tbuckley/cabot-search huggingface dataset:
The Adaptor Protein AMOT Promotes the Proliferation of Mammary Epithelial Cells via the Prolonged Activation of the Extracellular Signal-Regulated Kinases
Authors: William P. Ranahan, Zhang Han, Whitney Smith-Kinnaman, Sarah C. Nabinger, Brigitte Heller, Britney-Shea Herbert, Rebecca Chan, Clark D. Wells
Journal: Cancer Research (2011)

Abstract The asymmetric organization of epithelial cells is a basic counter to cellular proliferation. However, the mechanisms whereby pro-growth pathways are modulated by intracellular factors that control cell shape are not well understood. This study demonstrates that the adaptor protein Amot, in addition to its established role in regulating cellular asymmetry, also promotes extracellular signal-regulated kinase 1 and 2 (ERK1/2)–dependent proliferation of mammary cells. Specifically, expression of Amot80, but not a mutant lacking its polarity protein interaction domain, enhances ERK1/2-dependent proliferation of MCF7 cells. Further, expression of Amot80 induces nontransformed MCF10A cells to overgrow as disorganized cellular aggregates in Matrigel. Conversely, Amot expression is required for proliferation of breast cancer cells in specific microenvironmental contexts that require ERK1/2 signaling. Thus, Amot is proposed to coordinate the dysregulation of cell polarity with the induction of neoplastic growth in mammary cells. Cancer Res; 71(6); 2203–11. ©2011 AACR.
Involvement of chemokines in the spontaneous ankylosis mouse model: further evidence for the 'entheseal stress' hypothesis
Authors: K Braem, S Carter, C Deroose, F P Luyten, R J Lories
Journal: Annals of the Rheumatic Diseases (2010)

with lymph node expression profi les.Dexamethasone treatment did not affect the incidence or severity of ankylosis, but was associated with a reduction in infl ammatory changes in the paws at week 15 as measured by PET tracer uptake.Chemokines attracting neutrophils and lymphocytes were upregulated in affected paws.In vitro, BMP2 stimulation upregulated chemokines in different mesenchymal joint-associated cell types, but this effect was inhibited by dexamethasone.Cell stretch amplifi ed BMP2 induced reporter activation.Conclusion These experiments provide further evidence that entheseal stress, such as stretch, may contribute to activation of BMP signalling in the enthesis, triggering both new tissue formation and an infl ammatory phase.We therefore propose that anti-infl ammatory strategies only inhibit the latter and not the former aspect.
Cytotoxic effects of a recombinant chimeric toxin on rapidly proliferating vascular smooth muscle cells.
Authors: S E Epstein, C B Siegall, S Biro, Y M Fu, D FitzGerald, I Pastan
Journal: Circulation (1991)

Restenosis after percutaneous transluminal coronary angioplasty is associated with activation of medial smooth muscle cells (SMCs); they proliferate, migrate to the subintima, and narrow the vessel lumen. Cancer cells often express more cell surface receptors than do normal cells. This has allowed tumor cells to be specifically targeted using cytotoxic agents. We have examined whether a similar concept can be applied to rapidly proliferating but nontransformed SMCs. Pseudomonas exotoxin (PE; MW, 66 kDa) is a potent toxin that kills cells by inhibiting protein synthesis; its toxicity is diminished when its cell recognition domain is deleted to produce a 40-kDa protein (PE40).A complementary DNA encoding transforming growth factor alpha (TGF alpha) was ligated to that encoding PE40 and the chimeric toxin TGF alpha-PE40, which is cytotoxic to cancer cells displaying epidermal growth factor (EGF) receptors, was expressed in Escherichia coli. The ability of this toxin to kill proliferating SMCs was tested. When cells were seeded at low density (2,500 cells/cm2) and grown in medium supplemented with 10% fetal bovine serum, they were found to be rapidly proliferating; these cells were very sensitive to the cytotoxic effects of TGF alpha-PE40 (ID50, 4.0 +/- 0.17 ng/ml). In contrast, cytotoxicity was 30-fold less (ID50, 125 +/- 23 ng/ml; p less than 0.0004) when cells were in a quiescent state (grown in medium supplemented with 0.5% fetal bovine serum).Competition studies using excess EGF indicated that the cytotoxic effects of TGF alpha-PE40 are specifically mediated by the EGF receptor. EGF receptor binding analysis demonstrated that rapidly proliferating SMCs display 10-fold more EGF receptors than do quiescent SMCs in vitro. Thus, a chimeric toxin targeted toward the EGF receptor can selectively kill rapidly proliferating SMCs. Whether this toxin or other chimeric toxins directed against other cell surface receptors will effectively inhibit SMCs proliferating in vivo or be useful in preventing restenosis remains to be determined.
Control of Her-2 Tumor Immunity and Thyroid Autoimmunity by MHC and Regulatory T Cells
Authors: Jennifer B. Jacob, Yi-chi M. Kong, Chady Meroueh, Daniel P. Snower, Chella S. David, Ye-Shih Ho, Wei-Zen Wei
Journal: Cancer Research (2007)

Abstract Immune reactivity to self-antigens in both cancer and autoimmune diseases can be enhanced by systemic immune modulation, posing a challenge in cancer immunotherapy. To distinguish the genetic and immune regulation of tumor immunity versus autoimmunity, immune responses to human ErbB-2 (Her-2) and mouse thyroglobulin (mTg) were tested in transgenic mice expressing Her-2 that is overexpressed in several cancers, and HLA-DRB1*0301 (DR3) that is associated with susceptibility to several human autoimmune diseases, as well as experimental autoimmune thyroiditis (EAT). To induce Her-2 response, mice were electrovaccinated with pE2TM and pGM-CSF encoding the extracellular and transmembrane domains of Her-2 and the murine granulocyte macrophage colony-stimulating factor, respectively. To induce EAT, mice received mTg i.v. with or without lipopolysaccharide. Depletion of regulatory T cells (Treg) with anti-CD25 monoclonal antibody enhanced immune reactivity to Her-2 as well as mTg, showing control of both Her-2 and mTg responses by Treg. When immunized with, Her-2xDR3 and B6xDR3 mice expressing H2bxDR3 haplotype developed more profound mTg response and thyroid pathology than Her-2 or B6 mice that expressed the EAT-resistant H2b haplotype. In Her-2xDR3 mice, the response to mTg was further amplified when mice were also immunized with pE2TM and pGM-CSF. On the contrary, Her-2 reactivity was comparable whether mice expressed DR3 or not. Therefore, induction of Her-2 immunity was independent of DR3 but development of EAT was dictated by this allele, whereas Tregs control the responses to both self-antigens. These results warrant close monitoring of autoimmunity during cancer immunotherapy, particularly in patients with susceptible MHC class II alleles. [Cancer Res 2007;67(14):7020–7]
Nuclear Factor-κB Activation in Airway Epithelium Induces Inflammation and Hyperresponsiveness
Authors: Cristen Pantano, Jennifer L. Ather, John F. Alcorn, Matthew E. Poynter, Amy L. Brown, Amy S. Guala, Stacie L. Beuschel, Gilman B. Allen, Laurie A. Whittaker, Mieke Bevelander, Charles G. Irvin, Yvonne M. W. Janssen-Heininger
Journal: American Journal of Respiratory and Critical Care Medicine (2008)

Nuclear factor (NF)-kappaB is a prominent proinflammatory transcription factor that plays a critical role in allergic airway disease. Previous studies demonstrated that inhibition of NF-kappaB in airway epithelium causes attenuation of allergic inflammation.We sought to determine if selective activation of NF-kappaB within the airway epithelium in the absence of other agonists is sufficient to cause allergic airway disease.A transgenic mouse expressing a doxycycline (Dox)-inducible, constitutively active (CA) version of inhibitor of kappaB (IkappaB) kinase-beta (IKKbeta) under transcriptional control of the rat CC10 promoter, was generated.After administration of Dox, expression of the CA-IKKbeta transgene induced the nuclear translocation of RelA in airway epithelium. IKKbeta-triggered activation of NF-kappaB led to an increased content of neutrophils and lymphocytes, and concomitant production of proinflammatory mediators, responses that were not observed in transgenic mice not receiving Dox, or in transgene-negative littermate control animals fed Dox. Unexpectedly, expression of the IKKbeta transgene in airway epithelium was sufficient to cause airway hyperresponsiveness and smooth muscle thickening in absence of an antigen sensitization and challenge regimen, the presence of eosinophils, or the induction of mucus metaplasia.These findings demonstrate that selective activation NF-kappaB in airway epithelium is sufficient to induce airway hyperresponsiveness and smooth muscle thickening, which are both critical features of allergic airway disease.
Low basal serum cortisol in patients with severe atopic dermatitis: potent topical corticosteroids wrongfully accused
Authors: I.M. Haeck, L. Timmer-de Mik, E.G.W.M. Lentjes, E. Buskens, D.J. Hijnen, C. Guikers, C.A.F.M. Bruijnzeel-Koomen, M.S. de Bruin-Weller
Journal: British Journal of Dermatology (2007)

Journal Article Low basal serum cortisol in patients with severe atopic dermatitis: potent topical corticosteroids wrongfully accused Get access I.M. Haeck, I.M. Haeck Department of Dermatology and Allergology, Department of Clinical Chemistry and Haematology Correspondence: Inge Haeck. E‐mail: i.haeck@umcutrecht.nl Search for other works by this author on: Oxford Academic Google Scholar L. Timmer‐de Mik, L. Timmer‐de Mik Department of Dermatology and Allergology, Department of Clinical Chemistry and Haematology Search for other works by this author on: Oxford Academic Google Scholar E.G.W.M. Lentjes, E.G.W.M. Lentjes Department of Dermatology and Allergology, Department of Clinical Chemistry and Haematology Search for other works by this author on: Oxford Academic Google Scholar E. Buskens, E. Buskens Julius Center for Health Sciences and Primary Care, University Medical Centre Utrecht, 3584 CX Utrecht, The Netherlands Search for other works by this author on: Oxford Academic Google Scholar D.J. Hijnen, D.J. Hijnen Department of Dermatology and Allergology, Department of Clinical Chemistry and Haematology Search for other works by this author on: Oxford Academic Google Scholar C. Guikers, C. Guikers Department of Dermatology and Allergology, Department of Clinical Chemistry and Haematology Search for other works by this author on: Oxford Academic Google Scholar C.A.F.M. Bruijnzeel‐Koomen, C.A.F.M. Bruijnzeel‐Koomen Department of Dermatology and Allergology, Department of Clinical Chemistry and Haematology Search for other works by this author on: Oxford Academic Google Scholar M.S. De Bruin‐Weller M.S. De Bruin‐Weller Department of Dermatology and Allergology, Department of Clinical Chemistry and Haematology Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 156, Issue 5, 1 May 2007, Pages 979–985, https://doi.org/10.1111/j.1365-2133.2007.07753.x Published: 01 May 2007
Teaching landing skills in elite junior Australian football: evaluation of an injury prevention strategy
Authors: E Scase, J Cook, M Makdissi, B Gabbe, L Shuck
Journal: British Journal of Sports Medicine (2006)

Objective: To evaluate the effectiveness of a preseason physical training programme that taught landing and falling skills in improving landing skills technique and preventing injury in junior elite Australian football players. Methods: 723 male players who participated in an under 18 elite competition were studied prospectively in a non-randomised controlled trial over two consecutive football seasons. There were 114 players in the intervention group and 609 control players. The eight session intervention programme taught players six landing, falling, and recovery skills, which were considered fundamental for safe landing in Australian football. Landing skills taught in these sessions were rated for competence by independent and blinded assessors at baseline and mid-season. Results: Evaluation of landing skills found no significant differences between the groups at baseline. Evaluation after the intervention revealed overall improvement in landing skills, but significantly greater improvement in the intervention group (z = −7.92, p = 0.001). Players in the intervention group were significantly less likely (relative rate 0.72, 95% confidence interval 0.52 to 0.98) to sustain an injury during the season than the control group. In particular, the time to sustaining a landing injury was significantly less for the intervention group (relative rate 0.40, 95% confidence interval 0.17 to 0.92) compared with the control group. Conclusions: Landing and falling ability can be taught to junior elite Australian football players. Players in the intervention group were protected against injury, particularly injuries related to landing and falls.
The effect of Epstein–Barr virus status on outcome in age- andsex-defined subgroups of patients with advanced Hodgkin’s disease
Authors: K.J. Flavell, L.J. Billingham, J.P. Biddulph, L. Gray, J.R. Flavell, C.M. Constandinou, L.S. Young, P.G. Murray
Journal: Annals of Oncology (2003)
Correlated Expression of<i>CD47</i>and<i>SIRPA</i>in Bone Marrow and in Peripheral Blood Predicts Recurrence in Breast Cancer Patients
Authors: Makoto Nagahara, Koshi Mimori, Akemi Kataoka, Hideshi Ishii, Fumiaki Tanaka, Tsuyoshi Nakagawa, Takanobu Sato, Shinji Ono, Kenichi Sugihara, Masaki Mori
Journal: Clinical Cancer Research (2010)

CD47 plays a variety of roles in intercellular signaling. Herein, we focused on the clinicopathologic significance of CD47 expression in human breast cancer. Our data suggest that the correlation between CD47 and signal regulatory protein α (SIRPA) expression may play a key role in the progression of breast cancer.Quantitative real-time PCR was used to evaluate CD47 mRNA and SIRPA mRNA expression in bone marrow and in peripheral blood from 738 cases of breast cancer.In patients with high levels of CD47 expression in the bone marrow, survival was significantly poorer compared with patients with low levels of CD47 expression [disease-free survival (DFS), P = 0.0035; overall survival (OS), P = 0.015]. Furthermore, high CD47 expression group in a multivariate analysis showed significance as an independent variable for poorer prognosis in DFS (P = 0.024). In the peripheral blood, however, high CD47 expression in patients was not an independent and significant prognostic factor for DFS and OS in a multivariate analysis. CD47 expression was strongly correlated with SIRPA expression in both the bone marrow (P < 0.0001) and peripheral blood (P < 0.0001) of breast cancer patients.This is one of the first studies to show that a host factor in bone marrow confers prognostic importance. CD47 is an important biomarker in breast cancer, and functions as a prognostic factor for DFS. Moreover, we suggest that the poor prognosis of breast cancer patients with high expression of CD47 is due to an active CD47/SIRPA signaling pathway in circulating cells.
Maintenance of Fungal Pathogen Species That Are Specialized to Different Hosts: Allopatric Divergence and Introgression through Secondary Contact
Authors: P. Gladieux, E. Vercken, M. C. Fontaine, M. E. Hood, O. Jonot, A. Couloux, T. Giraud
Journal: Molecular Biology and Evolution (2010)

Sympatry of species that lack complete prezygotic isolation is ideal for the study of how species can be maintained in the face of potential gene flow. This is particularly important in the context of emerging diseases on new hosts because pathogen adaptation is facilitated by reduced gene flow from ancestral populations. Here, we investigated divergence and gene flow between two closely related fungal species, Microbotryum lychnidis-dioicae and M. silenes-dioicae, causing anther-smut disease on the wide-spread plant species Silene latifolia and S. dioica, respectively. Using model-based clustering algorithms on microsatellite data from samples across Europe, we identified rare disease transmission between the host species and rare pathogen hybrids. Using a coalescent-based approach and an isolation-with-migration model, the age of divergence between the two fungal species was estimated at approximately 4.2 × 105 years. Levels of gene flow were low and concentrated in very recent times. In addition, gene flow appeared unidirectional from M. silenes-dioicae to M. lychnidis-dioicae. Altogether, our findings are consistent with a scenario of recurrent introgressive hybridization but at a very low level and through secondary contact following initial divergence in allopatry. Asymmetry in the direction of gene flow mirrors previous findings on introgression between the two host plants. Our study highlights the consequences of bringing closely related pathogens into contact, which is increasing through modern global changes and favors cross-species disease transmission, hybridization, and introgression by pathogens.
Blocking costimulatory signal for treating steroid-resistant asthma model
Authors: Akio Mori, Akemi Abe, Satoshi Kouyama, Miyako Yamaguchi, Mika Enoki, Yo Iijima, Chihiro Mitsui, Chiyako Oshikata, Hidenori Tanimoto, Yuma Fukutomi, Kiyoshi Sekiya, Masami Taniguchi, Yuji Maeda, Mamoru Ohtomo, Maki Hasegawa, Kazuo Akiyama, Takayuki Ohtomo, Osamu Kaminua
Journal: European Respiratory Journal (2012)

Background:   We have constructed steroid sensitive (SS) and resistant (SR) murine asthma models by transferring SS and SR helper T (Th) clones into unprimed mice, respectively. Effect of CTLA4-Ig was analyzed both  in vitro  and  in vivo .    Method:   For  in vitro  experiments, ovalbumin (OVA) reactive Th clones were cultured with antigen presenting cells, OVA, and various concentrations of dexamethasone (DEX). The proliferative response of each Th clone was measured by  3 H-thymidine uptake. For  in vivo  experiments, unprimed BALB/c mice were transferred with Th clones, challenged with OVA, and administered with DEX subcutaneously. CTLA4-Ig was administered through nasal inhalation or venous injection. The number of infiltrating cells in bronchoalveolar lavage fluid (BALF) was measured.    Results:   SS and SR clones were selected in terms of the  in vitro  effect of DEX on the proliferative responses of antigen-stimulated clones. Airway infiltration of eosinophils and lymphocytes of mice transferred with SS clones were effectively inhibited by the administration of DEX. In contrast, those of mice transferred with SR clones were not significantly inhibited by DEX. Administration of CTLA4-Ig significantly suppressed  in vitro  proliferation of DEX-treated SR clones, and  in vivo  eosinophil infiltration of SR asthma model transferred with SR clones.    Conclusion:   Steroid sensitivity of Th clones measured  in vitro  were consistent with that of adoptively transferred asthma model measured  in vivo . Steroid resistant asthma models can be treated by blocking costimulatory signal mediated through CD28-CD80 and 86.
Analysis of gene expression in a developmental context emphasizes distinct biological leitmotifs in human cancers
Authors: Kamila Naxerova, Carol J Bult, Anne Peaston, Karen Fancher, Barbara B Knowles, Simon Kasif, Isaac S Kohane
Journal: Genome biology (2008)

In recent years, the molecular underpinnings of the long-observed resemblance between neoplastic and immature tissue have begun to emerge. Genome-wide transcriptional profiling has revealed similar gene expression signatures in several tumor types and early developmental stages of their tissue of origin. However, it remains unclear whether such a relationship is a universal feature of malignancy, whether heterogeneities exist in the developmental component of different tumor types and to which degree the resemblance between cancer and development is a tissue-specific phenomenon. We defined a developmental landscape by summarizing the main features of ten developmental time courses and projected gene expression from a variety of human tumor types onto this landscape. This comparison demonstrates a clear imprint of developmental gene expression in a wide range of tumors and with respect to different, even non-cognate developmental backgrounds. Our analysis reveals three classes of cancers with developmentally distinct transcriptional patterns. We characterize the biological processes dominating these classes and validate the class distinction with respect to a new time series of murine embryonic lung development. Finally, we identify a set of genes that are upregulated in most cancers and we show that this signature is active in early development. This systematic and quantitative overview of the relationship between the neoplastic and developmental transcriptome spanning dozens of tissues provides a reliable outline of global trends in cancer gene expression, reveals potentially clinically relevant differences in the gene expression of different cancer types and represents a reference framework for interpretation of smaller-scale functional studies.
Detection of Spontaneous CD4+ T-Cell Responses in Melanoma Patients against a Tyrosinase-Related Protein-2–Derived Epitope Identified in HLA-DRB1*0301 Transgenic Mice
Authors: Annette Paschen, Mingxia Song, Wolfram Osen, Xuan Duc Nguyen, Jan Mueller-Berghaus, Daniela Fink, Nadine Daniel, Mariel Donzeau, Wolfgang Nagel, Harald Kropshofer, Dirk Schadendorf
Journal: Clinical Cancer Research (2005)

Abstract Purpose: The frequently expressed differentiation antigen tyrosinase-related protein-2 (TRP-2) has repeatedly been described as a target of spontaneous cytotoxic T-cell responses in melanoma patients, suggesting that it might be an ideal candidate antigen for T cell–based immunotherapy. As a prerequisite for immunization, T-cell epitopes have to be identified. Whereas a number of HLA class I–presented TRP-2–derived epitopes are known, information about HLA class II–presented antigenic ligands recognized by CD4+ T helper (Th) cells is limited. Experimental Design: The search for TRP-2–derived Th epitopes was carried out by competitive in vitro peptide binding studies with predicted HLA-DRB1*0301 ligands in combination with peptide and protein immunizations of HLA-DRB1*0301 transgenic mice. In vivo selected candidate epitopes were subsequently verified for their immunogenicity in human T-cell cultures. Results: This strategy led to the characterization of TRP-260-74 as an HLA-DRB1*0301–restricted Th epitope. Importantly, TRP-260-74–reactive human CD4+ Th cell lines, specifically recognizing target cells loaded with recombinant TRP-2 protein, could be established by repeated peptide stimulation of peripheral blood lymphocytes from several HLA-DRB1*03+ melanoma patients. Even short-term peptide stimulation of patients' peripheral blood lymphocytes showed the presence of TRP-260-74–reactive T cells, suggesting that these T cells were already activated in vivo. Conclusion: Peptide TRP-260-74 might be a useful tool for the improvement of immunotherapy and immune monitoring of melanoma patients.