tbuckley/cabot-search huggingface dataset:
Activation of Tumor-Promoting Type 2 Macrophages by EGFR-Targeting Antibody Cetuximab
Authors: Jan Pander, Moniek Heusinkveld, Tahar van der Straaten, Ekaterina S. Jordanova, Renée Baak-Pablo, Hans Gelderblom, Hans Morreau, Sjoerd H. van der Burg, Henk-Jan Guchelaar, Thorbald van Hall
Journal: Clinical Cancer Research (2011)

In a recent randomized phase III clinical trial in metastatic colorectal cancer patients, the addition of the anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) cetuximab to bevacizumab and chemotherapy resulted in decreased progression-free survival, in particular for patients with the high-affinity FcγRIIIA.The presence of natural killer (NK) cells and type 2 (M2) macrophages in colorectal cancer was determined by immunohistochemistry, using antibodies to lineage-specific markers NKp46 and CD68 with CD163, respectively. Influence of tumor-bound cetuximab on M2 macrophages was carried out in vitro with EGFR-expressing tumor cells and short-term differentiated monocytes from blood donors, who were typed for the FcγRIIIA polymorphism (CD16).Antibody-dependent cellular cytotoxicity by NK cells is generally proposed as one of the antitumor mechanisms of mAbs. We found that CD163-positive M2 macrophages are much more abundant in colorectal carcinomas. In vitro analysis of M2 macrophages revealed high levels of Fc-gamma receptors (FcγR) and PD-L1 and production of IL-10 and VEGF but not IL-12. These anti-inflammatory and tumor-promoting mediators were released upon coculture with EGFR-positive tumor cells loaded with low concentrations of cetuximab. Macrophage activation depended on EGFR expression on the tumor cells, FcγRs, target specificity of the mAb and mobility of antibody complexes. Cetuximab-induced macrophage responses were more pronounced for FCGR3A 158-Val (high-affinity) carriers.These results suggest that tumor-promoting M2 macrophages are activated by the therapeutic mAb cetuximab in the local tumor microenvironment and argue that this immune mechanism should be taken into account for the application of therapeutic antibodies.
Cost-Utility Analysis Studies of Depression Management: A Systematic Review
Authors: Paul A Pirraglia, Allison B Rosen, Richard C Hermann, Natalia V Olchanski, Peter Neumann
Journal: American Journal of Psychiatry (2004)

Depression is common, costly, treatable, and a major influence on quality of life. Cost-utility analysis combines costs with quantity and quality of life into a metric that is meaningful for studies of interventions or care strategies and is directly comparable to measures in other such studies. The objectives of this study were to identify published cost-utility analyses of depression screening, pharmacologic treatment, nonpharmacologic therapy, and care management; to summarize the results of these studies in an accessible format; to examine the analytic methods employed; and to identify areas in the depression literature that merit cost-utility analysis.The authors selected articles regarding cost-utility analysis of depression management from the Harvard Center for Risk Analysis Cost-Effectiveness Registry. Characteristics of the publications, including study methods and analysis, were examined. Cost-utility ratios for interventions were arranged in a league table.Of the 539 cost-utility analyses in the registry, nine (1.7%) were of depression management. Methods for determining utilities and the source of the data varied. Markov models or cohort simulations were the most common analytic techniques. Pharmacologic interventions generally had lower costs per quality-adjusted life year than nonpharmacologic interventions. Psychotherapy alone, care management alone, and psychotherapy plus care management all had lower costs per quality-adjusted life year than usual care. Depression screening and treatment appeared to fall within the cost-utility ranges accepted for common nonpsychiatric medical conditions.There is a paucity of literature on cost-utility analysis of depression management. High-quality cost-utility analysis should be considered for further research in depression management.
Intrinsic risk factors of non-contact quadriceps and hamstring strains in soccer: a prospective study of 100 professional players
Authors: Konstantinos Fousekis, Elias Tsepis, Peter Poulmedis, Spyros Athanasopoulos, George Vagenas
Journal: British Journal of Sports Medicine (2010)

To identify the intrinsic risk factors of non-contact strains in the hamstrings and quadriceps muscles of professional soccer players via a cohort prospective design.A total of 100 professional soccer players (aged 19.4-27.8 years) from four professional teams underwent a composite musculoskeletal assessment at preseason. Intrinsic risk factors included dichotomies of asymmetries in muscle strength, flexibility, proprioception, anthropometry and knee joint stability, and of previous injuries. Muscle strains were prospectively monitored during the subsequent season using questionnaires. The data were analysed via binary logistic regression.Thirty-eight percent of the players sustained one or more lower-extremity muscle strains. Sixteen (42.1 %) and seven (18.4 %) of them were clinically diagnosed as having non-contact muscle strains at their hamstrings and quadriceps, respectively. Players with eccentric hamstring strength asymmetries (OR=3.88; 95% CI 1.13 to 13.23), functional leg length asymmetries (OR=3.80; 95% CI 1.08 to 13.33) and no previous hamstrings injuries (OR=0.15; 95% CI 0.029 to 0.79) were at greater risk of sustaining a hamstring muscle strain. Players with eccentric strength (OR=5.01; 95% CI 0.92 to 27.14) and flexibility asymmetries (OR=4.98; 95% CI 0.78 to 31.80) in their quadriceps as well as heavier (OR=10.70; 95% CI 0.73 to 156.37) and shorter players (OR=0.08; 95% CI 0.00 to 1.35) were at greater risk of sustaining a strain in this muscle group.Professional soccer players with functional asymmetries possess a higher risk of sustaining hamstring strains. Previous injury seems not to constitute a risk factor. The systematic isokinetic evaluation of the lower extremities during the preseason period can provide therapists and trainers with valuable data regarding the predictive elements of non-contact hamstring strains in professional soccer players.
Chromosomal Abnormalities Are Major Prognostic Factors in Elderly Patients With Multiple Myeloma: The Intergroupe Francophone du Myélome Experience
Authors: Hervé Avet-Loiseau, Cyrille Hulin, Loic Campion, Philippe Rodon, Gerald Marit, Michel Attal, Bruno Royer, Mamoun Dib, Laurent Voillat, Didier Bouscary, Denis Caillot, Marc Wetterwald, Brigitte Pegourie, Gerard Lepeu, Bernadette Corront, Lionel Karlin, Anne-Marie Stoppa, Jean-Gabriel Fuzibet, Xavier Delbrel, Francois Guilhot, Brigitte Kolb, Olivier Decaux, Thierry Lamy, Laurent Garderet, Olivier Allangba, Francois Lifermann, Bruno Anglaret, Philippe Moreau, Jean-Luc Harousseau, Thierry Facon
Journal: Journal of Clinical Oncology (2013)

Chromosomal abnormalities, especially t(4;14) and del(17p), are major prognostic factors in patients with multiple myeloma (MM). However, this has been especially demonstrated in patients age < 66 years treated with intensive approaches. The goal of this study was to address this issue in elderly patients treated with conventional-dose chemotherapy.To answer this important question, we retrospectively analyzed a series of 1,890 patients (median age, 72 years; range, 66 to 94 years), including 1,095 with updated data on treatment modalities and survival.This large study first showed that the incidence of t(4;14) was not uniform over age, with a marked decrease in the oldest patients. Second, it showed that both t(4;14) and del(17p) retained their prognostic value in elderly patients treated with melphalan and prednisone-based chemotherapy.t(4;14) and del(17p) are major prognostic factors in elderly patients with MM, both for progression-free and overall survival, indicating that these two abnormalities should be investigated at diagnosis of MM, regardless of age.
Interaction of TAp73 and <i>Breast Cancer–Associated Gene 3</i> Enhances the Sensitivity of Cervical Cancer Cells in Response to Irradiation-Induced Apoptosis
Authors: Thomas Ho-Yin Leung, Hextan Yuen-Sheung Ngan
Journal: Cancer Research (2010)

Identification of proteins that are involved in the sensitivity of radiotherapy of cancers is important to enhance the response to cancer treatment. Expression of TAp73 is associated with the sensitivity of radiotherapy in cervical cancer patients, suggesting it plays an important role in controlling radiosensitivity. Here, by using yeast two-hybrid system, we identify breast cancer-associated gene 3 (BCA3) as the first and novel protein interacting partner of TAp73. By coimmunoprecipitation and Western blot analysis, we confirm that TAp73 binds with and stabilizes BCA3 in cervical cancer cell line HeLa. Immunofluorescence staining indicates that BCA3 is localized in the cytoplasm and nucleus. Interestingly, when coexpressed with TAp73, BCA3 interacts and colocalizes with TAp73 at the mitochondria. Mutagenesis reveals that the oligomerization domain of TAp73 is responsible for the interaction with BCA3. Furthermore, BCA3 augments the transactivation activity of TAp73 on bax promoter and protein expression. In addition, the expression of BCA3 also increases the sensitivity of TAp73-transfected cells in response to gamma-irradiation-induced apoptosis. Western blot analysis also shows that TAp73 and BCA3 induce activation of caspase-7 and caspase-9. In summary, these findings suggested that BCA3 is a novel protein partner of TAp73, and they cooperate with each other to exert tumor-suppressive functions and sensitize the response of cervical cancer cells to radiotherapy.
Trop-2-targeting tetrakis-ranpirnase has potent antitumor activity against triple-negative breast cancer
Authors: Donglin Liu, Thomas M Cardillo, Yang Wang, Edmund A Rossi, David M Goldenberg, Chien-Hsing Chang
Journal: Molecular Cancer (2014)

Ranpirnase (Rap) is an amphibian ribonuclease with reported antitumor activity, minimal toxicity, and negligible immunogenicity in clinical studies, but the unfavorable pharmacokinetics and suboptimal efficacy hampered its further clinical development. To improve the potential of Rap-based therapeutics, we have used the DOCK-AND-LOCK™ (DNL™) method to construct a class of novel IgG-Rap immunoRNases. In the present study, a pair of these constructs, (Rap)2-E1-(Rap)2 and (Rap)2-E1*-(Rap)2, comprising four copies of Rap linked to the CH3 and CK termini of hRS7 (humanized anti-Trop-2), respectively, were evaluated as potential therapeutics for triple-negative breast cancer (TNBC). The DNL-based immunoRNases, (Rap)2-E1-(Rap)2 and (Rap)2-E1*-(Rap)2, were characterized and tested for biological activities in vitro on a panel of breast cancer cell lines and in vivo in a MDA-MB-468 xenograft model. (Rap)2-E1-(Rap)2 was highly purified (>95%), exhibited specific cell binding and rapid internalization in MDA-MB-468, a Trop-2-expressing TNBC line, and displayed potent in vitro cytotoxicity (EC50 ≤ 1 nM) against diverse breast cancer cell lines with moderate to high expression of Trop-2, including MDA-MB-468, BT-20, HCC1806, SKBR-3, and MCF-7. In comparison, structural counterparts of (Rap)2-E1-(Rap)2, generated by substituting hRS7 with selective non-Trop-2-binding antibodies, such as epratuzumab (anti-CD22), were at least 50-fold less potent than (Rap)2-E1-(Rap)2 in MDA-MB-468 and BT-20 cells, both lacking the expression of the cognate antigen. Moreover, (Rap)2-E1-(Rap)2 was less effective (EC50 > 50 nM) in MDA-MB-231 (low Trop-2) or HCC1395 (no Trop-2), and did not show any toxicity to human peripheral blood mononuclear cells. In a mouse TNBC model, a significant survival benefit was achieved with (Rap)2-E1*-(Rap)2 when given the maximal tolerated dose. A new class of immunoRNases was generated with enhanced potency for targeted therapy of cancer. The promising results from (Rap)2-E1-(Rap)2 and (Rap)2-E1*-(Rap)2 support their further investigation as a potential treatment option for TNBC and other Trop-2-expressing cancers.
FUS/TLS Is a Novel Mediator of Androgen-Dependent Cell-Cycle Progression and Prostate Cancer Growth
Authors: Greg N. Brooke, Rachel L. Culley, D. Alwyn Dart, David J. Mann, Luke Gaughan, Stuart R. McCracken, Craig N. Robson, Bradley Spencer-Dene, Simon C. Gamble, Sue M. Powell, Robin Wait, Jonathan Waxman, Marjorie M. Walker, Charlotte L. Bevan
Journal: Cancer Research (2010)

Progression of prostate cancer is highly dependent upon the androgen receptor pathway, such that knowledge of androgen-regulated proteins is vital to understand and combat this disease. Using a proteomic screen, we found the RNA-binding protein FUS/TLS (Fused in Ewing's Sarcoma/Translocated in Liposarcoma) to be downregulated in response to androgen. FUS has recently been shown to be recruited by noncoding RNAs to the regulatory regions of target genes such as cyclin D1, in which it represses transcription by disrupting complex formation. Here we show that FUS has some characteristics of a putative tumor suppressor, as its overexpression promoted growth inhibition and apoptosis of prostate cancer cells, whereas its knockdown increased cell proliferation. This effect was reproducible in vivo, such that increasing FUS levels in tumor xenografts led to dramatic tumor regression. Furthermore, FUS promoted conditions that favored cell-cycle arrest by reducing the levels of proliferative factors such as cyclin D1 and Cdk6 and by increasing levels of the antiproliferative Cdk inhibitor p27. Immunohistochemical analysis revealed that FUS expression is inversely correlated with Gleason grade, demonstrating that patients with high levels of FUS survived longer and were less likely to have bone metastases, suggesting that loss of FUS expression may contribute to cancer progression. Taken together, our results address the question of how androgens regulate cell-cycle progression, by demonstrating that FUS is a key link between androgen receptor signaling and cell-cycle progression in prostate cancer.
Tumor-Targeting Nanocomplex Delivery of Novel Tumor Suppressor RB94 Chemosensitizes Bladder Carcinoma Cells <i>In vitro</i> and <i>In vivo</i>
Authors: Kathleen F. Pirollo, Antonina Rait, Qi Zhou, Xin-qiao Zhang, Jain Zhou, Chang-Soo Kim, William F. Benedict, Esther H. Chang
Journal: Clinical Cancer Research (2008)

Abstract Purpose: RB94, a truncated form of RB110, has enhanced tumor suppressor potency and activity against all tumor types tested to date including bladder carcinoma. However, efficient, systemic delivery of the gene encoding RB94 specifically to tumors, is an obstacle to clinical application as an anticancer therapeutic. We have developed a systemically given, nanosized liposome DNA delivery system that specifically targets primary and metastatic disease. The ability of RB94, delivered via this nanocomplex, to sensitize bladder carcinoma to chemotherapy in vitro and in vivo was assessed. Experimental Design: The nanocomplex is an RB94 plasmid encapsulated by a cationic liposome, the surface of which is decorated with a tumor-targeting moiety, either transferrin (Tf/Lip/RB94) or an antitransferrin receptor single-chain antibody fragment (TfRScFv/Lip/RB94). The ability of the complex to sensitize human bladder carcinoma HTB-9 cells to chemotherapeutics was assessed in vitro by XTT assay. In vivo tumor specificity and efficacy were tested in mice carrying HTB-9 tumors by PCR and tumor growth inhibition, respectively. Results: Transfection with Tf/Lip/RB94 significantly sensitized HTB-9 cells to chemotherapeutic agents in vitro. Tumor specificity of the complex was shown in an orthotopic bladder tumor model by immunohistochemistry and PCR. Moreover, in mice bearing subcutaneous HTB-9 tumors, the combination of systemically given Tf/Lip/RB94 or TfRScFv/Lip/RB94 plus gemcitabine resulted in significant (P &amp;lt; 0.0005) tumor growth inhibition/regression and induction of apoptosis. Conclusions: Use of our tumor-targeting nanocomplex to specifically deliver the potent tumor suppressor RB94 efficiently to tumors has potential as a more effective treatment modality for genitourinary and other cancers.
Induction of interleukin 4 (IL-4) expression in T helper (Th) cells is not dependent on IL-4 from non-Th cells.
Authors: J Schmitz, A Thiel, R Kühn, K Rajewsky, W Müller, M Assenmacher, A Radbruch
Journal: The Journal of Experimental Medicine (1994)

Interleukin 4 (IL-4) is essential for the induction of immunoglobulin E (IgE) responses in mice. Recent in vitro studies have suggested that IL-4 derived from non T helper (Th) cells, in particular from mast cells and basophils, may be essential for triggering of IL-4 expression in Th cells and may directly contribute to IgE isotype switch induction. Here, we have generated mice carrying a functional IL-4 gene only in Th cells or non-Th cells, respectively, by reconstitution of IL-4-deficient mice (IL-4T mice) with CD4+ or CD4- spleen cells from congenic wild-type animals. In mice in which only CD4+ cells are able to express IL-4, antigen-specific IgE is produced in a T cell-dependent immune response. Thus, induction of IL-4 expression in Th cells can occur in the absence of IL-4 from non-Th cells, which suggests that at least some Th cells can express IL-4 in response to another signal which has yet to be identified. No IgE is detectable, however, in mice in which only CD4- cells can express IL-4, suggesting that Th cells are the primary, if not the only source of IL-4 for initial induction of IgE synthesis.
A major T cell antigen of Mycobacterium leprae is a 10-kD heat-shock cognate protein.
Authors: V Mehra, B R Bloom, A C Bajardi, C L Grisso, P A Sieling, D Alland, J Convit, X D Fan, S W Hunter, P J Brennan
Journal: The Journal of Experimental Medicine (1992)

Several mycobacterial antigens, identified by monoclonal antibodies and patient sera, have been found to be homologous to stress or heat-shock proteins (hsp) defined in Escherichia coli and yeast. A major antigen recognized by most Mycobacterium leprae-reactive human T cell lines and cell wall-reactive T cell clones is a 10-kD protein that has now been cloned and sequenced. The predicted amino acid sequence of this protein is 44% homologous to the hsp 10 (GroES) of E. coli. The purified native and recombinant 10-kD protein was found to be a stronger stimulator of peripheral blood T cell proliferation than other native and recombinant M. leprae proteins tested. The degree of reactivity paralleled the response to intact M. leprae throughout the spectrum of leprosy. Limiting-dilution analysis of peripheral blood lymphocytes from a patient contact and a tuberculoid patient indicated that approximately one third of M. leprae-reactive T cell precursors responded to the 10-kD antigen. T cell lines derived from lepromin skin tests were strongly responsive to the 10-kD protein. T cell clones reactive to both the purified native and recombinant 10-kD antigens recognized M. leprae-specific epitopes as well as epitopes crossreactive with the cognate antigen of M. tuberculosis. Further, the purified hsp 10 elicited strong delayed-type hypersensitivity reactions in guinea pigs sensitized to M. leprae. The strong T cell responses against the M. leprae 10-kD protein suggest a role for this heat-shock cognate protein in the protective/resistant responses to infection.
Development of a Reliable and Valid Chinese Version of the Diabetes Empowerment Scale
Authors: Ann T.Y. Shiu, Rebecca Y.M. Wong, David R. Thompson
Journal: Diabetes Care (2003)

OBJECTIVE—To translate the Diabetes Empowerment Scale (DES) into Chinese and establish its psychometric properties among Hong Kong Chinese people. RESEARCH DESIGN AND METHODS—A two-stage study design, incorporating qualitative and quantitative components, determined the cultural equivalency and content validity of the translated scale and established the psychometric properties of the Chinese DES (C-DES) in 207 patients. RESULTS—Psychometric analysis supported the reliability and validity of the 20-item Chinese DES (C-DES-20) and five subscales: overcoming barriers (α = 0.89), determining suitable methods (α = 0.79), achieving goals (α = 0.78), obtaining support (α = 0.78), and coping (α = 0.76). The test-retest reliability of the intraclass correlations was satifactory when a subsample of 20 patients was tested after a 2-week interval. There was criterion validity between the global scale and metabolic control (HbA1c) of respondents with type 2 diabetes (P = 0.03). CONCLUSIONS—The C-DES-20 is a reliable and valid outcome measure for patient education and psychosocial interventions among Hong Kong Chinese people with diabetes.
Direct evidence to support the immunosurveillance concept in a human regressive melanoma.
Authors: A Mackensen, G Carcelain, S Viel, M C Raynal, H Michalaki, F Triebel, J Bosq, T Hercend
Journal: Journal of Clinical Investigation (1994)

The concept of immunosurveillance against cancer has been an extensively debated question over the last decades. Multiple indirect arguments have supported the view that the immune system may control, at least in certain cases, malignant cell growth while direct demonstration is still lacking in the human. In an attempt to address this issue, we have selected a study model, namely spontaneously regressive melanoma. In previous series of experiments, the variability of T cell receptors (TCRs) in the lymphocytes infiltrating a regressive tumor lesion was investigated. Results demonstrated that clonal T cell populations, precisely defined through their V-D-J junctional sequences, were amplified in situ. One clone was predominant, expressing the V beta 16 variable gene segment. A specific anti-V beta 16 TCR mAb was generated here to purify and functionally characterize the corresponding cells. A tumor-infiltrating lymphocyte-derived V beta 16+ T cell line was developed using this reagent. These in vitro cultured cells were found to express the in vivo predominant TCR sequence exclusively and to display an HLA-B14-restricted cytotoxic activity against the autologous tumor cells. Immunohistochemical experiments, performed with the anti-V beta 16 mAb, showed that the corresponding CTLs are present in the tumor area, some of them being closely opposed to the melanoma cells. Together, these studies demonstrate the existence of a local adaptive immune response clinically associated to tumor regression, thus strongly supporting the validity of the immunosurveillance concept in certain human tumors.
In Vivo Imatinib Sensitivity in a Patient With GI Stromal Tumor Bearing a <i>PDGFRA</i> Deletion DIM842-844
Authors: Paul T. Fanta, Jason K. Sicklick, Bryan L. Betz, Michael R. Peterson
Journal: Journal of Clinical Oncology (2014)

In Vivo Imatinib Sensitivity in a Patient With GI Stromal Tumor Bearing a PDGFRA Deletion DIM842-844 Case ReportA 76-year-old Asian man presented with symptoms of postprandial epigastric pain and bloating for 3 months.He denied nausea, vomiting, diarrhea, melana, or hematochezia, but complained of chronic constipation.He was previously diagnosed with irritable bowel syndrome for which he was treated with fiber, dicyclomine, and a Chinese herb after a colonoscopy that revealed a tubulovillous adenoma and melanosis coli.Because of progressive upper abdominal discomfort, a computed tomography (CT) scan of his abdomen and pelvis was performed.Imaging revealed a 13.0-cm mass arising from the retrohepatic space and gastrohepatic ligament.The lesion was abutting the porta hepatis, vena cava, liver, duodenum, and right kidney.Metastatic omental involvement was noted.The primary location of the tumor (ie, stomach or duodenum) was indeterminate; however, given the extent of locally advanced and metastatic disease, the tumor was deemed unresectable.Before referral, percutaneous biopsy of the mass revealed a spindle cell neoplasm that was mostly comprised of epithelioid cells with mildly pleomorphic nuclei on