tbuckley/cabot-search huggingface dataset:
Anti-CD63 antibodies suppress IgE-dependent allergic reactions in vitro and in vivo
Authors: Stefan Kraft, Tony Fleming, James M. Billingsley, Shih-Yao Lin, Marie-Hélène Jouvin, Peter Storz, Jean-Pierre Kinet
Journal: The Journal of Experimental Medicine (2005)

High-affinity IgE receptor (FcεRI) cross-linking on mast cells (MCs) induces secretion of preformed allergy mediators (degranulation) and synthesis of lipid mediators and cytokines. Degranulation produces many symptoms of immediate-type allergic reactions and is modulated by adhesion to surfaces coated with specific extracellular matrix (ECM) proteins. The signals involved in this modulation are mostly unknown and their contribution to allergic reactions in vivo is unclear. Here we report the generation of monoclonal antibodies that potently suppress FcεRI-induced degranulation, but not leukotriene synthesis. We identified the antibody target as the tetraspanin CD63. Tetraspanins are membrane molecules that form multimolecular complexes with a broad array of molecules including ECM protein-binding β integrins. We found that anti-CD63 inhibits MC adhesion to fibronectin and vitronectin. Furthermore, anti-CD63 inhibits FcεRI-mediated degranulation in cells adherent to those ECM proteins but not in nonadherent cells. Thus the inhibition of degranulation by anti-CD63 correlates with its effect on adhesion. In support of a mechanistic linkage between the two types of inhibition, anti-CD63 had no effect on FcεRI-induced global tyrosine phosphorylation and calcium mobilization but impaired the Gab2–PI3K pathway that is known to be essential for both degranulation and adhesion. Finally, we showed that these antibodies inhibited FcεRI-mediated allergic reactions in vivo. These properties raise the possibility that anti-CD63 could be used as therapeutic agents in MC-dependent diseases.
Reply to the article “Metronomic therapy with cyclophosphamide induces rat lymphoma and sarcoma regression, and is devoid of toxicity” by V. R. Rozados et al. (Ann Oncol 2004; 15: 1543–1550): … and in humans?
Authors: T. De Pas, M. Colleoni, L. Orlando, G. Masci, A. Rocca, C. Catania, G. Curigliano, S. Manzoni, A. Goldhirsch, F. de Braud
Journal: Annals of Oncology (2005)
Prevalence of symptoms experienced by patients with different clinical types of psoriasis
Authors: F. Sampogna, P. Gisondi, C.F. Melchi, P. Amerio, G. Girolomoni, D. Abeni
Journal: British Journal of Dermatology (2004)

Background The main dermatology textbooks describe only in passing pruritus in psoriasis and rarely mention other symptoms. A quantification of the presence of symptoms is not available for clinical subgroups of psoriasis. Objectives To investigate the prevalence of symptoms experienced by patients with different clinical types of psoriasis. Methods The study was carried out in patients hospitalized for psoriasis between February 2000 and February 2002 at the inpatient wards of the Istituto Dermopatico dell'Immacolata, Rome, Italy. Symptoms were evaluated using the symptoms scale of Skindex-29. Clinical severity was assessed by the dermatologists using the Psoriasis Area and Severity Index (PASI), and by the patients completing the self-administered PASI. Psychiatric morbidity was evaluated using the 12-item General Health Questionnaire. Results In total, 936 eligible patients were analysed. The proportions of patients experiencing symptoms often or always in the 4 weeks before hospitalization were: 63·8% itching, 59·7% irritation, 46·1% burning/stinging, 39% sensitivity, 26% pain (from 10% in guttate psoriasis to 50% in arthropathic), 25·4% bleeding (17% pustular, 19% localized plaque, 36% palmoplantar), and 23·9% bothered by water (from 8·5% in the guttate form to 68% in palmoplantar). The prevalence of all symptoms was significantly higher in women and tended to increase with clinical severity. Conclusions Our study provides evidence of the high frequency of a number of symptoms in different subgroups of psoriasis patients determined by their sociodemographic characteristics, clinical type and disease severity. Symptoms represent a serious disabling factor in patients affected by psoriasis, including those with low levels of psychological distress. Dermatologists should include symptoms in the evaluation of disease severity both in clinical practice and in clinical trials.
Phase II Trial of the CDK4 Inhibitor PD0332991 in Patients With Advanced<i>CDK4</i>-Amplified Well-Differentiated or Dedifferentiated Liposarcoma
Authors: Mark A. Dickson, William D. Tap, Mary Louise Keohan, Sandra P. D'Angelo, Mrinal M. Gounder, Cristina R. Antonescu, Jonathan Landa, Li-Xuan Qin, Dustin D. Rathbone, Mercedes M. Condy, Yelena Ustoyev, Aimee M. Crago, Samuel Singer, Gary K. Schwartz
Journal: Journal of Clinical Oncology (2013)

CDK4 is amplified in > 90% of well-differentiated (WDLS) and dedifferentiated liposarcomas (DDLS). The selective cyclin-dependent kinase 4 (CDK4)/CDK6 inhibitor PD0332991 inhibits growth and induces senescence in cell lines and xenografts. In a phase I trial of PD0332991, several patients with WDLS or DDLS experienced prolonged stable disease. We performed an open-label phase II study to determine the safety and efficacy of PD0332991 in patients with advanced WDLS/DDLS.
Sirtuin-6-dependent genetic and epigenetic alterations are associated with poor clinical outcome in hepatocellular carcinoma patients
Authors: Jens U. Marquardt, Kerstin Fischer, Katharina Baus, Anubha Kashyap, Shengyun Ma, Markus Krupp, Matthias Linke, Andreas Teufel, Ulrich Zechner, Dennis Strand, Snorri S. Thorgeirsson, Peter R. Galle, Susanne Strand
Journal: Hepatology (2013)

Sirtuin 6 (SIRT6) is a member of the sirtuin family of NAD+-dependent deacetylases. Genetic deletion of Sirt6 in mice results in a severe degenerative phenotype with impaired liver function and premature death. The role of SIRT6 in development and progression of hepatocellular carcinoma is currently unknown. We first investigated SIRT6 expression in 153 primary human liver cancers and in normal and cirrhotic livers using microarray analysis. SIRT6 was significantly down-regulated in both cirrhotic livers and cancer. A Sirt6 knockout (KO) gene expression signature was generated from primary hepatoctyes isolated from 3-week-old Sirt6-deficient animals. Sirt6-deficient hepatocytes showed up-regulation of established hepatocellular carcinoma (HCC) biomarkers alpha-fetoprotein (Afp), insulin-like growth factor 2 (Igf2), H19, and glypican-3. Furthermore, decreased SIRT6 expression was observed in hepatoma cell lines that are known to be apoptosis-insensitive. Re-expression of SIRT6 in HepG2 cells increased apoptosis sensitivity to CD95-stimulation or chemotherapy treatment. Loss of Sirt6 was characterized by oncogenic changes, such as global hypomethylation, as well as metabolic changes, such as hypoglycemia and increased fat deposition. The hepatocyte-specific Sirt6-KO signature had a prognostic impact and was enriched in patients with poorly differentiated tumors with high AFP levels as well as recurrent disease. Finally, we demonstrated that the Sirt6-KO signature possessed a predictive value for tumors other than HCC (e.g., breast and lung cancer).Loss of SIRT6 induces epigenetic changes that may be relevant to chronic liver disease and HCC development. Down-regulation of SIRT6 and genes dysregulated by loss of SIRT6 possess oncogenic effects in hepatocarcinogenesis. Our data demonstrate that deficiency in one epigenetic regulator predisposes a tumorigenic phenotype that ultimately has relevance for outcome of HCC and other cancer patients.
Immortalization of Primary Human Prostate Epithelial Cells by c-Myc
Authors: Jesús Gil, Preeti Kerai, Matilde Lleonart, David Bernard, Juan Cruz Cigudosa, Gordon Peters, Amancio Carnero, David Beach
Journal: Cancer Research (2005)

Abstract A significant percentage of prostate tumors have amplifications of the c-Myc gene, but the precise role of c-Myc in prostate cancer is not fully understood. Immortalization of human epithelial cells involves both inactivation of the Rb/p16INK4a pathway and telomere maintenance, and it has been recapitulated in culture by expression of the catalytic subunit of telomerase, hTERT, in combination with viral oncoproteins. Here, we show the immortalization of human prostate epithelial cells (HPrEC) by a single genetic event, the expression of the c-Myc oncogene. Myc stabilizes telomere length in HPrEC through up-regulation of hTERT expression and overrides the accumulation of cell cycle inhibitory proteins, such as p16INK4a. Overall, HPrECs expressing c-Myc retain many characteristics of normal cells, such as the induction of a senescence-like growth arrest in response to oncogenic Ras, an intact p53 response, and an absence of gross karyotypic abnormalities. However, HPrECs expressing c-Myc lack a Rb/p16INK4a checkpoint and can be transformed without the need for additional genetic lesions in that pathway. These results give a partial explanation for the physiologic role of c-Myc overexpression in prostate cancer.
Expanded Granulocyte/Monocyte Compartment in Myeloid-Specific Triple FoxO Knockout Increases Oxidative Stress and Accelerates Atherosclerosis in Mice
Authors: Kyoichiro Tsuchiya, Marit Westerterp, Andrew J. Murphy, Vidya Subramanian, Anthony W. Ferrante, Alan R. Tall, Domenico Accili
Journal: Circulation Research (2013)

Rationale: Increased neutrophil and monocyte counts are often associated with an increased risk of atherosclerosis, but their relationship to insulin sensitivity is unknown. Objective: To investigate the contribution of forkhead transcription factors (FoxO) in myeloid cells to neutrophil and monocyte counts, atherosclerosis, and systemic insulin sensitivity. Methods and Results: Genetic ablation of the 3 genes encoding FoxO isoforms 1, 3a, and 4, in myeloid cells resulted in an expansion of the granulocyte/monocyte progenitor compartment and was associated with increased atherosclerotic lesion formation in low-density lipoprotein receptor knockout mice. In vivo and ex vivo studies indicate that FoxO ablation in myeloid cells increased generation of reactive oxygen species. Accordingly, treatment with the antioxidant N-acetyl- l -cysteine reversed the phenotype, normalizing atherosclerosis. Conclusions: Our data indicate that myeloid cell proliferation and oxidative stress can be modulated via the FoxO branch of insulin receptor signaling, highlighting a heretofore-unknown link between insulin sensitivity and leukocytosis that can affect the predisposition to atherosclerosis.
Long-term survival of surgically staged IIIA-N2 non-small-cell lung cancer treated with surgical combined modality approach: analysis of a 7-year prospective experience
Authors: N. Lorent, P. De Leyn, Y. Lievens, E. Verbeken, K. Nackaerts, C. Dooms, D. Van Raemdonck, B. Anrys, J. Vansteenkiste
Journal: Annals of Oncology (2004)
Circulating endothelial cells in relapse and limited granulomatous disease due to ANCA associated vasculitis
Authors: A Woywodt
Journal: Annals of the Rheumatic Diseases (2005)

<b>Objectives:</b> To evaluate numbers of circulating endothelial cells (CECs) in ANCA associated vasculitis and compare vasculitic relapse with limited granulomatous disease. <b>Methods:</b> Sixteen patients with vasculitic relapse of ANCA associated vasculitis and 12 patients with limited granulomatous disease due to Wegener's granulomatosis (WG) were studied. Six patients with newly diagnosed vasculitic disease and six patients with vasculitis with infectious complications were also studied. Twenty two patients in remission were studied, as were 20 healthy controls. Counting of CECs was performed with anti-CD146 driven immunomagnetic isolation and staining with Ulex Europaeus lectin 1(UEA-1). <b>Results:</b> Patients with vasculitic relapse had markedly increased numbers of circulating endothelial cells (12–800 cells/ml, median 88 cells/ml) as did patients with newly diagnosed systemic vasculitis (20–216 cells/ml, median 56 cells/ml). Patients with limited granulomatous disease due to WG had only slightly increased cell numbers (4–44 cells/ml, median 20 cells/ml), which were similar to those of patients in remission (4–36 cells/ml, median 16 cells/ml). Numbers of CECs in patients with granulomatous disease were significantly lower than in those patients with relapse or new onset vasculitis (p&lt;0.001). Cell numbers in patients with relapse and new onset vasculitis declined with immunosuppressive treatment. Patients with infection had 4–36 cells/ml (median 10 cells/ml). A cut off value of 20 cells/ml for a positive result yielded 64% specificity and 95% sensitivity for active systemic vasculitis; the positive predictive value was 63% and the negative predictive value 95%. <b>Conclusion:</b> Markedly increased numbers of CECs discriminate active vasculitis from limited granulomatous disease and remission. These findings add further proof to the concept of CECs as a marker of ANCA associated small vessel vasculitis.
Survival, Durable Tumor Remission, and Long-Term Safety in Patients With Advanced Melanoma Receiving Nivolumab
Authors: Suzanne L. Topalian, Mario Sznol, David F. McDermott, Harriet M. Kluger, Richard D. Carvajal, William H. Sharfman, Julie R. Brahmer, Donald P. Lawrence, Michael B. Atkins, John D. Powderly, Philip D. Leming, Evan J. Lipson, Igor Puzanov, David C. Smith, Janis M. Taube, Jon M. Wigginton, Georgia D. Kollia, Ashok Gupta, Drew M. Pardoll, Jeffrey A. Sosman, F. Stephen Hodi
Journal: Journal of Clinical Oncology (2014)

Programmed cell death 1 (PD-1) is an inhibitory receptor expressed by activated T cells that downmodulates effector functions and limits the generation of immune memory. PD-1 blockade can mediate tumor regression in a substantial proportion of patients with melanoma, but it is not known whether this is associated with extended survival or maintenance of response after treatment is discontinued.
Approaches for exposure characterization and data needs for hazardous waste site assessment.
Authors: J M Waldman
Journal: Environmental Health Perspectives (1995)

This article provides an understanding of the approaches for determining exposure and dose to populations in the vicinity of hazardous waste sites. A review of the federal legislation and jurisdiction for assessments is provided, and the approaches of the U.S. Environmental Protection Agency and the Agency for Toxic Substances and Disease Registry are compared. These methods strive to aid in the evaluation of public health impacts of contaminants that were, are, or may be released to the community, and they are concerned with various aspects of the contaminant fate, human contact, and toxic response for chemicals of concern. Such approaches have been designed for generic contamination scenarios, but they aim to be applicable to a wide range of chemicals and sites in the real world. Along with any modeling framework for exposure and dose characterization, detailed information or real data are requisite for the completion of any site-specific assessment. What kinds of data are needed and where they may be found are also discussed. A comprehensive framework for exposure characterization, recently proposed by Georgopoulos and Lioy, is outlined. The framework is one employing the following elements: chemodynamic analyses of sources and receptors; characterization of the target population; toxicokinetic/toxicodynamic analyses; uncertainty/error analyses; and evaluation of the characterization performance.
Utility of B-Type Natriuretic Peptide (BNP) as a Screen for Left Ventricular Dysfunction in Patients With Diabetes
Authors: Victoria Epshteyn, Katherine Morrison, Padma Krishnaswamy, Radmila Kazanegra, Paul Clopton, Sunder Mudaliar, Steven Edelman, Robert Henry, Alan Maisel
Journal: Diabetes Care (2003)

OBJECTIVE—Routine screening of diabetic patients with echocardiography is not feasible due to its limited availability and high cost. B-type natriuretic peptide (BNP) is secreted from the left ventricle in response to pressure overload and is elevated in both systolic and diastolic dysfunction. RESEARCH DESIGN AND METHODS—BNP levels were compared to echocardiographic findings in 263 patients. Patients were divided into two groups: clinical indication for echocardiography (CIE) (n = 172) and those without clinical indication for echocardiography (no-CIE) (n = 91). Cardiologists making the assessment of left ventricular function were blinded when measuring plasma levels of BNP. RESULTS—The 91 patients with no-CIE with echos had similar BNP levels (83 ± 16 pg/ml) to the 215 patients with no-CIE without echos (63 ± 10, P = 0.10). Patients with CIE and subsequent abnormal left ventricular function (n = 112) had a mean BNP concentration of 435 ± 41 pg/ml, compared with those with no-CIE, but had abnormal left ventricular function on echo (n = 32) (161 ± 40 pg/ml). Twenty-one of 32 patients with no-CIE but with abnormal left ventricular function had diastolic dysfunction (BNP 190 ± 60pg/ml). A receiver-operating characteristic (ROC) curve revealed that the area under the curve was 0.91 for CIE patients and 0.81 for no-CIE patients (P &amp;lt; 0.001). For those with no congestive heart failure (CHF) symptoms, BNP levels showed a high negative predictive value (91% for BNP values &amp;lt;39 pg/ml), while in those patients who had a CIE, BNP levels showed a high positive predictive value for the detection of left ventricular dysfunction (96% with BNP levels &amp;gt;90 pg/ml). CONCLUSIONS—BNP can reliably screen diabetic patients for the presence or absence of left ventricular dysfunction.
Tumor Stromal Architecture Can Define the Intrinsic Tumor Response to VEGF-Targeted Therapy
Authors: Neil R. Smith, Dawn Baker, Matthew Farren, Aurelien Pommier, Ruth Swann, Xin Wang, Sunita Mistry, Karen McDaid, Jane Kendrew, Chris Womack, Stephen R. Wedge, Simon T. Barry
Journal: Clinical Cancer Research (2013)

The aim of the study was to investigate the vascular and stromal architecture of preclinical tumor models and patient tumor specimens from malignancies with known clinical outcomes to VEGFi treatment, to gain insight into potential determinants of intrinsic sensitivity and resistance.The tumor stroma architecture of preclinical and clinical tumor samples were analyzed by staining for CD31 and α-smooth muscle actin (α-SMA). Tumor models representative of each phenotype were then tested for sensitivity to the VEGFR2-blocking antibody DC101.Human tumor types with high response rates to VEGF inhibitors (e.g., renal cell carcinoma) have vessels distributed amongst the tumor cells (a "tumor vessel" phenotype, TV). In contrast, those malignancies where single-agent responses are lower, such as non-small cell lung cancer (NSCLC), display a complex morphology involving the encapsulation of tumor cells within stroma that also supports the majority of vessels (a "stromal vessel" phenotype). Only 1 of 31 tumor xenograft models displayed the stromal vessel phenotype. Tumor vessel models were sensitive to VEGFR2-blocking antibody DC101, whereas the stromal vessel models were exclusively refractory. The tumor vessel phenotype was also associated with a better Response Evaluation Criteria in Solid Tumors (RECIST) response to bevacizumab + chemotherapy in metastatic colorectal cancer (CRC).The tumor stromal architecture can differentiate between human tumor types that respond to a VEGF signaling inhibitor as single-agent therapy. In addition to reconciling the clinical experience with these agents versus their broad activity in preclinical models, these findings may help to select solid tumor types with intrinsic sensitivity to a VEGFi or other vascular-directed therapies.
Neutrophil-specific Granule Deficiency Results from a Novel Mutation with Loss of Function of the Transcription Factor CCAAT/Enhancer Binding Protein ε
Authors: Julie A. Lekstrom-Himes, Susan E. Dorman, Piroska Kopar, Steven M. Holland, John I. Gallin
Journal: The Journal of Experimental Medicine (1999)

Neutrophil-specific granule deficiency (SGD) is a rare disorder characterized by recurrent pyogenic infections, defective neutrophil chemotaxis and bactericidal activity, and lack of neutrophil secondary granule proteins. CCAAT/enhancer binding protein (C/EBP)ε, a member of the leucine zipper family of transcription factors, is expressed primarily in myeloid cells, and its knockout mouse model possesses distinctive defects, including a lack of neutrophil secondary granule proteins. Sequence analysis of the genomic DNA of a patient with SGD revealed a five-basepair deletion in the second exon of the C/EBPε locus. The predicted frame shift results in a truncation of the 32-kD major C/EBPε isoform, with loss of the dimerization domain, DNA binding region, and transcriptional activity. The multiple functional defects observed in these early neutrophil progenitor cells, a consequence of C/EBPε deficiency, define SGD as a defect in myelopoiesis and establish the requirement for C/EBPε for the promyelocyte–myelocyte transition in myeloid differentiation.
Intestinal epithelial exosomes carry MHC class II/peptides able to inform the immune system in mice
Authors: G Van Niel
Journal: Gut (2003)

<b>Background:</b> Intestinal epithelial cells secrete exosome-like vesicles. The aim of this study was to characterise murine intestinal epithelial exosomes and to analyse their capacity to inform the immune system in vivo in mice. <b>Methods:</b> Epithelial exosomes were obtained from the murine epithelial cell line MODE K incubated in the presence or absence of interferon γ (IFN-γ) together with pepsin/trypsin ovalbumin hydrolysate (hOVA) to mimic luminal digestion. Exosomes isolated from MODE K conditioned media (EXO-hOVA and EXO-hOVA-IFN) were characterised by western blot, peptide mapping, and mass spectrometry. They were injected intraperitoneally to C3H/HeN mice to test their immunocompetence. <b>Results:</b> MODE K epithelial exosomes displayed major histocompatibility complex (MHC) class I and class II (upregulated by IFN-γ) molecules and tetraspan proteins (CD9, CD81, CD82) potentially involved in the binding to target cells. A33 antigen, an Ig-like molecule highly specific for intestinal epithelial cells, was enriched in exosomes and was also found in mice mesenteric lymph nodes, suggesting exosome migration towards the gut associated lymphoid tissues. Intraperitoneal injection of EXO-hOVA or EXO-hOVA-IFN did not induce humoral or cellular tolerance to OVA in mice. In contrast, exosomes obtained after incubation with IFN-γ (EXO-hOVA-IFN), bearing abundant MHC class II/OVA complexes, induced a specific humoral immune response. <b>Conclusions:</b> Epithelial exosomes are antigen presenting vesicles bearing MHC class II/peptide complexes that prime for an immunogenic rather than tolerogenic response in the context of a systemic challenge. In the intestine, both the mucosal microenvironment and local effector cells are probably key players in determining the outcome of the immune response to exosome derived epitopes.