tbuckley/cabot-search huggingface dataset:
Differential gene expression in anatomical compartments of the human eye.
Authors: Jennifer J Diehn, Maximilian Diehn, Michael F Marmor, Patrick O Brown
Journal: Genome biology (2005)

Abstract Background The human eye is composed of multiple compartments, diverse in form, function, and embryologic origin, that work in concert to provide us with our sense of sight. We set out to systematically characterize the global gene expression patterns that specify the distinctive characteristics of the various eye compartments. Results We used DNA microarrays representing approximately 30,000 human genes to analyze gene expression in the cornea, lens, iris, ciliary body, retina, and optic nerve. The distinctive patterns of expression in each compartment could be interpreted in relation to the physiology and cellular composition of each tissue. Notably, the sets of genes selectively expressed in the retina and in the lens were particularly large and diverse. Genes with roles in immune defense, particularly complement components, were expressed at especially high levels in the anterior segment tissues. We also found consistent differences between the gene expression patterns of the macula and peripheral retina, paralleling the differences in cell layer densities between these regions. Based on the hypothesis that genes responsible for diseases that affect a particular eye compartment are likely to be selectively expressed in that compartment, we compared our gene expression signatures with genetic mapping studies to identify candidate genes for diseases affecting the cornea, lens, and retina. Conclusion Through genome-scale gene expression profiling, we were able to discover distinct gene expression 'signatures' for each eye compartment and identified candidate disease genes that can serve as a reference database for investigating the physiology and pathophysiology of the eye.
Abstract 9617: Real Angiogenic Potential of Early or Late Outgrowth Endothelial Progenitor Cells is Rigorously Dependent on the Time of Emergence
Authors: Yoshiyasu Minami, Makoto Sahara, Toshiaki Nakajima, Masayasu Ikutomi, Toshihiro Morita, Hiroshi Yamashita, Yasunobu Hirata, Ryozo Nagai, Masataka Sata
Journal: Circulation (2012)

Background: Recent studies have suggested that late outgrowth endothelial progenitor cells (EPCs) emerging from cultured peripheral blood mononuclear cells (PBMNCs) might have higher angiogenic potential than that of classically defined early outgrowth EPCs (EOCs). However, it still remains undetermined which of EPC subpopulations rigorously defined by the time of emergence has the highest therapeutic angiogenic potency. Methods and Results: Human PBMNCs freshly isolated were cultured under the endothelial cell conditions. EOCs were defined as the cells attached on culture plates at days 3 to 7, and late outgrowth EPCs were defined as the cells forming clusters with cobble stone appearance at days 10 to 30. In addition, late outgrowth EPCs were newly defined according to the dates of colony emergence as follows: MOC at days 10-16, LOC at days 17-23 and VOC at days 24-30. Flow cytometry analyses revealed that the expression patterns of cell surface antigens relating to hematopoietic/endothelial lineages varied among EPC subpopulations, e.g., EOC: CD31 + CD34 + CD14 + CD105 low and LOC: CD31 + CD34 + CD14 - CD105 high . Using in vitro assays, we found that LOCs had the highest proliferation and tube formation potentials along with the highest expression of eNOS. Then, each EPC subpopulation was intravenously injected into immunocompromised mice at days 1, 3, 5 and 7 after unilateral hindlimb ischemia surgery (each 1×10 5 cells per time). Four weeks after surgery, the mice in LOC-injected group showed significantly enhanced blood flow recovery (blood flow ratios of ischemic/non ischemic leg: 1.02±0.02 [LOC group] versus 0.60±0.16 to 0.85±0.14 [other groups], P &lt;0.05) and augmented capillary collateral formation in ischemic leg. To evaluate how much percentage of CD31 + endothelial cells (ECs) of generated capillaries were derived from the injected EPCs, the GFP-labeled EPCs were injected into the mice with hindlimb ischemia. The proportions of human EPC-derived ECs among a total of CD31 + ECs in ischemic muscle were 14.3±2.8% in LOC group and 4.0±1.8% to 9.2±2.3% in other groups ( P &lt;0.05). Conclusions: Late outgrowth EPCs emerging at days 17-23 in ex vivo culture of human PBMNCs are superior to other EPC subpopulations as to the therapeutic angiogenic potency.
Focal adhesion kinase (FAK) activity promotes tumor growth and neo-vascularization via upregulation of angiogenic factors
Authors: Satyajit Mitra, John Molina, Daniel Hanson, Datsun Hsia, David Mikolon, Aileen Chi, Dwayne Stupack, David Cheresh, David Schlaepfer
Journal: Cancer Research (2005)

2029   FAK is a protein tyrosine kinase that facilitates integrin receptor signals controlling cell motility, survival, and cell division. In many human cancers, FAK expression is elevated yet its role in tumor progression remains undefined. Here, through comparisons of 4T1 breast carcinoma cells expressing a dominant-negative inhibitor of FAK activity or Src-transformed FAK-null cells reconstituted with various FAK mutants, we will show that FAK signaling promotes dramatic cell growth differences in vivo as tumors in mice, without detectable changes in cell proliferation in culture. 4T1 tumors in mice or grown on chicken chorioallantoic membranes were large and highly vascularized whereas 4T1 tumors with inhibited FAK activity were 6-fold smaller, contained fewer Tie-2-reactive blood vessels, and exhibited less VEGF staining. Dominant-negative inhibition of FAK activity in 4T1 cells was selectively associated with reduced FAK phosphorylation at Y925 (a Grb2 SH2 binding site) and Y576/Y577 within the FAK catalytic region. Impaired Grb2 binding to FAK and reduced ERK2/MAP kinase activation were detected in 4T1 cells with reduced FAK activity. As ERK2 activation can promote tumor growth through the increased production or release of pro-angiogenic factors, DNA micro-array analyses were performed. FAK signaling was associated with increased mRNA levels for VEGF, urokinase plasminogen activator (uPA), and hyaluronidase-5. To confirm the role of FAK catalytic activity and Grb2 binding in promoting tumor growth and neo-vascularization, kinase-inactive (R454) and Grb2 binding site (F925) mutant FAK constructs were used to stably reconstitute transformed FAK-null cells. Both mutations resulted in impaired VEGF production, reduced tumor growth and neo-vascularization in vivo compared to wildtype FAK-reconstituted cells. These studies support a novel role for FAK signaling leading to the production and release of pro-angiogenic factors from tumor cells. As FAK catalytic activity was required for elevated tumor growth and angiogenesis, FAK should be considered a potential target for therapeutic intervention in cancer.
The clinical significance of command hallucinations
Authors: D Hellerstein, W Frosch, H W Koenigsberg
Journal: American Journal of Psychiatry (1987)

Patients with command hallucinations (voices ordering particular acts, often violent or destructive ones) are commonly assumed to be at high risk for dangerous behavior. The authors reviewed 789 consecutive inpatient admissions. Of 151 patients with auditory hallucinations, 58 (38.4%) heard commands. The presence of auditory hallucinations was significantly associated with diagnosis, demographic variables, and use of maximal observation and seclusion. However, patients with command hallucinations were not significantly different from patients without commands on demographic and behavioral variables, including suicidal ideation or behavior and assaultiveness. These findings suggest that command hallucinations alone may not imply greater risk for acute, life-threatening behavior.
An assessment of the pain perceived during routine un-anaesthetised arterial puncture
Authors: Richard Glover, Julie Lloyd
Journal: European Respiratory Journal (2014)

Introduction:  Arterial puncture (AP) is perceived as a painful procedure. Despite this, obtaining arterial blood via AP to measure arterial gas tensions is vital when managing patients with respiratory failure.   Aim:  To determine the pain perceived during single AP, when performed by competent operator in a routine oxygen assessment (LTOT) clinic.   Methods:  34[M:F,20:14] subjects attending LTOT clinic for AP were recruited into the study. 100mm visual analogue scales (VAS) were used to rate pain perception. Subjects rated pain from the most recent venous puncture (VP), AP and immediately following the AP performed on the day. A clinically important difference between VAS scores (VASs) is 13mm 1    Results:  Group 1: There were no differences in VASs between AP[mean, 25.0mm] and VP[mean,21.8mm ] (p=0.488,  13mm absolute difference in mean VASs).   Conclusions:  Single un-anesthetised AP performed by competent operators in a routine environment elicits mild 2  pain and is perceived to be no more painful than routine VP. Guidelines 3  advocate use of local anaesthesia, but it is not used routinely in the UK; the results of this study support this practice. AP performed in an acute environment elicits significantly more pain; identifying why this may be was not within the scope of the study, but may support why AP is perceived by individuals to be excessively painful.   References    1 Todd  et al .  Annals of Emergency Medicine ,1996;27:485–489   2 Collins  et al. PAIN ,2012;2:175-184   3 BTS/ARTP.  Respiratory Medicine, 1994;88:165–194.
Use of gene expression microarrays to identify novel pharmacodynamic biomarkers of phosphatidylinositide-3’-kinase (PI3K) inhibition
Authors: Debashis Sarker, Paul Clarke, Lyndsey Welsh, Florence Raynaud, Melanie Valenti, Debbie Tandy, Ian Titley, Suzanne Eccles, Michelle Garrett, Paul Workman
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

3614 

Objective: Pharmacodynamic biomarkers are critical to the successful development of targeted agents as they provide proof-of-principle that the target is being modulated as intended. We proposed the use of gene expression microarray analysis to identify novel pharmacodynamic biomarkers for use in hypothesis-testing trials of PI3K inhibitors.    Methods: PI103, a potent inhibitor of class I PI3K signalling, was used on healthy volunteer peripheral blood mononuclear cells cultured ex-vivo. Drug-induced changes in gene expression were measured using 30k cDNA microarrays (www.crukdmf.icr.ac.uk). Potential changes in putative cell surface protein biomarkers were validated by flow cytometry, initially using ex vivo treated PBMCs and then whole blood obtained from Balb/C mice treated with PI103 in vivo.    Results: cDNA microarray analysis revealed that PI103 significantly altered the expression of 27 individual genes compared to vehicle-treated controls at 1 hour. Amongst the genes identified were those encoding for a transmembrane glycoprotein, and a cell surface protein of the immunoglobulin superfamily cell adhesion molecule. Changes in these proteins were validated by flow cytometry using ex-vivo PI103 treated healthy volunteer PBMCs. Time and dose-dependent changes were observed in both proteins following treatment with PI103. This was accompanied by decreased phosphorylation of ser473-Akt. Importantly, these changes were not observed following treatment with other anticancer agents including rapamycin, cisplatin and the MEK inhibitor PD325901. Blood obtained by cardiac puncture from Balb/C mice treated with PI103 at 30mg/kg showed time dependent changes in both cell surface proteins by flow cytometry. Mice treated with rapamycin at 15mg/kg showed no significant changes.    Conclusions: Using a gene expression profiling strategy we have identified two novel cell surface proteins, which can be used as pharmacodynamic biomarkers of PI3K inhibition. These markers are easily assayed in peripheral blood and have been validated in vivo by flow cytometry.
Dual-inhibition of Raf kinase and VEGFR2 reduces pancreatic cancer growth trough direct effects on tumor cells and endothelial cells.
Authors: Sven Lang, Christian Moser, Philipp Schachtschneider, Hans Schlitt, Edward Geissler, David Batt, Oliver Stoeltzing
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

2491 

The Ras/Raf/MEK/Erk pathway plays an important role in gastrointestinal cancer. We hypothesized that this oncogenic pathway is also important in pancreatic cancer, despite activating B-Raf mutations are infrequent in this cancer entity. In addition, we sought to investigate whether dual inhibition of Raf and VEGFR2 could be a valid approach for molecular targeted therapy of pancreatic cancer. Pancreatic cancer cells (PCs) and endothelial cells (ECs) were used for experiments. Dual inhibition of Raf/VEGFR2 was achieved by using a small molecule inhibitor (NVP-AAL881; Novartis Oncology, USA). The Raf-inhibitory component and its effect on ECs was investigated by using a selective VEGFR2 inhibitor. Effects on signaling pathways were determined by Western blotting and impact on cell migration in Boyden chambers. Changes in VEGF were assessed by RT-PCR and ELISA. Effect of NVP-AAL881 on pancreatic cancer growth was investigated in an orthotopic model. Raf kinases were activated in PCs and in ECs. NVP-AAL881 reduced phospho-B-Raf in cancer cells, and diminished activation of MEK, Akt, and Erk. In addition, phospho-STAT3 was substantially reduced, suggesting that a Ras/Raf/JAK/STAT3 pathway can effectively be blocked. Moreover, dual-inhibition of Raf/VEGFR2 significantly reduced VEGF expression and impaired cancer cell migration. Importantly, besides blocking VEGF-induced Erk and Akt phosphorylation in ECs, NVP-AAL881 also led to inhibition of B-Raf, C-Raf and STAT3 phosphorylation. This effect was mediated independently of its VEGFR2 blockade. In addition, EC proliferation and cell migration were significantly reduced. In vivo, therapy with NVP-AAL881 significantly reduced orthotopic tumor growth (P<0.05) and VEGF expression in tumors. Dual-inhibition of Raf and VEGFR2 led to interference with oncogenic signaling pathways in vitro and reduced pancreatic cancer growth in vivo. Importantly, blocking Raf also elicited direct effects on endothelial cells, suggesting that tumor angiogenesis could also be impaired. Hence, targeting Raf and VEGFR2 appears to be a promising strategy for therapy of human pancreatic cancer.
Abstract 2903: Myocardial Contrast Echocardiography in Subarachnoid Hemorrhage: Brain and Heart Relationship
Authors: Sahar S Abdelmoneim, Osman S Kozak, Vivien H Lee, Mathieu Bernier, Mary E Hagen, Wilson P Daugherty, Jae K Oh, Eelco F Wijdicks, Sharon L Mulvagh
Journal: Circulation (2007)
Abstract 14683: Endoglin and ALK1 Act Differently of Ischemia and Shear Stress Induced Neovascularization
Authors: Margreet R de Vries, Leonard Seghers, Imo E Hoefer, Evangelia Pardali, Beerend P van der Hierck, Marie Jose Goumans, Peter Ten Dijke, Paul H Quax
Journal: Circulation (2011)

Introduction:  TGF- β stimulates both ischemia induced angiogenesis and shear stress induced arteriogenesis, by signaling through different receptors. In this study the role of TGF-β receptors ALK1 and endoglin is assessed in a model for hind limb ischemia induced neovascularization in mice.   Methods and Results:  Femoral artery ligation was performed in mice heterozygous for either endoglin, or ALK1 and in littermate controls. Blood flow recovery, monitored by laser doppler perfusion imaging, was significantly hampered in both endoglin and ALK1 heterozygous mice compared to controls by maximal 40% and 49%, respectively. Collateral artery size was significantly reduced in endoglin heterozygous mice compared to controls, but not in ALK1 heterozygous mice. Capillary density in ischemic calf muscles was unaffected, but capillaries from endoglin and ALK1 heterozygous mice were significantly larger when compared to controls. To provide mechanistic evidence for the differential role of endoglin and ALK1 in shear induced or hypoxia induced neovascularization, murine endothelial cells were exposed to shear stress in vitro. This induced high levels of endoglin messengerRNA, but not ALK1.   Conclusion:  Here we demonstrated that both endoglin and ALK1 play a crucial role in blood flow recovery. Importantly, endoglin is essential in both shear induced collateral artery growth and in ischemia induced angiogenesis, whereas ALK1 is only involved in ischemia induced angiogenesis.
Severe deep white matter lesions and outcome in major depressive disorder
Authors: M. Schirmer, S. Fels, R. C Baldwin, S. Walker, A. Jackson, S. W Simpson, A. Burns
Journal: BMJ (1999)

Editor—The study by O’Brien et al clearly shows that deep white matter lesions on magnetic resonance imaging are relevant to the outcome in elderly depressed patients.1 It is not only psychiatrists for whom this result is important. Although the authors excluded all patients who had a known history of other diseases, depression with such an organic correlate might be secondary to a distinct disease of the central nervous system.

Neuropathological studies are difficult to perform. Interestingly, deep white matter lesions have also been described in vascular diseases such as systemic lupus erythematosus2 and Behcet’s disease.3 Patients with these diseases may present with depressive symptoms, possibly as a correlate of vasculitis in the central nervous system.

There is a good chance that the deep white matter lesions described by O’Brien et al represent localised vasculitis in the central nervous system. As patients with these lesions had a poor outcome, with a median survival time of only four months, clinical trials of immunosuppressive treatment would be justified despite lack of a proved pathogenetic mechanism. In severe forms of vasculitis in the central nervous system, regimens of corticosteroids, chlorambucil, and cyclophosphamide are well established.4 Lower doses of immunosuppressants might help to prevent serious side effects in this group of geriatric patients.
Infection of Human Marrow Stroma by Human Immunodeficiency Virus-1 (HIV-1) Is Both Required and Sufficient for HIV-1–Induced Hematopoietic Suppression In Vitro: Demonstration by Gene Modification of Primary Human Stroma
Authors: Ingrid Bahner, Karen Kearns, Sunita Coutinho, Earl H. Leonard, Donald B. Kohn
Journal: Blood (1997)
Abstract 15318: Arrhythmogenic Left Ventricular Cardiomyopathy: Familial versus Sporadic Forms
Authors: Ilaria Rigato, Martina Perazzolo Marra, Cristina Basso, Alessandra Rampazzo, Kalliopi Pilichou, Federico Migliore, Alessandro Zorzi, Emanuela Dazzo, Alessandra Lorenzon, Alexandros Klavdios Steriotis, Barbara Bauce, Sabino Iliceto, Gateano Thiene, Domenico Corrado
Journal: Circulation (2011)

BACKGROUND: Genetically proven arrhythmogenic left ventricular cardiomyopathy (ALVC) has been rarely reported. We further investigated the pathogenesis and the clinico-genetic profile of ALVC in a ...
Abstract 805: Subcellular distribution of RAGE affects its functions in melanoma growth and progression
Authors: Maike Reith, Wolf-Henning Gebhardt, Kathrin Tarnanidis, Nikolaus B. Wagner, Kristian Ikenberg, Coretta Kehrel, Jochen Utikal, Christoffer Gebhardt
Journal: Cancer Research (2015)

Abstract The receptor for advanced glycation end-products (RAGE) is known to act as a central driver of tumorigenesis by sustaining a chronic inflammatory tumor microenvironment. Until to date, RAGE has been exclusively described as a cell surface receptor being activated upon engagement with its various extra-cellular ligands, e.g. S100B, S100A8/A9, HMGB1, and others. This study aimed at elucidating the functional role of RAGE and its isoforms depending on their subcellular distribution in the context of melanoma development, growth and progression. Therefore, various in vitro models using melanoma cells or melanocytes and melanoma mouse models as well as tissue-microarrays representing human specimens of malignant melanoma and benign nevi were applied. The expression analyses revealed an overexpression of RAGE in melanoma cells compared to melanocytes/nevocytes. Moreover, RAGE protein was found to be localized primarily in the nucleus of melanocytes/nevocytes whereas a predominant cell surface/cytoplasmic localization of RAGE is observed in melanoma cells. Nuclear translocation of RAGE depends on the nuclear transport machinery and site-directed mutagenesis of predicted DNA binding sites within the RAGE protein was applied in order to study its functional role in the nucleus. Furthermore, knockdown of RAGE indicated its central function in apoptosis induction. In conclusion, RAGE and its isoforms are overexpressed and aberrantly localized in malignant melanoma cells compared to melanocytes/nevocytes. Our data point towards a novel tumor-protective function of RAGE in melanoma development depending on its nuclear localization. Citation Format: Maike Reith, Wolf-Henning Gebhardt, Kathrin Tarnanidis, Nikolaus B. Wagner, Kristian Ikenberg, Coretta Kehrel, Jochen Utikal, Christoffer Gebhardt. Subcellular distribution of RAGE affects its functions in melanoma growth and progression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 805. doi:10.1158/1538-7445.AM2015-805
Abstract 2258: Electrocardiographic Analyisis Of Arrhythmias Developing During Exercise In Patients With Catecholaminergic Polymorphic Ventricular Tachycardia: Insights For Mechanisms And Site Of Origin
Authors: Nicola Monteforte, Emilia Raytcheva-Buono, Raffaella Bloise, Jami Shakibi, Maria J Correia, Maurizio Gasparini, Carlo Napolitano, Silvia G Priori
Journal: Circulation (2007)
HRCT score to control and evaluate the prognosis in idiopathic pulmonary fibrosis
Authors: Ricardo Peris, Estrella Fernandez-Fabrellas, Ignacio Inchaurraga, M. Luisa Domingo, Julio Palop, Rafael Blanquer
Journal: European Respiratory Journal (2011)

Introduction: HRCT is not commonly used to assess the severity of idiopathic pulmonary fibrosis (IPF).

To assess: We sought to evaluate the usefulness of a semiquantitative HRCT score and its relation with respiratory function tests normally used to ascertain IPF severity and to monitor the evolution and progression of the fibrotic process.

Patients and methods: A prospective 4 years study including 36 consecutive IPF patients. A semiquantitative score was used to score every predefined IPF 4 patterns on HRCT. As a result of summing up all of them we had the Total Score of Fibrosis for each patient.

![Figure][1] 



We studied its relation with functional respiratory tests, bronchoalveolar lavage (BAL) cellularity and analyzed the differences found among the death patients.

Results: We found a significant correlation between the honeycomb score and% DLCO (r= -0.48, p=0.004), total score of fibrosis with% FEV1 (r= -0.41, p=0.01),% DLCO (r= -0.41, p=0.01) and% TLC (r= -0.36, p=0.03). The 6-minutes walking test (6MWT): the final SaO2 correlated with the total score (r= -0.48, p=0.04). A-aO2grad also correlated with the honeycomb score (r=0.43, p= 0.01) and the total score (r=0.48, p=0,005). Dead patients had a higher total score and a tendency of higher neutrophilia in BAL (p=0.059).

Conclusions: A semiquantitative score of HRCT is useful in assessing the initial severity of IPF and should be able to predict its development.

 [1]: pending:yes