tbuckley/cabot-search huggingface dataset:
Effect of Renal Cell Carcinomas on the Development of Type 1 T-Cell Responses
Authors: Patricia Rayman, Amy K. Wesa, Amy L. Richmond, Tanya Das, Kaushik Biswas, Gira Raval, Walter J. Storkus, Charles Tannenbaum, Andrew Novick, Ronald Bukowski, James Finke
Journal: Clinical Cancer Research (2004)

Abstract Purpose: We reported that in renal cell carcinoma patients with active disease, T-cell reactions to the tumor-associated antigens MAGE-6 and EphA2 are highly skewed toward TH2-type cytokine responses [interleukin (IL) 5]. Herein, we determined whether tumor-derived products, including gangliosides isolated from renal cell carcinoma patients, participate in the down-regulation of type 1 T-cell responses. Experimental Design: T cells from healthy volunteers or renal cell carcinoma patients were cultured in the presence and absence of supernatants derived from renal cell carcinoma explants or with gangliosides isolated from those tumor supernatants. T cells were stimulated or not with either autologous dendritic cells pulsed with superantigen (Staphylococcus enterotoxin B) or with phorbol 12-myristate 13-acetate and ionomycin and then were assessed for type 1 or type 2 responses (cytokine production and gene expression) and apoptosis. Results: Tumor supernatants efficiently inhibited the TH1-type responses [interferon (IFN) γ] of T cells stimulated with either S. enterotoxin B or phorbol 12-myristate 13-acetate and ionomycin but had no inhibitory effect on activated T-cell production of type 2 cytokines (IL-4, IL-5, and IL-10). Likewise, IFN-γ mRNA and protein production were inhibited when T cells were cocultured with either renal cell carcinoma supernatant-derived gangliosides or a commercial source of purified GD1a. It was also determined that gangliosides impair type 1 responses by inducing apoptosis of activated T cells. Conclusions: We propose that renal cell carcinoma-derived tumor products such as gangliosides can induce a type 2 bias in antitumor immunity by initiating apoptosis in the IFN-γ-producing type 1 effector cells. This represents a relevant mechanism by which renal cell carcinoma can inhibit protective antitumor immunity.
Bronchial Histamine Challenge in the Diagnosis of Asthma The Predictive Value of Changes in Airway Resistance Determined by the Interrupter Method
Authors: F. Madsen, N.‐H. Holstein‐Rathlou, L. Frølund, B. Weeke, U. G. Svendsen
Journal: Allergy (1986)

The predictive value of a bronchial challenge with histamine was determined in a prospective survey on a population with a high prevalence of asthma (0.62). Without knowledge of the bronchial responsiveness 133 patients were classified as asthmatics (83) or non‐asthmatics (50) according to variation in peak expiratory flow rate and medical history. Response to challenge was determined by the interrupter method, and the concentration of histamine inducing a 40% increase in resistance to breathing (PC 40 ‐R t ) was calculated from the log dose response curve. When defining a positive test as a test giving PC 40 ‐R t ‐values below 2.00 mg/ml, the predictive value of a positive test was 0.75 and the predictive value of a negative test was 0.72. By decreasing the limit for a positive test to 0.25 mg/ml the corresponding predictive value was increased to 0.91. When further increasing the limit to 4.00 mg/ml the predictive value of a negative test in the diagnosis of asthma was increased to 0.81. The interrupter technique is suitable for diagnostic purposes in the detection and exclusion of bronchial asthma.
Positive Inotropic Agents
Authors: A E Farah, A A Alousi, R P Schwarz
Journal: The Annual Review of Pharmacology and Toxicology (1984)

Over the past two decades, deadly coronaviruses, with the most recent being the severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) 2019 pandemic, have majorly challenged public health. The path for virus invasion into humans and other ...Read More
Limited tumor infiltration by activated T effector cells restricts the therapeutic activity of regulatory T cell depletion against established melanoma
Authors: Sergio A. Quezada, Karl S. Peggs, Tyler R. Simpson, Yuelei Shen, Dan R. Littman, James P. Allison
Journal: The Journal of Experimental Medicine (2008)

Interference with inhibitory immunological checkpoints controlling T cell activation provides new opportunities to augment cancer immunotherapies. Whereas cytotoxic T lymphocyte-associated antigen-4 blockade has shown promising preclinical and clinical results, therapeutic CD4(+)CD25(+) T reg cell depletion has failed to consistently enhance immune-based therapies. Using B16/BL6, a transplantable murine melanoma model, we show a dichotomy between the effects of T reg cell depletion on tumor rejection dependent on whether depletion occurs before (prophylactic) or after (therapeutic) tumor engraftment. Failure to promote rejection with therapeutic depletion is not related to lack of T reg cell depletion, to elimination of CD25(+) effector T cells, or to a failure to enhance systemic antitumor T cell responses, but correlates with failure of effector cells to infiltrate the tumor and increase the intratumor ratio of effector T cell/T reg cell. Finally, systemic antitumor responses generated upon therapeutic T reg cell depletion are significantly stronger than those generated in the presence of T reg cells, and are capable of eliciting rejection of established tumors after transfer into immunoablated recipients receiving combination immunotherapy. The data demonstrate a dissociation between measurable systemic responses and tumor rejection during CD25-directed T reg cell depletion, and suggest an alternative, clinically applicable strategy for the treatment of established tumors.
Transforming Growth Factor-β–Stimulated Clone-22 Is an Androgen-Regulated Gene That Enhances Apoptosis in Prostate Cancer following Insulin-Like Growth Factor-I Receptor Inhibition
Authors: Cynthia C.T. Sprenger, Kathleen Haugk, Shihua Sun, Ilsa Coleman, Peter S. Nelson, Robert L. Vessella, Dale L. Ludwig, Jennifer D. Wu, Stephen R. Plymate
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Inhibition of insulin-like growth factor (IGF) signaling using the human IGF-I receptor monoclonal antibody A12 is most effective at inducing apoptosis in prostate cancer xenografts in the presence of androgen. We undertook this study to determine mechanisms for increased apoptosis by A12 in the presence of androgens. Experimental Methods: The castrate-resistant human xenograft LuCaP 35 V was implanted into intact or castrate severe combined immunodeficient mice and treated with A12 weekly. After 6 weeks of tumor growth, animals were sacrificed and tumors were removed and analyzed for cell cycle distribution/apoptosis and cDNA arrays were done. Results: In castrate mice, the tumors were delayed in G2 with no apoptosis; in contrast, tumors from intact mice underwent apoptosis with either G1 or G2 delay. Transforming growth factor-β–stimulated clone-22 (TSC-22) was significantly elevated in tumors from the intact mice compared with castrate mice, especially in those tumors with the highest levels of apoptosis. To further determine the function of TSC-22, we transfected various human prostate cancer cell lines with a plasmid expressing TSC-22. Cell lines overexpressing TSC-22 showed an increase in apoptosis and a delay in G1. When these cell lines were placed subcutaneously in athymic nude mice, a decreased number of animals formed tumors and the rate of tumor growth was decreased compared with control tumors. Conclusions: These data indicate that IGF-I receptor inhibition in the presence of androgen has an enhanced effect on decreasing tumor growth, in part, through increased expression of the tumor suppressor gene TSC-22. (Clin Cancer Res 2009;15(24):7634–41)
Crucial Role for Interferon γ in the Synergism between Tumor Vasculature-Targeted Tumor Necrosis Factor α (NGR-TNF) and Doxorubicin
Authors: Angelina Sacchi, Anna Gasparri, Flavio Curnis, Matteo Bellone, Angelo Corti
Journal: Cancer Research (2004)

NGR-TNF is a derivative of TNF-alpha, consisting of TNF fused to CNGRCG, a tumor vasculature-targeting peptide. Previous studies showed that NGR-TNF can exert synergistic antitumor effects with doxorubicin and with other chemotherapeutic drugs in murine models. In this study, we have investigated the role of endogenous IFN-gamma on the antitumor activity of NGR-TNF in combination with doxorubicin. The study was carried out using murine B16F1 melanoma and TS/A mammary adenocarcinoma implanted subcutaneously in (a) immunocompetent mice, (b) athymic nude mice, and (c) IFN-gamma-knockout mice. Synergism between NGR-TNF and doxorubicin was observed in immunocompetent mice but not in nude or IFN-gamma-knockout mice. Preadministration of a neutralizing anti-IFN-gamma antibody to immunocompetent mice inhibited the NGR-TNF/doxorubicin synergism, whereas administration of IFN-gamma to nude and to IFN-gamma-knockout mice restored the synergistic activity. The synergism in nude mice was restored also by transfecting tumor cells with the IFN-gamma cDNA. Administration of NGR-TNF in combination with IFN-gamma to nude mice, but not of NGR-TNF alone, doubled the penetration of doxorubicin in TS/A tumors. These findings point to a crucial role for locally produced IFN-gamma in tumor vascular targeting with NGR-TNF and doxorubicin. Finally, addition of IFN-gamma to the treatment of immunocompetent mice with NGR-TNF/doxorubicin induced only modest improvement in response, suggesting that exogenous IFN-gamma can improve the therapeutic activity of these drugs only in case of suboptimal production of endogenous IFN-gamma.
Socioeconomic risk factors for lung function decline in a general population
Authors: A Johannessen, T M L Eagan, E R Omenaas, P S Bakke, A Gulsvik
Journal: European Respiratory Journal (2010)

The aim of our study was to examine sex-specific associations between different aspects of socioeconomic status (SES) (educational level, occupational status, income) and lung function in a general adult population. In the Hordaland County Cohort Study, 1,644 subjects aged 26–82 yrs at baseline answered questionnaires and performed post-bronchodilator spirometry both in 1996–1997 and in 2003–2006. We performed adjusted linear regression analysis on the effect of SES on decline in forced experimental volume in 1 s (FEV<sub>1</sub>), forced vital capacity (FVC) and FEV<sub>1</sub>/FVC. Mean annual decline in FEV<sub>1</sub> from baseline to follow-up was 57 mL (se 1.3) and 48 mL (se 1.0) for males and females, respectively. Males had a larger decline in FVC than females, while females had a larger decline in FEV<sub>1</sub>/FVC. Lower education and low occupational status were associated with larger male lung function decline. SES did not affect female lung function decline. However, marital status was a significant predictor; unmarried females had less decline than both married and widowed females in both FEV<sub>1</sub> (adjusted mean annual difference 8 mL and 16 mL) and FVC (adjusted mean annual difference 8 mL and 18 mL). Low SES was associated with increased lung function decline in males. For females, marital status was more important.
Clinical Activity and Safety of Combination Therapy with Temsirolimus and Bevacizumab for Advanced Melanoma: A Phase II Trial (CTEP 7190/Mel47)
Authors: Craig L. Slingluff, Gina R. Petroni, Kerrington R. Molhoek, David L. Brautigan, Kimberly A. Chianese-Bullock, Amber L. Shada, Mark E. Smolkin, Walter C. Olson, Alison Gaucher, Cheryl Murphy Chase, William W. Grosh, Geoffrey R. Weiss, Aubrey G. Wagenseller, Anthony J. Olszanski, Lainie Martin, Sofia M. Shea, Gulsun Erdag, Prahlad Ram, Jeffrey E. Gershenwald, Michael J. Weber
Journal: Clinical Cancer Research (2013)

A CTEP-sponsored phase II trial was conducted to evaluate safety and clinical activity of combination therapy with CCI-779 (temsirolimus) and bevacizumab in patients with advanced melanoma.Patients with unresectable stage III to IV melanoma were treated intravenously with temsirolimus 25 mg weekly and bevacizumab 10 mg every 2 weeks. Adverse events were recorded using CTCAE v3.0. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors and overall survival was recorded. Correlative studies measured protein kinases and histology of tumor biopsies and immune function in peripheral blood.Seventeen patients were treated. Most patients tolerated treatment well, but 2 had grade 4 lymphopenia and 1 developed reversible grade 2 leukoencephalopathy. Best clinical response was partial response (PR) in 3 patients [17.7%, 90% confidence interval (CI) 5, 0-39.6], stable disease at 8 weeks (SD) in 9 patients, progressive disease (PD) in 4 patients, and not evaluable in 1 patient. Maximal response duration for PR was 35 months. Ten evaluable patients had BRAF(WT) tumors, among whom 3 had PRs, 5 had SD, and 2 had PD. Correlative studies of tumor biopsies revealed decreased phospho-S6K (d2 and d23 vs. d1, P < 0.001), and decreased mitotic rate (Ki67(+)) among melanoma cells by d23 (P = 0.007). Effects on immune functions were mixed, with decreased alloreactive T-cell responses and decreased circulating CD4(+)FoxP3(+) cells.These data provide preliminary evidence for clinical activity of combination therapy with temsirolimus and bevacizumab, which may be greater in patients with BRAF(wt) melanoma. Mixed effects on immunologic function also support combination with immune therapies.
Expansion of Human T Regulatory Type 1 Cells in the Microenvironment of Cyclooxygenase 2 Overexpressing Head and Neck Squamous Cell Carcinoma
Authors: Christoph Bergmann, Laura Strauss, Reinhard Zeidler, Stephan Lang, Theresa L. Whiteside
Journal: Cancer Research (2007)

Abstract Cyclooxygenase 2 (COX-2) overexpression and production of prostaglandin E2 (PGE2) by head and neck squamous cell carcinomas (HNSCC) induce type 1 regulatory T (Tr1) cells and contribute to carcinogenesis by creating a tolerogenic milieu. To test this hypothesis, CD4+CD25− T cells obtained from the peripheral blood of 10 normal donors were cocultured with autologous dendritic cells, irradiated HNSCC cells and cytokines, interleukin 2 (IL-2), IL-10, and IL-15. HNSCC cells were either COX-2 negative, constitutively expressed COX-2, were transfected with COX-2, or had COX-2 expression knocked down by small interfering RNA. Other modifications included coculture plus or minus the COX-inhibitor, Diclofenac, or synthetic PGE2 in the absence of HNSCC. Lymphocytes proliferating in 10-day cocultures were phenotyped by flow cytometry, studied for cytokine production by ELISA and for suppressor function in CFSE inhibition assays plus or minus anti–IL-10 or anti–transforming growth factor-β1 (TGF-β1) monoclonal antibodies (mAb). COX-2+ HNSCC or exogenous PGE2 induced outgrowth of Tr1 cells with the CD3+CD4+CD25−IL2Rβ+IL2Rγ+FoxP3+CTLA-4+IL-10+TGF-β1+IL-4− phenotype and high suppressor functions (range, 46–68%). Small interfering RNA knockout of COX-2 gene in HNSCC led to outgrowth of lymphocytes with decreased IL2Rγ (P = 0.0001), FoxP3 (P = 0.05), and IL-10 (P = 0.035) expression and low suppressor activity (range, 26–34%). Whereas COX-2+ cocultures contained IL-10 and TGF-β1 (medians, 615 and 824 pg/mL), cytokine levels were decreased (P &amp;lt; 0.0001) in COX-2− cocultures. Inhibition of COX-2 enzymatic activity in HNSCC abrogated outgrowth of Tr1 cells. Neutralizing mAbs to IL-10 and/or TGF-β1 abolished Tr1-mediated suppression. COX-2 overexpression in HNSCC plays a major role in the induction of Tr1 cells in the tumor microenvironment. [Cancer Res 2007;67(18):8865–73]
Activation of protein kinase C results in the displacement of its myristoylated, alanine-rich substrate from punctate structures in macrophage filopodia.
Authors: A Rosen, K F Keenan, M Thelen, A C Nairn, A Aderem
Journal: The Journal of Experimental Medicine (1990)

The myristoylated, alanine-rich C kinase substrate (MARCKS) is a prominent substrate for protein kinase C (PKC) in a variety of cells, and has been implicated in diverse cellular processes including neurosecretion, fibroblast mitogenesis, and macrophage activation. In macrophages that have spread on the substratum, MARCKS has a punctate distribution at the cell-substratum interface of pseudopodia and filopodia. At these points, MARCKS co-localizes with vinculin and talin. Activation of PKC with phorbol esters results in the rapid disappearance of punctate staining of MARCKS, but not vinculin or talin, and is accompanied by cell spreading and loss of filopodia. The morphological changes and disappearance of punctate staining follow a time-course that closely approximates both the PKC-dependent phosphorylation of MARCKS, and its phosphorylation-dependent release from the plasma membrane. Our results suggest a role for PKC-dependent phosphorylation of MARCKS in the regulation of the membrane cytoskeleton.
Role of interferon regulatory factor 1 in induction of nitric oxide synthase.
Authors: E Martin, C Nathan, Q W Xie
Journal: The Journal of Experimental Medicine (1994)

Interferon gamma (IFN-gamma) interacts synergistically with bacterial lipopolysaccharide (LPS) to induce transcription of iNOS, the isoform of nitric oxide synthase whose activity is independent of elevated Ca2+ and exogenous calmodulin. To define a cis-acting element mediating IFN-gamma-dependent synergy, we made deletions in iNOS promoter constructs fused to reporter genes, transfected RAW 264.7 macrophages, and treated the cells with IFN-gamma and/or LPS. This analysis implicated the region from positions -951 to -911, a cluster of four enhancer elements known to bind IFN-gamma-responsive transcription factors, including an interferon regulatory factor binding site (IRF-E) at nucleotides -913 to -923. Site-specific substitution of two conserved nucleotides within IRF-E in the context of the full-length iNOS promoter ablated IFN-gamma's contribution to synergistic enhancement of transcription. Electromobility shift assays performed with a probe containing IRF-E revealed the existence of a complex in nuclei of RAW 264.7 macrophages that was present only after treatment with IFN-gamma, which reacted specifically with anti-IRF-1 immunoglobulin G and which included a species migrating at 40-45 kD, consistent with the apparent molecular weight of murine IRF-1. Thus, the synergistic contribution of IFN-gamma to transcription of iNOS in RAW 264.7 macrophages requires that IRF-1 bind to IRF-E in the iNOS promoter. In conjunction with the work of Kamijo et al. (Kamijo, R., H. Harada, T. Matsuyama, M. Bosland, J. Gerecitano, D. Shapiro, J. Le, K. S. Im, T. Kimura, S. Green et al. 1994. Science [Wash. DC]. 263:1612), these findings identify iNOS as the first gene that requires IRF-1 for IFN-gamma-dependent transcriptional regulation.
INCIDENCE AND OUTCOMES IN GLIOMAS FROM BRAIN TUMOR REGISTRY OF JAPAN 2001-2004
Authors: Y. Narita, S. Shibui
Journal: Neuro-Oncology (2014)

BACKGROUND: (blind field). METHODS: Data on primary or metastatic brain tumor cases that were newly diagnosed from 2001 to 2004 were collected from 2009 until the end of 2012. Approximately 330 neurosurgeons, medical doctors, and staff from 109 institutions collected 16,338 data from clinical records. These institutions included most universities, colleges, and hospitals with Japan Neurosurgical Society-authorized boards. These data were collected via the Internet Data and Information Center for Medical Research. Data, including the birthplace, age, tumor sites, diagnostic method, therapy (surgery, radiation, or chemotherapy), and the outcome of these treatments, according to the World Health Organization (WHO) 2007 brain tumor classification were collected. Survival data were analyzed using the Kaplan-Meier method. RESULTS: Overall survival (OS, months), progression free survival (PFS, months), 5-year OS, 5-year PFS of each grade of gliomas are as follows; pilocytic astrocytoma; NR (not reached), NR, 92.1%, 73.8%, diffuse astrocytoma: NR, 84.1, 75%, 57%, grade II oligodendroglial tumor: NR, NR, 90%, 74.6%, anaplastic astrocytoma: 38, 19, 41.1%, 28.7%, grade III anaplastic oligodendroglial tumor: NR, 71, 68.2%, 54%, glioblastoma: 15, 8.1, 10.1%, 9.2%. CONCLUSIONS: The 5-year OS of grade II and III gliomas improved compared to that in 1997-2000 but that of glioblastoma did not. Based on the data of BTRJ 2001-2004, trends and problems in treatment and outcomes of gliomas will be presented and discussed. SECONDARY CATEGORY: n/a.
Meta-Analysis on the Use of Zidovudine and Interferon-Alfa in Adult T-Cell Leukemia/Lymphoma Showing Improved Survival in the Leukemic Subtypes
Authors: Ali Bazarbachi, Yves Plumelle, Juan Carlos Ramos, Patricia Tortevoye, Zaher Otrock, Graham Taylor, Antoine Gessain, William Harrington, Gérard Panelatti, Olivier Hermine
Journal: Journal of Clinical Oncology (2010)

Human T-cell lymphotropic virus type-I-associated adult T-cell leukemia/lymphoma (ATL) is an aggressive, chemotherapy-resistant malignancy. Multiple small studies using zidovudine (AZT) and interferon-alfa (IFN-α) have shown response in patients with ATL. However, the impact of this innovative antiviral treatment strategy on long-term survival remains undetermined.We report a meta-analysis of antiviral therapy of ATL. Medical records of 254 patients with ATL who were treated in the United States, the United Kingdom, Martinique, and continental France were individually reviewed.According to Shimoyama classification, there were 116 patients with acute ATL, 18 patients with chronic ATL, 11 patients with smoldering ATL, and 100 patients with ATL lymphoma. In 231 patients with available survival data, first-line therapy was recorded in 207 patients. Five-year overall survival rates were 46% for 75 patients who received first-line antiviral therapy (P = .004), 20% for 77 patients who received first-line chemotherapy, and 12% for 55 patients who received first-line chemotherapy followed by antiviral therapy. Patients with acute, chronic, and smoldering ATL significantly benefited from first-line antiviral therapy, whereas patients with ATL lymphoma experienced a better outcome with chemotherapy. In acute ATL, achievement of complete remission with antiviral therapy resulted in 82% 5-year survival. Antiviral therapy in chronic and smoldering ATL resulted in 100% 5-year survival. Multivariate analysis confirmed that first-line antiviral therapy significantly improves overall survival of patients with ATL (hazard ratio, 0.47; 95% CI, 0.27 to 0.83; P = .021).These results confirm the high efficacy of AZT and IFN, which should now be considered the gold standard first-line therapy in leukemic subtypes of ATL.