might be because of the high dispersal capacity of this pine moth. Fragmentation resulted in the conversion of large and continuous habitats into isolated, small and insular patches, which was the primary effect on the genetic diversity of D. punctatus in TIL. The conclusion to emphasize from our research is that habitat fragmentation reduced the biological genetic diversity to some extent, further demonstrating the importance of habitat continuity in biodiversity protection.

  18. The shaped pulses control and operation on the SG-III prototype facility

    NASA Astrophysics Data System (ADS)

    Ping, Li; Wei, Wang; Sai, Jin; Wanqing, Huang; Wenyi, Wang; Jingqin, Su; Runchang, Zhao

    2018-04-01

    The laser driven inertial confined fusion experiments require careful temporal shape control of the laser pulse. Two approaches are introduced to improve the accuracy and efficiency of the close loop feedback system for long term operation in TIL; the first one is a statistical model to analyze the variation of the parameters obtained from previous shots, the other is a matrix algorithm proposed to relate the electrical signal and the impulse amplitudes. With the model and algorithm applied in the pulse shaping in TIL, a variety of shaped pulses were produced with a 10% precision in half an hour for almost three years under different circumstance.

  19. Validation of a HLA-A2 tetramer flow cytometric method, IFNgamma real time RT-PCR, and IFNgamma ELISPOT for detection of immunologic response to gp100 and MelanA/MART-1 in melanoma patients

    PubMed Central

    Xu, Yuanxin; Theobald, Valerie; Sung, Crystal; DePalma, Kathleen; Atwater, Laura; Seiger, Keirsten; Perricone, Michael A; Richards, Susan M

    2008-01-01

    Background HLA-A2 tetramer flow cytometry, IFNγ real time RT-PCR and IFNγ ELISPOT assays are commonly used as surrogate immunological endpoints for cancer immunotherapy. While these are often used as research assays to assess patient's immunologic response, assay validation is necessary to ensure reliable and reproducible results and enable more accurate data interpretation. Here we describe a rigorous validation approach for each of these assays prior to their use for clinical sample analysis. Methods Standard operating procedures for each assay were established. HLA-A2 (A*0201) tetramer assay specific for gp100209(210M) and MART-126–35(27L), IFNγ real time RT-PCR and ELISPOT methods were validated using tumor infiltrating lymphocyte cell lines (TIL) isolated from HLA-A2 melanoma patients. TIL cells, specific for gp100 (TIL 1520) or MART-1 (TIL 1143 and TIL1235), were used alone or spiked into cryopreserved HLA-A2 PBMC from healthy subjects. TIL/PBMC were stimulated with peptides (gp100209, gp100pool, MART-127–35, or influenza-M1 and negative control peptide HIV) to further assess assay performance characteristics for real time RT-PCR and ELISPOT methods. Validation parameters included specificity, accuracy, precision, linearity of dilution, limit of detection (LOD) and limit of quantification (LOQ). In addition, distribution was established in normal HLA-A2 PBMC samples. Reference ranges for assay controls were established. Results The validation process demonstrated that the HLA-A2 tetramer, IFNγ real time RT-PCR, and IFNγ ELISPOT were highly specific for each antigen, with minimal cross-reactivity between gp100 and MelanA/MART-1. The assays were sensitive; detection could be achieved at as few as 1/4545–1/6667 cells by tetramer analysis, 1/50,000 cells by real time RT-PCR, and 1/10,000–1/20,000 by ELISPOT. The assays met criteria for precision with %CV < 20% (except ELISPOT using high PBMC numbers with %CV < 25%) although flow cytometric assays and

  20. Antibodies Against Immune Checkpoint Molecules Restore Functions of Tumor-Infiltrating T Cells in Hepatocellular Carcinomas.

    PubMed

    Zhou, Guoying; Sprengers, Dave; Boor, Patrick P C; Doukas, Michail; Schutz, Hannah; Mancham, Shanta; Pedroza-Gonzalez, Alexander; Polak, Wojciech G; de Jonge, Jeroen; Gaspersz, Marcia; Dong, Haidong; Thielemans, Kris; Pan, Qiuwei; IJzermans, Jan N M; Bruno, Marco J; Kwekkeboom, Jaap

    2017-10-01

    Ligand binding to inhibitory receptors on immune cells, such as programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte associated protein 4 (CTLA4), down-regulates the T-cell-mediated immune response (called immune checkpoints). Antibodies that block these receptors increase antitumor immunity in patients with melanoma, non-small-cell lung cancer, and renal cell cancer. Tumor-infiltrating CD4 + and CD8 + T cells in patients with hepatocellular carcinoma (HCC) have been found to be functionally compromised. We analyzed HCC samples from patients to determine if these inhibitory pathways prevent T-cell responses in HCCs and to find ways to restore their antitumor functions. We collected HCC samples from 59 patients who underwent surgical resection from November 2013 through May 2017, along with tumor-free liver tissues (control tissues) and peripheral blood samples. We isolated tumor-infiltrating lymphocytes (TIL) and intra-hepatic lymphocytes. We used flow cytometry to quantify expression of the inhibitory receptors PD-1, hepatitis A virus cellular receptor 2 (TIM3), lymphocyte activating 3 (LAG3), and CTLA4 on CD8 + and CD4 + T cells from tumor, control tissue, and blood; we studied the effects of antibodies that block these pathways in T-cell activation assays. Expression of PD-1, TIM3, LAG3, and CTLA4 was significantly higher on CD8 + and CD4 + T cells isolated from HCC tissue than control tissue or blood. Dendritic cells, monocytes, and B cells in HCC tumors expressed ligands for these receptors. Expression of PD-1, TIM3, and LAG3 was higher on tumor-associated antigen (TAA)-specific CD8 + TIL, compared with other CD8 + TIL. Compared with TIL that did not express these inhibitory receptors, CD8 + and CD4 + TIL that did express these receptors had higher levels of markers of activation, but similar or decreased levels of granzyme B and effector cytokines. Antibodies against CD274 (PD-ligand1 [PD-L1]), TIM3, or LAG3 increased proliferation of CD8 + and CD4 + TIL

  1. Clinically Relevant Cytotoxic Immune Cell Signatures and Clonal Expansion of T Cell Receptors in High-risk MYCN-not-amplified Human Neuroblastoma.

    PubMed

    Wei, Jun S; Kuznetsov, Igor B; Zhang, Shile; Song, Young K; Asgharzadeh, Shahab; Sindiri, Sivasish; Wen, Xinyu; Patidar, Rajesh; Nagaraj, Sushma; Walton, Ashley; Guidry Auvil, Jaime M; Gerhard, Daniela S; Yuksel, Aysen; Catchpoole, Daniel R; Hewitt, Stephen M; Sondel, Paul M; Seeger, Robert C; Maris, John M; Khan, Javed

    2018-05-21

    High-risk neuroblastoma is an aggressive disease. DNA sequencing studies have revealed a paucity of actionable genomic alterations and a low mutation burden, posing challenges to develop effective novel therapies. We used RNA sequencing (RNA-seq) to investigate the biology of this disease including a focus on tumor-infiltrating lymphocytes (TILs). We performed deep RNA-seq on pre-treatment diagnostic tumors from 129 high-risk and 21 low- or intermediate-risk patients with neuroblastomas. We used single-sample gene set enrichment analysis to detect gene expression signatures of TILs in tumors and examined their association with clinical and molecular parameters including patient outcome. The expression profiles of 190 additional pre-treatment diagnostic neuroblastomas, a neuroblastoma tissue microarray, and T-cell receptor (TCR) sequencing were used to validate our findings. We found that MYCN -not-amplified ( MYCN -NA) tumors had significant higher cytotoxic TIL signatures compared to MYCN -amplified ( MYCN -A) tumors. A reported MYCN-activation-signature was significantly associated with poor outcome for high-risk patients with MYCN -NA tumors; however, a subgroup of these patients who had elevated activated NK cells, CD8+ T-cells, and cytolytic signatures showed improved outcome and expansion of infiltrating T-cell receptor (TCR) clones. Furthermore, we observed up-regulation of immune exhaustion marker genes, indicating an immune suppressive microenvironment in these neuroblastomas. Conclusions: This study provides evidence that RNA signatures of cytotoxic TIL are associated with the presence of activated NK-/T-cells and improved outcomes in high-risk neuroblastoma patients harboring MYCN -NA tumors. Our findings suggest that these high-risk patients with MYCN -NA neuroblastoma may benefit from additional immunotherapies incorporated into the current therapeutic strategies. Copyright ©2018, American Association for Cancer Research.

  2. 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

    2017-12-01

    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. Copyright © 2016 John Wiley & Sons, Ltd.

  3. Tumour-infiltrating lymphocytes predict response to definitive chemoradiotherapy in head and neck cancer.

    PubMed

    Balermpas, P; Michel, Y; Wagenblast, J; Seitz, O; Weiss, C; Rödel, F; Rödel, C; Fokas, E

    2014-01-21

    We aimed to investigate the prognostic value of tumour-infiltrating lymphocytes' (TILs) expression in pretreatment specimens from patients with head and neck squamous cell carcinoma (HNSCC) treated with definitive chemoradiotherapy (CRT). The prevalence of CD3+, CD8+, CD4+ and FOXP3+ TILs was assessed using immunohistochemistry in tumour tissue obtained from 101 patients before CRT and was correlated with clinicopathological characteristics as well as local failure-free- (LFFS), distant metastases free- (DMFS), progression-free (PFS) and overall survival (OS). Survival curves were measured using the Kaplan-Meier method, and differences in survival between the groups were estimated using the log-rank test. Prognostic effects of TIL subset density were determined using the Cox regression analysis. With a mean follow-up of 25 months (range, 2.3-63 months), OS at 2 years was 57.4% for the entire cohort. Patients with high immunohistochemical CD3 and CD8 expression had significantly increased OS (P=0.024 and P=0.028), PFS (P=0.044 and P=0.047) and DMFS (P=0.021 and P=0.026) but not LFFS (P=0.90 and P=0.104) in multivariate analysis that included predictive clinicopathologic factors, such as age, sex, T-stage, N-stage, tumour grading and localisation. Neither CD4 nor FOXP3 expression showed significance for the clinical outcome. The lower N-stage was associated with improved OS in the multivariate analysis (P=0.049). The positive correlation between a high number of infiltrating CD3+ and CD8+ cells and clinical outcome indicates that TILs may have a beneficial role in HNSCC patients and may serve as a biomarker to identify patients likely to benefit from definitive CRT.

  4. PD-L1, Galectin-9 and CD8+ tumor-infiltrating lymphocytes are associated with survival in hepatocellular carcinoma.

    PubMed

    Sideras, Kostandinos; Biermann, Katharina; Verheij, Joanne; Takkenberg, Bart R; Mancham, Shanta; Hansen, Bettina E; Schutz, Hannah M; de Man, Robert A; Sprengers, Dave; Buschow, Sonja I; Verseput, Maddy C M; Boor, Patrick P C; Pan, Qiuwei; van Gulik, Thomas M; Terkivatan, Turkan; Ijzermans, Jan N M; Beuers, Ulrich H W; Sleijfer, Stefan; Bruno, Marco J; Kwekkeboom, Jaap

    2017-01-01

    Novel systemic treatments for hepatocellular carcinoma (HCC) are strongly needed. Immunotherapy is a promising strategy that can induce specific antitumor immune responses. Understanding the mechanisms of immune resistance by HCC is crucial for development of suitable immunotherapeutics. We used immunohistochemistry on tissue-microarrays to examine the co-expression of the immune inhibiting molecules PD-L1, Galectin-9, HVEM and IDO, as well as tumor CD8 + lymphocyte infiltration in HCC, in two independent cohorts of patients. We found that at least some expression in tumor cells was seen in 97% of cases for HVEM, 83% for PD-L1, 79% for Gal-9 and 66% for IDO. In the discovery cohort (n = 94), we found that lack of, or low, tumor expression of PD-L1 ( p < 0.001), Galectin-9 ( p < 0.001) and HVEM ( p < 0.001), and low CD8 + TIL count ( p = 0.016), were associated with poor HCC-specific survival. PD-L1, Galectin-9 and CD8 + TIL count were predictive of HCC-specific survival independent of baseline clinicopathologic characteristics and the combination of these markers was a powerful predictor of HCC-specific survival (HR 0.29; p <0.001). These results were confirmed in the validation cohort (n = 60). We show that low expression levels of PD-L1 and Gal-9 in combination with low CD8 + TIL count predict extremely poor HCC-specific survival and it requires a change in two of these parameters to significantly improve prognosis. In conclusion, intra-tumoral expression of these immune inhibiting molecules was observed in the majority of HCC patients. Low expression of PD-L1 and Galectin-9 and low CD8 + TIL count are associated with poor HCC-specific survival. Combining immune biomarkers leads to superior predictors of HCC mortality.

  5. The Distribution of Intratumoral Macrophages Correlates with Molecular Phenotypes and Impacts Prognosis in Colorectal Carcinoma.

    PubMed

    Kim, Younghoon; Wen, Xianyu; Bae, Jeong Mo; Kim, Jung Ho; Cho, Nam-Yun; Kang, Gyeong Hoon

    2018-06-15

    The role of tumor-associated macrophages (TAMs) in colorectal cancer (CRC) remains elusive. In this study, we aimed to examine the correlation between TAMs, clinicopathological features, tumor-infiltrating lymphocytes (TILs), and prognosis in CRC via image analysis. Immunohistochemical staining for CD68 and CD163 was performed with pan-macrophage and M2-macrophage markers, respectively. Each marker was separately analyzed for intraepithelial and stromal area densities. All four macrophage densities showed a significant correlation with one another (p = 0.001). Intraepithelial CD68+ macrophage densities showed a correlation with pTNM stage (p = 0.008), microsatellite instability (p < 0.001), CpG island methylator phenotype (p < 0.001), and TIL densities (p < 0.001). Intraepithelial CD163+ macrophage densities were associated with perineural invasion, MSI, CIMP, and TIL densities (p < 0.001). Stromal CD68+ and CD163+ macrophage densities had a significant relationship with Intraepithelial and stromal CD3+ (p = 0.001 and p < 0.001, respectively) and CD8+ (p < 0.001) T cells. High intraepithelial CD68+ macrophage density was associated with worse overall survival (HR = 1.386, 95% CI = 1.043-1.843, p = 0.025) and progression-free survival (HR = 1.522, 95% CI = 1.146-2.020, p = 0.004). Intraepithelial CD68+ macrophage density was also an independent prognostic factor of the progression-free survival (HR = 1.447, 95% CI = 1.076-1.947, p = 0.015) of CRC patients regardless of pTNM stage, lymphatic, venous, and perineural invasions, and TIL densities. Our results indicate that the density of intratumoral macrophages are useful prognostic indicator for further stratifying T cell populations in CRC. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  6. Polymerase ε (POLE) ultra-mutation in uterine tumors correlates with T lymphocyte infiltration and increased resistance to platinum-based chemotherapy in vitro

    PubMed Central

    Bellone, Stefania; Eliana, Bignotti; Lonardi, Silvia; Ferrari, Francesca; Centritto, Floriana; Masserdotti, Alice; Pettinella, Francesca; Black, Jonathan; Menderes, Gulden; Altwerger, Gary; Hui, Pei; Lopez, Salvatore; de Haydu, Christopher; Bonazzoli, Elena; Predolini, Federica; Zammataro, Luca; Cocco, Emiliano; Ferrari, Federico; Ravaggi, Antonella; Romani, Chiara; Facchettie, Fabio; Sartori, Enrico; Odicino, Franco E.; Silasi, Dan-Arin; Litkouhi, Babak; Ratner, Elena; Azodi, Masoud; Schwartz, Peter E.; Santin, Alessandro D.

    2016-01-01

    Objective Up to 12 % of all endometrial-carcinomas (EC) harbor DNA-polymerase-ε-(POLE) mutations. It is currently unknown whether the favorable prognosis of POLE-mutated EC is derived from their low metastatic capability, extraordinary number of somatic mutations thus imparting immunogenicity, or a high sensitivity to chemotherapy. Methods Polymerase-chain-reaction-amplification and Sanger-sequencing were used to test for POLE exonuclease-domain-mutations (exons 9–14) 131 EC. Infiltration of CD4+ and CD8+ T-lymphocytes (TIL) and PD-1-expression in POLE-mutated vs POLE wild-type EC was studied by immunohistochemistry (IHC) and the correlations between survival and molecular features were investigated. Finally, primary POLE-mutated and POLE-wild-type EC cell lines were established and compared in-vitro for their sensitivity to chemotherapy. Results Eleven POLE-mutated EC (8.5%) were identified. POLE-mutated tumors were associated with improved progression-free-survival (P<0.05) and displayed increased numbers of CD4+ (44.5 vs 21.8; P = .001) and CD8+ (32.8 vs 13.5; P < .001) TILs when compared to wild-type POLE EC. PD-1 receptor was overexpressed in TILs from POLE-mutated vs wild-type-tumors (81% vs 28%; P < .001). Primary POLE tumor cell lines were significantly more resistant to platinum-chemotherapy in-vitro when compared to POLE-wild-type tumors (P < 0.004). Conclusions POLE ultra-mutated EC are heavily infiltrated with CD4+/CD8+ TIL, overexpress PD-1 immune-check-point (i.e., features consistent with chronic antigen-exposure), and have a better prognosis when compared to other molecular subtypes of EC patients. POLE-mutated tumor-cell lines are resistant to platinum-chemotherapy in-vitro suggesting that the better prognosis of POLE-patients is not secondary to a higher sensitivity to chemotherapy but likely linked to enhanced immunogenicity. PMID:27894751

  7. 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.

  8. Effectiveness of Flood Warning and Preparedness Alternatives.

    DTIC Science & Technology

    1981-08-01

    to shed light on the question of the effective- ness of flood warning and preparedness alternatives and to suggest means of improving effectiveness... dese -1 i he. ti I hc’d liv at lm’-wl’ t I C (I I til I (’W5 1r-d (’Jlls ()ca I tIl (I d Fr l w -ai (otltl 1t h is I- l wt I’ tfll’(d i t it’iI - t, ( 1...the major streams and their t ribu- taries. A-44 Agriculture in the county is gradually decreasing, due at least in part to expansion of urban areas and

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

    Walters, C.T.; Dulaney, J.L.; Campbell, B.E.

    Demonstrations of operation of a compact neodymium glass laser with average output powers greater than 1 kW for several seconds are reported. The laser is based on the thermal inertia laser (TIL) concept wherein a neodymium-doped glass rod is pumped uniformly without cooling during a burst mode of laser operation. Design principles for TIL devices and scaling to 100 kW class lasers are discussed. Experimental results for a low repetition-rate proof-of-concept pulsed device (30 J, 0.2 Hz) and a high repetition-rate pulsed prototype (40 J, 36 Hz) are presented and compared to numerical solutions for the laser rate equations withmore » temperature dependent cross-sections.« less

  10. T cell infiltrate and outcome following resection of intermediate-grade primary neuroendocrine tumours and liver metastases.

    PubMed

    Katz, Steven C; Donkor, Charan; Glasgow, Kristen; Pillarisetty, Venu G; Gönen, Mithat; Espat, N Joseph; Klimstra, David S; D'Angelica, Michael I; Allen, Peter J; Jarnagin, William; Dematteo, Ronald P; Brennan, Murray F; Tang, Laura H

    2010-12-01

    Tumour-infiltrating lymphocytes (TILs) have been shown to predict survival in numerous malignancies. The importance of TILs in primary pancreatic neuroendocrine tumours (NETs) and NET liver metastases (NETLMs) has not been defined. We identified 87 patients with NETs and 39 with NETLMs who had undergone resection. Immunohistochemistry was performed to determine TIL counts. Recurrence-free survival (RFS) and overall survival (OS) were determined using the log-rank test. The median follow-up time was 62 months in NET patients and 48 months in NETLM patients. Vascular invasion and histologic grade were the only independent predictors of outcome for NETs and NETLMs, respectively. Analysis of intermediate-grade NETs indicated that a dense T cell (CD3+) infiltrate was associated with a median RFS of 128 months compared with 61 months for those with low levels of intratumoral T cells (P= 0.05, univariate analysis). Examination of NETLMs revealed that a low level of infiltrating regulatory T cells (Treg, FoxP3+) was a predictor of prolonged survival (P < 0.01, univariate analysis). A robust T cell infiltrate is associated with improved RFS following resection of intermediate-grade NETs, whereas the presence of more Treg correlated with shorter OS after treatment of NETLMs. Further study of the immune response to intermediate-grade NETs and NETLMs is warranted.

  11. Single-cell profiling of breast cancer T cells reveals a tissue-resident memory subset associated with improved prognosis.

    PubMed

    Savas, Peter; Virassamy, Balaji; Ye, Chengzhong; Salim, Agus; Mintoff, Christopher P; Caramia, Franco; Salgado, Roberto; Byrne, David J; Teo, Zhi L; Dushyanthen, Sathana; Byrne, Ann; Wein, Lironne; Luen, Stephen J; Poliness, Catherine; Nightingale, Sophie S; Skandarajah, Anita S; Gyorki, David E; Thornton, Chantel M; Beavis, Paul A; Fox, Stephen B; Darcy, Phillip K; Speed, Terence P; Mackay, Laura K; Neeson, Paul J; Loi, Sherene

    2018-06-25

    The quantity of tumor-infiltrating lymphocytes (TILs) in breast cancer (BC) is a robust prognostic factor for improved patient survival, particularly in triple-negative and HER2-overexpressing BC subtypes 1 . Although T cells are the predominant TIL population 2 , the relationship between quantitative and qualitative differences in T cell subpopulations and patient prognosis remains unknown. We performed single-cell RNA sequencing (scRNA-seq) of 6,311 T cells isolated from human BCs and show that significant heterogeneity exists in the infiltrating T cell population. We demonstrate that BCs with a high number of TILs contained CD8 + T cells with features of tissue-resident memory T (T RM ) cell differentiation and that these CD8 + T RM cells expressed high levels of immune checkpoint molecules and effector proteins. A CD8 + T RM gene signature developed from the scRNA-seq data was significantly associated with improved patient survival in early-stage triple-negative breast cancer (TNBC) and provided better prognostication than CD8 expression alone. Our data suggest that CD8 + T RM cells contribute to BC immunosurveillance and are the key targets of modulation by immune checkpoint inhibition. Further understanding of the development, maintenance and regulation of T RM cells will be crucial for successful immunotherapeutic development in BC.

  12. Frameshift-mutation-derived peptides as tumor-specific antigens in inherited and spontaneous colorectal cancer.

    PubMed

    Saeterdal, I; Bjørheim, J; Lislerud, K; Gjertsen, M K; Bukholm, I K; Olsen, O C; Nesland, J M; Eriksen, J A; Møller, M; Lindblom, A; Gaudernack, G

    2001-11-06

    The functional role and specificity of tumor infiltrating lymphocytes (TIL) is generally not well characterized. Prominent lymphocyte infiltration is the hallmark of the most common form of hereditary colon cancer, hereditary nonpolyposis colon cancer (HNPCC) and the corresponding spontaneous colon cancers with the microsatellite instability (MSI) phenotype. These cancers are caused by inherited or acquired defects in the DNA mismatch-repair machinery. The molecular mechanism behind the MSI phenotype provides a clue to understanding the lymphocyte reaction by allowing reliable prediction of potential T cell epitopes created by frameshift mutations in candidate genes carrying nucleotide repeat sequences, such as TGF beta RII and BAX. These tumors therefore represent an interesting human system for studying TIL and characterizing tumor-specific T cells. We here describe T cell reactivity against several T helper cell epitopes, representing a common frameshift mutation in TGF beta RII, in TIL and peripheral blood lymphocytes from patients with MSI(+) tumors. The peptide SLVRLSSCVPVALMSAMTTSSSQ was recognized by T cells from two of three patients with spontaneous MSI(+) colon cancers and from all three patients with HNPCC. Because such mutations are present in 90% of cancers within this patient group, these newly characterized epitopes provide attractive targets for cancer vaccines, including a prophylactic vaccine for individuals carrying a genetic disposition for developing HNPCC.

  13. Frameshift-mutation-derived peptides as tumor-specific antigens in inherited and spontaneous colorectal cancer

    PubMed Central

    Sæterdal, Ingvil; Bjørheim, Jens; Lislerud, Kari; Gjertsen, Marianne K.; Bukholm, Ida K.; Olsen, Ole Christian; Nesland, Jahn M.; Eriksen, Jon Amund; Møller, Mona; Lindblom, Annika; Gaudernack, Gustav

    2001-01-01

    The functional role and specificity of tumor infiltrating lymphocytes (TIL) is generally not well characterized. Prominent lymphocyte infiltration is the hallmark of the most common form of hereditary colon cancer, hereditary nonpolyposis colon cancer (HNPCC) and the corresponding spontaneous colon cancers with the microsatellite instability (MSI) phenotype. These cancers are caused by inherited or acquired defects in the DNA mismatch–repair machinery. The molecular mechanism behind the MSI phenotype provides a clue to understanding the lymphocyte reaction by allowing reliable prediction of potential T cell epitopes created by frameshift mutations in candidate genes carrying nucleotide repeat sequences, such as TGFβRII and BAX. These tumors therefore represent an interesting human system for studying TIL and characterizing tumor-specific T cells. We here describe T cell reactivity against several T helper cell epitopes, representing a common frameshift mutation in TGFβRII, in TIL and peripheral blood lymphocytes from patients with MSI+ tumors. The peptide SLVRLSSCVPVALMSAMTTSSSQ was recognized by T cells from two of three patients with spontaneous MSI+ colon cancers and from all three patients with HNPCC. Because such mutations are present in 90% of cancers within this patient group, these newly characterized epitopes provide attractive targets for cancer vaccines, including a prophylactic vaccine for individuals carrying a genetic disposition for developing HNPCC. PMID:11687624

  14. Regression and Sentinel Lymph Node Status in Melanoma Progression

    PubMed Central

    Letca, Alina Florentina; Ungureanu, Loredana; Şenilă, Simona Corina; Grigore, Lavinia Elena; Pop, Ştefan; Fechete, Oana; Vesa, Ştefan Cristian

    2018-01-01

    Background The purpose of this study was to assess the role of regression and other clinical and histological features for the prognosis and the progression of cutaneous melanoma. Material/Methods Between 2005 and 2016, 403 patients with melanoma were treated and followed at our Department of Dermatology. Of the 403 patients, 173 patients had cutaneous melanoma and underwent sentinel lymph node (SLN) biopsy and thus were included in this study. Results Histological regression was found in 37 cases of melanoma (21.3%). It was significantly associated with marked and moderate tumor-infiltrating lymphocyte (TIL) and with negative SLN. Progression of the disease occurred in 42 patients (24.2%). On multivariate analysis, we found that a positive lymph node and a Breslow index higher than 2 mm were independent variables associated with disease free survival (DFS). These variables together with a mild TIL were significantly correlated with overall survival (OS). The presence of regression was not associated with DFS or OS. Conclusions We could not demonstrate an association between regression and the outcome of patients with cutaneous melanoma. Tumor thickness greater than 2 mm and a positive SLN were associated with recurrence. Survival was influenced by a Breslow thickness >2 mm, the presence of a mild TIL and a positive SLN status. PMID:29507279

  15. Formation of the Double Tropopause in midlatitudes: an analysis using both observations and models

    NASA Astrophysics Data System (ADS)

    Peevey, Tanya; Konopka, Paul; Homeyer, Cameron; Mueller, Rolf

    2014-05-01

    The double tropopause (DT) is defined using the thermal definition of the tropopause, is found in the upper troposphere lower stratosphere (UTLS) region of the atmosphere, and forms primarily poleward of the subtropical jets. Studies have shown that this thermal structure is associated with the poleward transport of upper tropospheric air into the lower stratosphere during Rossby wave breaking events. The potential for subsequent mixing of radiatively important species in the lower stratosphere highlights the potential importance of the DT in further understanding the dynamics and structure of the UTLS. A few recent studies have drawn attention to this by showing that our knowledge of the DT is not complete. These efforts specifically show that the origin of air within the DT is still under debate since there are currently three different answers to the same question: low latitudes, midlatitudes and high latitudes. Additionally, one of these studies also shows that the DT can not form with out the tropopause inversion layer (TIL) and that as the strength of the TIL increases so does the DT frequency of occurrence. This is interesting because those results emphasis a current gap in knowledge in our understanding of the DT and, consequently, the UTLS. The focus of this work is to address some of these current open questions. This study utilizes both observations from HIRDLS, a satellite instrument funded by NASA, and model output from CLaMS, a Lagrangian model developed at Forschungzentrum Juelich. Initially the DT is analysed within the baroclinic system to understand its relationship to the TIL. Results from a case study, which examines a baroclinic disturbance over the Pacific Ocean, shows that as the disturbance develop the DT extends equatorward as the TIL forms and increases in strength. The work presented here explores this further by investigating the movement of air within the DT as it expands and contracts meridionally during the growth and decay of this

  16. Improved Personalized Cancer Immunotherapy | 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.

  17. Upregulated Glucose Metabolism Correlates Inversely with CD8+ T-cell Infiltration and Survival in Squamous Cell Carcinoma.

    PubMed

    Ottensmeier, Christian H; Perry, Kate L; Harden, Elena L; Stasakova, Jana; Jenei, Veronika; Fleming, Jason; Wood, Oliver; Woo, Jeongmin; Woelk, Christopher H; Thomas, Gareth J; Thirdborough, Stephen M

    2016-07-15

    Antibodies that block T-cell-regulatory checkpoints have recently emerged as a transformative approach to cancer treatment. However, the clinical efficacy of checkpoint blockade depends upon inherent tumor immunogenicity, with variation in infiltrating T cells contributing to differences in objective response rates. Here, we sought to understand the molecular correlates of tumor-infiltrating T lymphocytes (TIL) in squamous cell carcinoma (SCC), using a systems biologic approach to integrate publicly available omics datasets with histopathologic features. We provide evidence that links TIL abundance and therapeutic outcome to the regulation of tumor glycolysis by EGFR and HIF, both of which are attractive molecular targets for use in combination with immunotherapeutics. Cancer Res; 76(14); 4136-48. ©2016 AACR. ©2016 American Association for Cancer Research.

  18. Combination therapy using intratumoral bacillus Calmette-Guerin (BCG) and vincristine in dogs with transmissible venereal tumours: therapeutic efficacy and histological changes.

    PubMed

    Mukaratirwa, S; Chitanga, S; Chimatira, T; Makuleke, C; Sayi, S T; Bhebhe, E

    2009-06-01

    Therapeutic efficacy and histological changes after bacillus Calmette-Guerin (BCG), vincristine and BCG/vincristine combination therapy of canine transmissible venereal tumours (CTVT) were studied. Twenty dogs with naturally occurring CTVT in the progression stage were divided into 4 groups and treated with intratumoral BCG, vincristine, BCG/vincristine combination therapy or intratumoral buffered saline (control group). Tumour sizes were determined weekly and tumour response to therapy was assessed. Tumour biopsies were taken weekly to evaluate histological changes. Complete tumour regression was observed in all the dogs treated with BCG, vincristine and BCG/vincristine combination therapy. BCG/vincristine combination therapy had a statistically significantly shorter regression time than BCG or vincristine therapy. No tumour regression was observed in the control group. Intratumoral BCG treatment resulted in the appearance of macrophages and increased numbers of tumour infiltrating lymphocytes (TILs) followed by tumour cell apoptosis and necrosis. Treatment with vincristine resulted in increased tumour cell apoptosis, reduction in the mitotic index and a decrease in the number of TILs. Tumours from dogs on BCG/vincristine combination were characterised by reduction in the mitotic index, and appearance of numerous TILs and macrophages followed by marked tumour cell apoptosis and necrosis. This study indicates that combined BCG and vincristine therapy is more effective than vincristine in treating CTVT, suggesting that the clinical course of this disease may be altered by immunochemotherapy.

  19. Challenging tumour immunological techniques that help to track cancer stem cells in malignant melanomas and other solid tumours.

    PubMed

    Kotlan, Beatrix; Plotar, Vanda; Eles, Klara; Horvath, Szabolcs; Balatoni, Timea; Csuka, Orsolya; Újhelyi, Mihaly; Sávolt, Ákos; Szollar, Andras; Vamosi-Nagy, Istvan; Toth, Laszlo; Farkas, Emil; Toth, Jozsef; Kasler, Miklos; Liszkay, Gabriella

    2018-03-01

    The arsenal of questions and answers about the minor cancer initiating cancer stem cell (CSC) population put responsible for cancer invasiveness and metastases, has left with an unsolved puzzle. Specific aims of a complex project were partly focused on revealing new biomarkers of cancer. We designed and set up novel techniques to facilitate the detection of cancerous cells. As a novel approach, we investigated B cells infiltrating breast carcinomas and melanomas (TIL-B) in terms of their tumour antigen binding potential. By developing the TIL-B phage display technology we provide here a new technology for the specific detection of highly tumour-associated antigens. Single chain Fv (scFv) antibody fragment phage ELISA, immunofluorescence (IF) FACS analysis, chamber slide technique with IF confocal laser microscopy and immunohistochemistry (IHC) in paraffin-embedded tissue sections were set up and standardized. We showed strong tumour-associated disialylated glycosphingolipid expression levels on various cancer cells using scFv antibody fragments, generated previously by uniquely invasive breast carcinoma TIL-B phage display library technology. We report herein a novel strategy to obtain antibody fragments of human origin that recognise tumour-associated ganglioside antigens. Our investigations have the power to detect privileged molecules in cancer progression, invasiveness, and metastases. The technical achievements of this study are being harnessed for early diagnostics and effective cancer therapeutics.

  20. A different representation of natural T cells and natural killer cells between tumor-infiltrating and periphery lymphocytes in human hepatocellular carcinoma.

    PubMed

    Li, Xiao-Feng; Dai, Dong; Song, Xiu-Yu; Liu, Jian-Jing; Zhu, Lei; Zhu, Xiang; Ma, Wenchao; Xu, Wengui

    2017-05-01

    Natural T cells [cluster of differentiation (CD) 3 + CD56 + ] and natural killer (NK) cells (CD3 - CD56 + ) are particularly abundant in the human liver and serve an important role in immune responses in the liver. The aim of the present study was to extensively determine the phenotypic and functional characteristics of natural T and NK cells in human hepatocellular carcinoma (HCC). Tumorous and non-tumorous tissue infiltrating lymphocytes (TILs and NILs, respectively) and peripheral blood mononuclear cells (PBMCs) from patients with hepatocellular carcinoma (HCC) were obtained to determine the frequency and phenotype of natural T/NK cells by a multicolor fluorescence activated cell sorting analysis. The abundance of natural T cells and NK cells was decreased in TILs vs. NILs (natural T cells, 6.315±1.002 vs. 17.16±1.804; NK cells, 6.324±1.559 vs. 14.52±2.336, respectively). However such results were not observed in PBMCs from HCC patients vs. that of healthy donors. Notably, a substantial fraction of the natural T cells (21.96±5.283) in TILs acquired forkhead box P3 (FOXP3) expression, and the FOXP3 + natural T cells lost the expression of interferon-γ and perforin. Conversely, being similar to the conventional FOXP3 + regulatory T cells, the FOXP3 + natural T cells assumed a specific phenotype that was characteristic of CD25 + , CD45RO + and cytotoxic T-lymphocyte-associated protein 4 + . Consistent with the phenotypic conversion, the present functional results indicate that FOXP3 expression in natural T cells contributes to the acquisition of a potent immunosuppressive capability. In conclusion, the present study describes a different representation of natural T cells and NK cells in local tumor tissues and in the periphery blood of patients with HCC, and identified a new type of FOXP3-expressing natural T cell spontaneously arising in the TILs of HCC.

  1. Four distinct immune microenvironment subtypes in gastric adenocarcinoma with special reference to microsatellite instability

    PubMed Central

    Heo, You Jeong; Kim, Seungtae; Kim, Nayoung KD; Park, Joon Oh; Kang, Won Ki; Lee, Jeeyun; Kim, Kyoung-Mee

    2018-01-01

    Introduction Programmed death-ligand 1 (PD-L1) can be overexpressed in tumours other than Epstein-Barr virus (EBV)-positive (EBV+) or microsatellite instability-high (MSI-H) gastric cancer (GC) subtypes. We aimed to determine the tumour immune microenvironment (TME) classification of GC to better understand tumour–immune interactions and help patient selection for future immunotherapy with special reference to MSI-H. Methods Immunohistochemistry (IHC) for PD-L1 and CD8+ T cells in three distinct subtypes of GC (43 EBV+, 79 MSI-H and 125 EBV−/MSS) were performed and analysed. In 66 MSI-H GC, mutation counts were compared with PD-L1 expression and survival of the patients. Results GC TME divided by PD-L1 IHC and tumour-infiltrating lymphocytes (TIL) measured by intratumoural CD8 density showed: (1) about 40% of GC are type I (PD-L1+/TIL+) consisting ~70% of MSI-H or EBV+ GC, and ~15% of EBV−/microsatellite stable (MSS) GC patients show the best survival in both disease-free (HR 2.044) and overall survival (HR 1.993); this type would respond to a checkpoint blockade therapy; (2) almost 30% of GC are type II (PD-L1−/TIL−) with the worst survival; (3) approximately 10% of GC are type III (PD-L1+/TIL−); and (4) up to 20% are type IV (PD-L1−/TIL+) and, unexpectedly, ~25% of EBV+ or MSI-H GC are within this subtype. In MSI-H GC, frequent frameshift mutations were observed in ARID1A, RNF43, NF1, MSH6, BRD3, NCOA3, BCORL1, TNKS2 and NPM1 and the numbers of frameshift mutation correlated significantly with PD-L1 expression (P<0.05). Discussion GC can be classified into four TME types based on PD-L1 and TIL, and numbers of frameshift mutation correlate well with PD-L1 expression in MSI-H GC. PMID:29636988

  2. Ex vivo enrichment of circulating anti-tumor T cells from both cutaneous and ocular melanoma patients: clinical implications for adoptive cell transfer therapy.

    PubMed

    Mazzarella, Tonia; Cambiaghi, Valeria; Rizzo, Nathalie; Pilla, Lorenzo; Parolini, Danilo; Orsenigo, Elena; Colucci, Annalisa; Modorati, Giulio; Doglioni, Claudio; Parmiani, Giorgio; Maccalli, Cristina

    2012-08-01

    Tumor-infiltrating lymphocytes (TILs) have been successfully used for adoptive cell transfer (ACT) immunotherapy; however, due to their scarce availability, this therapy is possible for a limited fraction of cutaneous melanoma patients. We assessed whether an effective protocol for ex vivo T-cell expansion from peripheral blood mononuclear cells (PBMCs), suitable for ACT of both cutaneous and ocular melanoma patients, could be identified. PBMCs from both cutaneous and ocular melanoma patients were stimulated in vitro with autologous, irradiated melanoma cells (mixed lymphocyte tumor cell culture; MLTCs) in the presence of IL-2 and IL-15 followed by the rapid expansion protocol (REP). The functional activity of these T lymphocytes was characterized and compared with that of TILs. In addition, the immune infiltration in vivo of ocular melanoma lesions was analyzed. An efficient in vitro MLTC expansion of melanoma reactive T cells was achieved from all PBMC's samples obtained in 7 cutaneous and ocular metastatic melanoma patients. Large numbers of melanoma-specific T cells could be obtained when the REP protocol was applied to these MLTCs. Most MLTCs were enriched in non-terminally differentiated T(EM) cells homogeneously expressing co-stimulatory molecules (e.g., NKG2D, CD28, CD134, CD137). A similar pattern of anti-tumor activity, in association with a more variable expression of co-stimulatory molecules, was detected on short-term in vitro cultured TILs isolated from the same patients. In these ocular melanoma patients, we observed an immune infiltrate with suppressive characteristics and a low rate of ex vivo growing TILs (28.5% of our cases). Our MLTC protocol overcomes this limitation, allowing the isolation of T lymphocytes with effector functions even in these patients. Thus, anti-tumor circulating PBMC-derived T cells could be efficiently isolated from melanoma patients by our novel ex vivo enrichment protocol. This protocol appears suitable for ACT studies

  3. T lymphocyte recruitment into renal cell carcinoma tissue: a role for chemokine receptors CXCR3, CXCR6, CCR5, and CCR6.

    PubMed

    Oldham, Kimberley A; Parsonage, Greg; Bhatt, Rupesh I; Wallace, D Michael A; Deshmukh, Nayneeta; Chaudhri, Shalini; Adams, David H; Lee, Steven P

    2012-02-01

    Evidence suggests that some patients with renal cell carcinoma (RCC) respond to immunomodulatory therapies that activate T lymphocytes. A prerequisite for effective T cell therapy is efficient targeting of effector T cells to the tumour site, yet the molecular basis of T cell recruitment to RCC is unknown. Furthermore, some T cells that naturally infiltrate this cancer are regulatory T cells (Tregs) that may suppress antitumour immune responses. Determine the mechanisms of effector and regulatory T cell recruitment to RCC to allow targeted therapy that promotes local anti-tumour immunity. Tumour-infiltrating and peripheral blood T cells were collected from 70 patients undergoing nephrectomy for RCC. T cells were analysed by multicolour flow cytometry for expression of 19 chemokine receptors and 7 adhesion molecules. Receptors that were expressed at higher levels on tumour-infiltrating lymphocytes (TILs) compared with matched peripheral blood lymphocytes (PBLs) were analysed further for their ability to mediate migration responses in TILs and for expression of corresponding ligands in tumour tissue. Three chemokine receptors-CCR5, CXCR3, and CXCR6-were significantly overexpressed on TILs compared with matched PBLs (n=16 cases) and were capable of promoting migration in vitro. Their corresponding ligands CCL4-5, CXCL9-11, and CXCL16 were all detected in RCC tissue. However, since they were present in all cases studied, it was not possible to correlate ligand expression with levels of T cell infiltration. Foxp3(+) Tregs were enriched within TILs compared with matched PBLs and expressed high levels of CCR5, CXCR3, and CXCR6, as well as CCR6, the ligand for which (CCL20) was detectable in RCC tissue. Our data support a role for CCR5, CXCR3, and CXCR6 in the selective recruitment of T cells into RCC tissue and, together with CCR6, in the recruitment of Tregs. Copyright © 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved.

  4. Toxicity of nanoparticles of CuO, ZnO and TiO2 to microalgae Pseudokirchneriella subcapitata.

    PubMed

    Aruoja, Villem; Dubourguier, Henri-Charles; Kasemets, Kaja; Kahru, Anne

    2009-02-01

    Toxicities of ZnO, TiO2 and CuO nanoparticles to Pseudokirchneriella subcapitata were determined using OECD 201 algal growth inhibition test taking in account potential shading of light. The results showed that the shading effect by nanoparticles was negligible. ZnO nanoparticles were most toxic followed by nano CuO and nano TiO2. The toxicities of bulk and nano ZnO particles were both similar to that of ZnSO4 (72 h EC50 approximately 0.04 mg Zn/l). Thus, in this low concentration range the toxicity was attributed solely to solubilized Zn2+ ions. Bulk TiO2 (EC50=35.9 mg Ti/l) and bulk CuO (EC50=11.55 mg Cu/l) were less toxic than their nano formulations (EC50=5.83 mg Ti/l and 0.71 mg Cu/l). NOEC (no-observed-effect-concentrations) that may be used for risk assessment purposes for bulk and nano ZnO did not differ (approximately 0.02 mg Zn/l). NOEC for nano CuO was 0.42 mg Cu/l and for bulk CuO 8.03 mg Cu/l. For nano TiO2 the NOEC was 0.98 mg Ti/l and for bulk TiO2 10.1 mg Ti/l. Nano TiO2 formed characteristic aggregates entrapping algal cells that may contribute to the toxic effect of nano TiO2 to algae. At 72 h EC50 values of nano CuO and CuO, 25% of copper from nano CuO was bioavailable and only 0.18% of copper from bulk CuO. Thus, according to recombinant bacterial and yeast Cu-sensors, copper from nano CuO was 141-fold more bioavailable than from bulk CuO. Also, toxic effects of Cu oxides to algae were due to bioavailable copper ions. To our knowledge, this is one of the first systematic studies on effects of metal oxide nanoparticles on algal growth and the first describing toxic effects of nano CuO towards algae.

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

    Klemt, M.

    Relative oscillator strengths of 139 Til lines were determined from emission measurements of a three chamber electric arc burning in an argon atmosphere. Introducing a small admixture of titanium chloride into the center of the arc, spectra of titanium could be observed end-on with no self-absorption and no selfreversal of the measured lines. The relative oscillator strengths were obtained from the Til line intensities and the measured arc temperature. Using absolute oscillator strengths of three resonance lines which had been measured by Reinke (1967), and several life time measurements from Hese (1970), Witt et al. (1971) and Andersen and Sorensenmore » (1972), the relative oscillator strengths were converted to an absolute scale. The accuracy of these absolute values is in the range of 20% to 40%. (auth)« less

  6. 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

    USDA-ARS?s Scientific Manuscript database

    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...

  7. Lovastatin inhibits T cell proliferation while preserving the cytolytic function of EBV-, CMV- and MART-1-specific CTLs

    PubMed Central

    Li, Dan; Li, Yufeng; Hernandez, Jessica A.; Patenia, Rebecca; Kim, Tae Kon; Khalili, Jahan; Dougherty, Mark C.; Hanley, Patrick J.; Bollard, Catherine M.; Komanduri, Krishna V.; Hwu, Patrick; Champlin, Richard E.; Radvanyi, Laszlo G.; Molldrem, Jeffrey J.; Ma, Qing

    2016-01-01

    Statin treatment has been shown to reduce graft-versus-host disease (GVHD) while preserving graft-versus-tumor (GVT) effect in allogeneic stem cell transplantation (allo-HCT). Herein, we investigated whether lovastatin treatment affects the function of human cytolytic T lymphocytes (CTLs). Upon TCR stimulation, lovastatin significantly inhibited the proliferation of both CD4+ and CD8+ T cells from healthy donors while their intracellular cytokine production including IFN-γ and TNF-α remained the same with a slight decrease of IL-2. Moreover, the specific lysis of target cells by CTL lines derived from patients and normal donors specific for EBV-encoded antigen LMP2 or CMV-encoded antigen pp65 was uncompromised in the presence of lovastatin. In addition, we evaluated the effect of lovastatin on the proliferation and effector function of the CD8+ tumor–infiltrating lymphocytes (TILs) derived from melanoma patients specific for MART-1 antigen. Lovastatin significantly reduced the expansion of antigen-specific TILs upon MART-1 stimulation. However, the effector function of TILs, including the specific lysis of target cells and secretion of cytokine IFN-γ, remained intact with lovastatin treatment. Taken together, these data demonstrated that lovastatin inhibits the proliferation of EBV-, CMV- and MART-1-specific CTLs without affecting cytolytic capacity. The differential effect of lovastatin on the proliferation versus cytoxicity of CTLs might shed some light on elucidating the possible mechanisms of GVHD and GVT effect elicited by alloimmune responses. PMID:20948439

  8. 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

  9. EBV+ and MSI Gastric Cancers Harbor High PD-L1/PD-1 Expression and High CD8+ Intratumoral Lymphocytes

    PubMed Central

    De Rosa, Simona; Tibiletti, Maria Grazia; Magnoli, Francesca; Vanoli, Alessandro; Sessa, Fausto; Chiaravalli, Anna Maria

    2018-01-01

    Both EBV+ and MSI gastric cancers (GCs) have high lymphoid infiltration which is rare in MSS/EBV− cancers. PD-L1/PD-1 interaction leads to a down-regulated immune response and it is one of the most promising targets for gastric cancer immunotherapy. PD-L1/PD-1 and CD8 expression were immunohistochemically investigated in a series of 169 FFPE GCs, including 33 EBV+, 59 MSI and 77 MSS/EBV− cases. PD-L1 membrane immunoreactivity in more than 5% of tumor cells was present in 31/169 GCs and was associated with high levels of CD8 intraepithelial lymphocytes (TILs; p < 0.001). PD-L1+ cases were mainly poorly differentiated (71%), intestinal type (85%) and high lymphoid response (HLR; 90%) tumors. PD-L1 expression was only present in EBV⁺ (46%), MSI (24%) and rare MSS/EBV− (3%) GCs with high CD8+ TILs (p < 0.001). Despite being associated with a better prognosis both in the whole series (p < 0.05) and in the MSI subset, PD-L1 is not an independent prognostic factor. PD-L1 gene amplification was detected in 3/17 cases, including 2/7 EBV+ and 1/8 MSI GC. PD-1⁺ TILs were significantly higher in EBV⁺ than MSI and MSS/EBV− cases. PD-L1/PD-1 pathway is selectively activated in HLR GCs and could be considered an emerging therapeutic target, particularly for EBV and MSI GCs. PMID:29614789

  10. Superfund Record of Decision: Fort Wayne Reduction, IN

    EPA Pesticide Factsheets

    ... lut ICII irjulilid tliidirdi It til I litil Iklt ll irilullii ulrr npoiytti Hi ti rilioM ind itpiopiiilt ••ill, U(Ulii| |iou«< .ilif idliclio* U fyklli kiiltk ir Iki iitlruitil, kiciuu idiom il (hi ...

  11. Trichotillomania (Hair-Pulling Disorder)

    MedlinePlus

    Trichotillomania (hair-pulling disorder) Overview Trichotillomania (trik-o-til-o-MAY-nee-uh), also called hair-pulling disorder, is a mental disorder that involves recurrent, irresistible urges to pull out hair from your scalp, eyebrows or other areas of ...

  12. Secondary Education in a Changing World: Reaching a Turning Point.

    ERIC Educational Resources Information Center

    Hunter, Eagan

    1985-01-01

    William Van Til's three proposed scenarios for the future of secondary education are examined 10 years later, and American education is found to have reached a critical point as it goes through a transition from one era to another. (DCS)

  13. Impact of aging on host immune response and survival in melanoma: an analysis of 3 patient cohorts.

    PubMed

    Weiss, Sarah A; Han, Joseph; Darvishian, Farbod; Tchack, Jeremy; Han, Sung Won; Malecek, Karolina; Krogsgaard, Michelle; Osman, Iman; Zhong, Judy

    2016-10-19

    Age has been reported as an independent prognostic factor for melanoma-specific survival (MSS). We tested the hypothesis that age impacts the host anti-tumor immune response, accounting for age-specific survival outcomes in three unique melanoma patient cohorts. We queried the U.S. population-based Surveillance, Epidemiology, and End Results Program (SEER), the prospective tertiary care hospital-based Interdisciplinary Melanoma Cooperative Group (IMCG) biorepository, and the Cancer Genome Atlas (TCGA) biospecimen database to test the association of patient age at time of melanoma diagnosis with clinicopathologic features and survival outcomes. Age groups were defined as ≤45 (young), 46-65 (intermediate), and >65 (older). Each age group in the IMCG and TCGA cohorts was stratified by tumor infiltrating lymphocyte (TIL) measurements and tested for association with MSS. Differential expression of 594 immunoregulatory genes was assessed in a subset of primary melanomas in the IMCG and TCGA cohorts using an integrative pathway analysis. We analyzed 304, 476 (SEER), 1241 (IMCG), and 292 (TCGA) patients. Increasing age at melanoma diagnosis in both the SEER and IMCG cohorts demonstrated a positive correlation with tumor thickness, ulceration, stage, and mortality, however age in the TCGA cohort did not correlate with mortality. Older age was associated with shorter MSS in all three cohorts. When the young age group in both the IMCG and TCGA cohorts was stratified by TIL status, there were no differences in MSS. However, older IMCG patients with brisk TILs and intermediate aged TCGA patients with high lymphocyte scores (3-6) had improved MSS. Gene expression analysis revealed top pathways (T cell trafficking, communication, and differentiation) and top upstream regulators (CD3, CD28, IFNG, and STAT3) that significantly changed with age in 84 IMCG and 43 TCGA primary melanomas. Older age at time of melanoma diagnosis is associated with shorter MSS, however age

  14. B7-H3 Negatively Modulates CTL-Mediated Cancer Immunity.

    PubMed

    Yonesaka, Kimio; Haratani, Koji; Takamura, Shiki; Sakai, Hitomi; Kato, Ryoji; Takegawa, Naoki; Takahama, Takayuki; Tanaka, Kaoru; Hayashi, Hidetoshi; Takeda, Masayuki; Kato, Sigeki; Maenishi, Osamu; Sakai, Kazuko; Chiba, Yasutaka; Okabe, Takafumi; Kudo, Keita; Hasegawa, Yoshikazu; Kaneda, Hiroyasu; Yamato, Michiko; Hirotani, Kenji; Miyazawa, Masaaki; Nishio, Kazuto; Nakagawa, Kazuhiko

    2018-06-01

    Purpose: Anti-programmed-death-1 (PD-1) immunotherapy improves survival in non-small cell lung cancer (NSCLC), but some cases are refractory to treatment, thereby requiring alternative strategies. B7-H3, an immune-checkpoint molecule, is expressed in various malignancies. To our knowledge, this study is the first to evaluate B7-H3 expression in NSCLCs treated with anti-PD-1 therapy and the therapeutic potential of a combination of anti-PD-1 therapy and B7-H3 targeting. Experimental Design: B7-H3 expression was evaluated immunohistochemically in patients with NSCLC ( n = 82), and its relationship with responsiveness to anti-PD-1 therapy and CD8 + tumor-infiltrating lymphocytes (TILs) was analyzed. The antitumor efficacy of dual anti-B7-H3 and anti-programmed death ligand-1 (PD-L1) antibody therapy was evaluated using a syngeneic murine cancer model. T-cell numbers and functions were analyzed by flow cytometry. Results: B7-H3 expression was evident in 74% of NSCLCs and was correlated critically with nonresponsiveness to anti-PD-1 immunotherapy. A small number of CD8 + TILs was observed as a subpopulation with PD-L1 tumor proportion score less than 50%, whereas CD8 + TILs were still abundant in tumors not expressing B7-H3. Anti-B7-H3 blockade showed antitumor efficacy accompanied with an increased number of CD8 + TILs and recovery of effector function. CD8 + T-cell depletion negated antitumor efficacy induced by B7-H3 blockade, indicating that improved antitumor immunity is mediated by CD8 + T cells. Compared with a single blocking antibody, dual blockade of B7-H3 and PD-L1 enhanced the antitumor reaction. Conclusions: B7-H3 expressed on tumor cells potentially circumvents CD8 + -T-cell-mediated immune surveillance. Anti-B7-H3 immunotherapy combined with anti-PD-1/PD-L1 antibody therapy is a promising approach for B7-H3-expressing NSCLCs. Clin Cancer Res; 24(11); 2653-64. ©2018 AACR . ©2018 American Association for Cancer Research.

  15. Tumor-Targeting Salmonella typhimurium A1-R Promotes Tumoricidal CD8+ T Cell Tumor Infiltration and Arrests Growth and Metastasis in a Syngeneic Pancreatic-Cancer Orthotopic Mouse Model.

    PubMed

    Murakami, Takashi; Hiroshima, Yukihiko; Zhang, Yong; Zhao, Ming; Kiyuna, Tasuku; Hwang, Ho Kyoung; Miyake, Kentaro; Homma, Yuki; Mori, Ryutaro; Matsuyama, Ryusei; Chishima, Takashi; Ichikawa, Yasushi; Tanaka, Kuniya; Bouvet, Michael; Endo, Itaru; Hoffman, Robert M

    2018-01-01

    The present study determined the effect of the tumor-targeting strain Salmonella typhimurium A1-R (S. typhimurium A1-R) on CD8 + tumor-infiltrating lymphocytes (TILs) in a syngeneic pancreatic-cancer orthotopic mouse model. The effect of tumor-targeting S. typhimurium A1-R on CD8 + TILs was determined on the Pan02 murine pancreatic-adenocarcinoma implanted orthotopically in the pancreatic tail of C57BL/6 immunocompromised mice. Three weeks after orthotopic implantation, mice were randomized as follows G1: untreated control group (n = 8); and G2: S. typhimurium A1-R-treatment group (n = 8, 1 × 10 7 colony forming units [CFU]/body, iv, weekly, 3 weeks). On the 22nd day from initial treatment, all mice were sacrificed and tumors were harvested. The tumor-volume ratio was defined as ratio of tumor volume on the 22nd day relative to the 1st day. The tumor volume ratio was significantly lower in the S. typhimurium A1-R-treated group (G2) (3.0 ± 2.8) than the untreated control (G1) (39.9 ± 30.7, P < 0.01). Hematoxylin and easin (H&E) staining on tumor sections was performed to evaluate tumor destruction which was classified according to the Evans grading system and found to be much greater in the S. typhimurium A1-R-treated mice (G2). Six mice in G1 had peritoneal dissemination, whereas no mice showed peritoneal dissemination in G2 (P < 0.01). Immunohistochemical staining with anti-mouse CD8 + antibody was performed in order to detect TILs determined by calculating the average number of CD8 + cells in three high power fields (200×) in the treated and untreated tumors. The TIL score was significantly higher in G2 (133.5 ± 32.2) than G1 (45.1 ± 19.4, P < 0.001). The present study demonstrates that S. typhimurium A1-R promotes CD8 + T cell infiltration and inhibition of tumor growth and metastasis. J. Cell. Biochem. 119: 634-639, 2018. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

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

    USDA-ARS?s Scientific Manuscript database

    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...

  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. Oxygen Isotope Measurements of the Reduced CV3 Chondrite Thiel Mountains 07007 Using a NanoSIMS: Implication to the Nebula Oxygen Isotope

    NASA Astrophysics Data System (ADS)

    Choi, B.-G.; Kim, H.; Hong, T. E.

    2013-09-01

    O-isotopic compositions of fine-grained CAIs in the reduced CV3 TIL 07007 using the NanoSIMS with permil-precision suggesting that O-isotopes of the nebula changed from ^16O-rich when spinel condensed to ^16O-depleted when melilite formed.

  19. 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…

  20. Persistence of Multiple Tumor-Specific T-Cell Clones Is Associated with Complete Tumor Regression in a Melanoma Patient Receiving Adoptive Cell Transfer Therapy

    PubMed Central

    Zhou, Juhua; Dudley, Mark E.; Rosenberg, Steven A.; Robbins, Paul F.

    2007-01-01

    Summary The authors recently reported that adoptive immunotherapy with autologous tumor-reactive tumor infiltrating lymphocytes (TILs) immediately following a conditioning nonmyeloablative chemotherapy regimen resulted in an enhanced clinical response rate in patients with metastatic melanoma. These observations led to the current studies, which are focused on a detailed analysis of the T-cell antigen reactivity as well as the in vivo persistence of T cells in melanoma patient 2098, who experienced a complete regression of all metastatic lesions in lungs and soft tissues following therapy. Screening of an autologous tumor cell cDNA library using transferred TILs resulted in the identification of novel mutated growth arrest-specific gene 7 (GAS7) and glyceral-dehyde-3-phosphate dehydrogenase (GAPDH) gene transcripts. Direct sequence analysis of the expressed T-cell receptor beta chain variable regions showed that the transferred TILs contained multiple T-cell clonotypes, at least six of which persisted in peripheral blood for a month or more following transfer. The persistent T cells recognized both the mutated GAS7 and GAPDH. These persistent tumor-reactive T-cell clones were detected in tumor cell samples obtained from the patient following adoptive cell transfer and appeared to be represented at higher levels in the tumor sample obtained 1 month following transfer than in the peripheral blood obtained at the same time. Overall, these results indicate that multiple tumor-reactive T cells can persist in the peripheral blood and at the tumor site for prolonged times following adoptive transfer and thus may be responsible for the complete tumor regression in this patient. PMID:15614045

  1. Single-Pass, Closed-System Rapid Expansion of Lymphocyte Cultures for Adoptive Cell Therapy

    PubMed Central

    Klapper, Jacob A.; Thomasian, Armen A.; Smith, Douglas M.; Gorgas, Gayle C.; Wunderlich, John R.; Smith, Franz O.; Hampson, Brian S.; Rosenberg, Steven A.; Dudley, Mark E.

    2009-01-01

    Adoptive cell therapy (ACT) for metastatic melanoma involves the ex vivo expansion and re-infusion of tumor infiltrating lymphocytes (TIL) obtained from resected specimens. With an overall objective response rate of fifty-six percent, this T-cell immunotherapy provides an appealing alternative to other therapies, including conventional therapies with lower response rates. However, there are significant regulatory and logistical concerns associated with the ex vivo activation and large scale expansion of these cells. The best current practice uses a rapid expansion protocol (REP) consisting of an ex vivo process that occurs in tissue culture flasks (T-flasks) and gas-permeable bags, utilizes OKT3 (anti-CD3 monoclonal antibody), recombinant human interleukin-2, and irradiated peripheral blood mononuclear cells to initiate rapid lymphocyte growth. A major limitation to the widespread delivery of therapy to large numbers of melanoma patients is the open system in which a REP is initiated. To address this problem, we have investigated the initiation, expansion and harvest at clinical scale of TIL in a closed-system continuous perfusion bioreactor. Each cell product met all safety criteria for patient treatment and by head-to-head comparison had a similar potency and phenotype as cells grown in control T-flasks and gas-permeable bags. However, the currently available bioreactor cassettes were limited in the total cell numbers that could be generated. This bioreactor may simplify the process of the rapid expansion of TIL under stringent regulatory conditions thereby enabling other institutions to pursue this form of ACT. PMID:19389403

  2. Static Stability in the Global Upper Troposphere and Lower Stratosphere: Observations of Long-term Mean Structure and Variability using GPS Radio Occultation Data

    NASA Astrophysics Data System (ADS)

    Grise, K. M.; Thompson, D. W.; Birner, T.

    2009-12-01

    Static stability is a fundamental dynamical quantity that measures the vertical temperature stratification of the atmosphere. The long-term mean static stability field is characterized by the well-known transition from low values in the troposphere to high values in the stratosphere. However, the magnitude and structure of fine-scale static stability features near the tropopause are difficult to discern in temperature data with low vertical resolution. In this study, the authors apply over six years of high vertical resolution Global Positioning System radio occultation temperature profiles to document the long-term mean structure and variability of static stability in the global upper troposphere and lower stratosphere (UTLS). The results of this study demonstrate that a shallow but pronounced maximum in static stability exists just above the tropopause at all latitudes (i.e., the “tropopause inversion layer,” or TIL). This study also uncovers two novel aspects of static stability in the global UTLS. In the tropical lower stratosphere, the results reveal a unique vertically and horizontally varying static stability structure, with maxima located at ~17 km and ~19 km. The upper feature peaks during the NH cold season and has its largest magnitude between 10 and 15 degrees latitude in both hemispheres; the lower feature exhibits a weaker seasonal cycle and is centered at the Equator. The results also demonstrate that the strength of the TIL is closely tied to stratospheric dynamic variability. The magnitude of the TIL is enhanced following sudden stratospheric warmings in the polar regions and the easterly phase of the quasi-biennial oscillation in the tropics.

  3. Static Stability in the Global Upper Troposphere and Lower Stratosphere: Observations of Long-term Mean Structure and Variability using GPS Radio Occultation Data

    NASA Astrophysics Data System (ADS)

    Grise, Kevin M.; Thompson, David W. J.; Birner, Thomas

    2010-05-01

    Static stability is a fundamental dynamical quantity that measures the vertical temperature stratification of the atmosphere. The long-term mean static stability field is characterized by the well-known transition from low values in the troposphere to high values in the stratosphere. However, the magnitude and structure of fine-scale static stability features near the tropopause are difficult to discern in temperature data with low vertical resolution. In this study, the authors apply over six years of high vertical resolution Global Positioning System radio occultation temperature profiles to document the long-term mean structure and variability of static stability in the global upper troposphere and lower stratosphere (UTLS). The results of this study demonstrate that a shallow but pronounced maximum in static stability exists just above the tropopause at all latitudes (i.e., the "tropopause inversion layer," or TIL). This study also uncovers two novel aspects of static stability in the global UTLS. In the tropical lower stratosphere, the results reveal a unique vertically and horizontally varying static stability structure, with maxima located at ~17 km and ~19 km. The upper feature peaks during the NH cold season and has its largest magnitude between 10 and 15 degrees latitude in both hemispheres; the lower feature exhibits a weaker seasonal cycle and is centered at the Equator. The results also demonstrate that the strength of the TIL is closely tied to stratospheric dynamic variability. The magnitude of the TIL is enhanced following sudden stratospheric warmings in the polar regions and the easterly phase of the quasi-biennial oscillation in the tropics.

  4. Prescribing of asthma drugs for children 2004-2015.

    PubMed

    Mikalsen, Ingvild Bruun; Karlstad, Øystein; Furu, Kari; Øymar, Knut

    2018-02-20

    Astma kan være vanskelig å diagnostisere hos barn. For barn under skolealder finnes det få tilgjengelige objektive diagnostiske undersøkelser, og retningslinjene for diagnose og behandling er basert på sykehistorie og klinisk undersøkelse. Dette kan gi rom for varierende behandlingspraksis. Data fra Reseptregisteret ble brukt til å studere forskrivning av legemidler mot astma til barn i aldersgruppene 0-4 år og 5-9 år fordelt på fylker fra 2004-15. Det var stor variasjon mellom fylkene i andelen per 1 000 barn som fikk forskrevet legemidler mot astma i perioden 2012-14 (aldersgruppen 0-4 år: median: 104/1 000; ekstremverdier: 64-147, aldersgruppen 5-9 år: 68/1000; 46-86). Inhalasjonssteroider var hyppigst forskrevet, og det var her variasjonen mellom fylkene var størst i begge aldersgruppene (aldersgruppen 0-4 år: 85/1 000; 42-116, aldersgruppen 5-9 år: 51/1 000; 31-70). De fleste fikk kun en eller få forskrivninger med inhalasjonssteroider over en treårsperiode. Endring i forskrivningen av inhalasjonssteroider fra 2004 til 2015 varierte betydelig mellom fylkene, mest for aldersgruppen 0-4 år. Stor forskjell i forskrivning av legemidler mot astma fylkene imellom, høy andel sporadisk bruk og endring over tid, særlig i den yngste aldersgruppen, kan tyde på en unaturlig variasjon i behandlingen som ikke kan forklares av forskjeller i astmaforekomst. Uklare retningslinjer som ikke er tilstrekkelig innarbeidet i klinisk praksis kan være én årsak.

  5. An Examination of the Local Cellular Immune Response to Examples of Both Ductal Carcinoma In Situ (DCIS) of the Breast and DCIS With Microinvasion, With Emphasis on Tertiary Lymphoid Structures and Tumor Infiltrating Lymphoctytes.

    PubMed

    Kim, Ahrong; Heo, Sun-Hee; Kim, Young-Ae; Gong, Gyungyub; Jin Lee, Hee

    2016-07-01

    We tried to describe cellular immune response (tertiary lymphoid structures (TLSs), lymphoid aggregates, tumor infiltrating lymphocytes (TILs)) in neoplastic microenvironment of ductal carcinoma in situ (DCIS) with or without associated microinvasion. The histopathologic parameters of 177 DCIS and 27 DCIS with microinvasion were evaluated. We determined number of ducts involved by DCIS, and calculated percentage of these ducts surrounded by TLSs. TILs were quantitated in 27 microinvasive cases. Tumors having higher percentage of DCIS ducts associated with TLSs had higher incidence of microinvasion (P < .001). Percentage of DCIS ducts involved by TLSs was also higher in hormone receptor (HR)-/human epidermal growth factor receptor 2 (HER2)+ and TNBC subtypes of DCIS than in HR+/HER2- and HR+/HER2+ subtypes (38.04 ± 25.8%, 32.6 ± 32.4%, 2.5 ± 7.3% and 17.4 ± 23.3%, respectively, P < .001). In DCIS without microinvasion, HR+/HER2- subtype predominated (P < .001). In microinvasive cases, HR-/HER2+ subtype was most common. TNBC was more common in microinvasive carcinoma than DCIS (P < .001). Among 27 microinvasive ductal carcinomas, increased TLS amount was associated with increased TILs (P = .013). TLS abundance around DCIS was associated with HER2+ and TNBC subtypes and microinvasion. Pathologists should be aware of microinvasion when diagnosing DCIS lesions with abundant TLSs. © American Society for Clinical Pathology, 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  6. U.S. EPA, Pesticide Product Label, TRI-CON 75/25, 09/07/1988

    EPA Pesticide Factsheets

    2011-04-19

    ... of ..... til ''''' h •• d ... I" •• t .. OII .1'.t .. foll_I" .. clo ..... of ." .. toff •• 1 ... . 3. If t .... h t. I .. M"a .. t ... tl1' p .. n •• 10, the .h ..... t. the ..... 1 ttl. U.14 ..... ...

  7. Role of Smac in Lung Carcinogenesis and Therapy

    DTIC Science & Technology

    2017-07-01

    tumor regression mediated by TNF-α as shown below. Debio 1143 enhances the efficacy of anti-PD1and increases tumor- infiltrating lymphocytes...agents in both tumor models, as measured by tumor volumes. Tumor infiltrating lymphocytes (TILs) were significantly increased in tumors treated with

  8. U.S. EPA, Pesticide Product Label, AGWAY MALATHION 5E, 03/14/1980

    EPA Pesticide Factsheets

    2011-04-21

    ... 1, til' ". :' I KEEP OUT OF REACH OF CHilDREN ,'!'I' .11111 1~,lI\\di jilt'! ... dtildl t'lll ,tlt • .!\\ Id~lf\\q (.11., III tll'( t' !hf' '!l(d~ 11I!1I "I! II ,lI ~ \\ ,jilt! 1 It'.: II' \\ ...

  9. U.S. EPA, Pesticide Product Label, PHOSDRIN 4E, 07/23/1970

    EPA Pesticide Factsheets

    2011-04-14

    ... of tl'''i('if~: til lah'lratf'ry :uHmals and to plant ..... and of re .... jrh,t· ... 1111 (qud crill''' , an.t UP"fl rt.'pqrt ... 4 'f fit'lel l'XJU'Tlf'rlf'I' ',· . t'" hr.,"" n.,t h(>('11 ...

  10. U.S. EPA, Pesticide Product Label, RCI 49-410 42% TECHNICAL GRADE 10:1 PAINTABLE, 06/14/1972

    EPA Pesticide Factsheets

    2011-04-14

    ... l,.,LH-,' tile.' IH:pli~'~ l' d.".UI(\\· llf H!~'/, IL.l!Ld}.Jlty, 'l',: .. hlpl'~ til!\\ r",.ill r .'" crt [1:(', ·r"".flllll..1"; , .. r 1 "t': III d:t. HI.t!It'.f!:'ut ,l.dt'Hh:U: I j{.,.' Hh\\c': ,'. 1..' ...

  11. U.S. EPA, Pesticide Product Label, TRIANGLE EPN-5EC, 12/12/1983

    EPA Pesticide Factsheets

    2011-04-14

    ... 1.1"'11\\1011. I'JIlt"j', Wi)dlill': ihi· IJr{Jdu~ t 1'1,111 'Jilt)ll, 10 "i ... h .,lId \\, .. jJdlil,·. ... 11"1'1.\\11\\' til 1 (JIlt ('lltl~t1l' ~Id.\\y,'r. Ht'IJIIi '\\Pl'ill .. 11 iun-.. ...

  12. Proceedings: Roles of Colleges and Universities in Volunteerism.

    ERIC Educational Resources Information Center

    Stubblefield, Harold W., Ed.; And Others

    The proceedings include sections on: keynote addresses (Paul A. Miller, Jon Van Til); who volunteers and why, the impact of volunteerism; evaluation, research design, and methodology; preparing volunteers and those who manage volunteers (evaluation of recruiting and training procedures, the effect of the student volunteer experience, effectiveness…

  13. 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…

  14. Manufacture of tumor- and virus-specific T lymphocytes for adoptive cell therapies

    PubMed Central

    Wang, X; Rivière, I

    2015-01-01

    Adoptive transfer of tumor-infiltrating lymphocytes (TILs) and genetically engineered T lymphocytes expressing chimeric antigen receptors (CARs) or conventional alpha/beta T-cell receptors (TCRs), collectively termed adoptive cell therapy (ACT), is an emerging novel strategy to treat cancer patients. Application of ACT has been constrained by the ability to isolate and expand functional tumor-reactive T cells. The transition of ACT from a promising experimental regimen to an established standard of care treatment relies largely on the establishment of safe, efficient, robust and cost-effective cell manufacturing protocols. The manufacture of cellular products under current good manufacturing practices (cGMPs) has a critical role in the process. Herein, we review current manufacturing methods for the large-scale production of clinical-grade TILs, virus-specific and genetically modified CAR or TCR transduced T cells in the context of phase I/II clinical trials as well as the regulatory pathway to get these complex personalized cellular products to the clinic. PMID:25721207

  15. Manufacture of tumor- and virus-specific T lymphocytes for adoptive cell therapies.

    PubMed

    Wang, X; Rivière, I

    2015-03-01

    Adoptive transfer of tumor-infiltrating lymphocytes (TILs) and genetically engineered T lymphocytes expressing chimeric antigen receptors (CARs) or conventional alpha/beta T-cell receptors (TCRs), collectively termed adoptive cell therapy (ACT), is an emerging novel strategy to treat cancer patients. Application of ACT has been constrained by the ability to isolate and expand functional tumor-reactive T cells. The transition of ACT from a promising experimental regimen to an established standard of care treatment relies largely on the establishment of safe, efficient, robust and cost-effective cell manufacturing protocols. The manufacture of cellular products under current good manufacturing practices (cGMPs) has a critical role in the process. Herein, we review current manufacturing methods for the large-scale production of clinical-grade TILs, virus-specific and genetically modified CAR or TCR transduced T cells in the context of phase I/II clinical trials as well as the regulatory pathway to get these complex personalized cellular products to the clinic.

  16. Recent variability of the tropical tropopause inversion layer

    NASA Astrophysics Data System (ADS)

    Wang, Wuke; Matthes, Katja; Schmidt, Torsten; Neef, Lisa

    2013-12-01

    The recent variability of the tropopause temperature and the tropopause inversion layer (TIL) are investigated with Global Positioning System Radio Occultation data and simulations with the National Center for Atmospheric Research's Whole Atmosphere Community Climate Model (WACCM). Over the past decade (2001-2011) the data show an increase of 0.8 K in the tropopause temperature and a decrease of 0.4 K in the strength of the tropopause inversion layer in the tropics, meaning that the vertical temperature gradient has declined, and therefore that the stability above the tropopause has weakened. WACCM simulations with finer vertical resolution show a more realistic TIL structure and variability. Model simulations show that the increased tropopause temperature and the weaker tropopause inversion layer are related to weakened upwelling in the tropics. Such changes in the thermal structure of the upper troposphere and lower stratosphere may have important implications for climate, such as a possible rise in water vapor in the lower stratosphere.

  17. Electronic transport properties of Ti-impurity band in Si

    NASA Astrophysics Data System (ADS)

    Olea, J.; González-Díaz, G.; Pastor, D.; Mártil, I.

    2009-04-01

    In this paper we show that pulsed laser melted high dose implantation of Ti in Si, above the Mott transition, produces an impurity band (IB) in this semiconductor. Using the van der Pauw method and Hall effect measurements we find strong laminated conductivity at the implanted layer and a temperature dependent decoupling between the Ti implanted layer (TIL) and the substrate. The conduction mechanism from the TIL to the substrate shows blocking characteristics that could be well explained through IB theory. Using the ATLAS code we can estimate the energetic position of the IB at 0.36 eV from the conduction band, the density of holes in this band which is closely related to the Ti atomic density and the hole mobility in this band. Band diagrams of the structure at low and high temperatures are also simulated in the ATLAS framework. The simulation obtained is fully coherent with experimental results.

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

    PubMed

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

    2016-09-27

    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.

  19. U.S. EPA, Pesticide Product Label, POLE TOPPER FLUID, 03/27/1986

    EPA Pesticide Factsheets

    2011-04-21

    ... I GIU tltt '11' fll~III •• U!, ""Ill .... I,. ~"1If Z 'ft, IWf''''1 "l!tf~ ... JIll ,III ,'Iatt u,I'''IJ_'' rou Ta,," ,'flHI.1 '11 '.llItllutt ."UU1ItI'A I Ir."""l .... 'hI'" til N ._he ..... zaltll"lI" ... ...

  20. Teacher Education for the Future. New Directions and New Developments.

    ERIC Educational Resources Information Center

    Tempero, Howard E., Ed.

    This booklet contains four addresses: (1) "Toward the Year 2000: Teacher Education" by William Van Til, Coffman Distinguished Professor in Education, Indiana State University. It includes projections regarding American society, American education, and teacher education for the next third century. (This address is available separately as ED 028…

  1. 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…

  2. Integrated palmer amaranth management in glufosinate-resistant cotton

    USDA-ARS?s Scientific Manuscript database

    Two separate three year field experiments were conducted to evaluate: 1) the role of soil-inversion, cover crops and herbicide regimes for Amaranthus palmeri between-row (BR) and within-row (WR) management in glufosinate-resistant cotton and 2) the role of soil inversion, cover crops and spring til...

  3. 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.

  4. At the bedside: adoptive cell therapy for melanoma-clinical development.

    PubMed

    Weber, Jeffrey S

    2014-06-01

    Adoptive cell therapy for melanoma, particularly using TIL, consists of a complex and difficult set of procedures, although it has a strong preclinical background and justification and has been pursued clinically by one small group of investigators over the last 20 years. More recent developments and a better understanding of the molecular basis of the anti-tumor immune response have led to the conduct of clinical trials that use lymphoid depletion with chemotherapy and/or TBI to exploit the favorable immune milieu of homeostatic lymphoid reconstitution during transfer of effector T cells. Improved ways of propagating T cells ex vivo have also simplified and shortened the cell-growth process. Current TIL trials have now been expanded beyond the initial center where it was developed, reproducing excellent objective response rates of 40-50% in previously treated melanoma patients and more importantly, demonstrating that a significant proportion of patients will be alive and free of disease 3-5 years after treatment, raising the possibility that those patients may be cured of their disease. Newer methods for growing the infiltrating T cells using immune-checkpoint antibodies or other agents to condition the tumor before harvest and improved technology to simplify the complex and often cumbersome cell-growth process suggest that this technology may be able to be disseminated to a wide selection of cancer centers and may be a candidate for testing in a randomized Phase III trial to show definitively its benefit in patients with metastatic melanoma. In the accompanying review, the preclinical work that supports the idea of adoptive cell therapy with TIL and expands the concept in promising new ways will be explored. © 2014 Society for Leukocyte Biology.

  5. Tropopause inversion layer formation and stratosphere-troposphere exchange during idealized baroclinic wave life cycle experiments

    NASA Astrophysics Data System (ADS)

    Kunkel, Daniel; Wirth, Volkmar; Hoor, Peter

    2014-05-01

    Recent simulations of baroclinic wave life cycles revealed that the tropopause inversion layer (TIL), commonly situated just above the thermal tropopause, is evident in such experiments and emerges after the onset of wave breaking. Furthermore, bidirectional stratosphere-troposphere exchange (STE) occurs during this non-linear stage of the wave evolution and might be affected by the appearance of the TIL. We study the evolution and the impact of the TIL on STE by using the COSMO model in an idealized mid-latitude channel geometry configuration without physical sub-grid scale parameterizations. We initialize the model with a geostrophically balanced upper level jet stream which is disturbed by an anomaly of potential vorticity to trigger the evolution of the baroclinic waves. Moreover, we use passive tracers of tropospheric or stratospheric origin to identify regions of potential STE. Our results show that the static stability is low in regions of stratosphere to troposphere exchange (STT), while it is high in regions dominated by exchange in the opposite direction (TST). Furthermore, inertia gravity waves, originating from regions with strong ageostrophic wind components, modulate the static stability as well as the vertical shear of the horizontal wind near and above the tropopause. While propagating away from their source, the inertia gravity waves lead to large values of the squared Brunt Vaisala frequency in regions which are simultaneously characterized by low bulk Richardson numbers. Thus, these regions are statically stable and turbulent at the same time and might be crucial for TST, thereby explaining tropospheric mixing ratio changes of e.g. CO across the tropopause which commonly change from tropospheric to stratospheric values a few hundred meters above the local thermal tropopause.

  6. 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.

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

    Bhadurihauck, Anjuli; Li, Lei; Li, Qianqian

    Adoptive cell transfer therapy (ACT) is one of the most promising immunotherapies against cancer, using tumor-infiltrating lymphocytes (TILs) expanded in vitro. Tumor-infiltrating cytotoxic T lymphocytes (TICTLs) play a prominent role in cancer control. TILs terminally differentiate in response to immunosuppressive environments within tumors, and thus are slow to expand and challenging to maintain both in vitro and in patients. To reverse this exhaustion, we utilize a nuclear protein delivery system that exposes TICTLs to the SOX2, Oct-4, and NANOG (SON) proteins. Unlike activated naïve CTLs (effector CTLs), TICTLs respond favorably to SON treatment, exhibiting steady proliferation and extended survivability independent of cytokinemore » and antigen stimulation. Though TICTLs treated with SON (STICTLs) still express T cell receptors as well as other critical downstream components, they are unresponsive to antigen challenge, suggesting that SON treatment regresses TICTLs into a state similar to that of an early double negative T cell. Our findings indicate the TICTL response to SON proteins is unique when compared to effector CTLs, suggesting TICTLs may be sensitive to regulation by other lineage-specific transcription factors and opening a promising new avenue into cancer immunotherapy. To our knowledge, this is the first report on lineage reprogramming of TILs using protein stem cell transcription factors delivered directly to the nucleus. -- Highlights: •TICTLs are sensitive to reprogramming by proteins of stem cell transcription factors, but effector CTLs were not. •TICTLs are regressed back to an early double negative T cell stage. •TCR signaling is deregulated by these transcription factors.« less

  8. Peritumoral granulomatous reaction in endometrial carcinoma: association with DNA mismatch repair protein deficiency, particularly loss of PMS2 expression.

    PubMed

    Stewart, Colin J R; Pearn, Amy; Pachter, Nicholas; Tan, Adeline

    2018-04-30

    The observation of peritumoral granulomatous reactions (PGRs) in two endometrial carcinomas (ECs) with a PMS2-deficient/MLH1-intact expression pattern led us to investigate whether PGRs in EC were specifically associated with DNA mismatch repair (MMR) protein deficiency, particularly PMS2 loss. Hysterectomy specimens from 22 MMR protein-intact and 54 MMR protein-deficient ECs were reviewed with specific attention to the presence of a PGR and a tumour-associated lymphoid reaction [including tumour-infiltrating lymphocytes (TILs) and stromal lymphoid infiltrates]. The MMR protein-deficient ECs included 22 cases with combined MLH1/PMS2 loss, 11 with combined MSH2/MSH6 loss, 11 with isolated MSH6 loss, and 10 with PMS2 loss but intact MLH1 staining (including the two 'index' cases). Overall, PGRs were identified in seven of 54 (13%) MMR protein-deficient ECs, five of which showed a PMS2-deficient/MLH1-intact immunophenotype; three of these patients had germline PMS2 mutations and one additional patient had a germline MSH6 mutation. None of the MMR protein-intact tumours showed a PGR. Although five of the seven PGR-positive ECs had a high-grade histological component, six were stage I. Most ECs with PGRs also showed TILs and stromal lymphoid reactions, similarly to MMR protein-deficient ECs in general. MMR protein-deficient ECs, particularly those with PMS2 loss, occasionally show PGRs in addition to stromal lymphoid infiltrates and TILs. Therefore, PGRs could be considered to constitute a histological prompt for consideration of Lynch syndrome. The potential prognostic significance of PGRs in EC requires further study. © 2018 John Wiley & Sons Ltd.

  9. Accumulation and suppressive function of regulatory T cells in malignant ascites: Reducing their suppressive function using arsenic trioxide in vitro.

    PubMed

    Hu, Zilong; Hu, Shidong; Wu, Youjun; Li, Songyan; He, Changzheng; Xing, Xiaowei; Wang, Yufeng; Du, Xiaohui

    2018-04-01

    Although adoptive cell therapy (ACT) has demonstrated effective and remarkable clinical responses in several studies, this approach does not lead to objective clinical responses in all cases. The function of ACT is often compromised by various tumor escape mechanisms, including the accumulation of immunoregulatory cells. As a result of peritoneal metastasis in the terminal stage, malignant ascites fluid lacks effectiveness and is a poor prognostic factor for gastric cancer. The present study assessed T-cell subsets in lymphocytes derived from malignant ascites, and investigated the effects of arsenic trioxide (As 2 O 3 ) on regulatory T cells (Tregs) and ascites-derived tumor-infiltrating lymphocytes (TILs) in vitro . In this study, lymphocytes were separated from malignant ascites and T-cell subsets were detected via flow cytometry. Forkhead box P3 (FoxP3) expression was assessed by immunohistochemistry and reverse transcription-quantitative polymerase chain reaction. In addition, cytokines, including interleukin-10 (IL-10), transforming growth factor-β (TGF-β), and interferon-γ (IFN-γ), were measured by enzyme-linked immunosorbent assay (ELISA). Abundant Tregs were observed in ascites lymphocytes, which and exhibited a significantly increased frequency compared with that in the peripheral blood of patients. Furthermore, As 2 O 3 treatment significantly reduced Treg numbers and Foxp3 mRNA levels in vitro (P<0.05). IFN-γ levels in the supernatant of ascites-derived TILs were increased by As 2 O 3 , whereas IL-10 and TGF-β levels were significantly reduced (P<0.05). As 2 O 3 may induce selective depletion and inhibit immunosuppressive function of Tregs, and may enhance the cytotoxic activity of ascites-derived TILs.

  10. Development of a novel immunoPET tracer to image human PD-1 checkpoint expression on tumor infiltrating lymphocytes in a humanized mouse model

    PubMed Central

    Natarajan, Arutselvan; Mayer, Aaron T; Reeves, Robert E; Nagamine, Claude M; Gambhir, Sanjiv S.

    2017-01-01

    Purpose It is well known that cancers exploit immune checkpoints (programmed death 1 receptor (PD-1) and its ligand (PD-L1)) to evade anti-tumor immune responses. Although immune checkpoint (IC) blockade is a promising approach, not all patients respond. Hence, the purpose of this study is imaging of tumor infiltrating lymphocytes (TILs), as they are known to express PD-1 during activation and subsequent exhaustion in the tumor microenvironment and are thought to be potentially predictive of therapeutic responses to IC blockade. Procedures We developed immunoPET tracers to image hPD-1 status of human peripheral blood mononuclear cells (hPBMC) adoptively transferred to NOD-scid IL-2Rγnull (NSG) mice (hNSG) bearing A375 human skin melanoma tumors. The anti-PD-1 human antibody (IgG; keytruda) labeled with either [89Zr]- or [64Cu]- radiometals to image PD-1 expressing human TILs in vivo. Results [89Zr]keytruda (groups = 2; NSG-ctl [control] and hNSG-nblk [non-blocking], n=3-5, 3.2 ± 0.4 MBq/15-16 μg/200 μL, and [64Cu]keytruda (groups = 3; NSG-ctl, NSG-blk [blocking], and hNSG-nblk) n=4, 7.4 ± 0.4 MBq /20-25μg/200 μL) were administered in mice. PET-CT scans were performed over 1-144 h ([89Zr]keytruda) and 1-48 h ([64Cu]keytruda) on mice. hNSG mice exhibited a high tracer uptake in the spleen lymphoid organs and tumors. At 24h, human TILs homing into melanoma of hNSG-nblk mice exhibited high signal (mean %ID/g ± SD) of 3.8 ± 0.4 ([89Zr]keytruda), and 6.4 ± 0.7 ([64Cu]keytruda), which was 1.5- and 3-fold higher uptake compared to NSG-ctl mice (p = 0.01), respectively. Biodistribution measurements of hNSG-nblk mice performed at 144 h ([89Zr]keytruda), and 48 h ([64Cu]keytruda) p.i. revealed tumor to muscle ratios as high as 45 and 12-fold, respectively. Conclusion This study clearly demonstrates specific imaging of human PD-1 expressing TILs within the tumor and lymphoid tissues. This suggests anti-human-PD-1 tracer could be clinically translatable to monitor

  11. 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

  12. Immune Checkpoint Molecules on Tumor-Infiltrating Lymphocytes and Their Association with Tertiary Lymphoid Structures in Human Breast Cancer

    PubMed Central

    Solinas, Cinzia; Garaud, Soizic; De Silva, Pushpamali; Boisson, Anaïs; Van den Eynden, Gert; de Wind, Alexandre; Risso, Paolo; Rodrigues Vitória, Joel; Richard, François; Migliori, Edoardo; Noël, Grégory; Duvillier, Hugues; Craciun, Ligia; Veys, Isabelle; Awada, Ahmad; Detours, Vincent; Larsimont, Denis; Piccart-Gebhart, Martine; Willard-Gallo, Karen

    2017-01-01

    There is an exponentially growing interest in targeting immune checkpoint molecules in breast cancer (BC), particularly in the triple-negative subtype where unmet treatment needs remain. This study was designed to analyze the expression, localization, and prognostic role of PD-1, PD-L1, PD-L2, CTLA-4, LAG3, and TIM3 in primary BC. Gene expression analysis using the METABRIC microarray dataset found that all six immune checkpoint molecules are highly expressed in basal-like and HER2-enriched compared to the other BC molecular subtypes. Flow cytometric analysis of fresh tissue homogenates from untreated primary tumors show that PD-1 is principally expressed on CD4+ or CD8+ T cells and CTLA-4 is expressed on CD4+ T cells. The global proportion of PD-L1+, PD-L2+, LAG3+, and TIM3+ tumor-infiltrating lymphocytes (TIL) was low and detectable in only a small number of tumors. Immunohistochemically staining fixed tissues from the same tumors was employed to score TIL and tertiary lymphoid structures (TLS). PD-L1+, PD-L2+, LAG3+, and TIM3+ cells were detected in some TLS in a pattern that resembles secondary lymphoid organs. This observation suggests that TLS are important sites of immune activation and regulation, particularly in tumors with extensive baseline immune infiltration. Significantly improved overall survival was correlated with PD-1 expression in the HER2-enriched and PD-L1 or CTLA-4 expression in basal-like BC. PD-1 and CTLA-4 proteins were most frequently detected on TIL, which supports the correlations observed between their gene expression and improved long-term outcome in basal-like and HER2-enriched BC. PD-L1 expression by tumor or immune cells is uncommon in BC. Overall, the data presented here distinguish PD-1 as a marker of T cell activity in both the T and B cell areas of BC associated TLS. We found that immune checkpoint molecule expression parallels the extent of TIL and TLS, although there is a noteworthy amount of heterogeneity between tumors even

  13. DMA (Defense Mapping Agency): The Digital Revolution,

    DTIC Science & Technology

    1984-06-21

    8217 , 𔃿DEFENSE APPING AGENCY: * TIlE DIGITAL REVOLUTION .. ..4 8 .O44 9 5* ; n : . . ., -. n I , . , : ’ . , , - n .’ ’.’- ;; : - COVER FIGURES Top... orthophoto bases. Development of the Continental Control Network and the procurement of an Off- Line Ortho-Photo System has expanded our ability to obtain

  14. U.S. EPA, Pesticide Product Label, BUDMOR 42, 11/28/1983

    EPA Pesticide Factsheets

    2011-04-14

    ... I.";tr 1 .. : .. 1 (,:.J \\!'.: of l..'(' tut !'Ia',; U.!\\ ,, tr r.·,: til r l-:f.tf .... 11. •• ~7 o! Ll:crt1 .• ·:lt ... t:r tt h~Lf\\\\ fl.l .. P&fU' c'.::ar ~..;rp;;.~f' rlortl.!cj tr Imo:.fJ (,ttl.tl. ...

  15. Adoptive Cell Therapy for Patients with Melanoma

    PubMed Central

    Dudley, Mark E.

    2011-01-01

    Adoptive cell therapy can be an effective treatment for some patients with advanced cancer. This report summarizes clinical trial results from the Surgery Branch, NCI, investigating tumor infiltrating lymphocytes (TIL) and gene engineered peripheral blood T cells for the therapy of patients with melanoma and other solid tumors. PMID:21716716

  16. 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…

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

    PubMed

    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

    2015-06-01

    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. To determine tumor characteristics and survival from primary melanoma by somatic NRAS and BRAF status. A population-based study with a median follow-up of 7.6 years (through 2007), including 912 patients from the United States and Australia in the Genes, Environment, and Melanoma (GEM) Study, with first primary cutaneous melanoma diagnosed in the year 2000 and analyzed for NRAS and BRAF mutations. Tumor characteristics and melanoma-specific survival of primary melanoma by NRAS and BRAF mutational status. The melanomas were 13% NRAS+, 30% BRAF+, and 57% with neither NRAS nor BRAF mutation (wildtype [WT]). In a multivariable model including clinicopathologic characteristics, relative to WT melanoma (with results reported as odds ratios [95% CIs]), NRAS+ melanoma was associated with presence of mitoses (1.8 [1.0-3.3]), lower tumor-infiltrating lymphocyte (TIL) grade (nonbrisk, 0.5 [0.3-0.8]; and brisk, 0.3 [0.5-0.7] [vs absent TILs]), and anatomic site other than scalp/neck (0.1 [0.01-0.6] for scalp/neck vs trunk/pelvis), and BRAF+ melanoma was associated with younger age (ages 50-69 years, 0.7 [0.5-1.0]; and ages >70 years, 0.5 [0.3-0.8] [vs <50 years]), superficial spreading subtype (nodular, 0.5 [0.2-1.0]; lentigo maligna, 0.4 [0.2-0.7]; and unclassified/other, 0.2 [0.1-0.5] [vs superficial spreading]), and presence of mitoses (1.7 [1.1-2.6]) (P < .05 for all). There was no significant difference in melanoma-specific survival (reported as hazard ratios [95% CIs]) for melanoma harboring mutations in NRAS (1.7 [0.8-3.4]) or BRAF (1.5 [0.8-2.9]) compared with WT melanoma, as adjusted for age

  18. Pathological characterisation of male breast cancer: Results of the EORTC 10085/TBCRC/BIG/NABCG International Male Breast Cancer Program.

    PubMed

    Vermeulen, Marijn A; Slaets, Leen; Cardoso, Fatima; Giordano, Sharon H; Tryfonidis, Konstantinos; van Diest, Paul J; Dijkstra, Nizet H; Schröder, Carolien P; van Asperen, Christi J; Linderholm, Barbro; Benstead, Kim; Foekens, Renee; Martens, John W M; Bartlett, John M S; van Deurzen, Carolien H M

    2017-09-01

    Several prognostic histological features have been established in female breast cancer (BC), but it is unknown whether these can be extrapolated to male BC patients. The aim of this study was to evaluate the prognostic value of several histological features in a large series of male BC. Central pathology review was performed for 1483 male BCs collected through part 1 of the European Organisation for Research and Treatment of Cancer (EORTC) International Male BC Program. Pathology review included histological subtype, grade, mitotic activity index (MAI), presence of a fibrotic focus and density of tumour-infiltrating lymphocytes (TILs). These features were correlated with clinical outcome. The relationship between these features and surrogate molecular subtypes using immunohistochemistry was also assessed. Median follow-up for overall survival (OS) was 7.1 years. Overall histological grade was not significantly associated with OS (p = 0.129). MAI, the presence of a fibrotic focus and a low TIL density however were correlated with unfavourable OS (p = 0.023, p = 0.004 and p = 0.011, respectively). BC subtype correlated with TIL density (p = 0.015), as we observed a higher density for human epidermal growth factor receptor type 2 (HER2) positive BC compared to luminal HER2-negative subtype. No association was observed between subtype and fibrotic focus. Histologic grade was not significantly correlated with clinical outcome in this series, unlike what is seen in female patients. These results contribute to our understanding of male BC and indicate the importance of further research on the optimisation of risk stratification and treatment decisions for male BC patients. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. Cytolytic Activity Score to Assess Anticancer Immunity in Colorectal Cancer.

    PubMed

    Narayanan, Sumana; Kawaguchi, Tsutomu; Yan, Li; Peng, Xuan; Qi, Qianya; Takabe, Kazuaki

    2018-05-16

    Elevated tumor-infiltrating lymphocytes (TILs) within the tumor microenvironment is a known positive prognostic factor in colorectal cancer (CRC). We hypothesized that since cytotoxic T cells release cytolytic proteins such as perforin (PRF1) and pro-apoptotic granzymes (GZMA) to attack cancer cells, a cytolytic activity score (CYT) would be a useful tool to assess anticancer immunity. Genomic expression data were obtained from 456 patients from The Cancer Genome Atlas (TCGA). CYT was defined by GZMA and PRF1 expression, and CIBERSORT was used to evaluate intratumoral immune cell composition. High CYT was associated with high microsatellite instability (MSI-H), as well as high levels of activated memory CD4+T cells, gamma-delta T cells, and M1 macrophages. CYT-high CRC patients had improved overall survival (p = 0.019) and disease-free survival (p = 0.016) compared with CYT-low CRC patients, especially in TIL-positive tumors. Multivariate analysis demonstrated that CYT- high associates with improved survival independently after controlling for age, lymphovascular invasion, colonic location, microsatellite instability, and TIL positivity. The levels of immune checkpoint molecules (ICMs)-programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T-lymphocyte-associated protein 4 (CTLA4), lymphocyte-activation gene 3 (LAG3), T cell immunoglobulin and mucin domain 3 (TIM3), and indoleamine 2,3-dioxygenase 1 (IDO1)-correlated significantly with CYT (p < 0.0001); with improved survival in CYT-high and ICM-low patients, and poorer survival in ICM-high patients. High CYT within CRC is associated with improved survival, likely due to increased immunity and cytolytic activity of T cells and M1 macrophages. High CYT is also associated with high expression of ICMs; thus, further studies to elucidate the role of CYT as a predictive biomarker of the efficacy of immune checkpoint blockade are warranted.

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

    PubMed

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

    2017-05-02

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

  1. Proteomic identification of differentially expressed proteins between male and female plants in Pistacia chinensis.

    PubMed

    Xiong, Erhui; Wu, Xiaolin; Shi, Jiang; Wang, Xiaoyan; Wang, Wei

    2013-01-01

    Pistacia chinensis is a strict dioecious plant with male and female flowers in individuals. In China, P. chinensis is widely planted for biodiesel oil due to high oil content in seeds. In practice it requires to grow more female plants for biodiesel production. At present, there are still no reliable methods for sex determination during the long juvenile stage of this species. In order to develop protein molecular markers for sex determination in P. chinensis, proteomic approach was used to identify differentially expressed proteins between male and female plants. Vegetative organs (leaf and stem) rather than reproductive organs/tissues were used for protein extraction so as to develop protein markers which can be used in siblings before flowering. Protein was extracted using a phenol-based protocol. By using two-dimensional electrophoresis, a total of 10 protein spots were found to be differentially expressed in leaf and stem between both sexes, of which 7 were successfully identified by mass spectrometry and matched to 6 functional proteins such as NB-ARC domain containing protein, light harvesting chlorophyll a/b binding protein, asorbate peroxidase (APX), eukaryotic translation initiation factor 5A2, temperature-induced lipocalin (TIL) and phosphoglycerate kinase (PGK). The sex-related difference displayed in a tissue-specific way, especially in stem. PGK existed in high abundance in stem phloem in the female, but was almost not detected in the male; APX and two TIL species were highly abundant in the stem of male plants, while their abundance was much lower in female plants. Moreover, these abundance differences were further confirmed in individual plants. Hence, it is assumed that APX, PGK and TIL might be promising candidates to serve as protein molecular markers for sex determination in P. chinensis. Our results form the basis for a further understanding of the biochemical mechanisms of sex determination in P. chinensis.

  2. 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

  3. Adoptive cell therapy with autologous tumor infiltrating lymphocytes and low-dose Interleukin-2 in metastatic melanoma patients.

    PubMed

    Ellebaek, Eva; Iversen, Trine Zeeberg; Junker, Niels; Donia, Marco; Engell-Noerregaard, Lotte; Met, Özcan; Hölmich, Lisbet Rosenkrantz; Andersen, Rikke Sick; Hadrup, Sine Reker; Andersen, Mads Hald; thor Straten, Per; Svane, Inge Marie

    2012-08-21

    Adoptive cell therapy may be based on isolation of tumor-specific T cells, e.g. autologous tumor infiltrating lymphocytes (TIL), in vitro activation and expansion and the reinfusion of these cells into patients upon chemotherapy induced lymphodepletion. Together with high-dose interleukin (IL)-2 this treatment has been given to patients with advanced malignant melanoma and impressive response rates but also significant IL-2 associated toxicity have been observed. Here we present data from a feasibility study at a Danish Translational Research Center using TIL adoptive transfer in combination with low-dose subcutaneous IL-2 injections. This is a pilot trial (ClinicalTrials.gov identifier: NCT00937625) including patients with metastatic melanoma, PS ≤1, age <70, measurable and progressive disease and no involvement of the central nervous system. Six patients were treated with lymphodepleting chemotherapy, TIL infusion, and 14 days of subcutaneous low-dose IL-2 injections, 2 MIU/day. Low-dose IL-2 considerably decreased the treatment related toxicity with no grade 3-4 IL-2 related adverse events. Objective clinical responses were seen in 2 of 6 treated patients with ongoing complete responses (30+ and 10+ months), 2 patients had stable disease (4 and 5 months) and 2 patients progressed shortly after treatment. Tumor-reactivity of the infused cells and peripheral lymphocytes before and after therapy were analyzed. Absolute number of tumor specific T cells in the infusion product tended to correlate with clinical response and also, an induction of peripheral tumor reactive T cells was observed for 1 patient in complete remission. Complete and durable responses were induced after treatment with adoptive cell therapy in combination with low-dose IL-2 which significantly decreased toxicity of this therapy.

  4. Proteomic Identification of Differentially Expressed Proteins between Male and Female Plants in Pistacia chinensis

    PubMed Central

    Shi, Jiang; Wang, Xiaoyan; Wang, Wei

    2013-01-01

    Pistacia chinensis is a strict dioecious plant with male and female flowers in individuals. In China, P. chinensis is widely planted for biodiesel oil due to high oil content in seeds. In practice it requires to grow more female plants for biodiesel production. At present, there are still no reliable methods for sex determination during the long juvenile stage of this species. In order to develop protein molecular markers for sex determination in P. chinensis, proteomic approach was used to identify differentially expressed proteins between male and female plants. Vegetative organs (leaf and stem) rather than reproductive organs/tissues were used for protein extraction so as to develop protein markers which can be used in siblings before flowering. Protein was extracted using a phenol-based protocol. By using two-dimensional electrophoresis, a total of 10 protein spots were found to be differentially expressed in leaf and stem between both sexes, of which 7 were successfully identified by mass spectrometry and matched to 6 functional proteins such as NB-ARC domain containing protein, light harvesting chlorophyll a/b binding protein, asorbate peroxidase (APX), eukaryotic translation initiation factor 5A2, temperature-induced lipocalin (TIL) and phosphoglycerate kinase (PGK). The sex-related difference displayed in a tissue-specific way, especially in stem. PGK existed in high abundance in stem phloem in the female, but was almost not detected in the male; APX and two TIL species were highly abundant in the stem of male plants, while their abundance was much lower in female plants. Moreover, these abundance differences were further confirmed in individual plants. Hence, it is assumed that APX, PGK and TIL might be promising candidates to serve as protein molecular markers for sex determination in P. chinensis. Our results form the basis for a further understanding of the biochemical mechanisms of sex determination in P. chinensis. PMID:23691188

  5. 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.

  6. 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.

  7. PD-1 and PD-L1 expression in HNSCC primary cancer and related lymph node metastasis - impact on clinical outcome.

    PubMed

    Schneider, Sven; Kadletz, Lorenz; Wiebringhaus, Robert; Kenner, Lukas; Selzer, Edgar; Füreder, Thorsten; Rajky, Orsolya; Berghoff, Anna S; Preusser, Matthias; Heiduschka, Gregor

    2018-05-09

    Expression profiles and clinical impact of programmed cell death ligand 1 (PD-L1) and programmed cell death 1 (PD-1) expressing tumour infiltrating lymphocytes (TILs) in head and neck squamous cell carcinoma (HNSCC) are not fully elucidated. This study evaluates expression patterns in primary HNSCC and related lymph node metastasis and impact on patients' clinical outcome. Immunohistochemical staining patterns of PD-L1 and PD-1 were evaluated in 129 specimens of primary HNSCC and 77 lymph node metastases. Results were correlated to patients' clinical data. PD-L1 expression was observed in 36% of primary carcinoma and 33% of lymph node metastasis and significantly correlates with decreased overall survival (OS) (p=0.01) and disease free survival (DFS) (p=0.001) in oral cavity squamous cell carcinoma patients. PD-L1 expression was associated with presence of lymph node metastasis (p=0.0223). Infiltration of PD-1 expressing lymphocytes significantly correlates with favorable OS (p=0.001) and DFS (p=0.001) in oropharyngeal cancer and hypopharyngeal cancer patients OS (p=0.007) and DFS (p=0.001). Presence of PD-1 TILs significantly correlates with better OS (p=0.005) and DFS (p=0) also in the HPV negative cohort. Cox regression multivariate analysis revealed PD-1 TIL expression as an independent prognostic marker for OS (p=0.004) and DFS (p=0.001) and T stage was validated as negative prognostic marker for OS (p=0.011). PD-1 expressing lymphocytes (p=0.0412) and PD-L1 expression (p=0.0022) patterns correlate significantly in primary cancers and matched lymph node metastases. Our results characterize the expression profiles of PD-1 axis proteins in HNSCC which might serve as possible clinical prognostic markers. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  8. A morphological and immunophenotypic map of the immune response in Merkel cell carcinoma.

    PubMed

    Walsh, Noreen M; Fleming, Kirsten E; Hanly, John G; Dakin Hache, Kelly; Doucette, Steve; Ferrara, Gerardo; Cerroni, Lorenzo

    2016-06-01

    The susceptibility of Merkel cell carcinoma to the host immune response has prompted a search for effective immunotherapy. CD8-positive T lymphocytes are considered key effectors of this response, but the cellular infiltrates also harbor tumor-protective agents. By developing a comprehensive morphological and immunophenotypic map of tumor-infiltrating lymphocytes (TILS) in Merkel cell carcinoma, we aimed to establish a useful template for future studies. Twenty-two cases (mean age, 79years [range, 52-95]; male-female ratio, 10:12) were studied. TILS were categorized as brisk (7), nonbrisk (9), and absent(6). Merkel cell polyomavirus (MCPyV)-positive (16) and -negative (6) cases were included, as were those with pure (18) and combined (4) morphologies. One MCPyV+ case had undergone spontaneous regression. Immunohistochemical markers included CD3, CD4, CD8, CD20, CD68, FoxP3, PD-1, and CD123. Statistical analysis used Fisher exact tests and Spearman correlations. There was a significant correlation between brisk TILs and MCPyV+ status (P=.025). CD8+ T lymphocytes predominated, were present in significantly higher proportions in brisk infiltrates (P=.003), and showed a significant predilection for the intratumoral environment (P=.003). Immune inhibitors including T regulatory cells (FOXP3+) and PD-1+ "exhausted" immunocytes were present in lower proportions. Our findings support (1) the link between a brisk immune response and MCPyV positivity, (2) the supremacy of CD8+ cells in effecting immunity, and (3) the incorporation of immune inhibitors within the global infiltrate. Efforts to therapeutically arm the "effectors" and disarm the "detractors" are well focused. These will likely have the greatest impact on MCPyV-positive cases. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Gut microbiota modulate T cell trafficking into human colorectal cancer.

    PubMed

    Cremonesi, Eleonora; Governa, Valeria; Garzon, Jesus Francisco Glaus; Mele, Valentina; Amicarella, Francesca; Muraro, Manuele Giuseppe; Trella, Emanuele; Galati-Fournier, Virginie; Oertli, Daniel; Däster, Silvio Raffael; Droeser, Raoul A; Weixler, Benjamin; Bolli, Martin; Rosso, Raffaele; Nitsche, Ulrich; Khanna, Nina; Egli, Adrian; Keck, Simone; Slotta-Huspenina, Julia; Terracciano, Luigi M; Zajac, Paul; Spagnoli, Giulio Cesare; Eppenberger-Castori, Serenella; Janssen, Klaus-Peter; Borsig, Lubor; Iezzi, Giandomenica

    2018-02-06

    Tumour-infiltrating lymphocytes (TILs) favour survival in human colorectal cancer (CRC). Chemotactic factors underlying their recruitment remain undefined. We investigated chemokines attracting T cells into human CRCs, their cellular sources and microenvironmental triggers. Expression of genes encoding immune cell markers, chemokines and bacterial 16S ribosomal RNA (16SrRNA) was assessed by quantitative reverse transcription-PCR in fresh CRC samples and corresponding tumour-free tissues. Chemokine receptor expression on TILs was evaluated by flow cytometry on cell suspensions from digested tissues. Chemokine production by CRC cells was evaluated in vitro and in vivo, on generation of intraperitoneal or intracecal tumour xenografts in immune-deficient mice. T cell trafficking was assessed on adoptive transfer of human TILs into tumour-bearing mice. Gut flora composition was analysed by 16SrRNA sequencing. CRC infiltration by distinct T cell subsets was associated with defined chemokine gene signatures, including CCL5, CXCL9 and CXCL10 for cytotoxic T lymphocytes and T-helper (Th)1 cells; CCL17, CCL22 and CXCL12 for Th1 and regulatory T cells; CXCL13 for follicular Th cells; and CCL20 and CCL17 for interleukin (IL)-17-producing Th cells. These chemokines were expressed by tumour cells on exposure to gut bacteria in vitro and in vivo. Their expression was significantly higher in intracecal than in intraperitoneal xenografts and was dramatically reduced by antibiotic treatment of tumour-bearing mice. In clinical samples, abundance of defined bacteria correlated with high chemokine expression, enhanced T cell infiltration and improved survival. Gut microbiota stimulate chemokine production by CRC cells, thus favouring recruitment of beneficial T cells into tumour tissues. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  10. 76 FR 78057 - Self-Regulatory Organizations; The NASDAQ Stock Market LLC; Notice of Filing and Immediate...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-15

    ... have a time-in-force designation of Good Til Cancelled (``GTC'').\\5\\ \\3\\ See Securities Exchange Act... Orders are evaluated at the time of entry with respect to locking or crossing other orders as follows: (i..., Chapter VI, Section 1(g). At this time, the Exchange proposes to amend the definition in Chapter VI...

  11. Antibody-targeted interleukin 2 stimulates T-cell killing of autologous tumor cells.

    PubMed Central

    Gillies, S D; Reilly, E B; Lo, K M; Reisfeld, R A

    1992-01-01

    A genetically engineered fusion protein consisting of a chimeric anti-ganglioside GD2 antibody (ch14.18) and interleukin 2 (IL2) was tested for its ability to enhance the killing of autologous GD2-expressing melanoma target cells by a tumor-infiltrating lymphocyte line (660 TIL). The fusion of IL2 to the carboxyl terminus of the immunoglobulin heavy chain did not reduce IL2 activity as measured in a standard proliferation assay using either mouse or human T-cell lines. Antigen-binding activity was greater than that of the native chimeric antibody. The ability of resting 660 TIL cells to kill their autologous GD2-positive target cells was enhanced if the target cells were first coated with the fusion protein. This stimulation of killing was greater than that of uncoated cells in the presence of equivalent or higher concentrations of free IL2. Such antibody-cytokine fusion proteins may prove useful in targeting the biological effect of IL2 and other cytokines to tumor cells and in this way stimulate their immune destruction. Images PMID:1741398

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

    PubMed

    Chen, Limo; Gibbons, Don L; 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

    2014-10-28

    Immunosuppression of tumour-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 tumour 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.

  13. Production and characterization of monoclonal antibodies against the antibiotic tilmicosin.

    PubMed

    Beier, Ross C; Creemer, Lawrence C; Ziprin, Richard L; Nisbet, David J

    2005-12-14

    Monoclonal antibodies (Mabs) were developed that specifically bind tilmicosin. Keyhole limpet hemocyanin (KLH) and bovine serum albumin (BSA) conjugates were used for the immunogen and plate coating antigen, respectively. The conjugates were synthesized by different methods, resulting in different linkages. Six hybridoma cell lines were isolated that produced Mabs that competed with tilmicosin, and have IgG1 isotype. The Til-1 and Til-5 Mabs had IC50 values for tilmicosin of 9.6 and 6.4 ng/well (48 and 32 ng/mL), respectively, and limits of detection at IC20 of 1.84 and 0.89 ng/well (9.2 and 4.45 ng/mL), respectively. The Mabs demonstrated high cross-reactivity to the macrolides containing 3,5-dimethylpiperidine at C20 and the amino sugar at C5. No cross-reactivity was observed for tylosin and other macrolides that did not contain 3,5-dimethylpiperidine. A competitive enzyme-linked immunosorbent assay (ELISA) was developed for the antibiotic tilmicosin by use of the developed Mabs. These Mabs may be excellent candidates for the determination and immunolocalization of tilmicosin.

  14. Interfaces of Malignant and Immunologic Clonal Dynamics in Ovarian Cancer.

    PubMed

    Zhang, Allen W; McPherson, Andrew; Milne, Katy; Kroeger, David R; Hamilton, Phineas T; Miranda, Alex; Funnell, Tyler; Little, Nicole; de Souza, Camila P E; Laan, Sonya; LeDoux, Stacey; Cochrane, Dawn R; Lim, Jamie L P; Yang, Winnie; Roth, Andrew; Smith, Maia A; Ho, Julie; Tse, Kane; Zeng, Thomas; Shlafman, Inna; Mayo, Michael R; Moore, Richard; Failmezger, Henrik; Heindl, Andreas; Wang, Yi Kan; Bashashati, Ali; Grewal, Diljot S; Brown, Scott D; Lai, Daniel; Wan, Adrian N C; Nielsen, Cydney B; Huebner, Curtis; Tessier-Cloutier, Basile; Anglesio, Michael S; Bouchard-Côté, Alexandre; Yuan, Yinyin; Wasserman, Wyeth W; Gilks, C Blake; Karnezis, Anthony N; Aparicio, Samuel; McAlpine, Jessica N; Huntsman, David G; Holt, Robert A; Nelson, Brad H; Shah, Sohrab P

    2018-05-07

    High-grade serous ovarian cancer (HGSC) exhibits extensive malignant clonal diversity with widespread but non-random patterns of disease dissemination. We investigated whether local immune microenvironment factors shape tumor progression properties at the interface of tumor-infiltrating lymphocytes (TILs) and cancer cells. Through multi-region study of 212 samples from 38 patients with whole-genome sequencing, immunohistochemistry, histologic image analysis, gene expression profiling, and T and B cell receptor sequencing, we identified three immunologic subtypes across samples and extensive within-patient diversity. Epithelial CD8+ TILs negatively associated with malignant diversity, reflecting immunological pruning of tumor clones inferred by neoantigen depletion, HLA I loss of heterozygosity, and spatial tracking between T cell and tumor clones. In addition, combinatorial prognostic effects of mutational processes and immune properties were observed, illuminating how specific genomic aberration types associate with immune response and impact survival. We conclude that within-patient spatial immune microenvironment variation shapes intraperitoneal malignant spread, provoking new evolutionary perspectives on HGSC clonal dispersion. Copyright © 2018 Elsevier Inc. All rights reserved.

  15. Observation of laser beam profile progression inside an extended laser cavity

    NASA Astrophysics Data System (ADS)

    Wu, Frank F.; Farrell, Thomas C.

    2013-03-01

    This report presents the result of the laser beam profile progression in target-in-the-loop (TIL) system. This simulation experiment is to verify whether it is possible to form a tight hot spot similar to a single transversal mode in an extended laser cavity. Therefore, it is very important to observe the progression of the laser profile at a laser cavity mirror when a seeded high energy laser pulse is injected into the TIL system. The extended laser cavity is formed with a high reflectivity mirror on one end and an optical phase conjugated mirror as the second mirror, with potential disturbance media inside. The laser oscillation occurs only when it is triggered with a single frequency high energy laser pulse to overcome the threshold condition. With a laser cavity length of around 11 meters and a seeded laser pulse of 10 ns, we have been able to acquire and distinguish the laser beam profiles of each round-trip. Inserting a scattering media and other distortion elements can simulate atmospheric effects.

  16. Tera-Op Reliable Intelligently Adaptive Processing System (TRIPS)

    DTIC Science & Technology

    2004-04-01

    flop creates a loadable FIFO queue, fifo pload. A prototype of the HML simulator is implemented using a functional language OCaml . The language type...Flow . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 7.1.2 Hardware Meta Language ...operates on the TRIPS Intermediate Language (TIL) produced by the Scale compiler. We also adapted the gnu binary utilities to implement an assembler and

  17. Rapid Annealing of Iron Implanted Hg(1-x)Cd(x)Te

    DTIC Science & Technology

    1990-03-01

    Alnrroveii rFoi’ PubikI Release; distributin tilIntl ted DTICELECTEJUN 12 IMU’ BEest Available Cop, D i ..:6 (J,•, 4iL& , AD Rapid Annealing of Ion...Recently, we have received from Or.J. Dinan of the Night Vision and Electro-optic Army Labs at Fort Belvoir a few electrically uncharacterized Hg

  18. Seattle FWS, Washington. Revised Uniform Summary of Surface Weather Observations (RUSSWO). Parts A-F

    DTIC Science & Technology

    1970-08-28

    FREQUENCY OF WIND DIRECTION AND SPEED til (FROM HOURLY OBSERVATIONS) 24244 SEATTLE wAHtIGTON FWC __iAR - -ALL WATHER _--- ~ALL -- CONDmON - SPEED 34MEAN (KNTS...10 PERCENTAGE FREQUENCY OF WIND DIRECTION AND SPEED 11J1 (FROM HOURLY OBSERVATIONS) 2.4244 SEATTLE WASHINGTOjN FW -6 C ALL WATHER - -M ~0-0 50O

  19. The Coast Artillery Journal. Volume 60, Number 4, April 1924

    DTIC Science & Technology

    1924-04-01

    and it is belie,’ed that this Bange Finder can be impro,’ed considerably, especially ,’arious mechanical and optical features, The Bausch and 322 TIlE...Esthonia over 17,000; Rumania over 190,000; Jugo -Slavonia over 160,000; Italy over 360,000, all in the peace establishment. This aggregates 2,267,000

  20. U.S. EPA, Pesticide Product Label, CARBARYL 50-W INSECTICIDE, 11/16/1972

    EPA Pesticide Factsheets

    2011-04-21

    ... lJ\\.· l til '1 IU'\\lIl(t~ 1", (II'" ".H'hPIIll ('Off1 IIJotW',rm .Idulh E.tHUp··,11l CoIn ho, .. r faH .lfrnyworm, 1" . .1 bo·.·t't·' J.lp,"lt· ... ... It',j b ... eU.' I, ~ .'Ider htJg ...

  1. Regulation of the Prostate Cancer Tumor Microenvironment

    DTIC Science & Technology

    2015-04-01

    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...damage-associated molecular patterns (DAMPs) released by the tumor stimulate the innate immune pathways through pattern recognition receptors (PRRs

  2. Regulation of the Prostate Cancer Tumor Microenvironment

    DTIC Science & Technology

    2016-04-01

    adenocarcinomas than wild-type controls at 30 weeks of age. Analysis of tumor infiltrating cells revealed increased infiltration of macrophage lineage...angiogenesis and proliferation2. Conversely, inflammation can trigger the infiltration of cytotoxic immune effector cells, resulting in the production of...clonal CD8+ T cells3. However, the contribution of the tumor infiltrating lymphocytes (TILs) to prostate cancer development, growth, and metastasis

  3. Report of Operations in North Africa

    DTIC Science & Technology

    1942-12-12

    puslhing thie skippers because while they are in the port they are still getting their war bonuses without the risks . Captain Gilbrcndson also tells me...for officers, SOS,’TF. I lnuve beor .. i’,ormied that .^ "( cimately 50 allotments for dea.itv i~ae u0 oL, Lcors O. trt SOS, 30 , ,r, in til’ : port

  4. Inhibition of CSF1 Receptor Improves the Anti-tumor Efficacy of Adoptive Cell Transfer Immunotherapy

    PubMed Central

    Tsui, Christopher; Xu, Jingying; Robert, Lídia; Wu, Lily; Graeber, Thomas; West, Brian L.; Bollag, Gideon; Ribas, Antoni

    2013-01-01

    Colony stimulating factor-1 (CSF-1) recruits tumor-infiltrating myeloid cells (TIMs) that suppress tumor immunity, including M2 macrophages and myeloid derived suppressor cells (MDSC). The CSF-1 receptor (CSF-1R) is a tyrosine kinase that is targetable by small molecule inhibitors such as PLX3397. In this study, we used a syngeneic mouse model of BRAFV600E-driven melanoma to evaluate the ability of PLX3397 to improve the efficacy of adoptive T-cell therapy (ACT). In this model, we found that combined treatment produced superior anti-tumor responses compared with single treatments. In mice receiving the combined treatment, a dramatic reduction of TIMs and a skewing of MHCIIlow to MHCIIhi macrophages was observed. Further, mice receiving the combined treatment exhibited an increase in tumor-infiltrating lymphocytes (TILs) and T cells, as revealed by real-time imaging in vivo. In support of these observations, TILs from these mice released higher levels of IFN-γ. In conclusion, CSF-1R blockade with PLX3397 improved the efficacy of ACT immunotherapy by inhibiting the intratumoral accumulation of immune suppressive macrophages. PMID:24247719

  5. A Simple Method to Optimize the Effectiveness of Chemotherapy: Modulation of Glucose Intake During Chemotherapy.

    PubMed

    Icard, Philippe; Teboul, Bernard; El Baze, Philip

    2017-11-01

    Cancer cells consume high amounts of glucose to produce ATP and molecules entering biosynthesis. Numerous experimental studies have demonstrated that glucose deprivation and/or glycolysis inhibition arrest cancer cell growth and may increase the efficiency of cytotoxic drugs. In contrast, increasing glycolysis in tumor-infiltrating lymphocytes (TILs) activates these cells that destroy cancer cells. We propose to increase the efficiency of chemotherapy by modulating glucose intake during the course of chemotherapy. Glucose and caloric intake should be drastically reduced the day before and during chemotherapy administration to deprive cancer cells of ATP and molecules required to repair cytotoxic lesions. Few hours after chemotherapy, glucose and caloric intake should be drastically increased for few days to promote the activation of TILs that reinforce the destruction of cancer cells. This strategy could improve the results of chemotherapy by first enhancing cytotoxic stress against tumor cells and then promoting activation of the anti-cancer immune response. The modulation of glucose intake during chemotherapy should be tested clinically. The proposed scheme is simple, surely easier to follow than a strict chronic diet, and should avoid weight loss. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  6. Impact Damage Thresholds in Brittle Materials Impacted by Water Drops.

    DTIC Science & Technology

    1979-03-01

    hardness AS$TNAC T (C 5M.. cc roc .. aId. It ,. m.p .id td ..tIl~- S~. block cad ..) The damage threshold for brittle materials impacted by water drops...center, vls-a-vls their(continued) ~~~ DO I JA N71 1Q3 EDITION OP 1 NOV IS iS OHOLETE UNCLASSIFIED SECURITY CLASSIFICATION OP ThiS RAGS (a. ONs

  7. Storage Reliability Missile Materiel Program. Storage Reliability Summary Report. Volume 2. Electromechanical Devices

    DTIC Science & Technology

    1978-02-01

    ii•t, difforonc wit h ono data not’ hoV14. a nq I til i. It n 1.1 y Hho i~r fitltrevi rato, TIhil # da tai ou t W~AP i’eiwivod and th I’ll oeitnniciw...consideration. Wolfram, molybdenum, and carbon are able to sustain an arc without reaching their melting point (sufficient thermionic emission occurs at

  8. Enhancing the Breadth and Efficacy of Therapeutic Vaccines for Breast Cancer

    DTIC Science & Technology

    2013-10-01

    function ...discovery,  we  isolated  CD8  TILs  as  indicated  in  Figure  1,  and  then  determined  their   function   after... functionality  can  be  assessed  by  binding  to  a  potential   target  and  measuring  the  release  of  IL-­‐2

  9. SOCS3 inhibits the pathological effects of IL-22 in non-melanoma skin tumor-derived keratinocytes

    PubMed Central

    Madonna, Stefania; Scarponi, Claudia; Morelli, Martina; Sestito, Rosanna; Scognamiglio, Pasqualina Liana; Marasco, Daniela; Albanesi, Cristina

    2017-01-01

    Basal cell carcinomas (BCC) and squamous-cell carcinomas (SCC) are common malignancies in humans, caused by neoplastic transformation of keratinocytes of the basal or suprabasal layers of epidermis, respectively. Tumor-infiltrating lymphocytes (TILs) are frequently found in BCC and SCC, and functionally promote epithelial carcinogenesis. TILs secreting IL-22, in particular, participate to BCC and SCC growth by inducing keratinocyte proliferation and migration, as well as the expression of inflammatory, anti-apoptotic and pro-angiogenic genes. In this study, we identified SOCS3 as a valid candidate to be manipulated for suppressing tumorigenic functions in BCC and SCC. We found that SOCS3 and SOCS1 expression was reduced in vivo, in tumor lesions of BCC and SCC, as compared to other skin inflammatory conditions such as psoriasis, despite the high number of IL-22-secreting TILs. Moreover, IL-22 was not able to induce in vitro the transcriptional expression of SOCS3 in BCC-or SCC-derived keratinocytes, contrarily to healthy cells. Aimed at rescuing SOCS3 activity in these tumor contexts, a SOCS3-derived peptide, named KIR-ESS, was synthesized, and its ability in suppressing IL-22-induced responses was evaluated in healthy and transformed keratinocytes. We found that KIR-ESS peptide efficiently suppressed the IL-22 molecular signaling in keratinocytes, by acting on STAT3 and Erk1/2 cascade, as well as on the expression of STAT3-dependent downstream genes. Interestingly, after treatment with peptide, both healthy and transformed keratinocytes could no longer aberrantly proliferate and migrate in response to IL-22. Finally, treatment of athymic nude mice bearing SCC xenografts with KIR-ESS peptide concomitantly reduced tumor growth and activated STAT3 levels. As a whole, these data provides the rationale for the use in BCC and SCC skin tumors of SOCS3 mimetics, being able to inhibit the deleterious effects of IL-22 in these contexts. PMID:28445952

  10. SOCS3 inhibits the pathological effects of IL-22 in non-melanoma skin tumor-derived keratinocytes.

    PubMed

    Madonna, Stefania; Scarponi, Claudia; Morelli, Martina; Sestito, Rosanna; Scognamiglio, Pasqualina Liana; Marasco, Daniela; Albanesi, Cristina

    2017-04-11

    Basal cell carcinomas (BCC) and squamous-cell carcinomas (SCC) are common malignancies in humans, caused by neoplastic transformation of keratinocytes of the basal or suprabasal layers of epidermis, respectively. Tumor-infiltrating lymphocytes (TILs) are frequently found in BCC and SCC, and functionally promote epithelial carcinogenesis. TILs secreting IL-22, in particular, participate to BCC and SCC growth by inducing keratinocyte proliferation and migration, as well as the expression of inflammatory, anti-apoptotic and pro-angiogenic genes.In this study, we identified SOCS3 as a valid candidate to be manipulated for suppressing tumorigenic functions in BCC and SCC. We found that SOCS3 and SOCS1 expression was reduced in vivo, in tumor lesions of BCC and SCC, as compared to other skin inflammatory conditions such as psoriasis, despite the high number of IL-22-secreting TILs. Moreover, IL-22 was not able to induce in vitro the transcriptional expression of SOCS3 in BCC-or SCC-derived keratinocytes, contrarily to healthy cells. Aimed at rescuing SOCS3 activity in these tumor contexts, a SOCS3-derived peptide, named KIR-ESS, was synthesized, and its ability in suppressing IL-22-induced responses was evaluated in healthy and transformed keratinocytes. We found that KIR-ESS peptide efficiently suppressed the IL-22 molecular signaling in keratinocytes, by acting on STAT3 and Erk1/2 cascade, as well as on the expression of STAT3-dependent downstream genes. Interestingly, after treatment with peptide, both healthy and transformed keratinocytes could no longer aberrantly proliferate and migrate in response to IL-22. Finally, treatment of athymic nude mice bearing SCC xenografts with KIR-ESS peptide concomitantly reduced tumor growth and activated STAT3 levels. As a whole, these data provides the rationale for the use in BCC and SCC skin tumors of SOCS3 mimetics, being able to inhibit the deleterious effects of IL-22 in these contexts.

  11. The Heterogeneity Between Lynch-Associated and Sporadic MMR Deficiency in Colorectal Cancers.

    PubMed

    Liu, Guo-Chen; Liu, Ran-Yi; Yan, Jun-Ping; An, Xin; Jiang, Wu; Ling, Yi-Hong; Chen, Jie-Wei; Bei, Jin-Xin; Zuo, Xiao-Yu; Cai, Mu-Yan; Liu, Ze-Xian; Zuo, Zhi-Xiang; Liu, Ji-Hong; Pan, Zhi-Zhong; Ding, Pei-Rong

    2018-02-20

    Previous studies demonstrated that prognosis of germline deficiency in mismatch repair protein (dMMR) was different from that of sporadic dMMR. The underlying mechanism has not been studied. From a prospectively maintained database, we collected dMMR colorectal cancer (CRC) patients identified by postoperative immunohistochemistry screening. According to genetic test, patients were grouped as Lynch-associated or sporadic dMMR. We compared the clinical-pathological features, prognosis, and immunoreactive differences between the two groups. By whole-exome sequencing and neoantigen detection pipeline, mutational frequencies and neoantigen burdens were also compared. All statistical tests were two-sided. Sixty-seven sporadic dMMR and 85 Lynch-associated CRC patients were included in the study. Sporadic dMMR patients were older (P < .001) and their tumors were poorly differentiated (P = .03). The survival was better in the Lynch-associated group (P = .001). After adjustment, the difference still remained statistically significant (hazard ratio = 0.29, 95% confidence interval = 0.09 to 0.95, P = .04). The scores of Crohn's-like reaction (CRO; P < .001), immunoreactions in the invasive margin (IM; P = .01), tumor stroma (TS; P = .009), and cancer nest (CN; P = .02) of the Lynch-associated group were statistically significantly higher. The numbers of CD3+, CD8+, Foxp3+ tumor-infiltrating lymphocytes (TILs) in IM; CD3+, CD4+ TILs in TS; and CD3+, CD4+, CD8+ TILs in CN were statistically significantly higher in Lynch-associated dMMR patients. Based on the 16 patients who under went whole-exome sequencing, there were also more somatic mutations and neoantigen burdens in the Lynch-associated group compared with the sporadic dMMR group (439/pt vs 68/pt, P = .006; 628/pt vs 97/pt, P = .009). There are heterogeneities in dMMR CRCs. Lynch-associated dMMR patients present with more somatic mutations and neoantigens compared with sporadic dMMR, which probably results in stronger

  12. Crown ether stereoisomerism: Implications in metal ion extraction and ionic liquid design

    NASA Astrophysics Data System (ADS)

    Pawlak, Alan J.

    Since their discovery more than four decades ago, crown ethers (CEs) have been the subject of intense investigation in a number of fields. Although many of the structural features that govern the behavior of these compounds have been thoroughly explored, the effect of their stereochemistry has received relatively little attention. In the present work, crown ether stereochemistry is shown to have important implications in both the design of ternary (i.e., three-component) ionic liquids (TILs) and metal ion extraction. Specifically, as a first step toward the development of guidelines for the rational design of ternary ionic liquids employing crown ethers as the neutral extractant, a systematic examination of the effect of crown ether stereochemistry (employing dicyclohexano-18-crown-6 (DCH18C6) as a representative crown compound), along with ring size, the nature and number of donor atoms, and the presence of functional groups, on the thermal properties (i.e., melting point or glass transition; decomposition or evaporation) of these compounds was carried out. Stereochemistry was found to have no appreciable impact on the onset temperature for mass loss. Rather, molecular weight and aromaticity were found to be more influential. Stereochemistry was, however, found to significantly affect the melting point of a TIL prepared from it; while the metal-CE formation constant, which varies with stereoisomer was observed to determine the onset temperature for mass loss of the TIL. To explore the implications of crown ether stereoisomerism in metal ion extraction, the formation constants for alkaline earth cation complexes with the isomers of DCH18C6 and selected stereoisomers of di-tert-butylcyclohexano-18-crown-6 (DtBuCH18C6) were measured. These values were found to vary inversely with the ligand strain (i.e., reorganizational) energy for the isomer, as determined by molecular mechanics calculations. Using this relationship (along with additional identification methods

  13. 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

  14. [Expression of DNA mismatch repair protein in endometrial carcinomas and its correlation with clinicopathologic features].

    PubMed

    Bi, R; Tu, X Y; Xiao, Y X; Shan, B E; Wang, H Y; Cai, X; Zhou, X Y; Yang, W T

    2016-05-08

    To study the expression of mismatch repair protein in a series of endometrial carcinomas and its correlation with clinicopathologic features. The clinical data of 150 consecutive cases of endometrial carcinoma were collected during the period from December, 2014 to August, 2015 in Fudan University Cancer Center. Morphologic features including tumor infiltrating lymphocytes (TIL), peritumoral lymphocytes and tumor heterogeneity were reviewed. Immunohistochemistry for expression of mismatch repair proteins was performed. The correlation with clinicopathologic features was analyzed. Loss of mismatch repair protein expression was observed in 43 cases (28.7%), including loss of MLH1/PMS2 in 27 cases (18%), loss of MSH2/MSH6 in 7 cases (4.7%), loss of MSH6 in 6 cases (4%) and loss of PMS2 in 3 cases (2%). There were 23.3% and 27.1% of mismatch repair protein-deficient endometrial carcinomas in women under and above 50 years of age, respectively, which was not statistically significant. Amongst the 12 cases with family history of tumors, 4 of the 6 mismatch repair protein-deficient cases were under 50 years of age, which was higher than that in the 6 cases with mismatch repair protein expression (P=0.014). The mismatch repair protein-deficient group showed significantly more prominent TIL and peritumoral lymphocytes than protein-expression group (P=0.033 and <0.001). Moreover, there were also significant differences in depth of myometrial invasion and occurrence of synchronous malignancy (2 cases of ovarian clear cell carcinoma and 1 case of colonic carcinoma) between the two groups (P=0.039 and 0.022). However, there were no significant differences in lymph node metastasis, tumor heterogeneity, lower uterine segment involvement and tumor stage between the two groups. Prominent TIL and peritumoral lymphocytes characteristically occur in mismatch repair protein-deficient endometrial carcinomas. Patient age does not significantly correlate with the loss of mismatch repair

  15. The combination of anti-KIR monoclonal antibodies with anti-PD-1/PD-L1 monoclonal antibodies could be a critical breakthrough in overcoming tumor immune escape in NSCLC.

    PubMed

    He, Yayi; Liu, Sangtian; Mattei, Jane; Bunn, Paul A; Zhou, Caicun; Chan, Daniel

    2018-01-01

    The anti-programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) monoclonal antibody has a good effect in the treatment of non-small cell lung cancer (NSCLC), but not all PD-1/PD-L1 positive patients can get benefit from it. Compensatory expression of other immune checkpoints may be correlated with the poor efficacy of anti-PD-1/PD-L1 monoclonal antibodies. The inhibitory human leukocyte antigen (HLA)/killer cell Ig-like receptor (KIR) can effectively block the killing effect of natural killer (NK) cells on tumors. Our previous studies have confirmed that high expression of KIR was correlated with poor prognosis of NSCLC. Inhibitory KIR expression was positively correlated with the expression of PD-1. The expressions of KIR 2D (L1, L3, L4, S4) (BC032422/ADQ31987/NP_002246/NP_036446, Abcam) and PD-1 (NAT 105, Cell marque) proteins was assessed by immunohistochemistry. The expression of inhibitory KIR in tumor cells or tumor infiltrating lymphocytes (TILs) is associated with PD-1 expression. Among PD-1 positive patients, 76.3% were KIR 2D (L1, L3, L4, S4) positive on tumor cells, and 74.6% were KIR 2D (L1, L3, L4, S4) positive on TILs. We compared the expression of inhibitory KIR before and after treatment with nivolumab in 11 patients with NSCLC. We found that five (45.5%) patients had positive expression of inhibitory KIR in tumor tissue after being treated with anti-PD-1 monoclonal antibodies, two of whom exhibited a significant increase in expression of inhibitory KIR, and three showed no change. PD-1 expression was correlated with KIR 2D (L1, L3, L4, S4) on tumor cells or TILs. The resistance to anti-PD-1 monoclonal antibody treatment might be related to KIR. The inhibitory HLA/KIR could combine with the PD-1/PD-L1 signaling pathway negatively regulating NSCLC tumor immunity.

  16. EGFR Mutations and ALK Rearrangements Are Associated with Low Response Rates to PD-1 Pathway Blockade in Non-Small Cell Lung Cancer: A Retrospective Analysis.

    PubMed

    Gainor, Justin F; Shaw, Alice T; Sequist, Lecia V; Fu, Xiujun; Azzoli, Christopher G; Piotrowska, Zofia; Huynh, Tiffany G; Zhao, Ling; Fulton, Linnea; Schultz, Katherine R; Howe, Emily; Farago, Anna F; Sullivan, Ryan J; Stone, James R; Digumarthy, Subba; Moran, Teresa; Hata, Aaron N; Yagi, Yukako; Yeap, Beow Y; Engelman, Jeffrey A; Mino-Kenudson, Mari

    2016-09-15

    PD-1 inhibitors are established agents in the management of non-small cell lung cancer (NSCLC); however, only a subset of patients derives clinical benefit. To determine the activity of PD-1/PD-L1 inhibitors within clinically relevant molecular subgroups, we retrospectively evaluated response patterns among EGFR-mutant, anaplastic lymphoma kinase (ALK)-positive, and EGFR wild-type/ALK-negative patients. We identified 58 patients treated with PD-1/PD-L1 inhibitors. Objective response rates (ORR) were assessed using RECIST v1.1. PD-L1 expression and CD8(+) tumor-infiltrating lymphocytes (TIL) were evaluated by IHC. Objective responses were observed in 1 of 28 (3.6%) EGFR-mutant or ALK-positive patients versus 7 of 30 (23.3%) EGFR wild-type and ALK-negative/unknown patients (P = 0.053). The ORR among never- or light- (≤10 pack years) smokers was 4.2% versus 20.6% among heavy smokers (P = 0.123). In an independent cohort of advanced EGFR-mutant (N = 68) and ALK-positive (N = 27) patients, PD-L1 expression was observed in 24%/16%/11% and 63%/47%/26% of pre-tyrosine kinase inhibitor (TKI) biopsies using cutoffs of ≥1%, ≥5%, and ≥50% tumor cell staining, respectively. Among EGFR-mutant patients with paired, pre- and post-TKI-resistant biopsies (N = 57), PD-L1 expression levels changed after resistance in 16 (28%) patients. Concurrent PD-L1 expression (≥5%) and high levels of CD8(+) TILs (grade ≥2) were observed in only 1 pretreatment (2.1%) and 5 resistant (11.6%) EGFR-mutant specimens and was not observed in any ALK-positive, pre- or post-TKI specimens. NSCLCs harboring EGFR mutations or ALK rearrangements are associated with low ORRs to PD-1/PD-L1 inhibitors. Low rates of concurrent PD-L1 expression and CD8(+) TILs within the tumor microenvironment may underlie these clinical observations. Clin Cancer Res; 22(18); 4585-93. ©2016 AACRSee related commentary by Gettinger and Politi, p. 4539. ©2016 American Association for Cancer Research.

  17. Abscopal Effects With Hypofractionated Schedules Extending Into the Effector Phase of the Tumor-Specific T-Cell Response.

    PubMed

    Zhang, Xuanwei; Niedermann, Gabriele

    2018-05-01

    Hypofractionated radiation therapy (hRT) combined with immune checkpoint blockade can induce T-cell-mediated local and abscopal antitumor effects. We had previously observed peak levels of tumor-infiltrating lymphocytes (TILs) between days 5 and 8 after hRT. Because TILs are regarded as radiosensitive, hRT schedules extending into this period might be less immunogenic, prompting us to compare clinically relevant, short and extended schedules with equivalent biologically effective doses combined with anti-programmed cell death 1 (PD1) antibody treatment. In mice bearing 2 B16-CD133 melanoma tumors, the primary tumor was irradiated with 3 × 9.18 Gy in 3 or 5 days or with 5 × 6.43 Gy in 10 days; an anti-PD1 antibody was given weekly. The mice were monitored for tumor growth and survival. T-cell responses were determined on days 8 and 15 of treatment. The role of regional lymph nodes was studied by administering FTY720, which blocks lymph node egress of activated T cells. Tumor growth measurements after combination treatment using short or extended hRT and control treatment were also performed in the wild-type B16 melanoma and 4T1 breast carcinoma models. In the B16-CD133 model, growth inhibition of irradiated primary and nonirradiated secondary tumors and overall survival were similar with all 3 hRT/anti-PD1 combinations, superior to hRT and anti-PD1 monotherapy, and was strongly dependent on CD8 + T cells. TIL infiltration and local and systemic tumor-specific CD8 + T-cell responses were also similar, regardless of whether short or extended hRT was used. Administration of FTY720 accelerated growth of both primary and secondary tumors, strongly reduced their TIL infiltration, and increased tumor-specific CD8 + T cells in the lymph nodes draining the irradiated tumor. In the 4T1 model, local and abscopal tumor control was also similar, regardless of whether short or extended hRT was used, although the synergy between hRT and anti-PD1 was weaker. No

  18. The United States Marine Corps in Cyberspace: Every Marine a Cyber Warrior

    DTIC Science & Technology

    2008-01-01

    information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and...maintaining the data needed, and completing and reviewing the collection of information. Send comments regarding this burden estimate or any other...TillS COLLECTION OF INFORMATION IS ESTIMATED TO AVERAGE I HOUR PER RESPONSE, INCWDING TIlE TIME FOR REVIEWING INSTRUCTIONS. SEARCHING E.’\\’lSTING

  19. An Exploration of Function Analysis and Function Allocation in the Commercial Flight Domain

    DTIC Science & Technology

    1991-11-01

    therefore, imperative that designers apply the most effective analytical methods available to optimize the baseline crew system design, prior to the test and...International Airport (LAX) to John F. Kennedy International Airport ( JFK ) in New York. This mission was also selected because a detailed task-timeline (TIL...International Airport (LAX) and terminating at New York International Airport ( JFK ). The weather at LAX is fair with temperature at 60° Fahrenheit

  20. New Bedford Harbor Superfund Project, Acushnet River Estuary Engineering Feasibility Study of Dredging and Dredged Material Disposal Alternatives. Report 11. Evaluation of Conceptual Dredging and Disposal Alternatives

    DTIC Science & Technology

    1989-07-01

    Y -- ma ma"o DIVIDENDS~~ 13ATUR -P 313ARM CORPS OF ENGINEERS A D z-. - N K 4 F~~ 1 /V. E C 7- GENERAL NOTES: - Soundtags are in fget a td t enths aid...usoAdter ine stae. Til %format ion depicted on these saps represents Ihq results of surveyjs made on the dates ihdica ted Ogu Ce on Iy .e Couasderedtas

  1. Translations on North Korea, Number 609, KULLOJA, Number 5, May 1978

    DTIC Science & Technology

    1978-08-14

    under tile roof. Supplying in greater quantities merchandise such as soft drinks, sugar, confection , roasted chestnuts, and also a variety of fruits...was hardly any commerce in foodstuffs worth mentioning. What there was then were Japanese merchants selling confection , and there were also some...been solved but minor necessities in their daily lite ^ucn s, and confection are not yet properly insured, leaving much to be desired in til

  2. Inhibition of tyrosine phenol-lyase by tyrosine homologues.

    PubMed

    Do, Quang; Nguyen, Giang T; Phillips, Robert S

    2016-09-01

    We have designed, synthesized, and evaluated tyrosine homologues and their O-methyl derivatives as potential inhibitors for tyrosine phenol lyase (TPL, E.C. 4.1.99.2). Recently, we reported that homologues of tryptophan are potent inhibitors of tryptophan indole-lyase (tryptophanase, TIL, E.C. 4.1.99.1), with K i values in the low µM range (Do et al. Arch Biochem Biophys 560:20-26, 2014). As the structure and mechanism for TPL is very similar to that of TIL, we postulated that tyrosine homologues could also be potent inhibitors of TPL. However, we have found that homotyrosine, bishomotyrosine, and their corresponding O-methyl derivatives are competitive inhibitors of TPL, which exhibit K i values in the range of 0.8-1.5 mM. Thus, these compounds are not potent inhibitors, but instead bind with affinities similar to common amino acids, such as phenylalanine or methionine. Pre-steady-state kinetic data were very similar for all compounds tested and demonstrated the formation of an equilibrating mixture of aldimine and quinonoid intermediates upon binding. Interestingly, we also observed a blue-shift for the absorbance peak of external aldimine complexes of all tyrosine homologues, suggesting possible strain at the active site due to accommodating the elongated side chains.

  3. 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.

  4. RECURRENT TWO-SIDED LOOP-TYPE JETS DUE TO A BIPOLE EMERGING BELOW TRANSEQUATORIAL LOOPS

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

    Jiang, Yunchun; Bi, Yi; Yang, Jiayan

    2013-10-01

    We report four successive two-sided loop-type jets centered around a small bipole emerging below transequatorial interconnecting loops (TILs). They occurred at the very first emerging stage of the bipole in a short recurrent period of only 12 minutes. During this term, the emerging flux consisted of a main bipole, but showed a mixed-polarity field morphology with the appearance and then disappearance of a small magnetic feature in its interior. However, no associated cancellation of the bipole with the nearby flux was observed in this process. In multi-wavelength EUV images, the jets started nearly simultaneously and were similar in appearance. Eachmore » jet consisted of a pair of components that connected to two bright footpoints around the bipole and were ejected from the emergence location to opposite directions. While the two bright footpoints were separated by a gap and had consistent evolution with that of the bipole, the jet base region covering them accordingly showed four episodes of emission enhancement that peaked approximately at the jet start times. Compatible with the magnetic-reconnection jet mechanism, the recurrent two-sided loop-type jets are explained as a result of reconnection between the emerging bipole and the overlying TILs.« less

  5. Thermophysical, Electrical, and Optical Properties of Selected Metal-Nonmetal Transition Materials: Comprehensive Bibliography with Typical Data.

    DTIC Science & Technology

    1978-02-01

    B.F., "High-Temperature Heat Contents of TiO, T12 03, Ti 30 5 , and TiO 2 ," J. Amer. Chem. Soc., 68, 1077-80, 1946. T006664. Vest, R.W., Griffel , M...Heats at Low Temperatures of Til, Ti20 3, Ti 305, and TiN," J. Amer. Chem. Soc., 68, 310-2, 1946. T008416. Vest, R.W., Griffel , M., and Smith, J.F., "Heat

  6. Synthesis of SYEP Plasticizer

    DTIC Science & Technology

    1975-10-01

    Decomposition of fluorodinitroethanol 15 — i<’*<<>mmtmmmmmmt^mm aoceie^s wW ** ^.^ -cUo. t^«t»-, « U.t a „«til reaction temperature U the...by formaldehyde make difficult to study this reaction quantitatively. Eplchlorohydrin homologues containing better leaving groups than chlorine ...dealt with study of reaction variables with emphasis of Im- proving the yield of l,3-blB(fluorodinltroethoxy)isopropanol, the key-inter- mediate, from

  7. Tumor infiltrating BRAFV600E-specific CD4 T cells correlated with complete clinical response in melanoma. | Office of Cancer Genomics

    Cancer.gov

    T cells specific for neoantigens encoded by mutated genes in cancers are increasingly recognized as mediators of tumor destruction after immune checkpoint inhibitor therapy or adoptive cell transfer. Unfortunately, most neoantigens result from random mutations and are patient specific, and some cancers contain few mutations to serve as potential antigens. We describe a patient with stage IV acral melanoma who obtained a complete response following adoptive transfer of tumor infiltrating lymphocytes (TIL).

  8. Functional Proteomics to Identify Moderators of CD8+ T-Cell Function in Melanoma

    DTIC Science & Technology

    2013-09-01

    could then be used to develop imaging agents that are targeted to the TILs. We used an M13 phage vector, which displays a pentavalent peptide as...of the identified transcript. To directly indentify inhibitory molecules, we have proposed to use phage - display expression libraries to perform...of TCD8. 3. To determine the ligands for molecules that can modulate the TCD8 functional state. Body: A. Phage Screen Summary Phage display

  9. A Procedure for Evaluating Subpotable Water Reuse Potential at Army Fixed Facilities.

    DTIC Science & Technology

    1981-11-01

    characteristic of phosphate waste waters from fume scrubbers. + Flue gas desulfurization sludge liquors. 75 Table B5 Base Housing Water Supply Quality (Also...ENGINEERING RESEARCH LABORATORY 4A762720A896-B-008 P.O. Box 4005, Champaign, IL 61820 1I. CONTROLLING OFFICE NAME AND ADDRESS 12. REPORT DATE November 1981 13...NUMBER OF PAGES 102 4. MONITORING AGENCY NAME & ADDRESS(If different from Controlling Office) IS. SECURITY CLASS. (of til, report) UNCLASSIFIED 15

  10. The Usefulness of Impact Dampers for Space Applications.

    DTIC Science & Technology

    1983-03-01

    5 ’DTIC ditfibutif’n is uni td . 14 1983 THDEPARTMENT OF THE AIR FORCER ’.’. AIR UNIVERSITY (ATC)FAIR FORCE INSTITUTE OF TECHNOLOGY TilES I W right...Laboratory with Important Parameters 88 -. . . . . . - 4.. X0 a >1 0 t 0.. 43 fqj 050i ONr 4*) flj $4 04 k5* 0 .0r 0V1: 5.4 0 4 (d P40 00 05 4.)v4 04

  11. Effect of Mass Flow on Stack Eductor Performance.

    DTIC Science & Technology

    1984-06-01

    absolute viscosity, lbf-sec/ft2 - density, Ibm/ft 3 "function of" ENGLISH LETTER SYMBOLS 2 A - area, in , ft B - atmospheric pressure, in Hg c - sonic... absolute temperature ratio T* - tertiary flow to primary flow absolute temperature t ratio - secondary -o primary mass flow rate ratio W* - tertiary to...secondary to primary absolute Tp temperature ratio TiL tertiary to primary absolute -TE temperature ratio secondary to primary flow density ratio

  12. 150 KVA Samarium Cobalt VSCF Starter Generator Electrical System

    DTIC Science & Technology

    1978-12-01

    also has protective circuits to limit damage to the system in evpnt tif failure. During normal operation , the system either starts up automatically when...determined during operation due to the external til loop . 4.2. 1. 1. 11 Temperature Sensor Four copper constantan thermocouples are located in stator...design and part of the vibration problem being experienced can be attributed to the shaft critical being too close to the top operating ,)eed range

  13. The Nozoe Autograph Books: "It ain't over 'til it's over".

    PubMed

    Seeman, Jeffrey I; Johnson, Brian P

    2015-02-01

    All are welcome! This issue contains the final of the 15 segments of the original Nozoe Autograph Books. But this project couldn't just stop here. A modern extension of the autograph books-a 16(th) segment-will be published and will include signatures from around today's chemistry community. All are welcome to participate and add their mark on the legacy of the Nozoe Autograph Books. See the Essay for details. This Essay and the interactive website that accompanies the Nozoe Autograph Book project are available free-access for at least a three-year period at http://www.tcr.wiley-vch.de/nozoe. Copyright © 2015 The Chemical Society of Japan and Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  14. Advanced TIL system for laser beam focusing in a turbulent regime

    NASA Astrophysics Data System (ADS)

    Sprangle, Phillip A.; Ting, Antonio C.; Kaganovich, Dmitry; Khizhnyak, Anatoliy I.; Tomov, Ivan V.; Markov, Vladimir B.; Korobkin, Dmitriy V.

    2014-10-01

    This paper discusses an advanced target in the loop (ATIL) system with its performance based on a nonlinear phase conjugation scheme that performs rapid adjustment of the laser beam wavefront to mitigate effects associated with atmospheric turbulence along the propagation path. The ATIL method allows positional control of the laser spot (the beacon) on a remote imaged-resolved target. The size of this beacon is governed by the reciprocity of two counterpropagating beams (one towards the target and another scattered by the target) and the fidelity of the phase conjugation scheme. In this presentation we will present the results of the thorough analysis of ATIL operation, factors that affect its performance, its focusing efficiency and the comparison of laboratory experimental validation and computer simulation results.

  15. Time to Procedure, Nuclear Imaging and Clinicopathological Characteristics as Predictive Factors for Sentinel Lymph Node Metastasis in Cutaneous Melanoma: A Single-Center Analysis.

    PubMed

    Jaukovic, Ljiljana; Rajović, Milica; Kandolf Sekulovic, Lidija; Radulovic, Marija; Stepic, Nenad; Mijuskovic, Zeljko; Petrov, Nenad; Ajdinovic, Boris

    2018-05-14

    Sentinel lymph node (SLN) biopsy is a widely accepted staging procedure for cutaneous melanoma patients who are at risk of clinically occult nodal metastases. Numerous predictive factors for regional lymph node metastases have been identified; however, few have been found to be reproducibly significant. Also, the role of blue dye in identification was questioned in recent trials. Time to procedure was also found to be predictive of SLN positivity, but this was not confirmed in other studies. In our study, predictive factors for metastatic involvement of SLN were analyzed, together with the role of addition blue dye in imaging on detection rate and false-negative SLN rate. An impact of time interval to procedure on the rate of SLN positivity was also explored. Data analysis was done in 362 cutaneous melanoma patients who underwent lymphoscintigraphy and SLN biopsy at our institution from 2010 to 2016, with a median follow-up of 29 months (1-98 months). To delineate the relation of each variable (demographical, time to procedure, and clinical and pathological variables, as well as the presence of in-transit nodes, the number of draining basins, and SLN localization on scintigraphy) with positive SLN status, we used univariate logistic regression with odds ratios representing effect size. Metastatic involvement SLN was found in 67 (18.8%) of 356 patients. Detection rate was similar with or without further intraoperative SLN identification with blue dye (98.8% vs 98.17%, P > 0.05). Time to procedure was not associated with higher SLN positivity rate (P > 0.05). In univariate analysis, Breslow thickness (P < 0.001), primary ulceration lesion (P = 0.001), and lymphovascular invasion (P = 0.006) were strongly correlated with SLN positivity, as well as the site of primary tumor (P = 0.024), tumor-infiltrating lymphocytes (TILs) (P = 0.021), and sex (P = 0.026). In multivariate analysis, Breslow thickness and TILs were found to be significant independent predictors of SLN

  16. Characteristic Changes in Decidual Gene Expression Signature in Spontaneous Term Parturition

    PubMed Central

    El-Azzamy, Haidy; Balogh, Andrea; Romero, Roberto; Xu, Yi; LaJeunesse, Christopher; Plazyo, Olesya; Xu, Zhonghui; Price, Theodore G.; Dong, Zhong; Tarca, Adi L.; Papp, Zoltan; Hassan, Sonia S.; Chaiworapongsa, Tinnakorn; Kim, Chong Jai; Gomez-Lopez, Nardhy; Than, Nandor Gabor

    2017-01-01

    Background The decidua has been implicated in the “terminal pathway” of human term parturition, which is characterized by the activation of pro-inflammatory pathways in gestational tissues. However, the transcriptomic changes in the decidua leading to terminal pathway activation have not been systematically explored. This study aimed to compare the decidual expression of developmental signaling and inflammation-related genes before and after spontaneous term labor in order to reveal their involvement in this process. Methods Chorioamniotic membranes were obtained from normal pregnant women who delivered at term with spontaneous labor (TIL, n = 14) or without labor (TNL, n = 15). Decidual cells were isolated from snap-frozen chorioamniotic membranes with laser microdissection. The expression of 46 genes involved in decidual development, sex steroid and prostaglandin signaling, as well as pro- and anti-inflammatory pathways, was analyzed using high-throughput quantitative real-time polymerase chain reaction (qRT-PCR). Chorioamniotic membrane sections were immunostained and then semi-quantified for five proteins, and immunoassays for three chemokines were performed on maternal plasma samples. Results The genes with the highest expression in the decidua at term gestation included insulin-like growth factor-binding protein 1 (IGFBP1), galectin-1 (LGALS1), and progestogen-associated endometrial protein (PAEP); the expression of estrogen receptor 1 (ESR1), homeobox A11 (HOXA11), interleukin 1β (IL1B), IL8, progesterone receptor membrane component 2 (PGRMC2), and prostaglandin E synthase (PTGES) was higher in TIL than in TNL cases; the expression of chemokine C-C motif ligand 2 (CCL2), CCL5, LGALS1, LGALS3, and PAEP was lower in TIL than in TNL cases; immunostaining confirmed qRT-PCR data for IL-8, CCL2, galectin-1, galectin-3, and PAEP; and no correlations between the decidual gene expression and the maternal plasma protein concentrations of CCL2, CCL5, and IL-8 were

  17. Clinically Relevant Cytotoxic Immune Cell Signatures and Clonal Expansion of T Cell Receptors in High-risk MYCN-not-amplified Human Neuroblastoma | Office of Cancer Genomics

    Cancer.gov

    Purpose: High-risk neuroblastoma is an aggressive disease. DNA sequencing studies have revealed a paucity of actionable genomic alterations and a low mutation burden, posing challenges to develop effective novel therapies. We used RNA sequencing (RNA-seq) to investigate the biology of this disease including a focus on tumor-infiltrating lymphocytes (TILs). Experimental Design: We performed deep RNA-seq on pre-treatment diagnostic tumors from 129 high-risk and 21 low- or intermediate-risk patients with neuroblastomas.

  18. Three-Dimensional Route Planning for a Cruise Missile for Minimal Detection by Observer

    DTIC Science & Technology

    1989-06-01

    detect the enemy’s weakest avenues of approach are needed. Such systems could also be used to identify our own deficiencies and allow for...vector-k (oval (line-segment-direction-vector (oval line-i))))) ( Tk2 (vector-k (eval (line-segment-direction-voctor (oval line-2))))) (Tval ’nil...zerop Tkl)) (not (zerop Tk2 ))) (setf Tval (/ Tkl Tk2 ))) (t (return-from parallel-lines ’nil))) (cond ((and (equal Til (* Tval Ti2)) (equal Tjl (* Tval

  19. Visual Perception of Elevation

    DTIC Science & Technology

    1992-01-20

    by bloe num r ) FIELD oOUP suB.O. ’Spatial localization, Pitch, Roll, Eve level, Visual Localizatiyn1 VPR, VPV, Perception,Focentri(i spatia ca...TIlEIPHONE NUMBER 22c. OFFICE SYMIO. Dr. John Tangney (202) 767-5021 AFOSR/N DO FORM 1473, 83 APR EDITION OF I JAN 73 I OBSOLETE. 19 SECURITY... Schermerhorn Hall New York, NY 10027 20 January 1992 Interim Report for Period 1 January 1991 - 31 December 1991 Unclassified Prepared for :i

  20. High-Output-Power Densities from MBE-grown n- and p-Type PbTeSe-based Thermoelectrics via Improved Contact Metallization

    DTIC Science & Technology

    2011-10-19

    is uncertain . . The results of these various studies seem consistent that the Fermi . level at the surface of PbTe or Pbi -xSnxTe is not inherently...Both sides: ~T=220"C n-type IS am P!!I~:Ii SE+l9 n++ 200 nm Til Device P=30W/cm2 1001!!!1 Pbi ~Se 3.5E+I8 a+ NDLS ISO am PI!I!::Bi SE+19 a++ 200nmNil

  1. Research on the precision measurement of super-low reflectivity

    NASA Astrophysics Data System (ADS)

    Yuan, Hao-yu; Lu, Zong-gui; Xia, Yan-wen; Peng, Zhi-tao; Liu, Hua; Xu, Long-bo; Sun, Zhi-hong; Tang, Jun

    2010-10-01

    Introduced a high-precision measurement of measured the super-low reflectivity and small sampling angle. Using single reflect way measured, and compare with re-swatch. Testing the reflectance of the sampling mirror which be used on TIL, and analyze the error. Research results indicate, the main factor which affect result is energy detector error and energy detector linearity. This methods is easy and have high-precision, it can be used to measure the super-low reflectivity sampling mirror reflectance.

  2. Daily Life Experience and Somatic Symptoms: A Preliminary Report.

    DTIC Science & Technology

    1981-03-01

    AAO7 9 859 STATE UNIV OF NEW YORK AT STONY BROOK FG 5/10 DAILY LIFE EXPERIENCE AND SOMATIC SYMPTOMS: A PRELIMINARY REPOR--ETC(U) MAR 8I A A STONE. J...Experience and Somatic Symptoms: A Preliminary Report Arthur A. Stone Long Island Research Institute and Department of Psychiatry arnd Behavioral...TITLE (and S..,til.) s. ALF - , rlA9OQ COVERED Daily Life Experience and Somatic Symptoms: A Technical p " Preliminary Report, EL..... S. PERFORMING

  3. MultiScheme: A Parallel Processing System Based on MIT (Massachusetts Institute of Technology) Scheme.

    DTIC Science & Technology

    1987-09-01

    Later, when these alloca- :t)il t rate(-ies beconme a p)erfornmance concern, the schieduler can be inolded 4 toN fit the p~ articular appllicationi... distracts attention from the more important points that this example is intended to demonstrate. The implementation, therefore, is described separately in...for the benefit of outsiders. From the object’s point of view the pipeline is nothing but a list of messages that tell it how to mutate its own state

  4. A chimeric switch-receptor targeting PD1 augments the efficacy of second generation CAR T-Cells in advanced solid tumors

    PubMed Central

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

    2015-01-01

    Chimeric antigen receptor (CAR)-modified adoptive T-cell therapy (ATC) 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 (TILs) by inhibitory receptors (IRs), 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 to 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. PMID:26979791

  5. 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.

  6. 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.

  7. 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.

  8. Immunohistochemical detection and correlation between MHC antigen and cell-mediated immune system in recurrent glioma by APAAP method.

    PubMed

    Miyagi, K; Ingram, M; Techy, G B; Jacques, D B; Freshwater, D B; Sheldon, H

    1990-09-01

    As part of an on-going clinical trial of immunotherapy for recurrent malignant gliomas, using alkaline phosphatase-anti-alkaline phosphatase method with monoclonal antibodies, we investigated the correlation between expression of the major histocompatibility complex (MHC) and the subpopulation of tumor-infiltrating lymphocytes (TILs) in 38 glioma specimens (20 grade IV, 11 grade III, and 7 grade II) from 33 patients. Thirty specimens (78.9%) were positive to class I MHC antigen and 20 (52.6%) were positive to class II MHC antigen. The correlations between class I MHC antigen expression and the number of infiltrating T8 (p less than 0.01), and also between class II MHC antigen expression and the number of infiltrating T4 (p less than 0.05) were significant. We conclude that TILs are the result of immunoreaction (host-defense mechanism). 31.6% of specimens had perivascular infiltration of T cells. The main infiltrating lymphocyte subset in moderate to marked perivascular cuffing was T4. Our results may indicate that lack of MHC antigen on the glioma cell surface has a share in the poor immunogenicity in glioma-bearing patients. In addition, considering the effector/target ratio, the number of infiltrating lymphocytes against glioma cells was too small, so the immunological intervention seems to be essential in glioma therapy. Previous radiation therapy and chemotherapy, including steroid therapy, did not influence lymphocyte and macrophage infiltration.

  9. A Software Planning and Development Methodology with Resource Allocation Capability

    DTIC Science & Technology

    1986-01-01

    vll ACKNOWLEDGEMENTS There are many people who must be acknowledged for the support they provided during my graduate program at Texas A&M Dr. Lee ...acquisition, research/development, and operations/ maintenance sources. The concept of a resource mm >^"^*»T’i»"<Wt"> i PH D« mm^ ivi i t-il^’lfn" i^ I...James, Unpublished ICAM Industry Days address. New Orleans, Louisiana, May 1982. IllllHUIIIIVf 127 46. Ledbetter , William N., et al., "Education

  10. Expeditionary Readiness Course Expansion Final Supplemental Environmental Assessment, Nevada Test and Training Range

    DTIC Science & Technology

    2010-09-01

    Mario Bermudez, Planning Manager Clark County Department of Comprehensive Planning...89191-7007 Mr. Mario Bermudez, Planning Manager Clark County Department of Comprehensive Planning P.O. Box 551744 Las Vegas, NV 89155 Dear Mr...hi ch no co ns tr uc tio n sh ou ld o cc ur . I t ta ke s a m in im um o f 74 d ay s fr om w he n eg gs a re l ai d un til c hi

  11. Overview of the Aerothermal Environment of Air-Launched Missiles.

    DTIC Science & Technology

    1981-12-01

    function of tinic of day. This tchnique has been verified by experiment .2 I Briefly. the method in- volves an energy balance between the solar...particularly di1- ficult to assign an accurate value to this parameter. The energy balance may be represented by the following equation: q m + aq + h(T - T...assuuicId frIlli hut til, ,implec ouc has prose ci adcquatc. 1𔃻C iiurul variation of solair radiation1. 11iffICIlt air temlperatuire. and xxinl spICcd

  12. FcγRIII in ITP: it ain't over 'til it's over.

    PubMed

    McCrae, Keith R

    2016-01-07

    In this issue of Blood, Yu et al describe a novel anti–Fcγ receptor III (FcγRIII)-albumin fusion protein that inhibits the development of thrombocytopenia in a murine model of immune thrombocytopenia (ITP).1 The unique aspect of this protein is that it blocks FcγRIII-mediated uptake of antibody-coated platelets without activating FcγRIII and the associated inflammatory response.

  13. 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…

  14. 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…

  15. CDK regulation of transcription by RNAP II: Not over 'til it's over?

    PubMed

    Fisher, Robert P

    2017-03-15

    Transcription by RNA polymerase (RNAP) II is regulated at multiple steps by phosphorylation, catalyzed mainly by members of the cyclin-dependent kinase (CDK) family. The CDKs involved in transcription have overlapping substrate specificities, but play largely non-redundant roles in coordinating gene expression. Novel functions and targets of CDKs have recently emerged at the end of the transcription cycle, when the primary transcript is cleaved, and in most cases polyadenylated, and transcription is terminated by the action of the "torpedo" exonuclease Xrn2, which is a CDK substrate. Collectively, various functions have been ascribed to CDKs or CDK-mediated phosphorylation: recruiting cleavage and polyadenylation factors, preventing premature termination within gene bodies while promoting efficient termination of full-length transcripts, and preventing extensive readthrough transcription into intergenic regions or neighboring genes. The assignment of precise functions to specific CDKs is still in progress, but recent advances suggest ways in which the CDK network and RNAP II machinery might cooperate to ensure timely exit from the transcription cycle.

  16. '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.

  17. Distributed Heterogeneous Simulation of a Hybrid-Electric Vehicle

    DTIC Science & Technology

    2006-03-29

    voltage dc bus via a fully controlled three-phase bridge converter. Also connc·:[uJ iu tilL UUS are the Lithium - ion battery bank, the ultra-capacitor...s~b~;~~~~·3 .... ! Lithium - Ion Battery Storage I _ .. ~:; Low-voltage Bus i I I] j i DC~ Converter ! -~~- ti~! 1 I --Ii! Battery i...devices in the propulsion system include the lithium - ion battery bank and the ultra-capacitor. Based on the range of the vehicle in the stealth model

  18. Discrete Analog Processing for Tracking and Guidance Control

    DTIC Science & Technology

    1980-11-01

    be called the multi- sample algorithm, satisfies -4 67 tD (Da - d) 0 (4.2.2.3) Thus, this descent algorithm will determine a coefficient vector a... flJ -TI:-* IS; 7" rR(VI Dr TH~I ("vFP)ALLCj TT$ C_ F 2C OH Til TPACK I! NC SYS TE ! f- 1I3 cc cc *’I cc. CC snUpcF FIL1j: C~T 01C 0 (1 cc CC OEJCT F I LF

  19. Air Force Global Weather Central System Architecture Study. Final System/Subsystem Summary Report. Volume 5. System Description

    DTIC Science & Technology

    1976-03-01

    ORGANIZATION AIR FORCE SYSTEMS COMMAND LOS ANGELES, CALIFORNIA 90009 339 /* nr ■■■■’ ■■ - -— MkteÄä^HlÜtilÜ • i T-^-’-^w^:—v-T^^-vwr-« -.— ^■.».,𔃾...NUMBER T CONTRACT OR CHANT NUMBER,«) F04701-75-C-0n4 9 PERFORMING ORGANIZATION NAM« AND ADDRESS SYSTEM DEVELOPMENT CORPORATION 2500 Colorado...22 Current AFGWC Organizational Structure 68 23 Operations Staff Organization 70 24 Satellite Data Processing Branch Organization 71 25 Data

  20. Image Segmentation Using Affine Wavelets

    DTIC Science & Technology

    1991-12-12

    accomplished by tile the matrixtoascii. c prograimi. TIl’ i’ rlage file is theim processed by the wave2 prograli which u ilizes MaIllat’s algo- 5-2 CLASS...1024 feet Figure 5.3. Frequency Content of Multiresolution Levels rithm. Details of the wave2 program can be found in the Appendix. One of the resulting...which comprise the wave2 program. 1. mainswave.c - The main driver program for wave. 2. loadimage.c - A routine to load the input image from an ascii

  1. Cytoplasmic expression of C-MYC protein is associated with risk stratification of mantle cell lymphoma.

    PubMed

    Gong, Yi; Zhang, Xi; Chen, Rui; Wei, Yan; Zou, Zhongmin; Chen, Xinghua

    2017-01-01

    To investigate the association of C-MYC protein expression and risk stratification in mantle cell lymphoma (MCL), and to evaluate the utility of C-MYC protein as a prognostic biomarker in clinical practice. We conducted immunohistochemical staining of C-MYC, Programmed cell death ligand 1 (PD-L1), CD8, Ki-67, p53 and SRY (sex determining region Y) -11 (SOX11) to investigate their expression in 64 patients with MCL. The staining results and other clinical data were evaluated for their roles in risk stratification of MCL cases using ANOVA, Chi-square, and Spearman's Rank correlation coefficient analysis. Immunohistochemical staining in our study indicated that SOX11, Ki-67 and p53 presented nuclear positivity of tumor cells, CD8 showed membrane positivity in infiltrating T lymphocytes while PD-L1 showed membrane and cytoplasmic positivity mainly in macrophage cells and little in tumor cells. We observed positive staining of C-MYC either in the nucleus or cytoplasm or in both subcellular locations. There were significant differences in cytoplasmic C-MYC expression, Ki-67 proliferative index of tumor cells, and CD8 positive tumor infiltrating lymphocytes (CD8+TIL) among three risk groups ( P  = 0.000, P  = 0.037 and P =0.020, respectively). However, no significant differences existed in the expression of nuclear C-MYC, SOX11, p53, and PD-L1 in MCL patients with low-, intermediate-, and high risks. In addition, patient age and serum LDH level were also significantly different among 3 groups of patients ( P  = 0.006 and P  = 0.000, respectively). Spearman's rank correlation coefficient analysis indicated that cytoplasmic C-MYC expression, Ki-67 index, age, WBC, as well as LDH level had significantly positive correlations with risk stratification ( P  = 0.000, 0.015, 0.000, 0.029 and 0.000, respectively), while CD8+TIL in tumor microenvironment negatively correlated with risk stratification of patients ( P  = 0.006). Patients with increased positive

  2. Preclinical efficacy of immune-checkpoint monotherapy does not recapitulate corresponding biomarkers-based clinical predictions in glioblastoma

    PubMed Central

    Vandenberk, Lien; Van Woensel, Matthias; Schaaf, Marco; De Vleeschouwer, Steven; Agostinis, Patrizia

    2017-01-01

    ABSTRACT Glioblastoma (GBM) is resistant to most multimodal therapies. Clinical success of immune-checkpoint inhibitors (ICIs) has spurred interest in applying ICIs targeting CTLA4, PD1 or IDO1 against GBM. This amplifies the need to ascertain GBM's intrinsic susceptibility (or resistance) toward these ICIs, through clinical biomarkers that may also “guide and prioritize” preclinical testing. Here, we interrogated the TCGA and/or REMBRANDT human patient-cohorts to predict GBM's predisposition toward ICIs. We exploited various broad clinical biomarkers, including mutational or predicted-neoantigen burden, pre-existing or basal levels of tumor-infiltrating T lymphocytes (TILs), differential expression of immune-checkpoints within the tumor and their correlation with particular TILs/Treg-associated functional signature and prognostic impact of differential immune-checkpoint expression. Based on these analyses, we found that predictive biomarkers of ICI responsiveness exhibited inconsistent patterns in GBM patients, i.e., they either predicted ICI resistance (as compared with typical ICI-responsive cancer-types like melanoma, lung cancer or bladder cancer) or susceptibility to therapeutic targeting of CTLA4 or IDO1. On the other hand, our comprehensive literature meta-analysis and preclinical testing of ICIs using an orthotopic GL261-glioma mice model, indicated significant antitumor properties of anti-PD1 antibody, whereas blockade of IDO1 or CTLA4 either failed or provided very marginal advantage. These trends raise the need to better assess the applicability of ICIs and associated biomarkers for GBM. PMID:28507806

  3. 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

  4. High Static Stability in the Mixed Layer Above the Extratropical Tropopause

    NASA Astrophysics Data System (ADS)

    Kunz, A.; Konopka, P.; Müller, R.; Schiller, C.

    2008-12-01

    A strong relationship between the static stability N2 and the strength of mixing in the mixed layer above the extratropical tropopause is evident from in-situ data observed during the SPURT aircraft campaigns. We present a method for quantifying the strength of mixing from O3/CO tracer correlations and we find that N2 is positively correlated with the strength of mixing. Age of air simulations with the CLaMS model reveal two different types of mixed regions. One type consisting of older airmasses with higher values of N2 which are created by radiative adjustment after a mixing event. These airmasses are within the TIL (Tropopause Inversion Layer), considering the TIL as part of the mixing layer. The second type comprises younger airmasses with somehow lower stratospheric N2 values within the mixing layer, because of recent intrusion processes due to the permeability or so-called mid-latitude-breaks associated with the jet stream. With the help of radiative transfer calculations we simulate the influence of trace gases such as O3 and H2O on the temperature gradient and thus on the static stability above the tropopause in the idealized case of non-mixing (L-shape) O3 and H2O profiles and in the reference case of mixed profiles. Within the altitude range of the SPURT campaigns the mean vertical SPURT profiles are used as reference, which are fitted to the HALOE climatological profiles above the UT/LS.

  5. Comparison of Q-switched Nd:YAG laser alone versus its combination with ultrapulse CO2 laser for the treatment of black tattoo.

    PubMed

    Vanarase, Mithila; Gautam, Ram Krishan; Arora, Pooja; Bajaj, Sonali; Meena, Neha; Khurana, Ananta

    2017-10-01

    Q-switched lasers are conventionally used for the treatment of black tattoo. However, they require multiple sittings, and the response may be slow due to competing epidermal pigment in dark skin. To compare the efficacy of Q-switched Nd:YAG laser alone with its combination with ultrapulse CO 2 for the removal of black tattoo. Sixty patients with black tattoo were randomized into two groups viz., group A and group B. Group A was treated with QS Nd:YAG laser (1064 nm) alone, and group B received combination of ablative ultrapulse CO 2 followed by fixed-dose QS Nd:YAG laser (1064 nm), at 6-week interval for a maximum of 6 sittings. After each sitting, 3 independent physicians noted percentage of improvement that was evaluated using visual analogue scale (VAS) and grading system for tattoo ink lightening (TIL). Combination laser (group B) showed statistically significant improvement in mean VAS score in the last 2 noted visits as compared to 1st session (p < 0.007, p < 0.001) and TIL mean score in last three noted visits as compared to 1st session (p < 0.008, p < 0.020, and p < 0.004). There was no statistically significant difference in the side effect profile of both the groups. For refractory professional tattoos, combination of ultrapulse CO 2 laser and QS Nd:YAG laser is superior to QS Nd:YAG laser alone.

  6. Microbial Forensics for Natural and Intentional Incidents of Infectious Disease Involving Animals

    DTIC Science & Technology

    2006-01-01

    Microbiologie medico-legale. ~ Microbiologia foren~e para ca£J~s de erderm®rdJ©lrdJ®$ DlTil~®©©D@$©l$ d® origen natural o intenciorm~d(il qa.u~ tEl~~ct...ll1 iBl ©lll1Dm©l~®$ S.A. McEwen, T.M Wilson, D.A. Ashford, E. D. Heegaard, T. Kuiken & B. Kournikakis Resumen La microbiologia forense es una... microbiologia y epidemiologia tradicionales, pero opera dentro de un marco juridico especifico. Entre las importantes razones que motivan una

  7. Department of the Air Force Justification of Estimates for Fiscal Year 1986 Submitted to Congress February 1985. Aircraft Procurement, Air Force

    DTIC Science & Technology

    1985-02-01

    air-to-grurod cruise missile planned for use c-i the bomber force. IAs one of the zany i,,eapons iu the manned tmorer’s arsenal, t.L AO’ stresses the...29.4 78.4 SPX Cuminication Replacent 8.9 - - tIL OIR PRO•XUJfIN C&X4 ES 1413.3 1877.4 2683.7 3382.3 i ," / Justification for the various line items is...COntROL SYSTEMS DJE TO THE STRESS CORROSION CRACKING TiAT DEVELOPS. THI$ MODIFICATION REPLACES ThE MAGNESIUM COMPONENTS IN THE FLIGHT CONTROL SYSTEM WITH

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

    Chimonas, G.

    We consider the motion of a sporadic E layer initially located at the top of the E region near the node of the north-south component of the tidal wind. We find that, as the layer descends to follow the phase progression of the winds, the relative enhancement of the importance of the cast-west wind component can erode the layer trapping mechanisms til at some instant it fails, and the layer is freed. Thereupon it moves with a much greater vertical velocity than it did formerly until it reaches a new trapping location. (auth)

  9. Methodology Investigation. Chamber Versus Environmental Deterioration Tests

    DTIC Science & Technology

    1979-01-01

    instructions do not apply to the record copy (AR 340-18). UNCLASSIFIED S.CURITY CLASSIFICATION OF I HIS PAGE ("eiln Daoe FKnterpd) I PAGE READ INSTRUCTIONS...D 4 - from P. Pin F 0-0 Figure 14 ->TIL 302 TL3 * 10 I , C 1:1 FiL r 16. Diia0lcto i yt m c e- t 1C 234 -.>11- tandem. The binary coded decimal ...Mexico State University and/or the University I of Texas at El Paso will be contracted to assist in this investigation by performing detailed, time

  10. Fake It 'Til You Make It: Pressures to Measure Up in Surgical Training.

    PubMed

    Patel, Priyanka; Martimianakis, Maria A; Zilbert, Nathan R; Mui, Carween; Hammond Mobilio, Melanie; Kitto, Simon; Moulton, Carol-Anne

    2018-05-01

    Expectations of certainty and confidence in surgical culture are a source of internal conflict for surgeons and learners, with surgeons describing a pressure to project an image that is, at times, inconsistent with how they feel internally. The authors explored surgical residents' perceptions of "impression management" and its effects on surgical judgment and decision making. The authors used a constructivist grounded theory approach to conduct and analyze 15 semistructured interviews with general surgery trainees at an urban Canadian academic health center between 2012 and 2014. Interviews explored impression management in the context of resident learning and performance. Analysis was inductive, whereby emergent themes contributed to a developing conceptual framework, and deductive, using an existing theory of impression management. Residents described sensing an "expectation" to portray an image aligned with the ideal surgical stereotype of confidence and certainty, and shared strategies used to mirror this image. Impression management strategies were used to portray an image of competence, with the aim to improve access to teaching and evaluations. Unintended consequences of impression management on decision making, patient safety, and resident wellness were identified. These findings contribute to a deeper understanding of the potential impact of the sociocultural context on residency training, and provide a language allowing for more explicit discussions about the impact of surgical culture on trainee behaviors. Translation includes formal instruction of these concepts in the curriculum so that trainees better recognize, reflect on, and cope with the pressures to perform in front of others.

  11. ''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…

  12. It Ain't Over 'til It's Over: An Exercise for Concluding a Course.

    ERIC Educational Resources Information Center

    Newman, David M.

    1992-01-01

    Describes an exercise for the last day of class that provides a sense of closure to the course. Explains that the instructor discusses major themes of the course, then evaluates his perfornamce along with the students'. Includes questions that students answer: what they will remember most about the class, and one thing they learned. (DK)

  13. If You Love Me in the Fall, Will You Keep Me 'til Spring?

    ERIC Educational Resources Information Center

    Jackson, Audrey

    1977-01-01

    A fifth-grade teacher in Kansas City, Missouri, wanted volunteers in her classroom--to help her individualize instruction, work with students who have emotional problems, and allow her more time to plan her instruction. But when two adults volunteered to help, she couldn't think of anything specific for them to do. Here are suggestions for…

  14. CDK regulation of transcription by RNAP II: Not over ‘til it's over?

    PubMed Central

    Fisher, Robert P.

    2017-01-01

    ABSTRACT Transcription by RNA polymerase (RNAP) II is regulated at multiple steps by phosphorylation, catalyzed mainly by members of the cyclin-dependent kinase (CDK) family. The CDKs involved in transcription have overlapping substrate specificities, but play largely non-redundant roles in coordinating gene expression. Novel functions and targets of CDKs have recently emerged at the end of the transcription cycle, when the primary transcript is cleaved, and in most cases polyadenylated, and transcription is terminated by the action of the “torpedo” exonuclease Xrn2, which is a CDK substrate. Collectively, various functions have been ascribed to CDKs or CDK-mediated phosphorylation: recruiting cleavage and polyadenylation factors, preventing premature termination within gene bodies while promoting efficient termination of full-length transcripts, and preventing extensive readthrough transcription into intergenic regions or neighboring genes. The assignment of precise functions to specific CDKs is still in progress, but recent advances suggest ways in which the CDK network and RNAP II machinery might cooperate to ensure timely exit from the transcription cycle. PMID:28005463

  15. Adoptive Cell Therapy for Patients With Metastatic Melanoma: Evaluation of Intensive Myeloablative Chemoradiation Preparative Regimens

    PubMed Central

    Dudley, Mark E.; Yang, James C.; Sherry, Richard; Hughes, Marybeth S.; Royal, Richard; Kammula, Udai; Robbins, Paul F.; Huang, JianPing; Citrin, Deborah E.; Leitman, Susan F.; Wunderlich, John; Restifo, Nicholas P.; Thomasian, Armen; Downey, Stephanie G.; Smith, Franz O.; Klapper, Jacob; Morton, Kathleen; Laurencot, Carolyn; White, Donald E.; Rosenberg, Steven A.

    2008-01-01

    Purpose The two approved treatments for patients with metastatic melanoma, interleukin (IL)-2 and dacarbazine, mediate objective response rates of 12% to 15%. We previously reported that adoptive cell therapy (ACT) with autologous antitumor lymphocytes in lymphodepleted hosts mediated objective responses in 51% of 35 patients. Here, we update that study and evaluate the safety and efficacy of two increased-intensity myeloablative lymphodepleting regimens. Patients and Methods We performed two additional sequential trials of ACT with autologous tumor-infiltrating lymphocytes (TIL) in patients with metastatic melanoma. Increasing intensity of host preparative lymphodepletion consisting of cyclophosphamide and fludarabine with either 2 (25 patients) or 12 Gy (25 patients) of total-body irradiation (TBI) was administered before cell transfer. Objective response rates by Response Evaluation Criteria in Solid Tumors (RECIST) and survival were evaluated. Immunologic correlates of effective treatment were studied. Results Although nonmyeloablative chemotherapy alone showed an objective response rate of 49%, when 2 or 12 Gy of TBI was added, the response rates were 52% and 72% respectively. Responses were seen in all visceral sites including brain. There was one treatment-related death in the 93 patients. Host lymphodepletion was associated with increased serum levels of the lymphocyte homeostatic cytokines IL-7 and IL-15. Objective responses were correlated with the telomere length of the transferred cells. Conclusion Host lymphodepletion followed by autologous TIL transfer and IL-2 results in objective response rates of 50% to 70% in patients with metastatic melanoma refractory to standard therapies. PMID:18809613

  16. 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.

  17. A global view of the extratropical tropopause transition layer from Atmospheric Chemistry Experiment Fourier Transform Spectrometer O3, H2O, and CO

    NASA Astrophysics Data System (ADS)

    Hegglin, M. I.; Boone, C. D.; Manney, G. L.; Walker, K. A.

    2009-04-01

    The global behavior of the extratropical tropopause transition layer (ExTL) is investigated using O3, H2O, and CO measurements from the Atmospheric Chemistry Experiment Fourier Transform Spectrometer (ACE-FTS) on Canada's SCISAT-1 satellite obtained between February 2004 and May 2007. The ExTL depth is derived using H2O-O3 and CO-O3 correlations. The ExTL top derived from H2O-O3 shows an increase from roughly 1-1.5 km above the thermal tropopause in the subtropics to 3-4 km (2.5-3.5 km) in the north (south) polar region, implying somewhat weaker troposphere-stratosphere-transport in the Southern Hemisphere. The ExTL bottom extends ˜1 km below the thermal tropopause, indicating a persistent stratospheric influence on the troposphere at all latitudes. The ExTL top derived from the CO-O3 correlation is lower, at 2 km or ˜345 K (1.5 km or ˜335 K) in the Northern (Southern) Hemisphere. Its annual mean coincides with the relative temperature maximum just above the thermal tropopause. The vertical CO gradient maximizes at the thermal tropopause, indicating a local minimum in mixing within the tropopause region. The seasonal changes in and the scales of the vertical H2O gradients show a similar pattern as the static stability structure of the tropopause inversion layer (TIL), which provides observational support for the hypothesis that H2O plays a radiative role in forcing and maintaining the structure of the TIL.

  18. Immune Consequences of Decreasing Tumor Vasculature with Antiangiogenic Tyrosine Kinase Inhibitors in Combination with Therapeutic Vaccines

    PubMed Central

    Farsaci, Benedetto; Donahue, Renee N.; Coplin, Michael A.; Grenga, Italia; Lepone, Lauren M.; Molinolo, Alfredo A.; Hodge, James W.

    2014-01-01

    This study investigated the effects on the tumor microenvironment of combining antiangiogenic tyrosine kinase inhibitors (TKI) with therapeutic vaccines, and in particular, how vascular changes affect tumor-infiltrating immune cells. We conducted studies using a TKI (sunitinib or sorafenib) in combination with recombinant vaccines in 2 murine tumor models: colon carcinoma (MC38-CEA) and breast cancer (4T1). Tumor vasculature was measured by immunohistochemistry using 3 endothelial cell markers: CD31 (mature), CD105 (immature/proliferating), and CD11b (monocytic). We assessed oxygenation, tight junctions, compactness, and pressure within tumors, along with the frequency and phenotype of tumor-infiltrating T lymphocytes (TIL), myeloid-derived suppressor cells (MDSC), and tumor-associated macrophages (TAM) following treatment with antiangiogenic TKIs alone, vaccine alone, or the combination of a TKI with vaccine. The combined regimen decreased tumor vasculature, compactness, tight junctions, and pressure, leading to vascular normalization and increased tumor oxygenation. This combination therapy also increased TILs, including tumor antigen-specific CD8 T cells, and elevated the expression of activation markers FAS-L, CXCL-9, CD31, and CD105 in MDSCs and TAMs, leading to reduced tumor volumes and an increase in the number of tumor-free animals. The improved antitumor activity induced by combining antiangiogenic TKIs with vaccine may be the result of activated lymphoid and myeloid cells in the tumor microenvironment, resulting from vascular normalization, decreased tumor-cell density, and the consequent improvement in vascular perfusion and oxygenation. Therapies that alter tumor architecture can thus have a dramatic impact on the effectiveness of cancer immunotherapy. PMID:25092771

  19. A Co-Receptor Independent Transgenic Human TCR Mediates Anti-Tumor and Anti-Self Immunity in Mice

    PubMed Central

    Mehrotra, Shikhar; Al-Khami, Amir A.; Klarquist, Jared; Husain, Shahid; Naga, Osama; Eby, Jonathan M.; Murali, Anuradha K.; Lyons, Gretchen E.; Li, Mingli; Spivey, Natali D.; Norell, Håkan; Martins da Palma, Telma; Onicescu, Georgiana; Diaz-Montero, C. Marcela; Garrett-Mayer, Elizabeth; Cole, David J.; Le Poole, I. Caroline; Nishimura, Michael I.

    2013-01-01

    Recent advancements in T cell immunotherapy suggest that T cells engineered with high affinity T cell receptors (TCR) can offer better tumor regression. However, whether a high affinity TCR alone is sufficient to control tumor growth, or the T cell subset bearing the TCR is also important remains unclear. Using the human tyrosinase epitope reactive, CD8 independent, high affinity TCR isolated from MHC class-I restricted CD4+ T cells obtained from tumor infiltrating lymphocytes of a metastatic melanoma patient, we developed a novel TCR transgenic mouse with a C57BL/6 background. This HLA-A2 restricted TCR was positively selected on both CD4+ and CD8+ single-positive (SP) cells. However, when the TCR transgenic mouse was developed with an HLA-A2 background, the transgenic TCR was primarily expressed by CD3+CD4-CD8- double-negative (DN) T cells. TIL 1383I TCR transgenic CD4+, CD8+ and CD4-CD8- T cells were functional and retained the ability to control tumor growth without the need for vaccination or cytokine support in vivo. Furthermore, the HLA-A2+/human tyrosinase TCR double transgenic mice developed spontaneous hair depigmentation and had visual defects that progressed with age. Our data show that the expression of the high affinity TIL 1383I TCR alone in CD3+ T cells is sufficient to control the growth of murine and human melanoma and the presence or absence of CD4 and CD8 co-receptors had little effect on its functional capacity. PMID:22798675

  20. [Color stability of porcelain-fused-to-titanium restorations after repeated firings].

    PubMed

    Wu, Xiao-min; Zhou, Zheng

    2004-08-01

    To study the effect of repeated firings on color of porcelain-fused-to-titanium restorations. Twenty standard porcelain-fused-to-titanium specimens were made with Dentsply DETREY TiBond C3 and Dentaurum rematitan Til. Then they were fired 1, 2, 4, 7, and 10 times. Color measurement was done after each firing. Most of the color parameters had no significant difference after firing except for a* and Hab. All the color difference among groups were smaller than 1.0 (deltaE < 1.0). Repeated firings will not affect the color stability of porcelain-fused-to-titanium restorations.

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

    NEMO Collaboration

    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.

  2. Recursive Definitions of Partial Functions and Their Computations

    DTIC Science & Technology

    1972-03-01

    standard simplifications of -’ terminate with the same term, which must be -/,. n Ncv, by the ptvvi’ius Lemna , wo kiuiw that tlu-re...Til »*ft<p»ubit (er,) (f»I Fsubst [aj (f,f)) by Lemna 5.2.2 of Chapter % *lKt,’ ^(ft«l,|H’-»9n(M«.f) ) • On the other hand; ¥^.f’,V...ly{f ,T) is in ^ and if if is not in A it must T must be a’. To prove (1)| we first noru that If the computation terminates with a, Lemna

  3. Installation Restoration Program Information Management System (IRPIMS) Data Loading Handbook. Version 2.1

    DTIC Science & Technology

    1989-09-01

    STEEL STL STEEL TFL TEFLON TIL TILE WD WOOD WRI WROUGHT IRON Z OTHER A-14 coam Bc~ai=L a TEST PIT ois rn iEI AR AIR - ROTARY 8 BORED OR AUGERED C CABLE-TOOL...CO CORING Cs CHILLED SHOT D DUG DH DOWN THE HOLE HAMMER HA HAND AUGERED HS HOLLOW STEM AUGER J JETTED MR DIRECT CIRCULATION ROTARY , MUD p AIR ...INSTITUTE WARI WATER AND AIR RESEARCH. INC. WIL WILSON AND CO. A-18 M 0E 7 PIT E V/n.. CK: N’Y ESCI ENGINEERING -SCIENCE NA NOT APPLICABLE RB MR

  4. A Study of Mechanical Alloying of Metal Powders

    DTIC Science & Technology

    1981-05-01

    UYON STAYt~ENT (d ida .... Approved for public release, distribution unlimited -𔄁. "’ I’ T PJIu TIO N IT A T EMT• ( ofe~ • e ao . m .. M•A 2-9, If...RELATIVE INTENSITY OF TIlE (1i1) BRAGG REFLECTION, 316 STAINLESS STEEL ,. 2.5 w/o Ti02 POWDER MILLED 98 HOURS AT 300 RPM...micrograph. 316.2.5 w/o Ti02 milled at 󈨋 300 RPM. Annealed 1.5 hours at 11000C. 30. Micrographs, iron - 10 w/o TiO2 milled 64 hours 72 at 300 RIh

  5. 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.

  6. Evidence of preorganization in quinonoid intermediate formation from L-Trp in H463F mutant Escherichia coli tryptophan indole-lyase from effects of pressure and pH.

    PubMed

    Phillips, Robert S; Kalu, Ukoha; Hay, Sam

    2012-08-21

    The effects of pH and hydrostatic pressure on the reaction of H463F tryptophan indole-lyase (TIL) have been evaluated. The mutant TIL shows very low activity for elimination of indole but is still competent to form a quinonoid intermediate from l-tryptophan [Phillips, R. S., Johnson, N., and Kamath, A. V. (2002) Biochemistry 41, 4012-4019]. Stopped-flow measurements show that the formation of the quinonoid intermediate at 505 nm is affected by pH, with a bell-shaped dependence for the forward rate constant, k(f), and dependence on a single basic group for the reverse rate constant, k(r), with the following values: pK(a1) = 8.14 ± 0.15, pK(a2) = 7.54 ± 0.15, k(f,min) = 18.1 ± 1.3 s(-1), k(f,max) = 179 ± 46.3 s(-1), k(r,min) = 11.4 ± 1.2 s(-1), and k(r,max) = 33 ± 1.6 s(-1). The pH effects may be due to ionization of Tyr74 as the base and Cys298 as the acid influencing the rate constant for deprotonation. High-pressure stopped-flow measurements were performed at pH 8, which is the optimum for the forward reaction. The rate constants show an increase with pressure up to 100 MPa and a subsequent decrease above 100 MPa. Fitting the pressure data gives the following values: k(f,0) = 15.4 ± 0.8 s(-1), ΔV(‡) = -29.4 ± 2.9 cm(3) mol(-1), and Δβ(‡) = -0.23 ± 0.03 cm(3) mol(-1) MPa(-1) for the forward reaction, and k(r,0) = 20.7 ± 0.8 s(-1), ΔV(‡) = -9.6 ± 2.3 cm(3) mol(-1), and Δβ(‡) = -0.05 ± 0.02 cm(3) mol(-1) MPa(-1) for the reverse reaction. The primary kinetic isotope effect on quinonoid intermediate formation at pH 8 is small (~2) and is not significantly pressure-dependent, suggesting that the effect of pressure on k(f) may be due to perturbation of an active site preorganization step. The negative activation volume is also consistent with preorganization of the ES complex prior to quinonoid intermediate formation, and the negative compressibility may be due to the effect of pressure on the enzyme conformation. These results support the

  7. Impaired Tumor-infiltrating T Cells in Patients with COPD Impacts Lung Cancer Response to PD-1 Blockade.

    PubMed

    Biton, Jérôme; Ouakrim, Hanane; Dechartres, Agnès; Alifano, Marco; Mansuet-Lupo, Audrey; Si, Han; Halpin, Rebecca; Creasy, Todd; Bantsimba-Malanda, Claudie; Arrondeau, Jennifer; Goldwasser, François; Boudou-Rouquette, Pascaline; Fournel, Ludovic; Roche, Nicolas; Burgel, Pierre-Régis; Goc, Jeremy; Devi-Marulkar, Priyanka; Germain, Claire; Dieu-Nosjean, Marie-Caroline; Cremer, Isabelle; Herbst, Ronald; Damotte, Diane

    2018-03-08

    Patients with chronic obstructive pulmonary disease (COPD) have a higher prevalence of lung cancer. The chronic inflammation associated with COPD probably promotes the earliest stages of carcinogenesis. However, once tumors have progressed to malignancy, the impact of COPD on the tumor immune microenvironment remains poorly defined, and its effects on immune-checkpoint blockers' efficacy are still unknown. To study the impact of COPD on the immune contexture of non-small cell lung cancer (NSCLC). We performed in depth immune profiling of lung tumors by immunohistochemistry and we determined its impact on patients' survival (n=435). Tumor-infiltrating T lymphocyte (TILs) exhaustion by flow cytometry (n=50) was also investigated. The effectiveness of an anti-PD-1 treatment (nivolumab) was evaluated in 39 advanced-stage NSCLC patients. All data were analyzed according to patients' COPD status. Measurments and Main Results: Remarkably, COPD severity is positively correlated with the coexpression of PD-1/TIM-3 by CD8 T cells. In agreement, we observed a loss of CD8 T cell-associated favorable clinical outcome in COPD+ patients. Interestingly, a negative prognostic value of PD-L1 expression by tumor cells was observed only in highly CD8 T cell-infiltrated tumors of COPD+ patients. Finally, data obtained on 39 advanced-stage NSCLC patients treated by an anti-PD-1 antibody showed longer progression free survival in COPD+ patients, and also that the association between the severity of smoking and the response to nivolumab was preferentially observed in COPD+ patients. COPD is associated with an increased sensitivity of CD8 TILs to immune escape mechanisms developed by tumors, thus suggesting a higher sensitivity to PD-1 blockade in patients with COPD.

  8. Induced pluripotent stem cells: challenges and opportunities for cancer immunotherapy.

    PubMed

    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.

  9. Immune complexome analysis reveals the specific and frequent presence of immune complex antigens in lung cancer patients: A pilot study.

    PubMed

    Ohyama, Kaname; Yoshimi, Haruka; Aibara, Nozomi; Nakamura, Yoichi; Miyata, Yasuyoshi; Sakai, Hideki; Fujita, Fumihiko; Imaizumi, Yoshitaka; Chauhan, Anil K; Kishikawa, Naoya; Kuroda, Naotaka

    2017-01-15

    Cancer immunotherapies such as antibodies targeting T cell checkpoints, or adaptive tumor-infiltrating lymphocyte (TIL) transfer, have been developed to boost the endogenous immune response against human malignancies. However, activation of T cells by such antibodies can lead to the risk of autoimmune diseases. Also, the selection of tumor-reactive T cells for TIL relies on information regarding mutated antigens in tumors and does not reflect other factors involved in protein antigenicity. It is therefore essential to engineer therapeutic interventions by which T cell reactivity against tumor cells is selectively enhanced (i.e., "focused cancer immunotherapy") based on tumor antigens that are specifically expressed in the tumor of a certain cancer and in many patients with this cancer. Immune complexes (ICs) are the direct and stable products of immunological recognition by humoral immunity. Here, we searched for tumor-specific IC antigens in each of five cancers (lung (n = 28), colon (n = 20), bladder (n = 20), renal cell (n = 15) and malignant lymphoma (n = 9)), by using immune complexome analysis that comprehensively identifies and profiles the constituent antigens in ICs. This analysis indicated that gelsolin and inter-alpha-trypsin inhibitor heavy chains were specifically and frequently detected (at a frequency higher than 80%), and that phosphoproteins (VENTX, VCIP135) were also specifically present in the ICs of lung cancer patients. Immune complexome analysis successfully identified several tumor-specific IC antigens with high detection frequency in lung cancer patients. These specific antigens are required to validate the clinical benefit by further analysis using a large number of patients. © 2016 UICC.

  10. Return to work for patients with diffuse large B-cell lymphoma and transformed indolent lymphoma undergoing autologous stem cell transplantation

    PubMed Central

    Arboe, Bente; Olsen, Maja Halgren; Goerloev, Jette Soenderskov; Duun-Henriksen, Anne Katrine; Johansen, Christoffer; Dalton, Susanne Oksbjerg; Brown, Peter de Nully

    2017-01-01

    Background Autologous stem cell transplantation (ASCT) is the standard treatment for patients with relapsed diffuse large B-cell lymphoma (DLBCL) or transformed indolent lymphoma (TIL). The treatment is mainly considered for younger patients still available for the work market. In this study, social outcomes after ASCT in terms of return to work (RTW) are described. Patients and methods Information from national administrative registers was combined with clinical information on patients, who received ASCT for relapse of DLBCL or TIL between 2000 and 2012. A total of 164 patients were followed until RTW, disability or old-age pension, death, or December 31, 2015, whichever came first. A total of 205 patients were followed with disability pension as the event of interest. Cox models were used to determine cause-specific hazards. Results During follow-up, 82 (50%) patients returned to work. The rate of returning to work in the first year following ASCT was decreased for patients being on sick leave at the time of relapse (hazard ratio [HR] 0.3 [0.2;0.5]) and increased for patients aged ≥55 years (HR 1.9 [1.1;3.3]). In all, 56 (27%) patients were granted disability pension. Being on sick leave at the time of relapse was positively associated with receiving a disability pension in the first 2 years after ASCT (HR 3.7 [1.8;7.7]). Conclusion Patients on sick leave at the time of relapse have a poorer prognosis regarding RTW and have a higher rate of disability pension. Furthermore, patients >55 are more likely to RTW compared to younger patients. These results indicate an unmet need for focused social rehabilitation. PMID:28652814

  11. The transition from HLA-I positive to HLA-I negative primary tumors: the road to escape from T-cell responses.

    PubMed

    Aptsiauri, Natalia; Ruiz-Cabello, Francisco; Garrido, Federico

    2018-04-01

    MHC/HLA class I loss in cancer is one of the main mechanisms of tumor immune escape from T-cell recognition and destruction. Tumor infiltration by T lymphocytes (TILs) and by other immune cells was first described many years ago, but has never been directly and clearly linked to the destruction of HLA-I positive and selection of HLA-I negative tumor cells. The degree and the pattern of lymphocyte infiltration in a tumor nest may depend on antigenicity and the developmental stages of the tumors. In addition, it is becoming evident that HLA-I expression and tumor infiltration have a direct correlation with tumor tissue reorganization. We observed that at early stages (permissive Phase I) tumors are heterogeneous, with both HLA-I positive and HLA-negative cancer cells, and are infiltrated by TILs and M1 macrophages as a part of an active anti-tumor Th1 response. At later stages (encapsulated Phase II), tumor nests are mostly HLA-I negative with immune cells residing in the peri-tumoral stroma, which forms a granuloma-like encapsulated tissue structure. All these tumor characteristics, including tumor HLA-I expression pattern, have an important clinical prognostic value and should be closely and routinely investigated in different types of cancer by immunologists and by pathologists. In this review we summarize our current viewpoint about the alterations in HLA-I expression in cancer and discuss how, when and why tumor HLA-I losses occur. We also provide evidence for the negative impact of tumor HLA-I loss in current cancer immunotherapies, with the focus on reversible ('soft') and irreversible ('hard') HLA-I defects. Copyright © 2018 Elsevier Ltd. All rights reserved.

  12. A high molecular weight-melanoma associated antigen-specific chimeric antigen receptor redirects lymphocytes to target human melanomas

    PubMed Central

    Burns, William R.; Zhao, Yangbing; Frankel, Timothy L.; Hinrichs, Christian S.; Zheng, Zhili; Xu, Hui; Feldman, Steven A.; Ferrone, Soldano; Rosenberg, Steven A.; Morgan, Richard A.

    2011-01-01

    Immunotherapy, particularly the adoptive cell transfer (ACT) of tumor infiltrating lymphocytes (TIL), is a very promising therapy for metastatic melanoma. Some patients unable to receive TIL have been successfully treated with autologous peripheral blood lymphocytes (PBL), genetically modified to express HLA class I antigen restricted, melanoma antigen-reactive T-cell receptors; however, substantial numbers of patients remain ineligible due to the lack of expression of the restricting HLA class I allele. We sought to overcome this limitation by designing a non-MHC-restricted, chimeric antigen receptor (CAR) targeting the high molecular weight-melanoma associated antigen (HMW-MAA), which is highly expressed on over 90% of human melanomas but has a restricted distribution in normal tissues. HMW-MAA-specific CARs containing an antigen recognition domain based on variations of the HMW-MAA-specific monoclonal antibody (mAb) 225.28S and a T-cell activation domain based on combinations of CD28, 4-1BB, and CD3ζ activation motifs were constructed within a retroviral vector to allow stable gene transfer into cells and their progeny. Following optimization of the HMW-MAA-specific CAR for expression and function in human PBL, these gene-modified T cells secreted cytokines, were cytolytic, and proliferated in response to HMW-MAA expressing cell lines. Furthermore, the receptor functioned in both CD4+ and CD8+ cells, was non-MHC-restricted, and reacted against explanted human melanomas. To evaluate this HMW-MAA-specific CAR in patients with metastatic melanoma, we developed a clinical-grade retroviral packaging line. This may represent a novel means to treat the majority of patients with advanced melanoma, most notably those unable to receive current ACT therapies. PMID:20395199

  13. Administration of 6-gingerol greatly enhances the number of tumor-infiltrating lymphocytes in murine tumors.

    PubMed

    Ju, Seong-A; Park, Sang-Min; Lee, Yea-Sol; Bae, Jun-Hyeong; Yu, Rina; An, Won G; Suh, Jae-Hee; Kim, Byung-Sam

    2012-06-01

    Tumor-infiltrating lymphocytes (TILs) play critical roles in host antitumor immune responses. It is known that cancer patients with tumor-reactive lymphocyte infiltration in their tumors have better prognoses, while patients with tumors infiltrated by immunosuppressive cells have worse prognoses. We found that administration of 6-gingerol, which is a component of ginger, inhibited tumor growth in several types of murine tumors, such as B16F1 melanomas, Renca renal cell carcinomas and CT26 colon carcinomas, which were established by inoculating tumor cells on the flanks of mice. However, administration of 6-gingerol did not lead to complete eradication of the tumors. 6-Gingerol treatment of tumor-bearing mice caused massive infiltration of CD4 and CD8 T-cells and B220(+) B-cells, but reduced the number of CD4(+) Foxp3(+) regulatory T-cells. The CD8 tumor-infiltrating T lymphocytes in 6-gingerol-treated mice strongly expressed IFN-γ, a marker of activation of cytotoxic T lymphocytes (CTL) CD107a and chemokine receptors that are expressed on T(H) 1 cells, such as CXCR3 and CCR5. To test whether 6-gingerol could promote infiltration of tumor antigen-specific CD8 T-cells into tumors, we adoptively transferred CFSE-labeled OT-1 CD8 T-cells into EG7 tumor-bearing mice. We found that CD8 T cells isolated from 6-gingerol pretreated OT-1 mice, but not from control OT-1 mice, massively infiltrated tumors and tumor draining lymph nodes and divided several times. Our results strongly suggest that 6-gingerol can be used in tumor immunotherapy to increase the number of TILs. Copyright © 2011 UICC.

  14. The role of Fas ligand and transforming growth factor beta in tumor progression: molecular mechanisms of immune privilege via Fas-mediated apoptosis and potential targets for cancer therapy.

    PubMed

    Kim, Ryungsa; Emi, Manabu; Tanabe, Kazuaki; Uchida, Yoko; Toge, Tetsuya

    2004-06-01

    Despite the fact that expression of Fas ligand (FasL) in cytotoxic T lymphocytes (CTLs) and in natural killer (NK) cells plays an important role in Fas-mediated tumor killing, During tumor progression FasL-expressing tumor cells are involved in counterattacking to kill tumor-infiltrating lymphocytes (TILs). Soluble FasL levels also increase with tumor progression in solid tumors, and this increase inhibits Fas-mediated tumor killing by CTLs and NK cells. The increased expression of FasL in tumor cells is associated with decreased expression of Fas; and the promoter region of the FASL gene is regulated by transcription factors, such as neuronal factor kappaB (NF-kappaB) and AP-1, in the tumor microenvironment. Although the ratio of FasL expression to Fas expression in tumor cells is not strongly related to the induction of apoptosis in TILs, increased expression of FasL is associated with decreased Fas levels in tumor cells that can escape immune surveillance and facilitate tumor progression and metastasis. Transforming growth factor beta (TGF-beta) is a potent growth inhibitor and has tumor-suppressing activity in the early phases of carcinogenesis. During subsequent tumor progression, the increased secretion of TGF-beta by both tumor cells and, in a paracrine fashion, stromal cells, is involved in the enhancement of tumor invasion and metastasis accompanied by immunosuppression. Herein, the authors review the clinical significance of FasL and TGF-beta expression patterns as features of immune privilege accompanying tumor progression in the tumor microenvironment. Potential strategies for identifying which molecules can serve as targets for effective antitumor therapy also are discussed. Copyright 2004 American Cancer Society.

  15. Reparo de aneurisma de artéria ilíaca roto em criança

    PubMed Central

    Hoshiko, Fernando Massaru; Zampieri, Elisa Helena Subtil; Dalio, Marcelo Bellini; Dezotti, Nei Rodrigues Alves; Joviliano, Edwaldo Edner

    2017-01-01

    Resumo Relatamos o caso de uma menina de 12 anos que deu entrada na unidade de emergência com quadro de abdome agudo hemorrágico, massa abdominal pulsátil e instabilidade hemodinâmica. Confirmado o diagnóstico de aneurisma roto de artéria ilíaca direita, foi realizada correção cirúrgica de emergência por reparo aberto com reconstrução extra-anatômica, utilizando enxerto sintético de fino calibre, compatível com a anatomia. O tratamento foi bem-sucedido e a criança apresentou evolução favorável em curto prazo.

  16. The new design of final optics assembly on SG-III prototype facility

    NASA Astrophysics Data System (ADS)

    Li, Ping; Zhao, Runchang; Wang, Wei; Jia, Huaiting; Chen, Liangmin; Su, Jingqin

    2014-09-01

    To improve the performance of SG-III prototype facility (TIL-Technical Integration Line), final optics assembly (FOA) is re-designed. It contains that stray light and focusing ghosts are optimized, operational performance and environments are improved and the total thickness of optics is reduced. With the re-designed FOA, Some performance advantages are achieved. First, the optics damages are mitigated obviously, especially crystals and Focus lens; Second, stray light and focusing ghosts are controlled better that organic contamination sources inside FOA are eliminated; Third, maintenance and operation are more convenient for the atoms environment; Fourth, the focusable power on target is increased for lower B-integral.

  17. The Effects of Engine Speed and Mixture Temperature on the Knocking Characteristics of Several Fuels

    DTIC Science & Technology

    1940-07-01

    only. NACA list dtd 28 Sep 1945; NASA TR Server website ‘ ,f. ; :,““’? ,. .--:- .— #..- “W!+ ‘ ‘:u:i’w W9SlFlCAT10#CAME1lEO~ . TilCH131CAL NOTES...A photograph of the engine ’”used.is shown in figure 1. The electric air heater is above the engine and the cathod.e- ray oscill”ograph used as a...indicated that increasing the con- “press,ion ratio fro@ 6 to 11 results in.’a decie~se in the ‘dbzisity correction fact-or of shout . “0.030 at 1,500

  18. Final Report on the Special Year in Numerical Analysis, 1980-81.

    DTIC Science & Technology

    1981-12-01

    C -NF L<N.; ~F 17E NAME AND...1!V I r iA llg oxperl.t5 kf tilO h Cor Co1rmal i t!’-! -;,1 1’’ 1iij . . 1! ’ni’~~’~; , 7rrk’rit pi’’bihrim;, 11id C iiir I’lf", i~2 DD I AN 7 1473...wcla cm[h1i %a plee Iol- , ujre ica I I inear al c ’’ !,:, tn rd numi~ i- , ii-l i, 1. . c ; 1,~ 1h a ce 1) 1. ~ i~; i Im: ion e ut hod: ~ tr IIIIj an

  19. Imposed-Solution Boundaries for Three-Dimensional Hull.

    DTIC Science & Technology

    1986-03-01

    STATE ARRAY DIMENSIONS. DATA IBNDNBND,@JMXKMXFNMXi31,6l,200,200,4000/ C NMX IS ADDED TO 1CM IN HULLIN (HULL9250). C SET TF1 TO -1.0 FOR INITIAL VALUES...DATA TF1 /-1.O1 C C SHIFT DATA FROM HULL COORDINATES TO BOUNDARY COORDINATES* T a TH + TSHIFT X a XH +XSHIFT Y m YH + YSHIFT Z a ZH + ZSHIFT C IS THIS...AFTER THE INITIAL ENTRY? IF( TF1 .GT. -0.9)GOTO 30 TF1 - 1.0 C READ FIRST HEADING, GRID, AND r4YDRO SET. CHECK. REWIND IBND READ( IBND)HEAD1,OLPROB,TIl1

  20. Department of the Army Procurement Programs. Committee Staff Procurement Backup Book FY 2001 Budget Estimate. Procurement of Ammunition, Army.

    DTIC Science & Technology

    2000-02-01

    tD c...UJ _i UJ 2 o o UJ 1- 2 O o 2 o w «N o 0. § >- u. Ü u z til < V 3 _i < 2 u. a. -b o 3 CN i 0. o a. CO ci a. T- T- 1^ tD ...Tf <=f >- CM CN CN u_ © CD •a a> J3 o o CD CO to Z c CM Ö Ö Ö £ E >• "*" T~ JB tD u_ ~ UJ a. E E ɘ o a. o c i o o CM CM CM W a CM