tbuckley/cabot-search huggingface dataset:
<i>EGFR</i> Mutations Predict Survival Benefit From Gefitinib in Patients With Advanced Lung Adenocarcinoma: A Historical Comparison of Patients Treated Before and After Gefitinib Approval in Japan
Authors: Toshimi Takano, Tomoya Fukui, Yuichiro Ohe, Koji Tsuta, Seiichiro Yamamoto, Hiroshi Nokihara, Noboru Yamamoto, Ikuo Sekine, Hideo Kunitoh, Koh Furuta, Tomohide Tamura
Journal: Journal of Clinical Oncology (2008)

This study evaluated whether the presence of epidermal growth factor receptor (EGFR) mutations is a predictive marker for survival benefit from gefitinib and/or a prognostic marker in patients with advanced lung adenocarcinoma.Overall survival (OS) was compared between patients with advanced lung adenocarcinoma who began first-line systemic therapy before and after gefitinib approval in Japan (January 1999 to July 2001 and July 2002 to December 2004, respectively). Deletional mutations in exon 19 or the L858R mutation in exon 21 of EGFR were evaluated using high-resolution melting analysis.EGFR mutations were detected in 136 (41%) of the 330 patients included in this study. OS was significantly longer among the EGFR-mutant patients treated after gefitinib approval compared with the OS of patients treated before gefitinib approval (median survival time [MST], 27.2 v 13.6 months, respectively; P < .001), whereas no significant survival improvement was observed in patients without EGFR mutations (MST, 13.2 v 10.4 months, respectively; P = .13). A significant interaction between the presence of EGFR mutations and a survival improvement was seen (P = .045). Among patients treated before gefitinib approval, those with EGFR mutations lived longer than those without EGFR mutations (MST, 13.6 v 10.4 months, respectively; P = .034). The response rates to first-line cytotoxic chemotherapy were not significantly different between patients with and without EGFR mutations (31% v 28%, respectively; P = .50).EGFR mutations significantly predict both a survival benefit from gefitinib and a favorable prognosis in patients with advanced lung adenocarcinoma.
Effect of γ-Linolenic Acid on the Transcriptional Activity of the Her-2/neu (erbB-2) Oncogene
Authors: Javier A. Menendez, Luciano Vellon, Ramon Colomer, Ruth Lupu
Journal: JNCI Journal of the National Cancer Institute (2005)

The omega-6 polyunsaturated fatty acid gamma-linolenic acid (GLA; 18:3n-6), which is found in several plant oils and is used as an herbal medicine, has antitumor activity in vitro. We examined the effect of GLA on the expression of the Her-2/neu (erbB-2) oncogene, which is involved in development of numerous types of human cancer. Flow cytometric and immunoblotting analyses demonstrated that GLA treatment substantially reduced Her-2/neu protein levels in the Her-2/neu-overexpressing cell lines BT-474, SK-Br3, and MDA-MB-453 (breast cancer), SK-OV3 (ovarian cancer), and NCI-N87 (gastrointestinal tumor derived). GLA exposure led to a dramatic decrease in Her-2/neu promoter activity and a concomitant increase in the levels of polyomavirus enhancer activator 3 (PEA3), a transcriptional repressor of Her-2/neu, in these cell lines. In transient transfection experiments, a Her-2/neu promoter bearing a PEA3 site-mutated sequence was not subject to negative regulation by GLA in Her-2/neu-overexpressing cell lines. Concurrent treatments of Her-2/neu-overexpressing cancer cells with GLA and the anti-Her-2/neu antibody trastuzumab led to synergistic increases in apoptosis and reduced growth and colony formation.
Progressive morphological changes and impaired retinal function associated with temporal regulation of gene expression after retinal ischemia/reperfusion injury in mice
Authors: Byung-Jin Kim, Terry A Braun, Robert J Wordinger, Abbot F Clark
Journal: Molecular Neurodegeneration (2013)

Abstract Retinal ischemia/reperfusion (I/R) injury is an important cause of visual impairment. However, questions remain on the overall I/R mechanisms responsible for progressive damage to the retina. In this study, we used a mouse model of I/R and characterized the pathogenesis by analyzing temporal changes of retinal morphology and function associated with changes in retinal gene expression. Transient ischemia was induced in one eye of C57BL/6 mice by raising intraocular pressure to 120 mmHg for 60 min followed by retinal reperfusion by restoring normal pressure. At various time points post I/R, retinal changes were monitored by histological assessment with H&amp;E staining and by SD-OCT scanning. Retinal function was also measured by scotopic ERG. Temporal changes in retinal gene expression were analyzed using cDNA microarrays and real-time RT-PCR. In addition, retinal ganglion cells and gliosis were observed by immunohistochemistry. H&amp;E staining and SD-OCT scanning showed an initial increase followed by a significant reduction of retinal thickness in I/R eyes accompanied with cell loss compared to contralateral control eyes. The greatest reduction in thickness was in the inner plexiform layer (IPL) and inner nuclear layer (INL). Retinal detachment was observed at days 3 and 7 post- I/R injury. Scotopic ERG a- and b-wave amplitudes and implicit times were significantly impaired in I/R eyes compared to contralateral control eyes. Microarray data showed temporal changes in gene expression involving various gene clusters such as molecular chaperones and inflammation. Furthermore, immunohistochemical staining confirmed Müller cell gliosis in the damaged retinas. The time-dependent changes in retinal morphology were significantly associated with functional impairment and altered retinal gene expression. We demonstrated that I/R-mediated morphological changes the retina closely associated with functional impairment as well as temporal changes in retinal gene expression. Our findings will provide further understanding of molecular pathogenesis associated with ischemic injury to the retina.
Safety and efficacy of decitabine in combination with temozolomide in metastatic melanoma: a phase I/II study and pharmacokinetic analysis
Authors: H.A. Tawbi, J.H. Beumer, A.A. Tarhini, S. Moschos, S.C. Buch, M.J. Egorin, Y. Lin, S. Christner, J.M. Kirkwood
Journal: Annals of Oncology (2012)
Combined presence of HCVRNA sequences and T(14;18) (q32;q21) translocation in PBMC from patients with chronic HCV infection
Authors: A. Mazzocca, F. Giannelli, R.G. Romanelli, S. Moscarella, P. Caini, C. Giannini, M. Monti, G. La Villa, G. Laffi, P. Gentilini, A.L. Zignego
Journal: Journal of Hepatology (2000)
Stat5 expression is critical for mast cell development and survival
Authors: Christopher P. Shelburne, Margaret E. McCoy, Roland Piekorz, Veronica Sexl, Kwan-Ho Roh, Sarah M. Jacobs-Helber, Sheila R. Gillespie, Daniel P. Bailey, Paria Mirmonsef, Meredith N. Mann, Mohit Kashyap, Harry V. Wright, Hey Jin Chong, L. Andrew Bouton, Brian Barnstein, Carlos D. Ramirez, Kevin D. Bunting, Steven Sawyer, Chris S. Lantz, John J. Ryan
Journal: Blood (2003)

Interleukin-3 (IL-3) and stem cell factor (SCF) are important mast cell growth and differentiation factors. Since both cytokines activate the transcription factor signal transducer and activator of transcription 5 (Stat5), a known regulator of proliferation and survival, we investigated the effects of Stat5 deficiency on mast cell development and survival. Bone marrow-derived mast cell (BMMC) populations cultured from Stat5A/B-deficient mice survived in IL-3 + SCF, but not in either cytokine alone. These cells demonstrated reduced expression of Bcl-2, Bcl-x(L), cyclin A2, and cyclin B1, with increased apoptosis and delayed cell cycle progression during IL-3 or SCF culture. Finally, the absence of Stat5 resulted in loss of in vivo mast cell development, as judged by assessments of Stat5-deficient mice and transplantation of Stat5-deficient bone marrow cells to mast cell-deficient recipient mice. These results indicate that Stat5A and Stat5B are critical regulators of in vitro and in vivo mast cell development and survival.
Network analysis: a way forward for understanding COPD multimorbidity
Authors: Rosa Faner, Alvar Agustí
Journal: European Respiratory Journal (2015)

Patients with chronic obstructive pulmonary disease (COPD) often suffer other concomitant diseases that negatively impact their prognosis and health status [1]. However, it is unclear if they are causally related to COPD or result from shared risk factors, such as ageing, smoking and/or inactivity [2]. Likewise, the precise underlying molecular mechanisms are also unclear [3], hence limiting targeted therapeutic interventions. The use of network analysis can help to elucidate this conundrum [4]. Network analysis of comorbidities in COPD patients provides new insights into the pathobiology of disease <http://ow.ly/Ph44T>
Regional diastolic dysfunction in postischaemic myocardium in calf: effect of nisoldipine
Authors: O N Krogmann, L Tjon-A-Meeuw, O M Hess, M Jacob, J Grimm, B Leskosek, M Pasic, L v Segesser
Journal: Cardiovascular Research (1993)

The aim was to assess the effect of nisoldipine on left ventricular systolic and diastolic function during prolonged myocardial ischaemia.The left circumflex coronary artery was ligated for 2 h and reperfused for 4 h in 12 calves. The animals were randomised to a control group (n = 6) or to treatment with 1.25 mg.h-1 intravenous nisoldipine (n = 6) during 2 h of ischaemia. Circulatory support by a ventricular assist device was performed throughout the experiment except for the time of haemodynamic measurements. Regional wall thickening of a normal and an ischaemic left ventricular region was determined using pairs of ultrasonic crystals. Left ventricular pressure was measured by micromanometry. Left ventricular wall thickness and regional wall stiffness at a common preload of 10 mm Hg were calculated using an elastic model with shifting asymptote.Ten animals survived after 6 h. No difference was observed in systolic function between controls and nisoldipine treated animals. Systolic thickening of the ischaemic wall remained depressed 4 h after reperfusion and showed some recovery after dopamine infusion. Ischaemic wall stiffness at a common preload was lower after nisoldipine during ischaemia and reperfusion than in controls. Control wall stiffness remained unchanged during the whole experiment with and without nisoldipine. Diastolic thinning of the ischaemic wall was prevented by nisoldipine during ischaemia and after reperfusion.Prolonged myocardial ischaemia is associated with increased myocardial stiffness of the ischaemic wall. Mechanical unloading can help to bridge the acute phase but cannot prevent postischaemic diastolic dysfunction of the ischaemic wall. Nisoldipine has a beneficial effect on regional diastolic function during ischaemia and reperfusion by decreasing regional wall stiffness and preventing diastolic thinning of the ischaemic wall.
Modulation of adverse cardiac remodeling by STARS, a mediator of MEF2 signaling and SRF activity
Authors: Koichiro Kuwahara, Gordon C. Teg Pipes, John McAnally, James A. Richardson, Joseph A. Hill, Rhonda Bassel-Duby, Eric N. Olson
Journal: Journal of Clinical Investigation (2007)

Cytoskeletal proteins have been implicated in the pathogenesis of cardiomyopathy, but how the cytoskeleton influences the transcriptional alterations associated with adverse cardiac remodeling remains unclear. Striated muscle activator of Rho signaling (STARS) is a muscle-specific actin-binding protein localized to the Z disc that activates serum response factor–dependent (SRF-dependent) transcription by inducing nuclear translocation of the myocardin-related SRF coactivators MRTF-A and -B. We show that STARS expression is upregulated in mouse models of cardiac hypertrophy and in failing human hearts. A conserved region of the STARS promoter containing an essential binding site for myocyte enhancer factor–2 (MEF2), a stress-responsive transcriptional activator, mediates cardiac expression of STARS, which in turn activates SRF target genes. Forced overexpression of STARS in the heart sensitizes the heart to pressure overload and calcineurin signaling, resulting in exaggerated deterioration in cardiac function in response to these hypertrophic stimuli. These findings suggest that STARS modulates the responsiveness of the heart to stress signaling by functioning as a cytoskeletal intermediary between MEF2 and SRF.
Erythroid colony formation by polycythemia vera bone marrow in vitro. Dependence on erythropoietin.
Authors: E D Zanjani, J D Lutton, R Hoffman, L R Wasserman
Journal: Journal of Clinical Investigation (1977)

In the plasma clot culture system both normal and polycythemia vera (PV) bone marrow cells respond to erythropoietin (Ep), giving rise to large numbers of colonies of erythroid cells. In PV, but not in normal individuals, the marrow produced endogenous erythroid colonies (EED) in the absence of exogenous Ep. The number of EEC formed varied from patient to patient comprising anywhere from 6 to 29% of the total number of colonies formed in the presence of Ep. Exposure, before use in culture, of fetal calf serum and citrated bovine plasma to the gammaglobulin fraction of rabbit anti-Ep serum followed by treatment with goat anti-rabbit gamma-globulin re sulted in a significant decrease in EEC formation. Addition of anti-Ep directly to the culture medium produced similar results. In addition, the production of EEC in response to added Ep was inhibited in the presence of anti-Ep. Addition of very small doses of highly purified Ep to anti-Ep-treated cultures resulted in the reappearance of a significantnumber of EEC formation in PV may be due to a population of erythroid-committed precursors that are abnormally sensitive to small concentrations of Ep which may be present in fetal calf serum and citrated plasma. Although the mechanism of formation of these cells is not known, it appears that the final steps in the formation of red cells derived from this clone of precursors is subject to the usual Ep control.
Select Heterozygous <i>Keap1</i> Mutations Have a Dominant-Negative Effect on Wild-Type Keap1 <i>In Vivo</i>
Authors: Takafumi Suzuki, Jonathan Maher, Masayuki Yamamoto
Journal: Cancer Research (2010)

Under homeostatic conditions, Keap1 constitutively mediates the proteasomal degradation Nrf2. However, tertiary changes in Keap1 in response to the cellular environment allow for liberation of Nrf2 to transcriptionally regulate downstream cytoprotective genes that aid in cell survival. KEAP1/NRF2 somatic mutations causing constitutive NRF2 activation have been estimated to occur in approximately 25% of human lung tumors, with similar rates believed to exist in other tissue subtypes. As the stoichiometry between Keap1 and Nrf2 is 2:1, we hypothesized that heterozygous Keap1 mutations could suppress wild-type Keap1 (Keap1(WT)) activity by functioning as a dominant-negative protein through heterodimerization of mutant Keap1 (Keap1(mutant)) with Keap1(WT). When Keap1(G430C) or Keap1(G364C) mutants were expressed in lieu of Keap1(WT), premature juvenile mortality was observed. To test the hypothesis of a dominant-negative effect, Keap1-null mice were engineered to coexpress both Keap1(WT) and Keap1(G430C) transgenes, a phenotype analogous to that previously observed from a human lung tumor. These mice were viable, but phenotypically displayed hyperactivation of downstream Nrf2 target genes and moderate esophageal hyperkeratosis. Similar to the transgenic mouse Keap1(G430C) mutant, Keap1(C273&288A) substitutions also diminished Keap1(WT) activity in vivo. To further delineate involvement of the dominant-negative heterodimer, transgenic mice with a deletion or strategic mutation in Broad-complex, Tramtrack and Bric-a-Brac (BTB) domain that disallowed Keap1 dimerization were generated in the presence of Keap1(WT), and failed to induce the dominant-negative effect in vivo. These results thus demonstrate that sequestration of Keap1(WT) into a Keap1(mutant)-Keap1(WT) heterodimer leads to a dominant-negative effect in vivo and gives rise to Nrf2 activation.
Cellular localization, membrane distribution, and possible function of guanylyl cyclases A and 1 in collecting ducts of rat
Authors: J Hirsch
Journal: Cardiovascular Research (2001)

Background: Natriuretic peptides regulate Na+ and H2O transport in the cortical collecting duct (CCD). We have shown that natriuretic peptides have no effect on ion conductances or water transport of principal cells (PC) even though a cGMP-regulated K+ channel is located in the basolateral membrane of these cells. Methods: RT-PCR was used to screen for different guanylyl cyclases (GC) in CCD and to look for the expression of GC-1 and GC-A mRNA in CCD of male and female Wistar and Sprague–Dawley rats. Polyclonal antibodies were raised against the detected GC. BCECF was used to investigate the effects of ANP on intracellular pH in intercalated cells (IC). Results: GC-A and GC-1 were detected. GC-A was immunolocalized in the luminal membrane of IC while GC-1 was mainly found in the luminal membrane of PC. GC-1 is expressed in Sprague–Dawley and Wistar rats except for male Sprague–Dawley rats, while GC-A is expressed in all strains. ANP (160 nM, n=11), urodilatin (140 nM, n=6), which had no effect in PC, significantly decreased pHi by 0.02±0.01 and 0.03±0.01 Units in IC, respectively. ANP as well as urodilatin and 8-Br-cGMP decreased the pHi recovery after acidification by 30±6% (n=12), 37±7% (n=8), and 19±3% (n=8), respectively. Conclusion: GC-A is located in the luminal membrane of IC of rat CCD and ANP acts through this receptor when regulating pHi via an inhibition of the Na+/H+-exchanger. PC do not possess GC-A. GC-1 seems to be the only GC in these cells of most rat strains tested and therefore, it could be responsible for the regulation of K+ channels in the basolateral membrane via cGMP-dependent protein kinase.
Induction Chemotherapy and Cetuximab for Locally Advanced Squamous Cell Carcinoma of the Head and Neck: Results From a Phase II Prospective Trial
Authors: Merrill S. Kies, Floyd Christopher Holsinger, J. Jack Lee, William N. William, Bonnie S. Glisson, Heather Y. Lin, Jan S. Lewin, Lawrence E. Ginsberg, Katharine A. Gillaspy, Erminia Massarelli, Lauren Byers, Scott M. Lippman, Waun K. Hong, Adel K. El-Naggar, Adam S. Garden, Vassiliki Papadimitrakopoulou
Journal: Journal of Clinical Oncology (2009)

PURPOSE To determine the potential efficacy of combining cetuximab with chemotherapy in patients with advanced nodal disease, we conducted a phase II trial with induction chemotherapy (ICT) consisting of six weekly cycles of paclitaxel 135 mg/m(2) and carboplatin (area under the curve = 2) with cetuximab 400 mg/m(2) in week 1 and then 250 mg/m(2) (PCC). PATIENTS AND METHODS Forty-seven previously untreated patients (41 with oropharynx primaries; 33 men, 14 women; median age, 53 years; performance status of 0 or 1) with squamous cell carcinoma of the head and neck (SCCHN; T1-4, N2b/c/3) were treated and evaluated for clinical and radiographic response. After ICT, patients underwent risk-based local therapy, which consisted of either radiation, concomitant chemoradiotherapy, or surgery, based on tumor stage and site at diagnosis. Results After induction PCC, nine patients (19%) achieved a complete response, and 36 patients (77%) achieved a partial response. The most common grade 3 or 4 toxicity was skin rash (45%), followed by neutropenia (21%) without fever. At a median follow-up time of 33 months, locoregional or systemic disease progression was observed in six patients. The 3-year progression-free survival (PFS) and overall survival (OS) rates were 87% (95% CI, 78% to 97%) and 91% (95% CI, 84% to 99%), respectively. Human papillomavirus (HPV) 16, found in 12 (46%) of 26 biopsies, was associated with improved PFS (P = .012) and OS (P = .046). CONCLUSION ICT with weekly PCC followed by risk-based local therapy seems to be feasible, effective, and well tolerated. PFS is promising, and this sequential treatment strategy should be further investigated. Patients with HPV-positive tumors have an excellent prognosis.
TNF polymorphisms and risk of psoriatic arthritis
Authors: P Rahman
Journal: Annals of the Rheumatic Diseases (2005)

<b>Background:</b> Tumour necrosis factor α (TNFα) is a cytokine of critical importance in psoriatic arthritis. <b>Objectives:</b> (1) To examine the association between TNFα promoter gene polymorphisms and psoriatic arthritis in two well characterised Canadian populations with the disease; (2) to carry out a meta-analysis of all TNFα association studies in white psoriatic arthritis populations. <b>Methods:</b> DNA samples were genotyped for five TNF variants by time of flight mass spectrometry using the Sequenom platform. All five single nucleotide polymorphisms were in the 5′ flanking region of TNFα gene at the following positions: −1031 (T→C), −863 (C→A), −857 (C→T), −308 (G→A), and −238 (G→A). Primary analyses were based on logistic regression. Summary estimates of disease/genotype relations from several studies were derived from random effects meta-analyses. <b>Results:</b> 237 psoriatic arthritis subjects and 103 controls from Newfoundland and 203 psoriatic arthritis subjects and 101 controls from Toronto were studied. A combined analysis of data from both populations, showed a significant association between disease status and the −238(A) variant (p = 0.01). The meta-analysis estimate for the −238(A) TNFα variant in eight psoriatic arthritis populations was also significant (odds ratio = 2.29 (95% confidence interval, 1.48 to 3.55)). <b>Conclusions:</b> Analysis of TNFα variants in psoriatic arthritis populations shows that the −238 (A) variant is a significant risk factor for this disease.
Regulation of human mononuclear phagocyte migration by cell surface-binding proteins for advanced glycation end products.
Authors: A M Schmidt, S D Yan, J Brett, R Mora, R Nowygrod, D Stern
Journal: Journal of Clinical Investigation (1993)

Nonenzymatic glycation of proteins occurs at an accelerated rate in diabetes and can lead to the formation of advanced glycation end products of proteins (AGEs), which bind to mononuclear phagocytes (MPs) and induce chemotaxis. We have isolated two cell surface-associated binding proteins that mediate the interaction of AGEs with bovine endothelial cells. One of these proteins is a new member of the immunoglobulin superfamily of receptors (termed receptor for AGEs or RAGE); and the second is a lactoferrin-like polypeptide (LF-L). Using monospecific antibodies to these two AGE-binding proteins, we detected immunoreactive material on Western blots of detergent extracts from human MPs. Radioligand-binding studies demonstrated that antibody to the binding proteins blocked 125I-AGE-albumin binding and endocytosis by MPs. Chemotaxis of human MPs induced by soluble AGE-albumin was prevented in a dose-dependent manner by intact antibodies raised to the AGE-binding proteins, F(ab')2 fragments of these antibodies and by soluble RAGE. When MP migration in response to N-formyl-Met-Leu-Phe was studied in a chemotaxis chamber with AGE-albumin adsorbed to the upper surface of the chamber membrane, movement of MPs to the lower compartment was decreased because of interaction of the glycated proteins with RAGE and LF-L on the cell surface. The capacity of AGEs to attract and retain MPs was shown by implanting polytetrafluoroethylene (PTFE) mesh impregnated with AGE-albumin into rats: within 4 d a florid mononuclear cell infiltrate was evident in contrast to the lack of a significant cellular response to PTFE with adsorbed native albumin. These data indicate that RAGE and LF-L have a central role in the interaction of AGEs with human mononuclear cells and that AGEs can serve as a nidus to attract MPs in vivo.